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 .
Status of the Claims
Claims 1-17 are pending and examined herein.
No claims are canceled.
Priority
As detailed on the 02 February 2023 filing receipt, the application claims priority as early as 07 September 2019 to CN 202010932026.5 and PCT CN 2020/140801. At this point in examination, all claims have been interpreted as being accorded this priority date as the effective filing date.
Information Disclosure Statement
An information disclosure statement (IDS) was filed on 29 December 2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the references are being considered by the examiner.
Drawings
The drawings are objected to because Figures 1-2 are blurry to the point of illegibility. Corrected drawing sheets in compliance with 37 CFR 1.121(d) 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. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. 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.
Specification
The disclosure is objected to “PARPi” is misspelled as “PRAPi” (pg. 2, line 12).
Appropriate correction is required.
Claim Objections
Claim 16-17 are objected to because of the following informality: “continuous variables comprises” should read “continuous variables comprise” for subject-verb agreement (claim 16) and “GSS score” is redundant as the second S in “GSS” stands for score (claim 17). Appropriate correction is required.
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 1-17 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). The claims as a whole, considering all claim elements individually and in combination, are directed to a judicial exception at Step 2A, Prong 2, and the additional elements of the claims, considered individually and in combination, do not provide significantly more at Step 2B than the abstract idea of constructing a genomic scar model.
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of
nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The claims are directed to a method (claims 1-17), which falls within one of the categories of statutory subject matter. [Step 1: Yes]
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
Mathematical concepts recited in claim 1 include training to obtain weights through a machine learning method then totalizing weights to obtain a model. The machine learning model is not particularly recited, and interpreted given its broadest reasonable interpretation in light of the specification, which discloses training may be performed using a logistic regression (pg. 5, line 15) and so reads on mathematical calculations to determine weights. Totalizing, interpreted as adding or summing, to calculate a score is also considered a mathematical concept. Substituting test values into the model to determine a score is using the mathematical concept determined in the training steps.
Mental processes recited in claim 1 include: analyzing copy number variation, where analyzing is broadly recited and reads on data evaluation or interpretation; determining BRCAness positive and negative events, which is also interpreted as data evaluation or interpretation; and verifying the model based on the score, where verification is interpreted as data evaluation or judgment.
Claim 2-5 and 8-9 recite further information about analyzing and evaluating BRCAness events and so directed to a mental process.
Claim 6-7 recite dividing CNV lengths, which is interpreted as a data organization step and thus a mental process.
Claim 10 recites training using different parameters and thus also directed to mathematical concepts.
Claims 11-13 recite outcomes of the model, and thus is directed to the data being input and output and thus also an abstract idea.
Claim 14 recites analyzing, calculating the CNV, joining regions, and determining types and quantities of CNV. These steps are interpreted as data analysis steps on the data generating from the sequencing and thus mental processes.
Claim 16 recites details of the construction of CNV segments in the data and thus a data organization step, which is an abstract mental process.
Claim 17 recites interpretation of the scores calculated by the model and thus is a mental process of data evaluation or judgment.
Thus, the claims do not recite elements in addition to the abstract ideas which integrate the judicial exception into a practical application and so the claims are interpreted as directed to one or more judicial exceptions. [Step 2A Prong One: Yes]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Because the claims recite judicial exceptions, direction under Step 2A Prong Two provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d)(III)).
Claim 1 recites additional elements that are not abstract ideas: collecting known BRCAness positive and negative samples and collecting additional samples.
Claims 14-15 recite sequencing the training set where the sequencing is performed on a whole genome, whole exome, target capture sequencing, or a chip of CNV.
