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 .
Notice of New Examiner
This case has been transferred to a new examiner for continued examination. Any further communications regarding this case may be directed to the contact information included in the conclusion of this office action.
Election/Restrictions
Applicant’s election without traverse of the following in the reply filed on 08/20/2025 is acknowledged: Group I (claims 1, 2, 4-11, and 18).
Claims 12-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 08/20/2025.
Status of Claims
Applicant’s amendment filed 08/20/2025 is acknowledged. Claim 3 has been cancelled. Claims 1-2 and 4-18 are pending in the instant application and claims 1-2, 4-11, and 18 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 an IDS, they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
The specification makes reference to Fig. 21-32 (pg. 32-42). No such drawings were included in the disclosure.
Appropriate correction is required.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
It is further noted the incorporation by reference of the sequence information may not be left at the end of the specification.
Content of Specification
(a) TITLE OF THE INVENTION: See 37 CFR 1.72(a) and MPEP § 606. The title of the invention should be placed at the top of the first page of the specification unless the title is provided in an application data sheet. The title of the invention should be brief but technically accurate and descriptive, preferably from two to seven words. It may not contain more than 500 characters.
(b) CROSS-REFERENCES TO RELATED APPLICATIONS: See 37 CFR 1.78 and MPEP § 211 et seq.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT: See MPEP § 310.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT. See 37 CFR 1.71(g).
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM: The specification is required to include an incorporation-by-reference of electronic documents that are to become part of the permanent United States Patent and Trademark Office records in the file of a patent application. See 37 CFR 1.77(b)(5) and MPEP § 608.05. See also the Legal Framework for Patent Electronic System posted on the USPTO website (https://www.uspto.gov/sites/default/files/documents/2019LegalFrameworkPES.pdf) and MPEP § 502.05
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR. See 35 U.S.C. 102(b) and 37 CFR 1.77.
(g) BACKGROUND OF THE INVENTION: See MPEP § 608.01(c). The specification should set forth the Background of the Invention in two parts:
(1) Field of the Invention: A statement of the field of art to which the invention pertains. This statement may include a paraphrasing of the applicable U.S. patent classification definitions of the subject matter of the claimed invention. This item may also be titled “Technical Field.”
(2) Description of the Related Art including information disclosed under 37 CFR 1.97 and 37 CFR 1.98: A description of the related art known to the applicant and including, if applicable, references to specific related art and problems involved in the prior art which are solved by the applicant’s invention. This item may also be titled “Background Art.”
(h) BRIEF SUMMARY OF THE INVENTION: See MPEP § 608.01(d). A brief summary or general statement of the invention as set forth in 37 CFR 1.73. The summary is separate and distinct from the abstract and is directed toward the invention rather than the disclosure as a whole. The summary may point out the advantages of the invention or how it solves problems previously existent in the prior art (and preferably indicated in the Background of the Invention). In chemical cases it should point out in general terms the utility of the invention. If possible, the nature and gist of the invention or the inventive concept should be set forth. Objects of the invention should be treated briefly and only to the extent that they contribute to an understanding of the invention.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S): See MPEP § 608.01(f). A reference to and brief description of the drawing(s) as set forth in 37 CFR 1.74.
(j) DETAILED DESCRIPTION OF THE INVENTION: See MPEP § 608.01(g). A description of the preferred embodiment(s) of the invention as required in 37 CFR 1.71. The description should be as short and specific as is necessary to describe the invention adequately and accurately. Where elements or groups of elements, compounds, and processes, which are conventional and generally widely known in the field of the invention described, and their exact nature or type is not necessary for an understanding and use of the invention by a person skilled in the art, they should not be described in detail. However, where particularly complicated subject matter is involved or where the elements, compounds, or processes may not be commonly or widely known in the field, the specification should refer to another patent or readily available publication which adequately describes the subject matter.
(k) CLAIM OR CLAIMS: See 37 CFR 1.75 and MPEP § 608.01(m). The claim or claims must commence on a separate sheet or electronic page (37 CFR 1.52(b)(3)). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation. There may be plural indentations to further segregate subcombinations or related steps. See 37 CFR 1.75 and MPEP 608.01(i) - (p).
