CTFR 18/030,662 CTFR 98639 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. Application Status The amended claims filed on February 26, 2026 are acknowledged. Claims 1-6, 9-11, 13, 16, 18, and 20 are amended. Claims 7-8 are canceled. Claims 21-23 are newly added. Claims 1-6 and 9-23 are pending and under examination herein. WITHDRAWN OBJECTIONS AND REJECTIONS The prior grounds of objection to the specification are withdrawn in view of Applicant’s amendments to the specification. The objections to Figures 7A and 23A are withdrawn in view of Applicant’s replacement drawings submitted February 26, 2026. All prior grounds of rejection over claims 7-8 are rendered moot by the cancellation of the claims. The objections to claims 4 and 20 are remedied by Applicant's amendments thereto. The prior grounds of rejection of claims 1-6 and 9-19 under 35 U.S.C. § 102 as being anticipated by Qi (US 2018/0346543 A1) is withdrawn in view of Applicant's claim amendments. The rejection of claims 1-2, 5-6, and 16-19 under 35 U.S.C. 102 as being anticipated by Ramello ( Science Signaling (2019) 12: eaap9777) as evidenced by Morrissey (eLife (2018) 7: e36688; cited in IDS) is withdrawn in view of Applicant's claim amendments. The rejection of claims 1-2, 6, 9-12, and 16-19 under 35 U.S.C. § 103 as being unpatentable over Salter ( Science Signaling (2018) 11 (544): eaat6753) in view of Dolnikov ( Experimental Hematology (2015) 43(9 Suppl): S59, Poster Abstract #3034), as evidenced by Morrissey (eLife (2018) 7: e36688), is withdrawn in view of Applicant's claim amendments. MAINTAINED OBJECTIONS AND NEW OBJECTIONS AND REJECTIONS NECESSITATED BY CLAIM AMENDMENT Specification (New) The specification is objected to for the following informalities: There are two tables designated as Table 1, starting at page 27 and at page 31. It is not apparent what differentiates the two tables each designated Table 1. The tables in the disclosure should be renumbered in numerical order in order of chronological appearance. Appropriate correction or clarification is required. Drawings (Maintained) 06-22 AIA The drawings are objected to because Figure 20B recites a trademark/trade name (“Nanobody®”) used in commerce without a proper symbol denoting its use in commerce . Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Response to Arguments 07-37 AIA Applicant's arguments filed February 26, 2026 have been fully considered but they are not persuasive. Applicant submits that the replacement drawings are believed to address the prior grounds of objection. However, Figure 20B still contains “nanobody”. Accordingly, the objection is maintained . Claim Objections 07-29-01 AIA Claim 16 is objected to because of the following informalities: The claim as presently amended does not end in a period. As set forth in MPEP § 608.01(m), each claim should end with a period . Appropriate correction is required. Claim Rejections - 35 USC § 112(b) 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. Claims 5, 12, and 14-17 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. This is a new rejection necessitated by claim amendment. Claim 5 recites the limitation “…wherein the fusion protein, when expressed in a mammalian cell , …” in lines 1-2. Claim 5 depends from claim 1, which recites a mammalian cell comprising said fusion protein. The claim scope is indefinite because it is unclear whether “a mammalian cell” as referred to in claim 5 is intended to refer specifically to the mammalian cell of claim 1 or to another mammalian cell not previously recited. Claim 12 recites the cell of claim 8, which is now canceled. The intended scope of the claim cannot be determined, rendering claim 12 indefinite. Claim 14 recites the limitation “the recombinant cell” in line 2. There is insufficient antecedent basis for this limitation in the claim. While the claim indirectly depends from claim 1, claim 1 is drawn to a mammalian cell, not a recombinant cell. Claim 15 also recites “the recombinant cell” and is similarly rejected. Claim 16 is drawn to a method for altering a cell, and recites limitations including “the second binding moiety” (lines 2, 3, and 4-5), “the extracellular binding domain of the fusion protein” (line 3), “the first binding moiety” (line 4), and “the cytoskeleton” (line 5). There is insufficient antecedent basis for these limitations in the claim. The claim does not earlier recite “a first binding moiety”, “a second binding moiety”, “an extracellular binding domain”, “a fusion protein”, or “a cytoskeleton”. For example, it is not apparent how the “fusion protein” recited in the claim relates to the cells recited in the claim, nor which cell’s cytoskeleton is changed by the method. In addition to these issues, the claim language is overall unclear and it is not apparent what the intended scope of the claimed method is. Claim 17 , which depends from claim 16 and does not remedy these deficiencies, is similarly rejected. Claim Rejections - 35 USC § 103 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. 