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Publication numberUS3791932 A
Publication typeGrant
Publication dateFeb 12, 1974
Filing dateJan 27, 1972
Priority dateFeb 10, 1971
Also published asCA958314A1, CA1040082B, DE2206103A1, DE2206103B2
Publication numberUS 3791932 A, US 3791932A, US-A-3791932, US3791932 A, US3791932A
InventorsA Schuurs, B Weemen
Original AssigneeAkzona Inc
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Process for the demonstration and determination of reaction components having specific binding affinity for each other
US 3791932 A
Abstract
The present invention relates to a process for the determination of a component of the reaction between a specific binding protein and the substance being specifically bound by such a protein comprising reacting the component to be determined with its binding partner in an insolubilized form, separating the solid phase of the reaction mixture from the liquid phase, reacting the solid phase with a determined amount of a coupling product of the substance to be determined with an enzyme, and finally determining the enzyme activity of the liquid or solid phase of the reaction mixture obtained.
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Description  (OCR text may contain errors)

United States Patent [191 Schuurs et al.

[451 Feb. 12, 1974 [75] Inventors: Antonius Hermanus Wilhelmus Maria Schuurs; Bauke Klaas Van Weemen, both of Oss, Netherlands [73] Assignee: Akzona Incorporated, Asheville,

22 Filed: Jan. 27, 1972 21 App]. No.: 221,447

[30] Foreign Application Priority Data Feb. 10, 1971 Netherlands 7101728 [52] US. Cl. 195/l03.5 R, 424/12, 23/230 B [51] Int. Cl. G0ln 31/14 [58] Field of Search 195/103.5 R; 23/230 B; 424/12 [56] References Cited UNITED STATES PATENTS 3,654,090 4/1972 Schuurs et al. 195/1035 R Primary Examiner-Alvin E. Tanenholtz Assistant ExaminerMax D. Hensley Attorney, Agent, or Firm--Hugo E. Weisberger [57] ABSTRACT The present invention relates to a process for the determination of a component of the reaction between a specific binding protein and the substance being specifically bound by such a protein comprising reacting the component to be determined with its binding partner in an insolubilized form, separating the solid phase of the reaction mixture from the liquid phase, reacting the solid phase with a determined amount of a coupling product of the substance to be determined with an enzyme, and finally determining the enzyme activity of the liquid or solid phase of the reaction mixture obtained.

4 Claims, N0 Drawings PROCESS FOR THE DEMONSTRATION AND DETERMINATION OF REACTION COMPONENTS HAVING SPECIFIC BINDING AFFINITY FOR EACH OTHER For the demonstration and determination of substances playing a prominent part in biochemical processes, i.e. low molecular substances, such as vitamins and steroids, or high molecular ones, such as proteins and carbohydrates, it is often possible to employ reactions of these substances with proteins having a specific binding affinity for these substances. Thus, it is possible to determine the concentration of a steroid by employing a protein capable of binding this steroid specifically. As examples of such combinations are mentioned cortisol and transcortin, l7B-oestradiol and the oestradiol-binding receptor protein of the uterus.

It is also possible to link a low molecular substance chemically with a protein, and to inject this conjugate into a test animal, which then reacts by forming antibodies against, among others, the low molecular substance. The latter is in this case to be regarded as a socalled hapten. The antibodies against the hapten may be regarded as a special case of specific binding proteins.

High molecular substances, such as simple and conjugated proteins and carbohydrates, are capable of causing the formation of antibodies on being injected into animals in the correct experimental conditions. Between these antibodies and the injected high molecular substance, the antigen, there is again question of specific binding affinity.

Determination methods in which these specific binding affinities are employed, are often based on the competition between the substance to be determined in the sample and the known quantity of the same substance, labelled radioactive, for a limited quantity of its binding partner. The quantity of substance to be determined determines what part of the radioactive labelled substance can be bound by its binding partner. It is also possible to determine an unknown quantity of specific binding protein by reacting a sample of it with a certain quantity of radioactive labelled, specific binding substance. The terms by which these methods are designated in the literature, depend upon the nature of the specific binding protein. They speak of competitive protein binding assays, where receptor or transport proteins are used, and of"radioimmunological determinations" where antibodies are employed as specificbinding protein.

Instead of labelling one of the components of the above-described reactions with a radioactive isotope, it is also possible to employ an enzyme as a labelling substance. Where use is made of the binding affinity between a low molecular substance and its specif c binding protein, the low molecular substance can be coupled with an enzyme. The coupling product, low molecular substance/enzyme, can then be used in experimental set-ups as described above. Where use is made of the binding affinity between an antigen and its antibody, the antigen may, for example, be coupled with an enzyme instead of labelling it with a radioactive isotope as is conventional in radioimmunological methods.

For all the methods in which such a labelled reaction component is employed, a suitable method for separating the free labelled compound attached to the binding partner, is essential. Dependent upon the nature of the substances participating in the reaction, various separation methods can be employed, for example electrophoresis, gel filtration, selective adsorption, application of one of the reaction components in an insolubilised form, and application of antibodies against one of the reaction components, also in an insolubilised form.

In spite of the high sensitivity that can be achieved by these methods, it is not always possible to demonstrate or determine substances occurring in extremely low concentrations in, for example, serum or urine. Thus, it is very difficult and often impossible to demonstrate adrenocorticotrophic hormone (ACTH) by a radioimmunological method, unless one has the disposal of a very rare antiserum containing antisubstances with an extremely high binding affinity for ACTH.

Also determinations of smaller peptide hormones such as oxytocin in non-extracted serum, causes great difficulties, because the required sensitivity cannot be reached.

Although, in principle, the immunological crossreaction between HCG and LH enables both hormones to be determined with one test-system, most methods for the determination of human chorionic gonadotrophin (HCG) by a coupling product of HCG and an enzyme cannot be used for the demonstration and determination of luteinizing hormone (LH). This is due to the fact that LH occurs in much lower concentrations in blood and urine than HCG during pregnancy, so that the sensitivity of the test systems are insufficient. This shortage of sensitivity can be decreased by extracting the substance to be determined from the medium in which it occurs or by concentrating the medium. These methods, however, are very laborious, and the results often unsatisfactory.

A process has now been found for the demonstration and determination of a component of the reaction between specific binding proteins and the substances that can be specifically bound by these proteins, using the known binding affinity of such components for each other, which comprises reacting the component to be determined with its binding partner, which has been or is insolubilised, separating the solid phase of the reaction mixture from the liquid phase, reacting the solid phase with a coupling product, obtained by binding a substance capable of reacting specifically with one of the reaction components, to an enzyme, and finally determining the enzyme activity of the liquid or the solid phase in the reaction mixture obtained, which is a measure for the quantity of the substance to be determined.

The binding partner required for the determination of the component present in an unknown quantity, is employed in an insoluble form. The determination can take place by adding the binding partner to the reaction mixture in an insoluble form and reacting the mixture in a heterogeneous medium, but the binding partner can also be added in a dissolved form, after which it can be insolubilised by adding antisubstances against it.

The substance capable of reacting specifically with one of the reaction components, and which is employed coupled with an enzyme, may be the other reaction component, but also a third substance that must possess a specific affinity for one of the components of the reaction.

The method can be applied to the various reaction systems described above, i.e. antigen/antibody, hapten- /antibody and a low molecular substance/specific binding protein. As third substance a second antibody may occur, that is to say, an antibody against the gammaglobulin fraction of the species of animal in which the first antibodies have been generated. This situation may occur in the systems antigen/(first) antibody and hapten/(first) antibody. As third substance may also occur an antibody against a specific binding protein.

The essence of the method is the performance in two steps, in between which a separation takes place of the liquid and the solid phase of the reaction mixture. With the solid phase the second step is performed. Only in this stage the enzyme coupling product is employed and the enzyme activity determined.

The most important advantages of the method found are:

l. the first step can be performed in a larger volume than is desirable or possible for the second step. This is of great importance when the substance to be determined occurs in too low concentrations to be determined by known methods.

2. In the liquid to be examined substances may be present influencing the reactions in the second step unfavourably. Especially the enzyme present in the coupling product and the enzymatic catalysing reaction may be sensitive to disturbing substances in the test liquid.

The method found can especially be employed for the determination of substances present in body liquids such as hormones, their antibodies and specific binding proteins, as well as enzymes. Also factors of bloodclotting, fibrinolysis and complement systems, pathological proteins in body liquids, as well as antibodies against pathogenic microorganisms and iso-antibodies can be determined in this manner.

The medium in which the first step of the determination takes place often consists for a large part of test liquid, such as urine or serum. If considered necessary, it can be adjusted to the pH required for the immunochemical reaction, viz. between 5 and 9, by adding a dry buffer salt or a small volume of a concentrated buffer solution. The medium of the second step is also a buffer of a pH required for the immunochemical reaction. For this purpose phosphate buffers, citrate buffers, tris(hydroxy methyl)-aminomethane, and imidazole buffers can be employed. It may be necessary to use for the relative enzyme reaction a buffer of another composition and pH, which depends upon the enzyme employed.

The manufacture of the insolubilised reaction component can take place in various manners, i.a. dependent upon the properties of this reaction component. Thus, antibodies, specific binding proteins and proteinlike antigen can be insolubilised by cross-linking, for example, glutaric aldehyde and chloroformic acid ethyl ester, by physical adsorption or chemical coupling with an insoluble carrier, such as cellulose compounds, agarose, cross-linked dextran, polystyrene and the like, or by coupling with antibodies against the relative protein coupled with an insoluble carrier. Low molecular substances can be bound by methods dependent upon the structure of the low molecular substance and the carrier material. Some of the low molecular substances may already possess groups capable of reacting with the reactive parts on the carrier material: in other cases such groups will have to be introduced by organic chemical reactions.

The manufacture of the enzyme coupling products is also performed by methods dependent upon the properties of the molecules incorporated into the coupling product. A covalent bond of proteins to enzymes can be effected by reagents such as carbodiimides, diisocyanates, glutaric aldehyde and bis-diazobenzidine. The coupling of low molecular substances can take place in various manners. Some of these substances may already possess groups that can be cross-linked with reactive groups of the enzyme; in other cases such groups will have to be introduced by organic chemical reactions. It stands to reason that in the manufacture of these coupling products the original binding properties of the substances bound to the enzyme may not change very much; no more may the enzyme activity be decreased considerably.

The choice of the enzyme that is to form a part of the coupling product, is determined by properties such as the specific binding activity (a high conversion rate raises the sensitivity of the test system) and the simplicity of the determination of the enzyme. The determination of an enzyme catalysing a conversion in which coloured reaction components are involved, is simple. Such colorimetric determinations can be automated in a simple manner.

According to the invention it is also possible to employ enzymes catalysing those conversions in which reaction components are involved that can be determined spectrophotometrically or fluorimetrically. These determinations can also be automated.

In the manufacture of the coupling products enzymes such as catalase, peroxidase, B-glucuronidase, B-B- glucosidase, ,B-D-galactosidase, urease, glucoseoxidase and galactose-oxidase are preferred, especially the group of the oxidoreductases.

The determinations according to the invention are broadly performed as follows: A certain volume of a test liquid, for example 10 ml, containing a very low concentration of the component to be determined, is mixed with a certain quantity of an insolubilised reaction partner of the substance to be determined. The test liquid may be urine, in which the component to be determined occurs in low concentration, or serum, which has been diluted to diminish the influence of disturbing factors. In order to enable the reaction to be performed in the heterogeneous system, the mixture is agitated. The resulting solid phase is separated from the test liquid, for example by centrifugation, and washed, if considered necessary. The first part of the determination can also be performed by incubating the test liquid with a certain quantity of the reaction partner of the substance to be determined in a dissolved form, after which a quantity of insolubilised antibody against that reaction partner is added and the mixture agitated and finally centrifuged. Separation by filtration and decantation is also possible.

The second part of the determination is performed by resuspending the insoluble substance, which forms the The enzyme activity of a phase of the reaction mixture is demonstrated or measured by incubating that phase with a substrate and other substances required for the relative enzyme reaction.

Preferably a reaction is employed in which a coloured compound is formed, or removed, whose adsorption can be easily quantitatively determined.

The form in which the reagents can be used are manifold. The component of the reaction system coupled with an enzyme may have been dissolved in a buffer, or freeze-dried. Also a solid carrier can be used, for example a strip of paper impregnated with the enzyme coupling product.

The insoluble component can be processed in the form of particles of various sizes, such as grains, plates and rods, or in the form of a strip of some or other carrier material.

For the performance of the process according to the invention a test-pack is usually employed, chiefly consisting of:

a. a certain quantity of the enzyme coupling product;

b. a corresponding quantity of one of the components of the reaction system in an insoluble form;

c. a substrate for the determination of the quantity of the enzyme employed.

The test-pack can contain the necessary auxiliaries, if required, to make a dilution series of the sample to be tested for a quantitative determination, such as test tubes, pipettes and flasks containing a diluent. For the determination of antigens or haptens, or their antibodies, the test-pack contains at least:

a. a certain quantity of the coupling product of the antigen or hapten, or an antibody against it, and an enzyme;

b. a corresponding quantity of an insolubilised component of the reaction system antigen/antibody, or hapten/antibody, and

c. a substrate for the determination of the enzyme activity.

The invention is further illustrated by the following examples, which are on no account intended to limit the invention.

