WO1993006121A1 - Method of synthesizing diverse collections of oligomers - Google Patents
Method of synthesizing diverse collections of oligomers Download PDFInfo
- Publication number
- WO1993006121A1 WO1993006121A1 PCT/US1992/007815 US9207815W WO9306121A1 WO 1993006121 A1 WO1993006121 A1 WO 1993006121A1 US 9207815 W US9207815 W US 9207815W WO 9306121 A1 WO9306121 A1 WO 9306121A1
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- oligomer
- beads
- monomer
- library
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
- C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/14—Pyrrolo-pyrimidine radicals
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
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- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
- Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
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Definitions
- the present invention relates generally to stochastic methods for synthesizing random oligomers, with particular emphasis on particle-based synthesi methods.
- the invention also relates to the use of identification tags on the particles to facilitate identification of the oligomer sequence synthesized.
- Yet another aspect o the invention relates to the use of tagged oligomer libraries in receptor-binding studies.
- Certain macromolecules are known to interact and bind to other molecules having a very specific three-dimensional spatial and electronic distribution. Any large molecule having such specificity can be considered a receptor, whether the molecule is an enzyme catalyzing hydrolysis of a metabolic intermediate, a cell-surface protein mediating membrane transport of ions, a glycoprotein serving to identify a particular cell to its neighbors, an IgG- class antibody circulating in the plasma, an oligonucleotide sequence of DNA in the genome, or the like.
- the various molecules that receptors selectively bind are known as ligands.
- a peptide is a polymer composed of amino acid monomers. When the twenty naturally occurring amino acids are ⁇ condensed into polymeric molecules, the resulting polymers form a wide variety of three-dimensional configurations, each resulting from a particular amino acid sequence and solvent condition.
- the number of possible pentapeptides of the 20 naturally occurring amino acids is 205 or 3.2 million different peptides.
- the likelihood that molecules of this size might be useful in receptor-binding studie is supported by epitope analysis studies showing that some antibodies recognize sequences as short as a few amino acids with high specificity.
- the average molecular weight of amino acids puts small peptides in the size range of many currently useful pharmaceutical products.
- larger peptides may be necessary for many purposes, and polypeptides having changes in only a small number of residues may also be useful for such purposes as the analysis of structure- activity relationships.
- Pharmaceutical drug discovery is one type of research that relies on studies of structure-activity relationships. In most cases, contemporary pharmaceutical research can be described as the process of discovering novel ligands with desirable patterns of specificity for biologically important receptors. Another example is research to discover new compounds for use in agriculture, such as pesticides and herbicides.
- a tubular reactor system may be used to synthesize a linear oligomer on a solid phase support by automated sequential addition of reagents. This method still does not enable the synthesis of a sufficiently large number of oligomer sequences for effective economical screening.
- Methods of preparing a plurality of oligomer sequences are also known in which a foraminous container encloses a known quantity of reactive solid supports, the solid supports being larger in size than openings of the container. See U.S. Patent No. 4,631,211, incorporated herein by reference.
- the containers may be selectively reacted with desired materials to synthesize desired sequences of product molecules. As with other methods known in the art, this method cannot practically be used to synthesize a sufficient variety of polypeptides for effective screening.
- the present invention provides a general stochastic method for synthesizing libraries of random oligomers.
- the random oligomers are synthesized on solid supports, or particles, but may be cleaved from these supports to provide a soluble library.
- the oligomers are composed of a sequence of monomers, the monomers being any member of the set of molecules that can be joined together to form an oligomer or polymer, i.e., amino acids, carbamates, sulfones, sulfoxides, nucleosides, carbohydrates, ureas, phosphonates, lipids, esters, combinations of the same, and the like.
- the library is then screened to isolate individual oligomers that bind to a receptor or possess some desired property.
- Each oligomer sequence in the library is unique, in a preferred embodiment.
- the solid supports are nonporous beads.
- the solid supports may be composed of a single particle, or two or more linked particles.
- a further embodiment of the invention relates to the use of an identifie tag to identify the sequence of monomers in the oligomer.
- the identifier tag which may be attached directly to the oligomer with or without an accompanying particle, t a linker attached to the oligomer, to the solid support upon which the oligomer is synthesized, or to a second particle attached to the oligomer-carrying particle, may be any recognizable feature that in some way carries the required information, and that i decipherable at the level of one or a few solid supports.
- the solid supports may be joined to the oligomers and the identifier tag by means of one or more linker molecules.
- the identifier tag will be an oligonucleotide, preferably composed of pyrimidines or pyrimidines and purine analogs or any type of nucleoside that will not degrade under the coupling conditions used to assemble the oligomer library.
- the oligonucleotide identifier tag may contain a 5' and a 3' amplification site, to allow amplification of the tag by, for example, the polymerase chain reaction (see U.S. Patent Nos. 4,683,202; and 4,965,188, each of which is incorporated herein by reference).
- a DNA sequencing primer site which may be specific for each step of the oligomer synthesis, may also be included in the oligonucleotide tag in addition to the amplification primer sites.
- the tag may be designed to include, in the oligonucleotide sequence, information allowing identification of the monomer associated with the addition of the particular tag.
- the oligonucleotide tag will be about 50 to 100 nucleotides in length, in a preferred embodiment.
- the identifier tag may be composed of a set of light-addressable compounds, such as fluorescent or phosphorescent compounds that can be photobleached, which compounds are incorporated into the beads or particles on which the oligomers of the oligomer library are synthesized.
- a set of light-addressable compounds such as fluorescent or phosphorescent compounds that can be photobleached, which compounds are incorporated into the beads or particles on which the oligomers of the oligomer library are synthesized.
- Such compounds are widely known in the art.
- Fig. 1 is a schematic representation of combinatorial oligomer synthesis on particles.
- Fig. 2 is a schematic representation of concurrent combinatorial oligomer synthesis and particle tagging.
- Fig. 3 describes one method of bead functionalization, the compatible chemistries for peptide synthesis and round by round attachment of oligonucleotide identifier tags, including synthesis of amino-functionalized beads, the structure of protected 5' maleimidyl oligonucleotides, amino acid coupling and introduction of a thiol "handle,” step-specific oligonucleotide attachment to a bead, subsequent amino acid coupling(s) and oligonucleotide attachment(s), and peptide and oligonucleotide deprotection.
- Fig. 4 is a schematic representation of one example of an oligonucleotide tag.
- Fig. 5 illustrates nucleoside phosphoramidites derivatized with photolabile protecting groups for parallel peptide /oligonucleotide synthesis.
- Fig. 6 illustrates 5'-DMT-3'-(0-allyl N,N'-diisopropyl phosphoramidite) nucleoside derivatives for parallel peptide /oligonucleotide synthesis.
- Fig. 7 illustrates the preparation of a bifunctional bead material for parallel synthesis of peptides and oligonucleotides.
- Fig. 8 illustrates the parallel assembly of oligonucleotide-tagged peptides on beads.
- Fig. 9 shows a schematic representation of the experiment described in Example 5, in which two populations of oligomers on beads are prepared, tagged, mixed, sorted, and identified by the method of the present invention.
- Fig. 10 shows resolution of the two populations of beads by FACS in the experiment described in Example 5. Values along the horizontal axis indicate relative fluorescence (log scale). Values along the vertical axis indicate relative numbers of beads. Non-fluorescently labeled beads are represented by peak A. Flourescently labeled beads are represented by peak B. The ratio of the larger peak to the smaller peak is 15:1. Fig.
- FIG. 11 shows pictures of ethidium bromide stained, UV irradiated agarose gels of PCR products obtained by amplification after FACS of two bead populations and amplification of the tags on the sorted beads, with controls, as described in Example 5.
- Gel A shows the results with sorted fluorescent beads: lane 1 — 2.4xl ⁇ 6 copies (100 bead equivalents) of 95 mer tag; lanes 2-7 — PCR product from single fluorescent beads; lanes 8-10 — PCR product from ten fluorescent beads; lanes 11-13 — PCR product from one hundred fluorescent beads; and lane 14 — 1.2x10 ⁇ copies (100 bead equivalents) of 110 mer tag.
- Gel B shows the result with sorted non- fluorescent beads: lane 1 — 1.2x10 ⁇ copies of 110 mer tag; lanes 2-7 — PCR product from single non-fluorescent beads; lanes 8-10 — PCR product from ten non- fluorescent beads; lanes 11-13 — PCR product from one hundred non-fluorescent beads; and lane 14 — 2.4x10 ⁇ copies of 95 mer tag.
- Gel C shows the results with the control reactions: lanes 1,12 — DNA size standards; lanes 2, 3 — no tag control reactions; lanes 4, 5 — 1 bead equivalent of soluble 95 mer tag; lanes 6, 7 — 10 bead equivalents of soluble 95 mer tag; lanes 8, 9 — 1 bead equivalent of soluble 110 mer tag; and lanes 10, 11 — 10 bead equivalents of soluble 110 mer tag.
- each member of such a library is uniquely labeled in a manner that specifies the identity of the sequence of the oligomer corresponding to that member.
- Methods for screening such libraries and reagents useful for producing the libraries are also provided.
- Complementary or substantially complementary refer to base pairing between nucleotides or nucleic acids, such as, for instance, between the two strands of a double stranded DNA molecule or between an oligonucleotide primer and a primer binding site on a single stranded nucleic acid to be sequenced or amplified.
- "Complementary" nucleotides are, generally, A and T (or A and U), and C and G, as is well known to those of skill in the art.
- Two single stranded RNA or DNA molecules are said to be “substantially complementary” when the nucleotides of one strand, optimally aligned, pair with at least about 80% or more of the nucleotides of the other strand.
- RNA or DN strand will hybridize under selective hybridization conditions to a complementary nucleic acid.
- selective hybridization will occur when there is at least about 55% complementarity over a stretch of at least 14 to 25 nucleotides, but more selective hybridization will occur as complementarity increases to 65%, 75%, 90%, and 100%.
- Stringent hybridization conditions will typically include salt concentrations of less than about 1 M, such as less than 500 mM, and will often include salt concentrations of less than 200 mM.
- the hybridization temperature for oligomers will typically be greater than 22°C, such as greater than about 30°C, and will often be in excess of about 37°C. Longer fragments may require higher hybridization temperatures for specific hybridization. As other factors may dramatically affect the stringency of hybridization (such factors include base composition, length of the complementary strands, presence of organic solvents, and extent of base mismatching), the combination of factors is more important than the absolute measure of any one factor alone.
- Epitope The portion of an antigen molecule delineated by the area of interaction with the subclass of receptors known as antibodies is an "epitope.”
- identifier tag is a physical attribute that provides a means whereby one can identify which monomer reactions an individual solid support has experienced in the synthesis of an oligomer.
- the identifier tag also records the step in the synthesis series in which the solid support visited that monomer reaction.
- the identifier tag may be any recognizable feature, including for example: a microscopically distinguishable shape, size, color, optical density, etc.; a differential absorbance or emission of light; chemically reactivity; magnetic or electronic encoded information; or any other distinctive mark with the required information, and decipherable at the level of one (or a few) solid support(s).
- a preferred example of such an identifier tag is an oligonucleotide sequence.
- identifier tag can be coupled directly to the oligomer synthesized, whether or not a solid support is used in the synthesis.
- the identifier tag serves as the "support” for oligomer synthesis.
- Ligand A "ligand” is a molecule that is recognized by a particular receptor.
- the agent bound by or reacting with a receptor is called a "ligand", a term which is definitionally meaningful only in terms of its counterpart receptor.
- the term “ligand” does not imply any particular molecular size or other structural or compositional feature other than that the substance in question is capable of binding or otherwise interacting with the receptor.
- a “ligand” may serve either as the natural ligand to which the receptor binds, or as a functional analogue that may act as an agonist or antagonist.
- Ligands that can be investigated by this invention include, but are not restricted to, agonists and antagonists for cell membrane receptors, toxins and venoms, viral epitopes, hormones, sugars, cofactors, peptides, enzyme substrates, cofactors, drugs (e.g., opiates, steroids, etc.), and proteins.
- Monomer A "monomer” is any member of the set of molecules which can be joined together to form an oligomer or polymer.
- the set of monomers useful in the present invention includes, but is not restricted to, for the example of peptide synthesis, the set of L-amino acids, D-amino acids, or synthetic amino acids.
- monomer refers to any member of a basis set for synthesis of an oligomer.
- dimers of L-amino acids form a basis set of 400 "monomers” for synthesis of polypeptides.
- Different basis sets of monomers may be used at successive steps in the synthesis of a polymer.
- Oligomer or Polymer are formed from the chemical or enzymatic addition of monomer subunits.
- oligomers include, for example, both linear, cyclic, and branched polymers of nucleic acids, polysaccharides, phospholipids, and peptides having either alpha-, beta-, or omega-amino acids, heteropolymers, polyurethanes, polyesters, polycarbonates, polyureas, polyamides, polyethyleneimines, polyarylene sulfides, polysiloxanes, polyimides, polyacetates, or other polymers, as will be readily apparent to one skilled in the art upon review of this disclosure.
- Peptide A "peptide” is an oligomer in which the monomers are alpha amino acids joined together through amide bonds. Alternatively, a “peptide” can be referred to as a "polypep tide.” In the context of this specification, one should appreciate that the amino acids may be the L-optical isomer or the D-optical isomer. Peptides are more than two amino acid monomers long, but more often are more than 5 to 10 amino acid monomers long and can be even longer than 20 amino acids, although peptides longer than 20 amino acids are more likely to be called “polypeptides.” Standard single letter abbreviations for amino acids are used (e.g., P for proline). These abbreviations are included in Stryer, Biochemistry. Third Ed.
- Oligonucleotide is a single-stranded DNA or RNA molecule, typically prepared by synthetic means. Those oligonucleotides employed in the present invention will usually be 50 to 150 nucleotides in length, preferably from 80 to 120 nucleotides, although oligonucleotides of different length may be appropriate in some circumstances. For instance, in one embodiment of the invention, the oligonucleotide tag and the polymer identified by that tag are synthesized in parallel.
- the oligonucleotide tag can be built nucleotide-by-nucleotide in coordination with the monomer-by-monomer addition steps used to synthesize the oligomer.
- very short, i.e., 2 to 10 nucleotides oligonucleotides may be used to extend an existing oligonucleotide tag to identify a monomer coupling step.
- Suitable oligonucleotides may be prepared by the phosphoramidite method described by Beaucage and Carruthers, Tetr. Lett. 22:1859- 1862 (1981), or by the triester method, according to Matteucci et al* / T. Am. Chem. Soc. 103:3185 (1981), both incorporated herein by reference, or by other methods such as by using commercial automated oligonucleotide synthesizers.
- a nucleic acid is "operably linked” when placed into a functional relationship with another nucleic acid sequence.
- a promoter or enhancer is “operably linked” to a coding sequence if the promoter causes the transcription of the sequence.
- operably linked means that the DNA sequences being linked are contiguous and, where necessary to join two protein coding regions, contiguous and in reading frame.
- Receptor A "receptor” is a molecule that has an affinity for a given ligand. Receptors may be naturally-occurring or manmade molecules. Also, receptors can be employed in their unaltered natural or isolated state or as aggregates with other species. Receptors may be attached, covalently or noncovalently, to a binding member, either directly or via a specific binding substance.
- receptors examples include, but are not restricted to, antibodies, cell membrane receptors, monoclonal antibodies, antisera reactive with specific antigenic determinants (such as on viruses, cells, or other materials), polynucleotides, nucleic acids, lectins, polysaccharides, cells, cellular membranes, and organelles.
- Receptors are sometimes referred to in the art as "anti- ligands.” As the term “receptor” is used herein, no difference in meaning is intended.
- a "ligand-receptor pair" is formed when two macromolecules have combined through molecular recognition to form a complex.
- Other examples of receptors that can be investigated by this invention include, but are not restricted to:
- Microorganism receptors Determination of ligands that bind to microorganism receptors, such as specific transport proteins or enzymes essential to survival of microorganisms, is useful in discovering new classes or types of antibiotics. Of particular value would be antibiotics against opportunistic fungi, protozoa, and those bacteria resistant to the antibiotics in current use.
- Enzymes For instance, the binding site of any enzyme, such as the enzymes responsible for cleaving neurotransmitters, is a receptor. Determination of ligands that bind to certain enzymes, and thus modulate the action of the enzymes that cleave the different neurotransmitters, is useful in the development of drugs that can be used in the treatment of disorders of neurotransmission.
- Antibodies For instance, the invention may be useful in investigating the ligand-binding site on an antibody molecule that combines with the epitope of an antigen of interest. Determining a sequence that mimics an antigenic epitope may lead to the development of vaccines or lead to the development of related diagnostic agents or compounds useful in therapeutic treatments such as for autoimmune diseases (e.g., by blocking the binding of the "self 1 antibodies).
- Nucleic Acids The invention may be useful in investigating sequences of nucleic acids acting as binding sites for cellular proteins ("trans-acting factors"). Such sequences may include, e.g., enhancers or promoter sequences.
- Catalytic Polypeptides Polymers, preferably polypeptides, which are capable of promoting a chemical reaction involving the conversion of one or more reactants to one or more products are "catalytic polypeptides.” Such polypeptides generally include a binding site specific for at least one reactant or reaction intermediate and an active functionality proximate to the binding site, which functionality is capable of chemically modifying the bound reactant. Catalytic polypeptides are described in, Lerner et al., Science 252: 659 (1991), which is incorporated herein by reference.
- Hormone receptors include the receptors for insulin and growth hormone. Determination of the ligands which bind with high affinity to a hormone receptor is useful in the development of, for example, an oral replacement of the daily injections which diabetics must take to relieve the symptoms of diabetes, and in the other case, a replacement for human growth hormone, which can only be obtained from cadavers or by recombinant DNA technology. Other examples include the vasoconstrictive hormone receptors; determination of ligands that bind to those receptors may lead to the development o drugs to control blood pressure.
- Opiate receptors Determination of ligands that bind to the opiate receptors in the brain is useful in the development of less-addictive replacements for morphine and related drugs.
- substrate or solid support is a material having a rigid or semi-rigid surface. Such materials will preferably take the form of small beads, pellets, disks, or other convenient forms, although other forms may be used. In some embodiments, at least one surface of the substrate will be substantially flat. A roughly spherical shape is preferred.
- Synthetic A compound is "synthetic" when produced by in vitro chemical or enzymatic synthesis.
- the synthetic libraries of the present invention ma be contrasted with those in viral or plasmid vectors, for instance, which may be propagated in bacterial, yeast, or other living hosts.
- a general method of random oligomer synthesis is provided by the present invention.
- the method can be used to produce the enormous numbers of compounds available with recombinant systems and to utilize the monomer set diversity available with chemical synthesis methods.
- By means of the present method one can readily produce up to 101 different oligomers, a dramatic improvement over previous methods.
- the invention also provides a facile means oligomer identification.
- the general method comprises producing a large, highly diverse collection or library, each member of such a library comprising a single oligomer sequence (e.g., a peptide).
- the sequence may be soluble or may be bound to a solid support.
- the oligomer is usually attached by means a linker.
- the linker prior to attachment, has an appropriate functional group at eac end, one group appropriate for attachment to the support and the other group appropriate for attachment to the oligomer.
- Such a collection may contain, for example, all combinations of n monomers assembled into X length oligomers yielding, n* different compounds.
- the collection may also contain oligomers havin different monomer units at, for example, only one or a small number of positions, while having an identical sequence at all other positions.
- the general method typically involves synthesizing the oligomers in a random combinatorial ("stochastic") fashion by chemical and/ or enzymatic assembly of monomer units.
- a synthetic oligomer library may be produced by synthesizing on each of a plurality of solid supports a single oligomer sequence, the oligomer sequence being different for different solid supports.
- the oligomer sequence is synthesized in a process comprising the steps of: (a) apportioning the supports in a stochastic manner among a plurality of reaction vessels; (b) exposing the supports in each reaction vessel to a first monomer; (c) pooling the supports; (d) apportioning the supports in a stochastic manner among the plurality of reaction vessels; (e) exposing the supports in each reaction vessel to a second monomer; and (f) repeating steps (a) through (e) from at least one to twenty times.
- substantially equal numbers of solid supports will be apportioned to each reaction vessel.
- the monomers are chosen from the set of amino acids, and the resulting oligomer is a peptide.
- the method may consider the synthesis of peptides three residues in length, assembled from a monomer set of three different monomers: A, B, and C.
- the first monomer is coupled to three different aliquots of beads, each different monomer in a different aliquot, and the beads from all the reactions are then pooled (see Fig. 1).
- the pool now contains approximately equal numbers of three different types solid supports, with each type characterized by the monomer in the first residue position.
- the pool is mixed and redistributed to the separate monomer reaction tubes or vessels containing A, B, or C as the monomer.
- the second residue is coupled.
- This method of assembling oligomers from many types of monomers requires using the appropriate coupling chemistry for a given set of monomer units or building blocks. Any set of building blocks that can be attached to one another in a step-by-step fashion can serve as the monomer set. The attachment may be mediated by chemical, enzymatic, or other means, or by a combination of any of these means.
- the resulting oligomers can be linear, cyclic, branched, or assume various other conformations as will be apparent to those skilled in the art. Techniques for solid state synthesis of polypeptides are described, for example, in Merrifield, supra. Peptide coupling chemistry is also described in The Peptides. Vol. 1 (eds. Gross, E., and J.
- oligomers To synthesize the oligomers, a collection of a large number of the solid supports is apportioned among a number of reaction vessels. In each reaction, a different monomer is coupled to the growing oligomer chain.
- the monomers may be of any type that can be appropriately activated for chemical coupling or accepted for enzymatic coupling. Because the reactions may be contained in separate reaction vessels, even monomers with different coupling chemistries can be used to assemble the oligomers (see The Peptides, supra). The coupling time for some of the monomer sets may be long. For this reason, the preferred arrangement is one in which the monomer reactions are carried out in parallel.
- the solid supports on which are synthesized the oligomers of the library are pooled and mixed prior to re-allocation to the individual vessels for the next coupling step.
- This shuffling process produces solid supports with many oligomer sequence combinations. If each synthesis step has high coupling efficiency, then substantially all the oligomers on a single solid support have the same sequence. That sequence is determined by the synthesis pathway (type and sequence of monomer reactions) for any given solid support at the end of the synthesis.
- the maximum length of the oligomers is typically less than about 20, usually from 3 to 8 residues in length, but in some cases a length of 10 to 12 residues is preferred.
- the monomer set may be expanded or contracted from step to step; or the monomer set could be changed completely for the next step (e.g., amino acids in one step, nucleosides in another step, carbohydrates in another step), if the coupling chemistry were available (see Gait, Oligonucleotide Synthesis: A Practical Approach, IRL Press, Oxford (1984); Friesen and Danishefsky, T. Amer. Chem. Soc. 111:6656 (1989) and Paulsen, Angew. Chem. Int. Ed. Engl. 25:212 (1986), all of which are incorporated herein by reference).
- a monomer unit for peptide synthesis may include single amino acids or larger peptide units, or both.
- One variation is to form several pools of various sequences on solid supports to be distributed among different monomer sets at certain steps of the synthesis.
- solid support as used herein embraces a particle with appropriate sites for oligomer synthesis and, in some embodiments, tag attachment and/ or synthesis.
- solid supports useful in preparation of the synthetic oligomer libraries of the present invention. Solid supports are commonly used for solid phase synthesis of, for example, peptides and nucleic acids and other oligomers as enumerated above, and thus are well known to those skilled in the art.
- the solid support size is in the range of 1 nm to 100 ⁇ m, but a more massive solid support of up to 1 mm in size may be used.
- the appropriate size of the solid support depends on (1) the number of oligomer synthesis sites and identifier tag attachment sites desired; (2) the number of different compounds to be synthesized (and the number of solid supports bearing each oligomer that are needed for screening); and (3) the effect of the size of the solid supports on the specific screening strategies [e.g., fluorescence-activated cell sorters (FACS)] to be used.
- FACS fluorescence-activated cell sorters
- solid supports of 1 ⁇ m in diameter may be vised. If each reaction contains approximately 0.2 mL of solid supports, and the oligomers are synthesized from a set of 50 monomers (50 parallel reactions), then a total of 10 mL of solid supports, or approximately 10* solid supports, would be required. If one wishes to make hexamers with these 50 monomers, then there are over 1.5 x 10l° possible sequences, and each specific sequence would be represented on about 103 solid supports. An estimated capacity of each bead, based on the capacity of commonly used peptide synthesizing resins, is about 0.1 pg of peptide per bead. By this estimation, then, each solid support would have about 100 amol or 108 oligomer chains.
- solid supports less porous than typical peptide synthesis resins are preferable. These supports will have a lower density of growing chains, but even with a decrease in capacity of several orders of magnitude, sufficient oligomer densities can be produced for efficient screening. With the less porous supports, a greater proportion of the oligomers will be accessible for binding t the receptor during the screening process. Also, the less porous supports will reduce the carryover of tags from one reaction to the next, thus improving the accuracy of reading the dominant (correct) tags.
- Such solid supports may be of any shape, although they will preferably b roughly spherical. The supports need not necessarily be homogenous in size, shape, or composition; although the supports usually and preferably will be uniform. In some embodiments, supports that are very uniform in size may be particularly preferred. In another embodiment, however, two or more distinctly different populations of solid supports may be used for certain purposes.
- Solid supports may consist of many materials, limited primarily by capacity for derivatization to attach any of a number of chemically reactive groups an compatibility with the chemistry of oligomer synthesis and tag attachment. Suitable support materials include glass, latex, heavily cross-linked polystyrene or similar polymers, gold or other colloidal metal particles, and other materials known to those skilled in the art. Except as otherwise noted, the chemically reactive groups with which such solid supports may be derivatized are those commonly used for solid stat synthesis of the respective oligomer and thus will be well known to those skilled in the art.
- the solid supports of the present invention do not include living cells, viruses, or cloning vectors such as phage vectors or plasmids.
- the oligomers comprising the library also are attached to an identifier tag that can be easily decoded to report the sequence of each oligomer.
- the identifier tags may be attached either to the oligomer or to the solid support to which the oligomer is attached.
- the attachment is preferabl by means of a linker that, prior to attachment, has an appropriate functional group at each end, one group appropriate for attachment to the support and the other group appropriate for attachment to the identifier tag.
- the identifier tag may be attached to a monomer incorporated into the oligomer or attached directly to the same linker that binds the oligomer to the solid support.
- the linker has, prior to attachment, a third functional group appropriate for the attachment of the identifier tag.
- a synthetic oligomer library that incorporates identifier tags is produced by synthesizing on each of a plurality of solid supports a single oligomer sequence and one or more identifier tags identifying the oligomer sequence.
- the tagged synthetic oligomer library is synthesized in a process comprising the steps of: (a) apportioning the supports among a plurality of reaction vessels; (b) exposing the supports in each reaction vessel to a first oligomer monomer and to a first identifier tag monomer; (c) pooling the supports; (d) apportioning the supports among a plurality of reaction vessels; and (e) exposing the supports to a second oligomer monomer and to a second identifier tag monomer.
- the steps of either process typically will be repeated one or more times, but usually, will be repeated less than 20 times.
- the solid supports can be exposed to (or coupled with) an oligomer monomer and an identifier tag at the same time, or sequentially. In either event, the supports are then pooled and exposed to the second oligomer monomer and second identifier tag. As before, these steps are repeated, typically from one to about 20 times.
- the invention is described herein primarily with regard to- the preparation of molecules containing sequences of amino acids, but the invention can readily be applied to the preparation of other oligomers and to any set of compounds that can be synthesized in a component-by-component fashion, as can be appreciated by those skilled in the art.
- the same solid support is used for synthesizing all members of the library, but the members are cleaved from the support prior to screening.
- synthesis of tagged oligomers may be accomplished utilizing very large scale immobilized polymer synthesis (VLSIPSTM) techniques. See U.S. Patent No. 5,143,854 and PCT patent publication No. 92/10092, each of which is incorporated herein by reference.
- VLSIPSTM very large scale immobilized polymer synthesis
- each oligonucleotide linked to the chip by a cleavable group such as a disulfide.
- each oligonucleotide tag has an amine group at the free end and only contains pyrimidine or pyrimidine and purine analog bases.
- each oligonucleotide contains binding sites for amplification, i.e., PCR primer sites and optionally a sequencing primer site. A short section of each oligonucleotide uniquely codes the monomer sequence of the oligomer to be tagged.
- peptides are synthesized, optionally from the free terminal amine groups on each oligonucleotide, so that each peptide is linked to a tag.
- the whole collection of oligonucleotide-peptide may be released from the chip to create a soluble tagged oligomer library.
- the oligomer library is constructed on beads o particles.
- One method of bead functionalization, with compatible chemistries for peptide synthesis and round by round attachment of oligonucleotide identifier tags, is shown in Figs. 3.1-3.6. Glass beads are derivatized using aminopropyltriethoxysilane and a beta-alanine spacer group is coupled using activated ester methodology.
- the oligonucleotide tags may optionally incorporate a biotin group to facilitate purification, hybridization, amplification, or detection (see Pierce ImmunoTechnology Catalog and Handbook, 1991, incorporated herein by reference).
- polypyrimidine oligonucleotide tags are relatively stable under typical peptide synthesis conditions, as opposed to oligonucleotide tags that contain natural purine nucleotides, but a polypyrimidine nucleotide tag may be somewhat refractory to amplification by PCR.
- the tag optionally may contain from 10 to 90%, more preferably 35 to 50%, and most preferably 33 to 35%, purine or purine analog nucleotides.
- the oligonucleotides optionally may contain phosphate protecting groups (e.g., O-methyl phosphates) with greater base stability than the standard beta- cyanoethyl group, which may be susceptible to piperidine cleavage.
- phosphate protecting groups e.g., O-methyl phosphates
- beta-cyanoethyl group which may be susceptible to piperidine cleavage.
- peptide and oligonucleotide deprotection can be effected by sequential treatment with thiophenol, trifluoroacetic acid, and ethanolic ethylenediamine at 55 degrees C.
- photolabile alpha-amino protecting groups are used in conjunction with base-labile side chain protecting groups for the amino acids, and standard beta-cyanoethyl protecting groups are used for the oligonucle
- oligonucleotides containing both modified or synthetic purines and pyrimidines may be synthesized in parallel with peptides using conventional Fmoc/tBu protected amino acids.
- the lability of purine nucleotides to strong acid is avoided by use of phosphoramidites of the purine nucleoside analogs 7-deaza-2'-deoxyadenosine and 7-deaza-2'- deoxyguanosine (see Barr et al.. BioTechniques 4:428-432 (1986), and Scheit, Nucleotide Analogs: Synthesis and Biological Function pp. 64-65 (John Wiley and Sons, New York), both incorporated herein by reference).
- the fully assembled peptide and oligonucleotide chains may be deprotected by first treating the products with 30% piperidine in DMF to remove amino-terminal Fmoc groups.
- the allylic protecting groups are removed using THF containing tris (dibenzylideneacetone) dipalladium-chloroform complex, triphenylphosphine, and n-butylamine/formic acid, followed by a THF wash, an aqueous sodium N,N-diethyldi thiocarbamate wash, and a water wash. Finally, the acid-labile amino acid protecting groups are removed by treatment with 95:5 TFA/water.
