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 .
Election/Restrictions
Applicant’s election of a CAR comprising an scFv of SEQ ID NO: 64 that binds TNF-alpha, a CD28 transmembrane domain of SEQ ID NO: 10, and a CD3 zeta intracellular domain of SEQ ID NO: 8 in the reply filed on 08/21/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Status
Claims 5, 7-10, 12-21, 23-37, 39-41, 43-53, 55-56, 58, 60-61, 63-64, 67-73, 75, 77-80, 82-96, and 98-103 are cancelled. Claims 1-3, 6, 11, 22, 38, 42, 54, 57, 59, 62, 65-66, 74, 76, 81, 97, and 104-106 as filed on 21 August 2026 are pending and are under examination.
Claim Objections
Claim 66 is objected to because of the following informalities: claim contains a list using periods. Claims should not contain internal periods, see MPEP 608.01(m). Periods can be replaced with a parenthesis or other non-period punctuation. Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 6, 11, 22, and 104 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hsu (US20190119407A1) (PTO-892), as evidenced by Sadelain et. al. Cancer Discov 3(4):388-398 (2013) (PTO-892).
Regarding claims 1-3, 6, and 104, Hsu teaches antigen binding domains comprising scFvs that bind TNFα (abstract). Hsu teaches scFv that matches applicant’s elected species of instant SEQ ID NO: 64 in SEQ ID NO: 355, 367, and 391. Hsu teaches antigen binding domains include chimeric antigen receptors (CAR) ([0058]). By teaching a CAR Hsu inherently teaches a receptor comprising an extracellular domain that binds a target, a transmembrane domain, and an intracellular domain, as evidenced by Sadelain (abstract and Figure 1).
Regarding claims 11 and 22, instant SEQ ID NO: 64 comprises instant SEQ ID NO: 65 and 66 and SEQ ID NO: 75, 77, 79, 67, 70, and 73 of subpart a of claims 11 and 22, respectively. Hsu by teaching instant SEQ ID NO: 64 teaches the CDRs of claims 11 and 22.
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 1-3, 6, 38, 57, 59, 62, 65-66, 74, 76, 81, 97, and 104-106 are rejected under 35 U.S.C. 103 as being unpatentable over Hsu (US20190119407A1) (PTO-892), Sadelain et. al. Cancer Discov 3(4):388-398 (2013) (PTO-892), and Frost (US 20170296678 A1) (PTO-892), as evidenced by Boroughs et. al. JCI Insight. 4(8):1-19. 2019. (PTO-892) and Rudensky et. al. Mnireview. 126(2):253-256. (2006) (PTO-892).
Regarding claims 1-3, 6, and 104, Hsu teaches antigen binding domains comprising scFvs that bind TNFα (abstract). Hsu teaches scFv that matches applicant’s elected species of instant SEQ ID NO: 64 in SEQ ID NO: 355, 367, and 391. Hsu teaches antigen binding domains include chimeric antigen receptors (CAR) ([0058]).
Regarding claim 97, Hsu teaches the use of the antigen binding domains of the invention in the inhibition of proinflammatory cytokines and treatment of GVHD ([0301]-[0302].
Hsu does not teach specific hinge, transmembrane domain, or intracellular domains of the antigen binding CAR. Hsu does not teach an engineered Treg cell comprising the CAR.
These deficiencies are filled by Sadelain and Frost.
Regarding claims 38 and 57, Sadelain teaches CAR T cells have varying components based on generation and intended function including CD28 transmembrane domain and intracellular domains of CD28 or 4-1BB, and CD3 zeta and teaches these components work with varying scFvs that target different antigens depending on disease being treated (Figure 1 and Tables 1).
Regarding claims 59 and 62, Sadelain teaches transduction of T cells using vectors that comprise polynucleotides that encode the CAR (page 395 in col 1 in par 2).
Regarding claim 76, Sadelain teaches improving CAR safety by limiting or preventing off-target effects and cytokines storms by including a suicide gene that can be used to eliminate CAR to prevent excessive response. Sadelain teaches the sue of Herpes simplex virus thymidine kinase and inducible caspase-9 as clinically tested systems (page 394 in col 2 in final paragraph).
Regarding claim 81, Sadelain teaches modified immune cells comprising CARs include Treg cells (page 395 in col 2 in lines 1-8).
Regarding claim 106, Frost teaches a CD28 transmembrane domain of SEQ ID NO: 50 and 76 which matches instant SEQ ID NO: 10 and teaches they are transmembrane domains that allow for the insertion of polypeptides into the cell membrane of eukaryotic cells ([0314]). Frost teaches the CD3 zeta intracellular domain for use in polypeptides including CARs of SEQ ID NO: 13 which matches instant SEQ ID NO: 8 ([0321]).
