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 .
Election/Restrictions
Upon further consideration the restriction dated 9/5/2025 is withdrawn. Pursuant to the procedures set forth in MPEP § 821.04(B), claims 30 and 62, previously withdrawn from consideration (in Applicant’s response received 10/29/2025) as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104, as presented in the amended claims dated 6/20/2023.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on 9/5/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Status of Claims
Claims 1, 16, 17, 20, 21, 23, 24, 30, 37-39, 41, 45, 47, 49, 51, 53, 62, 69, and 74 pending and examined on the merits.
Claims 2-15, 18, 19, 22, 25-29, 31-36, 40, 42-44, 46, 48, 50, 52, 54-61, 63-68, 70-73, and 75-148 cancelled.
Priority
The instant application filed on 12/5/2022 is a 371 national stage entry of PCT/US2021/035751 having an international filing date of 6/3/2021, and claims the benefit of priority to provisional U.S. Application No. 63/041,437 filed on 6/19/2020 and to provisional U.S. Application No. 63/035,572 filed on 6/5/2020. Thus, the effective filing date of the claims is 6/5/2020.
The applicant is reminded that amendments to the claims and specification must comply with 35 U.S.C. § 120 and 37 C.F.R. § 1.121 to maintain priority to an earlier-filed application. Claim amendments may impact the effective filing date if new subject matter is introduced that lacks support in the originally filed disclosure. If an amendment adds limitations that were not adequately described in the parent application, the claim may no longer be entitled to the priority date of the earlier filing.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 3/16/2023 has been entered and considered. A signed copy of the corresponding 1449 form has been included with this Office action. Examiner notes that under "Non-patent Literature Documents", there is a 5-page disclosure of a "foundationmedicine.com" URL that has no "Cite No." in the IDS on page 5, and no associated attached material for review. Therefore, it fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
The information disclosure statements (IDS) filed on 6/20/2023 and 10/29/2025 have been entered and considered. A signed copy of the corresponding 1449 forms have been included with this Office action.
Additionally, The listing of references in the specification (URLs in para.0087 and 0100) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
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 62 and 74 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.
Claim 62 attempts to claim a process without setting forth any steps involved in the process. The claim recites "selecting a cancer treatment modality based on the one or more identified somatic sequences; and treating the cancer using the selected cancer treatment modality" which does not recite a particular treatment for the cancer, and merely suggests selecting a cancer treatment based on the somatic sequences identified from the method of claim 16 without any specific steps for how one would match the identified somatic sequence with a cancer treatment. Therefore, the claim is indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced similar to the findings in Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986).
Claim 74 attempts to claim a process without setting forth any steps involved in the process. The claim recites "selecting, by the one or more processors, from the one or more genomic sequences of interest identified as somatic, a genomic sequence that encodes a neoantigen suitable as a cancer vaccine for the subject" which does not recite any specific steps for how one might determine whether or not a genomic sequence that encodes a neoantigen would be suitable as a cancer vaccine for the subject. Therefore, the claim is indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced similar to the findings in Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986).
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, 16, 17, 20, 21, 23, 24, 30, 37-39, 41, 45, 47, 49, 51, 53, 62, 69, and 74 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of a mental process, a mathematical concept, organizing human activity, or a law of nature or natural phenomenon without significantly more. In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 1: “selecting, by one or more processors, a genomic sequence of interest at a genomic locus from the one or more genomic loci; selecting, by the one or more processors, one or more proxy genomic sequences for the genomic sequence of interest” provides an evaluation information (making a selection) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“determining, by the one or more processors, an allele frequency distance using an observed allele frequency of the genomic sequence of interest and a summary statistic or distribution indicative of observed allele frequencies of the one or more proxy genomic sequences” provides a mathematical calculation (determining allele frequency distance, and a summary statistic or distribution requires calculations) that is considered a mathematical concept, which is an abstract idea.
