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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 7, 2025 has been entered.
Claim Status
Claim listing filed on August 7, 2025 is pending. Claims 2-7, 9-14, 16-17, 19, 21-22, 24-27, 29-31, and 35-39 are canceled. Claims 1, 8, 18, 20, 28, and 40-41 are amended. Claims 42-50 are new. Claims 1, 8, 15, 18, 20, 23, 28, 32-34, and 40-50 are examined upon their merits.
Withdrawn Claim Rejections
Applicant’s cancelation of Claims 5-6, 12-13, 16-17, 19, and 21-22 have rendered all previous rejections directed to these claims moot.
Sequence Compliance in Specification (New)
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821 (a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. § 1.821 through 1.825. Specifically, no sequence identification has been provided for primer sequences listed on page 101 of the specification. It appears that the primer sequences are in the sequence listing as SEQ ID NOs: 5-23. The instant specification will need to be amended so that it complies with 37 C.F.R. § 1.821(d) which requires a reference to a particular sequence identifier (SEQ ID NO:) be made in the specification and claims wherever a reference is made to that sequence. Applicant is reminded to comply with sequence rules as stated in MPEP§ 2422 and review the specification to ensure the application is in full sequence compliance in response to this action.
Claim Rejections - 35 USC § 112 (New)
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.
Claims 20, 47, and 49 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.
Claims 20, 47, and 49 recite wherein the tumor cells or the cancer are “associated with elevated expression of the tumor antigen.” This phrase includes relative terminology, specifically the term “elevated” (MPEP § 2173.05(b)). It is unclear what the threshold of elevated is (10% increase? 20% increase?). It is also unclear what the elevation is relative to (as compared to non-cancerous cells? As compared to other cancer cells?) The specification does not provide a definition of “associated with elevated expression” in such a way that one of ordinary skill in the art would understand the metes and bounds of what is claimed. Claims 20, 47, and 49 are rejected for indefinite relative terminology. For the purpose of compact prosecution, Claims 20, 47, and 49 will be interpreted as wherein the tumor cells or the cancer express the tumor antigen.
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claims 8, 28, 32-34, and 41-50 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 and enablement requirements is maintained. Note, this rejection was previously directed to Claims 8, 12-13, 28, and 41, but due to the amendments, the applicable claims are now Claims 8, 28, 32-34, and 41-50 wherein the same rationales apply.
Applicant's arguments filed August 7, 2025 have been fully considered but they are not persuasive. Applicant argues that the amended claims directed to targeting emergent tumor cells having MHC-I resistance are supported in the specification Examples, specifically Example 8. Claims 8 and 28 recite a method of “preventing emergence of tumor cells that are resistant to an MHC-dependent T cell response.” The specification does not define “emergence of tumor cells”, and the Examiner interprets the claims to mean preventing the occurrence of resistant tumor cells which is synonymous with preventing tumor cells from developing resistance (ie preventing acquired resistance which is on record as lacking proper written description and enablement).
Specification Example 8 states that treatment with anti-Trp1 antibody and RNA coding for mAlb-mIL-2 prevents acquired resistance during the course of immune checkpoint blockade; however, the mice used in the experiment were inoculated with 75% B16F10 and 25% B16F10-B2m-/- cells (page 112). The B2m-/- mutation confers loss of MHC class I and causes resistance against antibody-based immunotherapies (page 102, lines 26-29). Therefore, Example 8 uses a mixed tumor of non-resistant cells (B16F10) and intrinsically resistant cells (B16F10-B2m-/-). Based on the definitions of treatment and prevention in the specification put on the record in the non-final office action filed 12/05/2024, Example 8 provides written description and enablement for treating tumor cells that are inherently MHC resistant, but does not teach the prevention of tumor cells from developing MHC resistance (i.e., resistant tumor cells emerging) as the inoculated cells already possessed resistance. Applicant’s arguments are not persuasive and the rejections are maintained.
Claim Rejections - 35 USC § 102 (Maintained)
The rejection of Claims 1, 20, 23, and 49-50 under 35 U.S.C. 102(a)(1) as being anticipated by Zhu et al. Cancer Cell. 2015 Apr 13;27(4):489-501 (of record) is maintained. Note, this rejection was previously directed to Claims 1, 6, 16-17, and 20-23, but due to the amendments, the applicable claims are now Claims 1, 20, 23, and 49-50 wherein the same rationales apply.
