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THIRUTTUMTUMUTURUS009963747B2 (12 ) United States Patent ( 10 ) Patent No THIRUTTUMTUMUTURUS009963747B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 , 963, 747 B2 Bryant et al. (45 ) Date of Patent: *May 8 , 2018 (54 ) METHODS FOR THE IDENTIFICATION , ( 56 ) References Cited ASSESSMENT, AND TREATMENT OF PATIENTS WITH CANCER THERAPY U . S . PATENT DOCUMENTS 8 , 278, 038 B2 10 / 2012 Bryant et al. ( 71 ) Applicant : Millennium Pharmaceuticals , Inc. , 8 , 889 ,354 B2 11 /2014 Bryant et al . Cambridge , MA (US ) 2004 /0156854 A1 8 /2004 Mulligan et al. (72 ) Inventors : Barbara M . Bryant, Cambridge, MA FOREIGN PATENT DOCUMENTS (US ) ; Andrew I. Damokosh , West Hartford , CT (US ) ; George J . Wo WO 2003 / 053215 7 / 2003 Mulligan , Lexington ,MA (US ) WO WO 04 /053066 A2 6 / 2004 WO WO 2006 / 133420 12 /2006 @( 73 ) Assignee : Millennium Pharmaceuticals , Inc ., Cambridge , MA (US ) OTHER PUBLICATIONS Adams, Julian , et al. , " Proteasome Inhibitors: A Novel Class of ( * ) Notice : Subject to any disclaimer, the term of this Potent and Effective Antitumor Agents , ” Cancer Research , vol. 59 patent is extended or adjusted under 35 ( Jun . 1 , 1999 ) pp . 2615 - 2622 . U . S . C . 154 (b ) by 0 days . days . Adams, Julian , “ Development of the Proteasome Inhibitor PS - 341, " The Oncologist , vol. 7 ( 2002 ) pp . 9 - 16 . This patent is subject to a terminal dis Lightcap , Eric S . , et al. , " Proteasome Inhibition Measurements : claimer . Clinical Application , ” Clinical Chemsitry , vol. 46 , No. 5 ( 2000 ) pp . 673 -683 . (21 ) Appl . No. : 14 /516 , 719 Hochwald , Steven N . , et al. , “ Antineoplastic Therapy in Colorectal Cancer through Proteasome Inhibition ,” The American Surgeon , ( 22 ) Filed : Oct . 17 , 2014 vol. 69 ( Jan . 2003) pp . 15 - 23 . Richardson , Paul G . , et al. , “ A Phase 2 Study of Bortezomib in Relapsed , Refractory Myeloma, ” The New England Journal of (65 ) Prior Publication Data Medicine , vol. 348 , No. 26 ( Jun . 26 , 2003 ) pp . 2609 - 2617 . US 2015 / 0252430 A1 Sep . 10 , 2015 Van de Vijver , Marc J. , et al. , “ A Gene - Expression Signature as a Predictor of Survival in Breast Cancer , " The New England Journal of Medicine , vol. 347 , No. 25 (Dec . 19 , 2002 ) pp . 1999 -2009 . Related U . S . Application Data Barden , Catherine B ., et al . , “ Classification of Follicular Thyroid Tumors by Molecular Signature : Results of Gene Profiling , ” Clini (63 ) Continuation of application No . 13 /600 , 260 , filed on cal Cancer Research , vol. 9 (May 2003 ) pp . 1792 - 1800 . Aug . 31 , 2012 , now Pat. No. 8 , 889, 354 , which is a Mulligan , George , et al. , “Gene expression profiling and correlation continuation of application No . 11 /449 , 195 , filed on with outcome in clinical trials of the proteasome inhibitor Jun . 8 , 2006 , now Pat. No. 8 ,278 ,038 . bortezomib ,” Blood , vol. 109 , No . 8 ( Apr. 15 , 2007 ) pp . 3177 - 3188 . Toczyski , David P ., et al. , “ The Epstein -Barr virus (EBV ) small RNA EBER1 binds and relocalizes ribosomal protein L22 in (60 ) Provisional application No. 60 /688 ,634 , filed on Jun . EBV -infected human B lymphocytes , ” Proceedings of the National 8 , 2005 . Academy of Science USA , vol . 