“identifying, by the one or more processors, the genomic sequence of interest as germline or somatic using the allele frequency distance” provides an evaluation (identifying the sequences as germline or somatic) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 16: “selecting, by one or more processors, a genomic sequence of interest at a genomic locus from within a patient genomic sequence obtained for a patient sample comprising a mixture of tumor nucleic acid molecules and non-tumor nucleic acid molecules; selecting, by the one or more processors, one or more proxy genomic sequences for the genomic sequence of interest” provides an evaluation information (making a selection) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“determining, by the one or more processors, an allele frequency distance using an observed allele frequency of the genomic sequence of interest and a summary statistic or distribution indicative of observed allele frequencies of the one or more proxy genomic sequences” provides a mathematical calculation (determining allele frequency distance, and a summary statistic or distribution requires calculations) that is considered a mathematical concept, which is an abstract idea.
“identifying, by the one or more processors, the genomic sequence of interest as germline or somatic using the allele frequency distance” provides an evaluation (identifying the sequences as germline or somatic) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 24: “the allele frequency distance is determined using the observed allele frequency of the genomic sequence of interest and the distribution indicative of the observed frequencies of a plurality of proxy genomic sequences” provides a mathematical calculation (determining allele frequency distance, and a summary statistic or distribution requires calculations) that is considered a mathematical concept, which is an abstract idea.
“the genomic sequence of interest is identified as germline or somatic based on a probability that the observed allele frequency of the genomic sequence of interest fits within or does not fit within the distribution” provides an evaluation (identifying the sequences as germline or somatic) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 30: “identifying, by one or more processors, a genomic sequence of interest in a patient sample at a genomic locus; identifying, by the one or more processors, one or more proxy genomic sequences for the sequence of interest” provides an evaluation information (identifying genomic sequences and proxy sequences) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“comparing, by the one or more processors, an observed frequency of the genomic sequence of interest to a centrality measure of observed frequencies of the one or more proxy genomic sequences” provides a comparison (comparing frequency of genomic sequences) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“identifying, by the one or more processors, the genomic sequence of interest as germline or somatic based on the comparison” provides an evaluation (identifying the sequences as germline or somatic) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 39: “a function that associates the allele frequency distance with the value indicative of a likelihood that the genomic sequence of interest is germline or the value indicative of a likelihood that the genomic sequence of interest is somatic” provides a mathematical relationship (a function that associates allele frequency with likelihood of being germline or somatic describes a mathematical relationship) that is considered a mathematical concept, which is an abstract idea.
Claim 62: “identifying, by the one or more processors, one or more genomic sequences of interest as somatic using the method of claim 16” provides an evaluation (identifying sequences as somatic) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“selecting a cancer treatment modality based on the one or more identified somatic sequences” provides an evaluation (selecting a cancer treatment modality requires evaluating the data) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 69: “identifying, by the one or more processors, one or more genomic sequences of interest as somatic using the method of claim 16, wherein the patient sample is obtained from a patient having cancer; and detecting, by the one or more processors, the presence or absence of the one or more genomic sequences of interest identified as somatic within a second patient sample obtained from patient after the cancer has been treated” provides an evaluation and comparison (identifying sequences as somatic, then comparing presence or absence after a treatment) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 74: “identifying, by the one or more processors, one or more genomic sequences of interest as somatic using the method of claim 16, wherein the one or more genomic sequences of interest identified as somatic is located within an exon region of a gene” provides an evaluation (identifying sequences as somatic) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“selecting, by the one or more processors, from the one or more genomic sequences of interest identified as somatic, a genomic sequence that encodes a neoantigen suitable as a cancer vaccine for the subject” provides an evaluation (making a selection) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
These recitations are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or are mathematical relationships. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. As such, claims 1, 16, 17, 20, 21, 23, 24, 30, 37-39, 41, 45, 47, 49, 51, 53, 62, 69, and 74 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exceptions listed above are not integrated into a practical application because the claims do not recite an additional element or elements that reflects an improvement to technology. Specifically, the claims recite the following additional elements:
