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 .
Claims Status
Claims 47, 49-55, 57, 58, & 63-66 filed on 03/30/2026 are pending. Claims 47, 49-55, 57, 58, & 63-66 are currently under examination directed to the elected species of SNV in claim 55, of a coverage score in claim 58, and of an immunotherapeutic agent in claim 63 (see response dated 07/08/2025). Claims 59-62 are withdrawn from consideration as being drawn to a non-elected invention. The cancellation of claims 48 & 56 in the reply filed on 03/30/2026 is acknowledged. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
The attempt to incorporate subject matter into this application by reference to PCT/US2018/052087 is ineffective because an incorporation of essential material to a foreign application or patent is improper under 37 CFR 1.57(d) (see MPEP 608.01(p)(I)(A)(2)).
The incorporation by reference will not be effective until correction is made to comply with 37 CFR 1.57(c), (d), or (e). If the incorporated material is relied upon to meet any outstanding objection, rejection, or other requirement imposed by the Office, the correction must be made within any time period set by the Office for responding to the objection, rejection, or other requirement for the incorporation to be effective. Compliance will not be held in abeyance with respect to responding to the objection, rejection, or other requirement for the incorporation to be effective. In no case may the correction be made later than the close of prosecution as defined in 37 CFR 1.114(b), or abandonment of the application, whichever occurs earlier.
Any correction inserting material by amendment that was previously incorporated by reference must be accompanied by a statement that the material being inserted is the material incorporated by reference and the amendment contains no new matter. 37 CFR 1.57(g).
Claims 47, 49-55, 57, 58, & 63-66 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 47, claim 47 has been amended to recite “wherein classifying a plurality of variants… (A) determining a total molecule count (y) and a mutant allele count of the at least one germline heterozygous SNP; (B) calculating a probability value (p-value) for the nucleic acid variant by: 1. determining an estimate of μbin and ρ from a beta binomial distribution (x,y) ~ Beta binomial (μbin, ρ), … 2. calculating a two-tailed p-value from the below equation p-value = 2 * min(Prbb (x’>A | μbin, ρ, B), Prbb (x’<A | μbin, ρ, B))…” in lines 34-60 of the claim. The specification of the instant application has been thoroughly reviewed but support for this newly added limitation was not found. While there is no in haec verba requirement, newly added claims or claim limitations must be supported through express, implicit, or inherent disclosure. In the instant situation, this limitation and specifics of “determining an estimate of μbin and ρ from a beta binomial distribution (x,y) ~ Beta binomial (μbin, ρ), … 2. calculating a two-tailed p-value from the below equation p-value = 2 * min(Prbb (x’>A | μbin, ρ, B), Prbb (x’<A | μbin, ρ, B))…” is not expressly recited in the specification of the instant application. Additionally, there does not appear to be implicit or inherent support for this limitation because the specification of the instant application teaches “a betabinomial model may be used .. for example, the betabinomial model described in PCT/US2018/052087, hereby incorporated by reference” (paragraph [00171of instant specification) in which the attempt to incorporate subject matter into this application by reference to PCT/US2018/052087 is ineffective because an incorporation of essential material to a foreign application or patent is improper under 37 CFR 1.57(d) (see MPEP 608.01(p)(I)(A)(2)). Since it is not clear how the newly added limitations are implicitly or inherently disclosed, the claims are rejected under 35 USC 112(a). In response, applicant may cancel the new matter, or provide explanations as to where the limitations find express, implicit, or inherent support.
Claims 49-55, 57, 58, & 63-66 are rejected due to their dependence on claim 47.
Claims 47, 49-55, 57, 48, & 63-66 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 47, the recitation of “determining, for at least one variant of the plurality of variants, based on a first mutant allele fraction (MAF) at the first time point and a second MAF at the second time point, a first central tendency measure of the first MAFs and a second central tendency measure of the second MAFs” in lines 19-23 is unclear how to determine a first and second central tendency measure based on a single first MAF at the first time point and a single second MAF at the second time points as measures of central tendency require two or more data points. In addition, the claim recites the limitation “of the at least one germline heterozygous SNP” in lines 38-39 of the claim and there is insufficient antecedent basis for this limitation in the claim. In addition, the claim recites the limitation “for the nucleic acid variant” in lines 40 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the nucleic acid variant” is meant to refer to “classifying a plurality of variants” or refers to a different variant.
