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 the Claims
Applicant’s submission filed 05 June 2026 has been entered. Claims 5-10 are pending. Claims 5 and 8 have been amended. Therefore, prosecution on the merits continues for claims 5-10. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Claim Interpretation
Applicant has traversed the Examiner’s interpretation, asserting in Pages 8-9 of the Remarks filed 05 June 2026 that iPSC-derived CTLs are structurally distinguishable from directly modified T cells due to the fact iPSC-derived CTLs have an expression profile of PD1-CD27+CD28+CCR7+, whereas CTLs do express PD-1. See the disclosures of Ando et al (Experimental Hematology, 2017, provided on IDS filed 05 June 2026) and Gschweng et al. In response, the Examiner has fully considered Applicant’s arguments and finds them persuasive.
Therefore, the Examiner’s interpretation of the product-by-process limitation is withdrawn.
RE: Rejection of claims 5-10 under 35 USC 103 over Gschweng et al in view of Cooper et al
Applicant has amended independent claims 5 and 8 to require the cytotoxic T cell to comprise and express both of a gene encoding an HLA-A molecule and a gene encoding an HLA-E molecule, and to have an expression profile of PD1-CD27+CD28+CCR7+. As these are new limitations not previously considered, Applicant’s amendments obviate the rejection of record.
Therefore, the rejection is withdrawn.
New Grounds of Rejection
Claim Objections
Claims 5 and 8 are objected to because of the following informalities:
Regarding claims 5 and 8: The instant claims are each objected to for reciting “wherein the cytotoxic T cell comprises a gene encoding an HLA-A molecule and a gene encoding an HLA-E molecule, and expresses both the HLA-molecule, and the HLA-E molecule”, which has an extraneous comma in the recitation of “and expresses both the HLA-molecule[[,]] and the HLA-E molecule”.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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 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 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Ando et al (Experimental Hematology, 2017, of record on IDS filed 05 June 2026) in view of Niazi et al (US 10344280 B1).
Ando et al is considered prior art under 35 USC 102(a)(1), with a publication date greater than one year prior to the effective filing date of the instant invention. Niazi et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claim 5: Ando et al disclose rejuvenated induced-pluripotent stem cell (iPSC)-derived antigen-specific cytotoxic T cells (Abstract).
As such, Ando et al disclose that the rejuvenated cytotoxic T cells are produced from iPSCs derived from human T cells expressing a TCR having an antigen specificity (Pages 5-6; Figures 3-4). Ando et al further disclose that the rejuvenated cytotoxic T cell expresses a TCR having the same antigen specificity as the original T cell (Pages 5-6).
Ando et al further disclose that the rejuvenated cytotoxic T cells do not express PD-1, and express CD27, CD28, and CCR7 (Page 7, Column 1).
Ando et al further disclose that the rejuvenated cytotoxic T cells can be engineered to express exogenous TCRs and utilized in various therapeutic approaches (Pages 8-9).
Ando et al fail to disclose that the rejuvenated cytotoxic T cells are HLA-null and further engineered to comprise a gene encoding an HLA-A molecule in addition to a gene encoding an HLA-E molecule, wherein the HLA-A molecule matches the HLA restriction of the TCR within the rejuvenated cytotoxic T cells, as required by instant claim 5.
Niazi et al, however, disclose cytotoxic T cells that are engineered to lack expression of endogenous HLA class I molecules, and further express an exogenous recipient-matched HLA-A restricted gene and an exogenous HLA-E gene (Columns 2-6).
Niazi et al further disclose that expression of the recipient-matched HLA-A molecule and the HLA-E molecule allow for two separate mechanisms that individually suppress NK cell activity (Columns 4-6, 8). Therefore, the ordinary artisan would reasonably expect that the expression of both an HLA-A molecule and HLA-E molecule will have a more potent suppressive effect on the NK cells when compared to the individual suppression of the HLA molecules.
