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
Applicant’s election without traverse of the following in the reply filed on 04/10/2026 is acknowledged:
Species A (treatment/compounds): HSP90 inhibitor
Species B (neoplasm/cancer): bladder cancer
Species C (contact location of treatment/compound): in vivo
Species D (somatic mutation(s)): SNVs
Species E (means of assessing genetic material): assessing gene expression of genes comprising mutations
Upon further search and consideration, the election of species requirement of species C, D, and E is withdrawn. The election of species requirement for a treatment or compound (Species A) for the invention of claim 16 is also withdrawn upon further search and consideration.
Claims 13 and 14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/10/2026.
Status of Claims
Applicant’s claims filed 05/18/2023 is acknowledged. Claims 1-20 are pending in the instant application and 1-12 and 15-20 are the subject of this non-final office action.
Priority
The present application filed 05/18/2024 claims the benefit of 63/364,936, filed 05/18/2022.
‘936 is directed to the 1-15 and 20. No description was identified in ‘936 for a method of contacting a cell of a specimen that is a growth or tumor from which mutational burden has been determined with a compound, either in vitro or in vivo.
Accordingly, claims 16-19 have been given the priority date of 05/18/2023.
Further, as all claims are subject to 112(a) rejections, claims 1-12, 15, and 20 have also been given the priority date of 5/18/2023. See MPEP 211, which states that in order to be entitled to the benefit of the prior-filed application, the earlier application must disclose the claimed invention in the manner provided by 35 USC 112(a).
Specification
The disclosure is objected to because of the following informalities. Appropriate correction is required.
Para [0078] makes reference to “Supplemental Figs. 7B, 7C, and 7D”. These appear to be referencing Fig. 7B, 7C, and 7D rather than a separate set of supplemental figures.
Para [0060] and [0098] recites Table 1 and para [0062] recite Table 2; these appear to have been inadvertently omitted. See below.
As recited in MPEP 217, if all or a portion of the specification or drawing(s) is inadvertently omitted from an application, but the application contains a claim under 37 CFR 1.78 for the benefit of a prior-filed provisional that was present on the filing date of the application, and the inadvertently omitted portion of the specification or drawing(s) is completely contained in the prior-filed application, the claim for priority or benefit shall be considered an incorporation by reference of the prior-filed application as to the inadvertently omitted portion of the specification or drawings.
The instant application claims priority to 63/364,936, which fully contains Tables 1 and 2.
The Applicant is required to amend the disclosure to include the material inadvertently omitted. 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. See 37 CFR 1.57(b).
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1: The verb “determine” in line 5 is in a different tense than “assessing” in line.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-12 and 15 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Regarding claims 1-12 and 15, MPEP 2164.01(a) recites the Wands factors considered to determine compliance with the enablement requirement under 35 USC 112(a).
In the instant case, the claims are broad. Claim 1 recites “A method ... comprising, assessing genetic material of a neoplasm or cancer of an individual to determine a mutational burden; based on an amount of mutational burden, determine a treatment regime”.
The amount of mutational burden may be based on any assay of any selection of mutations, for any cancer (narrowed in claim 15; bladder cancer elected) in any species, for any sample (narrowed in claim 7), for any treatment regime (narrowed in claim 12; HSP inhibitor elected). The determination may be made through any means, wherein claim 8 narrows to comparing to a threshold, which claim 9 appears to attempt to narrow to “the top 25% of a particular cancer type or ... in the top 25% of all cancer types” or, respectively, 10% (claim 10) or 5% (claim 11); however, such remains broad as any “a particular cancer type” could be used and no particular database, population, ethnicity, geography, lifestyle characteristics (e.g., smoking) known to influence tumor mutational burden, etc. are required for either the “particular cancer” or “all cancer types” such that these values may encompass a variety of values. Further, the particular cancer may or may not be the same cancer as that of the tumor/cancer of the individual under the claims as written.
It is noted that there may have been an intention to narrow to somatic mutations in claims 2 and 4-5 and particular species of mutations in claims 3 and 20; however, the “an amount of mutational burden” is not required to be linked to the genetic material of the assessing. Nor would the broadest reasonable interpretation require any particular subset to be used. While claims 9-11 depend from claim 2 but so have been interpreted here as intending to depend from claim 8, where the threshold is recited.
