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, a method of managing treatment of a cancer by detection of a post-translation modification in the reply filed on 07/10/2025 is acknowledged.
Claim Status
Claims 1-97 and 108-118 are cancelled. Claims 98-107 as filed on are pending and under examination.
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 98-107 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon and abstract idea without significantly more. The claim(s) recite(s) a method of detecting the natural phenomenon of post-translational modification of EOMES-641K-Ac, EOMES-641K-Me, and EOMES-373K-Me and stratify as a likely responder or non-responder to therapy.
The claims are to a method of detecting the presence of EOMES-641K-Ac, EOMES-641K-Me, and EOMES-373K-Me and the stratification of a patient based on the presence of these post-translational modifications.
The claims are to a process so all fall within a statutory category, Step 1: Yes.
The claims are to a method and their patentability is not self-evident so does not
qualify for streamlined analysis.
The claims are to the natural phenomenon of the presence or level of the naturally occurring EOMES-641K-Ac, EOMES-641K-Me, and EOMES-373K-Me and stratifying to likely responder or non-responder to therapy, Step 2A: yes.
The claims do not recite additional elements applying the natural phenomenon. Step B is then no.
The active steps of the claims are taking a sample from a patient and detecting naturally occurring markers.
While the claims recite, they are part of a method of managing treatment of a cancer patient they do not recite an active method step in any patient population.
The required active method steps of the claims are the treatment or non-treatment of a cancer patient and the measurement of the presence or absence of one of the post-translational modifications. As the patient population of the claimed method would include all cancer patients regardless of treatment responsiveness and would then include those with and without the three listed markers.
Any measurement of post-translational modification would have the active method steps of the claims. The measurement of post-translational modifications including methylation and acetylation in cancer patients to asses tumor environment is routine and can be done in humans and mice and across multiple tissues or cell lines using various methods (Buuh et. al. Nucleic Acids Research. 40: D261-D270. (2012) (PTO-892) (Abstract).
Claim Rejections - 35 USC § 112
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 105 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.
Applicant uses the term PD EOMES-641K-Me. Examiner is unable to find a definition in the specification or the art that provides a definition for PD before a Post translational modification.
For the purposes of examination and search, Examiner read the claim as EOMES-641K-Me without the PD. Examiner requests that if PD is intended to be in the claim as an acronym the applicant writes out the full text of what is meant.
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 98-107 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of detecting responsiveness to immunotherapy targeting PD-1 and CTL-4 in patients with breast cancer and melanoma using the markers EOMES-641K-Ac, EOMES-641K-Me, and EOMES-373K-Me wherein high presence of EOMES-641K-Ac predicts non-responsive patients and high EOMES-641K-Me and EOMES-373K-Me predicts responsive patients, does not reasonably provide enablement for the active steps of the method of managing a treatment where the active steps are measurement of post-translational modification in any cancer and the treatment being considered is any treatment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described in In re Colianni, 195 USPQ 150 (CCPA 1977) and have been adopted by the Board of Patent Appeals and Interferences in Ex Parte Forman, 230 USPQ 546 (BPAI 1986). Among these factors are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the breadth of the claims,
5. the amount of direction or guidance present, and
6. the presence or absence of working examples.
The following is an analysis of these factors in relationship to this application.
Breadth of Claims
The claims are to a method of managing treatment of a cancer patient with any therapy. The required active method steps of the claims are the measurement of the presence or absence of one of the post-translational modifications. As the patient population of the claimed method would include all cancer patients regardless of treatment responsiveness and would then include those with and without the three listed markers.
Any measurement of post-translational modification would have the active method steps of the claims as global measurements of post-translational modification would have the
Guidance/Working Examples
The application discloses samples from breast cancer and melanoma that had been administered anti-PD-1 antibodies or an anti-CTL4 antibody either alone or in combination and were then grouped as complete response, partial response, or progressive disease, and these were compared to healthy donors.
Applicant discloses that those with progressive disease had a higher level of expression of EOMES than health donors and those that completely or partially responded to the therapy (Figure 1B). Applicant discloses that EOMES methylation at 641K changed the nuclear localization (Figure 1E). Applicant shows changes in nuclear versus cytoplasmic localization with presence of EOMES-641K-Ac, EOMES-641K-Me, or EOMES-373K-Me and a change in responsiveness to therapy (Figure 3 and Example 2).