Applicant's arguments filed August 7, 2025 have been fully considered but they are not persuasive. Applicant argues that the cells and methods disclosed in Zhu merely deplete or reduce responses based on CD8+ T cells, e.g. via IFNγ signaling, and Zhu fails to teach any cancer cells that are MHC-I T cell resistant. The MHC-dependent T cell response is a complex system comprising many moving parts wherein antigen presenting cells present peptide fragments of pathogens on their surface using MHC molecules, MHC class I molecules are recognized by CD8+ T cells, MHC class II molecules are recognized by CD4+ T cells, the T cells are activated by different signaling agents, and the activated T cells produce an immune response that ultimately destroys the infected cell. Due to the complexity of the MHC-dependent T cell response, there are multiple ways resistance to this response can develop. The specification defines that cancers that are resistant to MHC-dependent T cell response have a reduced response because the cancer has developed resistance mechanisms (page 27, lines 29-31). The specification teaches that the preferable resistance mechanisms are (1) mutation or full or partial loss of MHC-1 alleles or B2M, (2) deficiency in type I IFN or IFNγ signaling, or (3) have lost antigen that is presented in the context of MHC for recognition by T cells (page 28, lines 18-24). Therefore, the specification defines that cancers deficient in IFNγ signaling are resistant to MHC-dependent T cell response. Zhu teaches tumor cells that are treated with an anti-IFNγ antibody to block IFNγ signaling, and it is clear that this IFNγ deficiency confers resistance because the resulting tumor is less responsive to treatment as compared to a tumor with functioning IFNγ signaling (Figure 6H, of record). Arguments are not persuasive and the rejections are maintained.
Claim Rejections - 35 USC § 103 (Maintained)
The rejection of Claims 1, 15, 20, 23, 28, 32-34, 45, and 49-50 under 35 U.S.C. 103 as being unpatentable over Zhu et al. Cancer Cell. 2015 Apr 13;27(4):489-501 (of record) as applied to Claims 1, 20, 23, and 49-50 above, and further in view of Sahin et al. WO 2019/154985 A1 (of record) is maintained. Note, this rejection was previously directed to Claims 1, 6, 15-17, 19, 20-23, 28, and 32-34, but due to the amendments, the applicable claims are now Claims 1, 15, 20, 23, 28, 32-34, 45, and 49-50 wherein the same rationales apply.
Applicant's arguments filed August 7, 2025 have been fully considered but they are not persuasive. Applicant argues that Zhu does not teach tumor cells that are resistant to an MHC-dependent T cell response, and Sahin does not cure this deficiency. This argument was addressed in the 102 rejection above, and because Zhu teaches the treatment of tumor cells with blocked IFNγ signaling, the tumor cells are resistant to an MHC-dependent T cell response based on the definitions provided in the specification. Applicant further quotes a section from Zhu that highlights T cell-mediated efficacy, but Examiner maintains that this quote is taken out of context and is not in reference to the experiment performed in Figure 6H wherein IFNγ signaling was intentionally blocked. Arguments are not persuasive and the rejections are maintained.
The rejection of Claims 1, 18, 20, 23, and 49-50 under 35 U.S.C. 103 as being unpatentable over Zhu et al. Cancer Cell. 2015 Apr 13;27(4):489-501 (of record) as applied to Claims 1, 20, 23, and 49-50 above, and further in view of Thran et al. EMBO Mol Med. 2017 Oct;9(10):1434-1447 (of record) is maintained. Note, this rejection was previously directed to Claims 1, 6, 16-18, and 20-23, but due to the amendments, the applicable claims are now Claims 1, 18, 20, 23, and 49-50 wherein the same rationales apply.
Applicant's arguments filed August 7, 2025 have been fully considered but they are not persuasive. Applicant argues that Zhu does not teach tumor cells that are resistant to an MHC-dependent T cell response, and Thran does not cure this deficiency. This argument was addressed in the 102 rejection above, and because Zhu teaches the treatment of tumor cells with blocked IFNγ signaling, the tumor cells are resistant to an MHC-dependent T cell response based on the definitions provided in the specification. Arguments are not persuasive and the rejections are maintained.