- the present invention provides a method for identifying the composition and sequence of any of the oligomers in the library. By tracking the synthesis pathway that each oligomer has taken, one can deduce the sequence of monomers of any oligomer.
- the method involves linking an identifier tag to the oligomer that indicates the monomer reactions and corresponding step numbers tha define each oligomer in the library. After a series of synthesis steps (and concurrent identifier tag additions), one "reads" the identifier tag(s) associated with an oligomer to determine the sequence of that oligomer.
- the identifier tags therefore identify each monomer reaction that an individual library member or solid support has experienced and record the step in th synthesis series in which each monomer is added.
- the tags may be attached immediately before, during, or after the monomer addition reaction, as convenient and compatible with the type of identifier tag, modes of attachment, and chemistry o oligomer synthesis.
- the identifier tag is added when the solid supports that have undergone a specific monomer addition step are physically together and so can be tagged as a group, i.e., prior to the next pooling step.
- the identifier tag can be associated with the oligomer through a variety of mechanisms, either directly, through a linking molecule, or through a solid support upon which the oligomer is synthesized. In the latter mode, one could also attach the tag to another solid support that, in turn, is bound to the solid support upon which the oligomer is synthesized.
- the identifier tag may be any recognizable feature that is, for example: microscopically distinguishable in shape, size, color, optical density, etc.; differently absorbing or emitting of light; chemically reactive; magnetically or electronically encoded; or in some other way distinctively marked with the required information, and decipherable at the level of one (or few) solid supports.
- each bead or other solid support in the library incorporates a variety of fluorophores, or other light addressable type of molecules, the spectral properties of which can be changed and therefore used to store information.
- a bead incorporates a variety of fluorophors, each of which can be selectively photobleached, and so rendered incapable of fluorescence or of diminished fluoresence.
- the bead is irradiated (or not) to photobleach (or not) one or more particular types of fluorophors, thus recording the monomer identity in the oligomer synthesized. See Science 255: 1213 (6 Mar. 1992), incorporated herein by reference.
- the tags can be "machine readable” luminescent or radioactive labels.
- the identifier tag can also be an encodable molecular structure.
- the information may be encoded in the size (e.g. length of a polymer) or the composition of the molecule.
- the best example of this latter type of tag is a nucleic acid sequence, i.e., RNA or DNA assembled from natural or modified bases.
- Synthetic oligodeoxyribonudeotides are espedally preferred information-bearing identifier tags.
- Oligonucleotides are a natural, high density information storage medium. The identity of monomer type and the step of additio is easily encoded in a short oligonudeotide sequence and attached, for example, to each peptide synthesis bead.
- the attached oligonucleotides can be amplified by methods such as PCR (see PCR Protocols: A Guide to Methods and Applications. (Innis, M, Gelfand, Sninsky, J. and White, T., Academic Press, San Diego 1990), incorporated herein by reference), or by other nucleic add amplification techniques, such as the ligase chain reaction and the self-sustained sequence replication system.
- the amplified product can be easily sequenced or otherwise identified to decode the identity of the peptide o the bead. For this purpose, one can use any of a variety of sequendng methods, including sequendng by sequence-spedfic probe hybridization.
- the information may be encoded in the length rather tha or in addition to, the sequence of the oligonucleotide. If only oligonudeotide length is utilized to represent each specific monomer addition to the oligomer, then the identity of the oligomer can be decoded by amplifying the oligonucleotide, as describe above, and identifying the labels through any of a variety of size-separation techniques, induding polya ⁇ ylamide gel elertrophoresis or capillary electrophoresis. There are several ways that oligonudeotides can be used as identifier tags.
- the oligonucleotides can be assembled base-by-base before, during, or after the corresponding oligomer (e.g., peptide) synthesis step.
- the tag for each step is a single nudeotide, or at most a very few nudeotide (i.e., 2 to 5). This strategy preserves the order of the steps in the linear arrangement o the oligonucleotide chain grown in parallel with the oligomer.
- base-by-base assembly is the block-by-block approach; encoded sets of nudeotides ("codons") of 5 to 10 or more bases are added as protected, activated blocks.
- Each block carries the monomer-type information, and the order of addition represents the order of the monomer addition reaction.
- the block may encode the oligomer synthesis step number as well as the monomer-type information.
- protected (or unprotected) oligonudeotides containing amplification primer sites, monomer-spedfic information, and order-of- reaction information from 10 to 50 to 150 bases in length, at each step.
- oligonudeotide identifier tags assodated with each oligomer sequence.
- the associated oligonucleotides are amplified by PCR and sequenced to decode the identity of the oligomer.
- the identifier tags may be attached to chemically reactive groups (unmasked thiols or amines, for example) on the surface of a synthesis support functionalized to allow synthesis of an oligomer and attachment or synthesis of the oligonudeotide identifier tag.
- the tags could also be attached to monomers that are incorporated into a small proportion of the oligomer chains; or as caps on a small number of the oligomer chains; or to reactive sites on linkers joining the oligomer chains to the solid support.
- the solid supports will have chemically reactive groups that are proterted using two different or "orthogonal" types of protecting groups.
- the solid supports will then be exposed to a first deprotedion agent or activator, removing the first type of protecting group from, for example, the chemically reactive groups that serve as oligomer synthesis sites.
- the solid supports will then be exposed to a second activator which removes the second type of protecting group, exposing, for example, the chemically reactive groups that serve as identifier tag attachment sites.
- One or both of the activators may be in a solution that is contarted with the supports.
- the linker joining the oligomer and the solid support may have chemically reactive groups protected by the second type of protecting group. After reartion with the first monomer, the solid support bearing the linker and the "growing" oligomer will be exposed to a second activator which removes the second type of protecting group exposing the site that attaches the identifier tag directly to the linker, rather than attachment directly to the solid support.
- the method comprises: a) apportioning the solid supports among a plurality of reaction vessels; b) reacting the solid supports with a solution in each reaction vessel and treating sequentially with (1) a first activator to remove a first typ of protertive group from the solid support, (2) a first amino add or peptide to couple said amino acid or peptide to said solid support at sites where said first type of protective group has been removed; (3) a second activator to remove a second type of protective group from the solid support; and (4) a first nucieotide or oligonucleotide tag to couple said tag at sites where said second type of protective group has been removed; c) pooling the solid supports; d) apportioning the pool
- the invention can also be carried out in a mode in which there is no solid support, and the tag is attached dirertly (or through a linker) t the oligomer being synthesized.
- the size and composition of the library will be determined by the number of coupling steps and the monomers used during the synthesis. Those of skill in the art recognize that either the tag or the monomer may be coupled first, in either embodiment.
- Another possible embodiment is the use of two solid supports, such as beads, that are physically linked together, one with synthesis sites (or linkers) for the oligomer and one with attachment sites (or linkers) for the identifier tags.
- This arrangement allows the segregation of oligomers and identifier tags into discrete "zones" and permits the use of widely different chemically reactive groups and chemistries for attachment.
- the solid supports can be derivatized separately and then linked under conditions where all or nearly all of the synthesis solid supports will have a tag-attachment solid support in tow.
- the solid supports ca be of different sizes, as for example a large synthesis bead with several (or many) smaller tag-attachment beads linked.
- the first solid support will have at least one attached amino acid and the second solid support will have at least one attached nucieotide.
- the mode of linking the two beads is constrained by the chemistry of oligomer synthesis.
- the most obvious means of linking the beads is with a heterobifunctional cross-linking agent (for examples of such agents, see Pierce ImmunoTechnology Catalog and Handbook pp. E10-E18 (1991)) interacting with the dominant chemically reactive groups on each spedes of solid support.
- oligonudeotide identifier tag The choice of bases used in an oligonudeotide identifier tag is dictated by the chemistry of oligomer synthesis. For example, the use of strong acid to deprotect peptides would depurinate nudeic adds. Therefore, when standard chemistries for peptide synthesis are employed, the pyrimidines C and T could be used in a binary code. Thus, in a preferred embodiment, the identifier tag will be an oligopyrimidine sequence.
- the lability of purine nudeotides to strong add may be overcome through the use of the purine nudeoside analogs, sudi as 7-deaza- 2'-deoxyadenosine and 7-deaza-2'-deoxyguanosine (see Barr et al., BioTechniques 4:428-432 (1986), and Sdieit, Nudeotide Analogs: Synthesis and Biological Function pp. 64-65 (John Wiley and Sons, New York), both of which are herein incorporated by reference). Use of these or other analogs would permit the use of a quaternary or other, as opposed to a binary, encoding scheme.
- the oligomer sequence information is at least in part encoded in the length of the oligonudeotide.
- Each different monomer added at a given step in the oligomer synthesis may be represented by an oligonudeotide tag of unique length.
- the oligonudeotide inherently contains amplification sites, such as PCR priming sequences, characteristic of the given step-number in the oligomer synthesis.
- Determination of the oligomer composition at any given position in the sequence then involves amplifying the tag using the PCR priming sequence characteristic for that step in the synthesis and size-separating the amplification products utilizing techniques well known in the art, such as gd or capillary electrophoresis (using the tagging oligonudeotides as standards)
- This embodiment is particularly useful when one desires to make a library of compounds related to a lead sequence. One need only tag during steps in which a site being analoged is synthesized.
- oligomer sequence information can also be encoded in the sequence of bases comprising the oligonudeotide tag.
- This type of encryption is of value not only in the embodiment in which one attaches a different oligonudeotide tag at each coupling step but also in the embodiment in which one extends an oligonucleotide tag at each coupling step.
- oligonudeotides of up to about 100 bases (or somewhat longer), each having seven regions, as described below.
- Region 1 is a 3'-PCR primer site (20 to 25 bases). This site is used in conjunrtion with another PCR site (at the 5'-end of the oligonucleotide) to prime amplification by PCR. Other amplification methods may also be used.
- Region 2 is a "step-specific" DNA sequendng primer site (15-20 bases). This site is spedfic for the particular numbered step in the synthesis series. All the oligonudeotides added to all the beads at a particular step will have this sequence in common. Each numbered step will have a highly specific primer site representing that step.
- Region 3 is a spacer (20-30 bases).
- Region 5 is a step number confirmation region (4 bases plus 2 bases on either side for region distinction). Four bits in this short stretch encode the step number. This is redundant to the sequencing primer but can be used to confirm that the proper primers were used and that the right step is decoded.
- Region 6 is a repeat of the monomer identification region (8 bases). Thi region has the same information as region 4, and is used to confirm monomer identity. Installing this second monomer encoding region also increases the probability that a good sequencing "read" will be obtained.
- Region 7 is a 5'-PCR primer site (20 to 25 bases). This site serves as a site for annealing the second PCR primer for amplification of the sequence. The length o oligonucleotides with all seven of these features, some of which are optional, will commonly be between 75 and 125 bases.
- An 8 bit format can encode 256 different monomer types.
- the beads can be segregated individually by a number of means, induding: infinite dilution, micromanipulation, or preferably, fluorescence activated cell sorting (FACS), although, with respect to the present invention, FACS is more accurately "fluorescence activated oligomer or solid support sorting" (see Methods in Cell Biology, Vol. 33 (Darzynkiewicz, Z. and Crissman, H.A., eds., Academic Press); and Dangl and Herzenberg, T. Immunol. Methods 52:1-14 (1982), both incorporated herein by reference).
- FACS fluorescence activated cell sorting
- oligonudeotide tags carried by a single solid support or oligomer can be amplified in vivo, by doning, or in vitro, e.g., by PCR. If the limit of detection is on the order of 100 molecules, then at least 100 or more copies of each oligonudeotide tag on a bead would be required.
- Copies of the tag are produced, either as single stranded oligonudeotides, double-stranded nudeic adds, or mixtures of single and double-stranded nudeic adds, by any of a variety of methods, several of which are described below, and the amplified material is sequenced.
- a separate and distind oligonudeotide tag is added at eadi monomer addition step (as opposed to extending an existing tag at each step)
- tags so that each tag could be amplified separately from the other tags by appropriate choice of primer sequences.
- the sequencing reactions are performed and run on a standard sequendng gel, and the oligomer sequence is deduced from the code revealed in the resulting sequence information.
- An alternative strategy is to use common PCR primers and common sequendng primers (the sequencing primer may even overlap completely or partiall with a PCR primer site) and identify the step by hybridization to oligonudeotide probes that are complementary to each step-specific sequence in the oligonudeotides from the bead.
- a single set of sequendng reactions is performed on all of the amplified oligonucleotides from a single bead, and the reartion products are run in a single set of lanes on a gel.
- the reaction products are then transferred to a suitable hybridization membrane and hybridized to a single step-specific probe (see Maniatis al., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1982), which is incorporated herein by reference).
- Each lane set is then hybridized to one of a plurality of step-spedfic oligonucleotide probes (see “Uniplex DNA sequencing” and “Multiplex DNA sequencing,” in Plex Luminescent Kits Product Catalog, Bedfor MA, 1990, incorporated herein by reference).
- a single synthesis solid support may only comprise a few hundred copies of each oligonudeotide tag.
- These tags may be amplified, e.g., by PCR or other means well known to those skilled in the art, to provide sufficient DNA to be sequenced accurately.
- the ability to decode the oligomers depends on the number of available oligonucleotide identifier tags, the level of amplification that can be achieved from the available tags, and the accuracy of sequendng that amplified DNA. The most commonly used in vitro DNA amplification method is PCR.
- Alternate amplification methods include, for example, nudeic add sequence-based amplification (Compton, Nature 350:91-92 (1991), incorporated herein by reference) and amplified antisense RNA (Van Gelder et al.. Proc. Nat. Acad. Sci. USA 85:7652- 7656 (1988), incorporated herein by reference), and the self -sustained sequence replication system (3SR, see Guatelli et al.. Proc. Natl. Acad. Sci. USA 87: 1874-1878 (1990), incorporated herein by reference).
- nudeic add sequence-based amplification Compton, Nature 350:91-92 (1991), incorporated herein by reference
- amplified antisense RNA Van Gelder et al.. Proc. Nat. Acad. Sci. USA 85:7652- 7656 (1988), incorporated herein by reference
- 3SR self -sustained sequence replication system
- PCR product contamination caused by the product of one PCR reaction contaminating a subsequent PCR reaction mixture designed to amplify other tags having the same PCR primer binding sites.
- a specific example of this strategy, for which commerdal kits are sold by PECI and life Technologies, is to introduce dUMP into the product. Treating each new PCR reaction with uracil-N-glycosidase degrades any dU-containing DNA present, preventing amplification of the contaminant.
- the template DNA which contains no dU (only dT) is not affected. Of course, the glycosidase is removed or inactivated before amplification is begun.
- tags described above for peptide synthesis have the unusual characteristic of containing only pyrimidines. This means that the uracil glycosidase strategy (Perkin Elmer Cetus Instruments (PECI) Catalog, Alameda (1991), incorporated herein by reference) will work on only half of the strands produced— those containing T's (or U's).
- PECI Perkin Elmer Cetus Instruments
- One such means is asymmetric PCR, where an excess of one of the primers is used to amplify one strand to a level 10 to 100-fold higher than the other (see, for example, U.S. Patent No. 5,066,584, incorporated herein by reference).
- Another means of providing a single stranded template is to by biotinylate one of the primers and purify or remove the resulting strand by adsorption to immobilized streptavidin (Pierce Immunotechnology Catalog and Handbook. 1991, incorporated herein by reference).
- RNA transcripts (representing only one of the strands) from an RNA polymerase promoter and sequencing the transcripts with reverse transcriptase (Sommer et al., Chapter 25, In PCR Protocols: A Guide to Methods and Applications, supra, incorporated herein by reference). If the tags are composed of only pyrimidine nudeotides, then all purine strands can be eliminated by acid /base treatment, leaving the pyrimidine strand for sequencing.
- DNA sequencing enzymes which may be employed in the present invention indude Tag DNA polymerase, E. coli DNA polymerase I (or the Klenow fragment), T7 polymerase, SequenaseTM and Sequenase flTM (Modified T7 DNA polymerases), Bst DNA polymerase, and reverse transcriptase (from AMV, MMLV, RSV, etc., see USB Enzymes for DNA Sequencing, U.S. Biochemical Corp, 1991,
- sequence of an oligonudeotide tag may also be identified by a high fidelity DNA hybridization technique.
- very large scale immobilized polymer synthesis with oligonucleotides may be useful (see PCT patent publication Nos. 92/10587 and 92/10588, each of which is incorporated herein by reference).
- the tagged synthetic oligomer libraries of the present invention will have a wide variety uses.
- these libraries can be used in determining peptide and nucleic add sequences that bind to proteins, finding sequence-specific binding drugs, identifying epitopes recognized by antibodies, and evaluating a variety of drugs for dinical and diagnostic applications, as well as combinations of the above.
- Peptides as short as about five amino acids long might be useful in receptor-binding studies, for example.
- Synthetic oligomers displayed on small beads can be screened for the ability to bind to a receptor.
- the receptor may be contacted with the library of synthetic oligomers, forming a bound member between an receptor and the oligomer able to bind the receptor. The bound member may then be identified.
- the receptor may be an immunoglobulin.
- the techniques for selection of individual beads displaying ligands on their surface are analogous to FACS methods for cloning mammalian cells expressing cell surface antigens or receptors. Therefore, methods for selecting and sorting beads will be readily apparent to those skilled in the art of cell sorting.
- a receptor can be labelled with a fluorescent tag and then incubated with the mixture of beads displaying ohgomers. After washing away unbound or non-spe ⁇ fically bound receptors, one can then use FACS to sort the beads and to identify and isolate physically individual beads showing high fluorescence.
- affinity adsorption techniques can be employed in conduction with the libraries of the invention.
- the mixture of beads can be exposed to a surface on which a receptor has been immobilized (see PCT patent publication No. 91/07087, incorporated herein by reference). After washing to remove unbound beads, one can then elute beads bound to the surface using conditions that reduce the avidity of the oligomer/receptor interaction (low pH, for example). The process of affinity adsorption can be repeated with the eluted beads, if desirable.
- individual beads are physically separated, for example, by limited dilution, by FACS, or by methods similar to those in which cells are incubated with a receptor coupled to small superparamagnetic beads and then cells expressing a ligand for the receptor are extracted using a high power magnet (see Miltenyi et al confuse Cytometery 11:231-238 (1990), incorporated herein by reference). Magnetically selected cells can be further analyzed and sorted using FACS. Radionudeotides may also serve to labd a receptor.
- the present invention can be used to generate libraries of soluble tagged oligomers, which can be used with a variety of screening methods.
- the oligomer library can be synthesized on beads with an identifying tag encoding the oligomer sequence.
- the microscopic beads are placed in individual compartments or wells that have been "nanofabricated" in a silicon or other suitable surface.
- the ohgomers are deaved from the beads and remain contained within the compartment along with the bead and the attached identifier tag(s).
- the bottom surface is coated with the receptor, and after the addition of binding buffer and a known ligand for that receptor that is fluorescently labelled, one effectively has a solution phase competition assay for novel ligands for the receptor.
- the binding of the fluorescently labelled ligand to the receptor is estimated by confoc imaging of the monolayer of immobilized receptor. Wells with decreased fluorescence on the receptor surface indicate that the released oligomer competes wit the labelled ligand.
- the beads or the tag in wells showing competition are recovered and the oligonudeotide tag is amplified and sequenced to reveal the sequence of the oligomer.
- the beads are loaded in the wells by dispersing them in a volume of loading buffer suffident to produce an average of one bead per well.
- the solution of beads is placed in a reservoir above the wells, and the beads are allowed to settle into the wells. Cleavage of the oligomers from the beads may be accomplished using chemical or thermal systems, but a photodeavable syste is preferred.
- Recovery of identifier-tagged beads from positive wells may be effectuated by a micromanipulator plucking out individual beads.
- a preferred mode involves the use of beads that have been previously labelled with a fluorescent tag. A laser of the appropriate wavelength is then used to bleach the resident beads in only the positive wells. All the beads are then removed en masse and sorted by FACS to identify the bleached positives. The assodated tags may then b amplified and decoded.
- the oligomer and tag may be synthesized attached to a common linker, which, in turn, is bound to the solid support.
- an immobilized receptor such as a receptor bound to a bead or a receptor immobilized on one surface of the well, can be screened in a competition assay with the oligomer and a fluorescently labeled ligand.
- FACS Fluorescence Activated Cell Sorting
- soluble tagged oligomers produced either by cleavage of the linked oligomer and tag from the solid support as described above, or synthesized by the VLSIPSTM method described above, or synthesized in solution without a solid support, are incubated with an immobilized receptor. After wash step, the bound, tagged oligomers are released from the receptor by, e.g., acid treatment. The tags of the bound oligomers are amplified and decoded.
- the coupling steps for some of the monomer sets require a lengthy incubation time, and a system for performing many monomer additions in parallel is desirable. This can be accomplished with an automated instrument able to perform 50 to 100 parallel reactions (channels). Such a instrument is capable of distributing the reaction mixture or slurry of synthesis solid supports, under programmable control, to the various channels for pooling, mixing, and redistribution.
- Beads were vortexed with a 20% solution of piperidine in DMF and the release of the Fmoc-piperidine adduct quantitated by monitoring the absorbance spectrum of the supernatant at 302 nm ( e 302 - 7800 M- cm- 1). An estimate of the degree of substitution of 10 ⁇ moles of amino groups /g beads was thus obtained. Finally, the beads were washed with ethanol (5x) and methylene chloride (2x) and then dried at 85 degrees C for 12 hours.
- Boc-Gly-L-Phe-L-Leu-OH 44 mg, 0.1 mmol
- benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate 44 mg, 0.1 mmol
- 1-hydroxybenzotriazole hydrate 14 mg, 0.104 mmol
- Diisopropylethylamine (20 ⁇ l, 0.115 mmol) was then added and 0.65 mL of this solution was immediately transferred to a microcentrifuge tube containing 80 mg of amino derivatized glass beads.
- the sealed tube was vortexed for 3.5 hours, and the beads were then pelleted and washed with DMF (3x) and methylene chloride (2x). The beads were then deprotected with a 50% solution of trifluoroacetic add in methylene chloride for 30 min., washed with methylene chloride (2x), ethanol (2x), and methylene chloride (2x), and dried at 55 degrees C for 1 hour.
- Fmoc-glydne pentafluorophenyl ester (46 mg, 0.1 mmol) was dissolved in dry DMF (1 mL) containing diisopropylethylamine (17 ⁇ l, 0.1 mmol). About 0.65 mL of this solution was added to 20 mg of Gly-L -Phe-L-Leu beads in a microcentrifuge tube, and the tube was vortexed for 3 hours. The beads were pelleted and washed with DMF (4x) and methylene chloride (2x). Deprotection was effected by treatment with a 20% solution of piperidine in DMF for 30 min. The beads were washed with DMF (2x), ethanol (2x), and methylene chloride (2x) and dried at 60 degrees C for 4 hours.
- Fmoc-L-proline pentafluorophenyl ester 50 mg, 0.1 mmol was dissolved in dry DMF (1 mL) containing diisopropylethylamine (17 ⁇ l, 0.1 mmol). About 0.65 mL of this solution was added to 20 mg of Gly-L -Phe-L-Leu beads in a microcentrifuge tube, and the tube was vortexed for 3 hours. The beads were pelleted and washed with DMF (4x) and methylene chloride (2x). Deprotection was effected by treatment with a 20% solution of piperidine in DMF for 30 min. The beads were washed with DMF (2x), ethanol (2x), and methylene chloride (2x) and dried at 60 degrees C for 4 hours.
- the beads were pelleted, and to one portion was added a solution containing Fmoc-O-tert-butyl-L-tyrosine pentafluorophenyl ester (59 mg, 95 ⁇ mol), N-hydroxysuccinimidobiotin (1.7 mg, 5 ⁇ mol) and dusopropylethylamine (17 ⁇ l, 100 ⁇ mol) in dry DMF (1 L). After vortexing for 3 hours the beads were washed with distilled water (2x), ethanol (2x), methylene chloride (2x) and DMF (lx).
- Fmoc deprotection was effected by treatment with a 20% solution of piperidine in DMF for 30 min., and tert-butyl side chain protecting groups were removed by treatment with 25% trifluoroacetic acid in methylene d ⁇ oride for 3 min.
- the pelleted beads were washed with methylene chloride (2x), ethanol (2x), and TBS (lx).
- Biotinylated L-tyrosine beads from (G) above were suspended in TBS (0.5 mL) and treated with 10 ⁇ l of R-phycoerythrin-avidin conjugate (Molecular Probes) for 30 min. Pelleted beads were washed with TBS (5x).
- Fmoc deprotection was effected by treatment with a 20% solution of piperidine in DMF for 30 min., and by way of control, the beads were treated with 25% trifluoroacetic acid in methylene chloride for 30 min. The pelleted beads were washed with methylene chloride (2x), ethanol (2x), and TBS (lx).
- Biotinylated L-proline beads from (i) above are suspended in TBS (0.5 mL) and treated with 20 ⁇ l Tri-Color: sfreptavidin conjugate (Caltag Labs) for 30 min.
- a mixture of beads containing either YGGFL, YPGFL, PGGFL, or PPGFL and their respective tags are added in phosphate buffered saline (PBS) containing monodonal antibody 3E7 that has been previously conjugated to colloidal superparamagnetic microbeads (Miltenyi Biotec, West Germany). After a 16 hr incubation at 4 degrees C, beads which bind the 3E7 antibody are selected using a high strength magnet. The selected beads are then analyzed by flow cytometry. Analysis of the selected beads reveals that they contain both fluorescein and R-phycoery thrin, indicating that only beads displaying the peptide YGGFL are selected by the 3E7 antibody.
- PBS phosphate buffered saline
- EXAMPLE 2 SYNTHESIS ON GLASS BEADS OF 4 PENTAPEPTTDES TAGGED WITH
- the oligonucleotide identifier tags (_)-(IV) have the sequences shown below.
- the regions complementary to the 5' and 3' PCR primers are underlined.
- the regions complementary to the step-specific sequencing primers are shown in lower case: there are two steps in this example.
- the monomer encoding region is shown in bold type: CT7 encodes Gly, TCT6 encodes L-Pro, and TTCT5 encodes L-Tyr in this case.
- Oligos (I)-(rV) are synthesized on an ABI PCR-mate synthesizer using commercially available (Sigma) DMT-O-Me phosphoramidites.
- the N4-amino group of cytidine is protected as the benzoyl derivative.
- the 5' terminal (Bl) and penultimate (B2) phosphoramidites are respectively N-MMT-C6-AminoModifer (Clonetech) and Biotin Phosphoramidite (Glen Research) for each oligonucleotide.
- the fully protected O-methyl phosphotriester oligomers are cleaved from the CPG support by treatment with concentrated NH4OH at 25 degrees C for 1 hour.
- the crude products are purified by affinity chromatography on a monomeric avidin-agarose column (Pierce), and the full-length material is eluted with 2 mM biotin.
- MMT group is removed by treatment with 80% acetic add for 1 hour at 25 degrees C, and the solution is evaporated to dryness.
- the products are dissolved in PBS, pH 8.0, and treated with a 50-fold excess of suc ⁇ nimidyl 4-(p-maleimidophenyl) butyrate (Pierce) in DMF for 30 min.
- the modified, protected oligonucleotides are desalted by RP-HPLC, lyophilized and stored under nitrogen.
- the primers used for PCR and sequendng are prepared in the normal fashion and are shown below:
- Step #1 Sequendng Primer 5'-AGAGAGGGGAAAGGAAGA-3" (SEQ ID NO:6)
- Step #2 Sequencing Primer 5'-AGGAAAGGAGAGAAAGGG-3' (SEQ ID NO:7)
- the beads are quickly washed with ice-cold methanol (2x), pelleted, and then reacted for 20 min with 100 ⁇ l of a 0.1 mM solution of oligo (I) in methanol. After washing with methanol (2x) and then with DMF (2x), the beads are deprotected for 20 min. with 20% piperidine in DMF. Finally, the beads are washed with DMF (2x), methanol (2x), and then methylene chloride (2x) and dried at 45 degrees C for 1 hour.
- Beads from (b) and (c) are pooled and divided into two equal portions. One portion is treated as in (b), substituting Fmoc(OtBu)-L-Tyr-OH and Oligo (HI) as appropriate.
- the second pool is treated as before, substituting Fmoc-L-Pro-OH and Oligo (IV) as appropriate.
- Beads from (d) and (e) are pooled, and the phosphate, amino acid side- chain, and nudeotide exocyclic amino protecting groups are removed as follows.
- a one hour treatment with a 1:2:2 mixture of thiophenol: triethylamine: p-dioxane is followed by washing the beads with methanol (2x) and then methylene chloride (2x), and then the beads are treated for 5 min. with 95:5 trifluoroacetic add: ethanedithiol.
- After a wash with methanol (3x) the beads are treated at 55 degrees C with 1:1 ethylenediamine: ethanol for 1 hour and then washed first with ethanol (2x) and then with PBS (2x).
- each bead carries two distinct 113 bp oligonucleotide sequences encoding the identities of both the first and second amino acids of the peptide on that bead.
- the 2X buffer contains: 100 mM KC1; 20 mM Tris-Cl, pH 8.4, 20 degrees C; 6 mM MgCl2; 0.4 mM dNTP's; 1 ⁇ M of 5' PCR primer; 1 ⁇ M of 3' PCR primer; and 100 units /ml Taq DNA polymerase.
- the sample is covered with 50 ⁇ l of mineral oil and transferred to an automated thermal cycler.
- the samples are heat denatured at 95 degrees C for 2 min., and then cycled 35 times through 3 steps: 95 degrees C/30 sec, 60 degrees C/l min., 72 degrees C/l min., which steps are followed by an incubation at 72 degrees C for an additional 5 min. and then the tubes are cooled and held at 15 degrees C until ready for processing on sfreptavidin beads.
- the mixture is heated to 95 degrees C to denature the strands, and the biotinylated purine strand and excess 3' PCR primer are removed by addition of streptavidin-coa ted beads.
- the tubes are centrifuged at 12K rpm for 5 min. The supernatant is used in the sequencing reactions, as described below.
- the amplified oligonucleotides from individual bead isolates are sequenced in a pair of reactions (using ddA or ddG as chain terminators) with either the Step #l-spedfic or the Step #2-specific sequendng primers.
- DNA from the amplification supernatant above The samples are heated for 2 minutes at 65 degrees C and allowed to cool slowly to room temperature (approx. 10 minutes).
- the labeling reaction is performed as follows. SequenaseTM (v2.0) is diluted 1 : 20 with TE (10 mM Tris HCl, pH 7.5; and 1 mM EDTA), and a labeling cocktail containing a 2 : 3.5 ratio of diluted enzyme to labeling mix (i.e., a 4 : 2 : 1 mixture of 150 nM dGTP, 0.1 M dithiothreitol, alpha-35s-dATP, >1000 Ci/mmol) is prepared. About 5.5 ⁇ l of the cocktail are incubated with 10 ⁇ l of annealed template/primer (from (i)) at 25 degrees C for 5 min. The termination reactions are performed as follows.
