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
Claims 2-20, 22-27, and 31-34 were cancelled and claims 35-38 were newly added, as requested in the amendment filed on 04/14/2026., no new amendments being filed since the previous Office Action (05/14/2026). Following the amendment, claims 1, 21, 28-30, and 35-38 are pending in the instant application.
Claims 28-30 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and claims 37-38 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species of invention in the Response filed 07/21/2025 there being no allowable generic or linking claim.
Claims 1, 21, and 35-36 are under examination in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/29/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1, 21, and 35-36 stand as rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/184484 A1 (previously cited on PTO-892; herein after referred to as "Zhang18") in view of WO 2014/139468 A1 (previously cited on PTO-892; herein after referred to as “Xiao”) and WO 2019/147837 A2 (previously cited on PTO-892; herein after referred to as "Chen").
Response to Arguments - 35 USC § 103
Applicant's arguments filed 07/29/2026 (herein after referred to as “Remarks”) have been fully considered but they are not persuasive. Applicant argues the following on Pages 2-6 of Remarks:
The cited art references do not disclose which cytokines should be selected, how they should be ordered, what linker arrangement should be used between each domain, whether the resulting molecule would express, whether each cytokine domain would fold properly, whether each domain would retain receptor-binding activity, or whether the resulting single-chain molecule would retain anti-tumor activity in combination with an immune checkpoint inhibitor. The conclusion that known cytokine sequences and known linker motifs would "result in" SEQ ID NO: 29 is based on impermissible hindsight using Applicant's disclosure as a blueprint; the combination of references to reach the instant claims is only through hindsight reconstruction.
Zhangl8 would first have to be modified from simultaneous administration of separate cytokines into a single fusion protein. Xiao would then have to be generalized beyond its exemplified single-cytokine/targeting-moiety architecture to a standalone multi-cytokine fusion protein without the targeting-moiety context emphasized in Xiao. Chen would then have to be extended from two-cytokine fusions to a three-cytokine fusion comprising the specific cytokines IL12, IL2, and GMCSF. Finally, one would have to further combine that newly constructed three-cytokine fusion protein with an immune checkpoint inhibitor and expect anti-tumor efficacy. None of the cited references provides a teaching, suggestion, or reasonable expectation of success for this series of modifications.
The presently claimed fusion protein is not a trivial juxtaposition of known cytokines. Compared with each native cytokine component, the fusion protein creates new domain boundaries, linker environments, N-terminal and C-terminal contexts, and steric constraints. Whether such a newly designed fusion protein can be expressed normally and perform the expected biological function must be verified experimentally and cannot be predicted simply from the existence of the separate cytokines. Applicant has submitted the following references in support of unpredictability (see IDS dated 07/29/2026): the Alexander reference demonstrates that even a single amino acid substitution can cause a substantial conformational and functional change in a protein; the Tomala reference further confirms that even limited amino acid changes can destabilize a protein and materially alter its functional consequences; and the Medynski reference addresses protein structure/function relationships in the context of binding phenomena, including cytokine and growth factor/receptor interactions, and therefore directly supports Applicant's position that cytokine function cannot be assumed to survive major fusion-protein redesign. If a single amino acid substitution can change protein fold, destabilize protein structure, cause toxicity, or radically alter function, then a person of ordinary skill would not have reasonably expected that fusing IL12, IL2, and GMCSF into one single-chain molecule would preserve the functional activity of all three cytokines, much less produce anti-tumor efficacy in combination with an immune checkpoint inhibitor.
Regarding the previously submitted Declaration (filed 11/05/2025), Applicant submits that the Declaration remains relevant objective evidence because it confirms that Applicant's specific fusion protein is not merely a theoretical combination of known parts, but an experimentally verified molecule that retains biological functionality and produces anti-tumor activity when combined with an immune checkpoint inhibitor. The Declaration evidence is therefore probative of the unpredictability of the claimed fusion protein and the absence of a reasonable expectation of success, even if Applicant does not rely on the Declaration as the sole basis for patentability of the full scope of claim 1.
The unpredictability is especially significant because the cited art does not disclose the claimed three-cytokine fusion protein. Zhang 18 uses three cytokines in non-fusion form. Xiao' s examples use a single cytokine fused to a targeting region. Chen's examples are limited to two-cytokine fusions and involve cytokine combinations different from those presently claimed. Therefore, the prior art provides no experimental basis from which a person of ordinary skill could reasonably predict that Applicant's specific three-cytokine fusion protein would retain activity and function effectively in the claimed pharmaceutical composition.
