IMMUNE RECEPTORS WITH SYNTHETIC CO-STIMULATORY DOMAINS

§102 §103 §112

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 and/or Claims The amendment of 07 July 2026 has been entered in full. Claims 7 and 18 are amended. Claims 2, 4, 9-11, 14-17, and 19-22 are cancelled. Claims 1, 3, 5-8, 12, 13, 18, and 23-28 are pending. Election/Restrictions Applicant's election with traverse of YLVV as the species of PLCγ1-binding motif and Px(Q/E)xT (e.g., PVQTT) as the species of consensus sequence motif in the reply filed on 07 July 2026 is acknowledged. The traversal is on the ground(s) that the examiner has not established that the present invention lacks unity. Applicant’s detailed arguments at the middle of page 5 of the Response of 07 July 2026 are found to be persuasive and the species election requirements are withdrawn. All species of PLCγ1-binding motif and consensus sequence motif will be examined. Claims 1, 3, 5-8, 12, 13, 18, and 23-28 are under consideration in the instant application. Nucleotide and/or Amino Acid Sequence Disclosures After consideration of the Applicant’s arguments at pages 5-6 of the Response of 07 July 2026, the sequence listing issues raised bv the Examiner at the top of page 4 in the Restriction Election of 18 May 2026 are withdrawn. It is also noted to Applicant that the Examiner did not request an incorporation by reference statement. The Examiner only indicated that such statement would have been required if a new sequence listing sequence had been submitted (see page 4, section 1b, 5th bullet of the Restriction Election of 18 May 2026). Information Disclosure Statement The information disclosure statement (IDS) submitted on 28 July 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Specification 1. The disclosure is objected to because of the following informalities: 1a. The text in Table 1 at page 14 of the specification is blurry, making the words and amino acid sequences difficult to read. In addition, it is hard to tell the difference between “E”, “F”, “P” and “I”, “T” in the underlined core motif regions of the amino acid sequences. Appropriate correction is required. Claim Objections 2. Claim 1, 3, 6, and 18 are objected to because of the following informalities: 2a. Claims 1, 3, and 18 recite the acronyms “TRAF” and “PLCγ1” without first defining what they represent. While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym and/or in each independent claim. 2b. In claim 6, line 1, after the word “wherein”, the term “the” is missing and should be inserted. Appropriate correction is required. Claim Rejections - 35 USC § 112(b) The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. 3. Claims 1, 3, 5-8, 12, 13, 18, 23-28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. 3a. Claims 1, 3, 5-8, 12, 13, 18, 23-28 are rejected as being indefinite because claim 1, subpart (a) recites the phrase “an extracellular binding domain that binds to a protein on the surface of another cell”. However, the preamble of claim 1 recites “an engineered immune receptor”. Therefore, it is not clear what “cell” and consequently “another cell” subpart (a) is referring to. Please note that this issue could be overcome by amending claim 1, subpart (a) to recite “an extracellular binding domain that binds to a protein on the surface of a cell”. 3b. Claims 1, 5-8, 12, 13, 18, 23-28 are rejected as being indefinite because claim 1, subpart (c) recites the phrase “a co-stimulatory domain that comprises one or more TRAF protein binding motifs and one or more PLCγ1-binding motifs of the consensus sequence (Y)[AFILVWY]X[AFILVWY], wherein x is any amino acid”. It is not clear what the domain/motif the consensus sequence is referring to. For example, is it referencing the co-stimulatory domain, TRAF protein binding motif, or the PLCγ1 binding motif? Please note that this issue could be overcome by amending claim 1 to recite, for example, “a co-stimulatory domain that comprises one or more TRAF protein binding motifs and one or more PLCγ1-binding motifs, wherein the one or more PLCγ1-binding motifs comprises [of] the consensus sequence (Y)[AFILVWY]X[AFILVWY], wherein x is any amino acid”. Claim Rejections - 35 USC § 102 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 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)(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. 4. Claims 1, 3, 5-8, 12, 18, and 23-28 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Daniyan et al. (WO 2021/158850 or US 2023/0051064, priority to 05 February 2020). It is noted that WO 2021/158850 and US 2023/0051064 have the same disclosure. Thus, for brevity, relevant portions of WO 2021/158850 will be cited below. Daniyan et al. teach a chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain comprising at least one co-stimulatory signaling domain that comprises a CD28 polypeptide comprising a mutated YMNM motif, meeting the limitations of instant claim 1 (page 2, lines 2-7). Daniyan et al. disclose that the intracellular signaling domain of the CAR comprises a first co-stimulatory signaling domain that comprises a CD28 polypeptide comprising a mutated YMNM motif and a secondary co-stimulatory signaling domain that comprises an intracellular domain of a co-stimulatory molecule, meeting the limitations of instant claim 1 (page 34, lines 29-32). Daniyan et al. indicate that the co-stimulatory molecule is selected from the group that includes 4-1BB, OX40, ICOS, CD30, HVEM, meeting the limitations of instant claims 1 and 7 (page 34, lines 32-34). Daniyan et al. continue to teach that the second co-stimulatory domain comprises a 4-1BB polypeptide, wherein the 4-1BB polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 50 (reproduced below): 1 MGNSCYNIVA TLLLVLNFER TRSLQDPCSN CPAGTFCDNN RNQICSPCPP NSFSSAGGQR 61 TCDICRQCKG VFRTRKECSS TSNAECDCTP GFHCLGAGCS MCEQDCKQGQ ELTKKGCKDC 121 CFGTFNDQKR GICRPWTNCS LDGKSVLVNG TKERDVVCGP SPADLSPGAS SVTPPAPARE 181 PGHSPQIISF FLALTSTALL FLLFFLTLRF SVVKRGRKKL LYIFKQPFMR PVQTTQEEDG 241 CSCRFPEEEE GGCEL [SEQ ID NO: 50] It is noted that the 