Claim 1: “providing a plurality of nucleic acid molecules obtained from a sample from a subject, wherein the plurality of nucleic acid molecules comprises a mixture of tumor nucleic acid molecules and non-tumor nucleic acid molecules; optionally, ligating one or more adapters onto one or more nucleic acid molecules from the plurality of nucleic acid molecules; amplifying nucleic acid molecules from the plurality of nucleic acid molecules; capturing nucleic acid molecules from the amplified nucleic acid molecules, wherein the captured nucleic acid molecules are captured from the amplified nucleic acid molecules by hybridization to one or more bait molecules; sequencing, by a sequencer, the captured nucleic acid molecules to obtain a plurality of sequence reads corresponding to one or more genomic loci” provides insignificant extra-solution activities (obtaining, ligating adapters to, amplifying, bait capturing, and sequencing nucleic acid samples are all pre-solution activities involving sample and data gathering and manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 17: “sequencing, by a sequencer, the tumor nucleic acid molecules and the non-tumor nucleic acid molecules from the patient sample to determine the patient genomic sequence” provides insignificant extra-solution activities (sequencing nucleic acid samples are all pre-solution activities involving sample gathering and manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 21: “the patient genomic sequence is segmented into a plurality of segments based on copy number uniformity within each segment” provides insignificant extra-solution activities (segmenting sequences is a pre-solution activity involving data manipulation steps) that do not serve to integrate the judicial exceptions into a practical application (instant specification, para.0102 "A variety of segmentation procedures are known in the art").
Claim 37: “inputting an allele frequency distance into a trained statistical model; and outputting, from the trained statistical model, a value indicative of a likelihood that the genomic sequence of interest is germline or a value indicative of a likelihood that the genomic sequence of interest is somatic” provides insignificant extra-solution activities (inputting and outputting data into a model are pre- and post-solution activities involving data manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 38: “the allele frequency distance is adjusted to correct for a contamination level in the patient sample, a low sequencing read depth, a noisy estimation of allele frequencies, a low segment germline single nucleotide polymorphism (SNP) count, or high variability in segment germline SNP allele frequency” provides insignificant extra-solution activities (correcting data for contamination or noise is a post-solution activity involving data manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 41: “training the statistical model using data for tumor samples with known germline sequences, known somatic sequences, or both” provides insignificant extra-solution activities (training a model is a pre-solution activity involving data gathering and manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 45: “training the statistical model using data for variant allele frequencies that excludes variants located in genomic regions known to have allele frequencies that deviate from expected values” provides insignificant extra-solution activities (training a model is a pre-solution activity involving data gathering and manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 47: “training the statistical model using data that incorporates prior knowledge of the likelihood of a variant being a germline, a somatic variant, or a clonal hematopoiesis of indeterminate potential (CHIP) variant based on historical data or databases” provides insignificant extra-solution activities (training a model using historical data is a pre-solution activity involving data gathering and manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 49: “training the statistical model using data that accounts for a noise level for a given variant call and its genomic context” provides insignificant extra-solution activities (training a model including noisy data is a pre-solution activity involving data gathering and manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 62: “treating the cancer using the selected cancer treatment modality” restricts use to a particular environment or application without adding significant innovation that does not serve to integrate the judicial exceptions into a practical application because they are post-solution activities involving a mere field of use
The steps for obtaining, ligating adapters to, amplifying, bait capturing, and sequencing nucleic acid samples; segmenting, correcting, inputting, outputting sequence data; and training statistical models are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application because they are pre- and post-solution activities involving data gathering. Additionally, the steps for “treating the cancer” restricts use to a particular environment or application without adding significant innovation that does not serve to integrate the judicial exceptions into a practical application because they are post-solution activities involving a mere field of use (see MPEP 2106.04(d)(2) - Integration of a Judicial Exception Into A Practical Application; MPEP 2106.05(g) - Insignificant Extra-Solution Activity; and MPEP 2106.05(h) - Field of Use and Technological Environment). Examiner notes that in order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. An example of such a limitation is a step of "administering amazonic acid to a patient" or a step of "administering a course of plasmapheresis to a patient." If the limitation does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration. For example, a step of "prescribing a topical steroid to a patient with eczema" is not a positive limitation because it does not require that the steroid actually be used by or on the patient, and a recitation that a claimed product is a "pharmaceutical composition" or that a "feed dispenser is operable to dispense a mineral supplement" are not affirmative limitations because they are merely indicating how the claimed invention might be used. Therefore, claims 1, 16, 17, 20, 21, 23, 24, 30, 37-39, 41, 45, 47, 49, 51, 53, 62, 69, and 74 are directed to an abstract idea (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application, or equate to mere instructions to apply the recited exception in a generic way or in a generic computing environment.
