CTNF 18/420,525 CTNF 82301 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. 1. Claims 254-277 as amended on June 28, 2024 are pending and under consideration. Specification 2. The use of the term nanobody, which is a trade name or a mark used in commerce (see NANOBODY (Ser. No. 85573029, Reg. Date Dec. 13, 2016)), has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Claim Rejections - 35 USC § 112 07-30-02 AIA 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. 07-34-01 3. Claims 261, 266, and 272 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. 07-35-01 Regarding claim 261, it contains the trademark/trade name nanobody (see NANOBODY (Ser. No. 85573029, Reg. Date Dec. 13, 2016)). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph. See Ex parte Simpson , 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a single domain antibody (see De Vlieger et al. (Antibodies 2019; 8(1):1. https://doi.org/10.3390/antib8010001, abstract in particular)), accordingly, the identification/description is indefinite. Regarding claims 266 and 272, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 266 and 272 recite the broad recitations ILT and LMIR, and the claim also recites CD85 and CD300, respectively, which are the narrower statement of the limitations, respectively. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Additionally, neither the specification nor the claims define the terms ILT or LMIR. Thus, the scope of these terms is undefined and indefinite. Section 2171 of the M.P.E.P. states Two separate requirements are set forth in 35 U.S.C. 112(b) and pre-AIA 35 U.S.C. 112, second paragraph, namely that: (A) the claims must set forth the subject matter that the inventor or a joint inventor regards as the invention; and (B) the claims must particularly point out and distinctly define the metes and bounds of the subject matter to be protected by the patent grant. The first requirement is a subjective one because it is dependent on what the inventor or a joint inventor for a patent regards as his or her invention. Note that although pre-AIA 35 U.S.C. 112, second paragraph, uses the phrase "which applicant regards as his invention," pre-AIA 37 CFR 1.41(a) provides that a patent is applied for in the name or names of the actual inventor or inventors. The second requirement is an objective one because it is not dependent on the views of applicant or any particular individual, but is evaluated in the context of whether the claim is definite — i.e., whether the scope of the claim is clear to a hypothetical person possessing the ordinary level of skill in the pertinent art. In the instant case of ILT or LMIR, one of skill in the art could find representative examples in the art which have been defined in such terms, however, it is unclear at what point one of skill in the art would be infringing on the claims without limitations as to the metes and bounds of ILT or LMIR. Additionally, the claims contain both “or” and “and/or”, thus it is unclear which term is limiting and if the claims are in the alternative or a combination. Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 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. 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-12-aia AIA (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. 07-15-03-aia AIA 4. Claim (s) 254-263, 265, 266, 271, 272, and 275-277 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2015/0307623 (Abbot et al. Oct. 29 2015, effectively filed Dec. 20, 2012, IDS), “Abbot” evidenced by Pieper et al. (J Allergy Clin. Immunology March 8, 2013, 131: 959-71, IDS), “Pieper” . It is noted that although the preamble of the claim 256 is drawn to a nucleic acid comprising a sequence encoding an inhibitory killer cell immunoglobulin-like receptor chimeric antigen receptor (inhKIR-CAR), the body of the claim does not require the CAR to contain inhKIR domains and some dependent claims (e.g., claims 263 and 265) specifically exclude such domains. Thus, the inhKIR-CAR is not limited to containing inhKIR domains. Abbot teaches chimeric antigen receptors, able to direct an immune cell, e.g., a T lymphocyte to a target antigen, and able to cause the T cell to proliferate or to kill cells displaying the antigen when the antigen binds to the polypeptide, wherein the polypeptides comprise a transmembrane domain from a T cell co-inhibitory protein such as CTLA4 or PD-1 that normally transmits an