With regard to the arguments against individual art references, it is specifically noted that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references, as is relied upon in the instant case. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). With regard to motivation to combine the teachings of the references and a reasonable expectation of success, it is noted that: (i) there is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004); and (ii) obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
With regard to the art references and their combination, Zhang18 is relied upon because it explicitly discloses that administering three cytokines at the same time, wherein said cytokines are selected from IL12, GMCSF, FLT3L, IL2, IL15, IL21 and IL7, breaks the tumor immunosuppressive microenvironment and stimulates the immune response against the tumor, thereby effectively eliminating the tumor and combination of cytokines used exhibits a strong synergistic effect, whereas administration of a single cytokine, or a combination of two cytokines, does not effectively eliminate the effects of the tumor (see Page 7). Zhao18 further discloses that since different cytokines have different mechanisms of action, a combination of various cytokines is used so that both natural immunity and acquired immunity can be simultaneously activated to achieve effective tumor treatment (Id.). Thus, the simultaneous action of three cytokines results in synergistic effects. Xiao is relied upon for its disclosure of cytokine fusion proteins can comprise one or more cytokine moieties, including those instantly claimed (see Page 3). Chen is relied upon for the disclosure of cytokine fusion proteins which may comprise two or more cytokines fused together which may be administered with immune checkpoint modulatory agents (including PD-1 antagonist antibodies or antigen-binding fragments thereof). Data presented by Chen further discloses that the combination of two cytokines (i.e., fusion protein) inhibited tumor growth in a more pronounced manner when administered with a PD-1 antibody compared to administering the cytokines alone (see Figures 3-4, Page 7). Therefore, it is maintained that it would have been obvious to one of ordinary skill in the art that the invention of Zhang18, comprising co-administration of three cytokines into a tumor, could be modified such that the three cytokines (which in combination exhibit synergistic effects) are administered in the form of a fusion protein, as supported by the inventions of Xiao and Chen which comprise cytokine fusion proteins that can include one, two, or more cytokine moieties, because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success; one of ordinary skill in the art would reasonably expect that a fusion protein comprising three functional cytokine moieties (e.g., IL12, IL-2, GMCSF as supported by Zhang18 and Xiao) would be expected to have tumor-inhibitory function and when combined with an immune checkpoint inhibitor (as supported by Chen) would be expected to have further improved effects. The art supports fusion proteins comprising one, two, or more cytokines wherein exemplary embodiments of said fusion proteins are demonstrated to be functional; thus, absent evidence to the contrary, the addition of, for example, a third cytokine to such fusion proteins would also be expected to be functional as such embodiments are suggested by the prior art, and the use of three cytokines in the context of co-administration have demonstrated synergistic effects.
Regarding the arguments of hindsight, “[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). As provided above, the obviousness rejection relies only upon the teachings of the prior art references, which support the use of three cytokines simultaneously (e.g., including GMCSF, IL2, and IL12) to yield synergistic anti-tumor effects and fusion proteins comprising multiple cytokines (e.g., at least two) are established in the art. One of ordinary skill in the art could have reasonably arrived at the instantly elected fusion protein, which comprises three cytokines known and established in the art to function together in the treatment of tumors in a synergistic manner linked via known and established linkers in the fusion protein art. The combination of such a fusion protein with an immune checkpoint inhibitor, including an anti-PD-1 antibody, is also suggested by the art.
With regard to the arguments of unpredictability, it is noted that the arguments of Applicant regarding the Alexander, Tomala, and Medynski references are not commensurate in scope with the instant claims. The three references cited by Applicant are specifically drawn to amino acid modifications of protein sequences and their subsequent effects; there are no proposed modifications to the known cytokine sequences. Rather, the full-length sequences are being fused in tandem using established linkers in the fusion protein art, and as such arguments of unpredictability based on amino acid modifications are not commensurate in scope with the instant claims. Furthermore, regarding the previously submitted Declaration, it is unclear how the Declaration is supportive of unpredictability. The Declaration is drawn to data directed specifically at the claimed fusion proteins, and provides no comparisons to other, directly related cytokine fusion proteins that would be supportive of unpredictability. While it is acknowledged that the Declaration establishes the function of the claimed fusion proteins in combination with an anti-PD-1 antibody in the context of treating tumors, the pharmaceutical composition of the instant claims is not required to be administered according the method of the Declaration, and the recitation of “anti-tumor” in the preamble of instant claim 1 is merely an intended use, and is not given patentable weight. Even so, the use of cytokine fusion proteins, alone and/or in combination with immune checkpoint inhibitors, in the context of tumors is supported by the teachings of the prior art references. Furthermore, there is no evidence of novel function above and beyond the effects observed with co-administration of the components separately, as discussed by the cited prior art references.
In view of the above, the rejection of claims 1, 21, and 35-36 under 35 U.S.C. 103 over Zhang18, Xiao, and Chen are deemed proper and are maintained.
Double Patenting - Maintained
Claims 1, 21, and 35-36 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 12 of U.S. Patent No. 12,357,672 (herein after referred to as “reference patent”) in view of WO 2018/184484 A1 (previously cited on PTO-892; herein after referred to as "Zhang18"), WO 2014/139468 A1 (previously cited on PTO-892; herein after referred to as “Xiao”), and WO 2019/147837 A2 (previously cited on PTO-892; herein after referred to as "Chen").
Claims 1, 21, and 35-36 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,795,203 (herein after referred to as “second reference patent”) in view of WO 2018/184484 A1 (previously cited on PTO-892; herein after referred to as "Zhang18"), WO 2014/139468 A1 (previously cited on PTO-892; herein after referred to as “Xiao”), and WO 2019/147837 A2 (previously cited on PTO-892; herein after referred to as "Chen").
Claims 1, 21, and 35-36 stand as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 6-7 of U.S. Patent No. 11,535,656 (herein after referred to as “third reference patent”) in view of WO 2018/184484 A1 (previously cited on PTO-892; herein after referred to as "Zhang18"), WO 2014/139468 A1 (previously cited on PTO-892; herein after referred to as “Xiao”), and WO 2019/147837 A2 (previously cited on PTO-892; herein after referred to as "Chen").
Response to Arguments - Double Patenting
Applicant requested reconsideration of the above-listed claim rejections on the grounds of nonstatutory double patenting in light of the arguments as presented above (see Page 6 of Remarks). The arguments have been fully addressed above and are deemed not persuasive. As such, the above-listed claim rejections on the grounds of nonstatutory double patenting are maintained.
Conclusion
Claims 1, 21, 28-30, and 35-38 are pending. Claims 28-30 and 37-38 are withdrawn. Claims 1, 21, and 35-36 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