The steps of collecting samples and sequencing them are steps directed to generating data to perform the machine learning steps and scar model and thus data gathering steps. Data gathering is interpreted as insignificant extra-solution activity, which does not integrate the abstract idea(s) into a practical application. MPEP 2106.05(g) pertains. [Step 2A Prong Two: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
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 of 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05). The claims recite data gathering steps including collecting samples and sequencing. Lord (Nature Reviews Cancer 16: 110-120, 2016; newly cited) teaches, in a review regarding BRCAness, collecting samples and confirming BRCAness (pg. 114, col. 2, third paragraph; col. 3, last paragraph) and performing whole exome and whole genome sequencing combined with copy number profiling for HRR analysis (pg. 114, col. 1, first paragraph). Therefore, the recited additional elements, alone or in combination with the judicial exceptions, do not appear to provide an inventive concept. [Step 2B: No]
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole,
are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not
constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as
being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102(a)(1)
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.
Claim(s) 1-4, 10-13, 15, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Davies (Nature Medicine 23(4): 517-528, 2017; previously cited on the 29 December 2022 IDS form).
Claim 1 recites collecting known BRCAness positive samples and known BRCAness negative
samples to form a training set.
Davies teaches extraction of DNA from breast cancer cases (pg. 526, col. 1, second paragraph) to analyze for BRCAness qualities.
Claim 1 recites analyzing copy number variation (CNV) in the training set to determine types
and corresponding quantities of CNV.
Davies teaches copy number-based methods such as the homologous recombination deficiency index and genomic scars to detect BRCA deficiency (pg. 527, col. 2, third paragraph).
Claim 1 recites determining BRCAness positive events and BRCAness negative events.
Davies teaches determining BRCAness as loss of the wild-type allele (pg. 518, col. 1, third paragraph); signatures including substitutions, indels, and rearrangements (pg. 518, col. 1, second paragraph); and promoter region hypermethylation (pg. 518, col. 2, fifth paragraph).
Claim 1 recites training to obtain weights of different types of the CNV determined in the “analyzing” step through a machine learning method according to the BRCAness positive events and
the BRCAness negative events in the training set, and then totalizing the weights of the different types of the CNV to obtain the genomic scar model for calculating genomic scar score (GSS).
Davies teaches training a logistic regression model to define features of BRCA deficiency (pg. 518, col. 1, last paragraph) with allele-specific copy number profiles (pg. 526, col. 2, second paragraph). Davies teaches weighting genomic features relevant to predicting BRCAness (pg. 526, col. 2, last paragraph), where the weights of the different genomic features, interpreted as signatures, have different coefficients representing ability to predict BRCAness (Fig. 2B) and making a prediction on new samples based on copy number profile (pg. 528, col. 1, first paragraph). Davies teaches gains and losses of copy number (Fig. 1, caption), interpreted as types. The model produces a score with a cutoff of analysis (Fig. 3 caption).
Claim 1 recites collecting additional known BRCAness positive samples and known BRCAness negative samples to form a test set, and obtaining types and corresponding quantities of CNV in the test set according to the “analyzing” step and substituting results into the genomic scar model obtained in the “training” step to calculate GSS of the test set, and verifying the genomic scar model based on a score of the GSS.
Davies teaches using the variables determined in the training in the remaining 10% of test samples (pg. 518, col. 1, first paragraph).
Claim 2 recites the BRCAness positive events comprise a pathogenic or suspected pathogenic variation occurs in one allele and loss of heterozygosity occurs in another allele of BRCA1 or BRCA2, two pathogenic or suspected pathogenic variations occur in BRCA1 or BRCA2, and loss of heterozygosity occurs in one allele and methylation occurs in a promoter region of another allele of BRCA1.
Davies teaches BRCA qualities including: loss of the wild-type allele (pg. 518, col. 1, third paragraph); signatures including substitutions, indels, and rearrangements (pg. 518, col. 1, second paragraph); and promoter region hypermethylation (pg. 518, col. 2, fifth paragraph).
Claim 3 recites the BRCAness positive events further comprise homologous recombination repair related genes other than BRCAl/2 genes that have corresponding gene variations, homozygous deletions, and expression silencing configured to cause genome instability related events.
Davies teaches discovering other genes than BRCA1 and BRCA2 and their mutations which are known to be involved in DNA repair via homologous recombination (pg. 526, col. 2, third paragraph).
