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 3-124 are cancelled. Claims 1-2 and 125-145 as filed on 27 March 2026 are pending. Claims 137-138 and 142 are withdrawn. Claims 1-2, 125-136, 139-141, and 143-145 are under examination.
Rejections Maintained – Amended as Necessitated by Applicant Amendment of Claims
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 1-2, 125-135, 139-141, and 143-145 are rejected under 35 U.S.C. 103 as being unpatentable over June (WO 2013/126726 A1) (Of Record) and Baeuerle (WO 2016187349 A1) (Of Record).
Regarding claim 1, June teaches an invention comprising a TCR and a CAR wherein the TCR comprises a TCR alpha chain and a CAR (claim 1 and Figure 1). June teaches the CAR comprises an antigen binding domain, a transmembrane domain, an intracellular signaling domain (Figure 1 and claims 1-3 and 10). June teaches the TCR comprises a binding domain that binds a tumor antigen and further teaches where the TCR and CAR binding different antigens (claim 9). June teaches a method of stimulating T-cell mediated immune response against a cell population or tissue using the system (claim 23). June teaches a method of treating cancer using the system (claim 18). June further teaches the transmembrane domains that can be used as equivalent substitutes including applicant’s elected species of CD3 epsilon and as required by claim 126 (page 30 in lines 12-16). June teaches the CAR can comprise an anti-tumor antibodies, a CD8 transmembrane domain, a signaling domain of CD3 zeta and 4-1BB, as elected as applicant (page 33 in lines 3-7). June teaches the TCR binds a tumor antigen including CD19 (claim 5).
June teaches the use of the system including lymphoma, leukemia, and melanoma (page 12 in lines 3-10).
Regarding claims 2 and 125, June teaches the use of their system in the modulation of T cell activity (page 44 in lines 5-8). June teaches the domain of the CAR is responsible for activation of at least one of the normal effector functions of the immune cell in which the CAR has been placed in (page 30 in lines 28-30).
Regarding claims 130-131, June teaches the CAR can comprise an anti-tumor antibodies, a CD8 transmembrane domain, a signaling domain of CD3 zeta and 4-1BB, as elected as applicant (page 33 in lines 3-7).
Regarding claim 132, June teaches antibody includes scFv, Fab, and F(ab)2 (page 9 in lines 23-29, example 1, and claim 8).
Regarding claim 133, June teaches the TCR and CAR bind different antigens (page 2 in line 28).
Regarding claims 134-135, June teaches the TCR comprises a binder for the elected species CD19 (claim 5).
Regarding claims 139-141, June teaches its system as a double transgenic T cell (DTTC) (page 6 in lines 21-23) and further teaches the DTTCs are T cells including CD8+ T cells (Figures 1-3) including autologous lymphocytes (page 8 in lines 14-16).
June does not teach a modified TCR that comprises a second antigen binding domain that is covalently lined to the N-terminus of the epsilon, delta, or gamma chain of CD3.
This deficiency is filled by Baeuerle.
Regarding claims 1, 141, and 143, Baeuerle teaches a TFP which is a fusion polypeptide of an anti-CD19 scFv fused covalently to the CD3 epsilon domain as part of a reprogrammed TCR (Figure 1 pasted below). Baeuerle teaches the modified T cell comprising the TFP is a CD8+ or CD4+ T cell (claim 81).
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Regarding claim 144, Baeuerle teaches the binding domain is an scFv ([0020]).
Baeuerle teaches embodiments expressing two or more TFPs that binds different targets ([0225]-[0226]).
Baeuerle teaches the treatment of diseases using the TFP including leukemia (claims 104 and 106).
It would have been obvious at the time the application was filed to substitute the CD19 binding modified TCR of June that is in their system comprising a modified TCR and CAR with the CD19 binding modified TCR of Baeuerle. One of skill in the art would have been motivated to substitute the TCR of June with the modified TCR of Baeuerle as it would be the substitution of a CD19 binding TCR for use in treatment in leukemia with an improved TCR that binds CD19 also used in the treatment of leukemia. There would have been a reasonable expectation of success as both June and Baeuerle teach modified T cells comprising multiple binding domains.
Regarding claim 145, this biological activity would inherently come from the binding activity of the elements of claim 1. By teaching the elements of claim 1 the increased cytotoxicity would be present.
