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 06/18/2026.
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 Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.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.
Note on The Presentation of Claim Amendments
It is noted that the amendments of 06/18/2026 are not technically compliant with
37 CFR 1.121 (c)(2) which provides:
When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of "currently amended," and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of "currently amended," or "withdrawn" if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as "withdrawn— currently amended."
In the instant case claim 1 of the previous claims of 09/10/2025 recited “identifying gastric tumor specific mutations”, where the currently amended claim 1 recites “thereby, treating the subject identified as having tumor specific mutations”, but the term “gastric” is not accounted for in the amended claims.
In the interests of customer service and compact prosecution the claims are entered and are examined in this Office Action. Applicants are encouraged to thoroughly review any future submissions to ensure they meet the requirements of 37 CFR 1.121.
Election/Restrictions
In the reply filed on 09/10/2025 Applicants elected without traverse (MPEP § 818.01(a)) the invention of Group I (claims directed to methods of detecting cancer specific mutations), and the particular cancer that is gastric cancer, and the particular gene that is TP53 (it is noted that the election recites and election of “TP5”, which is interpreted to mean TP53) is acknowledged.
In light of the Examiner’s search and consideration of the elected invention, the species election requirement as it was applied between gastric cancer and colorectal cancer was withdrawn (see page 2 of the Office Action of 12/18/2025).
Claims 10 and 11 (directed to non elected cancer species), and claims 15, 20, 27 and 28 (directed to non elected methods) are withdrawn from further consideration pursuant to 37 CFR 1.142(b), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/10/2025.
It is noted that Applicants’ amendments to the claims of 06/18/2026 indicate that claims 9 and 13 are withdrawn, however these claims are currently under examination.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
The rejections of claims under 35 USC 112(b), as set forth on pages 2-3 of the Office Action of 12/18/2025, are withdrawn in light of the amendments to the claims.
New Claim Rejections - 35 USC § 112 – Indefiniteness
Necessitated by Claim Amendments
Claims 1, 3-5, 9, 13-14, 31 and 34-37 are 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.
Claims 1, 3-5, 9, 13-14, 31 and 34-37 are unclear over the stated purpose of the claimed methods, as recited in the preamble of claim 1, as “detecting and treating gastric, colorectal, lung and/or esophageal tumor specific mutations in a subject's circulating tumor DNA”. The claims are thus directed to “… treating … mutations in a subject's circulating tumor DNA”, but it is unclear how “mutations” are treated by the surgery or chemotherapy steps of the claims. Surgery or chemotherapy are therapeutic regimens that are directed to the treatment of pathology, such as the surgical removal of a tumor, but it is unclear how such therapeutic regimens are performed for treating mutations in a subject's circulating tumor DNA.
Claim 13 is unclear over the recitation “the method of claim 6” because claim 6 is cancelled, and thus where the rejected claim depends from a cancelled claim the required limitations of claim 13 are unclear.
Withdrawn Claim Rejections - 35 USC § 112 – Failure to Limit
The rejection of claims under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as set forth on pages 3-4 of the Office Action of 12/18/2025, is withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 101
The rejection of claims under 35 U.S.C. 101, as set forth on pages 4-6 of the Office Action of 12/18/2025, is withdrawn in light of the amendments to the claims.
Maintained Claim Rejections - 35 USC § 103
Modified as Necessitated by Claim Amendments
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.
Claim(s) 1, 3, 4, 5, 9, 13, 14, 31 and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xia et al (2017; as cited on the IDS of 05/25/2022) in view of Liu et al (2016).
