DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Applicant's amendment filed 06/26/2026 is acknowledged. Claims 1, 3, and 5-6 have been amended. Claims 4 and 7-8 have been cancelled and claims 17-18 remain withdrawn. Claims 1-3, 5-6, and 9-19 are pending in the instant application and claims 1-3, 5-6, and 9-16 are the subject of this final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
Previous Rejection
Status of Prior Rejections/Objections:
The drawings objections to Fig. 7 and 10-12 are withdrawn in view of the replacement drawings.
The specification objections are withdrawn in view of the amendments to the specification.
The objection to claim 3 is withdrawn in view of the amendment to the claim.
The 112(b) rejections of claims 1-16 are withdrawn in view of the
The subject matter eligibility rejections under 35 USC 101 directed to claims 1-16 are withdrawn in view of the amendment adding step (d) that recites a particular treatment that integrates the judicial exception into a practical application or, respectively, cancellation of the claims.
The written description and enablement rejections under 35 USC 112(a) directed to claims 1-3, 5-6, and 9-16 is/are maintained and modified as necessitated by claim amendments. See also Response to Arguments.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Objections
Claims 5-6 are objected to because of the following informalities:
Regarding claims 5 and 6, claim 5 recites “the PARP inhibitor or DNA agent is applied to breast cancer” and claim 6 recites “the PARP inhibitor or DNA agent is applied to ovarian cancer”. As amended, it is unclear whether this application is the same step as the administering of (d) or if these claims require an additional application of said inhibitor or agent.
Applicant may consider “wherein, when the cancer is breast cancer, the DNA-repair related genes are …” or, respectively, wherein, when the cancer is ovarian cancer, the DNA-repair related genes are …””.
Appropriate correction is required.
New Ground(s) of Rejections
The new ground(s) of rejections were necessitated by applicant’s amendment of the claims.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112(a)
Claim 1-3, 5-6, and 9-16 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.
In analyzing the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note that with regard to genus/species situations, 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 the members of the genus in view of the species disclosed.”
Regarding claims 1-3, 5-6, and 9-16, the claims, as amended, recite a method … comprising obtaining an expression level of each of non-functional transcripts of DNA repair related genes; calculating transcript usage ... for each gene ...; and determining that the subject has susceptibility ... when a value obtained by analyzing the calculated transcript usage is greater than or equal to a reference value, wherein the non-functional transcripts are minor isoforms … wherein the DNA-repair related genes are at least 10 genes selected from the claimed Markush group.
The claims are broad and encompass 1) any method of obtaining an expression level from any sample (limited in claim 3); 2) using a value based upon any non-functional transcript/minor isoform of a set of minor isoform transcripts of any of the set of genes so long as 10 genes have TU determined (limited, according to the best possible interpretation, in claims 5-6) from any species; 3) any PARP inhibitor or DNA damaging agent (limited in claims 15-16); and 4) any comparison of transcriptional usage to any reference value (limited, at least in part, in claims 9-14).
In particular, even where the claims are limited the scope of genes, the claims remain broad. Amended claim 1 recites at least 10 genes selected from a set of 157. Considering, for example purposes, only combinations of exactly 10, this would be n!/((n-r)!r!) = 157!/(147!*10!) = 1,871,392,332,785,690 possible combinations. Claims 5 and 6 recites lists of 35 and 25 genes, respectively, and at least 10 selected from that list. Again, for exemplary purposes, selecting exactly 10 genes in a list of 25 results in 3,268,760 combinations. The total breath reflects the summation of unique combinations for each claim. Beyond this, the claims are directed to “each of non-functional transcripts”, which may be interpreted to range from all of the non-primary transcripts to only a single non-primary transcript per gene (e.g., para [194], [235]).
In contrast to this, the specification describes the following predictors:
a set of 35 genes with a total of 104 transcripts for breast cancer (para [209]; Table 1; Fig. 6-7);
a set of 17 genes with a total of 20 transcripts for breast cancer (para [231]; Table 3; Fig. 8)
a set of 9 genes with a total of 10 transcripts for breast cancer (para [235]; Table 4; Fig. 9)
a set of 25 genes with a total of 89 transcripts for ovarian cancer (para [209] and Table 2; Fig. 10)
a set of 10 genes with a total of 10 transcripts for ovarian cancer (para [242] and Table 5: Fig. 11)
The disclosure recites using RNA-seq (para [178]) and a random forest modeling (para [218-221]).
