DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claim listing filed on September 10, 2025 is pending. Claims 1-50, 57, 61, and 65 are canceled. Claims 51-52, 56, 58, 60, and 62-64 are amended. Claims 66-70 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions or species. Claims 51-56, 58-60, and 62-64 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements filed on 09/10/2025 and 09/25/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 57, 61, and 65 have rendered all previous rejections directed to these claims moot.
The objection to the sequence compliance in the drawings is withdrawn in view of Applicant’s amendments to the drawings and Applicant’s remarks filed 09/10/2025 indicating that the SEQ ID NOs are listed in the Brief Description of the Drawings. Note, when a range of SEQ ID NOs are listed (such as SEQ ID NOs: 19-30 in Figs. 3A-3G description), it is interpreted that the SEQ ID NOs are correlated with the figures in order of appearance (wherein Fig. 3A is SEQ ID NO: 19, Fig. 3B is SEQ ID NO: 20, etc).
The objections to the specification are withdrawn in view of Applicant’s amendments.
The rejection of Claims 51-56, 58-60, and 62-64 under 35 U.S.C. 112(b) as being indefinite are withdrawn in view of Applicant’s amendments.
Claim Objections (New, necessitated by amendment)
Claim 58 is objected to because of the following informalities: “wherein the a β2M” should recite “wherein the β2M.” Appropriate correction is required.
Claim Rejections - 35 USC § 112 (Maintained)
The rejection of Claims 51-56, 58-60, and 62-63 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is maintained. The 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. Note, the rejection of record was directed to Claim 62 and now applies to Claims 51-56, 58-60, and 62-63 due to Applicant’s amendments.
Amended Claim 51 is directed to a TMMP comprising “a polypeptide specific for an epitope that is present in a cancer-associated antigen, wherein the polypeptide is an antibody fragment.” Therefore, Claim 51 encompasses a genus of possible antibodies without providing appropriate CDR structures, and Claims 52-56, 58-60, and 62-63 depend from Claim 51 without further defining the antibody fragments.
In order to provide adequate written description and evidence of possession of the claimed genus of antibody fragments, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. It is of record that describing antibodies by the antigen to which they bind is not adequate written description (Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017)), and it
Is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. In the instant claims, no CDR structures are provided for the genus of antibody fragments that are specific for any epitope that is present in any cancer-associated antigen.
Applicant's arguments filed September 10, 2025 have been fully considered but they are not persuasive.
Applicant argues that the Amgen case law is not applicable to the instant claims because Amgen was directed to novel antibodies and the instant claims are directed to TMMPs that comprise an antibody fragment. Regardless if the antibody is claimed on its own or as part of a fusion protein, appropriate written description of the antibody structure is necessary to demonstrate that the inventor was in possession of the invention (MPEP § 2163.I. and § 2163.II.A.3.).
Applicant argues that antibody fragments specific to cancer antigens were well-known to those of skill in the art and described throughout the published literature, and the written description requirement does not require an Applicant to fill its specification with information already known to skilled artisans. As currently claimed, the genus of possible antibody fragments is broader than what can be supported by the state of the art prior to filing. There are over a thousand characterized cancer antigens, and each antigen comprises many possible epitopes. For each epitope, multiple different antibody CDR structures can specifically bind the epitope. Therefore, the genus broadly claims millions of possible antibody fragments – more than can be understood from the art prior to the time of filing. The genus of antibody fragments is not described sufficiently to reasonably convey to one skilled in the art that the inventor had possession of the claimed invention at the time of filing, and the rejection is maintained.
Claims 51-56, 58-60, and 62-63 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for antibody fragments that specifically bind to Her2, CD19, WT1, MUC1, BCMA, mesothelin, or claudin as recited in Claim 64 and those known in the art prior to the time of filing, does not reasonably provide enablement for antibody fragments specific for any epitope that is present on any cancer-associated antigen. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. Note, the rejection of record was directed to Claim 62 and now applies to Claims 51-56, 58-60, and 62-63 due to Applicant’s amendments.
Claim 51 encompasses a genus of possible antibodies without providing appropriate CDR structures, and Claims 52-56, 58-60, and 62-63 depend from Claim 51 without further defining the antibody fragments. The specification teaches cancer-associated antigen-targeted antibodies known in the art prior to filing (paragraph [00248]) and specific heavy and light chain sequences for antibodies targeting Her2, CD19, MUC16, MUC1, BCMA, mesothelin, or claudin (paragraphs [00251]-[00305]). Therefore, enablement is provided for these antibody fragments, but the claimed genus of antibody fragments is significantly broader than those taught in the specification and known in the art (encompassing antibody fragments specific for any epitope in any cancer-associated antigen).