Xia et al teaches the detection of background somatic mutations in white blood cells (WBC) and the use of such mutations in filtering mutations detected in cell-free DNA from subjects with cancer to identify mutations in cell-free DNA that are of tumor-derived origin. Relevant to the limitations of the claims, Xia et al teaches generating sequence libraries and identification of sequence variations in cfDNA from plasma (e.g.: p.5- Blood plasma isolation) (relevant to claims 3 and 34) and cellular DNA from white blood cells obtained from whole blood (relevant to claim 4) as compared to a reference genomic sequence (e.g.: p.6 - Extraction of cfDNA; Multiplex PCR and sequencing library construction; Data filtering and analysis). The reference further teaches the comparison of detected mutants in the cfDNA and the cellular DNA from colon cancer subjects (relevant to claim 9) (e.g.: p.6 - Mutant allele frequency in cfDNA and WBCs in the population and in individuals; p.2 -Validating the detecting sensitivity using the standard reference and tumor samples; Table S2 – “… and all the three samples were filtered by using the white blood cells as the background” to remove background somatic mutations that do not originate from the tumor (relevant to claim 5).
Relevant to claims 13, 14 and 31, as consonant with the election, Xia et al teaches cfDNA mutations that are not in the WBC samples from the subject which are in the TP53 gene locus (e.g.: see Table S2 and the mutations in chromosome 17 in positions between chr17:7,661,779-7,687,546). Additionally, Xia et al notes that mutations in TP53 mutations are frequent in solid organ tumours (e.g.: p. 5).
Xia et al does not teach identifying mutations in cell-free DNA, which are not in white blood cell DNA, that are indicative of gastric cancer in particular (as recited in claim 1 and in claim 8). Xia et al does not teach performing surgery on a subject with tumor specific mutations (relevant to claim 1).
However, the detection of gastric cancer related mutations in tumor-derived cell-free DNA, and the treatment of gastric cancer with surgery, were each known in the prior art and are taught by Liu et al.
Liu et al teaches that a high frequency of gene mutations contained in circulating cell-free DNAs (cfDNAs) provides evidence to assess the tumor occurrence and progression, and that mutations in genes such TP53 occur with high frequency in human cancers (e.g.: p.2- Circulating DNAs with gene mutations). Additionally relevant to the rejected claims, Liu et al teaches the surgical resection is a typical treatment for gastric cancer (e.g.: p.1 – left col).
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 performed the analysis of mutations found cfDNA and WBC cellular DNA, for the diagnostic detection of a tumor in a subject, as taught by Xia et al, and to have treated the tumor by using surgery as taught by Liu et al. Where the prior art of Liu et al teaches that surgical resection is a typical treatment for cancer, the skilled artisan would recognize that applying such a treatment may help to alleviate the pathological effects of a tumor that is within the subject, and that a threshold of tumor-specific mutations may be defined by removing the background mutations identified in WBC. The skilled artisan would have a reasonable expectation of success based on the expressed teachings of Liu et al that cfDNA from subjects with gastric tumors contains tumor-derived DNA harboring mutations, and the specific suggestion of Xia et al that both cfDNA and genomic DNA from white blood cells can be sequenced for any individual and the teaching of Xia et al that accurate detection of ctDNA for cancer early diagnosis requires removal of the background of somatic mutations originating from blood cells.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 103 as obvious in light of the cited prior art. Applicants’ arguments (p.8-10 of the Remarks of 06/18/2026) have been considered but are not persuasive to withdraw the rejection as maintained above.
Applicants have initially argued that the cited prior art do not disclose a combination comprising cell free DNA (cfDNA) and cellular DNA as recited in the claims. This argument is not persuasive because it does not appear to take into account the teachings of Xia et al as cited in the rejection. Xia et al clearly teaches the separation of whole blood samples into plasma and blood cells, and the analysis of cfDNA extracted from plasma, and genomic DNA of white blood cells (i.e.: cellular DNA) (e.g.: p.3 – DNA extraction). To be clear, Xia et al specifically teaches that detection of circulating tumor DNA (i.e.: cfDNA) can be a biomarker for early diagnosis of cancer, and that in order to accurately detect the tumor DNA the background somatic mutations originating from the genomic DNA in blood cells must be removed. Xia et al in fact exemplifies the analysis of both cfDNA (obtained from the plasma portion of a blood sample) and blood cells (obtained from the cellular portion of a blood sample) to remove the background mutations contributed by blood cells (e.g.: p.5: The mutations detected in cfDNA are highly correlated with mutations in white blood cells; Reproducibility).