The limitations for obtaining, ligating adapters to, amplifying, bait capturing, and sequencing nucleic acid samples; segmenting, correcting, inputting, outputting sequence data; and training statistical models are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application. Furthermore, no inventive concept is claimed by these limitations as they are well-understood, routine, and conventional.
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, 16, 17, 20, 21, 23, 24, 30, 37-39, 41, 45, 47, 49, 51, 53, 62, 69, and 74 are not patent eligible.
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.
Claims 1, 16, 17, 20, 21, 23, 24, 30, 37-39, 41, 45, 47, 49, 51, 53, and 62 rejected under 35 U.S.C. 103 as being unpatentable over Nance et al. (WO-2019060640) in view of Hill et al. (Hill et al. "MMAPPR: mutation mapping analysis pipeline for pooled RNA-seq." Genome research 23.4 (2013): 687-697).
Regarding claims 1, 16-17, and 30, Nance teaches: obtaining, ligating adapters to, amplifying, bait capturing, and sequencing nucleic acid samples; selecting a genomic sequence of interest at a genomic locus from the one or more genomic loci; selecting one or more proxy genomic sequences for the genomic sequence of interest; and identifying the genomic sequence of interest as germline or somatic using the associated quantitative measures (Para.0104-0122 includes sampling nucleic acids (NAs) from tissues that also contain tumor Nas (Para.0104-0110), ligating barcodes/adapters via "tagging" (Para.0111-0115), amplification (Para.0116-0117), enrichment via baiting (Para.0118-0119), and sequencing (Para.0120-0122), and Abstract "a method of identifying a somatic or germline origin of a nucleic acid variant from a sample of nucleic acid molecules comprises: determining quantitative measures for the nucleic acid variant comprising a total allele count and minor allele count for the nucleic acid variant; identifying an associated variable of the nucleic acid variant; determining a quantitative value for the associated variable; generating a statistical model for expected germline mutant allele counts at a genomic locus of the nucleic acid variant; generating a probability value (p-value) for the nucleic acid variant based at least in part on the statistical model, the quantitative value, and at least one of the quantitative measures; and classifying the nucleic acid variant as (i) being of somatic origin when the p-value is below a predetermined threshold value, or as (ii) being of germline origin when the p-value is at or above the predetermined threshold value").
Nance does not explicitly teach determining an allele frequency distance using an observed allele frequency of the genomic sequence of interest and a summary statistic or distribution indicative of observed allele frequencies of the one or more proxy genomic sequences.
However, Hill teaches am allele frequency calculation as part of a method for identifying SNP candidates (Page 2 col 2 last paragraph "MMAPPR compensates for the noise inherent in RNA-seq data sets to map mutations. MMAPPR encompasses five steps: (1) RNA sequencing and mapping, (2) allele frequency distance calculation, (3) signal processing, (4) candidate single nucleotide polymorphism (SNP) identification, and (5) candidate confirmation").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Nance as taught by Hill in order to perform a noise-resistant sequence analysis without parental information (page 4 col 2 last paragraph "Given the reasons for rejecting the approaches outlined above, we chose to measure allele segregation using Euclidean distance (ED), as a metric that does not require parental strain information and is resistant to noise"). One skilled in the art would have a reasonable expectation of success because both methods utilize associated variables to the sequence of interest for statistical analysis of sequence data.
