Rosetta Inpharmatics, Inc.

Fred Hutchinson Cancer Center

Massachusetts Eye and Ear Infirmary

Whitehead Institute

University of California

Merck Sharp + Dohme Corp.

Cold Spring Harbor Laboratory

Sage Bionetworks

Microsoft Technology Licensing, LLC

Merck + Co., Inc.

The Netherlands Cancer Institute

Rosetta Impharmatics, Inc.

Stephen H Friend

Roland Stoughton

Yudong He

Julja Burchard

Thaddeus Peter Dryja

Leland H Hartwell

Gregory J Hannon

Kang Zhang

Patrick Paddison

Michele A Cleary

John Lamb

Trey Ideker

Justin Guinney

Gregory Hannum

David W Yandell

Ernest M Coffey

Peter S Linsley

Daniel D Shoemaker

Julian Simon

Laura Johanna Van't Veer

Hongyue Dai

Stewart Scherer

Kristopher A Kilian

Heather Dunstan

Kristopher A Killian

The invention provides for methods for predicting age of a subject based on the epigenome of the subject.

Methods for predicting age and identifying agents that induce or inhibit premature aging

The present invention provides methods of making a population of nucleic acid molecules, wherein each nucleic acid molecule comprises a predetermined nucleic acid sequence, each of said methods comprising the steps of: (a) synthesizing, on a substrate, a population of nucleic acid molecules wherein: i) each synthesized nucleic acid molecule comprises a predetermined nucleic acid sequence; and ii) each synthesized nucleic acid molecule is localized to a defined area of said substrate; (b) harvesting said population of synthesized nucleic acid molecules from said substrate to yield harvested nucleic acid molecules; and (c) introducing said harvested nucleic acid molecules into vector molecules.

Method for making populations of defined nucleic acid molecules

The present invention provides prognostic methods for conditions such as cancer, for example, breast cancer, comprising classifying an individual by a plurality of phenotypic, genotypic or clinical characteristics of the condition into a plurality of patient subsets, and analyzing the pattern of expression of prognosis-informative genes identified for that subset in a sample from the individual. The present invention also provides methods for constructing such patient subsets and of identifying prognosis-informative genesets for such subsets. The invention further provides methods of assigning a therapeutic regimen to an individual, microarrays useful for performing prognosis, kits comprising these microarrays, and computer systems and programs for implementing the methods of the invention.

Classification of breast cancer patients using a combination of clinical criteria and informative genesets

The present invention provides methods for analyzing exon expression profiles of a cell or type of cell. In the invention, the expression levels of a plurality of individual exons or multiexons for each of a plurality of genes in the genome of an organism are measured and analyzed to determine the biological state, such as the exon expression state or transcriptional state, of the cell or type of cell. The methods of the invention are useful for determination of alternative RNA splicing in a plurality of genes. The invention also provides nucleic acid probe arrays for determining in parallel the expression levels of a plurality of exons or multiexons for each of a plurality of genes in the genome of an organism. The invention further provides methods for determining the effects of perturbations, such as perturbations by drugs, on exon expression and alternative RNA splicing pathways.

Compositions and methods for exon profiling

The present invention provides methods for enhanced detection of biological response patterns. In one embodiment of the invention, genes are grouped into basis genesets according to the co-regulation of their expression. Expression of individual genes within a geneset is indicated with a single gene expression value for the geneset by a projection process. The expression values of genesets, rather than the expression of individual genes, are then used as the basis for comparison and detection of biological response with greatly enhanced sensitivity. In another embodiment of the invention, biological responses are grouped according to the similarity of their biological profile. The methods of the invention have many useful applications, particularly in the fields of drug development and discovery. For example, the methods of the invention may be used to compare biological responses with greatly enhanced sensitivity. The biological responses that may be compared according to these methods include responses to single perturbations, such as a biological response to a mutation or temperature change, as well as graded perturbations such as titration with a particular drug. The methods are also useful to identify cellular constituents, particularly genes, associated with a particular type of biological response. Further, the methods may also be used to identify perturbations, such as novel drugs or mutations, which effect one or more particular genesets. The methods may still further be used to remove experimental artifacts in biological response data.

Methods for using co-regulated genesets to enhance detection and classification of gene expression patterns

This invention relates to nucleic acid, or fragments thereof, encoding the retinoblastoma polypeptide, the retinoblastoma polypeptide itself, methods of detecting a defective retinoblastoma gene in human patients, and methods of treating these patients.

