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 .
Applicant’s Response
Applicant’s response, filed 05/14/2026, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claims Status
Claims 7-11 are new.
Claims 1-11 are pending.
Claims 1-11 are examined.
Withdrawn Objections/Rejections
The rejection of claims 1, 5, and 6 under 35 USC 102 over Landau et al. is withdrawn in view of amendments submitted
The provisional rejection on the ground of nonstatutory double patenting over copending Application No. 18/316,294 is withdrawn.
Claim Objections
Claims 1-3 are objected to because they include reference characters which are not enclosed within parentheses.
Reference characters corresponding to elements recited in the detailed description of the drawings and used in conjunction with the recitation of the same element or group of elements in the claims should be enclosed within parentheses so as to avoid confusion with other numbers or characters which may appear in the claims. See MPEP § 608.01(m).
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.
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 1-11 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to an abstract idea of mental steps, mathematic concepts, or a natural law without significantly more. Any newly recited portion is necessitated by claim amendments.
The MPEP at MPEP 2106.03 sets forth steps for identifying eligible subject matter:
(1) Are the claims directed to a process, machine, manufacture or composition of
matter?
(2A)(1) Are the claims directed to a judicially recognized exception, i.e. a law of nature,
a natural phenomenon, or an abstract idea?
(2A)(2) If the claims are directed to a judicial exception under Prong One, then is the
judicial exception integrated into a practical application?
(2B) If the claims are directed to a judicial exception and do not integrate the judicial
exception, do the claims provide an inventive concept?
With respect to step (1): Yes, the claims recite a method.
With respect to step (2A)(1): The claims recite abstract ideas of mental processes.
“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). Abstract ideas include mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations), certain methods of organizing human activity, and mental processes (procedures for observing, evaluating, analyzing/judging and organizing information (MPEP 2106.04(a)(2)). Laws of nature or natural phenomena include naturally occurring principles/relations that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature (MPEP 2106(b)).
Mental processes recited in claim 1:
performing a structural variant analysis on the whole-genome sequencing dataset, the structural variant analysis including copy-number alteration (CNA) identification, structural variant (SV) identification, and gene-level variant identification to identify clinically relevant structural variants indicative of AML or MDS within the whole-genome sequencing dataset, wherein the gene-level variant identification comprises identifying variants in a set of 40 predetermined genes selected from the group consisting of ASXL1, BCORL1, BCOR, BRAF, CALR, CBL, CEBPA, CSF3R, CUX1, DNMT3A, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PIGA, PPM1D, PTPN11, RAD21, RUNX1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, SUZ12, TET2, TP53, U2AF1, WT1, and ZRSR2
producing a report comprising the clinically relevant CNAs, SVs, and gene-level variants identified by the structural variant analysis
Dependent claims 2-5 and 11 recite additional steps that either are directed to abstract ideas or further limit the judicial exceptions in independent claim 1, and as such, are further directed to abstract ideas. Hence, the claims explicitly recite numerous elements that individually and in combination constitute abstract ideas. The relevant recitations are:
Claim 2: “transforming […] the alignments of the whole-genome sequencing dataset into a plurality of read counts over 500,000 bp nonoverlapping windows across the genome”; “transforming […] the plurality of read counts into a plurality of CNAs”; “filtering […] plurality of CNAs to retain only CNAs greater than 5Mbp”
Claim 3: “transforming […] the alignments of the whole-genome sequencing dataset into a plurality of SV calls”; “filtering […] the plurality of SVs to retain only SV calls greater than 100 kbp in length”; “filtering […] the SV calls greater than 100 kbp in length to identify translocations, deletions, duplications, and inversions that overlap a predefined list of recurrent and/or risk-defining SVs associated with AML or MDS”
Claim 4: “identifying […] the alignments of the whole-genome sequencing dataset within about 85kbp targeting of the set of 40 predetermined genes”
Claim 5: “wherein the clinically relevant CNAs, SVs, and gene-level variants identified by the structural variant analysis are indicative of a clinical outcome of the subject”
Claim 11: “wherein the structural variant analysis is limited to known mutations with established clinical relevance”
The abstract ideas in the claims are evaluated under Broadest Reasonable Interpretation (BRI) and determined herein to each cover mental processes and mathematic concepts because the claims recite no more than analyzing DNA sequences in order to identify differences indicative of a disease diagnosis.