EXAMPLE I Determination of human chorionic gonadotrophin (HCG) in serum.

a. Preparation of HCG-HRP. Five mg of HCG and 20 mg of horse-radish peroxidase (HRP) were dissolved in 2 ml of 0.05 M phosphate buffer of pH 6.2. After 40 u/ltr of 25 percent glutaric aldehyde solution had been added, the mixture was shaken at room temperature for 2 hours. Then the mixture was centrifuged for 5 minutes at 250 g, after which it was fractionated over Sephadex G-200 in 0.05 M phosphate buffer of pH 6.2. The fractions whose highest percentage of enzyme activity was bound by antibodies against HCG, were used in the test system.

b. Preparation of antibodies against HCG. Antibodies against HCG were generated in rabbits as described by Schuurs et. al. in Acta Endocr. (Kbh.) 59, (1968).

c. Preparation of the immuno-adsorbent, anti-HCG- cellulose. The y-globulin fraction of the anti-HCG- serum described under 1)) was prepared by precipitation with 18 percent (w/v) solid Na SO The precipitate was washed and then taken up in so much 0.05 M borate buffer of pH 8.6 that the ultimate protein concentration was 10 mg/ml. M-aminobenzyloxy methyl cellulose (350 mg) prepared by Gurvichs method, described in Biokhimiya 26, 934 (1961 was suspended in 50 ml of distilled water and diazotized by adding 10 ml of 36 percent hydrochloric acid and, dropwise, 10 ml of 10 percent NaNo -solution. The suspension was centrifuged and washed, and the precipitate resuspended in 43 ml of 0.05 M sodium borate of pH 8.6. 'yglobulin solution prepared 7 ml were added to this suspension. The mixture was stirred for 26 hours at 4C, centrifuged, and finally washed with 1 ltr of 0.02 M phosphate buffer of pH W V p 7 d. 'otr'ni'ifififiafimofi serum. A dilution series of HCG (8-4-2-l-0.5-0.25-0 l.U./ml) was prepared with a dilution liquid consisting of one part of mans serum and 2 part of 0.05 M phosphate buffer of pH 6.2. Of each of the thus prepared HCG dilutions 0.5 ml was rotated for 2 hours at room temperature with 0.5 ml of the immuno-adsorbent suspension (4 mg/ml), prepared in accordance with c), and then centrifuged. The precipitate was washed twice, each time with 2 ml of 0.05 M phosphate buffer of pH 6.2. The precipitate was mixed with 1.0 ml of HCG-HRP solution in a suitable dilution, as well as in 0.05 M phosphate buffer of pH 6.2, and rotated again at room temperature for 2 hours.

After centrifugation the enzyme activity was determined in the supernatant liquid by adding 0.5 ml of it to 1.5 ml of a substrate solution consisting of 10 ul of 30% H 0 and 20 mg of 5-amino salicylic acid in ml of0.02 M phosphate buffer of pH 6.0. After 30 minutes the extinction was measured at 460 nm.

In the test system described a HCG concentration of 0.25 I.U./ml caused a measurable increase in the enzyme activity in the supernatant liquid, while a concentration of 1 I.U./ml caused the maximum increase. in this test the centrifugation step proved to be of decisive significance, as omission of this step gave rise to wrong measuring results of the enzyme activity, La. owing to turbidity of the serum and the peroxidase-like activity of it.

The HCG content of serum of pregnant women could be determined in this experimental set-up provided that the serum sample was diluted in the ratio of at least 1:3.

EXAMPLE II Determination of HCG in low concentrations by means of an enzyme/antigen coupling product.

a. Preparation of antisubstances against rabbit-yglobulin. Rabbit-y-globulin was isolated from normal rabbit serum by precipitating it with 18 percent (w/v) solid Na SO Antibodies against it were generated in a sheep. The injection scheme was:

Day Quantity Freunds adjuvant Manner of injection 0.5 mg lntramuscularly 14 0.5 mg Do.

28 1 mg Do.

42 1 mg Intravenously 56 1 mg Do.

On day 70 the sheep was exsanguinated.

b. Preparation of [sheep-anti-(rabbit-'y-globulin)]- cellulose. The 'y-globulin fraction of the sheep serum described under a) was prepared by precipitating it with 16 percent (w/v) solid sodium sulphate. This y-globulin fraction was bound to maminobenzyloxymethyl-cellulose, as described in example I c).

c. Determination of human chorionic gonadotrophin (HCG). A dilution series of HCG was prepared in 0.01 M phosphate buffer of pH 6.0, which also contained 2 percent (v/v) normal sheep serum. The dilution series was in the range of 10 to 320 I.U./ l, the dilution factor being 2. v

To 5 ml of a HCG solution was added 0.1 ml of a rabbit (anti-HCG) serum (see example I b), diluted with the same buffer to the desired strength. The mixture was left to stand at room temperature for 30 minutes, after which 1.5 mg of [sheep-anti(rabbit-y-globulin)] cellulose were added and the mixture was rotated for 2 hours.

The cellulose was centrifuged for minutes at 3,000 rpm. and resuspended in 1 ml of a solution of HCG- l-IRP coupling product, prepared in accordance with example I a), diluted to the desired strength with 0.01 M phosphate buffer of pH 6.0 with 2 percent normal sheep serum. The mixture was stirred again for 2 hours. After centrifugation the enzyme activity was determined in the supernatant liquid by adding 0.5 m] of it to 1.5 ml of enzyme substrate consisting of 10 pl of 30 percent H 0 and 20 mg of 5-amino-salicylic acid in 150 ml of 0.01 M phosphate buffer of pH 6.0. The mixture was left to stand for 30 minutes at 25, after which the extinction was measured at 460 nm. In the supernatant liquid 100 percent enzyme activity is measured provided that no anti-HCG serum is added to the system.

A dilution series of HCG, prepared with childrens urine as dilution liquid, gave an identical pattern so that also measurings in urine samples can be performed.

The centrifugation step effects a ten times higher sensitivity than can be reached in a system without centrifugation.

EXAMPLE III Determination of HCG and LH in low concentrations by means of an enzyme/antibody coupling product.

a. Preparation of the immune-adsorbent HCG cellulose. This immuno-adsorbent was prepared by the method mentioned in example I c), but instead of rabbit-y-globulin, 100 mg of HCG were coupled to 500 mg of m-aminobenzyloxymethyl cellulose.

b. Purification of antibodies against HCG. Ten ml of rabbit-anti-HCG serum, prepared in accordance with example I b), was diluted with 90 ml of 0.05 M citrate of pH 5.0 and slowly led over the immuno-adsorbent, which has packed in a column and mixed with 10 parts of Sephadex G-25. The immunoadsorbent was washed with the same buffer till no more protein was eluted. The antisubstances were eluted with 0.05 M citrate of pH 2.0. The fractions were collected in one half volume of 0.25 M NaHCO;,, tested for their content of antibodies and protein, and the suitable fractions were frozen.

c. Preparation of the coupling product (anti-HCG)- HRP. Twenty mg of horse radish peroxidase (HRP) were dissolved in 2 ml of an antibody solution having a protein content of 2 mg/ml. To this solution were added 8 pl of 25 percent glutaric aldehyde solution, after which the mixture was shaken for 2 hours at room temperature. Finally the mixture was fractionated over a Sephadex G-200 column in 0.05 M phosphate buffer of pH 6.5. The fractions whose highest percentage of enzyme activity were bound to HCG cellulose, were used in the test system.

d. Determination of HCG and LH. Ten ml of a HCG dilution series of HCG and 10 ml ofa HCG dilution series of LH were mixed with 5 mg of anti-HCG cellulose, prepared in accordance with example I c), which was suspended in 1 ml of 0.15 M phosphate buffer of pH 6.0, and the mixtures rotate at room temperature for 2 hours. The immunoadsorbent was centrifuged and washed with 5 ml of 0.05 M phosphate buffer of pH 6.0.

To the immuno-adsorbent 1 ml of the (anti-HCG)- HRP coupling product was added in the desired dilution, after which the mixture was rotated again for 2 hours. Finally, after centrifugation, the enzyme activity of the supernatant liquid was determined as described in the previous examples.

By this method a concentration of from 5 to 10 I.U. of HCG and 10 to 20 I.U. of LH per litre respectively could be determined. If the centrifugation step is omitted the optimum sample size is 0.5 nl and the sensitivity about I.U. of HCG per litre, or about 200 I.U. of LH per litre, so that the method according to the invention yields a 10-20 fold increase in sensitivity.

EXAMPLE IV Determination of HCG and anti-HCG.

a. Rabbit-serum was fractionated over DEAE cellulose in accordance with the prescription of H.A. Sober and others in J. Am. Chem. Soc. 78, 756 (1956). The isolated y-globulin fraction, which was immuno-electrophoretically pure, was partly used for generating antibodies in a sheep in accordance with the scheme of example [I a), while besides 100 mg of rabbit-y-globulin was coupled to 500 mg of m-aminobenzyloxymethyl cellulose by the method described in example I c).

From the sheep [anti-(rabbit-y-y-globulin)] serum prepared the specific antibodies were isolated by the method described in example II b) with the immune-adsorbent III b. The coupling product [anti-(rabbit-y-globulinH- HRP was prepared analogous to the coupling product (anti-HCG)-HRP, described in example lll c).

0. Determination of anti-HCG. A dilution series of rabbit-(anti-HCG) serum was prepared with 0.05 M phosphate buffer of pH 6.0.

Rabbit-(anti-HCG) serum (0.5 ml) was rotated with 0.25 mg of HCG-cellulose for 2 hours (see example 111 a). The reaction mixture was centrifuged and the precipitate washed four times with phosphate buffer, each time with 3 ml, after which the precipitate was resuspended in 1 ml of a solution of the coupling product b. The mixture obtained was again rotated for 2 hours. After centrifugation the enzyme activity in the supernatant liquid was determined, as described in example l d).

d. Determination of HCG. With the reagents prepared, HCG was determined by incubating solutions of it with 0.5 ml of rabbit-(anti-HCG)-serum in a dilution which in the system described under just causes an almost maximum reduction in enzyme activity in the supernatant liquid, and performing the process described under c) with the mixture obtained.

Where use was made of ml of HCG solution, it

proved to be possible to demonstrate concentrations of about 1.U./l of HCG.

EXAMPLE v Determination of insulin in serum.

a. Preparation of insulin-(glucose-oxidase). Five mg of hog insulin and 25 ml of glucose-oxidase were dissolved in 2 ml of 0.05 M phosphate buffer of pH 6.5. To this solution 5 'yl of 25 percent glutaraldehyde solution were added, after which the mixture was shaken at room temperature for 90 minutes. The mixture was fractionated over Sephadex G-200 in 0.05 M phosphate buffer of pH 6.5. The fractions whose highest percentage of enzyme ac tivity could be bound by antibodies against insulin were used in the test system.

b. Preparation of antibodies against insulin. Ten caviae were injected intramuscularly, once a week, with 1 mg of hog insulin in complete Freunds adjuvant, over a period of from 4 to 8 weeks. After having been left alone for 2 weeks the animals were injected intravenously with another milligram of insulin without adjuvant. Another 2 weeks later the animals were exsanguinated. Hypoglycemia occurring occasionally was combated by intraperitoneal administration of glucose.

c. Preparation of anti-substances against cavia 'y-globulin. Cavia -y-globulin was prepared by adding one volume of a saturated ammonium sulphate solution to two volumes of cavia serum. The resulting precipitate was washed twice with 33 percent saturated (NH S0 solution and then taken up in a physiological salt solution. A sheep was immunized with increasing dosages of the 'y-globulin prepared, viz. 0, 5, 1 and 2 mg. The injections were given every 2 weeks, the immunogen being mixed with complete Freunds adjuvant. Two weeks after the last injection another 2 mg of y-globulin, in a physiological salt solution, were given. One week later the animal was exsanguinated.

d. Preparation of insoluble antibodies against cavia 'y-globulin. Ten gm of microcrystalline cellulose were activated by adding it, while stirring, to 400 ml of 2.5 percent (w/v) CNBr solution, after which the pH was adjusted to 10.5 with an 1 N NaOH- solution, and it was maintained at it for 2 minutes. The cellulose was washed with ice water and with 0.1 M NaHCO;,. To 10 ml of sheep-anti-(cavia y-globulin) serum 1.6 gm of NaSO, were added. After stirring for 1 hour at room temperature the precipitate was centrifuged, washed twice with 20 ml of 16 percent (w/v) Na SO. solution, and finally taken up in 10 ml of 0.1 M NaHCO;,.

The activated cellulose was mixed with 40 ml ofa 0.1

M NaHCO;, solution and the 10 ml of y-globulin solution. This suspension was rotated for 40 hours at 4C and washed, twice with 5 ml of 0.5 M NaHCO twice with 500 ml of 0.05 M citrate of pH 1.1, and two times with 500 ml of 0.05 M phosphate of pH 6.2.

e. Determination of insulin in serum. Four ml of an insulin dilution series in the range of from O-lOO ng/ml, were incubated at room temperature, for 4 hours, with 1.0 ml ofanti-insulin serum (with 0.15 M phosphate buffer of pH 6.0, diluted to the desired strength). After that 5 mg of the immunoadsorbent prepared under a), suspended in 1 ml of 0.15 M phosphate buffer of pH 6.0, were added, and the resulting mixture rotated overnight at 4C. Then the immuno-adsorbent was centrifuged and washed three times with 5 ml of 0.05 M phosphate buffer of pH 6.0 (each time with 5 ml), to which 2 percent sheep serum had been added. After that 1.0 ml of insulin-glucose oxidase, diluted to the desired strength with the wash buffer, was added to the immunoadsorbent. The mixture obtained was again rotated overnight and centrifuged, after which the enzyme activity in the supernatant liquid was measured by incubating 0.5 ml of it with 2.5 ml of a substrate solution, and the extinction measured at 460 nm. The substrate solution contained mg of glucose, 10 ugm of peroxidase and 1 mg of S-aminosalicylic acid per 2.5 ml of 0.05 M phosphate buffer of pH 6.0.

The centrifugation step, in this case serving both to raise the maximum volume of the test liquid to be employed and to remove serum factors disturbing the reaction, caused a lO-fold increase in sensitivity, so that a concentration of a few ng/ml of insulin could be demonstrated.

EXAMPLE VI Determination of oestradiol.

a. Preparation of oestradiol-l7-succinyl-l-1RP. Fifty mg of oestradiol-l7-haemisuccinate and 0.08 ml of tri-n-butylamine were dissolved in 2.5 ml of diox ane. To the cold solution (2C) 15 u] of isobutylchlorocarbonate were added. After 30 minutes this solution was mixed with mg of horse radish peroxidase (HRP) in 7.5 ml of a mixture of dioxane and water (2:3), which had been adjusted to pH 9.5 with caustic soda. This solution was stirred for 4 hours at 2C, after which it was dialysed for 18 hours. The precipitate obtained after the pH of the dialysate had been adjusted to 4.6 was centrifuged, washed, and taken up in 5 ml of distilled water, which had been adjusted to pH 8. The material was purified further by precipitating it twice with 10 ml of acetone. The ultimate product was taken up in 10 ml of 0.05 M phosphate buffer of pH 7.8.

b. Preparation of oestradiol-l7-succinyl-BSA. The preparation was prepared by the mixed anhydride method as described under a). The starting material was 100 mg of oestradiol-l7-haemisuccinate and mg of bovine serum albumin (BSA).

