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 application is a 371 of PCT/US2022/025344 filed 04/19/2022 and claims benefit of 63/176562 filed 04/19/2021.
Information Disclosure Statement
The five (5) information disclosure statements (IDS) submitted on 9/04/2025 and 10/18/2023 are acknowledged. Two of the submitted IDS forms are duplicates and the references cited have been lined through. The submission of the remaining three (3) are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See page 9, for example. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Correction is required.
Status of Claims
Claims 5-7, 14, 17, 21-22, 27-29, 34-38 and 43-45 have been canceled. Claims 1-4, 8-13, 18-20, 23-26, 30-33 39-42 and 46 are currently pending. No claims have been withdrawn from consideration.
35 USC 112b
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 1-4, 8-13, 18-20, 23-26, 30-33 39-42 and 46 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, 10, 11, 12, 30, and 39 incorporate limitations from Table2 into the listed claims. A review of the specification indicates Table 2 does not exist, however, Tables 2A and Table 2B are disclosed. Since the claims references Table 2 which is not found in the specification, these claims are indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention two distinct reasons.
Regarding reference to limitations not recited in the claims, such as references to a table, are addressed in MPEP 2173.05(s) which states that where possible the claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). In the instant case, even though the table are large, Table 2A, beginning at page 13 of the specification and consists of a list of signature labels ending at page 36, and Table 2B. comprises mutational signatures related to disease-specific survival and extends from page 37 through page 63, size is not a relevant consideration to allow references to date what is needed in the claims. Accordingly, all claims must still comply with 2173.05(s).
Claims 1-4, 8-13, 18-20, 23-26, 30-33 39-42 and 46 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.
The term “relative to a corresponding sample” in claims 1, 2 and 30 is a relative term which renders the claim indefinite. The term “relative to a corresponding sample” 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. In its full context in claim 1, the claim refers to a sample from a tumor that comprises one or more signatures from a table, these signatures are correlated with a specific disease. A corresponding sample that does not have the tumor signature is considered relative to the one that has the signature. It is not clear how the person of skill can make such as comparison? If the sample has one or more mutational markers what is considered the corresponding sample that does not have the markers? Are they taken from the same sample, or from a different sample, from the same person or another person? If taken from a mutational database it would seem that samples that did not have the mutational signatures would not be included. Correlation, does not mean causation, just as lack of a correlation does not mean a lack of causation. Even if the mutational markers are not present in a sample, in the absence of evidence of causation, their absence is, and cannot be correlated, to diseases-specific survival in the relative terms used. The presence of a mutational marker is an absolute, it is either there or not there. Just as the absence of the mutational marker is also an absolute. Accordingly, the claims fail to particularly point out and distinctly claim the subject matter which the inventor or joint inventor regard as the invention.
35 USC 112a
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.
The specification discloses that mutations signatures, such as SBS and DBS act as finger prints of DNA damage and have been associated with cancer incidence and influence disease specific survival (DSS). Data from The Cancer Genome Atlas was utilized in which eligible cancers with at least 50 disease specific survival events were in the database. The results indicate that, for example in solid tumors, 14 organ sites, constituting 16 distinct pathological entities or cancer types, and 6790 patients were included in the in-depth analysis, as these had at least 50DSS events.
Regarding claims 18 and 19, wherein the presence of one or more mutational signatures is indicative of increased survival lack an adequate written description. The specification has 6 recitations of “increased survival” but none of these citations clearly indicate what is encompassed by this limitation. Each citation states: “In one embodiment, the presence of the one or more mutational signatures is indicative of increased survival. In one embodiment, the presence of the one or more mutational signatures is indicative of decreased survival.” In regard to increased survival, at page 74 of the specification, the applicant cites (Gryfe et al. 2000), wherein it is possibly due to enhanced a response to therapy (Sinicrope et al., 2011) noting that a lack of MMR and concomitant reduced DNA repair may lead to increased cancer cell death in chemotherapy treatment, facilitating increased survival. Mismatch repair deficiencies also favor improved survival in immune checkpoints. However, nowhere in the specification is a specific correlation to increased survival and specific SBS mutations recited. Accordingly, applicants have not demonstrated a possession of the claimed invention and as such the specification lack an adequate written description.
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 1-4, 8-13, 18-20, 23-26, 30-33 39-42 and 46, are rejected under 35 U.S.C. §101 as being directed to patent-ineligible subject matter.
The claims are directed to a method for detecting the presence of one or more mutational signatures in a tumor sample and associating the presence or absence of such signatures with disease-specific survival or other clinical outcomes in a cancer patient. Under the two-step framework set forth in Mayo Collaborative Services v. Prometheus Labs, Inc., 566 U.S. 66 (2012), the claims are analyzed as follows:
Step 1: Judicial Exception
The claims are directed to a law of nature and/or natural phenomenon. The mutational signatures recited are naturally occurring DNA patterns present in tumor samples. The association between such signatures and clinical outcomes (e.g., survival) is a correlation that exists in nature, independent of human intervention.
Step 2: Inventive Concept
The claims do not recite additional elements that amount to significantly more than the judicial exception. The steps of “detecting” mutational signatures using standard sequencing, amplification, or probe-based methods, and “determining” or “associating” the presence of such signatures with clinical outcomes, are routine and conventional in the field of molecular diagnostics and oncology. The claims do not require a specific, concrete application (e.g., a particular treatment step, or a novel technical procedure) that transforms the natural phenomenon into a patent-eligible process. Instead, the claims merely instruct practitioners to observe a natural correlation and think about its implications, which is insufficient under §101.
