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 .
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 18, 2025 has been entered.
2. Claim 1 was amended. Claims 8-9, 16, 18-19, 21, 23-26, 28, 31, 36 and 40 are cancelled. Claims 1-7, 10-15, 17, 20, 22, 27, 29, 30, 32-35, 37-39 and 41 are pending.
3. Claims 12-15, 27, 29 and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim.
4. Claims 1-7, 10, 11, 17, 20, 22, 32-35, 37-39 and 41 are currently under consideration as drawn to the elected species of topoisomerase inhibitors and 5-fluorouracil
Rejections Maintained
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.
5. Claim(s) 1-7, 10, 11, 17, 20, 22, 32-35, 37-39 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Lin et al. (Autophagy Dec. 13, 2017, 14(5): 778-795, of record), “Lin” evidenced by Zhang et al. (PLOS ONE Nov. 2013 8(1): e81815, of record), “Zhang” in view of WO 2019/147844 A1 (Oberst A. et al. Aug. 01, 2019, of record), “Oberst” and in view of US 2019/0269711 A1 (Leong et al Sep. 5, 2019, of record), “Leong”.
The specification teaches that “[a]s used herein, the term “activated”, in the context of cells, refers to cancer cells treated with one or more genotoxic drug(s) and having an immunogenic state.” See p. 14-lines 5-7. Thus, the term activated is are indicative of process steps for obtaining the tumor cells. Similarly, the treatment of the cells with genotoxic drugs and/or MK2 inhibitors is a process step for obtaining the activated tumor cells. Claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. See MPEP 2113 (I). Therefore, the claims read on live, injured tumor cells and/or dead tumor cells that have undergone or are undergoing necroptosis having an immunogenic state, regardless of the prior manipulation or treatment of the cells.
Lin teaches that programmed necrosis, necroptosis, is a highly immunogenic activity often mediated via the release of damage associated molecular patterns (DAMPs). See abstract.
Lin teaches that shikonin (SK) can instigate RIPK1 and RIPK3 dependent necroptosis that is accompanied by autophagy in a mammary tumor cell line 4T1. See abstract, p. 779 and Fig. 1.
Lin teaches that SK activates NF-kB signaling. See p. 790-left column.
RIPK1 and NF-kB are part of a DNA damage signaling pathway. See ¶ [0392] of the instant published application.
Zhang teaches that shikonin (SK) is a topoisomerase I inhibitor. See title and abstract.
Lin teaches that SK can reduce cell viability, which would reduce cell growth, with an IC50 of 1.583 mM. See Fig. 1A.
Lin teaches that SK treated cells immunized mice against primary tumors. See pp. 779-781 and Fig. 2. Lin teaches using 105 or 5 x105 cells for immunization. See p. 779-righ column-2nd paragraph.
Lin teaches that SK treated cells co-cultured with dendritic cells (DC) produced a dendritic cell vaccine that lowered the levels of metastasis and prolonged survival time. See p. 781 and Fig. 3.
Lin teaches that SK treatment induced the DAMP released and ecto-localization including calreticulin (CALR). See p. 782 and Fig. 4.
Lin does not teach using primary tumor cells or an immune checkpoint inhibitor.
Oberst teaches inducing primary tumor cells to undergo necroptosis by expressing RIP1 kinase, RIP2 kinase, and RIP3 kinase effector domains in the tumor cells with nucleic acid expression vectors for cancer treatment with the necroptotic dying cells to inhibit tumor cell growth. See abstract, p. 5-line 3 to line 28, p. 28-line 22 to p. 30-line 34 and claims 1-5, 8, 10, 21-30, and 34-48.
Oberst teaches using autologous cells with respect to the tumor. See pp. 5-lines 19-20 p. 6-lines 24-25, p. 7-lines 10-15, p. 10-lines 3-10 and Figures 4A, 4B, 10A and 10B.
Oberst teaches that necroptotic cells are characterized cell swelling and lysis, with formation of membrane pores and induce immune responses. See p. 16-lines 32 to p. 17-line 2.
Oberst teaches administering the immune checkpoint inhibitors anti-PD1 antibody or anit-PD-L1. See p. 5-lines 29-33 and claims 43, 44, 60, and 61.
Oberst teaches stimulating anti-tumor immunity with dying necroptotic tumor cells by administering the cells prior to the death of the necroptotic tumor cells. See paragraph bridging pp. 32-33 and claim 50.
Oberst teaches that signaling downstream of the RIPK1/RIPK3 necrosome is required for therapeutic efficacy as lytic necrotic cells failed to recapitulate the anti-tumor responses. See p. 58-2nd paragraph. Oberst teaches that these results are consistent with reports of RIPKI- and NF-KB-dependent gene expression mediating the immunogenic effects of necroptotic cells with respect to dendritic cell maturation and priming of protective CD8+ T cells in vaccination models. See paragraph bridging pp. 58-59.