- 6 ⁇ l of labeling reaction mixture are added to 5 ⁇ l of each of the appropriate ddXTP termination reaction mixes (i.e., 80 ⁇ M dGTP, 80 ⁇ M dATP, 50 mM NaCl, and 8 ⁇ M ddGTP or 8 ⁇ M ddATP).
- the appropriate ddXTP termination reaction mixes i.e., 80 ⁇ M dGTP, 80 ⁇ M dATP, 50 mM NaCl, and 8 ⁇ M ddGTP or 8 ⁇ M ddATP.
- Stop Solution 95% formamide, 20 mM EDTA, 0.05% bromophenol blue, and 0.05% xylene cyanol
- the sequencing gel is comprised of 6% total acrylamide (19:1 acrylamide/bis), 0.09 M Tris base, 0.09 M boric add, 1 mM EDTA, and 7 M urea.
- the gel is polymerized by addition of 1.9 ⁇ l of 25% ammonium persulfate per mL and 0.72 ⁇ l of TEMED per mL of above gel solution.
- the gel is allowed to polymerize at least one hour and is prerun at least 20 minutes prior to sample loading. Gel plates are then maintained between 40 and 50 degrees C prior to and during the run.
- Reactions are heated to 85-95 degrees C for 2 minutes prior to loading, and the gel is run until the bromophenol blue dye reaches the bottom of the gel.
- the sequences of interest run between the bromophenol and xylene cyanol markers.
- the information required to identify the sequence of monomers in the oligomers attached to the bead is contained in the DNA sequence information.
- the beads were then pelleted with a microcentrifuge, the liquid supernatant decanted, and the remaining bead pellet successively washed (by vortexing, pelleting, and decanting: a process referred to as "washed") with water (3 x 1 mL) and dimethylformamide (DMF, 3 x 1 mL).
- HBTU 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate
- HOBT 1-hydroxybenzotriazole
- DMF 0.5 mL
- dichloromethane 0.5 mL
- the compound 4,9-dioxa-l,12-dodecanediamine (20 ⁇ l, 0.10 mmol) was then added, and the reaction was vortexed for 30 minutes.
- the reaction was then diluted with DMF (1 mL), the beads were pelleted, and the supernatant decanted.
- the pellet was treated with 9:1 DMF/water (1.0 mL) and vortexed for 15 minutes.
- the beads were then pelleted, the supernatant decanted, and the beads washed with DMF (3 x 1.0 mL).
- PCR priming site of 20-25 nucleotides is assembled as follows. Note that all reagents used are anhydrous, and reactions occur under an atmosphere of dry argon. About 10 mg of the beads are subjected to an eight-step reaction sequence to couple a protected phosphoramidite.
- the reaction steps are: (1) beads are washed for 0.5 minutes with acetonitrile (MeCN); (2) DMT groups are removed with 3% trichloroacetic add in CH2CI2 for 1.5 minute; (3) beads are washed with MeCN for 3 minutes; (4) beads are treated with 0.1 M phosphoramidite (I, ⁇ , IE, or IV) in MeCN containing either 0.5 M (4-nitrophenyl) tetrazole or 0.5 M pyridinium hydrochloride and 1.0 M imidazole for 2 min.; (5) beads are washed with MeCN for 0.5 minutes; (6) beads are capped with a mixture of Ac2 ⁇ /2,6-lutidine/THF (1:1:8) containing 5% DMAP; (7) beads are oxidized with 1 M tBuOH in CH2CI2 for 0.8 minutes; and (8) beads are washed for 0.5 minutes with MeCN. Steps one through eight are repeated from one to 25 times to assemble a PCR priming site of
- Figure 8 To couple an amino add (or peptide), the Fmoc group is first removed from the beads by treatment with 30% piperidine in DMF for 60 min. The beads are washed 3 times with DMF. The beads are then treated with a solution containing the appropriate amino add (0.1 M), HBTU (0.1 M), HOBt (0.1 M), and DIEA (0.1 M) in 9:1 CH2 ⁇ 2:DMF for 30 min. The coupling is then repeated with fresh reagents for a further 30 min. and the beads are washed with DMF (3x) and then with MeCN (3x).
- a "codon" of about 3 to 5 nudeotides uniquely representing the identity of the first amino add is then built at the 5' end of the oligonudeotide chain using the 8-step coupling cyde in procedure (d) above.
- the 8-step coupling cyde of procedure (d) is used to build a 20-25 nudeotide PCR priming site on the 5' terminus of the oligonucleotide chains.
- the fully assembled peptide and oligonudeotide drains are deprotected as follows.
- the amino-terminal Fmoc groups are removed by treatment with 30% piperidine in DMF and then a wash with THF (3x)_
- THF 3x
- the beads are treated with a THF solution containing tris(dibenzylideneacetone) dipalladium-chloroform complex (0.02 M), triphenylphosphine (0.2 M), and 1:1 n-butylamine /formic acid (1.2 M) at 50°C for 30 min. and the pelleted beads are washed with THF.
- the beads are washed with 0.1 M aqueous sodium N,N-diethyldithiocarbamate and then water to remove traces of palladium.
- the amino acid protecting groups are then removed by treatment with 95:5 TFA/water for 30 min.
- "Scavenger" reagents such as 1,2-ethanedithiol and thioanisole may also be included in this acidic deprotection medium (e.g., 2% of each by volume).
- the fully deprotected beads are washed with aqueous buffer and are ready for interaction with a biological receptor.
- two populations of amine derivatized beads were labeled with oligonucleotides possessing base sequences uniquely characteristic of each bead population.
- the population labeled with an oligonucleotde 95 bases in length (95 mer) was subsequently coupled to the peptide YGGFL.
- the population of beads labeled with an oligonucleotide 110 bases in length (110 mer) was coupled to phenyalanine (F).
- the beads were then mixed in the ratio of twenty F/110 mer beads for each YGGFL/ 95 mer bead and stained with a fluorescently labeled antibody 3E7 that binds the peptide YGGFL with high affinity.
- the oligonudeotides used in this experiment are the two tags, two PCR primers, and one sequencing primer. The same PCR and sequencing primers were used for the two tags. The two tags differ in their sequence and length. Both tags were composed of the bases 7-deazaA, C, and T.
- the 95 mer tag has the sequence: CCA CTC ACT ACC ACT CTA CTA TAA CCA CCC CTT CCT ATT CCA AAA TTA
- the 110 mer tag has the sequence:
- the underlined sequences represent PCR primer binding sites: the sense primer is at the 5'-end, and the anti-sense primer is at the 3'-end. Also, for each target the small case sequence represents the sequencing primer binding site.
- Beads were purchased from Bang's Laboratories (979 Keystone Way, Carmel, IN 46032) and are composed of carboxylated polystyrene (4.5 ⁇ m average diameter). These beads were subjected to diamine derivitization by the process described below.
- Beads (200 mg) were treated with 1.0 mL of 1 N HCl and vortexed 15 min. The beads were pelleted, decanted, and washed with three times (3x) with 1.0 mL of water each wash and then washed 3x with 1.0 mL of DMF each wash. To the washed pellet was added 2-(lH-benzotriazol-l-yl)-l,l,3 -tetramethyluronium hexafluorophosphate (HBTU; 38 mg, 0.1 mmole), 1-hydroxybenzotriazole hydrate
- oligonucleotide Attachment Two different target oligonudeotides were employed in this experiment: a 95 mer and a 110 mer. These oligonudeotides were composed of the bases cytidine, thymidine, and 7-deaza adenosine. The oligonudeotides were synthesized with a primary amino group on the 5'-terminus (5'-amino modifier C- 12, Glen Research). Lyophilized oligonudeotide (600 pmole) was dissolved in 5 ⁇ L of 0.5 M Na-phosphate, pH 7.7, and the solution was treated with 10 ⁇ L of 0.2 M disuccinimydylsuberate (DSS).
- DSS disuccinimydylsuberate
- the reaction proceeded 10 min., and then 85 ⁇ L of ice-cold water were added. Unreacted DSS was removed by centrifugation. The supernatant was passed through a G25 spin column that had been equilibrated with water. The eluant was immediately frozen and lyophilized to isolate the 5'-N- hydroxysuccinamide ester of the oligonucleotide. This activated oligonudeotide was dissolved in 50 ⁇ L of 0.1 M Na- phosphate, pH 7.5, which contained 0.1 mg/mL of sonicated salmon sperm DNA. This solution was added to 10 mg of diamine derivitized beads.
- the beads were washed 2x with 0.4 mL of 0.1 M Na-phosphate, pH 7.5, each wash, and then washed 2x with 0.4 mL of 0.1 N NaOH. Finally, the beads were washed with 3x with 0.4 mL of pH 7.5 buffer.
- the beads coupled with the 95 mer and YGGFL were mixed with the beads that were coupled to the 110 mer and F in the ratio of 1:20.
- 0.1 mg of 95 mer /YGGFL beads (2 million beads) were mixed with 2.0 mg of the 110 mer/Phe beads (40 million beads).
- the mixture was suspended in blocking buffer (PBS, 1% BSA, and 0.05% Tween-20) and incubated at room temperature for 1 hr.
- the beads were next pelleted by centrifugation and resuspended in a solution of an FTTC- labeled monodonal antibody 3E7 that binds the peptide YGGFL (1 ⁇ g/mL).
- the suspension was incubated 0.5 hr on ice and then centrifuged to isolate the bead pellet.
- the beads were resuspended in PBS for delivery into the fluorescence activated cell sorting (FACS) instrument (Becton Dickinson FACSORT Plus). Beads that had bound to the fluorescently labeled antibody were identified by their acquired fluorescence, and fluorescent beads were isolated by sorting into PCR tubes. One, ten, or one hundred fluorescent beads were sorted into each PCR tube. In an analogous manner, non-fluorescent beads were also sorted into PCR tubes.
- FACS fluorescence activated cell sorting
- PCR buffer (20 mM Tris-HCl, pH 8.7; 10 mM KCL; 10 mM (NH4)2S ⁇ 4; 2 mM MgCl2; 0.1% Triton X-100; 0.14 mg/mL BSA; 200 ⁇ m dATP; 200 ⁇ m dGTP; 200 ⁇ m dCTP; 200 ⁇ m dTTP; 2 ⁇ m primer #1; 2 ⁇ m primer #2; and 0.5 units of Pfu DNA polymerase). Reactions were subjected to 40 cydes of 95°C for 0.5 min., 55°C for 1 min., and 72°C for 1 min.
- FIG. 9 This example is illustrated schematically in Figure 9. Briefly, a single population of amine derivatized beads (prepared as described in Example 4) was coupled to glycine. The population was then divided into two equal parts, and each part was labeled with a characteristic oligonudeotide that would uniquely identify the bead subpopulation. The subpopulation that had been labeled with an oligonudeotde 95 bases in length (the 95 mer described in Example 4) was subsequently coupled to the peptide YGGFL. The population of beads that had been labeled with an oligonucleotide 110 bases in length (the 110 mer described in Example 4) was coupled to the peptide FLFLF.
- oligonucleotides Two different target oligonucleotides were employed in this experiment: the 95 mer and 110 mer described in Example 4. Half of the bead sample described above (25 mg) was labeled with the 95 mer, and the other half was labeled with the 110 mer.
- These oligonucleotides are composed of 2'-deoxy-cytidine, thymidine, and 2'-deoxy-7-deaza-adenosine.
- the oligonudeotides were synthesized with a primary amino group on the 5'-terminus (MMT-C12-Aminomodifier, Clonetech Laboratories, Inc.).
- Lyophilized oligonudeotide (1.5 nmole) was dissolved in 10 ⁇ L of 0.5 M Na-phosphate, pH 7.7, and the solution was then treated with 20 ⁇ L of 0.2 M disuccinimydylsuberate (DSS). The reaction proceeded 10 min., and then, 70 ⁇ L of ice-cold water were added. Unreacted DSS was removed by centrifugation. The supernatant was passed through a G-25 spin column that had been equilibrated with water. The eluant was immediately frozen and lyophilized to isolate the 5'-N-hydroxysucdnamide ester of the oligonucleotide.
- DSS disuccinimydylsuberate
- This activated oligonucleotide was dissolved in 100 ⁇ L of 0.1 M Na-phosphate, pH 7.5, which contained 0.1 mg/mL of sonicated salmon sperm DNA. This solution was added to 25 mg of glycine-coupled beads. After vortex treatment for 3 hr., the beads were washed twice with 0.4 mL of 0.1 M Na-phosphate, pH 7.5, and twice with 0.4 L of 0.1 N NaOH. Finally, the beads were washed three times with 0.4 mL of pH 7.5 buffer.
- HBTU 0.02 mmole
- HOBT 0.02 mmole
- DIEA 0.06 mmole
- the solution was diluted ten-fold in 10% DMF in methylene chloride. An aliquot of this solution (0.345 mL) was added to the glycine-coupled and oligonudeotide-labeled beads (25 mg).
- the solution containing Boc-YGGFL was added to beads labeled with the 95 mer, and the solution containing Boc-FLFLF was added to beads labeled with the 110 mer.
- the reaction mixtures were vortexed 30 min. and then diluted with DMF, centrifuged, decanted, and the bead pellets washed three times with 1.0 mL of THF.
- the Boc protecting groups were removed by treating the beads with 0.4 mL of 95% trifluoroacetic add for 10 min.
- the deprotection reaction was then diluted with THF, centrifuged, decanted, and the beads washed three times with 1.0 mL of DMF. Finally, the beads were washed three times with 0.5 mL of 0.1 M Na-phosphate, pH 7.5, and stored as a slurry (10 mg/mL).
- the beads coupled to the 110 mer and FLFLF were mixed with the beads that were coupled to the 95 mer and YGGFL in the ratio of 20:1.
- 0.1 mg of 95 mer/ YGGFL beads (2 million beads) were mixed with 2.0 mg of the 110 mer /FLFLF beads (40 million beads).
- the mixture was suspended in blocking buffer (PBS, 1% BSA, 0.05% Tween-20) and incubated at room temperature for 1 hr.
- the beads were next pelleted by centrifugation and resuspended in a solution of an FTTC- labeled monodonal antibody (3E7) that recognizes the peptide sequence YGGFL (1 ⁇ g/mL).
- the suspension was incubated 0.5 hr. on ice and then centrifuged to isolate the bead pellet.
- the beads were resuspended in PBS for delivery into the fluorescence activated cell sorting (FACS) instrument (Becton Dickinson FACSORT Plus). Beads that had bound to the fluorescently labeled antibody were identified by their acquired fluorescence (see Figure 10), and homogeneous samples of either fluorescent or non-fluorescent beads were isolated by sorting into PCR tubes. One, ten, or one hundred beads of each type were sorted into each PCR tube.
- FACS fluorescence activated cell sorting
- PCR mix (20 mM Tris-HCl, pH 8.7, 10 mM KCL, 10 mM (NH4)2S ⁇ 4, 2 mM MgC_2, 0.1% Triton X-100, 0.14 mg/mL BSA, 200 ⁇ M dATP, 200 ⁇ M dGTP, 200 ⁇ M dCTP, 200 ⁇ M dTTP, 2 ⁇ M of each primer (as described in Example 4), and 0.5 units of Pfu DNA polymerase). Reactions were subjected to 40 cycles of 95°C for 0.5 min., 55°C for 1 min., and 72°C for 1 min.
- MOLECULE TYPE cDNA
- cDNA SEQUENCE DESCRIPTION: SEQ ID NO:5: GGAAAGAAGA GAGAGAGGAG AGG 23
- MOLECULE TYPE cDNA
- SEQUENCE DESCRIPTION SEQ ID NO:6: AGAGAGGGGA AAGGAAGA 1
- MOLECULE TYPE cDNA
- xi SEQUENCE DESCRIPTION: SEQ ID NO:7: AGGAAAGGAG AGAAAGGG
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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JP50558793A JP2001524926A (en) | 1991-09-18 | 1992-09-16 | Method for synthesizing a heterogeneous library of oligomers |
AU26619/92A AU669489B2 (en) | 1991-09-18 | 1992-09-16 | Method of synthesizing diverse collections of oligomers |
EP92920422A EP0604552B1 (en) | 1991-09-18 | 1992-09-16 | Method of synthesizing diverse collections of oligomers |
DE69217497T DE69217497T2 (en) | 1991-09-18 | 1992-09-16 | METHOD FOR SYNTHESISING THE DIFFERENT COLLECTIONS OF OLIGOMERS |
GR970400818T GR3023156T3 (en) | 1991-09-18 | 1997-04-15 | Method of synthesizing diverse collections of oligomers. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US76252291A | 1991-09-18 | 1991-09-18 | |
US762,522 | 1991-09-18 |
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WO1993006121A1 true WO1993006121A1 (en) | 1993-04-01 |
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PCT/US1992/007815 WO1993006121A1 (en) | 1991-09-18 | 1992-09-16 | Method of synthesizing diverse collections of oligomers |
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US (7) | US5770358A (en) |
EP (2) | EP0604552B1 (en) |
JP (1) | JP2001524926A (en) |
AT (1) | ATE148889T1 (en) |
AU (1) | AU669489B2 (en) |
CA (1) | CA2118806A1 (en) |
DE (1) | DE69217497T2 (en) |
DK (1) | DK0604552T3 (en) |
ES (1) | ES2097925T3 (en) |
GR (1) | GR3023156T3 (en) |
WO (1) | WO1993006121A1 (en) |
Cited By (241)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995003315A2 (en) * | 1993-07-21 | 1995-02-02 | Oxford Glycosystems Ltd | Saccharides, their synthesis and use |
WO1995004160A1 (en) * | 1993-07-30 | 1995-02-09 | Isis Innovation Limited | Tag reagent and assay method |
EP0639276A1 (en) * | 1992-04-29 | 1995-02-22 | Affymax Technologies N.V. | Factorial chemical libraries |
EP0643778A1 (en) * | 1992-03-30 | 1995-03-22 | The Scripps Research Institute | Encoded combinatorial chemical libraries |
WO1995016209A1 (en) * | 1993-12-09 | 1995-06-15 | Ciba-Geigy Ag | Process for the production of combinatorial compound libraries |
EP0659188A1 (en) * | 1992-09-11 | 1995-06-28 | Affymax Technologies N.V. | Methods for the synthesis of phosphonate esters |
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WO1995021850A1 (en) * | 1994-02-09 | 1995-08-17 | Martek Biosciences Corporation | Generation and screening of synthetic drug libraries |
WO1995024186A1 (en) * | 1994-03-11 | 1995-09-14 | Pharmacopeia, Inc. | Sulfonamide derivatives and their use |
EP0675873A1 (en) * | 1992-12-11 | 1995-10-11 | Chiron Corporation | Synthesis of encoded polymers |
WO1996003418A1 (en) * | 1994-07-26 | 1996-02-08 | The Scripps Research Institute | Soluble combinatorial libraries |
US5503805A (en) * | 1993-11-02 | 1996-04-02 | Affymax Technologies N.V. | Apparatus and method for parallel coupling reactions |
WO1996012039A1 (en) * | 1994-10-13 | 1996-04-25 | Lynx Therapeutics, Inc. | Massively parallel sequencing of sorted polynucleotides |
WO1996012014A1 (en) * | 1994-10-13 | 1996-04-25 | Lynx Therapeutics, Inc. | Molecular tagging system |
GB2295152A (en) * | 1994-11-18 | 1996-05-22 | Pfizer Ltd | Preparation of a library of compounds by solid-phase synthesis |
US5525734A (en) * | 1994-06-22 | 1996-06-11 | Affymax Technologies N.V. | Methods for synthesizing diverse collections of pyrrolidine compounds |
US5525735A (en) * | 1994-06-22 | 1996-06-11 | Affymax Technologies Nv | Methods for synthesizing diverse collections of pyrrolidine compounds |
WO1996024061A1 (en) * | 1995-02-02 | 1996-08-08 | Ontogen Corporation | Methods and apparatus for synthesizing labeled combinatorial chemical libraries |
US5565324A (en) * | 1992-10-01 | 1996-10-15 | The Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
US5585069A (en) * | 1994-11-10 | 1996-12-17 | David Sarnoff Research Center, Inc. | Partitioned microelectronic and fluidic device array for clinical diagnostics and chemical synthesis |
WO1997003931A1 (en) * | 1995-07-22 | 1997-02-06 | Zeneca Limited | Intrinsically labelled solid support |
WO1997012680A2 (en) * | 1995-10-03 | 1997-04-10 | Irori | Matrices with memories, sensors with memories and uses thereof |
WO1997015390A1 (en) * | 1995-10-26 | 1997-05-01 | University Of Hertfordshire | Coded particles for process sequence tracking in combinatorial compound library preparation |
US5649576A (en) * | 1996-02-26 | 1997-07-22 | Pharmacopeia, Inc. | Partitioning device |
DE19609272A1 (en) * | 1996-02-27 | 1997-08-28 | Schering Ag | New 2,6-di:substituted quinoline derivatives |
WO1997049653A2 (en) * | 1996-06-24 | 1997-12-31 | Irori | Solid phase tyrphostin library linked to matrices with memories |
AU686186B2 (en) * | 1993-05-27 | 1998-02-05 | Aventisub Ii Inc. | Topologically segregated, encoded solid phase libraries |
US5721099A (en) * | 1992-10-01 | 1998-02-24 | Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
WO1998022487A1 (en) * | 1996-11-15 | 1998-05-28 | Synsorb Biotech, Inc. | Combinatorial synthesis of carbohydrate libraries |
US5770370A (en) * | 1996-06-14 | 1998-06-23 | David Sarnoff Research Center, Inc. | Nuclease protection assays |
WO1998029744A2 (en) * | 1997-01-03 | 1998-07-09 | Telik, Inc. | Method to classify gene products |
US5804563A (en) * | 1994-01-13 | 1998-09-08 | The Trustees Of Columbia University In The City Of New York | Synthetic receptors, libraries and uses thereof |
US5807683A (en) * | 1992-11-19 | 1998-09-15 | Combichem, Inc. | Combinatorial libraries and methods for their use |
US5840485A (en) * | 1993-05-27 | 1998-11-24 | Selectide Corporation | Topologically segregated, encoded solid phase libraries |
US5840484A (en) * | 1992-07-17 | 1998-11-24 | Incyte Pharmaceuticals, Inc. | Comparative gene transcript analysis |
WO1998053093A1 (en) * | 1997-05-23 | 1998-11-26 | Bioarray Solutions Llc | Color-encoding and in-situ interrogation of matrix-coupled chemical compounds |
US5846839A (en) * | 1995-12-22 | 1998-12-08 | Glaxo Group Limited | Methods for hard-tagging an encoded synthetic library |
US5846396A (en) * | 1994-11-10 | 1998-12-08 | Sarnoff Corporation | Liquid distribution system |
US5846719A (en) * | 1994-10-13 | 1998-12-08 | Lynx Therapeutics, Inc. | Oligonucleotide tags for sorting and identification |
WO1999018240A2 (en) * | 1997-10-06 | 1999-04-15 | Stratagene | Collections of uniquely tagged molecules |
WO1999024458A1 (en) * | 1997-11-12 | 1999-05-20 | The University Of Queensland | Carrier-reporter bead assemblies |
US5908755A (en) * | 1996-06-14 | 1999-06-01 | Sarnoff Corporation | Sequential step method for sequencing and identifying polynucleotides |
US5912124A (en) * | 1996-06-14 | 1999-06-15 | Sarnoff Corporation | Padlock probe detection |
US5914229A (en) * | 1996-06-14 | 1999-06-22 | Sarnoff Corporation | Method for amplifying a polynucleotide |
US5922545A (en) * | 1993-10-29 | 1999-07-13 | Affymax Technologies N.V. | In vitro peptide and antibody display libraries |
US5925562A (en) * | 1995-04-25 | 1999-07-20 | Irori | Remotely programmable matrices with memories |
US5932546A (en) * | 1996-10-04 | 1999-08-03 | Glaxo Wellcome Inc. | Peptides and compounds that bind to the thrombopoietin receptor |
US5939268A (en) * | 1994-07-26 | 1999-08-17 | The Scripps Research Institute | Combinatorial libraries of molecules and methods for producing same |
WO1999050658A2 (en) * | 1998-03-30 | 1999-10-07 | The Regents Of The University Of California | Methods and compounds for modulating nuclear receptor activity |
US5965719A (en) * | 1996-11-15 | 1999-10-12 | Sunsorb Biotech, Inc. | Combinatorial synthesis of carbohydrate libraries |
US5976894A (en) * | 1997-04-14 | 1999-11-02 | Pharmacopeia, Inc. | Combinatorial amide alcohol libraries |
US6001579A (en) * | 1993-10-01 | 1999-12-14 | The Trustees Of Columbia University | Supports and combinatorial chemical libraries thereof encoded by non-sequencable tags |
WO1999064867A1 (en) * | 1997-12-04 | 1999-12-16 | Amersham Pharmacia Biotech Uk Limited | Multiple assay method |
WO2000020639A1 (en) * | 1998-10-05 | 2000-04-13 | Lynx Therapeutics, Inc. | Enzymatic synthesis of oligonucleotide tags |
WO2000031536A2 (en) * | 1998-11-23 | 2000-06-02 | President And Fellows Of Harvard College | Detecting structural or synthetic information about chemical compounds |
US6114114A (en) * | 1992-07-17 | 2000-09-05 | Incyte Pharmaceuticals, Inc. | Comparative gene transcript analysis |
WO2001029079A1 (en) | 1999-10-18 | 2001-04-26 | Prince Henry's Institute Of Medical Research | IMMUNO-INTERACTIVE FRAGMENTS OF THE αC SUBUNIT OF INHIBIN |
US6265163B1 (en) | 1998-01-09 | 2001-07-24 | Lynx Therapeutics, Inc. | Solid phase selection of differentially expressed genes |
WO2001057249A1 (en) * | 2000-02-02 | 2001-08-09 | Solexa Ltd. | Synthesis of spatially addressed molecular arrays |
US6280935B1 (en) | 1994-10-13 | 2001-08-28 | Lynx Therapeutics, Inc. | Method of detecting the presence or absence of a plurality of target sequences using oligonucleotide tags |
WO2001062772A2 (en) * | 2000-02-23 | 2001-08-30 | Xenoport, Inc. | Self-encoded combinatorial synthesis of compound multiplets |
US6288055B1 (en) | 1998-06-08 | 2001-09-11 | Advanced Medicine, Inc. | Analgesic agents |
WO2001083502A1 (en) * | 2000-04-28 | 2001-11-08 | Aclara Biosciences, Inc. | Tag library compounds, compositions, kits and methods of use |
WO2001083751A2 (en) | 2000-04-28 | 2001-11-08 | Sangamo Biosciences, Inc. | Methods for binding an exogenous molecule to cellular chromatin |
US6380356B1 (en) | 1999-12-07 | 2002-04-30 | Advanced Medicine, Inc. | Multivalent polymyxin antibiotics |
JP2002515588A (en) * | 1998-05-15 | 2002-05-28 | イシス・イノベイション・リミテッド | Reagents and methods |
US6420354B1 (en) | 1998-06-08 | 2002-07-16 | Advanced Medicine, Inc. | Sodium channel drugs and uses |
WO2002063299A1 (en) * | 2001-02-05 | 2002-08-15 | Graffinity Pharmaceuticals Ag | Low affinity screening method |
US6468811B1 (en) | 1996-04-25 | 2002-10-22 | Bioarray Solutions | Light-controlled electrokinetic assembly of particles near surfaces |
US6479498B1 (en) | 1999-06-04 | 2002-11-12 | Theravance, Inc. | Sodium channel drugs and uses |
US6503759B1 (en) | 1992-10-01 | 2003-01-07 | The Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
US6511808B2 (en) | 2000-04-28 | 2003-01-28 | Sangamo Biosciences, Inc. | Methods for designing exogenous regulatory molecules |
WO2003035679A2 (en) | 2001-10-25 | 2003-05-01 | Medical Research Council | Molecules |
US6566515B1 (en) | 1995-12-15 | 2003-05-20 | Affymetrix, Inc. | Photocleavable protecting groups and methods for their use |
US6566509B1 (en) | 1998-06-08 | 2003-05-20 | Theravance, Inc. | Multivalent macrolide antibiotics |
US6610489B2 (en) | 2000-04-28 | 2003-08-26 | Sangamo Biosciences, Inc. | Pharmacogenomics and identification of drug targets by reconstruction of signal transduction pathways based on sequences of accessible regions |
US6627400B1 (en) | 1999-04-30 | 2003-09-30 | Aclara Biosciences, Inc. | Multiplexed measurement of membrane protein populations |
US6673550B2 (en) | 1999-04-30 | 2004-01-06 | Aclara Biosciences, Inc. | Electrophoretic tag reagents comprising fluorescent compounds |
WO2004011026A1 (en) | 2002-07-26 | 2004-02-05 | The Walter And Eliza Hall Institute Of Medical Research | Immunogenic compositions and diagnostic and therapeutic uses thereof |
US6689558B2 (en) | 2000-02-08 | 2004-02-10 | Sangamo Biosciences, Inc. | Cells for drug discovery |
US6696245B2 (en) | 1997-10-20 | 2004-02-24 | Domantis Limited | Methods for selecting functional polypeptides |
WO2004041067A2 (en) | 2002-11-01 | 2004-05-21 | Elan Pharmaceuticals, Inc. | Prevention and treatment of synucleinopathic disease |
US6770439B2 (en) | 1999-04-30 | 2004-08-03 | Sharat Singh | Sets of generalized target-binding e-tag probes |
WO2004069182A2 (en) | 2003-02-01 | 2004-08-19 | Neuralab Limited | Active immunization to generate antibodies to soluble a-beta |
WO2004083455A1 (en) | 2003-03-21 | 2004-09-30 | The Murdoch Childrens Research Institute | Therapeutic, prophylactic and diagnostic agents |
WO2005003778A2 (en) * | 2003-07-02 | 2005-01-13 | Nuevolution A/S | A method for identifying a synthetic molecule having affinity towards a target |
US6858394B1 (en) | 1998-12-28 | 2005-02-22 | Illumina, Inc. | Composite arrays utilizing microspheres |
US6864048B2 (en) | 1993-04-28 | 2005-03-08 | Affymetrix, Inc. | Factorial chemical libraries |
US6897305B2 (en) | 1998-06-08 | 2005-05-24 | Theravance, Inc. | Calcium channel drugs and uses |
WO2005058479A2 (en) * | 2003-12-17 | 2005-06-30 | Praecis Pharmaceuticals, Inc. | Methods for synthesis of encoded libraries |
WO2005058940A2 (en) | 2003-12-17 | 2005-06-30 | Wyeth | Immunogenic peptide carrier conjugates and methods of producing same |
WO2005061094A1 (en) | 2003-12-22 | 2005-07-07 | Versamatrix A/S | Identification of encoded beads |
