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 have been cancelled and claims 1 and 28-29 have been amended, as requested in the amendment filed on 11/05/2025. Following the amendment, claims 1, 21, and 28-30 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Claims 28-30 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 07/21/2025, there being no allowable generic or linking claim.
Claims 1 and 21 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 further noted that a translation of the foreign priority document has been provided with the Response dated 11/05/2025. As such, the claim to foreign priority has been perfected.
Claims 1 and 21 have an effective filing date of January 21, 2020 corresponding to CN202010071620.
Drawings - Objection Withdrawn
Applicant has submitted a replacement Figure 1 wherein the labels are clearer and more legible. As such, the objection to the drawings is withdrawn.
Claim Objections - Withdrawn
Claims 8 and 10 were objected to for minor informalities. Claims 8 and 10 have been cancelled, rendering the objection moot. As such, the objection to claims 8 and 10 is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 8 and 10 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. Claims 8 and 10 have been cancelled, rendering the rejection moot. As such, the rejection of claims 8 and 10 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1-2, 4-8, 10, and 21 were rejected under 35 U.S.C. 103 as being unpatentable over CN 111848810 A (previously cited on PTO-892; herein after referred to as “Zhang”) in view of WO 2019/147837 A2 (previously cited on PTO-892; herein after referred to as "Chen").
On Page 5 of Remarks (11/05/2025), Applicant argues that Zhang is excluded as prior art under the exception § 102(b)(1)(A); the Zhang reference, wherein the inventor Zhang of the cited reference and instant application are the same individual, was published 10/30/2020 which is 2.5 months prior to the effective filing date of the instant invention in view of the updated priority date detailed above, which falls within the one-year grace period. Thus, the Zhang reference is a disclosure made by the inventor or joint inventor within the one-year grace period. As such, the rejection of claims 1-2, 4-8, 10, and 21 under 35 U.S.C. 103 over Zhang in view of Chen is withdrawn.
Claims 2 and 10 were 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").
Claims 2 and 10 have been cancelled, rendering the rejection moot. As such, the rejection of claims 2 and 10 under 35 U.S.C. 103 over Zhang18 in view of Xiao and Chen is withdrawn.
Claims 4-8 were 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"), 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 applied to claims 1-2, 10, and 21, and in further view of WO 00/01822 A1 (previously cited on PTO-892; herein after referred to as “Williams”), WO 2010/078945 A2 (previously cited on PTO-892; herein after referred to as “Schwager”), and non-patent literature by Brinkmann and Kontermann (MABS, 2017, 9(2), 182-212; previously cited on PTO-892; herein after referred to as “Brinkmann”).
Claims 4-8 have been cancelled, rendering the rejection moot. As such, the rejection of claims 4-8 under 35 U.S.C. 103 over Zhang18 in view of Xiao, Chen, Williams, Schwager, and Brinkmann is withdrawn.
Double Patenting - Withdrawn
Claims 1-2, 4-8, 10, and 21 are 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 CN 111848810 A (previously cited on PTO-892; herein after referred to as “Zhang”) and WO 2019/147837 A2 (previously cited on PTO-892; herein after referred to as "Chen").
As detailed above, Zhang has been disqualified as prior art. As such, the rejection of claims 1-2, 4-8, 10, and 21 on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 12 of U.S. Patent No. 12,357,672 in view of Zhang and Chen is withdrawn.
Claims 2, 4-8, and 10 were 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 2, 4-8, and 10 have been cancelled, rendering the rejection moot. As such, the rejection of claims 2, 4-8, and 10 on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 12 of U.S. Patent No. 12,357,672 in view of Zhang18, Xiao, and Chen is withdrawn.
Claims 1-2, 4-8, 10, and 21 were 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 CN 111848810 A (previously cited on PTO-892; herein after referred to as “Zhang”) and WO 2019/147837 A2 (previously cited on PTO-892; herein after referred to as "Chen").
As detailed above, Zhang has been disqualified as prior art. As such, the rejection of claims 1-2, 4-8, 10, and 21 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,795,203 in view of Zhang and Chen is withdrawn.