inhibitory signal. See abstract and ¶¶ [0006-0008] and claims 1-80. Regarding the nucleic acids of claims 254-258, Abbot teaches nucleic acid vectors for producing the CARs of the invention. Abbot teaches nucleic acids useful in the production of the first and second polypeptides, e.g., within a modified T lymphocyte, include DNA, RNA, or nucleic acid analogs. See ¶¶ 0138-0139. Regarding claim 257, the nucleic acids when expressed in T lymphocytes would produce mRNA that would then would be translated into proteins. See ¶¶ 0074 and 0080 and Fig. 1 and Fig. 7. Regarding claims 258 and 259, Abbot teaches that the extracellular domain of the CAR can comprise an antibody or an antigen-binding portion thereof or a scFv antigen binding domains. See ¶¶ [0025] and [0033]-[0039]. Regarding claims 259-261, the scFv domain would comprise a single VH domain which is a nanobody or a sdAB and a single VL domain. Regarding claims 262-263, 265 and 266, Abbot teaches that the CAR can comprise a hinge polypeptide/peptide sequence, e.g., a CH2CH3 hinge sequence or a sequence from CD8, CD28, CTLA4, or PD-1. See ¶¶ [0027] and [0030]-[0039]. Regarding claims 271 and 272, Abbot teaches that the CAR can comprise amino acid sequences from the CTLA-4 or PD-1 intracellular, cytoplasmic domains. See ¶¶ [0027, 0028] and [0102]. Regarding claim 275, the CARs of Abbot do not comprise a KIR D domain. Regarding claim 276, Abbot teaches that the CARs can bind any antigen of interest like HER2, PSCA or CD19. See ¶¶ [0026] and Examples 1-9. These antigens are found on normal cells and are not always on a cancer cell. See, e.g., Pieper abstract and Fig. 2. 5. Claim(s) 254-258, 262-264, 267-269, 273, 274 and 276 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Montgomery et al. (Developmental and Comparative Immunology Sep. 16, 2011, 37:151-163, IDS), “Montgomery”, evidenced by Frazier (J. Immunology May 17, 2013 190:6198-6208, IDS), “Frazier”. Montgomery teaches a chimeric protein comprising the two extracellular regions and the transmembrane domain of KIR2DL3 (an inhKIR) fused to the inhibitory cytoplasmic tails of the inhibitory channel catfish leukocyte immune type receptor (IpLITR1.2a and IPLITR1.1b). See abstract, p.153-§ 2.2 and p. 154 § 3.1. Regarding claims 254-257, Montgomery teaches KIR/IpLITRCYT chimeras were expressed in the DNA of vaccinia viruses for expression in cells. See pp. 153-154, §§ 2.2 and 2.6 and Fig. 1. Regarding claims 256 and 257, the vaccinia viruses when expressed in cells would produce mRNA that would then would be translated into proteins. See Fig. 1. Regarding claims 259, 273 and 274, the KIR2DL3 extracellular domain comprises D1 and D2 ligand binding domains, a non-antibody scaffold. See Frazier-p. 6198-right column and Fig. 1A. Regarding claims 262 and 263, the KIR2DL3 extracellular domain comprises a hinge domain. See Frazier-abstract, p. 6198-right column, and p. 6200- Hinge angle calculation . Regarding claims 267-270, Montgomery teaches cytoplasmic tails of the inhibitory channel catfish leukocyte immune type receptor (IpLITR1.2a and IPLITR1.1b) contain ITIM and ITIM like motifs. See p. 154 § 3.1 and Supplementary Fig. 1. Regarding claims 276, the KIR2DL3 extracellular domain binds HLA-C, which is present on normal cells and not always on a cancer cell. See Frazier-abstract and Fig. 2 . 07-15 AIA 6. Claim (s) 254-258, 262-264, 267-270, 273, 274 and 276 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Katz et al. (J. Immunology 2001 166:7260-7267, IDS), “Katz”, evidenced by Graef et al. (Journal of Experimental Medicine Oct. 26, 2009, 206: 2557-2572, IDS), “Graef” and Debska-Zielkowska et al. (Cells July 14, 2021 10: 1777, pages 1-22, IDS), “Debska” . Regarding claims 254, 262-264 and 268-270, Katz teaches a chimeric molecule of the KIR2DS4 extracellular domain fused to the transmembrane and cytoplasmic portion KIR2DL1 (an inhKIR). See abstract and p. 7261-right column-3 rd paragraph. Regarding claims 254-257, Katz teaches making DNA plasmid vectors expressing the KIR2DS4/ KIR2DL1 chimeric receptors and expressing the plasmids in cells. See p. 7261-left column- Generation of YTS cells . . . and right column 3 rd paragraph and Fig. 1. Regarding claims 256 and 257, the KIR2DS4/ KIR2DL1 chimeric receptor vectors when expressed in cells would produce mRNA that would then would be translated into proteins. See Fig. 1. Regarding claims 258, 262, 263, 273 and 274, Graef teaches that the KIR2DS4 extracellular domain comprises D1 and D2 domains, a non-antibody scaffold that binds HLA-C and HLA-A*11, and a hinge domain. See Figs. 4, 6 and 7 and p. 2561-right column-last paragraph and p. 2563- right column-last paragraph. Regarding claim 267, Debska- teaches that the KIR2DL1 cytoplasmic domain comprises an ITIM domain. See Fig. 3. Katz teaches KIR2DS4 binds HLA-C, which is present on normal cells and not always on a cancer cell. See abstract and Figure 5 . 