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 .
Claim Status
Claims 1, 4 - 7, 9 - 11, 13 – 14, and 16 - 25 are pending.
Claims 1, 4 - 7, 9 - 11, 13 – 14, and 16 - 25 were considered.
Claims 1, 4 - 7, 9 - 11, 13 – 14, and 16 - 25 are rejected.
Claim 17 is objected to.
Priority
The instant application filed on 22 September 2023 claims priority to a PCT filed 21 March 2022 and foreign application GB 2104308.8 filed 26 March 2021. As such, claims 1, 4 - 7, 9 - 11, 13 – 14, and 16 - 25 have an effective filing date of 26 March 2021.
Information Disclosure Statement
The IDSs filed 22 September 2023 and 3 July 2024 were considered by the examiner.
Drawings
The drawings filed 22 September 2023 are accepted.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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.
The instant application contains the following hyperlinks in the specification:
Page 10: https://www.ncbi.nlm.nih.gov/snp/ and https://www.internationalgenome.org/
Page 11: https://signal.mutationalsignatures.com/explore/study/1
Page 12: https://signal.mutationalsignatures.com/explore/referenceCancerSignature/52, https://signal.mutationalsignatures.com/explore/referenceCancerSignature/56, and https://signal.mutationalsignatures.com/explore/study/1
Page 21: https://signal.mutationalsignatures.com/explore/cancer/consensusSubstitutionSignatures/6
Page 26: https://gatk.broadinstitute.org/hc/en-us/articles/360037225632-HaplotypeCaller
Page 30: https://signal.mutationalsignatures.com/explore/study/1 and https://cancer.sanger.ac.uk/cosmic/signatures/
Page 42: http://cancerit.github.io/CaVEMan/, http://cancerit.github.io/cgpPindel, and https://github.com/cancerit/BRASS
Page 73: https://www.encodeproject.org/
The attempt to incorporate essential subject matter into this application by reference to an NPL and/or website is ineffective because essential material may only be incorporated by reference to a U.S. patent or U.S. patent application publication. See MPEP § 608.01.
The specification, in pages 11-12, defines RefSig MMR1 and RefSig MR2 based on references to non-patent literature and websites. These mutational signatures are essential material as they are part of claim 24. As essential material, they may not be incorporated by reference to non-patent literature or websites.
The incorporation by reference will not be effective until correction is made to comply with 37 CFR 1.57(c), (d), or (e). If the incorporated material is relied upon to meet any outstanding objection, rejection, or other requirement imposed by the Office, the correction must be made within any time period set by the Office for responding to the objection, rejection, or other requirement for the incorporation to be effective. Compliance will not be held in abeyance with respect to responding to the objection, rejection, or other requirement for the incorporation to be effective. In no case may the correction be made later than the close of prosecution as defined in 37 CFR 1.114(b), or abandonment of the application, whichever occurs earlier.
Any correction inserting material by amendment that was previously incorporated by reference must be accompanied by a statement that the material being inserted is the material incorporated by reference and the amendment contains no new matter. 37 CFR 1.57(g).
Claim Objections
Claim 17 is objected to because of the following informalities:
The first limitation of the claim states: “determining the value of the similarity between a substitution or repeat mediated deletion profile of the sample and that of one or more MMR gene knockouts comprises determine the cosine similarity between pairs of profiles.” [Emphasis added.] The word “determine” here is a misspelling and should be replaced with “determining”.
Appropriate correction is required.
Claim Interpretation
Cloaim 23 includes a limitation for a “computer readable medium.” The specification states “there is provided a non-transitory computer readable medium or media” [page 18, lines 26-29] and “the term "computer readable media" includes, without limitation, any non-transitory medium or media which can be read and accessed directly by a computer or computer system” [page 27, lines 18-19]. For purposes of examination, the claimed computer readable medium is defined as a non-transitory computer readable medium.
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.