In the disclosure, the breast cancer sets were used to compare susceptibility of four PARP inhibitors and five DNA damaging agents and the ovarian cancer sets were used to predict progression free survival given platinum drug treatment (see Figures cited above). As is described in more detail in the enablement rejection below, there is variability in the combinations of the predictors including for the breast cancer, including the number and identity of drugs that reach significance at p < 0.05. Similarly, while not a significant change, the 10 transcript prediction displays a change in direction for two of the drugs compared to the other models.
Similar to this, Safikhani (Safikhani Z, et al. Gene isoforms as expression-based biomarkers predictive of drug response in vitro. Nat Commun. 2017 Oct 24;8(1):1126) teaches that isoform biomarker and drug sensitivity prediction validation was highly variable (pg. 5, Pre-validation in an independent breast cancer dataset) and that the variability depends on the particular drug (pg. 5, Pan-cancer validation of isoform-based biomarkers). Safikhani also teaches that the assay for drug sensitivity may influence the determination (pg. 8, col 1, para 1).
Further, the disclosure provides only the function of the PARP inhibitors and the DNA damaging agents. No structures, figures, diagrams, or formulas fully set forth the claimed PARP inhibitors or DNA damaging agents.
In contrast to the limited species disclosed for samples (para [178]), Brandao (Brandão RD, et al. Targeted RNA-seq successfully identifies normal and pathogenic splicing events in breast/ovarian cancer susceptibility and Lynch syndrome genes. Int J Cancer. 2019 Jul 15;145(2):401-414. Epub 2019 Feb 7) teaches that the frequency of alternative splicing depends on the species complexity and cell type (pg. 412, col 2, para 1) and is impacted by the means of measuring expression levels (pg. 412, col 2, para 1). Dvinge (Dvinge H, Bradley RK. Widespread intron retention diversifies most cancer transcriptomes. Genome Med. 2015 May 15;7(1):45), which focuses on one class of alternative transcripts, teaches that the preponderance said class of alternative transcripts is specific to the cancer of origin (pg. 6, col 2, para 1, spanning pg. 8) and that breast cancer has a unique overall splicing program relative to the other cancers included in the study (which did not include ovarian) (Abstract; pg. 6, col 1, para 1; Table 1).
In contrast to the implied correlation between an overexpression of alternative isoforms and susceptibility samples/tumors to PARP inhibitors and DNA damaging agents, Wang (Wang BD, Lee NH. Aberrant RNA Splicing in Cancer and Drug Resistance. Cancers (Basel). 2018 Nov 20;10(11):458) teaches that isoforms from the same gene can have distinct and sometimes opposing functions and that aberrant RNA splicing is relatively common in conferring drug resistance (Abstract). Wang provides examples directed to the DNA repair-related BRCA1 and BRCA2, wherein BRCA1 has an alternative isoform that leads to PARPi resistance and BRCA 2 has an alternative isoform that leads resistance to the DNA damaging agent mitomycin C (pg. 8, para 1).
In particular, these two examples demonstrate the variability within “non-functional” minor isoform transcripts such that the one artisan would not reasonably conclude that the applicant had possession of using any value obtained by analyzing a calculated TU of said transcript by any means compared to any threshold to determine a susceptibility to a PARPi or a DNA damaging agent.
Where the disclosure provides reduction to practice, there are an insufficient number of species of claimed sets of transcripts for the claimed sets of genes; of samples/classes of cancer; of PARP inhibitors and DNA damaging agents; and of susceptibility determination assays (i.e., particular means of obtaining values using the calculated TU) for the artisan to conclude that the applicant has possession of the full scope of the claimed invention at the time of filing.
For this reason, the claims do not comply with the 112(a) written description requirements.
