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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/14/2026 has been entered.
Claim Status
Claims 2-20, 22-27, and 31-34 have been cancelled and, claims 35-38 have been newly added, as requested in the amendment filed on 04/14/2026. 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Claims 28-30 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and new claims 37-38 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species in the Response filed 07/21/2025, there being no allowable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.
Priority - Updated
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. It is further noted that an English translation of the foreign priority document has been provided. As such, the claim to foreign priority has been perfected.
Claims 1, 21, and 35-36 have an effective filing date of January 21, 2020 corresponding to CN202010071620.
Claim Rejections - 35 USC § 103 - Maintained/Updated
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 1 and 21 stand as rejected, and new claims 35-36 are newly 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").
With regard to new claims 35-36, it is noted that claim 1 is rendered obvious in view of Zhang18, Xiao, and Chen for reasons of record. It is specifically noted that while the exact sequence of SEQ ID NO: 29 is not disclosed by the cited references, the sequences of the individual cytokines are known and fusing multiple cytokines is known, as supported by Zhao18 and Xiao, and their fusion using linkers known in the art, such as (GGGGS)3 as disclosed by Chen, would result in a single-stranded fusion protein of instant SEQ ID NO: 29, which is therefore deemed obvious based on the teachings of the cited references in combination to arrive at a three cytokine fusion protein (comprising IL-12, IL-2, and GMCSF). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Double Patenting - Maintained/Updated
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 21 stand as rejected, and new claims 35-36 are newly 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 and 21 stand as rejected, and new claims 35-36 are newly 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 and 21 stand as rejected, and new claims 35-36 are newly 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").
As noted above, with regard to new claims 35-36, it is noted that claim 1 is included in all of the above-listed nonstatutory double patenting rejections in view of Zhang18, Xiao, and/or Chen for reasons of record. It is specifically noted that while the exact sequence of SEQ ID NO: 29 is not disclosed by the cited references, the sequences of the individual cytokines are known and fusing multiple cytokines is known, as supported by Zhao18 and Xiao, and their fusion using linkers known in the art, such as (GGGGS)3 as disclosed by Chen, would result in a single-stranded fusion protein of instant SEQ ID NO: 29, which is therefore deemed obvious based on the teachings of the cited references in combination to arrive at a three cytokine fusion protein (comprising IL-12, IL-2, and GMCSF). Therefore, new claims 35-36 are further included in the above-listed nonstatutory double patenting rejections.
Response to Arguments
Applicant's arguments filed 04/16/2026 have been fully considered but they are not persuasive. Applicant argues the following on Pages 4-12 of Remarks (04/14/2026):
Zhang18 is drawn to a formulation approach to retain cytokines for a longer period of time at an injection site, wherein the cytokine in the cytokine combination can be prepared as a polylactic acid microsphere, in a calcium alginate gel, or by adding chitosan quaternary ammonium salt to increase viscosity of the cytokine solution; this formulation approach is the main mechanism of action and is employed consistently across all working examples. Applicant argues that a three-cytokine fusion protein cannot be separately formulated as three independent molecules retained locally via chitostatin; converting Zhang18’s approach to a fusion protein would fundamentally abandon the sustained local retention mechanism identified as being essential to efficacy and as such Zhang18 teaches away from fusion proteins.
The language of Xiao wherein the cytokine moiety “comprises one or more cytokines” describes the cytokine component within Xiao’s required cytokine-targeting moiety fusion architecture; it does not disclose or suggest a standalone multi-cytokine fusion without a targeting moiety. Furthermore, all of the working examples of Xiao disclose a single cytokine moiety fused to a targeting moiety; Xiao also provides no guidance on spatial arrangement, linker selection, or functional retention of characteristics of three therapeutic cytokines fused together without a targeting moiety.
All of the working examples of Chen are two-cytokine fusions; a person having ordinary skill in the art would have no basis, beyond impermissible hindsight, to extrapolate from Chen’s two-cytokine fusions that a three cytokine fusion would retain the activities of all three components while also cooperating with a checkpoint inhibitor as the art recognizes unpredictability (reference made to the previously submitted Meyer reference in support of unpredictability).
