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WO 2012/170711 Al 13 December 2012 (13.12.2012) P O P C T

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WO 2012/170711 Al 13 December 2012 (13.12.2012) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/170711 Al 13 December 2012 (13.12.2012) P O P C T (51) International Patent Classification: (72) Inventors; and G01N33/5 74 (2006.01) (75) Inventors/Applicants (for US only): PAWLOWSKI, Traci [US/US]; 2014 N Milkweed Loop, Phoenix, AZ (21) International Application Number: 85037 (US). YEATTS, Kimberly [US/US]; 109 E. Pierce PCT/US2012/041387 Street, Tempe, AZ 85281 (US). AKHAVAN, Ray (22) International Filing Date: [US/US]; 5804 Malvern Hill Ct, Haymarket, VA 201 69 7 June 2012 (07.06.2012) (US). (25) Filing Language: English (74) Agent: AKHAVAN, Ramin; Caris Science, Inc., 6655 N. MacArthur Blvd., Irving, TX 75039 (US). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 61/494,196 7 June 201 1 (07.06.201 1) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, 61/494,355 7 June 201 1 (07.06.201 1) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 61/507,989 14 July 201 1 (14.07.201 1) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (71) Applicant (for all designated States except US): CARIS HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, LIFE SCIENCES LUXEMBOURG HOLDINGS, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, S.A.R.L [LU/LU]; Rue De Maraichers, L2124 Luxem MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, bourg, Grand-Duche De Luxembourg (LU). OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, [Continued on nextpage] (54) Title: CIRCULATING BIOMARKERS FOR CANCER (57) Abstract: Biomarkers can be assessed for diagnostic, therapy-related or prognostic methods to identify phenotypes, such as a condition or disease, or 6100A the stage or progression of a disease, select candidate treatment regimens for diseases, conditions, disease stages, and stages of a condition, and to determ 6101 ine treatment efficacy. Circulating biomarkers from a bodily fluid can be used in profiling of physiological states or determining phenotypes. These include OBTAIN BIOLOGICAL SAMPLE nucleic acids, protein, and circulating structures such as vesicles, and nucleic acid-protein complexes. 6103 ISOLATE NUCLEIC ACID (NA) 6105 ANALYZE NA (MICRORNA, mRNA, MUTATIONS, etc.) 6107 IDENTIFY BIOMARKER AND/OR BIO-SIGNATURE FOR PHENOTYPE o FIG. 1A o o w o 2012/170711 Ai llll II II 11III II I 11II II III II IIII II I II SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (84) Designated States (unless otherwise indicated, for every GW, ML, MR, NE, SN, TD, TG). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Published: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, — with international search report (Art. 21(3)) TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, CIRCULATING BIOMARKERS FOR CANCER CROSS REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Application Nos. 61/494,196, filed June 7, 201 1; 61/494,355, filed June 7, 201 1; and 61/507,989, filed July 14, 201 1; all of which applications are incorporated herein by reference in their entirety. [0002] This application is a continuation-in-part of International Patent Application PCT/US2012/025741, filed February 17, 2012, which application claims the benefit of U.S. Provisional Patent Application Nos. 61/446,3 13, filed February 24, 201 1; 61/501,680, filed June 27, 201 1; 61/471,417, filed April 4, 201 1; 61/523,763, filed August 15, 201 1; and 61/445,273, filed February 22, 201 1; all of which applications are incorporated herein by reference in their entirety. [0003] This application is also a continuation-in-part of International Patent Application PCT/US201 1/048327, filed August 18, 201 1, which application claims the benefit of U.S. Provisional Patent Application Nos. 61/374,95 1, filed August 18, 2010; 61/379,670, filed September 2, 2010; 61/381,305, filed September 9, 2010; 61/383,305, filed September 15, 2010; 61/391,504, filed October 8, 2010; 61/393,823, filed October 15, 2010; 61/41 1,890, filed November 9, 2010; 61/414,870, filed November 17, 2010; 61/416,560, filed November 23, 2010; 61/421,85 1, filed December 10, 2010; 61/423,557, filed December 15, 2010; 61/428, 196, filed December 29, 2010; all of which applications are incorporated herein by reference in their entirety. [0004] This application is also a continuation-in-part of International Patent Application PCT/ US201 1/026750, filed March 1, 201 1, which application claims is a continuation-in-part application of U.S. Patent Application Serial No. 12/591,226, filed November 12, 2009, which claims the benefit of U.S. Provisional