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 .
Status of Application/Amendments/Claims
Applicant’s response filed on 5/12/2026 has been considered. Claims 1, 6, 9 and 27 are amended. Claims 51-57 are newly added. Claims 1-7, 9-10, 15, 19-20, 27 and 51-57 are pending and are the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 63/014,382 and 371 of PCT/US2021/028437 filed on 4/23/2020 and 4/21/2021, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 4/23/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/12/2026 was received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement was considered by the examiner.
Declaration
The declaration submitted on 5/12/2026 by Dr. Valentina Hoyos was received and fully considered. The declaration describes that the chimeric receptors of the instant invention lack CD3zeta purposely because otherwise the immune cells that express them would activate upon binding to a wide variety of normal cells that express the TRAIL-R2 antigen. CD3zeta acts as a primary intracellular signaling domain and is responsible for initiating T-cell activation upon antigen recognition. The declaration argues that this would be to toxic to a recipient, with reference to exhibit 2.
Withdrawn Claim Rejections
The 35 U.S.C. 102(a)(1) and 102(a)(2) rejection of claims 1-3, 6-7, 9-10, 15, 19, 22, 24 and 27 over Zhang has been withdrawn in light of applicants claim amendments which specify that the polynucleotide encodes a chimeric protein and a CAR or TCR.
The 35 U.S.C. 103 rejection of claims 1-7, 9-10, 15, 19-20, 22, 24 and 27 over Zhang in view of Murad has been withdrawn in light of applicants claim amendments to independent claim 1.
Response to Applicants Arguments
Applicant traverses the previous rejection by arguing that Zhang fails to anticipate the presently claimed invention because it fails to teach the use of a CAR or TCR in addition to the DR5-targeting CAR. Applicant argues that the DR5-targeting CAR lacks CD3zeta and the construct described by Zhang only has one receptor while the presently claimed invention requires a TRAIL-R2 chimeric receptor plus a separate CAR in the same cell.
With respect to Zhang failing to teach a DR5-targeting CAR lacks CD3zeta, it is noted that teaching away requires the prior art to criticize, discredit, or otherwise discourage the claimed solution, see MPEP § 2141.02(VI): “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed.” Since the prior art clearly does not do this, this argument is unconvincing. Nonpreferred and alternative embodiments constitute prior art. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure, see MPEP 2123.
With respect to Zhang failing to teach a TRAIL-R2 chimeric receptor plus a separate CAR in the same cell, it is noted that a new 103 rejection has been applied to cover these newly added limitations.
New 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 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.
Claims 1-3, 6-7, 9-10, 15, 19, 27 and 51-57 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. CN 109957020, Machine Translation, published 7/2/2019 (hereinafter Zhang, cited in applicants IDS) in view of Jensen, US 2015/0038684, published 2/5/2015 (hereinafter Jensen). This rejection is newly applied to address applicants claim amendments filed on 5/12/2026.
Claim 1: Zhang describes an engineered CAR T cell that specifically targets and kills malignant tumor cells that express TRAIL-R2, also known as Death Receptor 5 (DR5), on their surface while minimizing harm to normal cells which express low levels of DR5 (Zhang, para 4, 36). Zhang discloses a single-chain antibody (scFv) that binds to DR5 which is incorporated into the extracellular region of the CAR protein which is expressed on the surface of the T cell (Zhang, para 11-15). Zhang provides alternative embodiments, stating that “the intracellular signaling region includes a combination of one or more of the 4-1BB singling region, CD3zeta signaling region, ICOS signaling region, CD27 signaling region, OX40 signaling region, CD28 signaling region, IL1R1 signaling region, CD70 signaling region and TNFRSF19L signaling region” with preferred embodiments to a CD28 intracellular signal region (Zhang, para 24 and 27). Although CD3zeta is mentioned in the list of alternative embodiments, it is emphasized that alternative embodiments do not constitute a teaching away from a broader disclosure, see MPEP 2123. Zhang provides a preferred embodiment to a CD28 signaling region as a co-stimulatory signal to provide enhanced killing activity of the engineered T cells (Zhang, para 32-35). Zhang does not describe a bispecific CAR, in which the expression construct encodes for a TRAIL-R2 CAR and a CAR or TCR as described in newly amended claim 1.
Claims 2-3: Zhang discloses a single-chain monoclonal antibody (scFv) that binds to DR5 which is incorporated into the extracellular region of the CAR protein which is expressed on the surface of the T cell (Zhang, para 11-15).
Claims 6-7 and 9-10: Zhang discloses an intracellular signaling region which may include a combination of one or more of the 4-1BB singling region, ICOS signaling region, CD27 signaling region, OX40 signaling region, CD28 signaling region, IL1R1 signaling region, CD70 signaling region and TNFRSF19L signaling region (Zhang, para 24). Zhang describes a CD8 transmembrane domain (Zhang, para 83). Zhang describes a scFv that binds to DR5 and a intracellular region that comprises a costimulatory domain from 4-1BB (Zhang, para 11, 25).
