Cell Expressing Immune Modulatory Molecules and System for Expressing Immune Modulatory Molecules

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 . Priority This application was filed June 28, 2022, and is a 371 application of PCT/IB2020/001079 filed on December 28, 2020, which claims benefit to the provisional application 62/954,448 filed on December 28, 2019. Claim Status In the response filed April 22, 2026, Applicant has amended claims 1, 8, 28, 30, 64, and canceled claims 13-25, 29, 32-62, 66-68, 71-72, 76, 78-80 and filed new claims 84 and 85. In the reply filed on Sept. 2nd, 2025, Applicant’s election without traverse of Group I (claims 1-12, 14, 26-28, 30-32 and 38), drawn to an immune cell that comprises an expressed immune cell activator polypeptide comprising an intracellular signal transduction domain, a transmembrane domain, and an extracellular label domain, wherein the immune cell secretes one or more polypeptide effector molecules), and species: 1.) Immunomodulator - PD-I; 2.) Immune cell - T cell, 3.) Tumor- mesothelioma; 4.) Tumor cell - mesothelial cell; 5.) Cell surface protein of the tumor cell- mesothelin; 6.) Additional biochemical activity of the bi specific polypeptide - extending the half-life of the bispecific polypeptide in vivo is acknowledged. Currently, claims 7, 30, 69-70, 73-77, and 81-83 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/2/2025. Claims 1-6, 8-12, 26-28, 31, 63-65, and 84-85 are under examination in this application. Withdrawn Objections & Rejections Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. The rejection of claim 64 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, is withdrawn due to Applicants amendments to the claim. The rejection of claims 1, 31, and 63-65 under 35 U.S.C. 102(a)(1) as being anticipated by Karches, Clara H., et al. (Clinical Cancer Research 25.19: 5890-5900, published Oct. 2019) is withdrawn due to Applicants amendments (i.e. SEQ ID NO: 20) to the claims. The rejection of claims 1-6, 8-12, 26-28, 31, and 63-65 under 35 U.S.C. 102(a)(1) as being anticipated by Brogdon et al., (US2019/0000944A1; published Jan. 2019) is withdrawn due to Applicants amendments (i.e. SEQ ID NO: 20) to the 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. 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. Claims 1-6, 8-12, 26-28, 31, and 63-65 are rejected under 35 U.S.C. 103 as being unpatentable over Brogdon et al., (US2019/0000944A1; published Jan. 2019, previously presented), in further view of Wang et al., (US2018/0244796A1; published 2018), Davé, Emma, et al. (MAbs. Vol. 8. No. 7. Taylor & Francis, published 2016, hereinafter as “Dave”; previously presented)), and Karches, Clara H., et al. (Clinical Cancer Research 25.19: 5890-5900, published Oct. 2019; previously presented). This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on Dec. 22, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection. Regarding claim 1, Brogdon discloses an immune cell (i.e. immune effector cell, e.g. T cell)(see e.g. para. 239-240, 351, 393, claim 1) that comprises an expressed immune cell activator polypeptide comprising an intracellular signal transduction domain (i.e. CD3ζ)(e.g. para. 241, 281, 305, 416, claim 1), a transmembrane domain (i.e. CD28)(see e.g. 284, claim 1), and an extracellular label domain, wherein the label domain comprises a structurally inert domain derived from human mesothelin extracellular domain (ECD)(i.e. MSLN)(see e.g. claim 57, para. 77-78, claim 1). Further, Brogdon discloses that the immune cell is capable of specifically binding to a bispecific polypeptide (see e.g. para. 121, 224-227, 487), comprising (i) a label-binding domain comprising a single chain polypeptide and (ii) a cell surface protein-binding domain comprising a single chain polypeptide that binds to a cell surface protein receptor of a target cell (e.g. a first Ig variable domain of a scFv, which has binding specificity for [AltContent: textbox ([img-media_image1.png] [img-media_image2.png])]mesothelin)(see e.g. para. 121, 185, 224-227, 434). Brogdon does not explicitly disclose wherein the label domain comprises SEQ ID NO: 20. However, the prior art of Wang disclose immune effector cells targeting mesothelin and human anti-mesothelin antibodies (see e.g. abstract). Further, Wang discloses that the extracellular binding region (i.e. extracellular label domain) comprises a mesothelin (i.e. SEQ ID NO:2) that is 100% identical to SEQ ID NO:20 (see file “us-17-758-128-20.align150.rapbm”; Result 10 below, where QY is SEQ ID NO:20 and Db is SEQ ID NO: 2)(see e.g. para. 140-142, Example 1). Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have combined the immune cell, as taught by Brogdon, to incorporate mesothelin (i.e. SEQ ID NO: 20), as taught by Wang, with a reasonable expectation of success because one of ordinary skill in the art would know that mesothelin is known as both a therapeutic target as well as a bio-marker for disease activity and therapeutic response (as taught by Brogdon, see e.g. para. 4). A person of ordinary skill in the art would have had predictable results with a reasonable expectation of success because both Brogdon and Wang disclose methods regarding immune effector cells targeting mesothelin for cancer therapy (see e.g. backgrounds, respectively). Regarding claim 2 and 5, Brogdon discloses comprising an extracellular chimeric polypeptide (see e.g. para. 112-113), wherein the extracellular chimeric polypeptide comprises a binding domain of a VHH antibody (i.e. camelid VHH domains)(see e.g. para. 117, 119-120) or a single chain variable fragment and the label domain (i.e. antigen-recognition domain)(e.g. scFv)(see e.g. para. 113, 117, 434). Regarding claim 3-4 and 6, Brogdon discloses wherein the immune cell secretes one or more polypeptide effector molecules (see e.g. para. 114), wherein the polypeptide effector molecule comprises an antibody that specifically binds to one or more immunomodulators, where the immunomodulator is PD-1 (i.e. PD1)(see e.g. para. 246, 271, 273-276, 382 and 416). Regarding claim 8, as stated supra, Brogdon discloses wherein an immune cell that comprises a nucleic acid vector (see e.g. para. 280-294) comprising (a) a promoter region effective for transcription in the immune cell (see e.g. para. 161-169, 279, 292-301 and 303; table 1); (b) a polynucleotide encoding an amino acid sequence of the immune cell activator polypeptide (see e.g. para. 82-89, 121, 124 449, table 1, 6, claims 39-69), comprising an intracellular signal transduction domain (i.e. CD3ζ)(e.g. para. 241, 281, 305, 416, claim 1), a transmembrane domain (i.e. CD28)(see e.g. 284, claim 1), and an extracellular label domain, wherein the label domain comprises a structurally inert domain derived from human mesothelin extracellular domain (ECD)(i.e. MSLN)(see e.g. claim 57, para. 77-78, claim 1). Further, Brogdon discloses that the immune cell is capable of specifically binding to a bispecific polypeptide (see e.g. para. 121, 224-227, 487), comprising (i) a label-binding domain comprising a single chain polypeptide and (ii) a cell surface protein-binding domain comprising a single chain polypeptide that binds to a cell surface protein receptor of a target cell (e.g. a first Ig variable domain of a scFv, which has binding specificity for mesothelin)(see e.g. para. 121, 224-227, 422, 434) (c) a terminator region effective for ending transcription in the immune cell (see e.g. para. 115, 118, 171, and 174). Brogdon does not explicitly disclose wherein the label domain comprises SEQ ID NO: 20. As stated supra, the prior art of Wang disclose immune effector cells targeting mesothelin and human anti-mesothelin antibodies (see e.g. abstract). Further, Wang discloses that the extracellular binding region (i.e. extracellular label domain) comprises a mesothelin (i.e. SEQ ID NO:2) that is 100% identical to SEQ ID NO:20 (see file “us-17-758-128-20.align150.rapbm”; Result 10 above, where QY is SEQ ID NO:20 and Db is SEQ ID NO: 2)(see e.g. para. 140-142, Example 1). Accordingly, as stated supra, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have combined the immune cell, as taught of Brogdon, to incorporate mesothelin (i.e. SEQ ID NO: 20), as taught by Wang, with a reasonable expectation of success because one of ordinary skill in the art would know that mesothelin is known as both a therapeutic target as well as a bio-marker for disease activity and therapeutic response (as taught by