Niazi et al further disclose that the cytotoxic T cells are further engineered to comprise a chimeric T-cell receptor (Columns 5-7). Niazi et al further disclose that T cell antigen recognition of typical antigens is restricted by the recipient’s particular MHC class I haplotype (Column 2).
Therefore, it would have been prima facie obvious to have modified the rejuvenated cytotoxic T cells of Ando et al such that the final engineered rejuvenated cytotoxic T cells lack endogenous expression of HLA class I genes and comprise an exogenous HLA-A gene and an exogenous HLA-E gene, wherein the expressed HLA-A molecule matches the MHC-restricted TCR of the cytotoxic T cell, as detailed in Niazi et al. One of ordinary skill in the art would have been motivated to knockout the endogenous MHC class I molecules and exogenously express an HLA-A and HLA-E molecule, as it minimizes the risk of an immune response when administering the donor cytotoxic T cells to a subject in need thereof (Niazi et al: Columns 3-4), and would have had a reasonable expectation of success given the disclosures of Ando et al and Niazi et al are both concerned with the generation of antigen-specific cytotoxic T cells as therapeutics. Furthermore, the ordinary artisan would have been motivated to have the expressed HLA-A molecule match the MHC-restricted TCR of the cytotoxic T cell to allow for proper T cell antigen recognition, and would have had a reasonable expectation of success given that this is a well-known concept in the art (Niazi et al: Column 2). See MPEP § 2143(I)(G).
Consequently, Ando et al as modified by Niazi et al render obvious the generation of rejuvenated cytotoxic T cells comprising an exogenous HLA-A-restricted TCR specific for an antigen, wherein iPSCs derived from human T cells expressing TCRs having an antigen specificity are differentiated into cytotoxic T cells, wherein the resulting rejuvenated cytotoxic T cells express TCRs having the same antigen specificity as the original T cells, and have an expression profile of PD1-CD27+CD28+ CCR7+. As the resulting rejuvenated cytotoxic T cells also lack endogenous HLA class I expression, comprise an exogenous HLA-A molecule that matches the HLA-restricted TCR, and comprise an exogenous HLA-E molecule, such that the co-expression of HLA-A and HLA-E allows for a more potent NK cell suppression than the individual HLA-A and HLA-E molecules, this therefore renders obvious the cytotoxic T cell of instant claim 5.
Regarding claims 6-7: Following the discussion of claim 5, Niazi et al further disclose that the HLA-A molecule is an HLA-A2 molecule (Column 6). This therefore renders obvious the cytotoxic T cell of the instant claims.
Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Gschweng et al (WO 2019/161271 A1, of record) in view of Ando et al (Experimental Hematology, 2017, of record on IDS filed 05 June 2026) and Niazi et al (US 10344280 B1).
Ando et al is considered prior art under 35 USC 102(a)(1), with a publication date greater than one year prior to the effective filing date of the instant invention. Gschweng et al and Niazi et al are each considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claim 8: Gschweng et al disclose methods of generating modified T cells from engineered stem cells for use in an autologous or allogeneic setting for engineered immunotherapy (Abstract).
As such, Gschweng et al disclose methods of generating modified T cells, wherein induced pluripotent stem cells (iPSCs) derived from T cells are first engineered to eliminate endogenous HLA class I expression via the knockout of B2M (Paragraphs [0010]-[0011], [0013], [0032], [0035]-[0038], [0057]-[0059]). Gschweng et al further disclose that the HLA-null iPSCs are further engineered to comprise an exogenous HLA molecule, including an HLA-E gene (Paragraphs [0016]-[0017], [0040]). Gschweng et al further disclose that the HLA-null iPSCs are further engineered to comprise an exogenous MHC class I-restricted TCR that is specific for an antigen (Paragraphs [0016], [0023], [0045], [0247]-[0248]).
Gschweng et al further disclose that the engineered iPSCs are differentiated into cytotoxic T cells (Paragraphs [0060], [0063]-[0064], [0117]).
