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 .
Claim Status
Claim listing filed on February 3, 2026 is pending. Claims 3, 5, 7-9, 12-16, 19-22, 24-26, 28-33, and 37-38 are canceled. Claims 1-2, 4, 6, 10-11, 17-18, 23, 34-36, and 41-42 are amended. Claims 43-45 are new. Claims 1-2, 4, 6, 10-11, 17-18, 23, 27, 34-36, and 39-45 are examined upon their merits.
Information Disclosure Statement
The information disclosure statement filed on 02/03/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 20-21 and 25 have rendered all previous rejections directed to these claims moot.
The amendments to the claims have overcome all objections of record, and the claim objections are withdrawn.
The rejection of claims 10-11, 17-18, 34-35, and 42 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments to the claims.
The rejection of Claims 1-2, 4, 6, 18, 23, 27, 34-36, and 39-42 under 35 U.S.C. 103 as being unpatentable over Nakao US 2021/0315951 (of record) in view of Horn et al. Oncotarget 2017 (of record) is withdrawn in view of Applicant’s amendments to the claims. Specifically, Nakao and Horn fail to teach wherein the IL-7 fusion protein comprises an Fc moiety as required by amended Claims 1, 6, and 41.
Claim Rejections - 35 USC § 112 (New, necessitated by amendment)
Claims 1-2, 4, 6, 10-11, 17-18, 23, 27, 34, 36, and 39-45 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 1, 6, and 41 recite “wherein the bispecific antibody is administered at a reduced dose as compared to a reference method which comprises administering the bispecific antibody without the IL-7 fusion protein.” This limitation is considered indefinite relative terminology, specifically the term “reduced dose” (MPEP § 2173.05(b)). What quantitative change in dose is encompassed by “reduced”? For example, would a statistically non-significant change such as 0.500 µg to 0.499 µg be considered a “reduced dose”? Further, it is unclear to what the reduction in dose is being compared because the dose of bispecific antibody in the recited reference method is not quantitatively defined in the claims or in the specification. Even the dose of the reference method could vary depending on the reference method selected. One of ordinary skill in the art would not understand the distinct boundaries of “reduced dose” as compared to a “reference method” and would not know what dose to administer the bispecific antibody which is a critical step in the claimed methods. Claims 1-2, 4, 6, 10-11, 17-18, 23, 27, 34, 36, and 39-45 are rejected due to the indefinite relative terminology of “reduced dose.” Note, Claim 35 is not rejected because it clearly defines wherein the bispecific antibody is administered to the subject at a dose of 0.1 mg/kg to 20 mg/kg.
Note, Claims 1-2, 4, 6, 41, and 45 recite “reduced toxicity”; “improved anti-tumor efficacy”; “increased number of TILs”; “reduced number of regulatory T cells”; and “reduced loss in body weight.” These phrases comprise relative terminology but are not indefinite, because they are directed to inherent results of the methodological steps of drug administration (MPEP § 2112.01-.02). These phrases do not affect the methodological steps but are results of the methodological steps. As of record in the non-final office action filed 11/03/2025, these limitations are interpreted with the broadest reasonable interpretation to encompass any reduction or increase (even a non-significant change) using quantification methods known in the art prior to the time of filing.
Note, “Fc moiety” as recited in Claims 1, 6, and 41 is interpreted as defined in specification paragraph [0079].
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claims 1-2, 4, 6, 10-11, 17-18, 23, 27, 34-36, and 39-45 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 is maintained. The claims contain 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.
Applicant's arguments filed February 3, 2026 have been fully considered but they are not persuasive. Applicant argues that the amended claims narrow the scope to an IL-7 fusion protein comprising an IL-7 protein and a Fc moiety and a bispecific antibody capable of binding to a tumor antigen and a CD3 molecule. Applicant argues that the working example of administering an anti-PD-L1/CD3 bispecific antibody with IL-7-hyFc to treat mouse models of colon adenocarcinoma is an adequate representative species, and a skilled artisan would recognize that Applicant was in possession of the entire scope of amended Claims 1, 6, and 41. Examiner maintains that the claims are still directed to (1) a genus of IL-7 fusion proteins, (2) a genus of bispecific antibodies, and (3) a genus of tumors.
