DETAILED ACTION
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 .
Status of the Application
The Amendment and Response filed July 29, 2026 has been considered.
Claims 1-22 were pending. Claims 1-10 and 15-22 are being examined on the merits. Claims 11-14 are canceled.
Response to Arguments
Applicant’s arguments filed July 29, 2026 have been fully considered.
The following rejections are WITHDRAWN in view of Applicant’s arguments and amendments to the claims, and in view of the filing of the Terminal Disclaimer:
Rejections of claims 11-15 under 35 USC § 112(b), indefiniteness
Rejections of claim 21 under 35 USC § 112(b), lack of antecedent basis
Double patenting rejections
The following rejections are MAINTAINED OR MODIFIED in view of the instant claim amendments:
Prior art rejections
Response to arguments regarding prior art rejections
The prior art rejections are maintained as to independent claim 1 and its dependent claims, and modified as to the remaining claims in view of the instant amendments to independent claim 6. To the extent that Applicant’s arguments are relevant to the rejections below, the Examiner notes the following.
Applicant argues that the prior art rejection of independent claim 1 should be withdrawn because the cited art, Cani, does not teach each limitation of instant claim 1. Specifically, Applicant argues that Cani does not teach or suggest ranking truncal rearrangements based on a timeline of tumor progression, but rather teaches ranking alterations based on their prevalence in subclonal cells (Remarks, p. 8).
The Examiner disagrees. It is not clear what Applicant is arguing because they have not explained why the cited portions of Cani do not teach ranking truncal rearrangement based on a timeline of tumor progression. Further, the Examiner notes that the specification does not define the limitation “ranking” at all, much less “ranking … based on a timeline of tumor progression”. To the extent that Applicant intends for that to refer to something like “modeling”, as recited in instantly amended claim 6, the Examiner notes that the specification also doesn’t define or teach anything at all related to modeling. Further, the specification describes an “early truncal variant” as “a variant associated with early tumorigenesis” (p. 7), but does not further describe what is meant by “early”.
Applicant argues that the secondary references, Jackson and Saal, do not cure the deficiencies of Cani (Remarks, p. 9).
As noted, the Examiner disagrees with Applicant’s characterization of the teachings of Cani, and consequently disagrees with what the ordinary artisan would understand from the combined teachings of Cani plus the secondary references.
Applicant argues that the teachings of Cani and Jackson are incompatible, and thus cannot be combined, because combining the Cani whole genome amplification and sequencing with the Jackson target-specific amplification would render the methods of Jackson inoperable for their intended use (Remarks, p. 10).
The Examiner disagrees, and again notes that Applicant provides no reasoning or evidence to support their argument. Further, Applicant is incorrect. The prior art teaches methods where target-specific amplification and whole genome amplification/sequencing are combined. For example, see Jasper (US Patent App. Pub. No. 2019/0345538 A1; e.g., paras. 11, 97).
Claim Rejections - 35 USC § 102
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 –
(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.
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cani1 (Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection, Molecular Oncology, 16(10): 1969-1985, 2021).
Regarding independent claim 1, Cani teaches …
A method for cancer genome analysis, the method comprising the steps of: conducting whole genome sequencing on tumor tissue (abstract; section 2.4: circulating tumor cells (CTCs) were whole genome amplified and then sequenced; sections 2.7, 3.2);
identifying truncal rearrangements in tumor sequence produced in the conducting step
(section 3.2: p. 1972, right col., para. 3; section 3.5).
Cani additionally teaches ranking the truncal rearrangements, e.g., in the PIK3CA, c-KIT and CDH1 genes, based on a timeline of tumor progression, e.g., at baseline and at treatment discontinuation; selecting truncal arrangements that occur earliest in said timeline, e.g., at baseline; and producing a readout, e.g., a heatmap, that characterizes the tumor based on the earliest truncal rearrangements (Fig. 2; Table 1; sections 2.3, 3.5, 3.6).
Regarding dependent claim 2, Cani teaches that the readout is produced using digital PCR to detect the selected truncal rearrangements (Fig. 2).
Claim Rejections - 35 USC § 103
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.
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.