(l) ABSTRACT OF THE DISCLOSURE: See 37 CFR 1.72 (b) and MPEP § 608.01(b). The abstract is a brief narrative of the disclosure as a whole, as concise as the disclosure permits, in a single paragraph preferably not exceeding 150 words, commencing on a separate sheet following the claims. In an international application which has entered the national stage (37 CFR 1.491(b)), the applicant need not submit an abstract commencing on a separate sheet if an abstract was published with the international application under PCT Article 21. The abstract that appears on the cover page of the pamphlet published by the International Bureau (IB) of the World Intellectual Property Organization (WIPO) is the abstract that will be used by the USPTO. See MPEP § 1893.03(e).
(m) SEQUENCE LISTING: See 37 CFR 1.821 - 1.825 and MPEP §§ 2421 - 2431. The requirement for a sequence listing applies to all sequences disclosed in a given application, whether the sequences are claimed or not. See MPEP § 2422.01.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1: The claim recites “determining, the prediction”. The comma appears to be a typo.
Appropriate correction is required.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP 2111.
Regarding claim 11, it is noted that the Courts have generally found that “one or more of” A, B, and C and similar phrasings to mean that one of each of the items is required. See SuperGuide Corp v. DirecTV Enters., Inc., 358 F.3d 870 (Fed. Cir. 2004).
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.
Claim 1-2, 4-11, and 18 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 claims 1-2, 7-8, and 18, the claims recite “for example, 5, 6, … , or all”. The phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, the claims recites the broad recitation “five or more, and the claims also recite “for example, … , 6, 7, … , or all” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Further, the claims are indefinite for the recitation of “determining (…) the prediction of the radiotherapy response based on the gene expression profiles for the … immune defense response genes”. It is unclear which parameters in the gene expression profiles would allow for prediction of the radiotherapy response.
Claims 4-11 are also indefinite for depending from claim 1 and not rectifying the deficiency.
Regarding claim 11, the claim recites “such as androgen deprivation therapy”. The phrase "such as" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The claim also recites “the prediction of radiotherapy response is negative or positive” and “if the prediction is negative”. The terms “negative” and “positive in the claim are relative terms which renders the claim indefinite. The terms “negative” and “positive” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
No threshold, defined or exemplary, for what may be considered either “negative” or “positive” was identified in the specification. Broadly interpreted, the limitation does not place requirements on the amount of outcomes (i.e., a prediction may be determined to be “negative” out of a choice of “negative”, “intermediate”, “positive”, etc.), merely on what the prediction of the outcome is.
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 1-2, 4-11, and 18 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 1-2, 4-11, and 18, the claims are directed to a method comprising determining a prediction of radiotherapy response based on a gene expression profile of five or more immune defense response genes, wherein—excluding claim 18—the gene expression profiles are determined in a biological sample from a subject.
These claims have great breadth regarding at least:
Combinations of genes, wherein the prediction is broadly “based on” the expression profiles
Origins of gene expression profiles (i.e., biological samples for claims other than 18 and any source for claim 18)
Where C(n,r) = n!/(r![n-r]!) for n = 14 and r = the number of genes chosen, C(14, 6) = 2022, C(14, 6) = 3003, C(14, 7) = 3003, C(14,9) = 2002, C(14, 10) = 1001, C(14, 11) = 364, C(14, 12) = 91, and C(14, 13) = 14. Together, for 5 or more genes, plus the “all” condition, the total number of possible combinations is 14,913.
The Applicant provides working examples using the 14 gene set (e.g., pg. 21-25 corresponding to Fig. 2-3, 7, 10, 13, and 17; Tables 1 and 2) and a small subset of the 5 (8 examples) and 6 (4 examples) gene sets (pg. 26-27, wherein none of the corresponding Fig. 21-32 were provided; Tables 3 and 4). The small subset of the 5 gene sets have high variability in their stratification of the “low” and “high” risk cohorts, e.g., the number of patients of the set of 185 used in the descriptions of Fig. 21-32 (pg. 39-42) vary from 53 to 117 placed in the low cohort.