The application discloses high EOMES-641K-Ac is associated with patients non-responsive to anti-PD-1 and/or anti-CTL4 therapy and high EOMES-641K-Me and EOMES-373K-Me are associated with patients responsive to anti-PD-1 and/or anti-CTL4 therapy in patients with breast cancer or melanoma ([00203]-[00207]). The results in Example 2 specifically teaches not just the presence but high EOMES-641K-Ac in non-responsive patients and high EOMES-641K-Me and EOMES-373K-Me in responsive patients.
The application discloses the presence of EOMES-641K-Ac, EOMES-641K-Me, or EOMES-373K-Me in patients with brain cancer but does not disclose any data related to responsiveness to anti-PD-1 and/or anti-CTL4 therapy (Example 3).
State of the Art/Predictability
EOMES is a T-box transcription factor that plays a role in function and homeostasis of effector and memory T cells and is implicated in CD8+ T cell exhaustion especially in tumors. EOMES is known to play a role in anti-tumor CTLs, T cell exhaustion, tumor infiltrating T cells and exerts bimodal functions in CD8+ T cells in tumors (Li et. al. Frontiers in Immunology. 9(2961):1-13. (2018) (PTO-892).
The applicant discloses that the location of 641K and 373K was determined by tools known in the art for post-translational modification ([00193]). This tool is for general use and does not teach EOMES (Wen et. al. Bioinformatics. 32(20):3107-3115. (2016)) (PTO-892). Wen does teach post-translational modifications including methylation for use in cancer research and treatment development (abstract).
Conclusion
Neither the applicant nor prior art teaches one of skill in the art how measurement of post-translational modifications can be used to stratify patients with any type of cancer as responders or non-responders to all known cancer therapeutics. One of skill in the art would not know which cancers have the markers of EOMES-641K-Ac or EOMES-641K-Me or EOMES-373K-Me that the applicant did characterize as applicant only teaches their presence in breast cancer, melanoma, and brain cancer. Further, one of skill in the art would not know how these markers would be changed in patients in response to treatments other than anti-PD-1 and/or anti-CTL4 if found to be present as the applicant only showed stratification based on responsive or non-responsive to these two targets in breast cancer and melanoma.
The method of the specification is shown only to work in a method of managing treatment of breast cancer or melanoma were the markers EOMES-641K-Ac or EOMES-641K-Me and EOMES-373K-Me are detected and patients with high EOMES-641K-Ac are non-responders to PD-1 and/or CTL4 and would not be administered this treatment or have the treatment stopped and patients with high EOMES-641K-Me and EOMES-373K-Me are responsive and would have PD-1 and/or CTL4 administered.
The claims are enabled only in breast cancer and melanoma patients making the broadly claimed cancer not fully enabled.
The claims are only enabled in breast and melanoma with high EOMES-641K-Ac or high EOMES-641K-Me and EOMES-373K-Me and not for the current claims which would include patients with high or low levels of all markers or any combination of the listed markers. For example, one of skill in the art would have no teaching from the specification of whether a melanoma patient with low EOMES-641K-Ac, EOMES-641K-Me, and EOMES-373K-Me would be a responder or non-responder to anti-PD-1 and/or anti-CTL4. Further, while applicant has shown the presence of EOMES-641K-Ac, EOMES-641K-Me, and EOMES-373K-Me in brain tumors, the specification does not enable one of skill in the art to stratify patients with a brain tumor as a responsive or non-responsive patient to anti-PD-1 and/or anti-CTL4 or any other known cancer therapeutic. Cancer therapy is a broad term and would include surgery, the specification has provided no example of how levels of EOMES-641K-Ac, EOMES-641K-Me, and EOMES-373K-Me would impact a patient having a tumor surgically removed.
One of skill in the art would not have been able to make and use the method of the claims which comprises all levels of EOMES-641K-Ac, EOMES-641K-Me, or EOMES-373K-Me in any cancer and stratifying as responsive or non-responsive for any treatment.
