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WO 2017/210327 Al 07 December 2017 (07.12.2017) W !P O PCT

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WO 2017/210327 Al 07 December 2017 (07.12.2017) W !P O PCT (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 2017/210327 Al 07 December 2017 (07.12.2017) W !P O PCT (51) International Patent Classification: G06F 19/18 (201 1.01) G06F 19/28 (201 1.01) (21) International Application Number: PCT/US2017/035259 (22) International Filing Date: 31 May 2017 (3 1.05.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/345,526 03 June 2016 (03.06.2016) US 62/381,916 31 August 2016 (3 1.08.2016) US (71) Applicant: CELMATIX INC. [US/US]; 14 Wall St, Suite 16D, New York, NY 10005 (US). (72) Inventor: BEIM, Piraye, Yurttas; 70 Little West Street, PH1B, New York, NY 10004 (US). (74) Agent: MEYERS, Thomas, C. et al. ; Brown Rudnick LLP, = One Financial Center, Boston, MA 02 111 (US). = (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, = CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, = DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, ≡ HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, ≡ KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, = MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, = PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, ≡ SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, TR, = TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. = (84) Designated States (unless otherwise indicated, for every — kind of regional protection available): ARIPO (BW, GH, = GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, = UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, = TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, = EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 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, GW, = KM, ML, MR, NE, SN, TD, TG). = Published: — with international search report (Art. 21(3)) (54) Title: METHOD FOR ASSESSING FERTILITY BASED ON MALE AND FEMALE GENETIC AND PHENOTYPIC DATA (57) Abstract: The present invention generally relates to systems and methods for assessing female fertility and infertility, male fertility and infertility and the combined fertility profile of a male and a female. Systems and methods of the invention determine the fertility potential of a female and a male combined by conducting an assay on a sample obtained from the male and female to determine the presence of one or more fertility-associated genetic variants, obtain fertility-associated phenotypic and/or environmental data from the male and the female, accepting as input data, the genetic variants determined from the female and male and phenotypic and/or environmental exposure data from the male and female, analyze the input data using a prognosis predictor correlated with fertility, and generate a fertility profile that reflects the fertility potential of the male and the female combined by using the prognosis predictor on the input data. METHOD FOR ASSESSING FERTILITY BASED ON MALE AND FEMALE GENETIC AND PHENOTYPIC DATA Cross-Reference to Related Applications This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 62/345,526, filed June 3, 2016, and U.S. Provisional Patent Application Serial No. 62/381,916, filed August 31, 2016, the contents of each of which are incorporated by reference herein in their entirety. Technical Field The invention generally relates to methods for assessing the combined fertility profile of a male and a female. Background Approximately one in seven couples has difficulty conceiving. Infertility may be due to a single cause in either or both partner(s), or a combination of factors (e.g., genetic factors, diseases, or environmental factors) that may prevent a pregnancy from occurring or continuing. With respect to female infertility, every woman will become infertile in her lifetime due to menopause. On average, egg quality and number begins to decline precipitously at 35. However, some women experience this decline much earlier in life, while a number of women are fertile well into their 40's. Though, generally, advanced maternal age (35 and above) is associated with poorer fertility outcomes, there is at current time no way of diagnosing egg quality issues in younger women or knowing when a particular woman will start to experience decline in her egg quality or reserve, such that fertility is impacted. In addition to female infertility, it is estimated that for around a third of couples unable to conceive a child, subfertility of the male partner is the sole explanation. This subfertility remains unexplained for almost half of these men, even after extensive clinical evaluation. From the time a couple seeks medical assistance for difficulty conceiving, the couple is advised to undergo a number of diagnostic procedures to ascertain potential causes for why the couple is having difficulty conceiving. Often the procedures can be highly invasive, costly, and time consuming. Thus, there is a need for faster, non-invasive methods of assessing infertility. Additionally, given that couples are attempting to conceive well into their 30s and 40s, it may also be desirable for the couple to assess their fertility prior to any attempts to conceive. Summary The invention provides methods for assessing fertility and or infertility in by taking into consideration one or more factors, such as genetic variations (e.g., mutations, polymorphisms, expression levels) and phenotypic traits or environmental exposures in order to arrive at an assessment of fertility. According to the invention, certain genetic polymorphisms give rise to a predisposition to conditions that affect fertility, such as primary ovarian insufficiency or premature decline in ovarian function in a woman, which reduces egg count and/or viability, or for example, reduced sperm motility in a man. Moreover, specific combinations of genetic polymorphisms are significant with respect to a couple's combined fertility status. As discussed below, an array of genetic information concerning the status of, for example, various fertility-associated genes, such as maternal effect genes, is used in order to assess fertility status. The genetic information may include one or more polymorphisms in one or more infertility-related genetic regions, mutations in one or more of those genetic regions, or particular epigenetic signatures affecting the expression of those genetic regions. The molecular consequence of variants in one or more of those regions could be one or a combination of the following: alternative splicing, lowered or increased RNA expression, and/or alterations in protein expression. These alterations could also include a different protein product being produced, such as one with reduced or increased activity, or a protein that elicits an abnormal immunological reaction. All of this information is significant in terms of informing a couple of their fertility profile. In addition to looking exclusively at genomic information, the invention also contemplates combining genetic information (e.g., polymorphisms, mutations, etc.) with phenotypic and/or environmental data, methods of the invention to provide an additional level of clinical clarity. For example, polymorphisms in genes discussed below may provide information about a couple's fertility. However, in certain cases, the clinical outcome may not be determinative unless combined with certain phenotypic and/or environmental information. Thus, methods of the invention provide for a combination of genetic predispositional analysis in combination with phenotypic and environmental exposure data in order to assess the couple's fertility potential. Certain aspects of the invention provide methods for assessing infertility in a couple that involve conducting an assay on at least a portion of an infertility-related genetic region in the female and the male to determine presence or absence of one or more variants in a plurality of genes in which the presence of a variant in at least one of those genes is indicative of infertility. Variants detected according to the invention may be any type of genetic variant. Exemplary variants include a single nucleotide polymorphism, a deletion, an insertion, an inversion, other rearrangements, a copy number variation, chromosomal microdeletion, genetic mosaicism, karyotype abnormality, or a combination thereof, as shown in FIG. 2. Any method of detecting genetic variants is useful with methods of the invention, and numerous methods are known in the art. In certain embodiments, sequencing is used to determine the presence of genetic variants. In particularly-preferred embodiments, the sequencing is sequencing-by- synthesis. In other embodiments, one or more assays are performed on a gene product. In particular embodiments, the gene product is a product of a fertility-associated gene. The gene product may be RNA or protein. Any assay known in the art may be used to analyze the gene product(s). In certain embodiments, the assay involves determining an amount of the gene product and comparing the determined amount to a reference. Methods of the invention may further involve obtaining a sample from the mammal that includes the plurality of infertility-related genes. The sample may be a human tissue or body fluid. In particular embodiments, samples are derived from both the male and female partners who are trying to conceive. The sample may be collected at any age before, during, or after puberty. In particular embodiments, the sample from the female is of maternal origin, such as blood or saliva, and the sample from the male is from semen.
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