With respect to step (2A)(2): The claims must therefore be examined further to determine whether they integrate that abstract idea into a practical application (MPEP 2106.04(d)). The claimed additional elements are analyzed alone or in combination to determine if the judicial exception is 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 exception, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d).III).
Claim 1 recites the following additional elements that are not abstract ideas:
computer-implemented
providing a whole-genome sequencing dataset, the whole-genome sequencing dataset comprising a plurality of alignments of tumor DNA sequence fragments to a reference human genome to a computing device
The step of providing a whole-genome sequencing gathers the data on which the judicial exceptions are performed and is thus directed to data gathering. Data gathering does not impose any meaningful limitation on the abstract idea, or how the abstract idea is performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application (MPEP 2106.05(g)). The element of the method being computer-implemented is directed to applying the method to a generic computer. Hence, these are mere instructions to apply the abstract idea using a computer, and therefore the claim does not integrate that abstract idea into a practical application. The courts have weighed in and consistently maintained that when, for example, a memory, display, processor, machine, etc. ... are recited so generically (i.e., no details are provided) that they represent no more than mere instructions to apply the judicial exception on a computer, and these limitations may be viewed as nothing more than generally linking the use of the judicial exception to the technological environment of a computer (see MPEP 2106.05(f)).
Dependent claims 6-10 are directed to steps of data gathering as they describes the method of gathering the sequencing data of further limit the sequence data on which the judicial exceptions are performed.
None of these dependent claims recite additional elements, alone or in combination, which would integrate a judicial exception into a practical application.
Lastly, the claims have been evaluated with respect to step (2B): Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims lack a specific inventive concept. Under said analysis, Applicant is reminded that the judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they provide significantly more than the judicial exception (MPEP 2106.05.A i-vi).
With respect to the instant claims, the additional elements do not rise to the level of significantly more than the judicial exception. As set forth in the MPEP at 2106.05(d)(I), determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to claim 1: The additional element of a computer-implemented method, and providing whole-genome sequencing dataset do not rise to the level of significantly more than the judicial exception. With respect to the generic computer elements, as exemplified in the MPEP at 2106.05(f) with reference to Alice Corp. 573 US at 223, 110 USPQ2d at 1983 “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”. Therefore, the device constitutes no more than a general link to a technological environment, which is insufficient to constitute an inventive concept that would render the claims significantly more than the abstract idea (see MPEP 2105(b)I-III). Furthermore, with reference to Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546, analyzing DNA to provide sequence information or detect allelic variants is also a routine and conventional activity. As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 6: The additional element of performing whole-genome sequencing on a biological sample comprising tumor DNA from the subject with about 60x genome coverage does not rise to the level of significantly more than the judicial exception. The prior art Desai et al. (“Identification of Optimum Sequencing Depth Especially for De Novo Genome Assembly of Small Genomes Using Next Generation Sequencing Data”, PLOS One, 2013, cited in prior Office Action) discloses current Next Generation Sequencing that can easily achieve 60X to 100X coverage for large genomes (page 1, column 2, paragraph 2). As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 7: The additional element of the reference human genome being GRCh38 does not rise to the level of significantly more than the judicial exception. The prior art Jensen et al. (WO 2020/0167830 A1, published August 2020) discloses that generation of aligned reads by using bioinformatics methods for example Bowtie 2 with a human reference assembly GRCh38 is known in the art (paragraph [0216]). As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 8: The additional element of obtaining a biological sample comprising tumor DNA from the subject does not rise to the level of significantly more than the judicial exception. The Specification in paragraph [0006] discloses assay diagnostics routinely performed on formalin-fixed biopsies of solid tumors. As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 9: The additional element of performing whole-genome sequencing library preparation using the tumor DNA does not rise to the level of significantly more than the judicial exception. Several pieces of prior art such as the prior art to Zhao et al. (“Whole-Genome Sequencing in Cancer”, Cold Spring Harb Perspect Med, published online May 2018) discloses multiple references using whole-genome sequencing in studying cancer genetics (page 5, column 2; page 10, References). As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
With respect to claim 10: The additional element of an amount of tumor DNA used for library preparation is within a range of 35 ng and 500 ng does not rise to the level of significantly more than the judicial exception. The prior art Adalsteinsson et al. (“Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors”, Nature Communications, published 2017) discloses a range of DNA comprising 0-547.82 ng/mL in the plasma from metastatic cancer patients consistent with previous reporting (page 2, column 1, Section Results). As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
In combination, the collection or generation of the data, acted upon by the judicial exception, fail to rise to the level of significantly more. The data gathering steps provide the data for the judicial exception. No non-routine step or element has clearly been identified.