Claims 2, 4-8, and 10 were 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”), WO 2019/147837 A2 (previously cited on PTO-892; herein after referred to as "Chen"), WO 00/01822 A1 (previously cited on PTO-892; herein after referred to as “Williams”), WO 2010/078945 A2 (previously cited on PTO-892; herein after referred to as “Schwager”), and non-patent literature by Brinkmann and Kontermann (MABS, 2017, 9(2), 182-212; previously cited on PTO-892; herein after referred to as “Brinkmann”). Claims 2, 4-8, and 10 have been cancelled, rendering the rejection moot. As such, the rejection of claims 2, 4-8, and 10 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,795,203 in view of Zhang18, Xiao, Chen, Williams, Schwager, and Brinkmann is withdrawn.
Claims 1-2, 4-8, 10, and 21 were 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 CN 111848810 A (previously cited on PTO-892; herein after referred to as “Zhang”) and WO 2019/147837 A2 (previously cited on PTO-892; herein after referred to as "Chen").
As detailed above, Zhang has been disqualified as prior art. As such, the rejection of claims 1-2, 4-8, 10, and 21 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 in view of Zhang and Chen is withdrawn.
Claims 2, 4-8, and 10 were 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”), WO 2019/147837 A2 (previously cited on PTO-892; herein after referred to as "Chen"), WO 00/01822 A1 (previously cited on PTO-892; herein after referred to as “Williams”), WO 2010/078945 A2 (previously cited on PTO-892; herein after referred to as “Schwager”), and non-patent literature by Brinkmann and Kontermann (MABS, 2017, 9(2), 182-212; previously cited on PTO-892; herein after referred to as “Brinkmann”). Claims 2, 4-8, and 10 have been cancelled, rendering the rejection moot. As such, the rejection of claims 2, 4-8, and 10 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 in view of Zhang18, Xiao, Chen, Williams, Schwager, and Brinkmann is withdrawn.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1 and 21 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").
Double Patenting - Maintained
Claims 1 and 21 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 and 21 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 and 21 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"), and WO 2014/139468 A1 (previously cited on PTO-892; herein after referred to as “Xiao”).
Response to Arguments
On Pages 5-9 of Remarks, Applicant argues the following:
The examiner impermissibly combines references teaching fundamentally different approaches wherein: (i) Zhang18 is drawn to co-administration of individual cytokines via local tumor injection; (ii) Xiao is drawn to general fusion protein technology with targeting moieties; and (iii) Chen is drawn to two-cytokine fusion proteins with checkpoint inhibitors. Applicant argues that the cited prior art does not suggest combining a three-cytokine fusion protein specifically with immune checkpoint inhibitors and the examiner's reasoning requires multiple unpredictable leaps without proper motivation: converting co-administration to fusion format; selecting three specific cytokines from extensive lists; adding checkpoint inhibitor treatment; and incorporating bispecific targeting moieties.
The examiner's reliance on In re Kerkhoven, 626 F.2d 846 (CCPA 1980), is misplaced as Kerkhoven requires references to teach compositions "useful for the same purpose." Zhang 18 teaches local tumor injection therapy, Xiao teaches targeted fusion protein delivery, and Chen teaches systemic checkpoint inhibitor combinations. These serve different therapeutic purposes and do not flow logically toward the claimed invention. Zhangl8's co-administration approach, Xiao's general fusion protein teachings, and Chen's two-cytokine checkpoint inhibitor combinations do not logically lead to the specific three-cytokine fusion protein with checkpoint inhibitor combination claimed.
The additional references (Williams, Schwager, Brinkmann) compound the motivation problems. Combining multiple targeting specificities in a bispecific format with the three-cytokine fusion and checkpoint inhibitor represents a complex, multi-component invention not suggested by any reasonable combination of the prior art.
