CA2432350A1

CA2432350A1 - Method for inhibiting the expression of a target gene

Info

Publication number: CA2432350A1
Application number: CA002432350A
Authority: CA
Inventors: Roland Kreutzer; Stephan Limmer; Sylvia Rost; Philipp Hadwiger
Original assignee: Individual
Current assignee: Alnylam Europe AG
Priority date: 2001-01-09
Filing date: 2002-01-09
Publication date: 2002-07-18
Also published as: AU2002229701B2; EP1352061B1; DE50206993D1; DE10160151A1; EP1352061A2; WO2002055693A2; CN1630724A; ATE328075T1; EP1352061B9; WO2002055693A3; JP2004519458A; JP4210116B2

Abstract

The invention relates to a method for inhibiting the expression of a target gene in a cell, comprising the following steps: introduction of an amount of at least one dual-stranded ribonucleic acid (dsRNA I) which is sufficient to inhibit the expression of the target gene. The dsRNA I has a dual-stranded structure formed by a maximum of 49 successive nucleotide pairs. One strand (as1) or at least one section of the one strand (as1) of the dual-stranded structure is complementary to the sense strand of the target gene. The dsRNA
has an overhang on the end (E1) of dsRNA I formed by 1 - 4 nucleotides.

Description

Method for inhibiting the Expression of a Target Gene The invention concerns a method, a use, and a medicament for inhibiting expression of a target gene.
Methods to inhibit the expression of medically or biotechnologically interesting genes using a double-stranded ribonucleic acid (dsRNA) are known from WO 99/32619 and WO
00/44895. Although the known methods are highly effective, there is nonetheless a need to further enhance their efficiency.
The object of the present invention is to remove the shortcomings in accordance with the state-of-the-art. In particular, a method, a use, and a medicament are to be disclosed, by which even more efficient inhibition of the expression of a target gene is achievable.
This object is solved by the features of Claims 1, 41, and 81.
Advantageous embodiments result from features of Claims 2 to 40, 42 to 80, and 82 to 120.
Surprisingly, with the features claimed in this invention, a drastic enhancement is achieved in the effectiveness of inhibition of the expression of a target gene in vitro and in vivo. As a result of the particular formation of the dsRNA ends, both their efficiency in mediating the inhibitory action on the expression of a target gene as well as their stability can be affected in a targeted way. Active concentration in the cells is enhanced as a result of this enhanced stability.
In terms of the invention, "target gene" is understood to mean the DNA strand of a double-stranded DNA in the cell, which is complementary to a DNA strand, including all transcribed regions, that serves as a matrix for transcription. In other G:\Texte\Anmeldeunterlagen 2003\422497-Ribopharcna-an-2.doc words, the "target gene" is generally the sense strand. One strand, or antisense strand (as1) can be complementary to an RNA
transcript or its processing products, e.g., an mRNA, formed during expression of a target gene. The term "introduced into"
is understood to mean uptake in the cell. Uptake may occur by means of the cell itself. However, it may also be mediated by auxiliary agents or devices. "Overhang" is understood to mean a single-stranded projection located at an end, which does not exhibit Watson-Crick paired nucleotides. "Double-stranded structure" is understood to mean a structure in which the nucleotides of the individual strands are generally paired in accordance with Watson & Crick. In terms of the present invention, a double-stranded structure may also exhibit individual mismatches.
In a particularly advantageous embodiment, dsRNA I exhibits the overhang at the 3'-end of the strand or antisense strand as1 and/or at the 3'-end of the other strand or antisense strand ssl. dsRNA I may also be smooth at one end. In this case, the smooth end is advantageously located on the side of dsRNA I that (exhibits)1 the 5'-end of a strand (antisense strand; asl). In this embodiment, dsRNA I exhibits very good effectiveness as well as great stability in the living organism. Total in vivo effectiveness is outstanding. The overhang consists advantageously of 1 to 4 nucleotides, preferably of 1 or 2 nucleotides.
In accordance with a further embodiment, the effectiveness of the method can be further enhanced when at least one further dsRNA II corresponding to the dsRNA I in the invention is introduced into the Cell, whereby one strand, or at least a segment of one strand of the double-stranded structure of dsRNA
~ the word "exhibits" is missing.
\\SERVER\g$\Texte\Anmeideunterlagen 2003\422497-Ribopharma-an-2.doc I is complementary to a first region of the sense strand of the target gene, and whereby another strand, or at least a segment of the other strand of the double-stranded structure of the dsRNA II is complementary to a second region of the sense strand of the target gene. Inhibition of expression of the target gene is markedly enhanced in this case. The first and second region can overlap segmentally, be adjacent to each other, or be separated.
It has further been shown to be advantageous when the dsRNA I
and/or the further dsRNA II is fewer than 25 successive nucleotide pairs in length. A length of between 19 and 23 nucleotide pairs has been shown to be particularly effective.
Efficiency can be further enhanced when single-stranded overhangs containing 1 to 4 nucleotides are present in the double strands preferably formed by 19 to 23 nucleotide pairs.
The target gene can, in accordance with a further embodiment, exhibit one of the sequences SQ001 to SQ140 shown in the appended sequence protocol. It may be selected from the following group: an oncogene; cytokinin gene; Id protein gene;
prion gene; gene that expresses molecules that induce angiogenesis, adhesion molecules, and cell surface receptors;
genes of proteins that are involved in metastasizing and/or invasive processes; genes of proteinases as well as of molecules that regulate apoptosis and the cell cycle; genes that express the EGF receptor. In particular, the target gene can be a MDR1 gene. It may be used in this connection a dsRNA I/II consisting of one of the sequences SQ141-173 or a combination of one of the antisense (as) and sense sequences (ss) that belong together.
In accordance with another advantageous embodiment, expression is inhibited according to the principle of RNA interference.
1\SERVER\g$\Texte\Anmeldeunterlagen 2003~A22497-Ribopharma-an-2.doc The target gene is advantageously expressed in pathogenic organisms, preferably in plasmodia. It can be a component of a virus or viroid, particularly a virus or viroid that is pathogenic in humans. The virus or viroid can also be one that is pathogenic in animals or plants.
In another embodiment, it is provided that the unpaired nucleotides are substituted by nucleoside thiophosphates.
At least one end of the dsRNA I/II may be modified to counteract decomposition in the cell or dissociation in the individual strands. Advantageously, the cohesion of the double-stranded structure that results from the complementary nucleotide pairs is enhanced by at least one chemical bond. The chemical bond may be achieved either by a covalent or ionic bond, a hydrogen bond, hydrophobic interaction, preferably by means of van der Waals or stacking interactions, or by means of metal-ion coordination. In addition, it has also been shown to be advantageous and stability-enhancing if the chemical bond occurs in the vicinity of one end. Other advantageous embodiments with regard to chemical bonding can be found in the features in Claims 24 to 30, and no further explanation is required.
dsRNA I/II may be particularly easily introduced into the cell when it is enclosed in micellar structures, preferably in liposomes. For the transport of dsRNA I/II into the cell, it has been found to be advantageous that they be bound, associated, or enclosed by at least one viral coat protein that stems directly from a virus, is derived from it, or is synthetically produced.
The coat protein may be derived from a polyoma virus. In particular, the coat protein may contain Virus Protein 1 and/or Virus Protein 2 of the polyoma virus. In accordance with a further embodiment, it is provided that during formation of a capsid or capsid-like structure from coat protein, one side is \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc turned to the interior of in the capsid or capsid-like structure. Furthermore, it is advantageous that one strand of the dsRNA I/II (as1/2) is complementary to the primary or processed RNA transcript of the target gene. The cell may be 5 either a vertebrate cell or a human cell.
Furthermore, it has been demonstrated that dsRNA I/II may be administered to mammals, preferably human beings, even at a maximum dose of 5 mg/kg body weight per day. Even at this low dosage effectiveness is outstanding.
Surprisingly, it has been shown that dsRNA I/II may be mixed in a buffer solution and then administered orally or by injection or infusion, either intravenously, intratumorally, intraperitoneally, or inhalationally.
Furthermore, the invention provides the use of a double-stranded ribonucleic acid (dsRNA I) to inhibit expression of a target gene in the cell, whereby dsRNA I exhibits a double-stranded structure consisting of a maximum of 49 successive nucleotide pairs, and whereby one strand (antisense strand, as1) or at least one segment of the strand of the double-stranded structure is complementary to the sense strand of the target gene, and whereby dsRNA I exhibits an overhang at one end consisting of 1 to 4 nucleotides.
In accordance with another measure of the invention, a medicament containing one double-stranded ribonucleic acid (dsRNA I) in a quantity sufficient to inhibit expression of the target gene in a cell is provided, whereby dsRNA I exhibits a double-stranded structure consisting of a maximum of 49 successive nucleotide pairs, and whereby one strand (asl) or at least one segment of one strand (as1) of the double-stranded structure is complementary to the sense strand of target gene, 1\SERVER\g$\Texte\Anmeldeunterlagen 20031422497-Ribopharma-an-2.doc and whereby the dsRNA I exhibits at least one overhang at one end consisting of 1 to 4 nucleotides.
Refer to the previous discussion for other advantageous embodiments of dsRNA I/II.
The invention will be explained on the basis of drawings and examples as follows. These show:
Fig. la, b diagram of a first and second double-stranded RNA
and Fig. 2 diagram of a target gene, Fig. 3 relative YFP fluorescence after application of various dsRNAs in NIH/3T3 cells (first experiment), Fig. 4 relative YFP fluorescence after application of various dsRNAs in NIH/3T3 cells (second experiment), Fig. 5 relative YFP fluorescence after application of various dsRNAs in NIH/3T3 cells (third experiment), Fig. 6 relative YFP fluorescence after application of various dsRNAs in NIH/3T3 cells (fourth experiment), Fig. 7 relative YFP fluorescence after application of various dsRNAs in Hela-S3 cells (fifth experiment), Fig. 8 fluorescence microscopic imaging of NIH/3T3 cells after transfection with pcDNA-YFP or after cotransfection with pcDNA-YFP and various dsRNAs, \\SERVER\g$\Texte\Anmetdeunterlagen 20034422497-Ribopharma-an-2.doc Fig. 9 fluorescence microscopic imaging of HeLa-S3 cells after transfection with pcDNA-YFP or after cotransfection with pcDNA-YFP and various dsRNAs, Fig. 10 gel electrophoretic separation of S1 after incubation in mouse serum, Fig. 11 gel electrophoretic separation of S1 after incubation in human serum, IO
Fig. 12 gel electrophoretic separation of S7 after incubation in mouse serum, Fig. 13 gel electrophoretic separation of S7 after incubation in human serum, Fig. 14 gel electrophoretic separation of K3 after incubation in mouse serum, Fig. 15 gel electrophoretic separation of PKC1/2 after incubation in mouse serum, Fig. 16 gel electrophoretic separation of S1A/S4B after incubation in human serum, Fig. 17 gel electrophoretic separation of K2 after incubation in human serum, and Fig. 18 GFP-specific immunoperoxidase staining of kidney paraffin sections from transgenic GFP mice, Fig. 19 GFP-specific immunoperoxidase staining of heart paraffin sections from transgenic GFP mice, \\SERVER\g$\Texte\Anmeldeunterlagen 20031422497-Ribopharma-an-2.doc g Fig. 20 GFP-specific immunoperoxidase staining of pancreas paraffin sections from transgenic GFP mice, Fig. 21 Western blot analysis of GFP expression in plasma, Fig. 22 Western blot analysis of GFP expression in kidney, Fig. 23 Western blot analysis of GFP expression in heart, Fig. 24 Western blot analysis of EGFR expression in U-87 MG
glioblastoma cells, Fig. 25a Northern blot analysis of the MDRI mRNA level in colon carcinoma cell line LS174T, whereby the cells were harvested after 74 hours, Fig. 25b quantification of the bands in Figure 25a, whereby the averages are represented by two values, Fig. 26a Northern blot analysis of the MDRI mRNA level in colon carcinoma cell line LS174T, whereby the cells were harvested after 48 hours, Fig. 26b quantification of the bands in Figure 26a, whereby the averages of two values are represented, Fig. 27 comparison of a transmitted light- and fluorescence microscopic imaging of a transfection with 175 nM
dsRNA (Sequence R1 in Table 4).
The double-stranded ribonucleic acids dsRNA I and dsRNA II
depicted schematically in Figures 1a and 1b each exhibit a first end (E1) and a second end (E2). The first and the second ribonucleic acids dsRNA I/dsRNA II exhibit single-stranded \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc segments at both ends (E1, E2), being formed of approximately 1 to 4 unpaired nucleotides. Two possible variants are shown (Variants 1 and 2), whereby Variant 2 exhibits a smooth end (E2). The smooth end may, however, be situated at the other end (E1) in other variants.
Figure 2 shows schematically a target gene located on a DNA. The target gene has been made visible by means of a black line. It exhibits a first region (B1) and a second region (B2).
In each case, one strand of the first dsRNA I (as1) or of the second dsRNA II (as2) is complementary to the corresponding region B1 or B2 in the target gene, respectively.
Expression of the target gene is inhibited particularly effectively when dsRNA I/dsRNA II exhibits single-stranded segments at their ends (E1, E2). The single-stranded segments may be located both on strand as1 or as2, or on anti-strand (ss1 or ss2), or on strand asl, as2, and on the anti-strand.
Regions B1 and B2 may be separated from each other as shown in Figure 2. However, they may also adjoin or overlap.
I. Inhibition of the expression of the YFP gene in fibroblasts:
Double-stranded RNAs were derived from sequences of Yellow Fluorescent Proteins (YFP), a variant of GFP (Green Fluorescent Protein) from the Aequoria victoria alga, and microinjected into fibroblasts together with a YFP-coding plasmid. Subsequently, the decrease in fluorescence compared to cells without dsRNA was analyzed.
Experiment protocol:
Single RNA strands and their complementary single strands were synthesized from sequence protocols SQ148, SQ149 and SQ159, \\SERVER\g$\TexteWameldeunterlagen 20034422497-Ribopharma-an-2.doc using an RNA synthesizer (Expedite 8909, Applied Biosystems, Weiterstadt, Germany) and conventional chemical processes. These were subsequently purified using HPLC. Hybridization of the individual strands into double strands was done by heating up the stochiometric mixture of the single strands in 10 mM of sodium phosphate buffer, pH 6.8, and 100 mM NaCl to 90QC, and then allowing it to cool off slowly for 6 hours to room temperature. The dsRNA that was obtained in this way was microinjected into the test cells.
The test system used for this cell culture experiment was the murine fibroblast cell line NIH/3T3, ECACC No. 93061524 (European Collection of Animal Cell Culture). The pcDNA-YFP
plasmid, which contains an 800bp Bam HI/Eco RI-YFP fragment in the corresponding restriction site of the pcDNA3 vector, was used for the microinjections. Expression of YFP under the influence of simultaneously transfused sequence-homologous dsRNA
was studied. Analysis of green fluorescence under the fluorescence microscope was done 3 hours after injection at the earliest.
Preparation of the cell cultures:
The cells were incubated in DMEM with 4.5 g/1 glucose and 10~
fetal calf serum (FCS), 2 mM L-glutamine, and penicillin/streptomycin (100 IU/100 ug/ml, Biochrom) in an incubator in an atmosphere containing 5~ COz at 37QC. The cells were passaged every 3 days in order to maintain them in an exponential growth state. One day before transfection, the cells were trypsinized (10x trypsin/TEDTA, Biochrom) and placed in coated petri dishes (CORNING Cell Culture Dish, 35 mm, Corning Inc., Corning NY) at a cell density of 0.3x 105. The petri dishes were incubated for at least 30 minutes at 37QC with 0.2$ gelatin (Biochrom), washed once with PBS, and used immediately to \GSERVERIg$lTextelAnmeldeunter(agen 2003422497-Ribopharma-an-2.doc culture the cells. In order to find the individual cells again, CELLocate coverslips were used (square sized 55um, Eppendorf).
Microinjection:
The petri dishes were taken out of the incubator approximately minutes prior to microinjection. Approximately 50 cells per dish and per incubate were microinjected (FemtoJet, Micromanipulator 5171, Eppendorf). Glass capillaries (FemtoTip, Eppendorf) with an internal tip diameter of 0.5 um were used.
10 Injection time was 0.8 seconds at a pressure of 30 hPA.
Microinjection took place under an Olympus IX50 microscope equipped for fluorescence. The injection buffer used consisted of l4mM NaCl, 3 mM KC1, and 10 mM KH2P04, pH 7.0, which contained 0.01 ug/ul pcDNA-YFP. An injection solution of 0.08 (w/v) Texas red coupled with dextran 70000 (Molecular Probes, Leiden, Netherlands) was added to test for successful microinjection. In order to analyze the inhibition of YFP expression with specific dsRNA, dsRNAs were added to the injection solution: Assay 1:
0.01 uM dsRNA (sequence protocol SQ148/149); Assay 2: 0.01 uM
dsRNA (sequence protocol SQ148/159); Assay 3: without RNA. After microinjection, the cells were incubated for at least another 3 hours in an incubator. Intracellular YFP fluorescence was then analyzed under the microscope: the cells that fluoresced both red and green simultaneously: microinjection was successful, no inhibition of YFP expression as a result of dsRNA was observed, or there were control cells into which no dsRNA was injected;
only red fluorescent cells: microinjection was successful, dsRNA
inhibited YFP expression.
Results:
At a dsRNA concentration of 0.1 uM, the use of dsRNA with single-stranded regions with two-nucleotide overhangs each at both 3'-ends (sequence protocol SQ148/159) markedly enhanced inhibition of the expression of the YFP gene in fibroblasts in \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc comparison to dsRNA without end having single overhanging strands (Table 1).
The use of short dsRNA molecules, containing 19-25-base pairs with overhangs consisting of a few, preferably 1 to 3, non-base-paired single-stranded nucleotides thus makes possible a comparatively more powerful inhibition of gene expression in mammalian cells than does the use of dsRNAs with the same number of base pairs without the corresponding single-stranded overhangs at the same RNA concentrations.
Assay Name Sequence protocol No. 0.1 pM

1 S1A/ SQ148 +

2 S1A/ SQ148 (overhanging ends) +++

3 Without RNA -Table 1: The symbols give the relative proportion of non- or weakly-fluorescent cells (+++ > 90~; ++ 60-90~-+ 30-60~; - <
10~) .
II. Inhibition by dsRNA of gene expression of a target gene in cultured HELA-S3 cells and mouse fibroblasts:
The effectiveness of the inhibition of YFP expression after transient transfection of a YFP-coding plasmid on the basis of RNA interference with dsRNA may be modulated by manipulating the 3'-ends and the length of the base-paired region.
Example:
In order to determine the effectiveness of dsRNA in the specific inhibition of gene expression, transient transfected NIH/3T3 \\SERVER\g$lTexte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc cells (fibroblasts from NIH Swiss mouse embryo, ECCAC [European collection of animal cell culture] No. 93061524) and HELA-S3 (human cervical cancer cells, DSMZ [German collection of microorganisms and cell cultures] No. ACC 161) were used. The pcDNA-YFP plasmid, containing an 800-by Bam HI/Eco RI-YFP
fragment in the corresponding cleaving sites of the vector pcDNA
3, was used for transfection. Double-stranded RNAs (dsRNAs) derived from the sequence of the yellow fluorescent protein (YFP) were produced and transiently transfected into the fibroblasts along with the pcDNA-YFP plasmid (the antisense strands of the specific dsRNAs used are complementary to the corresponding segments of the gene sequences of both YFP and GFP). The reduction in fluorescence was quantified after 48 hours. Cells that were either transfected only with pcDNA-YFP or with pcDNA-YFP and a control dsRNA (not derived from the YFP
sequence) were used as controls.
Test protocol:
dsRNA synthesis:
The individual RNA strands seen in the sequence protocols as well as their complementary single strands were synthesized using an RNA synthesizer (Expedite 8909, Applied Biosystems, Weiterstadt, Germany), as well as by conventional chemical means. Purification of the raw synthesis products was then done with the help of the HPLC. The NucleoPac PA-100, 9 x 250 column (Dionex) was used with 20 mM tris, 10 mM NaC104, pH 6.8, 10~
acetonitrile were used as the low salt buffer, and 20 mM tris, 400 mM NaC104, pH 6.8, 10~ acetonitrile were used as the high salt buffer. Flow was 3 ml per minute. Hybridization of the single strands into a double-stranded was done by heating the stochiometric mixture of the single strands in 10 mM sodium phosphate buffer, pH 6.8, and 100 mM NaCl to 80-90pC and then allowing it to cool slowly over 6 hours to room temperature.
\\SERVER\g$\TexteWnmeldeunterlagen 2003\422497-Ribopharma-an-2.doc Seeding the cells:
All cell culturing was conducted under sterile conditions at an appropriate workstation (HS18/ Hera Safe, Kendro, Heraeus).
Culturing of the NIH/3T3 cells and the HELA-S3 was done in the incubator (C02-incubator T20, Hera Cell, Kendro, Heraeus) at 37$C, 5~ C02, and saturated atmospheric humidity in DMEM
(Dulbecco's modified eagle medium, Biochrom) for the mouse fibroblasts, and in Ham's F12 for the HELA cells, with 10~ FCS
(fetal calf serum, Biochrom), 2 mM L-glutamine (Biochrom), and penicillin/streptomycin (100 IU/100ug/ml, Biochrom). In order to maintain the cells in an exponential growth state, the cells were passaged every 3 days. Twenty-tour hours before transfection, the cells were trypsinized (10x trypsin/EDTA, Biochrom, Germany) and placed in a 96-well plate (Multiwell Schalen 96-well, flat-bottom, Schubert & Weiss Laboratories, GmbH) at a cell density of 1.0 x 104 cells/depression and cultured in 150 u1 growth medium.
Implementation of transient transfection:
Transfection was done using Lipofectamine PlusT"" reagent (Life Technologies) in accordance with manufacturer directions. 0.15 ug pcDNA-YFP plasmid was placed in each well. The entire transfection volume was 60 u1. In each case, 3 samples were started. First, the plasmid DNA was complexed together with the dsRNA. The plasmid DNA and dsRNA were diluted in serum-free medium, and 1 u1 PLUS reagent was used per 0.1 ug of plasmid DNA
(in a volume of 10 u1). This was then incubated at room temperature after mixing for 15 minutes. During incubation 0,5 ~1 lipofectamine was diluted in 10u1 serum-free medium per 0,1 ~g plasmsid-DNA, well mixed, added to the plasmid/dsRNA/PLUS-mixture and again incubated for 15 minutes. The medium was changed during incubation. The cells were washed once with 200 \\SERVER\g$\Texte\Anmeldeunterlagea 2003\422497-Ribophanna-an-2.doc 1$
u1 serum-free medium, and thereafter incubated with 40 u1 serum-free medium in the incubator until the addition of DNA/dsRNA/PLUS/Lipofectamine. After the addition of 20 u1 DNA/dsRNA/PLUS/Lipofectamine per well, the cells were incubated in an incubator for 2.5 hrs. After incubation, the cells were washed once with 200 u1 growth medium and incubated in the incubator for 24 hours in 200 u1 growth medium until fluorescence detection was done.
Fluorescence detection:
24 hours after the last medium change, cell fluorescence was photographed using a fluorescence microscope (IX50-S8F2,U-ULS100Hg fluorescence unit, Brenner U-RFL-T200, Olympus) with a USH I02D mercury lamp (Ushio Inc., Tokyo, Japan), fitted with a WIB fluorescence cube and a digital CCD camera (Orca IIIm, Hamamatsu), and a C4742-95 preview monitor. Analysis of the fluorescence images was done using Analysis Software 3.1 (Soft Imaging System GmbH, Germany. In order to relate YFP
fluorescence to cell density, cell nucleus staining was done (Hoechst staining). For this the cells were fixed, first in 100 u1 methylcarnoy (75% methanol, 25o glacial acetic acid) for 5 minutes, and then again for 10 minutes in methylcarnoy. After air drying, the fixed cells were incubated in the dark for 30 minutes with 100 u1 Hoechst stain per well (75 ng/ml). After washing twice with PBS (Dulbecco PBS w/o Ca2+, Mgz+~ Biochrom), the cells that had been Hoechst stained were photographed under the fluorescence microscope (Olympus, WU fluorescence cube for Hoechst).
The results regading inhibition of YFP expression in cultivated cells by dsRNA are summarized in Figures 3 to 9: The effects of YFP-specific dsRNAs and of control dsRNAs on YFP expression in NIH/3T3 mouse fibroblasts after transient transfection are summarized in Figures 3, 4, 5, and 6. The experiments were \\SERVER\g$\Texte\Anmeldeunterlagen 2003\42?A97-Ribopharma-an-2.doc carried out as described in the test protocol. The concentration of dsRNA relates to the concentration in the medium during the transfection reaction. The dsRNA designations may be seen in Table 2. It shows the relative fluorescence per photographic image in terms of surface percentage. Three different photographic images were analyzed per well. The average values are obtained from the three images.
Specific inhibition of YFP-gene expression by dsRNAs in HELA-S3 cells is shown in Figures 7 and 9. Figure 7 shows the inhibiting action of variously configured dsRNA constructs (Table 2) in various concentrations on expression of YFP in HeLa cells.
Figure 8 shows representative fluorescence microscopic images of NIH/3T3 mouse fibroblasts transiently transfected with YFP, without dsRNA and with specific anti-YFP-directed dsRNAs (100x enlargement).
8A: YFP control 8B: S1, 10 nM

8C: S4, 10 nM

8D: S7, 10 nM

8E: 57/511, 1 nM

8F: S7/S12, 1 nM

Figure 9 shows representative fluorescence microscopic images of HELA-3S cells transiently transfected with YFP, without dsRNA
and with specific anti-YFP-directed dsRNAs (100x enlargement).
9A: K2 control, 10 nM
9B: S1, 10 nM
9C: S4, 10 nM
9D: S7, 10 nM
9E: 57/11, 1 nM
9F: 57/12, 2 nM
9G: S1A/S4B, 10 nM
\\SERVER\g$\Texte\Anmeldeunterlagea 2003\422497-Ribopharma-aa-2.doc 9H: YFP control Figure 3 shows that YFP expression after transient cotransfection of mouse fibroblasts with the YFP plasmid and specific anti-YFP-sequence-directed dsRNAs can be particularly effectively inhibited when the 3'-ends of the 22- and 19-base-pair-containing regions of the dsRNAs exhibit single-stranded segments of 2 nucleotides (nt). V~hereas the S1 dsRNA with smooth 3'-ends exhibits no inhibitory effects on YFP expression at a concentration of 1 nM (relating to the concentration in the cell culture medium during transfection), the S7 dsRNA (19 nucleotide pairs) and the S4 (22 nucleotide pairs), each with 2nt overhangs at both 3'-ends, inhibited YFP expression by 50~ and 70~, respectively, in comparison to the corresponding control dsRNAs (K3 and K2). At a concentration of 10 nM, the dsRNA with the smooth ends designated S1 inhibits YFP expression by -65~, whereas the S4 dsRNA inhibits YFP expression by --93~ (Figure 4).
The inhibitory effects of the dsRNAs designated as S4 and S7 are concentration-dependent (Figure 3 and 4; see also Figure 7).
Figure 4 shows that the single-stranded configuration at both 3'-ends (of the sense and antisense strand) is not necessary for efficient suppression of YFP gene expression. To achieve effective inhibition of YFP expression, only the 2nt overhang at the 3'-end of the antisense strand is necessary. Thus, for both S4 dsRNAs (with 2nt overhangs at both 3'-ends) and S1A/S4B (with one 2nt overhang at the 3'-end of the antisense strand) inhibition of YFP expression at a concentration of 1 nM is -70~.
However, if on the other hand the 2nt overhang is located at the 3'-end of the sense strand (and the 3'-end of the antisense strand does not have a single-stranded region), inhibition of \\SERVER\g$\Texte\Anmeldeuntertagen 20034422497-Ribopharma-an-2.doc Ig YFP gene expression is 50~. Analogously, inhibition at higher concentrations is considerably better when at least the 3'-end of the antisense strand has a 2nt overhang.
A more marked inhibition of YFP expression is achieved when the base-paired region has 21 nucleotide pairs instead of 22 (S1 and S4), 20 (513 or 513/14, or 19 (S7) (Figures 5, 6, and 7). Thus, at a concentration of 5 nM, inhibition of YFP expression by S1 (22 base pairings with smooth ends) is -40~, while inhibition by S7/S12 (21 base pairings with smooth ends), also at 5 nM, is --92$. If the dsRNA with 21 base pairings exhibits another 2nt overhang at the antisense strand 3'-end (57/S11), inhibition is --97~ (compared with --73~ inhibition by S4 and -70~ inhibition by S7).
III. Analysis of serum stability of double-stranded RNA (dsRNA):
The object is to take the effectiveness of the inhibition on the gene expression of target genes mediated by dsRNAs found in cell cultures and enhance it for use in vivo. This is achieved by improving the stability of dsRNA in serum, and by increasing the retention time of the molecule in the blood circulation, or by increasing the effective concentration of the functional molecule that results from the foregoing.
Example:
Serum stability of GFP-expression-inhibiting dsRNAs was tested ex vivo in murine and human serum.
Test protocol:
Incubation of human and murine serum with corresponding dsRNA
was done at 37~C. In each case, 85u1 serum was incubated with 15 IiSERVERig$iTextelAnmeldeuntertagen 2003\422497-Ribopharma-an-2.doc 1~
u1 100uM dsRNA. After certain incubation spans (30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours) the samples were frozen at -80~C. DsRNA without serum (+85 u1 ddH20) and dsRNA with serum at Time 0 were used as controls.
In order to isolate dsRNA from the incubate, which was done on ice, 400 u1 0.1% SDS was added to each incubate, and these then underwent phenol extraction: 500 u1 phenol: chloroform:isoamyl alcohol (IAA, 25:24:1, Roti phenol, Roth, Karlsruhe) were added to each incubate, and then vortexed at the highest setting for 30 seconds (Vortex Genie-2, Scientific Industries). After incubation for 10 minutes on ice, phase separation was carried out by centrifugation at 12,000 xg at 4$C for 10 minutes (Sigma 3K30, Rotor 12131-H). The top aqueous phase (approximately 200 u1) was collected and then underwent digestion: first with DNase I and then with Proteinase K: 20 u1 lOx DNase buffer (100 mM
tris, pH 7.5, 25 mM MgCl2, 1 mM CaCl2) and 10 U DNase I (D 7291, Sigma-Aldrich) were added incubated for 30 minutes at 37~C, then 6 U DNase I were again added, incubated for another 20 minutes at 37~C. Then 5u1 Proteinase K (20 mg/ml, 04-1075, Peqlab, Germany) was added and incubated for 30 minutes at 37QC. Phenol extraction was then carried out. To this was added 500 u1 phenol:chloroform:IAA (25:24:1), vortexed for 30 seconds at the highest setting, and then centrifuged for 10 minutes at 12,000 xg and 44C. The supernatant fluid was drawn off and replaced sequentially with 40 u1 3 M Na-Ac (sodium acetate), pH 5.2, and 1 ml 100% EtOH; this was well mixed and precipitated for at least one hour at -80~C. The precipitate was pelleted by centrifugation at 12,000 xg for 30 minutes at 4pC, washed with 70% EtOH, and again centrifuged (10 minutes, 12,000 xg at 4~C).
The air-dried pellet was then mixed in 30 u1 RNA gel application buffer (7 M urea, 1 x TBE [0.09 M tris borate, 0.002 M EDTA, 0.02% [w/v] bromophenol blue, 0.2% [w/v] xylencyanol) and stored at -20~C until gel application.
\\SERVERIg$\Texte\Anmeldeunterlagen 2003\422497-Ribopham~a-an-2.doc In order to characterize the dsRNA, analytic, denaturing polyacrylamide gel electrophoresis (analytic PAGE) was carried out. The urea gels were produced shortly before the run: 7M urea 5 (21 g) was dissolved while stirring in 25 ml 40~ aqueous acrylamide/bisacrylamide solution (Rotiphoresis gel, A515.1, Roth) and 5 ml 10 x TBE (108 g tris, 55 g boric acid, 3.9 g EDTA
per liter distilled water) and diluted to 50 ml with of distilled water. Shortly before pouring, 50 u1 TEMED (N,N,N',N'-10 tetramethyl ethylendiamine) and 500 u1 10o APS (ammonium peroxide sulfate) were added. After polymerization, the gel was placed in a vertical electrophoresis apparatus (Merck, Darmstadt), and a first fraction was carried out for 30 minutes at a constant amperage of 40 mA. 1 x TBE buffer was used as the 15 running buffer. Before applying them to the gel, the RNA samples were heated for 5 minutes at 100~C, cooled on ice, and then centrifuged for 20 seconds on a table centrifuge (Eppendorf Minispin). 15 ~,1 of each sample was applied to the gel. The test run lasted for approximately two hours at a constant amperage of 20 40 mA. After the run, the gel was stained with Stains All staining solution (20 ml Stains All solution [200 mg Stains All dissolved in 200 ml formaldehyde] with 200 ml of distilled water and 100 ml formamide), and the background stain was then removed by rinsing with distilled water for 45 minutes. The gels were photographed using the Image Master VDS photodocumentation system from Pharmacia. Figures 10 to 17 show the serum stability of dsRNA after incubation with human or murine serum, and subsequent electrophoretic separation in 20~ 7M urea gel.
Figure lOs Incubation of S1 (0-22-0) in mouse serum 1. At Time 0 (without serum) 2. At Time 0 3. For 30 minutes 4. For 1 hour 5. For 2 hours ~1SERVER~g$lTexte~Anmeldeunterlagen 2003W22497-Ribopharma-an-2.doc 6. For 4 hours 7. For 12 hours 8. 2 u1 100 uM S1 without incubation S1A) sense strand S1 (10 u1 20 uM S1A) S1B) antisense strand S1 (10 u1 20 uM S1B) Figure 11s Tncubation of S1 (0-22-0) in human serum 1. 2 u1 100 uM S1 untreated (without incubation) 2. For 30 minutes 3. For 2 hours 4. For 4 hours 5. For 6 hours 6. For 8 hours 7. For 12 hours 8. For 24 hours S1A) sense strand S1 (10 u1 20 uM S1A) S1B) antisense strand S1 (10 u1 20 uM S1B) \\SERVER\g$\Texte\Anmeldeuntertagen 20031422497-Ribopharma-aa-2.doc Figure 12s Incubation of S7 (2-19-2) in mouse serum 1. At Time 0 (without serum) 2. For 30 minutes 3. For 4 hours 4. For 12 hours Figure 13: Incubation of (2-19-2) in human serum 1. Sense strand S7 (10 u1 20 uM S7A) 2. Antisense strand (10 u1 uM S7B) 3. For 30 minutes 4. For 1 hour 5. For 2 hours 6. For 4 hours 7. For 6 hours 8. For 12 hours 9. For 24 hours 10 . At Time 0 (withoutserum) Figure 14: Incubation of (2-19-2) in mouse serum 1. Sense strand K3 (10 u1 20 uM K3A) 2. Antisense strand (10 u1 uM K3B) 3. At Time 0 (without serum) 4. At Time 0 (with ser um) 5. For 30 minutes 6. For 1 hour 7. For 2 hours 8. For 4 hours 9. For 12 hours Figure 15: Incubation of -2) in mouse serum PKC1/2 (0-22 1. For 30 minutes 2. For 1 hour 3. For 2 hours 4. For 4 hours 5. For 12 hours 6. 2 u1 100uM PKC1/2 untreated) ( 1~SERVERIg$\TexteWnmeldeunterlagen 2003~422A97-Ribopharma-an-2.doc Figure 16: Incubation of S1A/S4H (0-ZZ-Z) in human serum 1. At Time 0 (without serum) 2. For 24 hours 3. For 12 hours 4. For 8 hours 5. For 6 hours 6. For 4 hours 7. For 2 hours 8. For 30 minutes 9. Sense strand S1A 0 u1 uM SlA) (1 20 10. Antisense strand 4B (10 u1 20 uM S4B) S

Figure (Z-2Z- Z) in human serum 17: Tncubation of K2 1. Sense strand K2 u1 20 uM K2A) (10 2. Antisense strand (10 20 uM K2B) K2 u1 3. At Time 0 (without serum) 4. For 30 minutes 5. For 2 hours 6. For 4 hours 7. For 6 hours 8. For 8 hours 9. For 12 hours 10. For 24 hours T'f..-...-.~1 L.. _ DsRNAs without single-stranded regions at the 3'-ends are considerably more stable in both human and mouse serum than are dsRNAs with single-stranded 2nt overhangs at the 3'-ends (Figures 10 to 14 and 17). After 12 and 24 hours, respectively, of incubation of S1 in both murine and human serum, one band of the original size remains almost completely intact. By contrast, the stability of dsRNAs with 2nt overhangs at both 3'-ends decreases considerably in both human and murine serum. Even \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc after only 4 hours of incubation of S7 (Figures 12 and 13) or K3 (Figure 14), no band of the original size is still detectable.
In order to enhance the stability of dsRNA in serum, it is sufficient if the dsRNA possesses one smooth end. The original size of the band has hardly been broken down at all in mouse serum after 4 hours incubation (Figure 15, Track 4) when compared to S7 (complete decomposition after 4 hours; Figure 12, Track 3) One optimal compromise with regard to the biological effectiveness of dsRNA may be the use of dsRNA with one smooth end and one single-stranded region of 2 nucleotides, whereby the single-stranded overhang is located at the 3'-end of the 1S antisense strand.
The sequences used here are reproduced in the following Table 2 and in the sequence protocols SQ148-151 and 153-167.
N~NLA Swqueaced$RNA-SBQ11Hl1CEt protocol No.

SQ148 (A) 5~- CCACAUGAAGCAGCACGACUUC -3~

81 SQ149 (g) 3'- GGUGUACUUCGUCGUGCUGAAG -5' 0-22-0 g~ SQ150 (A) 5~- CCACAUGAAGCAGCACGACUU -3' SQ151 (B) 3'- CUGGUGUACUUCGUCGUGCUG -5~ 2-19-2 SQ153 (A) 5~- ACAGGAUGAGGAUCGUUUCGCA -3~

SQ154 (B) 3'- UGUCCUACUCCUAGCAAAGCGU -5' 0-22-0 g3 SQ155 (A) 5~-GAUGAGGAUCGUUUCGCAUGA-3~

SQ156 (B) 3~-UCCUACUCCUAGCAAAGCGUA-5~ 2-19-2 SQ157 (A) 5'- ACAGGAUGAGGAUCGUUUCGCAUG -3~

\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc SQ158 (B) 3~- -5~ 2-22-2 UCUGUCCUACUCCUAGCAAAGCGU

S1A/ SQ148 (A) 5~- CCACAUGAAGCAGCACGACUUC -3~

S4B SQ159 (B) 3~- -5r 0-22-2 CUGGUGUACUUCGUCGUGCUGAAG

PRC 1/2 SQ160 (A) 5~- CUUCUCCGCCUCACACCGCUGCAA -3~

SQ161 (B) 3~- GAAGAGGCGGAGUGUGGCGACG -5~ 2-22-0 SQ150 (A) 5'- CCACAUGAAGCAGCACGACUU -3~ 0-21-0 SQ162 (B) 3'- GGUGUACUUCGUCGUGCUGAA -5~

S7/S11 SQ150 (A) 5'- CCACAUGAAGCAGCACGACUU -3~

SQ163 (B) 3'- 0-21-2 CUGGUGUACUUCGUCGUGCUGAA
-5~

S13 SQ164 (A) 5'- CCACAUGAAGCAGCACGACU -3~

SQ165 (B) 3'- 0-20-2 CUGGUGUACUUCGUCGUGCUGA
-5~

513/14 SQ164 (A) 5~- CCACAUGAAGCAGCACGACU -3~

SQ166 (B) 3~- GGUGUACUUCGUCGUGCUGA -5~ 0-20-0 S4 SQ167 (A) 5'- CCACAUGAAGCAGCACGACUUCUU -3~

SQ159 (B) 3'- -5~ 2-22-2 CUGGUGUACUUCGUCGUGCUGAAG

R1A/ SQ153 (A) 5'- ACAGGAUGAGGAUCGUUUCGCA -3~ 0-22-2 K28 SQ158 (B) 3'- -5~
UCUGUCCUACUCCUAGCAAAGCGU

K1B/ SQ154 (A) 5'- ACAGGAUGAGGAUCGUUUCGCAUG -3' K2A SQ157 (B) 3~- UGUCCUACUCCUAGCAAAGCGU ~ 2-22-0 S1B/ SQ149 (A) 5'- CCACAUGAAGCAGCACGACUUCUU -3~

S4A SQ167 (B) 3~- GGUGUACUUCGUCGUGCUGAAG -5' 2-22-0 Table 2 IV. In vivo study:

Double-stranded RNA (dsRNA) that was derived from the GFP
sequence and nonspecific dsRNA, respectively, was injected into \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc the caudal vein of "GFP lab mice" that express the green fluorescent protein (GFP) in all cells that are involved in protein biosynthesis. At the end of the experiment the animals were killed and tissue sections and plasma GFP expression were analyzed.
Test protocol:
dsRNA synthesis:
The individual RNA strands seen in the sequence protocols as well as their complementary individual strands were synthesized using an RNA synthesizer (Expedite 8909, Applied Biosystems, Weiterstadt, Germany), as well as by conventional chemical means. Purification of the raw synthesis products was then done with the help of the HPLC. The NucleoPac PA-100, 9 x 250 column (Dionex) was used: 20 mM tris, 10 mM NaC104, pH 6.8, 10$
acetonitrile was used as the low salt buffer, and 20 mM tris, 400 mM NaC104, pH 6.8, 10~ acetonitrile was used as the high salt buffer. Flow was 3 ml per minute. Hybridization of the individual strands into a double-stranded was done by heating the stochiometric mixture of the individual strands in 10 mM
sodium phosphate buffer, pH 6.8, 100 mM NaCl to 80-90~C and then allowing it to cool slowly over 6 hours to room temperature.
Test-animal conditions and course of the experiment:
The transgenic laboratory mouse strain TgN(GFPU)SNagy (Jackson Laboratory, Bar Harbor, ME) was used; this strain has been shown to express GFP (with a beta-actin promoter and a CMV
intermediate early enhancer) in all previously tested cells, (Hadjantonakis AK et al., 1993, Mech Dev. 76:79-90;
Hadjantonakis AK et al., 1998, Nature Genetics 19: 220-222). The GFP-transgenic mice may be readily differentiated from the corresponding wild type (WT) on the basis of fluorescence (using a hand-held UV lamp). The corresponding WT was always paired \\SERVER\g$\TexteWnmeldeunterlagen 2003\422A97-Ribopharma-an-2.doc with a heterozygote GFP type for purposes of breeding. The experiment was conducted in accordance with the German animal rights laws. The animals were kept in a controlled environment in groups of 3-5 animals in Type III Makrolon cages (Ehret, Emmendingen) at a constant temperature of 22~C and a day/night rhythm of 12 hours. Wood shavings of 8/15 granulated softwood (Altomin, Lage) were used. The animals received tap water and standard feed (Altormin 1324 pellets) ad libitum.
The heterozygote GFP animals that were used in the experiment were kept in cages in groups of 3 animals as described above.
Injection of dsRNA solution was done intravenously (i.v.) in the caudal vein in 12-hour cycles (between 5:30 and 7:00 and between 17:30 and 19:00) over a 5-day period. Injection volume was 60 u1 per 10 g of body weight, and the dosage was 2.5 mg dsRNA or 50 ug, respectively, per kg body weight. The groups were divided as follows:
Group A: PBS (phosphate buffered saline) 60 u1 per 10 g body weight each, Group B: 2.5 mg per kg body weight of a nonspecific control dsRNA (K1 control with smooth ends and a double-stranded region consisting of 22 nucleotide pairs ) , Group C: 2.5 mg per kg body weight of another nonspecific control dsRNA (K3 control with 2nt overhangs at both 3'-ends and a double-stranded region consisting of 19 nucleotide pairs), Group D: 2.5 mg per kg body weight dsRNA (specific anti-GFP directed, henceforth referred to as S1, with \1SERVER\g$\Texte\Anmetdeunterlagen 2003\422497-Ribopharn~a-an-2.doc smooth ends and a double-stranded region consisting of 22 nucleotide pairs), Group E: 2.5 mg dsRNA per kg body weight (specific anti-s GFP, henceforth referred to as S7, with 2nt overhangs at the 3'-ends of both strands and a double strand region consisting of 19 nucleotide pairs), Group F: 50 ug S1 dsRNA per kg body weight (in other words 1/50 of the dosage in Group D).
After the last of a total of 10 injections, the animals were killed after 14-20 hours, and the organs and blood were removed as described.
Organ removal:
Immediately after the animals were killed by means of C02 inhalation, their blood and various organs were removed (thymus, along, heart, spleen, stomach, intestines, pancreas, brain, kidneys, and liver). The organs were quickly rinsed with cold, sterile PBS and sectioned using a sterile scalpel. One portion was fixed for 24 hours in methyl carnoys (MC, 60~ methanol, 30~
chloroform, 10~ glacial acetic acid) for immunohistochemical staining; one portion was immediately flash-frozen in liquid nitrogen and stored at -80gC for making frozen sections and for protein isolation; and another, smaller portion, was frozen in RNAeasy Protect (Qiagen) at-80~C for RNA isolation. Immediately after removal, the blood was placed on the ice for 30 minutes, mixed, and centrifuged for 5 minutes at 2000 rpm (Mini spin, Eppendorf). The supernatant fluid (here referred to as plasma) was drawn off and stored at -80~C.
Processing the biopsies:
\\SERVER\g~\Texte\Anmeldeunterlagen 2003\422497-Ribopharn~a-an-2.doc After the tissues had been fixed for 24 hours in MC, the tissue pieces were dehydrated in an ascending alcohol series at room temperature: 40 minutes each, 70~ methanol, 80~ methanol, 2 x 96~ methanol and 3 x 100 isopropanol. After that, the tissue was warmed in an incubator in 100 isopropanol at 60~C, after which it was incubated for one hour in an isopropanol/paraffin mixture at 60~C and 3x for 2 hours in paraffin, and then bedded in paraffin. For the immunoperoxidase stains, the tissue sections 3 um in thickness were prepared, using a rotation microtome (Leica), placed on glass slides (Superfrost, Vogel) and incubated for 30 minutes in an incubator at 60~C.
Immunoperoxidase staining for GFP:
The sections were deparaffinized 3 x 5 minutes in xylol, rehydrated in a descending alcohol series (3 x 3 min., 100 ethanol, 2 x 2 min. 95~ ethanol), and then incubated in 3~
H2O2/methanol to block endogenous peroxidases. All incubation steps in the following were carried out in a moist chamber.
After washing with PBS 3 x 3 minutes, incubation was carried out with the first antibody (goat anti-GFP, sc-5384, Santa Cruz Biotechnology) 1:500 in 1~ BSA/PBS overnight at 4pC. Incubation with the biotinylated secondary antibody (donkey anti-goat;
Santa Cruz Biotechnology; dilution 1:2000) was then carried out for 30 minutes at room temperature, after which it was incubated with Avidin D peroxidase (dilution 1:2000, Vector Laboratories).
After each antibody incubation, the sections were washed in PBS
for 3 x 3 minutes, and the buffer residue and cell debris were removed from the sections. All antibodies were diluted in 1~
bovine serum albumin (BSA)/PBS. Staining with 3,3'-diaminobenzadine (DAB) was done using a DAB substrate kit (Vector Laboratories) in accordance with manufacturer instructions. Gill's Hematoxylin III was used for the nucleic counter stain (Merck). After dehydration in an ascending alcohol series and 3 x 5 minutes xylol, the sections were covered with \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc Entellan (Merck). Microscopic analysis of the stains was done using an Olympus IX50 microscope fitted with a CCD camera (Hamamatsu).
5 Protein isolation from tissue pieces:
800 u1 isolation buffer (50mM HEPES, pH 7.5; 150 mM NaCl; 1 mM
EDTA; 2.5 mM EGTA; 10% glycerol; 0.1% Tween; 1 mM DDT; 10 mM (3-glycerol phosphate; 1 mM NaF; 0.lmM Na3V04 with a "Complete"
protease inhibitor tablet manufactured by Roche) was added to 10 each of the still-frozen tissue pieces, and then homogenized 2 x 30 seconds using an Ultraturrax (DIAX 900, 6G disperser, Heidolph), and cooled on ice between homogenization steps. After incubation on ice for 30 minutes, it was mixed and centrifuged for 20 minutes at 10,000 xg, at 4~C (3K30, Sigma). The 15 supernatant fluid was then again incubated on ice for 10 minutes, mixed, and centrifuged for 20 minutes at 15,000 xg.
Protein determination was then done on the supernatant fluid according to Bradford, 1976, modified according to Zor &
Selinger, 1996, using the Roti-Nanoquant system from Roth, in 20 accordance with the manufacturer instructions. BSA (bovine serum albumin) was used for protein calibration at concentrations ranging from 10 to 100 ug/ml.
SDS gel electrophoresis:
25 Electrophoretic separation of the proteins was done in a Multigel-Long electrophoresis chamber from Biometra with a denaturing, discontinuous 15% SDS-PAGE (polyacrylamide gel electrophoresis) according to Lammli (Nature 277: 680-685, 1970). On top of this was poured a separation gel to a thickness 30 of 1.5 mm: 7.5 ml acrylarnide/bisacrylamide (30~, 0.9%), 3.8 ml 1.5 M tris/HC1, pH 8.4, 150 u1 IO% SDS, 3.3 ml bidistilled water, 250 u1 ammonium persulfate (10%], 9 u1 TEMED (N,N,N',N'-tetramethylendiamine) and layered with 0.1~ SDS until polymerization occurred. Then the collection gel was poured:
\\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc 0.83 u1 acrylamide/bisacrylamide (30~/0.9~), 630 u1 1 M
tris/HC1, pH 6.8, 3.3 ml bidistilled water, 50 u1 10~ SDS, 50 u1 loo ammonium persulfate, 5 u1 TEMED.
Before being applied to the gel, a corresponding quantity of 4x sample buffer (200 mM tris, pH 6.8, 4~ SDS, 100 mM DTT
[dithiotreithol), 0.02 bromphenol blue, 20~ glycerin) was added to the proteins, and denatured on a heat block at 100~C. After cooling off on ice, this was quickly centrifuged and applied to the gel. The same amounts of plasma or protein were used for each track (3 u1 plasma or 25 ug total protein). Hydro-cooled electrophoresis was done at room temperature and at a constant 50 V. The protein gel marker from BioRad (Kaleidoscope Pre-stained Standard) was used as the standard length.
Western blot and Immunodetection:
Transfer of the proteins from SDS-PAGE to a PVDF (polyvinyl difluoride) membrane (Hybond-P, Amersham) was done using a semidry method according to Kyhse-Anderson (J. Biochem. Biophys.
Methods 10:203-210, 1984) at room temperature and a constant amperage of 0.8 mA/cm2 for 1.5 hours. A tris/glycine buffer (39 mM Gly, 46 mM tris, 0.1~ SDS, and 20~ methanol) was used as the transfer buffer. In order to analyze electrophoretic transfer, both the post-blot gels and the blot membranes were stained after immunodetection using Coomassie (0.1~ Coomassie 6250, 45~
methanol, 10~ glacial acetic acid). The blot membrane was incubated after transfer in 1~ skim milk powder/PBS for one hour at room temperature in order to saturate nonspecific bonds.
After that, it was washed three times for 3 minutes with 0.1~
Tween-20/PBS. All subsequent antibody incubations and washings were done using 0.1~ Tween-20/PBS. Incubation with the primary antibody (goat anti-GFP, sc-5384, Santa Cruz Biotechnology) was done at a dilution of 1:1000 for 1 hour at room temperature.
After that, it was washed 3 x 5 minutes , labeled with the \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc secondary antibody (donkey anti-goat IgG horseradish peroxidase, Santa Cruz Biotechnology) for 1 hour at room temperature at a dilution of 1:10,000. Detection was then done using the ECL
system from Amersham in accordance with the manufacturer instructions.
Figures 18 to 20 show on, 3-um paraffin sections, the inhibition of GFP expression after intravenous injection of specific anti-GFP directed dsRNA with anti-GFP immunoperoxidase stain. In the test run, anti-GFP directed dsRNA with a double-stranded region consisting of 22 nucleotide pairs without overhangs at the 3'-ends (D) and the corresponding nonspecific control dsRNA (B), as well as the specific anti-GFP directed dsRNA with a double-stranded region comprising 19 nucleotide pairs with 2nt overhangs at the 3'-ends (E) and the corresponding nonspecific control dsRNA (C) were applied in 12-hour rotations over 5 days.
(F) received 1/50 of the dosage of Group D. Animals that received no dsRNA (A) and WT animals were also tested as a further control. Figure 18 shows the inhibition of GFP
expression in kidney sections, Figure 19 in heart tissue sections, and Figure 20 in pancreas tissue. Western blot analyses of GFP expression in plasma and tissue are shown in Figures 21 to 23. Figure 21 shows the inhibition of GFP
expression in plasma; Figure 22 in kidney tissue, and Figure 23 in heart tissue. The application of total protein isolates from various animals is shown in Figure 23. The same amounts of total protein were applied to each track. In the animals that received nonspecific control dsRNA (animals in Groups B and C), GFP
expression was not reduced in comparison to animals that received no dsRNA whatsoever. Animals that received specific anti-GFP directed dsRNA that contained 2nt overhangs at the 3'-ends of both strands and a double-stranded region consisting of 19 nucleotide pairs showed significant inhibition of GFP
expression in the tissues examined (heart, kidneys, pancreas, \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc and blood), compared with untreated animals (Figures 18 to 23).
In animals in Groups D and F that were given specific anti-GFP
directed dsRNA with smooth ends and a double-stranded region comprising 22 nucleotide pairs, only those animals that received S the dsRNA in a dosage of 50 ug/kg body weight per day exhibited a specific inhibition of GFP expression, which, however, was less marked than in the animals in Group E.
Summary analysis of GFP inhibition in tissue sections and on Western blot show that inhibition of GFP expression is strongest in the blood and kidneys (Figures 18, 21, and 22).
V. Inhibition of ene ex ression of the EGF rece for with dsRNA
as a therapeutic approach to forms of cancer characterized by EGFR overexpression or EGFR-induced proliferation:
The epidermal growth factor (=EGF) receptor (=EGFR) belongs to the tyrosin kinase receptors, transmembrane proteins with an intrinsic tyrosin kinase activity that are involved in the control of a series of cellular processes such as cell growth, cell differentiation, migratory processes, and cell vitality (overview in: Van der Geer et al., 2994). The EGFR family consists of 4 members, EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4) with a transmembrane domain, a cystein-rich extracellular domain, and a catalytic intracellular domain. The EGFR sequence, a 170-kDa protein, has been known since 1984 (Ullrich et al., 1984).
EGFR is activated by peptide growth factors such as EGF, TGFa (transforming growth factor), amphiregulin, betacellulin, HB-EGF
(heparin binding EGF-like growth factor), and neuregulins.
Ligand binding induces the formation of homodimes or heterodimes with subsequent autophosphorylation of cytoplasmic tyrosine (Ullrich & Schlessinger, 1990; Alroy & Yarden, 1997). The \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc phosphorylated amino acids form the binding sites of numerous proteins that are involved in the proximal stages of signal transmission in a complex network. EGFR is involved in the most varied tumoral diseases, and is therefore an appropriate target for therapeutic approaches (Huang & Harari, 1999). The mechanisms that lead to aberrant EGFR activity may be related to overexpression, amplification, constitutive activation of mutant receptor forms, or autocrine loops (Voldberg et al., 1997).
Overexpression of EGFR has been described for a series of tumors such as breast cancer (Walker & bearing, 1999), non-minor lung cancer (Fontaninii et al., 1998), pancreatic cancer, colon cancer (Salomon et al., 1995), and glioblastoma (Rieske et al., 1998). For malignant glioblastoma, in particular, there have to date been no effective and specific therapeutic agents.
Example:
To detect the effectiveness of dsRNA in the specific inhibition of EGFR gene expression, U-87 MG cells (human glioblastoma cells), ECCAC (European Collection of Animal Cell Culture) No.
89081402 was used, and was transfected with the specific anti-EGF-receptor-directed dsRNA (sequence protocol SQ 51). After approximately 72 hours of incubation, the cells were harvested, the protein was isolated, and EGFR expression was analyzed by Western blot.
Test protocol:
dsRNA synthesis:
The individual RNA strands seen in the sequence protocols as well as their complementary individual strands were synthesized using an RNA synthesizer (Expedite 8909, Applied Biosystems, Weiterstadt, Germany), as well as by traditional chemical means.
Purification of the raw synthesis products was then done with \1SERVER\g$lTexte\Anmetdeuntertagen ZOp3\422497-Ribopham~a-an-2.doc the help of the HPLC. The NucleoPac PA-100, 9 x 250 column (Dionex) was used with 20 mM tris; 10 mM NaC104, pH 6.8, 10~
acetonitrile was used as the low salt buffer, and 20 mM tris, 400 mM NaC104, pH 6.8, 10~ acetonitrile were used as the high 5 salt buffer. Flow was 3 ml per minute. Hybridization of the individual strands into a double-stranded was done by heating the stochiometric mixture of the individual strands in 10 mM
sodium phosphate buffer, pH 6.8, 100 mM NaCl to 80-90~C and then allowing them to cool slowly over 6 hours to room temperature.
Seeding the cells:
All cell culturing was done under sterile conditions at an appropriate workstation (HS18/ Hera Safe, Kendro, Heraeus).
Culturing of the U-87 MG cells was done in the incubator (C02-incubator T20, Hera Cell, Kendro, Heraeus) at 37QC, 5$ COZ and saturated atmospheric humidity in DMEM (Dulbecco's modified eagle medium, Biochrom) with 10~ FCS (fetal calf serum, Biochrom), 2 mM L-glutamine (Biochromone) mM sodium pyruvate (Biochrom), 1 x NEAR (nonessential amino acids, Biochrom), and penicillin/streptomycin (100 IU/100ug/ml, Biochrom). In order to maintain the cells in an exponential growth state, the cells were passaged every 3 days. 24 hours before dsRNA application by means of transfection, the cells were trypsinized (10 x trypsin/EDTA, Biochrom, Germany) and placed in a 6-well plate (6-well plates, Schubert & Weiss Laboratories, GmbH) in 1.5 u1 growth medium.
DsRNA application in cultured U-87 MG cells:
Application of dsRNA was done by means of transfection using the OLIGOFECTAMINET°' reagent (Life Technologies) in accordance with the manufacturer instructions. Total transfection volume was 1 ml.
First, the dsRNA was diluted in serum-free medium: 0.5u1 of a 20 uM stock solution of specific anti-EGFR directed dsRNA and 9.5 u1 of a 20 uM stock solution of nonspecific dsRNA (K1A/K2B) \\SERVER\g$\Texte\Anmeldeuntertagen 2003\422497-Ribopharma-an-2.doc diluted with 175 u1 serum-free medium (200 nM dsRNA in the transfection incubate or 10 nM specific EGFR-dsRNA) per well.
The OLIGOFECTAMINE'i''° reagent was also diluted in serum-free medium:
3 u1 with 12 u1 medium per well and then incubated for 10 minutes at room temperature. Then the diluted OLIGOFECTAMINET°' reagent was added to the medium of diluted dsRNA, mixed, and incubated for another 20 minutes at room temperature. The medium was changed during incubation. The cells were washed 1 x with 1 ml serum-free medium and continued to be incubated in the incubator with 800 u1 serum-free medium until the dsRNA/oLIGOFECTAMINE"' reagent was added. After the addition of 200 u1 dsRNA/oLIGOFECTAMINE'''°~ reagent per well, the cells continued to be incubated in the incubator until protein isolation.
Protein isolation:
Approximately 72 hours after transfection, the cells were harvested and the protein was isolated. The medium was removed, and the cell monolayer was washed once with PBS. After the addition of 200 u1 protein isolation buffer (lx "Complete"
protease inhibitor, Roche, 50 mM HEPES, pH 7.5, 150 mM NaCl, 1 mM EDTA, 2.5 mM EGTA, 10~ glycerin, 0.1$ Tween-20, 1 mM DTT, 10 mM ~i-glycerine phosphate, 1 mM NaF, 0.1 mM Na3V04) the cells were removed with the help of a cell scraper, incubated for 10 minutes on ice, transferred to an Eppendorf reagent vessel, and stored at -80pC for at least 30 minutes. After thawing, the lysate was homogenized at the third setting for 10 seconds with a disperser (DIAX 900, 6G disperser, Heidolph Instruments GmbH, Schwabach), incubated on ice for 10 minutes, and then centrifuged for 15 minutes at 14,000 xg at 4~C (3K30, Sigma).
Protein determination according to Bradford was done on the supernatant fluid using the Roti-Nanoquant system from Roth (Both GmbH, Karlsruhe) in accordance with the manufacturer's instructions. 200 ~1 protein solution at a suitable dilution is mixed with 800 u1 lx working solution, and extinction was \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc measured in semi-microcuvettes at 450 nm and 590 nm against distilled water in a Beckman spectrophotometer (DU 250). BSA
dilutions were used for calibration (beaded BSA, Sigma).
SDS gel electrophoresis:
Electrophoretic separation of the proteins was done in a Multigel-Long electrophoresis chamber from Biometra with a denaturing, discontinuous 7.5% SDS-PAGE (polyacrylamide gel electrophoresis) according to Lammli (Nature 277: 680-685, 1970). On top of this was poured a separation gel to a thickness of 2.5 mm: 3.75 ml acrylamide/bisacrylamide (30%, 0.9%), 3.8 ml 1 M tris/HC1, pH 8.4, 150 u1 10% SDS, 7.15 ml distilled water, 150 u1 ammonium persulfate (10%), 9 u1 TEMED (N,N,N',N'-tetramethylendiamine) and layered with 0.1 percent SDS until polymerization occurred. After that, the collection gel was poured: 0.83 ml acrylamide/bisacrylamide (30%/0.9%), 630 u1 1 M tris/HCl, pH 6.8, 3.4 ml distilled water, 50 u1 10% SDS, 50 u1 10% ammonium persulfate, 5 u1 TEMED.
Before being applied to the gel, a quantity of 4x sample buffer (200 mM tris, pH 6.8, 4% SDS, 100 mM DTT [dithiotreithol], 0.02%
bromphenol blue, 20% glycerin) was added to the proteins in a 1:3 ratio, and denatured at 100~C for 5 minutes. After cooling off on ice, this was quickly centrifuged and applied to the gel.
The same amount of protein was used for each track (35 ug total protein). The hydro-cooled gel run was done at room temperature and at a constant 50 V. Kaleidoscope Prestained Standard (BioRad) was used as the standard length.
Western blot and Immunodetection:
Transfer of the proteins from SDS-PAGE to a PVDF (polyvinyl difluoride) membrane (Hybond-P, Amersham) was done using a semidry method according to Kyhse-Anderson (J. Biochem. Biophys.
Methods 10:203-210, 1984) at room temperature and a constant 0.5 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharcna-an-2.doc mA/cm2 for 1.5 hours. A cathode buffer (30 mM tris, 40 mM
glycine, 10$ methanol, and 0.01 SDS, pH 9.4), anode buffer I
(300 mM tris, pH 10.4, 10~ methanol), and anode buffer II (30 mM
tris, pH 10.4, 10~ methanol) were used as the transfer buffers.
Before assembling the blot stack with 3MM Whatman paper (Schleicher & Schiill) the gel was incubated in cathode buffer, and the PVDF membrane (previously for 30 seconds in 100 methanol) in anode buffer II (5 minutes): 2 layers of 3MM paper (anode buffer I), 1 layer 3MM paper (anode buffer II), PVDF
membrane, gel, 3 layers 3MM paper (cathode buffer). To analyze electrophoretic transfer, both the post-blot gels and the blot membranes were stained after immunodetection using Coomassie (0.1~ Coomassie 6250, 45$ methanol, 10~ glacial acetic acid).
After transfer, the blot membrane was incubated in 1~ skim milk powder/PBS/0.1~ Tween-20 for one hour at room temperature. After that, it was washed three times for 3 minutes with 0.1~ Tween-20/PBS. All subsequent antibody incubations and washings were done using 0.1~ Tween-20/PBS. Incubation with the primary antibody (human EGFR extracellular domain, specific goat IgG, Catalogue No. AF231, R&D Systems) was done on a shaker for two hours at room temperature at a concentration of 1.5 ug/ml. After that it was washed 3 x 5 minutes and incubated for one hour at room temperature with the secondary antibody (labeled donkey anti-goat IgG horseradish peroxidase, Santa Cruz Biotechnology) at a dilution of 1:10,000. After washing (3 x 3 minutes in PBS/0.1~ Tween-20) detection was immediately done by means of ECL reaction (enhanced chemoluminescence). To 18 ml of distilled water was pipetted 200 u1 Solution A (250 mM luminol, Roth, dissolved in DMSO), 89 u1 Solution B (90 mM p-coumaric acid, Sigma, dissolved in DMSO), and 2 ml 30~ H202 solution. Depending on membrane size, 4-6 ml was pipetted directly onto the membrane, incubated for 1 minute at room temperature, and then layed immediately on x-ray film (Biomax MS, Kodak).
\\SERVERIg$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc The sequences used here are contained in Table 3 below, as well as in sequence protocols SQ153, 157, 158, 168-173.
SQ168 (A) 5~- AACACCGCAGCAUGUCAAGAU - 3~