Claims 49-55, 57, 58, & 63-66 are rejected due to their dependence on claim 47.
Response to Arguments
The response traverses the rejection. The response asserts that the allegedly confusing term “central tendency” is not with respect to the measurement of a first or second time point, but instead focuses on central tendency of mutant allele frequencies (MAFs) measured at each of a first and second time point and that, for example, paragraph [0236] of the specification describes “as shown, method 1210 includes determining mutant allele frequencies (MAFs) for a plurality of variants from sequence information…at a first and second time point to produce sets of first and second MAFs for a variant…the method 1210 comprises determining a central tendency measure obtained from the MAFs of somatic variants considered for a time point”. Further, the response asserts that in light of the specification, one of ordinary skill readily appreciate the metes and bounds of the term “central tendency”, which is sufficiently clear and definite as a result. This argument has been thoroughly reviewed but was not found persuasive as the claim, as currently amended, recites “based on a first mutant allele fraction (MAF) at a first time point and a second MAF at the second time point” in lines 20-21 of the claim and therefore requires measuring one MAF at a first time point and one MAF at a second time point and does not recite determining MAFs (plural) at a first and second time point to produce sets of first and second MAFs and then determining a central tendency measure obtained from the MAFs. Therefore, it is unclear how to determine a first and second central tendency measure based on a single first MAF at the first time point and a single second MAF at the second time points as measures of central tendency require two or more data points.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 101
Claims 47, 49-55, 57, 58, & 63-66 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method for treating a subject having cancer or suspected of having cancer with a therapeutic agent comprising determining whether the subject has a molecular response score below a predetermined cutoff point, indicating that the subject is a likely responder to the therapeutic agent through measuring mutant allele fractions (MAFs) and central tendency measures at a first timepoint before administering a therapeutic agent and a second time point after administering a therapy. This recitation is a natural correlation between MAFs measured in a plurality of variants in a subject having cancer or suspected of having cancer and likely responder or non-responder to treatment with a therapeutic agent. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites “classifying a plurality of variants…as somatic or germline”, “determining, for at least one variant of the plurality of variants…a first central tendency measure of the first MAFs and a second central tendency measure of the second MAFs”, “determining a ratio based on the first central tendency measure at the first time point and the second central tendency measure at the second time point”, and determining a molecular response score from the ratio and determining if the subject is likely responder when the molecular response score is below the predetermined cutoff value which are a recitations of abstract ideas because it encompasses mathematical concepts, calculations, conclusions, and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of determining a first and second plurality of sequence reads at a first and second time point, determining a ratio of the first and second central tendency measure determined by MAF at the first and second time point, and determining if a subject is likely responder to the therapeutic agent when the molecular response score is below the predetermined cutoff value, however, this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
Although the claims recite “continue administering the therapeutic agent to the subject”, this step is conditional as the therapeutic agent is administered after it is determined that the subject is likely responder. Accordingly, these generally recited elements are considered nothing more than instructions to apply the law of nature because no particular conditions are required by the step of determining if a likely responder. As such, the “administering” step is merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the step of obtaining or having obtained a biological sample is considered insignificant post solution activity. The steps of determining a molecular response score are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Response to Arguments
The response traverses the rejection. The response asserts that under Step 2A, prong one, that the claims at issue are not an abstract idea, as involving analytical complexity beyond that which can be performed in the human mind and that, further, the claims are not natural correlation as involving mathematical processing steps which are not decidedly natural phenomenon and are deployed as a form of disease signal generation given both significance and practical use through operation in combination together. This argument has been thoroughly reviewed but was not found persuasive. First, the recitations of “classifying a plurality of variants…as somatic or germline”, “determining, for at least one variant of the plurality of variants…a first central tendency measure of the first MAFs and a second central tendency measure of the second MAFs”, “determining a ratio based on the first central tendency measure at the first time point and the second central tendency measure at the second time point”, and determining a molecular response score from the ratio and determining if the subject is likely responder when the molecular response score is below the predetermined cutoff value which are a recitations of abstract ideas because it encompasses mathematical concepts, calculations, conclusions, and determinations which can occur entirely within the mind (see MPEP 2106.04(a)(2)(I)). In addition, the claimed invention recites a method for treating a subject having cancer or suspected of having cancer with a therapeutic agent comprising determining whether the subject has a molecular response score below a predetermined cutoff point, indicating that the subject is a likely responder to the therapeutic agent through measuring mutant allele fractions (MAFs) and central tendency measures at a first timepoint before administering a therapeutic agent and a second time point after administering a therapy in which this recitation is a natural correlation between MAFs measured in a plurality of variants in a subject having cancer or suspected of having cancer and likely responder or non-responder to treatment with a therapeutic agent.