Gschweng et al do not disclose that the HLA-null iPSCs are further engineered to comprise an HLA-A molecule in addition to the HLA-E molecule, wherein the HLA-A molecule matches the HLA restriction of the TCR within the cytotoxic T cell, nor that the cytotoxic T cells are PD1-CD27+CD28+ CCR7+, as required by instant claim 8.
Ando et al, however, disclose rejuvenated cytotoxic T cells produced from iPSCs derived from human T cells expressing a TCR having an antigen specificity (Pages 5-6; Figures 3-4). Ando et al further disclose that the rejuvenated cytotoxic T cells do not express PD-1, and express CD27, CD28, and CCR7 (Page 7, Column 1).
With that, Niazi et al disclose cytotoxic T cells that are engineered to lack expression of endogenous HLA class I molecules, and further express an exogenous recipient-matched HLA-A restricted gene and an exogenous HLA-E gene (Columns 2-6).
Niazi et al further disclose that expression of the recipient-matched HLA-A molecule and the HLA-E molecule allow for two separate mechanisms that individually suppress NK cell activity (Columns 4-6, 8). Therefore, the ordinary artisan would reasonably expect that the expression of both an HLA-A molecule and HLA-E molecule will have a more potent suppressive effect on the NK cells when compared to the individual suppression of the HLA molecules.
Niazi et al further disclose that the cytotoxic T cells are further engineered to comprise a chimeric T-cell receptor (Columns 5-7). Niazi et al further disclose that T cell antigen recognition of typical antigens is restricted by the recipient’s particular MHC class I haplotype (Column 2).
Therefore, it would have been prima facie obvious to have modified the method of Gschweng et al such that the HLA-null iPSCs are engineered to comprise an HLA-E molecule and an HLA-A molecule, wherein the exogenous HLA-A molecule matches the MHC-restricted TCR of the cytotoxic T cell, as detailed in Niazi et al. One of ordinary skill in the art would have been motivated to exogenously express an HLA-A and HLA-E molecule, as it minimizes the risk of an immune response when administering the donor cytotoxic T cells to a subject in need thereof (Niazi et al: Columns 3-4), and would have had a reasonable expectation of success given the disclosures of Gschweng et al and Niazi et al are both concerned with the generation of cytotoxic T cells that comprise MHC class I-restricted TCRs. Furthermore, the ordinary artisan would have been motivated to utilize the rejuvenated cytotoxic T cells of Ando et al within the method of Gschweng et al, as the rejuvenated cytotoxic T cells have a higher proliferative capacity and are functionally rejuvenated when compared to original cytotoxic T cells (Ando et al: Page 4), and would have had a reasonable expectation of success given that the disclosures of Gschweng et al and Ando et al are concerned with the generation of therapeutic cytotoxic T cells. See MPEP § 2143(I)(G).
Consequently, Gschweng et al as modified by Ando et al and Niazi et al render obvious a method of generating a modified cytotoxic T cell comprising an exogenous HLA-A-restricted TCR specific for an antigen, wherein T-cell derived iPSCs are first engineered to eliminate endogenous HLA class I expression via the knockout of B2M, which are then further engineered to comprise an exogenous HLA-A molecule and an exogenous HLA-E molecule, and then differentiated into cytotoxic T cells, such that the co-expression of HLA-A and HLA-E allows for a more potent NK cell suppression than the individual HLA-A and HLA-E molecules alone. As the exogenous HLA-A matches the HLA-restricted TCR of the cytotoxic T cell, the final cytotoxic T cells have an expression profile of PD1-CD27+CD28+ CCR7+, this therefore renders obvious the method of instant claim 8.
Regarding claims 9-10: Following the discussion of claim 8, Niazi et al further disclose that the HLA-A molecule is an HLA-A2 molecule (Column 6). This therefore renders obvious the method of the instant claims.
Conclusion
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 ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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