07-15 AIA 7. Claim (s) 254-263, 265, 266, 271, 272, 275, and 276 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Roberts et al. (WO 96/23814 Aug. 8, 1996, IDS), “Roberts” evidenced by Pieper et al. (J Allergy Clin. Immunology March 8, 2013, 131: 959-71, IDS), “Pieper” . It is noted that although the preamble of the claim 256 is drawn to a nucleic acid comprising a sequence encoding an inhibitory killer cell immunoglobulin-like receptor chimeric antigen receptor (inhKIR-CAR), the body of the claim does not require the CAR to contain inhKIR domains and some dependent claims (e.g. claims 263 and 265) specifically exclude such domains. Thus, the inhKIR-CAR is not limited to containing inhKIR domains. Regarding claims 254, 265, 266, 271, and 272, Roberts teaches chimeric antigen receptors comprising CTLA-4 transmembrane domain and cytoplasmic domain. See abstract, p. 15-lines 15-25, p. 16-line 30 to p. 17-line 5 and claims 1 and 5. Regarding claims 254-257, Roberts teaches nucleic acids encoding the chimeric acids, including DNA and mRNA. See abstract, p. 9-lines 28-35, p. 13-lines 1-22, and p. 24-line 14 to p. 25-lines 20-35. Regarding claims 258-260, Roberts teaches that antigen binding domain can comprise single chain antibodies comprising the VH and VL domain linked together, a scFv. See p.19. Regarding claims 258-261, Roberts teaches that antigen binding domain can be a single domain antibody comprising a VH domain, which is a nanobody. See paragraph bridging pp. 17-18. Regarding claims 262-263, Roberts teaches that the extracellular domain can comprise a hinge of the Ig heavy chain. See p. 18-lines 20-32 and p. 20-lines 1-12. Regarding claim 275, the CARs of Roberts do not comprise a KIR D domain. Regarding claim 276, Roberts teaches that the CARs can bind CD19 or CD20. See p. 29-lines 25-35. These antigens are found on normal cells and are not always on a cancer cell. See, e.g., Pieper abstract and Fig. 2 . Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 8 Claim 277 is rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0307623 (Abbot et al. Oct. 29 2015, effectively filed Dec. 20, 2012, IDS), “Abbot” evidenced by Pieper et al. (J Allergy Clin. Immunology March 8, 2013, 131: 959-71, IDS), “Pieper” as applied to claims 254-263, 265, 266, 271, 272, and 275-277 above, and further in view of US 2013/0280220 A1 (Ahmed et al. Oct. 24, 2013, filed March 7, 2013, IDS), “Ahmed”. Abbot teaches as set forth, but does not teach an antigen binding domain that binds an ephrin receptor. Ahmed teaches chimeric antigen receptors (CAR) that are specific for two or more antigens. See abstract and claims 1-17. Ahmed teaches that the CARs can bind to the ephrin receptor EphA2 and other tumor antigens like CD19. See ¶¶ [0013], [0017], and [0186] and claims 5 and 16. Ahmed teaches that by targeting two target molecules simultaneously, tandem CAR (TanCAR) T cells achieve better tumor control and confer a better survival advantage over targeting single molecules. Further, by docking to two targets simultaneously, enhanced T cell activation gives them an advantage over a pooled product targeting both antigens individually. See ¶¶ [0186]. It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Abbot and Ahmed and target two antigens like CD19 and EphA2 with the CARs of Abbot because Abbot teaches that the CARs can bind any antigen of interest like CD19 and Ahmed teaches that by targeting two target molecules simultaneously, like CD19 and EphA2, TanCAR T cells achieve better tumor control and confer a better survival advantage over targeting single molecule. Given the advantages taught by Ahmed one of skill in the art would have been motivated to target two antigens like CD19 and EphA2 with the CARs of Abbot. 