The response also asserts that turning to Step 2B, that the claims do recite additional steps that do both integration and a practical application and that the claims are not “generally recited elements” applying a law of nature, as described supra, a particular set of analysis, computation and determinations are provided and applied in use together. Further, the response asserts that specifically recited steps such as filtering somatic/germline, central tendency of MAFs distribution longitudinally, and the ratio of central tendency measurements against cutoff at a form of signal generation in combination together and therefore, rather than a menagerie of random measurements, the processing and generation of signal is derived from steps (a)(a)-(a)(f), including determination of therapy administration as a practical application. This argument has been thoroughly reviewed but was not found persuasive as the steps of determining a molecular response score are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). In addition, the recitation of administering a therapeutic agent to treat the subject is generally recited.
The response also asserts that the claims at issue involve administration of therapy in a manner providing for subject matter eligibility when proper evaluating the claims as a whole. Further, the response asserts that the presently amended claims cannot be interpreted as containing contingent language and presently amended step (a)(f) will always involve a determination of a subject as a molecular responder with further administration of continuing treatment and therefore, this ordered combination of step (a)(a) and (a)(e), followed by step (a)(f) administration of immunotherapy, satisfy both integration and practical application when properly taken together as a whole. This argument has been thoroughly reviewed but was not found persuasive. First, although the claims recite “continue administering the therapeutic agent to the subject”, this step is conditional as the therapeutic agent is administered after it is determined that the subject is likely responder, therefore, continuing treatment is the result of/conditional on determining a subject is a likely responder. Accordingly, these generally recited elements are considered nothing more than instructions to apply the law of nature because no particular conditions are required by the step of determining if a likely responder. Second, the administration of a therapeutic agent of an immunotherapeutic agent is very broad and encompasses a wide range of possible treatments and therefore are not meaningful constraints on the administration step such that the particular treatment consideration would apply because it is not limited to a particular immunotherapeutic agent (see example 49 of 2024 Guidance on Patent Subject Matter Eligibility).
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 103
Claim(s) 47, 49-55, & 63-66 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Zhang et al.; Cancer Discovery, Vol. 10, pages 1842-1853, August 2020), as cited in the IDS dated 09/12/2022, in view of Nance (WO 2019/060640 A1, March 2019), as cited on the IDS dated 09/12/2022, as evidenced by Garassino (Garassino et al.; The Lancet Oncology, Vol. 19, pages 521-536, April 2018).
Regarding amended claim 47, it is noted that paragraph [00811] of the instant specification teaches that “mutant allele frequency”, “variant allele frequency”, “mutant allele fraction”, “variant allele fraction”, “MAF”, or “VAF” refers to the frequency at which mutant alleles occur in a given population of nucleic acids. It is noted that paragraph [00217] of the instant specification teaches that in some embodiments the method includes using a molecule count to calculate to calculate the standard deviation for a MAF ratio in the set of ratios and that this method includes excluding one or more germline and/or clonal hematopoietic variants when determining the mutant allele frequencies.