The disclosure provided limited direction. In contrast to the breath of the means of determining a treatment regime “based on an amount of mutational burden”, limited guidance is provided on what to base this upon. The disclosure states that any appropriate threshold can be utilized (para [0062]). While the exemplary thresholds matching the claims of 9-11 are provided in para [0062], limited further guidance is given in how to choose from within such thresholds. Table 2 of incorporated by reference provisional application 63/364,936 recites a count of mutations for the 5%, 10%, and 25% mutation burdens, but it is in an unknown unit for unknown species of mutations (best interpretation is mutations per kilobase; see para [0052]; alternatively, these may be the log_10 of the protein coding mutations recited in para [0074]). The range for 5% appears to be 24 (UVM) to 10291 (UCEC), i.e., spanning 2-3 orders of magnitude. The method for producing the “all cancer types” values (e.g., weighting scheme across cancers of different prevalence, use of median or mean, inclusion of rare cancers or only the common categories, etc.) was not identified.
In contrast to the breadth of samples including blood samples and tumor specimens and mutation types including copy number variants, the only data associated with drugs was identified from cell lines (Fig. 11B; para [0087]), wherein the linear models identifying a correlation with drugs based on a mutational load of undisclosed mutations (Fig. 11B; para [0043] and [0087]). “MutLoad” from previous analyses is limited to protein coding mutations (para [0039]; Fig. 4), which the disclosure demonstrates is not correlated in the TCGA or CCLE datasets with copy number alterations (CNA; i.e., copy number variants), amplifications, or deletions, thus indicating the potential for high unpredictability as to whether any other class of mutational “burden” would be capable of predicting.
In contrast to the breath of the treatment regimens claimed, including those comprising the elected HSP90 inhibitors, ten HSP90 inhibitor were screen in cell lines (Fig. 11B; para [0043] and para [0087-88]), including the eight claimed in claim 12, with eleven proteasome inhibitors, of which three are described as ubiquitin-specific proteasome inhibitors. While the greyscale shading in the figure doesn’t allow for precise comparison, the instability across SNX-5422, including the apparent sign flip for ovarian cancer appears to undermine the claim that the regression estimates are stable in para [0043]. Further, instability in the estimates for at least colorectal cancer across multiple HSP90 drugs and a plurality of the proteasome inhibitors is noted.
The art teaches a high level of unpredictability regarding the usefulness of tumor burdens in predicting treatment efficacy. Mouawad (Mouawad A, et al. Tumor mutational burden: why is it still a controversial agnostic immunotherapy biomarker? Future Oncol. 2025 Feb;21(4):493-499. Epub 2024 Dec 23.) teaches mixed results for use of TMB-high as a biomarker for immunotherapy (Tables 1 and 2), and reports that, in contrast to the clinical trial that allowed for the approval of an immune checkpoint inhibitor for high TMB cancer, in many types of cancers no benefit was seen when MMR and Pol-d were intact, and concludes that the broad criterion based on high TMB should be reevaluated to target the patients most likely to benefit (pg. 494, col 2, para 1).
Mouawad states that the need to further study the efficacy of TMB as a biomarker is clear and necessary to improve our understanding of its underlying mechanism to explain the diverging results of different studies (pg. 495, col 2, para 1) and describes varied cutoffs across studies, cancers, and assays (pg. 496, col 2, para 1, spanning pg. 497 to pg. 497, para 1). Mouawad highlights the complexity of TMB as a biomarker, attributes unpredictability in study results to variations in different patient populations, bad cutoff definitions, and limited knowledge about the relationship of TMB with other biomarkers, as well as confounding factors like metabolic genes, sex, and race (pg. 497, 4. Conclusion and future perspective, para 1).
Mouawad, which it is noted is published after the instant application, concludes that more comprehensive data on the TMB levels among different patient populations, ages, and cancer types will be crucial to set a more accurate cutoff definition, which could then be used to study the relationship of TMB with other biomarkers and it efficacy in predicting response to treatment (pg. 497, 4. Conclusion and future perspective, para 1, spanning pg. 498). Mouawad further questions the usefulness of a single quantitative TMB cutoff as a predictor, at least for immunotherapy response, given tumor heterogeneity, patient characteristics, different tumor types, and sequencing assays pg. 497, 4. Conclusion and future perspective, para 1, spanning pg. 498).