As of record in the non-final filed 03/19/2025, in AMGEN INC. ET AL. v. SANOFI ET AL. (No. 21-757, decided May 18, 2023), scientists understand that changing even one amino acid in the sequence can alter an antibody' s structure and function. See id., at 14. But scientists cannot always accurately predict exactly how trading one amino acid for another will affect an antibody' s structure and function. Ibid.” Given that structure is essential to function, and given the unpredictability within the art with respect to creating antibodies, a person having ordinary skill in the art would have to perform further experimentation in order to make the variants encompassed by the claims (TMMPs comprising any antibody fragment specific for any epitope in any cancer-associated antigen) and use them to evaluate the T-cell modulatory activity, commensurate in scope with the breadth of the claims. Given the nature of the invention, a skilled artisan would have to make multiple variants of TMMPs with different antibody fragments that are essentially identical (except that the variants have one or more changes in a CDR(s)), validate their function as null variants according to the specification, then use them in order to demonstrate successful T-cell modulatory effect against the appropriate targets with a reasonable expectation of success. This amount of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the method for the breadth of what is claimed.
Applicant's arguments filed September 10, 2025 have been fully considered but they are not persuasive.
Applicant argues that the Amgen case law is not applicable to the instant claims because Amgen was directed to novel antibodies and the instant claims are directed to TMMPs that comprise an antibody fragment. Regardless if the antibody is claimed on its own or as part of a fusion protein, one of ordinary skill would have to screen millions of antibody fragments in order to determine whether the structure meets the functional limitations claimed which constitutes unreasonable experimentation and lack of enablement (MPEP § 2164.06).
Applicant argues that antibody fragments specific to cancer antigens were well-known to those of skill in the art and described throughout the published literature. While the disclosure is enabled for antibody fragments that specifically bind to Her2, CD19, WT1, MUC1, BCMA, mesothelin, or claudin as recited in Claim 64 and those known in the art prior to the time of filing, the genus of antibody fragments claimed is significantly broader. There are over a thousand characterized cancer antigens, and each antigen comprises many possible epitopes. For each epitope, multiple different antibody CDR structures can specifically bind the epitope. Therefore, the genus broadly claims millions of possible antibody fragments – more than can be understood from the specification or the art prior to the time of filing. Applicant’s arguments are not persuasive and the rejections are maintained.
Claim Rejections - 35 USC § 103 (New, necessitated by amendment)
Claims 51-55 are rejected under 35 U.S.C. 103 as being unpatentable over Seidel WO 2015/195531 (of record), and further in view of Georges US 2015/0344586 (of record). Note, the rejection of record is maintained and new sections of the cited references are relied upon to address Applicant’s amendments.
Seidel teaches a heterodimeric multimeric polypeptide comprising (a) a first polypeptide comprising (in order from N-terminus to C-terminus) (i) an epitope and (ii) a first MHC polypeptide and (b) a second polypeptide comprising (in order from N-terminus to C-terminus) (i) an immunomodulatory domain, (ii) a second MHC polypeptide, and (iii) an Ig Fc polypeptide (paragraph [0034]). The first MHC polypeptide is a β2M polypeptide, and the second MHC polypeptide is an MHC class I heavy chain polypeptide (paragraph [0034]). The multimeric proteins modulate T cell function (paragraphs [0013]-[0015]). Each component of each polypeptide is connected via a linker (paragraph [0010]), and the two polypeptides are connected via at least one disulfide bond (paragraph [0017]). The epitope can be between 7-20 amino acids (paragraph [0021]) and can be a viral epitope (paragraph [00327]). The Ig Fc domain can be an IgG1 Fe domain (paragraph [0021]). Two of the multimeric peptides can be joined via one or more disulfide bonds between the respective lg Fc domains (paragraph [0018]). The immunomodulatory domain can be a cytokine (paragraph [00140]). Alternatively, the immunomodulatory domain can be a scFv specific for co-stimulatory polypeptides expressed on the surface of an epitope-specific T cell (paragraph [00141]). The multimeric polypeptide can comprise one or more immunomodulatory domains wherein the domains are at the C-terminus of the first polypeptide, the N-terminus of the second polypeptide, or the C-terminus of the second polypeptide (paragraph [0035]).
Seidel fails to teach wherein the second polypeptide comprises a cancer-targeting polypeptide (Claim 51) and wherein the IgG1 Fc polypeptide comprises the amino acid substitutions L234A and L235A (Claim 54).
Georges teaches a disulfide-linked multivalent protein comprising two or more antigen presenting domains, one Fc-region, and one antigen binding site wherein the antigen presenting domain comprises a β2M polypeptide and a class I MHC molecule and wherein the antigen binding site binds to a cancer cell surface antigen (abstract). The multivalent protein is used to modulate T cell function (paragraph [0003]), and can be used specifically to eliminate cancer cells (paragraph [0358]). The Fc-region is an IgG1 Fc domain that comprises substitutions L234A and L235A (paragraph [0138]). Georges further teaches wherein the cancer-targeting polypeptide is an antibody or antibody fragment (paragraph [0045]) that binds to a cancer cell surface antigen (paragraph [0038]) such as melanoma-associated chondroitin sulfate proteoglycan (MCSP) (paragraph [0245]).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to combine prior art elements according to known methods to yield predictable results. It would have been obvious to alter the multimeric protein taught by Seidel to comprise the cancer-targeting polypeptide and IgG1 L234A and L235A substitutions as taught by Georges. Georges teaches linking a cancer antigen binding site to a T-cell modulatory protein to specifically target cancer cells. Georges further teaches that the L234A and L235A substitutions preferably decrease binding between the IgG1 Fc domain and the Fcγ receptor (paragraph [0421]). Therefore, it would have been obvious to improve upon the multimeric protein taught by Seidel to make alterations taught by Georges that decrease off-target binding by the Fc domain and increase on-target (cancer cell) binding with a reasonable expectation of success.