Cross Validated (Pleva L. Does adding more variables into a multivariable regression change coefficients of existing variables? [Internet]. Cross Validated; 2013 [cited 2025 Dec 26]. Available from: https://stats.stackexchange.com/questions/52067/does-adding-more-variables-into-a-multivariable-regression-change-coefficients-o) teaches that the variables of a binary regression are typically change in real-world data due to correlation between variables and/or inappropriately omitted variables that cause attribution of variation in the intercept variable to another variable (i.e., omitted variable bias).
The genes (variables of the model) in the IDR regression model of Tables 3 and 4 demonstrate the behavior expected with correlated variables, wherein the magnitude and even sign changes with different selections of variables (e.g., IFIT1 in Table 3 and 4).
Additionally, the claims encompass any other combination that could reasonably be “based on” the combinations of genes, not just those that are “solely” based on. No embodiments were identified that demonstrated further such additions (e.g., including grade, patient age, etc. in the regression). As described in Cross Validated, the artisan would anticipate that the addition of further variables may or may not improve models based on correlations or lack thereof with the additional variables. Thus, there is a high degree of variability encompassed in the breadth of any other possible variable encompassed by such a broadly claimed prediction.
For these reasons, there would be expected to be a high degree of variability in the genus claimed, such that the limited number of species demonstrated would not be sufficient for the skilled artisan to conclude that the applicant had possession of all claimed combinations sets of genes of the claimed invention at the time of filing.
Further, the claims recite determining gene expression profiles in “a biological sample obtained from the subjection” or, in claim 18, fail to state where the gene expression profiles used in the determining step originate.
Applicant describes that the data was generated using prostate cancer tissues obtained from radical prostatectomy (pg. 7, para 2), and while other samples are mentioned (pg. 17, para 3), no guidance was identified regarding translating the invention to such samples. There is no indication, for example, that non-cancerous tissues or a skin or fecal sample would be useful to the present invention.
Calfa (Calfa S, et al. Comparative evaluation of microRNA detection in plasma, urine and liquid-based cytology for high-grade cervical intraepithelial neoplasia. Oncol Lett. 2025 Nov 26;31(2):53.) teaches that specimen types differ both in detection efficiency and variability, and that diagnostic sensitivity relies on specimen selection (Abstract). Thus, there would be expected to be additional unpredictability and a high degree of experimentation required to expand the invention to the scope of the biological samples (any) claimed.
No examples or guidance was identified regarding, for example, imputed gene expression or other means of predicting a radiotherapy response, and optionally to provide a prediction/recommendation for a subject, based on gene expression profiles from any source. Andrews (Andrews TS, Hemberg M. False signals induced by single-cell imputation. F1000Research. 2019 Mar 5;7:1740) teaches that imputation may introduce false-positive and varies greatly depending on the method used (Abstract). Imputing based on signals other than those of a biological sample (e.g., patient characteristics) would be expected to have an even greater degree of variability.
For these reasons, there would be expected to be a high degree of variability in the genus claimed of gene expression profile sources, such that the single number of species demonstrated would not be sufficient for the skilled artisan to conclude that the applicant had possession of the entire genus of all biological samples or all possible sources at the time of filing.
Thus, the claims fail to meet the written description requirements of 112(a).
Claims 1-2, 4-11, and 18 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 1-2, 4-11, and 18, the claims are directed to a method comprising determining a prediction of radiotherapy response based on a gene expression profile of five or more immune defense response genes, wherein—excluding claim 18—the gene expression profiles are determined in a biological sample from a subject.
First, the claims are broad. The claims encompass 14!/(9!*5!) = 2002 possible combinations of 5 genes of the 14 possible, let alone all combinations of 6, 7, 8 … 13, or all of the 14 (aside from claims 5-6, which encompass the narrowed set of combinations for the respective numbers of genes). They encompass any biological sample from the subject, or in the case of claim 18 any set of profiles obtained from any source. They encompass, excluding claims 7 and 8, any method of analyzing the set of expression profiles, any method of determining (e.g., any set of threshold, any comparison, etc.). They encompass any direction of prediction, and in the optional recommendation, any recommendation.