WO2005078122A2 (en) | 2004-02-17 | 2005-08-25 | Nuevolution A/S | Method for enrichment involving elimination by mismatch hybridisation |
US6936477B2 (en) | 1994-04-13 | 2005-08-30 | The Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
US6958245B2 (en) | 1996-04-25 | 2005-10-25 | Bioarray Solutions Ltd. | Array cytometry |
WO2006001798A1 (en) * | 2004-06-15 | 2006-01-05 | Vanderbilt University | New chiral columns with broad chiral selectivity |
US7001725B2 (en) | 1999-04-30 | 2006-02-21 | Aclara Biosciences, Inc. | Kits employing generalized target-binding e-tag probes |
WO2006020581A2 (en) | 2004-08-09 | 2006-02-23 | Elan Pharmaceuticals, Inc. | Prevention and treatment of synucleinopathic and amyloidogenic disease |
US7041459B2 (en) | 2001-05-21 | 2006-05-09 | Monogram Biosciences, Inc. | Analyzing phosphorylated proteins |
US7041510B2 (en) | 1996-04-25 | 2006-05-09 | Bioarray Solutions Ltd. | System and method for programmable illumination pattern generation |
US7045311B2 (en) | 2001-10-25 | 2006-05-16 | Monogram Biosciences, Inc. | Whole cell assay systems for cell surface proteases |
WO2006053571A2 (en) * | 2004-11-22 | 2006-05-26 | Peter Birk Rasmussen | Template directed split and mix systhesis of small molecule libraries |
US7057704B2 (en) | 2000-09-17 | 2006-06-06 | Bioarray Solutions Ltd. | System and method for programmable illumination pattern generation |
US7056746B2 (en) | 1996-04-25 | 2006-06-06 | Bioarray Solutions Ltd. | Array cytometry |
US7070928B2 (en) | 2001-03-19 | 2006-07-04 | President And Fellows Of Harvard College | Evolving new molecular function |
WO2006088950A2 (en) | 2005-02-14 | 2006-08-24 | University Of Iowa Research Foundation | Methods and reagents for treatment and diagnosis of age-related macular degeneration |
US7101909B2 (en) | 1998-10-12 | 2006-09-05 | Theravance, Inc. | Calcium channel drugs and uses |
EP1726959A2 (en) * | 1996-04-25 | 2006-11-29 | BioArray Solutions Ltd. | Light-controlled electrokinetic Assembly of particles near surfaces |
US7153977B2 (en) | 2000-01-28 | 2006-12-26 | National University Of Singapore | Ligands and methods for preparing same |
US7160449B2 (en) | 2003-04-28 | 2007-01-09 | Vanderbilt University | Proline chiral columns with broad chiral selectivity |
US7160735B2 (en) | 2000-04-28 | 2007-01-09 | Monogram Biosciences, Inc. | Tagged microparticle compositions and methods |
WO2007053358A2 (en) | 2005-10-28 | 2007-05-10 | Praecis Pharmaceuticals, Inc. | Methods for identifying compounds of interest using encoded libraries |
US7217509B2 (en) | 2000-04-28 | 2007-05-15 | Sangamo Biosciences, Inc. | Databases of regulatory sequences; methods of making and using same |
US7255999B2 (en) | 2001-05-21 | 2007-08-14 | Monogram Biosciences, Inc. | Methods and compositions for analyzing proteins |
US7291504B2 (en) | 1996-04-25 | 2007-11-06 | Bioarray Solutions Ltd. | Assay involving detection and identification with encoded particles |
US7335153B2 (en) | 2001-12-28 | 2008-02-26 | Bio Array Solutions Ltd. | Arrays of microparticles and methods of preparation thereof |
WO2008037026A1 (en) | 2006-09-28 | 2008-04-03 | The Macfarlane Burnet Institute For Medical Research And Public Health Limited | A method of diagnosis and kit therefor |
WO2008042024A2 (en) | 2006-06-01 | 2008-04-10 | Elan Pharmaceuticals, Inc. | Neuroactive fragments of app |
US7358052B2 (en) | 2001-05-26 | 2008-04-15 | Monogram Biosciences, Inc. | Catalytic amplification of multiplexed assay signals |
WO2008063933A2 (en) | 2006-11-10 | 2008-05-29 | Massachusetts Institute Of Technology | Pak modulators |
US7402397B2 (en) | 2002-05-21 | 2008-07-22 | Monogram Biosciences, Inc. | Detecting and profiling molecular complexes |
US7413854B2 (en) | 2002-03-15 | 2008-08-19 | Nuevolution A/S | Method for synthesising templated molecules |
EP1994937A2 (en) | 1997-12-02 | 2008-11-26 | Elan Pharma International Limited | Prevention and treatment of amyloidogenic disease |
US7491494B2 (en) | 2002-08-19 | 2009-02-17 | President And Fellows Of Harvard College | Evolving new molecular function |
EP2026073A1 (en) | 2000-04-29 | 2009-02-18 | University Of Iowa Research Foundation | Diagnostics and therapeutics for macular degeneration-related disorders |
US7501245B2 (en) | 1999-06-28 | 2009-03-10 | Helicos Biosciences Corp. | Methods and apparatuses for analyzing polynucleotide sequences |
EP2033661A1 (en) | 1997-11-07 | 2009-03-11 | ConjuChem Biotechnologies Inc. | Methods of screening affinity marker libraries |
US7507546B2 (en) | 2001-06-11 | 2009-03-24 | Xenoport, Inc. | Methods of screening agents, conjugates or conjugate moieties for transport by a PEPT2 transporter |
WO2009078799A1 (en) | 2007-12-17 | 2009-06-25 | Marfl Ab | New vaccine for the treatment of mycobacterium related disorders |
WO2009086539A2 (en) | 2007-12-28 | 2009-07-09 | Elan Pharmaceuticals, Inc. | Treatment and prophylaxis of amyloidosis |
WO2009091586A2 (en) | 2008-01-18 | 2009-07-23 | North Carolina State University | Peptides and methods of use as therapeutics and screening agents |
US7572600B2 (en) | 2004-08-04 | 2009-08-11 | Chemocentryx, Inc. | Enzymatic activities in chemokine-mediated inflammation |
EP2116618A1 (en) | 2008-05-09 | 2009-11-11 | Agency for Science, Technology And Research | Diagnosis and treatment of Kawasaki disease |
WO2009014848A3 (en) * | 2007-06-25 | 2009-12-30 | Affymetrix, Inc. | Patterned microcodes |
US7645596B2 (en) | 1998-05-01 | 2010-01-12 | Arizona Board Of Regents | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US7648828B2 (en) | 2003-04-01 | 2010-01-19 | Monogram Biosciences, Inc. | Methods for detecting receptor complexes comprising PI3K |
US7666593B2 (en) | 2005-08-26 | 2010-02-23 | Helicos Biosciences Corporation | Single molecule sequencing of captured nucleic acids |
WO2010021415A1 (en) | 2008-08-18 | 2010-02-25 | Seoul National University Industry Foundation | Method for controlling cancer metastasis or cancer cell migration by modulating the cellular level of lysyl trna synthetase |
US7727713B2 (en) | 2001-06-20 | 2010-06-01 | Nuevolution A/S | Templated molecules and methods for using such molecules |
US7771929B2 (en) | 2000-04-28 | 2010-08-10 | Monogram Biosciences, Inc. | Tag library compounds, compositions, kits and methods of use |
EP2258870A2 (en) | 2005-06-09 | 2010-12-08 | Praecis Pharmaceuticals Inc. | Method for identifying compounds which bind to biological target molecule |
EP2267117A2 (en) | 2002-06-27 | 2010-12-29 | Verva Pharmaceuticals Pty Ltd | Differentiation modulating agents and uses therefor |
US7863029B2 (en) | 2004-06-04 | 2011-01-04 | Fox Chase Cancer Center | Alternate morpheeins of allosteric proteins as a target for the development of bioactive molecules |
EP2270034A2 (en) | 2004-06-03 | 2011-01-05 | Athlomics Pty Ltd | Agents and methods for diagnosing stress |
US7869011B2 (en) | 2003-12-22 | 2011-01-11 | Novo Norkisk A/S | Apparatus and methods for analysis and sorting of particles such as polymer beads |
EP2272539A2 (en) | 2004-10-19 | 2011-01-12 | Elan Pharmaceuticals, Inc. | Truncated fragments of alpha-synuclein in lewy body disease |
US7887753B2 (en) | 2000-11-16 | 2011-02-15 | California Institute Of Technology | Apparatus and methods for conducting assays and high throughput screening |
US7897345B2 (en) | 2003-11-12 | 2011-03-01 | Helicos Biosciences Corporation | Short cycle methods for sequencing polynucleotides |
EP2305808A1 (en) | 2001-06-20 | 2011-04-06 | Nuevolution A/S | Templated molecules and methods for using such molecules |
EP2305302A2 (en) | 1999-05-28 | 2011-04-06 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidogenic disease |
US7923542B2 (en) | 2000-04-28 | 2011-04-12 | Sangamo Biosciences, Inc. | Libraries of regulatory sequences, methods of making and using same |
EP2336147A2 (en) | 2003-12-17 | 2011-06-22 | Janssen Alzheimer Immunotherapy | A beta immunogenic peptide carrier conjugates and methods of producing same |
US7972994B2 (en) | 2003-12-17 | 2011-07-05 | Glaxosmithkline Llc | Methods for synthesis of encoded libraries |
US7981604B2 (en) | 2004-02-19 | 2011-07-19 | California Institute Of Technology | Methods and kits for analyzing polynucleotide sequences |
EP2360275A1 (en) * | 2000-11-15 | 2011-08-24 | Minerva Biotechnologies Corporation | Oligonucleotide identifiers |
EP2361928A1 (en) | 2003-05-19 | 2011-08-31 | Elan Pharmaceuticals Inc. | Truncated fragments of alpha-synuclein in Lewy body disease |
EP2364719A1 (en) | 1999-06-01 | 2011-09-14 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidogenic diseases |
US20110312613A1 (en) * | 1998-11-30 | 2011-12-22 | Nanomics Biosystems Pty Ltd | Carriers for combinatorial compound libraries |
USRE43097E1 (en) | 1994-10-13 | 2012-01-10 | Illumina, Inc. | Massively parallel signature sequencing by ligation of encoded adaptors |
US8101737B2 (en) | 2004-12-31 | 2012-01-24 | Affymetrix, Inc. | Parallel preparation of high fidelity probes in an array format |
WO2012016290A1 (en) | 2010-08-04 | 2012-02-09 | The Macfarlane Burnet Institute For Medical Research And Public Health Ltd | Modified hepatitis c virus proteins |
US8133987B2 (en) | 2004-12-31 | 2012-03-13 | Affymetrix, Inc. | Primer array synthesis and validation |
US8153410B2 (en) | 2003-07-07 | 2012-04-10 | Fox Chase Cancer Center | Alternate morpheein forms of allosteric proteins as a target for the development of bioactive molecules |
EP2450056A1 (en) | 2005-07-19 | 2012-05-09 | Elan Pharma International Limited | Prevention and treatment of synucleinopathic and amyloidogenic disease |
US8193328B2 (en) | 2005-09-08 | 2012-06-05 | Philadelphia Health & Education Corporation | Identification of modulators of serine protease inhibitor Kazal and their use as anti-cancer and anti-viral agents |
EP2468294A1 (en) | 2006-02-03 | 2012-06-27 | Crc For Asthma And Airways Ltd | A method of modulating cellular activity and agents for use therein |
US8222047B2 (en) | 2008-09-23 | 2012-07-17 | Quanterix Corporation | Ultra-sensitive detection of molecules on single molecule arrays |
EP2476703A1 (en) | 2011-01-14 | 2012-07-18 | Bracco Imaging S.p.A | Human antibodies cross-reacting with a bacterial and a self antigen from atherosclerotic plaques |
EP2476761A2 (en) | 2005-07-07 | 2012-07-18 | Athlomics Pty Ltd | Polynucleotide marker genes and their expression, for diagnosis of endotoxemia |
WO2012095516A1 (en) | 2011-01-14 | 2012-07-19 | Bracco Imaging Spa | Human antibodies cross-reacting with a bacterial and a self antigen from atherosclerotic plaques |
EP2481424A1 (en) | 2005-03-19 | 2012-08-01 | Medical Research Council | Improvements in or relating to treatment and prevention of hepatitis C viral infections |
US8236574B2 (en) | 2010-03-01 | 2012-08-07 | Quanterix Corporation | Ultra-sensitive detection of molecules or particles using beads or other capture objects |
WO2012148477A1 (en) | 2010-12-15 | 2012-11-01 | Cellular Research, Inc. | Digital counting of individual molecules by stochastic attachment of diverse label-tags |
US8415171B2 (en) | 2010-03-01 | 2013-04-09 | Quanterix Corporation | Methods and systems for extending dynamic range in assays for the detection of molecules or particles |
WO2013055101A1 (en) | 2011-10-10 | 2013-04-18 | Medicinal Bioconvergence Research Center | Method for screening an agent preventing or treating cancer using glycyl-trna synthetase and cadherin |
EP2583978A2 (en) | 2007-02-23 | 2013-04-24 | The Regents of the University of California | Prevention and treatment of synucleinopathic and amyloidogenic disease |
WO2013078138A1 (en) | 2011-11-21 | 2013-05-30 | OSI Pharmaceuticals, LLC | Proton nmr spectroscopy for biochemical screening |
US8460879B2 (en) | 2006-02-21 | 2013-06-11 | The Trustees Of Tufts College | Methods and arrays for target analyte detection and determination of target analyte concentration in solution |
US8691754B2 (en) | 2003-09-22 | 2014-04-08 | Bioarray Solutions, Ltd. | Microparticles with enhanced covalent binding capacity and their uses |
US8691729B2 (en) | 2005-07-15 | 2014-04-08 | President And Fellows Of Harvard College | Reaction discovery system |
AU2011205057B2 (en) * | 2003-12-17 | 2015-01-15 | Glaxosmithkline Llc | Methods for synthesis of encoded libraries |
US8969255B2 (en) | 2009-06-19 | 2015-03-03 | The Arizona Board Of Regents | Compound arrays for sample profiling |
US8975293B2 (en) | 2011-05-26 | 2015-03-10 | Regents Of The University Of Michigan | Epigenetic co-repressors of the gamma-globin gene and methods of using same |
US9057727B2 (en) | 2007-08-01 | 2015-06-16 | The General Hospital Corporation | Screening methods using G-protein coupled receptors and related compositions |
US9096951B2 (en) | 2003-02-21 | 2015-08-04 | Nuevolution A/S | Method for producing second-generation library |
US9096898B2 (en) | 1998-05-01 | 2015-08-04 | Life Technologies Corporation | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US9109248B2 (en) | 2002-10-30 | 2015-08-18 | Nuevolution A/S | Method for the synthesis of a bifunctional complex |
US9110025B2 (en) | 2010-03-01 | 2015-08-18 | Quanterix Corporation | Methods and systems for extending dynamic range in assays for the detection of molecules or particles |
US9121110B2 (en) | 2002-12-19 | 2015-09-01 | Nuevolution A/S | Quasirandom structure and function guided synthesis methods |
US9147037B2 (en) | 2004-08-02 | 2015-09-29 | Bioarray Solutions, Ltd. | Automated analysis of multiplexed probe-target interaction patterns: pattern matching and allele identification |
US9244069B2 (en) | 2009-07-29 | 2016-01-26 | Dynex Technologies | Sample plate systems and methods |
US9251583B2 (en) | 2002-11-15 | 2016-02-02 | Bioarray Solutions, Ltd. | Analysis, secure access to, and transmission of array images |
WO2016040895A1 (en) | 2014-09-12 | 2016-03-17 | xxTHE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY | Wnt signaling agonist molecules |
EP3018206A1 (en) * | 2005-12-01 | 2016-05-11 | Nuevolution A/S | Enzymatic encoding methods for efficient synthesis of large libraries |
US9359601B2 (en) | 2009-02-13 | 2016-06-07 | X-Chem, Inc. | Methods of creating and screening DNA-encoded libraries |
WO2016100857A1 (en) | 2014-12-19 | 2016-06-23 | Regeneron Pharmaceuticals, Inc. | Stem cells for modeling type 2 diabetes |
US9377388B2 (en) | 1997-03-14 | 2016-06-28 | Trustees Of Tufts College | Methods for detecting target analytes and enzymatic reactions |
US9436088B2 (en) | 2001-06-21 | 2016-09-06 | Bioarray Solutions, Ltd. | Un-supported polymeric film with embedded microbeads |
US9435807B2 (en) | 2011-09-22 | 2016-09-06 | Medicinal Bioconvergence Research Center | Use of leucyl tRNA synthetase |
EP3067066A1 (en) | 2007-02-23 | 2016-09-14 | Prothena Biosciences Limited | Prevention and treatment of synucleinopathic and amyloidogenic disease |
US9492508B2 (en) | 2010-05-13 | 2016-11-15 | The General Hospital Corporation | Parathyroid hormone analogs and uses thereof |
US9523701B2 (en) | 2009-07-29 | 2016-12-20 | Dynex Technologies, Inc. | Sample plate systems and methods |
US9637777B2 (en) | 2003-10-28 | 2017-05-02 | Bioarray Solutions, Ltd. | Optimization of gene expression analysis using immobilized capture probes |
US9678062B2 (en) | 2011-09-23 | 2017-06-13 | University Of Louisville Research Foundation, Inc. | Methods and compositions for expanding cells and improving engraftment |
US9678068B2 (en) | 2010-03-01 | 2017-06-13 | Quanterix Corporation | Ultra-sensitive detection of molecules using dual detection methods |
US9709559B2 (en) | 2000-06-21 | 2017-07-18 | Bioarray Solutions, Ltd. | Multianalyte molecular analysis using application-specific random particle arrays |
WO2017149097A1 (en) * | 2016-03-04 | 2017-09-08 | Apta Biosciences Limited | Oligonucleotides and methods for preparing |
US9809838B2 (en) | 2007-08-30 | 2017-11-07 | Trustees Of Tufts College | Methods for determining the concentration of an analyte in solution |
WO2017208210A1 (en) | 2016-06-03 | 2017-12-07 | Prothena Biosciences Limited | Anti-mcam antibodies and associated methods of use |
WO2018007979A1 (en) | 2016-07-06 | 2018-01-11 | Prothena Biosciences Limited | Assay for detecting total and s129 phosphorylated alpha-synuclein |
WO2018023014A1 (en) | 2016-07-29 | 2018-02-01 | Regeneron Pharmaceuticals, Inc. | Mice comprising mutations resulting in expression of c-truncated fibrillin-1 |
US9932626B2 (en) | 2013-01-15 | 2018-04-03 | Quanterix Corporation | Detection of DNA or RNA using single molecule arrays and other techniques |
WO2018060904A1 (en) | 2016-09-30 | 2018-04-05 | Nanjing Biopoint Diagnostic Technology Co. Ltd | Point of care assays |
WO2018071493A1 (en) | 2016-10-12 | 2018-04-19 | Janssen Biotech, Inc. | Methods for screening for modulators of gdf15-like biological activity |
US9952237B2 (en) | 2011-01-28 | 2018-04-24 | Quanterix Corporation | Systems, devices, and methods for ultra-sensitive detection of molecules or particles |
US9970932B2 (en) | 2013-03-15 | 2018-05-15 | Arizona Board Of Regents On Behalf Of Arizona State University | Non-covalent patterned chemical features and use thereof in MALDI-based quality control |
US10006919B2 (en) | 2013-03-15 | 2018-06-26 | Arizona Board Of Regents On Behalf Of Arizona State University | Peptide array quality control |
US10087221B2 (en) | 2013-03-21 | 2018-10-02 | Sanofi-Aventis Deutschland Gmbh | Synthesis of hydantoin containing peptide products |
US10107804B2 (en) | 2001-03-23 | 2018-10-23 | Trustees Of Tufts College | Methods for detecting target analytes and enzymatic reactions |
WO2018202850A1 (en) | 2017-05-05 | 2018-11-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Microtubule-targeting drugs as immune checkpoint inhibitors and methods of screening novel immune checkpoint inhibitors for the treatment of cancers and infectious diseases |
WO2019094735A1 (en) | 2017-11-10 | 2019-05-16 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising slc30a8 mutation and methods of use |
US10329321B2 (en) | 2016-02-09 | 2019-06-25 | Alexander Krantz | Site-selective functionalization of proteins using traceless affinity labels |
US10393759B2 (en) | 2011-04-12 | 2019-08-27 | Quanterix Corporation | Methods of determining a treatment protocol for and/or a prognosis of a patient's recovery from a brain injury |
US10393751B2 (en) | 2015-04-20 | 2019-08-27 | Roche Sequencing Solutions, Inc. | Specific peptide binders to proteins identified via systematic discovery, maturation and extension process |
US10415081B2 (en) | 2001-10-15 | 2019-09-17 | Bioarray Solutions Ltd. | Multiplexed analysis of polymorphic loci by concurrent interrogation and enzyme-mediated detection |
US10450343B2 (en) | 2013-03-21 | 2019-10-22 | Sanofi-Aventis Deutschland Gmbh | Synthesis of cyclic imide containing peptide products |
WO2020016433A1 (en) | 2018-07-20 | 2020-01-23 | Aicuris Gmbh & Co. Kg | Methods for screening and identifying agents that inhibit or modulate the nuclear egress complex of herpesviruses |
US10730906B2 (en) | 2002-08-01 | 2020-08-04 | Nuevolutions A/S | Multi-step synthesis of templated molecules |
WO2020159445A1 (en) | 2019-01-31 | 2020-08-06 | Agency For Science, Technology And Research | Cnx/erp57 inhibitor for use in the treatment or prevention of cancer |
US10758886B2 (en) | 2015-09-14 | 2020-09-01 | Arizona Board Of Regents On Behalf Of Arizona State University | Conditioned surfaces for in situ molecular array synthesis |
WO2020210724A1 (en) | 2019-04-10 | 2020-10-15 | University Of Utah Research Foundation | Htra1 modulation for treatment of amd |
US10865409B2 (en) | 2011-09-07 | 2020-12-15 | X-Chem, Inc. | Methods for tagging DNA-encoded libraries |
US11118215B2 (en) | 2003-09-18 | 2021-09-14 | Nuevolution A/S | Method for obtaining structural information concerning an encoded molecule and method for selecting compounds |
US11225655B2 (en) | 2010-04-16 | 2022-01-18 | Nuevolution A/S | Bi-functional complexes and methods for making and using such complexes |
US11237171B2 (en) | 2006-02-21 | 2022-02-01 | Trustees Of Tufts College | Methods and arrays for target analyte detection and determination of target analyte concentration in solution |
US11371990B2 (en) | 2016-11-11 | 2022-06-28 | Cowper Sciences Inc. | Methods for identifying candidate biomarkers |
US11400165B2 (en) | 2017-11-04 | 2022-08-02 | Advanced Proteome Therapeutics Inc. | Composition and method for modifying polypeptides |
US11674135B2 (en) | 2012-07-13 | 2023-06-13 | X-Chem, Inc. | DNA-encoded libraries having encoding oligonucleotide linkages not readable by polymerases |
US11747334B2 (en) | 2016-06-20 | 2023-09-05 | Cowper Sciences Inc. | Methods for differential diagnosis of autoimmune diseases |
US11774446B2 (en) | 2016-06-20 | 2023-10-03 | Cowper Sciences Inc. | Methods for diagnosis and treatment of autoimmune diseases |
US11828759B2 (en) | 2016-02-11 | 2023-11-28 | Peter Maccallum Cancer Institute | Method of diagnosis |
Families Citing this family (353)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0834576B1 (en) * | 1990-12-06 | 2002-01-16 | Affymetrix, Inc. (a Delaware Corporation) | Detection of nucleic acid sequences |
AU669489B2 (en) * | 1991-09-18 | 1996-06-13 | Affymax Technologies N.V. | Method of synthesizing diverse collections of oligomers |
WO1995012608A1 (en) * | 1993-11-02 | 1995-05-11 | Affymax Technologies N.V. | Synthesizing and screening molecular diversity |
US6335160B1 (en) | 1995-02-17 | 2002-01-01 | Maxygen, Inc. | Methods and compositions for polypeptide engineering |
US6406855B1 (en) | 1994-02-17 | 2002-06-18 | Maxygen, Inc. | Methods and compositions for polypeptide engineering |
CN1181720A (en) * | 1995-04-25 | 1998-05-13 | 伊萝莉公司 | Remotely programmable matrices with memories and uses thereof |
US6017496A (en) | 1995-06-07 | 2000-01-25 | Irori | Matrices with memories and uses thereof |
US6329139B1 (en) | 1995-04-25 | 2001-12-11 | Discovery Partners International | Automated sorting system for matrices with memory |
US6319668B1 (en) | 1995-04-25 | 2001-11-20 | Discovery Partners International | Method for tagging and screening molecules |
US6352854B1 (en) | 1995-04-25 | 2002-03-05 | Discovery Partners International, Inc. | Remotely programmable matrices with memories |
US5874214A (en) | 1995-04-25 | 1999-02-23 | Irori | Remotely programmable matrices with memories |
US6284459B1 (en) | 1995-04-25 | 2001-09-04 | Discovery Partners International | Solid support matrices with memories and combinatorial libraries therefrom |
US6340588B1 (en) | 1995-04-25 | 2002-01-22 | Discovery Partners International, Inc. | Matrices with memories |
US6100026A (en) * | 1995-04-25 | 2000-08-08 | Irori | Matrices with memories and uses thereof |
US6025129A (en) * | 1995-04-25 | 2000-02-15 | Irori | Remotely programmable matrices with memories and uses thereof |
ZA964814B (en) | 1995-06-07 | 1998-02-09 | Glaxo Group Ltd | Peptides and compounds that bind to a receptor. |
US20110028350A1 (en) * | 1995-12-15 | 2011-02-03 | Affymetrix, Inc. | Photocleavable protecting groups |
DE69727466T2 (en) * | 1996-04-08 | 2004-12-16 | Glaxo Group Ltd., Greenford | MASS-BASED CODING AND QUALITATIVE ANALYSIS OF COMBINATIONAL LIBRARIES |
US7144119B2 (en) * | 1996-04-25 | 2006-12-05 | Bioarray Solutions Ltd. | System and method for programmable illumination pattern generation |
US7091311B2 (en) * | 1996-06-07 | 2006-08-15 | Smithkline Beecham Corporation | Peptides and compounds that bind to a receptor |
US6355490B1 (en) | 1996-09-13 | 2002-03-12 | Jill Edie Hochlowski | Attached tags for use in combinatorial chemistry synthesis |
EP0985142A4 (en) * | 1997-05-23 | 2006-09-13 | Lynx Therapeutics Inc | System and apparaus for sequential processing of analytes |
US6969488B2 (en) * | 1998-05-22 | 2005-11-29 | Solexa, Inc. | System and apparatus for sequential processing of analytes |
US6096496A (en) * | 1997-06-19 | 2000-08-01 | Frankel; Robert D. | Supports incorporating vertical cavity emitting lasers and tracking apparatus for use in combinatorial synthesis |
US6168913B1 (en) | 1997-10-14 | 2001-01-02 | Abbott Laboratories | Coding combinatorial libraries with fluorine tags |
US6607829B1 (en) * | 1997-11-13 | 2003-08-19 | Massachusetts Institute Of Technology | Tellurium-containing nanocrystalline materials |
US6322901B1 (en) | 1997-11-13 | 2001-11-27 | Massachusetts Institute Of Technology | Highly luminescent color-selective nano-crystalline materials |
US6207392B1 (en) | 1997-11-25 | 2001-03-27 | The Regents Of The University Of California | Semiconductor nanocrystal probes for biological applications and process for making and using such probes |
JP2002514832A (en) * | 1998-05-13 | 2002-05-21 | スペクトラ システムズ コーポレーション | Microlaser beam generating beads and structures and methods therefor |
US6274725B1 (en) | 1998-06-02 | 2001-08-14 | Isis Pharmaceuticals, Inc. | Activators for oligonucleotide synthesis |
WO2000013018A2 (en) * | 1998-08-28 | 2000-03-09 | Febit Ferrarius Biotechnology Gmbh | Support for a method for determining analytes and a method for producing the support |
US6306610B1 (en) | 1998-09-18 | 2001-10-23 | Massachusetts Institute Of Technology | Biological applications of quantum dots |
US6251303B1 (en) | 1998-09-18 | 2001-06-26 | Massachusetts Institute Of Technology | Water-soluble fluorescent nanocrystals |
US6617583B1 (en) | 1998-09-18 | 2003-09-09 | Massachusetts Institute Of Technology | Inventory control |
US7071324B2 (en) * | 1998-10-13 | 2006-07-04 | Brown University Research Foundation | Systems and methods for sequencing by hybridization |
GB9822436D0 (en) * | 1998-10-14 | 1998-12-09 | Cambridge Combinatorial Ltd | Sintered/co-sintered materials |
US6264891B1 (en) | 1998-12-22 | 2001-07-24 | Eos Biotechnology, Inc. | Apparatus and method for concurrent chemical synthesis |
US6500609B1 (en) | 1999-02-11 | 2002-12-31 | Scynexis Chemistry & Automation, Inc. | Method and apparatus for synthesizing characterizing and assaying combinatorial libraries |
US20010051349A1 (en) * | 2000-02-17 | 2001-12-13 | Glycominds Ltd. | Combinatorial complex carbohydrate libraries and methods for the manufacture and uses thereof |
US6824866B1 (en) * | 1999-04-08 | 2004-11-30 | Affymetrix, Inc. | Porous silica substrates for polymer synthesis and assays |
AU4202400A (en) * | 1999-04-09 | 2000-11-14 | Glaxo Group Limited | Encoding scheme for solid phase chemical libraries |
US20030134330A1 (en) * | 1999-04-15 | 2003-07-17 | Ilya Ravkin | Chemical-library composition and method |
US20030129654A1 (en) * | 1999-04-15 | 2003-07-10 | Ilya Ravkin | Coded particles for multiplexed analysis of biological samples |
US20030207249A1 (en) * | 1999-04-15 | 2003-11-06 | Beske Oren E. | Connection of cells to substrates using association pairs |
US7253435B2 (en) | 1999-04-15 | 2007-08-07 | Millipore Corporation | Particles with light-polarizing codes |
US20030166015A1 (en) * | 1999-04-15 | 2003-09-04 | Zarowitz Michael A. | Multiplexed analysis of cell-substrate interactions |
WO2000063419A1 (en) * | 1999-04-15 | 2000-10-26 | Virtual Arrays, Inc. | Combinatorial chemical library supports having indicia at coding positions and methods of use |
