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 .
This Office Action is in reply to Applicants’ correspondence of 02/03/2026.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
In the reply filed on 06/17/2025 Applicants elected, without traverse, the invention of Group I (claims directed to methods of analyzing DNA), and the particular combination that is methylation and nucleosome footprint, in the reply filed on 06/17/2025 is acknowledged.
In light of the amendments to the claims, claims 1, 4, 9, 10 and 17 require the non elected “copy number alteration (CNA)” aspects of the methods, and so claims 1, 4, 9, 10 and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/17/2025.
Withdrawn Objection to the Specification
The objection to the disclosure, as set forth on page 2 of the Office Action of 09/04/2025 is withdrawn in light of the amendments to the specification, which are entered.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
The rejection so claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth on pages 3-4 of the Office Action of 09/04/2025 are withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections – Improper Markush Group
The rejection so claims for containing an improper Markush grouping of alternatives, as set forth on pages 4-5 of the Office Action of 09/04/2025 are withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 112 – Failure to Limit
The rejection so claims under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as set forth on pages 5-6 of the Office Action of 09/04/2025 are withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 101
The rejection so claims under 35 U.S.C. 101, as set forth on pages 6-8 of the Office Action of 09/04/2025 are withdrawn in light of the amendments to the claims.
Maintained Claim Rejections - 35 USC § 103
Modified as Necessitated by Claim Amendments
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Snyder et al (2016) as cited on the IDS of 09/27/2022 in view of Uehiro et al (2016).
Relevant to the method of the rejected claim, Snyder et al teaches methods that include computer-based evaluation of sequencing results (e.g.: p.65 - Sequencing and Primary Data Processing; p.67 - Coverage, Fragment Endpoints, and Windowed Protection Scores) to analyze genome-wide (e.g.: p.58 - A Genome-wide Map of In Vivo Nucleosome Protection Based on Deep cfDNA Sequencing; relevant to claim 2) nucleosome footprints (e.g.: p.67 - Nucleosome Peak Calling; Figure 5) to detect the tissue origin of cell free DNA from plasma (e.g.: p.65 – Plasma samples) of cancer subjects (e.g.: p.63 - Nucleosome Spacing in Cancer Patients’ cfDNA Identifies Non-hematopoietic Contributions).
Snyder et al teaches determination of a nucleosome score (e.g.: a “windowed protection score”, p.58 - cfDNA Fragments Correspond to Chromatosomes and Contain Substantial DNA Damage) that is distinctive in the cancer versus healthy subjects (e.g.: p.61 - Nucleosome Spacing in Cancer Patients’ cfDNA Identifies Non-hematopoietic Contributions).
Snyder et al does not exemplify a method that includes analyzing methylation in cfDNA of CpGs with a mean average methylation beta-value of less than 0.03 in cfDNA of healthy subjects. However the analysis of methylation in cfDNA of CpGs that are unmethylated in healthy subjects was known in the prior art and is taught by Uehiro et al.
Relevant to the method of the instantly rejected claim, Uehiro et al teaches analyzing the presence of CpG methylation in cell-free DNA in blood samples (e.g.: p.2 – Collection of clinical samples) comprising the analysis of CpG positions that are unmethylated in cell-free DNA from healthy control subjects (e.g.: p.2 - Comprehensive DNA methylation profiling). Uehiro et al teaches (e.g.: Fig. 2) that the detection of methylation of the CpGs in blood samples is indicative of the presence of breast cancer in the subject, and that a score in the form of a “detection index” that can be used to evaluate the presence of cancer (e.g.: p.7 - Development of a BC detection model using the ddMSP System; Fig. 4).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have modified the methods of analyzing nucleosome footprints associated with cancer in cell-free DNA as taught by Snyder et al to have included the analysis of CpG methylation associated with cancer in cell-free DNA as taught by Uehiro et al. The skilled artisan would have been motivated to combine the two analysis methods because Snyder et al teaches that a nucleosome footprint in cell-free DNA may be indicative of breast cancer, and Uehiro et al teaches that methylation of CpG dinucleotides in cell-free DNA may be also be indicative of breast cancer. The skilled artisan would recognize that combing the two analyses would provide a more comprehensive analysis of biomarkers associated with breast cancer, thus potentially providing a more sensitive or more specific test for the presence of breast cancer. It is noted that Uehiro et al specifies the use of CpG positions that are unmethylated in healthy samples (i.e.: non-breast cancer samples) with mean β-values <0.05, where the claims recite mean β-values <0.03 in healthy subjects. Where Uehiro et al teaches the analysis of markers asserted to be unmethylated in normal/healthy control samples, and the skilled artisan would recognize that β-values of zero would indicated a complete lack of methylation in any of those samples, the skilled artisan would recognize that different β-values of CpG sites in control samples would be a result-effective variable that may modify the sensitivity or specificity of the “detection index” taught by Uehiro et al. The skilled artisan would recognize that, for example, using CpG markers that are only methylated in cancer samples, and never methylated in normal/healthy control samples (i.e.: β-values of zero) may provide for a more sensitive detection of the presence of cancer.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC as rendered obvious by the cited prior art. Applicants’ arguments (p.7-8 of the Remarks of 02/03/2026) have been fully and carefully considered but are not persuasive to withdraw the rejection.
