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 .
Election of Species
Applicant’s election without traverse of the viral k-mer species in claim 138 in the reply filed 02/02/2026 is acknowledged.
Claim Status
Claims 1-122 are cancelled by Applicant.
Claims 123-142 are newly added by Applicant.
As discussed above in Election of Species, the viral species in claim 138 has been elected.
Claims 123-142 are currently pending and are herein under examination.
Claims 123-142 are rejected.
Claims 131 is objected.
Priority
The instant application claims domestic benefit as a 371 filing of international application PCT/US2021/064977 filed 12/22/2021, which claims domestic benefit to U.S. Provisional Application No. 63/128,971 filed 12/22/2020. The claims to domestic benefit are acknowledged for claims 123-142. As such, the effective filing date for claims 123-142 is 12/22/2020.
Information Disclosure Statement
The IDSs filed 07/24/2025, 02/09/2026 and 03/11/2026 follow the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of the list of references cited from these IDSs is included with this Office Action.
Abstract
The abstract of the disclosure is objected to because it contains less than 25 words. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: 302 in Figure 3 and 402 in Figure 4.
Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 131 is objected to because of the following informality: “stage I, or” should be “stage I or”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 USC 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 123-142 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.
Claim 123, step (c), recites “a probability of the cancer” which renders the claim indefinite. It is unclear which cancer is being referenced because step (b) recites “a given cancer” and step (c) recites “cancer of the subject”. To overcome this rejection, clarify which cancer is being referenced.
Furthermore, claims 124-142 are also rejected because they depend on claim 123, which is rejected, and because they do not resolve the issue of indefiniteness.
Claim 129 recites “the stage” which lacks antecedent basis. To overcome this rejection, change the phrase to “a stage”.
Claim 130 recites the relative term “low-stage”, which renders the claim indefinite. The term “low-stage” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Because low is a subjective term, the metes and bounds of what constitutes low are unclear. Claim 138 recites “the plurality of non-human nucleic acid molecule k-mer sequences” which renders the claim indefinite. It is unclear which plurality of non-human k-mer sequences are being referenced because there is a plurality for both a subject’s sample and a given cancer in claim 1 steps (a)-(b). To overcome this rejection, clarify which plurality of non-human k-mers is being referenced.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 123-142 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more.
Step 1:
Step 1 asks whether the claims recite statutory subject matter. In the instant application, claims 123-142 recite a method. As such, these claims recite statutory subject matter (Step 1: YES).
Step 2A, Prong 1:
Claims that recite statutory subject matter are analyzed under Step 2A, Prong 1 to determine if they recite any concepts that equate to an abstract idea, law of nature or natural phenomena. The instant claims recite the following limitations that equate to one or more categories of judicial exception:
Claim 123 recites “(a) receiving a plurality of somatic mutation and non-human nucleic acid molecule k-mer sequences of a subject's sample; (b) comparing the plurality of somatic mutation and of non-human nucleic acid molecule k-mer sequences of the subject with a plurality of somatic mutation and non-human nucleic acid molecule k-mer sequences for a given cancer; and (c) diagnosing cancer of the subject by providing a probability of the cancer based at least in part on the comparison of the subject's plurality of somatic mutation and non-human k-mer nucleic acid sequences and the plurality of somatic mutation and non-human nucleic acid molecule k- mer sequences for the given cancer.”
Claim 124 recites “comparing a count of the plurality of somatic mutation nucleic acid molecule k-mer sequences of the subject to a count of the plurality of somatic mutation nucleic acid molecule k-mer sequences of the given cancer.
Claim 125 recites “comparing a count of the plurality of non-human nucleic acid molecule k-mer sequences of the subject to a count of the plurality of non- human nucleic acid molecule k-mer sequences of the given cancer.
Claim 126 recites “wherein diagnosing the cancer of the subject further comprises determining a category or location of the subject's cancer.
Claim 127 recites “wherein diagnosing the cancer of the subject further comprises determining one or more types of the subject's cancer.
Claim 128 recites “wherein diagnosing the cancer of the subject further comprises determining one or more subtypes of the subject's cancer.
Claim 129 recites “wherein diagnosing the cancer of the subject further comprises determining the stage of the subject's cancer, cancer prognosis, or any combination thereof.
Claim 130 recites “wherein diagnosing the cancer of the subject further comprises determining a type of cancer at a low-stage.
Claim 131 recites “wherein the type of cancer at the low-stage comprises stage I, or stage II cancers.
Claim 132 recites “wherein diagnosing the cancer of the subject further comprises determining a mutation status of the subject's cancer.
Claim 133 recites “wherein diagnosing the cancer of the subject further comprises determining the subject's response to therapy to treat the subject's cancer.
Claim 134 recites “wherein the given cancer or the subject's cancer comprises: acute myeloid leukemia, adrenocortical carcinoma, bladder urothelial carcinoma, brain lower grade glioma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, rectum adenocarcinoma, sarcoma, skin cutaneous melanoma, stomach adenocarcinoma, testicular germ cell tumors, thymoma, thyroid carcinoma, uterine carcinosarcoma, uterine corpus endometrial carcinoma, uveal melanoma, or any combination thereof.