0. Preparation of anti-substances against oestradiol. A sheep was injected every 4 weeks with 4 mg of oestradiol-l7-succinyl-BSA in complete Freunds adjavant. With regular intervals blood was taken from the sheep. The serum was adsorbed with BSA.

Day Quantity Freund's adjuvant Manner of injection 200 ugm lntramuscularly 14 400 ugm Do.

28 800 tgm Do.

42 800 agm lntravenously Two weeks after the last injection the animals were exsanguinated.

e. Preparation of the immuno-adsorbent [rabbitanti(-sheep-y-globulin)] cellulose.

The 'y-globulin fraction of the anti-sera described under 12) was prepared by precipitation with 18 percent w/v Na SO The product obtained was coupled with cellulose by Gurvichs method described in example I c).

f. Determination of oestradiol. A dilution series of oestradiol (00.5124-8l6 ng/ml) was prepared in phisphate buffer of pH 6.0. Five ml of sample were mixed with 0.5 ml of the sheep-antioestradiol-serum in the desired dilution. After incubating the mixture for 2 hours at room temperature 1 ml of immunoadsorbent suspension (see e) of 60 mg/ml was added, after which the mixture was rotated for 4 hours at room temperature. The cellulose was centrifuged and washed with 5 ml of 0.05 M phosphate buffer of pH 6.0 containing 2 percent BSA. Then 1 ml of oestradiol-17-succinyl- HRP, diluted to the desired strength with the buffer with which the mixture was washed, was added to the cellulose. The mixture was rotated for 1 hour, after which it was centrifuged again and the enzyme activity in the supernatant liquid was measured as described in example I.

By the method described concentrations of 1 ng/ml of oestradiol could be demonstrated, which means an increase in sensitivity by a factor 10, compared with the test without centrifugation step.

EXAMPLE Vll Determination of cortisol.

a. Preparation of cortisol-21-galactose-oxidase.

Fifty mg of cortisol-2l-haemisuccinate and 100 mg of galactose-oxidase were coupled by the mixed anhydride method as described in example VI a).

b. Preparation of insoluble transcortine. One hundred mg of transcortine purified by DEAE cellulose chromatography, followed by hydroxylapatite chromatography, were coupled with 3 gm of Sepharose 4B by the CNBr method: Sepharose 4B suspension (3 gm) was activated by mixing it with 4 ml of 2.5 percent (w/v) CNBr-solution in distilled water, after which the pH was adjusted to 1 N NaOH between 10 and 11, at which value it was maintained for 6 minutes. Then the Sepharose was washed with ice-water and with 0.1 M NaHCO;,, after which mg of transcortine in 20 ml 0g 0.1 M NaHCO:, were added, and the suspension was shaken at 4C for 24 hours, After being washed successively with 0.5 M NaHCO;,, 0.05 M citrate buffer of pH 1.1 and 0.05 M phosphate buffer of pH 6.0, the Sepharose was kept in the last buffer, to which 0.1 percent merthiolate had been added.

0. Determination of cortisol. A cortisol dilution series, in the range of from 0.25-16 ng/ml was prepared in 0.05 M phosphate buffer of pH 6.0. File ml of each cortisol solution (in 0.5 M phosphate buffer of pH 6.0) were rotated overnight with 5 mg of transcortine-Sepharose, at 4C. After centrifugation 1 ml of cortisol-2l-galactose oxidase solution, diluted to a suitable concentration in the buffer mentioned before, was added, after which the mixture was rotated for 2 hours at 4C. After recentrifugation the enzyme activity in the supernatant liquid was determined by adding 0.5 ml of it to 1.5 ml of substrate constisting of 100 mg of D- galactose, 20 mg of S-amino-salicylic acid and 10 ugm of peroxidase in ml of 0.02 M phosphate buffer of pH 6.0. Finally, after 30 minutes, the extinction was measured at 460 nm.

By this method about 1 ng/ml cortisol could be demonstrated, which means an increase in sensitivity by a factor 10.

We claim:

1. Process for the demonstration and determination of a component of the reaction between a bindable substance selected from the group consisting of an antigen, a hapten, and a low molecular substance, and a protein capable of binding said bindable substance specifically, said protein being selected from the group consisting of an antibody and a specific binding protein, comprising the steps of:

a. providing a given quantity of the binding partner of the component to be determined, which binding partner is in an insoluble form;

b. reacting the component to be determined with its binding partner to form a reaction mixture having a solid phase and a liquid phase;

c. separating the solid phase from the liquid phase;

d. adding to said solid phase a given quantity of a coupling product of the component to be determined with an enzyme; and

e. determining the enzyme activity of the solid phase which is a measure of the quantity of reaction component to be determined.

2. Process for the demonstration and determination of a component of the reaction between a bindable substance selected from the group consisting of an antigen, a hapten, and a low molecular substance, and a protein capable of binding said bindable substance specifically, said protein being selected from the group consisting of an antibody and a specific binding protein, comprising the steps of:

a. providing a given quantity of the binding partner of the component to be determined in a soluble form;

b. adding a given quantity of an antibody against said binding partner, which antibody is in an insoluble 14 sure of the quantity of the reaction component to be determined.