Retinoblastoma nucleic acids

Detection of proteins whose absence is associated with a neoplasm

Methods for the treatment of a proliferative disorder are provided in which a subject in need of such treatment is administered an effective amount of a compound selected from: compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein Xand Xare independently H, Cl, F, Br, I, CN, CFor NO, and Aris a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; and compounds of formula (II) wherein Xand Xare each independently H, Cl, F, Br, I, CN, CFor NO; Y is (C&#x2013;C)alkylene or (C&#x2013;C)heteroalkylene; and Z is Cl, F, Br, I, CN, CFor NO.

Topoisomerase poisons for the treatment of proliferative disorders

The present invention provides methods for determining the level of protein activity in a cell by: (i) measuring abundances of cellular constituents in a cell in which the activity of a specific protein is to be determined so that a diagnostic profile is thus obtained; (ii) measuring abundances of cellular constituents that occur in a cell in response to perturbations in the activity of said protein to obtain response profiles and interpolating said response profiles to generate response curves; and (iii) determining a protein activity level at which the response profile extracted from the response curves best fits the measured diagnostic profile, according to some objective measure. In alternative embodiments, the present invention also provides methods for identifying individuals having genetic mutations or polymorphisms that disrupt protein activity, and methods for identifying drug activity in vivo by determining the activity levels of proteins which interact with said drugs.

Computer systems and computer programs for determining protein activity levels using gene expression profiles

The present invention provides methods for identifying targets of a drug in a cell by comparing (i) the effects of the drug on a wild-type cell, (ii) the effects on a wild-type cell of modifications to a putative target of the drug, and (iii) the effects of the drug on a wild-type cell which has had the putative target modified of the drug. In various embodiments, the effects on the cell can be determined by measuring gene expression, protein abundances, protein activities, or a combination of such measurements. In various embodiments, modifications to a putative target in the cell can be made by modifications to the genes encoding the target, modification to abundances of RNAs encoding the target, modifications to abundances of target proteins, or modifications to activities of the target proteins. The present invention also provides methods for drug development based on the methods for identifying drug targets.

Methods for drug target screening

Methods and compositions are provided that are useful for detecting and reporting a plurality of different target polynucleotide sequences in a sample, such as polynucleotides corresponding to a plurality of different genes expressed by a cell or cells. In particular, the invention provides methods for screening a plurality of candidate polynucleotide probes to evaluate both the sensitivity and the specificity with which each candidate probe hybridizes to a target polynucleoide sequence. Candidate polynucleotide probes can then be ranked according to both their sensitivity and specificity, and probes that have optimal sensitivity and specificity for a target polynucleotide sequence can be selected. In one embodiment, polynucleotide probes can be selected according to the methods described herein to prepare 'screening chips' wherein a large number of target polynucleotide sequences are detected using a single microarray have a few (e.g., 1&#x2013;5) probes for each target polynucleotide sequence. In a particularly preferred embodiment, the invention provides a screening chip that can detect genetic transcripts from the entire genome of an organism. In an alternative embodiment, polynucleotide probes can be selected according to the methods described herein to prepare 'signature chips' to more accurately detect certain selected &#x201c;signature genes&#x201d; using several polynucleotide probes (e.g., 10&#x2013;20) for each signature gene. The invention additionally provides microarrays containing polynucleotide probes for a large number of genes expressed by a cell or organism. Further, methods for detecting a plurality of polynucleotide molecules, including a large number of genes expressed by a cell or organism, are also provided.

Iterative probe design and detailed expression profiling with flexible in-situ synthesis arrays

The present invention provides methods for monitoring disease states in a subject, as well as methods for monitoring the levels of effect of therapies upon a subject having one or more disease states. The methods involve: (i) measuring abundances of cellular constituents in a cell from a subject to obtain a diagnostic profile, (ii) measuring abundances of cellular constituents in a cell of one or more analogous subjects to obtain perturbation response profiles which correlate to a particular disease or therapy, and (iii) determining the interpolated perturbation response profile or profiles which best fit the diagnostic profile. In other aspects, the invention also provides a computer system capable of performing the methods of the invention, databases comprising perturbation response profiles for one or more diseases and/or therapies, and kits for determining levels of disease states and/or therapeutic effects according to the methods of the invention.

Methods of diagnosing disease states using gene expression profiles

The invention provides methods for removing unwanted response components (i.e., 'artifacts') from a measured biological profile comprising measurements of a plurality of cellular constituents of a cell or organism in response to a perturbation. The methods involve subtracting from the measured biological profile one or more artifact patterns, each of which comprises measurements of changes in cellular constituents as a result of deviation of one or more experimental variables, such as cell culture density and temperature, hybridization temperature, as well as concentrations of total RNA and/or hybridization reagents, from desired values.

Methods for removing artifact from biological profiles

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Seattle, WA, United States of America

Stephen H Friend