Notice of Pre-AIA or AIA Status The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. DETAILED ACTION Priority This Application is a national phase application filed under 35 U.S.C. § 371 claiming priority to Application No. PCT/ US2022/020640 , filed on March 16 , 202 2 , which claims the benefit of U.S. Provisional Application No. 63/ 3 14, 647 , filed on February 2 8 , 202 2 and U.S. Provisional Application No. 63/162,750 , filed on March 18, 2021 that is hereby acknowledged by the Examiner. Status of the Claims The amendment dated 09 / 10 / 20 24 is acknowledged . Claims 1- 11, 17-22 and 29-31 are pending and under examination. Information Disclosure Statement The re was no information disclosure statement (IDS) submitted at the time of this Office action. Drawings The drawing filed on 09/15/2023 are acknowledged and accepted by the Examiner. Claim Objections Claims 21 and 22 are objected to for the following informalities: Claims 21 and 22 recite “ determining the rejection risk for the transplant recipient based on the amount of donor-derived cell-free DNA and/or the percentage of donor-derived cell-free DNA out of total cell-free DNA, and the amount of TTV DNA in the blood, plasma, serum, or urine sample of the transplant recipient”. Both claim limitations are identical and dependent upon claim 1. It is suggested that one of the claims be omitted. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. Claims 11 and 17-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The claims are direct ed to a method of administrating immunosuppressive therapy in a transplant recipient, comprising: (a) measuring the amount of Torque teno virus ( TT V ) in a blood, plasma, serum, or urine sample of the transplant recipient; and (b) measuring the amount of donor-derived cell-free DNA in a blood, plasma, serum, or urine sample of the transplant recipient; and (c) titrating the dosage of an immunosuppressive therapy according to the amount of TT V or a function thereof and the amount of donor-derived cell-free DNA or a function thereof. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The grounds for the written description rejection are as follows: (1) the claims are directed to a method of administrating immunosuppressive therapy in a transplant recipient ; however, the Applicant’s disclosure does not appear to provide sufficient recitation of compositions or therapies as claimed by Applicant. The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirement for a generic claim covering several distinct inventions: The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice .... reduction to drawings .... or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed. In this case, the Applicant has not described in the ir disclosure any description or working examples of an immunosuppressive therapy being administered based on the method steps claimed whereby TTV is measured and the therapy’s dosage is titrated . The prior art, citing Del V la minck (WO2015/070086) , discloses the load of viruses of the anelloviridae family comprising TTV is a predictor of immune strength, which is correlated with the probability of organ transplant rejection (instant claims 1 and 2 steps c and d and instant claim 3, para. [0017], [0049], [0050] and [0120] of De Vlaminck); and that sequence analysis can additionally provide information on the graft health through the quantification of donor-derived human DNA circulating in plasma (instant claim 6)( para. [0120], [0164] and [0168]). Although De Vlaminck teaches the amount of one or more microbiome nucleic acids (e.g. TTV) in a sample from the immunosuppressed recipient and dd-cfDNA can determine the transplant status or outcome, (para. [0120], [0140]-[141] and [0163]-[0164]), there is limited data on administration of a particular therapy as it relates to TTV in a sample of the transplant recipient. The claim only broadly discloses administering an immunosuppressive therapy to a transplant recipient comprising measuring an amount of TTV in a subject’s sample, measuring the amount of donor-derived cfDNA and titrating a dosage of an immunosuppressive therapy without any guidance on a therapy or administration of said therapy. Thus, t he claims are a broad interpretation of administrating immunosuppressive therapy in a transplant recipient comprising measuring a TTV virus and titrating dosage of a therapy , therefore, the Applicant’s disclosure does not support the claimed method with specific compounds and examples of such a broad claim of administering therapies to a transplant recipient. In view of the lack of disclosure of the broad interpretation of the administrating immunosuppressive therapy , the claims are rejected as lacking adequate descriptive support for the method of administrating therapies in a transplant recipient and adjusting therapy dosages thereof. Claim Rejections - 35 USC § 103 The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action: (a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made. This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a). Claims 1-10, 21-22 and 29-31 are re jected under 35 U.S.C. 103(a) as being unpatentable over Moshkevich et al. “ Moshkevich ” (WO2020/010255) in view of De Vlaminck et al. “De Vlaminck” (WO2015/070086) . The claims are directed to a method of preparing a composition of amplified DNA derived from a blood, plasma, serum or urine sample of a transplant recipient useful for