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 .
Claims 1, 3-5, 11-12, 14, 18-19, 23-24, 49, 54, 63-64, 72, and 75, of record 7/2/2026, are pending and subject to prosecution. Claims 1 and 75 are amended. Claims 26-27 are cancelled.
Declaration under 37 CFR 1.132
A declaration under 37 CFR 1.132 was submitted on 7/2/2026 by Dr. Puig-Saus. The declaration asserts that one of ordinary skill in the art could not have predicted in vivo antitumor activity from an anti-TYRP-1 CAR comprising a long spacer, based upon the data available at the time (Declaration, page 2). The references used in the rejections of record do not describe any functional anti-TYRP-1 CARs (Declaration, page 3). The sole reference that had actually constructed and tested an anti-TYRP-1 CAR (Kokalaki) showed only moderate in vitro and no in vivo efficacy, unlike the claimed construct (Declaration, page 2-3).
The declaration is insufficient to overcome the rejections of record. As an initial matter, independent claim 1 does not require the claimed chimeric polypeptide to possess in vivo antitumor activity, only the enumerated structural components. Further, the “reasonable expectation of success” required for a finding of obviousness refers to the likelihood of success in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See MPEP 2143.02(I). No arguments against the physical combination of the CAR of Mujasic et al. and the scFv of Balderes et al. have been presented.
Regarding the assertion that an anti-TYRP-1 CAR with in vivo efficacy had not been taught, conclusive proof of efficacy is not required to show a reasonable expectation of success. See MPEP 2143.02(I). The teachings of Kokalaki are not relied upon in the pending rejections of record. However, Kokalaki demonstrated that 1) a CAR comprising an antigen-binding scFv derived from an anti-TYRP-1 antibody can be constructed, and that 2) the CAR is able to exhibit specific cytotoxicity against TYRP-1-expressing cells in assays. While Kokalaki found that CAR-expressing cells had no significant antitumor activity, Smith et al., using a CAR with an antigen-binding domain derived from the same TA99 antibody as Kokalaki, demonstrated in mice modest, yet significant, antitumoral responses that synergized with STING agonists (See fig. 10). Given the state of the art at the time of the effective filing date of the claimed invention, one of ordinary skill could therefore reasonably assume that an anti-TYRP-1 CAR-T cell with in vivo efficacy could be achievable with at least some degree of predictability, as required by MPEP 2143.02(II).
Status of Prior Rejections
RE: Rejection of claims 1, 3-5, 11-12, 14, 18-19, 23-24, 26-27, 49, 54, 63-64, and 72 under 35 U.S.C. 103 over Mujacic et al. (WO 2019113557 A1) in view of Balderes et al. (US 7951370 B2):
The cancellation of claims 26-27 renders the rejection thereto moot.
The amendment to claim 1 is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claims 1, 3-5, 11-12, 14, 18-19, 23-24, 26-27, 49, 54, 63-64, 72, and 75 under 35 U.S.C. 103 over Mujacic et al. (WO 2019113557 A1) in view of Balderes et al. (US 7951370 B2), further in view of Forman et al. (US 20160333108 A1):
The cancellation of claims 26-27 renders the rejection thereto moot.
The applicant asserts that combination of the cited references would not have been “obvious to try”, based on the failure of Kokalaki to generate an anti-TYRP-1 CAR, not would there be any reasonable expectation of success in doing so (Applicant Remarks, page 6-8). The applicant again alleges unexpected results (Applicant Remarks, page 9-10).
The applicant’s arguments have been fully considered but are not found persuasive. The arguments raised in Dr. Puig-Saus’s declaration are addressed above.
The rationale underpinning the combination of the teachings of Mujasic et al. and Balderes et al. in the rejection of record is “teaching, suggestion, or motivation”, not “obvious to try” as alleged by the applicant. Mujasic et al. teach that the CAR can target TYRP-1 and that the antigen-binding domain can be an antibody or antibody fragment such as an scFv comprising VH and VL regions joined by a linker (See ¶0060, 0271, 0646, 0650-0651, 0662, and 0783). Balderes et al. teach antibody sequences that exemplify TYRP-1 binding and antitumor activity (See col. 2, line 43-58; col. 21, lines 7-50; and table 4-6). Sufficient motivation therefore exists for combining the prior art teachings to yield a CAR for targeting TYRP-1 that also reads on the claimed invention.
Regarding the assertion of unexpected results, the scope of the instant claims remain broader than the purported evidence. Evidence of nonobviousness must be fully commensurate with the scope of the claims the evidence of offered to support. See MPEP 716.02(d). The examples of the specification use CARs having linkers of differing lengths (the most efficacious being SEQ ID NO 16) but the same antigen-binding domain (comprising SEQ ID NOs 5 and 10). Such evidence does not support a CAR comprising the sequences of, or sequences at least 90% identical to, SEQ ID NOs 5, 10, and 16. Further, given that CARs had been shown to be able to target many different cancer antigens, that TYRP-targeting antibodies and fragments thereof were known, and that linkers meeting the claimed limitation could generate efficacious CAR-T cells, the applicant’s evidence is not wholly surprising, particularly as Smith et al. had previously demonstrated that anti-TYRP-1 CAR-T cells could have antitumor effects in vivo. Expected beneficial results are evidence of obviousness. See MPEP 716.02(c)(II).
The rejection is maintained in modified form to address amended limitations.
Maintained Rejections
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.