Applicant Arguments
Applicant argues June teaches a conventional TCR and does not teach the required elements of the modified TCR of the claims.
Applicant argues there is no motivation to substitute the TCR of June with the TCR of Baeuerle as June does not describe their conventional TCR is insufficient.
Applicant argues June does not disclose a CD19 binding TCR and only provides a laundry list of antigens TCR can bind in claim 5 with no indication to choose CD19.
Applicant argues Baeuerle teaches away from combining with a CAR based on "Described herein are novel fusion proteins that more efficiently kill target cells than CARs, but release comparable or lower levels of pro-inflammatory cytokines. These fusion proteins and methods of their use represent an advantage for TFPs relative to CARs because elevated levels of these cytokines have been associated with dose-limiting toxicities for adoptive CAR-T therapies" ([0004]). Applicant argues “Baeuerle shows the TFPs are better than CAR, and a person skilled in the art has no motivation to combine CAR with the fusion proteins to introduce the shortcomings of CARs mentioned by Baeuerle.”
Applicant argues there is no expectation of success as one of skill in the art would not expect a TCR to maintain activity with alterations to its secondary structure, subunits, and physical components.
Applicant argues Baeuerle never compared its TFP with June’s conventional TCR and there is no indication that Baeuerle’s TFP is superior to June’s. Applicant argues there is no reasonable expectation of success.
Applicant argues unexpected results and points to Figures 12-17 and in particular Figure 12A and Figure 17. Applicant argues Example 6 shows improved effectiveness of treating cancer with their modified TCR/CAR compared to either component alone or the TCR/TCR combination.
Example 6 is to an anti-BCMA sdAb fused to an epsilon-TCR, Example 6 in Figure 8 shows changing the sdAb binding BCMA had different effectiveness in the modified epsilon-TCR. Example 6 appears to only show a single CD19 epsilon TCR. Figure 12a appears to use a single CD19 binding domain. Figure 12a compares a BCMA binding epsilon TCR, a BCMA binding CAR, a CD19 binding epsilon TCR, a CD19 binding CAR, and a combinations of the BCMA epsilon TCR with the CD19 binding CAR or the CD19 binding epsilon TCR with the BCMA binding CAR. Figure 12 appears to use one CD19 binding domain and one BCMA binding domain. Figure 12a shows different effectiveness between BCMA epsilon TCR with the CD19 binding CAR and the CD19 binding epsilon TCR with the BCMA binding CAR. The varying effectiveness of the TCR/CAR of the applicant is supported by Figure 14. Figure 17 shows anti-BCMA2 and anti-BCMA3 in a tandem where one TCR is an epsilon and another is a gamma TCR. Figure 17 compares an epsilon-TCR/gamma-TCR that binds BCMA with a gamma-TCR/CAR where the TCR and CAR both bind BCMA. Figure 16 appears to show difference in effectiveness when combining a CAR comprising sdAb BCMA3 with sdAb BCMA2 TCR where the CD3 domain is varied. These are all shown to be more effective than BCMA2 epsilon TCR alone, but this could be due to variation between epsilon, gamma, and delta domains of the TCR or the combination with the BCMA3 comprising CAR.
varying the TCR CD3 domain with anti-BCMA2 has varying effectiveness. These
Applicant argues new claim 145 requiring biological activity is not obvious over June and Baeuerle.
Response to Arguments
Applicant's arguments filed 27 March 2026 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).
June is relied upon to teach a modified immune cell with the combination of a cancer antigen binding TCR and a cancer antigen binding CAR. June specifically teaches the TCRs of their invention include artificial TCRs (Figure 1 description).
June teaches in claim 5 multiple known in the art antigen targets for treating cancer. All listed antigens, including CD19, would be equally obvious for one of skill in the art developing a method of treating cancer or specifically lymphoma. The antigens remain obvious without unexpected results.
Baeuerle teaches the improvement of engineered T cells and that their novel fusions have the potential to overcome limitations of existing approaches ([0004]). One of skill in the art would know that existing approaches includes conventional TCRs which applicant has identified the invention of June using in their combination of a TCR with a CAR.
Baeuerle is not relied upon to teach the combination of a modified TCR with a CAR. June teaches the combination of a cancer antigen binding TCR with a cancer antigen binding CAR in a modified immune cell.
