Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-11-08
2004-03-02
Redding, David A. (Department: 1744)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S396000, C435S288400, C435S091500, C530S334000, C536S025300
Reexamination Certificate
active
06699665
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to multiple array systems for integrating arrays of biomolecules, including biological, chemical and biochemical elements.
BACKGROUND OF THE INVENTION
There is a need to rapidly assay compounds for their effects on various biological processes. Nearly all biological activity is regulated by the interactions of proteins in cells. Proteins are the catalysts, motion transducers, and signal mediators of cells. They control cell division, cell growth, cell differentiation, cell death, and mediate the responses of cells to their environments. Enzymologists have long sought better substrates, better inhibitors and better catalysts for enzymatic reactions. To understand cellular processes, we therefore need to monitor the activity of proteins, and to determine the networks of interactions of proteins within cells.
In the past, tools available to biologists only allowed the study of one interaction at a time because there were no analytical tools that would allow large numbers of protein interactions to be monitored simultaneously. Thus, a system that would allow parallel analyses of protein interactions would be of immense value and would speed the progress of biological discovery.
In addition, there is a need to rapidly assay or screen compounds for potential drug candidates. Drug discovery is a long, multiple step process involving the identification of specific disease targets, development of assays based on a specific target, validation of the assays, and optimization and automation of the assay to achieve screening of a large number of candidates. After high throughput screening of compound libraries using various assays, hit validation and hit compound optimization procedures are employed. Performing a screen on many thousands of compounds thus requires parallel processing of many compounds and assay component reagents. In addition, to find lead compounds for drug discovery programs, large numbers of compounds are often screened for their activity as enzyme inhibitors or receptor agonists/antagonists. Large libraries of compounds are needed for such screening. As a result of developments in this field, it is now possible to simultaneously produce combinatorial libraries containing hundreds of thousands of small molecules for screening. With such libraries on hand there is an ever increasing need to rapidly screen the thousands of these new potential drug candidates.
One common approach to drug discovery involves presenting macromolecules implicated in causing a disease (disease targets) in bioassays in which potential drug candidates are tested for therapeutic activity. Such molecules could be receptors, enzymes, transcription factors, co-factors, DNA, RNA, growth promoters, cell-death inducers, or non-enzymatic proteins and peptides. Another approach involves presenting whole cells or organisms that are representative of the causative agent of the disease. Such agents include bacteria and tumor cell lines. Thus, there is a need to be able to screen the effects of various drug candidates on assorted cells and cell lines.
The conventional methods for assessing the effects of various agents or physiological activities on biological materials utilize standard microtiter plates. See for example, U.S. Pat. No. 6,083,763. Unfortunately microtiter plates do not allow for expansion into multiple parameter assays. For example, assessment of the effect of a physiological agent, such as a drug, on a population of cells or tissue grown in culture conventionally provides information relating to the effect of the agent on the cell or tissue population only at specified points in time. In addition, current assessment techniques generally only provide information relating to a single or a small number of parameters. For example, candidate agents are systematically tested for cytotoxicity, which may be determined as a function of concentration. A population of cells is treated, and at one or several time points following treatment, cell survival is measured. Thus, cytotoxicity assays generally do not provide any information relating to the cause(s) or time course of cell death but merely show whether cells die or survive. To elucidate the mechanism of the interaction/activity of agents, an assay capable of simultaneously monitoring several parameters is required.
In addition, therapeutic agents are frequently evaluated based on their physiological effects on a particular metabolic function. An agent is administered to a population of cells or a tissue sample, and the metabolic function of interest is assayed to assess the effect of the agent. This type of assay provides useful information, but it does not provide information relating to the mechanism of action, the effect on other metabolic functions, the time course of the physiological effect, general cell or tissue health, and the like.
Despite the great value that screening libraries of molecules has for identifying useful pharmaceutical compounds and improving the properties of a lead compound, the difficulties of screening, and especially the lack of “functional” screening methods, of these libraries has limited the impact that these methods have had in drug discovery and development. Thus, there remains a need for an assay system that allows a simultaneous screen for multiple target-ligand interactions in drug discovery and in the development of lead compounds. There exists a strong need for a high throughput multilevel assay system to test potential drug candidates and to obtain biologically and clinically relevant information. This need is not limited to drug discovery but also concerns diagnostic and clinical diagnosis arenas as well.
The relationship between structure and function of molecules is a fundamental issue in the study of biological systems. Structure-function relationships are important for understanding biological phenomena such as enzyme function, cellular communication, and cellular control and feedback mechanisms to name a few. Understanding how various molecules interact with each other, such as protein-receptor interactions for example, often provides the first step in understanding biomolecule function.
Modern pharmaceutical drug discovery often relies on the study of structure-function relationships. Much contemporary drug discovery involves discovering novel ligands with desirable patterns of specificity for biologically important receptors. Thus, the length of time necessary to bring new drugs to market could be greatly reduced by assay systems that allow rapid screening of structure-function relationships of large numbers of ligands.
Within the general drug discovery 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 a standard 96 well micro-titer plate. See PCT Patent Publication Nos. 91/17271 and 91/19818, each of which is incorporated herein by reference. This method has been used to identify peptides that mimic discontinuous epitopes as described in Geysen et al., “Screening Chemically Synthesized Peptide Libraries for Biologically Relevant Molecules,” Bioorg Med Chem. Lett. 3: 397-404 (1993), and to generate benzodiazepine libraries as described in U.S. Pat. No. 5,288,514 and Bunin et al., “The Combinatorial Synthesis and Chemical and Biological Evaluation of a 1,4-Benzodiazepine Library,” Proc. Natl. Acad Sci. 91:4708-4712 (1994). The structures of the individual library members can be determined from the pin location in the micro titer plate and the sequence of reaction steps (called a “synthesis histogram”) performed during the synthesis.
In addition to the above-mentioned methods used in drug discovery, several trends are fueling interest in the application of cell-based assays for drug discovery. Cell-based screens offer the potential to shorten the time between target validation and lead drug discovery because these assays can be miniaturized to increase screening throughput and reduce costs. Informatio
Duffy David
Kim Enoch
Redding David A.
Surface Logix Inc.
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