Claim 24 is 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 24 includes specific mutational signatures that are defined in the specification (pages 11-12) based on references to non-patent literature and websites. Essential material may not be incorporated by reference to non-patent literature and websites. Without appropriate definitions of these mutational signatures, the claim lacks sufficient written description to determine the limitations set forth in the claim.
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, 6, 11, 14, 16, 19, 20, 21, 22, 23, 24, and claims 4-7, 9-11, 13-14, 16-20, 22, and 24-25 due to their dependency on claim 1, 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance,
Claims 1, 21, and 23, and claims 4-7, 9-11, 13-14, 16-20, 22, and 24-25 due to their dependency on claim 1, recite the broad recitation “determining the value of one or more mutational signature metrics for the sample by analysing sequence data associated with the sample”, and the claim also recites “wherein the at least two mutational signature metrics include” which is the narrower statement of the range/limitation.
Claim 6, in the limitations of claim 1, recites the broad recitation “determining the value of one or more mutational signature metrics for the sample by analysing sequence data associated with the sample” and further recites the broad limitation “comprises using said values of said one or more mutational signature metrics to classify said sample”, and the claim also recites, in the limitations of claim 1, “wherein the at least two mutational signature metrics include” which is the narrower statement of the range/limitation.
Claim 11 recites the broad recitation “the exposure of one or more mutational signatures of mismatch repair (MMR) has higher weight than any of”, and the claim also recites “the exposure of one or more mutational signatures of mismatch repair (MMR) and the similarity between the substitution profile of the sample and that of one or more MMR gene knockouts both have higher respective weight than any of” which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 1, 21, and 23, and claims 4-7, 9-11, 13-14, 16-20, 22, and 24-25 due to their dependency on claim 1, recite the limitation "where in the at least two mutational signature metrics" in line 17 of claim 1, line 18 of claim 21, and line 19 of claim 23. There is insufficient antecedent basis for this limitation in these claim as the claims earlier indicate “determining the value of one or more mutational signature metrics”.
Regarding claims 14 and 19, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 16 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The claim is missing limitations following the last use of the phrase “and/or”, and as such the claim is indefinite because it is unclear if the missing statement is essential.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: how to perform the step of “determining that the subject is likely to respond to immunotherapy”. The limitations of the claim are indefinite without language explaining how to determine if a subject is likely to respond to immunotherapy.
Claim 22 recites the limitation "based on said values of said one or more mutational signature metrics" in lines 12-13 of the claim. There is insufficient antecedent basis for this limitation in the claim as lines 3 and 9 reference a minimum of two mutational signature metrics.
Claim 24 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: the sequences of the referenced mutational signatures RefSig MMR1 and RefSig MMR2. The exact sequences are essential for determining the limitations of the claim.
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, 4 - 7, 9 - 11, 13 – 14, and 16 - 25 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to abstract ideas without significantly more.
