Automated sorting system for matrices with memory

Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid

Reexamination Certificate

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C209S597000, C209S604000, 36

Reexamination Certificate

active

06329139

ABSTRACT:

RELATED APPLICATIONS
This application is a continuation-in-part of U.S. application Ser. No. 08/826,253, filed Mar. 27, 1997, now abandoned which is a continuation-in-part of U.S. application Ser. No. 08/857,800, filed Jan. 22, 1997, now abandoned which is a continuation-in-part of U.S. application Ser. No. 08/741,685, filed Oct. 31, 1996, now abandoned which is a continuation-in-part of U.S. application Ser. No. 08/743,984 filed Oct. 28, 1996 which is a continuation-in-part of U.S. application Ser. No. 08/726,703, filed Oct. 7, 1996, now abandoned, which is a continuation-in-part of each of application Ser. No. 08/723,423, filed Sep. 30, 1996, now issued as U.S. Pat. No. 5,961,923 and International PCT application No. PCT/US96/15999, filed in the US/RO on Oct. 3, 1996 and published as WO 97/12680, which are continuations-in-part of U.S. application Ser. No. 08/709,435, filed on Sep. 6, 1996, now issued as U.S. Pat. No. 6,017,496 which is a continuation-in-part of U.S. application Ser. No. 08/711,426, filed on Sep. 5, 1996, which is a continuation-in-part of U.S. application Ser. No. 08/669,252, filed on Jun. 24, 1996, which is a continuation-in-part of U.S. application Ser. No. 08/633,410, now issued as U.S. Pat. No. 6,100,026 filed on Jun. 10, 1996, which is a continuation-in-part of International PCT application No. PCT/US96/06145 which designates the U.S. and which was filed on Apr. 25, 1996 and published as WO 96/36436, and U.S. application Ser. No. 08/639,813, filed Apr. 2, 1996, now abandoned, which is a continuation-in-part of U.S. application Ser. No. 08/567,746, filed Dec. 5, 1995, which is a continuation-in-part of U.S. application Ser. No. 08/538,387, filed Oct. 3, 1995, now issued as U.S. Pat. No. 5,874,214, which is a continuation-in-part of each of U.S. application Serial Nos. 08/480,147, 08/484,486, 08/484,504, now issued as U.S. Pat. No. 5,751,629, Ser. No. 08/480,196, now issued as U.S. Pat. No. 5,925,562 and Ser. No. 08/473,660, all filed on Jun. 7, 1995, which are all continuations-in-part of U.S. application Ser. No. 08/428,662, filed Apr. 25, 1995, now issued as U.S. Pat. No. 5,741,462.
This application is also related to U.S. application Ser. No. 08/881,248, filed Jun. 24, 1997.
The subject matter of each of above-noted U.S. applications and International PCT applications is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to the application of information and data storage and retrieval technology to drug discovery, including molecular tracking and identification and to biological, chemical, immunological and biochemical assays. The methods, combinations, and devices provided herein permit synthetic chemistry to be linked to analysis and high throughput screening on the same platform with seamless remote informatics management.
BACKGROUND OF THE INVENTION
Drug Discovery
Drug discovery relies on the ability to identify compounds that interact with a selected target, such as cells, an antibody, receptor, enzyme, transcription factor or the like. Traditional drug discovery relied on collections or “libraries” obtained from proprietary databases of compounds accumulated over many years, natural products, fermentation broths, and rational drug design. Recent advances in molecular biology, chemistry and automation have resulted in the development of rapid, High throughput screening (HTS) protocols to screen these collection. In connection with HTS, methods for generating molecular diversity and for detecting, identifying and quantifying biological or chemical material have been developed. These advances have been facilitated by fundamental developments in chemistry, including the development of highly sensitive analytical methods, solid state chemical synthesis, and sensitive and specific biological assay systems.
Analyses of biological interactions and chemical reactions, however, require the use of labels or tags to track and identify the results of such analyses. Typically biological reactions, such as binding, catalytic, hybridization and signaling reactions, are monitored by labels, such as radioactive, fluorescent, photoabsorptive, luminescent and other such labels, or by direct or indirect enzyme labels. Chemical reactions are also monitored by direct or indirect means, such as by linking the reactions to a second reaction in which a colored, fluorescent, chemiluminescent or other such product results. These analytical methods, however, are often time consuming, tedious and, when practiced in vivo, invasive. In addition, each reaction is typically measured individually, in a separate assay. There is, thus, a need to develop alternative and convenient methods for tracking and identifying analytes in biological interactions and the reactants and products of chemical reactions.
Combinatorial libraries
The provision and maintenance of compounds to support HTS have become critical. New methods for the lead generation and lead optimization have emerged to address this need for diversity. Among these methods is combinatorial chemistry, which has become a powerful tool in drug discovery and materials science. Methods and strategies for generating diverse libraries, primarily peptide- and nucleotide-based oligomer libraries, have been developed using molecular biology methods and/or simultaneous chemical synthesis methodologies [see, e.g., Dower et al. (1991)
Annu. Rep. Med. Chem
. 26:271-280; Fodor et al. (1991)
Science
251:767-773; Jung et al. (1992)
Angew. Chem. Ind. Ed. Engl
. 31:367-383; Zuckerman et al. (1992)
Proc. Natl. Acad. Sci. USA
89:4505-4509; Scott et al. (1990)
Science
249:386-390; Devlin et al. (1990)
Science
249:404-406; Cwirla et al. (1990)
Proc. Natl. Acad. Sci. USA
87:6378-6382; and Gallop et al. (1994)
J. Medicinal Chemistry
37:1233-12511. The resulting combinatorial libraries potentially contain millions of pharmaceutically relevant compounds and that can be screened to identify compounds that exhibit a selected activity.
The libraries fall into roughly three categories: fusion-protein-displayed peptide libraries in which random peptides or proteins are presented on the surface of phage particles or proteins expressed from plasmids; support-bound synthetic chemical libraries in which individual compounds or mixtures of compounds are presented on insoluble matrices, such as resin beads [see, e.g., Lam et al. (1991)
Nature
354:82-84] and cotton supports [see, e.g., Eichler et al. (1993)
Biochemistry
32:11035-11041]; and methods in which the compounds are used in solution [see, e.g., Houghten et al. (1991)
Nature
354:84-86, Houghten et al. (1992)
BioTechniques
313:412-421; and Scott et al. (1994)
Curr. Opin. Biotechnol
. 5:40-48]. There are numerous examples of synthetic peptide and oligonucleotide combinatorial libraries. The present direction in this area is to produce combinatorial libraries that contain non-peptidic small organic molecules. Such libraries are based on either a basis set of monomers that can be combined to form mixtures of diverse organic molecules or that can be combined to form a library based upon a selected pharmacophore monomer.
There are three critical aspects in any combinatorial library: (i) the chemical units of which the library is composed; (ii) generation and categorization of the library, and (iii) identification of library members that interact with the target of interest, and tracking intermediary synthesis products and the multitude of molecules in a single vessel. The generation of such libraries often relies on the use of solid phase synthesis methods, as well as solution phase methods, to produce collections containing tens of millions of compounds that can be screened in diagnostically or pharmacologically relevant in vitro assay systems. In generating large numbers of diverse molecules by stepwise synthesis, the resulting library is a complex mixture in which a particular compound is present at very low concentrations, so that it is difficult or impossible to determine its chemical structure.

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