Second, the invention is in the class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
Third, the prior art teaches the critical importance of study design and statistical analysis in limiting the unpredictability and amount of experimentation required of this type of invention. Zhao (Zhao SG, et al. Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. Lancet Oncol. 2016 Nov;17(11):1612-1620.; as cited in the IDS dated 09/01/2022) provides a similar 24-gene predictor of response to postoperative radiotherapy in prostate cancer (e.g., Title; Abstract). Zhao teaches that treatment selection bias is an inevitable consequence because patients were chosen to receive radiotherapy for specific clinical reasons, and that patients with a low score who had post operative radiotherapy had a higher incidence of distant metastasis than those who were not treated (pg. 1617, para 1). Zhao states that even matching for clinicopathological variables, they do not expect they were able to capture all possible extrinsic confounders that affect treatment selection such as treatment timing, duration, radiation dose, ethnicity, comorbidities, or other medications, wherein such may affect the results (pg. 1617, para 1).
Zhao teaches that overfitting is a well-known and unavoidable issue in model development, and teaches the importance of keeping a cohort of treated and untreated patients to evaluate for outcomes (pg. 1617, para 1, spanning pg. 1618).
Zhao also teaches that distinguishing between adjuvant and salvage therapy requires adequately powered matched cohorts (pg. 1619, col 1, para 2).
Further, Zhao teaches that prognostic signatures are those designed to risk-stratify patience independent of treatment, while predictive signatures are those that can select subsets of patients who would benefit from a particular intervention (pg. 1613, col 1, para 1; emphasis added). Zhao teaches that while prognostic biomarkers can identify which patients have aggressive disease and presumably need intensification of therapy, they do not identify which particular therapy should be given (pg. 1616, Discussion, para 2; emphasis added).
Zhao teaches an analysis of three widely used prognostic scores, including CAPRA-S, that do not predict response to postoperative radiotherapy within their validation cohort, finding that while certain prognostic signatures may contain predictive information these signatures are not predictive for post-prostatectomy radiation therapy when compared between high and low score for those that were treated and untreated with radiotherapy (pg. 1616, col 1, para 1, spanning col 2; Fig. 3).
Zhao teaches that the development of truly predictive (as opposed to prognostic) treatment response biomarkers is a difficult proposition, requiring balanced datasets from treated versus untreated patients, complicated by the scarcity of randomized clinical trials and high throughput genomic/transcriptomic data from trial samples (pg. 1616, Discussion, para 2).
Additionally, similar to Zhao, Sooriakumaran (Sooriakumaran P, et al. Comparative effectiveness of radical prostatectomy and radiotherapy in prostate cancer: observational study of mortality outcomes. BMJ. 2014 Feb 26;348:g1502.) teaches that stratification of patients by treatment is not randomly distributed, but rather patients who received radiotherapy were older and had higher comorbidity scores and those who received radical prostatectomies received a diagnosis at a later date; likewise, the choice of treatment differed by country, education level, socioeconomic status, and marriage status (Results, para 1).
Thus, the prior art teaches a high degree of uncertainty and experimentation required with prognostic markers in order to utilize them as predictive markers (i.e., to utilize them for the prediction of response to a particular therapy such as radiotherapy). Additionally, it teaches that patient characteristics taught to potentially influence outcomes differ by treatment choice, extrapolation without, for example matching, would lead to a high degree of uncertainty.
Fourth, while the claims are directed to what Zhao would call a “predictive signature” for “radiotherapy response”, contrary to the teachings of the art, the data and guidance provided in the disclosure are directed to a “prognostic signature”.
Applicant recites that they have identified 14 immune defense response gene for which the degree of expression in prostate cancer significantly corelates with morality after salvage radiotherapy in a cohort of 151 prostate cancer patients (pg. 29, para 3). Applicant relays that. of the 538 surgical cohort, approximately 30% experience biochemical recurrence or PSA relapse (i.e., 161 patients), of whom 151 underwent SRT either alone or in combination with anti-androgen treatments (pg. 29, para 6).
