DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-7 and 9-21 are pending and currently under examination.
Priority
This application 18/284,131filed on 09/26/2023 is a 371 national phase of PCT/US 2022/019757 filed on 03/10/2022, and claims the benefit of provisional U.S. Patent Application No. 63/166,658, filed on 03/26/2021.
The priority date of claim1 and claim 2 and its dependent claims is determined to be 03/26/2021, the filing date of provisional U.S. Patent Application No. 63/166,658.
Claim Interpretation
Claims 1, 2 and 9 recite the limitation "B cell related gene". The instant specification states that a B cell related gene can be selected from “BLK, CD19, FCRL2, MS4A1, KIAA0125, TNFRSF17, TCL1A, SPIB, PNOC, and combinations thereof” and “Examples of B cell related genes can include, but are not limited to, BLK, BLNK, BTK, NFAM1, LYN, CD5, CD19, CD21, CD45, CD22, CD79A, CD79B, CD81, FYN, FCRL1, FCRL2, FCRL3, FCRL4, FCRL5, LAX, PIR, CR1, BAFF, CS1, LILRB1, LILRB2, LILRB3, LILRB4, LILRA3, LAIR1, and combinations thereof” (p. 10). No further requirements are provided that define a gene as “B cell related”. For purposes of examination, any of the genes listed in the specification is considered to be a “B cell related gene”.
Claims 1, 2, and 10 recite the limitation “CD8+ T cell related gene”. The instant specification states that a CD8+ T cell related gene can be selected from “CD8A, GZMA, GZMB, IFNG, CXCL9, CXCL10, PRF1, TBX21 and combinations thereof” and that “Examples of CD8+ T cell related genes can include, but are not limited to, TNFRSF9, XCL1, XCL2, CRTAM, PSMB8, PSMB9, PSMB10, PSME2, TAP1, IRF1, FBOX6, ETV7, NKG7, GZMH, CCL4, LAG3, CD2, GBP5, CD3D, B2M, CD74, LAP3, CD7, HLA- DRA, HLA-C, HLA-DMA, and combinations thereof” (p. 11). No further requirements are provided that define a gene as “CD8+ T cell related”. For purposes of examination, any of the genes listed in the specification is considered to be a “CD8+ T cell related gene”.
The claims recite the limitations “the B cell gene signature and the CD8+ T cell gene signature (B8T gene signature)” and “B8T high/high”, “B8T high/low”, “B8T low/high”, and “B8T low/low”. For purposes of examination, it is assumed that the first element in the B8T gene signature refers to values for a B* cell gene signature and the second element in the B8T signature refers to values for a CD8+ T cell signature.
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 1-7 and 9-21 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.
Claims 1 and 2 recite the limitation “analyzing the B cell gene signature and the CD8+ T cell gene signature (B8T gene signature)”. It is unclear how the B cell gene signature and the CD8+ T cell gene signature correspond to the B8T gene signature or how the B cell and CD8+ T cell gene signatures are used to produce the B8T gene signature. For purposes of examination the B8T gene signature is interpreted to be a gene signature comprising a B cell gene signature and a CD8+ T cell gene signature.
Regarding claims 1 and 2, it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites “A method of determining treatment outcome in a subject having a disease”. However, the recited active method steps in the claim only require “evaluating RNA expression level” and “analyzing” gene signatures. The claims do not recite how evaluating RNA expression and analyzing gene signatures determine treatment outcome. It is thereby unclear as to whether the claims are intended to be directed to methods that only require evaluating RNA expression and analyzing gene signatures or to methods that require determining treatment outcome. In the latter instance, the claims omit the steps required to accomplish the objective set forth in the preamble of the claims of determining treatment outcome in a subject having a disease.
Claims 3-7 and 9-21 are similarly indefinite because they directly or indirectly depend from claim 2.
Claim 11 recites the limitations “B8T high/high”, “B8T high/low”, “B8T low/high”, and “B8T low/low”. Claim 12 recites the limitation “B8T high/high”. Claim 14 recites the limitations “B8T high/low” and “B8T low/high”. The terms “high/high”, “high/low”, “low/high”, and “low/low” are relative terms which render the claim indefinite. It is unclear what criteria are used to define high versus low values. It is also unclear how such values would be determined. The terms high and low are 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.
Claims 18-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. Claim 18 recites the limitation “wherein the treatment outcome is determined to be beneficial to the subject when the gender of the subject is identified as male”. Claim 19 recites the limitation “wherein the treatment outcome is determined to be non-beneficial to the subject when the gender of the subject is identified as female”. Claim 20 recites the limitation “wherein the treatment outcome is determined to be beneficial to the subject when the gender of the subject is identified as female”. Claim 21 recites the limitation “wherein the treatment outcome is determined to be non-beneficial to the subject when the gender of the subject is identified as male”. Claims 18-21 depend from claim 17 which recites the limitation “further comprises identifying the gender of the subject, wherein the B8T gene signature and the gender are used in combination to determine treatment outcome in the subject”. The omitted steps in claims 18-21 appear to be: a step of categorizing the particular B8T gene signature used in combination with the identified gender. Claims should clearly delineate all active steps required for performing the claimed methods.