In contrast to breadth of the claims about samples types, Huang (Huang Y, et al. DNA Input, sequencing depth, and maximum somatic allele frequency may affect the concordance between blood TMB and tumor TMB.. J Clin Oncol 37, e13163-e13163(2019)) teaches that the concordance of blood TMB and tissue TMB is not stable (Background), finding that at least a very high effective sequencing depth (cutoff of 2500x: correlation of 0.74 vs . 0.28) improved concordance for predicting efficacy of a therapy (Results; Conclusions). The instant disclosure, for example utilized TCGA WES for tissue-based analyses (e.g., para [0089]), which Wang (Wang VG, et al. Whole-exome sequencing capture kit biases yield false negative mutation calls in TCGA cohorts. PLoS One. 2018 Oct 3;13(10):e0204912) teaches has an average sequencing depth of about 100x coverage (Introduction, para 1), with a minority of cancer cohorts containing even at least 25% of samples with 25x coverage at their “case study” genes (Fig. 1). Accordingly, it is interpreted that the artisan would not have found it predictable to utilize the 5%, 10%, and 25% cutoffs of the instant disclosure or of the provisional incorporated by reference for non-tissues sample types.
Further, Wang also concludes that measurement biases across TCGA that indicate potentially false negative somatic mutation calls due to insufficient coverage (Introduction, para 3), and that over half of TCGA samples were found to undercover at least 4833 genes due to the bait kit chosen (Discussion, para 1). It was not identified in the instant disclosure/’936 provisional whether the Table 2 counts of mutations for 5%, 10%, and 25% correspond to CCLE or TCGA; however, the codes used for cancers are those of the TCGA data elsewhere (e.g., Fig. 9B; para [0038-39]). Accordingly, it is interpreted that exemplary tumor mutational burdens used in Table 2, which depend on mutation calls (para [0089]) would be subject to the same systematic biases, leading to unpredictability for the artisan.
In contrast to the disclosure which describe treatments Reddin (Reddin IG, et al. Large inherent variability in data derived from highly standardized cell culture experiments. Pharmacol Res. 2023 Feb;188:106671) recites that they performed 2.8 million compound/cell line experiments with >100 independent biological replicates, finding profound intra-laboratory data variability, although all experiments were executed following highly standardized protocols that avoid all known confounders of data quality (Abstract). Reddin teaches that this unpredictability remained high even after outlier removal, when only considering experiments that tested drugs at the same concentration range, and when only considering NCI60-provided quality-controlled data (Abstract). Reddin states that only about 5% of agents that enter phase I cancer trials are eventually approved as anti-cancer drugs (Introduction, para I) and also found no evidence that FDA-approved drugs displayed less variability than experimental compounds (pg. 6, col 1, para 6).
Reddin concludes that high variability is an intrinsic feature of anti-cancer drug testing, even among standardized experiments in a world-leading research environment (Abstract), and suggests follow-up testing including animal testing to identify drug leads and the involvement of patient-derived cancer models, which may improve data robustness (Discussion, para 7). Reddin states that the value of cell line studies lies in the generation and validation of hypothesis rather than prediction of clinical drug activity, noting that cell lines do not adequately represent the tumor environment (Discussion, para 6).
Goel (Goel B, Jaiswal S, Tripathi N. Recent advances in HSP90 inhibitors as targeted cancer therapy: Chemical scaffolds, isoform selectivity, and clinical progress. Bioorg Chem. 2025 Aug;163:108782. Epub 2025 Jul 20) describes the challenges faced in translating HSP90 inhibitors into effective anticancer agents (Abstract), noting the structural diversity of HSP90 inhibitor (pg. 26, 9. Conclusions and future perspectives, para 1). Goel teaches that HSP90i have had limited clinical success because of dose-limiting toxicities, poor pharmacokinetic profiles, and acquired resistance (pg. 26, 9. Conclusions and future perspectives, para 1). Goel describes that STA-9090 [ganetespib] and AUY922 have encountered significant limitations in clinical trials due to dose-limiting toxicities, including hepatotoxicity, ocular toxicity, and cardiotoxicity (pg. 27, col 1, para 1), wherein these include those claimed in claim 12. Goel teaches that despite promising preclinical results, clinical translation has been challenging (pg. 26, pg. 26, 9. Conclusions and future perspectives, para 1, spanning pg. 27). Therefore, the artisan would understand that even promising HSP90 inhibitors in preclinical testing such as a drug screen would be unpredictable in their ability be part of an effective treatment regimen.
Cagan (Cagan A, et al. Somatic mutation rates scale with lifespan across mammals. Nature. 2022 Apr;604(7906):517-524. Epub 2022 Apr 13) teaches that the somatic mutation rate per year varied greatly across species, and were corelated with lifespan, suggesting that somatic mutation rates are evolutionarily conserved (Abstract). Thus, the artisan would understand that there may be features selected for in non-human animal cells that influence the mutation rate, including that of cancer cells, such that the tumor mutational burden of would be unpredictable.