Claims 1-3, 5-6, and 9-16 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Regarding claims 1-3, 5-6, and 9-16, the claims, as amended, recite a method … comprising obtaining an expression level of each of non-functional transcripts of DNA repair related genes; calculating transcript usage ... for each gene ...; and determining that the subject has susceptibility ... when a value obtained by analyzing the calculated transcript usage is greater than or equal to a reference value, wherein the non-functional transcripts are minor isoforms … wherein the DNA-repair related genes are at least 10 genes selected from the claimed Markush group.
First, the claims are broad. The claims encompass 1) any method of obtaining an expression level from any sample (limited in claim 3); 2) using a value based upon any non-functional transcript/minor isoform of a set of minor isoform transcripts of any of the set of genes so long as 10 genes have TU determined (limited according to the best possible interpretation in claims 5-6) from any species; 3) any PARP inhibitor or DNA damaging agent (limited in claims 15-16); and 4) any comparison of transcriptional usage to any reference value (limited, at least in part, in claims 9-14).
Wherein the claims are limited in scope to the genes, the claims remain broad. Amended claim 1 recites at least 10 genes selected from a set of 157. Considering, for example purposes, only combinations of exactly 10, this would be n!/((n-r)!r!) = 157!/(147!*10!) = 1,871,392,332,785,690 possible combinations. Claims 5 and 6 recites lists of 35 and 25 genes, respectively, and at least 10 selected from that list. Again, for exemplary purposes, selecting exactly 10 genes in a list of 25 results in 3,268,760 combinations. The total breath reflects the summation of unique combinations for each claim.
Second, in contrast to this breadth, the working examples and guidance provided is directed to a specific sets of transcripts in breast and in ovarian cancer (e.g., para [215]; [231] and Table 3; [235] and Table 4; [242] and Table 5) used to predict drug response using a particular machine learning model (para [221]) for nine drugs in breast cancer cell lines (Fig. 6-9) and “platinum treatment” in ovarian cancer patients (Figs. 10-13). Of the nine drugs with data in breast cancer, para [222] recites that four are PARP inhibitors and five are DNA damaging agents. The artisan would understand that “platinum treatment” would be expected to include platinum-based DNA damaging agents commonly used in ovarian treatment in patients including cisplatin and carboplatin.
Namely, for breast cancer, the following sets were used for prediction:
a set of 35 genes with a total of 104 transcripts (para [209]; Table 1): Fig. 6-7
a set of 17 genes with a total of 20 transcripts (para [231]; Table 3): Fig. 8
a set of 9 genes with a total of 10 transcripts (para [235]; Table 4): Fig. 9
The specification recites using an alpha of 0.05 in para [205] for another significance test. The 35 gene predictor found differences between “tHRD+” and “tHRD-“ in all nine genes p < 0.05 in four of the nine drugs in Fig. 6 (olaparib, rucaparib, bleomycin, and doxorubicin). In contrast, the 20 transcript predictor finds a difference p < 0.05 in bleomycin, talazoparib, and etoposide. Yet, the 10 transcript predictor finds a difference p < 0.05 in olaparib, rucaparib, and bleomycin; additionally, while the shift is not significant at this level, it is noted that veliparib and cisplatin median values for tHRD+ and tHRD- shift directions compared to the other predictors.
The precision and recall curves are only provided for the 35 gene predictor and no calculated area under the curve (AUC-PR) or apparent optimal threshold based on the curve was identified. It is apparent from Fig. 7 that for certain drugs including veliparib, doxorubicin, and SN38, for most precision levels (minimizing false positives), the model is only able to correctly predict true positives about as well as a coin flip (i.e., about 0.5).
For ovarian cancer, the 25 gene (89 transcripts; para [209] and Table 2: Fig. 10) and 10 genes with a single transcript per gene (para [242] and Table 5: Fig. 11) were used with a proxy of progression-free survival (PFS) to estimate the efficacy of platinum treatments (see para [178] and [255]). The PFS is found to be significantly higher in tHRD+ patients under both models (Fig. 10-11). The precision and recall curves appear to indicate better predictors than the breast cancer cells lines.
