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 .
Application Status
The amended claims filed October 10, 2025 with the Response to the Non-Final Office Action, are acknowledged. Claims 11-12 are canceled. Claim 10 is amended.
Claims 10 and 13-18 are pending and under examination herein.
Terminal Disclaimer
The electronic terminal disclaimer filed on October 10, 2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration dates of U.S. Patent No. 11,207,349, U.S. Patent No. 11,439,665, U.S. Patent No. 11,633,430, U.S. Patent Application No. 17/721,647 (recently issued as U.S. Patent No. 12,448,432), U.S. Patent Application No. 17/911,524, and U.S. Patent Application No. 18/183,681, has been reviewed and is accepted. The terminal disclaimer has been recorded.
Objections to the Specification Withdrawn
All prior objections to the specification are withdrawn in view of Applicant's amendments thereto.
Claim Rejections Withdrawn
All prior rejections of claims 11-12 are rendered moot by the cancelation of the claims.
The rejections of claims 10 and 13-18 on the ground of non-statutory double patenting over U.S. Patent No. 11,207,349, U.S. Patent No. 11,439,665, and U.S. Patent No. 11,663,430 are withdrawn in view of the terminal disclaimer filed October 10, 2025.
The provisional rejections of claims 10 and 13-18 on the ground of non-statutory double patenting over U.S. Patent Application No. 17/721,647 (recently issued as U.S. Patent No. 12,448,432), U.S. Patent Application No. 17/911,524, and U.S. Patent Application No. 18/183,681 are withdrawn in view of the terminal disclaimer filed October 10, 2025.
MAINTAINED REJECTIONS
Claim Rejections - 35 USC § 103
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.
Claims 10 and 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 2017/0368098 A1; cited in PTO-892 mailed July 10, 2025) in view of Zah (Cancer Immunology Research (2016) 4(6): 498-508; cited in IDS) and Brannetti (US 2018/0125892 A1; cited in IDS). This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
Chen discloses a bispecific “CD19-OR-CD20” chimeric antigen receptor (CAR) construct that can detect CD19, CD20, or both (e.g., Abstract, page 1). Chen teaches that CD20 and CD19 are both pan-B-cell markers present on a majority of malignant B cells, and that an OR-gate CAR that triggers tumor killing provided that either CD20 or CD19 are present reduces the probability of antigen escape, addressing known issues with single-target anti-CD19 or anti-CD20 CAR T cells (¶ 0002-0005). The bispecific CAR taught by Chen comprises (from N-terminus to C-terminus): a signal sequence; an anti-CD20 scFv; a peptide linker; an anti-CD19 scFv; a spacer domain (e.g., a IgG4 hinge domain); a transmembrane domain (e.g., CD28); none, one or more cytoplasmic co-stimulatory signaling domain(s) (e.g., 4-1BB or CD28); and a CD3ζ cytoplasmic signaling domain (e.g., ¶ 0006, 0068; Figure 1). Relevant to claims 10 and 13,
Chen discloses that the anti-CD20 antibody ofatumumab (which comprises the VH and VL amino acid sequences set forth in instant SEQ ID NO: 3 and 4, respectively, as evidenced by pages 18-19 of the instant disclosure) may be converted into an scFv and used in the CAR of the invention (e.g., ¶ 0041);
Chen discloses that the anti-CD19 scFv comprised in the bispecific CAR of the invention is the FMC63 antibody (which comprises the VH and VL amino acid sequences set forth in instant SEQ ID NO: 6 and 5, respectively, as evidenced by pages 19-20 of the instant disclosure) (e.g., ¶ 0044);
Chen discloses that the transmembrane domain is a CD28 transmembrane domain comprising SEQ ID NO: 6, which shares 100% sequence identity to instant SEQ ID NO: 11 (e.g., page 7, ¶ 0069);
Chen discloses that the co-stimulatory signaling region is a 4-1BB signaling domain comprising SEQ ID NO: 8, which shares 100% sequence identity to instant SEQ ID NO: 12 (e.g., page 7, ¶ 0069); and
Chen discloses that the cytoplasmic signaling domain is a CD3ζ domain comprising SEQ ID NO: 9, which shares 100% sequence identity to instant SEQ ID NO: 14 (e.g., page 7, ¶ 0069).