SQ169 (B) 3'- UUUUGUGGCGUCGUACAGUUC -5~ 2-19-2 ES-8 SQ170 (A) 5~- AAGUUAAAAUUCCCGUCGCUAU -3 ~

SQ171 (B) 3'- CAAUUUUAAGGGCAGCGAUAGU -5~ Zs-19-2s ES2A/ SQ172 (A) 5~- AGUGUGAUCCAAGCUGUCCCAA -3~

ESSB SQ173 (B) 3'- ~CACACUAGGUUCGACAGGGUU -5~ 0-22-2 K2 SQ157 (A) 5~- ACAGGAUGAGGAUCGUUUCGCAUG
-3~

SQ158 (B) 3~- UCUGUCCUACUCCUAGCAAAGCGU -5~ 2-22-2 K1A/ SQ153 (A) 5~- ACAGGAUGAGGAUCGUUUCGCA -3~ 0-22-2 K2B SQ158 (B) 3'- UCUGUCCUACUCCUAGCAAAGCGU -5~

S
Table 3 Inhibition of EGFR expression in U-87 MG glioblastoma cells:
24 hours after seeding the cells, they were transfected with 10 nM dsRNA as noted (oligofectamine). After 72 hours, the cells were harvested and the proteins isolated. Separation of the proteins was done in 7.5o SDS-PAGE. 35 ug total protein was applied to each track. The corresponding Western blot analysis may be seen in Figure 24, which shows that with the specific anti-EGFR-directed dsRNA with a 2nt overhang at the 3'-end of the antisense strand, EGFR expression after transfection in U-87 MG cells is significantly inhibited in comparison to the corresponding controls. This inhibition of expression of an endogenous gene by means of specific dsRNA confirms the results noted in Example II, of the inhibition of the expression of an NSERVERig$\Texte\Anmeldeunterlagen 2003k122497-Ribopharma-an-2.doc Q~
artificial gene inserted into the cell after transient transfection. The inhibition of EGFR expression mediated by ES-7 and ES-8 is notably smaller. The dsRNAs used in Figure 24 are shown in Table 3.
VI. Inhibiting expression of multi-drug resistance gene 1 (MDR1):
Test protocol:
In vitro detection of the blocking of MDR1 expression was done using the colon cancer cell line LS174T (ATCC - .American Type Culture Collection; Tom et al., 1976). It is known of this cell line that expression of MDR1 is inducible by adding rifampicin to the culture medium (Geick et al., 2001). Transfection was done using a variety of commercially available transfection kits (Lipofectamine, Oligofectamine, both from Invitrogen;
TransMessenger, Qiagen), of which the TransMessenger kit proved to be the most suitable for this cell line.
Four short double-stranded ribonucleic acids (R1-R4) were used to conduct the RNA interference experiments. Their sequences are shown in Table 4. The ribonucleic acids are homologous with segments of the coding sequence of MDR1 (sequence protocol SQ
30). Sequences R1-R3 consist of a 22-mer sense strand and a 24-mer antisense strand, whereby the resulting double strand exhibits a 2-nucleotide overhang at its 3'-end (0-22-2).
Sequence R4 corresponds to R1; however it consists of a 19-mer double-stranded, each with 2-nucleotide overhangs at each 3'-end (2-19-2).
\\SERVER\g$\Texte\Anmeldeuntertagen 2003\422497-Ribopharma-an-2.doc Sequencege~gnC~ POSltlon protocol in Data No.

bank-#

Seq SQ141 5' - CCA UCU CGA AAA GAAGUU AAGA-3' 1320-1342 R1 SQ142 3' -UGGGU AGA GCU UUU CUUCAA UUCU-5' 1335-1318 Seq SQ143 5' - UAU AGG UUC CAG GCUUGC UGUA-3' 2599-2621 R2 SQ152 3' -CGAUA UCC AAG GUC CGAACG ACAU-5' 2621-2597 Seq SQ144 5' - CCA GAG AAG GCC GCACCU GCAU-3' 3778-3799 R3 SQ145 3' -UCGGU CUC UUC CGG CGUGGA CGUA-5' 3799-3776 Seq SQ146 5' - CCA UCU CGA AAA GAAGUU AAG-3' 1320-1341 R4 SQ147 3' -UGGGU AGA GCU UUU CUUCAA U -5' 1339-1318 Position in Data bank-#

K1A/ SQ153 5' - ACA GGA UGA GGA UCGUUU CGCA-3' 2829-2808 K2B SQ158 3' -UCUGU CCU ACU CCU AGCAAA GCGU-5' 2808-2831 Table 4 The sequences shown in Table 4 are designated as sequences SQ141-147, 152, 153, and 158 in the sequence protocol. The dsRNA
was in each case transfected into the cells as double assays at a concentration of 175 nM, which had on the day before been seeded in 12-well plates at 3.8 x 105 cells/well. For each transfection assay, 93.3 u1 EC-R buffer (TransMessenger kits, Qiagen, Hilden) was mixed with 3.2 u1 Enhancer R, and then 3.5 u1 of the particular 20 uM dsRNA was added, mixed well, and incubated for 5 minutes at room temperature. After the addition of 6u1 TransMessenger transfection reagent, the transfection \\SERVER\g$\Texte\Anmeldeuntertagen 2003\422497-Ribopharma-an-2.doc assay was mixed vigorously for 10 seconds, and then incubated for 10 minutes at room temperature. In the meantime, the medium was extracted from the cells, washed once with PBS (phosphate-buffered saline), and then 200 u1 fresh medium without FCS was added to the cells in each well. After 10-minute incubation, 100 u1 FCS-free medium was pipetted into each transfection assay, mixed, and the mixture was then pipetted drop by drop onto the cells (the dsRNA concentration of 175 uM relates to 400 u1 medium total volume). The dsRNA/TransMessenger complexes were incubated with the cells for 4 hours at 37~C in FCS-free medium.
The medium was then changed; the fresh medium contained 10 uM
rifampin and 10$ FCS. A non-specific dsRNA sequence that exhibits no homologies with the MDR1 gene sequence was used (K) as a control, and a MOCK transfection was conducted that contained all reagents except for dsRNA.
The cells were harvested after 24, 48, and 72 hours, and total RNA was extracted with the RNeasy mini kit from Qiagen. 10 ug total protein from each sample was then separated by electrophoresis on a 1~ agarose-formaldehyde gel, blotted on a nylon membrane, and then hybridized as an internal control with specific probes that had been random-marked with 5'-a32p-dCTP, first against MDR1, and after the blot had been stripped, against GAPDH, and then exposed on x-ray film.
The x-ray film was digitized (Image Master, VDS, Pharmacia) and quantified using Image-Quant software. At that time, adjustment between the MDR1-specific bands and the corresponding GAPDH
bands was done.
D~~.,.1 i-.. .
Figs. 25 and 26 show Northern blots (Figs. 26a, 26a) with quantitative analysis of the MDR1-specific bands after adjustment with the corresponding GAPDH values (Figs. 25b, 26p).
\\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc A reduction in the MDRl-mRNA by as much as 55~ was observed in comparison to the MOCK transfection, and by as much as 45~ in comparison to the non-specific control transfection. After 48 hours there was a significant reduction in the MDRI-mRNA level in the dsRNA constructs designated as R1, R2, and R3 (Table 4).
With the R4 dsRNA constructs, no significant reduction in comparison to the controls was observed after 48 hours (Figs.
26a and 26b). After 74 hours, there was a markedly stronger reduction in the MDR1-mRNA level with R1, R2, and R3 with the controls in comparison to the values at 48 hours (Figs. 25a and 26b). A significant decrease in the MDR1-mRNA level was seen at this time with R4 as well. Thus, the constructs with a 2nt overhang at the 3'-end of the antisense strand and a double-stranded region consisting of 22 nucleotide pairs reduces the MDR1-mRNA level more efficiently than do constructs with 2nt overhangs at the 3'-end of both strands (antisense strand and sent strand) and a double-stranded region consisting of 19 nucleotide pairs, relatively independent of the sequence region homologous to the MDR1 gene in each case (after 48 hours; Figure 26b). The results strengthen the findings in Example IV, which describe the inhibition of EGFR gene expression by means of specific dsRNAs after transfection in U-87 MG cells.
Transfection efficiency was determined in a separate experiment with the help of a DNA oligonucleotide marked with Texas red (TexRed-A[GATC]5T; also transfected with 175 nM) (Figs. 27a, 27b;
400x enlargement, 48 hours after transfection). Transfection efficiency was approximately 50~ on the basis of red fluorescent cells in comparison to total cell number. If one takes the transfection rate of cells of approximately 50~ into consideration, then it seems reasonable to conclude that given the observed decrease in the MDR1-mRNA level by approximately 45-55~ (compared with the controls), that MDR1-mRNA was almost USERVERtg$\TexteiAnmeldeunterlagen 2003142?A97-Ribopharma-an-2.doc completely and specifically broken down in all cells that were successfully transfected with specific dsRNA.
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\\SERVER\g$lTezte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc SEQUENCE PROTOCOL
<110> Ribopharma AG
<120> Method to inhibit expression of a target gene <130>
<140>
<141>
<160> 142 1$ <170> PatentIn Ver. 2.1 <210> 1 <211> 2955 <212> DNA
<213> Homo Sapiens <300>
<302> Eph A1 <310> NM00532 <300>
<302> ephrin A1 <310> NM00532 <400> 1 atggagcggcgctggcccctggggctagggctggtgctgctgctctgcgccccgctgccc60 ccgggggcgcgcgccaaggaagttactctgatggacacaagcaaggcacagggagagctg120 ggctggctgctggatcccccaaaagatgggtggagtgaacagcaacagatactgaatggg180 acacccctctacatgtaccaggactgcccaatgcaaggacgcagagacactgaccactgg240 cttcgctccaattggatctaccgcggggaggaggcttcccgcgtccacgtggagctgcag300 ttcaccgtgcgggactgcaagagtttccctgggggagccgggcctctgggctgcaaggag360 accttcaaccttctgtacatggagagtgaccaggatgtgggcattcagctccgacggccc420 ttgttccagaaggtaaccacggtggctgcagaccagagcttcaccattcgagaccttgcg480 tctggctccgtgaagctgaatgtggagcgctgctctctgggccgcctgacccgccgtggc540 ctctacctcgctttccacaacccgggtgcctgtgtggccctggtgtctgtccgggtcttc600 taccagcgctgtcctgagaccctgaatggcttggcccaattcccagacactctgcctggc660 cccgctgggttggtggaagtggcgggcacctgcttgccccacgcgcgggccagccccagg720 ccctcaggtgcaccccgcatgcactgcagccctgatggcgagtggctggtgcctgtagga780 cggtgccactgtgagcctggctatgaggaaggtggcagtggcgaagcatgtgttgcctgc840 cctagcggctcctaccggatggacatggacacaccccattgtctcacgtgcccccagcag900 agcactgctgagtctgagggggccaccatctgtacctgtgagagcggccattacagagct960 cccggggagggcccccaggtggcatgcacaggtcccccctcggccccccgaaacctgagc1020 ttctctgcctcagggactcagctctccctgcgttgggaacccccagcagatacgggggga1080 cgccaggatgtcagatacagtgtgaggtgttcccagtgtcagggcacagcacaggacggg1140 $0 gggccctgccagccctgtggggtgggcgtgcacttctcgccgggggcccgggcgctcacc1200 acacctgcagtgcatgtcaatggccttgaaccttatgccaactacacctttaatgtggaa1260 gcccaaaatggagtgtcagggctgggcagctctggccatgccagcacctcagtcagcatc1320 agcatggggcatgcagagtcactgtcaggcctgtctctgagactggtgaagaaagaaccg1380 aggcaactagagctgacctgggcggggtcccggccccgaagccctggggcgaacctgacc1440 $$ tatgagctgcacgtgctgaaccaggatgaagaacggtaccagatggttctagaacccagg1500 gtcttgctgacagagctgcagcctgacaccacatacatcgtcagagtccgaatgctgacc1560 ccactgggtcctggccctttctcccctgatcatgagtttcggaccagcccaccagtgtcc1620 aggggcctgactggaggagagattgtagccgtcatctttgggctgctgcttggtgcagcc1680 ttgctgcttgggattctcgttttccggtccaggagagcccagcggcagaggcagcagagg1740 60 cacgtgaccgcgccaccgatgtggatcgagaggacaagctgtgctgaagccttatgtggt1800 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc acctccaggcatacgaggaccctgcacagggagccttggactttacccggaggctggtct1860 aattttccttcccgggagcttgatccagcgtggctgatggtggacactgtcataggagaa1920 ggagagtttggggaagtgtatcgagggaccctcaggctccccagccaggactgcaagact1980 gtggccattaagaccttaaaagacacatccccaggtggccagtggtggaacttccttcga2040 S gaggcaactatcatgggccagtttagccacccgcatattctgcatctggaaggcgtcgtc2100 acaaagcgaaagccgatcatgatcatcacagaatttatggagaatgcagccctggatgcc2160 ttcctgagggagcgggaggaccagctggtccctgggcagctagtggccatgctgcagggc2220 atagcatctggcatgaactacctcagtaatcacaattatgtccaccgggacctggctgcc2280 agaaacatcttggtgaatcaaaacctgtgctgcaaggtgtctgactttggcctgactcgc2340 ctcctggatgactttgatggcacatacgaaacccagggaggaaagatccctatccgttgg2400 acagcccctgaagccattgcccatcggatcttcaccacagccagcgatgtgtggagcttt2460 gggattgtgatgtgggaggtgctgagctttggggacaagccttatggggagatgagcaat2520 caggaggttatgaagagcattgaggatgggtaccggttgccccctcctgtggactgccct2580 gcccctctgtatgagctcatgaagaactgctgggcatatgaccgtgcccgccggccacac2640 1S ttccagaagcttcaggcacatctggagcaactgcttgccaacccccactccctgcggacc2700 attgccaactttgaccccagggtgactcttcgcctgcccagcctgagtggctcagatggg2760 atcccgtatcgaaccgtctctgagtggctcgagtccatacgcatgaaacgctacatcctg2820 cacttccactcggctgggctggacaccatggagtgtgtgctggagctgaccgctgaggac2880 ctgacgcagatgggaatcacactgcccgggcaccagaagcgcattctttgcagtattcag2940 ggattcaaggactga 2955 <210> 2 <211> 3042 2S <212> DNA
<213> Homo Sapiens <300>
<302> ephrin A2 <310> XM002088 <400> 2 gaagttgcgcgcaggccggcgggcgggagcggacaccgaggccggcgtgcaggcgtgcgg60 gtgtgcgggagccgggctcggggggatcggaccgagagcgagaagcgcggcatggagctc120 3S caggcagcccgcgcctgcttcgccctgctgtggggctgtgcgctggccgcggccgcggcg180 gcgcagggcaaggaagtggtactgctggactttgctgcagctggaggggagctcggctgg240 ctcacacacccgtatggcaaagggtgggacctgatgcagaacatcatgaatgacatgccg300 atctacatgtactccgtgtgcaacgtgatgtctggcgaccaggacaactggctccgcacc360 aactgggtgtaccgaggagaggctgagcgtatcttcattgagctcaagtttactgtacgt420 gactgcaacagcttccctggtggcgccagctcctgcaaggagactttcaacctctactat480 gccgagtcggacctggactacggcaccaacttccagaagcgcctgttcaccaagattgac540 accattgcgcccgatgagatcaccgtcagcagcgacttcgaggcacgccacgtgaagctg600 aacgtggaggagcgctccgtggggccgctcacccgcaaaggcttctacctggccttccag660 gatatcggtgcctgtgtggcgctgctctccgtccgtgtctactacaagaagtgccccgag720 4S ctgctgcagggcctggcccacttccctgagaccatcgccggctctgatgcaccttccctg780 gccactgtggccggcacctgtgtggaccatgccgtggtgccaccggggggtgaagagccc840 cgtatgcactgtgcagtggatggcgagtggctggtgcccattgggcagtgcctgtgccag900 gcaggctacgagaaggtggaggatgcctgccaggcctgctcgcctggattttttaagttt960 gaggcatctgagagcccctgcttggagtgccctgagcacacgctgccatcccctgagggt1020 SO gccacctcctgcgagtgtgaggaaggcttcttccgggcacctcaggacccagcgtcgatg1080 ccttgcacacgacccccctccgccccacactacctcacagccgtgggcatgggtgccaag1140 gtggagctgcgctggacgccccctcaggacagcgggggccgcgaggacattgtctacagc1200 gtcacctgcgaacagtgctggcccgagtctggggaatgcgggccgtgtgaggccagtgtg1260 cgctactcggagcctcctcacggactgacccgcaccagtgtgacagtgagcgacctggag1320 SS ccccacatgaactacaccttcaccgtggaggcccgcaatggcgtctcaggcctggtaacc1380 agccgcagcttccgtactgccagtgtcagcatcaaccagacagagccccccaaggtgagg1440 ctggagggccgcagcaccacctcgcttagcgtctcctggagcatccccccgccgcagcag1500 agccgagtgtggaagtacgaggtcacttaccgcaagaagggagactccaacagctacaat1560 gtgcgccgcaccgagggtttctccgtgaccctggacgacctggccccagacaccacctac1620 60 ctggtccaggtgcaggcactgacgcaggagggccagggggccggcagcaaggtgcacgaa1680 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc ttccagacgctgtccccggagggatctggcaacttggcggtgattggcggcgtggctgtc1740 ggtgtggtcctgcttctggtgctggcaggagttggcttctttatccaccgcaggaggaag1800 aaccagcgtgcccgccagtccccggaggacgtttacttctccaagtcagaacaactgaag1860 cccctgaagacatacgtggacccccacacatatgaggaccccaaccaggctgtgttgaag1920 S ttcactaccgagatccatccatcctgtgtcactcggcagaaggtgatcggagcaggagag1980 tttggggaggtgtacaagggcatgctgaagacatcctcggggaagaaggaggtgccggtg2040 gccatcaagacgctgaaagccggctacacagagaagcagcgagtggacttcctcggcgag2100 gccggcatcatgggccagttcagccaccacaacatcatccgcctagagggcgtcatctcc2160 aaatacaagcccatgatgatcatcactgagtacatggagaatggggccctggacaagttc2220 cttcgggagaaggatggcgagttcagcgtgctgcagctggtgggcatgctgcggggcatc2280 gcagctggcatgaagtacctggccaacatgaactatgtgcaccgtgacctggctgcccgc2340 aacatcctcgtcaacagcaacctggtctgcaaggtgtctgactttggcctgtcccgcgtg2400 ctggaggacgaccccgaggccacctacaccaccagtggcggcaagatccccatccgctgg2460 accgccccggaggccatttcctaccggaagttcacctctgccagcgacgtgtggagcttt2520 1S ggcattgtcatgtgggaggtgatgacctatggcgagcggccctactgggagttgtccaac2580 cacgaggtgatgaaagccatcaatgatggcttccggctccccacacccatggactgcccc2640 tccgccatctaccagctcatgatgcagtgctggcagcaggagcgtgcccgccgccccaag2700 ttcgctgacatcgtcagcatcctggacaagctcattcgtgcccctgactccctcaagacc2760 ctggctgactttgacccccgcgtgtctatccggctccccagcacgagcggctcggagggg2820 gtgcccttccgcacggtgtccgagtggctggagtccatcaagatgcagcagtatacggag2880 cacttcatggcggccggctacactgccatcgagaaggtggtgcagatgaccaacgacgac2940 atcaagaggattggggtgcggctgcccggccaccagaagcgcatcgcctacagcctgctg3000 ggactcaaggaccaggtgaacactgtggggatccccatctga 3042 <210> 3 <211> 2953 <212> DNA
<213> Homo Sapiens <300>
<302> ephrin A3 <310> NM005233 3S <400> 3 atggattgtcagctctccatcctcctccttctcagctgctctgttctcgacagcttcggg60 gaactgattccgcagccttccaatgaagtcaatctactggattcaaaaacaattcaaggg120 gagctgggctggatctcttatccatcacatgggtgggaagagatcagtggtgtggatgaa180 cattacacacccatcaggacttaccaggtgtgcaatgtcatggaccacagtcaaaacaat240 tggctgagaacaaactgggtccccaggaactcagctcagaagatttatgtggagctcaag300 ttcactctacgagactgcaatagcattccattggttttaggaacttgcaaggagacattc360 aacctgtactacatggagtctgatgatgatcatggggtgaaatttcgagagcatcagttt420 acaaagattgacaccattgcagctgatgaaagtttcactcaaatggatcttggggaccgt480 attctgaagctcaacactgagattagagaagtaggtcctgtcaacaagaagggattttat540 4S ttggcatttcaagatgttggtgcttgtgttgccttggtgtctgtgagagtatacttcaaa600 aagtgcccatttacagtgaagaatctggctatgtttccagacacggtacccatggactcc660 cagtccctggtggaggttagagggtcttgtgtcaacaattctaaggaggaagatcctcca720 aggatgtactgcagtacagaaggcgaatggcttgtacccattggcaagtgttcctgcaat780 gctggctatgaagaaagaggttttatgtgccaagcttgtcgaccaggtttctacaaggca840 SO ttggatggtaatatgaagtgtgctaagtgcccgcctcacagttctactcaggaagatggt900 tcaatgaactgcaggtgtgagaataattacttccgggcagacaaagaccctccatccatg960 gcttgtacccgacctccatcttcaccaagaaatgttatctctaatataaacgagacctca1020 gttatcctggactggagttggcccctggacacaggaggccggaaagatgttaccttcaac1080 atcatatgtaaaaaatgtgggtggaatataaaacagtgtgagccatgcagcccaaatgtc1140 SS cgcttcctccctcgacagtttggactcaccaacaccacggtgacagtgacagaccttctg1200 gcacatactaactacacctttgagattgatgccgttaatggggtgtcagagctgagctcc1260 ccaccaagacagtttgctgcggtcagcatcacaactaatcaggctgctccatcacctgtc1320 ctgacgattaagaaagatcggacctccagaaatagcatctctttgtcctggcaagaacct1380 gaacatcctaatgggatcatattggactacgaggtcaaatactatgaaaagcaggaacaa1440 60 gaaacaagttataccattctgagggcaagaggcacaaatgttaccatcagtagcctcaag1500 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422A97-Ribopharrna-an-2.doc cctgacactatatacgtattccaaatccgagcccgaacagccgctggatatgggacgaac1560 agccgcaagtttgagtttgaaactagtccagactctttctccatctctggtgaaagtagc1620 caagtggtcatgatcgccatttcagcggcagtagcaattattctcctcactgttgtcatc1680 tatgttttgattgggaggttctgtggctataagtcaaaacatggggcagatgaaaaaaga1740 S cttcattttggcaatgggcatttaaaacttccaggtctcaggacttatgttgacccacat1800 acatatgaagaccctacccaagctgttcatgagtttgccaaggaattggatgccaccaac1860 atatccattgataaagttgttggagcaggtgaatttggagaggtgtgcagtggtcgctta1920 aaacttccttcaaaaaaagagatttcagtggccattaaaaccctgaaagttggctacaca1980 gaaaagcagaggagagacttcctgggagaagcaagcattatgggacagtttgaccacccc2040 1~aatatcattcgactggaaggagttgttaccaaaagtaagccagttatgattgtcacagaa2100 tacatggagaatggttccttggatagtttcctacgtaaacacgatgcccagtttactgtc2160 attcagctagtggggatgcttcgagggatagcatctggcatgaagtacctgtcagacatg2220 ggctatgttcaccgagacctcgctgctcggaacatcttgatcaacagtaacttggtgtgt2280 aaggtttctgatttcggactttcgcgtgtcctggaggatgacccagaagctgcttataca2340 1Sacaagaggagggaagatcccaatcaggtggacatcaccagaagctatagcctaccgcaag2400 ttcacgtcagccagcgatgtatggagttatgggattgttctctgggaggtgatgtcttat2460 ggagagagaccatactgggagatgtccaatcaggatgtaattaaagctgtagatgagggc2520 tatcgactgccaccccccatggactgcccagctgccttgtatcagctgatgctggactgc2580 tggcagaaagacaggaacaacagacccaagtttgagcagattgttagtattctggacaag2640 cttatccggaatcccggcagcctgaagatcatcaccagtgcagccgcaaggccatcaaac2700 cttcttctggaccaaagcaatgtggatatctctaccttccgcacaacaggtgactggctt2760 aatggtgtccggacagcacactgcaaggaaatcttcacgggcgtggagtacagttcttgt2820 gacacaatagccaagatttccacagatgacatgaaaaaggttggtgtcaccgtggttggg2880 ccacagaagaagatcatcagtagcattaaagctctagaaacgcaatcaaagaatggccca2940 2Sgttcccgtgtaaa 2953 <210> 4 <211> 2784 3~ <212> DNA
<213> Homo sapiens <300>
<302> ephrin A4 3S <310> XM002578 <400> 4 atggatgaaaaaaatacaccaatccgaacctaccaagtgtgcaatgtgatggaacccagc60 cagaataactggctacgaactgattggatcacccgagaaggggctcagagggtgtatatt120 4~ gagattaaattcaccttgagggactgcaatagtcttccgggcgtcatggggacttgcaag180 gagacgtttaacctgtactactatgaatcagacaacgacaaagagcgtttcatcagagag240 aaccagtttgtcaaaattgacaccattgctgctgatgagagcttcacccaagtggacatt300 ggtgacagaatcatgaagctgaacaccgagatccgggatgtagggccattaagcaaaaag360 gggttttacctggcttttcaggatgtgggggcctgcatcgccctggtatcagtccgtgtg420 4S ttctataaaaagtgtccactcacagtccgcaatctggcccagtttcctgacaccatcaca480 ggggctgatacgtcttccctggtggaagttcgaggctcctgtgtcaacaactcagaagag540 aaagatgtgccaaaaatgtactgtggggcagatggtgaatggctggtacccattggcaac600 tgcctatgcaacgctgggcatgaggagcggagcggagaatgccaagcttgcaaaattgga660 tattacaaggctctctccacggatgccacctgtgccaagtgcccaccccacagctactct720 S~ gtctgggaaggagccacctcgtgcacctgtgaccgaggctttttcagagctgacaacgat780 gctgcctctatgccctgcacccgtccaccatctgctcccctgaacttgatttcaaatgtc840 aacgagacatctgtgaacttggaatggagtagccctcagaatacaggtggccgccaggac900 atttcctataatgtggtatgcaagaaatgtggagctggtgaccccagcaagtgccgaccc960 tgtggaagtggggtccactacaccccacagcagaatggcttgaagaccaccaaagtctcc1020 SS atcactgacctcctagctcataccaattacacctttgaaatctgggctgtgaatggagtg1080 tccaaatataaccctaacccagaccaatcagtttctgtcactgtgaccaccaaccaagca1140 gcaccatcatccattgctttggtccaggctaaagaagtcacaagatacagtgtggcactg1200 gcttggctggaaccagatcggcccaatggggtaatcctggaatatgaagtcaagtattat1260 gagaaggatcagaatgagcgaagctatcgtatagttcggacagctgccaggaacacagat1320 f)0atcaaaggcctgaaccctctcacttcctatgttttccacgtgcgagccaggacagcagct1380 \\SERVER\g$\Texte\Anmeldeunterlagea 2003\422497-Ribopharma-an-2.doc ggctatggag acttcagtgagcccttggaggttacaaccaacacagtgccttcccggatc1440 attggagatg gggctaactccacagtccttctggtctctgtctcgggcagtgtggtgctg1500 gtggtaattc tcattgcagcttttgtcatcagccggagacggagtaaatacagtaaagcc1560 aaacaagaag cggatgaagagaaacatttgaatcaaggtgtaagaacatatgtggacccc1620 S tttacgtacg aagatcccaaccaagcagtgcgagagtttgccaaagaaattgacgcatcc1680 tgcattaaga ttgaaaaagttataggagttggtgaatttggtgaggtatgcagtgggcgt1740 ctcaaagtgc ctggcaagagagagatctgtgtggctatcaagactctgaaagctggttat1800 acagacaaac agaggagagacttcctgagtgaggccagcatcatgggacagtttgaccat1860 ccgaacatca ttcacttggaaggcgtggtcactaaatgtaaaccagtaatgatcataaca1920 10gagtacatgg agaatggctccttggatgcattcctcaggaaaaatgatggcagatttaca1980 gtcattcagc tggtgggcatgcttcgtggcattgggtctgggatgaagtatttatctgat2040 atgagctatg tgcatcgtgatctggccgcacggaacatcctggtgaacagcaacttggtc2100 tgcaaagtgt ctgattttggcatgtcccgagtgcttgaggatgatccggaagcagcttac2160 accaccaggg gtggcaagattcctatccggtggactgcgccagaagcaattgcctatcgt2220 1Saaattcacat cagcaagtgatgtatggagctatggaatcgttatgtgggaagtgatgtcg2280 tacggggaga ggccctattgggatatgtccaatcaagatgtgattaaagccattgaggaa2340 ggctatcggt taccccctccaatggactgccccattgcgctccaccagctgatgctagac2400 tgctggcaga aggagaggagcgacaggcctaaatttgggcagattgtcaacatgttggac2460 aaactcatcc gcaaccccaacagcttgaagaggacagggacggagagctccagacctaac2520 20actgccttgt tggatccaagctcccctgaattctctgctgtggtatcagtgggcgattgg2580 ctccaggcca ttaaaatggaccggtataaggataacttcacagctgctggttataccaca2640 ctagaggctg tggtgcacgtgaaccaggaggacctggcaagaattggtatcacagccatc2700 acgcaccaga ataagattttgagcagtgtccaggcaatgcgaacccaaatgcagcagatg2760 cacggcagaa tggttcccgtctga 2784 <210> 5 <211> 2997 <212> DNA

30<213> Homo sapiens <300>
<302> ephrin A7 <310> XM004485 <400> 5 atggtttttcaaactcggtacccttcatggattattttatgctacatctggctgctccgc60 tttgcacacacaggggaggcgcaggctgcgaaggaagtactactgctggattctaaagca120 caacaaacagagttggagtggatttcctctccacccaatgggtgggaagaaattagtggt180 40 ttggatgagaactataccccgatacgaacataccaggtgtgccaagtcatggagcccaac240 caaaacaactggctgcggactaactggatttccaaaggcaatgcacaaaggatttttgta300 gaattgaaattcaccctgagggattgtaacagtcttcctggagtactgggaacttgcaag360 gaaacatttaatttgtactattatgaaacagactatgacactggcaggaatataagagaa420 aacctctatgtaaaaatagacaccattgctgcagatgaaagttttacccaaggtgacctt480 4S ggtgaaagaaagatgaagcttaacactgaggtgagagagattggacctttgtccaaaaag540 ggattctatcttgcctttcaggatgtaggggcttgcatagctttggtttctgtcaaagtg600 tactacaagaagtgctggtccattattgagaacttagctatctttccagatacagtgact660 ggttcagaattttcctctttagtcgaggttcgagggacatgtgtcagcagtgcagaggaa720 gaagcggaaaacgcccccaggatgcactgcagtgcagaaggagaatggttagtgcccatt780 SO ggaaaatgtatctgcaaagcaggctaccagcaaaaaggagacacttgtgaaccctgtggc840 cgtgggttctacaagtcttcctctcaagatcttcagtgctctcgttgtccaactcacagt900 ttttctgataaagaaggctcctccagatgtgaatgtgaagatgggtattacagggctcca960 tctgacccaccatacgttgcatgcacaaggcctccatctgcaccacagaacctcattttc1020 aacatcaaccaaaccacagtaagtttggaatggagtcctcctgcagacaatgggggaaga1080 SS aacgatgtgacctacagaatattgtgtaagcggtgcagttgggagcagggcgaatgtgtt2140 ccctgtgggagtaacattggatacatgccccagcagactggattagaggataactatgtc1200 actgtcatggacctgctagcccacgctaattatacttttgaagttgaagctgtaaatgga1260 gtttctgacttaagccgatcccagaggctctttgctgctgtcagtatcaccactggtcaa1320 gcagctccctcgcaagtgagtggagtaatgaaggagagagtactgcagcggagtgtcgag1380 60 ctttcctggcaggaaccagagcatcccaatggagtcatcacagaatatgaaatcaagtat1440 \\SERVER\g$\TexteWnmeldeunterlagen 20034422497-Ribopharma-an-2.doc tacgagaaagatcaaagggaacggacctactcaacagtaaaaaccaagtctacttcagcc1500 tccattaataatctgaaaccaggaacagtgtatgttttccagattcgggcttttactgct1560 gctggttatggaaattacagtcccagacttgatgttgctacactagaggaagctacaggt1620 aaaatgtttgaagctacagctgtctccagtgaacagaatcctgttattatcattgctgtg1680 S gttgctgtagctgggaccatcattttggtgttcatggtctttggcttcatcattgggaga1740 aggcactgtggttatagcaaagctgaccaagaaggcgatgaagagctttactttcatttt1800 aaatttccaggcaccaaaacctacattgaccctgaaacctatgaggacccaaatagagct1860 gtccatcaattcgccaaggagctagatgcctcctgtattaaaattgagcgtgtgattggt1920 gcaggagaattcggtgaagtctgcagtggccgtttgaaacttccagggaaaagagatgtt1980 1Q gcagtagccataaaaaccctgaaagttggttacacagaaaaacaaaggagagactttttg2040 tgtgaagcaagcatcatggggcagtttgaccacccaaatgttgtccatttggaaggggtt2100 gttacaagagggaaaccagtcatgatagtaatagagttcatggaaaatggagccctagat2160 gcatttctcaggaaacatgatgggcaatttacagtcattcagttagtaggaatgctgaga2220 ggaattgctgctggaatgagatatttggctgatatgggatatgttcacagggaccttgca2280 1S gctcgcaatattcttgtcaacagcaatctcgtttgtaaagtgtcagattttggcctgtcc2340 cgagttatagaggatgatccagaagctgtctatacaactactggtggaaaaattccagta2400 aggtggacagcacccgaagccatccagtaccggaaattcacatcagccagtgatgtatgg2460 agctatggaatagtcatgtgggaagttatgtcttatggagaaagaccttattgggacatg2520 tcaaatcaagatgttataaaagcaatagaagaaggttatcgtttaccagcacccatggac2580 tgcccagctggccttcaccagctaatgttggattgttggcaaaaggagcgtgctgaaagg2640 ccaaaatttgaacagatagttggaattctagacaaaatgattcgaaacccaaatagtctg2700 aaaactcccctgggaacttgtagtaggccaataagccctcttctggatcaaaacactcct2760 gatttcactaccttttgttcagttggagaatggctacaagctattaagatggaaagatat2820 aaagataatttcacggcagctggctacaattcccttgaatcagtagccaggatgactatt2880 2S gaggatgtgatgagtttagggatcacactggttggtcatcaaaagaaaatcatgagcagc2940 attcagactatgagagcacaaatgctacatttacatggaactggcattcaagtgtga 2997 <210> 6 3~ <211> 3217 <212> DNA
<213> Homo sapiens <300>

3S <302> ephrin <310> XM001921 <400> 6 ncbsncvwrbmdnctdrtngnmstrctrsttanmymmsarchbmdrtnnctdstrctrgn60 40 mstmmtanmyrmtsndhstrycbardasnastagnbankgrahcsmdatvwashtmantt120 hdbrandnkbarggnbankhmsanshahartntanmycsmbmrnarnvdntnhmsansha180 hamrnaaccssnmvrsnmgatggcccccgcccggggccgcctgccccctgcgctctgggt240 cgtcacggccgcggcggcggcggccacctgcgtgtccgcggcgcgcggcgaagtgaattt300 gctggacacgtcgaccatccacggggactggggctggctcacgtatccggctcatgggtg360 4S ggactccatcaacgaggtggacgagtccttccagcccatccacacgtaccaggtttgcaa420 cgtcatgagccccaaccagaacaactggctgcgcacgagctgggtcccccgagacggcgc480 ccggcgcgtctatgctgagatcaagtttaccctgcgcgactgcaacagcatgcctggtgt540 gctgggcacctgcaaggagaccttcaacctctactacctggagtcggaccgcgacctggg600 ggccagcacacaagaaagccagttcctcaaaatcgacaccattgcggccgacgagagctt660 S~ cacaggtgccgaccttggtgtgcggcgtctcaagctcaacacggaggtgcgcagtgtggg720 tcccctcagcaagcgcggcttctacctggccttccaggacataggtgcctgcctggccat780 cctctctctccgcatctactataagaagtgccctgccatggtgcgcaatctggctgcctt840 ctcggaggcagtgacgggggccgactcgtcctcactggtggaggtgaggggccagtgcgt900 gcggcactcagaggagcgggacacacccaagatgtactgcagcgcggagggcgagtggct960 SS cgtgcccatcggcaaatgcgtgtgcagtgccggctacgaggagcggcgggatgcctgtgt1020 ggcctgtgagctgggcttctacaagtcagcccctggggaccagctgtgtgcccgctgccc1080 tccccacagccactccgcagctccagccgcccaagcctgccactgtgacctcagctacta1140 ccgtgcagccctggacccgccgtcctcagcctgcacccggccaccctcggcaccagtgaa1200 cctgatctccagtgtgaatgggacatcagtgactctggagtgggcccctcccctggaccc1260 f)~aggtggccgcagtgacatcacctacaatgccgtgtgccgccgctgcccctgggcactgag1320 \\SERVER\g$\TexteWnmetdeunterlagen 20034122497-Ribopharma-an-2.doc ccgctgcgaggcatgtgggagcggcacccgctttgtgccccagcagacaagcctggtgca1380 ggccagcctgctggtggccaacctgctggcccacatgaactactccttctggatcgaggc1440 cgtcaatggcgtgtccgacctgagccccgagccccgccgggccgctgtggtcaacatcac1500 cacgaaccaggcagccccgtcccaggtggtggtgatccgtcaagagcgggcggggcagac1560 S cagcgtctcgctgctgtggcaggagcccgagcagccgaacggcatcatcctggagtatga1620 gatcaagtactacgagaaggacaaggagatgcagagctactccaccctcaaggccgtcac1680 caccagagccaccgtctccggcctcaagccgggcacccgctacgtgttccaggtccgagc1740 ccgcacctcagcaggctgtggccgcttcagccaggccatggaggtggagaccgggaaacc1800 ccggccccgctatgacaccaggaccattgtctggatctgcctgacgctcatcacgggcct1860 ggtggtgcttctgctcctgctcatctgcaagaagaggcactgtggctacagcaaggcctt1920 ccaggactcggacgaggagaagatgcactatcagaatggacaggcacccccacctgtctt1980 cctgcctctgcatcaccccccgggaaagctcccagagccccagttctatgcggaacccca2040 cacctacgaggagccaggccgggcgggccgcagtttcactcgggagatcgaggcctctag2100 gatccacatcgagaaaatcatcggctctggagactccggggaagtctgctacgggaggct2160 1S gcgggtgccagggcagcgggatgtgcccgtggccatcaaggccctcaaagccggctacac2220 ggagagacagaggcgggacttcctgagcgaggcgtccatcatggggcaattcgaccatcc2280 caacatcatccgcctcgagggtgtcgtcacccgtggccgcctggcaatgattgtgactga2340 gtacatggagaacggctctctggacaccttcctgaggacccacgacgggcagttcaccat2400 catgcagctggtgggcatgctgagaggagtgggtgccggcatgcgctacctctcagacct2460 gggctatgtccaccgagacctggccgcccgcaacgtcctggttgacagcaacctggtctg2520 caaggtgtctgacttcgggctctcacgggtgctggaggacgacccggatgctgcctacac2580 caccacgggcgggaagatccccatccgctggacggccccagaggccatcgccttccgcac2640 cttctcctcggccagcgacgtgtggagcttcggcgtggtcatgtgggaggtgctggccta2700 tggggagcggccctactggaacatgaccaaccgggatgtcatcagctctgtggaggaggg2760 2S gtaccgcctgcccgcacccatgggctgcccccacgccctgcaccagctcatgctcgactg2820 ttggcacaaggaccgggcgcagcggcctcgcttctcccagattgtcagtgtcctcgatgc2880 gctcatccgcagccctgagagtctcagggccaccgccacagtcagcaggtgcccaccccc2940 tgccttcgtccggagctgctttgacctccgagggggcagcggtggcggtgggggcctcac3000 cgtgggggactggctggactccatccgcatgggccggtaccgagaccacttcgctgcggg3060 cggatactcctctctgggcatggtgctacgcatgaacgcccaggacgtgcgcgccctggg3120 catcaccctcatgggccaccagaagaagatcctgggcagcattcagaccatgcgggccca3180 gctgaccagcacccaggggccccgccggcacctctga 3217 3S <210> 7 <211> 1497 <212> DNA
<213> Homo sapiens <300>
<308> U83508 <300>
<302> angiopoietin 2 4S <310> U83508 <400> 7 atgacagttt tcctttcctt tgctttcctc gctgccattc tgactcacat agggtgcagc 60 aatcagcgcc gaagtccaga aaacagtggg agaagatata accggattca acatgggcaa 120 SO tgtgcctaca ctttcattct tccagaacac gatggcaact gtcgtgagag tacgacagac 180 cagtacaaca caaacgctct gcagagagat gctccacacg tggaaccgga tttctcttcc 240 cagaaacttc aacatctgga acatgtgatg gaaaattata ctcagtggct gcaaaaactt 300 gagaattaca ttgtggaaaa catgaagtcg gagatggccc agatacagca gaatgcagtt 360 cagaaccaca cggctaccat gctggagata ggaaccagcc tcctctctca gactgcagag 420 SS cagaccagaa agctgacaga tgttgagacc caggtactaa atcaaacttc tcgacttgag 480 atacagctgc tggagaattc attatccacc tacaagctag agaagcaact tcttcaacag 540 acaaatgaaa tcttgaagat ccatgaaaaa aacagtttat tagaacataa aatcttagaa 600 atggaaggaa aacacaagga agagttggac accttaaagg aagagaaaga gaaccttcaa 660 ggcttggtta ctcgtcaaac atatataatc caggagctgg aaaagcaatt aaacagagct 720 60 accaccaaca acagtgtcct tcagaagcag caactggagc tgatggacac agtccacaac 780 IISERVERIg$iTextelAnmeldeunterlagen 2003\422497-Ribopharma-an-2.doc $7 cttgtcaatc tttgcactaa agaaggtgtt ttactaaagg gaggaaaaag agaggaagag 840 aaaccattta gagactgtgc agatgtatat caagctggtt ttaataaaag tggaatctac 900 actatttata ttaataatat gccagaaccc aaaaaggtgt tttgcaatat ggatgtcaat 960 gggggaggtt ggactgtaat acaacatcgt gaagatggaa gtctagattt ccaaagaggc 1020 S tggaaggaat ataaaatggg ttttggaaat ccctccggtg aatattggct ggggaatgag 1080 tttatttttg ccattaccag tcagaggcag tacatgctaa gaattgagtt aatggactgg 1140 gaagggaacc gagcctattc acagtatgac agattccaca taggaaatga aaagcaaaac 1200 tataggttgt atttaaaagg tcacactggg acagcaggaa aacagagcag cctgatctta 1260 cacggtgctg atttcagcac taaagatgct gataatgaca actgtatgtg caaatgtgcc 1320 ctcatgttaa caggaggatg gtggtttgat gcttgtggcc cctccaatct aaatggaatg 1380 ttctatactg cgggacaaaa ccatggaaaa ctgaatggga taaagtggca ctacttcaaa 1440 gggcccagtt actccttacg ttccacaact atgatgattc gacctttaga tttttga 1497 1S <210> 8 <211> 3417 <212> DNA

<213> Homosapiens <300>

<310> XM001924 <300>

<302> Tie1 <400> 8 atggtctggcgggtgccccctttcttgctccccatcctcttcttggcttctcatgtgggc60 gcggcggtggacctgacgctgctggccaacctgcggctcacggacccccagcgcttcttc120 ctgacttgcgtgtctggggaggccggggcggggaggggctcggacgcctggggcccgccc180 ctgctgctggagaaggacgaccgtatcgtgcgcaccccgcccgggccacccctgcgcctg240 gcgcgcaacggttcgcaccaggtcacgcttcgcggcttctccaagccctcggacctcgtg300 ggcgtcttctcctgcgtgggcggtgctggggcgcggcgcacgcgcgtcatctacgtgcac360 aacagccctggagcccacctgcttccagacaaggtcacacacactgtgaacaaaggtgac420 accgctgtactttctgcacgtgtgcacaaggagaagcagacagacgtgatctggaagagc480 3S aacggatcctacttctacaccctggactggcatgaagcccaggatgggcggttcctgctg540 cagctcccaaatgtgcagccaccatcgagcggcatctacagtgccacttacctggaagcc600 agccccctgggcagcgccttctttcggctcatcgtgcggggttgtggggctgggcgctgg660 gggccaggctgtaccaaggagtgcccaggttgcctacatggaggtgtctgccacgaccat720 gacggcgaatgtgtatgcccccctggcttcactggcacccgctgtgaacaggcctgcaga780 gagggccgttttgggcagagctgccaggagcagtgcccaggcatatcaggctgccggggc840 ctcaccttctgcctcccagacccctatggctgctcttgtggatctggctggagaggaagc900 cagtgccaagaagcttgtgcccctggtcattttggggctgattgccgactccagtgccag960 tgtcagaatggtggcacttgtgaccggttcagtggttgtgtctgcccctctgggtggcat1020 ggagtgcactgtgagaagtcagaccggatcccccagatcctcaacatggcctcagaactg1080 4S gagttcaacttagagacgatgccccggatcaactgtgcagctgcagggaaccccttcccc1140 gtgcggggcagcatagagctacgcaagccagacggcactgtgctcctgtccaccaaggcc1200 attgtggagccagagaagaccacagctgagttcgaggtgccccgcttggttcttgcggac1260 agtgggttctgggagtgccgtgtgtccacatctggcggccaagacagccggcgcttcaag1320 gtcaatgtgaaagtgccccccgtgcccctggctgcacctcggctcctgaccaagcagagc1380 SO cgccagcttgtggtctccccgctggtctcgttctctggggatggacccatctccactgtc1440 cgcctgcactaccggccccaggacagtaccatggactggtcgaccattgtggtggacccc1500 agtgagaacgtgacgttaatgaacctgaggccaaagacaggatacagtgttcgtgtgcag1560 ctgagccggccaggggaaggaggagagggggcctgggggcctcccaccctcatgaccaca1620 gactgtcctgagcctttgttgcagccgtggttggagggctggcatgtggaaggcactgac1680 SS cggctgcgagtgagctggtccttgcccttggtgcccgggccactggtgggcgacggtttc1740 ctgctgcgcctgtgggacgggacacgggggcaggagcggcgggagaacgtctcatccccc1800 caggcccgcactgccctcctgacgggactcacgcctggcacccactaccagctggatgtg1860 cagctctaccactgcaccctcctgggcccggcctcgccccctgcacacgtgcttctgccc1920 cccagtgggcctccagccccccgacacctccacgcccaggccctctcagactccgagatc1980 60 cagctgacatggaagcacccggaggctctgcctgggccaatatccaagtacgttgtggag2040 \\SERVERIg$\Texte\Anmetdeunterlagen 2003\422497-Ribopharma-an-2.doc gtgcaggtggctgggggtgcaggagacccactgtggatagacgtggacaggcctgaggag2100 acaagcaccatcatccgtggcctcaacgccagcacgcgctacctcttccgcatgcgggcc2160 agcattcaggggctcggggactggagcaacacagtagaagagtccaccctgggcaacggg2220 ctgcaggctgagggcccagtccaagagagccgggcagctgaagagggcctggatcagcag2280 S ctgatcctggcggtggtgggctccgtgtctgccacctgcctcaccatcctggctgccctt2340 ttaaccctggtgtgcatccgcagaagctgcctgcatcggagacgcaccttcacctaccag2400 tcaggctcgggcgaggagaccatcctgcagttcagctcagggaccttgacacttacccgg2460 cggccaaaactgcagcccgagcccctgagctacccagtgctagagtgggaggacatcacc2520 tttgaggacctcatcggggaggggaacttcggccaggtcatccgggccatgatcaagaag2580 gacgggctgaagatgaacgcagccatcaaaatgctgaaagagtatgcctctgaaaatgac2640 catcgtgactttgcgggagaactggaagttctgtgcaaattggggcatcaccccaacatc2700 atcaacctcctgggggcctgtaagaaccgaggttacttgtatatcgctattgaatatgcc2760 ccctacgggaacctgctagattttctgcggaaaagccgggtcctagagactgacccagct2820 tttgctcgagagcatgggacagcctctacccttagctcccggcagctgctgcgtttcgcc2880 1S agtgatgcggccaatggcatgcagtacctgagtgagaagcagttcatccacagggacctg2940 gctgcccggaatgtgctggtcggagagaacctggcctccaagattgcagacttcggcctt3000 tctcggggagaggaggtttatgtgaagaagacgatggggcgtctccctgtgcgctggatg3060 gccattgagtccctgaactacagtgtctataccaccaagagtgatgtctggtcctttgga3120 gtccttctttgggagatagtgagccttggaggtacaccctactgtggcatgacctgtgcc3180 gagctctatgaaaagctgccccagggctaccgcatggagcagcctcgaaactgtgacgat3240 gaagtgtacgagctgatgcgtcagtgctggcgggaccgtccctatgagcgaccccccttt3300 gcccagattgcgctacagctaggccgcatgctggaagccaggaaggcctatgtgaacatg3360 tcgctgtttgagaacttcacttacgcgggcattgatgccacagctgaggaggcctga 3417 <210> 9 <211> 3375 <212> DNA
<213> Homo sapiens <300>
<302> TEK
<310> L06139 <400> 9 atggactctttagccagcttagttctctgtggagtcagcttgctcctttctggaactgtg60 gaaggtgccatggacttgatcttgatcaattccctacctcttgtatctgatgctgaaaca120 tctctcacctgcattgcctctgggtggcgcccccatgagcccatcaccataggaagggac180 tttgaagccttaatgaaccagcaccaggatccgctggaagttactcaagatgtgaccaga240 gaatgggctaaaaaagttgtttggaagagagaaaaggctagtaagatcaatggtgcttat300 ttctgtgaagggcgagttcgaggagaggcaatcaggatacgaaccatgaagatgcgtcaa360 caagcttccttcctaccagctactttaactatgactgtggacaagggagataacgtgaac420 atatctttcaaaaaggtattgattaaagaagaagatgcagtgatttacaaaaatggttcc480 ttcatccattcagtgccccggcatgaagtacctgatattctagaagtacacctgcctcat540 4S gctcagccccaggatgctggagtgtactcggccaggtatataggaggaaacctcttcacc600 tcggccttcaccaggctgatagtccggagatgtgaagcccagaagtggggacctgaatgc660 aaccatctctgtactgcttgtatgaacaatggtgtctgccatgaagatactggagaatgc720 atttgccctcctgggtttatgggaaggacgtgtgagaaggcttgtgaactgcacacgttt780 ggcagaacttgtaaagaaaggtgcagtggacaagagggatgcaagtcttatgtgttctgt840 SO ctccctgacccctatgggtgttcctgtgccacaggctggaagggtctgcagtgcaatgaa900 gcatgccaccctggtttttacgggccagattgtaagcttaggtgcagctgcaacaatggg960 gagatgtgtgatcgcttccaaggatgtctctgctctccaggatggcaggggctccagtgt1020 gagagagaaggcataccgaggatgaccccaaagatagtggatttgccagatcatatagaa1080 gtaaacagtggtaaatttaatcccatttgcaaagcttctggctggccgctacctactaat1140 SS gaagaaatgaccctggtgaagccggatgggacagtgctccatccaaaagactttaaccat1200 acggatcatttctcagtagccatattcaccatccaccggatcctcccccctgactcagga1260 gtttgggtctgcagtgtgaacacagtggctgggatggtggaaaagcccttcaacatttct1320 gttaaagttcttccaaagcccctgaatgccccaaacgtgattgacactggacataacttt1380 gctgtcatcaacatcagctctgagccttactttggggatggaccaatcaaatccaagaag1440 cttctatacaaacccgttaatcactatgaggcttggcaacatattcaagtgacaaatgag1500 \\SERVER\g$\TextelAnmeldeunterlagen 20031422497-Riboptuuma-an-2.doc attgttacactcaactatttggaacctcggacagaatatgaactctgtgtgcaactggtc1560 cgtcgtggagagggtggggaagggcatcctggacctgtgagacgcttcacaacagcttct1620 atcggactccctcctccaagaggtctaaatctcctgcctaaaagtcagaccactctaaat1680 ttgacctggcaaccaatatttccaagctcggaagatgacttttatgttgaagtggagaga1740 S aggtctgtgcaaaaaagtgatcagcagaatattaaagttccaggcaacttgacttcggtg1800 ctacttaacaacttacatcccagggagcagtacgtggtccgagctagagtcaacaccaag1860 gcccagggggaatggagtgaagatctcactgcttggacccttagtgacattcttcctcct1920 caaccagaaaacatcaagatttccaacattacacactcctcggctgtgatttcttggaca1980 atattggatggctattctatttcttctattactatccgttacaaggttcaaggcaagaat2040 gaagaccagcacgttgatgtgaagataaagaatgccaccatcattcagtatcagctcaag2100 ggcctagagcctgaaacagcataccaggtggacatttttgcagagaacaacatagggtca2160 agcaacccagccttttctcatgaactggtgaccctcccagaatctcaagcaccagcggac2220 ctcggaggggggaagatgctgcttatagccatccttggctctgctggaatgacctgcctg2280 actgtgctgttggcctttctgatcatattgcaattgaagagggcaaatgtgcaaaggaga2340 1S atggcccaagccttccaaaacgtgagggaagaaccagctgtgcagttcaactcagggact2400 ctggccctaaacaggaaggtcaaaaacaacccagatcctacaatttatccagtgcttgac2460 tggaatgacatcaaatttcaagatgtgattggggagggcaattttggccaagttcttaag2520 gcgcgcatcaagaaggatgggttacggatggatgctgccatcaaaagaatgaaagaatat2580 gcctccaaagatgatcacagggactttgcaggagaactggaagttctttgtaaacttgga2640 caccatccaaacatcatcaatctcttaggagcatgtgaacatcgaggctacttgtacctg2700 gccattgagtacgcgccccatggaaaccttctggacttccttcgcaagagccgtgtgctg2760 gagacggacccagcatttgccattgccaatagcaccgcgtccacactgtcctcccagcag2820 ctccttcacttcgctgccgacgtggcccggggcatggactacttgagccaaaaacagttt2880 atccacagggatctggctgccagaaacattttagttggtgaaaactatgtggcaaaaata2940 2S gcagattttggattgtcccgaggtcaagaggtgtacgtgaaaaagacaatgggaaggctc3000 ccagtgcgctggatggccatcgagtcactgaattacagtgtgtacacaaccaacagtgat3060 gtatggtcctatggtgtgttactatgggagattgttagcttaggaggcacaccctactgc3120 gggatgacttgtgcagaactctacgagaagctgccccagggctacagactggagaagccc3180 ctgaactgtgatgatgaggtgtatgatctaatgagacaatgctggcgggagaagccttat3240 gagaggccatcatttgcccagatattggtgtccttaaacagaatgttagaggagcgaaag3300 acctacgtgaataccacgctttatgagaagtttacttatgcaggaattgactgttctgct3360 gaagaagcggcctag 3375 3S <210> 10 <211> 2409 <212> DNA
<213> Homo sapiens <300>
<300>
<302> betas integrin <310> X53002 <400> to ncbsncvwra tgccgcgggc cccggcgccg ctgtacgcct gcctcctggg gctctgcgcg 60 ctcctgcccc ggctcgcagg tctcaacata tgcactagtg gaagtgccac ctcatgtgaa 120 gaatgtctgc taatccaccc aaaatgtgcc tggtgctcca aagaggactt cggaagccca 180 SO cggtccatca cctctcggtg tgatctgagg gcaaaccttg tcaaaaatgg ctgtggaggt 240 gagatagaga gcccagccag cagcttccat gtcctgagga gcctgcccct cagcagcaag 300 ggttcgggct ctgcaggctg ggacgtcatt cagatgacac cacaggagat tgccgtgaac 360 ctccggcccg gtgacaagac caccttccag ctacaggttc gccaggtgga ggactatcct 420 gtggacctgt actacctgat ggacctctcc ctgtccatga aggatgactt ggacaatatc 480 SS cggagcctgg gcaccaaact cgcggaggag atgaggaagc tcaccagcaa cttccggttg 540 ggatttgggt cttttgttga taaggacatc tctcctttct cctacacggc accgaggtac 600 cagaccaatc cgtgcattgg ttacaagttg tttccaaatt gcgtcccctc ctttgggttc 660 cgccatctgc tgcctctcac agacagagtg gacagcttca atgaggaagt tcggaaacag 720 agggtgtccc ggaaccgaga tgcccctgag gggggctttg atgcagtact ccaggcagcc 780 60 gtctgcaagg agaagattgg ctggcgaaag gatgcactgc atttgctggt gttcacaaca 840 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc gatgatgtgccccacatcgcattggatggaaaattgggaggcctggtgcagccacacgat900 ggccagtgccacctgaacgaggccaacgagtacacagcatccaaccagatggactatcca960 tcccttgccttgcttggagagaaattggcagagaacaacatcaacctcatctttgcagtg1020 acaaaaaaccattatatgctgtacaagaattttacagccctgatacctggaacaacggtg1080 S gagattttagatggagactccaaaaatattattcaactgattattaatgcatacaatagt1140 atccggtctaaagtggagttgtcagtctgggatcagcctgaggatcttaatctcttcttt1200 actgctacctgccaagatggggtatcctatcctggtcagaggaagtgtgagggtctgaag1260 attggggacacggcatcttttgaagtatcattggaggcccgaagctgtcccagcagacac1320 acggagcatgtgtttgccctgcggccggtgggattccgggacagcctggaggtgggggtc1380 10 acctacaactgcacgtgcggctgcagcgtggggctggaacccaacagcgccaggtgcaac1440 gggagcgggacctatgtctgcggcctgtgtgagtgcagccccggctacctgggcaccagg1500 tgcgagtgccaggatggggagaaccagagcgtgtaccagaacctgtgccgggaggcagag1560 ggcaagccactgtgcagcgggcgtggggactgcagctgcaaccagtgctcctgcttcgag1620 agcgagtttggcaagatctatgggcctttctgtgagtgcgacaacttctcctgtgccagg1680 1S aacaagggagtcctctgctcaggccatggcgagtgtcactgcggggaatgcaagtgccat1740 gcaggttacatcggggacaactgtaactgctcgacagacatcagcacatgccggggcaga1800 gatggccagatctgcagcgagcgtgggcactgtctctgtgggcagtgccaatgcacggag1860 ccgggggcctttggggagatgtgtgagaagtgccccacctgcccggatgcatgcagcacc1920 aagagagattgcgtcgagtgcctgctgctccactctgggaaacctgacaaccagacctgc1980 20 cacagcctatgcagggatgaggtgatcacatgggtggacaccatcgtgaaagatgaccag2040 gaggctgtgctatgtttctacaaaaccgccaaggactgcgtcatgatgttcacctatgtg2100 gagctccccagtgggaagtccaacctgaccgtcctcagggagccagagtgtggaaacacc2160 cccaacgccatgaccatcctcctggctgtggtcggtagcatcctccttgttgggcttgca2220 ctcctggctatctggaagctgcttgtcaccatccacgaccggagggagtttgcaaagttt2280 2S cagagcgagcgatccagggcccgctatgaaatggcttcaaatccattatacagaaagcct2340 atctccacgcacactgtggacttcaccttcaacaagttcaacaaatcctacaatggcact2400 gtggactga 30 <210> 11 <211> 2367 <212> DNA
<213> Homo sapiens 35 <300>
<302> beta3 integrin <310> NM000212 <400> 11 40 atgcgagcgcggccgcggccccggccgctctgggcgactgtgctggcgctgggggcgctg60 gcgggcgttggcgtaggagggcccaacatctgtaccacgcgaggtgtgagctcctgccag120 cagtgcctggctgtgagccccatgtgtgcctggtgctctgatgaggccctgcctctgggc180 tcacctcgctgtgacctgaaggagaatctgctgaaggataactgtgccccagaatccatc240 gagttcccagtgagtgaggcccgagtactagaggacaggcccctcagcgacaagggctct300 4S ggagacagctcccaggtcactcaagtcagtccccagaggattgcactccggctccggcca360 gatgattcgaagaatttctccatccaagtgcggcaggtggaggattaccctgtggacatc420 tactacttgatggacctgtcttactccatgaaggatgatctgtggagcatccagaacctg480 ggtaccaagctggccacccagatgcgaaagctcaccagtaacctgcggattggcttcggg540 gcatttgtggacaagcctgtgtcaccatacatgtatatctccccaccagaggccctcgaa600 SO aacccctgctatgatatgaagaccacctgcttgcccatgtttggctacaaacacgtgctg660 acgctaactgaccaggtgacccgcttcaatgaggaagtgaagaagcagagtgtgtcacgg720 aaccgagatgccccagagggtggctttgatgccatcatgcaggctacagtctgtgatgaa780 aagattggctggaggaatgatgcatcccacttgctggtgtttaccactgatgccaagact840 catatagcattggacggaaggctggcaggcattgtccagcctaatgacgggcagtgtcat900 SS gttggtagtgacaatcattactctgcctccactaccatggattatccctctttggggctg960 atgactgagaagctatcccagaaaaacatcaatttgatctttgcagtgactgaaaatgta1020 gtcaatctctatcagaactatagtgagctcatcccagggaccacagttggggttctgtcc1080 atggattccagcaatgtcctccagctcattgttgatgcttatgggaaaatccgttctaaa1140 gtagagctggaagtgcgtgacctccctgaagagttgtctctatccttcaatgccacctgc1200 60 ctcaacaatgaggtcatccctggcctcaagtcttgtatgggactcaagattggagacacg1260 \1SERVER\g$\TextelAnmeldeunterlagea 2003\422497-Ribopharma-ao-2.doc gtgagcttcagcattgaggccaaggtgcgaggctgtccccaggagaaggagaagtccttt1320 accataaagcccgtgggcttcaaggacagcctgatcgtccaggtcacctttgattgtgac1380 tgtgcctgccaggcccaagctgaacctaatagccatcgctgcaacaatggcaatgggacc1440 tttgagtgtggggtatgccgttgtgggcctggctggctgggatcccagtgtgagtgctca1500 $ gaggaggactatcgcccttcccagcaggacgaatgcagcccccgggagggtcagcccgtc1560 tgcagccagcggggcgagtgcctctgtggtcaatgtgtctgccacagcagtgactttggc1620 aagatcacgggcaagtactgcgagtgtgacgacttctcctgtgtccgctacaagggggag1680 atgtgctcaggccatggccagtgcagctgtggggactgcctgtgtgactccgactggacc1740 ggctactactgcaactgtaccacgcgtactgacacctgcatgtccagcaatgggctgctg1800 tgcagcggccgcggcaagtgtgaatgtggcagctgtgtctgtatccagccgggctcctat1860 ggggacacctgtgagaagtgccccacctgcccagatgcctgcacctttaagaaagaatgt1920 gtggagtgtaagaagtttgaccgggagccctacatgaccgaaaatacctgcaaccgttac1980 tgccgtgacgagattgagtcagtgaaagagcttaaggacactggcaaggatgcagtgaat2040 tgtacctataagaatgaggatgactgtgtcgtcagattccagtactatgaagattctagt2100 1S ggaaagtccatcctgtatgtggtagaagagccagagtgtcccaagggccctgacatcctg2160 gtggtcctgctctcagtgatgggggccattctgctcattggccttgccgccctgctcatc2220 tggaaactcctcatcaccatccacgaccgaaaagaattcgctaaatttgaggaagaacgc2280 gccagagcaaaatgggacacagccaacaacccactgtataaagaggccacgtctaccttc2340 accaatatcacgtaccggggcacttaa 2367 <210> 12 <211> 3147 <212> DNA