US6908737B2 (en) * | 1999-04-15 | 2005-06-21 | Vitra Bioscience, Inc. | Systems and methods of conducting multiplexed experiments |
SE9902479D0 (en) * | 1999-06-30 | 1999-06-30 | Amersham Pharm Biotech Ab | Particle classification as marker |
US7144700B1 (en) | 1999-07-23 | 2006-12-05 | Affymetrix, Inc. | Photolithographic solid-phase polymer synthesis |
US6524863B1 (en) | 1999-08-04 | 2003-02-25 | Scynexis Chemistry & Automation, Inc. | High throughput HPLC method for determining Log P values |
US6413431B1 (en) | 1999-08-10 | 2002-07-02 | Scynexis Chemistry & Automation, Inc. | HPLC method for purifying organic compounds |
WO2001015793A1 (en) | 1999-08-27 | 2001-03-08 | Scynexis Chemistry And Automation, Inc. | Sample preparation for high throughput purification |
WO2002102250A1 (en) * | 1999-10-22 | 2002-12-27 | Glaxo Group Limited | $g(in vivo) imaging |
US6958225B2 (en) | 1999-10-27 | 2005-10-25 | Affymetrix, Inc. | Complexity management of genomic DNA |
US6703480B1 (en) | 1999-11-24 | 2004-03-09 | Palani Balu | Peptide dimers as agonists of the erythropoientin (EPO) receptor, and associated methods of synthesis and use |
US7109299B1 (en) | 1999-12-16 | 2006-09-19 | Affymax, Inc. | Peptides and compounds that bind to the IL-5 receptor |
US6309889B1 (en) | 1999-12-23 | 2001-10-30 | Glaxo Wellcome Inc. | Nano-grid micro reactor and methods |
EP1257668B1 (en) * | 2000-02-16 | 2008-10-29 | Illumina, Inc. | Parallel genotyping of multiple patient samples |
US20020098513A1 (en) * | 2000-02-17 | 2002-07-25 | Glycominds Ltd. | Combinatorial complex carbohydrate libraries and methods for the manufacture and uses thereof |
US6783985B1 (en) | 2000-02-18 | 2004-08-31 | Elitra Pharmaceuticals Inc. | Gene disruption methodologies for drug target discovery |
AU2001250882A1 (en) * | 2000-03-20 | 2001-10-03 | Massachusetts Institute Of Technology | Inorganic particle conjugates |
US6884578B2 (en) | 2000-03-31 | 2005-04-26 | Affymetrix, Inc. | Genes differentially expressed in secretory versus proliferative endometrium |
WO2003036265A2 (en) * | 2001-10-26 | 2003-05-01 | Virtual Arrays, Inc. | Assay systems with adjustable fluid communication |
ES2259666T3 (en) | 2000-06-21 | 2006-10-16 | Bioarray Solutions Ltd | MOLECULAR ANALYSIS OF MULTIPLE ANALYTICS USING SERIES OF RANDOM PARTICLES WITH APPLICATION SPECIFICITY. |
US6759510B1 (en) * | 2000-06-30 | 2004-07-06 | Becton, Dickinson And Company | Peptides for use in culture media |
US6576472B1 (en) | 2000-07-26 | 2003-06-10 | Smithkline Beecham Corporation | Chemical constructs for solution phase chemistry |
US6584411B1 (en) | 2000-07-26 | 2003-06-24 | Smithkline Beecham Corporation | Methods to facilitate the calculation of yields of reaction products |
DE10042797C2 (en) * | 2000-08-30 | 2003-12-04 | Basf Lynx Bioscience Ag | Analysis chip |
US7108969B1 (en) | 2000-09-08 | 2006-09-19 | Affymetrix, Inc. | Methods for detecting and diagnosing oral cancer |
AU2001292142A1 (en) * | 2000-09-11 | 2002-03-22 | Affymetrix, Inc. | Photocleavable protecting groups |
DE10051396A1 (en) | 2000-10-17 | 2002-04-18 | Febit Ferrarius Biotech Gmbh | An integrated synthesis and identification of an analyte, comprises particles immobilized at a carrier to be coupled to receptors in a structured pattern to give receptor arrays for biochemical reactions |
JP2004537712A (en) * | 2000-10-18 | 2004-12-16 | バーチャル・アレイズ・インコーポレーテッド | Multiple cell analysis system |
GB0026560D0 (en) * | 2000-10-30 | 2000-12-13 | Novartis Ag | Organic compounds |
US7435390B2 (en) * | 2001-01-26 | 2008-10-14 | Third Wave Technologies, Inc. | Nucleic acid synthesizers |
US20030072689A1 (en) * | 2001-08-15 | 2003-04-17 | Third Wave Technologies, Inc. | Polymer synthesizer |
US6932943B1 (en) | 2001-01-26 | 2005-08-23 | Third Wave Technologies | Nucleic acid synthesizers |
US20020086294A1 (en) * | 2000-12-29 | 2002-07-04 | Ellson Richard N. | Device and method for tracking conditions in an assay |
US20030180953A1 (en) * | 2000-12-29 | 2003-09-25 | Elitra Pharmaceuticals, Inc. | Gene disruption methodologies for drug target discovery |
EP1385950B1 (en) * | 2001-01-19 | 2008-07-02 | Centocor, Inc. | Computer-directed assembly of a polynucleotide encoding a target polypeptide |
CA2445960A1 (en) * | 2001-02-21 | 2002-12-19 | Amnis Corporation | Method and apparatus for labeling and analyzing cellular components |
CA2445179A1 (en) * | 2001-04-23 | 2002-10-31 | Elitra Pharmaceuticals, Inc. | Identification of essential genes of aspegillus fumigatus and methods of use |
US20020160427A1 (en) * | 2001-04-27 | 2002-10-31 | Febit Ag | Methods and apparatuses for electronic determination of analytes |
DE10122357A1 (en) * | 2001-05-09 | 2002-11-14 | Febit Ferrarius Biotech Gmbh | Hybrid process for the production of supports for analyte determination |
US20060234231A1 (en) * | 2001-06-20 | 2006-10-19 | Nuevolution A/S | Microarrays displaying encoded molecules |
US6767731B2 (en) * | 2001-08-27 | 2004-07-27 | Intel Corporation | Electron induced fluorescent method for nucleic acid sequencing |
DE10147074A1 (en) * | 2001-09-25 | 2003-05-08 | Beru Ag | Method for operating a multi-stage electric heater consisting of several heating elements |
GB2380999B (en) * | 2001-10-17 | 2003-09-03 | Global Genomics Ab | Synthesis of oligonucleotide mixtures and polynucleotide assembly |
US20030219800A1 (en) * | 2001-10-18 | 2003-11-27 | Beske Oren E. | Multiplexed cell transfection using coded carriers |
US20080187949A1 (en) * | 2001-10-26 | 2008-08-07 | Millipore Corporation | Multiplexed assays of cell migration |
WO2003038558A2 (en) * | 2001-10-30 | 2003-05-08 | Nanomics Biosystems Pty, Ltd. | Device and methods for directed synthesis of chemical libraries |
DE20200926U1 (en) * | 2002-01-23 | 2002-04-18 | Hegenscheidt Mfd Gmbh & Co Kg | Deep rolling device of a deep rolling machine for crankshafts |
US20030166010A1 (en) * | 2002-02-25 | 2003-09-04 | Affholter Joseph A. | Custom ligand design for biomolecular filtration and purification for bioseperation |
EP1487850A2 (en) * | 2002-03-15 | 2004-12-22 | Nuevolution A/S | A building block forming a c-c or a c-hetero atom bond upon reaction |
AU2003253069A1 (en) * | 2002-03-15 | 2003-09-29 | Nuevolution A/S | A building block forming a c-c bond upon reaction |
EP1487849A2 (en) * | 2002-03-15 | 2004-12-22 | Nuevolution A/S | A building block capable of transferring a functional entity |
DE10214019A1 (en) * | 2002-03-30 | 2003-10-16 | Detlef Mueller-Schulte | Luminescent, spherical, non-autofluorescent silica gel particles with variable emission intensities and frequencies |
US20030215871A1 (en) * | 2002-05-01 | 2003-11-20 | Pharmacopeia, Inc. | Chemically inert molecular tags |
CA2486486A1 (en) * | 2002-05-17 | 2004-05-06 | Alfred E. Slanetz | Process for determining target function and identifying drug leads |
US20040126773A1 (en) * | 2002-05-23 | 2004-07-01 | Beske Oren E. | Assays with coded sensor particles to sense assay conditions |
US20040038331A1 (en) * | 2002-08-23 | 2004-02-26 | Reddy M. Parameswara | Solid phase synthesis of biomolecule conjugates |
ES2781475T3 (en) | 2002-09-18 | 2020-09-02 | Janssen Pharmaceuticals Inc | Methods to increase the production of hematopoietic stem cells and platelets |
US7919600B2 (en) * | 2002-09-23 | 2011-04-05 | Alcatel-Lucent Usa Inc. | Compositions that reversibly gel and de-gel |
US8389700B2 (en) * | 2002-09-23 | 2013-03-05 | Alcatel Lucent | Agent delivery system capable of selectively releasing an agent |
US20040110212A1 (en) * | 2002-09-30 | 2004-06-10 | Mccormick Mark | Microarrays with visual alignment marks |
CA2500783C (en) * | 2002-10-01 | 2012-07-17 | Nimblegen Systems, Inc. | Microarrays having multiple oligonucleotides in single array features |
US20040149235A1 (en) * | 2002-10-04 | 2004-08-05 | Pogue Albert S. | Apparatus and method for removal of waste from animal production facilities |
US20080207465A1 (en) * | 2002-10-28 | 2008-08-28 | Millipore Corporation | Assay systems with adjustable fluid communication |
GB0229443D0 (en) * | 2002-12-18 | 2003-01-22 | Avecia Ltd | Process |
US7615629B2 (en) * | 2002-12-31 | 2009-11-10 | Sigma-Aldrich Co. | Methods and compositions for the tandem synthesis of two or more oligonucleotides on the same solid support |
US20060269920A1 (en) * | 2003-02-21 | 2006-11-30 | Nuevolution A/S | Method for obtaining structural information about an encoded molecule |
DK1608748T3 (en) | 2003-03-20 | 2009-06-29 | Nuevolution As | Ligation coding of small molecules |
US8017323B2 (en) | 2003-03-26 | 2011-09-13 | President And Fellows Of Harvard College | Free reactant use in nucleic acid-templated synthesis |
US7917298B1 (en) | 2003-04-17 | 2011-03-29 | Nanosys, Inc. | Nanocrystal taggants |
US7141160B2 (en) * | 2003-04-28 | 2006-11-28 | V{dot over (a)}nderbilt University | Chiral columns with broad chiral selectivity |
DE10324063A1 (en) * | 2003-05-27 | 2004-12-23 | Robert Heinrich | Preparing nucleotides on controlled pore glass, useful for making libraries for screening to identify aptamers, by coupling protected deoxyphosphoramidite directly to amino groups on the glass |
US20040241659A1 (en) * | 2003-05-30 | 2004-12-02 | Applera Corporation | Apparatus and method for hybridization and SPR detection |
US20040259100A1 (en) | 2003-06-20 | 2004-12-23 | Illumina, Inc. | Methods and compositions for whole genome amplification and genotyping |
WO2005024043A2 (en) | 2003-09-03 | 2005-03-17 | Government Of The United States Of America, As Represented By Secretary, Department Of Health And Human Services | Methods for identifying, diagnosing, and predicting survival of lymphomas |
US8131475B2 (en) | 2003-09-03 | 2012-03-06 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Methods for identifying, diagnosing, and predicting survival of lymphomas |
WO2005026686A2 (en) * | 2003-09-09 | 2005-03-24 | Compass Genetics, Llc | Multiplexed analytical platform |
EP1676133A4 (en) * | 2003-09-15 | 2008-05-21 | Millipore Corp | Assays with primary cells |
US7488451B2 (en) * | 2003-09-15 | 2009-02-10 | Millipore Corporation | Systems for particle manipulation |
WO2005029705A2 (en) | 2003-09-18 | 2005-03-31 | Bioarray Solutions, Ltd. | Number coding for identification of subtypes of coded types of solid phase carriers |
ES2533876T3 (en) | 2003-10-29 | 2015-04-15 | Bioarray Solutions Ltd | Multiplexed nucleic acid analysis by double stranded DNA fragmentation |
US20050147977A1 (en) * | 2003-12-29 | 2005-07-07 | Tae-Woong Koo | Methods and compositions for nucleic acid detection and sequence analysis |
US20050266432A1 (en) * | 2004-02-26 | 2005-12-01 | Illumina, Inc. | Haplotype markers for diagnosing susceptibility to immunological conditions |
US20080139395A1 (en) * | 2004-03-04 | 2008-06-12 | Ryoichi Imanaka | Microarray and Spotting Apparatus |
EP1730277B1 (en) | 2004-03-22 | 2009-10-28 | Nuevolution A/S | Ligational encoding using building block oligonucleotides |
US7157233B2 (en) | 2004-03-24 | 2007-01-02 | Tripath Imaging, Inc. | Methods and compositions for the detection of cervical disease |
CA2565967A1 (en) * | 2004-06-10 | 2005-12-29 | Perkinelmer Las, Inc. | Multiplexing assays for analyte detection |
US7702466B1 (en) | 2004-06-29 | 2010-04-20 | Illumina, Inc. | Systems and methods for selection of nucleic acid sequence probes |
US20060014680A1 (en) * | 2004-07-13 | 2006-01-19 | Caiding Xu | Peptides and compounds that bind to the IL-5 receptor |
US20060063159A1 (en) * | 2004-09-22 | 2006-03-23 | Applera Corporation | Post-synthesis processing system for supported oligonucleotides, and method |
EA200700990A1 (en) * | 2004-11-11 | 2008-04-28 | Афимакс, Инк. | NEW PEPTIDES THAT BIND THE ERYTHROPOIETIN RECEPTOR |
US7393665B2 (en) | 2005-02-10 | 2008-07-01 | Population Genetics Technologies Ltd | Methods and compositions for tagging and identifying polynucleotides |
JP4882074B2 (en) | 2005-02-28 | 2012-02-22 | 国立大学法人東京工業大学 | Oligonucleotide derivative, gene detection probe and DNA chip |
EP3827747A1 (en) | 2005-04-28 | 2021-06-02 | Otsuka Pharmaceutical Co., Ltd. | Pharma-informatics system |
ES2429564T3 (en) | 2005-05-18 | 2013-11-15 | Novartis Ag | Procedures for the diagnosis and treatment of diseases that have an autoimmune and / or inflammatory component |
US8486629B2 (en) | 2005-06-01 | 2013-07-16 | Bioarray Solutions, Ltd. | Creation of functionalized microparticle libraries by oligonucleotide ligation or elongation |
US8324159B2 (en) * | 2005-06-03 | 2012-12-04 | Affymax, Inc. | Erythropoietin receptor peptide formulations and uses |
US7550433B2 (en) | 2005-06-03 | 2009-06-23 | Affymax, Inc. | Erythropoietin receptor peptide formulations and uses |
US7919461B2 (en) * | 2005-06-03 | 2011-04-05 | Affymax, Inc. | Erythropoietin receptor peptide formulations and uses |
SG162795A1 (en) | 2005-06-15 | 2010-07-29 | Callida Genomics Inc | Single molecule arrays for genetic and chemical analysis |
US8232092B2 (en) * | 2005-08-09 | 2012-07-31 | Maxwell Sensors, Inc. | Apparatus and method for digital magnetic beads analysis |
US20090201504A1 (en) * | 2005-08-09 | 2009-08-13 | Maxwell Sensors, Inc. | Hydrodynamic focusing for analyzing rectangular microbeads |
US7871770B2 (en) | 2005-08-09 | 2011-01-18 | Maxwell Sensors, Inc. | Light transmitted assay beads |
US7858307B2 (en) * | 2005-08-09 | 2010-12-28 | Maxwell Sensors, Inc. | Light transmitted assay beads |
US8178278B2 (en) * | 2005-09-13 | 2012-05-15 | Affymetrix, Inc. | Miniaturized microparticles |
US7745092B2 (en) | 2005-09-13 | 2010-06-29 | Affymetrix, Inc. | Multiple step printing methods for microbarcodes |
US7329860B2 (en) | 2005-11-23 | 2008-02-12 | Illumina, Inc. | Confocal imaging methods and apparatus |
EP1969506A1 (en) * | 2005-12-13 | 2008-09-17 | Erasmus University Medical Center Rotterdam | Genetic brain tumor markers |
US20070161031A1 (en) * | 2005-12-16 | 2007-07-12 | The Board Of Trustees Of The Leland Stanford Junior University | Functional arrays for high throughput characterization of gene expression regulatory elements |
WO2007090076A2 (en) | 2006-01-27 | 2007-08-09 | Tripath Imaging, Inc. | Methods for identifying patients with an increased likelihood of having ovarian cancer and compositions therefor |
GB0605584D0 (en) * | 2006-03-20 | 2006-04-26 | Olink Ab | Method for analyte detection using proximity probes |
EP2389946A1 (en) | 2006-03-23 | 2011-11-30 | Novartis AG | Anti-tumor cell antigen antibody therapeutics |
US20090263798A1 (en) * | 2006-05-15 | 2009-10-22 | Generation Biotech, Llc | Method For Identification Of Novel Physical Linkage Of Genomic Sequences |
FR2902799B1 (en) | 2006-06-27 | 2012-10-26 | Millipore Corp | METHOD AND UNIT FOR PREPARING A SAMPLE FOR THE MICROBIOLOGICAL ANALYSIS OF A LIQUID |
WO2008027558A2 (en) | 2006-08-31 | 2008-03-06 | Codon Devices, Inc. | Iterative nucleic acid assembly using activation of vector-encoded traits |
CA2663962A1 (en) | 2006-09-19 | 2008-03-27 | Asuragen, Inc. | Mir-15, mir-26, mir-31,mir-145, mir-147, mir-188, mir-215, mir-216, mir-331, mmu-mir-292-3p regulated genes and pathways as targets for therapeutic intervention |
WO2008036765A2 (en) | 2006-09-19 | 2008-03-27 | Asuragen, Inc. | Micrornas differentially expressed in pancreatic diseases and uses thereof |
WO2008066655A2 (en) | 2006-11-02 | 2008-06-05 | Yale University | Assessment of oocyte competence |
US8569464B2 (en) | 2006-12-21 | 2013-10-29 | Emd Millipore Corporation | Purification of proteins |
US8362217B2 (en) | 2006-12-21 | 2013-01-29 | Emd Millipore Corporation | Purification of proteins |
WO2008079280A1 (en) | 2006-12-21 | 2008-07-03 | Millipore Corporation | Purification of proteins |
EP2135080A4 (en) * | 2007-03-08 | 2010-12-01 | Switchgear Genomics | Functional arrays for high throughput characterization of regulatory elements in untranslated regions of genes |
CA2683559C (en) | 2007-04-13 | 2019-09-24 | Dana Farber Cancer Institute, Inc. | Methods for treating cancer resistant to erbb therapeutics |
CA2683804A1 (en) * | 2007-04-13 | 2008-10-23 | Dana Farber Cancer Institute, Inc. | Receptor tyrosine kinase profiling |
EP4011289A1 (en) | 2007-09-25 | 2022-06-15 | Otsuka Pharmaceutical Co., Ltd. | In-body device with virtual dipole signal amplification |
US8039817B2 (en) | 2008-05-05 | 2011-10-18 | Illumina, Inc. | Compensator for multiple surface imaging |
WO2009137521A2 (en) * | 2008-05-07 | 2009-11-12 | Illumina, Inc. | Compositions and methods for providing substances to and from an array |
WO2009158143A1 (en) | 2008-05-30 | 2009-12-30 | The University Of North Carolina At Chapel Hill | Gene expression profiles to predict breast cancer outcomes |
US20110195064A1 (en) | 2008-06-06 | 2011-08-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Serv | Survival predictor for diffuse large b cell lymphoma |
US8999702B2 (en) * | 2008-06-11 | 2015-04-07 | Emd Millipore Corporation | Stirred tank bioreactor |
US8808986B2 (en) | 2008-08-27 | 2014-08-19 | Gen9, Inc. | Methods and devices for high fidelity polynucleotide synthesis |
US20100087325A1 (en) * | 2008-10-07 | 2010-04-08 | Illumina, Inc. | Biological sample temperature control system and method |
WO2010051318A2 (en) * | 2008-10-31 | 2010-05-06 | Abbott Laboratories | Genomic classification of colorectal cancer based on patterns of gene copy number alterations |
JP5632382B2 (en) * | 2008-10-31 | 2014-11-26 | アッヴィ・インコーポレイテッド | Genomic classification of non-small cell lung cancer based on gene copy number change patterns |
CA2739462A1 (en) * | 2008-10-31 | 2010-05-06 | Abbott Laboratories | Methods for assembling panels of cancer cell lines for use in testing the efficacy of one or more pharmaceutical compositions |
CN102203789B (en) * | 2008-10-31 | 2015-06-03 | Abbvie公司 | Genomic classification of malignant melanoma based on patterns of gene copy number alterations |
EP2373817A4 (en) * | 2008-12-10 | 2013-01-02 | Illumina Inc | Methods and compositions for hybridizing nucleic acids |
SG171446A1 (en) * | 2008-12-16 | 2011-07-28 | Millipore Corp | Stirred tank reactor and method |
MX2011011506A (en) | 2009-04-28 | 2012-05-08 | Proteus Biomedical Inc | Highly reliable ingestible event markers and methods for using the same. |
US8815779B2 (en) * | 2009-09-16 | 2014-08-26 | SwitchGear Genomics, Inc. | Transcription biomarkers of biological responses and methods |
US10207240B2 (en) | 2009-11-03 | 2019-02-19 | Gen9, Inc. | Methods and microfluidic devices for the manipulation of droplets in high fidelity polynucleotide assembly |
EP3085791A1 (en) | 2009-11-25 | 2016-10-26 | Gen9, Inc. | Methods and apparatuses for chip-based dna error reduction |
WO2011066185A1 (en) | 2009-11-25 | 2011-06-03 | Gen9, Inc. | Microfluidic devices and methods for gene synthesis |
GB0922377D0 (en) | 2009-12-22 | 2010-02-03 | Arab Gulf University The | Mutant LDL receptor |
US9217144B2 (en) | 2010-01-07 | 2015-12-22 | Gen9, Inc. | Assembly of high fidelity polynucleotides |
ES2596655T3 (en) | 2010-02-01 | 2017-01-11 | Illumina Inc. | Focusing procedures and optical systems and assemblies that use them |
US8716467B2 (en) * | 2010-03-03 | 2014-05-06 | Gen9, Inc. | Methods and devices for nucleic acid synthesis |
US8481903B2 (en) | 2010-03-06 | 2013-07-09 | Alexander Triener | Systems, methods, and apparatuses including a moveable optical component for detecting optical signals from a sample |
GB201004292D0 (en) * | 2010-03-15 | 2010-04-28 | Olink Ab | Assay for localised detection of analytes |
WO2011143556A1 (en) | 2010-05-13 | 2011-11-17 | Gen9, Inc. | Methods for nucleotide sequencing and high fidelity polynucleotide synthesis |
SG10201804385YA (en) | 2010-05-17 | 2018-06-28 | Emd Millipore Corp | Stimulus responsive polymers for the purification of biomolecules |
WO2011150168A1 (en) | 2010-05-28 | 2011-12-01 | Gen9, Inc. | Methods and devices for in situ nucleic acid synthesis |
CA2800913C (en) | 2010-06-03 | 2019-07-23 | Pharmacyclics, Inc. | The use of inhibitors of bruton's tyrosine kinase (btk) |
JP2013529089A (en) | 2010-06-07 | 2013-07-18 | エフ.ホフマン−ラ ロシュ アーゲー | Gene expression markers for predicting response to drug treatment with monoclonal antibodies that inhibit interleukin-6 receptor |
EP2580349A2 (en) * | 2010-06-08 | 2013-04-17 | EMD Millipore Corporation | Methods of detecting residual amounts of polymers used in the purification of biomolecules |
WO2011159942A1 (en) | 2010-06-18 | 2011-12-22 | Illumina, Inc. | Conformational probes and methods for sequencing nucleic acids |
US8759038B2 (en) | 2010-09-29 | 2014-06-24 | Illumina Cambridge Limited | Compositions and methods for sequencing nucleic acids |
EP2633069B1 (en) | 2010-10-26 | 2015-07-01 | Illumina, Inc. | Sequencing methods |
WO2012058532A2 (en) | 2010-10-28 | 2012-05-03 | Yale University | Methods and compositions for assessing and treating cancer |
EP3000883B8 (en) | 2010-11-12 | 2018-02-28 | Gen9, Inc. | Methods and devices for nucleic acids synthesis |
WO2012064975A1 (en) | 2010-11-12 | 2012-05-18 | Gen9, Inc. | Protein arrays and methods of using and making the same |
US9574173B2 (en) | 2010-11-15 | 2017-02-21 | Accelerated Biosciences Corp. | Generation of neural stem cells from human trophoblast stem cells |
US9308255B2 (en) | 2010-11-24 | 2016-04-12 | Yale University | Methods of administering D-dopachrome tautomerase (D-DT) to treat ischemia-reperfusion injury |
US8951781B2 (en) | 2011-01-10 | 2015-02-10 | Illumina, Inc. | Systems, methods, and apparatuses to image a sample for biological or chemical analysis |
GB201101621D0 (en) | 2011-01-31 | 2011-03-16 | Olink Ab | Method and product |
CA2830240A1 (en) | 2011-03-15 | 2012-09-20 | The University Of North Carolina At Chapell Hill | Methods of treating breast cancer with anthracycline therapy |
WO2012134813A1 (en) | 2011-03-31 | 2012-10-04 | St. Jude Children's Research Hospital | Methods and compositions for identifying minimal residual disease in acute lymphoblastic leukemia |
WO2012170936A2 (en) | 2011-06-09 | 2012-12-13 | Illumina, Inc. | Patterned flow-cells useful for nucleic acid analysis |
EP2721154B1 (en) | 2011-06-15 | 2019-01-02 | Gen9, Inc. | Methods for preparative in vitro cloning |
US9752176B2 (en) | 2011-06-15 | 2017-09-05 | Ginkgo Bioworks, Inc. | Methods for preparative in vitro cloning |
WO2013009705A2 (en) | 2011-07-09 | 2013-01-17 | The Trustees Of Columbia University In The City Of New York | Biomarkers, methods, and compositions for inhibiting a multi-cancer mesenchymal transition mechanism |
DK3594340T3 (en) | 2011-08-26 | 2021-09-20 | Gen9 Inc | COMPOSITIONS AND METHODS FOR COLLECTING WITH HIGH ACCURACY OF NUCLEIC ACIDS |
WO2013040251A2 (en) | 2011-09-13 | 2013-03-21 | Asurgen, Inc. | Methods and compositions involving mir-135b for distinguishing pancreatic cancer from benign pancreatic disease |
WO2013063519A1 (en) | 2011-10-26 | 2013-05-02 | Asuragen, Inc. | Methods and compositions involving mirna expression levels for distinguishing pancreatic cysts |
US20130142728A1 (en) | 2011-10-27 | 2013-06-06 | Asuragen, Inc. | Mirnas as diagnostic biomarkers to distinguish benign from malignant thyroid tumors |
WO2013063382A2 (en) | 2011-10-28 | 2013-05-02 | Illumina, Inc. | Microarray fabrication system and method |
WO2013112216A1 (en) | 2012-01-24 | 2013-08-01 | Cd Diagnostics, Llc | System for detecting infection in synovial fluid |
GB201201547D0 (en) | 2012-01-30 | 2012-03-14 | Olink Ab | Method and product |
US10202628B2 (en) | 2012-02-17 | 2019-02-12 | President And Fellows Of Harvard College | Assembly of nucleic acid sequences in emulsions |
BR112014020499A2 (en) | 2012-02-22 | 2019-09-24 | Univ Pennsylvania | isolated nucleic acid sequence, t-cell, vector, and persistent t-cell population |
US9150853B2 (en) | 2012-03-21 | 2015-10-06 | Gen9, Inc. | Methods for screening proteins using DNA encoded chemical libraries as templates for enzyme catalysis |
AU2013243300B2 (en) | 2012-04-05 | 2018-12-06 | Oregon Health & Science University | Gene expression panel for breast cancer prognosis |
EP3543350B1 (en) | 2012-04-24 | 2021-11-10 | Gen9, Inc. | Methods for sorting nucleic acids and multiplexed preparative in vitro cloning |
EP2852689B1 (en) | 2012-05-22 | 2019-12-11 | Nanostring Technologies, Inc. | Nano46 genes and methods to predict breast cancer outcome |
US9012022B2 (en) | 2012-06-08 | 2015-04-21 | Illumina, Inc. | Polymer coatings |
IL236303B (en) | 2012-06-25 | 2022-07-01 | Gen9 Inc | Methods for nucleic acid assembly and high throughput sequencing |
EP2877598A1 (en) | 2012-07-24 | 2015-06-03 | Pharmacyclics, Inc. | Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (btk) |
US9701998B2 (en) | 2012-12-14 | 2017-07-11 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US10273541B2 (en) | 2012-08-14 | 2019-04-30 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US11591637B2 (en) | 2012-08-14 | 2023-02-28 | 10X Genomics, Inc. | Compositions and methods for sample processing |
US10221442B2 (en) | 2012-08-14 | 2019-03-05 | 10X Genomics, Inc. | Compositions and methods for sample processing |
US10323279B2 (en) | 2012-08-14 | 2019-06-18 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US9951386B2 (en) | 2014-06-26 | 2018-04-24 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
CA2881685C (en) | 2012-08-14 | 2023-12-05 | 10X Genomics, Inc. | Microcapsule compositions and methods |
US10752949B2 (en) | 2012-08-14 | 2020-08-25 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US10584381B2 (en) | 2012-08-14 | 2020-03-10 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US10895534B2 (en) | 2012-08-20 | 2021-01-19 | Illumina, Inc. | Method and system for fluorescence lifetime based sequencing |
US20140100124A1 (en) | 2012-10-04 | 2014-04-10 | Asuragen, Inc. | Diagnostic mirnas for differential diagnosis of incidental pancreatic cystic lesions |
EP3591036B1 (en) | 2012-11-30 | 2023-03-22 | Accelerated BioSciences Corp. | Methods of differentiating stem cells by modulating mir-124 |
EP3567116A1 (en) | 2012-12-14 | 2019-11-13 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US10533221B2 (en) | 2012-12-14 | 2020-01-14 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
EP2954065B1 (en) | 2013-02-08 | 2021-07-28 | 10X Genomics, Inc. | Partitioning and processing of analytes and other species |
US9512422B2 (en) | 2013-02-26 | 2016-12-06 | Illumina, Inc. | Gel patterned surfaces |
EP4219750A3 (en) | 2013-03-11 | 2023-12-13 | Meso Scale Technologies, LLC. | Improved methods for conducting multiplexed assays |
DK2970356T3 (en) | 2013-03-15 | 2018-08-27 | Illumina Cambridge Ltd | Modified nucleosides or nucleotides |
EP2970909A4 (en) | 2013-03-15 | 2017-02-15 | The University of Chicago | Methods and compositions related to t-cell activity |
AU2014237003B2 (en) | 2013-03-15 | 2018-11-15 | Gen9, Inc. | Compositions and methods for multiplex nucleic acids synthesis |
EP2978860B8 (en) | 2013-03-27 | 2019-12-11 | BlueGnome Ltd | Assessment of risk of aneuploidy |
PL3017065T3 (en) | 2013-07-01 | 2019-03-29 | Illumina, Inc. | Catalyst-free surface functionalization and polymer grafting |
AU2014317843A1 (en) | 2013-09-09 | 2016-03-24 | British Columbia Cancer Agency Branch | Methods and kits for predicting outcome and methods and kits for treating breast cancer with radiation therapy |