Oberst teaches that necroptosis can stimulate tumor antigen presenting cells and CD8+ T cell immunity in the tumor microenvironment which synergize with immune checkpoint blockade (ICB) to promote a durable tumor rejection. Oberst teaches that induced programmed tumor cell death (PCD) may be used to complement T cell based forms of immunotherapy. See p. 59-lines 12-29.
Oberst teaches that the treatment methods of the invention can be combined with other cancer therapeutic strategies like adoptive immune cell therapies and cancer vaccines. See p. 31-lines 22-28.
Oberst teaches injection of the cells into tumor or intravenously. See p. 5-lines 23-24 and p. 8, lines 1-2 and paragraph bridging pp. 48-49. It would have been obvious to one of skill in the art to use a syringe for injection of the cells into tumor or intravenously.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Lin and Oberst and use autologous primary tumor cells treated with SK in the methods of Oberst in place of the recombinant cells of Oberst because Lin teaches that treatment of tumors cells is effective to induced immunogenic necroptosis that can be used alone or in combination with dendritic cells for tumor prevention and treatment. One would have been motivated to generate SK treated primary tumor cells because treatment with SK is not as technically difficult as the recombinant techniques of Oberst and the autologous primary tumor cells would induce an immune response specific to the tumor to be treated. One of skill in the art would have motivated to optimize the SK treatment to produce the desired level of cell signaling and live and necrotopic to optimize the immune response.
Additionally, it would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Lin and Oberst and make the immunogenic necroptotic tumor cell compositions free from dead cells because Oberst teaches stimulating anti-tumor immunity with living necroptotic tumor cells by administering the cells prior to the death of the necroptotic tumor cells and lytic necrotic cells failed to recapitulate the anti-tumor responses. Thus, one would have been motivated to make the immunogenic necroptotic tumor cell compositions free from dead cells to optimize the anti-tumor response with the dying cell composition because the lytic, dead necrotic cells failed to stimulate an immune response.
Further, it would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the teachings of Lin and Oberst and combine the immunogenic necroptotic tumor cell compositions of Lin and Oberst with T cells and/or dendritic cells or checkpoint inhibitors because Lin teaches that SK treated cells co-cultured with dendritic cells (DC) produced a dendritic cell vaccine that lowered the levels of metastasis and prolonged survival time and Oberst teaches that necroptosis can stimulate tumor antigen presenting cells and CD8+ T cell immunity in the tumor microenvironment, Oberst teaches that induced programmed tumor cell death (PCD) may be used to complement T cell based forms of immunotherapy, and that the treatment methods of the invention can be combined with other cancer therapeutic strategies like adoptive immune cell therapies, cancer vaccines and checkpoint inhibitors. Thus, one would have been to combine the immunogenic necroptotic tumor cell compositions of Lin and Oberst with T cells and/or dendritic cells and/or checkpoint inhibitors to optimize the anti-tumor activity of the compositions and methods of Lin and Oberst.
Lin and Oberst teach as set forth above, but do not teach adding interferon gamma to the composition.
Leong teaches treating cancer with nucleoside analogues, like fluorouracil, and additional therapeutic agents like purified interferon gamma. See abstract and ¶¶ 0003, 0012-0014, 0035 and 0036. ,
Leong teaches treating interferon gamma and other chemotherapeutic agents can be synergistic in inducing cell death. See ¶¶ 003, 0055, 0125, 0348-0350 and Fig. 16.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Lin, Oberst and Leong and use interferon gamma in the compositions of Lin and Oberst because Leong teaches treating cancer with interferon gamma in combination with other therapeutics agents. One would have been motivated to use interferon gamma in the compositions of Lin and Oberst because Leong teaches treating interferon gamma and other chemotherapeutic agents can be synergistic in inducing cell death.
6. Claim(s) 3 and 35 are alternatively rejected under 35 U.S.C. 103 as being unpatentable over Lin et al. (Autophagy Dec. 13, 2017, 14(5): 778-795), “Lin” evidenced by Zhang et al. (PLOS ONE Nov. 2013 8(1): e81815), “Zhang” in view of WO 2019/147844 A1 (Oberst A. et al. Aug. 01, 2019, of record), “Oberst” and in view of US 2019/0269711 A1 (Leong et al Sep. 5, 2019, of record), “Leong” as applied to claims 1-7, 10, 11, 17, 20, 22, 32-35, 37-39 and 41 above, and further in view of Menon et al. (Nature Cell Biol. Oct. 2017 19(10): 1248-1259), “Menon”.
Lin and Oberst teach as set forth above, but do not teach treating the cells with an MK2 inhibitor.
Menon teaches that RIPK1 is a direct substrate of MK2 in LPS and stress stimulated embryonic fibroblasts. Menon teaches that MK2 inhibits RIPK1 autophosphorylation, inhibits RIPK1 cytoplasmic complex formation, and suppresses RIPK1 dependent apoptosis and necroptosis. See abstract and Figures 1-6.
Menon teaches that treatment with an MK2 inhibitor (PF3644022) led to increased necroptosis in TNF/zVAD treated cells. See p. 1252-left column and Fig. 4c.
