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(12) Patent Application Publication (10) Pub. No.: US 2015/0142331 A1 Beim Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0142331 A1 Beim Et Al US 2015O142331A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0142331 A1 Beim et al. (43) Pub. Date: May 21, 2015 (54) METHODS AND DEVICES FOR ASSESSING Publication Classification RISK OF FEMALE INFERTILITY (51) Int. Cl. (71) Applicant: Celmatix, Inc., New York, NY (US) G06F 9/18 (2006.01) G06F 9/00 (2006.01) (72) Inventors: Piraye Yurttas Beim, New York, NY CI2O I/68 (2006.01) (US); Michael Elashoff, Redwood City, (52) U.S. Cl. CA (US) CPC .............. G06F 19/18 (2013.01): CI2O 1/6883 (2013.01); G06F 19/3431 (2013.01); C12O (22) Filed: Jan. 26, 2015 Related U.S. Application Data (57) ABSTRACT (63) Rstates s f application No. 14/107.800, The invention generally relates to methods and devices for • u. Yu’s assessing risk of female infertility. In certain aspects, meth (60) Provisional application No. 61/932.226, filed on Jan. ods of the invention involve obtaining a sample, conducting 27, 2014, provisional application No. 61/889,738, an assay on at least one infertility-associated biomarker, and filed on Oct. 11, 2013, provisional application No. assessing risk to the patient of developing early-onset 61/737,693, filed on Dec. 14, 2012. decrease in fertility based upon results of the assay. FertiArray v .0 (xiikelihoxic; 3::ting pregnant xiikeliitto: of inter:::ity FertiiArray "F8 2. Patent Application Publication May 21, 2015 Sheet 1 of 15 US 201S/O142331 A1 FIGURE 1. FertiiArrayFM .0 wike.8oad of setting regat: 8:ikelihoot of infertity FertilArray 2 Patent Application Publication May 21, 2015 Sheet 2 of 15 US 201S/O142331 A1 FIGURE 2 Combining Clinical and Genetic Data Analytics 883 & 8:::::::::3:3: 8:::::::: citiy {{ is 3.x. {{C3s. :::::::: *::::::::::g. {}, cycles .38:S kia: Scies::::::::::::P:8: 38 333i:a:::::: 3: 3:3::::::::::: 33xis is 33 isie: ify 3:ties x838 as: : ; ::: 3 883 & 8tective y, 33:38; 3: 388:3:3 is 3:38 saixi (:: :::::::::::: ge:8 33:8:38, 3ic:::::::ixes, Patent Application Publication May 21, 2015 Sheet 3 of 15 US 201S/O142331 A1 FGURE3 88 * iii. 8: agistie 8x Bayesis: Riessed Patent Application Publication May 21, 2015 Sheet 4 of 15 US 201S/O142331 A1 FIGURE 4 Copy Number inversions ransiocations Variats Patent Application Publication May 21, 2015 Sheet 5 of 15 US 201S/O142331 A1 FIGURE 5 Patent Application Publication May 21, 2015 Sheet 6 of 15 US 201S/O142331 A1 FIGURE 6 Patent Application Publication May 21, 2015 Sheet 7 of 15 US 201S/O142331 A1 FIGURE 7 Compete SNPs Coirector for Sp$f ( efits 8 Se:O?ics Sinances Optiatio: asia: fect kiose Eements stratificatio: Predicif 4. Nis ( Variat-eye e Stixtural Significace tests Variants Gee-eye significance tests Patent Application Publication May 21, 2015 Sheet 8 of 15 US 201S/O142331 A1 FIGURE 8 & CNY INDE SNP x::::::::::::: ::::::::::::::::::: : x: : 8: 8:::::::::::::::::: Patent Application Publication May 21, 2015 Sheet 9 of 15 US 201S/O142331 A1 FG. 9 Patent Application Publication May 21, 2015 Sheet 10 of 15 US 201S/O142331 A1 togetPBC-op - . - - - , . v. W. W. - - - ico 3888 FG, 10 Patent Application Publication May 21, 2015 Sheet 11 of 15 US 201S/O142331 A1 togetPBiscip F.G. 11 Patent Application Publication May 21, 2015 Sheet 12 of 15 US 201S/O142331 A1 -log (PAYS Group A Group B Fertilom Gen log (PABys F.G. 12 Patent Application Publication May 21, 2015 Sheet 13 of 15 US 201S/O142331 A1 F.G. 13 Patent Application Publication May 21, 2015 Sheet 15 of 15 US 201S/O142331 A1 Processor Server 409 Data File Processor Sequencer 455 Interface Module Sequencer Computer Computer 433 451 Processor FIG. 5 US 2015/O 142331 A1 May 21, 2015 METHODS AND DEVICES FOR ASSESSING associated biomarker, and 3) assessing risk to the patient of RISK OF FEMALE INFERTILITY developing early-onset decrease in fertility. 0006. As discussed below, an array of genetic information RELATED APPLICATIONS concerning the status of various infertility-related genetic 0001. This application is a continuation-in-part of U.S. regions is used in order to assess the risk of a Subject having Non-Provisional Ser. No. 14/107.800, filed Dec. 16, 2013, an increased susceptibility to reduced fertility, premature which claims priority to U.S. Provisional Nos. 61/889,738, menopause, or infertility. The genetic information may filed Oct. 11, 2013, and 61/737,693, filed Dec. 14, 2012. This include one or more polymorphisms in one or more infertil application also claims priority to and the benefit of U.S. ity-related genetic regions, mutations in one or more of those Provisional No. 61/932,226, filed Jan. 27, 2014. The afore genetic regions, or particular epigenetic signatures affecting mentioned applications are incorporated by reference herein. the expression of those genetic regions. The molecular con sequence of these genetic region mutations could be one or a TECHNICAL FIELD combination of the following: alternative splicing, lowered or increased RNA