Claims 15, 19 and 27: Zhang discloses an engineered CAR T cell that expresses the CAR targeting DR5. As explained by Zhang, DR5 is widely expressed in various solid tumor cells such as liver cancer but is expressed as a weak cell surface antigen in ordinary cells (Zhang, para 4).
Claim 1: Jensen describes a bispecific chimeric antigen receptor and therapeutic uses thereof (Jensen, abstract). Jensen specifically lists TRAIL-R2 among other antigens specific for cancer that may be targeted by the expressed CARs (Jense, para 73 and claim 16). Jensen describes predictable methods for expressing the bispecific CAR constructs using viral transduction (Jensen, para 116). Jensen describes the advantages of a bispecific CAR in providing enhanced specificity and preventing antigen escape (Jensen, para 26, 72-75).
Claims 51-57: Jensen describes T cells that express an intrinsic cytokine signaling mechanism which have the ability to improve survival, persistence and in vivo engraftment (Jensen, example 9). Jensen specifically describes the use of IL-15 for generating the chimeric cytokine receptors (Jensen, example 9 and para 101).
It would have been prima facie obvious to one of ordinary skill in the art to further express a secondary CAR and/or an IL-15 chimeric cytokine receptor as described in the bispecific CAR methods of Jenson along with the DR5 targeting CAR described by Zhang. It would have been a matter of combining prior art elements according to known methods to yield predictable results following the bispecific CAR expression methods outline by Jensen. One would have been motivated to make this combination in order to provide enhanced specificity and prevent antigen escape by further expressing a secondary CAR in with the DR5 targeting CAR described by Zhang. One of ordinary skill would select an IL-15 chimeric cytokine receptor in particular given its ability to improve survival, persistence and in vivo engraftment (Jensen, example 9). One would have a reasonable expectation of success given that Jensen describes predictable methods for expressing the bispecific CAR constructs using viral transduction (Jensen, para 116). Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 1-3, 6-7, 9-10, 15, 19, 27 and 51-57 to have been prima facie obvious to at the time the invention was made.
Claims 1-7, 9-10, 15, 19, 20, 27 and 51-57 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (supra) and Jensen (supra) as applied to claims 1-3, 6-7, 9-10, 15, 19, 27 and 51-57 above in further view of Murad et al. "Advances in the use of natural receptor-or ligand-based chimeric antigen receptors (CARs) in haematologic malignancies." Best Practice & Research Clinical Haematology 31.2 (2018): 176-183 (hereinafter Murad, reference of record). This rejection is newly applied to address applicants claim amendments filed on 5/12/2026.
A description of Zhang and Jensen can be found above with respect to claims 1-3, 6-7, 9-10, 15, 19, 22, 24 and 27.
Claims 4-5: Zhang does not describe the TRAIL-R2 (DR5) binding agent as a ligand or TRAIL ligand. Instead of using the TRAIL ligand as the targeting mechanism, Zhang focuses on using a scFc as the DR5 binding component to achieve specificity. However, Zhang mentions that TRAIL is the naturally occurring ligand that binds to DR5 (Zhang, para 4).
Claim 20: Zhang describes isolating antigen-specific T lymphocytes by immunomagnetic bead method, wherein CD3-possitive T lymphocytes were isolated and transfected with the DR5 specific CAR. Although it is admitted that Zhang does not expressly state that the cells are 𝛼𝛽 T cells, the vast majority of CD3 positive T cells would be 𝛼𝛽 T cells which express the 𝛼𝛽 T cell receptor (TCR) along with the CD3 complex. Furthermore, the genus of T cell subtypes is sufficiently small that 𝛼𝛽 T cells would be considered immediately envisagable. A generic disclosure will anticipate a claimed species covered by that disclosure when the species can be “at once envisaged” from the disclosure, such is the case presently, see MPEP § 2131.02.
Claim 20: Furthermore, Jensen describes the use of “any one or more of T-lymphocytes” which are capable of giving rise to therapeutically relevant progeny (Jensen, para 118 and 124).
Claims 4-5: Murad describes the use of ligand-based CARs as an alternative to scFv derived CAR T cell therapy (Murad, abstract and Fig 1). Murad offers several advantages that ligand-based CARs have over scFv derived CAR T cells including reduced immunogenicity, structural stability and broad targeting (Murad, pg 177). Murad also discloses predictable methods for generating ligand-based CARs (Murad, pg 179).
It would have been prima facie obvious to one of ordinary skill in the art to use a TRAIL ligand-based CAR as described by Murad rather than the scFv derived CAR in the extracellular region of the chimeric protein. It would have been a matter of simple substitution of one known extracellular targeting domain for another with predictable results given the methods disclosed by Murad. One would have been motivated to make this substitution given that ligand-based CARs often exhibit reduced immunogenicity, structural stability and broad targeting when compared to scFv derived CAR T cells (Murad, pg 177). One would have a reasonable expectation of success given that Zhang discloses that TRAIL is the naturally occurring ligand that binds to DR5 (Zhang, para 4) and that there are predictable methods for generating ligand-based CARs (Murad, pg 179). Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the invention to have been prima facie obvious to at the time the invention was made.
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, 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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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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