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 1-7 and 9-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to the statutory category of a process.
Step 2A, Prong One
The claims are taken to be directed to abstract ideas and laws of nature, judicial exceptions.
Claim 1 is directed to a method comprising “(a) evaluating RNA expression level of a B cell related gene to determine a B cell gene signature; (b) evaluating RNA expression level of a CD8+ T cell related gene to determine a CD8+ T cell gene signature;” and “(c) analyzing the B cell gene signature and the CD8+ T cell gene signature (B8T gene signature); and (d) determining treatment outcome in the subject based on the B8T gene signature”. The evaluating, analyzing, and determining limitations are abstract mental processes (see MPEP 2106.04(a)(2)(III)). As written, the evaluating and analyzing steps encompass the mental step of looking at RNA expression and making mental judgements.
Claim 1 further sets forth the correlation between gene signatures and treatment outcome. This relationship is a natural phenomenon that exists apart from any human action and constitutes a law of nature.
Claim 2 is directed to a method comprising “(a) evaluating RNA expression level of a B cell related gene to determine a B cell gene signature; (b) evaluating RNA expression level of a CD8+ T cell related gene to determine a CD8+ T cell gene signature; (c) analyzing the B cell gene signature and the CD8+ T cell gene signature (B8T gene signature)” and “(d) determining treatment outcome in the subject based on the B8T gene signature”. These limitations are abstract mental processes (see MPEP 2106.04(a)(2)(III)). As written, the evaluating, analyzing, and determining steps encompass the mental step of looking at RNA expression and making mental judgements.
Claim 2 further sets forth the correlation between gene signatures and treatment outcome. This relationship is a natural phenomenon that exists apart from any human action and constitutes a law of nature.
Claims 3-7 and 9-21 depend from claim 2, and require the same steps of evaluating, analyzing, and determining.
Claim 15 is directed to a method comprising “identifying a prognostic biomarker in the subject”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). As written, the identifying step encompasses the mental step of looking at biomarker expression and making mental judgements.
Claim 17 is directed to a method comprising “identifying the gender of the subject”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)). As written, the identifying step encompasses the mental step of noting gender identity by looking at medical records.
Step 2A, Prong Two
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception.
While claim 2 recites ”administering a treatment to the subject when the subject is predicted to have a beneficial outcome based on the determined B8T gene signature”, this is not an integration of the exception into a practical application. The claims do not include a step of administering a particular agent to the subject to treat a particular disease after determining that the subject having a disease will be responsive to that particular agent. See MPEP 2106.04(d)(2).
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim does not add a specific limitation other than what is well-understood, routine, and conventional in the field. Steps directed to evaluating RNA expression, analyzing gene signatures and determining treatment outcome are recited at a high level of generality covering all conventional methods of assaying for gene expression. Methods of assaying for gene expression, analyzing gene signatures and determining treatment outcome were well-known, routine and conventional in the prior art as demonstrated in the 102 and 103 rejections documented below.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-7 and 9-16 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Srinivasan et al. (WO/2020/205644, on IDS dated 04/12/2024).
Regarding claim 1, Srinivasan teaches methods of determining a tumor microenvironment (TME) signature to determine a patient response to a therapeutic agent (para 5). Srinivasan teaches the TME signature may be detected by RNA sequencing (150), providing RNA expression. Srinivasan further teaches a TME signature may comprise a B cell signature (para 7 and example 4) or CD8+T cell signature (para 7 and example 3). Srinivasan teaches obtaining the expression level of genes in a TME signature and calculating a TME gene signature, which reads on “analyzing the B cell gene signature and the CD8+ T cell gene signature (B8T gene signature)”, and classifying a patient as biomarker positive for an outcome based on the TME signature (para 127). Srinivasan further teaches that a biomarker positive patient is determined to be likely experience a DCB (durable clinical benefit, i.e. a beneficial outcome) with the therapeutic agent (para 127).
Regarding claim 2, Srinivasan teaches methods of determining a tumor microenvironment (TME) signature to determine a patient response to a therapeutic agent (para 5). Srinivasan teaches the TME signature may be detected by RNA sequencing (150), providing RNA expression. Srinivasan further teaches a TME signature may comprise a B cell signature (para 7 and example 4) or CD8+T cell signature (para 7 and example 3). Srinivasan teaches obtaining the expression level of genes in a TME signature and calculating a TME gene signature, which reads on “analyzing the B cell gene signature and the CD8+ T cell gene signature (B8T gene signature)”, and classifying a patient as biomarker positive for an outcome based on the TME signature (para 127). Srinivasan further teaches that a biomarker positive patient is determined to be likely experience a DCB (durable clinical benefit, i.e. a beneficial outcome) with the therapeutic agent (para 127). Srinivasan teaches administering therapeutic agents to a biomarker positive patient (para 21)
Regarding claim 3, Srinivasan teaches the disease is cancer (para 270).