The Applicant has shown unexpected results in Example 6 in Figures 8, 12A, and 17. But these unexpected results are not commensurate with the scope of the claims. Applicant has shown the effectiveness varies with the single domain antibody even when binding the same target, BCMA, had varying results. Applicant has only shown TCR epsilon and TCR gamma in their modified TCR. The claims as written allow for an epsilon, delta, or gamma chain TCR that binds any antigen with a CAR that binds any antigen. Applicant has shown combinations of the BCMA epsilon TCR with the CD19 binding CAR or the CD19 binding epsilon TCR with the BCMA binding CAR as more effective then the TCR epsilon or CAR alone. Applicant has shown CAR comprising sdAb BCMA3 with BCMA2 as epsilon, gamma, or delta, TCR (Figure 16). Applicant has not shown the effectiveness of any antigen binding domain in the CAR or any antigen binding domain in the modified TCR of their invention. Applicant has not shown the effectiveness of the disclosed antigen binding domains of BCMA2 and anti-CD19 with any combination or sub-combinations of TCR domains or with any CAR.
Claims 1 and 136 are rejected under 35 U.S.C. 103 as being unpatentable over June (WO 2013/126726 A1) (Of Record) and Baeuerle (WO 2016187349 A1) (Of Record) as applied to claims 1-2, 125-135, 139-141, and 143-144 above, and further in view of Fan (US 10934363 B2) (Of Record).
The teachings of June and Baeuerle from the previous art rejection are incorporated here in full.
June and Baeuerle as previously shown teach the system of claim 1 comprising a CAR binding a cancer antigens one of which is BCMA and a modified TCR that binds CD19.
June and Baeuerle do not teach the anti-BCMA sdAbs and anti-CD19 VHH sequences of claim 136.
This deficiency is filled by Fan.
Regarding claim 136, Fan teaches an anti-BCMA single-domain antibody SEQ ID NO: 83 which matches instant SEQ ID NO: 10 (col 33 in lines 65-67 and col 34 in lines 1-2). Fan teaches
Fan teaches an anti-CD19 VHH of SEQ ID NO: 76 which matches instant SEQ ID NO: 38 (col 74 in lines 49-51). Fan further teaches the elected intracellular signaling domain of CD3 epsilon (col 110 in lines 4-5 and lines 26-30), the elected G4S linker (col 107 in lines 34-48), the transmembrane domain of CD8, intracellular domains of 4-1BB, and CD3 zeta (col 108 in lines 37-59 in particular lines 41).
Fan further teaches the combination of anti-CD19 and anti-BCMA in the same engineered immune effector cells (col 118 in lines 16-65). Fan teaches the use of these combination in the treatment of cancer (col 136 in section VI).
Fan teaches SEQ ID NO: 76 with SEQ ID NO: 83 in Embodiment 67 (col 159).
Fan teaches the use of the invention in a pharmaceutical composition for treating leukemia, lymphoma, and solid cancers (col 7 in lines 28-53 and col 137 in lines 25-28).
It would have been obvious to one of ordinary skill in the art at the time the application was filed to substitute the generic anti-cancer antigens within the system taught by June and Baeuerle with the specific cancer antigen binding antibodies taught by Fan. June, Baeuerle, and Fan teach dual binding engineered T cells for use in the treatment of leukemia and lymphoma. The components of CARs and TCRs were well known in the art as shown by June, Baeuerle, and Fan teaching the same components including the transmembrane domains and intracellular signaling domains in their engineered T cells. One of ordinary skill in the art would have been motivated to explore the system of June and Baeuerle with known antigen-binding molecules such as the ones taught by Fan. Fan teaches anti-BCMA and anti-CD19 antigen-binding antibodies, teaches they can be used in combination, and teaches they are useful in therapeutic compositions. There would have been a reasonable expectation of success as June and Fan are both teaching engineered T cells capable of binding more than one antigen for the treatment of the same patient populations.
Applicant Arguments
Applicant argues Fan does not rescue the defects in the rejection over June and Baeuerle.
Response to Arguments
Applicant's arguments filed 27 March 2026 have been fully considered but they are not persuasive.
The rejection over June and Baeuerle is maintained and there are then no defects to rescue.
Conclusion
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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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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