07-22-aia AIA 9. Claim 277 is rejected under 35 U.S.C. 103 as being unpatentable over Roberts et al. (WO 96/23814 Aug. 8, 1996, IDS), “Roberts” evidenced by Pieper et al. (J Allergy Clin. Immunology March 8, 2013, 131: 959-71, IDS), “Pieper” as applied to claim s 254-263, 265, 266, 271, 272, 275, and 276 above, and further in view of US 2013/0280220 A1(Ahmed et al. Oct. 24, 2013, IDS), “Ahmed” . Roberts teaches as set forth, but does not teach an antigen binding domain that binds an ephrin receptor. Ahmed teaches as set forth above. It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Roberts and Ahmed and target two antigens like CD19 and EphA2 with the CARs of Roberts because Roberts teaches that the CARs can bind CD19 and Ahmed teaches that by targeting two target molecules simultaneously, like CD19 and EphA2, TanCAR T cells achieve better tumor control and confer a better survival advantage over targeting single molecule. Given the advantages taught by Ahmed one of skill in the art would have been motivated to target two antigens like CD19 and EphA2 with the CARs of Roberts. Double Patenting 08-33 AIA The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp. 10. Claims 254-275 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 and 30-33 of U.S. Patent No. 10,577,417 (Beatty et al. March 3, 2020, IDS) evidenced by Debska-Zielkowska et al. (Cells July 14, 2021 10: 1777, pages 1-22, IDS), “Debska”. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘417 claims are drawn to: 1. An isolated nucleic acid molecule encoding a natural killer cell immune-function receptor-chimeric antigen receptor (NKR-CAR), wherein the encoded NKR-CAR comprises: (a) an extracellular antigen binding domain that binds to mesothelin, wherein the antigen binding domain comprises a heavy chain complementarity determining region 1 (HC CDR1), a heavy chain complementarity determining region 2 (HC CDR2), a heavy chain complementarity determining region 3 (HC CDR3), a light chain complementarity determining region 1 (LC CDR1), a light chain complementarity determining region 2 (LC CDR2), and a light chain complementarity determining region 3 (LC CDR3), wherein: (i) the HC CDR1, HC CDR2 and HC CDR3 are of the anti-mesothelin heavy chain amino acid sequence in SEQ ID NO: 234, and the LC CDR1, LC CDR2 and LC CDR3 are of the anti-mesothelin light chain amino acid sequence in SEQ ID NO: 234; or (ii) the HC CDR1, HC CDR2 and HC CDR3 are of the anti-mesothelin heavy chain amino acid sequence in SEQ ID NO: 240, and the LC CDR1, LC CDR2 and LC CDR3 are of the anti-mesothelin light chain amino acid sequence in SEQ ID NO: 240; (b) a NKR transmembrane domain; and (c) a cytoplasmic domain. 2. The isolated nucleic acid molecule of claim 1, wherein: (a) the antigen binding domain that binds mesothelin comprises: a heavy chain variable region comprising: i) the amino acid sequence of an anti-mesothelin heavy chain variable region in SEQ ID NO: 234 or 240; or ii) an amino acid sequence with at least 95% identity thereto; and/or a light chain variable region comprising: i) the amino acid sequence of an anti-mesothelin light chain variable region in SEQ ID NO: 234 or 240; or ii) an amino acid sequence with at least 95% identity thereto; and/or (b) the antigen binding domain that binds mesothelin comprises: i) the amino acid sequence of SEQ ID NO: 234 or 240; or ii) an amino acid sequence with at least 95% identity thereto. 3. The isolated nucleic acid molecule of claim 1, wherein the encoded NKR-CAR comprises: a killer cell immunoglobulin-like receptor chimeric antigen receptor (KIR-CAR), wherein the KIR-CAR comprises one or both of a transmembrane domain from a KIR (a KIR transmembrane domain) or a cytoplasmic domain comprising a functional signaling domain from a KIR (a KIR cytoplasmic domain); a natural cytotoxicity receptor chimeric antigen receptor (NCR-CAR), wherein the NCR-CAR comprises one or both of a transmembrane domain from a NCR (a NCR transmembrane domain) or a cytoplasmic domain comprising a functional signaling domain from a NCR (a NCR cytoplasmic domain ); a signaling lymphocyte activation molecule family chimeric antigen receptor (SLAMF-CAR), wherein the SLAMF-CAR comprises one or both of a transmembrane domain from a SLAMF (a SLAMF transmembrane domain) or a cytoplasmic domain comprising a functional signaling domain from a SLAMF (a SLAMF cytoplasmic domain); a Fc receptor chimeric antigen receptor (FcR-CAR), wherein the FcR-CAR comprises one or both of a transmembrane domain from a FcR selected from CD16 or CD64, or a cytoplasmic domain comprising a functional signaling domain from a FcR selected from CD16 or CD64; or a Ly49 receptor chimeric antigen receptor (Ly49-CAR), wherein the Ly49-CAR comprises one or both of a transmembrane domain from Ly49 (a Ly49 transmembrane domain) or a cytoplasmic domain comprising a functional signaling domain from Ly49 (a Ly49 cytoplasmic domain). 