<213> Homosapiens <300>
<302> alpha v intergrin <310> NM0022210 <400> 12 atggcttttccgccgcggcgacggctgcgcctcggtccccgcggcctcccgcttcttctc60 tcgggactcctgctacctctgtgccgcgccttcaacctagacgtggacagtcctgccgag120 tactctggccccgagggaagttacttcggcttcgccgtggatttcttcgtgcccagcgcg180 3S tcttcccggatgtttcttctcgtgggagctcccaaagcaaacaccacccagcctgggatt240 gtggaaggagggcaggtcctcaaatgtgactggtcttctacccgccggtgccagccaatt300 gaatttgatgcaacaggcaatagagattatgccaaggatgatccattggaatttaagtcc360 catcagtggtttggagcatctgtgaggtcgaaacaggataaaattttggcctgtgcccca420 ttgtaccattggagaactgagatgaaacaggagcgagagcctgttggaacatgctttctt480 caagatggaacaaagactgttgagtatgctccatgtagatcacaagatattgatgctgat540 ggacagggattttgtcaaggaggattcagcattgattttactaaagctgacagagtactt600 cttggtggtcctggtagcttttattggcaaggtcagcttatttcggatcaagtggcagaa660 atcgtatctaaatacgaccccaatgtttacagcatcaagtataataaccaattagcaact720 cggactgcacaagctatttttgatgacagctatttgggttattctgtggctgtcggagat780 ttcaatggtgatggcatagatgactttgtttcaggagttccaagagcagcaaggactttg840 ggaatggtttatatttatgatgggaagaacatgtcctccttatacaattttactggcgag900 cagatggctgcatatttcggattttctgtagctgccactgacattaatggagatgattat960 gcagatgtgtttattggagcacctctcttcatggatcgtggctctgatggcaaactccaa1020 gaggtggggcaggtctcagtgtctctacagagagcttcaggagacttccagacgacaaag1080 ctgaatggatttgaggtctttgcacggtttggcagtgccatagctcctttgggagatctg1140 gaccaggatggtttcaatgatattgcaattgctgctccatatgggggtgaagataaaaaa1200 ggaattgtttatatcttcaatggaagatcaacaggcttgaacgcagtcccatctcaaatc1260 cttgaagggcagtgggctgctcgaagcatgccaccaagctttggctattcaatgaaagga1320 gccacagatatagacaaaaatggatatccagacttaattgtaggagcttttggtgtagat1380 cgagctatcttatacagggccagaccagttatcactgtaaatgctggtcttgaagtgtac1440 cctagcattttaaatcaagacaataaaacctgctcactgcctggaacagctctcaaagtt1500 tcctgttttaatgttaggttctgcttaaaggcagatggcaaaggagtacttcccaggaaa1560 cttaatttccaggtggaacttcttttggataaactcaagcaaaagggagcaattcgacga1620 gcactgtttctctacagcaggtccccaagtcactccaagaacatgactatttcaaggggg1680 f)0ggactgatgcagtgtgaggaattgatagcgtatctgcgggatgaatctgaatttagagac1740 \\SERVER\g$\Texte\Aameldeuaterlagen 2003\422497-Ribopharma-an-2.doc aaactcactccaattactatttttatggaatatcggttggattatagaacagctgctgat1800 acaacaggcttgcaacccattcttaaccagttcacgcctgctaacattagtcgacaggct1860 cacattctacttgactgtggtgaagacaatgtctgtaaacccaagctggaagtttctgta1920 gatagtgatcaaaagaagatctatattggggatgacaaccctctgacattgattgttaag1980 S gctcagaatcaaggagaaggtgcctacgaagctgagctcatcgtttccattccactgcag2040 gctgatttcatcggggttgtccgaaacaatgaagccttagcaagactttcctgtgcattt2100 aagacagaaaaccaaactcgccaggtggtatgtgaccttggaaacccaatgaaggctgga2160 actcaactcttagctggtcttcgtttcagtgtgcaccagcagtcagagatggatacttct2220 gtgaaatttgacttacaaatccaaagctcaaatctatttgacaaagtaagcccagttgta2280 tctcacaaagttgatcttgctgttttagctgcagttgagataagaggagtctcgagtcct2340 gatcatatctttcttccgattccaaactgggagcacaaggagaaccctgagactgaagaa2400 gatgttgggccagttgttcagcacatctatgagctgagaaacaatggtccaagttcattc2460 agcaaggcaatgctccatcttcagtggccttacaaatataataataacactctgttgtat2520 atccttcattatgatattgatggaccaatgaactgcacttcagatatggagatcaaccct2580 ttgagaattaagatctcatctttgcaaacaactgaaaagaatgacacggttgccgggcaa2640 ggtgagcgggaccatctcatcactaagcgggatcttgccctcagtgaaggagatattcac2700 actttgggttgtggagttgctcagtgcttgaagattgtctgccaagttgggagattagac2760 agaggaaagagtgcaatcttgtacgtaaagtcattactgtggactgagacttttatgaat2820 aaagaaaatcagaatcattcctattctctgaagtcgtctgcttcatttaatgtcatagag2880 2o tttccttataagaatcttccaattgaggatatcaccaactccacattggttaccactaat2940 gtcacctggggcattcagccagcgcccatgcctgtgcctgtgtgggtgatcattttagca3000 gttctagcaggattgttgctactggctgttttggtatttgtaatgtacaggatgggcttt3060 tttaaacgggtccggccacctcaagaagaacaagaaagggagcagcttcaacctcatgaa3120 aatggtgaaggaaactcagaaacttaa 3147 <210> 13 <211> 402 <212> DNA

30 <213> Homosapiens <300>
<302> CaSm (cancer associated SM-like oncogene) <310> AF000177 <400> 13 atgaactata tgcctggcac cgccagcctc atcgaggaca ttgacaaaaa gcacttggtt 60 ctgcttcgag atggaaggac acttataggc tttttaagaa gcattgatca atttgcaaac 120 ttagtgctac atcagactgt ggagcgtatt catgtgggca aaaaatacgg tgatattcct 180 cgagggattt ttgtggtcag aggagaaaat gtggtcctac taggagaaat agacttggaa 240 aaggagagtg acacacccct ccagcaagta tccattgaag aaattctaga agaacaaagg 300 gtggaacagc agaccaagct ggaagcagag aagttgaaag tgcaggccct gaaggaccga 360 ggtctttcca ttcctcgagc agatactctt gatgagtact as 402 <210> 14 <211> 1923 <212> DNA
<213> Homo sapiens so <300>
<302> c-myb <310> NM005375 SS <400> 14 atggcccgaa gaccccggca cagcatatat agcagtgacg aggatgatga ggactttgag 60 atgtgtgacc atgactatga tgggctgctt cccaagtctg gaaagcgtca cttggggaaa 120 acaaggtgga cccgggaaga ggatgaaaaa ctgaagaagc tggtggaaca gaatggaaca 180 gatgactgga aagttattgc caattatctc ccgaatcgaa cagatgtgca gtgccagcac 240 60 cgatggcaga aagtactaaa ccctgagctc atcaagggtc cttggaccaa agaagaagat 300 1\SERVER\g$\Texte\Anmeldeunterlagen 2003\422A97-Ribopharma-an-2.doc cagagagtgatagagcttgtacagaaatacggtccgaaacgttggtctgttattgccaag360 cacttaaaggggagaattggaaaacaatgtagggagaggtggcataaccacttgaatcca420 gaagttaagaaaacctcctggacagaagaggaagacagaattatttaccaggcacacaag480 agactggggaacagatgggcagaaatcgcaaagctactgcctggacgaactgataatgct540 S atcaagaaccactggaattctacaatgcgtcggaaggtcgaacaggaaggttatctgcag600 gagtcttcaaaagccagccagccagcagtggccacaagcttccagaagaacagtcatttg660 atgggttttgctcaggctccgcctacagctcaactccctgccactggccagcccactgtt720 aacaacgactattcctattaccacatttctgaagcacaaaatgtctccagtcatgttcca780 taccctgtagcgttacatgtaaatatagtcaatgtccctcagccagctgccgcagccatt840 cagagacactataatgatgaagaccctgagaaggaaaagcgaataaaggaattagaattg900 ctcctaatgtcaaccgagaatgagctaaaaggacagcaggtgctaccaacacagaaccac960 acatgcagctaccccgggtggcacagcaccaccattgccgaccacaccagacctcatgga1020 gacagtgcacctgtttcctgtttgggagaacaccactccactccatctctgccagcggat1080 cctggctccctacctgaagaaagcgcctcgccagcaaggtgcatgatcgtccaccagggc1140 1S accattctggataatgttaagaacctcttagaatttgcagaaacactccaatttatagat1200 tctttcttaaacacttccagtaaccatgaaaactcagacttggaaatgccttctttaact1260 tccacccccctcattggtcacaaattgactgttacaacaccatttcatagagaccagact1320 gtgaaaactcaaaaggaaaatactgtttttagaaccccagctatcaaaaggtcaatctta1380 gaaagctctccaagaactcctacaccattcaaacatgcacttgcagctcaagaaattaaa1440 tacggtcccctgaagatgctacctcagacaccctctcatctagtagaagatctgcaggat1500 gtgatcaaacaggaatctgatgaatctggatttgttgctgagtttcaagaaaatggacca1560 cccttactgaagaaaatcaaacaagaggtggaatctccaactgataaatcaggaaacttc1620 ttctgctcacaccactgggaaggggacagtctgaatacccaactgttcacgcagacctcg1680 cctgtgcgagatgcaccgaatattcttacaagctccgttttaatggcaccagcatcagaa1740 2S gatgaagacaatgttctcaaagcatttacagtacctaaaaacaggtccctggcgagcccc1800 ttgcagccttgtagcagtacctgggaacctgcatcctgtggaaagatggaggagcagatg1860 acatcttccagtcaagctcgtaaatacgtgaatgcattctcagcccggacgctggtcatg1920 tga 1923 <210> 15 <211> 544 <212> DNA
<213> Homo sapiens <300>
<302> c-myc <310> J00120 <400> 15 gacccccgag ctgtgctgct cgcggccgcc accgccgggc cccggccgtc cctggctccc 60 ctcctgcctc gagaagggca gggcttctca gaggcttggc gggaaaaaga acggagggag 120 ggatcgcgct gagtataaaa gccggttttc ggggctttat ctaactcgct gtagtaattc 180 cagcgagagg cagagggagc gagcgggcgg ccggctaggg tggaagagcc gggcgagcag 240 4S agctgcgctg cgggcgtcct gggaagggag atccggagcg aatagggggc ttcgcctctg 300 gcccagccct cccgctgatc ccccagccag cggtccgcaa cccttgccgc atccacgaaa 360 ctttgcccat agcagcgggc gggcactttg cactggaact tacaacaccc gagcaaggac 420 gcgactctcc cgacgcgggg aggctattct gcccatttgg ggacacttcc ccgccgctgc 480 caggacccgc ttctctgaaa ggctctcctt gcagctgctt agacgctgga tttttttcgg 540 S0 gtag 544 <210> 16 <211> 618 SS <212> DNA
<213> Homo sapiens <300>
<302> 2phrin-A1 60 <310> NM004428 \\SERVER\g$iTexte\Anmeldeunterlagen 20031422497-Ribopharma-an-2.doc <400> 16 atggagttcc tctgggcccc tctcttgggt ctgtgctgca gtctggccgc tgctgatcgc 60 cacaccgtct tctggaacag ttcaaatccc aagttccgga atgaggacta caccatacat 120 S gtgcagctga atgactacgt ggacatcatc tgtccgcact atgaagatca ctctgtggca 180 gacgctgcca tggagcagta catactgtac ctggtggagc atgaggagta ccagctgtgc 240 cagccccagt ccaaggacca agtccgctgg cagtgcaacc ggcccagtgc caagcatggc 300 ccggagaagc tgtctgagaa gttccagcgc ttcacacctt tcaccctggg caaggagttc 360 aaagaaggac acagctacta ctacatctcc aaacccatcc accagcatga agaccgctgc 420 ttgaggttga aggtgactgt cagtggcaaa atcactcaca gtcctcaggc ccatgtcaat 480 ccacaggaga agagacttgc agcagatgac ccagaggtgc gggttctaca tagcatcggt 540 cacagtgctg ccccacgcct cttcccactt gcctggactg tgctgctcct tccacttctg 600 ctgctgcaaa ccccgtga 618 <210> 17 <211> 642 <212> DNA
<213> Homo sapiens <400> 17 atggcgcccg cgcagcgccc gctgctcccg ctgctgctcc tgctgttacc gctgccgccg 60 ccgcccttcg cgcgcgccga ggacgccgcc cgcgccaact cggaccgcta cgccgtctac 120 tggaaccgca gcaaccccag gttccacgca ggcgcggggg acgacggcgg gggctacacg 180 2$ gtggaggtga gcatcaatga ctacctggac atctactgcc cgcactatgg ggcgccgctg 240 ccgccggccg agcgcatgga gcactacgtg ctgtacatgg tcaacggcga gggccacgcc 300 tcctgcgacc accgccagcg cggcttcaag cgctgggagt gcaaccggcc cgcggcgccc 360 ggggggccgc tcaagttctc ggagaagttc cagctcttca cgcccttctc cctgggcttc 420 gagttccggc ccggccacga gtattactac atctctgcca cgcctcccaa tgctgtggac 480 30 cggccctgcc tgcgactgaa ggtgtacgtg cggccgacca acgagaccct gtacgaggct 540 cctgagccca tcttcaccag caataactcg tgtagcagcc cgggcggctg ccgcctcttc 600 ctcagcacca tccccgtgct ctggaccctc ctgggttcct ag 642 35 <210> is <211> 717 <212> DNA
<213> Homo Sapiens 40 <300>
<302> ephrin-A3 <310> XM001787 <400> 18 45 atggcggcgg ctccgctgct gctgctgctg ctgctcgtgc ccgtgccgct gctgccgctg 60 ctggcccaag ggcccggagg ggcgctggga aaccggcatg cggtgtactg gaacagctcc 120 aaccagcacc tgcggcgaga gggctacacc gtgcaggtga acgtgaacga ctatctggat 180 atttactgcc cgcactacaa cagctcgggg gtgggccccg gggcgggacc ggggcccgga 240 ggcggggcag agcagtacgt gctgtacatg gtgagccgca acggctaccg cacctgcaac 300 S0 gccagccagg gcttcaagcg ctgggagtgc aaccggccgc acgccccgca cagccccatc 360 aagttctcgg agaagttcca gcgctacagc gccttctctc tgggctacga gttccacgcc 420 ggccacgagt actactacat ctccacgccc actcacaacc tgcactggaa gtgtctgagg 480 atgaaggtgt tcgtctgctg cgcctccaca tcgcactccg gggagaagcc ggtccccact 540 ctcccccagt tcaccatggg ccccaatatg aagatcaacg tgctggaaga ctttgaggga 600 $5 gagaaccctc aggtgcccaa gcttgagaag agcatcagcg ggaccagccc caaacgggaa 660 cacctgcccc tggccgtggg catcgccttc ttcctcatga cgttcttggc ctcctag 717 <210> 19 60 <211> 606 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <212> DNA
<213> Homo sapiens <300>
S <302> ephrin-A3 <310> XM001784 <400> 19 atgcggctgc tgcccctgct gcggactgtc ctctgggccg cgttcctcgg ctcccctctg 60 10 cgcgggggct ccagcctccg ccacgtagtc tactggaact ccagtaaccc caggttgctt 120 cgaggagacg ccgtggtgga gctgggcctc aacgattacc tagacattgt ctgcccccac 180 tacgaaggcc cagggccccc tgagggcccc gagacgtttg ctttgtacat ggtggactgg 240 ccaggctatg agtcctgcca ggcagagggc ccccgggcct acaagcgctg ggtgtgctcc 300 ctgccctttg gccatgttca attctcagag aagattcagc gcttcacacc cttctccctc 360 1S ggctttgagt tcttacctgg agagacttac tactacatct cggtgcccac tccagagagt 420 tctggccagt gcttgaggct ccaggtgtct gtctgctgca aggagaggaa gtctgagtca 480 gcccatcctg ttgggagccc tggagagagt ggcacatcag ggtggcgagg gggggacact 540 cccagccccc tctgtctctt gctattactg ctgcttctga ttcttcgtct tctgcgaatt 600 ctgtga 606 <210> 20 <211> 687 <212> DNA
2S <213> Homo sapiens <300>
<302> ephrin-A5 <310> NM001962 <400> 20 atgttgcacg tggagatgtt gacgctggtg tttctggtgc tctggatgtg tgtgttcagc 60 caggacccgg gctccaaggc cgtcgccgac cgctacgctg tctactggaa cagcagcaac 120 cccagattcc agaggggtga ctaccatatt gatgtctgta tcaatgacta cctggatgtt 180 3S ttctgccctc actatgagga ctccgtccca gaagataaga ctgagcgcta tgtcctctac 240 atggtgaact ttgatggcta cagtgcctgc gaccacactt ccaaagggtt caagagatgg 300 gaatgtaacc ggcctcactc tccaaatgga ccgctgaagt tctctgaaaa attccagctc 360 ttcactccct tttctctagg atttgaattc aggccaggcc gagaatattt ctacatctcc 420 tctgcaatcc cagataatgg aagaaggtcc tgtctaaagc tcaaagtctt tgtgagacca 480 acaaatagct gtatgaaaac tataggtgtt catgatcgtg ttttcgatgt taacgacaaa 540 gtagaaaatt cattagaacc agcagatgac accgtacatg agtcagccga gccatcccgc 600 ggcgagaacg cggcacaaac accaaggata cccagccgcc ttttggcaat cctactgttc 660 ctcctggcga tgcttttgac attatag 687 SO
<210> 21 <211> 2955 <212> DNA
<213> Homo sapiens <400> 21 atggccctgg attatctact actgctcctc ctggcatccg cagtggctgc gatggaagaa 60 acgttaatgg acaccagaac ggctactgca gagctgggct ggacggccaa tcctgcgtcc 120 gggtgggaag aagtcagtgg ctacgatgaa aacctgaaca ccatccgcac ctaccaggtg 180 SS tgcaatgtct tcgagcccaa ccagaacaat tggctgctca ccaccttcat caaccggcgg 240 ggggcccatc gcatctacac agagatgcgc ttcactgtga gagactgcag cagcctccct 300 aatgtcccag gatcctgcaa ggagaccttc aacttgtatt actatgagac tgactctgtc 360 attgccacca agaagtcagc cttctggtct gaggccccct acctcaaagt agacaccatt 420 gctgcagatg agagcttctc ccaggtggac tttgggggaa ggctgatgaa ggtaaacaca 480 60 gaagtcagga gctttgggcc tcttactcgg aatggttttt acctcgcttt tcaggattat 540 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc ggagcctgtatgtctcttctttctgtccgtgtcttcttcaaaaagtgtcccagcattgtg600 caaaattttgcagtgtttccagagactatgacaggggcagagagcacatctctggtgatt660 gctcggggcacatgcatccccaacgcagaggaagtggacgtgcccatcaaactctactgc720 aacggggatggggaatggatggtgcctattgggcgatgcacctgcaagcctggctatgag780 $ cctgagaacagcgtggcatgcaaggcttgccctgcagggacattcaaggccagccaggaa840 gctgaaggctgctcccactgcccctccaacagccgctcccctgcagaggcgtctcccatc900 tgcacctgtcggaccggttattaccgagcggactttgaccctccagaagtggcatgcact960 agcgtcccatcaggtccccgcaatgttatctccatcgtcaatgagacgtccatcattctg1020 gagtggcaccctccaagggagacaggtgggcgggatgatgtgacctacaacatcatctgc1080 1~ aaaaagtgccgggcagaccgccggagctgctcccgctgtgacgacaatgtggagtttgtg1140 cccaggcagctgggcctgacggagtgccgcgtctccatcagcagcctgtgggcccacacc1200 ccctacacctttgacatccaggccatcaatggagtctccagcaagagtcccttcccccca1260 cagcacgtctctgtcaacatcaccacaaaccaagccgccccctccaccgttcccatcatg1320 caccaagtcagtgccactatgaggagcatcaccttgtcatggccacagccggagcagccc1380 1S aatggcatcatcctggactatgagatccggtactatgagaaggaacacaatgagttcaac1440 tcctccatggccaggagtcagaccaacacagcaaggattgatgggctgcggcctggcatg1500 gtatatgtggtacaggtgcgtgcccgcactgttgctggctacggcaagttcagtggcaag1560 atgtgcttccagactctgactgacgatgattacaagtcagagctgagggagcagctgccc1620 ctgattgctggctcggcagcggccggggtcgtgttcgttgtgtccttggtggccatctct1680 20 atcgtctgtagcaggaaacgggcttatagcaaagaggctgtgtacagcgataagctccag1740 cattacagcacaggccgaggctccccagggatgaagatctacattgaccccttcacttat1800 gaggatcccaacgaagctgtccgggagtttgccaaggagattgatgtatcttttgtgaaa1860 attgaagaggtcatcggagcaggggagtttggagaagtgtacaaggggcgtttgaaactg1920 ccaggcaagagggaaatctacgtggccatcaagaccctgaaggcagggtactcggagaag1980 25 cagcgtcgggactttctgagtgaggcgagcatcatgggccagttcgaccatcctaacatc2040 attcgcctggagggtgtggtcaccaagagtcggcctgtcatgatcatcacagagttcatg2100 gagaatggtgcattggattctttcctcaggcaaaatgacgggcagttcaccgtgatccag2160 cttgtgggtatgctcaggggcatcgctgctggcatgaagtacctggctgagatgaattat2220 gtgcatcgggacctggctgctaggaacattctggtcaacagtaacctggtgtgcaaggtg2280 30 tccgactttggcctctcccgctacctccaggatgacacctcagatcccacctacaccagc2340 tccttgggagggaagatccctgtgagatggacagctccagaggccatcgcctaccgcaag2400 ttcacttcagccagcgacgtttggagctatgggatcgtcatgtgggaagtcatgtcattt2460 ggagagagaccctattgggatatgtccaaccaagatgtcatcaatgccatcgagcaggac2520 taccggctgcccccacccatggactgtccagctgctctacaccagctcatgctggactgt2580 35 tggcagaaggaccggaacagccggccccggtttgcggagattgtcaacaccctagataag2640 atgatccggaacccggcaagtctcaagactgtggcaaccatcaccgccgtgccttcccag2700 cccctgctcgaccgctccatcccagacttcacggcctttaccaccgtggatgactggctc2760 agcgccatcaaaatggtccagtacagggacagcttcctcactgctggcttcacctccctc2820 cagctggtcacccagatgacatcagaagacctcctgagaataggcatcaccttggcaggc2880 4~ catcagaagaagatcctgaacagcattcattctatgagggtccagataagtcagtcacca2940 acggcaatggcatga 2955 <210> 22 45 <211> 3168 <212> DNA
<213> Homo Sapiens <400> 22 atggctctgc ggaggctggg ggccgcgctg ctgctgctgc cgctgctcgc cgccgtggaa 60 gaaacgctaa tggactccac tacagcgact gctgagctgg gctggatggt gcatcctcca 120 tcagggtggg aagaggtgag tggctacgat gagaacatga acacgatccg cacgtaccag 180 gtgtgcaacg tgtttgagtc aagccagaac aactggctac ggaccaagtt tatccggcgc 240 cgtggcgccc accgcatcca cgtggagatg aagttttcgg tgcgtgactg cagcagcatc 300 $$ cccagcgtgc ctggctcctg caaggagacc ttcaacctct attactatga ggctgacttt 360 gactcggcca ccaagacctt ccccaactgg atggagaatc catgggtgaa ggtggatacc 420 attgcagccg acgagagctt ctcccaggtg gacctgggtg gccgcgtcat gaaaatcaac 480 accgaggtgc ggagcttcgg acctgtgtcc cgcagcggct tctacctggc cttccaggac 540 tatggcggct gcatgtccct catcgccgtg cgtgtcttct accgcaagtg cccccgcatc 600 fi0 atccagaatg gcgccatctt ccaggaaacc ctgtcggggg ctgagagcac atrgctggtg 660 \\SERVER\g$\Texte\Anmeldeuntertagen 20031422497-Ribopharma-an-2.doc gctgcccggggcagctgcatcgccaatgcggaagaggtggatgtacccatcaagctctac720 tgtaacggggacggcgagtggctggtgcccatcgggcgctgcatgtgcaaagcaggcttc780 gaggccgttgagaatggcaccgtctgccgaggttgtccatctgggactttcaaggccaac840 caaggggatgaggcctgtacccactgtcccatcaacagccggaccacttctgaaggggcc900 S accaactgtgtctgccgcaatggctactacagagcagacctggaccccctggacatgccc960 tgcacaaccatcccctccgcgccccaggctgtgatttccagtgtcaatgagacctccctc1020 atgctggagtggacccctccccgcgactccggaggccgagaggacctcgtctacaacatc1080 atctgcaagagctgtggctcgggccggggtgcctgcacccgctgcggggacaatgtacag1140 tacgcaccacgccagctaggcctgaccgagccacgcatttacatcagtgacctgctggcc1200 cacacccagtacaccttcgagatccaggctgtgaacggcgttactgaccagagccccttc1260 tcgcctcagttcgcctctgtgaacatcaccaccaaccaggcagctccatcggcagtgtcc1320 atcatgcatcaggtgagccgcaccgtggacagcattaccctgtcgtggtcccagccagac1380 cagcccaatggcgtgatcctggactatgagctgcagtactatgagaaggagctcagtgag1440 tacaacgccacagccataaaaagccccaccaacacggtcaccgtgcagggcctcaaagcc1500 1S ggcgccatctatgtcttccaggtgcgggcacgcaccgtggcaggctacgggcgctacagc1560 ggcaagatgtacttccagaccatgacagaagccgagtaccagacaagcatccaggagaag1620 ttgccactcatcatcggctcctcggccgctggcctggtcttcctcattgctgtggttgtc1680 atcgccatcgtgtgtaacagacgggggtttgagcgtgctgactcggagtacacggacaag1740 ctgcaacactacaccagtggccacatgaccccaggcatgaagatctacatcgatcctttc1800 acctacgaggaccccaacgaggcagtgcgggagtttgccaaggaaattgacatctcctgt1860 gtcaaaattgagcaggtgatcggagcaggggagtttggcgaggtctgcagtggccacctg1920 aagctgccaggcaagagagagatctttgtggccatcaagacgctcaagtcgggctacacg1980 gagaagcagcgccgggacttcctgagcgaagcctccatcatgggccagttcgaccatccc2040 aacgtcatccacctggagggtgtcgtgaccaagagcacacctgtgatgatcatcaccgag2100 2S ttcatggagaatggctccctggactcctttctccggcaaaacgatgggcagttcacagtc2160 atccagctggtgggcatgcttcggggcatcgcagctggcatgaagtacctggcagacatg2220 aactatgttcaccgtgacctggctgcccgcaacatcctcgtcaacagcaacctggtctgc2280 aaggtgtcggactttgggctctcacgctttctagaggacgatacctcagaccccacctac2340 accagtgccctgggcggaaagatccccatccgctggacagccccggaagccatccagtac2400 cggaagttcacctcggccagtgatgtgtggagctacggcattgtcatgtgggaggtgatg2460 tcctatggggagcggccctactgggacatgaccaaccaggatgtaatcaatgccattgag2520 caggactatcggctgccaccgcccatggactgcccgagcgccctgcaccaactcatgctg2580 gactgttggcagaaggaccgcaaccaccggcccaagttcggccaaattgtcaacacgcta2640 gacaagatgatccgcaatcccaacagcctcaaagccatggcgcccctctcctctggcatc2700 3S aacctgccgctgctggaccgcacgatccccgactacaccagctttaacacggtggacgag2760 tggctggaggccatcaagatggggcagtacaaggagagcttcgccaatgccggcttcacc2820 tcctttgacgtcgtgtctcagatgatgatggaggacattctccgggttggggtcactttg2880 gctggccaccagaaaaaaatcctgaacagtatccaggtgatgcgggcgcagatgaaccag2940 attcagtctgtggagggccagccactcgccaggaggccacgggccacgggaagaaccaag3000 cggtgccagccacgagacgtcaccaagaaaacatgcaactcaaacgacggaaaaaaaaag3060 ggaatgggaaaaaagaaaacagatcctgggagggggcgggaaatacaaggaatatttttt3120 aaagaggattctcataaggaaagcaatgactgttcttgcgggggataa 3168 4S <210> 23 <211> 2997 <212> DNA
<213> Homo Sapiens SO <400> 23 atggccagag cccgcccgcc gccgccgccg tcgccgccgc cggggcttct gccgctgctc 60 cctccgctgc tgctgctgcc gctgctgctg ctgcccgccg gctgccgggc gctggaagag 120 accctcatgg acacaaaatg ggtaacatct gagttggcgt ggacatctca tccagaaagt 180 gggtgggaag aggtgagtgg ctacgatgag gccatgaatc ccatccgcac ataccaggtg 240 SS tgtaatgtgc gcgagtcaag ccagaacaac tggcttcgca cggggttcat ctggcggcgg 300 gatgtgcagc gggtctacgt ggagctcaag ttcactgtgc gtgactgcaa cagcatcccc 360 aacatccccg gctcctgcaa ggagaccttc aacctcttct actacgaggc tgacagcgat 420 gtggcctcag cctcctcccc cttctggatg gagaacccct acgtgaaagt ggacaccatt 480 gcacccgatg agagcttctc gcggctggat gccggccgtg tcaacaccaa ggtgcgcagc 540 f)0 tttgggccac tttccaaggc tggcttctac ctggccttcc aggaccaggg cgcctgcatg 600 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc tcgctcatctccgtgcgcgccttctacaagaagtgtgcatccaccaccgcaggcttcgca660 ctcttccccgagaccctcactggggcggagcccacctcgctggtcattgctcctggcacc720 tgcatccctaacgccgtggaggtgtcggtgccactcaagctctactgcaacggcgatggg780 gagtggatggtgcctgtgggtgcctgcacctgtgccaccggccatgagccagctgccaag840 S gagtcccagtgccgcccctgtccccctgggagctacaaggcgaagcagggagaggggccc900 tgcctcccatgtccccccaacagccgtaccacctccccagccgccagcatctgcacctgc960 cacaataacttctaccgtgcagactcggactctgcggacagtgcctgtaccaccgtgcca1020 tctccaccccgaggtgtgatctccaatgtgaatgaaacctcactgatcctcgagtggagt1080 gagccccgggacctgggtgtccgggatgacctcctgtacaatgtcatctgcaagaagtgc1140 catggggctggaggggcctcagcctgctcacgctgtgatgacaacgtggagtttgtgcct1200 cggcagctgggcctgtcggagccccgggtccacaccagccatctgctggcccacacgcgc1260 tacacctttgaggtgcaggcggtcaacggtgtctcgggcaagagccctctgccgcctcgt1320 tatgcggccgtgaatatcaccacaaaccaggctgccccgtctgaagtgcccacactacgc1380 ctgcacagcagctcaggcagcagcctcaccctatcctgggcacccccagagcggcccaac1440 1S ggagtcatcctggactacgagatgaagtactttgagaagagcgagggcatcgcctccaca1500 gtgaccagccagatgaactccgtgcagctggacgggcttcggcctgacgcccgctatgtg1560 gtccaggtccgtgcccgcacagtagctggctatgggcagtacagccgccctgccgagttt1620 gagaccacaagtgagagaggctctggggcccagcagctccaggagcagcttcccctcatc1680 gtgggctccgctacagctgggcttgtcttcgtggtggctgtcgtggtcatcgctatcgtc1740 tgcctcaggaagcagcgacacggctctgattcggagtacacggagaagctgcagcagtac1800 attgctcctggaatgaaggtttatattgacccttttacctacgaggaccctaatgaggct1860 gttcgggagtttgccaaggagatcgacgtgtcctgcgtcaagatcgaggaggtgatcgga1920 gctggggaatttggggaagtgtgccgtggtcgactgaaacagcctggccgccgagaggtg1980 tttgtggccatcaagacgctgaaggtgggctacaccgagaggcagcggcgggacttccta2040 2S agcgaggcctccatcatgggtcagtttgatcaccccaatataatccggctcgagggcgtg2100 gtcaccaaaagtcggccagttatgatcctcactgagttcatggaaaactgcgccctggac2160 tccttcctccggctcaacgatgggcagttcacggtcatccagctggtgggcatgttgcgg2220 ggcattgctgccggcatgaagtacctgtccgagatgaactatgtgcaccgcgacctggct2280 gctcgcaacatccttgtcaacagcaacctggtctgcaaagtctcagactttggcctctcc2340 cgcttcctggaggatgacccctccgatcctacctacaccagttccctgggcgggaagatc2400 cccatccgctggactgccccagaggccatagcctatcggaagttcacttctgctagtgat2460 gtctggagctacggaattgtcatgtgggaggtcatgagctatggagagcgaccctactgg2520 gacatgagcaaccaggatgtcatcaatgccgtggagcaggattaccggctgccaccaccc2580 atggactgtcccacagcactgcaccagctcatgctggactgctgggtgcgggaccggaac2640 3S ctcaggcccaaattctcccagattgtcaataccctggacaagctcatccgcaatgctgcc2700 agcctcaaggtcattgccagcgctcagtctggcatgtcacagcccctcctggaccgcacg2760 gtcccagattacacaaccttcacgacagttggtgattggctggatgccatcaagatgggg2$20 cggtacaaggagagcttcgtcagtgcggggtttgcatcttttgacctggtggcccagatg2880 acggcagaagacctgctccgtattggggtcaccctggccggccaccagaagaagatcctg2940 agcagtatccaggacatgcggctgcagatgaaccagacgctgcctgtgcaggtctga 2997 <210> 24 <211> 2964 4S <212> DNA
<213> Homo Sapiens <400> 24 atggagctcc gggtgctgct ctgctgggct tcgttggccg cagctttgga agagaccctg 60 SO ctgaacacaa aattggaaac tgctgatctg aagtgggtga cattccctca ggtggacggg 120 cagtgggagg aactgagcgg cctggatgag gaacagcaca gcgtgcgcac ctacgaagtg 180 tgtgaagtgc agcgtgcccc gggccaggcc cactggcttc gcacaggttg ggtcccacgg 240 cggggcgccg tccacgtgta cgccacgctg cgcttcacca tgctcgagtg cctgtccctg 300 cctcgggctg ggcgctcctg caaggagacc ttcaccgtct tctactatga gagcgatgcg 360 SS gacacggcca cggccctcac gccagcctgg atggagaacc cctacatcaa ggtggacacg 420 gtggccgcgg agcatctcac ccggaagcgc cctggggccg aggccaccgg gaaggtgaat 480 gtcaagacgc tgcgtctggg accgctcagc aaggctggct tctacctggc cttccaggac 540 cagggtgcct gcatggccct gctatccctg cacctcttct acaaaaagtg cgcccagctg 600 actgtgaacc tgactcgatt cccggagact gtgcctcggg agctggttgt gcccgtggcc 660 60 ggtagctgcg tggtggatgc cgtccccgcc cctggcccca gccccagcct ctactgccgt 720 \\SERVER\gS\Texte\Anmeldeunterlagen 2003\422497-Ribopharn~a-an-2.doc gaggatggccagtgggccgaacagccggtcacgggctgcagctgtgctccggggttcgag780 gcagctgaggggaacaccaagtgccgagcctgtgcccagggcaccttcaagcccctgtca840 ggagaagggtcctgccagccatgcccagccaatagccactctaacaccattggatctgcc900 gtctgccagtgccgcgtcggggacttccgggcacgcacagacccccggggtgcaccctgc960 S accacccctccttcggctccgcggagcgtggtttcccgcctgaacggctcctccctgcac1020 ctggaatggagtgcccccctggagtctggtggccgagaggacctcacctacgccctccgc1080 tgccgggagtgccgacccggaggctcctgtgcgccctgcgggggagacctgacttttgac1140 cccggcccccgggacctggtggagccctgggtggtggttcgagggctacgtccggacttc1200 acctatacctttgaggtcactgcattgaacggggtatcctccttagccacggggcccgtc1260 ccatttgagcctgtcaatgtcaccactgaccgagaggtacctcctgcagtgtctgacatc1320 cgggtgacgcggtcctcacccagcagcttgagcctggcctgggctgttccccgggcaccc1380 agtggggcgtggctggactacgaggtcaaataccatgagaagggcgccgagggtcccagc1440 agcgtgcggttcctgaagacgtcagaaaaccgggcagagctgcgggggctgaagcgggga1500 gccagctacctggtgcaggtacgggcgcgctctgaggccggctacgggcccttcggccag1560 1S gaacatcacagccagacccaactggatgagagcgagggctggcgggagcagctggccctg1620 attgcgggcacggcagtcgtgggtgtggtcctggtcctggtggtcattgtggtcgcagtt1680 ctctgcctcaggaagcagagcaatgggagagaagcagaatattcggacaaacacggacag1740 tatctcatcggacatggtactaaggtctacatcgaccccttcacttatgaagaccctaat1800 gaggctgtgagggaatttgcaaaagagatcgatgtctcctacgtcaagattgaagaggtg1860 attggtgcaggtgagtttggcgaggtgtgccgggggcggctcaaggccccagggaagaag1920 gagagctgtgtggcaatcaagaccctgaagggtggctacacggagcggcagcggcgtgag1980 tttctgagcgaggcctccatcatgggccagttcgagcaccccaatatcatccgcctggag2040 ggcgtggtcaccaacagcatgcccgtcatgattctcacagagttcatggagaacggcgcc2100 ctggactccttcctgcggctaaacgacggacagttcacagtcatccagctcgtgggcatg2160 2S ctgcggggcatcgcctcgggcatgcggtaccttgccgagatgagctacgtccaccgagac2220 ctggctgctcgcaacatcctagtcaacagcaacctcgtctgcaaagtgtctgactttggc2280 ctttcccgattcctggaggagaactcttccgatcccacctacacgagctccctgggagga2340 aagattcccatccgatggactgccccggaggccattgccttccggaagttcacttccgcc2400 agtgatgcctggagttacgggattgtgatgtgggaggtgatgtcatttggggagaggccg2460 tactgggacatgagcaatcaggacgtgatcaatgccattgaacaggactaccggctgccc2520 ccgcccccagactgtcccacctccctccaccagctcatgctggactgttggcagaaagac2580 cggaatgcccggccccgcttcccccaggtggtcagcgccctggacaagatgatccggaac2640 cccgccagcctcaaaatcgtggcccgggagaatggcggggcctcacaccctctcctggac2700 cagcggcagcctcactactcagcttttggctctgtgggcgagtggcttcgggccatcaaa2760 3S atgggaagatacgaagcccgtttcgcagccgctggctttggctccttcgagctggtcagc2820 cagatctctgctgaggacctgctccgaatcggagtcactctggcgggacaccagaagaaa2880 atcttggccagtgtccagcacatgaagtcccaggccaagccgggaaccccgggtgggaca2940 ggaggaccggccccgcagtactga 2964 <210> 25 <211> 1041 <212> DNA
<213> Homo sapiens <300>
<302> ephrin-B1 <310> NM004429 S0 <400> 25 atggctcggc ctgggcagcg ttggctcggc aagtggcttg tggcgatggt cgtgtgggcg 60 ctgtgccggc tcgccacacc gctggccaag aacctggagc ccgtatcctg gagctccctc 120 aaccccaagt tcctgagtgg gaagggcttg gtgatctatc cgaaaattgg agacaagctg 180 gacatcatct gcccccgagc agaagcaggg cggccctatg agtactacaa gctgtacctg 240 SS gtgcggcctg agcaggcagc tgcctgtagc acagttctcg accccaacgt gttggtcacc 300 tgcaataggc cagagcagga aatacgcttt accatcaagt tccaggagtt cagccccaac 360 tacatgggcc tggagttcaa gaagcaccat gattactaca ttacctcaac atccaatgga 420 agcctggagg ggctggaaaa ccgggagggc ggtgtgtgcc gcacacgcac catgaagatc 480 atcatgaagg ttgggcaaga tcccaatgct gtgacgcctg agcagctgac taccagcagg 540 fi0 cccagcaagg aggcagacaa cactgtcaag atggccacac aggcccctgg tagtcggggc 600 \\SERVER\g$\TextelAnmeldeunterlagen 2003\422497-Ribopharma-an-2.doc tccctgggtg actctgatgg caagcatgag actgtgaacc aggaagagaa gagtggccca 660 ggtgcaagtg ggggcagcag cggggaccct gatggcttct tcaactccaa ggtggcattg 720 ttcgcggctg tcggtgccgg ttgcgtcatc ttcctgctca tcatcatctt cctgacggtc 780 ctactactga agctacgcaa gcggcaccgc aagcacacac agcagcgggc ggctgccctc 840 S tcgctcagta ccctggccag tcccaagggg ggcagtggca cagcgggcac cgagcccagc 900 gacatcatca ttcccttacg gactacagag aacaactact gcccccacta tgagaaggtg 960 agtggggact acgggcaccc tgtctacatc gtccaagaga tgccgcccca gagcccggcg 1020 aacatctact acaaggtctg a 1041 <210> 26 <211> 1002 <212> DNA
<223> Homo sapiens <300>
<400> 26 atggctgtgagaagggactccgtgtggaagtactgctggggtgttttgatggttttatgc60 agaactgcgatttccaaatcgatagttttagagcctatctattggaattcctcgaactcc120 aaatttctacctggacaaggactggtactatacccacagataggagacaaattggatatt180 atttgccccaaagtggactctaaaactgttggccagtatgaatattataaagtttatatg240 gttgataaagaccaagcagacagatgcactattaagaaggaaaatacccctctcctcaac300 tgtgccaaaccagaccaagatatcaaattcaccatcaagtttcaagaattcagccctaac360 2S ctctggggtctagaatttcagaagaacaaagattattacattatatctacatcaaatggg420 tctttggagggcctggataaccaggagggaggggtgtgccagacaagagccatgaagatc480 ctcatgaaagttggacaagatgcaagttctgctggatcaaccaggaataaagatccaaca540 agacgtccagaactagaagctggtacaaatggaagaagttcgacaacaagtccctttgta600 aaaccaaatccaggttctagcacagacggcaacagcgccggacattcggggaacaacatc660 ctcggttccgaagtggccttatttgcagggattgcttcaggatgcatcatcttcatcgtc720 atcatcatcacgctggtggtcctcttgctgaagtaccggaggagacacaggaagcactcg780 ccgcagcacacgaccacgctgtcgctcagcacactggccacacccaagcgcagcggcaac840 aacaacggctcagagcccagtgacattatcatcccgctaaggactgcggacagcgtcttc900 tgccctcactacgagaaggtcagcggcgactacgggcacccggtgtacatcgtccaggag960 3S atgcccccgcagagcccggcgaacatttactacaaggtctga 1002 <210> 27 <221> 1023 <212> DNA
<213> Homo sapiens <400> 27 atggggcccccccattctgggccggggggcgtgcgagtcggggccctgctgctgctgggg60 4S gttttggggctggtgtctgggctcagcctggagcctgtctactggaactcggcgaataag120 aggttccaggcagagggtggttatgtgctgtaccctcagatcggggaccggctagacctg180 ctctgcccccgggcccggcctcctggccctcactcctctcctaattatgagttctacaag240 ctgtacctggtagggggtgctcagggccggcgctgtgaggcaccccctgccccaaacctc300 cttctcacttgtgatcgcccagacctggatctccgcttcaccatcaagttccaggagtat360 SO agccctaatctctggggccacgagttccgctcgcaccacgattactacatcattgccaca420 tcggatgggacccgggagggcctggagagcctgcagggaggtgtgtgcctaaccagaggc480 atgaaggtgcttctccgagtgggacaaagtccccgaggaggggctgtcccccgaaaacct540 gtgtctgaaatgcccatggaaagagaccgaggggcagcccacagcctggagcctgggaag600 gagaacctgccaggtgaccccaccagcaatgcaacctcccggggtgctgaaggccccctg660 SS ccccctcccagcatgcctgcagtggctggggcagcaggggggctggcgctgctcttgctg720 ggcgtggcaggggctgggggtgccatgtgttggcggagacggcgggccaagccttcggag780 agtcgccaccctggtcctggctccttcgggaggggagggtctctgggcctggggggtgga840 ggtgggatgggacctcgggaggctgagcctggggagctagggatagctctgcggggtggc900 ggggctgcagatccccccttctgcccccactatgagaaggtgagtggtgactatgggcat960 60 cctgtgtatatcgtgcaggatgggcccccccagagccctccaaacatctactacaaggta1020 \\SERVER\g$\Texte\Anmeldeunterlagen 20034422497-Ribopharma-an-2.doc tga 1023 <210> 28 S <211> 3399 <212> DNA
<213> Homo Sapiens <300>
<302> telomerase reverse transcriptase <310> AF015950 <400> 28 atgccgcgcgctccccgctgccgagccgtgcgctccctgctgcgcagccactaccgcgag60 1S gtgctgccgctggccacgttcgtgcggcgcctggggccccagggctggcggctggtgcag120 cgcggggacccggcggctttccgcgcgctggtggcccagtgcctggtgtgcgtgccctgg180 gacgcacggccgccccccgccgccccctccttccgccaggtgtcctgcctgaaggagctg240 gtggcccgagtgctgcagaggctgtgcgagcgcggcgcgaagaacgtgctggccttcggc300 ttcgcgctgctggacggggcccgcgggggcccccccgaggccttcaccaccagcgtgcgc360 agctacctgcccaacacggtgaccgacgcactgcgggggagcggggcgtgggggctgctg420 ctgcgccgcgtgggcgacgacgtgctggttcacctgctggcacgctgcgcgctctttgtg480 ctggtggctcccagctgcgcctaccaggtgtgcgggccgccgctgtaccagctcggcgct540 gccactcaggcccggcccccgccacacgctagtggaccccgaaggcgtctgggatgcgaa600 cgggcctggaaccatagcgtcagggaggccggggtccccctgggcctgccagccccgggt660 2S gcgaggaggcgcgggggcagtgccagccgaagtctgccgttgcccaagaggcccaggcgt720 ggcgctgcccctgagccggagcggacgcccgttgggcaggggtcctgggcccacccgggc780 aggacgcgtggaccgagtgaccgtggtttctgtgtggtgtcacctgccagacccgccgaa840 gaagccacctctttggagggtgcgctctctggcacgcgccactcccacccatccgtgggc900 cgccagcaccacgcgggccccccatccacatcgcggccaccacgtccctgggacacgcct960 tgtcccccggtgtacgccgagaccaagcacttcctctactcctcaggcgacaaggagcag1020 ctgcggccctccttcctactcagctctctgaggcccagcctgactggcgctcggaggctc1080 gtggagaccatctttctgggttccaggccctggatgccagggactccccgcaggttgccc1140 cgcctgccccagcgctactggcaaatgcggcccctgtttctggagctgcttgggaaccac1200 gcgcagtgcccctacggggtgctcctcaagacgcactgcccgctgcgagctgcggtcacc1260 3S ccagcagccggtgtctgtgcccgggagaagccccagggctctgtggcggcccccgaggag1320 gaggacacagacccccgtcgcctggtgcagctgctccgccagcacagcagcccctggcag1380 gtgtacggcttcgtgcgggcctgcctgcgccggctggtgcccccaggcctctggggctcc1440 aggcacaacgaacgccgcttcctcaggaacaccaagaagttcatctccctggggaagcat1500 gccaagctctcgctgcaggagctgacgtggaagatgagcgtgcgggactgcgcttggctg1560 4~ cgcaggagcccaggggttggctgtgttccggccgcagagcaccgtctgcgtgaggagatc1620 ctggccaagttcctgcactggctgatgagtgtgtacgtcgtcgagctgctcaggtctttc1680 ttttatgtcacggagaccacgtttcaaaagaacaggctctttttctaccggaagagtgtc1740 tggagcaagttgcaaagcattggaatcagacagcacttgaagagggtgcagctgcgggag1800 ctgtcggaagcagaggtcaggcagcatcgggaagccaggcccgccctgctgacgtccaga1860 4S ctccgcttcatccccaagcctgacgggctgcggccgattgtgaacatggactacgtcgtg1920 ggagccagaacgttccgcagagaaaagagggccgagcgtctcacctcgagggtgaaggca1980 ctgttcagcgtgctcaactacgagcgggcgcggcgccccggcctcctgggcgcctctgtg2040 ctgggcctggacgatatccacagggcctggcgcaccttcgtgctgcgtgtgcgggcccag2100 gacccgccgcctgagctgtactttgtcaaggtggatgtgacgggcgcgtacgacaccatc2160 SO ccccaggacaggctcacggaggtcatcgccagcatcatcaaaccccagaacacgtactgc2220 gtgcgtcggtatgccgtggtccagaaggccgcccatgggcacgtccgcaaggccttcaag2280 agccacgtctctaccttgacagacctccagccgtacatgcgacagttcgtggctcacctg2340 caggagaccagcccgctgagggatgccgtcgtcatcgagcagagctcctccctgaatgag2400 gccagcagtggcctcttcgacgtcttcctacgcttcatgtgccaccacgccgtgcgcatc2460 SS aggggcaagtcctacgtccagtgccaggggatcccgcagggctccatcctctccacgctg2520 ctctgcagcctgtgctacggcgacatggagaacaagctgtttgcggggattcggcgggac2580 gggctgctcctgcgtttggtggatgatttcttgttggtgacacctcacctcacccacgcg2640 aaaaccttcctcaggaccctggtccgaggtgtccctgagtatggctgcgtggtgaacttg2700 cggaagacagtggtgaacttccctgtagaagacgaggccctgggtggcacggcttttgtt2760 cagatgccggcccacggcctattcccctggtgcggcctgctgctggatacccggaccctg2820 \SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc gaggtgcaga gcgactactc cagctatgcc cggacctcca tcagagccag tctcaccttc 2880 aaccgcggct tcaaggctgg gaggaacatg cgtcgcaaac tctttggggt cttgcggctg 2940 aagtgtcaca gcctgtttct ggatttgcag gtgaacagcc tccagacggt gtgcaccaac 3000 atctacaaga tcctcctgct gcaggcgtac aggtttcacg catgtgtgct gcagctccca 3060 S tttcatcagc aagtttggaa gaaccccaca tttttcctgc gcgtcatctc tgacacggcc 3120 tccctctgct actccatcct gaaagccaag aacgcaggga tgtcgctggg ggccaagggc 3180 gccgccggcc ctctgccctc cgaggccgtg cagtggctgt gccaccaagc attcctgctc 3240 aagctgactc gacaccgtgt cacctacgtg ccactcctgg ggtcactcag gacagcccag 3300 acgcagctga gtcggaagct cccggggacg acgctgactg ccctggaggc cgcagccaac 3360 ccggcactgc cctcagactt caagaccatc ctggactga 3399 <210> 29 <211> 567 1S <212> DNA
<213> Homo Sapiens <300>
<302> K-ras <310> M54968 <400> 29 atgactgaat ataaacttgt ggtagttgga gcttgtggcg taggcaagag tgccttgacg 60 atacagctaa ttcagaatca ttttgtggac gaatatgatc caacaataga ggattcctac 120 2S aggaagcaag tagtaattga tggagaaacc tgtctcttgg atattctcga cacagcaggt 180 caagaggagt acagtgcaat gagggaccag tacatgagga ctggggaggg ctttctttgt 240 gtatttgcca taaataatac taaatcattt gaagatattc accattatag agaacaaatt 300 aaaagagtta aggactctga agatgtacct atggtcctag taggaaataa atgtgatttg 360 ccttctagaa cagtagacac aaaacaggct caggacttag caagaagtta tggaattcct 420 tttattgaaa catcagcaaa gacaagacag ggtgttgatg atgccttcta tacattagtt 480 cgagaaattc gaaaacataa agaaaagatg agcaaagatg gtaaaaagaa gaaaaagaag 540 tcaaagacaa agtgtgtaat tatgtaa 567 3S <210> 30 <211> 3840 <212> DNA
<213> Homo Sapiens <300>
<302> mdr-1 <320> AF016535 <400> 30 4S atggatcttgaaggggaccgcaatggaggagcaaagaagaagaacttttttaaactgaac60 aataaaagtgaaaaagataagaaggaaaagaaaccaactgtcagtgtattttcaatgttt120 cgctattcaaattggcttgacaagttgtatatggtggtgggaactttggctgccatcatc180 catggggctggacttcctctcatgatgctggtgtttggagaaatgacagatatctttgca240 aatgcaggaaatttagaagatctgatgtcaaacatcactaatagaagtgatatcaatgat300 SO acagggttcttcatgaatctggaggaagacatgaccaggtatgcctattattacagtgga360 attggtgctggggtgctggttgctgcttacattcaggtttcattttggtgcctggcagct420 ggaagacaaatacacaaaattagaaaacagttttttcatgctataatgcgacaggagata480 ggctggtttgatgtgcacgatgttggggagcttaacacccgacttacagatgatgtctcc540 aagattaatgaaggaattggtgacaaaattggaatgttctttcagtcaatggcaacattt600 SS ttcactgggtttatagtaggatttacacgtggttggaagctaacccttgtgattttggcc660 atcagtcctgttcttggactgtcagctgctgtctgggcaaagatactatcttcatttact720 gataaagaactcttagcgtatgcaaaagctggagcagtagctgaagaggtcttggcagca780 attagaactgtgattgcatttggaggacaaaagaaagaacttgaaaggtacaacaaaaat840 ttagaagaagctaaaagaattgggataaagaaagctattacagccaatatttctataggt900 60 gctgctttcctgctgatctatgcatcttatgctctggccttctggtatgggaccaccttg960 \\SERVER\g$\TexteWnmeldeunterlagen 2003\422497-Ribopharma-an-2.doc gtcctctcaggggaatattctattggacaagtactcactgtattttctgtattaattggg1020 gcttttagtgttggacaggcatctccaagcattgaagcatttgcaaatgcaagaggagca1080 gcttatgaaatcttcaagataattgataataagccaagtattgacagctattcgaagagt1140 gggcacaaaccagataatattaagggaaatttggaattcagaaatgttcacttcagttac1200 S ccatctcgaaaagaagttaagatcttgaagggtctgaacctgaaggtgcagagtgggcag1260 acggtggccctggttggaaacagtggctgtgggaagagcacaacagtccagctgatgcag1320 aggctctatgaccccacagaggggatggtcagtgttgatggacaggatattaggaccata1380 aatgtaaggtttctacgggaaatcattggtgtggtgagtcaggaacctgtattgtttgcc1440 accacgatagctgaaaacattcgctatggccgtgaaaatgtcaccatggatgagattgag1500 aaagctgtcaaggaagccaatgcctatgactttatcatgaaactgcctcataaatttgac1560 accctggttggagagagaggggcccagttgagtggtgggcagaagcagaggatcgccatt1620 gcacgtgccctggttcgcaaccccaagatcctcctgctggatgaggccacgtcagccttg2680 gacacagaaagcgaagcagtggttcaggtggctctggataaggccagaaaaggtcggacc1740 accattgtgatagctcatcgtttgtctacagttcgtaatgctgacgtcatcgctggtttc1800 1S gatgatggagtcattgtggagaaaggaaatcatgatgaactcatgaaagagaaaggcatt1860 tacttcaaacttgtcacaatgcagacagcaggaaatgaagttgaattagaaaatgcagct1920 gatgaatccaaaagtgaaattgatgccttggaaatgto caaatgattcaagatccagt1980 t ctaataagaaaaagatcaactcgtaggagtgtccgtggatcacaagcccaagacagaaag2040 cttagtaccaaagaggctctggatgaaagtatacctccagtttccttttggaggattatg2100 aagctaaatttaactgaatggccttattttgttgttggtgtattttgtgccattataaat2160 ggaggcctgcaaccagcatttgcaataatattttcaaagattataggggtttttacaaga2220 attgatgatcctgaaacaaaacgacagaatagtaacttgttttcactattgtttctagcc2280 cttggaattatttcttttattacatttttccttcagggtttcacatttggcaaagctgga2340 gagatcctcaccaagcggctccgatacatggttttccgatccatgctcagacaggatgtg2400 2S agttggtttgatgaccctaaaaacaccactggagcattgactaccaggctcgccaatgat2460 gctgctcaagttaaaggggctataggttccaggcttgctgtaattacccagaatatagca2520 aatcttgggacaggaataattatatccttcatctatggttggcaactaacactgttactc2580 ttagcaattgtacccatcattgcaatagcaggagttgttgaaatgaaaatgttgtctgga2640 caagcactgaaagataagaaagaactagaaggtgctgggaagatcgctactgaagcaata2700 gaaaacttccgaaccgttgtttctttgactcaggagcagaagtttgaacatatgtatgct2760 cagagtttgcaggtaccatacagaaactctttgaggaaagcacacatctttggaattaca2820 ttttccttcacccaggcaatgatgtatttttcctatgctggatgtttccggtttggagcc2880 tacttggtggcacataaactcatgagctttgaggatgttctgttagtattttcagctgtt2940 gtctttggtgccatggccgtggggcaagtcagttcatttgctcctgactatgccaaagcc3000 3S aaaatatcagcagcccacatcatcatgatcattgaaaaaacccctttgattgacagctac3060 agcacggaaggcctaatgccgaacacattggaaggaaatgtcacatttggtgaagttgta3120 ttcaactatcccacccgaccggacatcccagtgcttcagggactgagcctggaggtgaag3180 aagggccagacgctggctctggtgggcagcagtggctgtgggaagagcacagtggtccag3240 ctcctggagcggttctacgaccccttggcagggaaagtgctgcttgatggcaaagaaata3300 aagcgactgaatgttcagtggctccgagcacacctgggcatcgtgtcccaggagcccatc3360 ctgtttgactgcagcattgctgagaacattgcctatggagacaacagccgggtggtgtca3420 caggaagagattgtgagggcagcaaaggaggccaacatacatgccttcatcgagtcactg3480 cctaataaatatagcactaaagtaggagacaaaggaactcagctctctggtggccagaaa3540 caacgcattgccatagctcgtgcccttgttagacagcctcatattttgcttttggatgaa3600 4S gccacgtcagctctggatacagaaagtgaaaaggttgtccaagaagccctggacaaagcc3660 agagaaggccgcacctgcattgtgattgctcaccgcctgtccaccatccagaatgcagac3720 ttaatagtggtgtttcagaatggcagagtcaaggagcatggcacgcatcagcagctgctg3780 gcacagaaaggcatctatttttcaatggtcagtgtccaggctggaacaaagcgccagtga3840 SO
<210> 31 <211> 1318 <212> DNA
<213> Homo Sapiens SS
<300>
<302> UPAR (urokinase-type plasminogen activator receptor) <310> XM009232 60 <400> 31 \\SERVER\g~\Texte\Anmeldeunterlagen 2003\422497-Ribophara~a-an-2.doc atgggtcacccgccgctgctgccgctgctgctgctgctccacacctgcgtcccagcctct60 tggggcctgcggtgcatgcagtgtaagaccaacggggattgccgtgtggaagagtgcgcc120 ctgggacaggacctctgcaggaccacgatcgtgcgcttgtgggaagaaggagaagagctg180 gagctggtggagaaaagctgtacccactcagagaagaccaacaggaccctgagctatcgg240 S actggcttgaagatcaccagccttaccgaggttgtgtgtgggttagacttgtgcaaccag300 ggcaactctggccgggctgtcacctattcccgaagccgttacctcgaatgcatttcctgt360 ggctcatcagacatgagctgtgagaggggccggcaccagagcctgcagtgccgcagccct420 gaagaacagtgcctggatgtggtgacccactggatccaggaaggtgaagaagggcgtcca480 aaggatgaccgccacctccgtggctgtggctaccttcccggctgcccgggctccaatggt540 ttccacaacaacgacaccttccacttcctgaaatgctgcaacaccaccaaatgcaacgag600 ggcccaatcctggagcttgaaaatctgccgcagaatggccgccagtgttacagctgcaag660 gggaacagcacccatggatgctcctctgaagagactttcctcattgactgccgaggcccc720 atgaatcaatgtctggtagccaccggcactcacgaaccgaaaaaccaaagctatatggta780 agaggctgtgcaaccgcctcaatgtgccaacatgcccacctgggtgacgccttcagcatg840 1S aaccacattgatgtctcctgctgtactaaaagtggctgtaaccacccagacctggatgtc900 cagtaccgcagtggggctgctcctcagcctggccctgcccatctcagcctcaccatcacc960 ctgctaatgactgccagactgtggggaggcactctcctctggacctaaacctgaaatccc2020 cctctctgccctggctggatccgggggacccctttgcccttccctcggctcccagcccta1080 cagacttgctgtgtgacctcaggccagtgtgccgacctctctgggcctcagttttcccag1140 ctatgaaaacagctatctcacaaagttgtgtgaagcagaagagaaaagctggaggaaggc1200 cgtgggccaatgggagagctcttgttattattaatattgttgccgctgttgtgttgttgt1260 tattaattaatattcatattatttattttatacttacataaagattttgtaccagtgg 1318 ZS <210> 32 <211> 636 <212> DNA
<213> Homo sapiens <300>
<302> Bak <310> U16811 <400> 32 3S atggcttcgg ggcaaggccc aggtcctccc aggcaggagt gcggagagcc tgccctgccc 60 tctgcttctg aggagcaggt agcccaggac acagaggagg ttttccgcag ctacgttttt 120 taccgccatc agcaggaaca ggaggctgaa ggggtggctg cccctgccga cccagagatg 180 gtcaccttac ctctgcaacc tagcagcacc atggggcagg tgggacggca gctcgccatc 240 atcggggacg acatcaaccg acgctatgac tcagagttcc agaccatgtt gcagcacctg 300 cagcccacgg cagagaatgc ctatgagtac ttcaccaaga ttgccaccag cctgtttgag 360 agtggcatca attggggccg tgtggtggct cttctgggct tcggctaccg tctggcccta 420 cacgtctacc agcatggcct gactggcttc ctaggccagg tgacccgctt cgtggtcgac 480 ttcatgctgc atcactgcat tgcccggtgg attgcacaga ggggtggctg ggtggcagcc 540 ctgaacttgg gcaatggtcc catcctgaac gtgctggtgg ttctgggtgt ggttctgttg 600 4S ggccagtttg tggtacgaag attcttcaaa tcatga 636 <210> 33 <211> 579 SO <212> DNA
<213> Homo Sapiens <300>
<302> Bax alpha SS <310> L22473 <400> 33 atggacgggt ccggggagca gcccagaggc ggggggccca ccagctctga gcagatcatg 60 aagacagggg cccttttgct tcagggtttc atccaggatc gagcagggcg aatggggggg 120 fi0 gaggcacccg agctggccct ggacccggtg cctcaggatg cgtccaccaa gaagctgagc 180 \SERVER\g$\TexteWnmeldeunterlagen 2003\422497-Ribopharn~a-an-2.doc gagtgtctca agcgcatcgg ggacgaactg gacagtaaca tggagctgca gaggatgatt 240 gccgccgtgg acacagactc cccccgagag gtctttttcc gagtggcagc tgacatgttt 300 tctgacggca acttcaactg gggccgggtt gtcgcccttt tctactttgc cagcaaactg 360 gtgctcaagg ccctgtgcac caaggtgccg gaactgatca gaaccatcat gggctggaca 420 S ttggacttcc tccgggagcg gctgttgggc tggatccaag accagggtgg ttgggacggc 480 ctcctctcct actttgggac gcccacgtgg cagaccgtga ccatctttgt ggcgggagtg 540 ctcaccgcct cgctcaccat ctggaagaag atgggctga 579 10 <210> 34 <211> 657 <212> DNA
<213> Homo Sapiens 1S <300>
<302> Bax beta <310> L22474 <400> 34 20 atggacgggt ccggggagca gcccagaggc ggggggccca ccagctctga gcagatcatg 60 aagacagggg cccttttgct tcagggtttc atccaggatc gagcagggcg aatggggggg 120 gaggcacccg agctggccct ggacccggtg cctcaggatg cgtccaccaa gaagctgagc 180 gagtgtctca agcgcatcgg ggacgaactg gacagtaaca tggagctgca gaggatgatt 240 gccgccgtgg acacagactc cccccgagag gtctttttcc gagtggcagc tgacatgttt 300 2S tctgacggca acttcaactg gggccgggtt gtcgcccttt tctactttgc cagcaaactg 360 gtgctcaagg ccctgtgcac caaggtgccg gaactgatca gaaccatcat gggctggaca 420 ttggacttcc tccgggagcg gctgttgggc tggatccaag accagggtgg ttgggtgaga 480 ctcctcaagc ctcctcaccc ccaccaccgc gccctcacca ccgcccctgc cccaccgtcc 540 ctgccccccg ccactcctct gggaccctgg gccttctgga gcaggtcaca gtggtgccct 600 30 ctccccatct tcagatcatc agatgtggtc tataatgcgt tttccttacg tgtctga 657 <210> 35 <211> 432 35 <212> DNA
<213> Homo Sapiens <300>
<302> Bax delta 40 <310> U19599 <400> 35 atggacgggt ccggggagca gcccagaggc ggggggccca ccagctctga gcagatcatg 60 aagacagggg cccttttgct tcaggggatg attgccgccg tggacacaga ctccccccga 120 4S gaggtctttt tccgagtggc agctgacatg ttttctgacg gcaacttcaa ctggggccgg 180 gttgtcgccc ttttctactt tgccagcaaa ctggtgctca aggccctgtg caccaaggtg 240 ccggaactga tcagaaccat catgggctgg acattggact tcctccggga gcggctgttg 300 ggctggatcc aagaccaggg tggttgggac ggcctcctct cctactttgg gacgcccacg 360 tggcagaccg tgaccatctt tgtggcggga gtgctcaccg cctcgctcac catctggaag 420 SO aagatgggct ga <210> 36 <211> 495 SS <212> DNA
<213> Homo Sapiens <300>
<302> Bax epsolin 60 <310> AF007826 \1SERVER\g$\TexteWnmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <400> 36 atggacgggt ccggggagca gcccagaggc ggggggccca ccagctctga gcagatcatg 60 aagacagggg cccttttgct tcagggtttc atccaggatc gagcagggcg aatggggggg 120 S gaggcacccg agctggccct ggacccggtg cctcaggatg cgtccaccaa gaagctgagc 180 gagtgtctca agcgcatcgg ggacgaactg gacagtaaca tggagctgca gaggatgatt 240 gccgccgtgg acacagactc cccccgagag gtctttttcc gagtggcagc tgacatgttt 300 tctgacggca acttcaactg gggccgggtt gtcgcccttt tctactttgc cagcaaactg 360 gtgctcaagg ctggcgtgaa atggcgtgat ctgggctcac tgcaacctct gcctcctggg 420 ttcaagcgat tcacctgcct cagcatccca aggagctggg attacaggcc ctgtgcacca 480 aggtgccgga actga 495 <210> 37 1S <211> 582 <212> DNA
<213> Homo sapiens <300>
<302> bcI-w <310> U59747 <400> 37 atggcgaccc cagcctcggc cccagacaca cgggctctgg tggcagactt tgtaggttat 60 2S aagctgaggc agaagggtta tgtctgtgga gctggccccg gggagggccc agcagctgac 120 ccgctgcacc aagccatgcg ggcagctgga gatgagttcg agacccgctt ccggcgcacc 180 ttctctgatc tggcggctca gctgcatgtg accccaggct cagcccagca acgcttcacc 240 caggtctccg acgaactttt tcaagggggc cccaactggg gccgccttgt agccttcttt 300 gtctttgggg ctgcactgtg tgctgagagt gtcaacaagg agatggaacc actggtggga 360 caagtgcagg agtggatggt ggcctacctg gagacgcggc tggctgactg gatccacagc 420 agtgggggct gggcggagtt cacagctcta tacggggacg gggccctgga ggaggcgcgg 480 cgtctgcggg aggggaactg ggcatcagtg aggacagtgc tgacgggggc cgtggcactg 540 ggggccctgg taactgtagg ggcctttttt gctagcaagt ga 582 <210> 38 <211> 2481 <212> DNA
<213> Homo sapiens <300>
<302> HIF-alpha <310> U22431 4S <400> 38 atggagggcg ccggcggcgc gaacgacaag aaaaagataa gttctgaacg tcgaaaagaa 60 aagtctcgag atgcagccag atctcggcga agtaaagaat ctgaagtttt ttatgagctt 120 gctcatcagt tgccacttcc acataatgtg agttcgcatc ttgataaggc ctctgtgatg 180 aggcttacca tcagctattt gcgtgtgagg aaacttctgg atgctggtga tttggatatt 240 SO gaagatgaca tgaaagcaca gatgaattgc ttttatttga aagccttgga tggttttgtt 300 atggttctca cagatgatgg tgacatgatt tacatttctg ataatgtgaa caaatacatg 360 ggattaactc agtttgaact aactggacac agtgtgtttg attttactca tccatgtgac 420 catgaggaaa tgagagaaat gcttacacac agaaatggcc ttgtgaaaaa gggtaaagaa 480 caaaacacac agcgaagctt ttttctcaga atgaagtgta ccctaactag ccgaggaaga 540 SS actatgaaca taaagtctgc aacatggaag gtattgcact gcacaggcca cattcacgta 600 tatgatacca acagtaacca acctcagtgt gggtataaga aaccacctat gacctgcttg 660 gtgctgattt gtgaacccat tcctcaccca tcaaatattg aaattccttt agatagcaag 720 actttcctca gtcgacacag cctggatatg aaattttctt attgtgatga aagaattacc 780 gaattgatgg gatatgagcc agaagaactt ttaggccgct caatttatga atattatcat 840 60 gctttggact ctgatcatct gaccaaaact catcatgata tgtttactaa aggacaagtc 900 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc accacaggacagtacaggatgcttgccaaaagaggtggatatgtctgggttgaaactcaa960 gcaactgtcatatataacaccaagaattctcaaccacagtgcattgtatgtgtgaattac1020 gttgtgagtggtattattcagcacgacttgattttctcccttcaacaaacagaatgtgtc1080 cttaaaccggttgaatcttcagatatgaaaatgactcagctattcaccaaagttgaatca1140 gaagatacaagtagcctctttgacaaacttaagaaggaacctgatgctttaactttgctg1200 gccccagccgctggagacacaatcatatctttagattttggcagcaacgacacagaaact1260 gatgaccagcaacttgaggaagtaccattatataatgatgtaatgctcccctcacccaac1320 gaaaaattacagaatataaatttggcaatgtctccattacccaccgctgaaacgccaaag1380 ccacttcgaagtagtgctgaccctgcactcaatcaagaagttgcattaaaattagaacca1440 aatccagagtcactggaactttcttttaccatgccccagattcaggatcagacacctagt1500 ccttccgatggaagcactagacaaagttcacctgagcctaatagtcccagtgaatattgt1560 ttttatgtggatagtgatatggtcaatgaattcaagttggaattggtagaaaaacttttt1620 gctgaagacacagaagcaaagaacccattttctactcaggacacagatttagacttggag1680 atgttagctccctatatcccaatggatgatgacttccagttacgttccttcgatcagttg1740 1$ tcaccattagaaagcagttccgcaagccctgaaagcgcaagtcctcaaagcacagttaca1800 gtattccagcagactcaaatacaagaacctactgctaatgccaccactaccactgccacc1860 actgatgaattaaaaacagtgacaaaagaccgtatggaagacattaaaatattgattgca1920 tctccatctcctacccacatacataaagaaactactagtgccacatcatcaccatataga1980 gatactcaaagtcggacagcctcaccaaacagagcaggaaaaggagtcatagaacagaca2040 gaaaaatctcatccaagaagccctaacgtgttatctgtcgctttgagtcaaagaactaca2100 gttcctgaggaagaactaaatccaaagatactagctttgcagaatgctcagagaaagcga2160 aaaatggaacatgatggttcactttttcaagcagtaggaattggaacattattacagcag2220 ccagacgatcatgcagctactacatcactttcttggaaacgtgtaaaaggatgcaaatct2280 agtgaacagaatggaatggagcaaaagacaattattttaataccctctgatttagcatgt2340 2S agactgctggggcaatcaatggatgaaagtggattaccacagctgaccagttatgattgt2400 gaagttaatgctcctatacaaggcagcagaaacctactgcagggtgaagaattactcaga2460 gctttggatcaagttaactga 2481 <210> 39 <211> 481 <212> DNA
<213> Homo sapiens <300>
<302> ID1 <310> X77956 <400> 39 atgaaagtcg ccagtggcag caccgccacc gccgccgcgg gccccagctg cgcgctgaag 60 gccggcaaga cagcgagcgg tgcgggcgag gtggtgcgct gtctgtctga gcagagcgtg 120 gccatctcgc gctgccgggg cgccggggcg cgcctgcctg ccctgctgga cgagcagcag 180 gtaaacgtgc tgctctacga catgaacggc tgttactcac gcctcaagga gctggtgccc 240 accctgcccc agaaccgcaa ggtgagcaag gtggagattc tccagcacgt catcgactac 300 4S atcagggacc ttcagttgga gctgaactcg gaatccgaag ttgggacccc cgggggccga 360 gggctgccgg tccgggctcc gctcagcacc ctcaacggcg agatcagcgc cctgacggcc 420 gaggcggcat gcgttcctgc ggacgatcgc atcttgtgtc gctgaatggt gaaaaaaaaa 480 a 481 <210> 40 <211> 110 <212> DNA
<213> Homo sapiens <300>
<302> ID2B
<310> M96843 <400> 40 \iSERVER\g$iTexte\Anmeldeunterlagen 2003142249'7-Ribopharma-an-2.doc tgaaagcctt cagtcccgtg aggtccatta ggaaaaacag cctgttggac caccgcctgg 60 gcatctccca gagcaaaacc ccggtggatg acctgatgag cctgctgtaa 110 S <210> 41 <211> 486 <212> DNA
<213> Homo Sapiens <300>
<302> ID4 <310> Y07958 <400> 41 1S atgaaggcgg tgagcccggt gcgcccctcg ggccgcaagg cgccgtcggg ctgcggcggc 60 ggggagctgg cgctgcgctg cctggccgag cacggccaca gcctgggtgg ctccgcagcc 120 gcggcggcgg cggcggcggc agcgcgctgt aaggcggccg aggcggcggc cgacgagccg 180 gcgctgtgcc tgcagtgcga tatgaacgac tgctatagcc gcctgcggag gctggtgccc 240 accatcccgc ccaacaagaa agtcagcaaa gtggagatcc tgcagcacgt tatcgactac 300 atcctggacc tgcagctggc gctggagacg cacccggccc tgctgaggca gccaccaccg 360 cccgcgccgc cacaccaccc ggccgggacc tgtccagccg cgccgccgcg gaccccgctc 420 actgcgctca acaccgaccc ggccggcgcg gtgaacaagc agggcgacag cattctgtgc 480 cgctga 486 <210> 42 <211> 462 <212> DNA
<213> Homo Sapiens <300>
<302> IGF1 <310> NM000618 3S <400> 42 atgggaaaaa tcagcagtct tccaacccaa ttatttaagt gctgcttttg tgatttcttg 60 aaggtgaaga tgcacaccat gtcctcctcg catctcttct acctggcgct gtgcctgctc 120 accttcacca gctctgccac ggctggaccg gagacgctct gcggggctga gctggtggat 180 gctcttcagt tcgtgtgtgg agacaggggc ttttatttca acaagcccac agggtatggc 240 40 tccagcagtc ggagggcgcc tcagacaggc atcgtggatg agtgctgctt ccggagctgt 300 gatctaagga ggctggagat gtattgcgca cccctcaagc ctgccaagtc agctcgctct 360 gtccgtgccc agcgccacac cgacatgccc aagacccaga aggaagtaca tttgaagaac 420 gcaagtagag ggagtgcagg aaacaagaac tacaggatgt ag 462 <2I0> 43 <211> 591 <212> DNA
<2I3> Homo Sapiens <300>
<302> PDGFA
<310> NM002607 SS <400> 43 atgaggacct tggcttgcct gctgctcctc ggctgcggat acctcgccca tgttctggcc 60 gaggaagccg agatcccccg cgaggtgatc gagaggctgg cccgcagtca gatccacagc 120 atccgggacc tccagcgact cctggagata gactccgtag ggagtgagga ttctttggac 180 accagcctga gagctcacgg ggtccacgcc actaagcatg tgcccgagaa gcggcccctg 240 60 cccattcgga ggaagagaag catcgaggaa gctgtccccg ctgtctgcaa gaccaggacg 300 \\SERVER\g$\Texte\Anmeldeunterlagen 2003442?A97-Ribopharma-an-2.doc gtcatttacg agattcctcg gagtcaggtc gaccccacgt ccgccaactt cctgatctgg 360 cccccgtgcg tggaggtgaa acgctgcacc ggctgctgca acacgagcag tgtcaagtgc 420 cagccctccc gcgtccacca ccgcagcgtc aaggtggcca aggtggaata cgtcaggaag 480 aagccaaaat taaaagaagt ccaggtgagg ttagaggagc atttggagtg cgcctgcgcg 540 S accacaagcc tgaatccgga ttatcgggaa gaggacacgg atgtgaggtg a 591 <210> 44 <211> 528 I~ <212> DNA
<213> Homo Sapiens <300>
<302> PDGFRA
1S <310> XM003568 <400> 44 atggccaagc ctgaccacgc taccagtgaa gtctacgaga tcatggtgaa atgctggaac 60 agtgagccgg agaagagacc ctccttttac cacctgagtg agattgtgga gaatctgctg 120 20 cctggacaat ataaaaagag ttatgaaaaa attcacctgg acttcctgaa gagtgaccat 180 cctgctgtgg cacgcatgcg tgtggactca gacaatgcat acattggtgt cacctacaaa 240 aacgaggaag acaagctgaa ggactgggag ggtggtctgg atgagcagag actgagcgct 300 gacagtggct acatcattcc tctgcctgac attgaccctg tccctgagga ggaggacctg 360 ggcaagagga acagacacag ctcgcagacc tctgaagaga gtgccattga gacgggttcc 420 ZS agcagttcca ccttcatcaa gagagaggac gagaccattg aagacatcga catgatggat 480 gacatcggca tagactcttc agacctggtg gaagacagct tcctgtaa 528 <210> 45 30 <211> 1911 <212> DNA
<213> Homo Sapiens <300>
3S <302> PDGFRB
<310> XM003790 <400> 45 atgcggcttccgggtgcgatgccagctctggccctcaaaggcgagctgctgttgctgtct60 4~ ctcctgttacttctggaaccacagatctctcagggcctggtcgtcacacccccggggcca120 gagcttgtcctcaatgtctccagcaccttcgttctgacctgctcgggttcagctccggtg180 gtgtgggaacggatgtcccaggagcccccacaggaaatggccaaggcccaggatggcacc240 ttctccagcgtgctcacactgaccaacctcactgggctagacacgggagaatacttttgc300 acccacaatgactcccgtggactggagaccgatgagcggaaacggctctacatctttgtg360 4S ccagatcccaccgtgggcttcctccctaatgatgccgaggaactattcatctttctcacg420 gaaataactgagatcaccattccatgccgagtaacagacccacagctggtggtgacactg480 cacgagaagaaaggggacgttgcactgcctgtcccctatgatcaccaacgtggcttttct540 ggtatctttgaggacagaagctacatctgcaaaaccaccattggggacagggaggtggat600 tctgatgcctactatgtctacagactccaggtgtcatccatcaacgtctctgtgaacgca660 S~ gtgcagactgtggtccgccagggtgagaacatcaccctcatgtgcattgtgatcgggaat720 gaggtggtcaacttcgagtggacatacccccgcaaagaaagtgggcggctggtggagccg780 gtgactgacttcctcttggatatgccttaccacatccgctccatcctgcacatccccagt840 gccgagttagaagactcggggacctacacctgcaatgtgacggagagtgtgaatgaccat900 caggatgaaaaggccatcaacatcaccgtggttgagagcggctacgtgcggctcctggga960 SS gaggtgggcacactacaatttgctgagctgcatcggagccggacactgcaggtagtgttc1020 gaggcctacccaccgcccactgtcctgtggttcaaagacaaccgcaccctgggcgactcc1080 agcgctggcgaaatcgccctgtccacgcgcaacgtgtcggagacccggtatgtgtcagag1140 ctgacactggttcgcgtgaaggtggcagaggctggccactacaccatgcgggccttccat1200 gaggatgctgaggtccagctctccttccagctacagatcaatgtccctgtccgagtgctg1260 gagctaagtgagagccaccctgacagtggggaacagacagtccgctgtcgtggccggggc1320 \SERVER\g$\Texte\Anmetdeunterlagen 2003\422497-Ribopharma-an-2.doc atgccccagc cgaacatcat ctggtctgcc tgcagagacc tcaaaaggtg tccacgtgag 1380 ctgccgccca cgctgctggg gaacagttcc gaagaggaga gccagctgga gactaacgtg 1440 acgtactggg aggaggagca ggagtttgag gtggtgagca cactgcgtct gcagcacgtg 1500 gatcggccac tgtcggtgcg ctgcacgctg cgcaacgctg tgggccagga cacgcaggag 1560 S gtcatcgtgg tgccacactc cttgcccttt aaggtggtgg tgatctcagc catcctggcc 1620 ctggtggtgc tcaccatcat ctcccttatc atcctcatca tgctttggca gaagaagcca 1680 cgttacgaga tccgatggaa ggtgattgag tctgtgagct ctgacggcca tgagtacatc 1740 tacgtggacc ccatgcagct gccctatgac tccacgtggg agctgccgcg ggaccagctt 1800 gtgctgggac gcaccctcgg ctctggggcc tttgggcagg tggtggaggc cacggttcat 1860 ggcctgagcc attttcaagc cccaatgaaa gtggccgtca aaaatgctta a 1911 <210> 46 <211> 1176 1S <212> DNA
<213> Homo Sapiens <300>
<302> TGFbetal <310> NM000660 <400> 46 atgccgccctccgggctgcggctgctgccgctgctgctaccgctgctgtggctactggtg60 ctgacgcctggcccgccggccgcgggactatccacctgcaagactatcgacatggagctg120 2S gtgaagcggaagcgcatcgaggccatccgcggccagatcctgtccaagctgcggctcgcc180 agccccccgagccagggggaggtgccgcccggcccgctgcccgaggccgtgctcgccctg240 tacaacagcacccgcgaccgggtggccggggagagtgcagaaccggagcccgagcctgag300 gccgactactacgccaaggaggtcacccgcgtgctaatggtggaaacccacaacgaaatc360 tatgacaagttcaagcagagtacacacagcatatatatgttcttcaacacatcagagctc420 cgagaagcggtacctgaacccgtgttgctctcccgggcagagctgcgtctgctgaggagg480 ctcaagttaaaagtggagcagcacgtggagctgtaccagaaatacagcaacaattcctgg540 cgatacctcagcaaccggctgctggcacccagcgactcgccagagtggttatcttttgat600 gtcaccggagttgtgcggcagtggttgagccgtggaggggaaattgagggctttcgcctt660 agcgcccactgctcctgtgacagcagggataacacactgcaagtggacatcaacgggttc720 3S actaccggccgccgaggtgacctggccaccattcatggcatgaaccggcctttcctgctt780 ctcatggccaccccgctggagagggcccagcatctgcaaagctcccggcaccgccgagcc840 ctggacaccaactattgcttcagctccacggagaagaactgctgcgtgcggcagctgtac900 attgacttccgcaaggacctcggctggaagtggatccacgagcccaagggctaccatgcc960 aacttctgcctcgggccctgcccctacatttggagcctggacacgcagtacagcaaggtc1020 ctggccctgtacaaccagcataacccgggcgcctcggcggcgccgtgctgcgtgccgcag1080 gcgctggagccgctgcccatcgtgtactacgtgggccgcaagcccaaggtggagcagctg1140 tccaacatgatcgtgcgctcctgcaagtgcagctga 1176 4S <210> 47 <211> 1245 <212> DNA
<213> Homo Sapiens SO <300>
<302> TGFbeta2 <310> NM003238 <400> 47 SS atgcactact gtgtgctgag cgcttttctg atcctgcatc tggtcacggt cgcgctcagc 60 ctgtctacct gcagcacact cgatatggac cagttcatgc gcaagaggat cgaggcgatc 120 cgcgggcaga tcctgagcaa gctgaagctc accagtcccc cagaagacta tcctgagccc 180 gaggaagtcc ccccggaggt gatttccatc tacaacagca ccagggactt gctccaggag 240 aaggcgagcc ggagggcggc cgcctgcgag cgcgagagga gcgacgaaga gtactacgcc 300 60 aaggaggttt acaaaataga catgccgccc ttcttcccct ccgaaaatgc catcccgccc 360 \\SERVER\g$\Texte\Anmeldeunterlagen 20031422497-Ribopharma-an-2.doc actttctaca gaccctactt cagaattgtt cgatttgacg tctcagcaat ggagaagaat 420 gcttccaatt tggtgaaagc agagttcaga gtctttcgtt tgcagaaccc aaaagccaga 480 gtgcctgaac aacggattga gctatatcag attctcaagt ccaaagattt aacatctcca 540 acccagcgct acatcgacag caaagttgtg aaaacaagag cagaaggcga atggctctcc 600 S ttcgatgtaa ctgatgctgt tcatgaatgg cttcaccata aagacaggaa cctgggattt 660 aaaataagct tacactgtcc ctgctgcact tttgtaccat ctaataatta catcatccca 720 aataaaagtg aagaactaga agcaagattt gcaggtattg atggcacctc cacatatacc 780 agtggtgatc agaaaactat aaagtccact aggaaaaaaa acagtgggaa gaccccacat 840 ctcctgctaa tgttattgcc ctcctacaga cttgagtcac aacagaccaa ccggcggaag 900 aagcgtgctt tggatgcggc ctattgcttt agaaatgtgc aggataattg ctgcctacgt 960 ccactttaca ttgatttcaa gagggatcta gggtggaaat ggatacacga acccaaaggg 1020 tacaatgcca acttctgtgc tggagcatgc ccgtatttat ggagttcaga cactcagcac 1080 agcagggtcc tgagcttata taataccata aatccagaag catctgcttc tccttgctgc 1140 gtgtcccaag atttagaacc tctaaccatt ctctactaca ttggcaaaac acccaagatt 1200 1S gaacagcttt ctaatatgat tgtaaagtct tgcaaatgca gctaa 1245 <210> 48 <211> 1239 <212> DNA
<213> Homo Sapiens <300>
<302> TGFbeta3 2S <310> XM007417 <400> 48 atgaagatgcacttgcaaagggctctggtggtcctggccctgctgaactttgccacggtc60 agcctctctctgtccacttgcaccaccttggacttcggccacatcaagaagaagagggtg120 gaagccattaggggacagatcttgagcaagctcaggctcaccagcccccctgagccaacg180 gtgatgacccacgtcccctatcaggtcctggccctttacaacagcacccgggagctgctg240 gaggagatgcatggggagagggaggaaggctgcacccaggaaaacaccgagtcggaatac300 tatgccaaagaaatccataaattcgacatgatccaggggctggcggagcacaacgaactg360 gctgtctgccctaaaggaattacctccaaggttttccgcttcaatgtgtcctcagtggag420 3S aaaaatagaaccaacctattccgagcagaattccgggtcttgcgggtgcccaaccccagc480 tctaagcggaatgagcagaggatcgagctcttccagatccttcggccagatgagcacatt540 gccaaacagcgctatatcggtggcaagaatctgcccacacggggcactgccgagtggctg600 tcctttgatgtcactgacactgtgcgtgagtggctgttgagaagagagtccaacttaggt660 ctagaaatcagcattcactgtccatgtcacacctttcagcccaatggagatatcctggaa720 aacattcacgaggtgatggaaatcaaattcaaaggcgtggacaatgaggatgaccatggc780 cgtggagatctggggcgcctcaagaagcagaaggatcaccacaaccctcatctaatcctc840 atgatgattcccccacaccggctcgacaacccgggccaggggggtcagaggaagaagcgg900 gctttggacaccaattactgcttccgcaacttggaggagaactgctgtgtgcgccccctc960 tacattgacttccgacaggatctgggctggaagtgggtccatgaacctaagggctactat1020 4S gccaacttctgctcaggcccttgcccatacctccgcagtgcagacacaacccacagcacg1080 gtgctgggactgtacaacactctgaaccctgaagcatctgcctcgccttgctgcgtgccc1140 caggacctggagcccctgaccatcctgtactatgttgggaggacccccaaagtggagcag1200 ctctccaacatggtggtgaagtcttgtaaatgtagctga 1239 SO
SS
<210> 49 <211> 1704 <212> DNA
<213> Homo Sapiens <300>
<302> TGFbetaR2 <310> XM003094 60 <400> 49 \SERVER\galTextelAnmetdeunterlagen 20031422497-Ribopharn~a-an-2.doc $2 atgggtcgggggctgctcaggggcctgtggccgctgcacatcgtcctgtggacgcgtatc60 gccagcacgatcccaccgcacgttcagaagtcggttaataacgacatgatagtcactgac120 aacaacggtgcagtcaagtttccacaactgtgtaaattttgtgatgtgagattttccacc180 tgtgacaaccagaaatcctgcatgagcaactgcagcatcacctccatctgtgagaagcca240 S caggaagtctgtgtggctgtatggagaaagaatgacgagaacataacactagagacagtt300 tgccatgaccccaagctcccctaccatgactttattctggaagatgctgcttctccaaag360 tgcattatgaaggaaaaaaaaaagcctggtgagactttcttcatgtgttcctgtagctct420 gatgagtgcaatgacaacatcatcttctcagaagaatataacaccagcaatcctgacttg480 ttgctagtcatatttcaagtgacaggcatcagcctcctgccaccactgggagttgccata540 tctgtcatcatcatcttctactgctaccgcgttaaccggcagcagaagctgagttcaacc600 tgggaaaccggcaagacgcggaagctcatggagttcagcgagcactgtgccatcatcctg660 gaagatgaccgctctgacatcagctccacgtgtgccaacaacatcaaccacaacacagag720 ctgctgcccattgagctggacaccctggtggggaaaggtcgctttgctgaggtctataag780 gccaagctgaagcagaacacttcagagcagtttgagacagtggcagtcaagatctttccc840 1S tatgaggagtatgcctcttggaagacagagaaggacatcttctcagacatcaatctgaag900 catgagaacatactccagttcctgacggctgaggagcggaagacggagttggggaaacaa960 tactggctgatcaccgccttccacgccaagggcaacctacaggagtacctgacgcggcat1020 gtcatcagctgggaggacctgcgcaagctgggcagctccctcgcccgggggattgctcac1080 ctccacagtgatcacactccatgtgggaggcccaagatgcccatcgtgcacagggacctc1140 2~ aagagctccaatatcctcgtgaagaacgacctaacctgctgcctgtgtgactttgggctt1200 tccctgcgtctggaccctactctgtctgtggatgacctggctaacagtgggcaggtggga1260 actgcaagatacatggctccagaagtcctagaatccaggatgaatttggagaatgttgag1320 tccttcaagcagaccgatgtctactccatggctctggtgctctgggaaatgacatctcgc1380 tgtaatgcagtgggagaagtaaaagattatgagcctccatttggttccaaggtgcgggag1440 2S cacccctgtgtcgaaagcatgaaggacaacgtgttgagagatcgagggcgaccagaaatt1500 cccagcttctggctcaaccaccagggcatccagatggtgtgtgagacgttgactgagtgc1560 tgggaccacgacccagaggcccgtctcacagcccagtgtgtggcagaacgcttcagtgag1620 ctggagcatctggacaggctctcggggaggagctgctcggaggagaagattcctgaagac1680 ggctccctaaacactaccaaatag 1704 <210> 50 <211> 609 <212> DNA