CN112592975A (en) | 2013-09-23 | 2021-04-02 | 芝加哥大学 | Methods and compositions relating to DNA damaging agents for cancer treatment |
US9352315B2 (en) | 2013-09-27 | 2016-05-31 | Taiwan Semiconductor Manufacturing Company, Ltd. | Method to produce chemical pattern in micro-fluidic structure |
KR102392423B1 (en) | 2013-10-02 | 2022-05-02 | 더 보드 어브 트러스티스 어브 더 리랜드 스탠포드 주니어 유니버시티 | Wnt compositions and methods for purification |
CN106232831B (en) | 2013-11-06 | 2021-02-26 | 美国卫生和人力服务部 | Method for subtype classification of lymphoma types by expression profiling |
CN105934541B (en) | 2013-11-27 | 2019-07-12 | Gen9股份有限公司 | Nucleic acid library and its manufacturing method |
CN114089597A (en) | 2013-12-19 | 2022-02-25 | Illumina公司 | Substrate comprising a nanopatterned surface and method for the production thereof |
WO2015109234A1 (en) | 2014-01-16 | 2015-07-23 | Illumina, Inc. | Gene expression panel for prognosis of prostate cancer recurrence |
WO2015143400A1 (en) | 2014-03-20 | 2015-09-24 | Pharmacyclics, Inc. | Phospholipase c gamma 2 and resistance associated mutations |
AU2015243445B2 (en) | 2014-04-10 | 2020-05-28 | 10X Genomics, Inc. | Fluidic devices, systems, and methods for encapsulating and partitioning reagents, and applications of same |
US10829819B2 (en) | 2014-05-30 | 2020-11-10 | Genecentric Therapeutics, Inc. | Methods for typing of lung cancer |
CN106795553B (en) | 2014-06-26 | 2021-06-04 | 10X基因组学有限公司 | Methods of analyzing nucleic acids from individual cells or cell populations |
GB201414098D0 (en) | 2014-08-08 | 2014-09-24 | Illumina Cambridge Ltd | Modified nucleotide linkers |
US9982250B2 (en) | 2014-08-21 | 2018-05-29 | Illumina Cambridge Limited | Reversible surface functionalization |
JP6925265B2 (en) * | 2014-09-16 | 2021-08-25 | エスアールアイ インターナショナルSRI International | Discovery of Affinity Reagents and Catalysts by Fiber Optic Array Scanning Technology The present invention was made with national treasury assistance under Contract No. N66601-14-C-4059 awarded by Space and Naval Warfare Systems Command Systems Center Pacific. Government has certain rights with respect to the present invention. |
KR20170073667A (en) | 2014-10-29 | 2017-06-28 | 10엑스 제노믹스, 인크. | Methods and compositions for targeted nucleic acid sequencing |
PT3212684T (en) | 2014-10-31 | 2020-02-03 | Illumina Cambridge Ltd | Novel polymers and dna copolymer coatings |
US9975122B2 (en) | 2014-11-05 | 2018-05-22 | 10X Genomics, Inc. | Instrument systems for integrated sample processing |
GB2548059B (en) | 2014-11-26 | 2020-09-02 | Accelerated Biosciences Corp | Induced hepatocytes and uses thereof |
CN112126675B (en) | 2015-01-12 | 2022-09-09 | 10X基因组学有限公司 | Method and system for preparing nucleic acid sequencing library and library prepared by using same |
EP3262188B1 (en) | 2015-02-24 | 2021-05-05 | 10X Genomics, Inc. | Methods for targeted nucleic acid sequence coverage |
WO2016137973A1 (en) | 2015-02-24 | 2016-09-01 | 10X Genomics Inc | Partition processing methods and systems |
CA2976946C (en) | 2015-02-24 | 2023-09-19 | City Of Hope | Chemically encoded spatially addressed library screening platforms |
EP4089398A1 (en) | 2015-03-24 | 2022-11-16 | Illumina, Inc. | Carrier assemblies and systems for imaging samples for biological or chemical analysis |
WO2016196210A2 (en) | 2015-05-29 | 2016-12-08 | Illumina, Inc. | Sample carrier and assay system for conducting designated reactions |
US20180207920A1 (en) | 2015-07-17 | 2018-07-26 | Illumina, Inc. | Polymer sheets for sequencing applications |
US10066229B2 (en) | 2015-07-28 | 2018-09-04 | Otonomy, Inc. | Treatment using truncated Trk B and Trk C antagonists |
EP3331572A4 (en) | 2015-08-04 | 2019-05-01 | CD Diagnostics, Inc. | Methods for detecting adverse local tissue reaction (altr) necrosis |
WO2017034868A1 (en) | 2015-08-24 | 2017-03-02 | Illumina, Inc. | In-line pressure accumulator and flow-control system for biological or chemical assays |
US20180305748A1 (en) | 2015-10-18 | 2018-10-25 | Affymetrix, Inc. | Multiallelic Genotyping of Single Nucleotide Polymorphisms and Indels |
US11371094B2 (en) | 2015-11-19 | 2022-06-28 | 10X Genomics, Inc. | Systems and methods for nucleic acid processing using degenerate nucleotides |
US10774370B2 (en) | 2015-12-04 | 2020-09-15 | 10X Genomics, Inc. | Methods and compositions for nucleic acid analysis |
CN116509869A (en) | 2016-04-04 | 2023-08-01 | 希诺皮亚生物科学公司 | Treatment of extrapyramidal syndrome with trapidil |
CA3021569A1 (en) | 2016-04-20 | 2017-10-26 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Evaluation of mantle cell lymphoma and methods related thereto |
WO2017197338A1 (en) | 2016-05-13 | 2017-11-16 | 10X Genomics, Inc. | Microfluidic systems and methods of use |
EP3458611B1 (en) | 2016-05-17 | 2023-11-08 | Genecentric Therapeutics, Inc. | Methods for subtyping of lung squamous cell carcinoma |
CA3024747A1 (en) | 2016-05-17 | 2017-11-23 | Genecentric Therapeutics, Inc. | Methods for subtyping of lung adenocarcinoma |
KR102171865B1 (en) | 2016-05-18 | 2020-10-29 | 일루미나, 인코포레이티드 | Self-assembled patterning using patterned hydrophobic surfaces |
EP3260552A1 (en) | 2016-06-20 | 2017-12-27 | Istituto Europeo di Oncologia (IEO) | Methods and kits comprising gene signatures for stratifying breast cancer patients |
WO2018025242A2 (en) | 2016-08-04 | 2018-02-08 | Baylor Research Institute | Methods for diagnosing and treating esophageal cancer |
WO2018053228A1 (en) | 2016-09-15 | 2018-03-22 | The Regents Of The University Of California | Biomarkers for bipolar disorder and schizophrenia |
WO2018064116A1 (en) | 2016-09-28 | 2018-04-05 | Illumina, Inc. | Methods and systems for data compression |
WO2018098241A1 (en) | 2016-11-22 | 2018-05-31 | University Of Rochester | Methods of assessing risk of recurrent prostate cancer |
US10550429B2 (en) | 2016-12-22 | 2020-02-04 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US10815525B2 (en) | 2016-12-22 | 2020-10-27 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
US10011872B1 (en) | 2016-12-22 | 2018-07-03 | 10X Genomics, Inc. | Methods and systems for processing polynucleotides |
WO2018140966A1 (en) | 2017-01-30 | 2018-08-02 | 10X Genomics, Inc. | Methods and systems for droplet-based single cell barcoding |
US11746381B2 (en) | 2017-03-10 | 2023-09-05 | Cancer Diagnostics Research Innvovations, LLC | Methods for diagnosing and treating gastric cancer using miRNA expression |
JP7113842B2 (en) | 2017-03-29 | 2022-08-05 | クラウン バイオサイエンス,インコーポレイテッド(タイツァン) | Systems and methods for determining cetuximab susceptibility of gastric cancer |
WO2018213690A1 (en) | 2017-05-18 | 2018-11-22 | The Rockefeller University | Compositions and methods for diagnosing and treating diseases and disorders associated with mutant kcnj5 |
EP4230746A3 (en) | 2017-05-26 | 2023-11-01 | 10X Genomics, Inc. | Single cell analysis of transposase accessible chromatin |
US10844372B2 (en) | 2017-05-26 | 2020-11-24 | 10X Genomics, Inc. | Single cell analysis of transposase accessible chromatin |
CN110914448A (en) | 2017-06-02 | 2020-03-24 | 昂飞股份有限公司 | Array-based method for analyzing mixed samples using differentially labeled allele-specific probes |
US11441174B2 (en) | 2017-06-02 | 2022-09-13 | Affymetrix, Inc. | Array-based methods for analysing mixed samples using differently labelled allele-specific probes |
WO2018231589A1 (en) | 2017-06-14 | 2018-12-20 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Method for determining lymphoma type |
EP3655418A4 (en) | 2017-06-22 | 2021-05-19 | Triact Therapeutics, Inc. | Methods of treating glioblastoma |
US11739386B2 (en) | 2017-07-21 | 2023-08-29 | Genecentric Therapeutics, Inc. | Methods for determining response to PARP inhibitors |
US11628144B2 (en) | 2017-09-29 | 2023-04-18 | Triact Therapeutics, Inc. | Iniparib formulations and uses thereof |
WO2019084351A1 (en) | 2017-10-27 | 2019-05-02 | The Regents Of The University Of California | Salivary extracellular rna biomarkers for gingivitis |
AU2018358057B2 (en) | 2017-10-31 | 2023-03-02 | Encodia, Inc. | Kits for analysis using nucleic acid encoding and/or label |
EP3954782A1 (en) | 2017-11-15 | 2022-02-16 | 10X Genomics, Inc. | Functionalized gel beads |
US10829815B2 (en) | 2017-11-17 | 2020-11-10 | 10X Genomics, Inc. | Methods and systems for associating physical and genetic properties of biological particles |
MA51155A (en) | 2017-12-15 | 2020-10-21 | Flagship Pioneering Innovations Vi Llc | COMPOSITIONS CONSISTING OF CIRCULAR POLYRIBONUCLEOTIDES AND THEIR USES |
CN112262218A (en) | 2018-04-06 | 2021-01-22 | 10X基因组学有限公司 | System and method for quality control in single cell processing |
WO2019217758A1 (en) * | 2018-05-10 | 2019-11-14 | 10X Genomics, Inc. | Methods and systems for molecular library generation |
EP3827094A1 (en) | 2018-07-24 | 2021-06-02 | Affymetrix, Inc. | Array based method and kit for determining copy number and genotype in pseudogenes |
WO2020076897A1 (en) | 2018-10-09 | 2020-04-16 | Genecentric Therapeutics, Inc. | Detecting cancer cell of origin |
WO2020104482A1 (en) | 2018-11-20 | 2020-05-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting metastatic potential in patients suffering from sdhb-mutated paraganglioma |
CA3120895A1 (en) | 2018-12-20 | 2020-06-25 | Sergey N. Krylov | Binder selection using capillary electrophoresis |
US11293061B2 (en) | 2018-12-26 | 2022-04-05 | Illumina Cambridge Limited | Sequencing methods using nucleotides with 3′ AOM blocking group |
MA55082A (en) | 2019-03-01 | 2022-01-05 | Flagship Pioneering Innovations Vi Llc | COMPOSITIONS, METHODS, AND KITS FOR THE ADMINISTRATION OF POLYRIBONUCLEOTIDES |
CN113661242A (en) | 2019-03-25 | 2021-11-16 | 旗舰创业创新第六有限责任公司 | Compositions comprising modified cyclic polyribonucleotides and uses thereof |
US11421271B2 (en) | 2019-03-28 | 2022-08-23 | Illumina Cambridge Limited | Methods and compositions for nucleic acid sequencing using photoswitchable labels |
AU2020292427A1 (en) | 2019-06-14 | 2022-01-06 | Flagship Pioneering Innovations Vi, Llc | Circular RNAs for cellular therapy |
AU2020296190A1 (en) | 2019-06-19 | 2022-01-06 | Flagship Pioneering Innovations Vi, Llc | Methods of dosing circular polyribonucleotides |
EP4096681A1 (en) | 2020-01-29 | 2022-12-07 | Flagship Pioneering Innovations VI, LLC | Delivery of compositions comprising circular polyribonucleotides |
EP3907301A1 (en) | 2020-05-08 | 2021-11-10 | Istituto Europeo di Oncologia S.r.l. | Methods and kits for determining the risk of breast cancer recurrence |
CA3177293A1 (en) | 2020-06-22 | 2021-12-30 | Illumina Cambridge Limited | Nucleosides and nucleotides with 3' acetal blocking group |
US20220033900A1 (en) | 2020-07-28 | 2022-02-03 | Illumina Cambridge Limited | Substituted coumarin dyes and uses as fluorescent labels |
US20220195516A1 (en) | 2020-12-17 | 2022-06-23 | Illumina Cambridge Limited | Methods, systems and compositions for nucleic acid sequencing |
US20220195517A1 (en) | 2020-12-17 | 2022-06-23 | Illumina Cambridge Limited | Long stokes shift chromenoquinoline dyes and uses in sequencing applications |
US20220195196A1 (en) | 2020-12-17 | 2022-06-23 | Illumina Cambridge Limited | Alkylpyridinium coumarin dyes and uses in sequencing applications |
US20220195518A1 (en) | 2020-12-22 | 2022-06-23 | Illumina Cambridge Limited | Methods and compositions for nucleic acid sequencing |
WO2022175815A1 (en) | 2021-02-19 | 2022-08-25 | Pfizer Inc. | Methods of protecting rna |
KR20240004502A (en) | 2021-05-05 | 2024-01-11 | 일루미나 케임브리지 리미티드 | Fluorescent dyes containing bis-boron fused heterocycles and their use in sequencing |
EP4341434A1 (en) | 2021-05-20 | 2024-03-27 | Illumina, Inc. | Compositions and methods for sequencing by synthesis |
CN117677435A (en) | 2021-06-15 | 2024-03-08 | 伊鲁米纳公司 | Surface functionalization of non-aqueous gels for sequencing |
WO2023004357A1 (en) | 2021-07-23 | 2023-01-26 | Illumina, Inc. | Methods for preparing substrate surface for dna sequencing |
WO2023069927A1 (en) | 2021-10-20 | 2023-04-27 | Illumina, Inc. | Methods for capturing library dna for sequencing |
WO2023122758A1 (en) | 2021-12-22 | 2023-06-29 | Cornell University | Prognostic/predictive epigenetic breast cancer signature |
US20230215515A1 (en) | 2021-12-23 | 2023-07-06 | Illumina Software, Inc. | Facilitating secure execution of external workflows for genomic sequencing diagnostics |
WO2023122363A1 (en) | 2021-12-23 | 2023-06-29 | Illumina Software, Inc. | Dynamic graphical status summaries for nucelotide sequencing |
WO2023129764A1 (en) | 2021-12-29 | 2023-07-06 | Illumina Software, Inc. | Automatically switching variant analysis model versions for genomic analysis applications |
US20230330659A1 (en) | 2022-03-22 | 2023-10-19 | Illumina Cambridge Limited | Substrate with orthogonally functional nanodomains |
US20230304086A1 (en) | 2022-03-28 | 2023-09-28 | Illumina Cambridge Limited | Labeled avidin and methods for sequencing |
CA3223125A1 (en) | 2022-03-29 | 2023-10-05 | Illumina, Inc. | Chromenoquinoline dyes and uses in sequencing |
WO2023232829A1 (en) | 2022-05-31 | 2023-12-07 | Illumina, Inc | Compositions and methods for nucleic acid sequencing |
US20230416279A1 (en) | 2022-06-28 | 2023-12-28 | Illumina Cambridge Limited | Fluorescent dyes containing fused tetracyclic bis-boron heterocycle and uses in sequencing |
WO2024039516A1 (en) | 2022-08-19 | 2024-02-22 | Illumina, Inc. | Third dna base pair site-specific dna detection |
WO2024068889A2 (en) | 2022-09-30 | 2024-04-04 | Illumina, Inc. | Compositions and methods for reducing photo damage during sequencing |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4713326A (en) * | 1983-07-05 | 1987-12-15 | Molecular Diagnostics, Inc. | Coupling of nucleic acids to solid support by photochemical methods |
US4818681A (en) * | 1985-02-22 | 1989-04-04 | Molecular Diagnostics, Inc. | Fast and specific immobilization of nucleic acids to solid supports |
US4855225A (en) * | 1986-02-07 | 1989-08-08 | Applied Biosystems, Inc. | Method of detecting electrophoretically separated oligonucleotides |
US4882269A (en) * | 1985-12-13 | 1989-11-21 | Princeton University | Amplified hybridization assay |
Family Cites Families (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4182654A (en) * | 1974-09-18 | 1980-01-08 | Pierce Chemical Company | Production of polypeptides using polynucleotides |
US4315074A (en) * | 1978-05-19 | 1982-02-09 | Pierce Chemical Company | Molecular transformation procedure |
US4471072A (en) * | 1982-12-20 | 1984-09-11 | Uop Inc. | Preparation of carbonaceous pyropolymers |
NZ207394A (en) * | 1983-03-08 | 1987-03-06 | Commw Serum Lab Commission | Detecting or determining sequence of amino acids |
US4587044A (en) * | 1983-09-01 | 1986-05-06 | The Johns Hopkins University | Linkage of proteins to nucleic acids |
JPS60105691A (en) * | 1983-11-14 | 1985-06-11 | Nippon Zeon Co Ltd | Apparatus for synthesizing polynucleotide |
US4618600A (en) * | 1984-04-19 | 1986-10-21 | Biotechnology Research Associates, J.V. | Novel polypeptide diuretic/vasodilators |
US4631211A (en) * | 1985-03-25 | 1986-12-23 | Scripps Clinic & Research Foundation | Means for sequential solid phase organic synthesis and methods using the same |
US4965188A (en) * | 1986-08-22 | 1990-10-23 | Cetus Corporation | Process for amplifying, detecting, and/or cloning nucleic acid sequences using a thermostable enzyme |
US4701304A (en) * | 1985-04-19 | 1987-10-20 | Applied Protein Technologies, Inc. | Apparatus for automated synthesis of peptides |
WO1986006487A1 (en) * | 1985-04-22 | 1986-11-06 | Commonwealth Serum Laboratories Commission | Method for determining mimotopes |
NZ215865A (en) * | 1985-04-22 | 1988-10-28 | Commw Serum Lab Commission | Method of determining the active site of a receptor-binding analogue |
US4755558A (en) * | 1986-05-30 | 1988-07-05 | Beckman Instruments, Inc. | Using internal marker |
US4780423A (en) * | 1986-12-09 | 1988-10-25 | Ciba Corning Diagnostics Corp. | Heterogeneous fluorescence assays using controlled pore glass particles |
US4762881A (en) * | 1987-01-09 | 1988-08-09 | E. I. Du Pont De Nemours And Company | Photoreactive benzoylphenylalanines and related peptides |
US4794150A (en) * | 1987-03-11 | 1988-12-27 | Samuel Steel | Synthesis of peptide analogs |
US5010175A (en) * | 1988-05-02 | 1991-04-23 | The Regents Of The University Of California | General method for producing and selecting peptides with specific properties |
US4952707A (en) * | 1988-06-30 | 1990-08-28 | Tropix, Inc. | Enzymatically-cleavable chemiluminescent fused polycyclic ring-containing 1,2-dioxetanes |
AU3869289A (en) * | 1988-07-14 | 1990-02-05 | Baylor College Of Medicine | Solid phase assembly and reconstruction of biopolymers |
US4988625A (en) * | 1988-11-09 | 1991-01-29 | Merck & Co., Inc. | Method for determining the functionalization of a solid support |
US5049656A (en) * | 1988-12-21 | 1991-09-17 | Board Of Regents Of The University Of Nebraska | Sequential peptide and oligonucleotide syntheses using immunoaffinity techniques |
JPH02299598A (en) * | 1989-04-14 | 1990-12-11 | Ro Inst For Molecular Genetics & Geneteic Res | Determination by means of hybridization, together with oligonucleotide probe of all or part of extremely short sequence in sample of nucleic acid connecting with separate particle of microscopic size |
DE69028402T2 (en) * | 1989-05-22 | 1997-04-17 | Hoffmann La Roche | METHOD FOR MARKING AND DETECTING SUBSTANCES WITH NUCLEIC ACIDS |
US5143854A (en) * | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
US5427908A (en) * | 1990-05-01 | 1995-06-27 | Affymax Technologies N.V. | Recombinant library screening methods |
US5723286A (en) * | 1990-06-20 | 1998-03-03 | Affymax Technologies N.V. | Peptide library and screening systems |
US5650489A (en) * | 1990-07-02 | 1997-07-22 | The Arizona Board Of Regents | Random bio-oligomer library, a method of synthesis thereof, and a method of use thereof |
US5264563A (en) * | 1990-08-24 | 1993-11-23 | Ixsys Inc. | Process for synthesizing oligonucleotides with random codons |
WO1992003461A1 (en) * | 1990-08-24 | 1992-03-05 | Ixsys, Inc. | Methods of synthesizing oligonucleotides with random codons |
IL99553A0 (en) * | 1990-09-28 | 1992-08-18 | Ixsys Inc | Compositions containing oligonucleotides linked to expression elements,a kit for the preparation of vectors useful for the expression of a diverse population of random peptides and methods utilizing the same |
EP0558671B1 (en) * | 1990-11-21 | 1999-01-27 | Iterex Pharmaceuticals Ltd. Partnership | Synthesis of equimolar multiple oligomer mixtures, especially of oligopeptide mixtures |
ES2155822T3 (en) * | 1990-12-06 | 2001-06-01 | Affymetrix Inc | COMPOUNDS AND ITS USE IN A BINARY SYNTHESIS STRATEGY. |
AU669489B2 (en) * | 1991-09-18 | 1996-06-13 | Affymax Technologies N.V. | Method of synthesizing diverse collections of oligomers |
US5639603A (en) * | 1991-09-18 | 1997-06-17 | Affymax Technologies N.V. | Synthesizing and screening molecular diversity |
US5573905A (en) * | 1992-03-30 | 1996-11-12 | The Scripps Research Institute | Encoded combinatorial chemical libraries |
WO1994002515A1 (en) * | 1992-07-21 | 1994-02-03 | Bunsen Rush Laboratories Inc. | Oligomer library formats and methods relating thereto |
EP0665897B1 (en) * | 1992-10-01 | 2003-07-09 | The Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
US5324483B1 (en) * | 1992-10-08 | 1996-09-24 | Warner Lambert Co | Apparatus for multiple simultaneous synthesis |
US6087186A (en) * | 1993-07-16 | 2000-07-11 | Irori | Methods and apparatus for synthesizing labeled combinatorial chemistry libraries |
-
1992
- 1992-09-16 AU AU26619/92A patent/AU669489B2/en not_active Ceased
- 1992-09-16 JP JP50558793A patent/JP2001524926A/en not_active Ceased
- 1992-09-16 EP EP92920422A patent/EP0604552B1/en not_active Revoked
- 1992-09-16 US US07/946,239 patent/US5770358A/en not_active Expired - Fee Related
- 1992-09-16 DE DE69217497T patent/DE69217497T2/en not_active Expired - Fee Related
- 1992-09-16 CA CA002118806A patent/CA2118806A1/en not_active Abandoned
- 1992-09-16 DK DK92920422.0T patent/DK0604552T3/en active
- 1992-09-16 ES ES92920422T patent/ES2097925T3/en not_active Expired - Lifetime
- 1992-09-16 WO PCT/US1992/007815 patent/WO1993006121A1/en not_active Application Discontinuation
- 1992-09-16 AT AT92920422T patent/ATE148889T1/en not_active IP Right Cessation
- 1992-09-16 EP EP96202827A patent/EP0773227A1/en not_active Withdrawn
-
1995
- 1995-06-07 US US08/488,470 patent/US5708153A/en not_active Expired - Fee Related
- 1995-06-07 US US08/484,505 patent/US5789162A/en not_active Expired - Fee Related
-
1997
- 1997-04-15 GR GR970400818T patent/GR3023156T3/en unknown
-
1998
- 1998-03-06 US US09/036,599 patent/US6143497A/en not_active Expired - Fee Related
- 1998-05-13 US US09/078,403 patent/US6165717A/en not_active Expired - Fee Related
- 1998-09-11 US US09/151,467 patent/US6140493A/en not_active Expired - Fee Related
-
1999
- 1999-02-24 US US09/256,838 patent/US6416949B1/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4713326A (en) * | 1983-07-05 | 1987-12-15 | Molecular Diagnostics, Inc. | Coupling of nucleic acids to solid support by photochemical methods |
US4818681A (en) * | 1985-02-22 | 1989-04-04 | Molecular Diagnostics, Inc. | Fast and specific immobilization of nucleic acids to solid supports |
US4882269A (en) * | 1985-12-13 | 1989-11-21 | Princeton University | Amplified hybridization assay |
US4855225A (en) * | 1986-02-07 | 1989-08-08 | Applied Biosystems, Inc. | Method of detecting electrophoretically separated oligonucleotides |
Non-Patent Citations (3)
Title |
---|
Nature, Vol. 354, issued 07 November 1991, LAM et al., "A new synthetic peptide library for identifying ligand-binding activity", pages 82-84, see especially Figure 1. * |
Proceedings of the National Academy of Sciences, USA, Vol. 81, issued July 1984, GEYSEN et al., "Use of peptide synthesis to probe viral antigens for epitopes to a resolution of a single amino acid", pages 3998-4002, see Abstract. * |
Science, Vol. 251, issued 15 February 1991, FODOR et al., "Light-directed, spatially addressable parallel chemical synthesis", pages 767-773, see especially Figures 3 and 6. * |
Cited By (434)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0643778A4 (en) * | 1992-03-30 | 1995-09-20 | Scripps Research Inst | Encoded combinatorial chemical libraries. |
EP0643778A1 (en) * | 1992-03-30 | 1995-03-22 | The Scripps Research Institute | Encoded combinatorial chemical libraries |
EP1324045A3 (en) * | 1992-04-29 | 2003-09-10 | Affymetrix, Inc. (a Delaware Corporation) | Factorial chemical libraries |
EP0639276A1 (en) * | 1992-04-29 | 1995-02-22 | Affymax Technologies N.V. | Factorial chemical libraries |
EP1324045A2 (en) * | 1992-04-29 | 2003-07-02 | Affymetrix, Inc. (a Delaware Corporation) | Factorial chemical libraries |
EP0639276A4 (en) * | 1992-04-29 | 1995-09-20 | Affymax Tech Nv | Factorial chemical libraries. |
US6114114A (en) * | 1992-07-17 | 2000-09-05 | Incyte Pharmaceuticals, Inc. | Comparative gene transcript analysis |
US5840484A (en) * | 1992-07-17 | 1998-11-24 | Incyte Pharmaceuticals, Inc. | Comparative gene transcript analysis |
EP0659188A1 (en) * | 1992-09-11 | 1995-06-28 | Affymax Technologies N.V. | Methods for the synthesis of phosphonate esters |
EP0659188A4 (en) * | 1992-09-11 | 1995-11-22 | Affymax Tech Nv | Methods for the synthesis of phosphonate esters. |
EP0665897A4 (en) * | 1992-10-01 | 1995-09-27 | Univ Columbia | Complex combinatorial chemical libraries encoded with tags. |
US6503759B1 (en) | 1992-10-01 | 2003-01-07 | The Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
US5968736A (en) * | 1992-10-01 | 1999-10-19 | Cold Spring Harbor Laboratory | Methods for recording the reaction history of a solid support |
US5721099A (en) * | 1992-10-01 | 1998-02-24 | Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
EP0665897A1 (en) * | 1992-10-01 | 1995-08-09 | The Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
US5565324A (en) * | 1992-10-01 | 1996-10-15 | The Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
US5789172A (en) * | 1992-10-01 | 1998-08-04 | Trustees Of The Columbia University In The City Of New York | Methods of determining the structure of a compound encoded by identifiers having tags |
US5807683A (en) * | 1992-11-19 | 1998-09-15 | Combichem, Inc. | Combinatorial libraries and methods for their use |
EP0675873A4 (en) * | 1992-12-11 | 2000-03-29 | Chiron Corp | Synthesis of encoded polymers |
EP0675873A1 (en) * | 1992-12-11 | 1995-10-11 | Chiron Corporation | Synthesis of encoded polymers |
US6864048B2 (en) | 1993-04-28 | 2005-03-08 | Affymetrix, Inc. | Factorial chemical libraries |
US6090912A (en) * | 1993-05-27 | 2000-07-18 | Selectide Corporation | Topologically segregated, encoded solid phase libraries comprising linkers having an enzymatically susceptible bond |
AU686186B2 (en) * | 1993-05-27 | 1998-02-05 | Aventisub Ii Inc. | Topologically segregated, encoded solid phase libraries |
EP1310510A3 (en) * | 1993-05-27 | 2004-04-21 | Selectide Corporation | Topologically segregated, encoded solid phase libraries |
US5840485A (en) * | 1993-05-27 | 1998-11-24 | Selectide Corporation | Topologically segregated, encoded solid phase libraries |
US6087186A (en) * | 1993-07-16 | 2000-07-11 | Irori | Methods and apparatus for synthesizing labeled combinatorial chemistry libraries |
US5770455A (en) * | 1993-07-19 | 1998-06-23 | Ontogen Corporation | Methods and apparatus for synthesizing labeled combinatorial chemistrylibraries |
WO1995003315A3 (en) * | 1993-07-21 | 1995-06-01 | Oxford Glycosystems Ltd | Saccharides, their synthesis and use |
WO1995003315A2 (en) * | 1993-07-21 | 1995-02-02 | Oxford Glycosystems Ltd | Saccharides, their synthesis and use |
CN1088758C (en) * | 1993-07-30 | 2002-08-07 | 牛津基因技术有限公司 | Tag reagent and assay method |
US6576426B2 (en) | 1993-07-30 | 2003-06-10 | Oxford Gene Technology Limited | Tag reagent and assay method |
US6218111B1 (en) | 1993-07-30 | 2001-04-17 | Oxford Gene Technology Limited | Tag reagent and assay method |
EP0778280A2 (en) | 1993-07-30 | 1997-06-11 | Isis Innovation Limited | Tag reagent and assay method |
US5770367A (en) * | 1993-07-30 | 1998-06-23 | Oxford Gene Technology Limited | Tag reagent and assay method |
WO1995004160A1 (en) * | 1993-07-30 | 1995-02-09 | Isis Innovation Limited | Tag reagent and assay method |
US6001579A (en) * | 1993-10-01 | 1999-12-14 | The Trustees Of Columbia University | Supports and combinatorial chemical libraries thereof encoded by non-sequencable tags |
US5922545A (en) * | 1993-10-29 | 1999-07-13 | Affymax Technologies N.V. | In vitro peptide and antibody display libraries |
US5503805A (en) * | 1993-11-02 | 1996-04-02 | Affymax Technologies N.V. | Apparatus and method for parallel coupling reactions |
WO1995016209A1 (en) * | 1993-12-09 | 1995-06-15 | Ciba-Geigy Ag | Process for the production of combinatorial compound libraries |
US5804563A (en) * | 1994-01-13 | 1998-09-08 | The Trustees Of Columbia University In The City Of New York | Synthetic receptors, libraries and uses thereof |
WO1995021850A1 (en) * | 1994-02-09 | 1995-08-17 | Martek Biosciences Corporation | Generation and screening of synthetic drug libraries |