Applicant has also provided an Affidavit to supplement the data analyses submitted in the record previously. With regard to the new Affidavit, Applicant verified the significance of the differences in the data in Figures 7-9 in the Supplemental data and confirmed that they all had significant differences. Specifically, in Figure 7, the hIL12blL12alL2GMCSF group was compared with the hIL12blL12alL2GMCSF + PDI group, p < 0.001; in Figure 8, the hlL12blL12alL2DiaNHS76F8GMCSF group was compared with the hlL12blL12alL2DiaNHS76F8GMCSF + PDI group, p < 0.001; in Figure 9, the hlL12blL12alL2DiaNHS76F8GMCSF-Thr group was compared with the hlL12blL12alL2DiaNHS76F8GMCSF-Thr + PDI group, p < 0.001. Applicant argues that the results demonstrate synergy-not mere additive effects-that could not have been reasonably predicted from the prior art. The magnitude of improvement (67-80% reduction) and tumor regression represent clinically significant and unexpected therapeutic advances.
Fusion protein technology challenging work, and simply piecing parts together from disparate teachings does not provide a reasonable basis that one protein can suitably fuse to other proteins function. Fusion proteins connect several proteins together, thereby forming a spatial narrowing effect, which is easy to affect the binding between each component and its own receptor. Different cytokines have different functions, and the same cytokine may also play different roles in different environments. This means that even in the case of cytokine combinations, it is not that cytokine A plus cytokine B play function E, and cytokine B plus cytokine C play function G, then cytokines A+ B + C will reasonably function as E + G. The effects of multiple cytokines cannot be reasonably predicted, particularly in the context of fusion proteins.
Xiao generally mentions the cytokine moiety comprises one or more cytokines, but does not provide any example of a fusion protein with three cytokines. Even if a person skilled in the art can conceive of a fusion protein with three cytokines, they cannot reasonably predict the effect of such fusion protein simply. It is known in the art that fusing different proteins to form a fusion protein may result in reduced activity and/or function, and the reduced level is insufficient to exert therapeutic effects (for example, see the attached Elisabeth Meyer and Peter Fromherz, Ca2+ activation of hSlo K + channel is suppressed by N-terminal GFP tag, European Journal of Neuroscience, Vol.I 1, pp. 1105-1108, 1999, which demonstrates that fusion protein may cause damage to the original protein function). Therefore, the effect of the fusion protein of the present application is not reasonably predictable from the art cited in the rejections.
None of Zhang 18, Xiao and Chen teach the fusion protein as set forth in SEQ ID NOs: 27, 39, 29, 46 or 52, or a dimer composed of a first polypeptide chain as set forth in SEQ ID NO: 53 and a second polypeptide chain as set forth in SEQ ID NO: 57 as in present claim 1. As stated above, the function of a fusion protein is not a simple addition of functions of constituent proteins and as such the results obtained therewith are not reasonable predictable from the combined teachings of Zhang 18, Xiao and Chen.
Applicant’s arguments have been fully considered but are deemed not persuasive.
The following are noted in response to Applicant’s arguments:
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).
Applicant is reminded that 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).
The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c).
"[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992).
Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971) for examples of cases where indirect comparative testing was found sufficient to rebut a prima facie case of obviousness. The patentability of an intermediate may be established by unexpected properties of an end product "when one of ordinary skill in the art would reasonably ascribe to a claimed intermediate the ‘contributing cause’ for such an unexpectedly superior activity or property." In re Magerlein, 602 F.2d 366, 373, 202 USPQ 473, 479 (CCPA 1979). "In order to establish that the claimed intermediate is a ‘contributing cause’ of the unexpectedly superior activity or property of an end product, an applicant must identify the cause of the unexpectedly superior activity or property (compared to the prior art) in the end product and establish a nexus for that cause between the intermediate and the end product." Id. at 479.