Claim 135 recites “wherein the subject is a non-human mammal.
Claim 136 recites “wherein the subject is a human.
Claim 137 recites “where the subject is mammal.
Claim 138 recites “wherein the plurality of non-human nucleic acid molecule k-mer sequences originate from the following non-mammalian domains of life: viral, bacterial, archaeal, fungal, or any combination thereof.
Claim 139 recites “wherein the comparing is conducted with a predictive model.
Claim 140 recites “wherein the predictive model comprises an ensemble of predictive models.
Claim 141 recites “wherein the sample of the subject comprises a tissue sample, a liquid biopsy sample, or a combination thereof.
Claim 142 recites “wherein the liquid biopsy sample comprises: plasma, serum, whole blood, urine, cerebral spinal fluid, saliva, sweat, tears, exhaled breath condensate, or any combination thereof.
Limitations reciting a mental process.
Claims 123-133 and 139-140 contain limitations recited at such a high level of generality that they equate to a mental process because they are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), which the courts have identified as concepts that can be practically performed in the human mind. The paragraphs below discuss the broadest reasonable interpretation (BRI) of the limitations in these claims that recite a mental process.
Claim 123 step (a) includes collecting k-mers from a database of previously sequenced nucleic acids. Step (b) includes determining shared k-mers between the subject and given cancer, requiring mental evaluation. Step (c) includes inputting k-mer counts into a logistic regression and performing calculations to derive a probability.
Claims 124-125 include comparing numbers. Claims 126-131 include analyzing k-mer data and making mental determinations regarding status of a cancer. Claim 132 includes comparing k-mers of a somatic mutation to a reference genome and determining a mutation such as an SNP. Claim 133 includes determining that a cancer treatment for a specific cancer type will not treat the cancer type identified for the subject. Claims 139-140 includes performing on pen and paper calculations of logistic regressions.
Limitations reciting a mathematical concept.
Claims 139-140 recite limitations that equate to a mathematical concept because they are similar to the concepts of organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)), which the courts have identified as mathematical concepts. The paragraphs below discuss the broadest reasonable interpretation (BRI) of the limitations in these claims that recite a mathematical concept.
Claims 139-140 include performing calculations with a logistic regression or other mathematical model recited in the specification in para. [51] to produce a likelihood/probability.
Limitations reciting a natural phenomenon.
Claim 123 diagnoses cancer based on nucleic acids which is similar to the concept of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017), which the courts have established as a natural phenomenon.
Limitations included in the recited judicial exception.
Claims 134-138 and 141-142 further limit elements in the recited judicial exception in claim 123 but do not alter the fact that the elements are part of the judicial exception.
As such, claims 123-142 recite an abstract idea and a natural phenomenon (Step 2A, Prong 1: YES).
Once limitations have been identified that recite a judicial exception, the claims are evaluated for additional elements. The additional elements are analyzed under Step 2A, Prong 2 then Step 2B. However, the instant claims do not recite any additional elements. MPEP 2106.04.II.A.2 recites “For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B. If there are no additional elements in the claim, then it cannot be eligible.” As such, claims 123-142 are not patent eligible.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 123-132 and 134-142 are rejected under 35 USC 103 for being unpatentable over Maher et al. (“Maher”; FOR ref. 1 on IDS filed 07/24/2025; WO 2019/209954 A1) in view of Bayati et al. (“Bayati”; Scientific reports 10, no. 1 (28 January 2020): 1286).
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 123:
(a) receiving a plurality of somatic mutation and non-human nucleic acid molecule k-mer sequences of a subject's sample;
Maher determines whether a subject has cancer using pathogen and somatic nucleic acids derived from a human sample (abstract) [27]. A test subject biological sample is sequenced to produce nucleic acids from the test subject and from at least one pathogen in a set of pathogens 214 (Figure 2A) [1o]. A first assay measures a first feature from the nucleic acids which may be counts of a somatic mutation 215-216 (Figure 2A) [214][219]. A second assay measures an amount of reads that map to a sequence in pathogen target reference 239 (Figure 2C). The amount of reads that map to a pathogen target reference can be a number of k-mers [312] [322].
However, Maher does not teach that the counts of the first feature are k-mer counts.
Bayati classifies 3-mer and 5-mer mutational signatures and patterns in cancer genomes using whole genome somatic mutation datasets profiled by International Cancer Genome Consortium (ICGC) (abstract). Samples are grouped by raw mutation counts and/or composition of mutational signatures (pg. 2, para. 3) (Figure 1 caption) (pg. 4, sec. Clustering of samples). Figure 2 show 77 signatures across 18 tumor-types (Figures S2-S19).
