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Ccessooooooooooooo THAI MALENG MAT US010017821B2ERIALI MITTE (12 ) United States Patent ( 10 ) Patent No. : US 10 ,017 , 821 B2 Sharp et al. (45 ) Date of Patent : * Jul. 10 , 2018 ( 54 ) BIOMARKERS FOR DIAGNOSING ( 2013 .01 ) ; GOIN 2800 / 324 (2013 . 01 ) ; GOIN ISCHEMIA 2800 / 50 (2013 .01 ) ; GOIN 2800 /7019 ( 2013 .01 ) (71 ) Applicant : The Regents of the University of (58 ) Field of Classification Search California , Oakland , CA (US ) CPC .. .. .. C12Q 1 /6883 ; C12Q 2600 / 158 ; GOIN 33 /6893 ; GOIN 2800 / 2871 ; GOIN ( 72 ) Inventors : Frank Sharp , Davis , CA (US ) ; Glen C 2800 /324 ; GOIN 28 / 50 ; GOIN 2800 /7019 Jickling , Sacramento , CA (US ) See application file for complete search history . ( 73 ) Assignee : The Regents of the University of ( 56 ) References Cited California , Oakland , CA (US ) U . S . PATENT DOCUMENTS ( * ) Notice : Subject to any disclaimer , the term of this 9 ,057 ,109 B2 6 / 2015 Chang patent is extended or adjusted under 35 9 ,200 , 322 B2 12 /2015 Barr et al . U . S . C . 154 ( b ) by 0 days . 9 ,410 ,204 B2 * 8 /2016 Sharp .. .. ... C12Q 1 /6883 This patent is subject to a terminal dis (Continued ) claimer . FOREIGN PATENT DOCUMENTS (21 ) Appl. No. : 15 /226 ,844 WO WO 02 / 12892 2 /2002 WO WO 03 /016910 2 /2003 ( 22 ) Filed : Aug . 2 , 2016 ( Continued ) (65 ) Prior Publication Data OTHER PUBLICATIONS US 2017 /0029891 A1 Feb . 2 , 2017 PCT International Search Report and Written Opinion dated Jul . 25 , Related U . S . Application Data 2008 issued in PCT/ US2008 / 062064 . (63 ) Continuation of application No. 14 /370 ,709 , filed as (Continued ) application No . PCT /US2013 /020240 on Jan . 4 , Primary Examiner — Reza Ghafoorian 2013 , now Pat . No . 9 ,410 ,204 . (74 ) Attorney , Agent, or Firm — Weaver Austin (60 ) Provisional application No. 61/ 584 ,232 , filed on Jan . Villeneuve & Sampson LLP 7 , 2012 . (57 ) ABSTRACT (51 ) Int. Ci. The present invention provides methods and compositions C120 1 /68 ( 2018 .01 ) for diagnosing and predicting the occurrence of ischemia . C12Q 1 /6883 ( 2018 .01 ) For example , the present invention provides methods and GOIN 33868 ( 2006 .01 ) compositions for diagnosing and predicting the risk and (52 ) U . S . CI. cause of transient neurological events ( TNE ) as ischemic or CPC . .. .. C12Q 1 /6883 ( 2013 . 01 ) ; GOIN 33 /6893 non - ischemic . (2013 . 01 ) ; C12Q 2600 / 118 ( 2013 .01 ) ; C12Q 2600 / 158 (2013 . 01 ) ; GOIN 2800 /2871 11 Claims, 3 Drawing Sheets TIA (n = 26 ) VS ischemic Stroke (n = 94 ) ????????????????? VRF Control (n = 44 ) VS VRF Control (n = 44) Derivation ?????????? 86 ( 74 387 CCESSOOOOOOOOOOOOO pero S Cross Validation 26 Gene 10 - fold leave -one -out LDA Prediction Model TIA - DWI+ / Minor Stroke (n = 17 ) Validation Nonischemic TNE (n = 13 ) US 10 ,017 ,821 B2 Page 2 ( 56 ) References Cited " Affymetrix GeneChip Human Genome U133 Array Set HG -U133B , ” GEO Accession viewer (Mar . 11, 2002 ), U . S . PATENT DOCUMENTS XP002427171 pp . 1 - 4 . “ Affymetrix Genechip Human GenomeU133 plus 2 . 0 Array , ” GEO 9 , 803 ,243 B2 10 / 2017 Sharp et al . Accession viewer 7 (Nov . 7 , 2003 ) , XP002343693 pp . 1 - 3 . 2001/ 0053519 Al 12 / 2001 Fodor et al. Barr et al . (2010 ) “ Genomic biomarkers and cellular pathways of 2002 /0115120 A18 / 2002 Kapeller - Libermann et al. ischemic stroke by RNA gene expression profiling" Neurology 2003 /0119064 Al 6 / 2003 Valkirs et al . 2003 /0199000 Al 10 / 2003 Valkirs et al. 75 : 1009 - 1014 . 2004 /0191783 AL 9 /2004 Leclercq et al . 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( 2009 ) “ CD40 ligand and MCP - 1 as predictors of 2010 /0105046 A1 4 / 2010 Epstein et al . 2010 /0197518 A1 8 / 2010 Xu et al. cardiovascular events in diabetic patients with stroke ,” J . 2010 /0216115 AI 8 / 2010 Yan et al. Atheroscler. Thromb. 16 : 707 -713 . 2012 /0015904 AL 1 / 2012 Sharp et al . Ferronato et al . ( 2010 ) “ Upregulated Expression of Toll - like Recep 2012 / 0065087 A 3 / 2012 Sharp et al. tor 4 in Peripheral Blood of Ischaemic Stroke Patients Correlates 2012 / 0316076 A112 / 2012 Sharp et al. with Cyclooxygenase 2 Expression , ” European Journal of Vascular 2015 /0018234 A1 1 / 2015 Sharp et al. and Endovascular Surgery 41 ( 3 ) : 358 - 363 . 2016 /0222455 A1 8 / 2016 Xu et al. Fung et al. (2008 ) “ A biomarker panel for peripheral arterial 2016 /0237501 AL 8 / 2016 Sharp et al. disease, " Vase . Med . 13 :217 -224 . 2016 / 0265059 AL 9 / 2016 Sharp et al . Greenbaum et al . 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( 2006 ) “ Actual diagnostic approach to the PCT International Search Report and Written Opinion dated Apr. 12 , acute stroke patient, ” Neuro Eur Radiol , 16 : 1253 - 1269 . 2013 issued in PCT/ US2013 /020240 . Laskowitz et al. ( 2005 ) “ Panel of Biomarkers Predicts Stroke, ” Ann . PCT International Preliminary Report on Patentability dated Jul . 8 , N . Y . Acad . Sci ., 1053 : 30 . 2014 issued in PCT/ US2013 / 020240 . Leypoldt et al . (2009 ) “ Dimethylarginine Indian First Examination Report dated Dec . 13 , 2016 issued in IN Dimethylaminohydrolase - 1 Transgenic Mice are not Protected from 3762 /KOLNP / 2009 . Ischemic Stroke, ” PlosOne , 4 ( 10 ) :e7337 ( 1 - 4 ) . European Extended Search Report dated Mar. 16 , 2011 issued in EP Li et al. ( Oct. 2013 ) “ Transcriptome Analysis Reveals Distinct 10014221 . 5 . 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