CTNF 18/606,338 CTNF 77001 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claim Rejections - 35 USC § 112 07-30-02 AIA The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. 07-34-01 Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. 07-34-10 AIA Regarding claim 9(b) , the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim Rejections - 35 USC § 101 07-04-01 AIA 07-04 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claims 1, 3-9, 14-25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and a law of nature without significantly more. The claim(s) recite(s) determining a level of donor derived cell free DNA (dd-cfDNA) in a cfDNA sample by inputting into computer algorithm sample data wherein the algorithm identifies dd-cfDNA sequences by identifying a pattern. Mathematical concepts such as mathematical relationships/formulas (i.e. algorithms) are abstract ideas. An algorithm for calculating parameters indicating an abnormal condition was found to be an abstract idea (In re Grams). Furthermore, most of the claims place little limitation as to the number of loci in “the plurality of loci” or in the “database of human genomes” and these steps are mental process abstract ideas. The review of 1000 loci may be tedious and take a long time, but this could be accomplished by a human mind using pencil and paper. The fact that they are carried out on a general-purpose computer does not distinguish them from mental processes. Further, the claims recite “distinguishing non-rejection” by “comparing” and these two steps are also mental process abstract ideas. The relationship between the level of dd-cfDNA and the phenotype occurs outside of the intervention of man is considered a law of nature judicial exception that is set forth in claim 1. Claims 15-21 recite a series of clauses which describe circumstances in which “the recipient” is “indicated” as having a likelihood of a phenotype. The claims do not recite any further active step or appear to require any further action by the practitioner, they only describe what is “indicated” by the level of dd-cfDNA. The “indications” are naturally occurring correlations and are thus considered law of nature judicial exceptions. Claim 25 recites “selecting a treatment” for the recipient, which is an additional mental process abstract idea. These judicial exceptions are not integrated into a practical application because the steps in addition to the judicial exception (obtaining a sample, obtaining cfDNA and sequencing the cfDNA) are recited at an extremely high level of generality and do not use or apply the judicial exception in any way. The steps are data gathering steps necessary to practice the judicial exceptions. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps in addition to the judicial exceptions are extra-solution data gathering recited at an extremely high level of generality. The examiner takes Official notice that methods for high-throughput sequencing DNA from cellular and acellular samples were well established before the invention, and this is also evidenced by the references cited in this Office action which employ these techniques (Zhou and Sharon). These steps do not add significantly more to the judicial exceptions recited herein. Claim Rejections - 35 USC § 102 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-15-aia AIA Claim(s) 1, 2-9, 14-25 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Levitsky et al. (Am J Transplant. 2022;22:532–540. Available online 12 September 2021), as evidenced by Sharon et al. PLoS Comput Biol . 2017;13(8):e1005629) . PNG media_image1.png 128 1101 media_image1.png Greyscale The reference teaches the claimed method, see section 2.3 which teaches donor-derived cell-free DNA measurement via whole genome sequencing, mapping to the human genome and analyzed for dd-cfDNA% by the method taught by Sharon et al., referred to in Levitsky as “a bioinformatics pipeline licensed from Stanford University.” As evidenced by Sharon, this method includes determining the percentage of donor derived DNA using an algorithm identifies ddcfDNA by identifying a pattern of cfDNA sequences at loci that differ from the cfDNA sequences of the recipient but that correlate with a pattern of human DNA sequences found in a database of human genomes. See p. 2-3 and figure 1 of Sharon as evidence. The reference further teaches distinguishing non-rejection from one or both of AR and ADNR in the recipient by comparing the level of dd-cfDNA to a predetermined threshold value (Table 2). Levitsky teach the sample is a blood sample, specifically plasma which was separated from the blood sample (2.3). The reference additionally teaches performing genotyping