The claims have all been examined to identify the presence of one or more judicial exceptions. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether the additional limitations integrate the judicial exception into a practical application. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether those additional limitations provide an inventive concept which provides significantly more than those exceptions. Individually, the limitations of the claims and the claims as a whole have been found lacking.
Response to Arguments
Applicant states that “performing structural variant analysis using ‘a whole-genome sequencing dataset’ involves processing massive amounts of genomic data representing billions of data points that cannot be mentally processed, compared, or analyzed by a human. A human cannot mentally align DNA sequences, identify copy number alterations across multiple chromosomes, detect structural variants spanning large genomic regions, and identify gene-level mutations across dozens of genes as recited in the claims. Similarly, producing a report comprising the clinically relevant CNAs, SVs, and gene-level variants identified from billions of genomic data points requires computational processing to organize and present the results”.
It is respectfully submitted that this is not persuasive. While alignment of a whole-genome to a reference genome is not a mental process, the structural variant analysis is performed on the whole-genome sequencing dataset that comprises a plurality of alignments of tumor DNA sequence fragments. Thus, the DNA fragments are already aligned. Although it may take time, a person can mentally look at some number of aligned fragments and identify copy number alterations, structural variants, and gene variants in the 40 genes. Furthermore, producing the report does not require billions of data points, the claims just require the clinically relevant variants identified. Thus, one of ordinary skill can reasonable mentally produce the required report. Therefore, the rejection under 35 USC 101 is maintained.
Furthermore, Applicant states that the “dependent claims likewise recite computational genomic analysis steps, such as transforming alignments into read counts over genomic windows, filtering based on specific size thresholds, and identifying mutations within predetermined windows, that cannot practically be performed mentally due to the massive scale of ‘a whole-genome sequencing dataset’ and computational requirements involved”.
It is respectfully submitted that this is not persuasive. One of ordinary skill can, using a pencil and paper, divide an alignment into 500,000 bp pair windows given the additional element of aligning the sequences to a reference genome (see MPEP 2106.04(a)(2).III.B). As there is no limitation to how many CNAs are identified, one of ordinary skill can identify two CNAs or SVs based on read counts and mentally perform a step of filtering based on a given number. Therefore, the rejection under 35 USC 101 is maintained.
Furthermore, Applicant states that “the claims do not explicitly recite any mathematical concepts, formulas, or algorithms, At best, the claims recite limitations that may be based on or involve mathematical concepts, but no mathematical concepts are recited in the claims themselves”.
It is respectfully submitted that this is not persuasive. While the claims do not explicitly recite a mathematical formula, the dependent claims recite elements which may be interpreted as a mathematic concept, such as limitations to transforming alignments into read counts and then CNAs, which in the Specification in paragraph [0070] are described as being performed by a Hidden Markov Model, thus mathematical algorithms to identify CNAs. Therefore, the claims are directed to abstract ideas and the rejection under 35 USC 101 is maintained.
Furthermore, Applicant states that “the claims recite numerous specific improvements over the prior art in the field of cancer diagnosis. The specific combination of copy-number (CNA) identification, structural variant (SV) identification, and gene-level variant identification in a single platform analysis recited in Claim 1 improves upon prior methods that required multiple separate platforms and tests to detect different types of genetic abnormalities […] Experimental testing showed that the claimed whole-genome sequencing method detected 100% of the clinically significant abnormalities that had been identified by traditional methods and also identified new abnormalities in 25% of patients that had not been detected by the conventional cytogenetic analysis and clinical FISH assay performed karyotyping for chromosomal abnormalities […]. In contrast, the claimed invention integrates all three analysis types into a single workflow from a single tumor samples. […] This integration of three distinct genomic analyses with targeted clinical filtering in a tumor-only workflow was not a conventional approach at the time of filing.”