With regard to Applicant’s arguments regarding the cited prior art references, it is specifically noted that Zhang18, Xiao, and Chen are in the same field of cytokines, including cytokine fusion proteins, as therapeutic modalities. Thus, Zhang18, Xiao, and Chen are all in the same field of cytokine administration for therapeutic effects; thus generally all of the references are drawn to the use of cytokines for the same purpose of achieving therapeutic responses. As such, their combination is deemed proper. 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. 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). It is noted that by definition, an “antibody” of Chen encompasses intact polyclonal and monoclonal antibodies, fragments thereof, synthetic variants thereof, naturally occurring variants, fusion proteins comprising an antibody portion with an antigen-binding fragment of the required specificity, humanized antibodies, chimeric antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen-binding site or fragment ( epitope recognition site) of the required specificity; antibodies may be of “essentially type” wherein, as well known in the art, an antibody is an immunoglobulin molecule capable of specific binding to a target through at least one epitope recognition site (see Pages 35-36). Furthermore, Chen discloses that, with regard to “monoclonal antibodies”, it is not intended to be limited as regards the source of the antibody or the manner in which it is made (e.g., by hybridoma, phage selection, recombinant expression, transgenic animals) and the term includes whole immunoglobulins as well as the fragments etc. described above under the definition of "antibody" (see Pages 38-39). Thus, based on the generic definition of “antibody”/“monoclonal antibody”, antibodies from any source, such as murine antibodies, are included in the scope of the invention. Thus, Chen discloses administration of cytokine fusion proteins comprising two or more cytokines in combination with an immune checkpoint inhibitor. Data presented by Chen further discloses that the combination of two cytokines (i.e., fusion protein) inhibited tumor growth in a more pronounces 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. Zhang18 indicates synergistic effects when co-administering three cytokines into a tumor (see Page 7), Xiao indicates that fusion proteins may comprise one or more (which can include two, three, etc.) cytokines (see Page 2), and Chen demonstrates that fusion proteins comprising two cytokine moieties are functional in terms of tumor inhibition and enhanced effects are observed when cytokines are combined with immune checkpoint inhibitors (e.g., anti-PD-1 inhibitors, pembrolizumab) (see for example Page 7, Figures 3-4). Thus, 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. 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 (which may comprise IL-12, IL-2, and GMCSF). With regard to Applicant’s arguments against additional references Williams, Schwager, and Brinkmann as compounding motivation problems, it is noted that in view of the instant claim amendments Williams, Schwager, and Brinkmann are no longer relied upon, as the fusion protein of instant SEQ ID NO: 29 as presently recited in claim 1 does not require a targeting moiety. Thus, Applicant’s arguments regarding additional references Williams, Schwager, and Brinkmann are moot.
With regard to the Affidavit, it is specifically noted that the only data being considered in that of Examples 10 and 13, which are drawn to the instantly elected species of a single-stranded fusion protein as set forth in instant SEQ ID NO: 29. However, it is noted that even with the claims as instantly amended, it is noted that the data of Example 13 is not commensurate in scope with the instant claims; specifically claim 1 is drawn to any anti-mouse PD-1 antibody, whereas all of the Affidavit data is drawn specifically to BioXcell Inc. InVivoMAbanti-mouse PD-1 (CD279) (Item No. BE0146). Furthermore, it is noted that the instant claims are drawn to a pharmaceutical composition which may be used for any purpose; the pharmaceutical composition of the instant claims is not required to be administered according the method of the Affidavit. With regard to Example 13 specifically, it is noted that it is unclear from the Affidavit and Fig. 7 how significance is being measured/determined. It is unclear which conditions are being compared to establish statistical significance. Furthermore, no specific evidence of synergy is provided beyond the mere statement of synergistic effects in Remarks; the Affidavit merely suggests significant inhibition of tumor growth without any statistical tests as evidence of synergistic effects. Furthermore, there is not PD-1 antibody alone condition nor conditions of co-administered individual cytokines and/or cytokines on their own to provide evidence of synergistic effects (i.e., effects more than the additive effects of the individual components compared to the effects of the closest 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 Affidavit under 37 CFR 1.132 filed 11/05/2025 and Applicant’s arguments listed above are deemed insufficient to overcome the above-listed claim rejections under 35 U.S.C. 103 and nonstatutory double patenting. As such, the above-listed claim rejections under 35 U.S.C. 103 and nonstatutory double patenting are maintained.
Conclusion
Claims 1, 21, and 28-30 are pending. Claims 28-30 are withdrawn. Claims 1 and 21 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642