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Mai Muudatuntuu Ti on Man Mini MAIMUUDATUNTUU US009809854B2 TI ON MAN MINI (12 ) United States Patent ( 10 ) Patent No. : US 9 ,809 ,854 B2 Crow et al. (45 ) Date of Patent : Nov . 7 , 2017 Whitehead et al. (2005 ) Variation in tissue - specific gene expression ( 54 ) BIOMARKERS FOR DISEASE ACTIVITY among natural populations. Genome Biology, 6 :R13 . * AND CLINICAL MANIFESTATIONS Villanueva et al. ( 2011 ) Netting Neutrophils Induce Endothelial SYSTEMIC LUPUS ERYTHEMATOSUS Damage , Infiltrate Tissues, and Expose Immunostimulatory Mol ecules in Systemic Lupus Erythematosus . The Journal of Immunol @(71 ) Applicant: NEW YORK SOCIETY FOR THE ogy , 187 : 538 - 552 . * RUPTURED AND CRIPPLED Bijl et al. (2001 ) Fas expression on peripheral blood lymphocytes in MAINTAINING THE HOSPITAL , systemic lupus erythematosus ( SLE ) : relation to lymphocyte acti vation and disease activity . Lupus, 10 :866 - 872 . * New York , NY (US ) Crow et al . (2003 ) Microarray analysis of gene expression in lupus. Arthritis Research and Therapy , 5 :279 - 287 . * @(72 ) Inventors : Mary K . Crow , New York , NY (US ) ; Baechler et al . ( 2003 ) Interferon - inducible gene expression signa Mikhail Olferiev , Mount Kisco , NY ture in peripheral blood cells of patients with severe lupus . PNAS , (US ) 100 ( 5 ) : 2610 - 2615. * GeneCards database entry for IFIT3 ( obtained from < http : / /www . ( 73 ) Assignee : NEW YORK SOCIETY FOR THE genecards. org /cgi - bin / carddisp .pl ? gene = IFIT3 > on May 26 , 2016 , RUPTURED AND CRIPPLED 15 pages ) . * Navarra et al. (2011 ) Efficacy and safety of belimumab in patients MAINTAINING THE HOSPITAL with active systemic lupus erythematosus : a randomised , placebo FOR SPECIAL SURGERY , New controlled , phase 3 trial . The Lancet , 377 :721 - 731. * York , NY (US ) Abramson et al . ( 1983 ) Arthritis Rheum . 26 :630 - 6 . American College of Rheumatology Ad Hoc Committee on Sys @( * ) Notice: Subject to any disclaimer , the term of this temic Lupus Erythematosus Response Criteria (2004 ) Arthritis patent is extended or adjusted under 35 Rheum . 50 : 3418 - 26 . Baechler et al . (2003 ) Proc Natl Acad Sci USA 100 : 2610 - 5 . U . S . C . 154 ( b ) by 345 days . Barrat et al. (2005 ) J . Exp . Med . 202 : 1131 - 9 . Bauer et al . ( 2009 ) Arthritis Rheum . 60 : 3098 - 107 . (21 ) Appl . No. : 13/ 998 ,598 Bennett et al . (2003 ) J . Exp . Med . 197 :711 -23 . Brinkmann et al. ( 2004 ) Science 303 : 1532 - 5 . (22 ) Filed : Nov . 15 , 2013 Chaussabel et al. ( 2008 ) Immunity 29 : 150 -64 . Crow and Kirou ( 2008 ) Arthritis Res . Ther. 10 : 126 . (65 ) Prior Publication Data Crow ( 2007 ) Curr . Top . Microbiol. Immunol . 316 :359 - 86 . Crow and Wohlgemuth (2003 ) Arthritis Res. Ther . 5 :279 - 87 . US 2014 /0135225 A1 May 15 , 2014 Crow et al . (2003 ) Autoimmunity 36 :481 - 90 . Denny et al. ( 2010 ) J . Immunol. 6 :3284 -97 . Related U . S . Application Data De Waard et al . ( 1999 ) Gene 226 : 1 - 8 . Fan et al. ( 2004 ) Genome Res . 14 : 878 - 85 . (60 ) Provisional application No . 61/ 726 , 902, filed on Nov. Feng et al. (2006 ) Arthritis Rheum . 54 : 2951 -62 . 15 , 2012 Forsman and Dahlgren (2010 ) BMC Cell Biol . 11: 52 . Fukuda et al. (2009 ) Clin . Rheumatol. 28 : 301 - 4 . (51 ) Int. Ci. Garcia - Carrasco et al. (2002 ) J. Rheumatol. 29 :726 - 30 . Garcia - Romo et al . ( 2011) Sci . Trans . Med . 3 :73ra20 . C12Q 1/ 68 ( 2006 .01 ) Gray et al. (2010 ) J. Immunol. 184 :6359 -66 . (52 ) U . S . CI. Hakkim et al. ( 2010 ) Proc Natl Acad Sci USA 107 : 9813 - 8 . CPC . C12Q 1 /6883 (2013 . 01 ) ; C12Q 2600 / 158 Han et al . ( 2003 ) Genes Immun . 4 : 177 - 86 . (2013 .01 ) Hargraves et al. ( 1948 ) Mayo Clin . Proc . 23 :25 - 8 . ( 58 ) Field of Classification Search Hargraves ( 1969 ) Mayo Clin . Proc . 