In regard to (1) a genus of IL-7 fusion proteins, Claim 17 recites wherein the IL-7 fusion protein comprises an amino acid sequence having a sequence identity of at least 70% to the amino acid sequence set forth in any one of SEQ ID NOs: 1-6 and 15-27. It is of record in the non-final office action filed 11/03/2025 that “an amino acid sequence set forth in” encompasses any fragment of two or more amino acid residues within the recited sequence. Therefore, Claim 17 encompasses at least 70% identity to SEQ ID NOs: 1-6 and 15-27 and any fragment of the sequences thereof. To claim the sequences in their entirety, alternative claim language could recite “at least 70% to the amino acid sequence comprising any one of SEQ ID NOs: 1-6 and 15-27.” Even without the “set forth in” language, the specification does not provide proper written description for the genus of IL-7 fusion proteins wherein any combination of amino acids can be substituted, added, or deleted with any other amino acid such that at least 70% sequence identity is maintained, especially considering no IL-7 fusion mutational variants were evaluated in the specification. There is proper written description for an IL-7 fusion protein comprising an IL-7 protein and a Fc moiety wherein the IL-7 protein comprises amino acid residues 26-177 of the amino acid sequence of SEQ ID NO: 1 (as defined in Claims 42-44).
In regard to (2) a genus of bispecific antibodies, bispecific antibodies comprising an anti-CD3 domain are understood in the art. However, the art nor the instant specification provide proper written description for the other binding domain to broadly bind any tumor antigen. Considering there are thousands of tumor antigens, the single example of an anti-PD-L1/CD3 bispecific antibody does not sufficiently represent the variation within the claimed genus. Further, it was decided in Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017) that adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional (MPEP § 2163.II). There is proper written description for a bispecific antibody capable of specifically binding to a tumor antigen and an antigen expressed on an immune cell wherein the antigen expressed on an immune cell comprises a CD3 molecule and the tumor antigen comprises an immune checkpoint molecule (defined in Claim 23) as both of these antibody domains were well-understood in the art prior to filing (as evidenced by Khair et al. Front. Immunol. 2019; Tables 1-2; Fig. 2).
In regard to (3) a genus of tumors, it is of record that “tumor” encompasses any tumor type (cancerous or benign). One working example of treating colon adenocarcinoma does not provide proper written description for treating any type of cancer tumor or any type of benign tumor. Further, the working example comprises administering an anti-PD-L1/CD3 bispecific antibody to treat colon adenocarcinoma cells that express PD-L1, but there is no evidence that the claimed treatment would be effective in tumor types that do not express the tumor antigen (i.e., PD-L1). There is proper written description for treating colorectal cancer as this method was established in the specification.
There is insufficient written description for the claimed genera, and the rejection is maintained.
The rejection of Claims 1-2, 4, 6, 10-11, 17-18, 23, 27, 34-36, and 39-45 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is maintained because the specification, while being enabling for treating colorectal cancer by administering an anti-PD-L1/CD3 bispecific antibody and an IL-7 fused to an Fc domain (IL-7-hyFc), does not reasonably provide enablement for treating any tumor type by administering a genus of bispecific antibodies and a genus of IL-7 fusion proteins. 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 and use the invention commensurate in scope with these claims.