Claim Rejections - 35 USC § 103 (New, necessitated by amendment)
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 1, 28, 40, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Ardolino et al. J Clin Invest. 2014 Nov;124(11):4781-94 (of record) as evidenced by Golay et al. Haematologica 2003, and further in view of Sahin et al. WO 2019/154985 A1 (of record). Note, the previous rejection applied to Claims 1, 5, and 40 in view of Ardolino and now applies to Claims 1, 28, 40, and 42 in view of newly cited sections of Ardolino and Sahin due to Applicant’s amendments to the claims.
Ardolino teaches the treatment of mice with MHC class I-deficient cancer tumors by administering IL-2 (abstract) wherein loss of MHC class-I was generated by using CRISPR/Cas9 to knockout B2M (page 4785, paragraph 1). MHC class I-deficiency causes natural killer (NK) cell anergy, and the unfavorable anergic state can be reversed with cytokine treatment (abstract). Ardolino proposes that “the enhanced responsiveness the activating cytokines confer may provide therapeutic benefit when applied in conjunction with other agents that enhance NK cell activation, such as antibodies used for antibody-dependent cellular cytotoxicity or agents that enhance T cell responses against tumors, such as ipilimumab or antibodies that block PD-1 or its ligands” (page 4790, paragraph 2). “Antibodies used for antibody-dependent cellular cytotoxicity” read on antibodies directed against tumor antigens expressed by cancer cells as defined in Claim 1, as evidenced by Golay. Antibody-dependent cellular cytotoxicity (ADCC) is a process where antibodies bind to specific antigens on the surface of target cells and then immune cells, such as natural killer cells, recognize the antibodies and destroy the target cells. Golay teaches that an example of an ADCC antibody is rituximab, an antibody that targets the CD20 tumor antigen on the surface of tumor cells, wherein rituximab kills cancer cells by NK cell-mediated ADCC (Results paragraph 1 on page 1004).
Therefore, Ardolino as evidenced by Golay obviates a method of treating cancer resistant to an MHC-dependent T cell response by administering IL-2 and an antibody-based immunotherapy against cancer wherein the cancer has a loss of the MHC-I allele B2M (Claims 1, 40, and 42). Ardolino fails to teach a medical preparation comprising IL-2, an antibody-based immunotherapy, and instructions for use of the medical preparation for treating cancer that is resistant to an MHC-dependent T cell response (Claim 28).
Sahin teaches a medical preparation comprising RNA encoding extended-PK IL-2 and an antibody-based immunotherapy (page 6, lines 11-16) wherein the medical preparation further comprises instructions for use for treating cancer (page 6, lines 27-28).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to modify the method of treatment taught by Ardolino to comprise the specific therapeutic formulations taught by Sahin. Ardolino as evidenced by Golay obviates treating a cancer deficient in B2M with IL-2 and an antibody-based immunotherapy. Sahin teaches treating cancer with IL-2 and an antibody-based immunotherapy specifically wherein the agents are formulated as a medical preparation with instructions. Because both Ardolino and Sahin teach the combination of IL-2 and an antibody-based immunotherapy to treat cancer, it would be obvious to use the known therapeutic preparations taught by Sahin to specifically treat cancers deficient in B2M as taught by Ardolino. The motivation to formulate the agents as a medical preparation with instructions is for convenience and ease of medical use.
Applicant's arguments against Ardolino filed August 7, 2025 have been fully considered but they are not persuasive. Applicant argues that the cells in Ardolino are described as having “low MHC class I expression” which means that the cells retain some amount of MHC I expression which contrasts the cancers encompassed by the claims. Claim 1 is directed to cancer that is resistant to an MHC-dependent T cell response wherein “MHC-I [deficiency is] due to a mutation or partial or full loss of MHC-I alleles.” Because Ardolino teaches tumor cells wherein loss of MHC class-I was generated by using CRISPR/Cas9 to knockout the MHC-I allele B2M, Ardolino meets the limitations of Claim 1. The specification further defines that cancers that are resistant to MHC-dependent T cell response have a reduced response because the cancer has developed resistance mechanisms (page 27, lines 29-31), and a preferable resistance mechanism is a mutation or full or partial loss of the MHC-I allele B2M (page 28, lines 18-24). The tumor cells in Ardolino are resistant to an MHC-dependent T cell response based on the definitions in both the claims and the specification.