Frost teaches a method of transducing varying T cells, including Treg cells ([0236]), to express CARs with varying scFvs that bind varying targets for use in the treatment of disease (abstract, [0268]).
Regarding claims 65-66 and 74, Treg cells encode and express the immunosuppressive molecules IL-10 and TGFß (page 7 in par 2, and page 11 in par 2). A modified CAR Treg cell that comprises a CD28 stimulatory domain produces higher amounts of IL-10 in response to CAR stimulation, as evidenced by Boroughs (page 6 in par 2, page 7 in par 2, and page 11 in par 2). Frost by teaching a CAR Treg cell comprising a CD28 stimulatory domain ([0362] and [0537]) teaches a CAR Treg which expresses one or more immunosuppressive molecules when the modified T cell is activated as required by claim 65. The modified CAR Treg of Frost would comprise a first polynucleotide encoding the CAR and a second polynucleotide encoding the one or more immunosuppressive molecules as Frost teaches the Treg cells are modified by transduction with a vector encoding the CAR (abstract, [0268]) and the CAR Treg would comprise a polynucleotide sequence in its genomic DNA. Further, the Treg genome comprises a promoter comprising one or more NFAT binding sites as required by claim 66, as evidenced by Rudensky (page 255 in col 1 in lines 14-19 and Figure 1). A modified CAR Treg comprising a CD28 stimulatory domain of Frost would inherently comprise a second polynucleotide that encodes a promoter comprising one or more binding sites for NFAT and one or more immunosuppressive molecules including IL-10 and TGFß as required by claims 66 and 74.
It would have been obvious at the time the application was filed to combine the generic TNFα binding CAR of Hsu with the CD28 transmembrane domain, CD3 zeta intracellular domain, and Treg cells taught by Sadelain and Frost to produce the applicant elected CAR T comprising instant SEQ ID NO: 64, instant SEQ ID NO: 10, and instant SEQ ID NO: 8 into transduced Treg cells for use in treating GVHD. First, it would have been prima facie obvious to substitute the generic components of the CAR of Hsu with known functional species of these components taught by Sadelain and Frost. Second, one of skill in the art would have been motivated by the teachings of Sadelain and Frost of known in the art functional transmembrane and intracellular signaling domains and regulatory components for use in the generic CAR of Hsu. There would have been a reasonable expectation of success as Sadelain and Frost teach the CAR domains can be used with varying scFvs in varying diseases.
Claims 1, 42, and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Hsu (US20190119407A1) (PTO-892) and Martin et. al. Cytotherapy. 23(2):131-136. (2021) (PTO-892).
The teachings of Hsu from the previous rejections under 35 U.S.C. 102 and 103 are incorporated here in full.
Regarding claim 1, Hsu teaches antigen binding domains comprising scFvs that bind TNFα (abstract). Hsu teaches scFv that matches applicant’s elected species of instant SEQ ID NO: 64 in SEQ ID NO: 355, 367, and 391. Hsu teaches antigen binding domains include chimeric antigen receptors (CAR) ([0058]).
Hsu teaches the use of the antigen binding domains of the invention in the inhibition of proinflammatory cytokines and treatment of GVHD ([0301]-[0302].
Hsu does not teach a CAR cell encoding of the transcription factor FOXP3 or a self-cleavage site.
This deficiency is filled by Martin.
Regarding claims 42 and 54, Martin teaches a vector encoding a CAR comprising an antigen binding domain, a CD8α hinge, a CD28 transmembrane domain, a CD28 stimulatory domain, a CD3 zeta stimulatory domain, a T2A self-cleavage site, and the transcription factor FOXP3 (Figure 1). Martin teaches genetically modifying Treg cells that comprise a CAR and the FOXP3 transcription factor (abstract and Figure 1). Martin teaches the modified T-cells secreted IL-10 and in a GVHD model outperformed polyclonal Tregs by reducing liver and lung inflammation (abstract and Figures 2-3). Martin teaches the FOXP3 expression produces a stable regulatory phenotype independent from endogenous FOXP3 of the Treg cells (page 131 in col 2 in par 2 in lines 4-9 and page 132 in col 1 in line 1).
It would have been obvious at the time the application was filed to combine the generic CAR of Hsu with the CAR T cell comprising the specific components of a CD8α hinge, a CD28 transmembrane domain, a CD28 stimulatory domain, a CD3 zeta stimulatory domain, a T2A self-cleavage site, and the transcription factor FOXP3 taught by Martin to produce a fully defined CAR T cell for use in the treatment of GVHD. One of skill in the art would have been motivated by the Hsu and Martin both teaching the treatment of GVHD with CAR T cells and Martin teaching the production of a stable regulatory phenotype for the CAR Treg cells for use in treatment of GVHD. There would have been a reasonable expectation of success as Sadelain and Martin both teach the use of their CAR T cells in the treatment of GVHD.
Conclusion
No claims allowable.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