Zhang teaches a method for analyzing pretreatment (first time point before administering a therapeutic agent) and on-treatment (second time point after administering the therapy) circulating tumor DNA (ctDNA) samples across 16 advanced-stage tumor types from three phase I/II trials of durvalumab through measuring mean pretreatment (first time point) variant allele frequencies (VAF) and mean on-treatment (second time point) VAF to determine molecular response to enable early determination of responders to immune checkpoint blockades (abstract lines 2-13). In addition, Zhang teaches obtaining cell-free ctDNA from patients and sequencing the ctDNA at the pretreatment (first time point) and on-treatment (second time point) (determining a first plurality of sequence reads and a second plurality of sequence reads that are determined at a first time point before administering a therapeutic agent and a second time point after administering the therapy), characterizing the somatic genomic alterations (classifying the sequence reads as somatic or germline), determining the mean (central tendency) pretreatment (first time point) VAF and the mean (central tendency) on-treatment (second time point VAF) (wherein each central tendency measure comprises a mean), determining a ratio of the mean (central tendency) pretreatment (first time point) VAF and the mean (central tendency) on-treatment (second time point VAF) to determine the molecular response (determining a molecular response score from the ratio of the first central tendency measure at the first time point to the second central tendency measure at the second time point), and using the molecular response to determine associations with immunotherapy outcomes based on a cutoff point of a >50% decrease in VAF (determining the subject is likely responder to the therapeutic agent when the molecular response score a below the predetermined cutoff point), and further administering treatment when determined as molecular responders (pg. 1844 paragraph bridging column 1 & 2 lines 1-6; pg. 1844 column 2 1st full paragraph lines 1-11; pg. 1844-1846 paragraph bridging pg. 1844 & pg. 1846 lines 1-10; pg. 1846 paragraph bridging column 1 & 2 lines 29; pg. 1846 column 2 1st full paragraph lines 1-6; pg. 1848 column 2 1st full paragraph lines 1-18; pg. 1850 column 1 2nd full paragraph lines 1-9; pg. 1850 column 2 1st full paragraph lines 1-10; pg. 1850 column 2 2nd full paragraph lines 1-3; pg. 1850 column 2 5th full paragraph lines 1-7; pg. 1850 column 2 6th full paragraph line 1). Zhang also teaches that potential germline and clonal hematopoietic variants were filtered out and for each of the samples the somatic SNVs were used to calculate the mean and maximum VAF and the total mutation count (using a molecule count to calculate the MAF for at least one variant of the plurality of variants) (pg. 1850 column 2 1st full paragraph lines 1-10; pg. 1850 column 2 2nd full paragraph lines 1-3).
Zhang does not teach wherein classifying a plurality of variants in the first plurality of sequence reads and the second plurality of sequence reads as somatic or germline comprises steps (A)-(C).
Nance teaches a method of identifying a somatic or germline origin of a nucleic acid variant from a sample of nucleic acid molecules, comprising a sample of cell-free DNA, comprising determining a total allele count and a minor allele count (determining a total molecule count (y) and a mutant allele count, step (A)), generating a p-value for the nucleic acid variant comprising estimating beta binomial distribution parameters using (x,y) ~ Beta binomial (μbin, ρ) wherein y = a vector of total molecule count of the at least one germline heterozygous SNP, with one entry for each germline heterozygous SNP, x = a vector of min(mutant allele count of the at least one germline heterozygous SNP, y – mutant allele count of the at least one germline heterozygous SNP), with one entry for each germline heterozygous SNP, μbin = an estimate of the mean mutant allele count of heterozygous SNPs in a bin, wherein the bin is the specified genomic region relative to the nucleic acid variant, and ρ = an estimate of a dispersion parameter, and comprising calculating a two-tailed p-value for the nucleic acid variant using p-value = 2 * min(Prbb (x’>A | μbin, ρ, B), Prbb (x’<A | μbin, ρ, B), wherein Prbb = a probability of beta binomial, x’ = a random variable distributed with the beta binomial, A = a mutant allele count of the nucleic acid variant, and B = a total molecule count of the nucleic acid variant (step (B)), and classifying the nucleic acid variant as being of somatic origin when the p-value for the nucleic acid variant is at or below the predetermined threshold value or as being of germline origin when the p-value for the nucleic acid variant is at or above the predetermined threshold value (step (C)) (paragraph [004] lines 1-16; paragraph [005] lines 1-17; paragraph [011] lines 1-16). In addition, Nance teaches that this method accurately models the variance seen in nucleic acid molecule counts and can differentiate somatic and germline variants with high accuracy (paragraph [078] lines 1-15).