3. The process of claim 1 in which the enzyme is an oxido-reductase.

4. The process of claim 2 in which the enzyme is an oxido-reductase.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3654090 *Sep 24, 1968Jul 20, 1982 Title not available
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3875011 *Feb 1, 1974Apr 1, 1975Syva CoEnzyme immunoassays with glucose-6-phosphate dehydrogenase
US3904367 *Aug 15, 1973Sep 9, 1975Gen ElectricContrast enhancement for immunological film detection
US3951748 *Nov 11, 1974Apr 20, 1976Medical Products, Inc.Sensitized matrix for detection of disease
US4016043 *Sep 4, 1975Apr 5, 1977Akzona IncorporatedEnzymatic immunological method for the determination of antigens and antibodies
US4039652 *Oct 11, 1973Aug 2, 1977Miles Laboratories, Inc.Antigens, antibodies
US4116776 *Apr 19, 1976Sep 26, 1978International Radioimmune Systems, Inc.Cancer detection
US4200508 *Feb 9, 1978Apr 29, 1980Hidematsu HiraiImmunodiffision
US4203802 *Dec 5, 1977May 20, 1980Syva CompanyEnzyme bound to an estrogen ligand
US4240751 *Nov 9, 1978Dec 23, 1980Akzona IncorporatedMethod and apparatus for specific binding substances
US4248965 *Oct 3, 1977Feb 3, 1981Mochida Seiyaku Kabushiki KaishaImmunochemical process of measuring physiologically active substances
US4254223 *Apr 16, 1979Mar 3, 1981Akzona IncorporatedV-shaped transparent vessel
US4269938 *Mar 8, 1979May 26, 1981Eastman Kodak CompanyAssay of peroxidatively active materials
US4275149 *Nov 24, 1978Jun 23, 1981Syva CompanyImmunoassay
US4289748 *May 31, 1979Sep 15, 1981United States Of AmericaUltrasensitive enzymatic radioimmunoassay method
US4302534 *Mar 7, 1978Nov 24, 1981Israel Institute For Biological ResearchRedox system comprising a phenolic compound, peroxidase, and an antibody or antigen
US4318707 *Jun 3, 1980Mar 9, 1982Syva CompanyImmunoassay employing absorption particles
US4323647 *Oct 15, 1980Apr 6, 1982University Of MiamiSteric hindrance enzyme immunoassay
US4331444 *Mar 3, 1980May 25, 1982Fuji Photo Film Co., Ltd.Competitive immunoassay using silver halide fogging agent
US4337063 *Mar 3, 1980Jun 29, 1982Fuji Photo Film Co., Ltd.Competitive immunoassay using spectral sensitizer label
US4343896 *May 1, 1980Aug 10, 1982Akzona IncorporatedMethod and test pack for the demonstration and determination of an antigen or antibody
US4362531 *Apr 14, 1981Dec 7, 1982Technicon Instruments CorporationAgglutination immunoassays carried out with agent to reduce non-specific interferences
US4374925 *Feb 9, 1981Feb 22, 1983Syva CompanyMacromolecular environment control in specific receptor assays
US4376110 *Aug 4, 1980Mar 8, 1983Hybritech, IncorporatedForming a ternary comples between solid phase antibody, antigen, and lebelled antibody
US4446232 *Oct 13, 1981May 1, 1984Liotta Lance AEnzyme immunoassay with two-zoned device having bound antigens
US4446238 *Jan 25, 1982May 1, 1984Janssen Pharmaceutica N.V.Bright field light microscopic method of localizing tissue antigens
US4452886 *Sep 21, 1981Jun 5, 1984Henry Robert PLigands and receptors in chromophoric or fluorescent group-containing polymers
US4469787 *May 14, 1982Sep 4, 1984Mallinckrodt Inc.Direct, two-site; medical diagnosis
US4474878 *Sep 29, 1975Oct 2, 1984Cordis Laboratories, Inc.Sandwich EIA for antigen associated with hepatitis
US4486530 *Jun 24, 1981Dec 4, 1984Hybritech IncorporatedImmunometric assays using monoclonal antibodies
US4503143 *Aug 20, 1982Mar 5, 1985Btc Diagnostics Limited PartnershipEnzyme immunoassay with two-part solution of tetramethylbenzidine as chromogen
US4506009 *Mar 30, 1982Mar 19, 1985University Of CaliforniaDetermination of antibiotics, steroids, vitamins, viruses
US4517288 *Jan 23, 1981May 14, 1985American Hospital Supply Corp.Chromatography
US4530900 *Sep 13, 1982Jul 23, 1985Seragen Diagnostics Inc.Determining soluble antigen in sample; complexing; precipitating
US4592995 *Nov 16, 1983Jun 3, 1986Dainippon Pharmaceutical Co., Ltd.Reagent for streptococcal anti-esterase assay
US4604365 *May 28, 1982Aug 5, 1986Electro-Nucleonics, Inc.Immunoprecipitation assay
US4642285 *May 2, 1984Feb 10, 1987Diamedix CorporationEnzyme-immunoassay
US4665020 *May 30, 1984May 12, 1987United States Department Of EnergyFlow cytometer measurement of binding assays
US4713347 *Jan 14, 1985Dec 15, 1987Sensor Diagnostics, Inc.Measurement of ligand/anti-ligand interactions using bulk conductance
US4753875 *Jul 26, 1985Jun 28, 1988Ryan James WMethod for assaying proteases with tagged proteinaceous inhibitors
US4808522 *Apr 23, 1986Feb 28, 1989Moskovsky Gosudarstvennx Universitet Imeni M. V. Lomonoso VACrosslinking antibody
US4812395 *Aug 19, 1986Mar 14, 1989E. I. Du Pont De Nemours And CompanyRefractive particles with ligand coating
US4812396 *Jul 2, 1987Mar 14, 1989E. I. Du Pont De Nemours And CompanyRefractive particles with ligand coating
US4824784 *Nov 9, 1987Apr 25, 1989Hygeia Sciences, IncorporatedChromogenic solution for immunoassay
US4868108 *Dec 12, 1985Sep 19, 1989Hygeia Sciences, IncorporatedMultiple-antibody detection of antigen
US4931385 *Nov 21, 1988Jun 5, 1990Hygeia Sciences, IncorporatedEnzyme immunoassays and immunologic reagents
US5047330 *Jan 6, 1988Sep 10, 1991Commissariat A L'energie AtomiqueCompound labelled by the acetyl cholinesterase of Electrophorus electricus, its preparation process and its use as a tracer or marker in enzymoimmunological determinations
US5102788 *Apr 28, 1989Apr 7, 1992Hygeia Sciences, Inc.Of immunoreactive component, an organic performance enhancer and a sugar to prevent agglomeration; homogeneity, shelf life
US5328828 *Jul 20, 1992Jul 12, 1994Syntex (U.S.A.) Inc.Immunoassay for amphetamines with antibodies for conjugation and enzymes
US5334513 *Sep 3, 1992Aug 2, 1994Syntex (U.S.A.) Inc.Measuring migration distance between zones
US5348867 *Nov 15, 1991Sep 20, 1994George GeorgiouExpression of proteins on bacterial surface
US5451507 *May 10, 1994Sep 19, 1995Syntex (U.S.A.) Inc.Method for immunochromatographic analysis
US5468647 *Sep 1, 1994Nov 21, 1995Syntex (U.S.A.) Inc.Method for immunochromatographic analysis
US5534405 *Nov 18, 1994Jul 9, 1996The Scripps Research InstituteAntibodies, diagnostic systems and methods for assaying HBxAg
US5610077 *Jul 19, 1994Mar 11, 1997Unilever Patent Holdings B.V.Immunoassay
US5614504 *Apr 21, 1995Mar 25, 1997The University Of South FloridaMethod of making inosine monophosphate derivatives and immunopotentiating uses thereof
US5624809 *May 5, 1995Apr 29, 1997Behringwerke AgDevice for immunochromatographic analysis
US5672475 *Jan 20, 1995Sep 30, 1997Chiron Diagnostics CorporationMixed luminescent conjugate test
US5698686 *Apr 28, 1995Dec 16, 1997Arch Development CorporationYeast telomerase compositions
US5726015 *Jan 10, 1995Mar 10, 1998Vanderbilt UniversityMethod to determine metastatic potential of tumor cells
US5726023 *Jun 6, 1995Mar 10, 1998University Of WashingtonImmune reactivity to HER-2/neu protein for diagnosis and treatment of malignancies in which the HER-2/neu oncogene is associated
US5728807 *Jun 21, 1995Mar 17, 1998Ramot-University Authority For Applied Research And Industrial Development, Ltd.Genetic disorders
US5777093 *Jul 28, 1995Jul 7, 1998Ramot-University Authority For Applied Research & Industrial Development Ltd.cDNAs associated with ataxia-telangiectasia
US5801005 *Mar 31, 1995Sep 1, 1998University Of WashingtonImmune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated
US5807552 *Aug 4, 1995Sep 15, 1998Board Of Regents, The University Of Texas SystemCompositions for conferring immunogenicity to a substance and uses thereof
US5837535 *Feb 15, 1996Nov 17, 1998Henry Ford Health SystemNeuronal-neonatal gene: neuronatin
US5840322 *Dec 19, 1996Nov 24, 1998Ramot-University Authority For Applied Research & Industrial Devel. Ltd.Anti-oral-microbial adhesion fraction derived from vaccinium
US5843673 *Jun 7, 1995Dec 1, 1998Curators Of The University Of MissouriMethod of screening for endometriosis
US5846538 *Jun 7, 1995Dec 8, 1998University Of WashingtonImmune reactivity to HER-2/neu protein for diagnosis and treatment of malignancies in which the her-2/neu oncogene is associated
US5858661 *Apr 8, 1996Jan 12, 1999Ramot-University Authority For Applied Research And Industrial DevelopmentIsolation, purification, cloned nucleic acid sequence with mutation causing protein truncation or no initiation; detecting carriers by analysis of nucleic acids isolated from patients with hereditary muscular disorders
US5869445 *Apr 1, 1996Feb 9, 1999University Of WashingtonMethods for eliciting or enhancing reactivity to HER-2/neu protein
US5874423 *Sep 12, 1996Feb 23, 1999Yissum Research Development Co. Of The Hebrew University Of JerusalemCardiotonic agent
US5876712 *Jun 6, 1995Mar 2, 1999University Of WashingtonImmune reactivity to HER-2/neu protein for diagnosis and treatment of malignancies in which the HER-2/neu oncogene is associated
US5916752 *Sep 26, 1997Jun 29, 1999Arch Development CorporationTelomerase screening methods
US6075122 *Jun 6, 1995Jun 13, 2000University Of WashingtonA peptide for the detection, monitoring, and treatment of cancer in animals; anticarciongenic agents
US6187563Aug 4, 1999Feb 13, 2001Yale UniversityβIV-spectrin-polypeptides and nucleic acids encoding same
US6200749May 3, 1996Mar 13, 2001Ramot-University Authority For Applied Research And Industrial Development Ltd.Ajusted nucleic acid sequence; for detection of genome adjustments and preferential genetic disorders
US6284496Jan 2, 1998Sep 4, 2001University Of South FloridaPlasmid for detecting adjustments in open reading frame; for use in evaluation of polymerase chain reaction products
US6312901Sep 10, 1999Nov 6, 2001Burstein Technologies, Inc.Spatially addressable, cleavable reflective signal elements, assay device and method
US6331275Aug 3, 2000Dec 18, 2001Burstein Technologies, Inc.Spatially addressable, cleavable reflective signal elements, assay device and method
US6342349Jul 21, 1998Jan 29, 2002Burstein Technologies, Inc.A solid support substrate containing a cleavable signal element, a signal responsive moiety and a cleavable spacer; analytes bind the signal element, anchoring the responsive moiety to the element substrate-attaching end after cleavage
US6344443Jul 8, 1999Feb 5, 2002University Of South FloridaPeptide antagonists of tumor necrosis factor alpha
US6387619Jun 30, 1999May 14, 2002Arch DevelopmentTelomerase compositions and methods
US6391563Dec 8, 1993May 21, 2002Akzo Nobel N.V.Method for the determination of antigens with the aid of three or more monoclonal antibodies
US6406920Aug 7, 1996Jun 18, 2002Inverness Medical Switzerland GmbhProcesses and apparatus for carrying out specific binding assays
US6440682 *May 24, 2000Aug 27, 2002Detroit R&D Inc.Detection of hypertension using immunoreactive metabolic products
US6482389Oct 16, 1998Nov 19, 2002University Of South FloridaMethod to diagnose and monitor cellular immune deficiencies
US6531277Mar 19, 1998Mar 11, 2003The Curators Of The University Of MissouriEndometriosis-specific secretory protein
US6610838Sep 15, 1998Aug 26, 2003Symbicom AktiebolagIsolated nucleic acid encoding polypeptides which bind with a rabbit polyclonal antibody raised against another polypeptide; use in vaccines as well as diagnostic compositions and kits
US6656471Nov 16, 1999Dec 2, 2003Board Of Regents, The University Of Texas SystemMonitoring HLA-Cw7-restricted CTL response; AIDS prevention
US6664370Jul 15, 1999Dec 16, 2003University Of WashingtonImmune reactivity to HER-2/neu protein for diagnosis and treatment of malignancies in which the HER-2/neu oncogene is associated
US6689757Dec 28, 1998Feb 10, 2004M.L. Laboratories PlcMethods for vaccination and vaccines therefor
US6740738Dec 23, 2002May 25, 2004Quark Biotech, Inc.Antibodies binding to polypeptides encoded by the genes
US6770622Jun 8, 2001Aug 3, 2004Gary A. JarvisTumors, and metastasis
US6787318Jun 1, 2000Sep 7, 2004Roskamp Research Institute, LlcAssay for evaluating the therapeutic effectiveness of agents in reducing Alzheimer's disease pathology
US6867005Oct 24, 2001Mar 15, 2005Beckman Coulter, Inc.In which the presence, absence, activity or concentration of a target analyte is assayed by the emission or quenching of a light signal, or by a change of a light signal in two or more time intervals; automated biological binding tests
US6875582Aug 18, 2000Apr 5, 2005Omniscience Pharmaceuticals, Inc.Identifying drug resistant microorganisms and mechanisms of evolution; improving antitumor and bactericidal agents
US6953573Oct 6, 1998Oct 11, 2005University Of WashingtonCompounds for eliciting or enhancing immune reactivity to HER-2/neu protein for prevention or treatment of malignancies in which the HER-2/neu oncogene is associated
US6992176Feb 13, 2002Jan 31, 2006Technion Research & Development Foundation Ltd.Antibody having a T-cell receptor-like specificity, yet higher affinity, and the use of same in the detection and treatment of cancer, viral infection and autoimmune disease
US6998232Apr 4, 2001Feb 14, 2006Quark Biotech, Inc.determining, in a sample from a human subject, the level of expression of at least two polynucleotides, wherein a higher level of expression of the polynucleotides compared to cancer free human polynucleotide expression is an indication of cancer
US7033747Apr 11, 2002Apr 25, 2006Nagaoka & Co., LtdApparatus for use in the detection of preferential targets in sample
US7060462Nov 1, 2001Jun 13, 2006National University Of SingaporeAgrobacterium tumefaciens outer membrane protein;
US7087395Jan 16, 2001Aug 8, 2006Quest Diagnostics Investments IncorporatedDetermination concentration of vitamin d; releasing using aqueous base; solvent-free; coupling to antibody; detection signal
US7101839Aug 29, 2000Sep 5, 2006Yissum Research Development Company Of The Hebrew University Of JerusalemMethods of and compositions for inhibiting the proliferation of mammalian cells
US7138144Sep 9, 2002Nov 21, 2006Nadir AskenasyRestricting outflow of fluid from a portion of the circulatory system; administering a dose of bone marrow cells derived from donor to a body part delimiting portion of circulatory system, prior to, concomitantly with or following transplantation
US7223902Nov 15, 2000May 29, 2007Yissum Research Development Company Of The Hebrew University Of JerusalemGene expression of nucleic acid construct into a host cell comprising polynucleotide encoding polypeptide having a beta -glucosidase catalytic activity; genetic engineering; alcoholic beverages