Applicant argues that administration of an immune checkpoint inhibitor or antibodies that block PD-1 or its ligands cannot be reasonably expected to provide treatment of a cancer that is resistant to an MHC-I dependent T cell response. Ardolino addresses this point in the abstract and page 4790, paragraph 2 as referenced in the rejection above. Ardolino teaches that MHC class I-deficient tumors can escape from an immune response by functionally inactivating NK cells, but cytokine-based immunotherapy is a strategy to treat MHC class I-deficient tumors because cytokine treatment such as IL-2 reversed the anergic state of the NK cells (abstract). Ardolino proposes combining IL-2 treatment with antibodies used for ADCC because MHC class I-deficient tumors would likely evade the ADCC antibody immunotherapy on its own, but in combination with IL-2, the NK cells would be reactivated and resensitized to the antibody-based immunotherapy. Based on the teachings of Ardolino, one of ordinary skill in the art would understand that IL-2 resensitizes NK cells in MHC class I-deficient tumors, and IL-2 could be used in combination with antibody-based immunotherapy with a reasonable expectation of success. Arguments against Ardolino have been considered but are not persuasive.
Claims 1, 15, 20, 23, 28, 32-34, 45-46, and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. Cancer Cell. 2015 Apr 13;27(4):489-501 (of record) in view of Sahin et al. WO 2019/154985 A1 (of record) as applied to Claims 1, 15, 20, 23, 28, 32-34, 45, and 49-50 above, and further in view of Thran et al. EMBO Mol Med. 2017 Oct;9(10):1434-1447 (of record).
Zhu and Sahin as applied to Claims 1, 15, 20, 23, 28, 32-34, 45, and 49-50 teach a method of treating cancer that is resistant to an MHC-dependent T cell response by administering IL-2 and an antibody-based immunotherapy against cancer wherein the agents are formulated as a medical preparation with instructions. Zhu and Sahin fail to teach wherein the polynucleotide encoding the therapeutic antibody against cancer is RNA (Claim 46).
Thran teaches that administering mRNA encoding rituximab to lymphoma mouse models has an anti-tumor effect (page 1440, paragraph 4) wherein rituximab is an anti-CD20 monoclonal antibody.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to modify the method of treatment with antibody-based immunotherapy against cancer as taught by Zhu and Sahin to include administering RNA that encodes the antibody-based immunotherapy against cancer as outlined in Thran. The motivation to administer RNA encoding antibodies rather than antibodies is outlined in Thran: “In contrast to the manufacturing of many recombinant antibodies, mRNA has cost advantages, since different sequences can be produced by a generic process” (Thran page 1435, paragraph 2).
Double Patenting (Maintained)
The provisional rejection of Claims 1, 15, 20, 23, 28, 34, 40, 42, 45, and 49-50 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-11, 13, 23, 30, and 33 of copending Application No. 16/966,422 in view of Zhu et al. Cancer Cell. 2015 Apr 13;27(4):489-501 (of record) and Ardolino et al. J Clin Invest. 2014 Nov;124(11):4781-94 (of record) is maintained. Note, this rejection was previously directed to Claims 1, 5-6, 15-17, 19-23, 28, 34, and 40, but due to the amendments, the applicable claims are now Claims 1, 15, 20, 23, 28, 34, 40, 42, 45, and 49-50 wherein the same rationales apply.
Applicant's arguments filed August 7, 2025 have been fully considered but they are not persuasive. Applicant argues that the deficiencies of Zhu and Ardolino apply to the provisional double patenting rejection, and the arguments against Zhu and Ardolino have been addressed above. Applicant further requests that the rejection be held in abeyance. The rejection is maintained and not held in abeyance because MPEP § 804.I.B.1 states “As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance.”
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675