DETAILED ACTION
Claim Status
Claims 1-20 are rejected.
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 .
Priority
This application claims Domestic Benefit to applications 63/341,543 and 63/403,230, filed 05/13/2022 and 09/01/2022 respectively. Domestic Benefit is acknowledged. Therefore, the effective filing date of claim(s) is 05/13/2022.
Information Disclosure Statement
The Information Disclosure Statement filed on 04/25/2024 are in
compliance with the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of list of
references cited from each IDS is included with this Office Action.
Drawings
The drawings submitted on 05/12/2023 have been accepted.
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
In accordance with MPEP § 2106, claims found to recite statutory subject matter ( Step 1 : YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
1, 12. wherein the cfDNA-derived metric comprises at least one of a tumor fraction (TFx) value, a variant allele frequency (VAF) value and a tumor mutational burden (TMB) value; and
1, 12. determining the subject to have residual disease or no residual disease based on the cfDNA-derived metric;
3. The method of claim 1, wherein the determining comprises employing a machine learning model based on the cfDNA-derived metric.
5. The method of claim 1, wherein the cfDNA-derived metric consists of a TFx value, VAF value, and a TMB value.
6. The method of claim 3, wherein the machine learning model comprises a random forest model and is further based on a clinical variable selected from the group consisting of age, gender, ethnicity, smoking status, receipt of chemotherapy, tumor invasion status, and combinations thereof.
7. The method of claim 1, wherein the urinary tract-associated cancer is a bladder cancer.
8. The method of claim 7, wherein the bladder cancer is a muscle-invasive bladder cancer.
10. The method of claim 1, wherein determining the subject to have residual disease comprises determining a negative predictive value (NPV) of at least about 70%, a positive predictive value (PPV) of at least about 60%, or an area under the curve (AUC) of at least about 0.70.
11. The method of claim 3, wherein the machine learning model further predicts overall survival (OS) or progression-free survival of the subject based on the cfDNA-derived metric.
14. The method of claim 12, wherein the determining comprises employing a machine learning model based on the cfDNA-derived metric.
16. The method of claim 12, wherein the cfDNA-derived metric consists of a TFx value, VAF value, and a TMB value.
17. The method of claim 14, wherein the machine learning model is further based on a clinical variable selected from the group consisting of age, gender, ethnicity, smoking status, receipt of chemotherapy, tumor invasion status, and combinations thereof.
The limitations for “detecting” and “determining” are verbal equivalents for mathematical transformations made to sequencing data in order to arrive at a data output result. The limitations are broadly recited enough that there are embodiments that could be performed by a human being with a pen and paper. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. As such, claims 1-20 recite an abstract idea ( Step 2A, Prong 1 : YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). This judicial exception is not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology or applies or uses the recited judicial exception to effect a particular treatment for a condition. Rather, the instant claims recite additional elements that amount to mere instructions to implement the abstract idea in a generic computing environment or mere instructions to apply the recited judicial exception via a generic treatment. Specifically, the claims recite the following additional elements:
1, 12. detecting a cfDNA-derived metric using ultra-low-pass whole genome sequencing (ULP-WGS) and next-generation sequencing (NGS);4. The method of claim 1, wherein detecting the cfDNA-derived metric further comprises detecting single nucleotide variants (SNVs) or copy number alterations (CNAs) in the cfDNA.
9. The method of claim 1, wherein a cancer treatment was administered to the subject prior to obtaining the urine sample, and wherein the cancer treatment is a chemotherapy, a radiotherapy, or an immunotherapy.
2, 13. The method of claim 12, wherein the NGS comprises urine cancer personalized profiling by deep sequencing (uCAPP-Seq).
15. The method of claim 12, wherein detecting the cfDNA-derived metric further comprises detecting single nucleotide variants (SNVs) or copy number alterations (CNAs) in the cfDNA.
1, 12. obtaining a urine sample from the subject;
1, 12. extracting cell-free DNA (cfDNA) from the urine sample;
12. providing: a cancer treatment to the subject if the subject is determined to have residual disease, or active surveillance to the subject if the subject is determined to have no residual disease.
18. The method of claim 12, wherein the urinary tract-associated cancer is a bladder cancer, and wherein the cancer treatment comprises a chemotherapy, a radiotherapy, an immunotherapy, or a surgical treatment.
19. The method of claim 18, wherein the surgical treatment is a cystectomy.
20. The method of claim 12, wherein a cancer treatment was administered to the subject prior to obtaining the urine sample.