Applicant describe a Kaplan-Meier curve analysis in the SRT cohort; a salvage androgen deprivation therapy (SADT) (106 men; pg. 34, para 1; Fig. 7); and a SADT + cytotoxic therapy cohort (19 men; pg. 34, para 4, spanning pg. 35; Fig. 10) analyzed with the 14 gene set regression model, each finding a difference between the low and high model sets. All appear to have come from the SRT cohort.
Applicant also describes a subset of the post-surgical recurrent prostate cancer cohort of 130 men using a summation model (pg. 35, para 3; Fig. 13), finding a difference based on the score.
However, Applicant also describes similar separation in their cohorts with the CAPRA-S score where the cohort sizes were reasonably large (e.g., Figs. 5, 8, 14, 16), which, as described in Zhao, was not found to be predictive for radiotherapy response in a validation cohort when analyzed according to art-recognized matching protocols to control for the unpredictability in the patient cohort. Applicant further recites, in contrast to the teachings of Zhao to utilize a separate validation cohort for models, that the gene set was derived from analysis of the group of 538 prostate cancer patients treated with radical prostatectomy (pg. 7, para 2, spanning pg. 8).
Indeed, Applicant describes that the set of 14 genes was discovered based on selecting those patients who died from prostate cancer vs those who did not and that metastases and prostate specific death were enriched in the sub-cohort undergoing salvage RT of 151 patients and the total patient cohort of 538 (pg. 8, lines 27-30).
Thus, the artisan would expect that the model would show overfitting. Such a model, as mentioned by the Applicant, appears to broadly predict positive outcomes in the total patient cohort, i.e., to serve as a “prognostic signature”, as described by Zhao. Without the art-taught matching and validation techniques to demonstrate an underlying relationship with radiotherapy response, the artisan would find a high degree of uncertainty in utilizing this gene expression profile signature as a predictive signature for determining whether a patient would respond to radiotherapy given the potential confounding variables in patient selection bias of treatment and the overfitting that may have occurred since the “validation” occurred on the subset of the training set. For these reasons, the artisan would anticipate a high degree of experimentation in order to utilize the method as claimed.
Applicant describes that the data was generated using prostate cancer tissues obtained from radical prostatectomy (pg. 7, para 2), and while other samples are mentioned (pg. 17, para 3), no guidance was identified regarding translating the invention to such samples. There is no indication that non-cancerous or normal tissues would be useful in the present invention.
Calfa (Calfa S, et al. Comparative evaluation of microRNA detection in plasma, urine and liquid-based cytology for high-grade cervical intraepithelial neoplasia. Oncol Lett. 2025 Nov 26;31(2):53.) teaches that specimen types differ both in detection efficiency and variability, and that diagnostic sensitivity relies on specimen selection (Abstract). Thus, there would be expected to be additional unpredictability and a high degree of experimentation required to expand the invention to the scope of the biological samples (any) claimed.
Applicant likewise fails to provide guidance as to why the summation function cohort had a reduced number of 130 compared to 151 used in the regression model for the same treatment cohort. It is unclear whether there are additional limitations of this function, such as a high number of outlier patients that were chosen to be excluded, and therefore additional uncertainty exists as to whether further methods of determining a prediction would be sufficiently predictable to not require undue experimentation.
Applicant also describes applying regression model to five and six gene sets (Tables 3 and 4). While the Figures 21-32 have not been provided, the logrank p-values, hazard ratio, confidence intervals, and counts of patients have been provided (pg. 39-42). However, it is unclear where the patient cohort used in the analysis is derived from, as the descriptions of Fig. 21-32 recite cohorts of 185 (pg. 39, para 1 through pg. 41, para 4, spanning pg. 42). The Applicant provides 8 models for 5 variables (Table 3) and 4 for 6 variables (Table 4), finding significant models for each, but with a high degree of variability in, for example the number of patients in the low risk group (e.g., Fig. 21 has 53 starting compared to the model of Fig. 23, which has 96 starting patients). Specifically, such variability in the numbers of the low and high risk cohorts according to each stratification model would result in a high number of patients who would be “low” under one but “high” under others, thus requiring a high degree of experimentation. And, as detailed at the beginning, these 12 represent only a small fraction of the claimed combinations of gene sets.