Regarding claim 20, Nance in view of Hill teach the methods of Claim 16 on which this claim depends/these claims depend, respectively. Nance also teaches the one or more proxy genomic sequences are located within a defined segment of the patient genomic sequence, and the selected genomic sequence of interest is located within the same defined segment (Para.066 "Reference Sequence. As used herein, "reference sequence" refers to a known sequence used for purposes of comparison with experimentally determined sequences. For example, a known sequence can be an entire genome, a chromosome, or any segment thereof" and para.0101 "In some embodiments, the sequence information is obtained from targeted segments of the nucleic acids. Essentially any number of genomic regions may be optionally targeted. The targeted segments can include at least 10, at least 50, [etc] different and/or overlapping genomic regions").
Regarding claim 21, Nance in view of Hill teach the methods of Claim 20 on which this claim depends/these claims depend, respectively. Nance also teaches the patient genomic sequence is segmented into a plurality of segments based on copy number uniformity within each segment (Para.009 "the associated variable of the nucleic acid variant comprises one or more of: [] a copy number breakpoint" and para.048 "the term "copy number breakpoint" refers to a genomic locus at which the copy number (CN) of two neighboring genomic regions (within the same chromosome) on either side of that genomic locus is different").
Regarding claim 23, Nance in view of Hill teach the methods of Claim 16 on which this claim depends/these claims depend, respectively. Nance also teaches the summary statistic is a mean allele frequency or a median allele frequency (Para.009 "the method further comprises determining a mean and/or a variance value of one or more mutant allele counts for the associated variable of the nucleic acid variant").
Regarding claim 24, Nance in view of Hill teach the methods of Claim 16 on which this claim depends/these claims depend, respectively. Nance also teaches the allele frequency distance is determined using the observed allele frequency of the genomic sequence of interest and the distribution indicative of the observed frequencies of a plurality of proxy genomic sequences, and wherein the genomic sequence of interest is identified as germline or somatic based on a probability that the observed allele frequency of the genomic sequence of interest fits within or does not fit within the distribution (Para.005 "generating a probability value (p- value) for the nucleic acid variant based at least in part on the statistical model for expected germline mutant allele counts, the quantitative value for the associated variable of the nucleic acid variant, and at least one of the plurality of quantitative measures for the nucleic acid variant").
Regarding claims 37 and 39, Nance in view of Hill teach the methods of Claim 16 on which this claim depends/these claims depend, respectively. Nance also teaches: inputting an allele frequency distance into a trained statistical model; outputting, from the trained statistical model, a value indicative of a likelihood that the genomic sequence of interest is germline or a value indicative of a likelihood that the genomic sequence of interest is somatic; and the trained statistical model comprises a function that associates the allele frequency distance with the value indicative of a likelihood that the genomic sequence of interest is germline or the value indicative of a likelihood that the genomic sequence of interest is somatic (it would be obvious to use the allele frequency distance of Hill as input for the model of Nance. Nance Para.080 "Once a nucleic acid variant is identified from the nucleic acid molecules in the sample, quantitative values relating to the nucleic acid variant and associated variables may be established to provide input values for implementing the statistical model", para.082 "Another input value required for the model may be the quantitative value(s) for the associated variable(s). In operation 104, at least one associated variable may be identified. The associated variables may be used in estimating the expected germline mutant allele counts at the genomic locus of the nucleic acid variant. Such associated variables may include, but are not limited to, germline heterozygous SNP(s), GC content measure, probers - specific bias measure, fragment length value, sequencing statistics measure, copy number breakpoint, clinical data from the subject, or any combination thereof", and abstract "classifying the nucleic acid variant as (i) being of somatic origin when the p-value is below a predetermined threshold value, or as (ii) being of germline origin when the p-value is at or above the predetermined threshold value").