It is respectfully submitted that this is not persuasive. It is the additional elements that are analyzed to determine whether the claims are integrated into a practical application (MPEP 2106.04(d).I; MPEP 2106.05(a-h)), and it is the additional elements that are examined to determine if there is an inventive concept (MPEP 2106.05.A i-vi). Thus, the identification steps and the combination of all three analysis cannot provide the improvement that integrates the judicial exceptions into a practical application. The cited improvements are brought forth by abstract ideas, and the improvement cannot be in the judicial exceptions themselves. Therefore, the rejection under 35 USC 101 is maintained.
Furthermore, Applicant states that “the claims further recite particular machines (computing devices performing whole-genome sequencing analysis) and transformations (converting raw sequencing alignments into clinically-actionable reports of structural variants). Most importantly, the claims include non-conventional steps that go well beyond well-understood, routine, conventional activity in the art. The integration of three distinct genomic analyses with targeted clinical filtering in a tumor-only workflow was not a conventional approach at the time of filing”.
It is respectfully submitted that this is not persuasive. The claims do not require a particular machine. The claims require a generic computer that performs the claimed pipeline. The courts have weighed in and consistently maintained that when elements of a generic computer are recited so generically that they represent no more than mere instructions to apply the judicial exception on a computer, and these limitations may be viewed as nothing more than generally linking the use of the judicial exception to the technological environment of a computer (see MPEP 2106.05(f)). Furthermore, it is the additional elements that are analyzed to determine whether the claims are integrated into a practical application (MPEP 2106.04(d).I; MPEP 2106.05(a-h)), and it is the additional elements that are examined to determine if there is an inventive concept (MPEP 2106.05.A i-vi). Thus, the judicial exceptions cannot provide the improvement, and thus a transformation of data into a report does not integrate the judicial exceptions into a practical application. Therefore, the rejection under 35 USC 101 is maintained.
Finally, Applicant states that “in testing of this methodology, ‘[p]rospective real-time sequencing of samples obtained from consecutive patients, described below, showed that whole-genome sequencing yields complete genomic information in a clinically relevant timeframe.’ […] Accordingly, this application describes drastic improvement to the process of genome sequencing for diagnosis of disease. This improvement improves the technology to such a point that sequencing can be used within timeframes that allow for diagnosis the patient while it is relevant to the patient’s care.”
It is respectfully submitted that this is not persuasive. First, the claims are not directed to diagnosis a disease and thus this improvement is not reflected in the claims. Furthermore, numerous prior art references such as Landau et al. (paragraphs [0017], [0130]), and Ogawa (page 1050, column 1, Section Somatic mutations, paragraph 2) disclose whole genome sequencing, and Zhao et al. discloses several studies using whole genome sequencing on cancer DNA (page 10, References). Therefore, the rejection under 35 USC 101 is maintained.
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 1, and 3-11 are rejected under 35 U.S.C. 103 as being unpatentable over Landau et al. (US 2021/0002728 A1, published January 7, 2021, cited in prior Office Action) in view of Ogawa (“Genetics of MDS”, blood, published March 2019). This is a new grounds of rejection as necessitated by claim amendments.
Regarding claim 1, Landau et al. teaches a method of identifying structural variants in a subject with AML (paragraph [0065]) comprising:
providing a whole-genome sequencing dataset, the whole-genome sequencing dataset comprising a plurality of alignments of tumor DNA sequence fragments to a reference human genome to a computing device (paragraph [0017]);
performing a structural variant analysis on the whole-genome sequencing dataset, the structural variant analysis including copy-number alteration (CNA) identification, structural variant (SV) identification, and gene-level variant identification (paragraph [0018]) to identify clinically relevant structural variants indicative of AML or MDS within the whole-genome sequencing dataset (paragraph [0065]); and
producing a report comprising the clinically relevant DNAs, SVs, and gene-level variants identified by the structural variant analysis: Landau et al. teaches producing a report of the identified CNVs for further clinical applications such as tumor fraction estimation (Figure 8).
Furthermore, Landau et al. teaches the methods being performed by a computer system (paragraph [0037], [0038], and the like).
Landau does not teach the claim element of identifying variants in a set of 40 predetermined genes selected from the group consisting of ASXL1, BCORL1, BCOR, BRAF, CALR, CBL, CEBPA, CSF3R, CUX1, DNMT3A, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PIGA, PPM1D, PTPN11, RAD21, RUNX1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, SUZ12, TET2, TP53, U2AF1, WT1, and ZRSR2.