However, it is also emphasized that such a predictor where the outcome is the proxy of PFS does not directly demonstrate sensitivity (i.e., of the tumors) to platinum-based DNA damaging agents. No data has been identified in the disclosure to determine whether it may be instead detecting a general propensity for patients to not progress, given that only ovarian cancer samples for which platinum treatment response data was present were evaluated (para [178]). Further, it is noted that para [205] recites that Benjamini-Hochberg correction (see para [199]) was not applied to ovarian cancer, wherein the artisan would understand this correction to be for false discovery rates in multiple hypothesis testing (see also para [202]).
Third, the art teaches a high level of unpredictability regarding the ability to 1) validate such drug testing; 2) reproduce splicing changes across cancers/cell types/samples; and 3) determine the functional consequences of alternative splicing with regard to susceptibility/resistance.
Safikhani (Safikhani, 2017, as cited above) teaches that in vitro validation of drug response biomarkers has been shown to be challenging, and found that in their assessment of the predictive value of isoform biomarker candidates, the validation success rates ranged from 0% to 25% in a breast cancer cell line screen (pg. 5, Pre-validation in an independent breast cancer dataset). Safikhani teaches that the unpredictability depends on the particular drug (pg. 5, Pan-cancer validation of isoform-based biomarkers). Safikhani also recites that they and others have shown that the choice of pharmacological assay may influence drug sensitivity measurements (pg. 8, col 1, para 1). Thus, the teachings of Safikhani illustrate the unpredictability in assessing drug sensitivity using isoform biomarker, both in the ability to isoform biomarkers across datasets and the influence of the particular drug on that ability.
Kang (Kang, 2019, as cited in the IDS dated 04/28/2023) teaches a BRIP1 transcriptional usage predicted olaparib but not cisplatin sensitivity in cell lines (pg. 27, Fig. 23) and that a RAD51 transcriptional usage did not predict olaparib sensitivity (pg. 28, Fig. 25). Thus, the teachings of Kang illustrate the unpredictability in the transcriptional usage of at least some of the claimed genes to predict sensitivity differences in cell lines.
Brandao (Brandão, 2019, as cited above) teaches that the frequency of alternative splicing depends on the species complexity and cell type, and that it changes during development and upon cellular differentiation (pg. 412, col 2, para 1). Brandao teaches using RNA-seq with and without targeted sequencing, wherein targeted sequencing increases the mean coverage more than 50 times, impacting the conclusions about the number and type of alternative isoforms in the tissues (pg. 412, col 2, para 1). Brandao further notes that publicly available GTEx shows very low read numbers for several known splice events, and that only sequencing at very high coverage provides sufficient insight (pg. 412, col 2, para 1). Thus, the teachings of Brandao illustrate the unpredictability in the number and types of alternative isoform expression based on sample and the means of sample processing on the alternative isoforms that may be detected.
Similarly, Dvinge (Dvinge, 2015, as cited above) teaches that normal tissue adjacent to breast tumors exhibits higher levels of overall intron retention than the breast cancer, and that this is in contrast to the pattern common across all other cancers investigated (Abstract), and found that this was replicated across various breast cell lines, indicating a breast-specific splicing program (pg. 6, col 1, para 1). It is noted that ovarian cancer was not among the cancers investigated (e.g., Table 1). Dvinge teaches that retained introns are frequently specific to the cancer of origin, and that the preponderance of differentially retained introns in any given cancer sample is typically specific to that cancer (pg. 6, col 2, para 1, spanning pg. 8). Thus, the teachings of Dvinge illustrate the unpredictability in the application of the claimed specific sets of isoforms outside of the tissue in which they were identified (i.e., breast and ovarian tumor tissue), and in particular that the splicing program in breast cancer may be unusually unable to predict that of other tumor types.
Wang (Wang, 2018, as cited above) teaches that isoforms from the same gene can have distinct and sometimes opposing functions and that aberrant RNA splicing is relatively common in conferring drug resistance (Abstract). Wang teaches that BRCA1 and BRCA2 encode proteins required in HR-mediated repair of dsDNA breaks (pg. 8, para 1). Wang teaches that a BRCA1-delta11q splice variant that bypassing inactivating mutations in exon 11 promotes partial resistance to PARPi therapy and that a splice variant of BRCA2 missing exons 5 and 8 has been associated with the acquisition of resistance to the DNA cross-linking drug mitomycin C [i.e., a DNA damaging agent] (pg. 8, para 1). Thus, in contrast to the claims wherein “non-functional” minor isoforms being greater than a reference indicates susceptibility, the teachings of Wang illustrate that alternative isoforms of DNA repair-related genes may reduce susceptibility when upregulated and a high degree of unpredictability with regard to the phenotypic effects of particular isoforms, i.e., “non-functional” transcripts interpreted in view of the specification, including for two of the claimed genes.