4. The isolated nucleic acid molecule of claim 3, wherein: (i) the KIR transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: KIR2DS2, KIR2DL3, KIR2DL1, KIR2DL2, KIR2DL4, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DS1, KIR3DL2, KIR3DL3, KIR2DP1 and KIR3DP1; (ii) the KIR cytoplasmic domain comprises a functional signaling domain of a protein selected from the group consisting of: KIR2DS2, KIR2DL3, KIR2DL1, KIR2DL2, KIR2DL4, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DS1, KIR3DL2, KIR3DL3, KIR2DP1 and KIR3DP1; and/or (iii) the KIR-CAR further comprises one or more of a KIR D0 domain, a KIR D1 domain, and/or a KIR D2 domain . 5. The isolated nucleic acid molecule of claim 3, wherein: (i) the NCR transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: NKp46, NKp30, and NKp44; and/or (ii) the NCR cytoplasmic domain comprises a functional signaling domain of a protein selected from the group consisting of: NKp46, NKp30, and NKp44. 6. The isolated nucleic acid molecule of claim 3, wherein: (i) the SLAMF transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: SLAM, CD48, CD229, 2B4, CD84, NTB-A, CRACC, BLAME, and CD2F-10; and/or (ii) the SLAMF cytoplasmic domain comprises a functional signaling domain of a protein selected from the group consisting of: SLAM , CD48, CD229, 2B4, CD84, NTB-A, CRACC, BLAME, and CD2F-10. 7. The isolated nucleic acid molecule of claim 3, wherein: (i) the Ly49 transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: Ly49A, Ly49C, Ly49H, and Ly49D; and/or (ii) the Ly49 cytoplasmic domain comprises a functional signaling domain of a protein selected from the group consisting of: Ly49A, Ly49C, Ly49H, and Ly49D. 8. The isolated nucleic acid molecule of claim 1, wherein: (i) the encoded transmembrane domain comprises an NKR transmembrane domain comprising a transmembrane domain of a protein selected from the group consisting of KIR2DS2, KIR2DL3, NKp46, a killer cell immunoglobulin-like receptor (KIR), a natural cytotoxicity receptor (NCR), a signaling lymphocyte activation molecule family (SLAMF), a Fc receptor (FcR), and a Ly49 receptor (Ly49); (ii) the encoded transmembrane domain comprises the amino acid sequence of SEQ ID NO: 357, 358, or 359; an amino acid sequence comprising at least one modification, but not more than 5 modifications of the amino acid sequence of SEQ ID NO: 357, 358, or 359; or an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 357, 358, or 359; or (iii) the nucleic acid sequence encoding the transmembrane domain comprises nucleotides 771-830 of SEQ ID NO: 342, nucleotides 773-832 of SEQ ID NO: 344, or nucleotides 803-875 of SEQ ID NO: 346, or a nucleic acid sequence with at least 95% sequence identity thereto. 9. The isolated nucleic acid molecule of claim 1, wherein: (i) the encoded cytoplasmic domain comprises a NKR cytoplasmic domain comprising one or more functional signaling domains of a protein selected from the group consisting of KIR2DS2, KIR2DL3, NKp46, DAP12, a KIR, a NCR, a SLAM F, a FcR, and a Ly49 ; (ii) the encoded cytoplasmic domain comprises the amino acid sequence of SEQ ID NO: 360, 361, or 362; an amino acid sequence comprising at least one modification, but not more than 20 modifications of the amino acid sequence of SEQ ID NO: 360, 361, or 362; or an amino acid sequence with at least 95% sequence identity to SEQ ID NO: 360, 361, or 362; or (iii) the nucleic acid sequence encoding the cytoplasmic domain comprises nucleotides 831-947 of SEQ ID NO: 342, nucleotides 833-1060 of SEQ ID NO: 344, or nucleotides 876-949 of SEQ ID NO: 346, or a nucleic acid sequence with at least 95% sequence identity thereto. 11. The isolated nucleic acid molecule of claim 1, wherein the extracellular antigen binding domain that binds mesothelin is connected to the transmembrane domain by a hinge domain. 12. The isolated nucleic acid molecule of claim 11, wherein: (i) the encoded hinge domain is selected from the group consisting of a CD8 hinge, an IgG4 hinge, an IgD hinge, a KIR2DS2 hinge, a KIR hinge, a NCR hinge, a SLAMF hinge, a FcR hinge, and a LY49 hinge ; or (ii) the encoded hinge domain comprises the amino acid sequence of SEQ ID NO: 340, 3, or 4; an amino acid sequence comprising at least one modification, but not more than 5 modifications of the amino acid sequence of SEQ ID NO: 340, 3, or 4; or an amino acid sequence with at least 95% identity to the amino acid sequence of SEQ ID NO: 340, 3, or 4. 