Step 2A, Prong 1
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 abstract ideas:
Claim 1 and dependent claims 4-7, 9-11, 13-14, 16-20, 22, and 24-25, claim 21, and claim 23 recite:
Determining the value of signature metrics for a DNA sample
Determining exposure of mutational signatures of mismatch repair
Determining similarity between substitution profiles of sample and MMR gene knockouts
Determining number of repeat mediated indels in the mutational profile
Determining the similarity between repeat mediated deletions and MMR gene knockouts
Determining likelihood of sample being MMR-deficient
Claim 6 recites:
Classifying samples as either high or low likelihood of being MMR-deficient
Claim 7 and dependent claim 9 recite:
Generating a probabilistic score
Determining likelihood of being MMR-deficient based on the probabilistic score
Claim 9 recites:
Determining the probabilistic score using a linear regression model
Claim 10 recites:
Scaling metrics
Claim 11 recites:
Weighting metrics
Claim 13 recites:
Using a machine learning model
Claim 14 recites:
Cataloguing mutations
Claim 16 recites:
Determining values by summing or matrix
Claim 17 recites:
Determining cosine similarity
Claim 19 recites:
Obtaining sequence data
Claim 20 recites:
Determining subject is likely to respond to immunotherapy
Recommending treatment
Claim 21 recites:
Obtaining mutational signature profiles
Claim 22 recites:
Training a machine learning model
The limitations for the listed claims are evaluations or judgements that can be made through mental observations or mathematical calculations which fall under the “mental processes” and “mathematical concepts” groupings of abstract ideas. Under the broadest reasonable interpretation, the abstract ideas recited in the claims are determined to cover performance either in the mind (calculations by hand or pen and paper) or by mathematical operation (calculations/algorithms). See MPEP § 2106.04(a)(2), subsection III. The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation (see, e.g., Benson, 409 U.S. at 67, 65, 175 USPQ at 674-75, 674: noting that the claimed "conversion of [binary-coded decimal] numerals to pure binary numerals can be done mentally," i.e., "as a person would do it by head and hand."); Synopsys, Inc. V. Mentor Graphics Corp., 839 F.3d 1138, 1139, 120 USPQ2d 1473, 1474 (Fed. Cir. 2016): holding that claims to a mental process of "translating a functional description of a logic circuit into a hardware component description of the logic circuit" are directed to an abstract idea, because the claims "read on an individual performing the claimed steps mentally or with pencil and paper"). Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer. As the Federal Circuit has explained, "[c]ourts have examined claims that required the use of a computer and still found that the underlying, patent-ineligible invention could be performed via pen and paper or in a person's mind" (see Versata Dev. Group V. SAP Am., Inc., 793 F.3d 1306, 1335, 115 USPQ2d 1681, 1702 (Fed. Cir. 2015); Mortgage Grader, Inc. v. First Choice Loan Servs. Inc., 811 F.3d 1314, 1324, 117 USPQ2d 1693, 1699 (Fed. Cir. 2016): holding that computer-implemented method for "anonymous loan shopping" was an abstract idea because it could be "performed by
humans without a computer").
While claims 1, 21, and 23, claims 4-7, 9-11, 13-14, 16-20, 22, and 24-25 due to their dependency on claim 1, recite performing aspects of the methods with a “processor”, and/or “non-transitory computer readable medium”, there are no additional limitations that indicate that the processor or non-transitory computer readable medium would require anything other than carrying out the recited mental process or mathematical concept in a generic computer environment. Merely reciting that a mental process is being performed in a generic computer environment does not preclude the steps from being performed practically in the human mind or with pen and paper as claimed. If a claim limitation, under its broadest reasonable interpretation, covers performance of the limitation in the mind but for the recitation on generic computer components, then it falls into the “mental processes” grouping of abstract ideas. As such, claims 1, 4 - 7, 9 - 11, 13 – 14, and 16 - 25 recite abstract ideas (Step 2A, Prong 1: YES).
Step 2A, Prong 2
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 in some other
meaningful way. Rather, the instant claims recite additional elements that amount to mere
instructions to implement the abstract idea or insignificant extra-solution activity. Specifically,
the claims recite the following additional elements:
Claim 1, dependent claims 4-7, 9-11, 13-14, 16-20, 22, and 24-25 recite:
A processor
Claim 21 recites:
A processor
Administering an immunotherapy to a subject
Claim 23 recites:
A processor
A non-transitory computer readable medium
The limitations for defining terms describe mental processes with additional elements. This judicial exception is not integrated into a practical application because these additional
elements do not add any meaningful limitations. Although claim 21 includes the limitation of administering an immunotherapy, this limitation is conditional on the characteristics of the sample. As a result, this limitation will only apply when certain other limitations of the claim are met. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they only describe more specificity to the types of variables. As such, these limitations equate to mere instructions to implement the abstract ideas.
There are no limitations that indicate that the processor or non-transitory computer readable medium would require anything other than a generic computing system. As such, these limitations equate to mere instructions to implement the abstract ideas on a generic computer that the courts have stated do not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984.