Brogdon, see e.g. para. 4). A person of ordinary skill in the art would have had predictable results with a reasonable expectation of success because both Brogdon and Wang disclose methods regarding immune effector cells targeting mesothelin for cancer therapy (see e.g. backgrounds, respectively). Regarding claim 9, which further comprises a second nucleic acid vector (see e.g. para. 255-273) comprising (a) a promoter region effective for transcription in the immune cell (see e.g. para. 292, 297-300); (b) a polynucleotide encoding an amino acid sequence of one or more secreted polypeptide effector molecules (see e.g. para. 273, 600); (c) a terminator region effective for ending transcription in the immune cell (see e.g. para. 115, 118, 171, and 174). Regarding claims 10, 26, and 28, as stated supra, Brogdon discloses wherein the nucleic acid vector further comprises a polynucleotide encoding an amino acid sequence of a polypeptide effector molecule comprising an antibody or a binding fragment thereof that specifically binds to one or more immunomodulators wherein the immunomodulator is PD-1, wherein the immune cell secretes one or more polypeptide effector molecules (see e.g. para. 114, 246, 271, 273-276, 382 and 416). Regarding claim 11-12, and 27, Brogdon discloses wherein the immune cell activator polypeptide further comprises a binding domain of a VHH antibody (see e.g. para. 117, 119-120, 208, 212, 259, 262-266). Regarding claim 31, as stated supra, which is T cell or natural killer cell (see e.g. para. 622). Regarding claim 63-64, Brogdon discloses wherein the bispecific polypeptide further comprises one or more domains that provide additional biochemical activities or biological functions, such as specific binding of a fluorophore (e.g. GFP) (see e.g. para. 294, 303, 434). Further, Brogdon discloses an anti-cancer effect (biological effect)(i.e. additional biochemical activities or biological functions) which can be manifested by various means (see e.g. para. 126, Example 4). Brogdon does not explicitly state extending the half-life of the bi-specific polypeptide in vivo. However, the prior art of Dave discloses wherein the bispecific polypeptide (i.e. bispecific antibody Fab-dsFv) further comprises one or more domains (e.g. variable fragment (Fv) domain of a humanized albumin-binding antibody was fused to the C-termini of Fab constant domains, such that the VL and VH domains were individually connected to the Cκ and CH1 domains by peptide linkers) that provide additional biochemical activities or biological functions comprising extending the half-life of the bispecific polypeptide in vivo (see e.g. abstract, fig. 1, table 2, pages 1329, 1331-1332). Accordingly, it would have been obvious to one of ordinary skill in the art to combine the bi-specific polypeptide as taught by Brogdon with the bi-specific polypeptide as taught by Dave in a method of extending the half-life of the bi-specific polypeptide in vivo because Dave discloses that there is a need for antigen-binding therapeutics with enhanced serum half-life (see e.g. page 1329). Further, Dave discloses that while short serum half-life’s may be irrelevant or advantageous in some applications, it invokes impractical dosing regimens in the treatment of chronic disorders, and thus extending serum half-life has become increasingly important (see page 1319). Thus, a person of ordinary skill in the art would have had a reasonable expectation of success because both Brogdon and Dave disclose bi-specific polypeptides that utilize Fab, VH, CH1 domains and variable fragment (Fv) domains, as discussed above. Thus, person of ordinary skill in the art would have been able to use the additional domains such as those taught by Dave in combination with the bispecific polypeptide as taught by Brogdon to obtain predictable results with a reasonable expectation of success. Additionally, the prior art of Karches discloses that the bi-specific polypeptide (i.e. BiAb) may be engineered for half-lives according to the needs, and that the concentration could then be adjusted to maintain T cell efficacy (see e.g. page 11). Furthermore, an artisan of ordinary skill in the art of bi-specific antibodies has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007). Regarding