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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/24/2026 has been entered.
Response to Amendment
The amendment filed 24 April 2026 is acknowledged. The amendment largely clarified method steps in claims 1 and 11, as well as the addition of claim 25.
Regarding the Office Action mailed 24 February 2026 and in light of Applicant’s amendments:
The rejections of claims 1-10 are maintained. They have been modified to address the amendments and are otherwise reiterated below.
The rejections of claims 11-16 and 18-24 are withdrawn; however, the amendments have introduced a new ground of rejection which will follow.
The nonstatutory double patenting rejections of claims 1-10 over claims 1-13 of U.S. Patent No. 11,066,707 in view of Coccaro are maintained. The rejections of claims 11-16 and 18-24 are withdrawn.
The provisional nonstatutory double patenting rejections of claims 11-16 and 18-24 over claims 40-46 and 51-53 of copending Application No. 17/361,829 are withdrawn.
The provisional nonstatutory double patenting rejections of claims 1-16 and 18-24 over claims 6-22 of copending Application No. 18/204,703 are maintained.
Claim Objections
Claim 19 is objected to because of the presence of informalities, which are pointed out below. Appropriate correction is required.
“The method of claim 11, wherein the PCR is digital PCR (dPCR).”
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 11-16 and 18-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 11 states: “…determining quantities of the selected structural sequence rearrangements in the sample by dividing (i) counts of the partitions in which amplicons are detected by (ii) a measured pre-amplification efficiency.”
This mathematical formula describing how to back calculate initial quantity from the data obtained by the claimed method is not found in the applicant’s original disclosure. Therefore, this limitation is considered to be new matter.
Claims 12-16 and 18-24 are rejected as they depend from claim 11.
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.
Claims 1-10 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Jackson [Jackson et al., Journal of Molecular Diagnostics, 2016, Vol. 18(2), 235-43; previously cited] in view of McDonald [McDonald BR et al. Science translational medicine. 2019 Aug 7;11(504):eaax7392].
Regarding claims 1-5 and 10, Jackson teaches a method for detecting tumor-specific mutations present in a sample in low abundance relative to wild-type circulating, cell-free DNA (ccfDNA), which had previously made their detection technically challenging [abstract]. This method entails obtaining blood and tissue samples from cancer patient, performing pre-amplification on serum-derived ccfDNA, followed by analysis with droplet PCR (dPCR), ultimately resulting in the detection of cancer-relevant mutations [Jackson; abstract; p236, col2, para2-3].
Jackson does not teach first sequencing tumor nucleic acid to identify patient-specific targets for their method, nor the analysis of structural variants.
However, McDonald developed a target digital sequencing (TARDIS) method which allows for multiplexed analysis of patient-specific cancer mutations in order to track MRD [McDonald, abstract]. For each patient, McDonald identified an average of 65.8 putative founder somatic mutations using exome sequencing of tumor biopsies and matched germline samples. Primers were then rigorously developed such that 6 to 115 mutations per patient were analyzed from plasma sample collected at a variety of timepoints during treatment. In order to maximize the information that could be obtained from the analysis, samples were subjected to targeted linear pre-amplification, ligated with UMIs, subjected to targeted exponential PCR, and then sequenced [McDonald, pg2 C2, pg4].
While McDonald does not describe the class of each mutation analyzed for patient samples, they evaluated the assay’s performance using commercially available reference samples. In doing this, they targeted 8 mutations, two of which were structural variants (one insertion and one deletion) [McDonald, Table S1]. This shows the applicability of this method to a variety of mutation classes.
The similarity between the methods of Jackson and McDonald are apparent. Both analyze patient samples for tumor-specific mutations by conducting linear pre-amplification as well as exponential amplification using targeted primers. They differ in that Jackson concludes analysis via dPCR while McDonald performs additional sequencing. McDonalds teaches that using sensitive and accurate approaches such as TARDIS allows for the development of individualized and curative treatment plans while reducing the prevalence of overtreatment [McDonald, pg8 C2].
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filling date of the claimed invention to first sequence patient samples in order to identify personally relevant tumor mutations before performing the method of Jackson in order to generate individualized treatment plans so as to reduce overtreatment while maintaining clinical outcomes, thus improving the overall quality of life of the patient.
The use of a known technique to improve similar devices (methods or products) in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
Regarding claims 6 and 7, neither Jackson nor McDonald specifically state that the results of the described methods and assays could be used to report on the structural rearrangements and genomic mutations present or on the presence of a tumor in a subject.
However, both Jackson and McDonald discuss the use of their method to detect cancer relevant markers and it would have been obvious to one of ordinary skill in the art prior to the effective filling date of the claimed invention to report the presence of a tumor/structural rearrangement/genomic mutation based upon positive results obtained from Jackson’s method as modified by McDonald in order to aid in clinical diagnoses and decisions regarding treatment and prognosis.
Regarding claim 8 and 25, McDonald states that they targeted founder mutations as they are shared by all tumor cells. Subclonal mutations, on the other hand, are more likely to be lost during treatment and thus are less effective in tracking MRD [McDonald, p8 C1]. The skilled artisan would recognize the founder mutations of McDonald to be equivalent to the truncal mutations claimed by the Applicant.
Regarding claim 9, Jackson teaches partitioning the pre-amplified sample into droplets, and performing subsequent PCR and signal detection in these droplets [p237, col2, para4 – p238, col 1, para2].
Response to Arguments
Applicant’s arguments, see page 6 (I) and page 8 (II), filed 24 April 2026, with respect to the rejection(s) of claims 1-10 under U.S.C. § 103 have been fully considered and are persuasive. Applicant argued that neither Jackson nor Coccaro taught sequencing of patient samples to identify a plurality of structural variants. The Examiner agrees that that Jackson and Coccaro monitored previously known mutations, rather than mutations identified as a result of sequencing a patient sample. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Jackson and McDonald, as previously laid out.
Applicant’s arguments with respect to claims 11-16 and 17-24 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kara N Kovach whose telephone number is (571)272-8134. The examiner can normally be reached Monday - Friday, 9am - 3pm.
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, 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.
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.
/K.N.K./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
Prosecution Insights