The above recited additional elements do not provide a practical application of the recited
judicial exception. As such, claims 1, 4 - 7, 9 - 11, 13 – 14, and 16 - 25 are directed to an abstract idea (Step 2A, Prong 2:NO).
Step 2B
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 are known and commonly used techniques in the art and are mere instructions to apply the recited exception in a generic computing environment.
As discussed above, there are no additional limitations to indicate that the claimed
method requires more than routine use of technology. Additionally, there are no additional limitations to indicate that the program requires anything other than generic computer components in order to carry out the recited abstract ideas in the claims. Claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. In addition, mere display of collected and analyzed information that could be performed by the human mind do not render an abstract idea eligible. See Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016)
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, 4 - 7, 9 - 11, 13 – 14, and 16 - 25 are not patent eligible.
Claim Rejections - 35 USC § 102
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 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, 5, 6, 13, 16, 17, 18, 19, 22, 23, 24, and 25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zou, et al. (bioRxiv, 6 August 2020, pages 1-30, S1-S20, and Table S7) (Herein referred to as Zou.)
With respect to claims 1, 4, 5, 19, and 23, and claims 6, 13, 16-18, 22, and 24-25 due to their dependency on claim 1, Zou teaches using tumor samples and a decision tree classifier with parameters including the exposure of MMR-deficient substitution signatures, the similarity between repeat-mediated insertion profile of the tumor and that of MMR knockouts, and the similarity between repeat-mediated deletion profile of the tumor and that of MMR knockouts. (Page 9, paragraph 2). Zou further teaches using the number of repeat mediated indels as one of the mutational signature metrics, as listed in Table S7 (“Calculated Input Parameters for MMRDetect”) in column 6 (“RepIndel_num”). (bioRxiv Supplementary material, Table S7, first row) Zou additionally teaches a classifier for clinical detection of MMR-deficient tumors. (Page 1, Abstract)
With respect to claim 6, Zou teaches classifying samples as positive or negative (high or low likelihood) regarding MMR deficiency classification. (Page 25, line 11 and page 15, Figure 4E)
With respect to claim 13, Zou teaches a decision tree framework. (Page 24, last paragraph) The instant application lists a decision tree as an example of a machine learning model. [0013, page 5] Zou further teaches a training data set for the classifier. (Page 9, paragraph 2)
With respect to claim 16, Zou teaches that the sum of exposures of MMR1 and MMR2 was used as a feature in MMRDetect. (Page 25, lines 3-4) MMR1 and MMR2 refer to RefSig MMR1 and RefSig MMR2, respectively, which are described as mutational signatures. (Page 8, last paragraph) Additionally, the instant application also states that RefSig MMR1 is also referred to as “MMR1” and RefSig MMR2 is also referred to as MMR2. [0028, page 11]
With respect to claim 17, Zou teaches calculating cosine similarities between repeat-mediated indels profiles of cancer samples and MMR knockout indel signatures for insertion and deletion, respectively. (Page 25, paragraph 3) Zou further teaches summarized similarity values from a plurality of similarity values in Figures 1C, 1D, and 1E. (Page 11)
With respect to claim 18, Zou teaches characteristics of indel sequences, including repetitive sequences of <5 bp, ≥5 bp, and >1 bp. (Page 22, last paragraph)
With respect to claim 22, Zou teaches using 2,610 published WGS primary cancers that had ≥200 substitutions and ≥100 indels per tumor and the samples were randomly assigned into a training set or a test set. (Page 9, paragraph 2 and page 15, Figure 4C)
With respect to claim 24, Zou teaches using RefSig MMR1 and RefSig MMR2 as disclosed above and in Figure 4B. (Page 15-16)
With respect to claim 25, Zou teaches knockouts of five genes involved in the mismatch repair (MMR) pathway, MSH2, MSH6, MLH1, PMS2, and PMS1, produced substitution and indel signatures. (Page 6, paragraph 2)
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 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 7, 9, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Zou in view of Huang et al. (Scientific Reports, 26 August 2015, pages 1-10) (Herein referred to as Huang.)