Claim Rejections - 35 USC § 102
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.
Claims 98-104 and 106 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Buuh et. al. Nucleic Acids Research. 40: D261-D270. (2012) (PTO-892), as evidenced by Wayback Machine of PhosphoSitePlus: Browse MS2 Data by Cell line. 10/13/2016 (PTO-892).
The required active method steps of the claims are the treatment or non-treatment of a cancer patient and the measurement of the presence or absence of one of the post-translational modifications. As the patient population of the claimed method would include all cancer patients regardless of treatment responsiveness and would then include those with and without the three listed markers.
Any measurement of post-translational modification in a cancer patient would have the active method steps of the claims as the claims include any measured level of the markers listed and patients that are treated and not treated.
Regarding claims 98-99, 101, Buuh teaches the measurement of post-translational modification (PTM) in humans and mouse across multiple diseases including cancer and specifically T cells (abstract). The presence of cancer T cell data is evidenced by the presence of multiple T cell cancer cell lines including the T lymphocyte cells Jurkat in 2016 in Wayback Machine of PhosphoSitePlus.
Buuh teaches multiple methods of detecting PTM by immunoprecipitation pull-down and the use of chemical proteomics which tag substrate proteins allowing for instant labeling, detection, and pull down of target proteins within complex proteomes (page 248 in col 1 in par 3).
Buuh teaches the use of PTM characterization to determine cancer drug targets (page 3239 in col 1 into col 2 “Introduction”).
This would teach the measurement of acetylation and methylation as post translational modifications in T cell cancers. The detection of acetylation and methylation would inherently detect EOMES-641K-Ac, EOMES-641K-Me, and EOMES-373K-Me.
Regarding claims 106, Buuh teaches the detection of additional biomarkers associated with Alzheimer’s (page 3242 in col 1 in lines 12-14) and tumors (page 3248 in col 1 in lines 7-9).
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 98 and 105 are rejected under 35 U.S.C. 103 as being unpatentable over Grimes et. al. Sci. Signal. 11(531): 1-16. (2018) (PTO-892) and Buuh et. al. Nucleic Acids Research. 40: D261-D270. (2012) (PTO-892), as evidenced by Wayback Machine of PhosphoSitePlus: Browse MS2 Data by Cell line. 10/13/2016 (PTO-892).
The required active method steps of claim 98 are the treatment or non-treatment of a cancer patient and the measurement of the presence or absence of one of the post-translational modifications. As the patient population of the claimed method would include all cancer patients regardless of treatment responsiveness and would then include those with and without the three listed markers.
Any measurement of post-translational modification in a cancer patient would have the active method steps of the claims as the claims include any measured level of the markers listed and patients that are treated and not treated.
Claim 105 requires the detection of EOMES-641K-Ac, EOMES-641K-Me, and EOMES-373K-Me where an antigen-binding molecule is used to detect the marker. The claims do not require specificity to these specific modifications on EOMES only antigen-binding molecules that bind some part of EOMES-641K-Ac, EOMES-641K-Me, and EOMES-373K-Me in a T cell population. Claim 105 requires a first antigen-binding molecule that binds to EOMES-641K-Ac and a second antigen-binding molecule that binds to EOMES-373K-Me.
Grimes teaches the testing of post-translational modifications (PTM) in cancer cells lines using antibodies specific to acetylation, phosphorylation, and methylation (page 12 in col 2 in par 3 and page 13 in col 1 in first section, in particular in lines 6-20). Grimes teaches the examination of phosphorylation, methylation, and acetylation in 45 lung cancer cell lines compared to normal cell lines treated with anticancer drugs (abstract).
Grimes further teaches changes to PTMs in response to anti-cancer drugs (Figure 2).
Grimes teaches the testing of post-translational modifications (PTM) in cancer cells lines using antibodies specific to acetylation, phosphorylation, and methylation (page 12 in col 2 in par 3 and page 13 in col 1 in first section, in particular in lines 6-20). Grimes teaches the examination of phosphorylation, methylation, and acetylation in 45 lung cancer cell lines compared to normal cell lines treated with anticancer drugs (abstract).