expression, and/or alterations in protein 0002 The invention generally relates to methods and expression. These alterations could also include a different devices for assessing risk of female infertility. protein product being produced. Such as one with reduced or increased activity, or a protein that elicits an abnormal immu BACKGROUND nological reaction. All of this information is significant in 0003) Approximately one in seven couples has difficulty terms of informing a patient of her susceptibility to infertility conceiving. Infertility may be due to a single cause in either or reduced fertility relative to her age or other relevant phe partner, or a combination of factors (e.g., genetic factors, notypes such as hormone levels or ovarian follicle count. diseases, or environmental factors) that may prevent a preg 0007. In addition to looking exclusively at genomic infor nancy from occurring or continuing. Every woman will mation, by combining genetic information (e.g., polymor become infertile in her lifetime due to menopause. On aver phisms, mutations, etc.) with phenotypic and/or environmen age, egg quality and number begins to decline precipitously at tal data, methods of the invention provide an additional level 35. However, some women experience this decline much of clinical clarity. For example, polymorphisms in genes dis earlier in life, while a number of women are fertile well into cussed below may provide information about a disposition their 40's. Though, generally, advanced maternal age (35 and toward infertility or reduced fertility. However, in certain above) is associated with poorer fertility outcomes, there is no cases, the clinical outcome may not be determinative unless way of diagnosing egg quality issues in younger Women or combined with certain phenotypic and/or environmental knowing when a particular woman will start to experience information. Thus, methods of the invention provide for a decline in her egg quality or reserve. combination of genetic predispositional analyses in combi 0004. The elucidation of the genetic basis of female infer nation with phenotypic and environmental exposure data in tility disorders permits the development of powerful, rapid, order to assess the potential for infertility or reduced fertility and non-invasive diagnostic tools that will help clinicians relative to age. Thus, in certain cases, genetic predisposition direct patients to efficient and effective treatment options. may be sufficient to make a diagnosis, but in other cases, the Additionally, the discovery of the key genes underlying these clinical outcome may not be clear based upon genetic analy disorders holds great promise for the identification of novel sis alone and the combination of genetic and phenotypic or targets for drug development and therapeutics. Finally, a bet environmental data must be used in order to assess the like ter understanding of the crucial molecular pathways under lihood of infertility or reduced fertility. lying human fertility guides the next generation of targeted, 0008. In addition to providing information to women non-hormonal contraceptives. related to the risk of infertility or reduced fertility if she chooses to try for a child at a particular age, methods of the SUMMARY invention may also be used by a physician for treatment 0005. The invention provides applications and methods purposes, e.g., allowing a physician to make Vitamin/drug for determining the identity of genetic loci biologically or recommendations to help reduce or eliminate the risk to statistically correlated with increased risk of susceptibility of early-onset reduction in fertility. For example, data herein an individual to infertility or early-onset decrease in fertility show that a mutation in the CBS gene affects infertility. This (premature menopause). In one aspect, the invention provides data may be used by a physician to generate a treatment plan nucleic acid sequences that can be used to assess the presence that may help remediate the infertility risk in the woman. For or absence of particular nucleotides at polymorphic sites in an example, the physician may advise the woman to take a high individual’s RNA or genomic DNA that are associated with dose offolic acid or other vitamin Supplements/drugs in order susceptibility to decreased fertility. In certain aspects, the to improve fertility. Such a treatment plan may reduce or invention provides methods for observing commonly occur eliminate the infertility risk in the woman. ring or rare genetic variants within a Subset of genes of inter 0009. A biomarker generally refers to a molecule that acts est for human infertility and risk of premature menopause. In as an indicator of a biological state. In certain embodiments, certain aspects, the invention provides methods for ranking the biomarker is a genetic region. In particular embodiments, the relative importance of individual genetic variants, genes, the genetic region is an infertility-related genetic region.
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