91 ( Apr. 1994 ) pp . 3463 - 3467 . Maglott , Donna , et al. , “ Entrez Gene: gene -centered information at ( 51 ) Int . Cl. NCBI , ” Nucleic Acids Research , vol. 33 , Database issue ( 2005 ) pp . C120 1 /68 ( 2018 .01 ) D54 -D58 . GOIN 33 / 574 ( 2006 .01 ) (Continued ) G06F 19 / 20 ( 2011 .01 ) G06Q 50 / 22 ( 2018 .01 ) Primary Examiner — Sean E Aeder A61K 31 /69 ( 2006 .01 ) (74 ) Attorney , Agent, or Firm — Millennium G060 20 / 40 ( 2012 .01 ) Pharmaceuticals , Inc . G06F 19 /24 ( 2011. 01) U . S . CI. (57 ) ABSTRACT ??? . .. .. .. C12Q 1 /6886 (2013 .01 ) ; A61K 31/ 69 The present invention is directed to the identification of ( 2013 .01 ) ; GOIN 33 /57407 (2013 .01 ) ; GOIN predictive markers that can be used to determine whether 33 / 57415 (2013 .01 ) ; GOIN 33 / 57419 patients with cancer are clinically responsive or non - respon ( 2013 . 01 ) ; GOIN 33 /57423 ( 2013 .01 ) ; GOIN sive to a therapeutic regimen prior to treatment. In particular , 33 /57426 (2013 .01 ) ; GOIN 33 / 57434 the present invention is directed to the use of certain ( 2013 . 01 ) ; GOIN 33 / 57438 ( 2013 . 01 ) ; GOIN individual and /or combinations of predictive markers, 33 /57449 (2013 . 01 ) ; G06F 19 /20 ( 2013 .01 ) ; wherein the expression of the predictive markers correlates G06Q 20 /40 (2013 .01 ) ; G06Q 50 / 22 with responsiveness or non - responsiveness to a therapeutic ( 2013 . 01 ) ; C120 2600 / 106 ( 2013 . 01 ) ; C120 regimen . Thus , by examining the expression levels of indi 2600 / 136 ( 2013 .01 ) ; C12Q 2600 /158 vidual predictive markers and /or predictive markers com ( 2013 .01 ) ; GOIN 2800 / 44 (2013 .01 ) ; GOOF prising a marker set, it is possible to determine whether a 19 /24 (2013 .01 ) ; YO2A 90 /22 (2018 .01 ) ; YO2A therapeutic agent, or combination of agents , will be most 90 / 26 (2018 .01 ) likely to reduce the growth rate of tumors in a clinical (58 ) Field of Classification Search setting . None See application file for complete search history . 19 Claims, No Drawings US 9 , 963, 747 B2 Page 2 References Cited Alberts , Bruce, et al. , Molecular Biology of the Cell, Third Edition , (56 ) published by Garland Publishing, Inc ., New York , New York ( 1994 ) p . 465 . OTHER PUBLICATIONS Greenbaum , Dov, et al. , “ Comparing protein abundance and mRNA Affymetrix , Inc ., “ Annotation Methodology, ” Affymetrix — Anno expression levels on a genomic scale , " Genome Biology , vol. 4 , No. 9 (2003 ) pp . 117 . 1 - 117. 8 . tation Methodology Technical Note [ online ] Affymetrix , Santa Lichtinghagen , Ralf, et al. , “ DifferentmRNA and protein expression Clara , CA , downloaded Jul. 23 , 2008 ( 3 pages ) . of matrix metalloproteinases 2 and 9 and tissue inhibitor of metal Affymetrix , Inc ., “ GeneChip Human Genome U133 Set ,” [online ] loproteinases 1 in benign and malignant prostate tissue, ” European 701092 Rev . 3 ( Nov . 2004 ) downloaded Jul. 23 , 2008 ( 2 pages ) . Urology , vol . 42 ( 2002 ) pp . 398 - 406 . Affyrnetrix , Inc ., “ Human GenomeU133 Set - Support Materials , " Wessels , Lodewyk F . A . , et al. , “ A protocol for building and Affymetrix - Technical Support Documentation for Human evaluating predictors of disease state based on microarray data , " Genome U133 Set [ online ] downloaded Jul. 24 , 2008 ( 3 pages ) . Bioinformatics, vol . 