3S <213> HomoSapiens <300>
<302> TGFbeta3 <310> XM001924 <400> 50 atgtctcatt acaccattat tgagaatatt tgtcctaaag atgaatctgt gaaattctac 60 agtcccaaga gagtgcactt tcctatcccg caagctgaca tggataagaa gcgattcagc 120 tttgtcttca agcctgtctt caacacctca ctgctctttc tacagtgtga gctgacgctg 180 4S tgtacgaaga tggagaagca cccccagaag ttgcctaagt gtgtgcctcc tgacgaagcc 240 tgcacctcgc tggacgcctc gataatctgg gccatgatgc agaataagaa gacgttcact 300 aagccccttg ctgtgatcca ccatgaagca gaatctaaag aaaaaggtcc aagcatgaag 360 gaaccaaatc caatttctcc accaattttc catggtctgg acaccctaac cgtgatgggc 420 attgcgtttg cagcctttgt gatcggagca ctcctgacgg gggccttgtg gtacatctat 480 SO tctcacacag gggagacagc aggaaggcag caagtcccca cctccccgcc agcctcggaa 540 aacagcagtg ctgcccacag catcggcagc acgcagagca cgccttgctc cagcagcagc 600 acggcctag 609 SS <210> 51 <211> 3633 <212> DNA
<213> Homo Sapiens 60 <300>
\\SERVER\g~\TexteWnmeldeunterlagen 2003\422A9'7-Ribopharn~a-an-2.doc <302> EGFR
<310> X00588 <400> 51 $ atgcgaccctccgggacggccggggcagcgctcctggcgctgctggctgcgctctgcccg60 gcgagtcgggctctggaggaaaagaaagtttgccaaggcacgagtaacaagctcacgcag120 ttgggcacttttgaagatcattttctcagcctccagaggatgttcaataactgtgaggtg180 gtccttgggaatttggaaattacctatgtgcagaggaattatgatctttccttcttaaag240 accatccaggaggtggctggttatgtcctcattgccctcaacacagtggagcgaattcct300 1~ ttggaaaacctgcagatcatcagaggaaatatgtactacgaaaattcctatgccttagca360 gtcttatctaactatgatgcaaataaaaccggactgaaggagctgcccatgagaaattta420 caggaaatcctgcatggcgccgtgcggttcagcaacaaccctgccctgtgcaacgtggag480 agcatccagtggcgggacatagtcagcagtgactttctcagcaacatgtcgatggacttc540 cagaaccacctgggcagctgccaaaagtgtgatccaagctgtcccaatgggagctgctgg600 15 ggtgcaggagaggagaactgccagaaactgaccaaaatcatctgtgcccagcagtgctcc660 gggcgctgccgtggcaagtcccccagtgactgctgccacaaccagtgtgctgcaggctgc720 acaggcccccgggagagcgactgcctggtctgccgcaaattccgagacgaagccacgtgc780 aaggacacctgccccccactcatgctctacaaccccaccacgtaccagatggatgtgaac840 cccgagggcaaatacagctttggtgccacctgcgtgaagaagtgtccccgtaattatgtg900 20 gtgacagatcacggctcgtgcgtccgagcctgtggggccgacagctatgagatggaggaa960 gacggcgtccgcaagtgtaagaagtgcgaagggccttgccgcaaagtgtgtaacggaata1020 ggtattggtgaatttaaagactcactctccataaatgctacgaatattaaacacttcaaa1080 aactgcacctccatcagtggcgatctccacatcctgccggtggcatttaggggtgactcc1140 ttcacacatactcctcctctggatccacaggaactggatattctgaaaaccgtaaaggaa1200 2S atcacagggtttttgctgattcaggcttggcctgaaaacaggacggacctccatgccttt1260 gagaacctagaaatcatacgcggcaggaccaagcaacatggtcagttttctcttgcagtc1320 gtcagcctgaacataacatccttgggattacgctccctcaaggagataagtgatggagat1380 gtgataatttcaggaaacaaaaatttgtgctatgcaaatacaataaactggaaaaaactg1440 tttgggacctccggtcagaaaaccaaaattataagcaacagaggtgaaaacagctgcaag1500 30 gccacaggccaggtctgccatgccttgtgctcccccgagggctgctggggcccggagccc1560 agggactgcgtctcttgccggaatgtcagccgaggcagggaatgcgtggacaagtgcaag1620 cttctggagggtgagccaagggagtttgtggagaactctgagtgcatacagtgccaccca1680 gagtgcctgcctcaggccatgaacatcacctgcacaggacggggaccagacaactgtatc1740 cagtgtgcccactacattgacggcccccactgcgtcaagacctgcccggcaggagtcatg1800 35 ggagaaaacaacaccctggtctggaagtacgcagacgccggccatgtgtgccacctgtgc1860 catccaaactgcacctacggatgcactgggccaggtcttgaaggctgtccaacgaatggg1920 cctaagatcccgtccatcgccactgggatggtgggggccctcctcttgctgctggtggtg1980 gccctggggatcggcctcttcatgcgaaggcgccacatcgttcggaagcgcacgctgcgg2040 aggctgctgcaggagagggagcttgtggagcctcttacacccagtggagaagctcccaac2100 40 caagctctcttgaggatcttgaaggaaactgaattcaaaaagatcaaagtgctgggctcc2160 ggtgcgttcggcacggtgtataagggactctggatcccagaaggtgagaaagttaaaatt2220 cccgtcgctatcaaggaattaagagaagcaacatctccgaaagccaacaaggaaatcctc2280 gatgaagcctacgtgatggccagcgtggacaacccccacgtgtgccgcctgctgggcatc2340 tgcctcacctccaccgtgcaactcatcacgcagctcatgcccttcggctgcctcctggac2400 45 tatgtccgggaacacaaagacaatattggctcccagtacctgctcaactggtgtgtgcag2460 atcgcaaagggcatgaactacttggaggaccgtcgcttggtgcaccgcgacctggcagcc2520 aggaacgtactggtgaaaacaccgcagcatgtcaagatcacagattttgggctggccaaa2580 ctgctgggtgcggaagagaaagaataccatgcagaaggaggcaaagtgcctatcaagtgg2640 atggcattggaatcaattttacacagaatctatacccaccagagtgatgtctggagctac2700 $~ ggggtgaccgtttgggagttgatgacctttggatccaagccatatgacggaatccctgcc2760 agcgagatctcctccatcctggagaaaggagaacgcctccctcagccacccatatgtacc2820 atcgatgtctacatgatcatggtcaagtgctggatgatagacgcagatagtcgcccaaag2880 ttccgtgagttgatcatcgaattctccaaaatggcccgagacccccagcgctaccttgtc2940 attcagggggatgaaagaatgcatttgccaagtcctacagactccaacttctaccgtgcc3000 SS ctgatggatgaagaagacatggacgacgtggtggatgccgacgagtacctcatcccacag3060 cagggcttcttcagcagcccctccacgtcacggactcccctcctgagctctctgagtgca3120 accagcaacaattccaccgtggcttgcattgatagaaatgggctgcaaagctgtcccatc3180 aaggaagacagcttcttgcagcgatacagctcagaccccacaggcgccttgactgaggac3240 agcatagacgacaccttcctcccagtgcctgaatacataaaccagtccgttcccaaaagg3300 60 cccgctggctctgtgcagaatcctgtctatcacaatcagcctctgaaccccgcgcccagc3360 \\SERVER\g$\Texte\Anmeldeunterlagen 20034422A97-Ribopharcna-an-2.doc agagacccac actaccagga cccccacagc actgcagtgg gcaaccccga gtatctcaac 3420 actgtccagc ccacctgtgt caacagcaca ttcgacagcc ctgcccactg ggcccagaaa 3480 ggcagccacc aaattagcct ggacaaccct gactaccagc aggacttctt tcccaaggaa 3540 gccaagccaa atggcatctt taagggctcc acagctgaaa atgcagaata cctaagggtc 3600 S gcgccacaaa gcagtgaatt tattggagca tga 3633 <210> 52 <211> 3768 <212> DNA
<213> Homo Sapiens <300>

<302> ERBB2 1S <310> NM004448 <400> 52 atggagctggcggccttgtgccgctgggggctcctcctcgccctcttgccccccggagcc60 gcgagcacccaagtgtgcaccggcacagacatgaagctgcggctccctgccagtcccgag120 acccacctggacatgctccgccacctctaccagggctgccaggtggtgcagggaaacctg180 gaactcacctacctgcccaccaatgccagcctgtccttcctgcaggatatccaggaggtg240 cagggctacgtgctcatcgctcacaaccaagtgaggcaggtcccactgcagaggctgcgg300 attgtgcgaggcacccagctctttgaggacaactatgccctggccgtgctagacaatgga360 gacccgctgaacaataccacccctgtcacaggggcctccccaggaggcctgcgggagctg420 ZS cagcttcgaagcctcacagagatcttgaaaggaggggtcttgatccagcggaacccccag480 ctctgctaccaggacacgattttgtggaaggacatcttccacaagaacaaccagctggct540 ctcacactgatagacaccaaccgctctcgggcctgccacccctgttctccgatgtgtaag600 ggctcccgctgctggggagagagttctgaggattgtcagagcctgacgcgcactgtctgt660 gccggtggctgtgcccgctgcaaggggccactgcccactgactgctgccatgagcagtgt720 gctgccggctgcacgggccccaagcactctgactgcctggcctgcctccacttcaaccac780 agtggcatctgtgagctgcactgcccagccctggtcacctacaacacagacacgtttgag840 tccatgcccaatcccgagggccggtatacattcggcgccagctgtgtgactgcctgtccc900 tacaactacctttctacggacgtgggatcctgcaccctcgtctgccccctgcacaaccaa960 gaggtgacagcagaggatggaacacagcggtgtgagaagtgcagcaagccctgtgcccga1020 3S gtgtgctatggtctgggcatggagcacttgcgagaggtgagggcagttaccagtgccaat1080 atccaggagtttgctggctgcaagaagatctttgggagcctggcatttctgccggagagc1140 tttgatggggacccagcctccaacactgccccgctccagccagagcagctccaagtgttt1200 gagactctggaagagatcacaggttacctatacatctcagcatggccggacagcctgcct1260 gacctcagcgtcttccagaacctgcaagtaatccggggacgaattctgcacaatggcgcc1320 tactcgctgaccctgcaagggctgggcatcagctggctggggctgcgctcactgagggaa1380 ctgggcagtggactggccctcatccaccataacacccacctctgcttcgtgcacacggtg1440 ccctgggaccagctctttcggaacccgcaccaagctctgctccacactgccaaccggcca1500 gaggacgagtgtgtgggcgagggcctggcctgccaccagctgtgcgcccgagggcactgc1560 tggggtccagggcccacccagtgtgtcaactgcagccagttccttcggggccaggagtgc1620 4S gtggaggaatgccgagtactgcaggggctccccagggagtatgtgaatgccaggcactgt1680 ttgccgtgccaccctgagtgtcagccccagaatggctcagtgacctgttttggaccggag1740 gctgaccagtgtgtggcctgtgcccactataaggaccctcccttctgcgtggcccgctgc1800 cccagcggtgtgaaacctgacctctcctacatgcccatctggaagtttccagatgaggag1860 ggcgcatgccagccttgccccatcaactgcacccactcctgtgtggacctggatgacaag1920 SO ggctgccccgccgagcagagagccagccctctgacgtccatcgtctctgcggtggttggc1980 attctgctggtcgtggtcttgggggtggtctttgggatcctcatcaagcgacggcagcag2040 aagatccggaagtacacgatgcggagactgctgcaggaaacggagctggtggagccgctg2100 acacctagcggagcgatgcccaaccaggcgcagatgcggatcctgaaagagacggagctg2160 aggaaggtgaaggtgcttggatctggcgcttttggcacagtctacaagggcatctggatc2220 SS cctgatggggagaatgtgaaaattccagtggccatcaaagtgttgagggaaaacacatcc2280 cccaaagccaacaaagaaatcttagacgaagcatacgtgatggctggtgtgggctcccca2340 tatgtctcccgccttctgggcatctgcctgacatccacggtgcagctggtgacacagctt2400 atgccctatggctgcctcttagaccatgtccgggaaaaccgcggacgcctgggctcccag2460 gacctgctgaactggtgtatgcagattgccaaggggatgagctacctggaggatgtgcgg2520 60 ctcgtacacagggacttggccgctcggaacgtgctggtcaagagtcccaaccatgtcaaa2580 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc g$
attacagacttcgggctggctcggctgctggacattgacgagacagagtaccatgcagat2640 gggggcaaggtgcccatcaagtggatggcgctggagtccattctccgccggcggttcacc2700 caccagagtgatgtgtggagttatggtgtgactgtgtgggagctgatgacttttggggcc2760 aaaccttacgatgggatcccagcccgggagatccctgacctgctggaaaagggggagcgg2820 S ctgccccagccccccatctgcaccattgatgtctacatgatcatggtcaaatgttggatg2880 attgactctgaatgtcggccaagattccgggagttggtgtctgaattctcccgcatggcc2940 agggacccccagcgctttgtggtcatccagaatgaggacttgggcccagccagtcccttg3000 gacagcaccttctaccgctcactgctggaggacgatgacatgggggacctggtggatgct3060 gaggagtatctggtaccccagcagggcttcttctgtccagaccctgccccgggcgctggg3120 ggcatggtccaccacaggcaccgcagctcatctaccaggagtggcggtggggacctgaca3180 ctagggctggagccctctgaagaggaggcccccaggtctccactggcaccctccgaaggg3240 gctggctccgatgtatttgatggtgacctgggaatgggggcagccaaggggctgcaaagc3300 ctccccacacatgaccccagccctctacagcggtacagtgaggaccccacagtacccctg3360 ccctctgagactgatggctacgttgcccccctgacctgcagcccccagcctgaatatgtg3420 1S aaccagccagatgttcggccccagcccccttcgccccgagagggccctctgcctgctgcc3480 cgacctgctggtgccactctggaaagggccaagactctctccccagggaagaatggggtc3540 gtcaaagacgtttttgcctttgggggtgccgtggagaaccccgagtacttgacaccccag3600 ggaggagctgcccctcagccccaccctcctcctgccttcagcccagccttcgacaacctc3660 tattactgggaccaggacccaccagagcggggggctccacccagcaccttcaaagggaca3720 cctacggcagagaacccagagtacctgggtctggacgtgccagtgtga 3768 <210> 53 <211> 1986 Z$ <212> DNA
<213> Homo Sapiens <300>
<302> ERBB3 <310> XM006723 <400> 53 atgcacaacttcagtgttttttccaatttgacaaccattggaggcagaagcctctacaac60 cggggcttctcattgttgatcatgaagaacttgaatgtcacatctctgggcttccgatcc120 ctgaaggaaattagtgctgggcgtatctatataagtgccaataggcagctctgctaccac180 cactctttgaactggaccaaggtgcttcgggggcctacggaagagcgactagacatcaag240 cataatcggccgcgcagagactgcgtggcagagggcaaagtgtgtgacccactgtgctcc300 tctgggggatgctggggcccaggccctggtcagtgcttgtcctgtcgaaattatagccga360 ggaggtgtctgtgtgacccactgcaactttctgaatggggagcctcgagaatttgcccat420 gaggccgaatgcttctcctgccacccggaatgccaacccatggagggcactgccacatgc480 aatggctcgggctctgatacttgtgctcaatgtgcccattttcgagatgggccccactgt540 gtgagcagctgcccccatggagtcctaggtgccaagggcccaatctacaagtacccagat600 gttcagaatgaatgtcggccctgccatgagaactgcacccaggggtgtaaaggaccagag660 cttcaagactgtttaggacaaacactggtgctgatcggcaaaacccatctgacaatggct720 4$ ttgacagtgatagcaggattggtagtgattttcatgatgctgggcggcacttttctctac780 tggcgtgggcgccggattcagaataaaagggctatgaggcgatacttggaacggggtgag840 agcatagagcctctggaccccagtgagaaggctaacaaagtcttggccagaatcttcaaa900 gagacagagctaaggaagcttaaagtgcttggctcgggtgtctttggaactgtgcacaaa960 ggagtgtggatccctgagggtgaatcaatcaagattccagtctgcattaaagtcattgag1020 SO gacaagagtggacggcagagttttcaagctgtgacagatcatatgctggccattggcagc1080 ctggaccatgcccacattgtaaggctgctgggactatgcccagggtcatctctgcagctt1140 gtcactcaatatttgcctctgggttctctgctggatcatgtgagacaacaccggggggca1200 ctggggccacagctgctgctcaactggggagtacaaattgccaagggaatgtactacctt1260 gaggaacatggtatggtgcatagaaacctggctgcccgaaacgtgctactcaagtcaccc1320 $S agtcaggttcaggtggcagattttggtgtggctgacctgctgcctcctgatgataagcag1380 ctgctatacagtgaggccaagactccaattaagtggatggcccttgagagtatccacttt1440 gggaaatacacacaccagagtgatgtctggagctatggtgtgacagtttgggagttgatg1500 accttcggggcagagccctatgcagggctacgattggctgaagtaccagacctgctagag1560 aagggggagcggttggcacagccccagatctgcacaattgatgtctacatggtgatggtc1620 60 aagtgttggatgattgatgagaacattcgcccaacctttaaagaactagccaatgagttc2680 \\SERVER\g$lTexte\Anmeldeunterlagen 2003\422497-Ribophattna-an-2.doc accaggatgg cccgagaccc accacggtat ctggtcataa agagagagag tgggcctgga 1740 atagcccctg ggccagagcc ccatggtctg acaaacaaga agctagagga agtagagctg 1800 gagccagaac tagacctaga cctagacttg gaagcagagg aggacaacct ggcaaccacc 1860 acactgggct ccgccctcag cctaccagtt ggaacactta atcggccacg tgggagccag 1920 S agccttttaa gtccatcatc tggatacatg cccatgaacc agggtaatct tggggttctt 1980 ccttag 1986 <210> 54 <211> 1437 <212> DNA
<213> Homo sapiens <300>
<302> ERBB4 <310> XM002260 <400> 54 atgatgtacctggaagaaagacgactcgttcatcgggatttggcagcccgtaatgtctta60 gtgaaatctccaaaccatgtgaaaatcacagattttgggctagccagactcttggaagga120 gatgaaaaagagtacaatgctgatggaggaaagatgccaattaaatggatggctctggag180 tgtatacattacaggaaattcacccatcagagtgacgtttggagctatggagttactata240 tgggaactgatgacctttggaggaaaaccctatgatggaattccaacgcgagaaatccct300 gatttattagagaaaggagaacgtttgcctcagcctcccatctgcactattgacgtttac360 2S atggtcatggtcaaatgttggatgattgatgctgacagtagacctaaatttaaggaactg420 gctgctgagttttcaaggatggctcgagaccctcaaagatacctagttattcagggtgat480 gatcgtatgaagcttcccagtccaaatgacagcaagttctttcagaatctcttggatgaa540 gaggatttggaagatatgatggatgctgaggagtacttggtccctcaggctttcaacatc600 ccacctcccatctatacttccagagcaagaattgactcgaataggagtgaaattggacac660 agccctcctcctgcctacacccccatgtcaggaaaccagtttgtataccgagatggaggt720 tttgctgctgaacaaggagtgtctgtgccctacagagccccaactagcacaattccagaa780 gctcctgtggcacagggtgctactgctgagatttttgatgactcctgctgtaatggcacc840 ctacgcaagccagtggcaccccatgtccaagaggacagtagcacccagaggtacagtgct900 gaccccaccgtgtttgccccagaacggagcccacgaggagagctggatgaggaaggttac960 3S atgactcctatgcgagacaaacccaaacaagaatacctgaatccagtggaggagaaccct1020 tttgtttctcggagaaaaaatggagaccttcaagcattggataatcccgaatatcacaat1080 gcatccaatggtccacccaaggccgaggatgagtatgtgaatgagccactgtacctcaac1140 acctttgccaacaccttgggaaaagctgagtacctgaagaacaacatactgtcaatgcca1200 gagaaggccaagaaagcgtttgacaaccctgactactggaaccacagcctgccacctcgg1260 agcacccttcagcacccagactacctgcaggagtacagcacaaaatatttttataaacag1320 aatgggcggatccggcctattgtggcagagaatcctgaatacctctctgagttctccctg1380 aagccaggcactgtgctgccgcctccaccttacagacaccggaatactgtggtgtaa 1437 4$ <210> 55 <211> 627 <212> DNA
<213> Homo sapiens <300>
<302> FGF10 <310> NM004465 <400> 55 SS atgtggaaat ggatactgac acattgtgcc tcagcctttc cccacctgcc cggctgctgc 60 tgctgctgct ttttgttgct gttcttggtg tcttccgtcc ctgtcacctg ccaagccctt 120 ggtcaggaca tggtgtcacc agaggccacc aactcttctt cctcctcctt ctcctctcct 180 tccagcgcgg gaaggcatgt gcggagctac aatcaccttc aaggagatgt ccgctggaga 240 aagctattct ctttcaccaa gtactttctc aagattgaga agaacgggaa ggtcagcggg 300 accaagaagg agaactgccc gtacagcatc ctggagataa catcagtaga aatcggagtt 360 \\SERVER\g$\Texte\Anmeldeunterlagen 20034422497-Ribopharma-an-2.doc g7 gttgccgtca aagccattaa cagcaactat tacttagcca tgaacaagaa ggggaaactc 420 tatggctcaa aagaatttaa caatgactgt aagctgaagg agaggataga ggaaaatgga 480 tacaatacct atgcatcatt taactggcag cataatggga ggcaaatgta tgtggcattg 540 aatggaaaag gagctccaag gagaggacag aaaacacgaa ggaaaaacac ctctgctcac 600 S tttcttccaa tggtggtaca ctcatag 627 <210> 56 <211> 679 <212> DNA
<213> Homo Sapiens <300>
<302> FGF11 1S <310> XM008660 <400> 56 aatggcggcg ctggccagta gcctgatccg gcagaagcgg gaggtccgcg agcccggggg 60 cagccggccg gtgtcggcgc agcggcgcgt gtgtccccgc ggcaccaagt ccctttgcca 120 gaagcagctc ctcatcctgc tgtccaaggt gcgactgtgc ggggggcggc ccgcgcggcc 180 ggaccgcggc ccggagcctc agctcaaagg catcgtcacc aaactgttct gccgccaggg 240 tttctacctc caggcgaatc ccgacggaag catccagggc accccagagg ataccagctc 300 cttcacccac ttcaacctga tccctgtggg cctccgtgtg gtcaccatcc agagcgccaa 360 gctgggtcac tacatggcca tgaatgctga gggactgctc tacagttcgc cgcatttcac 420 ZS agctgagtgt cgctttaagg agtgtgtctt tgagaattac tacgtcctgt acgcctctgc 480 tctctaccgc cagcgtcgtt ctggccgggc ctggtacctc ggcctggaca aggagggcca 540 ggtcatgaag ggaaaccgag ttaagaagac caaggcagct gcccactttc tgcccaagct 600 cctggaggtg gccatgtacc aggagccttc tctccacagt gtccccgagg cctccccttc 660 cagtccccct gccccctga 67g <210> 57 <211> 732 <212> DNA
3S <213> Homo Sapiens <300>
<302> FGF12 <310> NM021032 <400> 57 atggctgcgg cgatagccag ctccttgatc cggcagaagc ggcaggcgag ggagtccaac 60 agcgaccgag tgtcggcctc caagcgccgc tccagcccca gcaaagacgg gcgctccctg 120 tgcgagaggc acgtcctcgg ggtgttcagc aaagtgcgct tctgcagcgg ccgcaagagg 180 4S ccggtgaggc ggagaccaga accccagctc aaagggattg tgacaaggtt attcagccag 240 cagggatact tcctgcagat gcacccagat ggtaccattg atgggaccaa ggacgaaaac 300 agcgactaca ctctcttcaa tctaattccc gtgggcctgc gtgtagtggc catccaagga 360 gtgaaggcta gcctctatgt ggccatgaat ggtgaaggct atctctacag ttcagatgtt 420 ttcactccag aatgcaaatt caaggaatct gtgtttgaaa actactatgt gatctattct 480 SO tccacactgt accgccagca agaatcaggc cgagcttggt ttctgggact caataaagaa 540 ggtcaaatta tgaaggggaa cagagtgaag aaaaccaagc cctcatcaca ttttgtaccg 600 aaacctattg aagtgtgtat gtacagagaa ccatcgctac atgaaattgg agaaaaacaa 660 gggcgttcaa ggaaaagttc tggaacacca accatgaatg gaggcaaagt tgtgaatcaa 720 gattcaacat ag SS
<210> 58 <211> 738 <212> DNA
60 <213> Homo Sapiens \\SERVER\g$\Texte\Anmeldeunter(agen 20031422497-Ribopharma-an-2.doc 8g <300>
<302> FGF13 <310> XM010269 <400> S8 atggcggcgg ctatcgccag ctcgctcatc cgtcagaaga ggcaagcccg cgagcgcgag 60 aaatccaacg cctgcaagtg tgtcagcagc cccagcaaag gcaagaccag ctgcgacaaa 120 aacaagttaa atgtcttttc ccgggtcaaa ctcttcggct ccaagaagag gcgcagaaga 180 agaccagagc ctcagcttaa gggtatagtt accaagctat acagccgaca aggctaccac 240 ttgcagctgc aggcggatgg aaccattgat ggcaccaaag atgaggacag cacttacact 300 ctgtttaacc tcatccctgt gggtctgcga gtggtggcta tccaaggagt tcaaaccaag 360 ctgtacttgg caatgaacag tgagggatac ttgtacacct cggaactttt cacacctgag 420 tgcaaattca aagaatcagt gtttgaaaat tattatgtga catattcatc aatgatatac 4$0 cgtcagcagc agtcaggccg agggtggtat ctgggtctga acaaagaagg agagatcatg 540 aaaggcaacc atgtgaagaa gaacaagcct gcagctcatt ttctgcctaa accactgaaa 600 gtggccatgt acaaggagcc atcactgcac gatctcacgg agttctcccg atctggaagc 660 gggaccccaa ccaagagcag aagtgtctct ggcgtgctga acggaggcaa atccatgagc 720 cacaatgaat caacgtag 738 <210> 59 <211> 624 <212> DNA
2S <213> Homo Sapiens <300>
<302> FGF16 <310> NM003868 <400> 59 atggcagagg tggggggcgt cttcgcctcc ttggactggg atctacacgg cttctcctcg 60 tctctgggga acgtgccctt agctgactcc ccaggtttcc tgaacgagcg cctgggccaa 120 atcgagggga agctgcagcg tggctcaccc acagacttcg cccacctgaa ggggatcctg 1$0 3$ cggcgccgcc agctctactg ccgcaccggc ttccacctgg agatcttccc caacggcacg 240 gtgcacggga cccgccacga ccacagccgc ttcggaatcc tggagtttat cagcctggct 300 gtggggctga tcagcatccg gggagtggac tctggcctgt acctaggaat gaatgagcga 360 ggagaactct atgggtcgaa gaaactcaca cgtgaatgtg ttttccggga acagtttgaa 420 gaaaactggt acaacaccta tgcctcaacc ttgtacaaac attcggactc agagagacag 480 tattacgtgg ccctgaacaa agatggctca ccccgggagg gatacaggac taaacgacac 540 cagaaattca ctcacttttt acccaggcct gtagatcctt ctaagttgcc ctccatgtcc 600 agagacctct ttcactatag gtaa 624 <210> 60 <211> 651 <212> DNA
<213> Homo sapiens SO <300>
<302> FGF17 <310> XM005316 <400> 60 SS atgggagccg cccgcctgct gcccaacctc actctgtgct tacagctgct gattctctgc 60 tgtcaaactc agggggagaa tcacccgtct cctaatttta accagtacgt gagggaccag 120 ggcgccatga ccgaccagct gagcaggcgg cagatccgcg agtaccaact ctacagcagg 180 accagtggca agcacgtgca ggtcaccggg cgtcgcatct ccgccaccgc cgaggacggc 240 aacaagtttg ccaagctcat agtggagacg gacacgtttg gcagccgggt tcgcatcaaa 300 60 ggggctgaga gtgagaagta catctgtatg aacaagaggg gcaagctcat cgggaagccc 360 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc agcgggaaga gcaaagactg cgtgttcacg gagatcgtgc tggagaacaa ctatacggcc 420 ttccagaacg cccggcacga gggctggttc atggccttca cgcggcaggg gcggccccgc 480 caggcttccc gcagccgcca gaaccagcgc gaggcccact tcatcaagcg cctctaccaa 540 ggccagctgc ccttccccaa ccacgccgag aagcagaagc agttcgagtt tgtgggctcc 600 S gcccccaccc gccggaccaa gcgcacacgg cggccccagc ccctcacgta g 651 <210> 61 <211> 624 <212> DNA
<213> Homo sapiens <300>
<302> FGF18 1S <310> AF075292 <400> 61 atgtattcag cgccctccgc ctgcacttgc ctgtgtttac acttcctgct gctgtgcttc 60 caggtacagg tgctggttgc cgaggagaac gtggacttcc gcatccacgt ggagaaccag 120 acgcgggctc gggacgatgt gagccgtaag cagctgcggc tgtaccagct ctacagccgg 180 accagtggga aacacatcca ggtcctgggc cgcaggatca gtgcccgcgg cgaggatggg 240 gacaagtatg cccagctcct agtggagaca gacaccttcg gtagtcaagt ccggatcaag 300 ggcaaggaga cggaattcta cctgtgcatg aaccgcaaag gcaagctcgt ggggaagccc 360 gatggcacca gcaaggagtg tgtgttcatc gagaaggttc tggagaacaa ctacacggcc 420 2S ctgatgtcgg ctaagtactc cggctggtac gtgggcttca ccaagaaggg gcggccgcgg 480 aagggcccca agacccggga gaaccagcag gacgtgcatt tcatgaagcg ctaccccaag 540 gggcagccgg agcttcagaa gcccttcaag tacacgacgg tgaccaagag gtcccgtcgg 600 atccggccca cacaccctgc ctag 624 <210> 62 <211> 651 <212> DNA
<213> Homo sapiens <300>
<302> FGF19 <310> AF110400 <400> 62 atgcggagcg ggtgtgtggt ggtccacgta tggatcctgg ccggcctctg gctggccgtg 60 gccgggcgcc ccctcgcctt ctcggacgcg gggccccacg tgcactacgg ctggggcgac 120 cccatccgcc tgcggcacct gtacacctcc ggcccccacg ggctctccag ctgcttcctg 180 cgcatccgtg ccgacggcgt cgtggactgc gcgcggggcc agagcgcgca cagtttgctg 240 4S gagatcaagg cagtcgctct gcggaccgtg gccatcaagg gcgtgcacag cgtgcggtac 300 ctctgcatgg gcgccgacgg caagatgcag gggctgcttc agtactcgga ggaagactgt 360 gctttcgagg aggagatccg cccagatggc tacaatgtgt accgatccga gaagcaccgc 420 ctcccggtct ccctgagcag tgccaaacag cggcagctgt acaagaacag aggctttctt 480 ccactctctc atttcctgcc catgctgccc atggtcccag aggagcctga ggacctcagg 540 SO ggccacttgg aatctgacat gttctcttcg cccctggaga ccgacagcat ggacccattt 600 gggcttgtca ccggactgga ggccgtgagg agtcccagct ttgagaagta a 651 <210> 63 SS <211> 468 <212> DNA
<213> Homo sapiens <400> 63 60 atggctgaag gggaaatcac caccttcaca gccctgaccg agaagtttaa tctgcctcca 60 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc gggaattaca agaagcccaa actcctctac tgtagcaacg ggggccactt cctgaggatc 120 cttccggatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180 ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240 gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300 S ctggaaaggc tggaggagaa ccattacaac acctatatat ccaagaagca tgcagagaag 360 aattggtttg ttggcctcaa gaagaatggg agctgcaaac gcggtcctcg gactcactat 420 ggccagaaag caatcttgtt tctccccctg ccagtctctt ctgattaa 468 10 <210> 64 <211> 636 <212> DNA
<213> Homo sapiens 1S <300>
<302> FGF20 <310> NM019851 <400> 64 20 atggctccct tagccgaagt cgggggcttt ctgggcggcc tggagggctt gggccagcag 60 gtgggttcgc atttcctgtt gcctcctgcc ggggagcggc cgccgctgct gggcgagcgc 120 aggagcgcgg cggagcggag cgcccgcggc gggccggggg ctgcgcagct ggcgcacctg 180 cacggcatcc tgcgccgccg gcagctctat tgccgcaccg gcttccacct gcagatcctg 240 cccgacggca gcgtgcaggg cacccggcag gaccacagcc tcttcggtat cttggaattc 300 ZS atcagtgtgg cagtgggact ggtcagtatt agaggtgtgg acagtggtct ctatcttgga 360 atgaatgaca aaggagaact ctatggatca gagaaactta cttccgaatg catctttagg 420 gagcagtttg aagagaactg gtataacacc tattcatcta acatatataa acatggagac 480 actggccgca ggtattttgt ggcacttaac aaagacggaa ctccaagaga tggcgccagg 540 tccaagaggc atcagaaatt tacacatttc ttacctagac cagtggatcc agaaagagtt 600 30 ccagaattgt acaaggacct actgatgtac acttga 636 <210> 6S

<211> 630 3S <212> DNA

<213> Homosapiens <300>

<302> FGF21 40 <310> XM009100 <400> 65 atggactcggacgagaccgggttcgagcactcaggactgtgggtttctgtgctggctggt60 cttctgctgggagcctgccaggcacaccccatccctgactccagtcctctcctgcaattc120 4S gggggccaagtccggcagcggtacctctacacagatgatgcccagcagacagaagcccac180 ctggagatcagggaggatgggacggtggggggcgctgctgaccagagccccgaaagtctc240 ctgcagctgaaagccttgaagccgggagttattcaaatcttgggagtcaagacatccagg300 ttcctgtgccagcggccagatggggccctgtatggatcgctccactttgaccctgaggcc360 tgcagcttccgggagctgcttcttgaggacggatacaatgtttaccagtccgaagcccac420 SO ggcctcccgctgcacctgccagggaacaagtccccacaccgggaccctgcaccccgagga480 ccagctcgcttcctgccactaccaggcctgccccccgcactcccggagccacccggaatc540 ctggccccccagccccccgatgtgggctcctcggaccctctgagcatggtgggaccttcc600 cagggccgaagccccagctacgcttcctga 630 SS