Zou teaches the limitations of claim 1 as applied above under 35 U.S.C. 102.
Zou does not teach a probabilistic score obtained using a linear regression model.
With respect to claims 7 and 9, Huang teaches determining a probabilistic score using a logistic regression model. (Page 4, Table 1 and paragraphs 3 and 4)
With respect to claim 14, Huang teaches a catalog of somatic single-nucleotide-substitution and microindels. (Page 3, last paragraph) Huang further teaches considering these types of mutations separately and describes types of repeat sequences included. (Page 4, paragraphs 1-2) Huang teaches using mononucleotides of length ≥5 and microsatellites consisting of di-, tri-, and tetranucleotide repeats. (Page 4, paragraph 1)
It would have been prima facie obvious to one of ordinary skill in the art at the effective
filing date of the invention to have combined the methods of Zou and Huang to determine the likelihood of a sequence being MMR-deficient. Huang discloses using four machine learning frameworks (including logistic regression) to validate their MSIseq model. (Page 4, paragraph 3) Huang also discloses that MMR deficiency leads to notably high microindel rates in simple repeats and these high rates that gave rise to the term microsatellite instability. (Page 4, lines 2-3) Huang further states an in-silico MSI-status classifier (MSIseq) that operates on somatic mutation data extracted from NGS of whole exomes or subsets of the exome that has high concordance with laboratory tests. (Page 8, last paragraph) Additionally, Huang states that the high concordance of multiple machine-learning frameworks indicate that catalogs of somatic mutations from whole-exome NGS contain sufficient information for assessing MSI status, and by extension, underlying deficiencies in MMR. (Page 8, last paragraph) Zou discloses trained an MSI classifier based on mutational signatures (MMRDetect) using the same decision tree framework that previously utilized by MSIseq. (Page 24, last paragraph) Therefore, one of ordinary skill in the art would have been motivated to utilize all the features of the methods of Huang when developing the methods of Zou. The invention is therefore prima facie obvious.
Claims 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Zou in view of Nik-Zainal, et al. (WO 2017/191076 A1, 9 November 2017) (Herein referred to as Nik-Zainal.)
Zou teaches the limitations of claim 1 as applied above under 35 U.S.C. 102.
Zou does not teach scaling the value of each mutational signature metric.
With respect to claim 10, Nik-Zainal teaches scaled mutational signature metrics. [Claim 8]
With respect to claim 11, Nik-Zainal teaches generating a probabilistic score using a predetermined weighting factor that represents the likelihood of the signature profile associated with that value causing the tumor to be HR deficient. (Page 9, lines 28-32) Nik-Zainal further teaches that the probabilistic score is a weighted score which gives weight to factors based on mutational signature metrics and these factors are weighted in an order of precedence (greatest first). (Page 9, lines 4-16) Nik-Zainal additionally teaches that these metrics are used in determining whether a sample has a high or low likelihood of being homologous recombination (HR) -deficient. (Page 8, lines 6-18) Zou teaches that MSI (microsatellite instability) samples had increased exposures of MMR1 and MMR2 signatures and these samples were further examined based on cosine similarities between repeat-mediated indels profiles of cancer samples and MMR knockout indel signatures for insertion and deletion. (Page 25, paragraph 3) Zou further teaches that the cosine similarities between repeat-mediated insertions and MMR knockouts was higher than the cosine similarity between repeat-mediated deletions and MMR knockouts. (Page 25, paragraph 3)
It would have been prima facie obvious to one of ordinary skill in the art at the effective
filing date of the invention to have combined the methods of Zou and Nik-Zainal to determine the likelihood of a sequence being MMR-deficient. Nik-Zainal discloses that scaling mutational signature metrics assists in determining the contributions of known mutational signatures to said mutational catalogue. [Claim 8] Nik-Zainal further discloses that extensive study of WGS from breast cancers determined the most influential factors and their order of importance for influencing whether a tumour is HR- deficient or not. (Page 9, lines 7-10 and 15-16) Nik-Zainal teaches a method that can identify the presence of mis-match repair (MMR) deficiency in the sample by using the presence or absence of base substitution signatures and indel signatures. [Claim 6] Zou discloses certain indel signatures are a characteristic feature of MMR-deficient cells known as microsatellite instability (MSI). (Page 7, paragraph 3) Therefore, one of ordinary skill in the art would have been motivated to combine the methods of Zou and Nik-Zainal when determining the likelihood of a sample being MMR-deficient. It would have been obvious to utilize the scaling and weighting methods of Nik-Zainal on the mutational signature metrics defined by Zou when assessing if a sample is MMR-deficient. The invention is therefore prima facie obvious.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Zou in view of Davies et al. (Cancer Research, 15 September 2017, pages 4755-4762) (Herein referred to as Davies.)