However, Ogawa teaches analysis of driver mutations in MDS and mutations showing significant overlap with AML, with mutations being acquired and positively selected allowing for expansion of the initiating clone to comprise normal hematopoiesis, ultimately giving rise to MDS and a subsequent transformation to AML in many patients (Abstract). Ogawa teaches that many driver alterations in DMS are shared by primary AML (page 1049, column 1). Ogawa teaches driver genes comprising ASXL1, BCORL1, BCOR, BRAF, CALR, CBL, CEBPA, CSF3R, CUX1, DNMT3A, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PTPN11, RAD21, RUNX1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, SUZ12, TET2, TP53, U2AF1, WT1, and ZRSR2 (Table 1). Furthermore, Ogawa teaches other mutations affecting genes frequently mutated in MDS/AML comprising PPM1D (page 1053, column 1), and teaches mutations in PIGA being associated with an elevated risk of progression to MDS/AML (page 1054, column 1, paragraph 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the genes of Ogawa to the method of Landau et al. because Landau et al. is directed to diagnosis residual tumor disease by analyzing tumor-specific markers (paragraph [0008]) and teaches the cancer being AML (paragraph [0065]). Ogawa is directed to analyzing the significant overlap between driver mutations of MDS and AML (page 1049, column 1), and teaches mutations being acquired and positively selected allowing for expansion of the initiating clone to comprise normal hematopoiesis, ultimately giving rise to MDS and a subsequent transformation to AML in many patients (Abstract). Thus, one of ordinary skill in the art would have a reasonable expectation of success of using the genes from Ogawa to identify AML markers in a tumor sample and would be motivated to do so because they are known driver genes and MDS can transform to AML, making gene mutations indicative of AML important to analyze.
Regarding claim 3, the claim is directed to transforming the alignments of the whole-genome sequencing dataset into a plurality of SV calls; filtering the plurality of SVs to retain only SV calls greater than 100 kbp in length; and filtering the SV calls greater than 100 kbp in length to identify translocations, deletions, duplications, and inversions that overlap a predefined list of recurrent and/or risk-defining SVs associated with AML or MDS. Landau et al. teaches the method of claim 1 in view of Ogawa. Landau et al. also teaches calling CNVs segments or SV calling that exceed a threshold length preferably greater than Mbps (paragraph [0034]) and Landau et al. teaches that CNVs or SVs are at least 5 Mbps in cumulative size or larger (paragraph [0022]).
Landau et al. does not teach the claim element of identifying translocations, deletions, duplications, and inversions that overlap a predefined list of recurrent and/or risk-defining SVs associated with AML or MDS.
However, Ogawa teaches identifying translocations, deletions, duplications, and inversions that overlap with a predefined list or recurrent or risk-defining SVs associated with AML and MDS (page 1050, column 1).
Regarding claim 4, the claim is directed to identifying, using the computing device, the alignments of the whole-genome sequencing dataset within about 85 kbp target the set of 40 predetermined genes. Landau et al. teaches the method of claim 1 in view of Ogawa.
Landau et al. does not teach the claim element of alignments of the whole-genome sequencing dataset within about 85 kbp target the set of 40 predetermined genes.
However, Ogawa teaches that extremely high resolution of SNP array-based analysis allows for identification of sub-chromosomal/focal lesions, as small as 20 kb in size, leading to the identification of relevant driver genes (page 1050, column 1), and teaches whole genome data (page 1050, column 1, Section Somatic mutations, paragraph 2).
Regarding claim 5, the claim is directed to the clinically relevant CNAs, SVs, and gene-level variants identified by the structural variant analysis are indicative of a clinical outcome of the subject. Landau et al. teaches the method of claim 1 in view of Ogawa. Landau et al. also teaches that the somatic alterations in cfDNA of a subject such as copy number variation, tandem repeats, gene mutations, etc. are indicators of pathogenic processes or pharmacological response to a therapeutic intervention (paragraph [0075]).
Regarding claim 6, the claim is directed to performing whole-genome sequencing on a biological sample comprising tumor DNA from the subject with about 60x genome coverage. Landau et al. teaches the method of claim 1 in view of Ogawa. Landau et al. also teaches performing whole-genome sequencing at a coverage of 70x or more (paragraph [0092]).
Regarding claim 7, the claim is directed to the reference human genome being GRCh38. Landau et al. teaches the method in view of Ogawa. Landau et al. also teaches the reference genome being hg38 (paragraph [0079]).