<210> 66 <211> 5I3 <212> DNA
<213> Homo sapiens \\SERVER\gS\Texte\Anmeldeunterlageu 2003\422497-Ribopharma-an-2.doc <300>
<302> FGF22 <310> XM009271 S <400> 66 atgcgccgcc gcctgtggct gggcctggcc tggctgctgc tggcgcgggc gccggacgcc 60 gcgggaaccc cgagcgcgtc gcggggaccg cgcagctacc cgcacctgga gggcgacgtg 120 cgctggcggc gcctcttctc ctccactcac ttcttcctgc gcgtggatcc cggcggccgc 180 gtgcagggca cccgctggcg ccacggccag gacagcatcc tggagatccg ctctgtacac 240 gtgggcgtcg tggtcatcaa agcagtgtcc tcaggcttct acgtggccat gaaccgccgg 300 ggccgcctct acgggtcgcg actctacacc gtggactgca ggttccggga gcgcatcgaa 360 gagaacggcc acaacaccta cgcctcacag cgctggcgcc gccgcggcca gcccatgttc 420 ctggcgctgg acaggagggg ggggccccgg ccaggcggcc ggacgcggcg gtaccacctg 480 tccgcccact tcctgcccgt cctggtctcc tga 513 <210> 67 <211> 621 <212> DNA
<213> Homo Sapiens <300>
<302> FGF4 <310> NM002007 <400> 67 atgtcggggc ccgggacggc cgcggtagcg ctgctcccgg cggtcctgct ggccttgctg 60 gcgccctggg cgggccgagg gggcgccgcc gcacccactg cacccaacgg cacgctggag 120 gccgagctgg agcgccgctg ggagagcctg gtggcgctct cgttggcgcg cctgccggtg 180 gcagcgcagc ccaaggaggc ggccgtccag agcggcgccg gcgactacct gctgggcatc 240 aagcggctgc ggcggctcta ctgcaacgtg ggcatcggct tccacctcca ggcgctcccc 300 gacggccgca tcggcggcgc gcacgcggac acccgcgaca gcctgctgga gctctcgccc 360 gtggagcggg gcgtggtgag catcttcggc gtggccagcc ggttcttcgt ggccatgagc 420 agcaagggca agctctatgg ctcgcccttc ttcaccgatg agtgcacgtt caaggagatt 480 ctccttccca acaactacaa cgcctacgag tcctacaagt accccggcat gttcatcgcc 540 ctgagcaaga atgggaagac caagaagggg aaccgagtgt cgcccaccat gaaggtcacc 600 cacttcctcc ccaggctgtg a 621 <210> 68 <211> 597 <212> DNA
<213> Homo Sapiens <300>
<302> FGF6 <310> NM020996 <400> 68 $0 atgtcccggg gagcaggacg tctgcagggc acgctgtggg ctctcgtctt cctaggcatc 60 ctagtgggca tggtggtgcc ctcgcctgca ggcacccgtg ccaacaacac gctgctggac 120 tcgaggggct ggggcaccct gctgtccagg tctcgcgcgg ggctagctgg agagattgcc 180 ggggtgaact gggaaagtgg ctatttggtg gggatcaagc ggcagcggag gctctactgc 240 aacgtgggca tcggctttca cctccaggtg ctccccgacg gccggatcag cgggacccac 300 gaggagaacc cctacagcct gctggaaatt tccactgtgg agcgaggcgt ggtgagtctc 360 tttggagtga gaagtgccct cttcgttgcc atgaacagta aaggaagatt gtacgcaacg 420 cccagcttcc aagaagaatg caagttcaga gaaaccctcc tgcccaacaa ttacaatgcc 480 tacgagtcag acttgtacca agggacctac attgccctga gcaaatacgg acgggtaaag 540 cggggcagca aggtgtcccc gatcatgact gtcactcatt tccttcccag gatctaa 597 \\SERVER\g$\Tezte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <210> 69 <211> 150 <212> DNA
S <213> Homo Sapiens <300>
<302> FGF7 <310> XM007559 <400> 69 atgtcttggc aatgcacttc atacacaatg actaatctat actgtgatga tttgactcaa 60 aaggagaaaa gaaattatgt agttttcaat tctgattcct attcaccttt tgtttatgaa 120 tggaaagctt tgtgcaaaat atacatataa 150 <210> 70 <211> 628 <212> DNA
<213> Homo sapiens <300>
<302> FGF9 <310> XM007105 <400> 70 gatggctccc ttaggtgaag ttgggaacta tttcggtgtg caggatgcgg taccgtttgg 60 gaatgtgccc gtgttgccgg tggacagccc ggttttgtta agtgaccacc tgggtcagtc 120 cgaagcaggg gggctcccca ggggacccgc agtcacggac ttggatcatt taaaggggat 180 tctcaggcgg aggcagctat actgcaggac tggatttcac ttagaaatct tccccaatgg 240 tactatccag ggaaccagga aagaccacag ccgatttggc attctggaat ttatcagtat 300 agcagtgggc ctggtcagca ttcgaggcgt ggacagtgga ctctacctcg ggatgaatga 360 gaagggggag ctgtatggat cagaaaaact aacccaagag tgtgtattca gagaacagtt 420 cgaagaaaac tggtataata cgtactcatc aaacctatat aagcacgtgg acactggaag 480 3S gcgatactat gttgcattaa ataaagatgg gaccccgaga gaagggacta ggactaaacg 540 gcaccagaaa ttcacacatt ttttacctag accagtggac cccgacaaag tacctgaact 600 gtataaggat attctaagcc aaagttga 628 <210> 71 <211> 2469 <212> DNA
<213> Homo Sapiens 4S <300>
<302> FGFR1 <310> NM000604 <400> 71 SO atgtggagct ggaagtgcct cctcttctgg gctgtgctgg tcacagccac actctgcacc 60 gctaggccgt ccccgacctt gcctgaacaa gcccagccct ggggagcccc tgtggaagtg 120 gagtccttcc tggtccaccc cggtgacctg ctgcagcttc gctgtcggct gcgggacgat 180 gtgcagagca tcaactggct gcgggacggg gtgcagctgg cggaaagcaa ccgcacccgc 240 atcacagggg aggaggtgga ggtgcaggac tccgtgcccg cagactccgg cctctatgct 300 SS tgcgtaacca gcagcccctc gggcagtgac accacctact tctccgtcaa tgtttcagat 360 gctctcccct cctcggagga tgatgatgat gatgatgact cctcttcaga ggagaaagaa 420 acagataaca ccaaaccaaa ccgtatgccc gtagctccat attggacatc cccagaaaag 480 atggaaaaga aattgcatgc agtgccggct gccaagacag tgaagttcaa atgcccttcc 540 agtgggaccc caaaccccac actgcgctgg ttgaaaaatg gcaaagaatt caaacctgac 600 60 cacagaattg gaggctacaa ggtccgttat gccacctgga gcatcataat ggactctgtg 660 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc gtgccctctgacaagggcaactacacctgcattgtggagaatgagtacggcagcatcaac720 cacacataccagctggatgtcgtggagcggtcccctcaccggcccatcctgcaagcaggg780 ttgcccgccaacaaaacagtggccctgggtagcaacgtggagttcatgtgtaaggtgtac840 agtgacccgcagccgcacatccagtggctaaagcacatcgaggtgaatgggagcaagatt900 S ggcccagacaacctgccttatgtccagatcttgaagactgctggagttaataccaccgac960 aaagagatggaggtgcttcacttaagaaatgtctcctttgaggacgcaggggagtatacg1020 tgcttggcgggtaactctatcggactctcccatcactctgcatggttgaccgttctggaa1080 gccctggaagagaggccggcagtgatgacctcgcccctgtacctggagatcatcatctat1140 tgcacaggggccttcctcatctcctgcatggtggggtcggtcatcgtctacaagatgaag1200 agtggtaccaagaagagtgacttccacagccagatggctgtgcacaagctggccaagagc1260 atccctctgcgcagacaggtaacagtgtctgctgactccagtgcatccatgaactctggg1320 gttcttctggttcggccatcacggctctcctccagtgggactcccatgctagcaggggtc1380 tctgagtatgagcttcccgaagaccctcgctgggagctgcctcgggacagactggtctta1440 ggcaaacccctgggagagggctgctttgggcaggtggtgttggcagaggctatcgggctg1500 1S gacaaggacaaacccaaccgtgtgaccaaagtggctgtgaagatgttgaagtcggacgca1560 acagagaaagacttgtcagacctgatctcagaaatggagatgatgaagatgatcgggaag1620 cataagaatatcatcaacctgctgggggcctgcacgcaggatggtcccttgtatgtcatc1680 gtggagtatgcctccaagggcaacctgcgggagtacctgcaggcccggaggcccccaggg1740 ctggaatactgctacaaccccagccacaacccagaggagcagctctcctccaaggacctg1800 gtgtcctgcgcctaccaggtggcccgaggcatggagtatctggcctccaagaagtgcata1860 caccgagacctggcagccaggaatgtcctggtgacagaggacaatgtgatgaagatagca1920 gactttggcctcgcacgggacattcaccacatcgactactataaaaagacaaccaacggc1980 cgactgcctgtgaagtggatggcacccgaggcattatttgaccggatctacacccaccag2040 agtgatgtgtggtctttcggggtgctcctgtgggagatcttcactctgggcggctcccca2100 2S taccccggtgtgcctgtggaggaacttttcaagctgctgaaggagggtcaccgcatggac2160 aagcccagtaactgcaccaacgagctgtacatgatgatgcgggactgctggcatgcagtg2220 ccctcacagagacccaccttcaagcagctggtggaagacctggaccgcatcgtggccttg2280 acctccaaccaggagtacctggacctgtccatgcccctggaccagtactcccccagcttt2340 cccgacacccggagctctacgtgctcctcaggggaggattccgtcttctctcatgagccg2400 ctgcccgaggagccctgcctgccccgacacccagcccagcttgccaatggcggactcaaa2460 cgccgctga 2469 <210> 72 3S <211> 2409 <212> DNA
<213> Homo Sapiens <300>
<302> FGFR4 <310> XM003910 <400> 72 atgcggctgctgctggccctgttgggggtcctgctgagtgtgcctgggcctccagtcttg60 4S tccctggaggcctctgaggaagtggagcttgagccctgcctggctcccagcctggagcag120 caagagcaggagctgacagtagcccttgggcagcctgtgcggctgtgctgtgggcgggct180 gagcgtggtggccactggtacaaggagggcagtcgcctggcacctgctggccgtgtacgg240 ggctggaggggccgcctagagattgccagcttcctacctgaggatgctggccgctacctc300 tgcctggcacgaggctccatgatcgtcctgcagaatctcaccttgattacaggtgactcc360 SO ttgacctccagcaacgatgatgaggaccccaagtcccatagggacctctcgaataggcac420 agttacccccagcaagcaccctactggacacacccccagcgcatggagaagaaactgcat480 gcagtacctgcggggaacaccgtcaagttccgctgtccagctgcaggcaaccccacgccc540 accatccgctggcttaaggatggacaggcctttcatggggagaaccgcattggaggcatt600 cggctgcgccatcagcactggagtctcgtgatggagagcgtggtgccctcggaccgcggc660 SS acatacacctgcctggtagagaacgctgtgggcagcatccgttataactacctgctagat720 gtgctggagcggtccccgcaccggcccatcctgcaggccgggctcccggccaacaccaca780 gccgtggtgggcagcgacgtggagctgctgtgcaaggtgtacagcgatgcccagccccac840 atccagtggctgaagcacatcgtcatcaacggcagcagcttcggagccgacggtttcccc900 tatgtgcaagtcctaaagactgcagacatcaatagctcagaggtggaggtcctgtacctg960 f)0cggaacgtgtcagccgaggacgcaggcgagtacacctgcctcgcaggcaattccatcggc1020 \\SERVERIg$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc ctctcctaccagtctgcctggctcacggtgctgccagaggaggaccccacatggaccgca1080 gcagcgcccgaggccaggtatacggacatcatcctgtacgcgtcgggctccctggccttg1140 gctgtgctcctgctgctggccaggctgtatcgagggcaggcgctccacggccggcacccc1200 cgcccgcccgccactgtgcagaagctctcccgcttccctctggcccgacagttctccctg1260 S gagtcaggctcttccggcaagtcaagctcatccctggtacgaggcgtgcgtctctcctcc1320 agcggccccgccttgctcgccggcctcgtgagtctagatctacctctcgacccactatgg1380 gagttcccccgggacaggctggtgcttgggaagcccctaggcgagggctgctttggccag1440 gtagtacgtgcagaggcctttggcatggaccctgcccggcctgaccaagccagcactgtg1500 gccgtcaagatgctcaaagacaacgcctctgacaaggacctggccgacctggtctcggag1560 atggaggtgatgaagctgatcggccgacacaagaacatcatcaacctgcttggtgtctgc1620 acccaggaagggcccctgtacgtgatcgtggagtgcgccgccaagggaaacctgcgggag1680 ttcctgcgggcccggcgccccccaggccccgacctcagccccgacggtcctcggagcagt1740 gaggggccgctctccttcccagtcctggtctcctgcgcctaccaggtggcccgaggcatg1800 cagtatctggagtcccggaagtgtatccaccgggacctggctgcccgcaatgtgctggtg1860 1S actgaggacaatgtgatgaagattgctgactttgggctggcccgcggcgtccaccacatt1920 gactactataagaaaaccagcaacggccgcctgcctgtgaagtggatggcgcccgaggcc1980 ttgtttgaccgggtgtacacacaccagagtgacgtgtggtcttttgggatcctgctatgg2040 gagatcttcaccctcgggggctccccgtatcctggcatcccggtggaggagctgttctcg2100 ctgctgcgggagggacatcggatggaccgacccccacactgccccccagagctgtacggg2160 ctgatgcgtgagtgctggcacgcagcgccctcccagaggcctaccttcaagcagctggtg2220 gaggcgctggacaaggtcctgctggccgtctctgaggagtacctcgacctccgcctgacc2280 ttcggaccctattccccctctggtggggacgccagcagcacctgctcctccagcgattct2340 gtcttcagccacgaccccctgccattgggatccagctccttccccttcgggtctggggtg2400 cagacatga 2409 <210> 73 <211> 1695 <212> DNA

<213> Homosapiens <300>
<302> MT2MMP
<310> D86331 <400> 73 atgaagcggccccgctgtggggtgccagaccagttcggggtacgagtgaaagccaacctg60 cggcggcgtcggaagcgctacgccctcaccgggaggaagtggaacaaccaccatctgacc120 tttagcatccagaactacacggagaagttgggctggtaccactcgatggaggcggtgcgc180 agggccttccgcgtgtgggagcaggccacgcccctggtcttccaggaggtgccctatgag240 gacatccggctgcggcgacagaaggaggccgacatcatggtactctttgcctctggcttc300 cacggcgacagctcgccgtttgatggcaccggtggctttctggcccacgcctatttccct360 ggccccggcctaggcggggacacccattttgacgcagatgagccctggaccttctccagc420 actgacctgcatggaaacaacctcttcctggtggcagtgcatgagctgggccacgcgctg480 4S gggctggagcactccagcaaccccaatgccatcatggcgccgttctaccagtggaaggac540 gttgacaacttcaagctgcccgaggacgatctccgtggcatccagcagctctacggtacc600 ccagacggtcagccacagcctacccagcctctccccactgtgacgccacggcggccaggc660 cggcctgaccaccggccgccccggcctccccagccaccacccccaggtgggaagccagag720 cggcccccaaagccgggccccccagtccagccccgagccacagagcggcccgaccagtat780 SO ggccccaacatctgcgacggggactttgacacagtggccatgcttcgcggggagatgttc840 gtgttcaagggccgctggttctggcgagtccggcacaaccgcgtcctggacaactatccc900 atgcccatcgggcacttctggcgtggtctgcccggtgacatcagtgctgcctacgagcgc960 caagacggtcgttttgtctttttcaaaggtgaccgctactggctctttcgagaagcgaac1020 ctggagcccggctacccacagccgctgaccagctatggcctgggcatcccctatgaccgc1080 SS attgacacggccatctggtgggagcccacaggccacaccttcttcttccaagaggacagg1140 tactggcgcttcaacgaggagacacagcgtggagaccctgggtaccccaagcccatcagt1200 gtctggcaggggatccctgcctcccctaaaggggccttcctgagcaatgacgcagcctac1260 acctacttctacaagggcaccaaatactggaaattcgacaatgagcgcctgcggatggag1320 cccggctaccccaagtccatcctgcgggacttcatgggctgccaggagcacgtggagcca1380 60 ggcccccgatggcccgacgtggcccggccgcccttcaacccccacgggggtgcagagccc1440 \\SERVER\g$\TexteWnmeldeunterlagen 2003\422497-Ribopharma-an-2.doc ggggcggaca gcgcagaggg cgacgtgggg gatggggatg gggactttgg ggccggggtc 1500 aacaaggaca ggggcagccg cgtggtggtg cagatggagg aggtggcacg gacggtgaac 1560 gtggtgatgg tgctggtgcc actgctgctg ctgctctgcg tcctgggcct cacctacgcg 1620 ctggtgcaga tgcagcgcaa gggtgcgcca cgtgtcctgc tttactgcaa gcgctcgctg 1680 caggagtggg tctga 1695 <210> 74 <211> 1824 1O <212> DNA
<213> Homo Sapiens <300>
<302> MT3MMP
1S <310> D85511 <400> 74 atgatcttactcacattcagcactggaagacggttggatttcgtgcatcattcgggggtg60 tttttcttgcaaaccttgctttggattttatgtgctacagtctgcggaacggagcagtat120 20 ttcaatgtggaggtttggttacaaaagtacggctaccttccaccgactgaccccagaatg180 tcagtgctgcgctctgcagagaccatgcagtctgccctagctgccatgcagcagttctat240 ggcattaacatgacaggaaaagtggacagaaacacaattgactggatgaagaagccccga300 tgcggtgtacctgaccagacaagaggtagctccaaatttcatattcgtcgaaagcgatat360 gcattgacaggacagaaatggcagcacaagcacatcacttacagtataaagaacgtaact420 2S ccaaaagtaggagaccctgagactcgtaaagctattcgccgtgcctttgatgtgtggcag480 aatgtaactcctctgacatttgaagaagttccctacagtgaattagaaaatggcaaacgt540 gatgtggatataaccattatttttgcatctggtttccatggggacagctctccctttgat600 ggagagggaggatttttggcacatgcctacttccctggaccaggaattggaggagatacc660 cattttgactcagatgagccatggacactaggaaatcctaatcatgatggaaatgactta720 30 tttcttgtagcagtccatgaactgggacatgctctgggattggagcattccaatgacccc780 actgccatcatggctccattttaccagtacatggaaacagacaacttcaaactacctaat840 gatgatttacagggcatccagaagatatatggtccacctgacaagattcctccacctaca900 agacctctaccgacagtgcccccacaccgctctattcctccggctgacccaaggaaaaat960 gacaggccaaaacctcctcggcctccaaccggcagaccctcctatcccggagccaaaccc1020 35 aacatctgtgatgggaactttaacactctagctattcttcgtcgtgagatgtttgttttc1080 aaggaccagtggttttggcgagtgagaaacaacagggtgatggatggatacccaatgcaa1140 attacttacttctggcggggcttgcctcctagtatcgatgcagtttatgaaaatagcgac1200 gggaattttgtgttctttaaaggtaacaaatattgggtgttcaaggatacaactcttcaa1260 cctggttaccctcatgacttgataacccttggaagtggaattccccctcatggtattgat1320 40 tcagccatttggtgggaggacgtcgggaaaacctatttcttcaagggagacagatattgg1380 agatatagtgaagaaatgaaaacaatggaccctggctatcccaagccaatcacagtctgg1440 aaagggatccctgaatctcctcagggagcatttgtacacaaagaaaatggctttacgtat1500 ttctacaaaggaaaggagtattggaaattcaacaaccagatactcaaggtagaacctgga1560 tatccaagatccatcctcaaggattttatgggctgtgatggaccaacagacagagttaaa1620 45 gaaggacacagcccaccagatgatgtagacattgtcatcaaactggacaacacagccagc1680 actgtgaaagccatagctattgtcattccctgcatcttggccttatgcctccttgtattg1740 gtttacactgtgttccagttcaagaggaaaggaacaccccgccacatactgtactgtaaa1800 cgctctatgcaagagtgggtgtga <210> 75 <211> 1818 <212> DNA
<213> Homo Sapiens <300>
<302> MT4MMP
<310> AB021225 <400> 75 \\SERVER\g$\TextelAnmeldeunterlagen 2003\422497-Ribopharma-an-2.doc atgcggcgccgcgcagcccggggacccggcccgccgcccccagggcccggactctcgcgg60 ctgccgctgctgccgctgccgctgctgctgctgctggcgctggggacccgcgggggctgc120 gccgcgccggaacccgcgcggcgcgccgaggacctcagcctgggagtggagtggctaagc180 aggttcggttacctgcccccggctgaccccacaacagggcagctgcagacgcaagaggag240 S ctgtctaaggccatcacagccatgcagcagtttggtggcctggaggccaccggcatcctg300 gacgaggccaccctggccctgatgaaaaccccacgctgctccctgccagacctccctgtc360 ctgacccaggctcgcaggagacgccaggctccagcccccaccaagtggaacaagaggaac420 ctgtcgtggagggtccggacgttcccacgggactcaccactggggcacgacacggtgcgt480 gcactcatgtactacgccctcaaggtctggagcgacattgcgcccctgaacttccacgag540 gtggcgggcagcaccgccgacatccagatcgacttctccaaggccgaccataacgacggc600 taccccttcgacgcccggcggcaccgtgcccacgccttcttccccggccaccaccacacc660 gccgggtacacccactttaacgatgacgaggcctggaccttccgctcctcggatgcccac720 gggatggacctgtttgcagtggctgtccacgagtttggccacgccattgggttaagccat780 gtggccgctgcacactccatcatgcggccgtactaccagggcccggtgggtgacccgctg840 1S cgctacgggctcccctacgaggacaaggtgcgcgtctggcagctgtacggtgtgcgggag900 tctgtgtctcccacggcgcagcccgaggagcctcccctgctgccggagcccccagacaac960 cggtccagcgccccgcccaggaaggacgtgccccacagatgcagcactcactttgacgcg1020 gtggcccagatccggggtgaagctttcttcttcaaaggcaagtacttctggcggctgacg1080 cgggaccggcacctggtgtccctgcagccggcacagatgcaccgcttctggcggggcctg1140 ccgctgcacctggacagcgtggacgccgtgtacgagcgcaccagcgaccacaagatcgtc1200 ttctttaaaggagacaggtactgggtgttcaaggacaataacgtagaggaaggatacccg1260 cgccccgtctccgacttcagcctcccgcctggcggcatcgacgctgccttctcctgggcc1320 cacaatgacaggacttatttctttaaggaccagctgtactggcgctacgatgaccacacg1380 aggcacatggaccccggctaccccgcccagagccccctgtggaggggtgtccccagcacg1440 ZS ctggacgacgccatgcgctggtccgacggtgcctcctacttcttccgtggccaggagtac1500 tggaaagtgctggatggcgagctggaggtggcacccgggtacccacagtccacggcccgg1560 gactggctggtgtgtggagactcacaggccgatggatctgtggctgcgggcgtggacgcg1620 gcagaggggccccgcgcccctccaggacaacatgaccagagccgctcggaggacggttac1680 gaggtctgctcatgcacctctggggcatcctctcccccgggggccccaggcccactggtg1740 gctgccaccatgctgctgctgctgccgccactgtcaccaggcgccctgtggacagcggcc1800 caggccctgacgctatga 1818 <210> 76 3S <211> 2938 <212> DNA
<213> Homo Sapiens <300>
<302> MT5MMP
<310> AB021227 <400> 76 atgccgaggagccggggcggccgcgccgcgccggggccgccgccgccgccgccgccgccg60 4S ggccaggccccgcgctggagccgctggcgggtccctgggcggctgctgctgctgctgctg120 cccgcgctctgctgcctcccgggcgccgcgcgggcggcggcggcggcggcgggggcaggg180 aaccgggcagcggtggcggtggcggtggcgcgggcggacgaggcggaggcgcccttcgcc240 gggcagaactggttaaagtcctatggctatctgcttccctatgactcacgggcatctgcg300 ctgcactcagcgaaggccttgcagtcggcagtctccactatgcagcagttttacgggatc360 SO ccggtcaccggtgtgttggatcagacaacgatcgagtggatgaagaaaccccgatgtggt420 gtccctgatcacccccacttaagccgtaggcggagaaacaagcgctatgccctgactgga480 cagaagtggaggcaaaaacacatcacctacagcattcacaactataccccaaaagtgggt540 gagctagacacgcggaaagctattcgccaggctttcgatgtgtggcagaaggtgacccca600 ctgacctttgaagaggtgccataccatgagatcaaaagtgaccggaaggaggcagacatc660 SS atgatcttttttgcttctggtttccatggcgacagctccccatttgatggagaaggggga720 ttcctggcccatgcctacttccctggcccagggattggaggagacacccactttgactcc780 gatgagccatggacgctaggaaacgccaaccatgacgggaacgacctcttcctggtggct840 gtgcatgagctgggccacgcgctgggactggagcactccagcgaccccagcgccatcatg900 gcgcccttctaccagtacatggagacgcacaacttcaagctgccccaggacgatctccag960 60 ggcatccagaagatctatggacccccagccgagcctctggagcccacaaggccactccct1020 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc acactccccg tccgcaggat ccactcacca tcggagagga aacacgagcg ccagcccagg 1080 ccccctcggc cgcccctcgg ggaccggcca tccacaccag gcaccaaacc caacatctgt 1140 gacggcaact tcaacacagt ggccctcttc cggggcgaga tgtttgtctt taaggatcgc 1200 tggttctggc gtctgcgcaa taaccgagtg caggagggct accccatgca gatcgagcag 1260 S ttctggaagg gcctgcctgc ccgcatcgac gcagcctatg aaagggccga tgggagattt 1320 gtcttcttca aaggtgacaa gtattgggtg tttaaggagg tgacggtgga gcctgggtac 1380 ccccacagcc tgggggagct gggcagctgt ttgccccgtg aaggcattga cacagctctg 1440 cgctgggaac ctgtgggcaa gacctacttt ttcaaaggcg agcggtactg gcgctacagc 1500 gaggagcggc gggccacgga ccctggctac cctaagccca tcaccgtgtg gaagggcatc 1560 ccacaggctc cccaaggagc cttcatcagc aaggaaggat attacaccta tttctacaag 1620 ggccgggact actggaagtt tgacaaccag aaactgagcg tggagccagg ctacccgcgc 1680 aacatcctgc gtgactggat gggctgcaac cagaaggagg tggagcggcg gaaggagcgg 1740 cggctgcccc aggacgacgt ggacatcatg gtgaccatca acgatgtgcc gggctccgtg 1800 aacgccgtgg ccgtggtcat cccctgcatc ctgtccctct gcatcctggt gctggtctac 1860 1S accatcttcc agttcaagaa caagacaggc cctcagcctg tcacctacta taagcggcca 1920 gtccaggaat gggtgtga 1938 <210> 77 <211> 1689 <212> DNA
<213> Homo Sapiens <300>
2S <302> MT6MMP
<320> AJ27137 <400> 77 atgcggctgcggctccggcttctggcgctgctgcttctgctgctggcaccgcccgcgcgc60 gccccgaagccctcggcgcaggacgtgagcctgggcgtggactggctgactcgctatggt120 tacctgccgccaccccaccctgcccaggcccagctgcagagccctgagaagttgcgcgat180 gccatcaaagtcatgcagaggttcgcggggctgccggagaccggccgcatggacccaggg240 acagtggccaccatgcgtaagccccgctgctccctgcctgacgtgctgggggtggcgggg300 ctggtcaggcggcgtcgccggtacgctctgagcggcagcgtgtggaagaagcgaaccctg360 3S acatggagggtacgttccttcccccagagctcccagctgagccaggagaccgtgcgggtc420 ctcatgagctatgccctgatggcctggggcatggagtcaggcctcacatttcatgaggtg480 gattccccccagggccaggagcccgacatcctcatcgactttgcccgcgccttccaccag540 gacagctaccccttcgacgggttggggggcaccctagcccatgccttcttccctggggag600 caccccatctccggggacactcactttgacgatgaggagacctggacttttgggtcaaaa660 gacggcgaggggaccgacctgtttgccgtggctgtccatgagtttggccacgccctgggc720 ctgggccactcctcagcccccaactccattatgaggcccttctaccagggtccggtgggc780 gaccctgacaagtaccgcctgtctcaggatgaccgcgatggcctgcagcaactctatggg840 aaggcgccccaaaccccatatgacaagcccacaaggaaacccctggctcctccgccccag900 cccccggcctcgcccacacacagcccatccttccccatccctgatcgatgtgagggcaat960 4S tttgacgccatcgccaacatccgaggggaaactttcttcttcaaaggcccctggttctgg1020 cgcctccagccctccggacagctggtgtccccgcgacccgcacggctgcaccgcttctgg1080 gaggggctgcccgcccaggtgagggtggtgcaggccgcctatgctcggcaccgagacggc1140 cgaatcctcctctttagcgggccccagttctgggtgttccaggaccggcagctggagggc1200 ggggcgcggccgctcacggagctggggctgcccccgggagaggaggtggacgccgtgttc1260 SO tcgtggccacagaacgggaagacctacctggtccgcggccggcagtactggcgctacgac1320 gaggcggcggcgcgcccggaccccggctaccctcgcgacctgagcctctgggaaggcgcg2380 cccccctcccctgacgatgtcaccgtcagcaacgcaggtgacacctacttcttcaagggc1440 gcccactactggcgcttccccaagaacagcatcaagaccgagccggacgccccccagccc1500 atggggcccaactggctggactgccccgccccgagctctggtccccgcgcccccaggccc1560 SS cccaaagcgacccccgtgtccgaaacctgcgattgtcagtgcgagctcaaccaggccgca1620 ggacgttggcctgctcccatcccgctgctcctcttgcccctgctggtggggggtgtagcc1680 tcccgctga 1689 60 <210> 78 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <211> 1749 <212> DNA
<213> Homo Sapiens S <300>
<302> MTMMP
<310> X90925 <400> 78 atgtctcccgccccaagaccctcccgttgtctcctgctccccctgctcacgctcggcacc60 gcgctcgcctccctcggctcggcccaaagcagcagcttcagccccgaagcctggctacag120 caatatggctacctgcctcccggggacctacgtacccacacacagcgctcaccccagtca180 ctctcagcggccatcgctgccatgcagaagttttacggcttgcaagtaacaggcaaagct240 gatgcagacaccatgaaggccatgaggcgcccccgatgtggtgttccagacaagtttggg300 1S gctgagatcaaggccaatgttcgaaggaagcgctacgccatccagggtctcaaatggcaa360 cataatgaaatcactttctgcatccagaattacacccccaaggtgggcgagtatgccaca420 tacgaggccattcgcaaggcgttccgcgtgtgggagagtgccacaccactgcgcttccgc480 gaggtgccctatgcctacatccgtgagggccatgagaagcaggccgacatcatgatcttc540 tttgccgagggcttccatggcgacagcacgcccttcgatggtgagggcggcttcctggcc600 catgcctacttcccaggccccaacattggaggagacacccactttgactctgccgagcct660 tggactgtcaggaatgaggatctgaatggaaatgacatcttcctggtggctgtgcacgag720 ctgggccatgccctggggctcgagcattccagtgacccctcggccatcatggcacccttt780 taccagtggatggacacggagaattttgtgctgcccgatgatgaccgccggggcatccag840 caactttatgggggtgagtcagggttccccaccaagatgccccctcaacccaggactacc900 ZS tcccggccttctgttcctgataaacccaaaaaccccacctatgggcccaacatctgtgac960 gggaactttgacaccgtggccatgctccgaggggagatgtttgtcttcaaggagcgctgg1020 ttctggcgggtgaggaataaccaagtgatggatggatacccaatgcccattggccagttc1080 tggcggggcctgcctgcgtccatcaacactgcctacgagaggaaggatggcaaattcgtc1140 ttcttcaaaggagacaagcattgggtgtttgatgaggcgtccctggaacctggctacccc1200 aagcacattaaggagctgggccgagggctgcctaccgacaagattgatgctgctctcttc1260 tggatgcccaatggaaagacctacttcttccgtggaaacaagtactaccgtttcaacgaa1320 gagctcagggcagtggatagcgagtaccccaagaacatcaaagtctgggaagggatccct1380 gagtctcccagagggtcattcatgggcagcgatgaagtcttcacttacttctacaagggg1440 aacaaatactggaaattcaacaaccagaagctgaaggtagaaccgggctaccccaagcca1500 3S gccctgagggactggatgggctgcccatcgggaggccggccggatgaggggactgaggag1560 gagacggaggtgatcatcattgaggtggacgaggagggcggcggggcggtgagcgcggct1620 gccgtggtgctgcccgtgctgctgctgctcctggtgctggcggtgggccttgcagtcttc1680 ttcttcagacgccatgggacccccaggcgactgctctactgccagcgttccctgctggac1740 aaggtctga 1749 <210> 79 <211> 744 <212> DNA

4S <213> HomoSapiens <300>
<302> FGF1 <310> XM003647 <400> 79 atggccgcgg ccatcgctag cggcttgatc cgccagaagc ggcaggcgcg ggagcagcac 60 tgggaccggc cgtctgccag caggaggcgg agcagcccca gcaagaaccg cgggctctgc 120 aacggcaacc tggtggatat cttctccaaa gtgcgcatct tcggcctcaa gaagcgcagg 180 SS ttgcggcgcc aagatcccca gctcaagggt atagtgacca ggttatattg caggcaaggc 240 tactacttgc aaatgcaccc cgatggagct ctcgatggaa ccaaggatga cagcactaat 300 tctacactct tcaacctcat accagtggga ctacgtgttg ttgccatcca gggagtgaaa 360 acagggttgt atatagccat gaatggagaa ggttacctct acccatcaga actttttacc 420 cctgaatgca agtttaaaga atctgttttt gaaaattatt atgtaatcta ctcatccatg 480 f)0 ttgtacagac aacaggaatc tggtagagcc tggtttttgg gattaaataa ggaagggcaa 540 \\SERVER\g$\Texte\Anmetdeunterlagen 20034422497-Ribopharma-an-2.doc gctatgaaag ggaacagagt aaagaaaacc aaaccagcag ctcattttct acccaagcca 600 ttggaagttg ccatgtaccg agaaccatct ttgcatgatg ttggggaaac ggtcccgaag 660 cctggggtga cgccaagtaa aagcacaagt gcgtctgcaa taatgaatgg aggcaaacca 720 gtcaacaaga gtaagacaac atag 744 S
<210> 80 <211> 468 <212> DNA
<213> Homo Sapiens <300>
<302> FGF2 <310> NM002006 <400> 80 atggcagccg ggagcatcac cacgctgccc gccttgcccg aggatggcgg cagcggcgcc 60 ttcccgcccg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggcttcttc 120 ctgcgcatcc accccgacgg ccgagttgac ggggtccggg agaagagcga ccctcacatc 180 aagctacaac ttcaagcaga agagagagga gttgtgtcta tcaaaggagt gtgtgctaac 240 cgttacctgg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tacggatgag 300 tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360 accagttggt atgtggcact gaaacgaact gggcagtata aacttggatc caaaacagga 420 cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468 <210> 81 <211> 756 <212> DNA
<213> Homo Sapiens <300>
<302> FGF23 <310> NM020638 <400> 81 atgttggggg cccgcctcag gctctgggtc tgtgccttgt gcagcgtctg cagcatgagc 60 gtcctcagag cctatcccaa tgcctcccca ctgctcggct ccagctgggg tggcctgatc 120 cacctgtaca cagccacagc caggaacagc taccacctgc agatccacaa gaatggccat 180 gtggatggcg caccccatca gaccatctac agtgccctga tgatcagatc agaggatgct 240 ggctttgtgg tgattacagg tgtgatgagc agaagatacc tctgcatgga tttcagaggc 300 aacatttttg gatcacacta tttcgacccg gagaactgca ggttccaaca ccagacgctg 360 gaaaacgggt acgacgtcta ccactctcct cagtatcact tcctggtcag tctgggccgg 420 gcgaagagag ccttcctgcc aggcatgaac ccacccccgt actcccagtt cctgtcccgg 480 4$ aggaacgaga tccccctaat tcacttcaac acccccatac cacggcggca cacccggagc 540 gccgaggacg actcggagcg ggaccccctg aacgtgctga agccccgggc ccggatgacc 600 ccggccccgg cctcctgttc acaggagctc ccgagcgccg aggacaacag cccgatggcc 660 agtgacccat taggggtggt caggggcggt cgagtgaaca cgcacgctgg gggaacgggc 720 ccggaaggct gccgcccctt cgccaagttc atctag 756 <210> 82 <211> 720 <212> DNA
J'S <213> Homo Sapiens <300>
<302> FGF3 <310> NM005247 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribophanna-an-2.doc <400> 82 atgggcctaa tctggctgct actgctcagc ctgctggagc ccggctggcc cgcagcgggc 60 cctggggcgc ggttgcggcg cgatgcgggc ggccgtggcg gcgtctacga gcaccttggc 120 ggggcgcccc ggcgccgcaa gctctactgc gccacgaagt accacctcca gctgcacccg 180 $ agcggccgcg tcaacggcag cctggagaac agcgcctaca gtattttgga gataacggca 240 gtggaggtgg gcattgtggc catcaggggt ctcttctccg ggcggtacct ggccatgaac 300 aagaggggac gactctatgc ttcggagcac tacagcgccg agtgcgagtt tgtggagcgg 360 atccacgagc tgggctataa tacgtatgcc tcccggctgt accggacggt gtctagtacg 420 cctggggccc gccggcagcc cagcgccgag agactgtggt acgtgtctgt gaacggcaag 480 ggccggcccc gcaggggctt caagacccgc cgcacacaga agtcctccct gttcctgccc 540 cgcgtgctgg accacaggga ccacgagatg gtgcggcagc tacagagtgg gctgcccaga 600 ccccctggta agggggtcca gccccgacgg cggcggcaga agcagagccc ggataacctg 660 gagccctctc acgttcaggc ttcgagactg ggctcccagc tggaggccag tgcgcactag 720 <210> 83 <211> 807 <212> DNA
<213> Homo sapiens <300>
<302> FGFS
<310> NM004464 2$ <400> 83 atgagcttgtccttcctcctcctcctcttcttcagccacctgatcctcagcgcctgggct60 cacggggagaagcgtctcgcccccaaagggcaacccggacccgctgccactgataggaac120 cctataggctccagcagcagacagagcagcagtagcgctatgtcttcctcttctgcctcc180 tcctcccccgcagcttctctgggcagccaaggaagtggcttggagcagagcagtttccag240 30 tggagcccctcggggcgccggaccggcagcctctactgcagagtgggcatcggtttccat300 ctgcagatctacccggatggcaaagtcaatggatcccacgaagccaatatgttaagtgtt360 ttggaaatatttgctgtgtctcaggggattgtaggaatacgaggagttttcagcaacaaa420 tttttagcgatgtcaaaaaaaggaaaactccatgcaagtgccaagttcacagatgactgc480 aagttcagggagcgttttcaagaaaatagctataatacctatgcctcagcaatacataga540 3S actgaaaaaacagggcgggagtggtatgttgccctgaataaaagaggaaaagccaaacga600 gggtgcagcccccgggttaaaccccagcatatctctacccattttcttccaagattcaag660 cagtcggagcagccagaactttctttcacggttactgttcctgaaaagaaaaatccacct720 agccctatcaagtcaaagattcccctttctgcacctcggaaaaataccaactcagtgaaa780 tacagactcaagtttcgctttggataa g07 <210> 84 <211> 649 <212> DNA

45 <213> Homosapiens <300>
<302> FGF8 <320> NM006129 <400> 84 atgggcagcc cccgctccgc gctgagctgc ctgctgttgc acttgctggt cctctgcctc 60 caagcccagg taactgttca gtcctcacct aattttacac agcatgtgag ggagcagagc 120 ctggtgacgg atcagctcag ccgccgcctc atccggacct accaactcta cagccgcacc 180 SS agcgggaagc acgtgcaggt cctggccaac aagcgcatca acgccatggc agaggacggc 240 gaccccttcg caaagctcat cgtggagacg gacacctttg gaagcagagt tcgagtccga 300 ggagccgaga cgggcctcta catctgcatg aacaagaagg ggaagctgat cgccaagagc 360 aacggcaaag gcaaggactg cgtcttcacg gagattgtgc tggagaacaa ctacacagcg 420 ctgcagaatg ccaagtacga gggctggtac atggccttca cccgcaaggg ccggccccgc 480 aagggctcca agacgcggca gcaccagcgt gaggtccact tcatgaagcg gctgccccgg 540 \\SERVER\g$\Texte\Anmeldeunterlagen 20034122497-Ribopharma-an-2.doc ggccaccaca ccaccgagca gagcctgcgc ttcgagttcc tcaactaccc gcccttcacg 600 cgcagcctgc gcggcagcca gaggacttgg gccccggaac cccgatagg 649 S <210> 85 <211> 2466 <212> DNA
<213> Homo Sapiens 1~ <300>
<302> FGFR2 <310> NM000141 <400> 85 1S atggtcagctggggtcgtttcatctgcctggtcgtggtcaccatggcaaccttgtccctg60 gcccggccctccttcagtttagttgaggataccacattagagccagaagagccaccaacc120 aaataccaaatctctcaaccagaagtgtacgtggctgcgccaggggagtcgctagaggtg180 cgctgcctgttgaaagatgccgccgtgatcagttggactaaggatggggtgcacttgggg240 cccaacaataggacagtgcttattggggagtacttgcagataaagggcgccacgcctaga300 20 gactccggcctctatgcttgtactgccagtaggactgtagacagtgaaacttggtacttc360 atggtgaatgtcacagatgccatctcatccggagatgatgaggatgacaccgatggtgcg420 gaagattttgtcagtgagaacagtaacaacaagagagcaccatactggaccaacacagaa480 aagatggaaaagcggctccatgctgtgcctgcggccaacactgtcaagtttcgctgccca540 gccggggggaacccaatgccaaccatgcggtggctgaaaaacgggaaggagtttaagcag600 2S gagcatcgcattggaggctacaaggtacgaaaccagcactggagcctcattatggaaagt660 gtggtcccatctgacaagggaaattatacctgtgtggtggagaatgaatacgggtccatc720 aatcacacgtaccacctggatgttgtggagcgatcgcctcaccggcccatcctccaagcc780 ggactgccggcaaatgcctccacagtggtcggaggagacgtagagtttgtctgcaaggtt840 tacagtgatgcccagccccacatccagtggatcaagcacgtggaaaagaacggcagtaaa900 3~ tacgggcccgacgggctgccctacctcaaggttctcaaggccgccggtgttaacaccacg960 gacaaagagattgaggttctctatattcggaatgtaacttttgaggacgctggggaatat1020 acgtgcttggcgggtaattctattgggatatcctttcactctgcatggttgacagttctg1080 ccagcgcctggaagagaaaaggagattacagcttccccagactacctggagatagccatt1140 tactgcataggggtcttcttaatcgcctgtatggtggtaacagtcatcctgtgccgaatg1200 3S aagaacacgaccaagaagccagacttcagcagccagccggctgtgcacaagctgaccaaa1260 cgtatccccctgcggagacaggtaacagtttcggctgagtccagctcctccatgaactcc1320 aacaccccgctggtgaggataacaacacgcctctcttcaacggcagacacccccatgctg1380 gcaggggtctccgagtatgaacttccagaggacccaaaatgggagtttccaagagataag1440 ctgacactgggcaagcccctgggagaaggttgctttgggcaagtggtcatggcggaagca1500 4~ gtgggaattgacaaagacaagcccaaggaggcggtcaccgtggccgtgaagatgttgaaa1560 gatgatgccacagagaaagacctttctgatctggtgtcagagatggagatgatgaagatg1620 attgggaaacacaagaatatcataaatcttcttggagcctgcacacaggatgggcctctc1680 tatgtcatagttgagtatgcctctaaaggcaacctccgagaatacctccgagcccggagg1740 ccacccgggatggagtactcctatgacattaaccgtgttcctgaggagcagatgaccttc1800 4S aaggacttggtgtcatgcacctaccagctggccagaggcatggagtacttggcttcccaa1860 aaatgtattcatcgagatttagcagccagaaatgttttggtaacagaaaacaatgtgatg1920 aaaatagcagactttggactcgccagagatatcaacaatatagactattacaaaaagacc1980 accaatgggcggcttccagtcaagtggatggctccagaagccctgtttgatagagtatac2040 actcatcagagtgatgtctggtccttcggggtgttaatgtgggagatcttcactttaggg2100 SO ggctcgccctacccagggattcccgtggaggaactttttaagctgctgaaggaaggacac2160 agaatggataagccagccaactgcaccaacgaactgtacatgatgatgagggactgttgg2220 catgcagtgccctcccagagaccaacgttcaagcagttggtagaagacttggatcgaatt2280 ctcactctcacaaccaatgaggaatacttggacctcagccaacctctcgaacagtattca2340 cctagttaccctgacacaagaagttcttgttcttcaggagatgattctgttttttctcca2400 SS gaccccatgccttacgaaccatgccttcctcagtatccacacataaacggcagtgttaaa2460 acatga 2466 <210> 86 6U <211> 2421 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422A97-Ribopharma-an-2.doc <212> DNA
<213> Homo sapiens <300>
S <302> FGFR3 <310> NM000142 <400> 86 atgggcgcccctgcctgcgccctcgcgctctgcgtggccgtggccatcgtggccggcgcc60 tcctcggagtccttggggacggagcagcgcgtcgtggggcgagcggcagaagtcccgggc120 ccagagcccggccagcaggagcagttggtcttcggcagcggggatgctgtggagctgagc180 tgtcccccgcccgggggtggtcccatggggcccactgtctgggtcaaggatggcacaggg240 ctggtgccctcggagcgtgtcctggtggggccccagcggctgcaggtgctgaatgcctcc300 cacgaggactccggggcctacagctgccggcagcggctcacgcagcgcgtactgtgccac360 1S ttcagtgtgcgggtgacagacgctccatcctcgggagatgacgaagacggggaggacgag420 gctgaggacacaggtgtggacacaggggccccttactggacacggcccgagcggatggac480 aagaagctgctggccgtgccggccgccaacaccgtccgcttccgctgcccagccgctggc540 aaccccactccctccatctcctggctgaagaacggcagggagttccgcggcgagcaccgc600 attggaggcatcaagctgcggcatcagcagtggagcctggtcatggaaagcgtggtgccc660 tcggaccgcggcaactacacctgcgtcgtggagaacaagtttggcagcatccggcagacg720 tacacgctggacgtgctggagcgctccccgcaccggcccatcctgcaggcggggctgccg780 gccaaccagacggcggtgctgggcagcgacgtggagttccactgcaaggtgtacagtgac840 gcacagccccacatccagtggctcaagcacgtggaggtgaacggcagcaaggtgggcccg900 gacggcacaccctacgttaccgtgctcaagacggcgggcgctaacaccaccgacaaggag960 2S ctagaggttctctccttgcacaacgtcacctttgaggacgccggggagtacacctgcctg1020 gcgggcaattctattgggttttctcatcactctgcgtggctggtggtgctgccagccgag1080 gaggagctggtggaggctgacgaggcgggcagtgtgtatgcaggcatcctcagctacggg1140 gtgggcttcttcctgttcatcctggtggtggcggctgtgacgctctgccgcctgcgcagc1200 ccccccaagaaaggcctgggctcccccaccgtgcacaagatctcccgcttcccgctcaag1260 cgacaggtgtccctggagtccaacgcgtccatgagctccaacacaccactggtgcgcatc1320 gcaaggctgtcctcaggggagggccccacgctggccaatgtctccgagctcgagctgcct1380 gccgaccccaaatgggagctgtctcgggcccggctgaccctgggcaagccccttggggag1440 ggctgcttcggccaggtggtcatggcggaggccatcggcattgacaaggaccgggccgcc1500 aagcctgtcaccgtagccgtgaagatgctgaaagacgatgccactgacaaggacctgtcg1560 3S gacctggtgtctgagatggagatgatgaagatgatcgggaaacacaaaaacatcatcaac1620 ctgctgggcgcctgcacgcagggcgggcccctgtacgtgctggtggagtacgcggccaag1680 ggtaacctgcgggagtttctgcgggcgcggcggcccccgggcctggactactccttcgac1740 acctgcaagccgcccgaggagcagctcaccttcaaggacctggtgtcctgtgcctaccag1800 gtggcccggggcatggagtacttggcctcccagaagtgcatccacagggacctggctgcc1860 cgcaatgtgctggtgaccgaggacaacgtgatgaagatcgcagacttcgggctggcccgg1920 gacgtgcacaacctcgactactacaagaagacaaccaacggccggctgcccgtgaagtgg1980 atggcgcctgaggccttgtttgaccgagtctacactcaccagagtgacgtctggtccttt2040 ggggtcctgctctgggagatcttcacgctggggggctccccgtaccccggcatccctgtg2100 gaggagctcttcaagctgctgaaggagggccaccgcatggacaagcccgccaactgcaca2160 4S cacgacctgtacatgatcatgcgggagtgctggcatgccgcgccctcccagaggcccacc2220 ttcaagcagctggtggaggacctggaccgtgtccttaccgtgacgtccaccgacgagtac2280 ctggacctgtcggcgcctttcgagcagtactccccgggtggccaggacacccccagctcc2340 agctcctcaggggacgactccgtgtttgcccacgacctgctgcccccggccccacccagc2400 agtgggggctcgcggacgtga 2421 SO

<210> 87 <211> 2102 <212> DNA

SS <213> Homosapiens <300>
<302> HGF
<310> E08541 \\,SERVER\g$\Texte\Anmeldeunterlagen 2003142?A97-Ribopharma-an-2.doc <400> 87 atgcagagggacaaaggaaaagaagaaatacaattcatgaattcaaaaaatcagcaaaga60 ctaccctaatcaaaatagatccagcactgaagataaaaaccaaaaaagtgaatactgcag120 accaatgtgctaatagatgtactaggaataaaggacttccattcacttgcaaggcttttg180 S tttttgataaagcaagaaaacaatgcctctggttccccttcaatagcatgtcaagtggag240 tgaaaaaagaatttggccatgaatttgacctctatgaaaacaaagactacattagaaact300 gcatcattggtaaaggacgcagctacaagggaacagtatctatcactaagagtggcatca360 aatgtcagccctggagttccatgataccacacgaacacagctttttgccttcgagctatc420 ggggtaaagacctacaggaaaactactgtcgaaatcctcgaggggaagaagggggaccct480 ggtgtttcacaagcaatccagaggtacgctacgaagtctgtgacattcctcagtgttcag540 aagttgaatgcatgacctgcaatggggagagttatcgaggtctcatggatcatacagaat600 caggcaagatttgtcagcgctgggatcatcagacaccacaccggcacaaattcttgcctg660 aaagatatcccgacaagggctttgatgataattattgccgcaatcccgatggccagccga720 ggccatggtgctatactcttgaccctcacacccgctgggagtactgtgcaattaaaacat780 1S gcgctgacaatactatgaatgacactgatgttcctttggaaacaactgaatgcatccaag840 gtcaaggagaaggctacaggggcactgtcaataccatttggaatggaattccatgtcagc900 gttgggattctcagtatcctcacgagcatgacatgactcctgaaaatttcaagtgcaagg960 acctacgagaaaattactgccgaaatccagatgggtctgaatcaccctggtgttttacca1020 ctgatccaaacatccgagttggctactgctcccaaattccaaactgtgatatgtcacatg1080 gacaagattgttatcgtgggaatggcaaaaattatatgggcaacttatcccaaacaagat1140 ctggactaacatgttcaatgtgggacaagaacatggaagacttacatcgtcatatcttct1200 gggaaccagatgcaagtaagctgaatgagaattactgccgaaatccagatgatgatgctc1260 atggaccctggtgctacacgggaaatccactcattccttgggattattgccctatttctc1320 gttgtgaaggtgataccacacctacaatagtcaatttagaccatcccgtaatatcttgtg1380 ZS ccaaaaggaaacaattgcgagttgtaaatgggattccaacacgaacaaacataggatgga1440 tggttagtttgagatacagaaataaacatatctgcggaggatcattgataaaggagagtt1500 gggttcttactgcacgacagtgtttcccttctcgagacttgaaagattatgaagcttggc1560 ttggaattcatgatgtccacggaagaggagatgagaaatgcaaacaggttctcaatgttt1620 cccagctggtatatggccctgaaggatcagatctggttttaatgaagcttgccaggcctg1680 ctgtcctggatgattttgttagtacgattgatttacctaattatggatgcacaattcctg1740 aaaagaccagttgcagtgtttatggctggggctacactggattgatcaactatgatggcc1800 tattacgagtggcacatctctatataatgggaaatgagaaatgcagccagcatcatcgag1860 ggaaggtgactctgaatgagtctgaaatatgtgctggggctgaaaagattggatcaggac1920 catgtgagggggattatggtggcccacttgtttgtgagcaacataaaatgagaatggttc1980 3S ttggtgtcattgttcctggtcgtggatgtgccattccaaatcgtcctggtatttttgtcc2040 gagtagcatattatgcaaaatggatacacaaaattattttaacatataaggtaccacagt2100 ca 2102 <210> 88 <211> 360 <212> DNA
<213> Homo Sapiens 4S <300>
<302> ID3 <310> XM001539 <400> 88 SO atgaaggcgc tgagcccggt gcgcggctgc tacgaggcgg tgtgctgcct gtcggaacgc 60 agtctggcca tcgcccgggg ccgagggaag ggcccggcag ctgaggagcc gctgagcttg 120 ctggacgaca tgaaccactg ctactcccgc ctgcgggaac tggtacccgg agtcccgaga 180 ggcactcagc ttagccaggt ggaaatccta cagcgcgtca tcgactacat tctcgacctg 240 caggtagtcc tggccgagcc agcccctgga ccccctgatg gcccccacct tcccatccag 300 SS acagccgagc tcactccgga acttgtcatc tccaacgaca aaaggagctt ttgccactga 360 <210> 89 <211> 743 f)0 < 212 > DNA
\\SERVER\g$\Texte\Anmetdeunterlagen 20034122497-Ribopharma-an-2.doc <213> Homo sapiens <300>
<302> IGF2 S <310> NM000612 <400> 89 atgggaatcc caatggggaa gtcgatgctg gtgcttctca ccttcttggc cttcgcctcg 60 tgctgcattg ctgcttaccg ccccagtgag accctgtgcg gcggggagct ggtggacacc 120 ctccagttcg tctgtgggga ccgcggcttc tacttcagca ggcccgcaag ccgtgtgagc 180 cgtcgcagcc gtggcatcgt tgaggagtgc tgtttccgca gctgtgacct ggccctcctg 240 gagacgtact gtgctacccc cgccaagtcc gagagggacg tgtcgacccc tccgaccgtg 300 cttccggaca acttccccag ataccccgtg ggcaagttct tccaatatga cacctggaag 360 cagtccaccc agcgcctgcg caggggcctg cctgccctcc tgcgtgcccg ccggggtcac 420 1S gtgctcgcca aggagctcga ggcgttcagg gaggccaaac gtcaccgtcc cctgattgct 480 ctacccaccc aagaccccgc ccacgggggc gcccccccag agatggccag caatcggaag 540 tgagcaaaac tgccgcaagt ctgcagcccg gcgccaccat cctgcagcct cctcctgacc 600 acggacgttt ccatcaggtt ccatcccgaa aatctctcgg ttccacgtcc ccctggggct 660 tctcctgacc cagtccccgt gccccgcctc cccgaaacag gctactctcc tcggccccct 720 ccatcgggct gaggaagcac agc 743 <210> 90 <211> 7476 2S <212> DNA
<213> Homo sapiens <300>