US5593853A (en) * | 1994-02-09 | 1997-01-14 | Martek Corporation | Generation and screening of synthetic drug libraries |
WO1995024186A1 (en) * | 1994-03-11 | 1995-09-14 | Pharmacopeia, Inc. | Sulfonamide derivatives and their use |
US5756810A (en) * | 1994-03-11 | 1998-05-26 | Pharmacopeia, Inc. | Process of preparing 3-nitro benzoate compounds in lower alkanol |
US5618825A (en) * | 1994-03-11 | 1997-04-08 | Pharmacopeia, Inc. | Combinatorial sulfonamide library |
US6936477B2 (en) | 1994-04-13 | 2005-08-30 | The Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
US5525734A (en) * | 1994-06-22 | 1996-06-11 | Affymax Technologies N.V. | Methods for synthesizing diverse collections of pyrrolidine compounds |
US5525735A (en) * | 1994-06-22 | 1996-06-11 | Affymax Technologies Nv | Methods for synthesizing diverse collections of pyrrolidine compounds |
US5939268A (en) * | 1994-07-26 | 1999-08-17 | The Scripps Research Institute | Combinatorial libraries of molecules and methods for producing same |
WO1996003418A1 (en) * | 1994-07-26 | 1996-02-08 | The Scripps Research Institute | Soluble combinatorial libraries |
USRE43097E1 (en) | 1994-10-13 | 2012-01-10 | Illumina, Inc. | Massively parallel signature sequencing by ligation of encoded adaptors |
US5846719A (en) * | 1994-10-13 | 1998-12-08 | Lynx Therapeutics, Inc. | Oligonucleotide tags for sorting and identification |
US5604097A (en) * | 1994-10-13 | 1997-02-18 | Spectragen, Inc. | Methods for sorting polynucleotides using oligonucleotide tags |
US6172218B1 (en) | 1994-10-13 | 2001-01-09 | Lynx Therapeutics, Inc. | Oligonucleotide tags for sorting and identification |
USRE39793E1 (en) | 1994-10-13 | 2007-08-21 | Solexa, Inc. | Compositions for sorting polynucleotides |
US5635400A (en) * | 1994-10-13 | 1997-06-03 | Spectragen, Inc. | Minimally cross-hybridizing sets of oligonucleotide tags |
US6150516A (en) * | 1994-10-13 | 2000-11-21 | Lynx Therapeutics, Inc. | Kits for sorting and identifying polynucleotides |
US6140489A (en) * | 1994-10-13 | 2000-10-31 | Lynx Therapeutics, Inc. | Compositions for sorting polynucleotides |
US6138077A (en) * | 1994-10-13 | 2000-10-24 | Lynx Therapeutics, Inc. | Method, apparatus and computer program product for determining a set of non-hybridizing oligonucleotides |
US6172214B1 (en) | 1994-10-13 | 2001-01-09 | Lynx Therapeutics, Inc. | Oligonucleotide tags for sorting and identification |
EP1724348A3 (en) * | 1994-10-13 | 2008-10-08 | Solexa, Inc. | Solid phase supports with PNA and amidate tag compliments |
US6352828B1 (en) | 1994-10-13 | 2002-03-05 | Lynx Therapeutics, Inc. | Oligonucleotide tags for sorting and identification |
WO1996012014A1 (en) * | 1994-10-13 | 1996-04-25 | Lynx Therapeutics, Inc. | Molecular tagging system |
WO1996012039A1 (en) * | 1994-10-13 | 1996-04-25 | Lynx Therapeutics, Inc. | Massively parallel sequencing of sorted polynucleotides |
EP0952216A3 (en) * | 1994-10-13 | 2000-01-19 | Lynx Therapeutics, Inc. | Solid phase supports with PNA and amidate tag compliments |
US6235475B1 (en) | 1994-10-13 | 2001-05-22 | Lynx Therapeutics, Inc. | Oligonucleotide tags for sorting and identification |
AU712929B2 (en) * | 1994-10-13 | 1999-11-18 | Lynx Therapeutics, Inc. | Molecular tagging system |
US6280935B1 (en) | 1994-10-13 | 2001-08-28 | Lynx Therapeutics, Inc. | Method of detecting the presence or absence of a plurality of target sequences using oligonucleotide tags |
EP0952216A2 (en) * | 1994-10-13 | 1999-10-27 | Lynx Therapeutics, Inc. | Solid phase supports with PNA and amidate tag compliments |
EP2110445A3 (en) * | 1994-10-13 | 2010-06-02 | Solexa, Inc. | Molecular tagging system |
US5681484A (en) * | 1994-11-10 | 1997-10-28 | David Sarnoff Research Center, Inc. | Etching to form cross-over, non-intersecting channel networks for use in partitioned microelectronic and fluidic device arrays for clinical diagnostics and chemical synthesis |
US5846396A (en) * | 1994-11-10 | 1998-12-08 | Sarnoff Corporation | Liquid distribution system |
US5858804A (en) * | 1994-11-10 | 1999-01-12 | Sarnoff Corporation | Immunological assay conducted in a microlaboratory array |
US5643738A (en) * | 1994-11-10 | 1997-07-01 | David Sarnoff Research Center, Inc. | Method of synthesis of plurality of compounds in parallel using a partitioned solid support |
US5755942A (en) * | 1994-11-10 | 1998-05-26 | David Sarnoff Research Center, Inc. | Partitioned microelectronic device array |
US5863708A (en) * | 1994-11-10 | 1999-01-26 | Sarnoff Corporation | Partitioned microelectronic device array |
US5585069A (en) * | 1994-11-10 | 1996-12-17 | David Sarnoff Research Center, Inc. | Partitioned microelectronic and fluidic device array for clinical diagnostics and chemical synthesis |
US6153375A (en) * | 1994-11-18 | 2000-11-28 | Cambridge Combinatorial Limited | Method of making a library of compounds using a functionalized polymer support resin affixed to a laminar material |
GB2295152A (en) * | 1994-11-18 | 1996-05-22 | Pfizer Ltd | Preparation of a library of compounds by solid-phase synthesis |
USRE39606E1 (en) | 1995-02-02 | 2007-05-01 | Nexus Biosystems, Inc. | Methods and apparatus for synthesizing labeled combinatorial chemistry libraries |
WO1996024061A1 (en) * | 1995-02-02 | 1996-08-08 | Ontogen Corporation | Methods and apparatus for synthesizing labeled combinatorial chemical libraries |
USRE39545E1 (en) * | 1995-02-02 | 2007-04-03 | Nexus Biosystems, Inc. | Methods and apparatus for synthesizing labeled combinatorial chemistry libraries |
US5925562A (en) * | 1995-04-25 | 1999-07-20 | Irori | Remotely programmable matrices with memories |
WO1997003931A1 (en) * | 1995-07-22 | 1997-02-06 | Zeneca Limited | Intrinsically labelled solid support |
WO1997012680A2 (en) * | 1995-10-03 | 1997-04-10 | Irori | Matrices with memories, sensors with memories and uses thereof |
WO1997012680A3 (en) * | 1995-10-03 | 1997-08-21 | Irori | Matrices with memories, sensors with memories and uses thereof |
EP1018365A3 (en) * | 1995-10-26 | 2000-10-11 | University Of Hertfordshire | Coded particles for process sequence tracking in combinatorial compound library preparation |
EP1018365A2 (en) * | 1995-10-26 | 2000-07-12 | University Of Hertfordshire | Coded particles for process sequence tracking in combinatorial compound library preparation |
WO1997015390A1 (en) * | 1995-10-26 | 1997-05-01 | University Of Hertfordshire | Coded particles for process sequence tracking in combinatorial compound library preparation |
AU696505B2 (en) * | 1995-10-26 | 1998-09-10 | 3D Molecular Sciences Limited | Coded particles for process sequence tracking in combinatorial compound library preparation |
US6566515B1 (en) | 1995-12-15 | 2003-05-20 | Affymetrix, Inc. | Photocleavable protecting groups and methods for their use |
US7470783B2 (en) | 1995-12-15 | 2008-12-30 | Affymetrix, Inc. | Photocleavable protecting groups and methods for their use |
US6881836B2 (en) | 1995-12-15 | 2005-04-19 | Affymetrix, Inc | Photocleavable protecting groups and methods for their use |
US5846839A (en) * | 1995-12-22 | 1998-12-08 | Glaxo Group Limited | Methods for hard-tagging an encoded synthetic library |
US6368874B1 (en) | 1995-12-22 | 2002-04-09 | Affymax, Inc. | Methods for hard-tagging an encoded synthetic library |
US5649576A (en) * | 1996-02-26 | 1997-07-22 | Pharmacopeia, Inc. | Partitioning device |
DE19609272C2 (en) * | 1996-02-27 | 2000-05-25 | Schering Ag | Process for the parallel synthesis of large numbers of 2,6-disubstituted quinoline derivatives |
DE19609272A1 (en) * | 1996-02-27 | 1997-08-28 | Schering Ag | New 2,6-di:substituted quinoline derivatives |
EP1726959A3 (en) * | 1996-04-25 | 2007-07-11 | BioArray Solutions Ltd. | Light-controlled electrokinetic Assembly of particles near surfaces |
US7090759B1 (en) | 1996-04-25 | 2006-08-15 | Bioarray Solutions Ltd. | Apparatus and method for light-controlled electrokinetic assembly of particles near surfaces |
EP1726958A3 (en) * | 1996-04-25 | 2007-07-11 | BioArray Solutions Ltd. | Light-controlled electrokinetic assembly of particles near surfaces |
US8691594B2 (en) | 1996-04-25 | 2014-04-08 | Bioarray Solutions, Ltd. | Method of making a microbead array with attached biomolecules |
US6955751B1 (en) | 1996-04-25 | 2005-10-18 | Bioarray Solutions Ltd. | Light-controlled electrokinetic assembly of particles near surfaces |
EP1726958A2 (en) * | 1996-04-25 | 2006-11-29 | BioArray Solutions Ltd. | Light-controlled electrokinetic assembly of particles near surfaces |
US6958245B2 (en) | 1996-04-25 | 2005-10-25 | Bioarray Solutions Ltd. | Array cytometry |
US7749774B2 (en) | 1996-04-25 | 2010-07-06 | Michael Seul | Arrays formed of encoded beads having ligands attached |
US7291504B2 (en) | 1996-04-25 | 2007-11-06 | Bioarray Solutions Ltd. | Assay involving detection and identification with encoded particles |
EP1726959A2 (en) * | 1996-04-25 | 2006-11-29 | BioArray Solutions Ltd. | Light-controlled electrokinetic Assembly of particles near surfaces |
EP1726957A3 (en) * | 1996-04-25 | 2007-07-11 | BioArray Solutions Ltd. | Light-controlled electrokinetic assembly of particles near surfaces |
US7615345B2 (en) | 1996-04-25 | 2009-11-10 | Bio Array Solutions Ltd. | Arrays formed of encoded beads having oligonucleotides attached |
US9400259B2 (en) | 1996-04-25 | 2016-07-26 | Bioarray Solutions, Ltd. | Method of making a microbead array with attached biomolecules |
US6514771B1 (en) | 1996-04-25 | 2003-02-04 | Bioarray Solutions | Light-controlled electrokinetic assembly of particles near surfaces |
US6797524B1 (en) | 1996-04-25 | 2004-09-28 | Bioarray Solutions Ltd. | Light-controlled electrokinetic assembly of particles near surfaces |
US7427512B2 (en) | 1996-04-25 | 2008-09-23 | Bioarray Solutions Ltd. | Light-controlled electrokinetic assembly of particles near surfaces |
EP2290364A1 (en) * | 1996-04-25 | 2011-03-02 | BioArray Solutions Ltd. | Light-controlled electrokinetic assembly of particles near surfaces |
US6991941B1 (en) | 1996-04-25 | 2006-01-31 | Bioarray Solutions Ltd. | Light-controlled electrokinetic assembly of particles near surfaces |
US6468811B1 (en) | 1996-04-25 | 2002-10-22 | Bioarray Solutions | Light-controlled electrokinetic assembly of particles near surfaces |
US7041510B2 (en) | 1996-04-25 | 2006-05-09 | Bioarray Solutions Ltd. | System and method for programmable illumination pattern generation |
US7056746B2 (en) | 1996-04-25 | 2006-06-06 | Bioarray Solutions Ltd. | Array cytometry |
US5914229A (en) * | 1996-06-14 | 1999-06-22 | Sarnoff Corporation | Method for amplifying a polynucleotide |
US5912124A (en) * | 1996-06-14 | 1999-06-15 | Sarnoff Corporation | Padlock probe detection |
US5908755A (en) * | 1996-06-14 | 1999-06-01 | Sarnoff Corporation | Sequential step method for sequencing and identifying polynucleotides |
US5770370A (en) * | 1996-06-14 | 1998-06-23 | David Sarnoff Research Center, Inc. | Nuclease protection assays |
WO1997049653A3 (en) * | 1996-06-24 | 1998-02-26 | Irori | Solid phase tyrphostin library linked to matrices with memories |
WO1997049653A2 (en) * | 1996-06-24 | 1997-12-31 | Irori | Solid phase tyrphostin library linked to matrices with memories |
US5932546A (en) * | 1996-10-04 | 1999-08-03 | Glaxo Wellcome Inc. | Peptides and compounds that bind to the thrombopoietin receptor |
WO1998022487A1 (en) * | 1996-11-15 | 1998-05-28 | Synsorb Biotech, Inc. | Combinatorial synthesis of carbohydrate libraries |
US5965719A (en) * | 1996-11-15 | 1999-10-12 | Sunsorb Biotech, Inc. | Combinatorial synthesis of carbohydrate libraries |
WO1998029744A2 (en) * | 1997-01-03 | 1998-07-09 | Telik, Inc. | Method to classify gene products |
WO1998029744A3 (en) * | 1997-01-03 | 1998-11-12 | Terrapin Tech Inc | Method to classify gene products |
US9377388B2 (en) | 1997-03-14 | 2016-06-28 | Trustees Of Tufts College | Methods for detecting target analytes and enzymatic reactions |
US10241026B2 (en) | 1997-03-14 | 2019-03-26 | Trustees Of Tufts College | Target analyte sensors utilizing microspheres |
US5976894A (en) * | 1997-04-14 | 1999-11-02 | Pharmacopeia, Inc. | Combinatorial amide alcohol libraries |
WO1998053093A1 (en) * | 1997-05-23 | 1998-11-26 | Bioarray Solutions Llc | Color-encoding and in-situ interrogation of matrix-coupled chemical compounds |
AU756945B2 (en) * | 1997-05-23 | 2003-01-30 | Bioarray Solutions Ltd | Color-encoding and in-situ interrogation of matrix-coupled chemical compounds |
US7083914B2 (en) | 1997-05-23 | 2006-08-01 | Bioarray Solutions Ltd. | Color-encoding and in-situ interrogation of matrix-coupled chemical compounds |
US9945051B2 (en) | 1997-05-23 | 2018-04-17 | Rutgers, The State University Of New Jersey | Color-encoding and in-situ interrogation of matrix-coupled chemical compounds |
WO1999018240A2 (en) * | 1997-10-06 | 1999-04-15 | Stratagene | Collections of uniquely tagged molecules |
US6607878B2 (en) | 1997-10-06 | 2003-08-19 | Stratagene | Collections of uniquely tagged molecules |
WO1999018240A3 (en) * | 1997-10-06 | 1999-09-30 | Stratagene Inc | Collections of uniquely tagged molecules |
US6696245B2 (en) | 1997-10-20 | 2004-02-24 | Domantis Limited | Methods for selecting functional polypeptides |
EP2230335A2 (en) | 1997-10-20 | 2010-09-22 | Domantis Limited | Method to screen phage display libraries with different ligands |
EP2308973A1 (en) | 1997-10-20 | 2011-04-13 | Domantis Limited | Method to screen phage display libraries with different ligands |
EP2033661A1 (en) | 1997-11-07 | 2009-03-11 | ConjuChem Biotechnologies Inc. | Methods of screening affinity marker libraries |
WO1999024458A1 (en) * | 1997-11-12 | 1999-05-20 | The University Of Queensland | Carrier-reporter bead assemblies |
US7338768B1 (en) | 1997-11-12 | 2008-03-04 | Nanomics Biosystems Pty. Ltd. | Carrier-reporter bead assemblies |
EP2305282A2 (en) | 1997-12-02 | 2011-04-06 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidogenic disease |
EP1994937A2 (en) | 1997-12-02 | 2008-11-26 | Elan Pharma International Limited | Prevention and treatment of amyloidogenic disease |
WO1999064867A1 (en) * | 1997-12-04 | 1999-12-16 | Amersham Pharmacia Biotech Uk Limited | Multiple assay method |
US6265163B1 (en) | 1998-01-09 | 2001-07-24 | Lynx Therapeutics, Inc. | Solid phase selection of differentially expressed genes |
WO1999050658A2 (en) * | 1998-03-30 | 1999-10-07 | The Regents Of The University Of California | Methods and compounds for modulating nuclear receptor activity |
WO1999050658A3 (en) * | 1998-03-30 | 2001-08-16 | Univ California | Methods and compounds for modulating nuclear receptor activity |
US9540689B2 (en) | 1998-05-01 | 2017-01-10 | Life Technologies Corporation | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US9096898B2 (en) | 1998-05-01 | 2015-08-04 | Life Technologies Corporation | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US9458500B2 (en) | 1998-05-01 | 2016-10-04 | Life Technologies Corporation | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US10214774B2 (en) | 1998-05-01 | 2019-02-26 | Life Technologies Corporation | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US9725764B2 (en) | 1998-05-01 | 2017-08-08 | Life Technologies Corporation | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US9957561B2 (en) | 1998-05-01 | 2018-05-01 | Life Technologies Corporation | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US10208341B2 (en) | 1998-05-01 | 2019-02-19 | Life Technologies Corporation | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US9212393B2 (en) | 1998-05-01 | 2015-12-15 | Life Technologies Corporation | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US7645596B2 (en) | 1998-05-01 | 2010-01-12 | Arizona Board Of Regents | Method of determining the nucleotide sequence of oligonucleotides and DNA molecules |
US6780981B1 (en) | 1998-05-15 | 2004-08-24 | Oxford Gene Technology Ip Limited | Libraries of oligomers labeled with different tags |
US7399846B2 (en) | 1998-05-15 | 2008-07-15 | Oxford Gene Technology Ip Limited | Libraries of oligomers labeled with different tags |
US7741044B2 (en) | 1998-05-15 | 2010-06-22 | Oxford Gene Technology Ip Limited | Libraries of oligomers labeled with different tags |
JP2002515588A (en) * | 1998-05-15 | 2002-05-28 | イシス・イノベイション・リミテッド | Reagents and methods |
US6897305B2 (en) | 1998-06-08 | 2005-05-24 | Theravance, Inc. | Calcium channel drugs and uses |
US6420354B1 (en) | 1998-06-08 | 2002-07-16 | Advanced Medicine, Inc. | Sodium channel drugs and uses |
US6566509B1 (en) | 1998-06-08 | 2003-05-20 | Theravance, Inc. | Multivalent macrolide antibiotics |
US6288055B1 (en) | 1998-06-08 | 2001-09-11 | Advanced Medicine, Inc. | Analgesic agents |
WO2000020639A1 (en) * | 1998-10-05 | 2000-04-13 | Lynx Therapeutics, Inc. | Enzymatic synthesis of oligonucleotide tags |
US7101909B2 (en) | 1998-10-12 | 2006-09-05 | Theravance, Inc. | Calcium channel drugs and uses |
WO2000031536A3 (en) * | 1998-11-23 | 2000-11-16 | Harvard College | Detecting structural or synthetic information about chemical compounds |
US6541203B2 (en) * | 1998-11-23 | 2003-04-01 | President And Fellows Of Harvard College | Detecting structural or synthetic information about chemical compounds |
WO2000031536A2 (en) * | 1998-11-23 | 2000-06-02 | President And Fellows Of Harvard College | Detecting structural or synthetic information about chemical compounds |
US20110312613A1 (en) * | 1998-11-30 | 2011-12-22 | Nanomics Biosystems Pty Ltd | Carriers for combinatorial compound libraries |
US6858394B1 (en) | 1998-12-28 | 2005-02-22 | Illumina, Inc. | Composite arrays utilizing microspheres |
EP1141712B2 (en) † | 1998-12-28 | 2015-12-09 | Illumina, Inc. | Composite arrays utilizing microspheres |
EP1593967A3 (en) * | 1998-12-28 | 2007-04-25 | Illumina, Inc. | Composite arrays utilising microspheres |
US6818399B2 (en) | 1999-04-30 | 2004-11-16 | Aclara Biosciences, Inc. | Methods employing generalized target-binding e-tag probes |
US6627400B1 (en) | 1999-04-30 | 2003-09-30 | Aclara Biosciences, Inc. | Multiplexed measurement of membrane protein populations |
US6673550B2 (en) | 1999-04-30 | 2004-01-06 | Aclara Biosciences, Inc. | Electrophoretic tag reagents comprising fluorescent compounds |
US7001725B2 (en) | 1999-04-30 | 2006-02-21 | Aclara Biosciences, Inc. | Kits employing generalized target-binding e-tag probes |
US6770439B2 (en) | 1999-04-30 | 2004-08-03 | Sharat Singh | Sets of generalized target-binding e-tag probes |
EP2305302A2 (en) | 1999-05-28 | 2011-04-06 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidogenic disease |
EP2364719A1 (en) | 1999-06-01 | 2011-09-14 | Janssen Alzheimer Immunotherapy | Prevention and treatment of amyloidogenic diseases |
US6479498B1 (en) | 1999-06-04 | 2002-11-12 | Theravance, Inc. | Sodium channel drugs and uses |
US7501245B2 (en) | 1999-06-28 | 2009-03-10 | Helicos Biosciences Corp. | Methods and apparatuses for analyzing polynucleotide sequences |
WO2001029079A1 (en) | 1999-10-18 | 2001-04-26 | Prince Henry's Institute Of Medical Research | IMMUNO-INTERACTIVE FRAGMENTS OF THE αC SUBUNIT OF INHIBIN |
EP2112159A2 (en) | 1999-10-18 | 2009-10-28 | Prince Henry's Institute of Medical Research | Immuno-interactive fragments of the alpha C subunit of inhibin |
US6380356B1 (en) | 1999-12-07 | 2002-04-30 | Advanced Medicine, Inc. | Multivalent polymyxin antibiotics |
US7153977B2 (en) | 2000-01-28 | 2006-12-26 | National University Of Singapore | Ligands and methods for preparing same |
WO2001057249A1 (en) * | 2000-02-02 | 2001-08-09 | Solexa Ltd. | Synthesis of spatially addressed molecular arrays |
US7384737B2 (en) | 2000-02-02 | 2008-06-10 | Solexa Limited | Synthesis of spatially addressed molecular arrays |
US7045304B2 (en) | 2000-02-08 | 2006-05-16 | Sangamo Biosciences, Inc. | Cells for drug discovery |
US6989269B2 (en) | 2000-02-08 | 2006-01-24 | Sangamo Biosciences, Inc. | Cells for drug discovery |
US6689558B2 (en) | 2000-02-08 | 2004-02-10 | Sangamo Biosciences, Inc. | Cells for drug discovery |
EP2207032A1 (en) | 2000-02-08 | 2010-07-14 | Sangamo BioSciences, Inc. | Cells expressing zinc finger protein for drug discovery |
WO2001062772A2 (en) * | 2000-02-23 | 2001-08-30 | Xenoport, Inc. | Self-encoded combinatorial synthesis of compound multiplets |
WO2001062772A3 (en) * | 2000-02-23 | 2002-03-28 | Xenoport Inc | Self-encoded combinatorial synthesis of compound multiplets |
US7097978B2 (en) | 2000-04-28 | 2006-08-29 | Sangamo Biosciences, Inc. | Screening methods based on isolating a collection of polynucleotides corresponding to accessible regions of chromatin |
US7217509B2 (en) | 2000-04-28 | 2007-05-15 | Sangamo Biosciences, Inc. | Databases of regulatory sequences; methods of making and using same |
US7160735B2 (en) | 2000-04-28 | 2007-01-09 | Monogram Biosciences, Inc. | Tagged microparticle compositions and methods |
US7923542B2 (en) | 2000-04-28 | 2011-04-12 | Sangamo Biosciences, Inc. | Libraries of regulatory sequences, methods of making and using same |
WO2001083751A2 (en) | 2000-04-28 | 2001-11-08 | Sangamo Biosciences, Inc. | Methods for binding an exogenous molecule to cellular chromatin |
AU2001212402B2 (en) * | 2000-04-28 | 2004-11-04 | Monogram Biosciences, Inc. | Tag library compounds, compositions, kits and methods of use |
US6511808B2 (en) | 2000-04-28 | 2003-01-28 | Sangamo Biosciences, Inc. | Methods for designing exogenous regulatory molecules |
WO2001083502A1 (en) * | 2000-04-28 | 2001-11-08 | Aclara Biosciences, Inc. | Tag library compounds, compositions, kits and methods of use |
US7771929B2 (en) | 2000-04-28 | 2010-08-10 | Monogram Biosciences, Inc. | Tag library compounds, compositions, kits and methods of use |
US6610489B2 (en) | 2000-04-28 | 2003-08-26 | Sangamo Biosciences, Inc. | Pharmacogenomics and identification of drug targets by reconstruction of signal transduction pathways based on sequences of accessible regions |
EP2026073A1 (en) | 2000-04-29 | 2009-02-18 | University Of Iowa Research Foundation | Diagnostics and therapeutics for macular degeneration-related disorders |
US9709559B2 (en) | 2000-06-21 | 2017-07-18 | Bioarray Solutions, Ltd. | Multianalyte molecular analysis using application-specific random particle arrays |
US7057704B2 (en) | 2000-09-17 | 2006-06-06 | Bioarray Solutions Ltd. | System and method for programmable illumination pattern generation |
EP2360275A1 (en) * | 2000-11-15 | 2011-08-24 | Minerva Biotechnologies Corporation | Oligonucleotide identifiers |
US7887753B2 (en) | 2000-11-16 | 2011-02-15 | California Institute Of Technology | Apparatus and methods for conducting assays and high throughput screening |
EP2381116A1 (en) | 2000-11-16 | 2011-10-26 | California Institute of Technology | Apparatus and methods for conducting assays and high throughput screening |
US8673645B2 (en) | 2000-11-16 | 2014-03-18 | California Institute Of Technology | Apparatus and methods for conducting assays and high throughput screening |
US8455258B2 (en) | 2000-11-16 | 2013-06-04 | California Insitute Of Technology | Apparatus and methods for conducting assays and high throughput screening |
US10509018B2 (en) | 2000-11-16 | 2019-12-17 | California Institute Of Technology | Apparatus and methods for conducting assays and high throughput screening |
US9176137B2 (en) | 2000-11-16 | 2015-11-03 | California Institute Of Technology | Apparatus and methods for conducting assays and high throughput screening |
US8273574B2 (en) | 2000-11-16 | 2012-09-25 | California Institute Of Technology | Apparatus and methods for conducting assays and high throughput screening |
WO2002063299A1 (en) * | 2001-02-05 | 2002-08-15 | Graffinity Pharmaceuticals Ag | Low affinity screening method |
US7223545B2 (en) | 2001-03-19 | 2007-05-29 | President And Fellows Of Harvard College | Evolving new molecular function |
US7070928B2 (en) | 2001-03-19 | 2006-07-04 | President And Fellows Of Harvard College | Evolving new molecular function |
US10107804B2 (en) | 2001-03-23 | 2018-10-23 | Trustees Of Tufts College | Methods for detecting target analytes and enzymatic reactions |
US9110075B2 (en) | 2001-05-21 | 2015-08-18 | Monogram Biosciences, Inc. | Compositions for analyzing proteins |
US9939447B2 (en) | 2001-05-21 | 2018-04-10 | Monogram Biosciences, Inc. | Methods and compositions for analyzing proteins |
US7255999B2 (en) | 2001-05-21 | 2007-08-14 | Monogram Biosciences, Inc. | Methods and compositions for analyzing proteins |
US7041459B2 (en) | 2001-05-21 | 2006-05-09 | Monogram Biosciences, Inc. | Analyzing phosphorylated proteins |
US7358052B2 (en) | 2001-05-26 | 2008-04-15 | Monogram Biosciences, Inc. | Catalytic amplification of multiplexed assay signals |
US7507546B2 (en) | 2001-06-11 | 2009-03-24 | Xenoport, Inc. | Methods of screening agents, conjugates or conjugate moieties for transport by a PEPT2 transporter |
US7919454B2 (en) | 2001-06-11 | 2011-04-05 | Xenoport, Inc. | Methods of treating using conjugates transported by a PEPT2 transporter |
US10669538B2 (en) | 2001-06-20 | 2020-06-02 | Nuevolution A/S | Templated molecules and methods for using such molecules |
US7727713B2 (en) | 2001-06-20 | 2010-06-01 | Nuevolution A/S | Templated molecules and methods for using such molecules |
EP2305808A1 (en) | 2001-06-20 | 2011-04-06 | Nuevolution A/S | Templated molecules and methods for using such molecules |
US8932992B2 (en) | 2001-06-20 | 2015-01-13 | Nuevolution A/S | Templated molecules and methods for using such molecules |
US9436088B2 (en) | 2001-06-21 | 2016-09-06 | Bioarray Solutions, Ltd. | Un-supported polymeric film with embedded microbeads |
US10415081B2 (en) | 2001-10-15 | 2019-09-17 | Bioarray Solutions Ltd. | Multiplexed analysis of polymorphic loci by concurrent interrogation and enzyme-mediated detection |
WO2003035679A2 (en) | 2001-10-25 | 2003-05-01 | Medical Research Council | Molecules |
US7045311B2 (en) | 2001-10-25 | 2006-05-16 | Monogram Biosciences, Inc. | Whole cell assay systems for cell surface proteases |
US9611507B2 (en) | 2001-12-28 | 2017-04-04 | Bioarray Solutions, Ltd. | Arrays of microparticles and methods of preparation thereof |
US7335153B2 (en) | 2001-12-28 | 2008-02-26 | Bio Array Solutions Ltd. | Arrays of microparticles and methods of preparation thereof |
US10138511B2 (en) | 2001-12-28 | 2018-11-27 | Bioarray Solutions Ltd. | Arrays of microparticles and methods of preparation thereof |
US10731151B2 (en) | 2002-03-15 | 2020-08-04 | Nuevolution A/S | Method for synthesising templated molecules |
US7413854B2 (en) | 2002-03-15 | 2008-08-19 | Nuevolution A/S | Method for synthesising templated molecules |
US8808984B2 (en) | 2002-03-15 | 2014-08-19 | Neuvolution A/S | Method for synthesising templated molecules |
US7402397B2 (en) | 2002-05-21 | 2008-07-22 | Monogram Biosciences, Inc. | Detecting and profiling molecular complexes |
EP2267117A2 (en) | 2002-06-27 | 2010-12-29 | Verva Pharmaceuticals Pty Ltd | Differentiation modulating agents and uses therefor |
WO2004011026A1 (en) | 2002-07-26 | 2004-02-05 | The Walter And Eliza Hall Institute Of Medical Research | Immunogenic compositions and diagnostic and therapeutic uses thereof |
US10730906B2 (en) | 2002-08-01 | 2020-08-04 | Nuevolutions A/S | Multi-step synthesis of templated molecules |
