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 .
DETAILED ACTION
The amendment filed November 18, 2025 in response to the Office Action of August 19, 2025 is acknowledged and has been entered.
Claims 1, 15 and 19 have been amended.
Claims 2-4, 9 and 10 have been cancelled.
Claims 27-29 have been added.
Claims 1, 6-8, 12, 14, 15, and 19-29 are pending.
Claims 12, 14 and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1, 6-8, 15, 19-24 and 26-29 are currently under consideration as drawn to the elected invention.
MAINTAINED/MODIFIED REJECTION
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 19 and 27-29 are rejected 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. The claim(s) contains 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. This is a WRITTEN DESCRIPTION rejection.
Claim 19 recites a full length PD-1 antibody fusion protein, but only provides partial structures critical for PD-1 binding (heavy chain). Thus, given Broadest Reasonable Interpretation, the claims would encompass a broad genus of antibodies with known heavy chain sequences but novel/unknown light chain sequences. The specification does not provide the written description support for the broadly claimed genus.
Vas-Gath, Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed".
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. (See Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001, especially page 1106 3rd column). A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. MPEP 2163 II.A.3a.ii.
MPEP 2163 II A 3(a) states: Disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract). Thus, the specific antibody disclosed by the specification would not tell structure of other antibodies to PR3 or variants of thereof.
In view of above, although claim 19 recites the sequences for two heavy chains, as set forth above, the two heavy chains comprise only partial structure of monoclonal antibody required for antigen-binding. As set forth above, for specific antigen binding, a complete HCDRs 1-3 and LCDRs 1-3 are required. The specification does not disclose any antibody which comprise partial CDR sequences, e.g. only heavy chains, as evidenced by Table 1 of the specification all antibodies has a pairing light chain of SEQ ID NO: 52.
Furthermore, the written description provision of 35 USC § 112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. The Guidelines for Examination of Patent Applications under the 35 USC §112 paragraph 1, "Revision 1" of Written Description Requirement (66 FR 1099-1111, March 25, 2008) state, "[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the Applicant was in possession of the claimed invention (Id. At 1104). Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was "ready for patenting" by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Claims 27-29, which depend on claim 19, encompass the same antibodies of claim 19.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Response to Arguments
For the 112(a) rejection, applicant argues:
Applicant has amended claim 1 and 19 to address the Examiner's rejections, and it is believed that the written description rejections are moot in view of the claim amendments.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, claim 19 recites a full length PD-1 antibody fusion protein, but only provides partial structures critical for PD-1 binding (heavy chain). Thus, given Broadest Reasonable Interpretation, the claims would encompass a broad genus of antibodies with known heavy chain sequences but novel/unknown light chain sequences. The specification does not provide the written description support for the broadly claimed genus, as set forth above. Thus, the rejection is maintained for the reasons of record.
NEW REJECTION
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 6-8, 15, 20-24 and 26 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.
The amended claim 1 added the limitation: “wherein the monoclonal antibody is full length anti-PD-1 antibody, wherein one heavy chain of the monoclonal antibody is connected ….”. It is unclear whether these two “wherein” conditions are alternative options (“or” ), or these two “wherein” conditions are inclusive combination (“and”).
Claims 6-8, 15, 20-24 and 26 are rejected because these claims depend on claim 1 directly or indirectly.
Claim Rejections - 35 USC § 103
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 following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 6-8, 15, 20-24 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Deak (Deak et al., US 2018/0326010 A1, Publication Date: 11/15/2018) in view of Ast (Ast et al., US 2012/0276125 A1, Publication Date: 11/01/2012, of record) and Jahn (Jahn et al., PLOS One, Vol. 7, Issue 9, e44482, Publication Date: 09/18/2012, cited by IDS of 09/01/2023, of record).
Deak teaches a fusion protein comprising a mutant interleukin-2 and an antibody that binds to PD-1 (Abstract, claim 1-2).
Deak teaches that mutant interleukin-2 is linked to the C-terminal of a heavy chain of a full length antibody (Fig. 1), and method of making the fusion protein (Example 1).
Deak teaches that the antibody can be a monoclonal antibody ([0094], [0095]). Deak teaches a monoclonal PD-1 antibody IL-2 fusion proteins with good yields and are stable (Example 1A, [0311]).
Deak teaches that the full-length anti-PD-1 antibody and IL-2 fusion protein leads to good activation and proliferation of CD8 and CD4 T cells (Example 2C, [0331], and Fig. 6); leads to proliferation of NK92 cells (Example 2D, [0333], and Fig. 7).