<302> IGF2R

<310> NM000876 <400> 90 atgggggccgccgccggccggagcccccacctggggcccgcgcccgcccgccgcccgcag60 cgctctctgctcctgctgcagctgctgctgctcgtcgctgccccggggtccacgcaggcc120 3S caggccgccccgttccccgagctgtgcagttatacatgggaagctgttgataccaaaaat180 aatgtactttataaaatcaacatctgtggaagtgtggatattgtccagtgcgggccatca240 agtgctgtttgtatgcacgacttgaagacacgcacttatcattcagtgggtgactctgtt300 ttgagaagtgcaaccagatctctcctggaattcaacacaacagtgagctgtgaccagcaa360 ggcacaaatcacagagtccagagcagcattgccttcctgtgtgggaaaaccctgggaact420 cctgaatttgtaactgcaacagaatgtgtgcactactttgagtggaggaccactgcagcc480 tgcaagaaagacatatttaaagcaaataaggaggtgccatgctatgtgtttgatgaagag540 ttgaggaagcatgatctcaatcctctgatcaagcttagtggtgcctacttggtggatgac600 tccgatccggacacttctctattcatcaatgtttgtagagacatagacacactacgagac660 ccaggttcacagctgcgggcctgtccccccggcactgccgcctgcctggtaagaggacac720 4S caggcgtttgatgttggccagccccgggacggactgaagctggtgcgcaaggacaggctt780 gtcctgagttacgtgagggaagaggcaggaaagctagacttttgtgatggtcacagccct840 gcggtgactattacatttgtttgcccgtcggagcggagagagggcaccattcccaaactc900 acagctaaatccaactgccgctatgaaattgagtggattactgagtatgcctgccacaga960 gattacctggaaagtaaaacttgttctctgagcggcgagcagcaggatgtctccatagac1020 SO ctcacaccacttgcccagagcggaggttcatcctatatttcagatggaaaagaatatttg1080 ttttatttgaatgtctgtggagaaactgaaatacagttctgtaataaaaaacaagctgca1140 gtttgccaagtgaaaaagagcgatacctctcaagtcaaagcagcaggaagataccacaat1200 cagaccctccgatattcggatggagacctcaccttgatatattttggaggtgatgaatgc1260 agctcagggtttcagcggatgagcgtcataaactttgagtgcaataaaaccgcaggtaac1320 SS gatgggaaaggaactcctgtattcacaggggaggttgactgcacctacttcttcacatgg1380 gacacggaatacgcctgtgttaaggagaaggaagacctcctctgcggtgccaccgacggg1440 aagaagcgctatgacctgtccgcgctggtccgccatgcagaaccagagcagaattgggaa1500 gctgtggatggcagtcagacggaaacagagaagaagcattttttcattaatatttgtcac1560 agagtgctgcaggaaggcaaggcacgagggtgtcccgaggacgcggcagtgtgtgcagtg1620 60 gataaaaatggaagtaaaaatctgggaaaatttatttcctctcccatgaaagagaaagga1680 \\SERVER\g$\Texte\Anmetdeunterlagen 2003\42249-Ribopharma-an-2.doc aacattcaactctcttattcagatggtgatgattgtggtcatggcaagaaaattaaaact1740 aatatcacacttgtatgcaagccaggtgatctggaaagtgcaccagtgttgagaacttct1800 ggggaaggcggttgcttttatgagtttgagtggcgcacagctgcggcctgtgtgctgtct1860 aagacagaaggggagaactgcacggtctttgactcccaggcagggttttcttttgactta1920 S tcacctctcacaaagaaaaatggtgcctataaagttgagacaaagaagtatgacttttat1980 ataaatgtgtgtggcccggtgtctgtgagcccctgtcagccagactcaggagcctgccag2040 gtggcaaaaagtgatgagaagacttggaacttgggtctgagtaatgcgaagctttcatat2100 tatgatgggatgatccaactgaactacagaggcggcacaccctataacaatgaaagacac2160 acaccgagagctacgctcatcacctttctctgtgatcgagacgcgggagtgggcttccct2220 gaatatcaggaagaggataactccacctacaacttccggtggtacaccagctatgcctgc2280 ccggaggagcccctggaatgcgtagtgaccgacccctccacgctggagcagtacgacctc2340 tccagtctggcaaaatctgaaggtggccttggaggaaactggtatgccatggacaactca2400 ggggaacatgtcacgtggaggaaatactacattaacgtgtgtcggcctctgaatccagtg2460 ccgggctgcaaccgatatgcatcggcttgccagatgaagtatgaaaaagatcagggctcc2520 1S ttcactgaagtggtttccatcagtaacttgggaatggcaaagaccggcccggtggttgag2580 gacagcggcagcctccttctggaatacgtgaatgggtcggcctgcaccaccagcgatggc2640 agacagaccacatataccacgaggatccatctcgtctgctccaggggcaggctgaacagc2700 caccccatcttttctctcaactgggagtgtgtggtcagtttcctgtggaacacagaggct2760 gcctgtcccattcagacaacgacggatacagaccaggcttgctctataagggatcccaac2820 agtggatttgtgtttaatcttaatccgctaaacagttcgcaaggatataacgtctctggc2880 attgggaagatttttatgtttaatgtctgcggcacaatgcctgtctgtgggaccatcctg2940 ggaaaacctgcttctggctgtgaggcagaaacccaaactgaagagctcaagaattggaag3000 ccagcaaggccagtcggaattgagaaaagcctccagctgtccacagagggcttcatcact3060 ctgacctacaaagggcctctctctgccaaaggtaccgctgatgcttttatcgtccgcttt3120 2S gtttgcaatgatgatgtttactcagggcccctcaaattcctgcatcaagatatcgactct3180 gggcaagggatccgaaacacttactttgagtttgaaaccgcgttggcctgtgttccttct3240 ccagtggactgccaagtcaccgacctggctggaaatgagtacgacctgactggcctaagc3300 acagtcaggaaaccttggacggctgttgacacctctgtcgatgggagaaagaggactttc3360 tatttgagcgtttgcaatcctctcccttacattcctggatgccagggcagcgcagtgggg3420 tcttgcttagtgtcagaaggcaatagctggaatctgggtgtggtgcagatgagtccccaa3480 gccgcggcgaatggatctttgagcatcatgtatgtcaacggtgacaagtgtgggaaccag3540 cgcttctccaccaggatcacgtttgagtgtgctcagatatcgggctcaccagcatttcag3600 cttcaggatggttgtgagtacgtgtttatctggagaactgtggaagcctgtcccgttgtc3660 agagtggaaggggacaactgtgaggtgaaagacccaaggcatggcaacttgtatgacctg3720 3S aagcccctgggcctcaacgacaccatcgtgagcgctggcgaatacacttattacttccgg3780 gtctgtgggaagctttcctcagacgtctgccccacaagtgacaagtccaaggtggtctcc3840 tcatgtcaggaaaagcgggaaccgcagggatttcacaaagtggcaggtctcctgactcag3900 aagctaacttatgaaaatggcttgttaaaaatgaacttcacggggggggacacttgccat3960 aaggtttatcagcgctccacagccatcttcttctactgtgaccgcggcacccagcggcca4020 gtatttctaaaggagacttcagattgttcctacttgtttgagtggcgaacgcagtatgcc4080 tgcccacctttcgatctgactgaatgttcattcaaagatggggctggcaactccttcgac4140 ctctcgtccctgtcaaggtacagtgacaactgggaagccatcactgggacgggggacccg4200 gagcactacctcatcaatgtctgcaagtctctggccccgcaggctggcactgagccgtgc4260 cctccagaagcagccgcgtgtctgctgggtggctccaagcccgtgaacctcggcagggta4320 4S agggacggacctcagtggagagatggcataattgtcctgaaatacgttgatggcgactta4380 tgtccagatgggattcggaaaaagtcaaccaccatccgattcacctgcagcgagagccaa4440 gtgaactccaggcccatgttcatcagcgccgtggaggactgtgagtacacctttgcctgg4500 cccacagccacagcctgtcccatgaagagcaacgagcatgatgactgccaggtcaccaac4560 ccaagcacaggacacctgtttgatctgagctccttaagtggcagggcgggattcacagct4620 SO gcttacagcgagaaggggttggtttacatgagcatctgtggggagaatgaaaactgccct4680 cctggcgtgggggcctgctttggacagaccaggattagcgtgggcaaggccaacaagagg4740 ctgagatacgtggaccaggtcctgcagctggtgtacaaggatgggtccccttgtccctcc4800 aaatccggcctgagctataagagtgtgatcagtttcgtgtgcaggcctgaggccgggcca4860 accaataggcccatgctcatctccctggacaagcagacatgcactctcttcttctcctgg4920 SS cacacgccgctggcctgcgagcaagcgaccgaatgttccgtgaggaatggaagctctatt4980 gttgacttgtctccccttattcatcgcactggtggttatgaggcttatgatgagagtgag5040 gatgatgcctccgataccaaccctgatttctacatcaatatttgtcagccactaaatccc5100 atgcacgcagtgccctgtcctgccggagccgctgtgtgcaaagttcctattgatggtccc5160 cccatagatatcggccgggtagcaggaccaccaatactcaatccaatagcaaatgagatt5220 fi0tacttgaattttgaaagcagtactccttgcttagcggacaagcatttcaactacacctcg5280 1~,SERVERIg$lTextelAnmeldeunterlagen 20034422497-Ribopharma-an-2.doc ctcatcgcgtttcactgtaagagaggtgtgagcatgggaacgcctaagctgttaaggacc5340 agcgagtgcgactttgtgttcgaatgggagactcctgtcgtctgtcctgatgaagtgagg5400 atggatggctgtaccctgacagatgagcagctcctctacagcttcaacttgtccagcctt5460 tccacgagcacctttaaggtgactcgcgactcgcgcacctacagcgttggggtgtgcacc5520 S tttgcagtcgggccagaacaaggaggctgtaaggacggaggagtctgtctgctctcaggc5580 accaagggggcatcctttggacggctgcaatcaatgaaactggattacaggcaccaggat5640 gaagcggtcgttttaagttacgtgaatggtgatcgttgccctccagaaaccgatgacggc5700 gtcccctgtgtcttccccttcatattcaatgggaagagctacgaggagtgcatcatagag5760 agcagggcgaagctgtggtgtagcacaactgcggactacgacagagaccacgagtggggc5820 ttctgcagacactcaaacagctaccggacatccagcatcatatttaagtgtgatgaagat5880 gaggacattgggaggccacaagtcttcagtgaagtgcgtgggtgtgatgtgacatttgag5940 tggaaaacaaaagttgtctgccctccaaagaagttggagtgcaaattcgtccagaaacac6000 aaaacctacgacctgcggctgctctcctctctcaccgggtcctggtccctggtccacaac6060 ggagtctcgtactatataaatctgtgccagaaaatatataaagggcccctgggctgctct6120 1S gaaagggccagcatttgcagaaggaccacaactggtgacgtccaggtcctgggactcgtt6180 cacacgcagaagctgggtgtcataggtgacaaagttgttgtcacgtactccaaaggttat6240 ccgtgtggtggaaataagaccgcatcctccgtgatagaattgacctgtacaaagacggtg6300 ggcagacctgcattcaagaggtttgatatcgacagctgcacttactacttcagctgggac6360 tcccgggctgcctgcgccgtgaagcctcaggaggtgcagatggtgaatgggaccatcacc6420 aaccctataaatggcaagagcttcagcctcggagatatttattttaagctgttcagagcc6480 tctggggacatgaggaccaatggggacaactacctgtatgagatccaactttcctccatc6540 acaagctccagaaacccggcgtgctctggagccaacatatgccaggtgaagcccaacgat6600 cagcacttcagtcggaaagttggaacctctgacaagaccaagtactaccttcaagacggc6660 gatctcgatgtcgtgtttgcctcttcctctaagtgcggaaaggataagaccaagtctgtt6720 2S tcttccaccatcttcttccactgtgaccctctggtggaggacgggatccccgagttcagt6780 cacgagactgccgactgccagtacctcttctcttggtacacctcagccgtgtgtcctctg6840 ggggtgggctttgacagcgagaatcccggggacgacgggcagatgcacaaggggctgtca6900 gaacggagccaggcagtcggcgcggtgctcagcctgctgctggtggcgctcacctgctgc6960 ctgctggccctgttgctctacaagaaggagaggagggaaacagtgataagtaagctgacc7020 acttgctgtaggagaagttccaacgtgtcctacaaatactcaaaggtgaataaggaagaa7080 gagacagatgagaatgaaacagagtggctgatggaagagatccagctgcctcctccacgg7140 cagggaaaggaagggcaggagaacggccatattaccaccaagtcagtgaaagccctcagc7200 tccctgcatggggatgaccaggacagtgaggatgaggttctgaccatcccagaggtgaaa7260 gttcactcgggcaggggagctggggcagagagctcccacccagtgagaaacgcacagagc7320 3S aatgcccttcaggagcgtgaggacgatagggtggggctggtcaggggtgagaaggcgagg7380 aaagggaagtccagctctgcacagcagaagacagtgagctccaccaagctggtgtccttc7440 catgacgacagcgacgaggacctcttacacatctga 7476 <210> 91 <211> 4104 <212> DNA
<213> Homo Sapiens 4S <300>
<302> IGF1R
<310> NM000875 <400> 91 SO atgaagtctg gctccggagg agggtccccg acctcgctgt gggggctcct gtttctctcc 60 gccgcgctct cgctctggcc gacgagtgga gaaatctgcg ggccaggcat cgacatccgc 120 aacgactatc agcagctgaa gcgcctggag aactgcacgg tgatcgaggg ctacctccac 180 atcctgctca tctccaaggc cgaggactac cgcagctacc gcttccccaa gctcacggtc 240 attaccgagt acttgctgct gttccgagtg gctggcctcg agagcctcgg agacctcttc 300 SS cccaacctca cggtcatccg cggctggaaa ctcttctaca actacgccct ggtcatcttc 360 gagatgacca atctcaagga tattgggctt tacaacctga ggaacattac tcggggggcc 420 atcaggattg agaaaaatgc tgacctctgt tacctctcca ctgtggactg gtccctgatc 480 ctggatgcgg tgtccaataa ctacattgtg gggaataagc ccccaaagga atgtggggac 540 ctgtgtccag ggaccatgga ggagaagccg atgtgtgaga agaccaccat caacaatgag 600 60 tacaactacc gctgctggac cacaaaccgc tgccagaaaa tgtgcccaag cacgtgtggg 660 \\SERVER\g$\Texte\Anmeldeunterlagen 20031422497-Ribopharma-an-2.doc aagcgggcgtgcaccgagaacaatgagtgctgccaccccgagtgcctgggcagctgcagc720 gcgcctgacaacgacacggcctgtgtagcttgccgccactactactatgccggtgtctgt780 gtgcctgcctgcccgcccaacacctacaggtttgagggctggcgctgtgtggaccgtgac840 ttctgcgccaacatcctcagcgccgagagcagcgactccgaggggtttgtgatccacgac900 S ggcgagtgcatgcaggagtgcccctcgggcttcatccgcaacggcagccagagcatgtac960 tgcatcccttgtgaaggtccttgcccgaaggtctgtgaggaagaaaagaaaacaaagacc1020 attgattctgttacttctgctcagatgctccaaggatgcaccatcttcaagggcaatttg1080 ctcattaacatccgacgggggaataacattgcttcagagctggagaacttcatggggctc1140 atcgaggtggtgacgggctacgtgaagatccgccattctcatgccttggtctccttgtcc1200 1~ ttcctaaaaaaccttcgcctcatcctaggagaggagcagctagaagggaattactccttc1260 tacgtcctcgacaaccagaacttgcagcaactgtgggactgggaccaccgcaacctgacc1320 atcaaagcagggaaaatgtactttgctttcaatcccaaattatgtgtttccgaaatttac1380 cgcatggaggaagtgacggggactaaagggcgccaaagcaaaggggacataaacaccagg1440 aacaacggggagagagcctcctgtgaaagtgacgtcctgcatttcacctccaccaccacg1500 1S tcgaagaatcgcatcatcataacctggcaccggtaccggccccctgactacagggatctc1560 atcagcttcaccgtttactacaaggaagcaccctttaagaatgtcacagagtatgatggg1620 caggatgcctgcggctccaacagctggaacatggtggacgtggacctcccgcccaacaag1680 gacgtggagcccggcatcttactacatgggctgaagccctggactcagtacgccgtttac1740 gtcaaggctgtgaccctcaccatggtggagaacgaccatatccgtggggccaagagtgag1800 20 atcttgtacattcgcaccaatgcttcagttccttccattcccttggacgttctttcagca1860 tcgaactcctcttctcagttaatcgtgaagtggaaccctccctctctgcccaacggcaac1920 ctgagttactacattgtgcgctggcagcggcagcctcaggacggctacctttaccggcac1980 aattactgctccaaagacaaaatccccatcaggaagtatgccgacggcaccatcgacatt2040 gaggaggtcacagagaaccccaagactgaggtgtgtggtggggagaaagggccttgctgc2100 2S gcctgccccaaaactgaagccgagaagcaggccgagaaggaggaggctgaataccgcaaa2160 gtctttgagaatttcctgcacaactccatcttcgtgcccagacctgaaaggaagcggaga2220 gatgtcatgcaagtggccaacaccaccatgtccagccgaagcaggaacaccacggccgca2280 gacacctacaacatcaccgacccggaagagctggagacagagtaccctttctttgagagc2340 agagtggataacaaggagagaactgtcatttctaaccttcggcctttcacattgtaccgc2400 3~ atcgatatccacagctgcaaccacgaggctgagaagctgggctgcagcgcctccaacttc2460 gtctttgcaaggactatgcccgcagaaggagcagatgacattcctgggccagtgacctgg2520 gagccaaggcctgaaaactccatctttttaaagtggccggaacctgagaatcccaatgga2580 ttgattctaatgtatgaaataaaatacggatcacaagttgaggatcagcgagaatgtgtg2640 tccagacaggaatacaggaagtatggaggggccaagctaaaccggctaaacccggggaac2700 3S tacacagcccggattcaggccacatctctctctgggaatgggtcgtggacagatcctgtg2760 ttcttctatgtccaggccaaaacaggatatgaaaacttcatccatctgatcatcgctctg2820 cccgtcgctgtcctgttgatcgtgggagggttggtgattatgctgtacgtcttccataga2880 aagagaaataacagcaggctggggaatggagtgctgtatgcctctgtgaacccggagtac2940 ttcagcgctgctgatgtgtacgttcctgatgagtgggaggtggctcgggagaagatcacc3000 40 atgagccgggaacttgggcaggggtcgtttgggatggtctatgaaggagttgccaagggt3060 gtggtgaaagatgaacctgaaaccagagtggccattaaaacagtgaacgaggccgcaagc3120 atgcgtgagaggattgagtttctcaacgaagcttctgtgatgaaggagttcaattgtcac3180 catgtggtgcgattgctgggtgtggtgtcccaaggccagccaacactggtcatcatggaa3240 ctgatgacacggggcgatctcaaaagttatctccggtctctgaggccagaaatggagaat3300 4S aatccagtcctagcacctccaagcctgagcaagatgattcagatggccggagagattgca3360 gacggcatggcatacctcaacgccaataagttcgtccacagagaccttgctgcccggaat3420 tgcatggtagccgaagatttcacagtcaaaatcggagattttggtatgacgcgagatatc3480 tatgagacagactattaccggaaaggaggcaaagggctgctgcccgtgcgctggatgtct3540 cctgagtccctcaaggatggagtcttcaccacttactcggacgtctggtccttcggggtc3600 SO gtcctctgggagatcgccacactggccgagcagccctaccagggcttgtccaacgagcaa3660 gtccttcgcttcgtcatggagggcggccttctggacaagccagacaactgtcctgacatg3720 ctgtttgaactgatgcgcatgtgctggcagtataaccccaagatgaggccttccttcctg3780 gagatcatcagcagcatcaaagaggagatggagcctggcttccgggaggtctccttctac3840 tacagcgaggagaacaagctgcccgagccggaggagctggacctggagccagagaacatg3900 SS gagagcgtccccctggacccctcggcctcctcgtcctccctgccactgcccgacagacac3960 tcaggacacaaggccgagaacggccccggccctggggtgctggtcctccgcgccagcttc4020 gacgagagacagccttacgcccacatgaacgggggccgcaagaacgagcgggccttgccg4080 ctgccccagtcttcgacctgctga 4104 \\SERVER\g$\TextelAnmeldeunterlagen 20031422497-Ribopharma-an-2.doc 1~g S
<210> 92 <211> 726 <212> DNA
<213> Homo sapiens <300>
<302> PDGFB
<310> NM002608 <400> 92 atgaatcgct gctgggcgct cttcctgtct ctctgctgct acctgcgtct ggtcagcgcc 60 gagggggacc ccattcccga ggagctttat gagatgctga gtgaccactc gatccgctcc 120 tttgatgatc tccaacgcct gctgcacgga gaccccggag aggaagatgg ggccgagttg 180 gacctgaaca tgacccgctc ccactctgga ggcgagctgg agagcttggc tcgtggaaga 240 IS aggagcctgg gttccctgac cattgctgag ccggccatga tcgccgagtg caagacgcgc 300 accgaggtgt tcgagatctc ccggcgcctc atagaccgca ccaacgccaa cttcctggtg 360 tggccgccct gtgtggaggt gcagcgctgc tccggctgct gcaacaaccg caacgtgcag 420 tgccgcccca cccaggtgca gctgcgacct gtccaggtga gaaagatcga gattgtgcgg 480 aagaagccaa tctttaagaa ggccacggtg acgctggaag accacctggc atgcaagtgt 540 gagacagtgg cagctgcacg gcctgtgacc cgaagcccgg ggggttccca ggagcagcga 600 gccaaaacgc cccaaactcg ggtgaccatt cggacggtgc gagtccgccg gccccccaag 660 ggcaagcacc ggaaattcaa gcacacgcat gacaagacgg cactgaagga gacccttgga 720 gcctag 726 <210> 93 <211> 1512 <212> DNA
<213> Homo Sapiens <300>
<302> TGFbetaRl <310> NM004612 3S <400> 93 atggaggcggcggtcgctgctccgcgtccccggctgctcctcctcgtgctggcggcggcg60 gcggcggcggcggcggcgctgctcccgggggcgacggcgttacagtgtttctgccacctc120 tgtacaaaagacaattttacttgtgtgacagatgggctctgctttgtctctgtcacagag180 accacagacaaagttatacacaacagcatgtgtatagctgaaattgacttaattcctcga240 4~ gataggccgtttgtatgtgcaccctcttcaaaaactgggtctgtgactacaacatattgc300 tgcaatcaggaccattgcaataaaatagaacttccaactactgtaaagtcatcacctggc360 cttggtcctgtggaactggcagctgtcattgctggaccagtgtgcttcgtctgcatctca420 ctcatgttgatggtctatatctgccacaaccgcactgtcattcaccatcgagtgccaaat480 gaagaggacccttcattagatcgcccttttatttcagagggtactacgttgaaagactta540 4S atttatgatatgacaacgtcaggttctggctcaggtttaccattgcttgttcagagaaca600 attgcgagaactattgtgttacaagaaagcattggcaaaggtcgatttggagaagtttgg660 agaggaaagtggcggggagaagaagttgctgttaagatattctcctctagagaagaacgt720 tcgtggttccgtgaggcagagatttatcaaactgtaatgttacgtcatgaaaacatcctg780 ggatttatagcagcagacaataaagacaatggtacttggactcagctctggttggtgtca840 SD gattatcatgagcatggatccctttttgattacttaaacagatacacagttactgtggaa900 ggaatgataaaacttgctctgtccacggcgagcggtcttgcccatcttcacatggagatt960 gttggtacccaaggaaagccagccattgctcatagagatttgaaatcaaagaatatcttg1020 gtaaagaagaatggaacttgctgtattgcagacttaggactggcagtaagacatgattca1080 gccacagataccattgatattgctccaaaccacagagtgggaacaaaaaggtacatggcc1140 SS cctgaagttctcgatgattccataaatatgaaacattttgaatccttcaaacgtgctgac1200 atctatgcaatgggcttagtattctgggaaattgctcgacgatgttccattggtggaatt1260 catgaagattaccaactgccttattatgatcttgtaccttctgacccatcagttgaagaa1320 atgagaaaagttgtttgtgaacagaagttaaggccaaatatcccaaacagatggcagagc1380 tgtgaagccttgagagtaatggctaaaattatgagagaatgttggtatgccaatggagca1440 f)0gctaggcttacagcattgcggattaagaaaacattatcgcaactcagtcaacaggaaggc1500 \\SERVER\g$\TexteWameldeunterlagen 20034422497-Ribopharma-an-2.doc atcaaaatgt as 1512 <210> 94 S <211> 4044 <212> DNA
<213> Homo Sapiens <300>
<302> Flkl <310> AF035121 <400> 94 atgcagagcaaggtgctgctggccgtcgccctgtggctctgcgtggagacccgggccgcc60 1S tctgtgggtttgcctagtgtttctcttgatctgcccaggctcagcatacaaaaagacata120 cttacaattaaggctaatacaactcttcaaattacttgcaggggacagagggacttggac180 tggctttggcccaataatcagagtggcagtgagcaaagggtggaggtgactgagtgcagc240 gatggcctcttctgtaagacactcacaattccaaaagtgatcggaaatgacactggagcc300 tacaagtgcttctaccgggaaactgacttggcctcggtcatttatgtctatgttcaagat360 tacagatctccatttattgcttctgttagtgaccaacatggagtcgtgtacattactgag420 aacaaaaacaaaactgtggtgattccatgtctcgggtccatttcaaatctcaacgtgtca480 ctttgtgcaagatacccagaaaagagatttgttcctgatggtaacagaatttcctgggac540 agcaagaagggctttactattcccagctacatgatcagctatgctggcatggtcttctgt600 gaagcaaaaattaatgatgaaagttaccagtctattatgtacatagttgtcgttgtaggg660 2S tataggatttatgatgtggttctgagtccgtctcatggaattgaactatctgttggagaa720 aagcttgtcttaaattgtacagcaagaactgaactaaatgtggggattgacttcaactgg780 gaatacccttcttcgaagcatcagcataagaaacttgtaaaccgagacctaaaaacccag840 tctgggagtgagatgaagaaatttttgagcaccttaactatagatggtgtaacccggagt900 gaccaaggattgtacacctgtgcagcatccagtgggctgatgaccaagaagaacagcaca960 tttgtcagggtccatgaaaaaccttttgttgcttttggaagtggcatggaatctctggtg1020 gaagccacggtgggggagcgtgtcagaatccctgcgaagtaccttggttacccaccccca1080 gaaataaaatggtataaaaatggaataccccttgagtccaatcacacaattaaagcgggg1140 catgtactgacgattatggaagtgagtgaaagagacacaggaaattacactgtcatcctt1200 accaatcccatttcaaaggagaagcagagccatgtggtctctctggttgtgtatgtccca1260 3S ccccagattggtgagaaatctctaatctctcctgtggattcctaccagtacggcaccact1320 caaacgctgacatgtacggtctatgccattcctcccccgcatcacatccactggtattgg1380 cagttggaggaagagtgcgccaacgagcccagccaagctgtctcagtgacaaacccatac1440 ccttgtgaagaatggagaagtgtggaggacttccagggaggaaataaaattgaagttaat1500 aaaaatcaatttgctctaattgaaggaaaaaacaaaactgtaagtacccttgttatccaa1560 gcggcaaatgtgtcagctttgtacaaatgtgaagcggtcaacaaagtcgggagaggagag1620 agggtgatctccttccacgtgaccaggggtcctgaaattactttgcaacctgacatgcag1680 cccactgagcaggagagcgtgtctttgtggtgcactgcagacagatctacgtttgagaac1740 ctcacatggtacaagcttggcccacagcctctgccaatccatgtgggagagttgcccaca1800 cctgtttgcaagaacttggatactctttggaaattgaatgccaccatgttctctaatagc1860 4S acaaatgacattttgatcatggagcttaagaatgcatccttgcaggaccaaggagactat1920 gtctgccttgctcaagacaggaagaccaagaaaagacattgcgtggtcaggcagctcaca1980 gtcctagagcgtgtggcacccacgatcacaggaaacctggagaatcagacgacaagtatt2040 ggggaaagcatcgaagtctcatgcacggcatctgggaatccccctccacagatcatgtgg2100 tttaaagataatgagacccttgtagaagactcaggcattgtattgaaggatgggaaccgg2160 SO aacctcactatccgcagagtgaggaaggaggacgaaggcctctacacctgccaggcatgc2220 agtgttcttggctgtgcaaaagtggaggcatttttcataatagaaggtgcccaggaaaag2280 acgaacttggaaatcattattctagtaggcacggcggtgattgccatgttcttctggcta2340 cttcttgtcatcatcctacggaccgttaagcgggccaatggaggggaactgaagacaggc2400 tacttgtccatcgtcatggatccagatgaactcccattggatgaacattgtgaacgactg2460 SS ccttatgatgccagcaaatgggaattccccagagaccggctgaagctaggtaagcctctt2520 ggccgtggtgcctttggccaagtgattgaagcagatgcctttggaattgacaagacagca2580 acttgcaggacagtagcagtcaaaatgttgaaagaaggagcaacacacagtgagcatcga2640 gctctcatgtctgaactcaagatcctcattcatattggtcaccatctcaatgtggtcaac2700 cttctaggtgcctgtaccaagccaggagggccactcatggtgattgtggaattctgcaaa2760 fi0tttggaaacctgtccacttacctgaggagcaagagaaatgaatttgtcccctacaagacc2820 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc I1~
aaaggggcacgattccgtcaagggaaagactacgttggagcaatccctgtggatctgaaa2880 cggcgcttggacagcatcaccagtagccagagctcagccagctctggatttgtggaggag2940 aagtccctcagtgatgtagaagaagaggaagctcctgaagatctgtataaggacttcctg3000 accttggagcatctcatctgttacagcttccaagtggctaagggcatggagttcttggca3060 S tcgcgaaagtgtatccacagggacctggcggcacgaaatatcctcttatcggagaagaac3120 gtggttaaaatctgtgactttggcttggcccgggatatttataaagatccagattatgtc3180 agaaaaggagatgctcgcctccctttgaaatggatggccccagaaacaatttttgacaga3240 gtgtacacaatccagagtgacgtctggtcttttggtgttttgctgtgggaaatattttcc3300 ttaggtgcttctccatatcctggggtaaagattgatgaagaattttgtaggcgattgaaa3360 gaaggaactagaatgagggcccctgattatactacaccagaaatgtaccagaccatgctg3420 gactgctggcacggggagcccagtcagagacccacgttttcagagttggtggaacatttg3480 ggaaatctcttgcaagctaatgctcagcaggatggcaaagactacattgttcttccgata3540 tcagagactttgagcatggaagaggattctggactctctctgcctacctcacctgtttcc3600 tgtatggaggaggaggaagtatgtgaccccaaattccattatgacaacacagcaggaatc3660 1S agtcagtatctgcagaacagtaagcgaaagagccggcctgtgagtgtaaaaacatttgaa3720 gatatcccgttagaagaaccagaagtaaaagtaatcccagatgacaaccagacggacagt3780 ggtatggttcttgcctcagaagagctgaaaactttggaagacagaaccaaattatctcca3840 tcttttggtggaatggtgcccagcaaaagcagggagtctgtggcatctgaaggctcaaac3900 cagacaagcggctaccagtccggatatcactccgatgacacagacaccaccgtgtactcc3960 agtgaggaagcagaacttttaaagctgatagagattggagtgcaaaccggtagcacagcc4020 cagattctccagcctgactcgggg 4044 <210> 95 ZS <211> 4017 <212> DNA
<213> Homo sapiens <300>
<302> Flt1 <310> AF063657 <400> 95 atggtcagctactgggacaccggggtcctgctgtgcgcgctgctcagctgtctgcttctc60 3S acaggatctagttcaggttcaaaattaaaagatcctgaactgagtttaaaaggcacccag120 cacatcatgcaagcaggccagacactgcatctccaatgcaggggggaagcagcccataaa180 tggtctttgcctgaaatggtgagtaaggaaagcgaaaggctgagcataactaaatctgcc240 tgtggaagaaatggcaaacaattctgcagtactttaaccttgaacacagctcaagcaaac300 cacactggcttctacagctgcaaatatctagctgtacctacttcaaagaagaaggaaaca360 gaatctgcaatctatatatttattagtgatacaggtagacctttcgtagagatgtacagt420 gaaatccccgaaattatacacatgactgaaggaagggagctcgtcattccctgccgggtt4$0 acgtcacctaacatcactgttactttaaaaaagtttccacttgacactttgatccctgat540 ggaaaacgcataatctgggacagtagaaagggcttcatcatatcaaatgcaacgtacaaa600 gaaatagggcttctgacctgtgaagcaacagtcaatgggcatttgtataagacaaactat660 4S ctcacacatcgacaaaccaatacaatcatagatgtccaaataagcacaccacgcccagtc720 aaattacttagaggccatactcttgtcctcaattgtactgctaccactcccttgaacacg780 agagttcaaatgacctggagttaccctgatgaaaaaaataagagagcttccgtaaggcga840 cgaattgaccaaagcaattcccatgccaacatattctacagtgttcttactattgacaaa900 atgcagaacaaagacaaaggactttatacttgtcgtgtaaggagtggaccatcattcaaa960 SO tctgttaacacctcagtgcatatatatgataaagcattcatcactgtgaaacatcgaaaa1020 cagcaggtgcttgaaaccgtagctggcaagcggtcttaccggctctctatgaaagtgaag1080 gcatttccctcgccggaagttgtatggttaaaagatgggttacctgcgactgagaaatct1140 gctcgctatttgactcgtggctactcgttaattatcaaggacgtaactgaagaggatgca1200 gggaattatacaatcttgctgagcataaaacagtcaaatgtgtttaaaaacctcactgcc1260 SS actctaattgtcaatgtgaaaccccagatttacgaaaaggccgtgtcatcgtttccagac1320 ccggctctctacccactgggcagcagacaaatcctgacttgtaccgcatatggtatccct1380 caacctacaatcaagtggttctggcacccctgtaaccataatcattccgaagcaaggtgt1440 gacttttgttccaataatgaagagtcctttatcctggatgctgacagcaacatgggaaac1500 agaattgagagcatcactcagcgcatggcaataatagaaggaaagaataagatggctagc1560 60 accttggttgtggctgactctagaatttctggaatctacatttgcatagcttccaataaa1620 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc gttgggactgtgggaagaaacataagcttttatatcacagatgtgccaaatgggtttcat1680 gttaacttggaaaaaatgccgacggaaggagaggacctgaaactgtcttgcacagttaac1740 aagttcttatacagagacgttacttggattttactgcggacagttaataacagaacaatg1800 cactacagtattagcaagcaaaaaatggccatcactaaggagcactccatcactcttaat1860 S cttaccatcatgaatgtttccctgcaagattcaggcacctatgcctgcagagccaggaat1920 gtatacacaggggaagaaatcctccagaagaaagaaattacaatcagagatcaggaagca1980 ccatacctcctgcgaaacctcagtgatcacacagtggccatcagcagttccaccacttta2040 gactgtcatgctaatggtgtccccgagcctcagatcacttggtttaaaaacaaccacaaa2100 atacaacaagagcctggaattattttaggaccaggaagcagcacgctgtttattgaaaga2160 gtcacagaagaggatgaaggtgtctatcactgcaaagccaccaaccagaagggctctgtg2220 gaaagttcagcatacctcactgttcaaggaacctcggacaagtctaatctggagctgatc2280 actctaacatgcacctgtgtggctgcgactctcttctggctcctattaaccctctttatc2340 cgaaaaatgaaaaggtcttcttctgaaataaagactgactacctatcaattataatggac2400 ccagatgaagttcctttggatgagcagtgtgagcggctcccttatgatgccagcaagtgg2460 1S gagtttgcccgggagagacttaaactgggcaaatcacttggaagaggggcttttggaaaa2520 gtggttcaagcatcagcatttggcattaagaaatcacctacgtgccggactgtggctgtg2580 aaaatgctgaaagagggggccacggccagcgagtacaaagctctgatgactgagctaaaa2640 atcttgacccacattggccaccatctgaacgtggttaacctgctgggagcctgcaccaag2700 caaggagggcctctgatggtgattgttgaatactgcaaatatggaaatctctccaactac2760 ctcaagagcaaacgtgacttattttttctcaacaaggatgcagcactacacatggagcct2820 aagaaagaaaaaatggagccaggcctggaacaaggcaagaaaccaagactagatagcgtc2880 accagcagcgaaagctttgcgagctccggctttcaggaagataaaagtctgagtgatgtt2940 gaggaagaggaggattctgacggtttctacaaggagcccatcactatggaagatctgatt3000 tcttacagttttcaagtggccagaggcatggagttcctgtcttccagaaagtgcattcat3060 2S cgggacctggcagcgagaaacattcttttatctgagaacaacgtggtgaagatttgtgat3120 tttggccttgcccgggatatttataagaaccccgattatgtgagaaaaggagatactcga3180 cttcctctgaaatggatggctcctgaatctatctttgacaaaatctacagcaccaagagc3240 gacgtgtggtcttacggagtattgctgtgggaaatcttctccttaggtgggtctccatac3300 ccaggagtacaaatggatgaggacttttgcagtcgcctgagggaaggcatgaggatgaga3360 gctcctgagtactctactcctgaaatctatcagatcatgctggactgctggcacagagac3420 ccaaaagaaaggccaagatttgcagaacttgtggaaaaactaggtgatttgcttcaagca3480 aatgtacaacaggatggtaaagactacatcccaatcaatgccatactgacaggaaatagt3540 gggtttacatactcaactcctgccttctctgaggacttcttcaaggaaagtatttcagct3600 ccgaagtttaattcaggaagctctgatgatgtcagatatgtaaatgctttcaagttcatg3660 3S agcctggaaagaatcaaaacctttgaagaacttttaccgaatgccacctccatgtttgat3720 gactaccagggcgacagcagcactctgttggcctctcccatgctgaagcgcttcacctgg3780 actgacagcaaacccaaggcctcgctcaagattgacttgagagtaaccagtaaaagtaag3840 gagtcggggctgtctgatgtcagcaggcccagtttctgccattccagctgtgggcacgtc3900 agcgaaggcaagcgcaggttcacctacgaccacgctgagctggaaaggaaaatcgcgtgc3960 tgctccccgcccccagactacaactcggtggtcctgtactccaccccacccatctag 4017 <210> 96 <211> 3897 4S <212> DNA
<213> Homo sapiens <300>
<302> Flt4 SO <310> XM003852 <400> 96 atgcagcggg gcgccgcgct gtgcctgcga ctgtggctct gcctgggact cctggacggc 60 ctggtgagtg gctactccat gacccccccg accttgaaca tcacggagga gtcacacgtc 120 SS atcgacaccg gtgacagcct gtccatctcc tgcaggggac agcaccccct cgagtgggct 180 tggccaggag ctcaggaggc gccagccacc ggagacaagg acagcgagga cacgggggtg 240 gtgcgagact gcgagggcac agacgccagg ccctactgca aggtgttgct gctgcacgag 300 gtacatgcca acgacacagg cagctacgtc tgctactaca agtacatcaa ggcacgcatc 360 gagggcacca cggccgccag ctcctacgtg ttcgtgagag actttgagca gccattcatc 420 60 aacaagcctg acacgctctt ggtcaacagg aaggacgcca tgtgggtgcc ctgtctggtg 480 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422A97-Ribopharma-an-2.doc tccatccccggcctcaatgtcacgctgcgctcgcaaagctcggtgctgtggccagacggg540 caggaggtggtgtgggatgaccggcggggcatgctcgtgtccacgccactgctgcacgat600 gccctgtacctgcagtgcgagaccacctggggagaccaggacttcctttccaaccccttc660 ctggtgcacatcacaggcaacgagctctatgacatccagctgttgcccaggaagtcgctg720 S gagctgctggtagg'ggagaagctggtcctgaactgcaccgtgtgggctgagtttaactca780 ggtgtcacctttgactgggactacccagggaagcaggcagagcggggtaagtgggtgccc840 gagcgacgctcccagcagacccacacagaactctccagcatcctgaccatccacaacgtc900 agccagcacgacctgggctcgtatgtgtgcaaggccaacaacggcatccagcgatttcgg960 gagagcaccgaggtcattgtgcatgaaaatcccttcatcagcgtcgagtggctcaaagga1020 cccatcctggaggccacggcaggagacgagctggtgaagctgcccgtgaagctggcagcg1080 taccccccgcccgagttccagtggtacaaggatggaaaggcactgtccgggcgccacagt1140 ccacatgccctggtgctcaaggaggtgacagaggccagcacaggcacctacaccctcgcc1200 ctgtggaactccgctgctggcctgaggcgcaacatcagcctggagctggtggtgaatgtg1260 cccccccagatacatgagaaggaggcctcctcccccagcatctactcgcgtcacagccgc1320 1$ caggccctcacctgcacggcctacggggtgcccctgcctctcagcatccagtggcactgg1380 cggccctggacaccctgcaagatgtttgcccagcgtagtctccggcggcggcagcagcaa1440 gacctcatgccacagtgccgtgactggagggcggtgaccgcgcaggatgccgtgaacccc1500 atcgagagcctggacacctggaccgagtttgtggagggaaagaataagactgtgagcaag1560 ctggtgatccagaatgccaacgtgtctgccatgtacaagtgtgtggtctccaacaaggtg1620 ggccaggatgagcggctcatctacttctatgtgaccaccatccccgacggcttcaccatc1680 gaatccaagccatccgaggagctactagagggccagccggtgctcctgagctgccaagcc1740 gacagctacaagtacgagcatctgcgctggtaccgcctcaacctgtccacgctgcacgat1800 gcgcacgggaacccgcttctgctcgactgcaagaacgtgcatctgttcgccacccctctg1860 gccgccagcctggaggaggtggcacctggggcgcgccacgccacgctcagcctgagtatc1920 2S ccccgcgtcgcgcccgagcacgagggccactatgtgtgcgaagtgcaagaccggcgcagc1980 catgacaagcactgccacaagaagtacctgtcggtgcaggccctggaagcccctcggctc2040 acgcagaacttgaccgacctcctggtgaacgtgagcgactcgctggagatgcagtgcttg2100 gtggccggagcgcacgcgcccagcatcgtgtggtacaaagacgagaggctgctggaggaa2160 aagtctggagtcgacttggcggactccaaccagaagctgagcatccagcgcgtgcgcgag2220 3~ gaggatgcgggacgctatctgtgcagcgtgtgcaacgccaagggctgcgtcaactcctcc2280 gccagcgtggccgtggaaggctccgaggataagggcagcatggagatcgtgatccttgtc2340 ggtaccggcgtcatcgctgtcttcttctgggtcctcctcctcctcatcttctgtaacatg2400 aggaggccggcccacgcagacatcaagacgggctacctgtccatcatcatggaccccggg2460 gaggtgcctctggaggagcaatgcgaatacctgtcctacgatgccagccagtgggaattc2520 3S ccccgagagcggctgcacctggggagagtgctcggctacggcgccttcgggaaggtggtg2580 gaagcctccgctttcggcatccacaagggcagcagctgtgacaccgtggccgtgaaaatg2640 ctgaaagagggcgccacggccagcgagcagcgcgcgctgatgtcggagctcaagatcctc2700 attcacatcggcaaccacctcaacgtggtcaacctcctcggggcgtgcaccaagccgcag2760 ggccccctcatggtgatcgtggagttctgcaagtacggcaacctctccaacttcctgcgc2820 40 gccaagcgggacgccttcagcccctgcgcggagaagtctcccgagcagcgcggacgcttc2880 cgcgccatggtggagctcgccaggctggatcggaggcggccggggagcagcgacagggtc2940 ctcttcgcgcggttctcgaagaccgagggcggagcgaggcgggcttctccagaccaagaa3000 gctgaggacctgtggctgagcccgctgaccatggaagatcttgtctgctacagcttccag3060 gtggccagagggatggagttcctggcttcccgaaagtgcatccacagagacctggctgct3120 4S cggaacattctgctgtcggaaagcgacgtggtgaagatctgtgactttggccttgcccgg3180 gacatctacaaagaccccgactacgtccgcaagggcagtgcccggctgcccctgaagtgg3240 atggcccctgaaagcatcttcgacaaggtgtacaccacgcagagtgacgtgtggtccttt3300 ggggtgcttctctgggagatcttctctctgggggcctccccgtaccctggggtgcagatc3360 aatgaggagttctgccagcggctgagagacggcacaaggatgagggccccggagctggcc3420 $0 actcccgccatacgccgcatcatgctgaactgctggtccggagaccccaaggcgagacct3480 gcattctcggagctggtggagatcctgggggacctgctccagggcaggggcctgcaagag3540 gaagaggaggtctgcatggccccgcgcagctctcagagctcagaagagggcagcttctcg3600 caggtgtccaccatggccctacacatcgcccaggctgacgctgaggacagcccgccaagc3660 ctgcagcgccacagcctggccgccaggtattacaactgggtgtcctttcccgggtgcctg3720 $5 gccagaggggctgagacccgtggttcctccaggatgaagacatttgaggaattccccatg3780 accccaacgacctacaaaggctctgtggacaaccagacagacagtgggatggtgctggcc3840 tcggaggagtttgagcagatagagagcaggcatagacaagaaagcggcttcaggtag 3897 <210> 97 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharcna-an-2.doc <211> 4071 <212> DNA
<213> Homo sapiens <300>
<302> KDR
<310> AF063658 <400> 97 atggagagcaaggtgctgctggccgtcgccctgtggctctgcgtggagacccgggccgcc60 tctgtgggtttgcctagtgtttctcttgatctgcccaggctcagcatacaaaaagacata120 cttacaattaaggctaatacaactcttcaaattacttgcaggggacagagggacttggac180 tggctttggcccaataatcagagtggcagtgagcaaagggtggaggtgactgagtgcagc240 gatggcctcttctgtaagacactcacaattccaaaagtgatcggaaatgacactggagcc300 tacaagtgcttctaccgggaaactgacttggcctcggtcatttatgtctatgttcaagat360 tacagatctccatttattgcttctgttagtgaccaacatggagtcgtgtacattactgag420 aacaaaaacaaaactgtggtgattccatgtctcgggtccatttcaaatctcaacgtgtca480 ctttgtgcaagatacccagaaaagagatttgttcctgatggtaacagaatttcctgggac540 agcaagaagggctttactattcccagctacatgatcagctatgctggcatggtcttctgt600 gaagcaaaaattaatgatgaaagttaccagtctattatgtacatagttgtcgttgtaggg660 tataggatttatgatgtggttctgagtccgtctcatggaattgaactatctgttggagaa720 aagcttgtcttaaattgtacagcaagaactgaactaaatgtggggattgacttcaactgg780 gaatacccttcttcgaagcatcagcataagaaacttgtaaaccgagacctaaaaacccag840 tctgggagtgagatgaagaaatttttgagcaccttaactatagatggtgtaacccggagt900 2$ gaccaaggattgtacacctgtgcagcatccagtgggctgatgaccaagaagaacagcaca960 tttgtcagggtccatgaaaaaccttttgttgcttttggaagtggcatggaatctctggtg1020 gaagccacggtgggggagcgtgtcagaatccctgcgaagtaccttggttacccaccccca1080 gaaataaaatggtataaaaatggaataccccttgagtccaatcacacaattaaagcgggg1140 catgtactgacgattatggaagtgagtgaaagagacacaggaaattacactgtcatcctt1200 accaatcccatttcaaaggagaagcagagccatgtggtctctctggttgtgtatgtccca1260 ccccagattggtgagaaatctctaatctctcctgtggattcctaccagtacggcaccact1320 caaacgctgacatgtacggtctatgccattcctcccccgcatcacatccactggtattgg1380 cagttggaggaagagtgcgccaacgagcccagccaagctgtctcagtgacaaacccatac1440 ccttgtgaagaatggagaagtgtggaggacttccagggaggaaataaaattgaagttaat1500 aaaaatcaatttgctctaattgaaggaaaaaacaaaactgtaagtacccttgttatccaa1560 gcggcaaatgtgtcagctttgtacaaatgtgaagcggtcaacaaagtcgggagaggagag1620 agggtgatctccttccacgtgaccaggggtcctgaaattactttgcaacctgacatgcag1680 cccactgagcaggagagcgtgtctttgtggtgcactgcagacagatctacgtttgagaac1740 ctcacatggtacaagcttggcccacagcctctgccaatccatgtgggagagttgcccaca1800 cctgtttgcaagaacttggatactctttggaaattgaatgccaccatgttctctaatagc1860 acaaatgacattttgatcatggagcttaagaatgcatccttgcaggaccaaggagactat1920 gtctgccttgctcaagacaggaagaccaagaaaagacattgcgtggtcaggcagctcaca1980 gtcctagagcgtgtggcacccacgatcacaggaaacctggagaatcagacgacaagtatt2040 ggggaaagcatcgaagtctcatgcacggcatctgggaatccccctccacagatcatgtgg2100 4S tttaaagataatgagacccttgtagaagactcaggcattgtattgaaggatgggaaccgg2160 aacctcactatccgcagagtgaggaaggaggacgaaggcctctacacctgccaggcatgc2220 agtgttcttggctgtgcaaaagtggaggcatttttcataatagaaggtgcccaggaaaag2280 acgaacttggaaatcattattctagtaggcacggcggtgattgccatgttcttctggcta2340 cttcttgtcatcatcctacggaccgttaagcgggccaatggaggggaactgaagacaggc2400 SO tacttgtccatcgtcatggatccagatgaactcccattggatgaacattgtgaacgactg2460 ccttatgatgccagcaaatgggaattccccagagaccggctgaagctaggtaagcctctt2520 ggccgtggtgcctttggccaagtgattgaagcagatgcctttggaattgacaagacagca2580 acttgcaggacagtagcagtcaaaatgttgaaagaaggagcaacacacagtgagcatcga2640 gctctcatgtctgaactcaagatcctcattcatattggtcaccatctcaatgtggtcaac2700 SS cttctaggtgcctgtaccaagccaggagggccactcatggtgattgtggaattctgcaaa2760 tttggaaacctgtccacttacctgaggagcaagagaaatgaatttgtcccctacaagacc2820 aaaggggcacgattccgtcaagggaaagactacgttggagcaatccctgtggatctgaaa2880 cggcgcttggacagcatcaccagtagccagagctcagccagctctggatttgtggaggag2940 aagtccctcagtgatgtagaagaagaggaagctcctgaagatctgtataaggacttcctg3000 60 accttggagcatctcatctgttacagcttccaagtggctaagggcatggagttcttggca3060 \\SERVER\g$\TexteWnmeldeunterlagen 2003\422497-Ribophanna-an-2.doc tcgcgaaagt gtatccacag ggacctggcg gcacgaaata tcctcttatc ggagaagaac 3120 gtggttaaaa tctgtgactt tggcttggcc cgggatattt ataaagatcc agattatgtc 3180 agaaaaggag atgctcgcct ccctttgaaa tggatggccc cagaaacaat ttttgacaga 3240 gtgtacacaa tccagagtga cgtctggtct tttggtgttt tgctgtggga aatattttcc 3300 S ttaggtgctt ctccatatcc tggggtaaag attgatgaag aattttgtag gcgattgaaa 3360 gaaggaacta gaatgagggc ccctgattat actacaccag aaatgtacca gaccatgctg 3420 gactgctggc acggggagcc cagtcagaga cccacgtttt cagagttggt ggaacatttg 3480 ggaaatctct tgcaagctaa tgctcagcag gatggcaaag actacattgt tcttccgata 3540 tcagagactt tgagcatgga agaggattct ggactctctc tgcctacctc acctgtttcc 3600 tgtatggagg aggaggaagt atgtgacccc aaattccatt atgacaacac agcaggaatc 3660 agtcagtatc tgcagaacag taagcgaaag agccggcctg tgagtgtaaa aacatttgaa 3720 gatatcccgt tagaagaacc agaagtaaaa gtaatcccag atgacaacca gacggacagt 3780 ggtatggttc ttgcctcaga agagctgaaa actttggaag acagaaccaa attatctcca 3840 tcttttggtg gaatggtgcc cagcaaaagc agggagtctg tggcatctga aggctcaaac 3900 1$ cagacaagcg gctaccagtc cggatatcac tccgatgaca cagacaccac cgtgtactcc 3960 agtgaggaag cagaactttt aaagctgata gagattggag tgcaaaccgg tagcacagcc 4020 cagattctcc agcctgactc ggggaccaca ctgagctctc ctcctgttta a 4071 <210> 98 <211> 1410 <212> DNA
<213> Homo Sapiens <300>
<302> MMP1 <310> M13509 <400> 98 atgcacagctttcctccactgctgctgctgctgttctggggtgtggtgtctcacagcttc60 ccagcgactctagaaacacaagagcaagatgtggacttagtccagaaatacctggaaaaa120 tactacaacctgaagaatgatgggaggcaagttgaaaagcggagaaatagtggcccagtg180 gttgaaaaattgaagcaaatgcaggaattctttgggctgaaagtgactgggaaaccagat240 gctgaaaccctgaaggtgatgaagcagcccagatgtggagtgcctgatgtggctcagttt300 3S gtcctcactgagggaaaccctcgctgggagcaaacacatctgaggtacaggattgaaaat360 tacacgccagatttgccaagagcagatgtggaccatgccattgagaaagccttccaactc420 tggagtaatgtcacacctctgacattcaccaaggtctctgagggtcaagcagacatcatg480 atatcttttgtcaggggagatcatcgggacaactctccttttgatggacctggaggaaat540 cttgctcatgcttttcaaccaggcccaggtattggaggggatgctcattttgatgaagat600 gaaaggtggaccaacaatttcagagagtacaacttacatcgtgttgcggctcatgaactc660 ggccattctcttggactctcccattctactgatatcggggctttgatgtaccctagctac720 accttcagtggtgatgttcagctagctcaggatgacattgatggcatccaagccatatat780 ggacgttcccaaaatcctgtccagcccatcggcccacaaaccccaaaagcgtgtgacagt840 aagctaacctttgatgctataactacgattcggggagaagtgatgttctttaaagacaga900 4S ttctacatgcgcacaaatcccttctacccggaagttgagctcaatttcatttctgttttc960 tggccacaactgccaaatgggcttgaagctgcttacgaatttgccgacagagatgaagtc1020 cggtttttcaaagggaataagtactgggctgttcagggacagaatgtgctacacggatac1080 cccaaggacatctacagctcctttggcttccctagaactgtgaagcatatcgatgctgct1140 ctttctgaggaaaacactggaaaaacctacttctttgttgctaacaaatactggaggtat1200 $0 gatgaatataaacgatctatggatccaagttatcccaaaatgatagcacatgactttcct1260 ggaattggccacaaagttgatgcagttttcatgaaagatggatttttctatttctttcat1320 ggaacaagacaatacaaatttgatcctaaaacgaagagaattttgactctccagaaagct1380 aatagctggttcaactgcaggaaaaattga 1410 <210> 99 <211> 1743 <212> DNA
<213> Homo sapiens \\SERVER\g$\Texte\Anmeldeunterlagen 20034122497-Ribophartna-an-2.doc <300>
<302> MMP10 <310> XM006269 S <400> 99 aaagaaggtaagggcagtgagaatgatgcatcttgcattccttgtgctgttgtgtctgcc60 agtctgctctgcctatcctctgagtggggcagcaaaagaggaggactccaacaaggatct120 tgcccagcaatacctagaaaagtactacaacctcgaaaaggatgtgaaacagtttagaag180 aaaggacagtaatctcattgttaaaaaaatccaaggaatgcagaagttccttgggttgga240 1~ ggtgacagggaagctagacactgacactctggaggtgatgcgcaagcccaggtgtggagt300 tcctgacgttggtcacttcagctcctttcctggcatgccgaagtggaggaaaacccacct360 tacatacaggattgtgaattatacaccagatttgccaagagatgctgttgattctgccat420 tgagaaagctctgaaagtctgggaagaggtgactccactcacattctccaggctgtatga480 aggagaggctgatataatgatctcttttgcagttaaagaacatggagacttttactcttt540 1S tgatggcccaggacacagtttggctcatgcctacccacctggacctgggctttatggaga600 tattcactttgatgatgatgaaaaatggacagaagatgcatcaggcaccaatttattcct660 cgttgctgctcatgaacttggccactccctggggctctttcactcagccaacactgaagc720 tttgatgtacccactctacaactcattcacagagctcgcccagttccgcctttcgcaaga780 tgatgtgaatggcattcagtctctctacggacctccccctgcctctactgaggaacccct840 ggtgcccacaaaatctgttccttcgggatctgagatgccagccaagtgtgatcctgcttt900 gtccttcgatgccatcagcactctgaggggagaatatctgttctttaaagacagatattt960 ttggcgaagatcccactggaaccctgaacctgaatttcatttgatttctgcattttggcc1020 ctctcttccatcatatttggatgctgcatatgaagttaacagcagggacaccgtttttat1080 ttttaaaggaaatgagttctgggccatcagaggaaatgaggtacaagcaggttatccaag1140 ZS aggcatccataccctgggttttcctccaaccataaggaaaattgatgcagctgtttctga1200 caaggaaaagaagaaaacatacttctttgcagcggacaaatactggagatttgatgaaaa1260 tagccagtccatggagcaaggcttccctagactaatagctgatgactttccaggagttga1320 gcctaaggttgatgctgtattacaggcatttggatttttctacttcttcagtggatcatc1380 acagtttgagtttgaccccaatgccaggatggtgacacacatattaaagagtaacagctg1440 30 gttacattgctaggcgagatagggggaagacagatatgggtgtttttaataaatctaata1500 attattcatctaatgtattatgagccaaaatggttaatttttcctgcatgttctgtgact1560 gaagaagatgagccttgcagatatctgcatgtgtcatgaagaatgtttctggaattcttc1620 acttgcttttgaattgcactgaacagaattaagaaatactcatgtgcaataggtgagaga1680 atgtattttcatagatgtgttattacttcctcaataaaaagttttattttgggcctgttc1740 35 ctt 1743 <210> 100 <211> 1467 4~ <212> DNA
<213> Homo Sapiens <300>
<302> MMP11 4$ <310> XM009873 <400> 100 atggctccgg ccgcctggct ccgcagcgcg gccgcgcgcg ccctcctgcc cccgatgctg 60 ctgctgctgc tccagccgcc gccgctgctg gcccgggctc tgccgccgga cgcccaccac 120 SO ctccatgccg agaggagggg gccacagccc tggcatgcag ccctgcccag tagcccggca 180 cctgcccctg ccacgcagga agccccccgg cctgccagca gcctcaggcc tccccgctgt 240 ggcgtgcccg acccatctga tgggctgagt gcccgcaacc gacagaagag gttcgtgctt 300 tctggcgggc gctgggagaa gacggacctc acctacagga tccttcggtt cccatggcag 360 ttggtgcagg agcaggtgcg gcagacgatg gcagaggccc taaaggtatg gagcgatgtg 420 5$ acgccactca cctttactga ggtgcacgag ggccgtgctg acatcatgat cgacttcgcc 480 aggtactggc atggggacga cctgccgttt gatgggcctg ggggcatcct ggcccatgcc 540 ttcttcccca agactcaccg agaaggggat gtccacttcg actatgatga gacctggact 600 atcggggatg accagggcac agacctgctg caggtggcag cccatgaatt tggccacgtg 660 ctggggctgc agcacacaac agcagccaag gccctgatgt ccgccttcta cacctttcgc 720 fi0 tacccactga gtctcagccc agatgactgc aggggcgttc aacacctata tggccagccc 780 \\SERVER\g$\Texte\Anmeldeunterlagen 20031422497-Ribopharma-an-2.doc tggcccactg tcacctccag gaccccagcc ctgggccccc aggctgggat agacaccaat 840 gagattgcac cgctggagcc agacgccccg ccagatgcct gtgaggcctc ctttgacgcg 900 gtctccacca tccgaggcga gctctttttc ttcaaagcgg gctttgtgtg gcgcctccgt 960 gggggccagc tgcagcccgg ctacccagca ttggcctctc gccactggca gggactgccc 1020 S agccctgtgg acgctgcctt cgaggatgcc cagggccaca tttggttctt ccaaggtgct 1080 cagtactggg tgtacgacgg tgaaaagcca gtcctgggcc ccgcacccct caccgagctg 1140 ggcctggtga ggttcccggt ccatgctgcc ttggtctggg gtcccgagaa gaacaagatc 1200 tacttcttcc gaggcaggga ctactggcgt ttccacccca gcacccggcg tgtagacagt 1260 cccgtgcccc gcagggccac tgactggaga ggggtgccct ctgagatcga cgctgccttc 1320 caggatgctg atggctatgc ctacttcctg cgcggccgcc tctactggaa gtttgaccct 1380 gtgaaggtga aggctctgga aggcttcccc cgtctcgtgg gtcctgactt ctttggctgt 1440 gccgagcctg ccaacacttt cctctga 1467 IS <210> 101 <211> 1653 <212> DNA
<213> Homo Sapiens <300>
<302> MMP12 <310> XM006272 <400> 101 2S atgaagtttcttctaatactgctcctgcaggccactgcttctggagctcttcccctgaac60 agctctacaagcctggaaaaaaataatgtgctatttggtgagagatacttagaaaaattt120 tatggccttgagataaacaaacttccagtgacaaaaatgaaatatagtggaaacttaatg180 aaggaaaaaatccaagaaatgcagcacttcttgggtctgaaagtgaccgggcaactggac240 acatctaccctggagatgatgcacgcacctcgatgtggagtccccgatgtccatcatttc300 agggaaatgccaggggggcccgtatggaggaaacattatatcacctacagaatcaataat360 tacacacctgacatgaaccgtgaggatgttgactacgcaatccggaaagctttccaagta420 tggagtaatgttacccccttgaaattcagcaagattaacacaggcatggctgacattttg480 gtggtttttgcccgtggagctcatggagacttccatgcttttgatggcaaaggtggaatc540 ctagcccatgcttttggacctggatctggcattggaggggatgcacatttcgatgaggac600 3S gaattctggactacacattcaggagnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn660 nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn720 nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn780 nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn840 nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn900 nnnnnnnnnnnnnnnnnnnnnnnnngagaggatccaaaggccgtaatgttccccacctac960 aaatatgttgacatcaacacatttcgcctctctgctgatgacatacgtggcattcagtcc1020 ctgtatggagacccaaaagagaaccaacgcttgccaaatcctgacaattcagraccagct1080 ctctgtgaccccaatttgagttttgatgctgtcactaccgtgggaaataagatctttttc1140 ttcaaagacaggttcttctggctgaaggtttctgagagaccaaagaccagtgttaattta1200 4S atttcttccttatggccaaccttgccatctggcattgaagctgcttatgaaattgaagcc1260 agaaatcaagtttttctttttaaagatgacaaatactggttaattagcaatttaagacca1320 gagccaaattatcccaagagcatacattcttttggttttcctaactttgtgaaaaaaatt1380 gatgcagctgtttttaacccacgtttttataggacctacttctttgtagataaccagtat1440 tggaggtatgatgaaaggagacagatgatggaccctggttatcccaaactgattaccaag1500 SO aacttccaaggaatcgggcctaaaattgatgcagtcttctactctaaaaacaaatactac1560 tatttcttccaaggatctaaccaatttgaatatgacttcctactccaacgtatcaccaaa1620 acactgaaaagcaatagctggtttggttgttag 1653 SS <210> 102 <211> 1416 <212> DNA
<213> Homo Sapiens f0 <400> 102 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopham~a-an-2.doc atgcatccaggggtcctggctgccttcctcttcttgagctggactcattgtcgggccctg60 ccccttcccagtggtggtgatgaagatgatttgtctgaggaagacctccagtttgcagag120 cgctacctgagatcatactaccatcctacaaatctcgcgggaatcctgaaggagaatgca180 gcaagctccatgactgagaggctccgagaaatgcagtctttcttcggcttagaggtgact240 S ggcaaacttgacgataacaccttagatgtcatgaaaaagccaagatgcggggttcctgat300 gtgggtgaatacaatgttttccctcgaactcttaaatggtccaaaatgaatttaacctac360 agaattgtgaattacacccctgatatgactcattctgaagtcgaaaaggcattcaaaaaa420 gccttcaaagtttggtccgatgtaactcctctgaattttaccagacttcacgatggcatt480 gctgacatcatgatctcttttggaattaaggagcatggcgacttctacccatttgatggg540 ccctctggcctgctggctcatgcttttcctcctgggccaaattatggaggagatgcccat600 tttgatgatgatgaaacctggacaagtagttccaaaggctacaacttgtttcttgttgct660 gcgcatgagttcggccactccttaggtcttgaccactccaaggaccctggagcactcatg720 tttcctatctacacctacaccggcaaaagccactttatgcttcctgatgacgatgtacaa780 gggatccagtctctctatggtccaggagatgaagaccccaaccctaaacatccaaaaacg840 ccagacaaatgtgacccttccttatcccttgatgccattaccagtctccgaggagaaaca900 atgatctttaaagacagattcttctggcgcctgcatcctcagcaggttgatgcggagctg960 tttttaacgaaatcattttggccagaacttcccaaccgtattgatgctgcatatgagcac1020 ccttctcatgacctcatcttcatcttcagaggtagaaaattttgggctcttaatggttat1080 gacattctggaaggttatcccaaaaaaatatctgaactgggtcttccaaaagaagttaag1140 2~ aagataagtgcagctgttcactttgaggatacaggcaagactctcctgttctcaggaaac1200 caggtctggagatatgatgatactaaccatattatggataaagactatccgagactaata1260 gaagaagacttcccaggaattggtgataaagtagatgctgtctatgagaaaaatggttat1320 atctattttttcaacggacccatacagtttgaatacagcatctggagtaaccgtattgtt1380 cgcgtcatgccagcaaattccattttgtggtgttaa 1416 <210> 103 <211> 1749 <212> DNA

<213> Homosapiens <300>
<302> MMP14 <310> NM004995 <400> 103 atgtctcccgccccaagacccccccgttgtctcctgctccccctgctcacgctcggcacc60 gcgctcgcctccctcggctcggcccaaagcagcagcttcagccccgaagcctggctacag120 caatatggctacctgcctcccggggacctacgtacccacacacagcgctcaccccagtca180 4~ ctctcagcggccatcgctgccatgcagaagttttacggcttgcaagtaacaggcaaagct240 gatgcagacaccatgaaggccatgaggcgcccccgatgtggtgttccagacaagtttggg300 gctgagatcaaggccaatgttcgaaggaagcgctacgccatccagggtctcaaatggcaa360 cataatgaaatcactttctgcatccagaattacacccccaaggtgggcgagtatgccaca420 tacgaggccattcgcaaggcgttccgcgtgtgggagagtgccacaccactgcgcttccgc480 4$ gaggtgccctatgcctacatccgtgagggccatgagaagcaggccgacatcatgatcttc540 tttgccgagggcttccatggcgacagcacgcccttcgatggtgagggcggcttcctggcc600 catgcctacttcccaggccccaacattggaggagacacccactttgactctgccgagcct660 tggactgtcaggaatgaggatctgaatggaaatgacatcttcctggtggctgtgcacgag720 ctgggccatgccctggggctcgagcattccagtgacccctcggccatcatggcacccttt780 SO taccagtggatggacacggagaattttgtgctgcccgatgatgaccgccggggcatccag840 caactttatgggggtgagtcagggttccccaccaagatgccccctcaacccaggactacc900 tcccggccttctgttcctgataaacccaaaaaccccacctatgggcccaacatctgtgac960 gggaactttgacaccgtggccatgctccgaggggagatgtttgtcttcaaggagcgctgg1020 ttctggcgggtgaggaataaccaagtgatggatggatacccaatgcccattggccagttc1080 $S tggcggggcctgcctgcgtccatcaacactgcctacgagaggaaggatggcaaattcgtc1140 ttcttcaaaggagacaagcattgggtgtttgatgaggcgtccctggaacctggctacccc1200 aagcacattaaggagctgggccgagggctgcctaccgacaagattgatgctgctctcttc1260 tggatgcccaatggaaagacctacttcttccgtggaaacaagtactaccgtttcaacgaa1320 gagctcagggcagtggatagcgagtaccccaagaacatcaaagtctgggaagggatccct1380 60 gagtctcccagagggtcattcatgggcagcgatgaagtcttcacttacttctacaagggg1440 \\SERVER\g$\Texte\Anmeldeunterlagen 20031422497-Ribopharma-an-2.doc aacaaatact ggaaattcaa caaccagaag ctgaaggtag aaccgggcta ccccaagtca 1500 gccctgaggg actggatggg ctgcccatcg ggaggccggc cggatgaggg gactgaggag 1560 gagacggagg tgatcatcat tgaggtggac gaggagggcg gcggggcggt gagcgcggct 1620 gccgtggtgc tgcccgtgct gctgctgctc ctggtgctgg cggtgggcct tgcagtcttc 1680 S ttcttcagac gccatgggac ccccaggcga ctgctctact gccagcgttc cctgctggac 1740 aaggtctga 1749 <210> 104 <211> 2010 <212> DNA
<213> Homo Sapiens <300>
1S <302> MMP15 <310> NM002428 <400> 104 atgggcagcgacccgagcgcgcccggacggccgggctggacgggcagcctcctcggcgac60 cgggaggaggcggcgcggccgcgactgctgccgctgctcctggtgcttctgggctgcctg120 ggccttggcgtagcggccgaagacgcggaggtccatgccgagaactggctgcggctttat180 ggctacctgcctcagcccagccgccatatgtccaccatgcgttccgcccagatcttggcc240 tcggcccttgcagagatgcagcgcttctacgggatcccagtcaccggtgtgctcgacgaa300 gagaccaaggagtggatgaagcggccccgctgtggggtgccagaccagttcggggtacga360 ZS gtgaaagccaacctgcggcggcgtcggaagcgctacgccctcaccgggaggaagtggaac420 aaccaccatctgacctttagcatccagaactacacggagaagttgggctggtaccactcg480 atggaggcggtgcgcagggccttccgcgtgtgggagcaggccacgcccctggtcttccag540 gaggtgccctatgaggacatccggctgcggcgacagaaggaggccgacatcatggtactc600 tttgcctctggcttccacggcgacagctcgccgtttgatggcaccggtggctttctggcc660 cacgcctatttccctggccccggcctaggcggggacacccattttgacgcagatgagccc720 tggaccttctccagcactgacctgcatggaaacaacctcttcctggtggcagtgcatgag780 ctgggccacgcgctggggctggagcactccagcaaccccaatgccatcatggcgccgttc840 taccagtggaaggacgttgacaacttcaagctgcccgaggacgatctccgtggcatccag900 cagctctacggtaccccagacggtcagccacagcctacccagcctctccccactgtgacg960 3S ccacggcggccaggccggcctgaccaccggccgccccggcctccccagccaccaccccca1020 ggtgggaagccagagcggcccccaaagccgggccccccagtccagccccgagccacagag1080 cggcccgaccagtatggccccaacatctgcgacggggactttgacacagtggccatgctt1140 cgcggggagatgttcgtgttcaagggccgctggttctggcgagtccggcacaaccgcgtc1200 ctggacaactatcccatgcccatcgggcacttctggcgtggtctgcccggtgacatcagt1260 gctgcctacgagcgccaagacggtcgttttgtctttttcaaaggtgaccgctactggctc1320 tttcgagaagcgaacctggagcccggctacccacagccgctgaccagctatggcctgggc1380 atcccctatgaccgcattgacacggccatctggtgggagcccacaggccacaccttcttc1440 ttccaagaggacaggtactggcgcttcaacgaggagacacagcgtggagaccctgggtac1500 cccaagcccatcagtgtctggcaggggatccctgcctcccctaaaggggccttcctgagc1560 4S aatgacgcagcctacacctacttctacaagggcaccaaatactggaaattcgacaatgag1620 cgcctgcggatggagcccggctaccccaagtccatcctgcgggacttcatgggctgccag1680 gagcacgtggagccaggcccccgatggcccgacgtggcccggccgcccttcaacccccac1740 gggggtgcagagcccggggcggacagcgcagagggcgacgtgggggatggggatggggac1800 tttggggccggggtcaacaaggacgggggcagccgcgtggtggtgcagatggaggaggtg1860 S0 gcacggacggtgaacgtggtgatggtgctggtgccactgctgctgctgctctgcgtcctg1920 ggcctcacctacgcgctggtgcagatgcagcgcaagggtgcgccacgtgtcctgctttac1980 tgcaagcgctcgctgcaggagtgggtctga 2010 S$ <210> 105 <211> 1$24 <212> DNA
<213> Homo Sapiens 60 <300>
\\SERVER\g~\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <302> MMP16 <310> NM005941 <400> 105 S atgatcttactcacattcagcactggaagacggttggatttcgtgcatcattcgggggtg60 tttttcttgcaaaccttgctttggattttatgtgctacagtctgcggaacggagcagtat120 ttcaatgtggaggtttggttacaaaagtacggctaccttccaccgactgaccccagaatg180 tcagtgctgcgctctgcagagaccatgcagtctgccctagctgccatgcagcagttctat240 ggcattaacatgacaggaaaagtggacagaaacacaattgactggatgaagaagccccga300 1~ tgcggtgtacctgaccagacaagaggtagctccaaatttcatattcgtcgaaagcgatat360 gcattgacaggacagaaatggcagcacaagcacatcacttacagtataaagaacgtaact420 ccaaaagtaggagaccctgagactcgtaaagctattcgccgtgcctttgatgtgtggcag480 aatgtaactcctctgacatttgaagaagttccctacagtgaattagaaaatggcaaacgt540 gatgtggatataaccattatttttgcatctggtttccatggggacagctctccctttgat600 1S ggagagggaggatttttggcacatgcctacttccctggaccaggaattggaggagatacc660 cattttgactcagatgagccatggacactaggaaatcctaatcatgatggaaatgactta720 tttcttgtagcagtccatgaactgggacatgctctgggattggagcattccaatgacccc780 actgccatcatggctccattttaccagtacatggaaacagacaacttcaaactacctaat840 gatgatttacagggcatccagaaaatatatggtccacctgacaagattcctccacctaca900 2~ agacctctaccgacagtgcccccacaccgctctattcctccggctgacccaaggaaaaat960 gacaggccaaaacctcctcggcctccaaccggcagaccctcctatcccggagccaaaccc1020 aacatctgtgatgggaactttaacactctagctattcttcgtcgtgagatgtttgttttc1080 aaggaccagtggttttggcgagtgagaaacaacagggtgatggatggatacccaatgcaa1240 attacttacttctggcggggcttgcctcctagtatcgatgcagtttatgaaaatagcgac1200 2S gggaattttgtgttctttaaaggtaacaaatattgggtgttcaaggatacaactcttcaa1260 cctggttaccctcatgacttgataacccttggaagtggaattccccctcatggtattgat1320 tcagccatttggtgggaggacgtcgggaaaacctatttcttcaagggagacagatattgg1380 agatatagtgaagaaatgaaaacaatggaccctggctatcccaagccaatcacagtctgg1440 aaagggatccctgaatctcctcagggagcatttgtacacaaagaaaatggctttacgtat1500 3~ ttctacaaaggaaaggagtattggaaattcaacaaccagatactcaaggtagaacctgga1560 catccaagatccatcctcaaggattttatgggctgtgatggaccaacagacagagttaaa1620 gaaggacacagcccaccagatgatgtagacattgtcatcaaactggacaacacagccagc1680 actgtgaaagccatagctattgtcattccctgcatcttggccttatgcctccttgtattg1740 gtttacactgtgttccagttcaagaggaaaggaacaccccgccacatactgtactgtaaa1800 3S cgctctatgcaagagtgggtgtga 1824 <210> 106 <211> 1560 4O <212> DNA
<213> Homo Sapiens <300>
<302> MMP17 4S <310> NM004141 <400> 106 atgcagcagt ttggtggcct ggaggccacc ggcatcctgg acgaggccac cctggccctg 60 atgaaaaccc cacgctgctc cctgccagac ctccctgtcc tgacccaggc tcgcaggaga 120 S~ cgccaggctc cagcccccac caagtggaac aagaggaacc tgtcgtggag ggtccggacg 180 ttcccacggg actcaccact ggggcacgac acggtgcgtg cactcatgta ctacgccctc 240 aaggtctgga gcgacattgc gcccctgaac ttccacgagg tggcgggcag caccgccgac 300 atccagatcg acttctccaa ggccgaccat aacgacggct accccttcga cggccccggc 360 ggcaccgtgg cccacgcctt cttccccggc caccaccaca ccgccgggga cacccacttt 420 SS gacgatgacg aggcctggac cttccgctcc tcggatgccc acgggatgga cctgtttgca 480 gtggctgtcc acgagtttgg ccacgccatt gggttaagcc atgtggccgc tgcacactcc 540 atcatgcggc cgtactacca gggcccggtg ggtgacccgc tgcgctacgg gctcccctac 600 gaggacaagg tgcgcgtctg gcagctgtac ggtgtgcggg agtctgtgtc tcccacggcg 660 cagcccgagg agcctcccct gctgccggag cccccagaca accggtccag cgccccgccc 720 aggaaggacg tgccccacag atgcagcact cactttgacg cggtggccca gatccggggt 780 \\SERVER\g$\Texte\Anmeldeunterlagen 20034422497-Ribopharma-an-2.doc gaagctttct tcttcaaagg caagtacttc tggcggctga cgcgggaccg gcacctggtg 840 tccctgcagc cggcacagat gcaccgcttc tggcggggcc tgccgctgca cctggacagc 900 gtggacgccg tgtacgagcg caccagcgac cacaagatcg tcttctttaa aggagacagg 960 tactgggtgt tcaaggacaa taacgtagag gaaggatacc cgcgccccgt ctccgacttc 1020 S agcctcccgc ctggcggcat cgacgctgcc ttctcctggg cccacaatga caggacttat 1080 ttctttaagg accagctgta ctggcgctac gatgaccaca cgaggcacat ggaccccggc 1140 taccccgccc agagccccct gtggaggggt gtccccagca cgctggacga cgccatgcgc 1200 tggtccgacg gtgcctccta cttcttccgt ggccaggagt actggaaagt gctggatggc 1260 gagctggagg tggcacccgg gtacccacag tccacggccc gggactggct ggtgtgtgga 1320 gactcacagg ccgatggatc tgtggctgcg ggcgtggacg cggcagaggg gccccgcgcc 1380 cctccaggac aacatgacca gagccgctcg gaggacggtt acgaggtctg ctcatgcacc 1440 tctggggcat cctctccccc gggggcccca ggcccactgg tggctgccac catgctgctg 1500 ctgctgccgc cactgtcacc aggcgccctg tggacagcgg cccaggccct gacgctatga 1560 <210> 107 <211> 1983 <212> DNA
<213> Homo Sapiens <300>
<302> MMP2 <310> NM004530 2S <400> 107 atggaggcgctaatggcccggggcgcgctcacgggtcccctgagggcgctctgtctcctg60 ggctgcctgctgagccacgccgccgccgcgccgtcgcccatcatcaagttccccggcgat120 gtcgcccccaaaacggacaaagagttggcagtgcaatacctgaacaccttctatggctgc180 cccaaggagagctgcaacctgtttgtgctgaaggacacactaaagaagatgcagaagttc240 tttggactgccccagacaggtgatcttgaccagaataccatcgagaccatgcggaagcca300 cgctgcggcaacccagatgtggccaactacaacttcttccctcgcaagcccaagtgggac360 aagaaccagatcacatacaggatcattggctacacacctgatctggacccagagacagtg420 gatgatgcctttgctcgtgccttccaagtctggagcgatgtgaccccactgcggttttct480 cgaatccatgatggagaggcagacatcatgatcaactttggccgctgggagcatggcgat540 3S ggatacccctttgacggtaaggacggactcctggctcatgccttcgccccaggcactggt600 gttgggggagactcccattttgatgacgatgagctatggaccttgggagaaggccaagtg660 gtccgtgtgaagtatggcaacgccgatggggagtactgcaagttccccttcttgttcaat720 ggcaaggagtacaacagctgcactgatactggccgcagcgatggcttcctctggtgctcc780 accacctacaactttgagaaggatggcaagtacggcttctgtccccatgaagccctgttc840 accatgggcggcaacgctgaaggacagccctgcaagtttccattccgcttccagggcaca900 tcctatgacagctgcaccactgagggccgcacggatggctaccgctggtgcggcaccact960 gaggactacgaccgcgacaagaagtatggcttctgccctgagaccgccatgtccactgtt1020 ggtgggaactcagaaggtgccccctgtgtcttccccttcactttcctgggcaacaaatat1080 gagagctgcaccagcgccggccgcagtgacggaaagatgtggtgtgcgaccacagccaac1140 4S tacgatgacgaccgcaagtggggcttctgccctgaccaagggtacagcctgttcctcgtg1200 gcagcccacgagtttggccacgccatggggctggagcactcccaagaccctggggccctg1260 atggcacccatttacacctacaccaagaacttccgtctgtcccaggatgacatcaagggc1320 attcaggagctctatggggcctctcctgacattgaccttggcaccggccccacccccaca1380 ctgggccctgtcactcctgagatctgcaaacaggacattgtatttgatggcatcgctcag1440 S0 atccgtggtgagatcttcttcttcaaggaccggttcatttggcggactgtgacgccacgt1500 gacaagcccatggggcccctgctggtggccacattctggcctgagctcccggaaaagatt1560 gatgcggtatacgaggccccacaggaggagaaggctgtgttctttgcagggaatgaatac1620 tggatctactcagccagcaccctggagcgagggtaccccaagccactgaccagcctggga1680 ctgccccctgatgtccagcgagtggatgccgcctttaactggagcaaaaacaagaagaca1740 SS tacatctttgctggagacaaattctggagatacaatgaggtgaagaagaaaatggatcct1800 ggctttcccaagctcatcgcagatgcctggaatgccatccccgataacctggatgccgtc1860 gtggacctgcagggcggcggtcacagctacttcttcaagggtgcctattacctgaagctg1920 gagaaccaaagtctgaagagcgtgaagtttggaagcatcaaatccgactggctaggctgc1980 tga 11SERVERIg$~TextelAameldeunterlagen 20031422497-Ribopharma-aa-2.doc <210> 108 <211> 1434 <212> DNA
$ <213> Homo sapiens <300>
<302> MMP2 <310> XM006271 <300>
<302> MMP3 <310> XM006271 1$ <400> 108 atgaagagtcttccaatcctactgttgctgtgcgtggcagtttgctcagcctatccattg60 gatggagctgcaaggggtgaggacaccagcatgaaccttgttcagaaatatctagaaaac120 tactacgacctcgaaaaagatgtgaaacagtttgttaggagaaaggacagtggtcctgtt180 gttaaaaaaatccgagaaatgcagaagttccttggattggaggtgacggggaagctggac240 tccgacactctggaggtgatgcgcaagcccaggtgtggagttcctgacgttggtcacttc300 agaacctttcctggcatcccgaagtggaggaaaacccaccttacatacaggattgtgaat360 tatacaccagatttgccaaaagatgctgttgattctgctgttgagaaagctctgaaagtc420 tgggaagaggtgactccactcacattctccaggctgtatgaaggagaggctgatataatg480 atctcttttgcagttagagaacatggagacttttacccttttgatggacctggaaatgtt540 2$ ttggcccatgcctatgcccctgggccagggattaatggagatgcccactttgatgatgat600 gaacaatggacaaaggatacaacagggaccaatttatttctcgttgctgctcatgaaatt660 ggccactccctgggtctctttcactcagccaacactgaagctttgatgtacccactctat720 cactcactcacagacctgactcggttccgcctgtctcaagatgatataaatggcattcag780 tccctctatggacctccccctgactcccctgagacccccctggtacccacggaacctgtc840 cctccagaacctgggacgccagccaactgtgatcctgctttgtcctttgatgctgtcagc900 actctgaggggagaaatcctgatctttaaagacaggcacttttggcgcaaatccctcagg960 aagcttgaacctgaattgcatttgatctcttcattttggccatctcttccttcaggcgtg1020 gatgccgcatatgaagttactagcaaggacctcgttttcatttttaaaggaaatcaattc1080 tgggccatcagaggaaatgaggtacgagctggatacccaagaggcatccacaccctaggt1140 3$ ttccctccaaccgtgaggaaaatcgatgcagccatttctgataaggaaaagaacaaaaca1200 tatttctttgtagaggacaaatactggagatttgatgagaagagaaattccatggagcca1260 ggctttcccaagcaaatagctgaagactttccagggattgactcaaagattgatgctgtt1320 tttgaagaatttgggttcttttatttctttactggatcttcacagttggagtttgaccca1380 aatgcaaagaaagtgacacacactttgaagagtaacagctggcttaattgttga 1434 <220> 209 <211> 1404 <212> DNA