Claim 18 further broadens the claims to encompass use of any signature in a determining a prediction of radiotherapy response. No examples or guidance was identified regarding, for example, imputed gene expression. Andrews (Andrews TS, Hemberg M. False signals induced by single-cell imputation. F1000Research. 2019 Mar 5;7:1740) teaches that imputation may introduce false-positive and varies greatly depending on the method used (Abstract). Imputing based on signals other than those of a biological sample (e.g., patient characteristics) would be expected to have an even greater degree of uncertainty.
Taken together, there is a high degree of uncertainty and experimentation required due to the 1) breadth of all possible combinations of biomarkers, samples, and methods of analysis; 2) general unpredictability of the art; 3) the art that teaches (a) the importance of analytical techniques such as matching and using a validation cohort to control for the high level of unpredictability (e.g., due to biases in patient selection of treatments) and (b) the inability of the CAPRA-S score to predict response when so controlled; and 4) the limited working examples and guidance that (a) fail to utilize such controls and that instant signature functions similarly to CAPRA-S in the instant cohort, (b) detail only a single sample and expression analysis type, (c) characterize only a limited number of 5- and 6-gene models that display high variability in stratifying patient cohorts, and (d) fail to provide examples or guidance of use of methods of predicting a response based on signals other than those of the claimed genes (i.e., use of expression profiles not from a biological sample of a subject). Balanced only against the high level of art in the skill, it is held that the level of experimentation to utilize the invention claimed would be undue.
For this reason, the claims do not comply with the 112(a) enablement requirements.
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 1-2, 4-11, and 18 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 abstract ideas/natural phenomena. 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)?
Regarding claims 1 and 2, the claims recite determining a gene expression profile for each of five or more immune defense response genes selected from a group of 14, wherein the profiles are determined in a biological sample from a subject and determining a prediction of radiotherapy response based on the gene expression profiles of the immune defense response genes.
The step of determining a gene expression profile encompasses abstract ideas, including mental processes (e.g., observation, evaluation, and judgement) and mathematical calculations that may be performed by a human mind (e.g., simple calculations such as subtracting the value of a level of a gene with that of a control).
The step of determining the prediction of radiotherapy response based on the gene expression profiles likewise encompasses mental processes (e.g., forming a judgement, evaluation, and/or opinion based on values in a table) and/or mathematical calculations, including those that may be performed in the human mind (e.g., simple machine learning/classification functions such as regression). Thus, the claims are directed to abstract ideas.
Further, the claim is directed to the natural phenomenon of a correlation between the expression of five or more genes of the fourteen immune defense response genes in the subject and their response to radiotherapy. Thus, the claim is likewise directed to a natural phenomenon.
Regarding claim 18, the claim recite using a gene expression profile for each of five or more immune defense response genes selected from a group of 14 and determining using a processor a prediction of radiotherapy response based on the gene expression profiles of the immune defense response genes.
As above in claims 1 and 2, the claim is directed to the same abstract ideas.
The broader claim is directed to the natural phenomenon of a correlation between the expression of five or more genes of the fourteen immune defense response genes in profiles of undisclosed origin (inclusive of those from the patient, imputed from other values, etc.) and the response to radiotherapy in a subject. As such, it is also directed to a natural phenomenon.
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
Regarding claim 1, the claims encompass no more than judicial exceptions and thus fail to integrate the claim into a practical application.
It is noted that even under an interpretation where determination of a gene expression profile for each immune defense response gene in a biological sample requires practical steps, such would be considered necessary data gathering to perform the judicial exception (e.g., the well-known amplifying and sequencing of nucleic acid sequences of University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)), i.e., insignificant extra-solution activity. See MPEP 2106.04(d) and 2106.5(g).