Therefore, given the breadth of the claims discussed herein, limited guidance discussed in the disclosure, and the state of the prior art that teaches unpredictability in the ability of TMB as a predictor of treatments across cancers, assays, and samples and unpredictability in cancer cell line drug screen and HSP90 inhibitor preclinical drug screening, balanced only against the high level of art in the skill, the amount of experimentation required to make the claimed invention is held to be undue.
For this reason the claims do not comply with the 112(a) enablement requirements.
Claim 1-12 and 15-20 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.
To satisfy the written description requirement with regard to genus/species situation, a “satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by members of the genus in view of the species disclosed.”
Regarding claims 1-12 and 15, claim 1 recites a method comprising assessing genetic material of a neoplasm or cancer of an individual to determine a mutational burden; based on an amount of mutational burden, determine a treatment regimen.
The claims are broad. The amount of mutational burden may be based on any assay of any selection of mutations, for any cancer (narrowed in claim 15; bladder cancer elected) in any species, for any sample (narrowed in claim 7), for any treatment regime (narrowed in claim 12; HSP inhibitor elected). The determination may be made through any means, wherein claim 8 narrows to comparing to a threshold, which claim 9 attempts to narrows to “the top 25% of a particular cancer type or ... in the top 25% of all cancer types” or, respectively, 10% (claim 10) or 5% (claim 11); however, such remains broad as any “a particular cancer type” could be used and no particular database, population, ethnicity, geography, lifestyle characteristics (e.g., smoking) known to influence tumor mutational burden, etc. are required for either the “particular cancer” or “all cancer types” such that these values may encompass a variety of values.
It is noted that there may have been an intention to narrow to somatic mutations in claims 2 and 4-5 and particular species of mutations in claims 3; however, the “an amount of mutational burden” is not required to be linked to the genetic material of the assessing. Nor would the broadest reasonable interpretation require any particular subset to be used. As discussed above, claims 9-11 appear to have been intended to depend from claim 8 where the threshold is first recited.
As cited and discussed in the 112(a) enablement above, Mouawad teaches a high degree of variability in the art regarding the determination of tumor mutational burdens for treatment prediction, at least because of the variability in assays and patient populations. Huang and Wang teach variability between sample types (i.e., tissue vs. blood) at the depth of sequencing utilized by TCGA, which appears to have been utilize to set the exemplary thresholds. Reddin and Goel teach, respectively, teach high variability in cancer cell line drug screening and in the ability of preclinical HSP90 testing to predict the ability to translate into effective treatments. Cagan teaches variability in the somatic mutation rate across species, such that the artisan would conclude that there may be variability across species for tumor mutational burdens.
In contrast to the broad claims and high variability in the art, the disclosure via provision ‘936 recites the limited exemplary mutational burden thresholds of Table 2, which appear to be based on the single dataset of TCGA in humans. As discussed above, Wang teaches that this dataset biases in mutational counts from the assays chosen, which would be understood to lead to variability in mutational burden counts. Further, as discussed and cite in the 112(a) enablement, the disclosure recites that any appropriate threshold may be utilized. In contrast to the threshold of Table 2, a median protein coding mutation amount of > 25 is utilized for one analysis of TCGA (para [0039]) and >1000 in protein coding mutations for the splicing analysis (para [0079]).
The disclosure recites only the single drug screen of Fig. 11B based on human cell lines for HSP90 inhibitors and proteasome inhibitors, including ubiquitin-specific inhibitors, which utilizes a linear model utilizing the data of all cancer cell lines (with jackknife leave-one-out resampling to estimate uncertainty/variability of beta parameters for individual cancer cohorts) to establish a correlation between drug cytotoxicity and all cancers in one experimental dataset (para [0043] and [0087]). These experiments are apparently performed in “high mutational load cell lines” but it was not identified which threshold was utilized to subset the cell lines (para [0043]).
Therefore, given the high variability in the geneses of mutational burden assessments (e.g., assays), mutational burden amount considerations (e.g., thresholds), treatment regimes, samples, cancers in any species, and for any treatment regime compared to the limited species of thresholds for a single dataset in humans, the inconsistent application thereof throughout the disclosure, and a single drug screen experiment in cancer cell lines, the skilled artisan would not have concluded that the applicant had described the claimed invention in sufficient detail to have possession of the claimed invention at the time of filing.
Thus the claims fail to comply with the 112(a) written description requirement.