US7247703Aug 21, 2003Jul 24, 2007University Of WashingtonAnticancer agents; protein complex
US7270810Dec 28, 2000Sep 18, 2007Yeda Research And Development Co. Ltd.Veto cells effective in preventing graft rejection and devoid of graft versus host potential
US7294701Apr 2, 2003Nov 13, 2007Technion Research & Development Foundation Ltd.Antibody fragment capable of modulating multidrug resistance and compositions and kits and methods using same
US7306804Sep 29, 2003Dec 11, 2007Board Of Regents, The University Of Texas SystemHIV-specific T-cell induction
US7347972Jul 22, 1998Mar 25, 2008Jin Po LeeMultiple analyte assay device
US7355079Apr 5, 2005Apr 8, 2008The Regents Of The University Of CaliforniaThyronamine derivatives and analogs and methods of use thereof
US7385106Jan 10, 2001Jun 10, 2008Ramot At Tel Aviv University Ltd.Comprises nucleotide sequences coding polypeptied for use in generation of stress and drought resistant plant
US7423139Jan 20, 2004Sep 9, 2008Insight Biopharmaceuticals Ltd.Expresion vector comprising nucleotide sequences coding secreted glycoprotein hormone with modified untranslated region for use in enhancement of blood production; directed protein evolution
US7442781Aug 15, 2002Oct 28, 2008Urifer Ltd.Diagnosis, prevention and treatment of cancer
US7498428Jun 20, 2004Mar 3, 2009Evogene Ltd.Nucleotide sequences for regulating gene expression in plant trichomes and constructs and methods utilizing same
US7534605May 17, 2005May 19, 2009Yissum Research Development Company Of The Hebrew University Of JerusalemCD44 polypeptides, polynucleotides encoding same, antibodies directed thereagainst and method of using same for diagnosing and treating inflammatory diseases
US7534609Apr 11, 2005May 19, 2009Pluristem Life Systems Inc.Method of expanding undifferentiated hemopoietic stem cells
US7553940Feb 1, 2007Jun 30, 2009Modigene Inccomprising at least two carboxy-terminal peptides (CTP) of chorionic gonadotrophin attached to an EPO (erythropoietin) peptide ; improving a biological half life of an hGH polypeptide
US7553941Feb 1, 2007Jun 30, 2009Modigene IncLong-acting polypeptides and methods of producing same
US7554007Nov 22, 2005Jun 30, 2009Evogene Ltd.by expressing within the plant an exogenous polynucleotide homologous to SEQ ID NO:13;
US7601697May 3, 2005Oct 13, 2009University Of WashingtonPolypeptides; nucleic acid molecules and viral vectors which direct gene expression of such polypeptides; vaccines; genetic engineering; transfecting cells of animal ex vivo with nucleic acid molecule and delivering transfected cells animal
US7605149Jul 13, 1999Oct 20, 2009University Of South FloridaModulation of the phospholipase A2 pathway as a therapeutic
US7611723Mar 20, 2003Nov 3, 2009Nanocyte Inc.Stinging cells expressing an exogenous polynucleotide encoding a therapeutic, diagnostic or a cosmetic agent and methods compositions and devices utilizing such stinging cells or capsules derived therefrom for delivering the therapeutic, diagnostic or cosmetic agent into a tissue
US7625707Sep 27, 2004Dec 1, 2009Ramot At Tel Aviv University Ltd.Identifying site of interaction between bacterial toxin and antitoxin polypeptides thus enabling ability to identify or design novel antibiotics which target this site of interaction and thus enable bacterial cell killing; identifying agents with activity against antibacterial drug-resistant strains
US7632522Jan 10, 2006Dec 15, 2009Nanocyte Inc.Use of stinging cells/capsules for the delivery of active agents to keratinous substances
US7632923Mar 9, 2005Dec 15, 2009Technion Research & Development Foundation Ltd.Lymphotropic retrovirus disease treatment and diagnosis such as acquired immunodeficiency syndrome (AIDS); Specifically binds with high specificity and affinity a particular human APM:pathogen-derived antigen complex
US7638124Mar 25, 2004Dec 29, 2009Technion Research & Development Foundation Ltd.Specifically binds with high specificity and affinity a particular human APM:pathogen-derived antigen complex
US7655225Feb 19, 2008Feb 2, 2010Gamida Cell, Ltd.Methods of expanding stem and progenitor cells and expanded cell populations obtained thereby
US7655239Jun 21, 2007Feb 2, 2010University Of WashingtonPeptides for use in diagnosis, prevention and treatment of cell proliferative disorders
US7678573Apr 11, 2005Mar 16, 2010Pluristem Ltd.Using plug flow bioreactor system which mimics bone marrow microenvironment for propagation and maintenance of stromal cells
US7687057Dec 17, 2002Mar 30, 2010Yissum Research Development Company Of The Hebrew University Of JerusalemIn vitro micro-organs, and uses related thereto
US7695927Mar 17, 2006Apr 13, 2010Detroit R & DDetection of hypertension using glucuronidated metabolic products
US7718777Oct 18, 2006May 18, 2010Technion Research & Development Foundation Ltd.MHC-peptide complex binding ligands
US7781396Jun 21, 2006Aug 24, 2010Tel Aviv University Future Technology Development L.P.Peptides directed for diagnosis and treatment of amyloid-associated disease
US7781402Oct 11, 2005Aug 24, 2010Closed Loop Therapies Ltd.Methods and implantable devices for treating supraventricular arrhythmias
US7786267Jan 31, 2008Aug 31, 2010Baylor Research InstituteMultivariable antigens complexed with targeting humanized monoclonal antibody
US7790673Jun 12, 2006Sep 7, 2010New York UniversityMethods and compositions relating to cystatin C
US7811981Sep 29, 2004Oct 12, 2010Yissum Research Development Company Of The Hebrew University Of JerusalemMethods of and compositions for inhibiting the proliferation of mammalian cells
US7855075May 19, 2008Dec 21, 2010Gamida Cell Ltd.Methods of controlling proliferation and differentiation of stem and progenitor cells
US7888003Sep 2, 2005Feb 15, 2011The United States Of America As Represented By The Department Of Health And Human ServicesMethods for the detection of HIV-1 antibodies employing polypeptides obtained from gag P6 protein
US7893240Jul 25, 2008Feb 22, 2011Insight Biopharmaceuticals Ltd.High level expression of recombinant human erythropoietin having a modified 5′-UTR
US7910800Aug 15, 2006Mar 22, 2011Evogene Ltd.Methods of increasing abiotic stress tolerance and/or biomass in plants and plants generated thereby
US7928083Jan 16, 2008Apr 19, 2011Yissum Research Development Company Of The Hebrew University Of JerusalemH19 silencing nucleic acid agents for treating rheumatoid arthritis
US7947499Nov 30, 2003May 24, 2011Technion Research & Development Foundation Ltd.Method of dynamically culturing embryonic stem cells
US7955852Feb 9, 2004Jun 7, 2011Gamida Cell Ltd.Expansion of stem cells; prevent cell differentiation; culturing
US8000900Dec 30, 2005Aug 16, 2011Microsoft CorporationAssociation-based predictions of pathogen characteristics
US8007847Aug 7, 2006Aug 30, 2011Eytan BidermanFeeding formula appliance
US8012929Jul 2, 2009Sep 6, 2011Tel Aviv University Future Technology Development L.P.Peptides directed for diagnosis and treatment of amyloid-associated diseases
US8017586Jan 5, 2009Sep 13, 2011Ramot At Tel-Aviv University Ltd.Peptide nanostructures encapsulating a foreign material and method of manufacturing same
US8019818Jan 16, 2007Sep 13, 2011Zlango Ltd.Communications network system and methods for using same
US8034914Sep 21, 2006Oct 11, 2011Yissum Research Development Company Of The Hebrew University Of JerusalemNucleic acid constructs, pharmaceutical compositions and methods of using same for treating cancer
US8039240Sep 28, 2005Oct 18, 2011Yissum Reseach Development Company Of The Hebrew University Of JerusalemRNA degrading polypeptides for use in prevention and treatment of arthritis, inflammation, restenosis, nervous system and cell proliferative diseases
US8053554Jan 2, 2009Nov 8, 2011Ramot At Tel-Aviv University Ltd.Peptide nanostructures and methods of generating and using the same
US8057798Feb 1, 2008Nov 15, 2011Baylor Research InstituteVaccines based on targeting antigen to DCIR expressed on antigen-presenting cells
US8062660Mar 15, 2006Nov 22, 2011Nanocyte Inc.Methods compositions and devices utilizing stinging cells/capsules for delivering a therapeutic or a cosmetic agent into a tissue
US8067573Jul 6, 2006Nov 29, 2011Yissum Research Development Company Of The Hebrew University Of JerusalemNucleic acid agents for downregulating H19 and methods of using same
US8067574Jan 16, 2008Nov 29, 2011Yissum Research Development Company Of The Hebrew University Of JerusalemNucleic acid agents for downregulating H19, and methods of using same
US8071323Apr 6, 2007Dec 6, 2011The United States Of America As Represented By The Secretary Of The Department Of Health And Human ServicesHuman monoclonal antibodies that bind human insulin like growth factors and their use
US8080417Nov 29, 2006Dec 20, 2011Gamida-Cell Ltd.Methods of ex vivo hematopoietic stem cell expansion by co-culture with mesenchymal cells
US8088160Jun 2, 2009Jan 3, 2012Multi-Gene Vascular Systems Ltd. (“MGVS”)Drug-eluting intravascular prostheses and methods of use
US8129514Feb 9, 2009Mar 6, 2012Evogene Ltd.Nucleotide sequences for regulating gene expression in plant trichomes and constructs and methods utilizing same
US8153383Mar 18, 2009Apr 10, 2012Wisconsin Alumni Research FoundationMycobacterial culture screening test for Mycobacterium avium complex bacteria
US8158371Oct 14, 2010Apr 17, 2012Wisconsin Alumni Research FoundationAssay for antibodies to Mycobacterium paratuberculosis
US8163494Nov 27, 2003Apr 24, 2012Technion Research & Development Foundation Ltd.Method for assessing metastatic properties of breast cancer
US8168180Sep 30, 2009May 1, 2012Technion Research & Development Foundation Ltd.Methods and compositions for modulating angiogenesis
US8168857Dec 20, 2007May 1, 2012Evogene Ltd.for improving fiber quality and/or yield of a fiber producing plant, as well as methods of using such polynucleotides for producing plants having increased biomass/vigor/yield
US8178128Dec 5, 2002May 15, 2012Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Nanoparticles containing polymeric nucleic acid homologs
US8193311Feb 7, 2011Jun 5, 2012Yissum Research Development Company Of The Hebrew University Of JerusalemCD44 polypeptides, polynucleotides encoding same, antibodies directed thereagainst and method of using same for diagnosing and treating inflammatory diseases
US8202724Oct 6, 2010Jun 19, 2012Gamida Cell Ltd.Methods of controlling proliferation and differentiation of stem and progenitor cells
US8236543Sep 27, 2010Aug 7, 2012Yissum Research Development Company Of The Hebrew University Of JerusalemMethods of and compositions for inhibiting the proliferation of mammalian cells
US8236934Feb 2, 2008Aug 7, 2012Baylore Research Institutecomplexing of multiple antigens or proteins in a controlled, multivariable fashion, to one single primary recombinant monoclonal antibody; activate dendritic cells and other cells; bound to one half of a Coherin/Dockerin pair
US8252588Apr 7, 2004Aug 28, 2012Yeda Research And Development Co. Ltd.Stem cells having increased sensitivity to SDF-1 and methods of generating and using same
US8293209Oct 22, 2009Oct 23, 2012Segev Laboratories LimitedSystem for delivering therapeutic agents into living cells and cells nuclei
US8323636Jul 28, 2011Dec 4, 2012Prolor Biotech Ltd.Long-acting interferons and derivatives thereof and methods thereof
US8352031May 24, 2007Jan 8, 2013Impulse Dynamics NvProtein activity modification
US8367392Sep 8, 2009Feb 5, 2013Transalgae Ltd.Genetic transformation of algal and cyanobacteria cells by microporation
US8375327Jan 16, 2006Feb 12, 2013Zlango Ltd.Iconic communication
US8388954Apr 8, 2004Mar 5, 2013Laboratoire Francais Du Fractionnement Et Des BiotechnologiesStabilising formulation for immunoglobulin G compositions in liquid form and in lyophilised form
US8415318Jun 20, 2011Apr 9, 2013Vascular Biogenics Ltd.Polynucleotide constructs, pharmaceutical compositions and methods for targeted downregulation of angiogenesis and anticancer therapy
US8426166Jul 27, 2011Apr 23, 2013Prolor Biotech Inc.Long-acting polypeptides and methods of producing same
US8426682Apr 19, 2012Apr 23, 2013Evogene Ltd.Isolated polypeptides, polynucleotides useful for modifying water user efficiency, fertilizer use efficiency, biotic/abiotic stress tolerance, yield and biomass in plants
US8449888Sep 16, 2011May 28, 2013Baylor Research InstituteVaccines based on targeting antigen to DCIR expressed on antigen-presenting cells
US8450269Aug 2, 2011May 28, 2013Prolor Biotech Ltd.Long-acting growth hormone and methods of producing same
US8461303Aug 1, 2008Jun 11, 2013Gilead Biologics, Inc.LOX and LOXL2 inhibitors and uses thereof
US8465948Jul 28, 2011Jun 18, 2013Prolor Biotech Ltd.Long-acting veterinary polypeptides and methods of producing and administering same
US8478535Dec 30, 2005Jul 2, 2013Microsoft CorporationSystems and methods that utilize machine learning algorithms to facilitate assembly of aids vaccine cocktails
US8481314Feb 22, 2008Jul 9, 2013Baylor Research InstituteUsing low density lipoprotein receptor specific immunoglobulin to increase receptor expression on antigen presenting cells; immunotherapy; treating infection, autoimmune, graft vs host and allergic disorders
US8481812Jun 3, 2009Jul 9, 2013Evogene Ltd.Methods of increasing abiotic stress tolerance and/or biomass in plants generated thereby
US8512990Aug 20, 2010Aug 20, 2013Gilead Biologics, Inc.Catalytic domains from lysyl oxidase and LOXL2
US8513488Apr 9, 2008Aug 20, 2013Evogene Ltd.Polynucleotides, polypeptides and methods for increasing oil content, growth rate and biomass of plants
US8524491Sep 4, 2009Sep 3, 2013University Of Washington Through Its Center For CommercializationCompounds for eliciting or enhancing immune reactivity to HER-2/neu protein for prevention or treatment of malignancies in which the HER-2/neu oncogene is associated
US8563273Apr 9, 2009Oct 22, 2013Tel Aviv University Future Technology Development L.P.Method of screening for compounds that disaggregate amyloid aggregates
US8586052Apr 24, 2012Nov 19, 2013Baylor Research InstituteVaccines based on targeting antigen to DCIR expressed on antigen-presenting cells
US8617867Jan 1, 2012Dec 31, 2013Yissum Research Develpment Company Of The Hebrew University Of JerusalemMethods of and compositions for inhibiting the proliferation of mammalian cells