4-1BB amino acid sequence of SEQ ID NO: 50 of Daniyan et al. comprises one or more TRAF protein binding motifs (Px(Q/E)E (PEEE) and Px(Q/E)xT (PVQTT)), meeting the limitations of instant claim 18 (see bolded and underlined motifs in sequence above). Furthermore, regarding the CAR comprising at least one co-stimulatory signaling domain that comprises a CD28 polypeptide comprising a mutated YMNM motif, Daniyan et al. disclose that the mutated YMNM motif is YLIP or YLRV (page 3, lines 14-15; page 33, line 30). These sequences are 100% identical to the motifs of instant SEQ ID NOs: 3 and 4, respectively, and thus meet the limitations of instant claim 3. Daniyan et al. indicate that CAR T cells that comprise mutated YMNM motifs show enhanced tumor control in vivo (outperforming standard CD28-based T cells), as well as enhanced proliferation in vitro (pages 60-62). Daniyan et al. teach that the CAR’s intracellular signaling domain may comprise a CD3ξ polypeptide, which activates a cell (such as a T cell), meeting the limitations of instant claim 5 (page 29, lines 1-9). Daniyan et al. state that CD3ξ comprises ITAMs, meeting the limitations of instant claims 6 and 12 (page 29, lines 1-9). Daniyan et al. teach that the extracellular antigen-binding domain of the CAR comprises a scFv, meeting the limitations of instant claim 8 (page 13, lines 17-25; page 20, lines 33-34 through page 25). Daniyan et al. disclose a nucleic acid sequence encoding a CAR as described, as well as a lymphoid cell (T cell, B cell, or natural killer cell) comprising the nucleic acid, meeting the limitations of instant claims 23-26 (page 5, lines 21-33 through page 6, lines 1-5; page 13, lines 26-29; pages 41-42; page 45, lines 4-30). Daniyan et al. also state that the cell utilized may be a myeloid cell (page 41, liens 13-14; page 42, 4th full paragraph). Lastly, Daniyan et al. teach methods of inducing and/or increasing an immune response in a subject, for reducing tumor burden in a subject, and for treating a pathogen infection in a subject comprising administering cells comprising the disclosed CAR, meeting the limitations of instant claims 27-28 (page 42, lines 27-33 through page 43, lines 1-7; pages 54-57). 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. 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. 5. Claims 1, 3, 5-8, 12, 13, 18, and 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over Daniyan et al. (WO 2021/158850 or US 2023/0051064, priority to 05 February 2020) and Kloss et al. Nature Biotechnol 31(1): 71-76, 2013). The teachings of Daniyan et al. are set forth above. Daniyan et al. do not teach that the receptor is a chimeric costimulatory receptor (CCR) and that the receptor does not contain a T cell activation domain. Kloss et al. teach a strategy to render T cells specific for a tumor in the absence of a truly-tumor-restricted antigen (abstract; page 71, column 1, 2nd paragraph). Kloss et al. teach a dual-target approach wherein T cells are transduced with both a CAR that provides suboptimal activation upon binding of one antigen and a chimeric costimulatory receptor (CCR) that recognizes a second antigen (abstract; page 71, column 1, 2nd paragraph through column 2). Kloss et al. disclose that the generation of a CCR specific for PMSA, wherein a scFv is fused to extracellular, transmembrane, and signaling domains of CD28, which was then fused to a 4-1BB cytosolic signaling domain [and no CD3ξ] (Figure 3; supplemental Figure 1 and description). Kloss et al. indicate that co-transduced T cells destroy tumors that express both antigens, but do not affect tumors expressing either antigen alone (abstract). It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the CAR comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain comprising (i) a first co-stimulatory signaling domain that comprises a CD28 polypeptide comprising a mutated YMNM motif, (ii) a secondary co-stimulatory signaling domain that comprises an intracellular domain of co-stimulatory molecule 4-1BB, and (iii) a CD3ξ polypeptide as taught by Daniyan et al. by removing the CD3ξ polypeptide from the intracellular domain to generate a chimeric costimulatory receptor as taught by Kloss et al. The person of ordinary skill in the art would have been motivated to make that modification to generate a construct for combinatorial costimulatory antigen targeting with a different CAR molecule, wherein cancer cell targeting can be increased and reactivity against healthy tissues expressing either antigen alone can be reduced (see Kloss et al., page 74, 2nd and 3rd full paragraphs). One skilled in the art also would have been motivated to make that modification in order to broaden the applicability and avoid some of the side effects of targeted T-cell therapies (Kloss et al., abstract). The person of ordinary skill in the art reasonably would have expected success because similar constructs were already being performed at the time the invention was made (see Kloss et al.). Additionally, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Therefore, the claimed invention as a whole was clearly prima facie obvious over the prior art. Conclusion No claims are allowable. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Boucher et al. Cancer Immunol Res 9: 62-74, 2021 (published online 12 November 2020; teach “FMNM” mutation in CD28 costimultory domain (page 63, column 1, last paragraph) Guedan et al. Mol Ther 26. no. 5 (Suppl 1): 299, #650, 2018 (teach that replacement of the YMNM CD28 motif for the YMFM ICOS motif within the CAR could improve the persistence of CD28-costimulated CAR-T cells) Sadelain et al. Cancer Discovery 3(4): 388-398, 2013 (discuss coexpression of CCRs (pages 392-393; page 395, last paragraph)) Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIDGET E BUNNER whose telephone number is (571)272-0881. The examiner can normally be reached Monday-Friday 9:00 am-6:00 pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. BEB Art Unit 1647 01 October 2026 /BRIDGET E BUNNER/Primary Examiner, Art Unit 1647