Zhang and Nance are considered to be analogous to the claimed invention because they are all in the same field of detecting VAFs in cell free DNA samples. 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 modified the method of classifying a plurality of variants in the first plurality of sequence reads and the second plurality of sequence reads as somatic or germline in Zhang to incorporate the identification of a somatic or germline origin of a nucleic acid variant from a sample of cell-free DNA comprising steps (A)-(C) as taught in Nance because Nance teaches that doing so would provide the ability to accurately model the variance seen in nucleic acid molecule counts and differentiate somatic and germline variants with high accuracy.
Regarding claim 49, Zhang teaches determining the molecular response based on a cutoff point of 50% to determine molecular responders and nonresponders (determining subject is a likely non-responder to the therapeutic agent when the molecular response score is at or above the predetermined cutoff point) (pg. 1846 paragraph bridging column 1 & 2 lines 29; pg. 1850 column 2 6th full paragraph line 1).
Regarding claim 50, Zhang teaches further treating molecular responders with radiologic treatment (further administering one or more therapies for the cancer to the subject in view of the molecular response score (pg.1846-1847 paragraph bridging pg. 1846 & pg. 1847 lines 3-23).
Regarding claim 51, Zhang teaches filtering against potential germline and clonal hematopoietic variants from the plurality of variants (pg. 1850 column 2 1st full paragraph lines 8-10).
Regarding claim 52, Zhang teaches a VAF of 0.3% was the limit of detection and that variants with VAF <0.3% were removed unless variants with VAF <0.3% and the exact variant was also detected in the paired sample with VAF ≥ 0.3% (excluding one or more somatic variants having MAFs that are less than about 0.3% at first and second time points) (pg. 1850 column 2 2nd full paragraph lines 1-7).
Regarding claim 53, Zhang teaches that the ctDNA is extracted for sequencing is from tumor tissues of the subjects (generating the first and second plurality of sequence reads from nucleic acid molecules obtained from one or more tissues or cells of the subject) (pg. 1850 column 1 2nd full paragraph lines 1-5).
Regarding claim 54, Zhang teaches that the cell-free nucleic acids for sequencing of the pretreatment (first time point) and on-treatment (second time point) samples is from extracted ctDNA from the subjects (pg. 1850 column 2 1st full paragraph line 1).
Regarding claim 55, Zhang teaches that somatic genomic alterations of single nucleotide variants (SNV) were characterized (pg. 1850 column 2 1st full paragraph lines 1-4).
Regarding claims 63 & 64, Zhang teaches the therapeutic agent is the immunotherapeutic immune checkpoint inhibitor durvalumab (abstract lines 2-4; pg. 1850 column 1 2nd full paragraph lines 1-3).
Regarding claim 65, Zhang teaches that the on-treatment (second time point) sample collection was as 6 to 8 weeks after the first dose (the second time point is at least 1-24 hours, 1-180 days, 1-12 weeks, 1-25 weeks, or 1-30 weeks after the first time point) (pg. 1850 column 1 2nd full paragraph lines 6-9).
Regarding claim 66, Zhang teaches three studies, including ATLANTIC, were used in this study in which the pretreatment (first time point) sample is collected before the initiation of treatment and then in the ATLANTIC study the durvalumab treatment is administered every 2 weeks, as evidenced by Garassino (pg. 524 column 1 1st full paragraph lines 1-6 of Garassino) (the therapeutic agent is administered at least 1-2 weeks or 1-2 months after the first time point) (pg. 1850 column 1 2nd full paragraph lines 1-9).