Claim 4 recites the BRCAness negative events comprises Homologous Recombination Repair (HRR)-related genes are wild-type, and no loss of heterozygosity occurs in corresponding alleles or no methylation occurs in a promoter region of the corresponding alleles.
Davies teaches loss of heterozygosity associated with BRCAness (pg. 518, col. 1, fourth paragraph) and both no mutation of BRCA and hypermethylation of promoters not being observed (pg. 519, col. 2, last paragraph).
Claim 10 recites the training to obtain the weights of the different types of the CNV comprises
training to obtain the weights of the different types of the CNV according to the BRCAness types of the known positive samples and the known negative samples to construct the genomic scar model.
Davies teaches weights (or coefficients) on different genomic features (pg. 527, col. 1, first paragraph), where genomic features include deletions, substitutions, and rearrangements (Fig. 2B) and making a prediction of new samples based on copy number profile (pg. 528, col. 1, first paragraph).
Claim 11 recites to accumulate populations with HRR-related variations.
Davies teaches determining abrogation of the DSB repair pathways (pg. 518, col. 1, second paragraph), where homologous recombination repair is a type of double stranded damage repair.
Claim 12 recites to accumulate sensitive populations to platinum drugs.
Davies teaches sensitivity to platinum-based salts (pg. 524, col. 1, third paragraph).
Claim 13 recites to accumulate sensitive populations to PARPi drugs.
Davies teaches sensitivity to PARP inhibition (pg. 524, col. 1, third paragraph).
Claim 15 recites the sequencing and the analyzing is based on whole genome, whole exome, target capture sequencing, or a chip of CNV.
Davies teaches whole genome sequencing (pg. 517, col. 2, last paragraph), whole exome sequencing (pg. 521, col. 1, third paragraph), and sequencing other HR genes (pg. 526, col. 2, third paragraph) which is interpreted as target capture of specific loci.
Claim 17 recites calculating samples to be tested by the genomic scar model to determine a sample with a GSS less than 0.5 as a BRCAness negative sample and a sample with a GSS greater than 0.5 as a BRCAness positive sample.
Davies teaches a threshold of 0.7 (pg. 521, col. 1, last paragraph). While not the same as the instant threshold, a prima facie case of obviousness exists when the values do not overlap but are close and also optimization of a result-effective variable (MPEP 2144.05(I)).
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 5 and 9
Claims 5 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Davies as applied to claims 1-4, 10-13, 15, and 17, rejected under 35 USC 102(a)(1) above, and further in view of Zhang (Human Molecular Genetics 25(5): 1019-1030, 2016; newly cited).
Claim 5 recites the types of the CNV in the “analyzing” step are determined according to lengths of CNV segments, types of the CNV segments, and genomic location of the CNV segments.
Davies teaches types as loss of heterozygosity (pg. 522, col. 2, third paragraph), allele-specific copy number analysis (pg. 526, col. 2, second paragraph), and gains and losses of copy number (Fig. 1, caption), interpreted as types, but not lengths or locations.
Zhang teaches copy number lengths and location, such as the telomere (pg. 1026, col. 1, first paragraph).
Claim 9 recites a location of the CNV segments on a genome comprises the CNV segments located on a side of telomere, the CNV segments located on an inner side of a centromeric region, and the CNV segments located on positions other than the side of the telomere and the inner side of the centromere region.
Zhang teaches interstitial and telomere-bound copy number alterations as well as distance to the centromere (pg. 1023, col. 1, first paragraph and Fig. 3), which would account for the required locations on the chromosome.
Combining Davies and Zhang
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Davies with that of Zhang because Zhang teaches different regions of the chromosome, such as the telomere, have different mechanisms of copy number variation and thus are importance to account for (pg. 1020, col. 1, last paragraph). Both Davies and Zhang are directed to the shared field of endeavor of analyzing the relationship of copy number variation to cancer, and their combination would be expected to succeed. Therefore, the invention is prima facie obvious.