Deak teaches that the anti-PD-1 antibody and IL-2 fusion protein shows significantly superior efficacy in vivo in terms of enhanced median and overall survival compared to other single agents tested (Example 3, Fig. 10 and Table 1).
Deak teaches as set forth above. However, Deak does not explicitly teach combination of IL-2 and IL-12, in a configuration as instantly claimed.
Ast teaches immunoconjugate comprising antibody heavy chain and light chain. The Fc domain comprise a modification promoting heterodimerization of two non-identical polypeptide chains and one effector moiety (Fig. 2A and [0036]). The antibody can be monoclonal antibody ([0090]). The effector moiety is a cytokine, such as IL-2 or IL-12 ([0187]).
Ast teaches full length antibody-cytokine fusion protein, wherein the cytokine is linked to two heavy chain of the full length antibody (Fig. 1).
Jahn teaches IL-12 and IL-2 dual cytokine antibody fusion protein has superior power in activating T and NK cells (Figs. 5A and 5B, and page 3).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a monoclonal antibody-IL-2 fusion proteins as taught by Deak, and to use both IL-2 and IL-12 in the monoclonal antibody-fusion, to modify the fusion format by connecting IL-2 to the C-terminus of one heavy chain and IL-12 to the C-terminus of the other heavy chain of a monoclonal antibody, because Jahn teaches that IL-12 and IL-2 dual cytokine antibody fusion protein has superior power in activating T and NK cells, and Ast teaches both IL-2 and IL-12 can be fused with Fc domain of a monoclonal antibody and teaches the configuration with one cytokine molecule fused with each heavy chain (Fig. 1). Thus, one of ordinary skill in the art would have been motivated to expand options to combine IL-2 and IL-12 in a monoclonal antibody-cytokine fusion format. Given all the components and methods are well known in the art, as evidenced by, Deak, Ast and Jahn, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed invention. The motivation would have been to expand the options of the fusion proteins and to develop a better fusion proteins for immunotherapy.
Regarding claim 7 and 8, Deak teaches that the first Fc domain bearing mutations S354C and T366W for heterodimerization “knob”, and the other Fc domain bearing Y349C, T366S, L368A, Y410V for heterodimerization “hole” ([0182-0184], [0306], Example 1A, and claim 14).
Regarding claim 15, Ast teaches that IL-12 effector moiety comprises the polypeptide sequence of SEQ ID NO: 4. As shown below, SEQ ID NO: 4 of Ast is identical to SEQ ID NO: 4 of the instant application:
US-13-457-039-4
Query Match 100.0%; Score 2741; Length 518;
Best Local Similarity 100.0%;
Matches 518; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEF 60
Qy 61 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTC 120
Qy 121 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 WWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAA 180
Qy 181 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 EESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTW 240
Qy 241 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 STPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW 300
Qy 301 ASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEF 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 ASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEF 360
Qy 361 YPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 YPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMA 420
Qy 421 LCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKS 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 LCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKS 480
Qy 481 SLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS 518
||||||||||||||||||||||||||||||||||||||
Db 481 SLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS 518
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use sequence of IL-12 taught by Ast, because it is well known in the art and has been used as an example for making antibody-cytokine fusion so that one of ordinary skill in the art would have a reasonable expectation that the sequence would suitable for the fusion protein as instantly claimed.
Regarding claims 20 and 21, Deak teaches that cytokine is fused to the C-terminal of the Fc domain, through a linker peptide (the bridging paragraph of cols. 1-2 on page 48), the linker sequence is SEQ ID NO: 21 (page 48, col. 2, para. 2), SEQ ID NO: 21 has the sequence of (G4S)3 (page 31).
Regarding claims 22-24, Deak teaches polynucleotides encoding such immunoconjugates, and vectors and host cells comprising such polynucleotides or the expression vector (page 48, embodiments 23-25).
Regarding claim 26, Ast teaches a pharmaceutical composition comprising the immunoconjugate and a pharmaceutically acceptable carrier (page 48, embodiment 28).
Response to Arguments
For the rejection under 35 U.S.C. 103, applicant argues:
The Examiner cites Jahn for motivation to combine IL-2 and IL-12. Jahn teaches an antibody fusion where both cytokines (IL-2 and IL-12) are fused linearly on a single heavy chain. Jahn does not teach or suggest the claimed format where IL-2 is fused to a first heavy chain and IL-12 is fused to a second heavy chain of a full-length IgG heterodimer. Jahn does not have any structural teaching that distributing IL-2 and IL-12 across two separate heavy chains would be functionally beneficial or even feasible.