Without the benefit of hindsight, a person having ordinary skill in the art seeking to combine Zhang18, Xiao, and Chen would face multiple independent, unpredictable steps: (1) abandoning Zhang 18's chitosan sustained-release mechanism; (2) extending Xiao's cytokine-targeting moiety fusions to a standalone multi-cytokine fusion without a targeting moiety; (3) extrapolating from Chen's two- cytokine fusions to a three-cytokine fusion; (4) selecting IL-12, IL-2, and GMCSF from the seven cytokines contemplated by Zhang 18; and (5) achieving a specific three-cytokine arrangement capable of retaining all three activities.
Anti-tumor effects of the instantly claimed pharmaceutical composition are demonstrated in working of the instant application; Examples 13-15 of the previously filed Affidavit demonstrate that the combination treatment of the fusion protein of instant SEQ ID NO: 29 and an anti-PD-1 antibody significantly inhibit the growth of tumors in the LLC lung cancer model. This efficacy is observed in tumor models known to be resistant to anti-PD-1 monotherapy. In Examples 4 and 7, 8, 9, and 13-15 the significant tumor inhibition achieved by Applicant’s fusion protein in combination with an anti-PD-1 antibody in resistant models, wherein anti-PD-1 antibody treatment alone has no meaningful therapeutic effect, demonstrates the beneficial combination effect cannot be attributed to additive contribution of either component alone and constitutes evidence of synergistic activity unexpected in light of the prior art. Instant claim 1 recites a pharmaceutical composition for anti-tumor use; a person of ordinary skill in the art can readily determine appropriate administration methods based on established practices in the field.
Specifically with regard to arguments (1)-(4) it is noted that:
One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. 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).
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).
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).
“Any 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).
Preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also > Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); < Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
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. It is also noted that Zhao18 discloses the sequences of all listed cytokines as well. It is noted that the while Zhao18 discloses specific formulations of the three separate cytokines to enhance retention time the injection site, this argument does not discredit the observation that three cytokines acting in the same local area (i.e., a tumor) results in synergistic, anti-tumor effects; the exemplary formulation approach to further improve upon the action of said three co-administered cytokines does not “teach away” from the instant invention. While it is acknowledged that Xiao discloses fusion protein architectures that comprise targeting moieties, such an architecture does not discredit a fusion protein that “comprises cytokines IL12, IL2, and GMCSF” as required by instant claim 1. The recitation of “comprising” is open claim language, and as such the fusion protein may or may not include elements beyond IL12, IL2, and GMCSF. Thus, 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.
With regard to argument (5), as specifically pertains to “unexpected” results and the previously filed Affidavit, it is noted that:
Applicant’s arguments rely on language solely recited in preamble recitations in claim(s). When reading the preamble in the context of the entire claim, the recitation anti-tumor" is not limiting because the body of the claim describes a complete invention and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention’s limitations. Thus, the preamble of the claim(s) is not considered a limitation and is of no significance to claim construction. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See MPEP § 2111.02.
The instant claims are drawn to a pharmaceutical composition which may be used for any purpose, wherein the pharmaceutical composition of the instant claims is not required to be administered according the method of the Affidavit or the above-cited working examples; thus the argument of unexpected results is not commensurate in scope with the instant claims because the instant claims are not drawn to the administration of the pharmaceutical composition. The recitation of “anti-tumor” in the preamble 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, it is noted that the argued improved properties are not considered to be “unexpected”; 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 and 21 under 35 U.S.C. 103 over Zhang18, Xiao, and Chen are maintained and the rejection of new claims 35-36 are deemed proper.
Similarly, the above-listed rejections of claims 1 and 21 under nonstatutory double patenting are maintained, and the rejection of new claims 35-36 are deemed proper.
Specifically regarding the above-listed nonstatutory double patenting rejections over U.S. Patent No. 12,357,672, Patent No. 11,795,203, and Patent No. 11,536,656, it is specifically noted that a Terminal Disclaimer that has been approved over the above-listed patents, along with a complete reply, would be sufficient to overcome the nonstatutory double patenting rejections. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a).
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.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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