Applicant's arguments filed February 3, 2026 have been fully considered but they are not persuasive. Applicant argues that the amended claims narrow the scope to an IL-7 fusion protein comprising an IL-7 protein and a Fc moiety and a bispecific antibody capable of binding to a tumor antigen and a CD3 molecule. Applicant argues that a skilled artisan would have been able to carry out the entire scope of amended Claims 1, 6, and 41 without undue experimentation. Examiner maintains that the claims are still directed to (1) a genus of IL-7 fusion proteins, (2) a genus of bispecific antibodies, and (3) a genus of tumors for the reasons outlined in the written description response above. Further, Applicant cites Seol et al. and Krystek-Korpacka et al. to teach that there is unpredictability in treating cancer by administering an IL-7 fusion protein and a bispecific antibody, because IL-7 is elevated in select cancer types and/or promotes metastasis in select cancer types. This art further supports that administering an IL-7 fusion protein and an anti-CD3/anti-tumor antigen bispecific cannot be expected to successfully treat any type of cancerous tumor or any type of benign tumor with a reasonable expectation of success without proof-of-concept working examples provided by the specification or the state of the art. Both the specification and the state of the art prior to filing (Nakao US 2021/0315951, of record) demonstrate that administering IL-7 in combination with an anti-PD-L1 antibody can effectively treat colorectal cancer. There is no evidence that the instant treatment has efficacy in other cancer types or benign tumors, and one of ordinary skill would have to perform multiple further experiments, in human clinical trials or in animal models, that are predictive of treatment in a representative number of tumor types in order to demonstrate the invention could be used with a reasonable expectation of success. Applicant’s arguments have been considered but are not persuasive, and the rejection is maintained.
Claim Rejections - 35 USC § 103 (Modified, necessitated by amendment)
Claims 1-2, 4, 6, 10-11, 17-18, 23, 27, 34-36, and 39-45 are rejected under 35 U.S.C. 103 as being unpatentable over Nakao US 2021/0315951 (of record) in view of Horn et al. Oncotarget 2017 (of record) and Yang US 2017/0158746 (of record).
In regard to Claims 1-2, 4, 41, and 45 Nakao teaches administering a polynucleotide encoding IL-7 in combination with an immune checkpoint inhibitor to treat cancerous tumors (paragraph [0007]). IL-7 is reported to contribute to survival, proliferation, and differentiation of T cells and B cells (paragraph [0077]), and the IL-7 can comprise an insertion of 10 amino acids (paragraph [0079]) which reads on an IL-7 fusion protein comprising an oligopeptide. The immune checkpoint inhibitor can be an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody (paragraph [0016]). Claims 2, 4, 41, and 45 are interpreted as inherent results of the methodological step comprising administering the combination treatment (MPEP § 2112.01-.02).
In regard to Claims 6 and 40, Nakao teaches administering the polynucleotide encoding IL-7 and an immune checkpoint inhibitor to treat mouse models of colorectal cancer wherein the combination treatment had a greater anti-tumor effect than the immune checkpoint inhibitor as a single agent (Example 1, pages 12-13).
In regard to Claim 27, the polynucleotide encoding IL-7 can be administered simultaneously or sequentially with the immune checkpoint inhibitor (paragraph [0188]).
In regard to Claim 34, Nakao teaches that “30 µL of IL-7-carrying vaccinia virus diluted with a solvent up to a concentration of 6.7X108 PFU/mL was injected (2X107 PFU) in a tumor in the mouse right lateral region of the abdomen” (paragraph [0204]). Nakao further teaches that the effective dose of the vaccinia virus to be used varies depending on the degree of symptom and age of the patient, dosage form of the preparation to be used, and titer of the virus (paragraph [0150]) which teaches that the specific dose of IL-7 is a matter of routine optimization. Further, MPEP § 2144.05 teaches that, generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art, and a mere carrying forward of an original patented conception involving only change of form, proportions, or degree is not such an invention as will sustain a patent.
In regard to Claim 36, the polynucleotide encoding IL-7 and the immune checkpoint inhibitor can be administered intratumorally, intravenously, or intraperitoneally (paragraph [0158]).
In regard to Claim 39, a polynucleotide encoding IL-12 can be administered in addition to the polynucleotide encoding IL-7 and the immune checkpoint inhibitor (abstract).
In regard to Claims 42-44, Nakao teaches wherein the IL-7 polypeptide contains the amino acid sequence as shown in Accession No. NP_000871.1 which is 100% identical to instant SEQ ID NO: 1 (as evidenced by NCBI sequence database – of record).
Nakao fails to teach wherein the immune checkpoint inhibitor is a bispecific antibody, specifically anti-PD-L1/CD3 (Claims 1, 6, 18, 23, 35, and 41).