US8642330Aug 8, 2006Feb 4, 2014Onconon, LlcAntibody compositions, methods for treating neoplastic disease and methods for regulating fertility
US8658167Dec 6, 2012Feb 25, 2014Gilead Biologics, Inc.Methods and compositions for treatment and diagnosis of fibrosis, tumor invasion, angiogenesis, and metastasis
US8679485Aug 1, 2008Mar 25, 2014Gilead Biologics, Inc.Methods and compositions for treatment and diagnosis of fibrosis, tumor invasion, angiogenesis, and metastasis
US8680062Jun 1, 2007Mar 25, 2014Deliversir Ltd.System for delivering therapeutic agents into living cells and cells nuclei
US8680246Feb 4, 2011Mar 25, 2014Gilead Biologics, Inc.Antibodies that bind to lysyl oxidase-like 2 (LOXL2)
US8685402Jul 27, 2009Apr 1, 2014Institute For Research In BiomedicineNeutralizing anti-influenza A virus antibodies and uses thereof
US8686227Jul 24, 2008Apr 1, 2014Evogene Ltd.Polynucleotides, polypeptides encoded thereby, and methods of using same for increasing abiotic stress tolerance and/or biomass and/or yield in plants expressing same
US8697634Dec 22, 2009Apr 15, 2014Tel Aviv University Future Technology Development L.P.Peptides and methods using same for diagnosis and treatment of amyloid-associated disease
US8722324Dec 23, 2010May 13, 2014The United States Of America, As Represented By The Secretary Department Of Health And Human ServicesMethods for the detection of HIV-1-specific antibodies employing GP41 polypeptides
US8728481Jul 17, 2012May 20, 2014Baylor Research InstituteAgents that engage antigen-presenting cells through dendritic cell asialoglycoprotein receptor (DC-ASGPR)
US8735127Sep 9, 2013May 27, 2014Yissum Research Development Company Of The Hebrew University Of JerusalemMethods of and compositions for inhibiting the proliferation of mammalian cells
US8747855Apr 5, 2009Jun 10, 2014Technion Research & Development Foundation LimitedAnti human immunodeficiency antibodies and uses thereof
US8759292Feb 14, 2012Jun 24, 2014Prolor Biotech, LlcLong-acting coagulation factors and methods of producing same
US8775526Jan 16, 2007Jul 8, 2014Zlango Ltd.Iconic communication
USRE31006 *Mar 2, 1978Aug 3, 1982Akzona IncorporatedProcess for the demonstration and determination of reaction components having specific binding affinity for each other
USRE32696 *Dec 22, 1978Jun 14, 1988Akzona IncorporatedEnzymatic immunological method for determination of antigens and antibodies
DE2643829A1 *Sep 29, 1976Apr 14, 1977Cordis CorpVerfahren zum feststellen der anwesenheit eines der hepatitis zuzuordnenden antigens
EP0060700A1 *Mar 12, 1982Sep 22, 1982Immuno-Mycologics, Inc.Assay method and device
EP1683874A2Aug 29, 2001Jul 26, 2006YEDA RESEARCH AND DEVELOPMENT Co. LTD.Methods of isolating genes encoding proteins of specific function and of screening for pharmaceutically active agents
EP2050826A2Oct 13, 2008Apr 22, 2009Roche Diagnostics GmbHReagents and methods for detecting neisseria gonorrhoeae
EP2058275A1Jan 7, 2004May 13, 2009Ramot at Tel-Aviv University Ltd.Peptide nanostructures encapsulating a foreign material and method of manufacturing same
EP2062918A2Nov 27, 2003May 27, 2009Technion Research and Development Foundation, Ltd.Pharmaceutical compositions and methods useful for modulating angiogenesis, inhibiting metastasis and tumor fibrosis, and assessing the malignancy of colon cancer tumors
EP2062919A2Nov 27, 2003May 27, 2009Technion Research and Development Foundation, Ltd.Pharmaceutical compositions and methods useful for modulating angiogenesis, inhibiting metastasis and tumor fibrosis, and assessing the malignancy of colon cancer tumors
EP2071021A2Dec 12, 2008Jun 17, 2009University of South FloridaBone marrow-derived neuronal cells
EP2072045A2Feb 11, 2003Jun 24, 2009Technion Research and Development Foundation, Ltd.Antibody having a t-cell receptor-like specificity, yet higher affinity, and the use of same in the detection and treatment of cancer, viral infection and autoimmune disease
EP2149585A1Nov 4, 2004Feb 3, 2010Novartis Vaccines and Diagnostics, Inc.Antagonist anti-CD40 monoclonal antibodies and methods for their use
EP2174668A2Nov 14, 2005Apr 14, 2010Vascular Biogenics Ltd.Promoters exhibiting endothelial cell specificity and methods of using same for regulation of angiogenesis
EP2182052A1Oct 7, 2003May 5, 2010Technion Research and Development Foundation, Ltd.Human foreskin cells suitable for culturing stem cells
EP2186530A1Nov 15, 2001May 19, 2010Vascular Biogenics Ltd.Promoters exhibiting endothelial cell specificity and methods of using same
EP2208782A2Feb 4, 2000Jul 21, 2010Pluristem Ltd.Method and apparatus for maintenance and expansion of hemopoietic stem cells and/or progenitor cells
EP2216033A2Mar 4, 2004Aug 11, 2010Yeda Research and Development Co. Ltd.Methods of treating disease by transplantation of allogeneic or xenogeneic organs or tissues
EP2243491A1Nov 4, 2004Oct 27, 2010Novartis Vaccines and Diagnostics, Inc.Use of antagonist anti-CD40 monoclonal antibodies for treatment of chronic lymphocytic leukemia
EP2243492A1Nov 4, 2004Oct 27, 2010Novartis Vaccines and Diagnostics, Inc.Use of antagonist anti-cd40 monoclonal antibodies for treatment of multiple myeloma
EP2248830A1Nov 4, 2004Nov 10, 2010Novartis Vaccines and Diagnostics, Inc.Use of antagonist anti-CD40 antibodies for treatment of autoimmune and inflammatory diseases and organ transplant rejection
EP2279726A2May 25, 2006Feb 2, 2011Biorest Ltd.Compositions and methods using same for delivering agents into a target organ protected by a blood barrier
EP2289567A2Dec 15, 2004Mar 2, 2011Regentis Biomaterials Ltd.Matrix comprising naturally-occurring crosslinked protein backbone
EP2292762A2Dec 22, 2003Mar 9, 2011Board of Regents, The University of Texas SystemVMP-like sequences of pathogenic Borrelia species and strains
EP2295973A1Sep 2, 2005Mar 16, 2011THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by the Secretary, Department of Health and Human ServicesCompositions and methods for the detection of HIV-1/HIV-2 infection.
EP2295974A1Sep 2, 2005Mar 16, 2011THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICESCompositions and methods for the detection of HIV-1/HIV-2 infection
EP2295980A1Oct 30, 2003Mar 16, 2011Yissum Research Development Company, of The Hebrew University of JerusalemMolecules and methods using same for measuring non-transferrin bound iron
EP2301575A1Nov 4, 2004Mar 30, 2011Novartis Vaccines and Diagnostics, Inc.Methods of therapy for solid tumors expressing the CD40 cell-surface antigen
EP2305794A1Jan 26, 2003Apr 6, 2011Gamida Cell Ltd.Expansion of renewable stem cell populations
EP2308994A1Mar 21, 2002Apr 13, 2011Yeda Research And Development Co., Ltd.Methods for determining a risk to develop cancer
EP2309269A1Sep 2, 2005Apr 13, 2011THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICESCompositions and methods for the detection of HIV-1/HIV-2 infection.
EP2311938A1Feb 4, 2000Apr 20, 2011Pluristem Ltd.Method and apparatus for maintenance and expansion of hemopoietic stem cells and/or progenitor cells
EP2312315A1May 18, 2006Apr 20, 2011Novartis AGMethods for diagnosis and treatment of diseases having an autoimmune and/or inflammatory component
EP2316441A1Feb 16, 2006May 4, 2011Hadasit Medical Research Services And DevelopmentBisphosphonates for treating endometriosis
EP2316950A1Mar 19, 2001May 4, 2011Technion Research and Development Foundation, Ltd.Single chain class I major histo-compatibility complexes, constructs encoding same and methods of generating same
EP2319857A2Mar 4, 2004May 11, 2011Yeda Research And Development Co., Ltd.Pon polypeptides, polynucleotides encoding same and compositions and methods utilizing same
EP2322561A1Oct 5, 2004May 18, 2011Yeda Research And Development Co., Ltd.Anti-NIK antibodies and uses thereof
EP2329814A1Feb 11, 2003Jun 8, 2011Technion Research and Development Foundation, Ltd.Antibody having a T-cell receptor-like specificity, yet higher affinity, and the use of same in the detection and treatment of cancer
EP2330132A1Apr 4, 2004Jun 8, 2011Yeda Research and Development Co. Ltd.Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins
EP2336330A2Jun 14, 2005Jun 22, 2011Evogene Ltd.Polynucleotides and polypeptides involved in plant fiber development and methods of using same
EP2338896A2Dec 11, 2003Jun 29, 2011R.B.T. (Rakuto Bio Technologies) Ltd.Use of lignin peroxidase in skin and hair lightening
EP2343373A1Jun 14, 2005Jul 13, 2011Evogene Ltd.Polynucleotides and polypeptides involved in plant fiber development and methods of using same
EP2354164A1Oct 5, 2004Aug 10, 2011Yeda Research And Development Co., Ltd.Anti-NIK antibodies and uses thereof
EP2357478A2Nov 30, 2001Aug 17, 2011Crawford Healthcare Holdings LimitedDiagnosis of disease
EP2359853A1Aug 7, 2001Aug 24, 2011Technion Research and Development Foundation, Ltd.Pharmaceutical compositions and methods useful for modulating angiogenesis
EP2359854A1Aug 7, 2001Aug 24, 2011Technion Research and Development Foundation, Ltd.Pharmaceutical compositions and methods useful for modulating angiogenesis
EP2365087A2May 20, 2004Sep 14, 2011Evogene Ltd.Methods of increasing abiotic stress tolerance and/or biomass in plants and plants generated thereby
EP2366775A1Mar 22, 2007Sep 21, 2011Pluristem Ltd.Methods for cell expansion and uses of cells and conditioned media produced thereby for therapy
EP2368569A2Jan 18, 2007Sep 28, 2011University Of ChicagoCompositions and methods related to staphylococcal bacterium proteins
EP2368570A2Jan 18, 2007Sep 28, 2011University Of ChicagoCompositions and methods related to staphylococcal bacterium proteins
EP2383345A1Dec 20, 2007Nov 2, 2011Evogene Ltd.Polynucleotides and polypeptides involved in plant fiber development and methods of using same
EP2390312A1Nov 29, 2006Nov 30, 2011Gamida Cell Ltd.Methods of improving stem cell homing and engraftment
EP2425841A1Nov 22, 2001Mar 7, 2012Vascular Biogenics Ltd.Methods Employing and Compositions Containing Defined Oxidized Phospholipids for Prevention and Treatment of Atherosclerosis
EP2441840A1Jul 18, 2006Apr 18, 2012Protalix Ltd.Mucosal or enteral administration of biologically active macromolecules
EP2457999A2Dec 7, 2003May 30, 2012Technion Research & Development Foundation Ltd.Culture medium for pluropotent stem cells
EP2463382A1Dec 7, 2011Jun 13, 2012Enterologics, Inc.Method for identifying E. Coli M-17
EP2465920A2Feb 25, 2010Jun 20, 2012Tel HaShomer Medical Research Infrastructure and Services Ltd.Isolated populations of renal stem cells and methods of isolating and using same
EP2465924A2Jun 18, 2006Jun 20, 2012Ramot at Tel-Aviv University Ltd.Isolated cells and populations comprising same for the treament of cns diseases
EP2471807A1Feb 5, 2007Jul 4, 2012Modigene IncLong-acting polypeptides and methods of producing and administering same
EP2478924A1Jan 31, 2008Jul 25, 2012Technion Research & Development FoundationAlbumin fibers and fabrics and methods of generating and using same
EP2484768A2Jul 18, 2006Aug 8, 2012Protalix Ltd.Mucosal or enteral administration of biologically active macromolecules
EP2487182A2Jul 9, 2006Aug 15, 2012FULCRUM SP Ltd.SP1 polypeptides, modified SP1 polypeptides and uses thereof
EP2487187A2Jan 3, 2008Aug 15, 2012Institute for Research in BiomedicineHuman cytomegalovirus neutralising antibodies and use thereof
EP2492279A1Feb 25, 2011Aug 29, 2012Laboratorios Del. Dr. Esteve, S.A.Rapid immunogen selection method using lentiviral display
EP2500428A2Jul 10, 2008Sep 19, 2012Yeda Research and Development Co. Ltd.Nucleic acid construct systems capable of diagnosing or treating a cell state
EP2508596A2Feb 21, 2003Oct 10, 2012Bayer HealthcareMN/CA IX-specific monoclonal antibodies generated from MN/CA IX-deficient mice and methods of use
EP2514315A2Aug 21, 2006Oct 24, 2012Yeda Research and Development Co. Ltd.Universal donor-derived tolerogenic cells for inducing non-syngeneic transplantation tolerance
EP2514766A2Mar 27, 2008Oct 24, 2012Technion Research & Development Foundation Ltd.Antibodies, methods and kits for diagnosing and treating melanoma
EP2522718A1Feb 22, 2008Nov 14, 2012Baylor Research InstituteTherapeutic applications of activation of human antigen-presenting cells through dectin-1
EP2526952A1Jul 15, 2004Nov 28, 2012Bar-Ilan UniversityMethods and pharmaceutical compositions for healing wounds
EP2526953A1Jul 15, 2004Nov 28, 2012Bar-Ilan UniversityMethods and pharmaceutical compositions for healing wounds
EP2527363A1Feb 1, 2008Nov 28, 2012Baylor Research InstituteVaccines based on targeting antigen to dcir expressed on antigen-presenting cells
EP2527441A2Jul 15, 2008Nov 28, 2012Technion Research & Development FoundationCompositions and methods for treating tumors, fibrosis, and pulmonary alveolar proteinosis
EP2529754A1May 3, 2008Dec 5, 2012Agency For Science, Technology And Research (A*star)Antibodies binding to an intracellular PRL-1 or PRL-3 polypeptide
EP2532674A1Feb 5, 2007Dec 12, 2012Modigene IncLong-acting polypeptides and methods of producing and administering same
EP2532675A1Feb 5, 2007Dec 12, 2012Modigene IncLong-acting polypeptides and methods of producing and administering same
EP2540301A2Jul 15, 2004Jan 2, 2013Bar-Ilan UniversityMethods and pharmaceutical compositions for healing wounds
EP2540302A1Jul 15, 2004Jan 2, 2013Bar-Ilan UniversityMethods and pharmaceutical compositions for healing wounds
EP2548951A1Mar 22, 2007Jan 23, 2013Pluristem Ltd.Methods for cell expansion and uses of cells and conditioned media produced thereby for therapy
EP2550982A1Jul 26, 2012Jan 30, 2013Technion Research & Development Foundation Ltd.Devices for surgical applications
EP2561889A2Jul 31, 2003Feb 27, 2013Yeda Research and Development Co. Ltd.Method and composition for protecting neuronal tissue from damage induced by elevated glutamate levels
EP2581445A1Aug 7, 2008Apr 17, 2013Yeda Research And Development Co. Ltd.Regulators of MMP-9 and uses thereof
EP2591789A2Sep 2, 2008May 15, 2013Pluristem Ltd.Adherent cells from adipose or placenta tissues and use thereof in therapy
EP2599790A1Nov 26, 2008Jun 5, 2013Yissum Research Development Company of The Hebrew University of JerusalemCompositions comprising fibrous polypeptides and polysachharides
EP2620493A1May 26, 2009Jul 31, 2013Ramot at Tel Aviv University Ltd.Mesenchymal stem cells for the treatment of CNS diseases
EP2626417A1Mar 22, 2007Aug 14, 2013Pluristem Ltd.Methods for cell expansion and uses of cells and conditioned media produced thereby for therapy