It would have been prima facie obvious to have modified counting somatic single nucleotide variants to classify cancer in Maher [27] [219] (Figure 2G) by counting k-mers associated with single base substitutions as taught by Bayati (Figures 3-4). The motivation for doing so is to identify cancer type specific somatic mutation signatures in order to increase accuracy of classification in Maher. Bayati teaches that their counts of 3-mers and 5-mers created accurate signatures of cancer types (pg. 10, para. 1). There would have been a reasonable expectation of success because the nucleic acids of Maher can be use as input into the method of Bayati, wherein 3-mer and 5-mer counts would be used as the counts for somatic mutation signature in Maher that is inputted into the classifier of Maher.
(b) comparing the plurality of somatic mutation and of non-human nucleic acid molecule k-mer sequences of the subject with a plurality of somatic mutation and non-human nucleic acid molecule k-mer sequences for a given cancer; and (c) diagnosing cancer of the subject by providing a probability of the cancer based at least in part on the comparison of the subject's plurality of somatic mutation and non-human k-mer nucleic acid sequences and the plurality of somatic mutation and non-human nucleic acid molecule k- mer sequences for the given cancer.
Maher applies a classifier to somatic mutation counts and pathogen specific k-mer counts derived from the test subject (Figure 2G, ref. chara. 267-270). The classifier is trained on a cohort that contains subjects with and without cancer, and each subject in the cohort has a count of pathogen specific k-mers (Figure 2G, ref. chara. 272). Thus, the counts of a test subject are compared to the counts of subjects in a training cohort for cancer classification. The classifier determines if the subject has the cancer condition or a likelihood that the test subject has the cancer condition [10] (Figure 2G).
However, Maher does not teach counts of the first feature as k-mer counts. Bayati in combination with Maher teach this limitation, as taught above.
Claims 124-125:
These limitations are taught above by the combination of Maher and Bayati in claim 123 step (b), which compares somatic mutation k-mer counts and pathogen k-mer counts between a test subject and a subject from a training cohort.
Claims 126-127, 129-131 and 134:
Maher classifies a cancer condition as early or late stage, including stages 1-5, and can be of a specific cancer type such hepatocellular carcinoma or lung cancer (category, location, type, stage of cancer, low-stage, stages I-II) (Figures 8 and 11) [93] [149] [181-182] [315].
Claim 128:
Maher classifies a cancer condition as having an APOBEC induced mutational signature [12].
Claim 132:
Maher determines somatic copy number variations [213].
Claims 135-137:
Maher defines a subject as a human, reptile, or monkey [117].
Claim 138:
Maher defines a pathogen as “a virus, a bacterium, a parasite, or any organism that is external to the test subject organism” [10].
Claims 139-140:
Maher uses a classifier which may be a logistic regression, a binomial classifier, or an ensemble of classifiers [57][169].
Claims 141-142:
Maher defines a biological sample as a tissue or plasma sample [91].
Claim 133 is rejected under 35 USC 103 for being unpatentable over Maher et al. (“Maher”; FOR ref. 1 on IDS filed 07/24/2025; WO 2019/209954 A1) in view of Bayati et al. (“Bayati”; Scientific reports 10, no. 1 (28 January 2020): 1286), as applied above to claim 123, and in further view of Hubbell et al. (“Hubbell”; US Patent App. no. 3 on IDS filed 07/24/2025; US 2019/0316209 A1).
The limitations of claim 123 have been taught in the rejection above by Maher and Bayati.
Claim 133:
Maher provides a therapeutic intervention based on classifying a test subject’s cancer condition [33]. Bayati suggests investigating correlation of clustering cancer types with treatment history and response to therapies to identify potential biological associations (pg. 4, sec. Clustering of samples, para. 1) (pg. 6). However, Maher and Bayati do not determine a subject’s treatment response.
Hubbell predicts cancer based on viral-derived nucleic acids and copy number aberrations from a test subject sample [17] (claims 1, 5 and 19-20). A predictive model is applied to the nucleic acid features to predict a likelihood response to a treatment [160].
It would have been prima facie obvious to modify the cancer classification method of Maher and Bayati based on pathogen and non-pathogen nucleic acids from a subject by also predicting a response to cancer treatment based on the nucleic acids, as taught by Hubbell. The motivation for doing so is to determine an effective treatment for a patient based on their cancer type because Maher provides a therapeutic intervention based on a cancer classification [34]. The combination would provide a therapeutic predicted to be effective for the subject. There would have been a reasonable expectation of success because Maher measures the same type of nucleic acids used in Hubbell to predict cancer treatment response (i.e., pathogen and non-pathogen nucleic acids from a subject).
Conclusion
No claims are allowed.
Notable, but not relied upon, prior art includes: Brown et al. (US 2022/0380755 A1) and Burns et al. (PLoS genetics 14, no. 6 (2018): e1007376) who correlates gut microbiome with host tumor mutations using whole-exome sequencing.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Noah A. Auger whose telephone number is (703)756-4518. The examiner can normally be reached M-F 7:30-4:30 EST.
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/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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