Regarding claims 16-20, claim 16 recites “A method of assessing cytotoxicity of a compound ... comprising: ... quantifying the amount of somatic mutations within the genetic material; determining that the specimen has a mutational burden that is greater than a threshold; contacting a neoplastic cell ... to assess the cytotoxicity of the compound ...”.
The claims are broad, they encompass any means of quantifying the amount of any selection of somatic mutations within the genetic material of any type of cancer. (While performing high-throughput sequencing is required by the claim, the sequencing is unlinked to the quantifying.) They encompass any mutational burden of any set of mutations (narrowed in claim 20) for any threshold for any compound (narrowed in claim 19) in any setting (elected in vivo of claim 18).
While Table 1 referenced in the disclosure and included in the provisional ‘936 described a number of potential compounds of the classes of claim 19, as discussed in the 112(a) rejections of claims 1-12 and 15, the variability taught in the art at least by Mouawad is high.
As discussed above, it was not identified in the disclosure which mutational burden threshold was used for the PRISM drug screen in Fig. 11B and the instant disclosure fails to describe means, diagrams, or formulas for setting such a threshold. Where thresholds are provided, as discussed and cited previously in the 112(a) rejections above, they are inconsistently used.
Further, while Table 1 discloses multiple drugs for many of the classes of claim 19, it discloses only HSP inhibitors for “chaperone inhibitors” and does not provide sufficient descriptive means in words, structure, figures, diagrams, or formulas to adequately describe the scope of “protein inhibitor”.
Altinok (Altinok S, et al. With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage. Cells. 2021 Nov 11;10(11):3121) teaches that HSPs have vast functions and often utilize co-chaperones that make drug targeting challenging (Abstract), including CHIP which appears to play an opposing role to HSP chaperones in cancer (2.4. Cancer). Altinok teaches that multiple co-chaperones have varied pro-folding or pro-degradation roles across varied cancers (Fig. 4). This indicates a high level of variability across the genus of “chaperones” and the much larger genus of “protein” inhibitors.
Accordingly, the artisan would not have concluded that the applicant had described the claimed invention in sufficient detail to possess the entire genus of compound screens of any type of any level of mutational burden threshold in neoplastic/cancer/tumor cells at the time of filing.
Thus the claims fail to comply with the 112(a) written description requirement.
Claim Rejections - 35 USC § 112(b)
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 5, 9-11, and 19-20 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 5, the claim recites “aligning the sequencing result of the control sample against a reference genome; aligning the sequencing result of the ... cancer with the sequencing result of the control sample”. Claim 4 recites “aligning the sequencing result of the ... cancer against a reference genome”.
It is unclear whether the alignment of the sequencing result of the cancer “with” the sequencing result of the control same is intended to be an alignment of a mixture of the sequencing result (i.e., “combined with”) or an alignment against the sequencing results of the control sample, at least because of the difference in preposition compared to an alignment against the reference genome.
For the sake of compact prosecution, it is also noted that the claims do not require a particular order; if applicant wishes to require alignment to reference-genome aligned cancer and/or control samples, such should be reflected in the claims.
Regarding claim 9-11, the claims recite “wherein the threshold is a mutational burden the top 25% of a particular cancer type or ... in the top 25% of all cancer types” (claim 9) or, respectively, 10% (claim 10) or 5% (claim 11) for either a particular cancer or all cancer types.
First, the claims recite “the threshold”. There is insufficient antecedent basis for this limitation in the claim. “A threshold” is recited in claim 8, but the claims depend from claim 2.
Second, the terms “mutational burden in the top ...% of a particular cancer type” and “mutational burden in the top ...% of all cancer types” are unclear. The values require a relative calculation that is a function of whichever dataset or population is used to generate the distribution of mutational burdens. As discussed in the 112(a) rejections, mutational burden to known to vary across assays, patient populations, etc. such that different these and different sample sizes will each produce as different “top ...% of a particular cancer type” or “top ...% of all cancer types”. As such, the same mutational burden may fall inside or outside the scope of the claim dependent solely on which reference dataset a practitioner selects.
Third, further “a particular cancer type” is unclear. The term “cancer type” is ambiguous such that the artisan may consider a metastatic hepatoblastoma a “carcinoma”, a “liver cancer”, a “hepatoblastoma”, etc. as the art has various levels of grouping “cancer types” that depend on various characteristics and levels of granularity (e.g., TCGA vs ICD 50) such that it would not be reasonably clear to the artisan which values would be infringing.