Regarding claim 4, Srinivasan teaches performing the methods on metastatic tumors that have undergone surgical removal (para 378), which reads on metastatic solid tumor.
Regarding claim 5, Srinivasan teaches the cancer is bladder cancer (paras 32, 62, 270).
Regarding claim 6, Srinivasan teaches cancers selected from bladder cancer, breast cancer, and cervical cancer (para 270).
Regarding claim 7, Srinivasan teaches administering an immune checkpoint inhibitor (para 378).
Regarding claim 9, Srinivasan teaches the B-cell signature comprises expression of CD19 (para 104).
Regarding claim 10, Srinivasan teaches signatures comprising CD8A (para 106), which reads on a CD8+ T cell related gene.
Regarding claim 11, Srinivasan teaches B cell signatures that are high and low correlated with durable clinical benefit (Fig. 5) and CD8+ T cell signatures that are high and low correlated with durable clinical benefit (Fig. 3), which reads on B8T signatures that are high/high, B8T high/low, B8T low/high, and B8T low/low, where the first element is B cell signatures and the second element is CD8+ T cell signatures.
Regarding claim 12, Srinivasan teaches a patient with high DCB (durable clinical benefit, i.e. a beneficial outcome) has high B cell (para 129) and a patient with DCB has high CXCL9 (para 133), which reads on a signature that is B cell signature high/CD8+ T cell signature high as required by the limitation.
Regarding claim 13, Srinivasan teaches using the method to determine durable clinical benefits (para 2), defined as progression-free survival (para 289).
Regarding claim 14, Srinivasan teaches low B cell signatures associated with no DCB (durable clinical benefit, i.e. a non-beneficial outcome) (Fig. 5) and CD8+ T cell signatures that are low associated with durable clinical benefit (Fig. 3), which reads on B8T signatures that are low/high and B8T high/low, where the first element is B cell signatures and the second element is CD8+ T cell signatures.
Regarding claims 15 and 16, Srinivasan teaches identifying the tumor mutational burden in patients and correlation with durable clinical benefit (Example 2, Fig. 2).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 2 and 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Srinivasan et al. (WO/2020/205644. On IDS dated 04/12/2024) in view of Conforti et al. (Cancer immunotherapy efficacy and patients' sex: a systematic 11. review and meta-analysis. 2018. Lancet Oncology. 19(6):737-746. On IDS dated 04/12/2024).
The teachings of Srinivasan as they relate to claim 2 are stated in the 102 rejection above in this office action.
Regarding claim 17, Srinivasan teaches identifying the gender of a subject (Tables 3 and 4), but does not teach identifying the gender of the subject, wherein the B8T gene signature and the gender are used in combination to determine treatment outcome in the subject.
Conforti teaches differences in immune checkpoint inhibitor efficacy between men and women (p. 737, Summary).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Srinivasan and Conforti to arrive at the instantly claimed invention. The modification would have entailed using the gender data collected by Srinivasan as a factor in determining a patient response to a therapeutic agent by adding it as a variable to consider as in Conforti. One would have been motivated to do so by the interest of both Srinivasan and Conforti in increasing predictiveness of treatment efficacy. Conforti teaches that sex-related dimorphism in immune system response is well known (p. 737, Summary), and Srinivasan is interested in considering complex factors responsible for determining treatment outcome (paras 2 and 3). There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 18-21, Srinivasan does not teach the treatment outcome is determined to be beneficial to the subject when the gender of the subject is identified as male (claim 18) or the treatment outcome is determined to be non-beneficial to the subject when the gender of the subject is identified as female (claim 19).
Conforti teaches examples wherein intervention is favored (treatment outcome is beneficial) when the subject is male; control is favored (treatment outcome is non-beneficial) when the subject is female; intervention is favored (treatment outcome is beneficial) when the subject is female; control is favored (treatment outcome is non-beneficial) when the subject is male (Fig. 2). Conforti states that there is heterogeneity in the efficacy of immune checkpoint inhibitors according to the patient’s sex (p. 743, col. 1) and that other factors could explain the association between sex and immune checkpoint inhibitor efficacy (p. 745, col. 1), including individual patent variables such as gene expression and mutations (p. 744).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Srinivasan and Conforti to arrive at the instantly claimed invention. The modification would have entailed using the gender data collected by Srinivasan as a factor in determining a patient response to a therapeutic agent by adding it as a variable to consider as in Conforti. One would have been motivated to do so by the interest of both Srinivasan and Conforti in increasing predictiveness of treatment efficacy. Conforti teaches that sex-related dimorphism in immune system response is well known (p. 737, Summary), and Srinivasan is interested in considering complex factors responsible for determining treatment outcome (paras 2 and 3). Further, Conforti recognizes that sex differences in treatment outcome is only one of many variables to be considered to understand heterogeneity of response. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Conclusion
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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682