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 Group I, claims 1-16 in the reply filed on 12/08/2025 is acknowledged.
Claims 17-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/08/2025.
The requirement for the species elections of a drug, a particular sample and a specific set of genes is withdrawn upon further consideration.
Status of Claims
Applicant’s amendment filed 04/28/2023 is acknowledged. Claims 17-19 have been amended. Claims 1-19 are pending in the instant application and claims 1-16 are the subject of this non-final office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or marked as considered on a submitted IDS, they have not been considered.
The information disclosure statements (IDS) submitted on 11/01/2024 and 04/28/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement have been considered by the examiner.
Drawings
The drawings are objected to because Fig. 7 and 10-12 include text that is too small to be legible.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Hyperlinks are found in para [177] and [181].
The disclosure is objected to because of the following informalities:
Paragraph [209] recites 36 genes in breast cancer. This appears to be a typo. 35 genes are recited in Table 1.
Appropriate correction is required.
Claim Objections
Claim 3 is objected to because of the following informalities:
Claim 3: Step (a-iii) recites “constructing a library by enriching DNA repair-related genes for the purified nucleic acid”. There appears to be a typo/translation error. It may have been intended to be “enriching the purified nucleic acids for DNA repair-related genes” or “enriching ... genes from purified nucleic acids”.
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.
Claim 1-16 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 1-16, the claims recite a method of determining susceptibility to a PARP inhibitor or DNA damaging agent 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 there is susceptibility ... when a value obtained by analyzing the calculated transcript usage is greater than or equal to a reference value.
The claims are broad and encompass 1) any method of obtaining an expression level from any sample (limited in claim 3); 2) any set of “non-functional” transcripts of any set of genes with any broadly interpreted DNA repair-related function (limited in claim 4 and 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 claim are limited the scope of genes, the claims remain broad. Claim 4 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 gene 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 and the 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 predict 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 full 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).
While the claims are directed to “non-functional” transcripts, the disclosure recites that the transcript annotation uses the APPRIS database (para [191]) and removing only “principal” forms (para [193]). No functional annotation beyond this was identified. The disclosure provides data on predictors for susceptibility using IC50 measurements of breast cancer cell lines and progression free survival in ovarian cancer patient samples (para [178], [228], Fig. 6-9, [240], [246], Fig. 10-12).
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).
Further, the breadth of the claims includes susceptibility outside of just an oncological context. The term “susceptibility” may also encompass being influence by these drugs. Berger (Berger NA, et al. Opportunities for the repurposing of PARP inhibitors for the therapy of non-oncological diseases. Br J Pharmacol. 2018 Jan;175(2):192-222. Epub 2017 Mar 26.) teaches that olaparib has been shown to exert neuroprotective effects on human cortical neurons derived from the human ESC H9 cell line (Many of the protective effects of PARP inhibitors are gender-dependent, para 1).
The disclosure provides an insufficient number of species of claimed set of transcripts for the claimed sets of genes of the class of DNA-repair related genes; of samples/classes of diseases; of PARP inhibitors and DNA damaging agents; and of susceptibility determination assays for the artisan to conclude that the applicant has possession 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 1-16 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 1-16, the claims recite a method of determining susceptibility to a PARP inhibitor or DNA damaging agent 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 there is susceptibility ... when a value obtained by analyzing the calculated transcript usage is greater than or equal to a reference value.
First, the claims are broad. The claims encompass 1) any method of obtaining an expression level from any sample (limited in claim 3); 2) any set of “non-functional” transcripts of any set of genes with any broadly interpreted DNA repair-related function (limited in claim 4 and 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. Claim 4 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 the 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 legible (Fig. 7). It was interpreted that the that dark line was the “tHRD” 35 gene predictor. It is apparent from the graphs 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 (Fig. 7).
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; any provided statistics are not legible.
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., cancer and sample types and means of measuring expression), 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.
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 1-16 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 1, first, the claim recites “non-functional transcripts of ... genes”. It is not clear what level of function must be eliminated to meet this criteria. Therefore, it is unclear whether the claim is intended to require only “minor isoform transcripts” or if additional functional characterization is required.
Step (c) recites “DNA damaging agent (genotoxic drug)”. It is not clear if the information in the parentheses is intended to be a claim limitation or not.
It is not clear what is being determined to be susceptible. It is not clear whether this is intended to apply to the biological sample—in which case it is noted that there is no nexus between the sample and the obtaining the expression level and, thus, any of the following steps—or that susceptibility exists to PARP inhibitors in general.
Claims 2-16 are rejected for depending from claim 1 and not rectifying the deficiency. Claim 7 rectifies the first issue regarding non-functional transcripts.
Regarding claim 3, step (a-i) recites “collecting nucleic acid from blood, ... , FFPE samples, and mixtures thereof”. It is unclear if the claim is intended to require collection of each of the sample types and mixtures of two or more; each of the sample types and mixtures of all; or if there was a typo/translation error and these were intended in the alternative.
Step (a-v) recites “sequence information (reads)”. It is not clear if the information in the parentheses is intended to be a claim limitation or not.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Regarding claim 8, claim 1 recites in step (b) “calculating a transcript usage (TU)”. The specification defines that in the present invention, “the TU value is a ratio in which the sum of TPM values of all transcripts occurring in one gene is used as the denominator and the TPM of each transcript is used as the numerator” in para [86].
The artisan would understand the definition of TPM to be transcripts per million given the scope of the disclosure and claims. The equation of claim 8 implies no more than what is defined in the specification for the term “transcript usage”.