Regarding claim 38, Nance in view of Hill teach the methods of Claim 16 on which this claim depends/these claims depend, respectively. Nance also teaches the allele frequency distance is adjusted to correct for a contamination level in the patient sample, a low sequencing read depth, a noisy estimation of allele frequencies, a low segment germline single nucleotide polymorphism (SNP) count, or high variability in segment germline SNP allele frequency (Para.085 "the method further comprises determining a MAR In some embodiments, the MAF [mutant allele fraction] is adjusted to a reduced scale").
Regarding claims 41, 45, 47, and 49, Nance in view of Hill teach the methods of Claim 37 on which this claim depends/these claims depend, respectively. Nance also teaches: training the statistical model using data for tumor samples with known germline sequences, known somatic sequences, or both; training the statistical model using data for variant allele frequencies that excludes variants located in genomic regions known to have allele frequencies that deviate from expected values; training the statistical model using data that incorporates prior knowledge of the likelihood of a variant being a germline, a somatic variant, or a clonal hematopoiesis of indeterminate potential (CHIP) variant based on historical data or databases; training the statistical model using data that accounts for a noise level for a given variant call and its genomic context (Para.055 "Historic Sample Set. As used herein, the term "historic sample set" refers to a set of samples which are obtained from normal subjects (having no disease/cancer), subjects having any disease or cancer, subjects having a particular cancer type and/or subjects who are receiving or have received a particular therapy" and para.089 "the p comprises a median value of at least one set of p values from a historic sample set", as the historical data may be used for training).
Regarding claims 51 and 53, Nance in view of Hill teach the methods of Claim 16 on which this claim depends/these claims depend, respectively. Nance also teaches: the one or more proxy genomic sequences includes a single nucleotide polymorphism (SNP) or an allele; and the genomic sequence of interest includes a genomic variant (Para.006 "the sequencing information comprises cell-free nucleic acid sequencing reads comprising the nucleic acid variant and the associated variable of the nucleic acid variant, which associated variable comprises at least one heterozygous single nucleotide polymorphism (het SNP) within a specified genomic region relative to the nucleic acid variant").
Regarding claim 62, Nance in view of Hill teach the methods of Claim 16 on which this claim depends/these claims depend, respectively. Nance also teaches a method of treating cancer in a patient, comprising: identifying, by the one or more processors, one or more genomic sequences of interest as somatic using the method of claim 16; selecting a cancer treatment modality based on the one or more identified somatic sequences; and treating the cancer using the selected cancer treatment modality (Para.026 "the present disclosure provides a method of treating a disease in a subject, the method comprising administering one or more customized therapies to the subject, thereby treating the disease in the subject").
Claims 69 and 74 rejected under 35 U.S.C. 103 as being unpatentable over Nance et al. (WO-2019060640) in view of Hill et al. (Hill et al. "MMAPPR: mutation mapping analysis pipeline for pooled RNA-seq." Genome research 23.4 (2013): 687-697) as applied to claims 1, 16, 17, 20, 21, 23, 24, 30, 37-39, 41, 45, 47, 49, 51, 53, and 62 above, and further in view of Alexander et al. (US-20200049599).
Nance et al. in view of Hill et al. are applied to claims 1, 16, 17, 20, 21, 23, 24, 30, 37-39, 41, 45, 47, 49, 51, 53, and 62.
Regarding claim 69, Nance in view of Hill teach the methods of Claim 16 on which this claim depends/these claims depend.
Nance nor Hill explicitly teach a method of monitoring cancer progression or recurrence in a patient, comprising detecting the presence or absence of the one or more genomic sequences of interest identified as somatic within a second patient sample obtained from patient after the cancer has been treated.