Applicant's arguments filed September 10, 2025 have been fully considered but they are not persuasive.
Applicant argues that in Georges, the antibody component is (i) always C-terminal to both the MHC class I heavy chain polypeptide and the β2M, and (ii) always on the same polypeptide chain as the β2M. In contrast, Applicant argues that the antibody fragments presently claimed are always N-terminal to the MHC class I heavy chain polypeptide, and never on the same polypeptide chain with the β2M. Examiner maintains that it would be obvious to add a cancer-antigen targeting antibody fragment as taught by Georges to the multimeric polypeptide taught by Seidel. Seidel teaches that the multimeric polypeptide can comprise multiple immunomodulatory domains that can comprise a cytokine or an scFv targeting co-stimulatory proteins that can be located at the C-terminus of the first polypeptide, the N-terminus of the second polypeptide, or the C-terminus of the second polypeptide (paragraph [0035]). One of ordinary skill would have understood that an scFv targeting co-stimulatory proteins could be substituted with an scFv targeting cancer-antigens for targeted delivery as taught in Georges. If the IL-2 immunomodulatory domain is positioned at the C-terminus of the second polypeptide, that leaves two possible positions to place a cancer-antigen targeting scFv, either at the C-terminus of the first polypeptide or the N-terminus of the second polypeptide (ie at the two available ends that do not block the epitope on the first polypeptide or the IL-2 on the second polypeptide). With only two possible positions to place the cancer-antigen targeting scFv, it is obvious to try placing it at the N-terminus of the second polypeptide with a reasonable expectation of success (MPEP § 2143.I.E). Therefore, the order of the domains on the first and second polypeptides is not a patentably distinct feature in view of the prior art.
Claims 51-56, 58-60, and 62-63 are rejected under 35 U.S.C. 103 as being unpatentable over Seidel WO 2015/195531 (of record) in view of Georges US 2015/0344586 (of record) as applied to Claims 51-55 above, and further in view of Gillies US 7,186,804 (of record) and Butz WO 2016/164937 (of record).
The rejection of record is maintained and new sections of the cited references are relied upon to address Applicant’s amendments. Specifically in regard to Claim 58, Seidel teaches the amino acid sequence of β2M comprises SEQ ID NO: 78 (paragraph [0063]) and the amino acid sequence of MHC class I heavy chain comprises SEQ ID NO: 5 (paragraphs [00218]-[00219]) wherein SEQ ID NOs: 78 and 5 are 100% identical to instant SEQ ID NOs: 31 and 53 respectively. All other components of the 103 rejection are on record in the non-final office action filed 03/19/2025.
Applicant's arguments filed September 10, 2025 have been fully considered but they are not persuasive. Applicant argues that Gillies and Butz do not remedy the deficiencies of Seidel and Georges which are addressed in the rejection above.
Claim Rejections - 35 USC § 103 (Maintained)
The rejection of Claims 51-56, 58-60, and 62-64 under 35 U.S.C. 103 as being unpatentable over Seidel WO 2015/195531 (of record) and Georges US 2015/0344586 (of record) in view of Gillies US 7,186,804 (of record) and Butz WO 2016/164937 (of record) as applied to Claims 51-56, 58-60, and 62-63 above, and further in view of Hedley et al. Hum Pathol. 2014 (of record) is maintained.
Applicant's arguments filed September 10, 2025 have been fully considered but they are not persuasive. Applicant argues that Hedley does not remedy the deficiencies of Seidel and Georges which are addressed in the rejection above.
Double Patenting
1. The provisional rejection of Claims 51-52, 55-57, 61, 63, and 65 on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending U.S. App. No. 18/950,811 (of record) is maintained.
2. The provisional rejection of Claims 51-63 and 65 on ground of nonstatutory double patenting as being unpatentable over claims 1-13, 16-18, 21-28, and 30 of copending U.S. App. No. 18/201,911 (of record) is maintained.
Applicant's arguments filed September 10, 2025 have been fully considered but they are not persuasive. Applicant argues that the USPTO recently determined that ODP rejections based on later-filed applications or patents issuing therefrom are improper by citing Baurin. Applicant argues that because the copending applications have later filing dates than the instant application, any claim issuing from the present application will expire before the expiration of the copending claims. As such, Applicant argues that the copending applications are not permissible ODP references. MPEP § 804.I.B.1(b)(i) states “If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent” (emphasis added). In Baurin, it appears as though the nonstatutory double patenting rejections were the only rejections remaining of record. As the instant application still has outstanding rejections of record, the provisional nonstatutory double patenting rejections are maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675