determination of transplant rejection, comprising: (a) extracting cell-free DNA from the blood, plasma, serum or urine sample of the transplant recipient, wherein the extracted cell-free DNA comprises donor-derived cell-free DNA and recipient-derived cell-free DNA; (b) preparing a composition of amplified DNA by performing targeted amplification of the extracted DNA at 200-50,000 target loci in a singles reaction volume, and sequencing the amplified DNA by high-throughput sequencing to obtain sequencing reads and quantifying the amount of donor-derived cell-free DNA based on the sequencing reads; (c) measuring the amount of Torque teno virus ( TTV ) in a blood, plasma, serum, or urine sample of the transplant recipient; and (d) determining whether the amount of donor-derived cell-free DNA or a function thereof exceeds a cutoff threshold indicating transplant rejection and whether the transplant recipient has an increased or decreased amount of TTV indicating decreased or increased immune response. Regarding claim s 1 -3 and 6 , Moshkevich discloses methods for determining the status of an allograft within a transplant recipient from genotypic data measured from a mixed sample of DNA comprising DNA from both the transplant recipient and from the donor. The mixed sample of DNA may be preferentially enriched at a plurality of polymorphic loci in a way that minimizes the allelic bias, for example using massively multiplexed targeted PCR (Abstract). Moshkevich discloses a method of detecting donor-derived cell-free DNA (dd-cfDNA) in a blood sample of a transplant recipient, useful for determination of transplant rejection (steps a- b and steps c-d (measuring amount of virus in sample and determining threshold cutoff threshold indicating transplant rejection) , claims 1-16, 21-22 and 34-38 of Moshkevich ). Moshkevich does not teach wherein the virus is of Torque teno virus ( TTV ). De Vlaminck, however, discloses analyzing cell-free nucleic acid from an individual, e.g. a transplant recipient, for identifying microorganisms, e.g., viruses, that indicate immunosuppression. In particular, the load of viruses of the anelloviridae family comprising TTV is a predictor of immune strength, which is correlated with the probability of organ transplant rejection ( instant claims 1 and 2 steps c and d and instant claim 3 , para. [0017], [0049], [0050] and [0120] of DeVlaminck ); and sequence analysis can additionally provide information on the graft health through the quantification of donor-derived human DNA circulating in plasma (instant claim 6) (para. [0120], [0164] and [0168]). Thus, De Vlaminck teaches determination of both; the amount of one or more microbiome nucleic acids (e.g. TTV) in a sample from the immunosuppressed recipient and dd-cfDNA, to determine the transplant status or outcome, (para. [0120], [0140]-[141] and [0163]-[0164]). Accordingly, it would have been obvious to one of ordinary skill in the art to generate a method of preparing a composition of amplified DNA derived from a blood, plasma, serum or urine sample of a transplant recipient useful for determination of transplant rejection as disclosed by Moshkevich , whereby the composition of amplified DNA is of Torque ten virus as disclosed by De Vlaminck. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success for the advantage of improving prediction or determination of transplant rejection . Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Regarding claim 4 , Moshkevich discloses the subject is human (page 2 lines 23-24). Regarding claim 5, Moshkevich discloses the transplant recipient has received one or more transplanted organs of pancreas, kidney, liver, heart, lung, intestinal, thymus and uterus (page 2 lines 25-31 and page 3 lines 1-2). Regarding claim 7, Moshkevich discloses target loci comprise single nucleotide polymorphisms (SNPs) (page 32 lines 16-30 , page 51 line 31). Regarding claim 8, Moshkevich discloses step (b) comprises PCR amplification of 200-50,000 target loci using 200-50,000 pairs of forward and reverse PCR primers ( page 71 lines 19-31, page 81 lines 1-11 and claim 20 of Moshkevich ). Regarding claims 9 and 10, Moshkevich discloses the cutoff threshold is an estimated percentage of donor-derived cell-free DNA out of a total cell-free DNA ; proportional to an absolute donor-derived cell-free DNA concentration (page 95 lines 1-12, Example 9, Table 20 and claims 34-38 of Moshkevich ). Regarding claim s 21 and 22 , Moshkevich discloses determining the rejection risk for the transplant recipient based on the amount of donor-derived cell-free DNA and/or the percentage of donor-derived cell-free DNA out of total cell-free DNA from the sample of the transplant recipient ( page 204 lines 23-25, Table 15, page 213 lines 15-31) . Regarding claim s 29 and 30 , Moshkevich discloses the use of logistic regression further incorporating selected parameters (e.g. total cell-free DNA in blood, serum or urine sample) ( page 188 lines 17-30, page 231 Embodiments 61 and 63, Tables 9 and 10). Regarding claim 31, Moshkevich discloses the blood, serum or urine sample is obtained from the transplant recipient less than 18 months post-transplantation (page 6 lines 1-11). Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Conclusion No claims are allowed. 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Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /BARRY A CHESTNUT/ Primary Examiner, Art Unit 1672