However, Alexander teaches a method of monitoring disease (cancer) progression in a patient (Para.0421 "the disclosure is related to a method of monitoring a disease in a patient [] the disease is cancer").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Nance and Hill as taught by Alexander in order to monitor therapy outcomes over time or between patients having different therapies (para.0400 " the representative data is generated by measuring the same or multiple markers at different time points, e.g., before and after therapy and in one aspect, can be used to monitor therapy or a patient's condition over the course of treatment" and para.0414 "the method is useful to monitor therapy and disease progression in patient or across different patients with the same or similar disease receiving the same or different therapies"). Additionally, in order to identify neoantigens for cancer treatment by screening tumor cells and production of a tumor vaccine (para.0713 "another application of the subject samples is for the isolation of tumor cells and antigens derived therefrom which may be used in the production of tumor specific antibodies or in the manufacture of cancer or tumor vaccines" and Para.0720 "Identifying neoantigens from isolated tumor cells is of paramount importance for treatment of a subject with cancer(s)"). One skilled in the art would have a reasonable expectation of success because both methods are concerned with employing sequencing for identifying cancer progression and treatments.
Regarding claim 74, Nance in view of Hill teach the methods of Claim 16 on which this claim depends/these claims depend, respectively. Nance also teaches a method of selecting a neoantigen for a cancer vaccine personalized for a subject having cancer, comprising selecting from the one or more genomic sequences of interest identified as somatic, a genomic sequence that encodes a neoantigen suitable as a cancer vaccine for the subject (Para.0720 "samples generated using the disclosure may be subject to any relevant diagnostic methods, such as but not limited to those discussed in the present application, for identification of a neoantigen biomarker with a tumor sample").
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 16, 17, 20, 21, 23, 24, 30, 37-39, 41, 45, 47, 49, 51, 53, 62, 69, and 74 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US-20250014678 in view of Hill et al. (Hill et al. "MMAPPR: mutation mapping analysis pipeline for pooled RNA-seq." Genome research 23.4 (2013): 687-697). Although the claims at issue are not identical, they are not patentably distinct from each other because both involve obtaining, ligating adapters to, amplifying, bait capturing, and sequencing nucleic acid samples; selecting a genomic sequence of interest at a genomic locus from the one or more genomic loci; selecting one or more proxy genomic sequences for the genomic sequence of interest; and identifying the genomic sequence of interest as germline or somatic using the associated quantitative measures.
While US-20250014678 does not explicitly teach using allelic frequence distance as the associative measure, it would have been obvious to one of ordinary skill in the art to modify these methods, with those taught by Hill as described above for claim 16 of the instant application, in order to perform a noise-resistant sequence analysis without parental information (page 4 col 2 last paragraph "Given the reasons for rejecting the approaches outlined above, we chose to measure allele segregation using Euclidean distance (ED), as a metric that does not require parental strain information and is resistant to noise"). One skilled in the art would have a reasonable expectation of success because both methods utilize associated variables to the sequence of interest for statistical analysis of sequence data.
Claims 1, 16, 17, 20, 21, 23, 24, 30, 37-39, 41, 45, 47, 49, 51, 53, 62, 69, and 74 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US-20250283167 in view of Hill et al. (Hill et al. "MMAPPR: mutation mapping analysis pipeline for pooled RNA-seq." Genome research 23.4 (2013): 687-697). Although the claims at issue are not identical, they are not patentably distinct from each other because both involve obtaining, ligating adapters to, amplifying, bait capturing, and sequencing nucleic acid samples; selecting a genomic sequence of interest at a genomic locus from the one or more genomic loci; selecting one or more proxy genomic sequences for the genomic sequence of interest; and identifying the genomic sequence of interest as germline or somatic using the associated quantitative measures.
While US-20250283167 does not explicitly teach using allelic frequence distance as the associative measure, it would have been obvious to one of ordinary skill in the art to modify these methods, with those taught by Hill as described above for claim 16 of the instant application, in order to perform a noise-resistant sequence analysis without parental information (page 4 col 2 last paragraph "Given the reasons for rejecting the approaches outlined above, we chose to measure allele segregation using Euclidean distance (ED), as a metric that does not require parental strain information and is resistant to noise"). One skilled in the art would have a reasonable expectation of success because both methods utilize associated variables to the sequence of interest for statistical analysis of sequence data.
Conclusion
No claims are allowed.
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/R.A.P./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686