Accordingly, the claims are directed to patent-ineligible subject matter under 35 U.S.C. §101 because they are drawn to a law of nature or natural phenomenon, and do not include additional elements that amount to significantly more than the judicial exception. To overcome this rejection, applicant may: Amend the claims to recite a specific, practical application of the detected signatures to particular diseases (e.g., administering a particular therapy based on the detection). Add novel technical steps or limitations that are not routine or conventional in the field or claim a specific, non-natural composition (e.g., a kit or probe with defined novel sequences).
In responding to this rejection applicant are advised that any addition or deletion to the claims must have clear antecedent basis so as to avoid a rejection based on new matter.
Prior art
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, 8–13, 18–20, 23–26, 30–33, 39–42, and 46 are rejected under 35 U.S.C. §103 as being unpatentable over Venn (WO 2018/085862) in view of Alexandrov et al. (Nature, 2013; Nature, 2020), Gryfe et al. (NEJM, 2000) (IDS), and Weinstein et al. (TCGA, 2013) (IDS).
Venn (WO 2018/085862) teaches a computer-implemented method for detecting the presence of a cancer in a patient comprising receiving data comprises a plurality of sequence reads obtained by sequencing a plurality of nucleic acids in a biological test sample from the patient, identify one or more somatic mutations in the biological test sample and generate a somatic mutational profile that comprises the one or more somatic mutations wherein the somatic mutations are identified by aligning the plurality of sequence reads to a reference genome. Venn then deconvolute the somatic mutational profile into one or more mutational signatures which serve to distinguish the mutational signatures from the non-mutational signatures. Thus, the method of Venn correlates the presence of cancer in the patient based on one or more mutational signatures relative to their absence. Venn does not teach the specific somatic mutations claimed, however, these mutations were well known in the art.
Alexandrov et al. (Nature 2020 and Nature 2013) teach the identification of single base substitution (SBS) mutational signatures and identify 84,729,690 somatic mutations in cancer using DNA sequencing and computational analysis. Specific cancer signatures are listed in Table 2 (Nature 2020), comprising multiple occurrences of signatures: SBS1 through SBS6, SBS7a-d, SBS8-SB9, SB10a-b, SBS11-SBS16, SBS17a-SBS17b, SBS18-SBS26, SBS28-SBS42, SBS44, and SBS84-SBS85. See Fig. 1 @p96. Also identified as SBS signatures that are correlated to specific cancers, for example, SBS4 is known to be associate with tobacco mutagens, SBS7s UV light, SBS24 aflatoxins. Regarding claims 2, 4-10 and 23, Alexandrov et al. (Nature 2013, supplementary Table 3) complied 4,938,363 somatic substitutions and indels from 7,042 primary cancers of 30 different classes which encompass cancers comprising stages I- IV, comprising mutational signature. Alexandrov et al. (2013 Methods) discusses methodology at filtering, estimating mutation prevalence and generating mutational catalogues by using normal DNA from the same individuals had been sequenced to establish the somatic origin of variants. Extensive filtering was performed to remove any residual germline mutations and technology-specific sequencing artefacts before analyzing the data.
Gryfe et al. teaches the association of specific mutational signatures to colorectal cancer, such as DNA repair deficiency, with clinical outcomes including disease-specific survival in cancer patients. They conclude that because most cancers are believed to arise from the accumulation of genetic alterations, through instabilities in microsatellites or chromosome, that cancers arising from different mutations differ clinically. In this study, survival advantage was observed to correlate with specific instabilities. Regarding claims 8-9, Gryfe et al. teach the method is useful to detect cancers in stages 1 though IV (table 1@ p72.) Regarding claims and 30- 33, drawn to `mutational signatures correlated with disease specific survival, and 39-42, drawn to the treatment of cancers by administering anti-cancer therapy and claims 24-26, drawn to one or more mutational signatures indicative to the response to therapy, teach a comparison of adjuvant therapy, chemotherapy and radiation therapy are useful in treating cancers correlating to genetic instabilities. Regarding claim 46, Gryfe et al., teach the detection of specific dinucleotide and mononucleotide aberrations detected via primer selection in PCR and gel electrophoresis. Similarly, Weinstein et al. (TCGA) teach methodology for detecting mutational signatures in tumor samples using conventional sequencing, amplification, or probe-based techniques.
It would have been obvious to a person of ordinary skill in the art at the time of the invention, in light of Venn teaches as seen further in view of Alexandrov et al. (2013 & 2020), Gryfe et al., and Weinstein et al. to combine the known detection of mutational signatures in tumor samples with the known correlation of those signatures to disease-specific survival, using routine sequencing methods as taught by Gryfe et al. and Weinstein et al. to arrive at the claimed invention. The motivation to combine these teachings arises from the desire to improve cancer prognosis and personalize treatment, as suggested in the prior art.
No claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Gary Benzion whose telephone number is (571)272-0782. The examiner can normally be reached M-F, 7 am to 4pm.
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/GARY BENZION, Ph.D./ Supervisory Patent Examiner, Art Unit 1681