Chemistry: analytical and immunological testing – Involving an insoluble carrier for immobilizing immunochemicals
Reexamination Certificate
1999-03-03
2002-07-09
Ponnaluri, Padmashri (Department: 1618)
Chemistry: analytical and immunological testing
Involving an insoluble carrier for immobilizing immunochemicals
C436S523000, C436S524000, C436S525000, C436S526000, C436S527000, C436S528000, C435S006120, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C435S091500, C530S334000, C235S439000, C340S572100, C455S092000
Reexamination Certificate
active
06417010
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to labeled combinatorial synthesis libraries and methods and apparatus for labeling individual library members of a combinatorial synthesis library with unique identification tags that facilitate elucidation of the structures of the individual library members synthesized.
BACKGROUND OF THE INVENTION
The relationship between structure and function of molecules is a fundamental issue in the study of biological systems. Structure-function relationships are important in understanding, for example, the function of enzymes, cellular communication, and cellular control and feedback mechanisms. Certain macromolecules are known to interact and bind to other molecules having a specific three-dimensional spatial and electronic distribution. Any macromolecule having such specificity can be considered a receptor, whether the macromolecule is an enzyme, a protein, a glycoprotein, an antibody, an oligonucleotide sequence of DNA, RNA or the like. The various molecules that receptors bind are known as ligands.
Pharmaceutical drug discovery is one type of research that relies on the study of structure-function relationships. Most contemporary drug discovery involves discovering novel ligands with desirable patterns of specificity for biologically important receptors. Thus, the time necessary to bring new drugs to market could be greatly reduced by the discovery of novel methods which allow rapid screening of large numbers of potential ligands.
Since the introduction of solid phase synthesis methods for peptides and polynucleotides new methods employing solid phase strategies have been developed that are capable of generating thousands, and in some cases even millions, of individual peptide or nucleic acid polymers using automated or manual techniques. These synthesis strategies, which generate families or libraries of compounds, are generally referred to as “combinatorial chemistry” or “combinatorial synthesis” strategies.
Combinatorial chemistry strategies can be a powerful tool for rapidly elucidating novel ligands to receptors of interest. These methods show particular promise for identifying new therapeutics. See generally, Gorgon et al., “Applications of Combinatorial Technologies to Drug Discovery: II. Combinatorial Organic Synthesis, Library Screening Strategies, and Future Directions,”
J. Med. Chem
37:1385-401 (1994) and Gallop et al., “Applications of Combinatorial Technologies to Drug Discovery: I. Background and Peptide Combinatorial Libraries,”
J. Med. Chem
37:1233-51 (1994). For example, combinatorial libraries have been used to identify nucleic acid aptamers, Latham et al., “The Application of a Modified Nucleotide in Aptamer Selection: Novel Thrombin Aptamers Containing 5-(1-Pentynyl)-2′-Deoxy Uridine,”
Nucl. Acids Res.
22:2817-2822 (1994); to identify RNA ligands to reverse transcriptase, Chen & Gold, “Selection of High-Affinity RNA Ligands to Reverse Transcriptase: Inhibition of CDNA Synthesis and RNase H Activity,”
Biochemistry
33:8746-56 (1994); and to identify catalytic antibodies specific to a particular reaction transition state, Posner et al., “Catalytic Antibodies: Perusing Combinatorial Libraries,”
Trends. Biochem. Sci.
19:145-50 (1994).
The diversity of libraries generated using combinatorial strategies is impressive. For example, these methods have been used to generate a library containing four trillion decapeptides, Pinilla et al., “Investigation of Antigen-Antibody Interactions Using a Soluble, Non-Support-Bound Synthetic Decapeptide Library Composed of Four Trillion (4×10
12
) Sequences,”
Biochem. J.
301:847-53 (1994); 1,4-benzodiazepines libraries, Bunin et al., “The Combinatorial Synthesis and Chemical and Biological Evaluation of a 1,4,-Benzodiazepine Library,”
Proc. Natl. Acad. Sci.