Regarding claim 19, the claim recites “the compound”. Claim 19 depends upon claim 15, which depends upon claim 1, neither of which recites “a compound”. The phrase “a compound” is recited in claim 16. For the purposes of examination, this was interpreted as depending from claim 16.
Regarding claim 20, the claim recites “the somatic mutations”. Claim 20 depends upon claim 15, which depends upon claim 1, neither of which recite “somatic mutations”. There is insufficient antecedent basis for this limitation in the claim. Claim 2 or claim 16 first recite “somatic mutations”; it is not clear from which independent this claim was intended to depend. For the purposes of examination, this was interpreted as depending from claim 16.
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 1-12 and 15-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) without significantly more. The claim(s) recite(s) abstract ideas and/or natural phenomenon. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, the claims are directed to processes (methods).
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
Claim 1 recites “A method of determining a treatment regime .... comprising: assessing genetic material of a neoplasm or cancer ... to determine a mutational burden; based on an amount of mutational burden, determine a treatment regimen”.
This and dependent claims, under their broadest reasonable interpretation, recite a mathematical calculation (i.e., to determine the mutational burden, e.g., by counting some quantity of mutations and, optionally, dividing by a value such as the amount of genome considered), wherein, as currently claimed, such may be completed as a mental process, i.e., abstract idea(s).
Further, these claims also are directed to the natural phenomenon of the existence of a particular amount of mutational burden the correlation to dependency on particular proteins, e.g., the chaperone HSP90 to help with protein folding.
Claim 16 recites “A method of assessing cytotoxicity of a compound ... comprising: ... quantifying the amount of somatic mutations ...; determining that the ... mutational burden ... is greater than a threshold; ...”
This and dependent claims, under their broadest reasonable interpretation, recite a mathematical calculation (i.e., quantifying the somatic mutation, e.g., via the high-throughput sequencing and the mathematical inequality comparison to the threshold), wherein such may be completed as a mental process, i.e., abstract idea(s).
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
Regarding claims 1, claim 1 further recites determine a treatment regime. The determination amounts to an abstract idea itself and fails to integrate, as it fails to affirmatively recite an action that effects a particular treatment or prophylaxis, as required by MPEP 2106.04(d)(2).
Regarding claims 2-3, claims 2 and 3 recite quantifying somatic mutations (claim 2) and specific mutations (claim 3). Under the BRI, such encompasses, for example, counting the number of labelled mutations within an aligned sequence print out and thus encompasses the same abstract ideas. As it fails to require more than judicial exceptions, it fails to integrate the claims.
Regarding claims 4-6, claims 4 and 5 recite performing a high-throughput sequencing reaction, aligning to a reference genome, and, in claim 4, further aligning the sequencing of the neoplasm with a control sample.
Procuring and aligning sequencing are necessary data gathering where the choice of alignment either to the reference genome or “with” a control sample (e.g., against a control sample to remove germline mutations) represents a selection of data on which to apply the judicial exception(s). Accordingly, such represents insignificant extra-solution activity.
Regarding claim 7, the claim recites obtaining a biopsy as a tumor excision, liquid biopsy, or a biological waste biopsy and extracting the genetic material of the biopsy.
First, the claim does not require that the judicial exception of determining a treatment regime based on an amount of mutational burden to be linked to the obtaining the biopsy and extracting the genetic material. Accordingly, this is interpreted to be insignificant extra-solution activity as an insignificant application.
Second, should the claim be amended to require the mutation burden to be the mutation burden of the genetic material of claims 1 and 7, such is still interpreted to be insignificant extra-solution activity. Namely, such amounts to mere data gathering, wherein selection of a particular sample may also be considered selection of a particular data source to be manipulated, as described in MPEP 2106.05(g).
Regarding claims 8-12, claims 8 and 12 also fail to administer a particular treatment. While claim 12 recites specific HSP90 inhibitors, it is directed to all cancers including those not demonstrated by the instant application to have a specific relationship with HSP90 inhibitor and includes HSP90 inhibitors with low and insignificant beta values, including those that do not appear to change which the fibroblast cell lines (negative control if non-cancerous fibroblast cell lines?) are removed in the jackknife analysis (Fig. 11B), indicating the association with cancer may not be specific.
In claims 9-11, the limitations recite mutational burdens under which the generic treatment regime of claim 8 is to be administered. Such represents a further limitation of the mathematical calculation and does not integrate the claim.
As such, these limitations do not integrate the claims into practical application(s).
Regarding claim 15, the claim recites a variety of cancers to which the judicial exception(s) may be applied. Such represents a field of use and/or the choice of data to which to apply the judicial exception(s) and thus does not integrate the claim.