Claims 6-7 and 16
Claims 6-7 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Davies in view of Zhang as applied to claims 1-5, 9-13, 15, and 17 above, and further in view of Nik-Zainal (Nature 534: 47-67, 2016; newly cited).
Claim 6 recites the lengths of the CNV segments are divided into a short segment of 5-10 M, a medium segment of greater than 10 M and less than or equal to 15 M, and a long segment of greater than 15 M.
Davies teaches large rearrangements of over 0.1 M (pg. 518, col. 1, fourth paragraph) and Zhang teaches 1Mb segments (pg. 1028, col. 1, first paragraph) but not 5-10, 10-15, and 15 or more megabases.
Nik-Zainal teaches stretches of tandem duplication in 1-10 kb, 10-100 kb, 100 kb -1 Mb, 1-10 Mb, and 10+ Mb sections (pg. --51, Figure 4b).
Claim 7 recites the length of the CNV segments are divided into continuous variables.
Nik-Zainal teaches at least length of palindromes as a continuous variable (Fig. 2b).
Claim 16 recites the continuous variables comprises 5-30 M (million base pairs) lengths of the CNV segments.
Nik-Zainal teaches CNV of 1 kb to more than 10 Mb (Fig. 4b) and continuous analysis of mutation count (Fig. 2b, 2c).
Combining Davies, Zhang, and Nik-Zainal
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the previously combined works with that of Nik-Zainal because Nik-Zainal teaches ranges of segments of repeats largely overlapping with those of Davies, and teaches relating palindrome lengths as continuous variables and thus the possibility of analyzing repeat data as continuous. Nik-Zainal and in particular Davies are directed to the shared field of endeavor of mutations in breast cancer sequences, and thus the invention is prima facie obvious.
Claim 8
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Davies in view of Zhang as applied to claims 1-5, 9-13, 15, and 17 above, and further in view of Silver (Cancer Discovery 679-684, 2012; newly cited).
Claim 8 recites the types of the CNV segments comprise loss of heterozygosity, allele specific CNV, and balance CNV.
Davies teaches CNV profiles as well as loss of heterozygosity (pg. 522, col. 2, third paragraph), allele-specific copy number analysis (pg. 526, col. 2, second paragraph), but not balance.
Silver teaches imbalance in the telomeres being correlated with tumor development (pg. 682, col. 2, third paragraph).
Combining Davies, Zhang, and Silver
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the previously combined works with that of Silver because Silver teaches telomeric imbalance was observed in BRCA1-mutated ovarian cancers and were found to be located at a disproportionately high rate in the vicinity of regions of copy number variation, making them of particular interest for related copy number variation to BRCAness as taught by Davies. The combined art is directed to the shared field of endeavor of the genetics of BRCA and thus the invention is prima facie obvious.
Claim 14
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Davies as applied to claims 1-4, 10-13, 15, and 17, rejected under 35 USC 102(a)(1) above, and further in view of Popova (Genome Biology 10(128), 14 pgs., 2009; newly cited).
Claim 14 recites sequencing and analyzing the training set obtained in the first step, calculating the CNV in results of the sequencing and the analyzing, joining adjacent regions with a same CNV into fragments to avoid double counting, and determining the types and the corresponding quantities of the CNV.
Davies teaches sequencing and analysis (pg. 526, col. 1, paragraphs 1-3), generating copy number profiles (pg. 526, col. 2, second paragraph) but not joining adjacent regions to avoid double counting.
Popova teaches merging regions to minimize double counting (pg. 8, col. 1, second paragraph).
Combining Davies and Popova
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Davies with that of Popova because Popova teaches avoiding double counting a single break point, where it is understood that counting a single break point as more than one would introduce an artifact into the dataset. Davies and Popova are directed to the shared field of endeavor of copy number variation and cancer, and their combination would be expected to succeed. Thus, the invention is prima facie obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert J Kallal whose telephone number is (571)272-6252. The examiner can normally be reached Monday through Friday 8 AM - 4 PM EST.
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/Robert J. Kallal/Examiner, Art Unit 1685
Prosecution Insights