Abstract

The present invention relates to compositions, apparatus and methods useful for concurrently performing multiple, high throughput, biological or chemical assays, using repeated arrays of probes. A combination of the invention comprises a surface, which comprises a plurality of test regions, at least two of which, and in a preferred embodiment, at least twenty of which, are substantially identical, wherein each of the test regions comprises an array of generic anchor molecules. The anchors are associated with bifunctional linker molecules, each containing a portion which is specific for at least one of the anchors and a portion which is a probe specific for a target of interest. The resulting array of probes is used to analyze the presence or test the activity of one or more target molecules which specifically interact with the probes. In one embodiment of the invention, the test regions (which can be wells) are further subdivided into smaller subregions (indentations, or dimples).

Other References

• DP. Little et al., Anal. Chem., vol. 69, No. 22. pp. 4540-4546 (1997): "MALDI on a Chip: Analysis of Arrays of Low-Femtomole to Subfemtomole Quantities of . . . "
• D. Sarracino et al., Bioorganic & Medicinal Chemistry Letters, vol. 6, No. 21, pp. 2543-2548 (1996): "Quantitative Maldi-tof MS of Oligonucleotides and a Nuclease Assay"
• K. Tang et al., Rapid Comm. in Mass Spectrometry, vol. 8, pp. 183-186 (1994): "Matrix-assisted laser desorption/ionization of restriction enzyme-digested DNA"
• A.C. Pease et al., Proc. Natl. Acad. Sci. USA, vol. 91, pp. 5022-5026 (1994): "Light-generated oligonucleotide arrays for rapid DNA sequence analysis"
• International Search Report for PCT/US99/30515, Jun. 1999
• International Search Report for PCT/US98/27191, Jun. 1998
• Maier et al. (1997). Drug Discovery Today, vol. 2 (8). pp. 315-324
• Alper, "Weighing DNA for Fast Genetic Diagnosis", Science, vol. 279, Mar. 27, 1998, pp. 2044-2045
• Anderson et al., "Polynucleotide Arrays for Genetic Sequence Analysis", Topics in Current Chemistry, vol. 194, 1998, pp. 118-129
• Beattie et al., "Advances in Genosensor Research", Clinical Chemistry, vol. 41, No. 5, 1995, pp. 700-706
• Chee et al., "Accessing Genetic Information with High-Density DNA Arrays", Science, vol. 274, Oct. 25, 1996, pp. 610-614
• Chetverin et al., "Oligonucleotide Arrays: New Concepts and Possibilities", Bio/Technology, vol. 12, Nov. 12, 1994, pp. 1093-1099
• DeRisi et al., "Use of a cDNA Microarray to Analyse Gene Expression Patterns in Human Cancer", Nature Genetics, vol. 14, Dec. 1996, pp. 457-460
• Eggers et al., "A Microchip for Quantitative Detection . . . ", BioTechniques, vol. 17, No. 3 (1994), pp. 516-524
• Eggers et al., "A Review of Microfabricated Devices for Gene-Based Diagnostics", Hematologic Pathology 9(1), 1-15 (1995)
• Gautheret et al., "Alternate Polyadenylation in Human nRNAs . . . ", Genome Research, 8:524-530 (1998)
• Maskos et al., "A Novel Method for the Parallel Analysis of Multiple Mutations in Multiple Samples", Nucleic Acids Research, 1993, vol. 21, No. 9, pp. 2269-2270
• Hoheisel, "Oligomer-chip Technology", BioTechnology TIBTECH, Nov. 1997, vol. 15, No. 1 (166), pp. 465-469
• Lipshutz et al., "Using Oligonucleotide Probe Arrays to Access Genetic Diversity", BioTechniques, vol. 19, No. 3 (1995), pp. 442-447
• Lockhart et al., "Expression Monitoring by Hybridization to High-Density Oligonucleotide Arrays", Nature Biotechnology, vol. 14, Dec. 1996, pp. 1675-1680
• Marshall et al., "DNA chips: An array of possibilities", Nature Biotechnology, vol. 16, Jan. 1998, pp. 27-31
• Niemeyer et al., "Oligonucleotide-directed self-assembly of proteins . . . ", Nucleic Acids Research, 1994, vol. 22, No. 25, pp. 5530-5539
• O'Donnell-Maloney et al., "The Development of Microfabricated Arrays for DNA Sequencing and Analysis", TIBTECH, vol. 14, Oct. 1996
• Sapolsky et al., "Mapping Genomic Library Clones Using Oligonucleotide Arrays", Genomics, 33, 445-456 (1996)
• Schullek et al., "A High-Density Screening Format for Encoded Combinatorial Libraries . . . ", Analytical Biochemistry, 246, 20-29 (1997)
• Shoemaker et al., "Quantitative Phenotypic Analysis of Yeast Deletion . . . ", Nature Genetics, vol. 14, Dec. 1996, pp. 450-456
• Shuber et al., "High Throughput Parallel Analysis of Hundreds of Patient Samples . . . ", Human Molecular Genetics, 1997, vol. 6, No. 3, pp. 337-347
• Southern, "DNA chips: analysing sequence by hybridization . . . ", Trends in GENETICS, vol. 12, 1996
• Southern, "High-density gridding: techniques and applications", Current Opinion in Biotechnology, vol. 7, No. 1, Feb. 1996, pp. 85-88
• Kowalak et al., "Posttranscriptional Modification of the Central Loop of Domain V . . . ", The Journal of Biological Chemistry, vol. 270, No. 30, Issue of Jul. 28, pp. 17758-17765, 1995
• Kowalak, J., et al. "Posttranscriptional Modification of the Central Loop of Domain V in Escherichia coli 23 S Ribosomal RNA", The Journal of Biological Chemistry, vol. 270, No. 30, Jul. 28, 1995, pp. 17758-17764
• Gautheret, D., et al. "Alternate Polyadenylation in Human mRNAs: A Large-Scale Analysis by EST Clustering", Genome Research, vol. 8, 1998, pp. 524-530
• Sapolsky, R., et al. "Mapping Genomic Library Clones Using Oligonucleotide Arrays", Genomics, vol. 33, 1996, pp. 445-456