44 :579 - 9 . None (Continued ) See application file for complete search history . Primary Examiner — Neil P Hammell (56 ) References Cited ( 74) Attorney , Agent, or Firm — Leason Ellis LLP U . S . PATENT DOCUMENTS (57 ) ABSTRACT 7 ,571 , 055 B2 * 8 / 2009 Behrens .. .. .. .. C12Q 1 /6883 This invention related to methods and assays for screening 435 /6 . 11 for, identifying , and predicting the severity and clinical 2010 /0113293 Al * 5 /2010 Pascual .. C12Q 1 /6883 manifestations of systemic lupus erythematosus ( SLE ) . Spe 506 / 8 cifically, this invention provides various biomarkers for the 2010 /0261172 A1 * 10 /2010 Yao . .. .. .. .. .. C12Q 1 /6883 prediction of flares of the disease both in number and 435 / 6 . 12 severity , as well as clinical manifestations of the disease , and methods of using these biomarkers to correctly subclassify OTHER PUBLICATIONS patients with this disease , and prescribe appropriate treat Manzi et al . “ Systemic Lupus Erythematosus: Treatment and ment. The invention also provides for biomarkers of lupus Assessment” in Klippel et al. , Primer on the Rheumatic Diseases , disease activity , i. e ., flares , as well as biomarkers for the 13th ed . ( New York , Springer, 2008 ) , pp . 327 - 338 .* prediction of future flares, and methods of using these Affymetrix HG -U133A Annotation File ( filtered excerpt , obtained biomarkers . The invention also provides , in these biomark from < http :/ / www .affymetrix . com / Auth /analysis /downloads / na35 / ers , targets and methods for drug development and basic ivt/ HG -U133A .na35 .annot . csv .zip > on Apr. 29 , 2016 , 1 page ). * research for SLE . Mannucci et al. ( 2003) Von Willebrand factor cleaving protease ( ADAMTS - 13 ) in 123 patients with connective tissue diseases 6 Claims, 17 Drawing Sheets Journal of Hematology , 88 ( 8 ) :914 - 918 . * ( 5 of 17 Drawing Sheet ( s ) Filed in Color ) US 9 ,809 , 854 B2 Page 2 ( 56 ) References Cited OTHER PUBLICATIONS Irizarry et al . ( 2003 ) Biostatistics 4 : 249 -64 . Karlovich et al . ( 2009 ) BMC Med . Genomics . 2 : 33 . Kirou et al. ( 2004 ) Arthritis Rheum . 50 :3958 -67 . Kurien and Scofield (2006 ) Scand . J . Immunol . 64 : 227 - 35 . Kurien et al . ( 2000 ) Clin . Exp . Immunol. 120 : 209 - 17 . Lande et at . (2011 ) Sci. Transl . Med . 3 : 73ra 19 . Lovgren et al. (2004 ) Arthritis Rheum . 50 : 1861 -72 . Mantovani et al. ( 1998 ) Ann . N Y Acad . Sci. 840 : 338 -51 . Milner and Day ( 2003 ) J. Cell . Sci . 116 : 1863 - 73 . Nathan ( 2006 ) Nat. Rev . Immunol. 6 : 173 - 82 . Samarajiwa et al. (2009 ) Nucleic Acids Research (Database Issue ) :D852 - 7 . Tan et at . ( 1982 ) Arthritis Rheum . 25 : 1271 - 7 . Theilgaard -Mönch et al . ( 2005 ) Blood 105 : 1785 - 96 . Velculescu et at . ( 1995 ) Science 270 ;484 -487 . Velculescu et al. ( 1997 ) Cell 88 . Villanueva et al. ( 2011) J . Immunol. 187 : 538 - 52 . Yee et al. ( 2009 ) Rheumatology 48 :691 - 5 . Zhao et al . (2009 ) Drug Metab . Dispos . 37 : 282 -91 . * cited by examiner U. S . Patentatent NovNov . 7 , 2017 Sheet 1 of 17 US 9 ,809 , 854 B2 IF07 IF04 F12 ( 1726 w XR IF17 * * 1714 w * IF03 * IF32 W * * 8931 * 6031W 9051 1931 F51 * F16* 1F28w wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww w F44 F18w 19 IF IFOS IF50 Figure1 MWA IF39 1F24 9OQHwww. HD03 HD01 HD04 ZOOM Frittlnitionin Wwwwwww Clusters FIG ColorXey ginagmanager me02Value *NR 404 U . S . Patent Nov . 7, 2017 Sheet 2 of 17 US 9, 809 , 854 B2 5202 W * 80080 WW *00mm 60-699999699$WSK 301)KOAX06SK 1280 100000 4703SAS 4903 x20 1470 * * 38:* oxoxo * XX 23348070 om voryCosta *80W8 * Oviaccogs WS$58 0900W Wow! VXXOE semua402 cometo 18W8 400 sro 23. MORNI xos Xin . * W20694 XCIWSS W8 :. 20125000 * 15378129899 8208285YMM * . % 2209 * 50 * VA KONSX1040 * * * * CY3X85X 62202wiss 6K. 23 * 20 * SN * * * : 907 * . 3. 3 * 167 * POR2 . .CHOWS . * Voccan 34 : 8 . wX750 , 202012 40 sa som .. 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