Relevant to claims 16-17, Chen discloses T cells expressing the CAR of the invention (e.g., ¶ 0007-0011, 0050). Relevant to claim 18, Chen teaches compositions comprising therapeutic cytotoxic T lymphocytes (CTLs) modified to comprise a CAR of the invention (e.g., pages 5-6).In addition, Chen teaches that the bispecific CAR of the invention comprises an IgG4 hinge domain/spacer, comprising the amino acid sequence of SEQ ID NO: 5 (e.g., ¶ 0014-0015, 0038, 0068-0069), which shares 100% sequence identity to the hinge region set forth in instant SEQ ID NO: 9 (relevant to claim 14).
However, Chen does not expressly teach that the VL region is located N-terminally to the VH region of the anti-CD20 antigen-binding region of the bispecific CAR, and that the VH region is located N-terminally to the VL region of the anti-CD19 antigen-binding region of the bispecific CAR. Chen also does not teach a signal peptide comprising an amino acid sequence set forth in instant SEQ ID NO: 8.
Zah describes a bispecific CAR “CAR19-OR-CD20” capable of preventing antigen escape by performing true OR-gate signal computation (e.g., Abstract). The bispecific CAR construct comprises an anti-CD19 scFv derived from the FMC63 monoclonal antibody, an anti-CD20 scFv derived from Leu-16 monoclonal antibody, an IgG4-based extracellular spacer (i.e., hinge), a CD28 transmembrane domain, and cytoplasmic domains of 4-1BB and CD3ζ (page 499, Materials and Methods). Zah teaches that each CAR was constructed in the scFv #1 (VL-VH) – scFv #2 (VH-VL) orientation to minimize potential mispairing of VL and VH domains between the two scFvs (page 500; Figure 1), relevant to claims 10 and 15. The CARs were expressed in primary CD8+ human T cells (page 499).
Brannetti teaches CARs specific for CD20, comprising an anti-CD20 antigen-binding domain (e.g., scFv), a hinge region, a transmembrane domain, and an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain (e.g., Abstract; pages 1-3). Brannetti provides that the anti-CD20 antigen-binding domain comprises an scFv arranged in the orientation of VL-linker-VH or VH-linker-VL (e.g., ¶ 0018), further relevant to claim 10. Brannetti further teaches that the CAR constructs of the invention comprise a human sequence leader at the N-terminus, e.g., a human CD8α sequence, e.g., a 21-residue signal peptide comprising the amino acid sequence of SEQ ID NO: 1080 (e.g., ¶ 0273, 0600, 1221, 1367, e.g., pages 102-158), which shares 100% identity to the signal peptide comprising instant SEQ ID NO: 8, relevant to claim 14.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the anti-CD19/anti-CD20 CAR disclosed by Chen to arrive at a bispecific anti-CD20/anti-CD19 CAR comprising (from N-terminus to C-terminus):
A signal peptide (leader sequence) comprising SEQ ID NO: 8 (as taught by Brannetti),
An anti-CD20 antigen-binding domain comprising an scFv comprising a VL region comprising the amino acid sequence of instant SEQ ID NO: 4 and a VH region comprising the amino acid sequence of instant SEQ ID NO: 3, arranged in a VL-linker-VH orientation based on the teachings of Zah and Brannetti,
An anti-CD19 antigen-binding domain comprising an scFv comprising a VH region comprising instant SEQ ID NO: 6 and a VL region comprising the amino acid sequence of instant SEQ ID NO: 5, arranged in a VH-linker-VL orientation based on the teachings of Zah,
A hinge region comprising the amino acid sequence of instant SEQ ID NO: 9,
A transmembrane domain comprising the amino acid sequence of instant SEQ ID NO: 11,
A co-stimulatory signaling region comprising the amino acid sequence of instant SEQ ID NO: 12, and
A cytoplasmic signaling domain comprising the amino acid sequence of SEQ ID NO: 14.