on PBMC samples (2.3). Claims 15-21 recites a series of clauses which describe circumstances in which “the recipient” is “indicated” as having a likelihood of a phenotype. The claims do not recite any further active step or appear to require any further action by the practitioner, they only describe what is “indicated” by the level of dd-cfDNA. Regarding claims 15-21, the claim does not require any further or different action, it merely sets forth a relationship between percentage of dd-cfDNA and “indicated” rejection. Nonetheless, cutoffs are disclosed in Table 2 of the reference. Levitsky teaches obtaining and analyzing blood samples at month 1 and many months following (2.1). Levitsky teaches that the patients tested had their alanine aminotransferase tested and had levels that were ≤60 U/L (males) ≤36 U/L (females), see section 2.1. Levitsky teaches patients had liver biopsy (section 2.1). Levitsky is a report of summarizing patient data . Claim Rejections - 35 USC § 103 07-20-aia AIA The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. 07-20-02-aia AIA This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. 07-21-aia AIA Claim (s) 1, 3-8, 14-22, 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (Scientific Reports (2021) 11:1138, 9 pages. Published: 13 January 2021) in view of Sharon et al. (PLoS Comput Biol 13(7): e1005629.; 19 pages) . Zhao teaches distinguishing non-rejection of a liver transplant from acute rejection by obtaining a sample from a liver transplant recipient, obtaining cell-free (cfDNA) from the sample. The reference further teaches determining the level of donor derived cell-free DNA in the cfDNA sample by sequencing the cfDNA and inputting the data into a computer-implemented algorithm. Zhao teaches that the method does not require genotype information from the donor- that is the algorithm identifies dd-cfNDA absent a priori genotype information from the donor. Zhao teach the sample is a blood sample, specifically plasma which was separated from the blood sample. The reference further teaches distinguishing non-rejection from one or both of AR and ADNR in the recipient by comparing the level of dd-cfDNA to a predetermined threshold value. For example, Zhao teaches an “optimal cut-point” of dd-cfDNA threshold of 28.7% dd-cfDNA to distinguish rejection from non-rejection (p. 5). Claims 15-21 recites a series of clauses which describe circumstances in which “the recipient” is “indicated” as having a likelihood of a phenotype. The claims do not recite any further active step or appear to require any further action by the practitioner, they only describe what is “indicated” by the level of dd-cfDNA. Regarding claims 15-21, the claim does not require any further or different action, it merely sets forth a relationship between percentage of dd-cfDNA and “indicated” rejection. Nonetheless it is noted that Zhao teaches an “optimal cut-point” of dd-cfDNA threshold of 28.7% dd-cfDNA, thus teaches that patients with a level “greater than” 25% are indicated as having rejection. Figure 4 illustrates that rejection patients had a range of percent dd-cfDNA as low as 17.6% and as high as 54.9% (p. 2, Results). Thus, following Zhao et al., any of a patient with a dd-cfDNA level of 30%, 40% or more would be classified or indicated as having acute rejection. The claims do not require anything further. Furthermore, the reference teaches percentages for non-rejection patients in a range of 3-18% (p. 2) and a patient having below any of these values would be indicated as non-rejection. Claim 21 is included in this rejection because it states a property but does not require any further action, such as observing this range and indicating (active tense) the individual or diagnosing the individual. Further, the reference teaches that the %ddcfDNA in rejection was higher than in different types of ADNR (p. 2, figure 3A). Regarding claim 22, the reference teaches obtaining samples 3.6-12.6 months post-transplant (p. 2). Regarding claim 24, Zhao additionally teaches obtaining liver biopsies from the recipient (p. 2). Regarding claim 25, the reference is a report summarizing the level of dd-cfDNA for the patients, see Figure 2. The reference does not teach determining the percentage of donor derived DNA using an algorithm identifies ddcfDNA by identifying a pattern of cfDNA sequences at loci that differ from the cfDNA sequences of the recipient but that correlate with a pattern of human DNA sequences found in a database of human genomes. Like Zhao, Sharon teaches using the percentage of ddcfDNA in a recipient blood sample as an indicator of organ donation rejection or success (abstract and throughout). The reference