The steps for obtaining the urine sample and extracting the sample are “mere data gathering,” similar to performing clinical tests on individuals to obtain input for an equation, In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989). The steps for providing treatment in claims 9 and 20 is an attempt to limit the field of use of the invention specifically to cancer treatment, similar to: a step of administering a drug providing 6-thioguanine to patients with an immune-mediated gastrointestinal disorder, because limiting drug administration to this patient population did no more than simply refer to the relevant pre-existing audience of doctors who used thiopurine drugs to treat patients suffering from autoimmune disorders, Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 78, 101 USPQ2d 1961, 1968 (2012). The steps for providing a cancer treatment in claim 12 does not recite a “particular” treatment as there is no indication of the type of drug or treatment that is applied that would have more than a nominal or insignificant relationship to the exception. Rather, these limitations equate to “apply it” steps that merely apply the exception in a generic way and do no integrate the recited exception into a practical application (see MPEP 2106.04(d)(2)). Claims 18 and 19 have embodiments where no treatment is applied, with only surveillance. It is those embodiments that are rejected. As such, claims 1-20 are directed to an abstract idea ( Step 2A, Prong 2 : NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that equate to mere instructions to apply the recited exception in a generic way or in a generic computing environment. The instant claims recite additional elements enumerated above, in the section on step 2A.
Evidentiary reference Wan et al. (Med, Volume 2, Issue 12, 10 December 2021, Pages 1292-1313) provides evidence that the extraction of cell-free DNA (Box 2), and cystectomy before and after treatment (pg 1300 ¶ 3) are well-understood, routine, and conventional. Evidentiary reference Chadhuri et al. (JCO Precision Oncology, 2020) provides evidence that uCAPP-seq, which uses low-coverage NGS to identify cell-free DNA in the urine of bladder cancer patients, is well-understood, routine and conventional (pg 810 right col ¶ 1). The limitation for providing a cancer treatment equates to mere instructions to apply the judicial exception in a generic way because the treating step is so generically recited. MPEP 2106.05(f) discloses that mere instructions to apply the judicial exception cannot provide an inventive concept to the claims. The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself ( Step 2B : No). As such, claims 1-20 are not patent eligible.
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 1-4 and 7-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chauhan et al. (PLOS Medicine, 2021, henceforth “Chauhan”).
Regarding claim 1, Chauhan obtained a urine sample from subjects and extracted cfDNA (pg 1 ¶ 2) using ultra-low-pass (pg 4 ¶ 2) next generation sequencing (pg 1 ¶ 2). Chauhan calculates TMB (pg 9 ¶ 1) and VAF (pg 8 ¶ 2). Chauhan’s method classifies residual disease based on these metrics (pg 2 ¶ 1).
Regarding claim 2, Chauhan’s method uses uCAPP-Seq. (pg 1 ¶ 2).
Regarding claim 3, a regression model is built from the metrics in Chauhan, which is a type of machine learning (pg 19 ¶ 1).
Regarding claim 4, SNV’s were detected in the cfDNA in Chauhan (pg 22 ¶ 3).
Regarding claims 7 and 8, Chauhan’s method is meant for detecting muscle-invasive bladder cancer.
Regarding claim 9, subjects received chemotherapy prior to sampling (pg 1 ¶ 2).
Regarding claim 10, Chauhan’s method has an AUC of 0.78 (fig. 2).
Regarding claim 11, Chauhan’s method predicts progression-free survival (fig. 4).
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, 4, 7, 9, 12, 15, 18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Puranachot (University of Heidelberg Thesis, 2021).
Regarding claim 1, Puranachot teaches extraction of urine samples and cfDNA sequencing using NGS (pg 39 ¶ 2-3). Puranachot teaches using “low-coverage” sequencing which has a coverage of 0.5x-2x (pg 31 ¶ 1). The ultra-low-pass sequencing of the instant application has a coverage of 2x (table 1 footnotes).
Puranachot’s “cfdnakit” package calculates tumor fraction and tumor burden fraction (pg 99 ¶ 4).
Puranachot provides a suggestion that their method could be useful in detecting residual disease (pg 100 ¶ 2).
Regarding claim 4, Puranachot teaches detecting copy number alterations in cfDNA (fig. 30).
Regarding claim 7, Puranachot teaches that their method is applicable to bladder cancer data (pg 28 ¶ 1).
Regarding claim 9, post-chemotherapy urine samples are analyzed in Puranachot (pg 35 ¶ 1).