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 (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. 07-21-aia AIA Claim s 1-6, 9-11, 13-19, and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Qi (US 2018/0346543 A1; cited in PTO-892 mailed November 12, 2025). These are updated/new grounds of rejection necessitated by Applicant's claim amendments . Qi discloses systems for immune cell regulation, comprising a chimeric receptor polypeptide, a chimeric adaptor polypeptide, a gene modulating polypeptide (GMP), and a cleavage moiety, as well as methods of use thereof in immunotherapy (e.g., Abstract; Figure 1, reproduced below). PNG media_image1.png 361 344 media_image1.png Greyscale Qi teaches that said systems for conditional regulation of an immune cell comprise a chimeric transmembrane receptor polypeptide comprising (i) an extracellular domain comprising an antigen interacting domain that binds an antigen (designated “101” in the figure above) and (ii) an intracellular region comprising an immune cell signaling domain (designated “102” in the figure above) (e.g., ¶ 0006, 0034, 0043-0050, 0156-0191). Qi teaches that the extracellular region comprising an antigen interacting domain can be linked to the intracellular region by a membrane spanning segment (e.g., ¶ 0186), which reads on a transmembrane domain. Relevant to claims 1 and 9-11 , Qi recites that the systems of the disclosure can be introduced into a variety of (mammalian) immune cells, including lymphocytes (e.g., natural killer (NK) cells, B cells, T cells), dendritic cells, and macrophages, among others, and does not induce phagocytosis upon antigen binding (e.g., ¶ 0007, 0126, 0276-0278, 0295-0299). Relevant to claims 2 and 6 , Qi discloses that the antigen interacting domain comprised in the extracellular region can be a scFv or VHH (e.g., ¶ 0008-0012, 0159-0162) and that the antigen can be membrane-bound or non-membrane-bound antigen on a target cell which is associated with a disease (e.g., ¶ 0165-0166). Relevant to claims 3-5, 21, and 23 , Qi discloses that in embodiments of the invention the intracellular immune cell signaling domain comprises an ITIM, e.g., an ITIM of PECAM-1 1 (e.g., ¶ 0013, 0187-0190), or that the intracellular immune cell signaling domain comprises a co-stimulatory domain, e.g., a signaling domain of ITGB1 or ITGB2 2 , or ICAM-1 3 , or ITGAE 4 (e.g., ¶ 0014). Each of these exemplary signaling domains would be expected to interact with the cytoskeleton of the cell as evidenced by Applicant's disclosure. Relevant to claims 13-15 , Qi discloses in vitro or ex vivo with viral delivery systems comprising pharmaceutical compositions of the disclosure that can be implanted in a patient to treat a disease (e.g., ¶ 0431-0446). Relevant to claims 16-17 , as best understood in view of the 35 U.S.C. § 112(b) issues raised above, contacting a cell expressing the chimeric transmembrane receptors disclosed by Qi, comprising an antigen interacting domain which binds a disease-associated antigen, would be expected to alter their binding characteristics (e.g., ¶ 0043-0048, 0055-0068). Relevant to claims 18-19 , Qi discloses using immune cells regulated by a system of the invention in applications such as immunotherapy, to treat disorders including cancer or inflammatory conditions (e.g., ¶ 0276, 0296). Regarding claim 22 , Qi teaches that the immune cells expressing the chimeric receptor polypeptides of the invention may be cells that are not T cells (e.g., NK cells, macrophages). Accordingly, the limitation that the cell additionally comprises a CAR that, when stimulated, activates the T cell is not required to meet the limitations of the claim. In contrast to the instant claims, Qi does not expressly recite a cell comprising a fusion protein comprising an extracellular binding domain, one or more transmembrane domains, and an intracellular domain capable of signaling to the cytoskeleton of the cell upon binding of the extracellular binding domain to a binding moiety, wherein under the condition that the cell is a T cell, the intracellular domain is not a co-stimulatory domain in a CAR that, when stimulated, activates said cell. However, Qi does provide for methods of using said engineered immune cells to induce cytotoxicity of antigen-expressing target cells, or for regulating gene expression and/or cellular activity, which one of ordinary skill in the art would recognize can be accomplished using multiple cell types (e.g., NK cells) (e.g., ¶ 0276-0279, 0295-0299; claims 1-3). For example, Qi expressly mentions that NK cells expressing a chimeric receptor polypeptide of the invention can mediate killing of a target cell upon activation (e.g., ¶ 0297). Furthermore, as evidenced by the instant disclosure, the exemplary intracellular primary signaling domains disclosed by Qi would be expected to engage with the cell cytoskeleton upon binding of the chimeric receptor polypeptide to a target cell expressing the target antigen. Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a mammalian cell comprising a fusion protein comprising (i) an extracellular domain comprising a first binding moiety that binds to a second binding moiety, (ii) at least one transmembrane domain, and (iii) an intracellular domain capable of signaling to the cytoskeleton, based on the teachings of Qi. The skilled artisan would have been motivated to do so because said cells have utility in immunotherapy applications including inducing death of or regulating gene expression of a target cell. There would have been a reasonable expectation of success because the recited elements of the chimeric receptor polypeptides comprised in the engineered mammalian cells disclosed by Qi (i.e., an extracellular domain comprising an antigen-binding domain; an intracellular domain with an ITIM capable of signaling to the cytoskeleton) are known and understood by those of ordinary skill in the art to carry out these respective functions . 07-22-aia AIA Claim s 1 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Qi (US 2018/0346543 A1; supra ) as applied to claim s 1-6, 9-11, 13-19, and 21-23 above, and further in view of Primo Ramos (WO 2019/077062 A1) . The teachings of Qi are recited in the 35 U.S.C. § 102 above. In addition, Qi teaches that the target cell bound by the chimeric receptor polypeptide-expressing immune cells of the invention is a cancer cell (e.g., ¶ 0058). However, Qi does not expressly disclose a method for adhering a cell of the invention to a scaffold. The disclosure of Primo Ramos relates to CAR-T cells (e.g., Abstract). As understood by those of ordinary skill in the art, CARs typically comprise an extracellular antigen-binding domain, a transmembrane domain, and one or more intracellular signaling domains. Primo Ramos discloses methods using 3D cell culture constructs, wherein ex vivo 3D cell culture constructs built to mimic the tumor microenvironment are used to activate T cells or to evaluate activated CAR-T cells (page 139). Primo Ramos teaches that these constructs can be generated “by culturing primary tissues or established cell lines within … synthetic scaffolds” (page 139). Based on the further teachings of Primo Ramos, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to adhere a cell such as that taught by Qi, with a scaffold such as taught by Primo Ramos, e.g., a scaffold that simulates the tumor microenvironment. The skilled artisan would have been motivated to do so because the scaffold could be used to evaluate the activity and/or efficacy of the engineered cells in a particular microenvironment, e.g., prior to administering the cells to a human subject. There would have been a reasonable expectation of success because the CAR-T cells recited for use in the method by Primo Ramos, similarly to the engineered immune cells of Qi, are immune cells comprising a polypeptide construct having a similar structure (i.e., an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain), and it is recognized in the art known work in one field of endeavor may prompt variations of it for use in the same field. Conclusion 07-40 AIA Applicant's 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 Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm 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, Julie Wu can be reached at (571) 272-5205. 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. /ELIZABETH A SHUPE/Examiner, Art Unit 1643 /JULIE WU/Supervisory Patent Examiner, Art Unit 1643 Application/Control Number: 18/030,662 Page 2 Art Unit: 1643 Application/Control Number: 18/030,662 Page 3 Art Unit: 1643 Application/Control Number: 18/030,662 Page 4 Art Unit: 1643 Application/Control Number: 18/030,662 Page 5 Art Unit: 1643 Application/Control Number: 18/030,662 Page 6 Art Unit: 1643 Application/Control Number: 18/030,662 Page 7 Art Unit: 1643 Application/Control Number: 18/030,662 Page 8 Art Unit: 1643 Application/Control Number: 18/030,662 Page 9 Art Unit: 1643 Application/Control Number: 18/030,662 Page 10 Art Unit: 1643 Application/Control Number: 18/030,662 Page 11 Art Unit: 1643 Application/Control Number: 18/030,662 Page 12 Art Unit: 1643 1 As evidenced by the instant disclosure, PECAM-1 is an immunoglobulin adhesion molecule. See page 36. 2 As evidenced by the instant disclosure, ITGB1 and ITGB2 are integrin beta chain family cell adhesion molecules. See page 36. 3 As evidenced by the instant disclosure, ICAM-1 is an immunoglobulin adhesion molecule. See page 36 4 As evidenced by the instant disclosure, ITGAE is an integrin alpha chain cell adhesion molecule. See page 36.
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