13. The isolated nucleic acid molecule of claim 1, wherein: i) the encoded transmembrane domain and cytoplasmic domain collectively comprise: the amino acid sequence of amino acids 413-487 of SEQ ID NO: 333 or amino acids 386-454 of SEQ ID NO: 335; an amino acid sequence having at least one modification, but not more than 30 modifications to amino acids 413-487 of SEQ ID NO: 333 or amino acids 386-454 of SEQ ID NO: 335; or an amino acid sequence with at least 95% identity to amino acids 413-487 of SEQ ID NO: 333 or amino acids 386-454 of SEQ ID NO: 335; or ii) the nucleic acid sequence encoding the transmembrane domain and the cytoplasmic domain comprises nucleotides 1237-1464 of SEQ ID NO: 332 or nucleotides 1156-1365 of SEQ ID NO: 334, or a sequence having at least 95% identity thereto. 18. The isolated nucleic acid molecule of claim 1, further comprising a nucleic acid sequence encoding a T cell based-chimeric antigen receptor (TCAR) or a second NKR-CAR. 19. The isolated nucleic acid molecule of claim 18, wherein the encoded TCAR or the second NKR-CAR comprises an antigen binding domain that binds to a target antigen that is not mesothelin. 20. An isolated NKR-CAR polypeptide encoded by the nucleic acid molecule of claim 1. 24. A vector comprising the nucleic acid molecule of claim 1, wherein the vector is a DNA vector or an RNA vector. 25. An isolated cell, comprising the nucleic acid molecule of claim 1. 26. A method of making a cell, comprising introducing into the cell the nucleic acid molecule of claim 1. 30. The isolated nucleic acid molecule of claim 1, wherein the encoded NKR-CAR is an inhibiting NKR-CAR. 31. The isolated nucleic acid molecule of claim 1, wherein the cytoplasmic domain is a NKR cytoplasmic domain. Regarding claim 257, the nucleic acids when expressed in the host cells would produce mRNA that would then would be translated into protein. Regarding claim 259 the VH and/or VL are on the same polypeptide, see claims 1 and 21, thus the CAR comprises a scFv. Regarding claims 259-261, the scFv domain would comprise a single VH domain which is nanobody or sdAB and a single VL and claim 260comprises the VH or VL domain in the alternative. Regarding claim 267, Debska- teaches that the KIR2DL and the KIR2DL3 cytoplasmic domains comprise an ITIM domain. See Fig. 3. Thus, the instant claims are not patentably distinct from the patented claims because they relate to the same inventive concept and would have been obvious in view of the patented claims which have all of the characteristics of the claimed inhKIR-CAR as set forth above. 11. Claims 276 and 277 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 and 30-33 of U.S. Patent No. 10,577,417 (Beatty et al. March 3, 2020, IDS) evidenced by Debska-Zielkowska et al. (Cells July 14, 2021 10: 1777, pages 1-22), “Debska” as applied to claims 254-275 are in further view of US 2013/0280220 (Ahmed et al. Oct. 24, 2013, IDS), “Ahmed” evidenced by Pieper et al. (J Allergy Clin. Immunology March 8, 2013, 131: 959-71, IDS), “Pieper”. The ‘417 claims teach as set forth above, but do not teach binding an antigen of claims 276 and 277. Ahmed teaches as set forth above. It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘417 claims and Ahmed and target two antigens like CD19 and EphA2 with the CARs of the ‘417 claims because Ahmed teaches that by targeting two target molecules simultaneously, like CD19 and EphA2, TanCAR T cells achieve better tumor control and confer a better survival advantage over targeting single molecule. Given the advantages taught by Ahmed one of skill in the art would have been motivated to target two antigens like mesothelin and CD19 or mesothelin and EphA2 with the combined CARs of the ‘417 claims and Ahmed. CD19 and EphA2 antigens are found on normal cells and are not always on a cancer cell. See, e.g., Pieper abstract and Fig. 2. 12. Claims 254-275 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,981,731 B2 (Beatty et al. May 14, 2024) evidenced by Debska-Zielkowska et al. (Cells July 14, 2021 10: 1777, pages 1-22, IDS), “Debska”. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘731 claims are drawn to: 1. An isolated nucleic acid molecule encoding a natural killer cell immune-function receptor-chimeric antigen receptor (NKR-CAR), wherein the NKR-CAR comprises an antigen binding domain that binds to mesothelin, and: (i) a NKR transmembrane domain and a cytoplasmic domain; or (ii) a transmembrane domain and a NKR cytoplasmic domain, wherein the antigen binding domain that binds mesothelin comprises: a heavy chain complementarity determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3), a light chain complementarity determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3), and wherein: (a) the HC CDR1, HC CDR2, and HC CDR3 are of the anti-mesothelin heavy chain amino acid sequence of SEQ ID NO:229, and the LC CDR1, LC CDR2, and LC CDR3 are of the anti-mesothelin light chain amino acid sequence of SEQ ID NO:229; . . . and wherein the NKR-CAR further comprises: a killer cell immunoglobulin-like receptor chimeric antigen receptor (KIR-CAR), wherein the KIR-CAR comprises one or both of a transmembrane domain from a KIR (a KIR transmembrane domain) or a cytoplasmic domain comprising a functional signaling domain from a KIR (a KIR cytoplasmic domain), wherein the KIR transmembrane or cytoplasmic domain comprises a transmembrane or cytoplasmic domain of a protein selected from the group consisting of: KIR2DL1, KIR2DL2, KIR2DL4, KIR2DL5A, KIR2DL5B, KIR2DS1, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DS1, KIR3DL2, KIR3DL3, KIR2DP1 and KIR3DP1; a natural cytotoxicity receptor chimeric antigen receptor (NCR-CAR), wherein the NCR-CAR comprises one or both of a transmembrane domain from a NCR (a NCR transmembrane domain) or a cytoplasmic domain comprising a functional signaling domain from a NCR (a NCR cytoplasmic domain), wherein the NCR transmembrane or cytoplasmic domain comprises a transmembrane or cytoplasmic domain of a protein selected from the group consisting of: NKp30 and NKp44; a signaling lymphocyte activation molecule family chimeric antigen receptor (SLAMF-CAR), wherein the SLAMF-CAR comprises one or both of a transmembrane domain from a SLAMF (a SLAMF transmembrane domain) or a cytoplasmic domain comprising a functional signaling domain from a SLAMF (a SLAMF cytoplasmic domain); a Fc receptor chimeric antigen receptor (FcR-CAR), wherein the FcR-CAR comprises one or both of a transmembrane domain from a FcR selected from CD16 or CD64, or a cytoplasmic domain comprising a functional signaling domain from a FcR selected from CD16 or CD64; or a Ly49 receptor chimeric antigen receptor (Ly49-CAR), wherein the Ly49-CAR comprises one or both of a transmembrane domain from Ly49 (a Ly49 transmembrane domain) or a cytoplasmic domain comprising a functional signaling domain from Ly49 (a Ly49 cytoplasmic domain). 3. The isolated nucleic acid molecule of claim 1, wherein: (i) the KIR-CAR further comprising one or more of a KIR DO domain, a KIR D1 domain, and/or a KIR D2 domain; (ii) the SLAMF transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: SLAM , CD48, CD229, 2B4, CD84, NTB-A, CRACC, BLAME, and CD2F-10; (iii) the SLAMF cytoplasmic domain comprises a functional signaling domain of a protein selected from the group consisting of: SLAM, CD48, CD229, 2B4, CD84, NTB-A, CRACC, BLAME, and CD2F-10; (iv) the Ly49 transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: Ly49A, Ly49C, Ly49H, and Ly49D; or (v) the Ly49 cytoplasmic domain comprises a functional signaling domain of a protein selected from the group consisting of: Ly49A, Ly49C, Ly49H, and Ly49D. 5. The isolated nucleic acid molecule of claim 1, wherein the antigen binding domain that binds mesothelin is connected to the transmembrane domain by a hinge domain. 6. The isolated nucleic acid molecule of claim 5, wherein: (i) the hinge domain is selected from the group consisting of a CD8 hinge, a GS hinge, an IgG4 hinge, an IgD hinge, a KIR2DS2 hinge, a KIR hinge, a NCR hinge, a SLAMF hinge, a FcR hinge, and a LY49 hinge; (ii) the hinge domain comprises the amino acid sequence of SEQ ID NOs: 5, 2, 3, or 4; or an amino acid sequence with 95-99% identity to the amino acid sequence of SEQ ID NOs: 5, 2, 3, or 4; or (iii) the nucleic acid sequence encoding the hinge domain comprises the nucleic acid sequence of SEQ ID NO: 356, 16, 13, 14, or 15, or a nucleic acid sequence with 95-99% identity thereto. 13. A vector comprising the nucleic acid molecule of claim 1, wherein the vector is a DNA vector or an RNA vector. 