4$ <213> Homosapiens <300>
<302> MMPB
<310> NM002424 $0 <400> 109 atgttctccc tgaagacgct tccatttctg ctcttactcc atgtgcagat ttccaaggcc 60 tttcctgtat cttctaaaga gaaaaataca aaaactgttc aggactacct ggaaaagttc 120 taccaattac caagcaacca gtatcagtct acaaggaaga atggcactaa tgtgatcgtt 180 S$ gaaaagctta aagaaatgca gcgatttttt gggttgaatg tgacggggaa gccaaatgag 240 gaaactctgg acatgatgaa aaagcctcgc tgtggagtgc ctgacagtgg tggttttatg 300 ttaaccccag gaaaccccaa gtgggaacgc actaacttga cctacaggat tcgaaactat 360 accccacagc tgtcagaggc tgaggtagaa agagctatca aggatgcctt tgaactctgg 420 agtgttgcat cacctctcat cttcaccagg atctcacagg gagaggcaga tatcaacatt 480 60 gctttttacc aaagagatca cggtgacaat tctccatttg atggacccaa tggaatcctt 540 11SERVERIg$lTextelAnmeideunterlagen 20031422497-Ribopharcna-an-2.doc gctcatgcct ttcagccagg ccaaggtatt ggaggagatg ctcattttga tgccgaagaa 600 acatggacca acacctccgc aaattacaac ttgtttcttg ttgctgctca tgaatttggc 660 cattctttgg ggctcgctca ctcctctgac cctggtgcct tgatgtatcc caactatgct 720 ttcagggaaa ccagcaacta ctcactccct caagatgaca tcgatggcat tcaggccatc 780 S tatggacttt caagcaaccc tatccaacct actggaccaa gcacacccaa accctgtgac 840 cccagtttga catttgatgc tatcaccaca ctccgtggag aaatactttt ctttaaagac 900 aggtacttct ggagaaggca tcctcagcta caaagagtcg aaatgaattt tatttctcta 960 ttctggccat cccttccaac tggtatacag gctgcttatg aagattttga cagagacctc 1020 attttcctat ttaaaggcaa ccaatactgg gctctgagtg gctatgatat tctgcaaggt 1080 tatcccaagg atatatcaaa ctatggcttc cccagcagcg tccaagcaat tgacgcagct 1140 gttttctaca gaagtaaaac atacttcttt gtaaatgacc aattctggag atatgataac 1200 caaagacaat tcatggagcc aggttatccc aaaagcatat caggtgcctt tccaggaata 1260 gagagtaaag ttgatgcagt tttccagcaa gaacatttct tccatgtctt cagtggacca 1320 agatattacg catttgatct tattgctcag agagttacca gagttgcaag aggcaataaa 1380 1S tggcttaact gtagatatgg ctga 1404 <210> 110 <211> 2124 <212> DNA
<213> Homo sapiens <300>
<302> MMP9 2S <310> XM009491 <400> 110 atgagcctctggcagcccctggtcctggtgctcctggtgctgggctgctgctttgctgcc60 cccagacagcgccagtccacccttgtgctcttccctggagacctgagaaccaatctcacc120 gacaggcagctggcagaggaatacctgtaccgctatggttacactcgggtggcagagatg180 cgtggagagtcgaaatctctggggcctgcgctgctgcttctccagaagcaactgtccctg240 cccgagaccggtgagctggatagcgccacgctgaaggccatgcgaaccccacggtgcggg300 gtcccagacctgggcagattccaaacctttgagggcgacctcaagtggcaccaccacaac360 atcacctattggatccaaaactactcggaagacttgccgcgggcggtgattgacgacgcc420 3S tttgcccgcgccttcgcactgtggagcgcggtgacgccgctcaccttcactcgcgtgtac480 agccgggacgcagacatcgtcatccagtttggtgtcgcggagcacggagacgggtatccc540 ttcgacgggaaggacgggctcctggcacacgcctttcctcctggccccggcattcaggga600 gacgcccatttcgacgatgacgagttgtggtccctgggcaagggcgtcgtggttccaact660 cggtttggaaacgcagatggcgcggcctgccacttccccttcatcttcgagggccgctcc720 tactctgcctgcaccaccgacggtcgctccgacggcttgccctggtgcagtaccacggcc780 aactacgacaccgacgaccggtttggcttctgccccagcgagagactctacacccaggac840 ggcaatgctgatgggaaaccctgccagtttccattcatcttccaaggccaatcctactcc900 gcctgcaccacggacggtcgctccgacggctaccgctggtgcgccaccaccgccaactac960 gaccgggacaagctcttcggcttctgcccgacccgagctgactcgacggtgatggggggc1020 4S aactcggcgggggagctgtgcgtcttccccttcactttcctgggtaaggagtactcgacc1080 tgtaccagcgagggccgcggagatgggcgcctctggtgcgctaccacctcgaactttgac1140 agcgacaagaagtggggcttctgcccggaccaaggatacagtttgttcctcgtggcggcg1200 catgagttcggccacgcgctgggcttagatcattcctcagtgccggaggcgctcatgtac1260 cctatgtaccgcttcactgaggggccccccttgcataaggacgacgtgaatggcatccgg1320 SO cacctctatggtcctcgccctgaacctgagccacggcctccaaccaccaccacaccgcag1380 cccacggctcccccgacggtctgccccaccggaccccccactgtccacccctcagagcgc1440 cccacagctggccccacaggtcccccctcagctggccccacaggtccccccactgctggc1500 ccttctacggccactactgtgcctttgagtccggtggacgatgcctgcaacgtgaacatc1560 ttcgacgccatcgcggagattgggaaccagctgtatttgttcaaggatgggaagtactgg1620 SS cgattctctgagggcagggggagccggccgcagggccccttccttatcgccgacaagtgg1680 cccgcgctgccccgcaagctggactcggtctttgaggagcggctctccaagaagcttttc1740 ttcttctctgggcgccaggtgtgggtgtacacaggcgcgtcggtgctgggcccgaggcgt1800 ctggacaagctgggcctgggagccgacgtggcccaggtgaccggggccctccggagtggc1860 agggggaagatgctgctgttcagcgggcggcgcctctggaggttcgacgtgaaggcgcag1920 f)0atggtggatccccggagcgccagcgaggtggaccggatgttccccggggtgcctttggac1980 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc S
acgcacgacg tcttccagta ccgagagaaa gcctatttct gccaggaccg cttctactgg 2040 cgcgtgagtt cccggagtga gttgaaccag gtggaccaag tgggctacgt gacctatgac 2100 atcctgcagt gccctgagga ctag 2124 <210> 111 <211> 2019 <212> DNA
<213> Homo Sapiens <300>
<302> PKC alpha <310> NM002737 1S <400> 111 atggctgacgttttcccgggcaacgactccacggcgtctcaggacgtggccaaccgcttc60 gcccgcaaaggggcgctgaggcagaagaacgtgcacgaggtgaaggaccacaaattcatc120 gcgcgcttcttcaagcagcccaccttctgcagccactgcaccgacttcatctgggggttt180 gggaaacaaggcttccagtgccaagtttgctgttttgtggtccacaagaggtgccatgaa240 tttgttactttttcttgtccgggtgcggataagggacccgacactgatgaccccaggagc300 aagcacaagttcaaaatccacacttacggaagccccaccttctgcgatcactgtgggtca360 ctgctctatggacttatccatcaagggatgaaatgtgacacctgcgatatgaacgttcac420 aagcaatgcgtcatcaatgtccccagcctctgcggaatggatcacactgagaagaggggg480 cggatttacctaaaggctgaggttgctgatgaaaagctccatgtcacagtacgagatgca540 2S aaaaatctaatccctatggatccaaacgggctttcagatccttatgtgaagctgaaactt600 attcctgatcccaagaatgaaagcaagcaaaaaaccaaaaccatccgctccacactaaat660 ccgcagtggaatgagtcctttacattcaaattgaaaccttcagacaaagaccgacgactg720 tctgtagaaatctgggactgggatcgaacaacaaggaatgacttcatgggatccctttcc780 tttggagtttcggagctgatgaagatgccggccagtggatggtacaagttgcttaaccaa840 gaagaaggtgagtactacaacgtacccattccggaaggggacgaggaaggaaacatggaa900 ctcaggcagaaattcgagaaagccaaacttggccctgctggcaacaaagtcatcagtccc960 tctgaagacaggaaacaaccttccaacaaccttgaccgagtgaaactcacggacttcaat1020 ttcctcatggtgttgggaaaggggagttttggaaaggtgatgcttgccgacaggaagggc1080 acagaagaactgtatgcaatcaaaatcctgaagaaggatgtggtgattcaggatgatgac1140 3S gtggagtgcaccatggtagaaaagcgagtcttggccctgcttgacaaacccccgttcttg1200 acgcagctgcactcctgcttccagacagtggatcggctgtacttcgtcatggaatatgtc1260 aacggtggggacctcatgtaccacattcagcaagtaggaaaatttaaggaaccacaagca1320 gtattctatgcggcagagatttccatcggattgttctttcttcataaaagaggaatcatt1380 tatagggatctgaagttagataacgtcatgttggattcagaaggacatatcaaaattgct1440 gactttgggatgtgcaaggaacacatgatggatggagtcacgaccaggaccttctgtggg1500 actccagattatatcgccccagagataatcgcttatcagccgtatggaaaatctgtggac1560 tggtgggcctatggcgtcctgttgtatgaaatgcttgccgggcagcctccatttgatggt1620 gaagatgaagacgagctatttcagtctatcatggagcacaacgtttcctatccaaaatcc1680 ttgtccaaggaggctgtttctatctgcaaaggactgatgaccaaacacccagccaagcgg1740 4S ctgggctgtgggcctgagggggagagggacgtgagagagcatgccttcttccggaggatc1800 gactgggaaaaactggagaacagggagatccagccaccattcaagcccaaagtgtgtggc1860 aaaggagcagagaactttgacaagttcttcacacgaggacagcccgtcttaacaccacct1920 gatcagctggttattgctaacatagaccagtctgattttgaagggttctcgtatgtcaac1980 ccccagtttgtgcaccccatcttacagagtgcagtatga 2019 <210> 112 <211> 2022 <212> DNA

SS <213> HomoSapiens <300>
<302> PKC beta <310> X07109 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <400> 112 atggctgacccggctgcggggccgccgccgagcgagggcgaggagagcaccgtgcgcttc60 gcccgcaaaggcgccctccggcagaagaacgtgcatgaggtcaagaaccacaaattcacc120 gcccgcttcttcaagcagcccaccttctgcagccactgcaccgacttcatctggggcttc180 S gggaagcagggattccagtgccaagtttgctgctttgtggtgcacaagcggtgccatgaa240 tttgtcacattctcctgccctggcgctgacaagggtccagcctccgatgacccccgcagc300 aaacacaagtttaagatccacacgtactccagccccacgttttgtgaccactgtgggtca360 ctgctgtatggactcatccaccaggggatgaaatgtgacacctgcatgatgaatgtgcac420 aagcgctgcgtgatgaatgttcccagcctgtgtggcacggaccacacggagcgccgcggc480 1~ cgcatctacatccaggcccacatcgacagggacgtcctcattgtcctcgtaagagatgct540 aaaaaccttgtacctatggaccccaatggcctgtcagatccctacgtaaaactgaaactg600 attcccgatcccaaaagtgagagcaaacagaagaccaaaaccatcaaatgctccctcaac660 cctgagtggaatgagacatttagatttcagctgaaagaatcggacaaagacagaagactg720 tcagtagagatttgggattgggatttgaccagcaggaatgacttcatgggatctttgtcc780 1S tttgggatttctgaacttcagaaggccagtgttgatggctggtttaagttactgagccag840 gaggaaggcgagtacttcaatgtgcctgtgccaccagaaggaagtgaggccaatgaagaa900 ctgcggcagaaatttgagagggccaagatcagtcagggaaccaaggtcccggaagaaaag960 acgaccaacactgtctccaaatttgacaacaatggcaacagagaccggatgaaactgacc1020 gattttaacttcctaatggtgctggggaaaggcagctttggcaaggtcatgctttcagaa1080 2~ cgaaaaggcacagatgagctctatgctgtgaagatcctgaagaaggacgttgtgatccaa1140 gatgatgacgtggagtgcactatggtggagaagcgggtgttggccctgcctgggaagccg1200 cccttcctgacccagctccactcctgcttccagaccatggaccgcctgtactttgtgatg1260 gagtacgtgaatgggggcgacctcatgtatcacatccagcaagtcggccggttcaaggag1320 ccccatgctgtattttacgctgcagaaattgccatcggtctgttcttcttacagagtaag1380 2S ggcatcatttaccgtgacctaaaacttgacaacgtgatgctcgattctgagggacacatc1440 aagattgccgattttggcatgtgtaaggaaaacatctgggatggggtgacaaccaagaca1500 ttctgtggcactccagactacatcgcccccgagataattgcttatcagccctatgggaag1560 tccgtggattggtgggcatttggagtcctgctgtatgaaatgttggctgggcaggcaccc1620 tttgaaggggaggatgaagatgaactcttccaatccatcatggaacacaacgtagcctat1680 30 cccaagtctatgtccaaggaagctgtggccatctgcaaagggctgatgaccaaacaccca1740 ggcaaacgtctgggttgtggacctgaaggcgaacgtgatatcaaagagcatgcatttttc1800 cggtatattgattgggagaaacttgaacgcaaagagatccagcccccttataagccaaaa1860 gcttgtgggcgaaatgctgaaaacttcgaccgatttttcacccgccatccaccagtccta1920 acacctcccgaccaggaagtcatcaggaatattgaccaatcagaattcgaaggattttcc1980 3S tttgttaactctgaatttttaaaacccgaagtcaagagctas 2022 <210> 113 <211> 2031 4U <212> DNA
<213> Homo sapiens <300>
<302> PKC delta 45 <310> NM006254 <400> 113 atggcgccgt tcctgcgcat cgccttcaac tcctatgagc tgggctccct gcaggccgag 60 gacgaggcga accagccctt ctgtgccgtg aagatgaagg aggcgctcag cacagagcgt 120 SO gggaaaacac tggtgcagaa gaagccgacc atgtatcctg agtggaagtc gacgttcgat 180 gcccacatct atgaggggcg cgtcatccag attgtgctaa tgcgggcagc agaggagcca 240 gtgtctgagg tgaccgtggg tgtgtcggtg ctggccgagc gctgcaagaa gaacaatggc 300 aaggctgagt tctggctgga cctgcagcct caggccaagg tgttgatgtc tgttcagtat 360 ttcctggagg acgtggattg caaacaatct atgcgcagtg aggacgaggc caagttccca 420 SS acgatgaacc gccgcggagc catcaaacag gccaaaatcc actacatcaa gaaccatgag 480 tttatcgcca ccttctttgg gcaacccacc ttctgttctg tgtgcaaaga ctttgtctgg 540 ggcctcaaca agcaaggcta caaatgcagg caatgtaacg ctgccatcca caagaaatgc 600 atcgacaaga tcatcggcag atgcactggc accgcggcca acagccggga cactatattc 660 cagaaagaac gcttcaacat cgacatgccg caccgcttca aggttcacaa ctacatgagc 720 cccaccttct gtgaccactg cggcagcctg ctctggggac tggtgaagca gggattaaag 780 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc tgtgaagactgcggcatgaatgtgcaccataaatgccgggagaaggtggccaacctctgc840 ggcatcaaccagaagcttttggctgaggccttgaaccaagtcacccagagagcctcccgg900 agatcagactcagcctcctcagagcctgttgggatatatcagggtttcgagaagaagacc960 ggagttgctggggaggacatgcaagacaacagtgggacctacggcaagatctgggagggc1020 S agcagcaagtgcaacatcaacaacttcatcttccacaaggtcctgggcaaaggcagcttc1080 gggaaggtgctgcttggagagctgaagggcagaggagagtactctgccatcaaggccctc1140 aagaaggatgtggtcctgatcgacgacgacgtggagtgcaccatggttgagaagcgggtg1200 ctgacacttgccgcagagaatccctttctcacccacctcatctgcaccttccagaccaag1260 gaccacctgttctttgtgatggagttcctcaacgggggggacctgatgtaccacatccag1320 gacaaaggccgctttgaactctaccgtgccacgttttatgccgctgagataatgtgtgga1380 ctgcagtttctacacagcaagggcatcatttacagggacctcaaactggacaatgtgctg1440 ttggaccgggatggccacatcaagattgccgactttgggatgtgcaaagagaacatattc1500 ggggagagccgggccagcaccttctgcggcacccctgactatatcgcccctgagatccta1560 cagggcctgaagtacacattctctgtggactggtggtctttcggggtccttctgtacgag1620 1S atgctcattggccagtcccccttccatggtgatgatgaggatgaactcttcgagtccatc1680 cgtgtggacacgccacattatccccgctggatcaccaaggagtccaaggacatcctggag1740 aagctctttgaaagggaaccaaccaagaggctgggaatgacgggaaacatcaaaatccac1800 cccttcttcaagaccataaactggactctgctggaaaagcggaggttggagccacccttc1860 aggcccaaagtgaagtcacccagagactacagtaactttgaccaggagttcctgaacgag1920 z0 aaggcgcgcctctcctacagcgacaagaacctcatcgactccatggaccagtctgcattc1980 gctggcttctcctttgtgaaccccaaattcgagcacctcctggaagattga 2031 <210> 114 2S <211> 2049 <212> DNA
<213> Homo Sapiens <300>
30 <302> PKC eta <310> NM006255 <400> 114 atgtcgtctggcaccatgaagttcaatggctatttgagggtccgcatcggtgaggcagtg60 3S gggctgcagcccacccgctggtccctgcgccactcgctcttcaagaagggccaccagctg120 ctggacccctatctgacggtgagcgtggaccaggtgcgcgtgggccagaccagcaccaag180 cagaagaccaacaaacccacgtacaacgaggagttttgcgctaacgtcaccgacggcggc240 cacctcgagttggccgtcttccacgagacccccctgggctacgacttcgtggccaactgc300 accctgcagttccaggagctcgtcggcacgaccggcgcctcggacaccttcgagggttgg360 40 gtggatctcgagccagaggggaaagtatttgtggtaataacccttaccgggagtttcact420 gaagctactctccagagagaccggatcttcaaacattttaccaggaagcgccaaagggct480 atgcgaaggcgagtccaccagatcaatggacacaagttcatggccacgtatctgaggcag540 cccacctactgctctcactgcagggagtttatctggggagtgtttgggaaacagggttat600 cagtgccaagtgtgcacctgtgtcgtccataaacgctgccatcatctaattgttacagcc660 4S tgtacttgccaaaacaatattaacaaagtggattcaaagattgcagaacagaggttcggg720 atcaacatcccacacaagttcagcatccacaactacaaagtgccaacattctgcgatcac780 tgtggctcactgctctggggaataatgcgacaaggacttcagtgtaaaatatgtaaaatg840 aatgtgcatattcgatgtcaagcgaacgtggcccctaactgtggggtaaatgcggtggaa900 cttgccaagaccctggcagggatgggtctccaacccggaaatatttctccaacctcgaaa960 SO ctcgtttccagatcgaccctaagacgacagggaaaggagagcagcaaagaaggaaatggg1020 attggggttaattcttccaaccgacttggtatcgacaactttgagttcatccgagtgttg1080 gggaaggggagttttgggaaggtgatgcttgcaagagtaaaagaaacaggagacctctat1140 gctgtgaaggtgctgaagaaggacgtgattctgctggatgatgatgtggaatgcaccatg1200 accgagaaaaggatcctgtctctggcccgcaatcaccccttcctcactcagttgttctgc1260 SS tgctttcagacccccgatcgtctgttttttgtgatggagtttgtgaatgggggtgacttg1320 atgttccacattcagaagtctcgtcgttttgatgaagcacgagctcgcttctatgctgca1380 gaaatcatttcggctctcatgttcctccatgataaaggaatcatctatagagatctgaaa1440 ctggacaatgtcctgttggaccacgagggtcactgtaaactggcagacttcggaatgtgc1500 aaggaggggatttgcaatggtgtcaccacggccacattctgtggcacgccagactatatc1560 fi0gctccagagatcctccaggaaatgctgtacgggcctgcagtagactggtgggcaatgggc1620 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc gtgttgctct atgagatgct ctgtggtcac gcgccttttg aggcagagaa tgaagatgac 1680 ctctttgagg ccatactgaa tgatgaggtg gtctacccta cctggctcca tgaagatgcc 1740 acagggatcc taaaatcttt catgaccaag aaccccacca tgcgcttggg cagcctgact 1800 cagggaggcg agcacgccat cttgagacat ccttttttta aggaaatcga ctgggcccag 1860 S ctgaaccatc gccaaataga accgcctttc agacccagaa tcaaatcccg agaagatgtc 1920 agtaattttg accctgactt cataaaggaa gagccagttt taactccaat tgatgaggga 1980 catcttccaa tgattaacca ggatgagttt agaaactttt cctatgtgtc tccagaattg 2040 caaccatag 2049 <210> 115 <211> 948 <212> DNA
<213> Homo Sapiens <300>
<302> PKC epsilon <320> XM002370 <400> 115 atgttggcagaactcaagggcaaagatgaagtatatgctgtgaaggtcttaaagaaggac60 gtcatccttcaggatgatgacgtggactgcacaatgacagagaagaggattttggctctg120 gcacggaaacacccgtaccttacccaactctactgctgcttccagaccaaggaccgcctc180 tttttcgtcatggaatatgtaaatggtggagacctcatgtttcagattcagcgctcccga240 2S aaattcgacgagcctcgttcacggttctatgctgcagaggtcacatcggccctcatgttc300 ctccaccagcatggagtcatctacagggatttgaaactggacaacatccttctggatgca360 gaaggtcactgcaagctggctgacttcgggatgtgcaaggaagggattctgaatggtgtg420 acgaccaccacgttctgtgggactcctgactacatagctcctgagatcctgcaggagttg480 gagtatggcccctccgtggactggtgggccctgggggtgctgatgtacgagatgatggct540 ggacagcctccctttgaggccgacaatgaggacgacctatttgagtccatcctccatgac600 gacgtgctgtacccagtctggctcagcaaggaggctgtcagcatcttgaaagctttcatg660 acgaagaatccccacaagcgcctgggctgtgtggcatcgcagaatggcgaggacgccatc720 aagcagcacccattcttcaaagagattgactgggtgctcctggagcagaagaagatcaag780 ccacccttcaaaccacgcattaaaaccaaaagagacgtcaataattttgaccaagacttt840 3S acccgggaagagccggtactcacccttgtggacgaagcaattgtaaagcagatcaaccag900 gaggaattcaaaggtttctcctactttggtgaagacctgatgccctga 948 <210> 116 44 <211> 1764 <212> DNA
<213> Homo Sapiens <300>
4S <302> PKC iota <310> NM002740 <400> 116 atgtcccaca cggtcgcagg cggcggcagc ggggaccatt cccaccaggt ccgggtgaaa 60 SQ gcctactacc gcggggatat catgataaca cattttgaac cttccatctc ctttgagggc 120 ctttgcaatg aggttcgaga catgtgttct tttgacaacg aacagctctt caccatgaaa 180 tggatagatg aggaaggaga cccgtgtaca gtatcatctc agttggagtt agaagaagcc 240 tttagacttt atgagctaaa caaggattct gaactcttga ttcatgtgtt cccttgtgta 300 ccagaacgtc ctgggatgcc ttgtccagga gaagataaat ccatctaccg tagaggtgca 360 SS cgccgctgga gaaagcttta ttgtgccaat ggccacactt tccaagccaa gcgtttcaac 420 aggcgtgctc actgtgccat ctgcacagac cgaatatggg gacttggacg ccaaggatat 480 aagtgcatca actgcaaact cttggttcat aagaagtgcc ataaactcgt cacaattgaa 540 tgtgggcggc attctttgcc acaggaacca gtgatgccca tggatcagtc atccatgcat 600 tctgaccatg cacagacagt aattccatat aatccttcaa gtcatgagag tttggatcaa 660 60 gttggtgaag aaaaagaggc aatgaacacc agggaaagtg gcaaagcttc atccagtcta 720 \\SERVER\g$\Texte\Anmeldeunterlagen 20034122497-Ribopharma-an-2.doc ggtcttcagg attttgattt gctccgggta ataggaagag gaagttatgc caaagtactg 780 ttggttcgat taaaaaaaac agatcgtatt tatgcaatga aagttgtgaa aaaagagctt 840 gttaatgatg atgaggatat tgattgggta cagacagaga agcatgtgtt tgagcaggca 900 tccaatcatc ctttccttgt tgggctgcat tcttgctttc agacagaaag cagattgttc 960 S tttgttatag agtatgtaaa tggaggagac ctaatgtttc atatgcagcg acaaagaaaa 1020 cttcctgaag aacatgccag attttactct gcagaaatca gtctagcatt aaattatctt 1080 catgagcgag ggataattta tagagatttg aaactggaca atgtattact ggactctgaa 1140 ggccacatta aactcactga ctacggcatg tgtaaggaag gattacggcc aggagataca 1200 accagcactt tctgtggtac tcctaattac attgctcctg aaattttaag aggagaagat 1260 tatggtttca gtgttgactg gtgggctctt ggagtgctca tgtttgagat gatggcagga 1320 aggtctccat ttgatattgt tgggagctcc gataaccctg accagaacac agaggattat 1380 ctcttccaag ttattttgga aaaacaaatt cgcataccac gttctctgtc tgtaaaagct 1440 gcaagtgttc tgaagagttt tcttaataag gaccctaagg aacgattggg ttgtcatcct 1500 caaacaggat ttgctgatat tcagggacac ccgttcttcc gaaatgttga ttgggatatg 1560 1S atggagcaaa aacaggtggt acctcccttt aaaccaaata tttctgggga atttggtttg 1620 gacaactttg attctcagtt tactaatgaa cctgtccagc tcactccaga tgacgatgac 1680 attgtgagga agattgatca gtctgaattt gaaggttttg agtatatcaa tcctcttttg 2740 atgtctgcag aagaatgtgt ctga 1764 <210> 117 <211> 2451 <212> DNA
<213> Homo Sapiens <300>
<302> PKC mu <310> XM007234 <400> 117 atgtatgataagatcctgctttttcgccatgaccctacctctgaaaacatccttcagctg60 gtgaaagcggccagtgatatccaggaaggcgatcttattgaagtggtcttgtcagcttcc120 gccacctttgaagactttcagattcgtccccacgctctctttgttcattcatacagagct180 ccagctttctgtgatcactgtggagaaatgctgtgggggctggtacgtcaaggtcttaaa240 tgtgaagggtgtggtctgaattaccataagagatgtgcatttaaaatacccaacaattgc300 agcggtgtgaggcggagaaggctctcaaacgtttccctcactggggtcagcaccatccgc360 acatcatctgctgaactctctacaagtgcccctgatgagccccttctgcaaaaatcacca420 tcagagtcgtttattggtcgagagaagaggtcaaattctcaatcatacattggacgacca480 attcaccttgacaagattttgatgtctaaagttaaagtgccgcacacatttgtcatccac540 tcctacacccggcccacagtgtgccagtactgcaagaagcttctgaaggggcttttcagg600 cagggcttgcagtgcaaagattgcagattcaactgccataaacgttgtgcaccgaaagta660 ccaaacaactgccttggcgaagtgaccattaatggagatttgcttagccctggggcagag720 tctgatgtggtcatggaagaagggagtgatgacaatgatagtgaaaggaacagtgggctc780 atggatgatatggaagaagcaatggtccaagatgcagagatggcaatggcagagtgccag840 4S aacgacagtggcgagatgcaagatccagacccagaccacgaggacgccaacagaaccatc900 agtccatcaacaagcaacaatatcccactcatgagggtagtgcagtctgtcaaacacacg960 aagaggaaaagcagcacagtcatgaaagaaggatggatggtccactacaccagcaaggac1020 acgctgcggaaacggcactattggagattggatagcaaatgtattaccctctttcagaat1080 gacacaggaagcaggtactacaaggaaattcctttatctgaaattttgtctctggaacca1140 SO gtaaaaacttcagctttaattcctaatggggccaatcctcattgtttcgaaatcactacg1200 gcaaatgtagtgtattatgtgggagaaaatgtggtcaatccttccagcccatcaccaaat1260 aacagtgttctcaccagtggcgttggtgcagatgtggccaggatgtgggagatagccatc1320 cagcatgcccttatgcccgtcattcccaagggctcctccgtgggtacaggaaccaacttg1380 cacagagatatctctgtgagtatttcagtatcaaattgccagattcaagaaaatgtggac1440 SS atcagcacagtatatcagatttttcctgatgaagtactgggttctggacagtttggaatt1500 gtttatggaggaaaacatcgtaaaacaggaagagatgtagctattaaaatcattgacaaa1560 ttacgatttccaacaaaacaagaaagccagcttcgtaatgaggttgcaattctacagaac1620 cttcatcaccctggtgttgtaaatttggagtgtatgtttgagacgcctgaaagagtgttt1680 gttgttatggaaaaactccatggagacatgctggaaatgatcttgtcaagtgaaaagggc1740 fi0aggttgccagagcacataacgaagtttttaattactcagatactcgtggctttgcggcac1800 USERVERig$iTextelAnmeldeunterlagen 2003\42?ft97-Ribopharma-an-2.doc cttcatttta aaaatatcgt tcactgtgac ctcaaaccag aaaatgtgtt gctagcctca 1860 gctgatcctt ttcctcaggt gaaactttgt gattttggtt ttgcccggat cattggagag 1920 aagtctttcc ggaggtcagt ggtgggtacc cccgcttacc tggctcctga ggtcctaagg 1980 aacaagggct acaatcgctc tctagacatg tggtctgttg gggtcatcat ctatgtaagc 2040 S ctaagcggca cattcccatt taatgaagat gaagacatac acgaccaaat tcagaatgca 2100 gctttcatgt atccaccaaa tccctggaag gaaatatctc atgaagccat tgatcttatc 2160 aacaatttgc tgcaagtaaa aatgagaaag cgctacagtg tggataagac cttgagccac 2220 ccttggctac aggactatca gacctggtta gatttgcgag agctggaatg caaaatcggg 2280 gagcgctaca tcacccatga aagtgatgac ctgaggtggg agaagtatgc aggcgagcag 2340 gggctgcagt accccacaca cctgatcaat ccaagtgcta gccacagtga cactcctgag 2400 actgaagaaa cagaaatgaa agccctcggt gagcgtgtca gcatcctatg a 2451 <210> 118 <211> 2673 <212> DNA
<213> Homo Sapiens <300>
<302> PKC nu <310> NM005813 <400> 118 atgtctgcaaataattcccctccatcagcccagaagtctgtattacccacagctattcct60 2S gctgtgcttccagctgcttctccgtgttcaagtcctaagacgggactctctgcccgactc120 tctaatggaagcttcagtgcaccatcactcaccaactccagaggctcagtgcatacagtt180 tcatttctactgcaaattggcctcacacgggagagtgttaccattgaagcccaggaactg240 tctttatctgctgtcaaggatcttgtgtgctccatagtttatcaaaagtttccagagtgt300 ggattctttggcatgtatgacaaaattcttctctttcgccatgacatgaactcagaaaac360 attttgcagctgattacctcagcagatgaaatacatgaaggagacctagtggaagtggtt420 ctttcagctttagccacagtagaagacttccagattcgtccacatactctctatgtacat480 tcttacaaagctcctactttctgtgattactgtggtgagatgctgtggggattggtacgt540 caaggactgaaatgtgaaggctgtggattaaattaccataaacgatgtgccttcaagatt600 ccaaataactgtagtggagtaagaaagagacgtctgtcaaatgtatctttaccaggaccc660 ggcctctcagttccaagacccctacagcctgaatatgtagcccttcccagtgaagagtca720 catgtccaccaggaaccaagtaagagaattccttcttggagtggtcgcccaatctggatg780 gaaaagatggtaatgtgcagagtgaaagttccacacacatttgctgttcactcttacacc840 cgtcccacgatatgtcagtactgcaagcggttactgaaaggcctctttcgccaaggaatg900 cagtgtaaagattgcaaattcaactgccataaacgctgtgcatcaaaagtaccaagagac960 tgccttggagaggttactttcaatggagaaccttccagtctgggaacagatacagatata1020 ccaatggatattgacaataatgacataaatagtgatagtagtcggggtttggatgacaca1080 gaagagccatcacccccagaagataagatgttcttcttggatccatctgatctcgatgtg1140 gaaagagatgaagaagccgttaaaacaatcagtccatcaacaagcaataatattccgcta1200 atgagggttgtacaatccatcaagcacacaaagaggaagagcagcacaatggtgaaggaa1260 gggtggatggtccattacaccagcagggataacctgagaaagaggcattattggagactt1320 gacagcaaatgtctaacattatttcagaatgaatctggatcaaagtattataaggaaatt1380 ccactttcagaaattctccgcatatcttcaccacgagatttcacaaacatttcacaaggc1440 agcaatccacactgttttgaaatcattactgatactatggtatacttcgttggtgagaac1500 aatggggacagctctcataatcctgttcttgctgccactggagttggacttgatgtagca1560 cagagctgggaaaaagcaattcgccaagccctcatgcctgttactcctcaagcaagtgtt1620 tgcacttctccagggcaagggaaagatcacaaagatttgtctacaagtatctctgtatct1680 aattgtcagattcaggagaatgtggatatcagtactgtttaccagatctttgcagatgag1740 gtgcttggttcaggccagtttggcatcgtttatggaggaaaacatagaaagactgggagg1800 gatgtggctattaaagtaattgataagatgagattccccacaaaacaagaaagtcaactc1860 SS cgtaatgaagtggctattttacagaatttgcaccatcctgggattgtaaacctggaatgt1920 atgtttgaaaccccagaacgagtctttgtagtaatggaaaagctgcatggagatatgttg1980 gaaatgattctatccagtgagaaaagtcggcttccagaacgaattactaaattcatggtc2040 acacagatacttgttgctttgaggaatctgcattttaagaatattgtgcactgtgattta2100 aagccagaaaatgtgctgcttgcatcagcagagccatttcctcaggtgaagctgtgtgac2160 tttggatttgcacgcatcattggtgaaaagtcattcaggagatctgtggtaggaactcca2220 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc S tttgttatag agtatgtaaa tggaggagac ctaatgtttc atatgcagcg acaaagaaaa 1020 cttcctgaag aacatgccag attttactct gcagaaatca gtctagcatt gcatacttag cccctgaagt tctccggagc aaaggttaca accgttccct agatatgtgg 2280 tcagtgggag ttatcatcta tgtgagcctc agtggcacat ttccttttaa tgaggatgaa 2340 gatataaatg accaaatcca aaatgctgca tttatgtacc caccaaatcc atggagagaa 2400 atttctggtg aagcaattga tctgataaac aatctgcttc aagtgaagat gagaaaacgt 2460 S tacagtgttg acaaatctct tagtcatccc tggctacagg actatcagac ttggcttgac 2520 cttagagaat ttgaaactcg cattggagaa cgttacatta cacatgaaag tgatgatgct 2580 cgctgggaaa tacatgcata cacacataac cttgtatacc caaagcactt cattatggct 2640 cctaatccag atgatatgga agaagatcct taa 2673 <210> 119 <211> 2121 <212> DNA
<213> Homo sapiens <300>
<302> PKC tau <310> NM006257 <400> 1I9 atgtcgccatttcttcggattggcttgtccaactttgactgcgggtcctgccagtcttgt60 cagggcgaggctgttaacccttactgtgctgtgctcgtcaaagagtatgtcgaatcagag120 aacgggcagatgtatatccagaaaaagcctaccatgtacccaccctgggacagcactttt180 gatgcccatatcaacaagggaagagtcatgcagatcattgtgaaaggcaaaaacgtggac240 2S ctcatctctgaaaccaccgtggagctctactcgctggctgagaggtgcaggaagaacaac300 gggaagacagaaatatggttagagctgaaacctcaaggccgaatgctaatgaatgcaaga360 tactttctggaaatgagtgacacaaaggacatgaatgaatttgagacggaaggcttcttt420 gctttgcatcagcgccggggtgccatcaagcaggcaaaggtccaccacgtcaagtgccac480 gagttcactgccaccttcttcccacagcccacattttgctctgtctgccacgagtttgtc540 tggggcctgaacaaacagggctaccagtgccgacaatgcaatgcagcaattcacaagaag600 tgtattgataaagttatagcaaagtgcacaggatcagctatcaatagccgagaaaccatg660 ttccacaaggagagattcaaaattgacatgccacacagatttaaagtctacaattacaag720 agcccgaccttctgtgaacactgtgggaccctgctgtggggactggcacggcaaggactc780 aagtgtgatgcatgtggcatgaatgtgcatcatagatgccagacaaaggtggccaacctt840 3S tgtggcataaaccagaagctaatggctgaagcgctggccatgattgagagcactcaacag900 gctcgctgcttaagagatactgaacagatcttcagagaaggtccggttgaaattggtctc960 ccatgctccatcaaaaatgaagcaaggccgccatgtttaccgacaccgggaaaaagagag1020 cctcagggcatttcctgggagtctccgttggatgaggtggataaaatgtgccatcttcca1080 gaacctgaactgaacaaagaaagaccatctctgcagattaaactaaaaattgaggatttt1140 atcttgcacaaaatgttggggaaaggaagttttggcaaggtcttcctggcagaattcaag1200 aaaaccaatcaatttttcgcaataaaggccttaaagaaagatgtggtcttgatggacgat1260 gatgttgagtgcacgatggtagagaagagagttctttccttggcctgggagcatccgttt1320 ctgacgcacatgttttgtacattccagaccaaggaaaacctcttttttgtgatggagtac1380 ctcaacggaggggacttaatgtaccacatccaaagctgccacaagttcgacctttccaga1440 4S gcgacgttttatgctgctgaaatcattcttggtctgcagttccttcattccaaaggaata1500 gtctacagggacctgaagctagataacatcctgttagacaaagatggacatatcaagatc1560 gcggattttggaatgtgcaaggagaacatgttaggagatgccaagacgaataccttctgt1620 gggacacctgactacatcgccccagagatcttgctgggtcagaaatacaaccactctgtg1680 gactggtggtccttcggggttctcctttatgaaatgctgattggtcagtcgcctttccac1740 SO gggcaggatgaggaggagctcttccactccatccgcatggacaatcccttttacccacgg1800 tggctggagaaggaagcaaaggaccttctggtgaagctcttcgtgcgagaacctgagaag1860 aggctgggcgtgaggggagacatccgccagcaccctttgtttcgggagatcaactgggag1920 gaacttgaacggaaggagattgacccaccgttccggccgaaagtgaaatcaccatttgac1980 tgcagcaatttcgacaaagaattcttaaacgagaagccccggctgtcatttgccgacaga2040 SS gcactgatcaacagcatggaccagaatatgttcaggaacttttccttcatgaaccccggg2100 atggagcggctgatatcctga 2121 <210> 120 60 <21I> 1779 \\SERVER\g$\Texte\Anmetdeanterlagen 20031422497-Ribopharma-an-2.doc <212> DNA
<213> Homo Sapiens <300>
S <302> PKC zeta <310> NM2744 <400> 120 atgcccagcaggaccgaccccaagatggaagggagcggcggccgcgtccgcctcaaggcg60 cattacgggggggacatcttcatcaccagcgtggacgccgccacgaccttcgaggagctc120 tgtgaggaagtgagagacatgtgtcgtctgcaccagcagcacccgctcaccctcaagtgg180 gtggacagcgaaggtgacccttgcacggtgtcctcccagatggagctggaagaggctttc240 cgcctggcccgtcagtgcagggatgaaggcctcatcattcatgttttcccgagcacccct300 gagcagcctggcctgccatgtccgggagaagacaaatctatctaccgccggggagccaga360 1S agatggaggaagctgtaccgtgccaacggccacctcttccaagccaagcgctttaacagg420 agagcgtactgcggtcagtgcagcgagaggatatggggcctcgcgaggcaaggctacagg480 tgcatcaactgcaaactgctggtccataagcgctgccacggcctcgtcccgctgacctgc540 aggaagcatatggattctgtcatgccttcccaagagcctccagtagacgacaagaacgag600 gacgccgaccttccttccgaggagacagatggaattgcttacatttcctcatcccggaag660 catgacagcattaaagacgactcggaggaccttaagccagttatcgatgggatggatgga720 atcaaaatctctcaggggcttgggctgcaggactttgacctaatcagagtcatcgggcgc780 gggagctacgccaaggttctcctggtgcggttgaagaagaatgaccaaatttacgccatg840 aaagtggtgaagaaagagctggtgcatgatgacgaggatattgactgggtacagacagag900 aagcacgtgtttgagcaggcatccagcaaccccttcctggtcggattacactcctgcttc960 2S cagacgacaagtcggttgttcctggtcattgagtacgtcaacggcggggacctgatgttc1020 cacatgcagaggcagaggaagctccctgaggagcacgccaggttctacgcggccgagatc1080 tgcatcgccctcaacttcctgcacgagagggggatcatctacagggacctgaagctggac1140 aacgtcctcctggatgcggacgggcacatcaagctcacagactacggcatgtgcaaggaa1200 ggcctgggccctggtgacacaacgagcactttctgcggaaccccgaattacatcgccccc1260 gaaatcctgcggggagaggagtacgggttcagcgtggactggtgggcgctgggagtcctc1320 atgtttgagatgatggccgggcgctccccgttcgacatcatcaccgacaacccggacatg1380 aacacagaggactaccttttccaagtgatcctggagaagcccatccggatcccccggttc1440 ctgtccgtcaaagcctcccatgttttaaaaggatttttaaataaggaccccaaagagagg1500 ctcggctgccggccacagactggattttctgacatcaagtcccacgcgttcttccgcagc1560 3S atagactgggacttgctggagaagaagcaggcgctccctccattccagccacagatcaca1620 gacgactacggtctggacaactttgacacacagttcaccagcgagcccgtgcagctgacc1680 ccagacgatgaggatgccataaagaggatcgaccagtcagagttcgaaggctttgagtat1740 atcaacccattattgctgtccaccgaggagtcggtgtga 1779 <210> 121 <211> 576 <212> DNA
<213> Homo sapiens <300>
<302> VEGF
<310> NM003376 SO <400> 121 atgaactttc tgctgtcttg ggtgcattgg agccttgcct tgctgctcta cctccaccat 60 gccaagtggt cccaggctgc acccatggca gaaggaggag ggcagaatca tcacgaagtg 120 gtgaagttca tggatgtcta tcagcgcagc tactgccatc caatcgagac cctggtggac 180 atcttccagg agtaccctga tgagatcgag tacatcttca agccatcctg tgtgcccctg 240 SS atgcgatgcg ggggctgctg caatgacgag ggcctggagt gtgtgcccac tgaggagtcc 300 aacatcacca tgcagattat gcggatcaaa cctcaccaag gccagcacat aggagagatg 360 agcttcctac agcacaacaa atgtgaatgc agaccaaaga aagatagagc aagacaagaa 420 aatccctgtg ggccttgctc agagcggaga aagcatttgt ttgtacaaga tccgcagacg 480 tgtaaatgtt cctgcaaaaa cacagactcg cgttgcaagg cgaggcagct tgagttaaac 540 60 gaacgtactt gcagatgtga caagccgagg cggtga 576 \SERVER\g$\Texte\Anmetdeunterlagen 2003\422497-Itibopharma-an-Z.doc <210> 122 <211> 624 $ <212> DNA
<213> Homo sapiens <300>
<302> VEGF B
<310> NM003377 <400> 122 atgagccctc tgctccgccg cctgctgctc gccgcactcc tgcagctggc ccccgcccag 60 gcccctgtct cccagcctga tgcccctggc caccagagga aagtggtgtc atggatagat 120 1S gtgtatactc gcgctacctg ccagccccgg gaggtggtgg tgcccttgac tgtggagctc 180 atgggcaccg tggccaaaca gctggtgccc agctgcgtga ctgtgcagcg ctgtggtggc 240 tgctgccctg acgatggcct ggagtgtgtg cccactgggc agcaccaagt ccggatgcag 300 atcctcatga tccggtaccc gagcagtcag ctgggggaga tgtccctgga agaacacagc 360 cagtgtgaat gcagacctaa aaaaaaggac agtgctgtga agccagacag ggctgccact 420 ccccaccacc gtccccagcc ccgttctgtt ccgggctggg actctgcccc cggagcaccc 480 tccccagctg acatcaccca tcccactcca gccccaggcc cctctgccca cgctgcaccc 540 agcaccacca gcgccctgac ccccggacct gccgccgccg ctgccgacgc cgcagcttcc 600 tccgttgcca agggcggggc ttag 624 <210> 123 <211> 1260 <212> DNA
<213> Homo sapiens <300>
<302> VEGF C
<310> NM005429 3S <400> 123 atgcacttgctgggcttcttctctgtggcgtgttctctgctcgccgctgcgctgctcccg60 ggtcctcgcgaggcgcccgccgccgccgccgccttcgagtccggactcgacctctcggac120 gcggagcccgacgcgggcgaggccacggcttatgcaagcaaagatctggaggagcagtta180 cggtctgtgtccagtgtagatgaactcatgactgtactctacccagaatattggaaaatg240 tacaagtgtcagctaaggaaaggaggctggcaacataacagagaacaggccaacctcaac300 tcaaggacagaagagactataaaatttgctgcagcacattataatacagagatcttgaaa360 agtattgataatgagtggagaaagactcaatgcatgccacgggaggtgtgtatagatgtg420 gggaaggagtttggagtcgcgacaaacaccttctttaaacctccatgtgtgtccgtctac480 agatgtgggggttgctgcaatagtgaggggctgcagtgcatgaacaccagcacgagctac540 4S ctcagcaagacgttatttgaaattacagtgcctctctctcaaggccccaaaccagtaaca600 atcagttttgccaatcacacttcctgccgatgcatgtctaaactggatgtttacagacaa660 gttcattccattattagacgttccctgccagcaacactaccacagtgtcaggcagcgaac720 aagacctgccccaccaattacatgtggaataatcacatctgcagatgcctggctcaggaa780 gattttatgttttcctcggatgctggagatgactcaacagatggattccatgacatctgt840 SO ggaccaaacaaggagctggatgaagagacctgtcagtgtgtctgcagagcggggcttcgg900 cctgccagctgtggaccccacaaagaactagacagaaactcatgccagtgtgtctgtaaa960 aacaaactcttccccagccaatgtggggccaaccgagaatttgatgaaaacacatgccag1020 tgtgtatgtaaaagaacctgccccagaaatcaacccctaaatcctggaaaatgtgcctgt1080 gaatgtacagaaagtccacagaaatgcttgttaaaaggaaagaagttccaccaccaaaca1140 SS tgcagctgttacagacggccatgtacgaaccgccagaaggcttgtgagccaggattttca1200 tatagtgaagaagtgtgtcgttgtgtcccttcatattggaaaagaccacaaatgagctaa1260 <210> 124 60 <211> 1074 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <212> DNA
<213> Homo Sapiens <300>
S <302> VEGF D
<310> AJ000185 <400> 124 atattcaaaatgtacagagagtgggtagtggtgaatgttttcatgatgttgtacgtccag60 ctggtgcagggctccagtaatgaacatggaccagtgaagcgatcatctcagtccacattg120 gaacgatctgaacagcagatcagggctgcttctagtttggaggaactacttcgaattact180 cactctgaggactggaagctgtggagatgcaggctgaggctcaaaagttttaccagtatg240 gactctcgctcagcatcccatcggtccactaggtttgcggcaactttctatgacattgaa300 acactaaaagttatagatgaagaatggcaaagaactcagtgcagccctagagaaacgtgc360 1S gtggaggtggccagtgagctggggaagagtaccaacacattcttcaagcccccttgtgtg420 aacgtgttccgatgtggtggctgttgcaatgaagagagccttatctgtatgaacaccagc480 acctcgtacatttccaaacagctctttgagatatcagtgcctttgacatcagtacctgaa540 ttagtgcctgttaaagttgccaatcatacaggttgtaagtgcttgccaacagccccccgc600 catccatactcaattatcagaagatccatccagatccctgaagaagatcgctgttcccat660 tccaagaaactctgtcctattgacatgctatgggatagcaacaaatgtaaatgtgttttg720 caggaggaaaatccacttgctggaacagaagaccactctcatctccaggaaccagctctc780 tgtgggccacacatgatgtttgacgaagatcgttgcgagtgtgtctgtaaaacaccatgt840 cccaaagatctaatccagcaccccaaaaactgcagttgctttgagtgcaaagaaagtctg900 gagacctgctgccagaagcacaagctatttcacccagacacctgcagctgtgaggacaga960 ZS tgcccctttcataccagaccatgtgcaagtggcaaaacagcatgtgcaaagcattgccgc1020 tttccaaaggagaaaagggctgcccaggggccccacagccgaaagaatccttga 1074 <210> 125 <211> 1314 <212> DNA
<213> Homo Sapiens <300>
3S <302> E2F
<310> M96577 <400> 125 atggccttggccggggcccctgcgggcggcccatgcgcgccggcgctggaggccctgctc60 ggggccggcgcgctgcggctgctcgactcctcgcagatcgtcatcatctccgccgcgcag120 gacgccagcgccccgccggctcccaccggccccgcggcgcccgccgccggcccctgcgac180 cctgacctgctgctcttcgccacaccgcaggcgccccggcccacacccagtgcgccgcgg240 cccgcgctcggccgcccgccggtgaagcggaggctggacctggaaactgaccatcagtac300 ctggccgagagcagtgggccagctcggggcagaggccgccatccaggaaaaggtgtgaaa360 4S tccccgggggagaagtcacgctatgagacctcactgaatctgaccaccaagcgcttcctg420 gagctgctgagccactcggctgacggtgtcgtcgacctgaactgggctgccgaggtgctg480 aaggtgcagaagcggcgcatctatgacatcaccaacgtccttgagggcatccagctcatt540 gccaagaagtccaagaaccacatccagtggctgggcagccacaccacagtgggcgtcggc600 ggacggcttgaggggttgacccaggacctccgacagctgcaggagagcgagcagcagctg660 SO gaccacctgatgaatatctgtactacgcagctgcgcctgctctccgaggacactgacagc720 cagcgcctggcctacgtgacgtgtcaggaccttcgtagcattgcagaccctgcagagcag780 atggttatggtgatcaaagcccctcctgagacccagctccaagccgtggactcttcggag840 aactttcagatctcccttaagagcaaacaaggcccgatcgatgttttcctgtgccctgag900 gagaccgtaggtgggatcagccctgggaagaccccatcccaggaggtcacttctgaggag960 SS gagaacagggccactgactctgccaccatagtgtcaccaccaccatcatctcccccctca1020 tccctcaccacagatcccagccagtctctactcagcctggagcaagaaccgctgttgtcc1080 cggatgggcagcctgcgggctcccgtggacgaggaccgcctgtccccgctggtggcggcc1140 gactcgctcctggagcatgtgcgggaggacttctccggcctcctccctgaggagttcatc1200 agcctttccccaccccacgaggccctcgactaccacttcggcctcgaggagggcgagggc1260 60 atcagagacctcttcgactgtgactttggggacctcacccccctggatttctga 1314 \\SERVER\g$\TextelAnmeldeunterlagen 2003\422497-Ribopharn~a-an-2.doc <210> 126 <211> 166 S <212> DNA
<213> Human papillomavirus <300>
<302> EBER-1 <310> Jo2078 <400> 126 ggacctacgc tgccctagag gttttgctag ggaggagacg tgtgtggctg tagccacccg 60 tcccgggtac aagtcccggg tggtgaggac ggtgtctgtg gttgtcttcc cagactctgc 120 1S tttctgccgt cttcggtcaa gtaccagctg gtggtccgca tgtttt 166 <210> 127 <211> 172 <212> DNA
<213> Hepatitis C virus <300>
<302> EBER-2 2S <310> J02078 <400> 127 ggacagccgt tgccctagtg gtttcggaca caccgccaac gctcagtgcg gtgctaccga 60 cccgaggtca agtcccgggg gaggagaaga gaggcttccc gcctagagca tttgcaagtc 120 aggattctct aatccctctg ggagaagggt attcggcttg tccgctattt tt 172 <210> 128 <211> 651 3S <212> DNA
<213> Hepatitis C virus <300>
<302> NS2 <310> AJ238799 <400> 128 atggaccggg agatggcagc atcgtgcgga ggcgcggttt tcgtaggtct gatactcttg 60 accttgtcac cgcactataa gctgttcctc gctaggctca tatggtggtt acaatatttt 120 4S atcaccaggg ccgaggcaca cttgcaagtg tggatccccc ccctcaacgt tcgggggggc 180 cgcgatgccg tcatcctcct cacgtgcgcg atccacccag agctaatctt taccatcacc 240 aaaatcttgc tcgccatact cggtccactc atggtgctcc aggctggtat aaccaaagtg 300 ccgtacttcg tgcgcgcaca cgggctcatt cgtgcatgca tgctggtgcg gaaggttgct 360 gggggtcatt atgtccaaat ggctctcatg aagttggccg cactgacagg tacgtacgtt 420 SO tatgaccatc tcaccccact gcgggactgg gcccacgcgg gcctacgaga ccttgcggtg 480 gcagttgagc ccgtcgtctt ctctgatatg gagaccaagg ttatcacctg gggggcagac 540 accgcggcgt gtggggacat catcttgggc ctgcccgtct ccgcccgcag ggggagggag 600 atacatctgg gaccggcaga cagccttgaa gggcaggggt ggcgactcct c 651 SS
<210> 129 <211> 161 <212> DNA
<213> Hepatitis C virus \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <300>
<302> NS4A
<310> AJ238799 <400> 129 gcacctgggt gctggtaggc ggagtcctag cagctctggc cgcgtattgc ctgacaacag 60 gcagcgtggt cattgtgggc aggatcatct tgtccggaaa gccggccatc attcccgaca 120 gggaagtcct ttaccgggag ttcgatgaga tggaagagtg c 161 <210> 130 <211> 783 <212> DNA
<213> Hepatitis C virus <300>
<302> NS4B
<310> AJ238799 <400> 130 gcctcacacctcccttacatcgaacagggaatgcagctcgccgaacaattcaaacagaag60 gcaatcgggttgctgcaaacagccaccaagcaagcggaggctgctgctcccgtggtggaa120 tccaagtggcggaccctcgaagccttctgggcgaagcatatgtggaatttcatcagcggg180 atacaatatttagcaggcttgtccactctgcctggcaaccccgcgatagcatcactgatg240 2S gcattcacagcctctatcaccagcccgctcaccacccaacataccctcctgtttaacatc300 ctggggggatgggtggccgcccaacttgctcctcccagcgctgcttctgctttcgtaggc360 gccggcatcgctggagcggctgttggcagcataggccttgggaaggtgcttgtggatatt420 ttggcaggttatggagcaggggtggcaggcgcgctcgtggcctttaaggtcatgagcggc480 gagatgccctccaccgaggacctggttaacctactccctgctatcctctcccctggcgcc540 ctagtcgtcggggtcgtgtgcgcagcgatactgcgtcggcacgtgggcccaggggagggg600 gctgtgcagtggatgaaccggctgatagcgttcgcttcgcggggtaaccacgtctccccc660 acgcactatgtgcctgagagcgacgctgcagcacgtgtcactcagatcctctctagtctt720 accatcactcagctgctgaagaggcttcaccagtggatcaacgaggactgctccacgcca780 tgc 783 <210> 131 <211> 1341 <212> DNA