Menon teaches that MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate. See abstract.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Lin, Oberst, and Menon and treat the autologous primary tumor cells SK treated cells of Lin and Oberst with an MK2 inhibitor because Menon teaches that MK2 suppresses RIPK1 dependent necroptosis and treatment with an MK2 inhibitor led to increased necroptosis. Thus, one would have been motivated to additionally treat the autologous primary tumor cells SK treated cells of Lin and Oberst with an MK2 inhibitor to increase the level of necroptosis in the cells.
Response to Arguments
7. Applicant argues that without acquiescing to the allegations and conclusions in the Office Action, the Examiner’s attention is drawn to the enclosed Declaration of co-inventor Michael Yaffe. The Declaration provides evidence that treatment with interferon gamma can convert live, injured, activated, tumor cells into a new immunogenic state that directly activates naive CD8+ T-cells. As described in the Declaration, “[t]his activation of naive T-cells by live DNA-damaged tumor cells occurs in the complete absence of professional antigen presenting cells (i.e. dendritic cells). This occurs through direct contact between the live injured tumor cells and the T-cells, because transwell experiments show loss of T-cell activation when the plate blocks tumor cell:T- cell contact. This is entirely unexpected and goes against all conventional wisdom of how naive T-cells are normally activated. It means that tumor cells themselves are converted into antigen presenting cells capable of activating anti-tumor T-cell responses.”
Applicant argues that “Rebuttal evidence may also include evidence that the claimed invention yields unexpectedly improved properties or properties not present in the prior art.” MPEP § 2145.Such is the case here. Specifically, interferon gamma transforms the live, injured, activated, tumor cells to a new cell type with advantageous immunogenic properties. For at least this reason, all of the pending claims are non-obvious over the combination of references.
Rejoinder of the withdrawn claims, and allowance of all of the pending claims is respectfully requested.
8. Applicant’s arguments have been considered, but have not been found persuasive. The Declaration of Michael Yaffe under 37 CFR 1.132 filed July 18, 2025 is insufficient to overcome the rejection of claims 1-7, 10, 11, 17, 20, 22, 32-35, 37-39 and 41 based upon being obvious over Lin et al. (Autophagy Dec. 13, 2017, 14(5): 778-795), “Lin” evidenced by Zhang et al. (PLOS ONE Nov. 2013 8(1): e81815), “Zhang” in view of WO 2019/147844 A1 (Oberst A. et al. Aug. 01, 2019, of record), “Oberst” and in view of US 2019/0269711 A1 (Leong et al Sep. 5, 2019, of record), “Leong” or claims 3 and 35 in further view of Menon et al. (Nature Cell Biol. Oct. 2017 19(10): 1248-1259), “Menon” for the reasons previously set forth and above.
The claims encompass a composition comprising interferon gamma and a large genus of any type of primary tumor cells that are live, ex vivo injured, activated and at least a portion of the cells are undergoing necroptosis. The cells can be activated with a large genus of genotoxic drugs. See, e.g., claims 3 and 5. However, the Declaration only presents evidence with an ovarian cancer cell line (1D8-OVA) and a melanoma cell line (B16OVA) treated with two genotoxic agents (etoposide and doxorubicin) and interferon gamma. The Declaration evidence does not use primary tumor cells and there is no indication that the cells are injured or if any portion of the cells are undergoing necroptosis. Additionally, not all genotoxic agents induce an immunogenic cell death like necroptosis in all tumor cell types. In particular, US 2008/0214452 A1 (Obeid M., Sep. 4, 2008) teaches that DNA damaging agents like etoposide and mitomycin C do not induced immunogenic cell death in the CT26 colon tumor cell line without additional treatments. See abstract, Examples 4 and 5, Figs. 4D, 5F, and 5G. Further, Gerdes et al. (Front. Oncol. 12/18/2014 doi: 10.3389/fonc.2014.00366, pp. 1-12) teach that cancer is a multifaceted disease characterized by heterogeneous genetic alterations, cellular metabolism at the organ, tissue, and cellular levels and these conditions vary between cancers. See abstract and Fig. 1. Thus cancer cells are diverse in structure and function.
MPEP 716.02 (d) teaches:
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.”
Given that the presented evidence relates to treatment of two cancer cell lines, not primary tumor cells, with two genotoxic agents and there is no indication that the cells are injured or if any portion of the cells are undergoing necroptosis, the presented evidence is not commensurate in scope with the claimed invention and is not sufficient to support Applicant’s assertion of non-obviousness of the claimed invention. In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness. Thus, the rejection is maintained for the reasons of record.
Conclusion
9. All other objections and rejections recited in the Office Action of March 19, 2025 are withdrawn in view of Applicant’s amendments and arguments.
10. No claims allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached on M-F 8:30-5:30 Eastern Time
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Janet L Epps-Smith can be reached on 571-272-0757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Peter J Reddig/
Primary Examiner, Art Unit 1642