Likewise, for the sake of compact prosecution, it is noted that neither providing a prediction nor a therapy recommendation integrates the claim into a practical application. As discussed in MPEP 2106.04(d)(2), limitations that do not actually provide a treatment of prophylaxis cannot integrate a judicial exception under the “treatment or prophylaxis” consideration.
Regarding claims 4-6, the claims recite, respectively, six, nine, or twelve, genes. As such, they merely alter the judicial exceptions and thus fail to integrate the claims.
Regarding claims 7 and 8, the claims recite particular mathematical functions (regression and sum functions, respectively) used in the determining step. As such they remain directed to mathematical functions, including those that may be accomplished by the human mind. As such, the claims fail to integrate the judicial exception(s) into a practical application.
Regarding claims 9-10, the claims recites particular timing of biological samples or radiotherapy. As such, they are directed to either a selection of samples (insignificant extra-solution activity) or a variation in the abstract ideas (i.e., the natural phenomenon and/or mathematical calculations). Thus, the claims fail to integrate the judicial exception(s) into a practical application.
Regarding claim 11, the claim recites a further limitation of the prediction and the recommendation of the therapy. As above, modifications of the judicial exception do not integrate the claim. Likewise, a recommendation is not sufficient, as discussed above, to integrate the claim as it does not actually require administration of said therapy. See MPEP 2106.04(2).
It is further noted, for the sake of compact prosecution, that as described in Claim Interpretation, that the current treatments would be interpreted to be one joint treatment requiring one from each category. If Applicant decides to amend (e.g., to replace “and” with “or”) to instruct the artisan to treat with “one or more of…or iv) an alternative therapy that is not radiation therapy”, at least “an alternative therapy” alone would not be considered particular to the judicial exception.
Regarding claims 2 and 18, These claims fall for the same reasons as claim 1. Additionally, the claims recite “determining, by a processor, the prediction”. The term “processor” is a generic computer component. While a “particular machine” can integrate an abstract idea into a practical application, the Courts are clear that a generically recited computer component merely used to implement an abstract idea, such as an idea that could be done by a human analog, does not. See MPEP 2106.05(b) and 2106.05(d)(II). See also MPEP 2106.05(h), which discusses field of use and technological environments, particularly (iv) relating to execution of an abstract on a generic computer.
Step 2B. Does the claim amount to significantly more?
No claims amount to significantly more.
MPEP 2106.05(I) discusses the search for the inventive concept, which must be furnished beyond the judicial exceptions(s). In the instant case, the claims encompass only abstract ideas/natural phenomenon and/or generically recited insignificant extra-solution activity, as discussed above. Taken together, no claim is sufficient to amount to significantly more than the judicial exception.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1-2, 4-7, 9-11, and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-18 of copending Application No. 18/023,598 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Both sets of claims are directed to a set of genes encompassing 5 or more of the immune defense response genes AIM2, APOBEC3A, CIAO1, DDX58, DHX9, IFI16, IFIH1, IFIT1, IFIT3, LRRFIP1, MYD88, OAS1, TLR8, and ZBP, obtaining a gene expression profile for each of the selected genes determined in a biological sample obtained from a prostate cancer subject and determining a prediction of a therapy response based on a set of expression profiles including said immune defense response genes (claim 1), wherein the [predicted] therapy may be radiotherapy (claims 9 and 10).
Boths sets of claims also teach a processor adapted to perform the method (claim 12), wherein it would be obvious to utilize such an apparatus in the method of claim 1 of ‘598 motivated by the desire to make the method simpler to use in the clinical setting.
Both sets of claims teach a prediction using a regression function derived from a population of prostate cancer patients (claim 3), obtaining the same before the start of therapy (claim 8), that the radiotherapy may be radical or salvage (claim 9), that the prediction is negative or positive and the set of recommended therapies of instant claim 11 (claim 10).
Any additional limitations of the ‘598 claims are encompassed by the open claim language “comprising” and/or ”based on” found in the instant claims.
Therefore, the claims are deemed to be patentably indistinct.
Conclusion
No claims are allowed.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636