DETAILED ACTION
The present Office Action is responsive to the Amendment received on August 14, 2026.
Preliminary Remark
Claims 2, 4, 5, 12, 16, 19, and 20 are canceled.
Claims 21-24 are new.
Claim Rejections - 35 USC § 112
The rejection of claims 6, 12, 16, and 17 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to particularly point out and distinctly claim the subject matter, made in the Office Action mailed on May 15, 2026 is withdrawn in view of the Amendment received on August 14, 2026.
Claim Rejections - 35 USC § 101
The rejection of claim 2, 16, and 20 under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception/naturally existing phenomenon without significantly more, made in the Office Action mailed on May 15, 2026 is withdrawn in view of the Amendment received on August 14, 2026, canceling the rejected claims.
Claim Rejections - 35 USC § 103
The rejection of claims 1-4, 13, and 16-20 under 35 U.S.C. 103 as being unpatentable over Hao et al. (Scientific Reports, January 2016, pages 1-5) in view of Okunieff et al. (WO 2017/176834 A2, published October 2017), made in the Office Action mailed on May 15, 2026 is withdrawn in view of the Amendment received on August 14, 2026.
The rejection of claims 5, 6, 14, and 15 under 35 U.S.C. 103 as being unpatentable over Hao et al. (Scientific Reports, January 2016, pages 1-5) in view of Okunieff et al. (WO 2017/176834 A2, published October 2017) as applied to claims 1-4, 13, and 16-20 above, and further in view of Kaneda et al. (J. Biochem, 2014, vol. 156, no. 2, pages 63-72), made in the Office Action mailed on May 15, 2026 is withdrawn in view of the Amendment received on August 14, 2026.
Rejection – New Grounds, Necessitated by Amendment
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.
Claims 1, 3, 13, 17, 18, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Hao et al. (Scientific Reports, January 2016, pages 1-5) in view of Okunieff et al. (WO 2017/176834 A2, published October 2017) and Robinson et al. (Nature Genetics, 2021, vol. 53, pages 1434-1442).
With regard to claims 1, 2, and 20, Hao et al. teach that mutation accumulation rate determined from the a subject’s sample, wherein the increase in the accumulated rate is correlated with increased likelihood of developing cancer:
“the accumulation of mutations in somatic cells is hypothesized to be fundamental reason for tumorigenesis” (page 1)
Hao et al. teach that mutation rate of ancestral somatic cells is correlated with tumorigenesis:
“mutations revealed by bulk tumor sequencing are largely a reflection of the mutations accumulated in the ancestral cell that gives rise to tumor … This supposition is strongly supported by the finding that half or more of the mutations detected in tumor bulk occur prior to tumor initiation” (page 2, 1st paragraph)
Therefore, Hao et al. teach the sequencing of a subject’s sample for determining mutation accumulation and its use to determine cancer predisposition.
“Our analyses support that tumor mutation frequency is a reliable predictor for cancer incidence in most of the human cancers, probably because that the tumor mutation frequency mirrors the normal somatic mutation rate in all the analyzed tissues. Indeed the mutations present in a tumor bulk provide a lifetime record of the mutation accumulation contributed by stem cell division over the full course of self-renewal and tissue specific differentiation, as well as anything else such as being exposure to environmental or inherited factors.” (page 3)
Hao et al. do not explicitly teach that a sample from a subject was obtained at two different time points (i.e., first and second time points), and the rate of mutation accumulation was determined at each time point (claim 1, in-part; claim 3).
Hao et al. also do not teach that the accumulation of somatic rate of mutation is regarding “high-confidence” somatic single nucleotide variants (SNV), wherein the high-confidence somatic SNVs are obtained by the removal of: 1) putative germline SNVs, 2) SNVs having a frequency of at least 30%, or 3) SNVs mapping to single nucleotide polymorphism having an allele frequency of at least 0.01% (claim 1, in-part), at least two of 1)-3) (claim 21), or all of 1)-3) (claim 22).
Okunieff et al. also teach a method of assessing mutational accumulation rate of a subject’s genome, wherein the increase in the mutational accumulate rate is related to a subject’s predisposition to cancer:
“Accumulated mutations and the rate of mutations in the genome are directly proportional to genomic age and the risk of cancer” (page 2, lines 27-28)
Okunieff et al. explicitly teach that when determining the mutational accumulation rate, samples are taken from the subject at multiple points in time:
“a first sample is obtained from the subject at Time 1 and a second sample is obtained from the subject at Time 2. The accumulated mutations in the target sequence within the target SINE and/or target LINE and/or target sequence within the genome are estimated in the first and the second sample … rate of mutation … within the genome can be calculated based on the difference in the number of accumulated mutations in the target sequence within the target SINE and/or target LINE and/or target sequence within the genome and the duration between Time 1 and Time 2.” (page 29, line 29 to page 30, line 4).
Robinson et al. teach a method of determining mutation accumulation in somatic cells and their contribution to cancer development, wherein the artisans teach the well-reasoned practice of removing the mutation data from germline:
“[m]utation accumulation in somatic cells contribute to cancer development and is proposed as a cause of aging” (Abstract)
“Filters applied: (1) common single-nucleotide polymorphisms (SNPs) were removed … remove mapping artifacts … remove germline variants and potential artifacts …” (appended Methods section)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Hao et al. with the teachings of Okunieff et al., and Robinson et al., thereby arriving at the invention as claimed for the following reasons.
As discussed above, Hao et al. explicitly teach that the accumulation of mutation in a subject’s genome is intimately tied to the subject’s predisposition to developing cancer. While the artisans did not explicitly teach taking samples from the subject at different points in time, one ordinary skill in the art would have concluded that determining whether the mutational accumulation rate had increased would have required taking the samples from the subject at multiple periods of time, as evidenced by Okunieff et al.