EP2633854A1Dec 3, 2009Sep 4, 2013Yeda Research And Development Co. Ltd.miRNA-9 or miRNA-9* for use in treating MND
EP2641606A1May 26, 2009Sep 25, 2013Pluristem Ltd.Methods of treating inflammatory colon diseases
EP2657342A1Aug 10, 2009Oct 30, 2013Genisphere Inc.DNA dendrimers protected against nuclease degradation are useful as vectors for the delivery of siRNA
EP2684889A2Jan 31, 2008Jan 15, 2014Baylor Research InstituteMultivariable antigens complexed with targeting humanized monoclonal antibody
EP2698377A1Aug 17, 2012Feb 19, 2014Laboratorios Del. Dr. Esteve, S.A.Enhanced rapid immunogen selection method for HIV gp120 variants
EP2716654A1Oct 24, 2006Apr 9, 2014Evogene Ltd.Isolated polypeptides, polynucleotides encoding same, transgenic plants expressing same and methods of using same
EP2719394A1Jun 29, 2004Apr 16, 2014Tel Aviv University Future Technology Development L.P.Peptides antibodies directed thereagainst for diagnosing and treating amyloid-associated diseases
WO1980002747A1 *May 19, 1980Dec 11, 1980Rapidex LtdUltrasensitive enzymatic radioimmunoassay method
WO1981002792A1 *Mar 20, 1981Oct 1, 1981Res Triangle InstDetection of antibiotics in milk
WO1982002601A1 *Jan 13, 1982Aug 5, 1982American Hospital Supply CorpSolid phase system for ligand assay
WO1983000877A1 *Aug 12, 1982Mar 17, 1983Icl ScientGlucose oxidase immunohistochemical detection of antinuclear antibodies
WO1985002260A1 *Nov 8, 1983May 23, 1985QuidelRapid plunger immunoassay method and apparatus
WO1985003950A1 *Mar 6, 1985Sep 12, 1985Scripps Clinic ResA sv40 expression vector containing hbxag as an expression marker
WO1985004397A1Mar 19, 1985Oct 10, 1985OncogenPlatelet related growth regulator
WO1986004421A1 *Jan 17, 1985Jul 31, 1986Hygeia Sciences Limited PartneEnzyme immunoassay with two-part solution of tetramethylbenzidine as chromogen
WO1997005886A1 *Aug 5, 1996Feb 20, 1997Univ TexasCompositions for conferring immunogenicity to a peptide
WO2002044736A2Nov 30, 2001Jun 6, 2002Molecular Skincare LtdDiagnosis and treatment of epidermal or skin diseases
WO2003046201A2Oct 1, 2002Jun 5, 2003Kimberly Clark CoDetection and identification of enteric bacteria
WO2004018698A2Aug 20, 2003Mar 4, 2004Genitrix LlcLectin compositions and methods for modulating an immune response to an antigen
WO2004060135A2Dec 31, 2003Jul 22, 2004Andrew P LevyMethods of predicting a benefit of antioxidant therapy for prevention of cardiovascular disease in hyperglycemic patients
WO2005033142A2Oct 5, 2004Apr 14, 2005Yeda Res & DevAnti-nik antibodies and uses thereof
WO2005033145A1Oct 5, 2004Apr 14, 2005Yeda Res & DevAntibodies to nik, their preparation and use
WO2005051423A2Nov 30, 2004Jun 9, 2005Yeda Res & DevMethods and agents for immune modulation and methods for identifying immune modulators
WO2006134602A2Jun 18, 2006Dec 21, 2006Univ RamotIsolated cells and populations comprising same for the treatment of cns diseases
WO2007031996A1Sep 11, 2006Mar 22, 2007Rappaport Family Inst For ResCompositions and methods for diagnosing and treating an inflammation
WO2007034487A1Sep 21, 2006Mar 29, 2007Yissum Res Dev CoNucleic acid constructs, pharmaceutical compositions and methods of using same for treating cancer
WO2007091254A1Feb 6, 2007Aug 16, 2007Rappaport Family Inst For ResMethods and kit for diagnosing t1dm
WO2007094985A2Feb 5, 2007Aug 23, 2007Modigene IncLong-acting polypeptides and methods of producing and administering same
WO2007110869A2Mar 28, 2007Oct 4, 2007Tel Hashomer Medical Res InfraMethods and kits for determining predisposition to warfarin resistance
WO2007124299A2Apr 17, 2007Nov 1, 2007Novartis AgAntagonist anti-cd40 antibody pharmaceutical compositions
WO2008041183A2Oct 2, 2007Apr 10, 2008Technion Res & Dev FoundationMicrotubes and methods of producing same
WO2008084410A2Jan 3, 2008Jul 17, 2008Humabs LlcHuman cytomegalovirus neutralising antibodies and use thereof
WO2008093341A2Jan 31, 2008Aug 7, 2008Technion Res & Dev FoundationElectrospun scaffolds and methods of generating and using same
WO2008093342A2Jan 31, 2008Aug 7, 2008Technion Res & Dev FoundationAlbumin fibers and fabrics and methods of generating and using same
WO2008097870A2Feb 2, 2008Aug 14, 2008Baylor Res InstAgents that engage antigen - presenting cells through dendritic cell asialoglycoprotein receptor (dc- asgpr)
WO2008120202A2Mar 27, 2008Oct 9, 2008Technion Res & Dev FoundationAntibodies, methods and kits for diagnosing and treating melanoma
WO2008120216A1Apr 2, 2008Oct 9, 2008Univ RamotMethods of detecting cancer cells and use of same for diagnosing and monitoring treatment of the disease
WO2009010968A2Jul 15, 2008Jan 22, 2009Yitzchak HillmanDisease treatment via antimicrobial peptides or their inhibitors
WO2009083958A2Dec 23, 2008Jul 9, 2009Evogene LtdIsolated polypeptides, polynucleotides useful for modifying water user efficiency, fertilizer use efficiency, biotic/abiotic stress tolerance, yield and biomass in plants
WO2009104174A2Feb 12, 2009Aug 27, 2009Technion Research & Development Foundation Ltd .A method of attaching a cell-of-interest to a microtube
WO2010017544A2Aug 10, 2009Feb 11, 2010Genisphere, Inc.Long-acting dna dendrimers and methods thereof
WO2010029545A2Sep 10, 2009Mar 18, 2010Ben Gurion University Of The Negev Research And Development AuthorityCompositions and methods for treating s. pneumoniae infection
WO2010042481A1Oct 6, 2009Apr 15, 2010University Of ChicagoCompositions and methods related to bacterial eap, emp, and/or adsa proteins
WO2010055525A1Nov 17, 2009May 20, 2010Technion Research & Development Foundation Ltd.Method for predicting a patient's responsiveness to anti-folate therapy
WO2010058396A1Nov 17, 2009May 27, 2010Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.A cd44vra antibody and diagnostic and therapeutic methods using same
WO2010061383A1Nov 24, 2009Jun 3, 2010Biodalia Microbiological Technologies Ltd.A method of in-situ enrichment of foods with fructan
WO2010064231A1Nov 29, 2009Jun 10, 2010Tel Hashomer Medical Research Infrastructure And Services Ltd.Methods of analyzing a-i rna editing and nucleic acid constructs capable of same
WO2010064247A1Dec 3, 2009Jun 10, 2010Tel Hashomer Medical Research Infrastructure And Services Ltd.Methods and kits for determining predisposition to cancer
WO2010071610A1Dec 21, 2009Jun 24, 2010Agency For Science, Technology And Research (A*Star)Severe chikungunya biomarkers
WO2010076642A1Dec 28, 2009Jul 8, 2010Tel Hashomer Medical Research, Infrastructure And Services LtdPeptides and compositions for prevention of cell adhesion and methods of using same
WO2010076788A2Dec 29, 2009Jul 8, 2010Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Methods of predicting responsiveness to interferon treatment and treating hepatitis c infection
WO2010076794A1Dec 30, 2009Jul 8, 2010Technion Research & Development Foundation Ltd.Method of denitrifying brine and systems capable of same
WO2010086856A2Jan 31, 2010Aug 5, 2010Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Methods of generating tissue using devitalized, acellular scaffold matrices derived from micro-organs
WO2010086867A2Feb 2, 2010Aug 5, 2010Ramot At Tel Aviv University Ltd.Peptides, pharmaceutical compositions comprising same and uses thereof
WO2010089707A1Feb 4, 2010Aug 12, 2010Yeda Research And Development Co. Ltd.Methods and kits for determining sensitivity or resistance of prostate cancer to radiation therapy
WO2010097793A2Feb 25, 2010Sep 2, 2010Tel Hashomer Medical Research Infrastructure And Services Ltd.Isolated populations of renal stem cells and methods of isolating and using same
WO2010097794A1Feb 25, 2010Sep 2, 2010Tel Hashomer Medical Research Infrastructure And Services Ltd.Methods of reprogramming renal cells
WO2010103517A1Mar 10, 2010Sep 16, 2010Rappaport Family Institute For Research In The Medical SciencesSoluble compositions for the treatment of cxcr3-ligand associated diseases
WO2010113096A1Mar 28, 2010Oct 7, 2010Tel Hashomer Medical Research Infrastructure And Services Ltd.Methods of predicting clinical course and treating multiple sclerosis
WO2010113146A1Feb 28, 2010Oct 7, 2010The Medical Research, Infrastructure, And Health Services Fund Of The Tel Aviv Medical CenterA method of regulating proliferation and differentiation of keratinocyes
WO2010116375A1Apr 8, 2010Oct 14, 2010Yeda Research And Development Co. Ltd.Isolated peptides for regulating apoptosis
WO2010135663A2May 21, 2010Nov 25, 2010The United States Of America , As Represented By The Secretary, Department Of Health And Human ServicesCompositions and methods for the detection of hiv-1/hiv-2 infection
WO2010137013A1May 25, 2010Dec 2, 2010Ramot At Tel Aviv University Ltd.Crystallized photosystem i units from the pea plant and their use in solid state devices
WO2010137017A2May 26, 2010Dec 2, 2010Yeda Research And Development Co. Ltd.Proteasome inhibitors and uses thereof
WO2010137020A1May 27, 2010Dec 2, 2010Yeda Research And Development Co. Ltd.Methods of treating inflammation
WO2010137021A2May 27, 2010Dec 2, 2010Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Method of generating connective tissue
WO2010150259A1Jun 24, 2010Dec 29, 2010Fund For Medical Research Development Of Infrastructure And Health Services -Rambam Medical CenterMethods and kits for isolating placental derived microparticles and use of same for diagnosis of fetal disorders
WO2011004379A1Jul 8, 2010Jan 13, 2011Tel Hashomer Medical Research Infrastructure And Services Ltd.Compositions and methods for treating cancer
WO2011010309A1Jul 21, 2010Jan 27, 2011Tel Hashomer Medical Research Infrastructure And Services Ltd.A method of diagnosing cancer
WO2011013130A2Jul 29, 2010Feb 3, 2011Ramot At Tel-Aviv University Ltd.Cell-targeting nanoparticles comprising polynucleotide agents and uses thereof
WO2011021171A1Aug 22, 2010Feb 24, 2011Beeologics, LlcPreventing and curing beneficial insect diseases via plant transcribed molecules
WO2011021194A2Aug 17, 2010Feb 24, 2011Technion Research & Development Foundation Ltd.Pericyte progenitor cells and methods of generating and using same
WO2011024172A2Aug 26, 2010Mar 3, 2011Technion Research & Development Foundation Ltd.Liposomal compositions and uses of same
WO2011030329A1Aug 31, 2010Mar 17, 2011Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Method of treating tumors
WO2011030332A2Sep 5, 2010Mar 17, 2011Yeda Research And Development Co. Ltd.Methods for hematopoietic precursor mobilization
WO2011030336A1Sep 6, 2010Mar 17, 2011Ramot At Tel-Aviv University Ltd.Methods of diagnosing amyotrophic lateral sclerosis (als)
WO2011033506A2Sep 15, 2010Mar 24, 2011Yeda Research And Development Co. Ltd.Isolated pon1 polypeptides, polynucleotides encoding same and uses thereof in treating or preventing organophosphate exposure associated damage
WO2011033511A1Sep 16, 2010Mar 24, 2011Ramot At Tel-Aviv University Ltd.Peptides for the treatment of oxidative stress related disorders
WO2011045796A1Oct 14, 2010Apr 21, 2011Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Compositions for controlling varroa mites in bees
WO2011048600A1Oct 21, 2010Apr 28, 2011Danziger Innovations Ltd.Generating genotypic variations in plant genomes by gamete infection
WO2011055366A1Nov 8, 2010May 12, 2011Medical Research & Development Fund For Health Services Bnai Zion Medical Center, The State Of IsraelMo-1 conditional knock-out non-human animal and uses thereof
WO2011058555A1Nov 11, 2010May 19, 2011Yeda Research And Development Co. Ltd.A method of editing dna in a cell and constructs capable of same
WO2011058557A1Nov 11, 2010May 19, 2011Ramot At Tel-Aviv University Ltd.Compositions comprising pedf and uses of same in the treatment and prevention of ovary-related syndromes
WO2011061736A1Nov 17, 2010May 26, 2011Protalix Ltd.Alkaline alpha galactosidase for the treatment of fabry disease
WO2011063198A2Nov 19, 2010May 26, 2011St. Jude Children's Research HospitalMethods and compositions for modulating the activity of the interleukin-35 receptor complex
WO2011064669A2Nov 29, 2010Jun 3, 2011Pluristem Ltd.Adherent cells from placenta and use of same in disease treatment
WO2011064773A1Nov 24, 2010Jun 3, 2011Collplant Ltd.Method of generating collagen fibers
WO2011067745A2Dec 6, 2010Jun 9, 2011Rosetta Green Ltd.Compositions and methods for enhancing plants resistance to abiotic stress
WO2011072091A1Dec 9, 2010Jun 16, 2011Quark Pharmaceuticals, Inc.Methods and compositions for treating diseases, disorders or injury of the cns
WO2011080740A1Dec 29, 2010Jul 7, 2011Gamida-Cell Ltd.Methods for enhancing natural killer cell proliferation and activity
WO2011086509A1Jan 12, 2011Jul 21, 2011Vascular Biogenics Ltd.Methods of producing adenovirus vectors and viral preparations generated thereby
WO2011092700A1Jan 27, 2011Aug 4, 2011Yeda Research And Development Co. Ltd.Antibodies that inhibit metalloproteins
WO2011099006A2Feb 10, 2011Aug 18, 2011Yeda Research And Development Co. Ltd.Enzymatic systems for carbon fixation and methods of generating same
WO2011107939A1Mar 1, 2011Sep 9, 2011Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Methods of predicting efficacy of an anti-vegfa treatment for solid tumors
WO2011107994A1Mar 3, 2011Sep 9, 2011Yeda Research And Development Co. Ltd.Methods of measuring protein stability
WO2011111034A1Jan 25, 2011Sep 15, 2011Yeda Research And Development Co. Ltd.Recombinant protein production in heterologous systems
WO2011111050A2Mar 10, 2011Sep 15, 2011Jacob EdreiMethods of generating hydrogen
WO2011125015A2Apr 4, 2011Oct 13, 2011Bar-Ilan UniversityProtease-activatable pore-forming polypeptides
WO2011128897A1Apr 12, 2011Oct 20, 2011Technion Research & Development Foundation Ltd.Populations of pancreatic progenitor cells and methods of isolating and using same
WO2011132182A1Mar 22, 2011Oct 27, 2011Yeda Research And Development Co. Ltd.MOLECULES AND METHODS OF USING SAME FOR TREATING ErbB/ErbB LIGANDS ASSOCIATED DISEASES
WO2011138778A2May 4, 2011Nov 10, 2011Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Methods of identifying inhibitors of polypeptides-of-interest
WO2011138785A2May 5, 2011Nov 10, 2011Rappaport Family Institute For Research In The Medical SciencesUse of ccl1 in therapy
WO2011141914A1May 12, 2011Nov 17, 2011Tel Hashomer Medical Research Infrastructure And Services Ltd.Isolated populations of adult renal cells and methods of isolating and using same