The skilled artisan would have been motivated to do so because Chen and Zah teach that a bispecific CAR targeting both CD19 and CD20 would have a competitive advantage compared to CARs that target only CD20 or CD19 individually in mitigating the known issue of tumor (antigen) escape. One would have further been motivated to orient the anti-CD20 antigen-binding domain such that the VL region is N-terminal to the VH region, and the anti-CD19 antigen-binding domain such that the VH region is N-terminal to the VL region, since Zah teaches that this configuration minimizes potential mispairing of VL and VH domains between the two scFvs in a bispecific CAR. There would have been a reasonable expectation of success because the skilled artisan would have recognized there are a finite number of possible configurations of the VH/VL domains to choose from, and it would have been obvious to try orienting the VH and VL regions in either orientation, but furthermore, Zah teaches an advantage to the specific orientation recited in instant claim 15.
Further, regarding claim 14, one of ordinary skill in the art would have been motivated to, and had a reasonable expectation of success for, substituting the CD8α signal peptide taught by Brannetti in the bispecific anti-CD20/anti-CD19 CAR construct taught by Chen. This is because the signal peptide (leader sequence) would target the bispecific CAR construct to the cell membrane of the target cell. There would have been a reasonable expectation of success because the ordinary artisan would have recognized that both of the signal peptides (leader sequences) taught by Chen and Brannetti achieve the same functional purpose (e.g., targeting a CAR construct to the cell membrane) and are suitable for use in a CAR construct comprising an anti-CD20 antigen-binding domain.
Response to Arguments
Applicant's arguments filed October 10, 2025 have been fully considered but they are not persuasive.
Applicant argues that the cited references of Chen, Zah, and Brannetti, alone or in combination, fail to teach the bispecific anti-CD20/CD19 CAR as presently claimed. Applicant states that Chen fails to teach or suggest a bispecific CAR comprising an anti-CD20 antigen-binding domain and an anti-CD19 antigen-binding domain in the specified order required by the amended claims. Applicant states that Zah and Brannetti fail to cure this deficiency because neither teach the specific anti-CD20 and anti-CD19 antigen-binding region sequences required by the instant claims. Remarks at pages 7-8.
Applicant further asserts that their experimental data illustrate that the presently claimed bispecific anti-CD20/CD19 CAR construct has unexpectedly higher activity and specificity than bispecific CARs having the reversed anti-CD20 scFv-anti-CD19 scFv order or the reversed VL/VH order, as supported by Exhibit A (Declaration under 37 C.F.R. 1.132 by inventor Yihong Yao filed in U.S. Patent Application No. 16/877,069, now issued as U.S. Patent No. 11,207,349). Remarks at pages 7-10. Applicant submits that the bispecific CAR construct (“TN-OF-19”) showed approximately 28%, 30%, and 53% greater activity (i.e., induction of IFN-γ release) in A549-CD19-CD20 double positive cells and 9%, 21%, and 32% greater activity (i.e., induction of IFN-γ release) in Raji double positive cells relative to three other bispecific constructs having alternative VH/VL arrangements (Exhibit A, pages 15-17). Applicant submits that the remaining bispecific CAR constructs also showed higher non-specific activity in the absence of target antigen (e.g., “T cell only” or “A549” binding in Figure 4 of Exhibit A). Remarks at pages 7-9. Applicant further asserts that the instantly claimed bispecific CAR constructs show superior therapeutic efficacy (e.g., overall response rate and complete response rate) compared to Shah (Nature Medicine (2020) 26(6): 1569-1575; “Exhibit C” in the ‘069 1.132 Declaration) and Tong (Blood (2020) 136(14): 1632-1644; “Exhibit D” in the ‘069 1.132 Declaration). Remarks at pages 9-12.