Regarding claim 8, the claim is directed to obtaining a biological sample comprising tumor DNA from the subject. Landau et al. teaches the method of claim 1 in view of Ogawa. Landau et al. also teaches DNA obtained from a tumor sample (paragraph [0014]).
Regarding claim 9, the claim is directed to performing whole-genome sequencing library preparation using the tumor DNA. Landau et al. teaches the method of claim 8 in view of Ogawa. Landau et al. also teaches performing whole-genome sequencing of a subject’s tumor sample (paragraph [0017]).
Regarding claim 10, the claim is directed to an amount of tumor DNA used for the library preparation being within a range of 35 ng and 500 ng. Landau et al. teaches the method of claim 9 in view of Ogawa. Landau et al. also teaches low abundances of DNA in the sample and teaches amounts that are less than about 20 ng/mL, e.g., about 15 ng/mL, about 10 ng/mL, or less, e.g., about 9 ng/mL, 8 ng/mL, 7 ng/mL, 6 ng/mL, 5 ng/mL, 4 ng/mL, 3 ng/mL, 2 ng/mL, 1 ng/mL, 0.7 ng/mL, 0.5 ng/mL, 0.3 ng/mL, or less, e.g., 0.1 ng/mL or even 0.05 ng/mL, and teaches that in some instances the abundance can comprise greater than 20 ng/mL (paragraph [0089]). Thus, the amount can comprise 35ng/mL but the method of Landau et al. is able to detect variants with smaller amounts of DNA.
Regarding claim 11, the claim is directed to the structural variant analysis being limited to known mutations with established clinical relevance. Landau et al. teaches the method of claim 1 in view of Ogawa. Landau et al. teaches known amplifications and deletions being used as a CNV reference set (paragraph [0272]).
However, Landau et al. teaches using these known mutations for Noninvasive Prenatal Testing.
However, Ogawa teaches known mutations for a structural variant analysis for MDS and AML (Abstract).
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Landau et al. in view of Ogawa, as applied to claims 1, and 3-11 above, and further in view of Rava et al. (US 10388403 B2, published August 2019, IDS reference).
The claim is directed to transforming the alignments of the whole-genome sequencing dataset into a plurality of read counts over 500,000 bp nonoverlapping windows across the genome; transforming the plurality of read counts into a plurality of CNAs; and filtering plurality of CNAs to retain only CNAs greater than 5 Mbp. Landau et al. teaches the method of claim 1 in view of Ogawa. Landau et al. also teaches calling CNVs segments or SV calling that exceed a threshold length preferably greater than Mbps (paragraph [0034]) and Landau et al. teaches that CNVs or SVs are at least 5 Mbps in cumulative size or larger (paragraph [0022]).
Neither Landau et al. nor Ogawa teach the claim element of transforming the alignments of the whole-genome sequencing dataset into a plurality of read counts over 500,000 bp nonoverlapping windows.
However, Rava et al. teaches identifying aneuploidy by binning sequences into blocks wherein the block length is 1 million base pairs, or potentially 100kb, etc. and these lengths do not overlap. The blocks are analyzed to identify aneuploidy (column 144, line 31).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the predetermined markers of Rava et al. to the method of Landau et al. because Landau et al. is directed to detecting residual tumor disease in human cancer patients (Abstract) using structural markers such as copy number variations (paragraph [0008]) and Rava et al. is also directed to analysis of copy number variations of a sequence in a sample to determine structural variations associated with medical conditions such as cancer (Abstract). Thus, one of ordinary skill in the art would have a reasonable expectation of identifying marker copy number variations in a patient’s sample in order to detect cancer.
Response to Arguments
Applicant states that they have amended Claim 1 to recite the list of 40 predetermined genes and gene hotspots. In the previous Office Action is was states that Landau et al. does not teach the claim element of 40 predetermined genes and gene hotspots that are recurrently mutated in AML or MDS. This limitation was rejected using Rava et al. Applicant further states that “Rava does not teach or suggest the set of 40 AML/MDS-associated genes. Accordingly, Rava does not cure the deficiencies of Landau”.
It is acknowledged that neither Landau et al. nor Rava et al. teach the claimed set of 40 genes, although Rava et al. does teach some of the recited genes. The specific set of genes was not recited in prior claim listings, and a new rejection has been set forth in view of these amendments.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/E.A.S./Examiner, Art Unit 1686
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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