US7491494B2 (en) | 2002-08-19 | 2009-02-17 | President And Fellows Of Harvard College | Evolving new molecular function |
US9109248B2 (en) | 2002-10-30 | 2015-08-18 | Nuevolution A/S | Method for the synthesis of a bifunctional complex |
US10077440B2 (en) | 2002-10-30 | 2018-09-18 | Nuevolution A/S | Method for the synthesis of a bifunctional complex |
US9487775B2 (en) | 2002-10-30 | 2016-11-08 | Nuevolution A/S | Method for the synthesis of a bifunctional complex |
US9284600B2 (en) | 2002-10-30 | 2016-03-15 | Neuvolution A/S | Method for the synthesis of a bifunctional complex |
US9885035B2 (en) | 2002-10-30 | 2018-02-06 | Nuevolution A/S | Method for the synthesis of a bifunctional complex |
US11001835B2 (en) | 2002-10-30 | 2021-05-11 | Nuevolution A/S | Method for the synthesis of a bifunctional complex |
WO2004041067A2 (en) | 2002-11-01 | 2004-05-21 | Elan Pharmaceuticals, Inc. | Prevention and treatment of synucleinopathic disease |
EP2361629A1 (en) | 2002-11-01 | 2011-08-31 | Elan Pharmaceuticals Inc. | Prevention and treatment of synucleinopathic disease |
US9251583B2 (en) | 2002-11-15 | 2016-02-02 | Bioarray Solutions, Ltd. | Analysis, secure access to, and transmission of array images |
US9121110B2 (en) | 2002-12-19 | 2015-09-01 | Nuevolution A/S | Quasirandom structure and function guided synthesis methods |
WO2004069182A2 (en) | 2003-02-01 | 2004-08-19 | Neuralab Limited | Active immunization to generate antibodies to soluble a-beta |
US9096951B2 (en) | 2003-02-21 | 2015-08-04 | Nuevolution A/S | Method for producing second-generation library |
WO2004083455A1 (en) | 2003-03-21 | 2004-09-30 | The Murdoch Childrens Research Institute | Therapeutic, prophylactic and diagnostic agents |
US7648828B2 (en) | 2003-04-01 | 2010-01-19 | Monogram Biosciences, Inc. | Methods for detecting receptor complexes comprising PI3K |
USRE44437E1 (en) | 2003-04-01 | 2013-08-13 | Monogram Biosciences, Inc. | Methods for detecting receptor complexes comprising PI3K |
US7160449B2 (en) | 2003-04-28 | 2007-01-09 | Vanderbilt University | Proline chiral columns with broad chiral selectivity |
EP2361928A1 (en) | 2003-05-19 | 2011-08-31 | Elan Pharmaceuticals Inc. | Truncated fragments of alpha-synuclein in Lewy body disease |
WO2005003778A2 (en) * | 2003-07-02 | 2005-01-13 | Nuevolution A/S | A method for identifying a synthetic molecule having affinity towards a target |
WO2005003778A3 (en) * | 2003-07-02 | 2005-04-14 | Nuevolution As | A method for identifying a synthetic molecule having affinity towards a target |
US8153410B2 (en) | 2003-07-07 | 2012-04-10 | Fox Chase Cancer Center | Alternate morpheein forms of allosteric proteins as a target for the development of bioactive molecules |
US11118215B2 (en) | 2003-09-18 | 2021-09-14 | Nuevolution A/S | Method for obtaining structural information concerning an encoded molecule and method for selecting compounds |
US8691754B2 (en) | 2003-09-22 | 2014-04-08 | Bioarray Solutions, Ltd. | Microparticles with enhanced covalent binding capacity and their uses |
US9637777B2 (en) | 2003-10-28 | 2017-05-02 | Bioarray Solutions, Ltd. | Optimization of gene expression analysis using immobilized capture probes |
US7897345B2 (en) | 2003-11-12 | 2011-03-01 | Helicos Biosciences Corporation | Short cycle methods for sequencing polynucleotides |
US9657344B2 (en) | 2003-11-12 | 2017-05-23 | Fluidigm Corporation | Short cycle methods for sequencing polynucleotides |
US9012144B2 (en) | 2003-11-12 | 2015-04-21 | Fluidigm Corporation | Short cycle methods for sequencing polynucleotides |
US7935658B2 (en) | 2003-12-17 | 2011-05-03 | Praecis Pharmaceuticals, Inc. | Methods for synthesis of encoded libraries |
WO2005058479A2 (en) * | 2003-12-17 | 2005-06-30 | Praecis Pharmaceuticals, Inc. | Methods for synthesis of encoded libraries |
RU2592673C2 (en) * | 2003-12-17 | 2016-07-27 | ГЛЭКСОСМИТКЛАЙН ЭлЭлСи | Biologically active compound containing coding oligonucleotide and library of compounds |
EP2366705A1 (en) | 2003-12-17 | 2011-09-21 | Praecis Pharmaceuticals Incorporated | Methods for synthesis of encoded libraries |
US7972992B2 (en) | 2003-12-17 | 2011-07-05 | Praecis Pharmaceuticals, Inc. | Methods for synthesis of encoded libraries |
WO2005058479A3 (en) * | 2003-12-17 | 2005-10-13 | Praecis Pharm Inc | Methods for synthesis of encoded libraries |
AU2011205057B2 (en) * | 2003-12-17 | 2015-01-15 | Glaxosmithkline Llc | Methods for synthesis of encoded libraries |
EP2479184A2 (en) | 2003-12-17 | 2012-07-25 | Janssen Alzheimer Immunotherapy | Beta immunogenic peptide carrier conjugates and methods of producing the same |
AU2004299145B2 (en) * | 2003-12-17 | 2011-08-25 | Glaxosmithkline Llc | Methods for synthesis of encoded libraries |
US7972994B2 (en) | 2003-12-17 | 2011-07-05 | Glaxosmithkline Llc | Methods for synthesis of encoded libraries |
EP2336147A2 (en) | 2003-12-17 | 2011-06-22 | Janssen Alzheimer Immunotherapy | A beta immunogenic peptide carrier conjugates and methods of producing same |
US8410028B2 (en) | 2003-12-17 | 2013-04-02 | Glaxosmithkline Llc | Methods for synthesis of encoded libraries |
AU2009200121B2 (en) * | 2003-12-17 | 2012-11-15 | Glaxosmithkline Llc | Methods for synthesis of encoded libraries |
WO2005058940A2 (en) | 2003-12-17 | 2005-06-30 | Wyeth | Immunogenic peptide carrier conjugates and methods of producing same |
EP2460813A1 (en) | 2003-12-17 | 2012-06-06 | Janssen Alzheimer Immunotherapy | A beta immunogenic peptide carrier conjugates and methods of producing same |
RU2470077C2 (en) * | 2003-12-17 | 2012-12-20 | ГЛЭКСОСМИТКЛАЙН ЭлЭлСи | Biologically active compound containing coding oligonucleotide (versions), method for synthesis thereof, library of compounds (versions), method for synthesis thereof, and method of searching for compound bound with biological target (versions) |
US7869011B2 (en) | 2003-12-22 | 2011-01-11 | Novo Norkisk A/S | Apparatus and methods for analysis and sorting of particles such as polymer beads |
WO2005061094A1 (en) | 2003-12-22 | 2005-07-07 | Versamatrix A/S | Identification of encoded beads |
WO2005078122A2 (en) | 2004-02-17 | 2005-08-25 | Nuevolution A/S | Method for enrichment involving elimination by mismatch hybridisation |
US7981604B2 (en) | 2004-02-19 | 2011-07-19 | California Institute Of Technology | Methods and kits for analyzing polynucleotide sequences |
EP2527447A1 (en) | 2004-06-03 | 2012-11-28 | Athlomics Pty Ltd | Agents and methods for diagnosing stress |
EP2527446A1 (en) | 2004-06-03 | 2012-11-28 | Athlomics Pty Ltd | Agents and methods for diagnosing stress |
EP2270034A2 (en) | 2004-06-03 | 2011-01-05 | Athlomics Pty Ltd | Agents and methods for diagnosing stress |
US7863029B2 (en) | 2004-06-04 | 2011-01-04 | Fox Chase Cancer Center | Alternate morpheeins of allosteric proteins as a target for the development of bioactive molecules |
WO2006001798A1 (en) * | 2004-06-15 | 2006-01-05 | Vanderbilt University | New chiral columns with broad chiral selectivity |
US9147037B2 (en) | 2004-08-02 | 2015-09-29 | Bioarray Solutions, Ltd. | Automated analysis of multiplexed probe-target interaction patterns: pattern matching and allele identification |
US7572600B2 (en) | 2004-08-04 | 2009-08-11 | Chemocentryx, Inc. | Enzymatic activities in chemokine-mediated inflammation |
WO2006020581A2 (en) | 2004-08-09 | 2006-02-23 | Elan Pharmaceuticals, Inc. | Prevention and treatment of synucleinopathic and amyloidogenic disease |
EP3369433A1 (en) | 2004-08-09 | 2018-09-05 | Janssen Alzheimer Immunotherapy | Prevention and treatment of synucleinopathic and amyloidogenic disease |
EP2371396A1 (en) | 2004-10-19 | 2011-10-05 | Elan Pharmaceuticals Inc. | Truncated fragments of alpha synuclein in lewy body disease |
EP2272539A2 (en) | 2004-10-19 | 2011-01-12 | Elan Pharmaceuticals, Inc. | Truncated fragments of alpha-synuclein in lewy body disease |
US8168381B2 (en) | 2004-11-22 | 2012-05-01 | Peter Birk Rasmussen | Template directed split and mix systhesis of small molecule libraries |
US8951728B2 (en) | 2004-11-22 | 2015-02-10 | Chemgene Holding Aps | Template directed split and mix synthesis of small molecule libraries |
WO2006053571A3 (en) * | 2004-11-22 | 2006-08-17 | Peter Birk Rasmussen | Template directed split and mix systhesis of small molecule libraries |
WO2006053571A2 (en) * | 2004-11-22 | 2006-05-26 | Peter Birk Rasmussen | Template directed split and mix systhesis of small molecule libraries |
US8101737B2 (en) | 2004-12-31 | 2012-01-24 | Affymetrix, Inc. | Parallel preparation of high fidelity probes in an array format |
US8338585B2 (en) | 2004-12-31 | 2012-12-25 | Affymetrix, Inc. | Parallel preparation of high fidelity probes in an array format |
US8133987B2 (en) | 2004-12-31 | 2012-03-13 | Affymetrix, Inc. | Primer array synthesis and validation |
US8338093B2 (en) | 2004-12-31 | 2012-12-25 | Affymetrix, Inc. | Primer array synthesis and validation |
US8729251B2 (en) | 2004-12-31 | 2014-05-20 | Affymetrix, Inc. | Parallel preparation of high fidelity probes in an array format |
EP2302076A1 (en) | 2005-02-14 | 2011-03-30 | University of Iowa Research Foundation | Methods and reagents for treatment and diagnosis of age-related macular degeneration |
WO2006088950A2 (en) | 2005-02-14 | 2006-08-24 | University Of Iowa Research Foundation | Methods and reagents for treatment and diagnosis of age-related macular degeneration |
EP2357254A1 (en) | 2005-02-14 | 2011-08-17 | University of Iowa Research Foundation | Methods and reagents for treatment and diagnosis of age-related macular degeneration |
EP2481424A1 (en) | 2005-03-19 | 2012-08-01 | Medical Research Council | Improvements in or relating to treatment and prevention of hepatitis C viral infections |
EP2258870A2 (en) | 2005-06-09 | 2010-12-08 | Praecis Pharmaceuticals Inc. | Method for identifying compounds which bind to biological target molecule |
EP2311786A2 (en) | 2005-06-09 | 2011-04-20 | Praecis Pharmaceuticals Inc. | Methods for synthesis of encoded libraries |
AU2006257915B2 (en) * | 2005-06-09 | 2011-09-08 | Glaxosmithkline Llc | Methods for synthesis of encoded libraries |
EP2338990A2 (en) | 2005-06-09 | 2011-06-29 | Praecis Pharmaceuticals Inc. | Methods for synthesis of encoded libraries |
EP2476761A2 (en) | 2005-07-07 | 2012-07-18 | Athlomics Pty Ltd | Polynucleotide marker genes and their expression, for diagnosis of endotoxemia |
US8691729B2 (en) | 2005-07-15 | 2014-04-08 | President And Fellows Of Harvard College | Reaction discovery system |
EP2450056A1 (en) | 2005-07-19 | 2012-05-09 | Elan Pharma International Limited | Prevention and treatment of synucleinopathic and amyloidogenic disease |
US9868978B2 (en) | 2005-08-26 | 2018-01-16 | Fluidigm Corporation | Single molecule sequencing of captured nucleic acids |
US7666593B2 (en) | 2005-08-26 | 2010-02-23 | Helicos Biosciences Corporation | Single molecule sequencing of captured nucleic acids |
US8193328B2 (en) | 2005-09-08 | 2012-06-05 | Philadelphia Health & Education Corporation | Identification of modulators of serine protease inhibitor Kazal and their use as anti-cancer and anti-viral agents |
US7989395B2 (en) | 2005-10-28 | 2011-08-02 | Glaxosmithkline Llc | Methods for identifying compounds of interest using encoded libraries |
EP2368868A1 (en) | 2005-10-28 | 2011-09-28 | Praecis Pharmaceuticals Inc. | Methods for identifying compounds of interest using encoded libraries |
WO2007053358A2 (en) | 2005-10-28 | 2007-05-10 | Praecis Pharmaceuticals, Inc. | Methods for identifying compounds of interest using encoded libraries |
EP3018206A1 (en) * | 2005-12-01 | 2016-05-11 | Nuevolution A/S | Enzymatic encoding methods for efficient synthesis of large libraries |
US9574189B2 (en) | 2005-12-01 | 2017-02-21 | Nuevolution A/S | Enzymatic encoding methods for efficient synthesis of large libraries |
US11702652B2 (en) | 2005-12-01 | 2023-07-18 | Nuevolution A/S | Enzymatic encoding methods for efficient synthesis of large libraries |
EP2468294A1 (en) | 2006-02-03 | 2012-06-27 | Crc For Asthma And Airways Ltd | A method of modulating cellular activity and agents for use therein |
US8460879B2 (en) | 2006-02-21 | 2013-06-11 | The Trustees Of Tufts College | Methods and arrays for target analyte detection and determination of target analyte concentration in solution |
US8492098B2 (en) | 2006-02-21 | 2013-07-23 | The Trustees Of Tufts College | Methods and arrays for target analyte detection and determination of reaction components that affect a reaction |
US11237171B2 (en) | 2006-02-21 | 2022-02-01 | Trustees Of Tufts College | Methods and arrays for target analyte detection and determination of target analyte concentration in solution |
US11874279B2 (en) | 2006-02-21 | 2024-01-16 | Trustees Of Tufts College | Methods and arrays for target analyte detection and determination of target analyte concentration in solution |
US9395359B2 (en) | 2006-02-21 | 2016-07-19 | Trustees Of Tufts College | Methods and arrays for target analyte detection and determination of target analyte concentration in solution |
US8460878B2 (en) | 2006-02-21 | 2013-06-11 | The Trustees Of Tufts College | Methods and arrays for detecting cells and cellular components in small defined volumes |
US10261089B2 (en) | 2006-02-21 | 2019-04-16 | Trustees Of Tufts College | Methods and arrays for target analyte detection and determination of target analyte concentration in solution |
WO2008042024A2 (en) | 2006-06-01 | 2008-04-10 | Elan Pharmaceuticals, Inc. | Neuroactive fragments of app |
WO2008037026A1 (en) | 2006-09-28 | 2008-04-03 | The Macfarlane Burnet Institute For Medical Research And Public Health Limited | A method of diagnosis and kit therefor |
WO2008063933A2 (en) | 2006-11-10 | 2008-05-29 | Massachusetts Institute Of Technology | Pak modulators |
EP3067066A1 (en) | 2007-02-23 | 2016-09-14 | Prothena Biosciences Limited | Prevention and treatment of synucleinopathic and amyloidogenic disease |
EP2583978A2 (en) | 2007-02-23 | 2013-04-24 | The Regents of the University of California | Prevention and treatment of synucleinopathic and amyloidogenic disease |
US8883691B2 (en) | 2007-06-25 | 2014-11-11 | Affymetrix, Inc. | Encoded microparticles |
CN102083575B (en) * | 2007-06-25 | 2014-09-17 | 阿费梅特里克斯公司 | Patterned microcodes |
WO2009014848A3 (en) * | 2007-06-25 | 2009-12-30 | Affymetrix, Inc. | Patterned microcodes |
US9057727B2 (en) | 2007-08-01 | 2015-06-16 | The General Hospital Corporation | Screening methods using G-protein coupled receptors and related compositions |
US9809838B2 (en) | 2007-08-30 | 2017-11-07 | Trustees Of Tufts College | Methods for determining the concentration of an analyte in solution |
US8779088B2 (en) | 2007-12-17 | 2014-07-15 | Marfl Ab | Vaccine for the treatment of Mycobacterium related disorders |
WO2009078799A1 (en) | 2007-12-17 | 2009-06-25 | Marfl Ab | New vaccine for the treatment of mycobacterium related disorders |
EP2730659A2 (en) | 2007-12-28 | 2014-05-14 | Elan Pharmaceuticals Inc. | Treatment and Prophylaxis of Amyloidosis |
EP3693470A1 (en) | 2007-12-28 | 2020-08-12 | Prothena Therapeutics Limited | Treatment and prophylaxis of amyloidosis |
WO2009086539A2 (en) | 2007-12-28 | 2009-07-09 | Elan Pharmaceuticals, Inc. | Treatment and prophylaxis of amyloidosis |
WO2009091586A2 (en) | 2008-01-18 | 2009-07-23 | North Carolina State University | Peptides and methods of use as therapeutics and screening agents |
EP2116618A1 (en) | 2008-05-09 | 2009-11-11 | Agency for Science, Technology And Research | Diagnosis and treatment of Kawasaki disease |
WO2010021415A1 (en) | 2008-08-18 | 2010-02-25 | Seoul National University Industry Foundation | Method for controlling cancer metastasis or cancer cell migration by modulating the cellular level of lysyl trna synthetase |
US8846415B2 (en) | 2008-09-23 | 2014-09-30 | Quanterix Corporation | Ultra-sensitive detection of molecules on single molecule arrays |
US8222047B2 (en) | 2008-09-23 | 2012-07-17 | Quanterix Corporation | Ultra-sensitive detection of molecules on single molecule arrays |
US9359601B2 (en) | 2009-02-13 | 2016-06-07 | X-Chem, Inc. | Methods of creating and screening DNA-encoded libraries |
US11168321B2 (en) | 2009-02-13 | 2021-11-09 | X-Chem, Inc. | Methods of creating and screening DNA-encoded libraries |
US9709558B2 (en) | 2009-06-19 | 2017-07-18 | Arizona Board Of Regents On Behalf Of Arizona State University | Compound arrays for sample profiling |
US10422793B2 (en) | 2009-06-19 | 2019-09-24 | Arizona Board Of Regents On Behalf Of Arizona State University | Compound arrays for sample profiling |
US8969255B2 (en) | 2009-06-19 | 2015-03-03 | The Arizona Board Of Regents | Compound arrays for sample profiling |
US9244069B2 (en) | 2009-07-29 | 2016-01-26 | Dynex Technologies | Sample plate systems and methods |
US10207268B2 (en) | 2009-07-29 | 2019-02-19 | Dynex Technologies, Inc. | Sample plate systems and methods |
US9857367B2 (en) | 2009-07-29 | 2018-01-02 | Dynex Technologies, Inc. | Sample plate systems and methods |
US9523701B2 (en) | 2009-07-29 | 2016-12-20 | Dynex Technologies, Inc. | Sample plate systems and methods |
US10969386B2 (en) | 2009-07-29 | 2021-04-06 | Dynex Technologies, Inc. | Sample plate systems and methods |
US8415171B2 (en) | 2010-03-01 | 2013-04-09 | Quanterix Corporation | Methods and systems for extending dynamic range in assays for the detection of molecules or particles |
US10725032B2 (en) | 2010-03-01 | 2020-07-28 | Quanterix Corporation | Ultra-sensitive detection of molecules or particles using beads or other capture objects |
US9678068B2 (en) | 2010-03-01 | 2017-06-13 | Quanterix Corporation | Ultra-sensitive detection of molecules using dual detection methods |
US9310360B2 (en) | 2010-03-01 | 2016-04-12 | Quanterix Corporation | Ultra-sensitive detection of molecules or particles using beads or other capture objects |
US11619631B2 (en) | 2010-03-01 | 2023-04-04 | Quanterix Corporation | Ultra-sensitive detection of molecules or particles using beads or other capture objects |
US9110025B2 (en) | 2010-03-01 | 2015-08-18 | Quanterix Corporation | Methods and systems for extending dynamic range in assays for the detection of molecules or particles |
US10989713B2 (en) | 2010-03-01 | 2021-04-27 | Quanterix Corporation | Methods and systems for extending dynamic range in assays for the detection of molecules or particles |
US9551663B2 (en) | 2010-03-01 | 2017-01-24 | Quanterix Corporation | Methods and systems for extending dynamic range in assays for the detection of molecules or particles |
US9482662B2 (en) | 2010-03-01 | 2016-11-01 | Quanterix Corporation | Ultra-sensitive detection of molecules or particles using beads or other capture objects |
US9846155B2 (en) | 2010-03-01 | 2017-12-19 | Quanterix Corporation | Methods and systems for extending dynamic range in assays for the detection of molecules or particles |
US8236574B2 (en) | 2010-03-01 | 2012-08-07 | Quanterix Corporation | Ultra-sensitive detection of molecules or particles using beads or other capture objects |
US11225655B2 (en) | 2010-04-16 | 2022-01-18 | Nuevolution A/S | Bi-functional complexes and methods for making and using such complexes |
US9492508B2 (en) | 2010-05-13 | 2016-11-15 | The General Hospital Corporation | Parathyroid hormone analogs and uses thereof |
US9079950B2 (en) | 2010-08-04 | 2015-07-14 | The Macfarlane Burnet Institute For Medical Research And Public Health Ltd | Modified Hepatitis C virus proteins |
WO2012016290A1 (en) | 2010-08-04 | 2012-02-09 | The Macfarlane Burnet Institute For Medical Research And Public Health Ltd | Modified hepatitis c virus proteins |
WO2012148477A1 (en) | 2010-12-15 | 2012-11-01 | Cellular Research, Inc. | Digital counting of individual molecules by stochastic attachment of diverse label-tags |
WO2012095516A1 (en) | 2011-01-14 | 2012-07-19 | Bracco Imaging Spa | Human antibodies cross-reacting with a bacterial and a self antigen from atherosclerotic plaques |
EP2476703A1 (en) | 2011-01-14 | 2012-07-18 | Bracco Imaging S.p.A | Human antibodies cross-reacting with a bacterial and a self antigen from atherosclerotic plaques |
US11112415B2 (en) | 2011-01-28 | 2021-09-07 | Quanterix Corporation | Systems, devices, and methods for ultra-sensitive detection of molecules or particles |
US9952237B2 (en) | 2011-01-28 | 2018-04-24 | Quanterix Corporation | Systems, devices, and methods for ultra-sensitive detection of molecules or particles |
US10393759B2 (en) | 2011-04-12 | 2019-08-27 | Quanterix Corporation | Methods of determining a treatment protocol for and/or a prognosis of a patient's recovery from a brain injury |
US11275092B2 (en) | 2011-04-12 | 2022-03-15 | Quanterix Corporation | Methods of determining a treatment protocol for and/or a prognosis of a patient's recovery from a brain injury |
US8975293B2 (en) | 2011-05-26 | 2015-03-10 | Regents Of The University Of Michigan | Epigenetic co-repressors of the gamma-globin gene and methods of using same |
US10865409B2 (en) | 2011-09-07 | 2020-12-15 | X-Chem, Inc. | Methods for tagging DNA-encoded libraries |
US9435807B2 (en) | 2011-09-22 | 2016-09-06 | Medicinal Bioconvergence Research Center | Use of leucyl tRNA synthetase |
US9678062B2 (en) | 2011-09-23 | 2017-06-13 | University Of Louisville Research Foundation, Inc. | Methods and compositions for expanding cells and improving engraftment |
WO2013055101A1 (en) | 2011-10-10 | 2013-04-18 | Medicinal Bioconvergence Research Center | Method for screening an agent preventing or treating cancer using glycyl-trna synthetase and cadherin |
US9274113B2 (en) | 2011-10-10 | 2016-03-01 | Medicinal Bioconvergence Research Center | Method for screening an agent preventing or treating cancer using glycyl-tRNA synthetase and cadherin |
WO2013078138A1 (en) | 2011-11-21 | 2013-05-30 | OSI Pharmaceuticals, LLC | Proton nmr spectroscopy for biochemical screening |
US11674135B2 (en) | 2012-07-13 | 2023-06-13 | X-Chem, Inc. | DNA-encoded libraries having encoding oligonucleotide linkages not readable by polymerases |
US9932626B2 (en) | 2013-01-15 | 2018-04-03 | Quanterix Corporation | Detection of DNA or RNA using single molecule arrays and other techniques |
US10640814B2 (en) | 2013-01-15 | 2020-05-05 | Quanterix Corporation | Detection of DNA or RNA using single molecule arrays and other techniques |
US10006919B2 (en) | 2013-03-15 | 2018-06-26 | Arizona Board Of Regents On Behalf Of Arizona State University | Peptide array quality control |
US10578623B2 (en) | 2013-03-15 | 2020-03-03 | Arizona Board of Regents of behalf of Arizona State University | Peptide array quality control |
US11067582B2 (en) | 2013-03-15 | 2021-07-20 | Arizona Board Of Regents On Behalf Of Arizona State University | Peptide array quality control |
US9970932B2 (en) | 2013-03-15 | 2018-05-15 | Arizona Board Of Regents On Behalf Of Arizona State University | Non-covalent patterned chemical features and use thereof in MALDI-based quality control |
US10450343B2 (en) | 2013-03-21 | 2019-10-22 | Sanofi-Aventis Deutschland Gmbh | Synthesis of cyclic imide containing peptide products |
US10087221B2 (en) | 2013-03-21 | 2018-10-02 | Sanofi-Aventis Deutschland Gmbh | Synthesis of hydantoin containing peptide products |
WO2016040895A1 (en) | 2014-09-12 | 2016-03-17 | xxTHE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY | Wnt signaling agonist molecules |
EP4219564A1 (en) | 2014-09-12 | 2023-08-02 | The Board of Trustees of the Leland Stanford Junior University | Wnt signaling agonist molecules |
WO2016100857A1 (en) | 2014-12-19 | 2016-06-23 | Regeneron Pharmaceuticals, Inc. | Stem cells for modeling type 2 diabetes |
US10393751B2 (en) | 2015-04-20 | 2019-08-27 | Roche Sequencing Solutions, Inc. | Specific peptide binders to proteins identified via systematic discovery, maturation and extension process |
US10758886B2 (en) | 2015-09-14 | 2020-09-01 | Arizona Board Of Regents On Behalf Of Arizona State University | Conditioned surfaces for in situ molecular array synthesis |
US10329321B2 (en) | 2016-02-09 | 2019-06-25 | Alexander Krantz | Site-selective functionalization of proteins using traceless affinity labels |
US11828759B2 (en) | 2016-02-11 | 2023-11-28 | Peter Maccallum Cancer Institute | Method of diagnosis |
WO2017149097A1 (en) * | 2016-03-04 | 2017-09-08 | Apta Biosciences Limited | Oligonucleotides and methods for preparing |
WO2017208210A1 (en) | 2016-06-03 | 2017-12-07 | Prothena Biosciences Limited | Anti-mcam antibodies and associated methods of use |
US11747334B2 (en) | 2016-06-20 | 2023-09-05 | Cowper Sciences Inc. | Methods for differential diagnosis of autoimmune diseases |
US11774446B2 (en) | 2016-06-20 | 2023-10-03 | Cowper Sciences Inc. | Methods for diagnosis and treatment of autoimmune diseases |
WO2018007979A1 (en) | 2016-07-06 | 2018-01-11 | Prothena Biosciences Limited | Assay for detecting total and s129 phosphorylated alpha-synuclein |
WO2018023014A1 (en) | 2016-07-29 | 2018-02-01 | Regeneron Pharmaceuticals, Inc. | Mice comprising mutations resulting in expression of c-truncated fibrillin-1 |
WO2018060904A1 (en) | 2016-09-30 | 2018-04-05 | Nanjing Biopoint Diagnostic Technology Co. Ltd | Point of care assays |
WO2018071493A1 (en) | 2016-10-12 | 2018-04-19 | Janssen Biotech, Inc. | Methods for screening for modulators of gdf15-like biological activity |
US11371990B2 (en) | 2016-11-11 | 2022-06-28 | Cowper Sciences Inc. | Methods for identifying candidate biomarkers |
WO2018202850A1 (en) | 2017-05-05 | 2018-11-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Microtubule-targeting drugs as immune checkpoint inhibitors and methods of screening novel immune checkpoint inhibitors for the treatment of cancers and infectious diseases |
US11400165B2 (en) | 2017-11-04 | 2022-08-02 | Advanced Proteome Therapeutics Inc. | Composition and method for modifying polypeptides |
WO2019094735A1 (en) | 2017-11-10 | 2019-05-16 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising slc30a8 mutation and methods of use |
WO2020016433A1 (en) | 2018-07-20 | 2020-01-23 | Aicuris Gmbh & Co. Kg | Methods for screening and identifying agents that inhibit or modulate the nuclear egress complex of herpesviruses |
WO2020159445A1 (en) | 2019-01-31 | 2020-08-06 | Agency For Science, Technology And Research | Cnx/erp57 inhibitor for use in the treatment or prevention of cancer |
WO2020210724A1 (en) | 2019-04-10 | 2020-10-15 | University Of Utah Research Foundation | Htra1 modulation for treatment of amd |
Also Published As
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ATE148889T1 (en) | 1997-02-15 |
EP0604552B1 (en) | 1997-02-12 |
US6165717A (en) | 2000-12-26 |
DE69217497T2 (en) | 1997-06-12 |
EP0604552A1 (en) | 1994-07-06 |
DE69217497D1 (en) | 1997-03-27 |
AU2661992A (en) | 1993-04-27 |
EP0604552A4 (en) | 1993-08-02 |
US6416949B1 (en) | 2002-07-09 |
CA2118806A1 (en) | 1993-04-01 |
US5708153A (en) | 1998-01-13 |
US6140493A (en) | 2000-10-31 |
EP0773227A1 (en) | 1997-05-14 |
AU669489B2 (en) | 1996-06-13 |
GR3023156T3 (en) | 1997-07-30 |
US5770358A (en) | 1998-06-23 |
US6143497A (en) | 2000-11-07 |
ES2097925T3 (en) | 1997-04-16 |
JP2001524926A (en) | 2001-12-04 |
US5789162A (en) | 1998-08-04 |
DK0604552T3 (en) | 1997-08-04 |
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