teaches the method for solid organ transplants, and contrasts it with invasive methods for detecting transplant failure such as liver biopsy (p. 2, last ¶). Sharon teaches that donor derived DNA in recipient blood is quantified in the absence of donor genotype information (title, throughout). Sharon teaches a method for detecting transplant rejection, and teaches that for an unrelated donor, the probability of a specific donor allele is its frequency in the population (p. 3, 3 rd paragraph). Sharon teaches comparing the data to the 1000 Genomes Database to detect the most likely ancestral population of the donor (p. 3, 3 rd paragraph and following). Percent of dd-cfDNA is determined using this method, see Figure 1. Thus, Sharon teaches determining the percentage of donor derived DNA using an algorithm identifies ddcfDNA by identifying a pattern of cfDNA sequences at loci that differ from the cfDNA sequences of the recipient but that correlate with a pattern of human DNA sequences found in a database of human genomes. Sharon teaches genotyping 600-700K SNPs across the genome by whole genome sequencing (Abstract (“shotgun sequencing,” p. 8). It would have been obvious to have modified the method taught by Zhao so as to have employed the algorithm and model taught by Sharon for determining the percentage of donor-derived DNA in a patient sample without knowledge of the donor genotype. It would have been obvious to do this because Zhao teaches a method for determining donor derived DNA percentage based on only the recipient cfDNA, and so does Sharon. The substitution of one known element for another would have yielded predictable results to one or ordinary skill in the art, namely determining the percentage of donor-derived DNA in a recipient DNA sample and inferring whether or not the recipient is rejecting the donor organ. Zhao also teaches extracting gDNA from whole blood, which inherently includes all PMBC. See p. 8, DNA extraction. Zhao does not teach isolating the PMBC before determining the patient genotype. Sharon teaches that a blood sample, cellular fraction, is used to genotype the recipient (p. 4, Figure 1 description). Therefore, it would have been obvious to have isolated the cellular fraction from blood samples, which inherently contains the PMBC, in order to obtain the patient’s genomic DNA for genotyping. The substitution of one known element for another would have yielded predictable results to one or ordinary skill in the art, namely determining the providing a DNA sample to determine the patient’s cellular genotype . 07-22-aia AIA Claim (s) 9 and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhao in view of Sharon as applied to claim s 1, 3-8, 14-22, 24-25 above, and further in view of Goh et al. ( Transplantation Direct 2019;5: e462; doi: 10.1097/TXD.0000000000000902. Published online 21 June, 2019; 11 pages, plus 6 pages supplemental materials) . The teachings of Zhao in view of Sharon as they pertain to claim 1 are given previously in this Office action and are fully incorporated here. These do not teach measure the patient’s serum alanine aminotransferase concentration, nor do the level. Goh et al. also teaches methods for evaluating ddcfDNA in liver transplant patients. Goh et al. teaches monitoring patient serum alanine aminotransferase (ALT) at baseline (day 0) and up to 42 days past transplant, as part of liver function tests performed on a regular basis to monitor the clinical course, see p. 2 second column and Figure S2. All tested patients had a serum ALT that has not doubled compared to the baseline determined after transplantation. PNG media_image2.png 180 559 media_image2.png Greyscale It would have been obvious to have modified the method taught by Zhao in view of Sharon so as to have additionally completed liver function tests along with monitoring dd-cfDNA. One would have been motivated to do so by the teachings of Goh that such testing is part of monitoring the clinical course of response to liver transplant. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. Juliet Switzer Primary Examiner Art Unit 1682 /JULIET C SWITZER/Primary Examiner, Art Unit 1682 Application/Control Number: 18/606,338 Page 2 Art Unit: 1682 Application/Control Number: 18/606,338 Page 3 Art Unit: 1682 Application/Control Number: 18/606,338 Page 4 Art Unit: 1682 Application/Control Number: 18/606,338 Page 6 Art Unit: 1682 Application/Control Number: 18/606,338 Page 7 Art Unit: 1682 Application/Control Number: 18/606,338 Page 8 Art Unit: 1682 Application/Control Number: 18/606,338 Page 9 Art Unit: 1682 Application/Control Number: 18/606,338 Page 10 Art Unit: 1682
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