Applicants initially argue that because the Examiner has concluded that the skilled artisan would “potentially” find a benefit in the combination of the analysis of Snyder et al with the analysis of Uehiro et al, the rejection of claims under 35 USC 103 is inappropriate. This argument is not persuasive. As noted in MPEP 2145, absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that "[g]ood science and useful contributions do not necessarily result in patentability." The use of the particular language of “potentially providing a more sensitive or more specific test for the presence of breast cancer” in the conclusion of obviousness as set forth in the rejection does not support Applicants’ argument that the skilled artisan would not have a reasonable expectation of success in combining the analysis of Snyder et al and the analysis of Uehiro et al. Snyder et al clearly sets forth that tissue of origin can be established for cfDNA fragments using an analysis of nucleosome footprint of the fragments, and that such an analysis has utility in the identification of fragments originating from breast tissue cells and related to breast cancer (e.g.: Figure 5). Uehiro et al clearly teaches that cfDNA contains methylation that is indicative of the presence of breast cancer in a subject, and provides teachings relevant to the cfDNA in a subject containing DNA derived from tumor cells in the body. Combining two known elements (i.e.: nucleosome footprint analysis and methylation analysis) that utilize the same analyte (i.e.: cell free DNA) and provide related information (i.e.: the presence of cfDNA from breast tumor tissue; and the presence methylation in cfDNA that is indicative of breast cancer tissue) presents a reasonable expectation of success to the skilled artisan. The Examiner maintains that the skilled artisan would have found ample motivation (e.g.: both analyses provide information related to breast cancer) to combine the teachings of Snyder et al and Uehiro et al, and it would have been obvious to try the known methods for cfDNA analysis with a reasonable expectation of success.
Applicants have further argued that the prior art does not teach the claimed combination as necessary or preferred for cancer testing, or that the combination would provide increased sensitivity or specificity. This argument is not persuasive because, as set forth above, the teachings of each reference are pertaining to the analysis of different characteristics (i.e.: nucleosome foot protein; CpG methylation) the same analyte (i.e.: cfDNA) for the same detection (i.e.: cancer). The skilled artisan would expect that the combination of the detection of the different characteristics would provide an increased sensitivity and specificity (e.g.: the detection in cfDNA of the methylation of loci that a methylate in the genome of cancerous breast tissue cells would be confirmed to be detected in cfDNA that originates from breast tissue). And so there is no evidence that any improved results in using a combination of assays is in fact greater than what would be expected for the combination of assays. Further relevant to Applicants arguments in this regard, there is no evidence of the asserted improvement is relevant to claimed combination (i.e.: nucleosome footprint and CpG methylation) because the combination results in the specification include a measure of DNA copy number (i.e.: gw-z) (see for example Figures 10 and 14). Finally, Applicants’ argument appear to be directed to a feature that is not claimed, because the claim is directed only to a computer implemented methods for analyzing cfDNA, and does not require that any cancer is in fact detected using the analyses, and does not require that any particular sensitivity or specificity is achieved in a detection.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683