Regarding claim 12, Puranachot provides a suggestion that their method may help in guiding a medical doctor’s decision to treat with chemotherapy (pg 15 ¶ 1), and also suggests the importance of routine surveillance with cfDNA extraction (pg 24 ¶ 1).
Claims 15, 16, 18 and 20 are restatements of claims 4 and 9 with differing dependencies. The arguments against claims 4 and 9 apply, mutatis mutandis.
Regarding claims 1, 4, 7, 9, 12, 15, 18, and 20, An invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some teaching, suggestion, or motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a suggestion to use the calculated scores for residual disease detection in the text of Puranachot, in order to monitor prognosis (pg 100 ¶ 2). There is also a suggestion that the method can guide a doctor in their decision to treat with chemotherapy or to continue surveillance, in order to better provide help to the patient (pg 15 ¶ 1, pg 24 ¶ 1). There would be a reasonable expectation of success in making this combination to a person of ordinary skill in the art, as the suggestions are made within the text with explanatory detail. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Puranachot by adding treatment decision and residual disease calculation, in order to help the patient’s chances of survival.
Claims 2 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Puranachot as applied to claims 1, 4, 7, 9, 12, 15, 18, and 20 above, and further in view of Dudley et al (Cancer Discov. 2018 Dec 21;9(4):500–509, henceforth “Dudley”).
Regarding claims 2 and 13, uCAPP-Seq is taught by Dudley (abstract).
Regarding claims 2 and 13, An invention would have been prima facie obvious to one of ordinary
skill in the art at the time of the effective filing date of the invention if some teaching, suggestion, or motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a teaching to use uCAPP-Seq in the text of Dudley, because it is specifically adapted for bladder cancer (abstract). There would be a reasonable expectation of success in making this combination to a person of ordinary skill in the art, as Puranachot is a bladder cancer detection method using sequencing methods not specifically adapted for bladder cancer. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Puranachot by using uCAPP-Seq, in order to take advantage of the benefits of a specifically adapted sequencing method (abstract).
Claims 3, 5-6, 10, 14, 16, 17 are rejected under 35 U.S.C. 103 as being unpatentable over Puranachot as applied to claims 1, 4, 7, 9, 12, 15, 18, and 20 above, and further in view of Ganguli et al. (Scientific Reports volume 12, Article number: 2738 (2022), henceforth “Ganguli”).
Regarding claims 5 and 16, Puranachot teaches the specific values (pg 48 ¶ 2, pg 99 ¶ 4). Ganguli combines several features into a single metric (abstract, table 1, 2, 3).
Regarding claim 3 and 14, Ganguli teaches a machine learning model for predicting residual disease (abstract).
Regarding claims 6 and 17, Ganguli uses a random forest model (abstract), and tumor invasion status is used as a clinical variable (table 1, 2, 3).
Regarding claim 10, Ganguli’s model has an AUC of 0.90 (abstract).
Regarding claims 3, 5-6, 10, 14, 16, 17, An invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some teaching, suggestion, or motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a teaching to use machine learning for residual disease detection in the text of Ganguli. There would be a reasonable expectation of success in making this combination to a person of ordinary skill in the art, as Puranachot suggests using their features for residual disease detection (pg 100 ¶ 2). Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Puranachot by using machine learning model, in order to detect residual disease more accurately (Puranachot pg 100 ¶ 2) (Ganguli abstract).
Claims 8, 11, 19 are rejected under 35 U.S.C. 103 as being unpatentable over Puranachot as applied to claims 1, 4, 7, 9, 12, 15, 18, and 20 above, and further in view of Chung et al. (THE JOURNAL OF UROLOGY® Vol. 206, No. 3S, Supplement, Sunday, September 12, 2021, henceforth “Chung”).
Regarding claim 8, Chung uses data from muscle-invasive bladder cancer (introduction).
Regarding claim 11, Chung teaches predicting overall survival based on therapy type (methods).
Regarding claim 19, Chung teaches cystectomy as a bladder cancer treatment (introduction).
Regarding claims 8, 11, and 19, An invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some teaching, suggestion, or motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a teaching to use survival analysis in the text of Chung. There would be a reasonable expectation of success in making this combination to a person of ordinary skill in the art, as both are adapted to urinary cancer monitoring. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Puranachot by adding the survival analysis of Chung, in order to better identify cancer prognosis (abstract).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GRACELYN M HILL whose telephone number is (571)272-9871. The examiner can normally be reached Monday-Friday 8:30-5pm.
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/G.M.H./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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