Claims 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Cani (Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection, Molecular Oncology, 16(10): 1969-1985, 2021) as applied to claims 1-2 above, and further in view of Jackson2 (Multiplex Preamplification of Serum DNA to Facilitate Reliable Detection of Extremely Rare Cancer Mutations in Circulating DNA by Digital PCR, Journal of Molecular Diagnostics, 18(2): 235-243, 2016).
Regarding dependent claims 3-4, Jackson teaches preamplification of the selected
rearrangements using PCR (i.e., exponential) amplification (p. 236, right col., para. 2).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Cani method, discussed above, to incorporate a preamplification step. Cani teaches the need for methods with improved sensitivity. Jackson teaches that preamplification improves the detection sensitivity of low frequency mutants. Thus, the ordinary artisan would have been motivated to incorporate the preamplification step into the Cani method to achieve the expected advantage of a highly sensitive method for monitoring genomic alterations in tumor cells. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid amplification assays is well-known in the art.
Regarding dependent claim 5, Cani teaches that the digital PCR is conducted on blood or
plasma comprising cell-free DNA (Fig. 3; sections 2.3, 3.4).
Claims 6-7, 10 and 15-22 are rejected under 35 U.S.C. 103 as being unpatentable over Jackson (Multiplex Preamplification of Serum DNA to Facilitate Reliable Detection of Extremely Rare Cancer Mutations in Circulating DNA by Digital PCR, Journal of Molecular Diagnostics, 18(2): 235-243, 2016) in view of Cani (Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection, Molecular Oncology, 16(10): 1969-1985, 2021).
Regarding independent claim 6, Jackson teaches …
A method for variant detection, the method comprising the steps of: providing a sample
comprising target nucleic acids from the subject (abstract);
performing pre-amplification to increase abundance of the target nucleic acid in the sample (p. 236, right col., para. 2);
aliquoting the sample into a plurality of subsamples, e.g., droplets (p. 237, right col., para. 3 through p. 238, left col., para. 2);
conducting polymerase chain reaction (PCR) on the subsamples (p. 237, right col., para. 3 through p. 238, left col., para. 2);
and detecting the target nucleic acids (p. 238, left col., para. 3).
Further, Cani teaches sequencing tumor DNA from tumor tissue of a subject to identify tumor mutations, modeling a timeline of progression of the tumor mutations, and identifying at least one of the tumor mutations that is an early truncal variant, and further teaches that the target nucleic acids comprise an early truncal variant and that the early truncal variant is detected (abstract; section 2.4: circulating tumor cells (CTCs) were whole genome amplified and then sequenced; sections 2.7, 3.2; section 3.2: p. 1972, right col., para. 3; section 3.5; Figs. 2-3; Table 1; sections 2.3, 3.6).
Regarding dependent claim 22, Jackson additionally teaches that the target nucleic acid molecule includes a single nucleotide variant (p. 236, right col., para. 4), and Cani teaches that the tumor mutations include a structural variation, specifically a copy number variation3 (p. 1973, right col., para. 3).
Prior to the effective filing date of the instant invention, it would have been prima facie
obvious to modify the Jackson method to incorporate the Cani sequencing, progression modeling steps and targets. Jackson teaches the need for improvements in treatment monitoring for cancer. Cani teaches the sequencing and progression modeling steps can be used to identify tumor biomarkers that can be non-invasively tracked over the course of treatment. Thus, the ordinary artisan would have been motivated to incorporate the Cani steps into the Jackson method to achieve the expected advantage of a method that is capable of non-invasively monitoring cancer over the course of treatment. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid amplification assays is well-known in the art.
Regarding dependent claim 7, Jackson teaches that the pre-amplification is exponential (PCR) amplification (p. 236, right col., para. 2).
Regarding dependent claims 10, 17 and 21, Jackson teaches that the PCR comprises digital PCR with fluorescent hydrolysis probes (Table 1; p. 237, right col., para. 3), as recited in claim 10. Further, regarding claims 17 and 21, Jackson teaches that the PCR comprises multiplex digital PCR, which uses pairs of primers that are capable of amplification of different target nucleic acid sequences (Table 1; Fig. 1; p. 237, right col., para. 3 through p. 238, left col., para. 3).
Regarding dependent claim 15, Jackson additionally teaches that the sample is a liquid
biopsy sample and the target nucleic acids comprise ctDNA (p. 236, right col., para. 2).