Therefore, one ordinary skill in the art would have been motivated to take the teachings of Hao et al. and arrive at a method determining somatic mutations in a genome of an individual by generating sequencing reads from the individual at multiple time points.
As well, Okunieff et al. teach that the accumulated mutations involve largely point mutations (or SNVs, see page 9, lines 9-11).
The sequence data comprise sequence data for non-cancer risk associated genes or cancer-risk associated genes or specific loci or genes within the genome of the individual (SINE, LINE, for example).
With regard to claim 17, the rate data for a total number of mutations as a function of time is generated (see Fig. 4).
With regard to claim 18, based on the mutation accumulation rate, it would have been obvious to one of ordinary skill in the art to test the individual for cancer as the predisposition to cancer would have been greater for subjects with higher mutation accumulation rate in view of the below disclosure made by Okunieff et al.:
“if the accumulated mutations and/or the rate of mutations in the genome of a subject 30 years of age is equal to the average accumulated mutations and/or the average rate of mutations in the genome of a subject 40 years of age, then the genomic age of the subject 30 years of age is 40 years” (page 11, line 2-5)
Since higher mutation accumulation rate is associated with a subject’s predisposition to cancer, testing for the subject for cancer based on the mutation accumulatio rate would have been an obvious conclusion to the ordinarily skilled artisan.
With regard to claim 13 in employing conventionally known sequencing means such as long read sequencing, doing so would have yielded no more than a predicted outcome of providing sequence reads from which the presence of mutations would be detected, and therefore is deemed obvious.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
Lastly, regarding the determination of SNVs and various filter parameters utilized to gain high-confidence SNV accumulation rate, doing so would have been obvious based on the rationale behind the method disclosed by Okunieff et al. who suggest that their method also encompass SNV (or point mutation1) and with mutation accumulation determination being directed to somatic, not germline mutation (somatic mutation accumulates occurs over time, whereas germline mutations are inherited)2. Since the artisans were interested in determining the accumulation rate of only the somatic mutations, employing filters that would remove interfering mutation data, such as germline mutations, sequence artifacts, SNPs which are commonly found with higher allelic frequencies would have been an obvious application, as evidenced by Robinson et al.:
“[m]utation accumulation in somatic cells contribute to cancer development and is proposed as a cause of aging” (Abstract)
“Filters applied: (1) common single-nucleotide polymorphisms (SNPs) were removed … remove mapping artifacts … remove germline variants and potential artifacts …” (appended Methods section)
Therefore, one of ordinary skill in the art would have been motivated to determine the mutation accumulation of somatic mutations, such as single point mutations (or SNV) in a genome of an individual while filtering out mutation data from non-somatic (e.g., germline) mutations and other common mutations such as SNP with higher frequencies.
Claims 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Hao et al. (Scientific Reports, January 2016, pages 1-5) in view of Okunieff et al. (WO 2017/176834 A2, published October 2017) and Robinson et al. (Nature Genetics, 2021, vol. 53, pages 1434-1442) as applied to claims 1, 3, 13, 17, 18, 21, and 22 above, and further in view of Kaneda et al. (J. Biochem, 2014, vol. 156, no. 2, pages 63-72).
The teachings of Hao et al., Okunieff et al., and Robinson et al. have already been discussed above.
While Okunieff et al. suggest that mutation accumulation rate is associated with cancer predisposition, the artisans do not explicitly teach that rate of epigenetic changes are also observed at a first and a second time point, wherein the changes are methylation status (claims 14 and 15, respectively).
Kaneda et al. teach that DNA methylation accumulation is associated with cancer predisposition:
“Malignant tumours arise through the accumulation of genomic alterations as well as epigenomic changes” (page 63, 2nd column, 1st paragraph)
“Aberrant DNA methylation is suggested to accumulate during the early stages of carcinogenesis and may predetermine the future cancer phenotype” (page 63, 2nd column, bottom paragraph)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Hao et al., Okunieff et al., and Robinson et al. with the teachings of Kaneda et al., thereby arriving at the invention as claimed for the following reasons.
While Hao et al., Okunieff et al., and Robinson et al. did not explicitly teach to determine the methylation status and its accumulation with their disclosed method, one of ordinary skill in the art would have been reasonably motivated to determine the methylation accumulation as taught by Kaneda et al. for the advantage of providing an assay that comprehensively measures a subject’s risk of cancer.
MPEP 2144.06, in discussing art recognized equivalence for the same purpose, mentions In re Kerkhoven, wherein the court expressed the following:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose…[T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Conclusion
No claims are allowed.
Claims 6-9 are free of prior art because the prior art does not teach or provide a sufficient motivation to generate high confidence sequence reads that involve control sequencing reads from a control genome as presently recited in claim 7 (and dependent claims 8 and 9).
Claims 10, 11, 23, and 24 are also free of prior art because the prior art does not teach or provide a sufficient motivation to sequence the polynucleotides from a control genome at the first and/or second timepoints as presently claimed.
Claims 6-11, 23, and 24 are objected to for being dependent on a rejected base claim.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 August 27, 2026
/YJK/
1 “invention also provides an assay to measure point mutation and indels … in a target sequence … accumulated mutation and/or the rate of mutations in a target sequence within a target SINE or genome of the cell can be extrapolated to measure point mutations and indels in the genome”, page 9, lines 9-16, Okunieff et al.
2 Hao et al. also expressly teach the accumulation determination of somatic mutation, see Abstract, “the accumulation of mutations in somatic cells is hypothesized to be the fundamental reason for tumorigenesis”.
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