91:4708-12 (1994) and U.S. Pat. No. 5,288,514, entitled “Solid Phase and Combinatorial Synthesis of Benzodiazepine Compounds on a Solid Support,” issued Feb. 22, 1994; libraries containing multiple small ligands tied together in the same molecules, Wallace et al., “A Multimeric Synthetic Peptide Combinatorial Library,”
Pent. Res.
7:27-31 (1994); libraries of small organics, Chen et al., “‘Analogous’ Organic Synthesis of Compound Libraries: Validation of Combinatorial Chemistry in Small-Molecule Synthesis,”
J. Am. Chem. Soc.
116:2661-2662 (1994); libraries of peptidosteroidal receptors, Boyce & Nestler, “Peptidosteroidal Receptors for Opioid Peptides: Sequence-Selective Binding Using a Synthetic Receptor Library,”
J. Am. Chem. Soc.
116:7955-7956 (1994); and peptide libraries containing non-natural amino acids, Kerr et al., “Encoded Combinatorial Peptide Libraries Containing Non-Natural Amino Acids,”
J. Am. Chem. Soc.
115:2529-31 (1993).
To date, three general strategies for generating combinatorial libraries have emerged: “spatially-addressable,” “split-bead” and recombinant strategies.
These methods differ in one or more of the following aspects: reaction vessel design, polymer type and composition, control of physical constants such as time, temperature and atmosphere, isolation of products, solid-phase or solution-phase methods of assay, simple or complex mixtures, and method for elucidating the structure of the individual library members.
Of these general strategies, several sub-strategies have been developed. One spatially-addressable strategy that has emerged involves the generation of peptide libraries on immobilized pins that fit the dimensions of standard microtitre plates. See PCT Publication Nos. 91/17271 and 91/19818, each of which is incorporated herein by reference. This method has been used to identify peptides which mimic discontinuous epitopes, Geysen et al.,
BioMed. Chem. Lett.
3:391-404 (1993), and to generate benzodiazepine libraries, U.S. Pat. No. 5,288,514, entitled “Solid Phase and Combinatorial Synthesis of Benzodiazepine Compounds on a Solid Support,” issued Feb. 22, 1994 and Bunin et al., “The Combinatorial Synthesis and Chemical and Biological Evaluation of a 1,4-Benzodiazepine Library,”
Proc. Natl. Acad. Sci.
91:4708-12 (1994). The structures of the individual library members can be decoded by analyzing the pin location in conjunction with the sequence of reaction steps used during the synthesis.
A second, related spatially-addressable strategy that has emerged involves solid-phase synthesis of polymers in individual reaction vessels, where the individual vessels are arranged into a single reaction unit. An illustrative example of such a reaction unit is a standard 96-well microtitre plate; the entire plate comprises the reaction unit and each well corresponds to a single reaction vessel. This approach is an extrapolation of traditional single-column solid-phase synthesis.
As is exemplified by the 96-well plate reaction unit, each reaction vessel is spatially defined by a two-dimensional matrix. Thus, the structures of individual library members can be decoded by analyzing the sequence of reactions to which each well was subjected.
Another spatially-addressable strategy employs “tea bags” to hold the synthesis resin. The reaction sequence to which each tea bag is subject is recorded, which determines the structure of the oligomer synthesized in each tea bag. See for example, Lam et al., “A New Type of Synthetic Peptide Library for Identifying Ligand-Binding Activity,”
Nature
354:82-84 (1991); Houghten et al., “Generation and Use of Synthetic Peptide Combinatorial Libraries for Basic Research and Drug Discovery,”
Nature
354:84-86 (1991); Houghten, “General Method for the Rapid Solid-Phase Synthesis of Large Numbers of Peptides: Specificity of Antigen-Antibody Interaction at the Level of Individual Amino Acids,”
Proc. Natl. Acad. Sci.
82:5131-5135 (1985); and Jung et al.,
Agnew. Chem. Int. Ed. Engl.
91:367-383 (1992), each of which is incorporated herein by reference.
In another recent development, scientists combined the techniques of photolithography, chemistry and biology to create large collections of oligomers and other compounds on the surface of a subs
Armstrong Robert W.
Cargill John
Brown Martin Haller & McClain
Discovery Partners International
Ponnaluri Padmashri
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