First, 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). It is held that the combination of cited references together disclose (1) a bispecific anti-CD20/CD19 CAR having an anti-CD20 antigen-binding domain, anti-CD19 antigen-binding domain, transmembrane domain, costimulatory signaling domain, and cytoplasmic signaling domain which are identical in structure (amino acid sequence) as that set forth by Chen, and (2) a clear and specific motivation for arranging the structurally identical CAR construct in the order instantly claimed, based on the teachings set forth by Zah and Brannetti. Applicant's arguments appear to emphasize that the structural arrangement of the VH and VL in each of the antigen-binding domains confers the superior functional qualities of the instantly claimed CAR construct. However, one of ordinary skill in the art would have recognized that there are a finite number of ways in which the scFv antigen-binding domains of the anti-CD20 and anti-CD19 binding components can be structurally arranged in a bispecific CAR, and it is within the skill of someone in the relevant art to construct a CAR with these differing configurations and to subsequently determine their respective abilities to bind to CD19 and/or CD20 and effect anti-tumor activity through the process of routine optimization. Furthermore, Zah sets forth a clear motivation – namely, minimizing mispairing of the VL and VH domains between the two scFvs – for choosing the specific structural arrangement set forth in the instant claims. (It is noted that Tong, cited by Applicant, also notes that a VL-VH VH-VL configuration was adopted to “avoid the formation of an artificial scFv between the two scFv’s (page 1633), further suggesting this was a known problem in the art for which a solution already existed.)
With respect to Applicant's arguments regarding unexpected results, it is held that while the bispecific CAR construct having the instantly claimed configuration does appear to elicit higher in vitro activity (IFN-γ release), the instant claims only require the specific function of being capable of binding to CD19 and CD20, which is a function demonstrated by all of the tested CAR constructs. The claims do not require additional functional limitations. While the instantly claimed configuration does appear to have higher antigenic specificity as set forth by Applicant, this is not unexpected in view of Zah’s teaching that the instantly claimed configuration minimizes VH/VL mispairing. Minimizing VH/VL mispairing would be expected to increase specificity of the respective antigen-binding domains for CD19 and CD20 since the correct VH/VL pairings would be favored.
Further, regarding the ‘069 1.132 Declaration in Exhibit A used to support Applicant's position regarding the non-obviousness of the instantly claimed invention, Applicant is advised that MPEP § 716.02(e) states: “[a]n affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness” (emphasis added). It is first noted that Shah (Exhibit C in the 1.132 Declaration for the ‘069 application) was published on October 5, 2020, and that Tong (Exhibit D in the 1.132 Declaration for the ‘069 application) was pre-printed online on June 18, 2020, which are both later than the earliest priority date of the instant application (March 17, 2020). Accordingly, Shah and Tong cannot be considered prior art in the present case. Further regarding Shah, the bispecific anti-CD20/CD19 CAR construct disclosed by Shah, like that of Zah, comprises an anti-CD20 antigen-binding domain derived from Leu-16 antibody (VH-VL) and an anti-CD19 antigen-binding domain derived from FMC63 (VL-VH) (e.g., Extended Data Figure 1). However, Shah cannot be said to be “closer” art than Zah because the constructs disclosed by Zah are arranged in the specific VL-VH and VH-VL configuration set forth in the instant claims, whereas the construct disclosed by Shah is not. Further regarding Tong, Tong discloses eight tandem (tan)CAR constructs, including “tanCAR7”, which comprises an anti-CD20 scFv derived from Leu-16 (in a VL-VH orientation) situated N-terminally to an anti-CD19 scFv derived from FMC63 (in a VH-VL orientation) (e.g., Figure 1A), which Tong noted to have “dual antigen targeting of CD19 and CD20” and which “formed superior and stable immunological synapse (IS) structures, which may be related to their robust antitumor activity” relative to the remaining structures (Abstract; Results, page 1633). Tong also notes that the tandem CAR constructs were “constructed as “VHVL-VLVH or VLVH-VHVL to avoid the formation of an artificial scFv between the 2 scFv’s” (page 1633, Results), echoing the teachings of Zah. Because the tanCAR7 construct described by Tong and the instantly claimed construct both share a similar structural arrangement of the anti-CD20 and anti-CD19 antigen-binding domains, it is likely that any apparent differences in CD19/CD20 binding specificity and/or anti-tumor efficacy between the two constructs are explained by one or more factors other than the structural configuration of the anti-CD20 and anti-CD19 scFvs.
For these reasons, the rejection is maintained.
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.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643