Regarding claim 16-19, claim 16 further recites performing high-throughput sequencing on genetic material of a specimen and contacting a cell of the growth or tumor with a compound to assess the cytotoxicity.
As described in 2111.01(II), the courts have found that “it was improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims did not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order” (emphasis added). It is noted that no order of the contacting relative to the quantifying and determining is required by the logic, grammar, or language of the claims and there is no requirement that the contacting be performed as a result of the judicial exception.
Both steps amount to insignificant extra-solution activity. High-throughput sequencing amounts to mere data gathering and selecting a particular data type to be manipulated in the judicial exception. At least because of the lack of the tie to the judicial exception, contacting the cell amounts to an insignificant application, as described in MPEP 2106.05(g). See also 2106.04(d)(2), which contrasts treatments (e.g., “contacting ... with a compound”) that have at best a nominal connection to a judicial exception—which in the case of an assessment of cytotoxicity appears intended to establish such a relationship rather than to utilize known “significant” relationship to effect a treatment—in section b and a step of prophylaxis step based on the result of the output of a judicial exception in step c.
It is also noted that where the method may be considered to the abstract idea of “assessing toxicity” the contacting may also be considered necessary data gathering to perform this judicial exception.
Claims 17 and 18, respectively recite the two options for where such contact may occur: in vitro or in vivo. Such limitations remain only nominally related to the exception(s) and therefore do not integrate the claim into a practical application.
Claim 19 recites broad classes of compounds including, for example, “a protein inhibitor”. As above, the contact does not have more than a nominal relationship to the judicial exception(s). Further, such classes of compounds include those that have not been demonstrated to be particular treatments or prophylaxis. Thus the limitations to not integrate the claim.
Regarding claim 20, the claim recites that the somatic mutations comprise at least one of particular types of mutations. As above, the choice of mutations analyzed represent a choice of data in the judicial exception(s) and thus fail to integrate the claim.
Step 2B. Does the claim amount to significantly more?
As discussed in MPEP 2106.05(I), the inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016). See also Alice Corp., 573 U.S. at 21-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 78, 101 USPQ2d at 1968 (after determining that a claim is directed to a judicial exception, "we then ask, ‘[w]hat else is there in the claims before us?") (emphasis added)); RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract").
Likewise, the courts have also found adding insignificant extra-solution activity or appending well-understood, routine, and conventional activities previously known are not sufficient to qualify as “significantly more”. See MPEP 2106.05(A). As discussed in the step above, each limitation represents further elements of the judicial exceptions and/or insignificant extra-solution activity.
Further, where the claims are directed to high-throughput sequencing and alignment to a reference genome or sequencing to a control sample, such is well-known and conventional within the art. Chapman (Chapman MA, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011 Mar 24;471(7339):467-72) teaches performing high-throughput sequencing of tumor and normal samples (Supplementary Information, pg. 5, The Cancer Genome Analysis pipeline), aligning each sample against a reference genome (Supplementary Information, pg. 4, The sequencing data-processing pipeline), and quantifying an amount of somatic mutations/mutation rate [i.e. burden] (Supplementary Information, pg. 6) as part of the TCGA pipeline.
Chapman also teaches that same process performed on samples with “tumor-in-normal contamination”, wherein detection of somatic events was possible for a subset (Supplementary Information, pg. 7, Exclusion of tumor-in-normal samples), i.e., alignment of “mixed” samples and quantifying somatic mutations.
As an alternative interpretation of claim 5, Umer (Umer HM, et al. A Significant Regulatory Mutation Burden at a High-Affinity Position of the CTCF Motif in Gastrointestinal Cancers. Hum Mutat. 2016 Sep;37(9):904-13. Epub 2016 Jun 2) teaches use of the GATK utility FastaAlternateReferenceMaker to build an alternative reference genome utilizing sequence information derived from a control cell-line and mapping reads against this alternative reference to count SNPs (pg. 906, col 1, para 5, spanning col 2, para 2) and determine a mutation burden in a cancer (Title), as well as aligning high throughput sequencing datasets of samples to a conventional reference genome (pg. 906, col 1, para 5, spanning col 2, para 2).
Also, where the claims are directed to contacting with a compound, Frampton, as cited in the 103 below, teaches contacting a cancer cell with a compound is well known within the art as “screening.”
As such none of the claims recite additional elements that amount to significantly more than the judicial exception individually or in combination.
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.
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.
Claim(s) 16-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Frampton (US 2019/0085403 A1; published 03/21/2019).