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, 3-5, 11-12, 14, 18-19, 23-24, 49, 54, 63-64, 72, and 75 remain rejected under 35 U.S.C. 103 as being unpatentable over Mujacic et al. (WO 2019113557 A1), of record, in view of Balderes et al. (US 7951370 B2), of record, further in view of Forman et al. (US 20160333108 A1), of record.
Regarding claims 1, 3, 49, 54, 64, and 75: Mujacic et al. teach methods for producing a population of T cells expressing a recombinant receptor, such as a CAR (which reads on “a chimeric polypeptide”) (See ¶0007, 0014, 0060, and 0089). Cells can be treated or contacted with a nucleic acid that encodes the receptor (See ¶0161, 0325, and 0330). The CAR can comprise an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain (See ¶0060-0062). Mujacic et al. teach that the CAR can comprise a IgG4 hinge, an IgG4 hinge linked to CH2 and CH3 domains, or an IgG4 hinge linked to a CH3 domain and that that the hinge region (which reads on “extracellular spacer”) can be about 10-229 amino acids in length (which reads on “a length of at least 120 amino acids” and “between 200 and 300 amino acids in length”) (See ¶0684-0685). The antigen-binding domain can be an antibody or antibody fragment such as an scFv comprising VH and VL regions joined by a linker (See ¶0060, 0271, 0646, and 0662). The antigen binding domain can target TYRP-1 (See ¶0650-0651 and 0783). Mujacic et al. do not teach the antigen-binding domain as comprising specific sequences for targeting TYRP-1 or the CAR as comprising a spacer having the sequence of instant SEQ ID NO 16.
Balderes et al. teach human antibodies specific for TYRP-1 (See Abstract). Balderes et al. teach a monoclonal antibody having a light chain comprising the sequence of instant SEQ ID NO 5 (See col. 3, lines 27-30; SEQ ID NO 32; and alignment below). The sequence taught by Balderes et al. also encompasses instant SEQ ID NOs 6 (RASQSVSSYLA), 7 (DASNRAT), and 8 (QQRSNWLMYT) (See col. 2, lines 43-58 and alignment below).
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Balderes et al. teach the monoclonal antibody as having a heavy chain comprising the sequence of instant SEQ ID NO 10 (See col. 3, lines 27-30; SEQ ID NO 30; and alignment below). The sequence also encompasses instant SEQ ID NOs 11 (GYTFTSYAMN), 12 (WINTNTGNPTYAQGFTG), and 13 (RYSSSWYLDY) (See col. 2, lines 43-58 and alignment below).
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Forman et al. teach a CAR spacer derived from a modified IgG4 Fc region triple mutated to comprise S228P, L235E and N297Q mutations (See ¶0050-0052, SEQ ID NO 19, and alignment below (first 120 aa displayed)) which is identical to the sequence of instant SEQ ID NO 16 (which reads on “comprising the amino acid sequence of SEQ ID NO: 16, or a sequence at least 90% identical to SEQ ID NO: 16” and “consists of SEQ ID NO: 16”).
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It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the CAR of Mujacic et al. to comprise the sequences taught by Balderes et al. for targeting TYRP-1-expressing tumor cells. One would be motivated to make this modification because Balderes et al. teach these sequences as exemplary sequences for binding TYRP-1 and activity against TYRP-1-expressing tumors, as exhibited by construct 20D7S (See col. 2, line 43-58; col. 21, line 47-50; and table 4-6). There would be a reasonable expectation of success in doing so because the CAR of Mujacic et al. could be readily engineered to comprise the sequences taught by Balderes et al.
It also would have been obvious to modify the CAR of Mujacic et al. to substitute the spacer taught by Forman et al. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results. See MPEP 2143(I)(B).
Regarding claims 4-5: Following the discussion of claims 1, 3, 49, 54, 64, and 75, Mujacic et al. teach that the linker between VH and VL regions can be between about 5-50 amino acids in length (See ¶0662). An exemplary linker comprises 2-5 repeats of GGGGS (which reads on “a Whitlow linker, (G4S)n… wherein n is 1, 2, 3, 4, 5, or 6”) (See ¶0662). Where the claimed ranges overlap or lie inside ranges disclosed by the prior art, a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding claims 11-12: Following the discussion of claims 1, 3, 49, 54, 64, and 75, Mujacic et al. teach that the transmembrane domain of the CAR can be derived from a TCR alpha or beta chain, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154 (See ¶0690).
Regarding claims 14 and 18-19: Following the discussion of claims 1, 3, 49, 54, 64, and 75, Mujacic et al. teach that the CAR can comprise a primary signaling sequence derived from CD3zeta and a signaling region and/or transmembrane portion of a costimulatory receptor such as CD28, 4-1BB, OX40, and ICOS (See ¶0696-0697).
Regarding claims 23-24: Following the discussion of claims 1, 3, 49, 54, 64, and 75, Mujacic et al. teach embodiments wherein the VH region is amino-terminal to the VL region and wherein the VH region is carboxy-terminal to the VL region (See ¶0653).
Regarding claims 63 and 72: Following the discussion of claims 1, 3, 49, 54, 64, and 75, Mujacic et al. teach that a therapeutically effective amount of cells expressing the CAR can be formulated with a pharmaceutically acceptable excipient for administration to a subject (See ¶0055, 0102, 0463, 0469). The cells can be administered for treating a subject with a disease such as cancer (See ¶0538-0539, 0778, and 0788).
Conclusion
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 JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M Babic, can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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