14. An isolated cell comprising the nucleic acid molecule of claim 1. 15. A method of making a cell comprising introducing into the cell the nucleic acid molecule of claim 1. 17. A vector comprising the nucleic acid molecule of claim 1, wherein the vector is a plasmid, a lentiviral vector, an adenoviral vector, or a retroviral vector. Regarding claim 257, the nucleic acids when expressed in the host cells would produce mRNA that would then would be translated into protein. Regarding claim 259 the VH and/or VL are on the same polypeptide, see claim 1 and 9, thus the CAR comprises a scFv. Regarding claims 259-261, the scFv domain would comprise a single VH domain which is a nanobody or sdAB and a single VL and claim 260 comprises the VH or VL domain in the alternative. Regarding claim 267, Debska- teaches that the KIR2DL and the KIR2DL3 cytoplasmic domains comprise an ITIM domain. See Fig. 3. Thus, the instant claims are not patentably distinct from the patented claims because they relate to the same inventive concept and would have been obvious in view of the patented claims which have all of the characteristics of the claimed inhKIR-CAR as set forth above. 13. Claims 276 and 277 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,981,731 B2 (Beatty et al. May 14, 2024) evidenced by Debska-Zielkowska et al. (Cells July 14, 2021 10: 1777, pages 1-22), “Debska” as applied to claims 254-275 are in further view of US 2013/0280220 (Ahmed et al. Oct. 24, 2013, IDS), “Ahmed” evidenced by Pieper et al. (J Allergy Clin. Immunology March 8, 2013, 131: 959-71, IDS), “Pieper”. The ‘731 claims teach as set forth above, but do not teach binding an antigen of claims 276 and 277. Ahmed teaches as set forth above. It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘731 claims and Ahmed and target two antigens like CD19 and EphA2 with the CARs of the ‘731 claims because Ahmed teaches that by targeting two target molecules simultaneously, like CD19 and EphA2, TanCAR T cells achieve better tumor control and confer a better survival advantage over targeting single molecule. Given the advantages taught by Ahmed one of skill in the art would have been motivated to target two antigens like mesothelin and CD19 or mesothelin and EphA2 with the combined CARs of the ‘731 claims and Ahmed. CD19 and EphA2 antigens are found on normal cells and are not always on a cancer cell. See, e.g., Pieper abstract and Fig. 2. Conclusion 12. No claims allowed. 13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time. 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, Greg Emch can be reached at 571-272-8149. 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. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /PETER J REDDIG/ Primary Examiner, Art Unit 1646 Application/Control Number: 18/420,525 Page 2 Art Unit: 1646 Application/Control Number: 18/420,525 Page 3 Art Unit: 1646 Application/Control Number: 18/420,525 Page 4 Art Unit: 1646 Application/Control Number: 18/420,525 Page 5 Art Unit: 1646 Application/Control Number: 18/420,525 Page 6 Art Unit: 1646 Application/Control Number: 18/420,525 Page 7 Art Unit: 1646 Application/Control Number: 18/420,525 Page 8 Art Unit: 1646 Application/Control Number: 18/420,525 Page 9 Art Unit: 1646 Application/Control Number: 18/420,525 Page 10 Art Unit: 1646 Application/Control Number: 18/420,525 Page 11 Art Unit: 1646 Application/Control Number: 18/420,525 Page 12 Art Unit: 1646 Application/Control Number: 18/420,525 Page 13 Art Unit: 1646 Application/Control Number: 18/420,525 Page 14 Art Unit: 1646 Application/Control Number: 18/420,525 Page 15 Art Unit: 1646 Application/Control Number: 18/420,525 Page 16 Art Unit: 1646 Application/Control Number: 18/420,525 Page 17 Art Unit: 1646 Application/Control Number: 18/420,525 Page 18 Art Unit: 1646 Application/Control Number: 18/420,525 Page 19 Art Unit: 1646 Application/Control Number: 18/420,525 Page 20 Art Unit: 1646 Application/Control Number: 18/420,525 Page 21 Art Unit: 1646 Application/Control Number: 18/420,525 Page 22 Art Unit: 1646 Application/Control Number: 18/420,525 Page 23 Art Unit: 1646 Application/Control Number: 18/420,525 Page 24 Art Unit: 1646 Application/Control Number: 18/420,525 Page 25 Art Unit: 1646 Application/Control Number: 18/420,525 Page 26 Art Unit: 1646 Application/Control Number: 18/420,525 Page 27 Art Unit: 1646
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