Regarding claim 16, Frampton teaches a method for screening agents that can be used to treat a tumor having a predetermined level of mutational load (para [0515]), comprising:
contacting a tumor cell or tissue having a predetermined level of mutational load [i.e., mutational burden greater than threshold; see para (0158) and (0359)] with a candidate agent and detecting a change associated with tumor growth or apoptosis (para [0516]), i.e., cytotoxicity.
Regarding claim 17, Frampton teaches the contacting may in a cell culture (para [0518]), i.e., in vitro.
Regarding claim 18, Frampton teaches the contacting may be in an in vivo animal model (para [0520]).
Regarding claim 19, Frampton teaches the candidate agent may be an inhibitor of PD-1 (par [0522]), i.e., a protein inhibitor, or a small molecule compound, a nucleic acid, or an antibody molecule, wherein the candidate agent may be obtained from a library or designed (para [0522]; see also para [0523-29]).
Regarding claim 20, Frampton teaches that mutations of the somatic alterations may include point mutations [i.e., SNVs], deletion, and insertions, amplifications, translocation, and inter- and intra-chromosomal rearrangements [i.e., CNVs] (para [0278], [0148]; Fig. 4C).
In the method of screening, Frampton does not explicitly teach performing high-throughput sequencing and quantifying the amount of somatic mutations, wherein the predetermined level is above any arbitrary threshold.
Frampton teaches using a hybrid capture-based next-generation sequencing platform from patient samples (para [0006], [0265], [0425-438]); and
quantifying a level of somatic alteration in a set of genes from the genetic material (para [0268]; Table 1).
Frampton teaches generating a personalized cancer treatment report by obtaining a tumor sample from a subject, acquiring a value of responder status to a therapy, determining a mutation load in the sample, and selecting treatment based on the value of the responder status (para [0441]).
Frampton teaches administering therapy or selecting therapy for a subject responsive to an increased reference value relative to a non-responder to the therapy (para [0055-61], [0066]]). Frampton teaches stratifying patients to assess the likelihood of therapy, wherein the use of three groups with >23.1 mutations/MB, 3.3-23.1 mutations/MB, and <3.3 mutations/MB showed superior performance (para [0743]).
It is also noted that Frampton teaches that hybrid capture-based NGS total genomic mutational load [tumor mutation burden] strongly correlated with total exome mutation number from WES, particularly in sample with high mutational loads (para [0748]) and alternatively determining mutational load on a whole genome or exome basis (para [0384] and [0390]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the method of screening on the tumor sample of the patient as part of generating the report, motivated by the desire to further personalize the cancer treatment, as suggested by Frampton. In incorporating the screening method as part of the report for selecting a therapy, it would have been obvious to the POSITA before the EFD of the claimed invention to have selected the specimen from among those predicted to be responders (i.e., greater than a threshold) using the same selection(s) of mutation types for the same reasons as this is the population Frampton is concerned with providing treatment to.
Additionally, in incorporating the screening method as part of the report for selecting a therapy, it would have been obvious to the POSITA before the EFD of the claimed invention to have utilized the same methods for acquiring the level of somatic alteration in the genetic material of the patient sample comprising hybrid capture NGS for the same reasons or alternatively to substitute whole exome or whole genome sequencing, as Frampton teaches that such are art accepted equivalents for the same purpose for high mutational burden samples. See MPEP 2144.06 regarding substituting equivalents known for the same purpose.
There would have been a strong expectation of success as each of the elements was taught by Frampton for use with tumor cells/samples for the purpose of administering a drug or determining the efficacy of a drug, wherein each was known within the art.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Zavareh (Zavareh RB, et al. HSP90 Inhibition Enhances Cancer Immunotherapy by Modulating the Surface Expression of Multiple Immune Checkpoint Proteins. Cell Chem Biol. 2021 Feb 18;28(2):158-168.e5) teaches a cell-based chemical screen comprising HSP90 inhibitors and further testing in a mouse model, finding that such inhibitors reduced the expression of PD-L1 on the surface of tumor cells, concluding that their findings provided a rationale to explore HSP90 inhibitors as part of combination immunotherapies for the treatment of cancer (Abstract).
It is noted that Frampton teaches combination therapies (para [0305-312]) and administering an additional agent in combination to a non-responder or partial responder (para [0608]).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Emma R Hoppe whose telephone number is (703)756-5550. The examiner can normally be reached Mon - Fri 11:00 am - 7:00 pm.
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/EMMA R HOPPE/ Examiner, Art Unit 1683 /ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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