Chemical apparatus and process disinfecting – deodorizing – preser – Analyzer – structured indicator – or manipulative laboratory... – Means for analyzing liquid or solid sample
Reexamination Certificate
2000-06-16
2003-06-24
Warden, Jill (Department: 1743)
Chemical apparatus and process disinfecting, deodorizing, preser
Analyzer, structured indicator, or manipulative laboratory...
Means for analyzing liquid or solid sample
C422S050000, C422S068100, C422S091000, C422S105000, C436S045000, C436S174000, C436S177000, C436S180000
Reexamination Certificate
active
06582662
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to methods and apparatus for performing microanalytic and microsynthetic analyses and procedures. In particular, the invention relates to microminiaturization of genetic, biochemical and bioanalytic processes. Specifically, the present invention provides devices and methods for the performance of miniaturized biochemical assays. These assays may be performed for a variety of purposes, including but not limited to screening of drug candidate compounds, life sciences research, and clinical and molecular diagnostics. Methods for performing any of a wide variety of such microanalytical or microsynthetic processes using the microsystems apparatus of the invention are also provided.
2. Background of the Related Art
Recent developments in a variety of investigational and research fields have created a need for improved methods and apparatus for performing analytical, particularly bioanalytical assays at microscale (i.e., in volumes of less than 100 &mgr;L). In the field of pharmaceuticals, for example, an increasing number of potential drug candidates require assessment of their biological function. As an example, the field of combinatorial chemistry combines various structural sub-units with differing chemical affinities or configurations into molecules; in theory, a new molecule having potentially unique biochemical properties can be created for each permutation of the sub-units. In this way, large libraries of compounds may be synthesized from relatively small numbers of constituents, each such compound being a potential drug lead compound of usually unknown biological activity and potency.
More traditional approaches to compound library development are also yielding growing numbers of candidates, including the use of naturally-derived compounds extracted from plants, fungi, and bacteria. In part, this is due to a growing understanding of the function of these compounds, including how they affect the metabolic pathways of the organisms which synthesize and use them; the increasing refinement in identifying and understanding compounds based on small structural and compositional differences; and improved methods for extracting and purifying these compounds.
Increased numbers of potential targets for these drug candidates are also being identified. Recent advances in biology, most notably the human genome project, have discovered many molecules whose biochemical activity is implicated in various disease states. Although these novel targets can provide exquisitely precise and specific indicia of how biological processes underlying disease can be effectively controlled and manipulated, drugs must be identified, usually by screening processes, to find compounds that can enhance, diminish, or otherwise alter these targets' ability to affect the metabolic pathways associated with disease.
The function of drug candidates, targets, and the effect of the candidates on targets is assessed in the early stages of pharmaceutical development through a process of screening that typically includes: binding of a drug candidate to a portion or domain of the target molecule; immunoassays that bind to drug candidate target domains correlated with drug efficacy; enzymatic assays, in which the inhibition of an enzymatic activity of the target by the drug candidate can be used as a sign of efficacy; protein/protein binding; and protein/DNA(RNA) binding. Additional assays involve the use of living cells and include gene expression, in which levels of transcription in response to a drug candidate are monitored, and functional assays designed to investigate both macroscopic effects, such as cell viability, as well as biochemical effects and products produced in and by the cells as a result of treatment with the drug lead compound. (Wallace & Goldman, 1997, “Bioassay Design and Implementation”, in
High
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Throughput Screening: The Discovery of Bioactive Substances,
J. P. Devlin, ed., Marcel Dekker, Inc.: New York, pp. 279-305).
In initial screening of compounds against targets, the number of possible screens is roughly the number of candidates multiplied by the number of targets. As a result of the growth in both the number of candidates and the number of targets, the number of assays that must be performed is growing rapidly. In addition to the increasing the number of assays to be performed, it is desirable to reduce the time required to perform the assays in order to obtain results of such screenings in a timely and useful fashion. Finally, “multiplexing” technology that allows the performance of multiple assays on one sample within a single reaction well—for example, by using readily-distinguishable signals, such as fluorescent moieties with different characteristic wavelengths—can be used to increase throughput.
In addition to drug screening assays, biological research has uncovered a vast reservoir of genetic information and diversity having little if any correlation with the function of the gene products encoded by the deciphered DNA. On the one hand, the identification of the nucleotide sequence of the human genome, coupled with bioinformatics analysis of these sequences, has identified a larger number of protein coding sequences (termed “open reading frames”) that can and probably do encode functional proteins. However, since these sequences have been uncovered by simply “reading” a sequence without any information (such as the correlation of a genetic locus with a mutation associated with a disease), the function of the gene products of such a locus must be determined in order to fully understand and identify what protein target is encoded thereby and what utility drug candidates directed to such a target might have. On the other hand, human genome sequencing efforts have also identified genetic mutations (such as single nucleotide polymorphisms, or “SNPs”) that may or may not be associated with human disease. In either instance, the products of this human genetic information must be assayed to determine the activity of the genes, both “wild-type” and mutant, encoded at each new genetic locus. Progress in life sciences research requires researchers to perform large numbers of assays as they investigate the structure and function of proteins coded by the growing number of identified genes in the human genome. Many of the same assays and assay formats used in drug screening may be used in other life sciences research.
Large numbers of assays must also be performed in the field of molecular diagnostics, in which individuals can now be assayed for genetic mutation associated with a disease state or the propensity to develop a disease state. For example, any particular disease or propensity for disease may be associated with several different mutations in more than one gene that can determine disease susceptibility or severity. In the monitoring of a disease state, a disease may have a “fingerprint” consisting of certain genes the expression level of which can be used diagnostically to predict the severity of the disease. Monitoring expression levels of these genes can provide an indication of the response (or lack of response) to different treatment modalities.
For these and other applications in drug discovery, life sciences research, and molecular and clinical diagnostics there exists a need for systems and assay methods that can perform very many assays in a highly-parallel fashion at low cost. The primary approach has been and will continue to be to miniaturize existing assays in order to decrease compound and reagent costs (that scale with the volume required for performing the assay). Miniaturization has been accompanied by the development of more sensitive detection schemes, including both better detectors for conventional signals (e.g., calorimetric absorption, fluorescence, and chemiluminescence) as well as new chemistries or assay formats (e.g., imaging, optical scanning, and confocal microscopy).
Miniaturization can also confer performance advantages. At short length scales, diffusionally-limited mixing is rap
Duffy David C.
Kellogg Gregory J.
Handy Dwayne K.
McDonnell & Boehnen Hulbert & Berghoff
Tecan Trading AG
Warden Jill
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