Grimes further teaches changes to PTMs in response to anti-cancer drugs (Figure 2).
Grimes does not teach the method of detecting PTM in a T-cell or T-cell population.
This deficiency is filled by Buuh.
Buuh teaches the measurement of post-translational modification (PTM) in humans and mouse across multiple diseases including cancer and specifically T cells (abstract). The presence of cancer T cell data is evidenced by the presence of multiple T cell cancer cell lines including the T lymphocyte cells Jurkat in 2016 in Wayback Machine of PhosphoSitePlus.
It would have been obvious at the time the application was filed to substitute the generic solid tumor cells of Grimes with the T cells of Buuh to produce a method of antibody based detection of acetylation, phosphorylation, and methylation in the T cell population in cancer. One of skill in the art would have been motivated to use the method of Grimes as Grimes teaches a successful and selective method of identifying PTM in cancer and Buuh teaches PTM in cancer T cells. Buuh teaches towards the large scale use of PTM identification for use in identifying effective cancer therapies. There would have been a reasonable expectation of success as PTM analysis is an area of high skill in the art as shown by Buuh and the PhosphoSitePlus database.
Claims 98 and 106-107 are rejected under 35 U.S.C. 103 as being unpatentable over Buuh et. al. Nucleic Acids Research. 40: D261-D270. (2012) (PTO-892) and Kamphorst et. al. Immunology and Inflammation. 114(19):4993-4998 (2017) (PTO-892), as evidenced by Wayback Machine of PhosphoSitePlus: Browse MS2 Data by Cell line. 10/13/2016 (PTO-892).
Regarding claims 98-99, 101, Buuh teaches the measurement of post-translational modification (PTM) in humans and mouse across multiple diseases including cancer and specifically T cells (abstract). The presence of cancer T cell data is evidenced by the presence of multiple T cell cancer cell lines including the T lymphocyte cells Jurkat in 2016 in Wayback Machine of PhosphoSitePlus.
Buuh teaches multiple methods of detecting PTM by immunoprecipitation pull-down and the use of chemical proteomics which tag substrate proteins allowing for instant labeling, detection, and pull down of target proteins within complex proteomes (page 248 in col 1 in par 3).
Buuh teaches the use of PTM characterization to determine cancer drug targets (page 3239 in col 1 into col 2 “Introduction”).
This would teach the measurement of acetylation and methylation as post translational modifications in T cell cancers. The detection of acetylation and methylation would inherently detect EOMES-641K-Ac, EOMES-641K-Me, and EOMES-373K-Me.
Regarding claims 106, Buuh teaches the detection of additional biomarkers associated with Alzheimer’s (page 3242 in col 1 in lines 12-14) and tumors (page 3248 in col 1 in lines 7-9).
Buuh does not teach the detection of the biomarkers PD-1 and Ki67.
This deficiency is filled by Kamphorst.
Kamphorst teaches important markers for therapy response including PD-1 and Ki67 in CD8 T cells from cancer patients (abstract). Kamphorst teaches the importance in PD-1 as a target for cancer therapies, but further teaches targeting of PD-1 alone does not guarantee clinical response (page 4993 in col 1 in pars 1-2). Kamphorst teaches further characterization of cells provides improved guidance for selecting cancer therapies (Figures 1-4 and in particular Figure 5). Kamphorst teaches there are partial and non-responsive patients to PD-1 targeted therapy (Figure 5).
It would have been obvious at the time the application was filed to substitute the generic cancer biomarkers of Buuh with the biomarkers of PD-1 and Ki67 taught by Kamphorst to have a method of characterizing the PTM of PD-1+ and Ki67+ cells. One of skill in the art would have been motivated by the teachings of Buuh which teaches characterizing cells by cancer biomarkers and Kamphorst which teaches PD-1 and Ki67 as known markers of cells that have partial or no response to therapy. The patients of Kamphorst that do not respond to therapy would be an obvious population for further study to identify additional therapy targets. There would have been a reasonable expectation of success as Buuh teaches the development of improved cancer characterization for therapy targeting.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA EDGINGTON-GIORDANO whose telephone number is (571)272-8232. The examiner can normally be reached Mon - Fri 8:00 - 5:00.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643