Regarding dependent claim 16, Jackson teaches that the said conducting step comprises: providing a pair of primers capable of specific amplification of a target nucleic acid; providing a nucleic acid polymerase having a polymerase activity at an elongation temperature; preparing PCR reactions, wherein each PCR reaction comprises a part of the sample, the pair of primers, the nucleic acid polymerase, PCR reagents, and optionally detection reagents; and performing symmetrical exponential amplification (Table 1; Fig. 1; p. 237, right col., para. 3 through p. 238, left col., para. 3).
Regarding dependent claims 18-19, Jackson additionally teaches that a portion of the pre-amplification is used as direct input for the PCR (p. 237, right col., para. 3), as recited in claim 18, and that the portion of the reaction mixture is not subject to any clean-up step and the PCR is performed by adding components of a PCR reagent mixture to the portion of the reaction mixture (p. 237, right col., para. 3), as recited in claim 19.
Regarding dependent claim 20, Jackson additionally teaches determining quantities of the target nucleic acid in the sample using (i) counts of the subsamples in which amplicons are detected and (ii) a measure of the increase in the abundance of the target nucleic acid yielded by the pre-amplification (p. 242, left col., para. 3 through p. 242, right col., para. 1; p. 239, left col., para. 2 through p. 240, right col., para. 1).
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Jackson (Multiplex Preamplification of Serum DNA to Facilitate Reliable Detection of Extremely Rare Cancer Mutations in Circulating DNA by Digital PCR, Journal of Molecular Diagnostics, 18(2): 235-243, 2016) in view of Cani (Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection, Molecular Oncology, 16(10): 1969-1985, 2021) as applied to claim 6 above, and further in view of Saal4 (US 2018/0340230 A1).
Regarding dependent claims 7-8, Saal teaches that the pre-amplification is incremental
amplification comprising the steps of providing a pair of primers capable of amplification of a target nucleic acid, wherein the pair of primers comprises a primer-H and a primer-L, wherein the melting temperature of primer-H is at least about 10 °C higher than the melting temperature of primer-L, and wherein primer-L comprises a sequence complementary to an elongation product of primer-H; and thermocycling the sample with an annealing temperature at which primer-H anneals but primer-L does not anneal (abstract; paras. 20-37).
Regarding dependent claim 9, Saal teaches that the performing step is asymmetric
incremental amplification comprising the steps of: providing a set of primers comprising at least one primer specifically capable of amplification of only one strand of the target nucleic acid sequence; preparing PCR reactions each comprising a part of the sample, the set of primers, the nucleic acid polymerase, and PCR reagents; and performing an incremental polymerase reaction (paras. 11, 14-15, 19-37).
Prior to the effective filing date of the instant invention, it would have been prima facie
obvious to further modify the modified Jackson method, discussed above, to incorporate the incremental amplification steps of Saal. Jackson teaches the need for detection methods with improved sensitivity. Saal teaches that the various incremental amplification steps achieve “exceedingly high sensitivity”. Thus, the ordinary artisan would have been motivated to incorporate the incremental amplification steps into the Jackson method to achieve the expected advantage of a highly sensitive method for monitoring genomic alterations in tumor cells. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid amplification assays is well-known in the art.
Conclusion
Claims 1-10 and 15-22 are being examined and are rejected. No claims are 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 CAROLYN GREENE whose telephone number is (571)272-3240. The examiner can normally be reached M-Th 7:30-5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CAROLYN L GREENE/Primary Examiner, Art Unit 1681
1 Cani was cited in the PTO-892 Notice of References Cited mailed January 15, 2026.
2 Jackson was cited in the PTO-892 Notice of References Cited mailed January 15, 2026.
3 The instant specification teaches that Mahmoud (Structural variant calling: the long and short of it, Genome Biology, 20:246, 1-14, 2019), which is incorporated by reference, describes structural variants. Mahmoud, in turn, states that “[s]tructural variants … are large genomic alterations, …[c]opy number variations … are a particular subtype” of structural variants (p. 1, left col., para. 1: Introduction).
4 Saal was cited in the PTO-892 Notice of References Cited mailed January 15, 2026.