Given the large breadth of the claims; the limited guidance and working examples; and the unpredictability in the art and working examples related to 1) validation of drug susceptibility for isoform biomarkers, 2) reproducibility of transcript usage across contexts (e.g., different cancers, sample types, and means of measuring expression, which would thus require testing of each across the breadth claimed), and 3) phenotypic effects of “non-functional” transcripts on drug susceptibility/resistance, the quantity of experimentation—balanced only against the high level of skill in the art—required to use the invention would be undue.
For this reason, the claims fail to comply with the 112(a) enablement requirements.
Response to Arguments
Applicant's arguments filed 06/26/2026 have been fully considered but they are not persuasive.
Regarding the 112(a) written description and enablement rejections, Applicant argues on pg. 13-15, that the amended claims further limit the scope and enable a skilled artisan to sufficiently carry out the invention based on the disclosure. Applicant argues that, in contrast to the contention of the Office Action that argues that the predictive performance for some drugs is comparable to that of a coin toss, the tHRD-based method still demonstrates superior performance as compared to the gHRD-based method. Applicant argues that the drug sensitivity method of amended claim 1, in contrast to variability/unpredictability discussed with the genes of Wang, assesses drug sensitivity with a higher sensitivity than existing methods using a weight-based artificial intelligence model for the relevant genes and when applied to ovarian cancer patient samples, yields significantly superior predictive results compared to existing methods, as further demonstrated by a lower incidence of cancer metastasis within classified patients, citing Table 6 and Fig. 13.
While it is appreciated that the tHRD-based method described in the disclosure may represent an improvement over prior methods, the scope of the claims remains broader than the reduction to practice/working examples and direction, particularly given the variability/unpredictability in the art, such that the requirements under 112(a) are not met as amended.
In particular, given the variability in transcript usage/isoforms predicting susceptibility to the claimed drugs, as taught by at least Safikhani and Wang, the species of model(s) that use a value obtained by analyzing the calculated TU and determine that a subject has susceptibility to a PARPi or DNA damaging agent is not sufficiently representative of all sets of transcripts from any (claim 1; or all 10 in claims 9-10 and 13-14) of all sets of at least 10 sets of genes to adequately describe the entire genus. Likewise, given the unpredictability discussed here and above, the breadth of the claims, the working example of ovarian cancer is not sufficient to enable the full scope of the claimed invention as the quantity of experimentation needed to use the invention based on the content of the disclosure would be undue. Discussing advances over the prior art that do not meet the requirements under 112(a) for enablement, MPEP 2161.01(III) recites:
In MagSil Corp. v. Hitachi Global Storage Techs., Inc. 687 F.3d 1377, 103 USPQ2d 1769 (Fed. Cir. 2012), the Federal Circuit stated that "a patentee chooses broad claim language at the peril of losing any claim that cannot be enabled across its full scope of coverage," finding "one skilled in the art could not have taken the disclosure in the specification regarding ‘change in the resistance by at least 10% at room temperature’ and achieved a change in resistance in the full scope of that term without undue experimentation." 687 F.3d at 1381-82, 103 USPQ2d at 1771. "Thus, the specification enabled a marginal advance over the prior art, but did not enable at the time of filing a tunnel junction of resistive changes reaching even up to 20%, let alone the more recent achievements above 600%." The court held that the "claims [were] invalid for lack of enablement because their broad scope [was] not reasonably supported by the scope of enablement in the specification." 687 F.3d at 1381-1382, 1384, 103 USPQ2d at 1771, 1772, 1774 ("MagSil did not fully enable its broad claim scope. Therefore, it cannot claim an exclusive right to exclude later tri-layer tunnel junctions that greatly exceed a 10% resistive change.").
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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