<213> Hepatitis C virus <300>
<302> NSSA
<310> AJ238799 <400> 131 tccggctcgt ggctaagaga tgtttgggat tggatatgca cggtgttgac tgatttcaag 60 acctggctcc agtccaagct cctgccgcga ttgccgggag tccccttctt ctcatgtcaa 120 cgtgggtaca agggagtctg gcggggcgac ggcatcatgc aaaccacctg cccatgtgga 180 gcacagatca ccggacatgt gaaaaacggt tccatgagga tcgtggggcc taggacctgt 240 agtaacacgt ggcatggaac attccccatt aacgcgtaca ccacgggccc ctgcacgccc 300 tccccggcgc caaattattc tagggcgctg tggcgggtgg ctgctgagga gtacgtggag 360 gttacgcggg tgggggattt ccactacgtg acgggcatga ccactgacaa cgtaaagtgc 420 ccgtgtcagg ttccggcccc cgaattcttc acagaagtgg atggggtgcg gttgcacagg 480 SS tacgctccag cgtgcaaacc cctcctacgg gaggaggtca cattcctggt cgggctcaat 540 caatacctgg ttgggtcaca gctcccatgc gagcccgaac cggacgtagc agtgctcact 600 tccatgctca ccgacccctc ccacattacg gcggagacgg ctaagcgtag gctggccagg 660 ggatctcccc cctccttggc cagctcatca gctagccagc tgtctgcgcc ttccttgaag 720 gcaacatgca ctacccgtca tgactccccg gacgctgacc tcatcgaggc caacctcctg 780 f>0 tggcggcagg agatgggcgg gaacatcacc cgcgtggagt cagaaaataa ggtagtaatt 840 \\SERVER\g$\TexteWnmeldeunterlagen 2003\f122497-Ribopharma-an-2.doc ttggactctt tcgagccgct ccaagcggag gaggatgaga gggaagtatc cgttccggcg 900 gagatcctgc ggaggtccag gaaattccct cgagcgatgc ccatatgggc acgcccggat 960 tacaaccctc cactgttaga gtcctggaag gacccggact acgtccctcc agtggtacac 1020 gggtgtccat tgccgcctgc caaggcccct ccgataccac ctccacggag gaagaggacg 1080 S gttgtcctgt cagaatctac cgtgtcttct gccttggcgg agctcgccac aaagaccttc 1140 ggcagctccg aatcgtcggc cgtcgacagc ggcacggcaa cggcctctcc tgaccagccc 1200 tccgacgacg gcgacgcggg atccgacgtt gagtcgtact cctccatgcc cccccttgag 1260 ggggagccgg gggatcccga tctcagcgac gggtcttggt ctaccgtaag cgaggaggct 1320 agtgaggacg tcgtctgctg c 1341 <210> 132 <211> 1772 <212> DNA
1S <213> Hepatitis C virus <300>
<302> NS5B
<310> AJ238799 <400> 132 tcgatgtcctacacatggacaggcgccctgatcacgccatgcgctgcggaggaaaccaag60 ctgcccatcaatgcactgagcaactctttgctccgtcaccacaacttggtctatgctaca120 acatctcgcagcgcaagcctgcggcagaagaaggtcacctttgacagactgcaggtcctg180 2S gacgaccactaccgggacgtgctcaaggagatgaaggcgaaggcgtccacagttaaggct240 aaacttctatccgtggaggaagcctgtaagctgacgcccccacattcggccagatctaaa300 tttggctatggggcaaaggacgtccggaacctatccagcaaggccgttaaccacatccgc360 tccgtgtggaaggacttgctggaagacactgagacaccaattgacaccaccatcatggca420 aaaaatgaggttttctgcgtccaaccagagaaggggggccgcaagccagctcgccttatc480 gtattcccagatttgggggttcgtgtgtgcgagaaaatggccctttacgatgtggtctcc540 accctccctcaggccgtgatgggctcttcatacggattccaatactctcctggacagcgg600 gtcgagttcctggtgaatgcctggaaagcgaagaaatgccctatgggcttcgcatatgac660 acccgctgttttgactcaacggtcactgagaatgacatccgtgttgaggagtcaatctac720 caatgttgtgacttggcccccgaagccagacaggccataaggtcgctcacagagcggctt780 3S tacatcgggggccccctgactaattctaaagggcagaactgcggctatcgccggtgccgc840 gcgagcggtgtactgacgaccagctgcggtaataccctcacatgttacttgaaggccgct900 gcggcctgtcgagctgcgaagctccaggactgcacgatgctcgtatgcggagacgacctt960 gtcgttatctgtgaaagcgcggggacccaagaggacgaggcgagcctacgggccttcacg1020 gaggctatgactagatactctgccccccctggggacccgcccaaaccagaatacgacttg1080 gagttgataacatcatgctcctccaatgtgtcagtcgcgcacgatgcatctggcaaaagg1140 gtgtactatctcacccgtgaccccaccaccccccttgcgcgggctgcgtgggagacagct1200 agacacactccagtcaattcctggctaggcaacatcatcatgtatgcgcccaccttgtgg1260 gcaaggatgatcctgatgactcatttcttctccatccttctagctcaggaacaacttgaa1320 aaagccctagattgtcagatctacggggcctgttactccattgagccacttgacctacct1380 4S cagatcattcaacgactccatggccttagcgcattttcactccatagttactctccaggt1440 gagatcaatagggtggcttcatgcctcaggaaacttggggtaccgcccttgcgagtctgg1500 agacatcgggccagaagtgtccgcgctaggctactgtcccagggggggagggctgccact1560 tgtggcaagtacctcttcaactgggcagtaaggaccaagctcaaactcactccaatcccg1620 gctgcgtcccagttggatttatccagctggttcgttgctggttacagcgggggagacata1680 SO tatcacagcctgtctcgtgcccgaccccgctggttcatgtggtgcctactcctactttct1740 gtaggggtaggcatctatctactccccaaccg 1772 <210> 133 SS <211> 1892 <212> DNA
<213> Hepatitis C virus <300>
60 <302> NS3 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribophanma-an-2.doc <310> AJ238799 <400> 133 cgcctattacggcctactcccaacagacgcgaggcctacttggctgcatcatcactagcc60 S tcacaggccgggacaggaaccaggtcgagggggaggtccaagtggtctccaccgcaacac120 aatctttcctggcgacctgcgtcaatggcgtgtgttggactgtctatcatggtgccggct180 caaagacccttgccggcccaaagggcccaatcacccaaatgtacaccaatgtggaccagg240 acctcgtcggctggcaagcgccccccggggcgcgttccttgacaccatgcacctgcggca300 gctcggacctttacttggtcacgaggcatgccgatgtcattccggtgcgccggcggggcg360 acagcagggggagcctactctcccccaggcccgtctcctacttgaagggctcttcgggcg420 gtccactgctctgcccctcggggcacgctgtgggcatctttcgggctgccgtgtgcaccc480 gaggggttgcgaaggcggtggactttgtacccgtcgagtctatggaaaccactatgcggt540 ccccggtcttcacggacaactcgtcccctccggccgtaccgcagacattccaggtggccc600 atctacacgcccctactggtagcggcaagagcactaaggtgccggctgcgtatgcagccc660 1S aagggtataaggtgcttgtcctgaacccgtccgtcgccgccaccctaggtttcggggcgt720 atatgtctaaggcacatggtatcgaccctaacatcagaaccggggtaaggaccatcacca780 cgggtgcccccatcacgtactccacctatggcaagtttcttgccgacggtggttgctctg840 ggggcgcctatgacatcataatatgtgatgagtgccactcaactgactcgaccactatcc900 tgggcatcggcacagtcctggaccaagcggagacggctggagcgcgactcgtcgtgctcg960 20 ccaccgctacgcctccgggatcggtcaccgtgccacatccaaacatcgaggaggtggctc1020 tgtccagcactggagaaatccccttttatggcaaagccatccccatcgagaccatcaagg1080 gggggaggcacctcattttctgccattccaagaagaaatgtgatgagctcgccgcgaagc1140 tgtccggcctcggactcaatgctgtagcatattaccggggccttgatgtatccgtcatac1200 caactagcggagacgtcattgtcgtagcaacggacgctctaatgacgggctttaccggcg1260 2S atttcgactcagtgatcgactgcaatacatgtgtcacccagacagtcgacttcagcctgg1320 acccgaccttcaccattgagacgacgaccgtgccacaagacgcggtgtcacgctcgcagc1380 ggcgaggcaggactggtaggggcaggatgggcatttacaggtttgtgactccaggagaac1440 ggccctcgggcatgttcgattcctcggttctgtgcgagtgctatgacgcgggctgtgctt1500 ggtacgagctcacgcccgccgagacctcagttaggttgcgggcttacctaaacacaccag1560 ggttgcccgtctgccaggaccatctggagttctgggagagcgtctttacaggcctcaccc1620 acatagacgcccatttcttgtcccagactaagcaggcaggagacaacttcccctacctgg1680 tagcataccaggctacggtgtgcgccagggctcaggctccacctccatcgtgggaccaaa1740 tgtggaagtgtctcatacggctaaagcctacgctgcacgggccaacgcccctgctgtata1800 ggctgggagccgttcaaaacgaggttactaccacacaccccataaccaaatacatcatgg1860 3S catgcatgtcggctgacctggaggtcgtcacg 1892 <210> 134 <211> 822 <212> DNA
<213> Homo Sapiens <300>
<302> stmn cell factor 4S <310> M59964 <400> 134 atgaagaaga cacaaacttg gattctcact tgcatttatc ttcagctgct cctatttaat 60 cctctcgtca aaactgaagg gatctgcagg aatcgtgtga ctaataatgt aaaagacgtc 120 SO actaaattgg tggcaaatct tccaaaagac tacatgataa ccctcaaata tgtccccggg 180 atggatgttt tgccaagtca ttgttggata agcgagatgg tagtacaatt gtcagacagc 240 ttgactgatc ttctggacaa gttttcaaat atttctgaag gcttgagtaa ttattccatc 300 atagacaaac ttgtgaatat agtcgatgac cttgtggagt gcgtcaaaga aaactcatct 360 aaggatctaa aaaaatcatt caagagccca gaacccaggc tctttactcc tgaagaattc 420 SS tttagaattt ttaatagatc cattgatgcc ttcaaggact ttgtagtggc atctgaaact 480 agtgattgtg tggtttcttc aacattaagt cctgagaaag attccagagt cagtgtcaca 540 aaaccattta tgttaccccc tgttgcagcc agctccctta ggaatgacag cagtagcagt 600 aataggaagg ccaaaaatcc ccctggagac tccagcctac actgggcagc catggcattg 660 ccagcattgt tttctcttat aattggcttt gcttttggag ccttatactg gaagaagaga 720 f)0 cagccaagtc ttacaagggc agttgaaaat atacaaatta atgaagagga taatgagata 780 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc agtatgttgc aagagaaaga gagagagttt caagaagtgt as 822 <210> 135 $ <211> 483 <212> DNA
<213> Homo sapiens <300>
<302> TGFalpha <310> AF12323$
<400> 135 atggtcccct cggctggaca gctcgccctg ttcgctctgg gtattgtgtt ggctgcgtgc 60 1S caggccttgg agaacagcac gtccccgctg agtgcagacc cgcccgtggc tgcagcagtg 120 gtgtcccatt ttaatgactg cccagattcc cacactcagt tctgcttcca tggaacctgc 180 aggtttttgg tgcaggagga caagccagca tgtgtctgcc attctgggta cgttggtgca 240 cgctgtgagc atgcggacct cctggccgtg gtggctgcca gccagaagaa gcaggccatc 300 accgccttgg tggtggtctc catcgtggcc ctggctgtcc ttatcatcac atgtgtgctg 360 atacactgct gccaggtccg aaaacactgt gagtggtgcc gggccctcat ctgccggcac 420 gagaagccca gcgccctcct gaagggaaga accgcttgct gccactcaga aacagtggtc 480 tga 483 2S <210> 136 <211> 2071 <212> DNA
<213> Homo sapiens <300>
<302> GD3 synthase <310> NM003034 <400> 136 3S atgagcccctgcgggcgggcccggcgacaaacgtccagaggggccatggctgtactggcg60 tggaagttcccgcggacccggctgcccatgggagccagtgccctctgtgtcgtggtcctc120 tgttggctctacatcttccccgtctaccggctgcccaacgagaaagagatcgtgcagggg180 gtgctgcaacagggcacggcgtggaggaggaaccagaccgcggccagagcgttcaggaaa240 caaatggaagactgctgcgaccctgcccatctctttgctatgactaaaatgaattcccct300 atggggaagagcatgtggtatgacggggagtttttatactcattcaccattgacaattca360 acttactctctcttcccacaggcaaccccattccagctgccattgaagaaatgcgcggtg420 gtgggaaatggtgggattctgaagaagagtggctgtggccgtcaaatagatgaagcaaat480 tttgtcatgcgatgcaatctccctcctttgtcaagtgaatacactaaggatgttggatcc540 aaaagtcagttagtgacagctaatcccagcataattcggcaaaggtttcagaaccttctg600 4S tggtccagaaagacatttgtggacaacatgaaaatctataaccacagttacatctacatg660 cctgccttttctatgaagacaggaacagagccatctttgagggtttattatacactgtca720 gatgttggtgccaatcaaacagtgctgtttgccaaccccaactttctgcgtagcattgga780 aagttctggaaaagtagaggaatccatgccaagcgcctgtccacaggactttttctggtg840 agcgcagctctgggtctctgtgaagaggtggccatctatggcttctggcccttctctgtg900 SO aatatgcatgagcagcccatcagccaccactactatgacaacgtcttacccttttctggc960 ttccatgccatgcccgaggaatttctccaactctggtatcttcataaaatcggtgcactg1020 agaatgcagctggacccatgtgaagatacctcactccagcccacttcctag 1071 SS <210> 137 <211> 744 <212> DNA
<213> Homo sapiens 60 <300>
l4SERVERIg$tTextelAnmeldeunterlagen 20034422497-Ribopharn~a-an-2.doc <302> FGF14 <310> NM004115 <400> 137 S atggccgcgg ccatcgctag cggcttgatc cgccagaagc ggcaggcgcg ggagcagcac 60 tgggaccggc cgtctgccag caggaggcgg agcagcccca gcaagaaccg cgggctctgc 120 aacggcaacc tggtggatat cttctccaaa gtgcgcatct tcggcctcaa gaagcgcagg 180 ttgcggcgcc aagatcccca gctcaagggt atagtgacca ggttatattg caggcaaggc 240 tactacttgc aaatgcaccc cgatggagct ctcgatggaa ccaaggatga cagcactaat 300 tctacactct tcaacctcat accagtggga ctacgtgttg ttgccatcca gggagtgaaa 360 acagggttgt atatagccat gaatggagaa ggttacctct acccatcaga actttttacc 420 cctgaatgca agtttaaaga atctgttttt gaaaattatt atgtaatcta ctcatccatg 480 ttgtacagac aacaggaatc tggtagagcc tggtttttgg gattaaataa ggaagggcaa 540 gctatgaaag ggaacagagt aaagaaaacc aaaccagcag ctcattttct acccaagcca 600 1S ttggaagttg ccatgtaccg agaaccatct ttgcatgatg ttggggaaac ggtcccgaag 660 cctggggtga cgccaagtaa aagcacaagt gcgtctgcaa taatgaatgg aggcaaacca 720 gtcaacaaga gtaagacaac atag 744 <210> 138 <211> 1503 <212> DNA
<213> Human immunodeficiency virus 2S <300>
<302> gag (HIV) <310> NC001802 <400> 138 atgggtgcgagagcgtcagtattaagcgggggagaattagatcgatgggaaaaaattcgg60 ttaaggccagggggaaagaaaaaatataaattaaaacatatagtatgggcaagcagggag120 ctagaacgattcgcagttaatcctggcctgttagaaacatcagaaggctgtagacaaata180 ctgggacagctacaaccatcccttcagacaggatcagaagaacttagatcattatataat240 acagtagcaaccctctattgtgtgcatcaaaggatagagataaaagacaccaaggaagct300 3S ttagacaagatagaggaagagcaaaacaaaagtaagaaaaaagcacagcaagcagcagct360 gacacaggacacagcaatcaggtcagccaaaattaccctatagtgcagaacatccagggg420 caaatggtacatcaggccatatcacctagaactttaaatgcatgggtaaaagtagtagaa480 gagaaggctttcagcccagaagtgatacccatgttttcagcattatcagaaggagccacc540 ccacaagatttaaacaccatgctaaacacagtggggggacatcaagcagccatgcaaatg600 ttaaaagagaccatcaatgaggaagctgcagaatgggatagagtgcatccagtgcatgca660 gggcctattgcaccaggccagatgagagaaccaaggggaagtgacatagcaggaactact720 agtacccttcaggaacaaataggatggatgacaaataatccacctatcccagtaggagaa780 atttataaaagatggataatcctgggattaaataaaatagtaagaatgtatagccctacc840 agcattctggacataagacaaggaccaaaggaaccctttagagactatgtagaccggttc900 4S tataaaactctaagagccgagcaagcttcacaggaggtaaaaaattggatgacagaaacc960 ttgttggtccaaaatgcgaacccagattgtaagactattttaaaagcattgggaccagcg1020 gctacactagaagaaatgatgacagcatgtcagggagtaggaggacccggccataaggca1080 agagttttggctgaagcaatgagccaagtaacaaattcagctaccataatgatgcagaga1140 ggcaattttaggaaccaaagaaagattgttaagtgtttcaattgtggcaaagaagggcac1200 SO acagccagaaattgcagggcccctaggaaaaagggctgttggaaatgtggaaaggaagga1260 caccaaatgaaagattgtactgagagacaggctaattttttagggaagatctggccttcc1320 tacaagggaaggccagggaattttcttcagagcagaccagagccaacagccccaccagaa1380 gagagcttcaggtctggggtagagacaacaactccccctcagaagcaggagccgatagac1440 aaggaactgtatcctttaacttccctcaggtcactctttggcaacgacccctcgtcacaa1500 SS taa 1503 <210> 139 <211> 1101 <212> DNA
\\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <213> Human immunodeficiency virus <300>
<302> TARBP2 S <310> NM004178 <400> 139 atgagtgaagaggagcaaggctccggcactaccacgggctgcgggctgcctagtatagag60 caaatgctggccgccaacccaggcaagaccccgatcagccttctgcaggagtatgggacc120 agaatagggaagacgcctgtgtacgaccttctcaaagccgagggccaagcccaccagcct180 aatttcaccttccgggtcaccgttggcgacaccagctgcactggtcagggccccagcaag240 aaggcagccaagcacaaggcagctgaggtggccctcaaacacctcaaaggggggagcatg300 ctggagccggccctggaggacagcagttctttttctcccctagactcttcactgcctgag360 gacattccggtttttactgctgcagcagctgctaccccagttccatctgtagtcctaacc420 1S aggagcccccccatggaactgcagccccctgtctcccctcagcagtctgagtgcaacccc480 gttggtgctctgcaggagctggtggtgcagaaaggctggcggttgccggagtacacagtg540 acccaggagtctgggccagcccaccgcaaagaattcaccatgacctgtcgagtggagcgt600 ttcattgagattgggagtggcacttccaaaaaattggcaaagcggaatgcggcggccaaa660 atgctgcttcgagtgcacacggtgcctctggatgcccgggatggcaatgaggtggagcct720 gatgatgaccacttctccattggtgtgggcttccgcctggatggtcttcgaaaccggggc780 ccaggttgcacctgggattctctacgaaattcagtaggagagaagatcctgtccctccgc840 agttgctccctgggctccctgggtgccctgggccctgcctgctgccgtgtcctcagtgag900 ctctctgaggagcaggcctttcacgtcagctacctggatattgaggagctgagcctgagt960 ggactctgccagtgcctggtggaactgtccacccagccggccactgtgtgtcatggctct1020 2S gcaaccaccagggaggcagcccgtggtgaggctgcccgccgtgccctgcagtacctcaag1080 atcatggcaggcagcaagtga 1101 <210> 140 <211> 219 <212> DNA
<213> Human immunodeficiency virus <300>
3S <302> TAT (HIV) <310> U44023 <400> 140 atggagccag tagatcctag cctagagccc tggaagcatc caggaagtca gcctaagact 60 gcttgtacca cttgctattg taaagagtgt tgctttcatt gccaagtttg tttcataaca 120 aaaggcttag gcatctccta tggcaggaag aagcggagac agcgacgaag aactcctcaa 180 ggtcatcaga ctaatcaagt ttctctatca aagcagtaa 219 4S <210> 141 <211> 22 <212> RNA
<213> Synthetic sequence SO <220>
<223> Description of the synthetic sequence: sense strand (R1A) of a dsRNA that is homologous to an MDR1 sequence <400> 141 SS ccaucucgaa aagaaguuaa ga 22 <210> 142 <211> 24 60 <212> RNA
\\SERVER\g$\TextelAnmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
S antisense strand (R1B) of a dsRNA, that it complementary to an MDR1 sequence <400> 142 ucuuaacuuc uuuucgagau gggu 24 <210> 143 <211> 22 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence: sense strand (R2A) of a dsRNA that is homologous to an MDR1 sequence <400> 143 uauagguucc aggcuugcug ua 22 2S <210> 144 <211> 22 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence: sense strand (R3A) of a dsRNA that is homologous to an MDR1 sequence <400> 144 3$ ccagagaagg ccgcaccugc au 22 <210> 145 <211> 24 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand (R3B) of a dsRNA, that it complementary to an MDR1 sequence <400> 145 augcaggugc ggccuucucu ggcu 24 SO
<210> 146 <211> 21 <212> RNA
SS <213> Synthetic sequence <220>
<223> Description of the synthetic sequence: sense strand (R4A) of a dsRNA that is homologous to an MDR1 sequence \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <400> 146 ccaucucgaa aagaaguuaa g 21 <210> 147 <211> 21 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand (R4B) of a dsRNA, that it complementary to an MDR1 sequence 1S <400> 147 uaacuucuuu ucgagauggg a 21 <210> 148 <211> 22 <212> RNA
<213> Synthetic sequence <220>
2S <223> Description of the synthetic sequence: sense strand (S1A) of a dsRNA, that is homologous to the YFP- and GFP sequence, respectively <400> 148 ccacaugaag cagcacgacu uc 22 <210> 149 <211> 22 3S <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(S1B) of a dsRNA that is complementary to the YFP- and GFP sequence, respectively <400> 149 gaagucgugc ugcuucaugu gg 22 <210> 150 <211> 21 <212> RNA
SO <213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(S7A) of a dsRNA that is homologous to the YFP- and GFP sequence, respectively <400> 150 ccacaugaag cagcacgacu a 21 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribophamia-an-2.doc <210> 151 <211> 21 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(S7B) of a dsRNA, that is complementary to the YFP- and GFP sequence, respectively <400> 151 gucgugcugc uucauguggu c 21 1S <210> 152 <211> 24 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(R2B) of a dsRNA that is complementary to the MDR-1 sequence 2S <400> 152 uacagcaagc cuggaaccua uagc 24 <210> 153 <211> 22 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence: sense strand (K1A) of a dsRNA that is homologous to the 5'-UTR of the neomycin sequence <400> 153 acaggaugag gaucguuucg ca 22 <210> 154 <211> 22 4S <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(K1B) of a dsRNA that is complementary to the 5'-UTR of the neomycin sequence <400> 154 ugcgaaacga uccucauccu gu 22 <210> 155 <211> 21 <212> RNA
<213> Synthetic sequence \\SERVER\g$\TexteWnmeldeuntertagen 2003\422497-Ribopharma-an-2.doc <220>
<223> Description of the synthetic sequence: sense strand (K3A) of a dsRNA that is homologous to the 5'-UTR of the $ neomycin sequence <400> 155 gaugaggauc guuucgcaug a 21 <210> 156 <211> 21 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(K3B) of a dsRNA that complementary to the 5'-UTR of the neomycin sequence <400> 156 augcgaaacg auccucaucc a 21 2S <210> 157 <211> 24 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence: sense strand (K2A) of a dsRNA that is homologous to the 5'-UTR of the neomycin sequence <400> 157 acaggaugag gaucguuucg caug 24 <210> 158 <211> 24 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(K2B) of a dsRNA that is complementary to the 5'-UTR of the neomycin sequence <400> 158 SO ugcgaaacga uccucauccu gucu 24 <210> 159 <211> 24 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(S4B) of a dsRNA that is \\SERVER\g$\Texte\Anmeldeuntertagen 2003\422497-Ribopharma-an-2.doc complementary to the YFP- and GFP sequence, respectively <400> 159 gaagucgugc ugcuucaugu gguc 24 <210> 160 <211> 24 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence: sense strand (PKC1 A) of a dsRNA that is homologous to the proteinkinase C sequence <400> 160 cuucuccgcc ucacaccgcu gcaa 24 <210> 161 <211> 22 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(PKC2 B) of a dsRNA that is complementary to the proteinkinase C sequence <400> 161 gcagcggugu gaggcggaga ag 22 3$ <210> 162 <211> 21 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(S12B) of a dsRNA that is complementary to the YFP- and GFP sequence, respectively 4S <400> 162 aagucgugcu gcuucaugug g <210> 163 <211> 23 <212> RNA
<213> Synthetic sequence <220>
SS <223> Description of the synthetic sequence:
antisense strand(S11B) of a dsRNA that is complementary to the YFP- and GFP sequence, respectively <400> 163 f)0 aagucgugcu gcuucaugug guc \\SERVER\g$lTexte\Anmeldeuntcrlagen 20034422497-Ribopharma-an-2.doc <210> 164 <211> 20 S <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence: sense strand (S13A) of a dsRNA that is homologous to the YFP- and GFP sequence, respectively <400> 164 ccacaugaag cagcacgacu 20 <210> 165 <211> 22 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(S13B) of a dsRNA that is complementary to the YFP- and GFP sequence, respectively <400> 165 agucgugcug cuucaugugg uc 22 <210> 166 <211> 20 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(S14B) of a dsRNA that is complementary to the YFP- and GFP sequence, respectively <400> 166 agucgugcug cuucaugugg 20 4S <210> 167 <211> 24 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence: sense strand (S4A) of a dsRNA that is homologous to the YFP- and GFP sequence, respectively <400> 167 ccacaugaag cagcacgacu ucuu 24 <210> 168 <211> 21 \\SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence: sense strand (ES-7A) of a dsRNA that is homologous to the human EGFR sequence <400> 168 aacaccgcag caugucaaga a 21 <210> 169 <211> 21 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(ES-7B) of a dsRNA that is complementary to the human EGFR sequence <400> 169 cuugacaugc ugcgguguuu a 21 <210> 170 <211> 22 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence: sense strand (ES-8A) of a dsRNA that is homologous to the human EGFR sequence <400> 170 aaguuaaaau ucccgucgcu au 22 <210> 171 <211> 22 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(ES-8B) of a dsRNA that is complementary to the human EGFR sequence <400> 171 ugauagcgac gggaauuuua ac <210> 172 <211> 22 <212> RNA
<213> Synthetic sequence (70 <220>
\4SERVER\g$\Texte\Anmeldeunterlagen 2003\422497-Ribopharma-an-2.doc <223> Description of the synthetic sequence: sense strand (ES-2A) of a dsRNA that is homologous to the human EGFR sequence S <400> 172 agugugaucc aagcuguccc as , 22 <210> 173 <211> 24 <212> RNA
<213> Synthetic sequence <220>
<223> Description of the synthetic sequence:
antisense strand(ES-5B) of a dsRNA that is complementary to the human EGFR sequence <400> 173 uugggacagc uuggaucaca cuuu \\SERVER\g$\Texte\Anmeldeunterlagen 2003\42?A97-Ribopharma-an-2.doc

Claims

1. Method for inhibiting the expression of a target gene in a cell, comprising the following steps:
Introduction of at least one double-stranded ribonucleic acid (dsRNA I) in a quantity sufficient to inhibit expression of the target gene, whereby dsRNA I exhibits a double-stranded structure consisting of a maximum of 49 successive nucleotide pairs, and whereby one strand (as1) or at least one segment of the strand (as1) of the double-stranded structure is complementary to the target gene, and whereby at least one end (E1, E2) of dsRNA I exhibits an overhang consisting of 1 to 4 nucleotides.

2. Method in accordance with Claim 1, whereby dsRNA I exhibits the overhang at the 3'-end of one strand (as1) and/or at the 3'-end of the other strand (ss1).

3. Method in accordance with Claim 1 or 2, whereby dsRNA I has a smooth configuration at one end (E1, E2).

4. Method in accordance with Claim 3, whereby the smooth end (E1, E2) contains the 5'-end of one strand (as1).

5. Method in accordance with one of the preceding claims, whereby the overhang consists of 1 to 4 nucleotides, preferably of 1 or 2 nucleotides.

6. Method in accordance with one of the preceding claims, whereby at least one further double-stranded ribonucleic acid (dsRNA II) having a configuration according to the dsRNA I as defined in the preceding claims, is introduced into the cell, whereby one strand (as1) of dsRNA I is complementary to a first region (B1) of the target gene, and whereby another strand (as2) or at least one segment of the other strand (as2) of dsRNA II is complementary to a second region (B2) of the target gene.

7. Method in accordance with one of the preceding claims, whereby dsRNA I and/or dsRNA II exhibits a length of fewer than 25 successive nucleotide pairs, preferably 19 to 23.

8. Method in accordance with one of the preceding claims, whereby the first (B1) and the second (B2) region overlap segmentally or adjoin each other.

9. Method in accordance with one of the preceding claims, whereby the first (B1) and the second (B2) region are separated from each other.

10. Method in accordance with one of the preceding claims, whereby the target gene exhibits one of the sequences SQ001 to SQ140.

11. Method in accordance with one of the preceding claims, whereby the target gene is selected from the following group: oncogene, cytokine gene, Id protein gene, prion gene, genes from angiogenesis-inducing molecules, from adhesion molecules, and from cell-surface receptors; genes from proteins that are involved in metastatic and/or invasive processes; genes from proteinases as well as molecules that regulate apoptosis and the cell cycle.

12. Method in accordance with one of the preceding claims, whereby the target gene is the MDR1 gene.

13. Method in accordance with one of the preceding claims, whereby one of the sequences SQ141-173 or a dsRNA construct being combined of two antisense- (as1/2) and sense sequences (ss1/2) belonging together and belonging to sequences SQ141-173 are used as the dsRNA I/II.

14. Method in accordance with one of the preceding claims, whereby expression is inhibited according to the principle of RNA interference.

15. Method in accordance with one of the preceding claims, whereby the target gene is expressed in pathogenic organisms, preferably in plasmodia.

16. Method in accordance with one of the preceding claims, whereby the target gene is a component of a virus or viroid.

17. Method in accordance with Claim 16, whereby the virus is a human pathogenic virus or viroid.

18. Method in accordance with Claim 16, whereby the virus or viroid is a virus or viroid that is pathogenic in animals or plants.

19. Method in accordance with one of the preceding claims, whereby unpaired nucleotides are substituted by nucleoside thiophosphates.

20. Method in accordance with one of the preceding claims, whereby at least one end (E1, E2) of dsRNA I/II is modified in order to counter decomposition in the cell or dissociation in the individual strands.

21. Method in accordance with one of the preceding claims, whereby the cohesion of the double-stranded structure effected by the complementary nucleotide pairs is increased by at least one chemical bond.

22. Method in accordance with one of the preceding claims, whereby the chemical link is achieved either by a covalent or ionic bond, a hydrogen bond, hydrophobic interaction, preferably by means of van der Waals or stacking interactions, or by means of metal-ion coordination.

23. Method in accordance with one of the preceding claims, whereby the chemical link is formed in the vicinity of one end (E1, E2).

24. Method in accordance with one of the preceding claims, whereby the chemical link is created by one or several linkage groups, whereby the linkage groups are preferably poly-(oxyphosphinico-oxy-1,3-propandiol) and/or oligoethyleneglycol chains.

25. Method in accordance with one of the preceding claims, whereby the chemical link is formed by using branched nucleotide analogs instead of nucleotides.

26. Method in accordance with one of the preceding claims, whereby the chemical link is formed by purine analogs.

27. Method in accordance with one of the preceding claims, whereby the chemical link is formed by azabenzene units.

28. Method in accordance with one of the preceding claims, whereby at least one of the following groups is used in creating the chemical link: methylene blue; bifunctional groups, preferably bis-(2-chlorethyl)-amine; N-acetyl-N'-(p-glyoxyl-benzoyl)-cystamine; 4-thiouracil; psoralen.

29. Method in accordance with one of the preceding claims, whereby the chemical link is formed by thiophosphoryl groups that are attached in the vicinity of the ends (E1, E2) of the double-stranded region.

30. Method in accordance with one of the preceding claims, whereby the chemical link is formed by triple helix bonds that are present in the vicinity of the ends (E1, E2).

31. Method in accordance with one of the preceding claims, whereby the dsRNA I/II is enclosed in micellar structures, most advantageously in liposomes.

32. Method in accordance with one of the preceding claims, whereby the dsRNA I/II is bound to, associated with, or enclosed by at least one viral case protein that stems from a virus, is derived from it, or is synthetically produced.

33. Method in accordance with one of the preceding claims, whereby the coat protein is derived from polyomavirus.

34. Method in accordance with one of the preceding claims, whereby the coat protein contains Virus Protein 1 (VP1) and/or Virus Protein 2 (VP2) of the polyomavirus.

35. Method in accordance with one of the preceding claims, whereby at the formation of a capsid or capsid-like structure, the one side is turned toward the inside of the capsid or capsid-like structure.

36. Method in accordance with one of the preceding claims, whereby the one strand (as1, as2) of dsRNA I/II is complementary to the primary or processed RNA transcript of the target gene.

37. Method in accordance with one of the preceding claims, whereby the cell is a vertebrate cell or a human cell.

38. Method in accordance with one of the preceding claims, whereby the dsRNA I/II is administered to a mammal at a maximum dosage of 5 mg/kg body weight per day, preferably to a human.

39. Method in accordance with one of the preceding claims, whereby the dsRNA I/II is mixed in a buffer solution for application.

40. Method in accordance with one of the preceding claims, whereby the dsRNA I/II is administered orally or by intravenous, intratumoral, or intraperitoneal injection or infusion, or by inhalation.

41. Use of a double-stranded ribonucleic acid (dsRNA I) for inhibiting the expression of the target gene in a cell, whereby dsRNA I exhibits a double-stranded structure consisting of a maximum of 49 successive nucleotide pairs, and whereby one strand (as1) or at least one segment of a strand (as1) of the double-stranded structure is complementary to the target gene, and whereby dsRNA I exhibits an overhang consisting of 1 to 4 nucleotides at at least one end (E1, E2).

42. Use in accordance with Claim 41, whereby dsRNA I exhibits the overhang at the 3'-end of one strand (as1) and/or at the 3'-end of the other strand (ss1).

43. Use in accordance with Claim 41 or 42, whereby dsRNA I has a smooth configuration at one end (E1, E2).

44. Use in accordance with Claim 43, whereby the smooth end (E1, E2) contains the 5'-end of one strand (as1).

45. Use in accordance with one of the Claims 41 to 44, whereby the overhang consists of 1 to 4 nucleotides, preferably of 1 or 2 nucleotides.

46. Use in accordance with Claims 41 to 45, whereby at least one further double-stranded ribonucleic acid (dsRNA II) having a configuration according to dsRNA I as defined in claims 41 to 45, is introduced into the cell, whereby the one strand (as1) or at least one segment of the strand (as1) of the double-stranded structure of the dsRNA I is complementary to a first region (B1) of the sense strand of the target gene, and whereby the other strand (as2) or at least one segment of the other strand (as2) of the double-stranded structure of dsRNA II is complementary to a second region (B2) of the target gene.

47. Use in accordance with one of the Claims 41 to 46, whereby the dsRNA I and/or dsRNA II exhibits a length of fewer than 25, preferably 19 to 23, successive nucleotide pairs.

48. Use in accordance with one of the Claims 41 to 47, whereby the first (B1) and second region (B2) overlap segmentally or adjoin each other.

49. Use in accordance with one of the Claims 41 to 48, whereby the first (B1) and second region (B2) are separated from each other.

50. Use in accordance with one of the Claims 41 to 49, whereby the target gene exhibits one of the sequences SQ001 to SQ140.

51. Use in accordance with one of the Claims 41 to 50, whereby the target gene is selected from the following group:
oncogene, cytokine gene, Id protein gene, prion gene, genes from angiogenesis-inducing molecules, from adhesion molecules, and from cell-surface receptors; genes from proteins that are involved in metastatic and/or invasive processes; genes from proteinases as well as molecules that regulate apoptosis and the cell cycle.

52. Use in accordance with one of the Claims 41 to 51, whereby the target gene is the MRD1 gene.

53. Use in accordance with one of the Claims 41 to 52, whereby one of the sequences SQ141-173 or a dsRNA construct being combined of two antisense- (as1/2) and sense sequences (ss1/2) belonging together and belonging to sequences SQ141-173 are used as the dsRNA I/II.

54. Use in accordance with one of the Claims 41 to 53, whereby expression is inhibited according to the principal of RNA
interference.

55. Use in accordance with one of the Claims 41 to 54, whereby the target gene is expressed in pathogenic organisms, preferably in plasmodia.

56. Use in accordance with one of the Claims 41 to 55, whereby the target gene is a component of a virus or viroid.

57. Use in accordance with Claim the 56, whereby the virus is a human pathogenic virus or viroid.

58. Use in accordance with claim 56, whereby the virus or viroid is a virus or viroid that is pathogenic in animals or plants.

59. Use in accordance with one of the Claims 41 to 58, whereby unpaired nucleotides are substituted by nucleoside thiophosphates.

60. Use in accordance with one of the Claims 41 to 59, whereby at least one end (E1, E2) of the dsRNA is modified in order to counter decomposition in the cell or dissociation in the individual strands.

61. Use in accordance with one of the Claims 41 to 60, whereby the cohesion of the double-stranded structure effected by the complementary nucleotide pairs is increased by at least one chemical bond.

62. Use in accordance with one of the Claims 41 to 61, whereby the chemical link is achieved either by a covalent or ionic bond, a hydrogen bond, hydrophobic interaction, preferably by means of van der Waals or stacking interactions, or by means of metal-ion coordination.

63. Use in accordance with one of the Claims 41 to 62, whereby the chemical link is formed in the vicinity of one end (E1, E2).

64. Use in accordance with one of the Claims 41 to 63, whereby the chemical link is created by one or several linkage groups, whereby the linkage groups are preferably poly-(oxyphosphinico-oxy-1,3-propandiol) and/or oligoethyleneglycol chains.

65. Use in accordance with one of the Claims 41 to 64, whereby the chemical link is formed by using branched nucleotide analogs instead of nucleotides.

66. Use in accordance with one of the Claims 41 to 65, whereby the chemical link is formed by purine analogs.

67. Use in accordance with one of the Claims 41 to 66, whereby the chemical link is formed by azabenzene units.

68. Use in accordance with one of the Claims 41 to 67, whereby at least one of the following groups is used in creating the chemical link: methylene blue; bifunctional groups, preferably bis-(2-chlorethyl)-amine; N-acetyl-N'-(p-glyoxyl-benzoyl)-cystamine; 4-thiouracil; psoralen.

69. Use in accordance with one of the Claims 41 to 68, whereby the chemical link is formed by thiophosphoryl groups that are attached in the vicinity of the ends (E1, E2) of the double-stranded region.

70. Use in accordance with one of the Claims 41 to 69, whereby the link is produced by triple helix bonds present in the vicinity of the ends (E1, E2).

71. Use in accordance with one of the Claims 41 to 70, whereby the dsRNA I/II is enclosed in micellar structures, most advantageously in liposomes.

72. Use in accordance with one of the Claims 41 to 71, whereby the dsRNA I/II is bound to, associated with, or enclosed by at least one viral case protein that stems from a virus, is derived from it, or is synthetically produced.

73. Use in accordance with one of the Claims 41 to 72, whereby the case protein is derived from polyomavirus.

74. Use in accordance with one of the Claims 41 to 73, whereby the case protein contains Virus Protein 1 (VP1) and/or Virus Protein 2 (VP2) of the polyomavirus.

75. Use in accordance with one of the Claims 41 to 74, whereby at the formation of a capsid or capsid-like structure, the one side is turned toward the inside of the capsid or capsid-like structure.

76. Use in accordance with one of the Claims 41 to 75, whereby the one strand (as1, as2) of dsRNA I/II is complementary to the primary or processed RNA transcript of the target gene.

77. Use in accordance with one of the Claims 41 to 76, whereby the cell is a vertebrate cell or a human cell.

78. Use in accordance with one of the Claims 41 to 77, whereby the dsRNA I/II is administered to a mammal at a maximum dosage of 5 mg/kg body weight per day, preferably to human being.

79. Use in accordance with one of the Claims 41 to 78, whereby the dsRNA I/II is mixed with a buffer solution for application.

80. Use in accordance with one of the Claims 41 to 79, whereby the dsRNA I/II is administered orally or by intravenous, intratumoral, or intraperitoneal injection or infusion, or by inhalation.

81. Medicament for inhibiting the expression of a target gene in a cell, containing a double-stranded ribonucleic acid (dsRNA
I) in a dosage sufficient to inhibit the expression of the target gene, whereby dsRNA I exhibits a double-stranded structure consisting of a maximum of 49 successive nucleotide pairs, and whereby one strand (as1) or at least one segment of the strand (as1) of the double-stranded structure is complementary to the target gene, and whereby at least one end (E1, E2) of the dsRNA I
exhibits an overhang consisting of 1 to 4 nucleotides.

82. Medicament in accordance with Claim 81, whereby dsRNA I
exhibits the overhang at the 3'-end of one strand (as1) and/or at the 3'-end of the other strand (ss1).

83. Medicament in accordance with Claim 81 or 82, whereby the dsRNA I has a smooth configuration at one end (E1, E2).

84. Medicament in accordance with Claim 83, whereby the smooth end (E1, E2) contains the 5'-end of the first strand (as1).

85. Medicament in accordance with Claims 81 to 84, whereby the overhang consists of 1 to 4 nucleotides, preferably of 1 or 2 nucleotides.

86. Medicament in accordance with one of the Claims 81 to 85, whereby at least one further double-stranded ribonucleic acid (dsRNA II) having a configuration according to the dsRNA I as defined in Claims 81 to 85, and whereby the one strand (as1) of dsRNA I is complementary to a first region (B1) of the target gene, and whereby another strand (as2) or at least one segment of the other strand (as2) of dsRNA II
is complementary to a second region (B2) of the target gene.

87. Medicament in accordance with one of the Claims 81 to 86, whereby the dsRNA I and/or dsRNA II exhibits a length of fewer than 25, preferably in 19 to 23, successive nucleotide pairs.

88. Medicament in accordance with one of the Claims 81 to 87, whereby the first (B1) and the second region (B2) overlap segmentally or adjoin each other.

89. Medicament in accordance with one of the Claims 81 to 88, whereby the target gene exhibits one of the sequences SQ001 to SQ140.

90. Medicament in accordance with one of the Claims 81 to 89, whereby the target gene is selected from the following group: oncogene, cytokine gene, Id protein gene, prion gene, genes from angiogenesis-inducing molecules, from adhesion molecules, and from cell-surface receptors; genes from proteins that are involved in metastatic and/or invasive processes; genes from proteinases as well as molecules that regulate apoptosis and the cell cycle.

91. Medicament in accordance with one of the Claims 81 to 90, whereby the target gene is the MRD1 gene.

92. Medicament in accordance with one of the Claims 81 to 91, whereby one of the sequences SQ141-173 or a dsRNA construct being combined of two antisense- (as1/2) and sense sequences (ss1/2) belonging together and belonging to sequences SQ141-173 are used as the dsRNA I/II.

93. Medicament in accordance with one of the Claims 81 to 92, whereby expression is inhibited according to the principle of RNA interference.

94. Medicament in accordance with one of the Claims 81 to 93, whereby the target gene is expressed in pathogenic organisms, most advantageously in plasmodia.

95. Medicament in accordance with one of the Claims 81 to 94, whereby the target gene is a component of a virus or viroid.

96. Medicament in accordance with Claim 95, whereby the virus is a human pathogenic virus or viroid.

97. Medicament in accordance with Claim 95, whereby the virus or viroid is a virus or viroid that is pathogenic in animals or plants.

98. Medicament in accordance with one of the Claims 81 to 97, whereby unpaired nucleotides are substituted with nucleoside thiophosphates.

99. Medicament in accordance with one of the Claims 81 to 98, whereby at least one end (E1, E2) of dsRNA I/II is modified in order to counter decomposition in the cell or dissociation in the individual strand.

100. Medicament in accordance with one of the Claims 81 to 99, whereby the cohesion of the double-stranded structure effected by the complementary nucleotide pairs is increased by at least one chemical bond.

101. Medicament in accordance with one of the Claims 81 to 100, whereby the chemical link is achieved either by a covalent or ionic bond, a hydrogen bond, hydrophobic interaction, preferably by means of van der Waals or stacking interactions, or by means of metal-ion coordination.

102. Medicament in accordance with one of the Claims 81 to 101, whereby the chemical link is formed in the vicinity of one end (E1, E2).

103. Medicament in accordance with one of the Claims 81 to 102, whereby the chemical link is created by one or several linkage groups, whereby the linkage groups are preferably poly-(oxyphosphinico-oxy-1,3-propandiol) and/or oligoethyleneglycol chains.

104. Medicament in accordance with one of the Claims 81 to 103, whereby the chemical link is formed by using branched nucleotide analogs instead of nucleotides.

105. Medicament in accordance with one of the Claims 81 to 104, whereby the chemical link is formed by purine analogs.

106. Medicament in accordance with one of the Claims 81 to 105, whereby the chemical link is formed by azabenzene units.

107. Medicament in accordance with one of the Claims 81 to 106, whereby at least one of the following groups is used in creating the chemical link: methylene blue; bifunctional groups, preferably bis-(2-chlorethyl)-amine; N-acetyl-N'-(p-glyoxyl-benzoyl)-cystamine; 4-thiouracil; psoralen.

108. Medicament in accordance with one of the Claims 81 to 107, whereby the chemical link is formed by thiophosphoryl groups that are attached in the vicinity of the ends (E1, E2) of the double-stranded region.

109. Medicament in accordance with one of the Claims 81 to 108, whereby the chemical link is formed by triple helix bonds that are present in the vicinity of the ends (E1, E2).

110. Medicament in accordance with one of the Claims 81 to 109, whereby the dsRNA I/II is enclosed in micellar structures, most advantageously in liposomes.

111. Medicament in accordance with one of the Claims 81 to 110, whereby the dsRNA I/II is bound to, associated with, or enclosed by at least one viral case protein that stems from a virus, is derived from it, or is synthetically produced.

112. Medicament in accordance with one of the Claims 81 to 111, whereby the coat protein is derived from polyomavirus.

113. Medicament in accordance with one of the Claims 81 to 112, whereby the coat protein contains Virus Protein 1 (VP1) and/or Virus Protein 2 (VP2) of the polyomavirus.

114. Medicament in accordance with one of the Claims 81 to 113, whereby at the formation of a capsid or capsid-like structure, the one side is turned toward the inside of the capsid or capsid-like structure.

115. Medicament in accordance with one of the Claims 81 to 114, whereby the one strand (as1, as2) of dsRNA I/II is complementary to the primary or processed RNA transcript of the target gene.

116. Medicament in accordance with one of the Claims 81 to 115, whereby the cell is a vertebrate cell or a human cell.

117. Medicament in accordance with one of the Claims 81 to 116, whereby the first (B1) and the second region (B2) are separated from each other.

118. Medicament in accordance with one of the Claims 81 to 117, whereby the dsRNA is administered at a maximum amount of 5 mg per dose.

119. Medicament in accordance with one of the Claims 81 to 118, whereby the dsRNA is mixed in a buffer solution for application.

120. Medicament in accordance with one of the Claims 81 to 119, whereby the dsRNA is administered orally or by intravenous, intratumoral, or intraperitoneal injection or infusion, or by inhalation.

121. Method for inhibiting the expression of a target gene in a cell, comprising the following steps:
Introduction of at least one double-stranded ribonucleic acid (dsRNA I) in a quantity sufficient to inhibit expression of the target gene, whereby dsRNA I exhibits a double-stranded structure consisting of a maximum of 49 successive nucleotide pairs, and whereby one strand (as1) or at least one segment of the strand (as1) of the double-stranded structure is complementary to the target gene, and whereby at least one end (E1, E2) of the dsRNA I
exhibits an overhang consisting of 1 to 4 nucleotides.

122. Method in accordance with Claim 1, whereby dsRNA I exhibits the overhang at the 3'-end of one strand (as1) and/or at the 3'-end of the other strand (ss1).

123. Method in accordance with Claim 1 or 2, whereby the dsRNA I
has a smooth configuration at one end (E1, E2).

124. Method in accordance with Claim 3, whereby the smooth end (E1, E2) contains the 5'-end of one strand (as1).

125. Method in accordance with one of the preceding claims, whereby the overhang consists of 1 to 4 nucleotides, preferably of 1 or 2 nucleotides.

126. Method in accordance with one of the preceding claims, whereby at least one further double-stranded ribonucleic acid (dsRNA II) having a configuration according to the dsRNA I as defined in the preceding claims, is introduced into the cell, whereby the one strand (as1) of dsRNA I is complementary to a first region (B1) of the target gene, and whereby another strand (as2) or at least one segment of the other strand (as2) of dsRNA II is complementary to a second region (B2) of the target gene.

127. Method in accordance with one of the preceding claims, whereby the dsRNA I and/or dsRNA II exhibits a length of fewer than 25 successive nucleotide pairs, preferably 19 to 23.

128. Method in accordance with one of the preceding claims, whereby the first (B1) and the second (B2) region overlap segmentally or adjoin each other.

129. Method in accordance with one of the preceding claims, whereby the first (B1) and the second (B2) region are separated from each other.

130. Method in accordance with one of the preceding claims, whereby the target gene exhibits one of the sequences SQ001 to SQ140.

131. Method in accordance with one of the preceding claims, whereby the target gene is selected from the following group: oncogene, cytokine gene, Id protein gene, prion gene, genes from angiogenesis-inducing molecules, from adhesion molecules, and from cell-surface receptors; genes from proteins that are involved in metastatic and/or invasive processes; genes from proteinases as well as molecules that regulate apoptosis and the cell cycle.

132. Method in accordance with one of the preceding claims, whereby the target gene is the MDR1 gene.

133. Method in accordance with one of the preceding claims, whereby one of the sequences SQ141-173 or a dsRNA construct being combined of two antisense- (as1/2) and sense sequences (ss1/2) belonging together and belonging to sequences SQ141-173 are used as the dsRNA I/II.

134. Method in accordance with one of the preceding claims, whereby expression is inhibited according to the principle of RNA interference.

135. Method in accordance with one of the preceding claims, whereby the target gene is expressed in pathogenic organisms, preferably in plasmodia.

136. Method in accordance with one of the preceding claims, whereby the target gene is a component of a virus or viroid.

137. Method in accordance with Claim 16, whereby the virus is a human pathogenic virus or viroid.

138. Method in accordance with Claim 16, whereby the virus or viroid is a virus or viroid that is pathogenic in animals or plants.

139. Method in accordance with one of the preceding claims, whereby unpaired nucleotides are substituted by nucleoside thiophosphates.

140. Method in accordance with one of the preceding claims, whereby at least one end (E1, E2) of dsRNA I/II is modified in order to counter decomposition in the cell or dissociation in the individual strand.

141. Method in accordance with one of the preceding claims, whereby the cohesion of the double-stranded structure effected by the complementary nucleotide pairs is increased by at least one chemical bond.

142. Method in accordance with one of the preceding claims, whereby the chemical link is achieved either by a covalent or ionic bond, a hydrogen bond, hydrophobic interaction, preferably by means of van der Waals or stacking interactions, or by means of metal-ion coordination.

143. Method in accordance with one of the preceding claims, whereby the chemical link is formed in the vicinity of one end (E1, E2).

144. Method in accordance with one of the preceding claims, whereby the chemical link is created by one or several linkage groups, whereby the linkage groups are preferably poly-(oxyphosphinico-oxy-1,3-propandiol) and/or oligoethyleneglycol chains.

145. Method in accordance with one of the preceding claims, whereby the chemical link is formed by using branched nucleotide analogs instead of nucleotides.

146. Method in accordance with one of the preceding claims, whereby the chemical link is formed by purine analogs.

147. Method in accordance with one of the preceding claims, whereby the chemical link is formed by azabenzene units.

148. Method in accordance with one of the preceding claims, whereby at least one of the following groups is used in creating the chemical link: methylene blue; bifunctional groups, preferably bis-(2-chlorethyl)-amine; N-acetyl-N'-(p-glyoxyl-benzoyl)-cystamine; 4-thiouracil; psoralen.

149. Method in accordance with one of the preceding claims, whereby the chemical link is formed by thiophosphoryl groups that are attached in the vicinity of the ends (E1, E2) of the double-stranded region.

150. Method in accordance with one of the preceding claims, whereby the chemical link is formed by triple helix bonds that are present in the vicinity of the ends (E1, E2).

151. Method in accordance with one of the preceding claims, whereby the dsRNA I/II is enclosed in micellar structures, most advantageously in liposomes.

152. Method in accordance with one of the preceding claims, whereby the dsRNA I/II is bound to, associated with, or enclosed by at least one viral case protein that stems from a virus, is derived from it, or is synthetically produced.

153. Method in accordance with one of the preceding claims, whereby the coat protein is derived from polyomavirus.

154. Method in accordance with one of the preceding claims, whereby the coat protein contains Virus Protein 1 (VP1) and/or Virus Protein 2 (VP2) of the polyomavirus.

155. Method in accordance with one of the preceding claims, whereby at the formation of a capsid or capsid-like structure, the one side is turned toward the inside of the capsid or capsid-like structure.

156. Method in accordance with one of the preceding claims, whereby the one strand (as1, as2) of dsRNA I/II is complementary to the primary or processed RNA transcript of the target gene.

157. Method in accordance with one of the preceding claims, whereby the cell is a vertebrate cell or a human cell.

158. Method in accordance with one of the preceding claims, whereby the dsRNA I/II is administered to a mammal at a maximum dosage of 5 mg/kg body weight per day, preferably to human being.

159. Method in accordance with one of the preceding claims, whereby the dsRNA I/II is mixed in a buffer solution for application.

160. Method in accordance with one of the preceding claims, whereby the dsRNA I/II is administered orally or by intravenous, intratumoral, or intraperitoneal injection or infusion, or by inhalation.

161. Use of a double-stranded ribonucleic acid (dsRNA I) for inhibiting the expression of the target gene in a cell, whereby dsRNA I exhibits a double-stranded structure consisting of a maximum of 49 successive nucleotide pairs, and whereby one strand (as1) or at least one segment of a strand (as1) of the double-stranded structure is complementary to the target gene, and whereby dsRNA I
exhibits an overhang consisting of 1 to 4 nucleotides at at least one end (E1, E2).

162. Use in accordance with Claim 41, whereby dsRNA I exhibits the overhang at the 3'-end of one strand (as1) and/or at the 3'-end of the other strand (ss1).

163. Use in accordance with Claim 41 or 42, whereby the dsRNA I
has a smooth configuration at one end (E1, E2).

164. Use in accordance with Claim 43, whereby the smooth end(E1, E2) contains the 5'-end of one strand (as1).

165. Use in accordance with one of the Claims 41 to 44, whereby the overhang consists of 1 to 4 nucleotides, preferably of 1 or 2 nucleotides.

166. Use in accordance with Claims 41 to 45, whereby at least one further double-stranded ribonucleic acid (dsRNA II), having a configuration according to the dsRNA I as defined in the preceding claims 41 to 45, is introduced into the cell, whereby the one strand (as1) or at least one segment of the strand (as1) of the double-stranded structure of the dsRNA I
is complementary to a first region (B1) of the sense strand of the target gene, and whereby the other strand (as2) or at least one segment of the other strand (as2) of the double-stranded structure of dsRNA II is complementary to a second region (B2) of the target gene.

167. Use in accordance with one of the Claims 41 to 47, whereby the dsRNA I and/or dsRNA II exhibits a length of fewer than 25, preferably 19 to 23, successive nucleotide pairs.

168. Use in accordance with one of the Claims 41 to 47, whereby the first (B1) and second region (B2) overlap segmentally or adjoin each other.

169. Use in accordance with one of the Claims 41 to 48, whereby the first (B1) and second region (B2) are separated from each other.

170. Use in accordance with one of the Claims 41 to 49, whereby the target gene exhibits one of the sequences SQ001 to SQ140.

171. Use in accordance with one of the Claims 41 to 50, whereby the target gene is selected from the following group:
oncogene, cytokine gene, Id protein gene, prion gene, genes from angiogenesis-inducing molecules, from adhesion molecules, and from cell-surface receptors; genes from proteins that are involved in metastatic and/or invasive processes; genes from proteinases as well as molecules that regulate apoptosis and the cell cycle.

172. Use in accordance with one of the Claims 41 to 51, whereby the target gene is the MRD1 gene.

173. Use in accordance with one of the Claims 41 to 52, whereby one of the sequences SQ141-173 or a dsRNA construct being combined of two antisense- (as1/2) and sense sequences (ss1/2) belonging together and belonging to sequences SQ141-173 are used as the dsRNA I/II.

174. Use in accordance with one of the Claims 41 to 53, whereby expression is inhibited according to the principal of RNA
interference.

175. Use in accordance with one of the Claims 41 to 54, whereby the target gene is expressed in pathogenic organisms, preferably in plasmodia.

176. Use in accordance with one of the Claims 41 to 55, whereby the target gene is a component of a virus or viroid.

177. Use in accordance with Claim 56, whereby the virus is a human pathogenic virus or viroid.

178. Use in accordance with Claim 56 whereby the virus or viroid is a virus or viroid that is pathogenic in animals or plants.

179. Use in accordance with one of the Claims 41 to 58, whereby unpaired nucleotides are substituted by nucleoside thiophosphates.

180. Use in accordance with one of the Claims 41 to 59, whereby at least one end (E1, E2) of the dsRNA is modified in order to counter decomposition in the cell or dissociation in the individual strand.

181. Use in accordance with one of the Claims 41 to 60, whereby the cohesion of the double-stranded structure effected by the complementary nucleotide pairs is increased by at least one chemical bond.

182. Use in accordance with one of the Claims 41 to 61, whereby the chemical link is achieved either by a covalent or ionic bond, a hydrogen bond, hydrophobic interaction, preferably by means of van der Waals or stacking interactions, or by means of metal-ion coordination.

183. Use in accordance with one of the Claims 41 to 62, whereby the chemical link is formed in the vicinity of one end (E1, E2).

184. Use in accordance with one of the Claims 41 to 63, whereby the chemical link is created by one or several linkage groups, whereby the linkage groups are preferably poly-(oxyphosphinico-oxy-1,3-propandiol) and/or oligoethyleneglycol chains.

185. Use in accordance with one of the Claims 41 to 64, whereby the chemical link is formed by using branched nucleotide analogs instead of nucleotides.

186. Use in accordance with one of the Claims 41 to 65, whereby the chemical link is formed by purine analogs.

187. Use in accordance with one of the Claims 41 to 66, whereby the chemical link is formed by azabenzene units.

188. Use in accordance with one of the Claims 41 to 67, whereby at least one of the following groups is used in creating the chemical link: methylene blue; bifunctional groups, preferably bis-(2-chlorethyl)-amine; N-acetyl-N'-(p-glyoxyl-benzoyl)-cystamine; 4-thiouracil; psoralen.

189. Use in accordance with one of the Claims 41 to 68, whereby the chemical link is formed by thiophosphoryl groups that are attached in the vicinity of the ends (E1, E2) of the double-stranded region.

190. Use in accordance with one of the Claims 41 to 69, whereby the link is produced by triple helix bonds present in the vicinity of the ends (E1, E2).

191. Use in accordance with one of the Claims 41 to 70, whereby the dsRNA I/II is enclosed in micellar structures, most advantageously in liposomes.

192. Use in accordance with one of the Claims 41 to 71, whereby the dsRNA I/II is bound to, associated with, or enclosed by at least one viral case protein that stems from a virus, is derived from it, or is synthetically produced.

193. Use in accordance with one of the Claims 41 to 72, whereby the case protein is derived from polyomavirus.

194. Use in accordance with one of the Claims 41 to 73, whereby the case protein contains Virus Protein 1 (VP1) and/or Virus Protein 2 (VP2) of the polyomavirus.

195. Use in accordance with one of the Claims 41 to 74, whereby at the formation of a capsid or capsid-like structure, the one side is turned toward the inside of the capsid or capsid-like structure.

196. Use in accordance with one of the Claims 41 to 75, whereby the one strand (asl, as2) of dsRNA I/II is complementary to the primary or processed RNA transcript of the target gene.

197. Use in accordance with one of the Claims 41 to 76, whereby the cell is a vertebrate cell or a human cell.

198. Use in accordance with one of the Claims 41 to 77, whereby the dsRNA I/II is administered to a mammal at a maximum dosage of 5 mg/kg body weight per day, preferably to human being.

199. Use in accordance with one of the Claims 41 to 78, whereby the dsRNA I/II is mixed with a buffer solution for application.

200. Use in accordance with one of the Claims 41 to 79, whereby the dsRNA I/II is administered orally or by intravenous, intratumoral, or intraperitoneal injection or infusion, or by inhalation.

201. Medicament for inhibiting the expression of a target gene in a cell containing a double-stranded ribonucleic acid (dsRNA
I) in a dosage sufficient to inhibit the expression of the target gene.
whereby dsRNA I exhibits a double-stranded structure consisting of a maximum of 49 successive nucleotide pairs, and whereby one strand (as1) or at least one segment of the strand (as1) of the double-stranded structure is complementary to the target gene, and whereby at least one end (E1, E2) of the dsRNA I
exhibits an overhang consisting of 1 to 4 nucleotides.

202. Medicament in accordance with Claim 81, whereby dsRNA I
exhibits the overhang at the 3'-end of one strand (asl) and/or at the 3'-end of the other strand (ss1).

203. Medicament in accordance with Claim 81 or 82, whereby the dsRNA I has a smooth configuration at one end (E1, E2).

204. Medicament in accordance with Claim 83, whereby the smooth end (E1, E2) contains the 5'-end of the first strand (asl).

205. Medicament in accordance with Claims 81 to 84, whereby the overhang consists of 1 to 4 nucleotides, preferably of 1 or 2 nucleotides.

206. Medicament in accordance with one of the Claims 81 to 85, whereby at least one further double-stranded ribonucleic acid (dsRNA II) having a configuration according to the dsRNA I as defined in Claims 81 to 85, and whereby the one strand (as1) of dsRNA I is complementary to a first region (B1) of the target gene, and whereby another strand (as2) or at least one segment of the other strand (as2) of dsRNA II
is complementary to a second region (B2) of the target gene.

207. Medicament in accordance with one of the Claims 81 to 86, whereby the dsRNA I and/or dsRNA II exhibits a length of fewer than 25, preferably in 19 to 23, successive nucleotide pairs.

208. Medicament in accordance with one of the Claims 81 to 87, whereby the first (B1) and the second region (B2) overlap segmentally or adjoin each other.

209. Medicament in accordance with one of the Claims 81 to 88, whereby the target gene exhibits one of the sequences SQ001 to SQ140.

210. Medicament in accordance with one of the Claims 81 to 89, whereby the target gene is selected from the following group: oncogene, cytokine gene, Id protein gene, prion gene, genes from angiogenesis-inducing molecules, from adhesion molecules, and from cell-surface receptors; genes from proteins that are involved in metastatic and/or invasive processes; genes from proteinases as well as molecules that regulate apoptosis and the cell cycle.

211. Medicament in accordance with one of the Claims 81 to 90, whereby the target gene is the MRD1 gene.

212. Medicament in accordance with one of the Claims 81 to 91, whereby one of the sequences SQ141-173 or a dsRNA construct being combined of two antisense- (as1/2) and sense sequences (ss1/2) belonging together and belonging to sequences SQ141-173 are used as the dsRNA I/II.

213. Medicament in accordance with one of the Claims 81 to 92, whereby expression is inhibited according to the principle of RNA interference.

214. Medicament in accordance with one of the Claims 81 to 93, whereby the target gene is expressed in pathogenic organisms, most advantageously in plasmodia.

215. Medicament in accordance with one of the Claims 81 to 94, whereby the target gene is a component of a virus or viroid.

216. Medicament in accordance with Claim 95, whereby the virus is a human pathogenic virus or viroid.

217. Medicament in accordance with Claim 95, whereby the virus or viroid is a virus or viroid that is pathogenic in animals or plants.

218. Medicament in accordance with one of the Claims 81 to 97, whereby unpaired nucleotides are substituted with nucleoside thiophosphates.

219. Medicament in accordance with one of the Claims 81 to 98, whereby at least one end (E1, E2) of dsRNA I/II is modified in order to counter decomposition in the cell or dissociation in the individual strand.

220. Medicament in accordance with one of the Claims 81 to 99, whereby the cohesion of the double-stranded structure effected by the complementary nucleotide pairs is increased by at least one chemical bond.

221. Medicament in accordance with one of the Claims 81 to 100, whereby the chemical link is achieved either by a covalent or ionic bond, a hydrogen bond, hydrophobic interaction, preferably by means of van der Waals or stacking interactions, or by means of metal-ion coordination.

222. 102. Medicament in accordance with one of the Claims 81 to 101, whereby the chemical link is formed in the vicinity of one end (E1, E2).

223. Medicament in accordance with one of the Claims 81 to 102, whereby the chemical link is created by one or several linkage groups, whereby the linkage groups are preferably poly-(oxyphosphinico-oxy-1,3-propandiol) and/or oligoethyleneglycol chains.

224. Medicament in accordance with one of the Claims 81 to 103, whereby the chemical link is formed by using branched nucleotide analogs instead of nucleotides.

225. Medicament in accordance with one of the Claims 81 to 104, whereby the chemical link is formed by purine analogs.

226. Medicament in accordance with one of the Claims 81 to 105, whereby the chemical link is formed by azabenzene units.

227. Medicament in accordance with one of the Claims 81 to 106, whereby at least one of the following groups is used in creating the chemical link: methylene blue; bifunctional groups, preferably bis-(2-chlorethyl)-amine; N-acetyl-N'-(p-glyoxyl-benzoyl)-cystamine; 4-thiouracil; psoralen.

228. Medicament in accordance with one of the Claims 81 to 107, whereby the chemical link is formed by thiophosphoryl groups that are attached in the vicinity of the ends (E1, E2) of the double-stranded region.

229. Medicament in accordance with one of the Claims 81 to 108, whereby the chemical link is formed by triple helix bonds that are present in the vicinity of the ends (E1, E2).

230. Medicament in accordance with one of the Claims 81 to 109, whereby the dsRNA I/II is enclosed in micellar structures, most advantageously in liposomes.

231. Medicament in accordance with one of the Claims 81 to 110, whereby the dsRNA I/II is bound to, associated with, or enclosed by at least one viral case protein that stems from a virus, is derived from it, or is synthetically produced.

232. Medicament in accordance with one of the Claims 81 to 111, whereby the coat protein is derived from polyomavirus.

233. Medicament in accordance with one of the Claims 81 to 112, whereby the coat protein contains Virus Protein 1 (VP1) and/or Virus Protein 2 (VP2) of the polyomavirus.

234. Medicament in accordance with one of the Claims 81 to 113, whereby at the formation of a capsid or capsid-like structure, the one side is turned toward the inside of the capsid or capsid-like structure.

235. Medicament in accordance with one of the Claims 81 to 114, whereby the one strand (as1, as2) of dsRNA I/II is complementary to the primary or processed RNA transcript of the target gene.

236. Medicament in accordance with one of the Claims 81 to 115, whereby the cell is a vertebrate cell or a human cell.

237. Medicament in accordance with one of the Claims 81 to 116, whereby the first (B1) and the second region (B2) are separated from each other.

238. Medicament in accordance with one of the Claims 81 to 117, whereby the dsRNA is administered at a maximum amount of 5 mg per dose.

239. Medicament in accordance with one of the Claims 81 to 118, whereby the dsRNA is mixed in a buffer solution for application.

240. Medicament in accordance with one of the Claims 81 to 119, whereby the dsRNA is administered orally or by intravenous, intratumoral, or intraperitoneal injection or infusion, or by inhalation.