Claim(s) 57 & 58 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Zhang et al.; Cancer Discovery, Vol. 10, pages 1842-1853, August 2020), as cited in the IDS dated 09/12/2022, and Nance (WO 2019/060640 A1, March 2019), as cited on the IDS dated 09/12/2022, as applied to claims 47, 49-55, & 63-66 above, and further in view of Strijker (Strijker et al.; International Journal of Cancer, Vol. 146, pages 1445-1456, July 2019), as cited on the IDS dated 09/12/2022.
The teachings of Zhang and Nance with respect to claim 47 is discussed above.
Regarding claims 57 & 58, Zhang and Nance does not teach a method further comprising one or more additional genomic data sources of a coverage to determine the molecular response score.
Strijker teaches a method of detecting sequences of cell-free ctDNA in cancer samples to measure the VAF in the samples along with measuring the median coverage of the KRAS mutation at a baseline time point before treatment (first time point) and follow-up time point after treatment (using one or more additional genomic data sources comprising a coverage) (second time point (abstract lines 3-8; pg. 1447 column 2 1st full paragraph lines 1-12; pg. 1448 column 2 1st full paragraph lines 1-14; pg. 1448-1450 paragraph bridging pg. 1448 & pg. 1450 lines 8-11). In addition, Strijker teaches the need for extensive coverage and patient-tailored primers for developing a comprehensive cancer panel that can cover more than a single locus (pg. 1454 column 2 1st full paragraph lines 1-6).
Zhang, Nance, and Strijker are considered to be analogous to the claimed invention because they are all in the same field of detecting VAFs in cell free DNA samples. 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 modified the method of determining the molecular response through determining a ratio of the mean (central tendency) pretreatment (first time point) VAF and the mean (central tendency) on-treatment (second time point VAF) in Zhang to incorporate the determination of the additional genomic data source as taught in Strijker because Strijker teaches that doing so would provide the ability to develop a more comprehensive cancer panel with extensive coverage beyond a single locus.
Response to Arguments
The response traverses the rejection. The response asserts that the presently amended claims refer to subject continuing their existing treatment as recited in step (a)(f) and Zhang does not particularly express description of step (a)(f) of continued administration of treatment based on a comparison to a cutoff. This argument has been thoroughly reviewed but was not found persuasive as Zhang teaches using the molecular response to determine associations with immunotherapy outcomes based on a cutoff point of a >50% decrease in VAF (determining the subject is likely responder to the therapeutic agent when the molecular response score a below the predetermined cutoff point), and further administering treatment when determined as molecular responders and further teaches that this method can be used in clinical practice to inform decisions about continuation or early transition of therapy (continued treatment based on comparison to cutoff) (pg. 1844-1846 paragraph bridging pg. 1844 & pg. 1846 lines 1-10; pg. 1846 paragraph bridging column 1 & 2 lines 29; pg. 1846 column 2 1st full paragraph lines 1-6; pg. 1848 column 2 1st full paragraph lines 1-18; pg. 1850 column 1 2nd full paragraph lines 1-9).
The response also asserts that the claims at issue are further distinguishable from Zhang by using a particular “beta-binomial” probabilistic distribution measurement for determining somatic and germline variants of step (a)(c) and Zhang does not describe use of this algorithm for discrimination between somatic and germline variants and the present amended claims are further distinguishable as a result. This argument has been thoroughly reviewed but was not found persuasive as the prior art of Zhang and Nance, as evidenced by Garassino, as applied to amended independent claim 47 as necessitated by amendment, teaches every element of claim 47 as currently amended as discussed above.
The response also asserts that the deficiencies of Zhang are not remedied in combination with Strijker which also fails to describe either of these claimed features and as sch Zhang and/or Strijker cannot teach, suggest, motivate, or in any other way make obvious the presently amended claims. This argument has been thoroughly reviewed but was not found persuasive for the reasons set for above and as the prior art of Zhang, Nance, and Strijker, as applied to claims 57 & 58 as necessitated by amendment, teaches each and every element of amended claim 47 and dependent claims 57 & 58 as discussed above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
Claims 47, 49-55, 57, 58, & 63-66 are rejected.
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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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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