However, Horn teaches a bispecific antibody anti-PD-L1/CD3 that has anti-tumor activity by activating cytotoxic T cells (anti-CD3) and concomitantly bridging the activated T cells to cancerous PD-L1-expressing tumor cells (anti-PD-L1), thereby eliminating tumor cells that drive PD1 immune suppression (page 57965, paragraph 3). The bispecific anti-PD-L1/CD3 antibody is an improvement from a monoclonal anti-PD-L1 antibody because it is able to activate T cells and bring them into contact with the tumor cells (page 57965, paragraph 2). Anti-PD-L1/CD3 had more effective anti-tumor activity than an anti-PD-L1 monoclonal antibody (page 57966, paragraph 3 and Supp. Fig. 3). Anti-PD-L1/CD3 has anti-tumor effects across cancer types (leukemia, breast, lung) as long as the tumor cells are positive for PD-L1 expression (page 57967, paragraph 1). Mice were treated with 8 ng/kg anti-PD-L1/CD3 on Days 8, 9, 10, 11, and 32 (page 57977, paragraph 5) which reads on Claims 1, 6, 35, and 41 because effective doses are a matter of routine experimentation (MPEP § 2144.05).
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 use a known technique to improve similar methods in the same way. Specifically, it would have been obvious to substitute the anti-PD-L1 immune checkpoint inhibitor in the method of treating colorectal cancer taught by Nakao to instead administer the bispecific antibody anti-PD-L1/CD3 taught by Horn. Horn teaches that the anti-PD-L1/CD3 targets the same tumor antigen as the antibody of Nakao (PD-L1) but improves the therapy by simultaneously activating T cells with the anti-CD3 portion of the bispecific antibody. Further, the anti-PD-L1/CD3 construct brings the activated T cells into close proximity of the tumor cells. Because Nakao teaches that IL-7 promotes T cells which benefits anti-PD-L1 immune checkpoint inhibitor therapy, it is obvious that combining IL-7 with anti-PD-L1/CD3 would have the same beneficial mechanism of action. The motivation to use anti-PD-L1/CD3 instead of anti-PD-L1 is because anti-PD-L1/CD3 showed greater anti-tumor activity as compared to anti-PD-L1 (Horn page 57966, paragraph 3 and Supp. Fig. 3).
Nakao and Horn fail to teach wherein the IL-7 fusion protein comprises an oligopeptide consisting of 1 to 10 amino acid residues and an Fc moiety (Claims 1, 6, 10, and 41); wherein the oligopeptide is MGM (Claim 11); and wherein the IL-7 fusion protein comprises SEQ ID NO: 24 (Claim 17).
Yang teaches that IL-7 promotes survival and proliferation of T cells and is an excellent candidate for an immune therapeutic agent in cancer (paragraph [0005]); however, IL-7 degradation makes manufacturing IL-7 with high stability and purity a difficult process (paragraph [0011]). Yang overcomes this problem by teaching modified IL-7 proteins that can be produced in large-scale and by an easy manufacturing process (paragraph [0012]). Specifically, Yang teaches an IL-7 comprising the oligopeptide MGM and an Fc domain wherein the IL-7 fusion protein comprises SEQ ID NO: 24 which is 100% identical to instant SEQ ID NO: 24 (pages 27-28). The IL-7 comprising MGM and Fc (termed MGM-IL-7-hyFc) was administered in a 1 µg dose to treat mouse models of endometrial cancer (Example 13).
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 use a known technique to improve similar methods in the same way. Specifically, it would have been obvious to substitute the IL-7 fusion protein taught by Nakao with the IL-7 fusion protein taught by Yang. Yang teaches that the motivation to use the MGM-IL-7hyFc fusion protein is because it maintains anti-tumor effects while being easier to manufacture recombinantly (paragraph [0012] and Example 13).
Applicant's arguments filed February 3, 2026 have been fully considered but they are not persuasive. Applicant argues that Nakao provides data showing that only through the use of a genetically modified vaccinia virus vector was complete remission achieved in subjects, and Nakao at best highlights the importance of the disclosed genetically modified vaccinia virus in delivering a polynucleotide encoding a cytokine to a subject. Examiner maintains that one of ordinary skill would understand that the vaccinia virus is a delivery platform used to express IL-7. The therapeutic agent is the IL-7 cytokine, not the viral vector (as evidenced by Nakao paragraphs [0002], [0077], [0104], and [0194]). Note, new sections of Nakao are referenced solely in response to Applicant’s arguments and not as new grounds of rejection.