claim 65, Brogdon discloses wherein the bispecific polypeptide comprises additional cell surface protein-binding domains comprising a single chain polypeptide domains that bind to different cell surface receptors of the same cell (i.e. one domain for scFv for mesothelin and another for an antigen other than mesothelin e.g. FAP)(see e.g. para. 226-229). Response to Traversal: Applicant argues that Brogdon does not disclose a label domain comprising the sequence of SEQ ID NO:20 (Remarks, page 8). Applicants’ arguments with respect to the previous rejection has been fully considered and are persuasive in view of the amendments to the claims. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Brogdon et al., (US2019/0000944A1; published Jan. 2019, previously presented), in further view of Wang et al., (US2018/0244796A1; published 2018), Davé, Emma, et al. (MAbs. Vol. 8. No. 7. Taylor & Francis, published 2016, hereinafter as “Dave”; previously presented)), and Karches, Clara H., et al. (Clinical Cancer Research 25.19: 5890-5900, published Oct. 2019; previously presented), due to Applicants amendments to the claims. Applicant argues that Brogdon does not disclose “a BiAb-bridged system and that the anti-mesothelin scFv binding domain on the CAR directly recognizes mesothelin on the tumor cell” (Remarks, page 8). Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. 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). Contrary to Applicants’ belief Brogdon discloses that the immune cell is capable of specifically binding to a bispecific polypeptide (see e.g. para. 121, 224-227, 487). It is noted that the independent claims recite “is capable of binding” and does not recite a “BiAb-bridged system”. Furthermore, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Applicant argues that Dave does not cure the deficiencies of Brogdon and that the prior art references (i.e. Brogdon, Karches, and Dave) do not disclose SEQ ID NO: 20. Further, Applicant argues that the SEQ ID NO: 20’s potent selective cytotoxicity’s are demonstrated in the application (e.g. Examples 2-16). As stated supra, Applicants’ arguments with respect to the previous rejection has been fully considered and are persuasive in view of the amendments to the claims. Therefore, the rejection has been withdrawn. Therefore, the prior art references (i.e. Brogdon, Karches, and Dave) are not relied on for disclosing SEQ ID NO: 20. Applicant is reminded submitting evidence asserted to establish unobvious results (i.e. potent selective cytotoxicity’s), there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964). It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D'Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971 ). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992). In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness. Closest Prior Art Art made of record but not relied upon for art rejection: Art cannot be applied to the claims as written without reading limitations into the claims. Nonetheless, the following prior art references teaches many of the element/steps inferred by the disclosure as filed. [AltContent: textbox ([img-media_image3.png])]Regarding claims 84 and 85, wherein the label-binding domain of the bispecific polypeptide comprises the sequence SEQ ID NO: 28, the prior art of Rothbauer et al., (cited as US2012/0149028A1, Application No. 13/382,302, Results date: 6/23/2026, database: Issued_Patents_AA, file type “.rai”, Result 2, see below) has SEQ ID NO: 2 that has about 70% Query Match and about 75% Local similarity to SEQ ID NO: 28. Claims 84 and 85 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Conclusion No claim is allowed. Applicants’ 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. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE GONZALES whose telephone number is (571)272-1794. The examiner can normally be reached M-Th: 10AM - 5:00PM (EST). 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, Tracy Vivlemore can be reached at (571) 272-2914. 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. Josephine Gonzales PhD Examiner Art Unit 1638 /JOSEPHINE GONZALES/ Examiner, Art Unit 1638 /Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638