For this reason, the claim fails to further limit the subject matter of the claim upon which it depends and, thus, does not comply with the requirements of 112(d).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-16 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 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 a process/method.
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
The claims recite abstract ideas. Claim 1 recites obtaining an expression level of ... genes; calculating transcript usage ... ; and determining that there is susceptibility to a ... inhibitor or ... agent ... when a value obtained ... is greater ... than a reference value. Obtaining an expression level encompasses looking up values in a table, for example, i.e., a mental process. Calculating transcript usage encompasses mathematical calculations that may be performed by the human mind. Determining that there is susceptibility includes mental processes (e.g., looking at the result of a calculation and determining it is greater) and/or mathematical calculations, including those that may be performed by the human mind.
The claims also recite natural phenomenon. The claims are directed to determining a transcript usage signature of DNA repair-related genes such that, when a transcript usage is above or equal to a reference value (encompassing “overexpression”) in, under the best possible interpretation, the sample, said sample is determined to be susceptible to drugs that restrict the ability to repair DNA damage or DNA damage itself, i.e., has decreased functionality of DNA repair.
It is noted that MPEP 2106.04(b) recites that in a method of treating a cancer with chemotherapy, the inability to survive chemotherapy is not a law of nature. However, in contrast that that example, what is recited here is a predicted susceptibility purely in the realm of gene regulation via splicing differences rather than a physical application of human-made products and a determination stemming from said application. While the claims may include samples that have been treated by said inhibitor or agent, this is not required by the claims.
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
Regarding claim 1, in addition to the previously discussed abstract ideas, the claim recites “extracting a nucleic acid from a biological sample”. This is insignificant extra-solution activity. The claim lacks a nexus to the obtaining an expression level, and, as such, it is insignificant application. Even should it be connected to the expression levels; however, the limitation would represent mere data gathering. As such, it fails to integrate the claim. See MPEP 2106.05(g).
Regarding claim 2, as above, the sample is not sufficient to integrate the claim. As in the advisement in the 112(d), under the best possible interpretation of the intended claim, the RNA sample would not further limit.
Regarding claim 3, the claim recites steps of collecting nucleic acid, from sample type(s); obtaining purified nucleic acids; constructing a library including enriching; reacting in a sequencer; and obtaining sequence information.
The claim amounts to mere data gathering and selection of a particular data type to be manipulated. Both the choice of sequencing and enriched (i.e., targeted) sequencing is a selection of particular data type/source. Targeted sequencing is known in the art to increase the number of isoforms available for analysis. Specifically, Curion (Curion F, et al. Targeted RNA sequencing enhances gene expression profiling of ultra-low input samples. RNA Biol. 2020 Dec;17(12):1741-1753. Epub 2020 Jun 28.) teaches a greater than 5-fold increase in identified gene isoforms using CaptureSeq (Abstract).
Further the choice of particular sources of nucleic acids are likewise directed to particular data source choices.
Thus, the limitations fail to integrate the claim.
Regarding claim 4-6, claim 4-6 recites a particular set of genes, which is directed to the judicial exception(s). Under the best possible interpretation of claims 5-6, the limitation of the application of the PARP inhibitor or DNA agent application to breast (claim 5) or ovarian (claim 6) cancer is directed to the susceptibility determination and/or the sample. As such, it would be directed to the judicial exception(s) and/or sample choice (insignificant extra-solution activity), and does not integrate the claim.
It further is noted that in order to qualify for integration under a “treatment”/”prophylaxis” limitation, the claim limitation must affirmatively recite an action that effects a particular treatment for a disease or medical condition, such that it is specific/particular to the judicial exception. See MPEP 2106.04(d)(2).
Regarding claim 7, the claim recites “the ... transcripts ... are minor isoforms”. Such is directed to the judicial exceptions and further would represent a selection of data even under a different interpretation of obtaining. Thus, the claim is not integrated.
Regarding claim 8, the claim recites a limitation directed to the calculating. As discussed in the 112(d), it does not further limit. And even in the alternative, it would be directed to the judicial exception(s) encompassing calculations and does not integrate.
Regarding claims 9-14, the claims recites limitations directed to the reference value or obtaining said value, i.e., to the judicial exception(s) including calculations, including those that may be performed in the human mind. It is noted that simple machine learning models may be performed in the human mind and/or with paper including, for example, KNN and linear regression. It is further noted that claims that claims that do not require new machinery (“machine learning”) may still recite performing mental processes. See MPEP 2106.04(a)(2)(I) and (III).
Regarding claims 15-16, the claims recites PARP inhibitors (claim 15) and DNA damaging agents (claim 16). This limitation is directed to the susceptibility, which is directed to the judicial exception. Therefore, it does not integrate the claim. The note about limitations directed to treatment/prophylaxis is reiterated.
Step 2B. Does the claim amount to significantly more?
No, the claims as a whole do not amount to significantly more. As above, the claims are directed to judicial exception(s) with insignificant extra-solution activity. MPEP 2106.05 makes clear that the inventive concept cannot be furnished by the judicial exception itself nor is insignificant extra-solution activity sufficient to qualify as “significantly more”.
It is further noted for claim 3 that Curion (cited above) further teaches that targeted RNA sequencing of genes of interest (Abstract) has been used on various sample types and has been widely applied in both research and clinical settings (Introduction, para 1). Thus, the limitation also represents well-known and conventional activity.
The choice of enrichment of particular targets is a matter of insignificant extra-solution activity as it is a selection of data. Thus, it also would not be sufficient to represent “significantly more”.
Conclusion
No claims are allowed.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636