Thus, Jahn's tandem format is structurally and functionally distinct from the claimed dual chain heterodimer.
Applicant’s arguments have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, 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). As set forth above, Deak explicitly teaches full-length anti-PD-1 antibody fused with cytokine at the C-terminal of heavy chain Fc region, Ast teaches the configuration one full-length antibody fused with two cytokine molecules at each of the heavy chain Fc region, and Jahn teaches the advantages to fuse both IL-2 and IL-12 to an antibody. Thus, one of ordinary skill in the art would have been motivated to expand options to combine IL-2 and IL-12 in a monoclonal antibody-cytokine fusion format. Given all the components and methods are well known in the art, as evidenced by, Deak, Ast and Jahn, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed invention.
In addition, in the field of biological technology, no invention has absolute certainty of success before experimental tests. Thus, only a reasonable expectation of success (not absolute) would have motivated an artisan to make the claimed fusion protein. Given the teachings from references, an ordinary skilled in the art would have would have had a reasonable expectation of success in producing the claimed invention.
Applicant further argues:
Where Ast teaches that dual-cytokine IgGs lead to poor properties, the present application shows that combining IL-2 and IL-12 in the dual-fusion IgG format of Claim 1 yields unexpected synergistic increases in cytokine activity and antibody blocking function. Paragraph [0109] states:
"the IL-12 cytokine activity of the antibody-cytokine fusion protein simultaneously fused with IL-12 and IL-2 is higher than the fusion protein only fused with IL-12, this shows that IL-12 and IL-2 may have a synergistic effect, and it is further proved that the structure of the monoclonal antibody-cytokine fusion protein based on the antibody heterodimer technology can significantly improve the activity of IL-12."
This result is not a predictable additive effect of delivering two cytokines. Only the claimed single-molecule dual-fusion IgG, with IL-2 on one heavy chain and IL-12 on the other, demonstrates this synergy. Co-administration or single-cytokine fusions do not achieve the same effect. Thus, the construct of Claim 1 as amended exhibits surprising and superior performance, rebutting obviousness.
Applicant’s arguments and experimental data have been fully considered but they are not persuasive. As set forth above, combining teachings from Deak, Ast and Jahn, one of ordinary skill in the art would have reasonable expectation that antibody fused with IL-2 and IL-12 would have better therapeutic activity than fusion protein fused with IL-12.
In addition, although paragraph [0109] alleges that IL-12 and IL-2 may have a synergistic effect, the data shown in cited Figures (e.g. Fig. 9) do not support this. No proper controls are used in the experiment, e.g. anti-PD-1/IL-2 vs anti-PD-1/IL-2/IL-12.
Furthermore, the claims are not limited to the fusion proteins tested in Examples, i.e. the fusion proteins encompass different anti-PD-1 antibodies, different IL-12 sequences and different IL-2 sequences. Thus, the example is not commensurate in scope with the claimed invention and is not probative on the non-obviousness of the claimed invention.
Double Patenting
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, 6-8, 15, 20-24 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, and 9-11 of copending Application No. 18/881,400 (hereinafter Appl. 400) in view of Deak (Deak et al., US 2018/0326010 A1, Publication Date: 11/15/2018), Ast (Ast et al., US 2012/0276125 A1, Publication Date: 11/01/2012, of record) and Jahn (Jahn et al., PLOS One, Vol. 7, Issue 9, e44482, Publication Date: 09/18/2012, cited by IDS of 09/01/2023, of record).
The claims of Appl. 400 teach:
1. A heterodimeric fusion protein, comprising: a first heavy chain, wherein the first heavy chain comprises an Fc region, an immunomodulator fused to the Fc region; a light chain and a second heavy chain, wherein the light chain and the second heavy chain are complexed to form a targeting portion exhibiting binding specificity to a tumor antigen or an immune checkpoint; and wherein the light chain, the first heavy chain, and the second heavy chain are complexed to form the heterodimeric fusion protein.
2. The heterodimeric fusion protein of claim 1, wherein the immunomodulator is a cytokine, …; preferably, the immunomodulator is selected from the group consisting of: …, IL-2, …, IL-12….