WO2011151833A1Jun 2, 2011Dec 8, 2011Ramot At Tel-Aviv University Ltd.Methods of treating diabetes and compositions capable of same
WO2011154940A1Jun 6, 2011Dec 15, 2011Osnat Ashur-FabianMethods and kits for diagnosing conditions related to hypoxia
WO2011158242A2Jun 16, 2011Dec 22, 2011Futuragene Israel Ltd.Pest -resistant plants containing a combination of a spider toxin and a chitinase
WO2011158243A2Jun 16, 2011Dec 22, 2011Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Method of diagnosing and treating cancer
WO2012007919A2Jul 14, 2011Jan 19, 2012Technion Research & Development Foundation Ltd.Nucleic acid construct for increasing abiotic stress tolerance in plants
WO2012007950A2Jul 14, 2011Jan 19, 2012Technion Research & Development Foundation Ltd.Isolated high affinity entities with t-cell receptor like specificity towards native complexes of mhc class ii and diabetes-associated autoantigenic peptides
WO2012007951A1Jul 14, 2011Jan 19, 2012Technion Research & Development Foundation Ltd.Isolated high affinity entities with t-cell receptor like specificity towards native complexes of mhc class ii and glutamic acid decarboxylase (gad) autoantigenic peptides
WO2012011113A2Jul 21, 2011Jan 26, 2012Shai YarkoniRegulatory immune cells with enhanced targeted cell death effect
WO2012014205A1Jul 27, 2011Feb 2, 2012Technion Research & Development Foundation Ltd.Isolated mesenchymal progenitor cells and extracellular matrix produced thereby
WO2012014207A2Jul 27, 2011Feb 2, 2012Technion Research & Development Foundation Ltd.Method for generating induced pluripotent stem cells from keratinocytes derived from plucked hair follicles
WO2012014208A2Jul 27, 2011Feb 2, 2012Yeda Research And Development Co. Ltd.Methods and systems for assessing clonality of cell cultures
WO2012017439A2Aug 4, 2011Feb 9, 2012Ramot At Tel-Aviv University Ltd.Methods of treating autoimmune diseases of the central nervous system (cns) and neurodegenerative diseases
WO2012025914A1Jul 7, 2011Mar 1, 2012Ramot At Tel-Aviv University Ltd.Induced pluripotent stem cells derived from human pancreatic beta cells
WO2012025925A1Aug 24, 2011Mar 1, 2012Fund For Medical Research Development Of Infrastructure And Health Services - At Rambam Medical CenterMethods of improving transplantation using sdf-1alpha
WO2012032510A1Sep 6, 2011Mar 15, 2012Yeda Research And Development Co. Ltd.Primers for amplifying dna and methods of selecting same
WO2012032519A2Sep 7, 2011Mar 15, 2012Hadasit Medical Research Services And Development Ltd.Methods of diagnosing parkinson's disease
WO2012032520A1Sep 7, 2011Mar 15, 2012Protalix Ltd.Readthrough acetylcholinesterase (ache-r) for treating or preventing parkinson's disease
WO2012032521A2Sep 7, 2011Mar 15, 2012Technion Research & Development Foundation Ltd.Novel methods and culture media for culturing pluripotent stem cells
WO2012032525A2Sep 8, 2011Mar 15, 2012Yeda Research And Development Co. Ltd.An immunosuppressive drug combination for a stable and long term engraftment
WO2012032526A2Sep 8, 2011Mar 15, 2012Yeda Research And Development Co. Ltd.Use of anti third party central memory t cells for anti-leukemia/lymphoma treatment
WO2012034067A1Sep 9, 2011Mar 15, 2012The University Of ChicagoMethods and compositions involving protective staphylococcal antigens
WO2012035539A1Sep 15, 2011Mar 22, 2012Ramot At Tel-Aviv University Ltd.Methods of expanding and redifferentiating islet beta cells
WO2012038956A1Sep 20, 2011Mar 29, 2012Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Method of treating neurodegenerative diseases
WO2012052872A2Oct 10, 2011Apr 26, 2012Yeda Research And Development Co. Ltd.Methods and compositions for the treatment of insulin-associated medical conditions
WO2012052878A1Oct 12, 2011Apr 26, 2012Vascular Biogenics Ltd.Isolated polynucleotides and nucleic acid constructs for directing expression of a gene-of-interest in cells
WO2012056452A2Oct 27, 2011May 3, 2012Nanocyte (Israel) Ltd.Pharmaceutical compositions and delivery devices comprising stinging cells or capsules
WO2012056455A1Oct 27, 2011May 3, 2012Yeda Research And Development Co. Ltd.Methods of generating antibodies to metalloenzymes
WO2012059922A2Nov 3, 2011May 10, 2012Futuragene Israel Ltd.Transgenic plants with improved saccharification yields and methods of generating same
WO2012075111A1Nov 30, 2011Jun 7, 2012Novartis AgUses of anti-cd40 antibodies in combination therapy for b cell-related cancers
WO2012090205A2Dec 28, 2011Jul 5, 2012Bio-Fd&C Co. Ltd.Plant extracts for the treatment and prevention of infections
WO2012098537A1Sep 7, 2011Jul 26, 2012Protalix Ltd.Nucleic acid construct for expression of alpha-galactosidase in plants and plant cells
WO2012104851A1Jan 31, 2012Aug 9, 2012Yeda Research And Development Co. Ltd.Methods of diagnosing disease using overlap extension pcr
WO2012113921A1Feb 24, 2012Aug 30, 2012Fundació Privada Institut De Recerca De La Sida - CaixaRapid selection method for hiv gp-120 variants
WO2012114339A1Feb 23, 2012Aug 30, 2012Rappaport Family Institute For Research In The Medical SciencesHigh affinity molecules capable of binding a type a plexin receptor and uses of same
WO2012117373A1Mar 1, 2012Sep 7, 2012Ramot At Tel-Aviv University Ltd.Genetically modified muscle cells which express neurotrophic factors
WO2012117406A2Mar 1, 2012Sep 7, 2012Futuragene Israel Ltd.Bacterial resistant transgenic plants
WO2012120500A2Mar 5, 2012Sep 13, 2012BAR-SHIMON, MeiravLow fucose cell lines and uses thereof
WO2012120518A1Mar 8, 2012Sep 13, 2012Ramot At Tel-Aviv University Ltd.Compositions and methods for diagnosing and treating phenylketonuria (pku)
WO2012123938A1Feb 26, 2012Sep 20, 2012Tel Hashomer Medical Research Infrastructure And Services Ltd.Quinolone analogs for treating autoimmune diseases
WO2012123949A1Mar 15, 2012Sep 20, 2012Ramot At Tel-Aviv University Ltd.Bi- and monospecific, asymmetric antibodies and methods of generating the same
WO2012127320A1Mar 22, 2012Sep 27, 2012Pluristem Ltd.Methods for treating radiation or chemical injury
WO2012127475A1Mar 22, 2012Sep 27, 2012Neurim Pharmaceuticals (1991) Ltd.Neuroprotective peptides
WO2012131680A2Mar 28, 2012Oct 4, 2012Yeda Research And Development Co. Ltd.Compositions and methods for treating inflammation
WO2012137202A1Apr 3, 2012Oct 11, 2012Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Composition comprising an iron indicator attached to a microparticle and uses of same for quantifying non-transferrin bound iron (ntbi) and cellular labile iron (lci)
WO2012137207A1Apr 4, 2012Oct 11, 2012Ramot At Tel-Aviv University Ltd.Methods of monitoring and analyzing metabolic activity profiles diagnostic and therapeutic uses of same
WO2012140519A2Apr 15, 2012Oct 18, 2012Pluristem Ltd.Methods and systems for harvesting cells
WO2012150600A2May 3, 2012Nov 8, 2012Ramot At Tel-Aviv University Ltd.Regulation of amyloid beta molecular composition for the treatment of alzheimer's disease
WO2012153333A1May 9, 2012Nov 15, 2012Hadasit Medical Research Services And Development Ltd.Regeneration and repair of mesenchymal tissue using amelogenin
WO2012153336A2May 10, 2012Nov 15, 2012Rakuto Bio Technologies Ltd.Methods and device for lightening skin complexion
WO2012156976A1May 16, 2012Nov 22, 2012Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Methods of producing artemisinin in non-host plants and vectors for use in same
WO2012160526A2May 23, 2012Nov 29, 2012Ofir MenasheFormulations of microorganism comprising particles and uses of same
WO2012164380A2May 31, 2012Dec 6, 2012Hutchison Biofilm Medical Solutions LimitedDispersion and detachment of cell aggregates
WO2012164565A1May 31, 2012Dec 6, 2012Yeda Research And Development Co. Ltd.Compositions and methods for downregulating prokaryotic genes
WO2012176203A1Jun 19, 2012Dec 27, 2012Kaiima Bio Agritech Ltd.Common wheat, plants or parts thereof having partially or fully multiplied genome, hybrids and products thereof and methods of generating and using same
WO2013011347A1Jul 18, 2011Jan 24, 2013Institute For Research In BiomedicineNeutralizing anti-influenza a virus antibodies and uses thereof
WO2013011507A1Jul 17, 2012Jan 24, 2013Kaiima Bio Agritech Ltd.Maize plants having a partially or fully multiplied genome and uses thereof
WO2013018060A2Aug 2, 2012Feb 7, 2013Yeda Research And Development Co. Ltd.Micro-rnas and compositions comprising same for the treatment and diagnosis of serotonin-, adrenalin-, noradrenalin-, glutamate-, and corticotropin-releasing hormone- associated medical conditions
WO2013021389A2Aug 9, 2012Feb 14, 2013Yeda Research And Development Co.Ltd.Downregulation of mir-7 for promotion of beta cell differentiation and insulin production
WO2013024481A1Aug 13, 2012Feb 21, 2013Kaiima Bio Agritech Ltd.Durum wheat plants having a partially or fully multiplied genome and uses thereof
WO2013035099A1Sep 6, 2012Mar 14, 2013Yeda Research And Development Co. Ltd.Anti third party central memory t cells, methods of producing same and use of same in transplantation and disease treatment
WO2013061328A2Oct 25, 2012May 2, 2013Yeda Research And Development Co. Ltd.Method of treating cancer
WO2013067076A2Nov 1, 2012May 10, 2013Quark Pharmaceuticals, Inc.Methods and compositions for neuroprotection
WO2013070821A1Nov 8, 2012May 16, 2013Quark Pharmaceuticals, Inc.Methods and compositions for treating diseases, disorders or injury of the nervous system
WO2013076729A1Nov 22, 2012May 30, 2013Danziger Dan Flower FarmOtomeria plants
WO2013076730A1Nov 27, 2012May 30, 2013Yeda Research And Development Co. Ltd.Methods of regulating angiogenesis and compositions capable of same
WO2013084190A1Dec 6, 2012Jun 13, 2013Yeda Research And Development Co. Ltd.Mammalian fetal pulmonary cells and therapeutic use of same
WO2013093921A1Dec 20, 2012Jun 27, 2013Collplant Ltd.Collagen coated synthetic polymer fibers
WO2013098813A1Dec 31, 2012Jul 4, 2013Qbi Enterprises Ltd.Endo180-targeted particles for selective delivery of therapeutic and diagnostic agents
WO2013098820A1Dec 26, 2012Jul 4, 2013Kaiima Bio Agritech Ltd.Cultivated sorghum plant having a partially or fully multiplied genome and uses of same
WO2013114363A2Jan 30, 2013Aug 8, 2013Yeda Research And Development Co.Ltd.Antimicrobial agents
WO2013114373A1Jan 31, 2013Aug 8, 2013Protalix Ltd.Inhalable liquid formulations of dnase i
WO2013114374A1Jan 31, 2013Aug 8, 2013Protalix Ltd.Dnase i polypeptides, polynucleotides encoding same, methods of producing dnase i and uses thereof in therapy
WO2013121405A1Feb 19, 2013Aug 22, 2013Protalix Ltd.Oral unit dosage forms and uses of same for the treatment of gaucher disease
WO2013121426A1Feb 13, 2013Aug 22, 2013Gamida-Cell Ltd.Culturing of mesenchymal stem cells
WO2013121427A1Feb 13, 2013Aug 22, 2013Gamida-Cell Ltd.Mesenchymal stem cells conditioned medium and methods of generating and using the same
WO2013124816A2Feb 21, 2013Aug 29, 2013Brainstem Biotec Ltd.Generation of neural stem cells and motor neurons
WO2013124817A2Feb 21, 2013Aug 29, 2013Brainstem Biotec Ltd.MicroRNAS FOR THE GENERATION OF ASTROCYTES
WO2013128454A1Feb 28, 2013Sep 6, 2013The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization, (A.R.O.), Volcani CenterMale sterile garlic plants, hybrid offspring of same and methods of generating and using same
WO2013132495A1Mar 7, 2013Sep 12, 2013Yeda Research And Development Co. Ltd.Compositions for inhibition of quiescin sulfhydryl oxidase (qsox1) and uses of same
WO2013136335A1Mar 14, 2013Sep 19, 2013Yeda Research And Development Co. Ltd.Isolated pon1 polypeptides, polynucleotides encoding same and uses thereof in treating or preventing organophosphate exposure associated damage
WO2013140247A1Mar 14, 2013Sep 26, 2013Humabs Biomed SaAntibodies that neutralize rsv, mpv and pvm and uses thereof
WO2013153553A2Apr 11, 2013Oct 17, 2013Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.Compositions for controlling varroa mites in bees
WO2013160895A1Apr 24, 2013Oct 31, 2013Biokine Therapeutics Ltd.Peptides and use thereof in the treatment of large cell lung cancer
WO2013168164A1May 9, 2013Nov 14, 2013Yeda Research And Development Co. Ltd.Variants of tace pro-domain as tnf-a inhibitor and their medical use
WO2013183048A1Jun 3, 2013Dec 12, 2013Ben-Gurion University Of The Negev Research And Development AuthorityFunctionalized titanium binding peptides and implants coated with same
WO2014006621A1Jul 3, 2013Jan 9, 2014Nanospun Technologies Ltd.Methods and devices for adsorption and biodegradation of petroleum
WO2014020599A1Jul 29, 2013Feb 6, 2014Yeda Research And Development Co. Ltd.Use of the reductive glycine pathway for generating formatotrophic and autotrophic microorganisms
WO2014020608A1Jul 31, 2013Feb 6, 2014Yeda Research And Development Co. Ltd.Methods of diagnosing and treating motor neuron diseases
WO2014024183A1Aug 4, 2013Feb 13, 2014Brainstorm Cell Therapeutics Ltd.Methods of generating mesenchymal stem cells which secrete neurotrophic factors
WO2014027082A1Aug 16, 2013Feb 20, 2014Laboratorios Del Dr. Esteve, S.A.Enhanced rapid immunogen selection method for hiv gp120 variants
WO2014033723A1Sep 3, 2013Mar 6, 2014A.B. Seeds Ltd.Method of improving abiotic stress tolerance of plants and plants generated thereby
WO2014041544A1Sep 12, 2013Mar 20, 2014Ramot At Tel-Aviv University Ltd.Immunoparticles and methods of generating and using same
WO2014052588A1Sep 26, 2013Apr 3, 2014Research Development FoundationAttenuated chikungunya virus
WO2014068553A1Oct 27, 2013May 8, 2014Yeda Research And Development Co. Ltd.Aptamers, multimeric aptamers and uses thereof
WO2014083567A2Nov 28, 2013Jun 5, 2014Yeda Research And Development Co. Ltd.Methods of preventing tumor metastasis, treating and prognosing cancer and identifying agents which are putative metastasis inhibitors
WO2014106837A2Dec 30, 2013Jul 10, 2014A. B. Seeds Ltd.ISOLATED dsRNA MOLECULES AND METHODS OF USING SAME FOR SILENCING TARGET MOLECULES OF INTEREST
WO2014106838A2Dec 30, 2013Jul 10, 2014A.B. Seeds Ltd.Methods of introducing dsrna to plant seeds for modulating gene expression
Classifications
U.S. Classification435/7.8, 435/188, 436/530, 436/518, 436/818, 436/533, 436/808, 435/13, 435/25, 435/7.94, 435/971, 435/7.92
International ClassificationG01N33/541, G01N33/543, G01N33/74
Cooperative ClassificationY10S436/808, Y10S436/818, Y10S435/971, G01N33/743, G01N33/541, G01N33/54306
European ClassificationG01N33/74B, G01N33/543B, G01N33/541