Application Nos. 61/1 14,045, filed November 12, 2008; 61/1 14,058, filed November 12, 2008; 61/1 14,065, filed November 13, 2008; 61/15 1, 183, filed February 9, 2009; 61/278,049, filed October 2, 2009; 61/250,454, filed October 9, 2009; and 61/253,027 filed October 19, 2009; and which application also claims the benefit of U.S. Provisional Application Nos. 61/274, 124, filed March 1, 2010; 61/357,5 17, filed June 22, 2010; 61/364,785, filed July 15, 2010; all of which applications are incorporated herein by reference in their entirety. [0005] This application is also a continuation-in-part of International Patent Application PCT/US201 1/03 1479, filed April 6, 201 1, which application claims the benefit of U.S. Provisional Patent Application Nos. 61/321,392, filed April 6, 2010; 61/321,407, filed April 6, 2010; 61/332,174, filed May 6, 2010; 61/348,214, filed May 25, 2010, 61/348,685, filed May 26, 2010; 61/354,125, filed June 11, 2010; 61/355,387, filed June 16, 2010; 61/356,974, filed June 21, 2010; 61/357,5 17, filed June 22, 2010; 61/362,674, filed July 8, 2010; 61/413,377, filed November 12, 2010; 61/322,690, filed April 9, 2010; 61/334,547, filed May 13, 2010; 61/364,785, filed July 15, 2010; 61/370,088, filed August 2, 2010; 61/379,670, filed September 2, 2010; 61/381,305, filed September 9, 2010; 61/383,305, filed September 15, 2010; 61/391,504, filed October 8, 2010; 61/393,823, filed October 15, 2010; 61/41 1,890, filed November 9, 2010; and 61/416,560, filed November 23, 2010; all of which applications are incorporated herein by reference in their entirety. BACKGROUND [0006] Biomarkers for conditions and diseases such as cancer include biological molecules such as proteins, peptides, lipids, RNAs, DNA and variations and modifications thereof. [0007] The identification of specific biomarkers, such as DNA, RNA and proteins, can provide biosignatures that are used for the diagnosis, prognosis, or theranosis of conditions or diseases. Biomarkers can be detected in bodily fluids, including circulating DNA, RNA, proteins, and vesicles. Circulating biomarkers include proteins such as PSA and CA125, and nucleic acids such as SEPT9 DNA and PCA3 messenger RNA (mRNA). Circulating biomarkers can be associated with circulating vesicles. Vesicles are membrane encapsulated structures that are shed from cells and have been found in a number of bodily fluids, including blood, plasma, serum, breast milk, ascites, bronchoalveolar lavage fluid and urine. Vesicles can take part in the communication between cells as transport vehicles for proteins, RNAs, DNAs, viruses, and prions. MicroRNAs are short RNAs that regulate the transcription and degradation of messenger RNAs. MicroRNAs have been found in bodily fluids and have been observed as a component within vesicles shed from tumor cells. The analysis of circulating biomarkers associated with diseases, including vesicles and/or microRNA, can aid in detection of disease or severity thereof, determining predisposition to a disease, as well as making treatment decisions. [0008] Vesicles present in a biological sample provide a source of biomarkers, e.g., the markers are present within a vesicle (vesicle payload), or are present on the surface of a vesicle. Characteristics of vesicles (e.g., size, surface antigens, determination of cell-of-origin, payload) can also provide a diagnostic, prognostic or theranostic readout. There remains a need to identify biomarkers that can be used to detect and treat disease. microRNA, proteins and other biomarkers associated with vesicles as well as the characteristics of a vesicle can provide a diagnosis, prognosis, or theranosis. [0009] The present invention provides methods and systems for characterizing a phenotype by detecting biomarkers that are indicative of disease or disease progress. The biomarkers can be circulating biomarkers including without limitation vesicle markers, protein, nucleic acids, mRNA, or microRNA. The biomarkers can be nucleic acid-protein complexes. SUMMARY [0010] Disclosed herein are methods and compositions for characterizing a phenotype by analyzing circulating biomarkers, such as a vesicle, microRNA or protein present in a biological sample. Characterizing a phenotype for a subject or individual may include, but is not limited to, the diagnosis of a disease or condition, the prognosis of a disease or condition, the determination of a disease stage or a condition stage, a drug efficacy, a physiological condition, organ distress or organ rejection, disease or condition progression, therapy-related association to a disease or condition, or a specific physiological or biological state.
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