6. Wherein the tumor antigen or immune checkpoint is one or more of …, PD-L1,…, CD279 (PD-1),…, TIGIT,….
7. Both the light chain and the second heavy chain comprise a complementary determining region, and the complementary determining region comprises an amino acid sequence having at least 80% identity to the amino acid sequence of the corresponding CDR of the light or heavy chain the antibody that specifically binds the tumor antigen or the immune checkpoint.
9. A pharmaceutical composition, comprising the fusion protein and at least one pharmaceutically acceptable excipient, diluent or carrier.
Thus, the claims of Appl. 400 teach antibody-fusion protein dimer, wherein the antibody can be anti-PD1 antibody, wherein the cytokines can be IL-2 or IL-12. The claims of Appl. 400 also teach polynucleotides encoding the fusion protein dimers, and a pharmaceutical composition containing the fusion protein and a pharmaceutically acceptable carrier. However, the claims of Pat. 537 do not explicitly teach that the antibody is a full-length monoclonal antibody, or wherein the two Fc region are not identical (e.g. with the specific mutation combinations), wherein the IL-12 has sequence of SEQ ID NO: 6 (identical to SEQ ID NO: 4 of the instant application), or wherein the IL-12 has sequence of SEQ ID NO: 4, or wherein the cytokine is connected to Fc regions by linkers, such as (G4S)1-3, or a polynucleotide encoding the fusion protein, or specific mutation combinations in Fc domain, or vector comprising the said polynucleotides, or a host cell comprising the said vector.
Deak, Ast and Jahn teach as set forth above. In particular, Deak teaches monoclonal anti-PD1 antibody fused with cytokine (e.g. IL-2) through Fc domain. Deak also teaches specific modifications in Fc domains, such as mutation combination recited by instant claim 8, linker sequences, and polynucleotides encoding the fusion protein dimers, vectors comprising the said polynucleotides, or a host cell comprising the said vectors, or a pharmaceutical composition comprising pharmaceutically acceptable carrier. Ast teaches monoclonal antibody fused with cytokine (e.g. IL-2 or IL-12) through Fc domain. Ast also teaches specific modifications in Fc domains, such as mutation combination recited by instant claim 8, linker sequences and polynucleotides encoding the fusion protein dimers, vectors comprising the said polynucleotides, or a host cell comprising the said vectors, or a pharmaceutical composition comprising pharmaceutically acceptable carrier. Ast further teaches specific IL-12 sequence: SEQ ID NO: 4 which is identical to the sequence recited by the instant claim 15, as set forth above. Jahn teaches that IL-12 and IL-2 dual cytokine antibody fusion protein has superior power in activating T and NK cells.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make an antibody-cytokine fusion protein, as taught by the claims of Appl. 400, and to use full length monoclonal anti-PD-1 antibody comprising two heavy chains fused with IL-2 and IL-12 respectively, as taught by Deak, Ast and Jahn. One of ordinary skill in the art would have been motivated to expand the options of anti-PD1 antibodies (e.g. antibodies taught by Deak) for the fusion proteins and to use the IL-12 and IL-2 taught by Ast and Jahn in the fusion protein because the sequence has been used in antibody fusion and dual-cytokine fusion protein would have better activity in immunotherapy as taught by Jahn. Given that all the components are well known in the field and monoclonal antibody-cytokine Fc fusion are commonly used in the field, as evidenced by Deak, Ast and Jahn, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed inventions.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
For the Double Patenting rejection, applicant argues:
Applicant submits that as the result of extensive amendments of the claims, the nonstatutory obviousness type double patent rejections are not applicable to the amended claims. Should the Examiner disagree, Applicant respectfully requests that the nonstatutory double patenting rejections be held in abeyance until allowable subject matter is indicated in this application, upon which time Applicant can consider filing a terminal disclaimer, if necessary or suitable.
Applicant’s arguments and experimental data have been fully considered but they are only partially persuasive. In view of the claim amendments, the rejection over Pat. 11,970,537 is hereby withdrawn, because the instant claims are drawn to full-length anti-PD-1 antibody and the claims of Pat. 11, 970,537 are drawn to single-body antibodies.
However, the rejection over Appl. No. 18/881,400 is maintained with updated references in view of the claim amendments.
Conclusion
No claims are allowed.
All other rejections set forth in the previous Office Action of 08/19/2025 are hereby withdrawn in view of the claim amendments and applicant’s arguments.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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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.
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/CHENG LU/Examiner, Art Unit 1642
/PETER J REDDIG/Primary Examiner, Art Unit 1646