21, No . 19 ( Apr. 7 , 2005 ) pp . 3755 - 3762 . International Preliminary Examination Report ( IPER ) and Written International Prelminary Examination Report (IPER ) and Written Opinion of the International Seaarching Authority dated Dec . 11 , Opinion of the International Searching Authority dated Dec . 11 , 2007 in corresponding PCT Application PCT/ US06 /022515 . 2007 in corresponding PCT Application PCT/ US06 / 022515 . Office Action dated Jun . 23. 2008 in co -pending U . S . Appl . No . Office Action dated Jun . 23 , 2008 in co - pending U . S . Appl. No. 10 / 728 ,055 . 10 / 728 ,055 . Maglott , Donna , et al. , “ Entrez Gene : gene - centered information at Supplementary Partial European Search Report dated Jun . 24 , 2009 NCBI, ” Nucleic Acids Research , vol. 33, Database issue (2005 ) pp . in European Patent Application No . 06784710 . 3 which corresponds D54 -D58 . to U . S . Appl. No. 11/ 449 , 195 . Affymetrix , Inc . , “ Human Genome U133 Set - Support Materials ,” Glatt , Christine M . , et al ., “ Molecular characterization of thyroid Affymetrix — Technical Support Documentation for Human Genome U133 Set [online ] downloaded Jul . 24 , 2008 ( 3 pages ). toxicity : anchoring gene expression profiles to biochemical and Toczyski, David P . , et al. , “ The Epstein - Barr virus (EBV ) small pathologic end points ,” Environmental Health Perspectives , vol. RNA EBER1 binds and relocalizes ribosomal protein L22 in 113 , No . 10 ( Oct . 2005 ) pp . 1354 - 1361. EBV -infected human B lymphocytes, ” Proceedings of the National Wessels , Lodewyk F . A . , et al ., " A protocol for building and Academy of Science US, vol. 91 ( Apr. 1994 ) pp . 3463 - 3467 . evaluating predictors of disease state based on microarray data ,” Chauhan , Dharminder, et al. , “ Identification of genes regulated by Bioinfomatics , vol . 21, No . 19 ( Apr. 7 , 2005 ) pp . 3755 - 3762 . Dexamethasone in multiple myeloma cells using oligonucleotide Tockman , Melvyn S . , et al. , “ Considerations in bringing a cancer arrays, ” Oncogene , vol . 21 ( 2002 ) pp . 1346 - 1358 . biomarker to clinical application , ” Cancer Research (Supplement ) , International Search Report of the International Searching Authority vol . 52 (May 1 , 1992 ) pp . 27118 -27182 . dated Nov . 26 , 2007 issued in International Application No . PCT/ Ferrandina , Gabriella , et al. , “ Cyclooxygenase - 2 (Cox - 2 ) expres US06 /022515 , which corresponds to U . S . Appl. No . 11/ 449 , 195 . sion and resistance to platinum versus platinum / paclitaxel contain Search Report dated Jan . 2 , 2014 of co -pending European patent ing chemotherapy in advanced ovarian cancer ,” BMC Cancer , vol. application No . 13181515 . 1 6 No. 182 ( Jul. 11 , 2006 ) pp . 1 - 5 . Bohen et al. , “ Variation in Gene Expression Patterns in Follicular Chauhan , Dharminder, et al. , “ Identification of genes regulated by Lymphoma and the Response to Rituximab ” , PNAS, 2003 , vol. 100 , Dexamethasone in multiple myeloma cells using oligonudeotide No . 4 , pp . 1926 - 1930 . arrays ,” Oncogene , vol. 21 ( 2002 ) pp . 1346 - 1358 . Barlow , et
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