Applicant argues that a skilled artisan would not have reasonably predicted that the IL-7 fusion protein of current Claims 1, 6, and 41 would be useful in achieving the current claims at issue because Seol et al. and Krystek-Korpacka et al. teach that IL-7 enhances the invasion of prostate cancer cells and IL-7 is elevated in patients with colorectal cancer, respectively. Different cancer types have different etiologies and require different treatments. The instant application is only enabled for the treatment of colorectal cancer (see enablement rejection above) which is the cancer type taught by Nakao. Seol’s teachings are only directed to prostate cancer which are not relevant in the instant application. Krystek-Korpacka is directed to colorectal cancer and specifically teaches that IL-7 is known to enhance immune responses and is being evaluated in combination with immunotherapies to treat colorectal cancer (introduction paragraph 2). Krystek-Korpacka teaches that IL-7 is elevated in colorectal cancer patients (page 176, paragraph 1) but does not teach wherein administering an IL-7 fusion protein in combination with an immune checkpoint inhibitor is incapable of treating colorectal cancer. On the contrary, Krystek-Korpacka references multiple studies that showed success in administering IL-7 to treat colorectal cancer (page 177, paragraph 3) and concludes that the IL-7 elevation in colorectal cancer patients “should be considered when designing IL-7-based immunotherapies” (page 177, paragraph 4). Therefore, Krystek-Korpacka acknowledges the potential of IL-7-based immunotherapies in colorectal cancer despite the elevated IL-7 expression levels observed in patients. In light of the teachings of Nakao (a polynucleotide encoding IL-7 in combination with an immune checkpoint inhibitor had a greater anti-tumor effect in colorectal cancer mouse models than the immune checkpoint inhibitor as a single agent; of record), one of ordinary skill would have understood that the combination could treat colorectal cancer with a reasonable expectation of success. Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007). MPEP § 2145.
Applicant argues that Horn does not overcome the deficiencies of Nakao, and even when combined, the two references could not have reasonably predicted that a bispecific antibody could be administered at lower doses and achieve potent anti-tumor response with reduced toxicity when used in combination with an IL-7 fusion protein. Nakao teaches that immune checkpoint inhibitors anti-PD-1 and anti-CTLA-4 as single agents achieved 0/10 complete remission (CR); the IL-7/IL-12 viral vector as a single agent achieved 1/10 CR; and the combination of IL-7/IL-12 viral vector with anti-PD-1 or anti-CTLA-4 achieved 6/10 CR and 4/10 CR respectively (Fig. 1). This data demonstrates that it was understood in the art that IL-7 and immune checkpoint inhibitor antibodies were known to be more effective when used in combination than as single agents. Therefore, the demonstrated efficacy of the instant drug combination is not surprising in view of the prior art. Note, new sections of Nakao are referenced solely in response to Applicant’s arguments and not as new grounds of rejection. The exact dosing of the instant bispecific antibody when in combination with an IL-7 fusion protein is a matter of routine optimization as stated in the rejection above (MPEP § 2144.05). Wang et al. Inform. Sci. 2018 teaches that it is important for oncologists to adjust the drug dose to reduce toxicity or improve the efficacy based on the patient’s response to treatment, especially in combination therapy (abstract and introduction paragraph 3). Further, in In re Aller, 220 F. 2d454, 456, 105 USPQ 233,235 (CCPA 1955) the courts maintained that: "Where the general condition of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." As dosage optimization is routine in the art of medicine, pharmacology, and oncology, the claims are maintained as prima facie obvious.
Applicant argues that Yang fails to remedy the deficiencies of Nakao and Horn, specifically because there is nothing in Yang that would have allowed a skilled artisan to reasonably predict that, when administered with an IL-7 fusion protein, a bispecific antibody could be administered at lower doses and yet achieve potent anti-tumor response with reduced toxicity. This argument is addressed in the paragraph above in light of the teachings of Nakao and routine optimization of drug dosing. Applicant’s arguments have been considered but are not persuasive, and the rejection is maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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