Applicants have next argued that the cited prior art “would still not result in identifying TP53”. Initially it is noted that it is unclear how Applicants’ are applying this argument to the claimed methods and the cited prior art. Initially it is noted that the particular gene TP53 is only relevant to the limitations of claims 13, 14 and 31. Furthermore, the claims are not directed to identifying any gene, but are directed to the identification of tumor specific mutations (e.g..: mutations found in the cfDNA that are not also found in the cellular DNA from white blood cells). While claims 13, 14 and 31 recite limitations, consonant with the election, that tumor specific mutations are identified in the TP53 gene, this is not any requirement for “identifying TP53” as provided in the argument. Nonetheless it is noted that the limitations of the claim with regard to the identification of tumor specific mutations in TP53 are suggested by the cited prior art. Xia et al teaches that TP53 mutations are more frequent in solid organ tumors, and Liu et al teaches that TP53 is frequently mutated in various human cancers. Therefore, the Examiner maintains that the skilled artisan would have a reasonable expectation of success in finding TP53 mutation in cell free DNA from a subject with a solid tumor based on the expressed teachings of both Xia et al and Liu et al, because both reference indicate that mutations in TP53 are related to solid tumors. The identification of a TP53 mutation in cfDNA as a tumor-specific mutation, when the same mutation is absent from a sample WBC cellular DNA is suggested by Liu et al, which teaches that cfDNA contains a background of somatic mutations originating from blood cells and that the background mutations should be removed for the use of cell-free DNA in an accurate diagnostic assay.
Claim(s) 35-37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xia et al (2017; as cited on the IDS of 05/25/2022) in view of Liu et al (2016) as applied to claims 1, 3, 4, 5, 9, 13, 14, 31 and 34 above, and further in view of Clark et al 2011.
Xia et al in view of Liu et al renders obvious methods comprising identification of tumor specific mutations as compared to a reference that are present in cfDNA but are not present in cellular DNA from a subject, and treatment of the subject comprising performing a surgery. Further relevant to the instantly rejected claims, Xia et al teaches the analysis of libraries sequenced at high coverage including sequence alignment, error correction, and variant calling (e.g.: p.3 - Data filtering and analysis; p.4 - Mutation rate in cfDNA and white blood cells in the population and in individuals), relevant to claim 36, and suggests the removal of mutations detected in WBCs identified in cfDNA for the identification of tumor-specific mutations in cfDNA (e.g.: p.5 - These results also highlighted the importance of sequencing both cfDNA and blood cells, to remove the background mutations contributed by blood cells.”). Xia et al further teaches using a multiplex PCR method to enrich 50 cancer-associated genes multiplex PCR for sequencing library construction (e.g.: p.3).
Xia et al in view of Liu et al does not particularly teach capturing library targets with RNA oligonucleotide pools targeting genes associated with cancer, as required by claim 35 from which claims 36 and 37 depend.
However, the use of RNA oligonucleotide pools targeting genes associated with cancer for to enrich for desired targets for sequencing-based analyses was known in the prior art and is taught by Clark et al (e.g.: Fig 1).
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 used a capture step using oligonucleotide pools targeting genes, as taught by Clark et al, in the detection of tumor specific mutations in cfDNA rendered obvious by Xia et al in view of Liu et al. The skilled artisan would have been motivated to used oligos to capture cancer genes for sequencing based on the expressed teachings Clark et al that enriching for targets of interest by oligo based capturing of targets can increase the sensitive of detection of some mutations (e.g.: Figure 5).
Conclusion
No claim is allowed.
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.
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
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