Zou teaches the limitations of claim 1 as applied above under 35 U.S.C. 102.
Zou does not teach determining if the subject is likely to respond to immunotherapy.
Davies teaches that mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies. (Page 4755, Abstract)
It would have been prima facie obvious to one of ordinary skill in the art at the effective
filing date of the invention to have combined the observations of Davies with the method of Zou.
Davies teaches that because mutational signatures are a direct pathophysiologic readout of MMR pathway abrogation, they confer a higher degree of sensitivity and specificity for tumor classification and could possibly out-perform current biomarkers of MMR deficiency. (Page 4761, left column, first paragraph) Therefore, one of ordinary skill in the art would have been motivated to add the known responsiveness of MMR-deficient cancers to immunotherapy with the method of identifying MMR-deficient tumor samples in order to develop potential treatment recommendations. The invention is therefore prima facie obvious.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Zou in view of Westdorp et al. (Cancer Letters, 10 September 2017, pages 159-164) (Herein referred to as Westdorp.)
Zou teaches the limitations of claim 1 as applied above under 35 U.S.C. 102.
Zou does not teach administering an immunotherapy when a sample is determined to have a high likelihood of being MMR-deficient.
Westdorp teaches growing evidence on the clinical efficacy of immunotherapies for treatment of patients with CMMRD (constitutional mismatch repair deficiency) and combining neoantigen-based vaccination strategies and immune checkpoint inhibitors could be an effective way to conquer CMMRD-related tumors. (Page 159, Abstract)
It would have been prima facie obvious to one of ordinary skill in the art at the effective
filing date of the invention to have combined the methods of Zou and Westdorp. Westdorp discloses that MMR deficient cells are profoundly resistant to alkylating antineoplastic agents, such as temozolomide, cisplatin or busulfan and this is of clinical importance in patients with CMMRD, since it has become clear that these agents are less effective in MMR-deficient tumors and even may provide a growth advantage for the tumor cells. (Page 161, left column, last paragraph) Westdorp further discloses that data strongly suggest that treatment with immune checkpoint blockade can be very attractive for MMR deficient tumors independent of the underlying tumor type and immunotherapy with checkpoint inhibitors could hold the key to an effective cancer treatment and prevention strategy of CMMRD syndrome. (Page 162, left column, top paragraph) Therefore, one of ordinary skill in the art would have been motivated to incorporate the known MMR-deficient cancers treatments with the method of identifying MMR-deficient tumor samples in order to develop treatment options. The invention is therefore prima facie obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHARON LEVINE GRAFF whose telephone number is (571)317-0219. The examiner can normally be reached Mon - Fri 7:30 AM - 4 PM.
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, Karlheinz Skowronek can be reached at (571) 272-9047. 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.
/S.L.G./Examiner, Art Unit 1687
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687
