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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 26 February 2026 has been entered.
Status of the Claims
Applicant’s submission filed 26 February 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: Objection to claim 5
Applicant’s amendment to independent claim 5 correct the minor informalities, thus obviating the objection of record.
Therefore, the objection is withdrawn.
RE: Rejection of claims 5-7 under 35 USC 112(b)
Applicant’s amendments to independent claim 5 clarify the claim scope, thus obviating the rejection of record.
Therefore, the rejection is withdrawn.
RE: Claim Interpretation
Applicant has traversed the Examiner’s interpretation, asserting in Page 5 of the Remarks filed 26 February 2026 that iPSC-derived CTLs are structurally distinguishable from directly modified T cells by virtue of distinct epigenetic profiles, restored telomere length, and naïve-like phenotype resulting from iPSC reprogramming and re-differentiation. In response, the Examiner respectfully submits that Applicant has not provided any supporting evidence for these asserted distinguishments, and reminds Applicant that a showing of nonobviousness in a product-by-process claim must be based on evidence, not argument or speculation. See MPEP § 716.01 and 2113(II).
Therefore, the Examiner’s interpretation of the product-by-process limitation is maintained.
RE: Rejection of claims 5-10 under 35 USC 103 over Gschweng et al in view of Cooper et al
Applicant's arguments filed 26 February 2026 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting in Pages 5-6 and 9 of the Remarks filed 26 February 2026 that the combination of Gschweng et al and Cooper et al fail to teach that the re-introduced HLA-A allele matches the HLA restriction of the TCR within the cytotoxic T cell. In response, the Examiner respectfully submits that Gschweng et al disclose that the cytotoxic T cell can comprise an HLA-class I-restricted TCR. See, for example, Paragraphs [0247]-[0248] of Gschweng et al. Although Gschweng et al do not disclose that the HLA-class I-restricted TCR is an HLA-A-restricted TCR nor the introduction of a matching exogenous HLA-A allele, Cooper et al disclose the introduction of a chimeric HLA-E and HLA-A2 construct into a T cell expressing an HLA-A2-restricted TCR. See Paragraphs [0073]-[0077] of Cooper et al. Therefore, the combination of Gschweng et al and Cooper et al reasonably suggest the introduction of an HLA-A2 molecule to the cytotoxic T cell, wherein the HLA-A2 molecule matches the HLA restriction of the TCR within the cytotoxic T cell.
Applicant has further traversed the rejection, asserting in Page 6 of the Remarks filed 26 February 2026 that Cooper et al fail to teach the introduction of a full-length HLA-A2 molecule, and instead disclose the use of an HLA-A2 signal peptide within a chimeric HLA-E construct. In response, the Examiner respectfully submits that the broadest reasonable interpretation of the claims does not require the full-length sequences of the HLA-A molecule or the HLA-E molecule. More specifically, the instant disclosure does not define the term “molecule”, which can plainly be interpreted to mean either a full-length or a fragment of the HLA allele. With that, the instant disclosure states that plasmids comprising half of HLA-A and half of HLA-E can be knocked into the T-iPSCs. See, for example, Paragraph [0057] of the instant Specification filed 05 August 2022. Accordingly, the HLA-A2 signal peptide within the chimeric HLA-E and HLA-A2 construct of Cooper et al reads on the “HLA-A molecule” of the instant claims.
Applicant has lastly traversed the rejection, asserting in Pages 7-10 of the Remarks filed 26 February 2026 the technical significance of the claimed cytotoxic T cell, including the introduction of a TCR restriction-matched HLA-A allele, evasion of the HLA-A- and HLA-E-expressing cytotoxic T cells from NK cell-mediated killing, as well as the claimed cytotoxic T cells enhanced in vivo therapeutic efficacy. Applicant cites Examples 3 and 5-7 of the instant disclosure to support these assertions. In response, the Examiner first respectfully notes that the functions allegedly associated with cytotoxic T cells comprising an exogenous HLA-E molecule and HLA-A molecule that is matched to the TCR restriction in Examples 3 and 5-7 are not required by, nor recited in, the pending claims. Although the claims are interpreted in light of the Specification, limitations from the Specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Thus, the cytotoxic T cells of Gschweng et al and/or Cooper et al need not anticipate nor render obvious the same functions. As noted in the rejection of record, Cooper et al disclose that the cytotoxic T cells expressing the chimeric HLA-E and HLA-A2 construct are capable of avoiding NK mediated targeting at Paragraph [0074]. Furthermore, the Examiner respectfully reminds Applicant that, in submitting evidence asserted to establish unobvious results, there is a burden on 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. The evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter relative to the prior art subject matter. See MPEP § 2145. It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. See MPEP § 716.02(b). In the instant case, the Examiner notes that the evidence relied upon is not commensurate in scope with the pending claims. More specifically, the cytotoxic T cells of at least independent claims 5 and 8 require an HLA-A molecule that is matched to the TCR’s HLA restriction – which is broader than the cytotoxic T cells within the referenced examples comprising an exogenous HLA-A24 molecule that is matched to the TCR’s HLA restriction. Thus, the cytotoxic T cells relied upon as evidence are not of the same scope as the pending claims.
Therefore, the rejection is maintained and amended to encompass the claims as written.
Maintained Grounds of Rejection
Claim Interpretation
Instant claims 5-7 are directed to products, which utilize product-by-process language. The limitations of the process of production are considered only in so far as the process of production imparts distinct structural or chemical characteristics or properties to the claimed product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e. is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. See MPEP § 2113.
Claims 5-7 further define the cytotoxic T cells as being derived from human T cell-derived iPS cells, wherein the cytotoxic T cell expresses a TCR that exhibits the same antigen specificity as the original T cell from which the iPS cells are derived from, and wherein the cytotoxic T cells do not express any endogenous HLA class I molecules. When defining the source of cells, the source of the cells is only considered in as far as the source defines the cell as having distinct biochemical or morphological characteristics. In the instant case, the source of the cytotoxic T cells does not impart a distinction to the cells, other than requiring the cytotoxic T cells to have an antigen specificity and express no endogenous HLA class I molecules.
Therefore, the claims will be interpreted as if cytotoxic T cells having an antigen specificity, lacking endogenous expression of HLA class I molecules, and exogenously expressing an HLA-E molecule and an HLA-A molecule, wherein the HLA-A molecule is matched to the cytotoxic T cell TCR’s HLA restriction, from any source fulfills the limitations detailed in the instant claims.
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 5-10 remain rejected under 35 U.S.C. 103 as being unpatentable over Gschweng et al (WO 2019/161271 A1, of record) in view of Cooper et al (US 2007/0036773 A1, of record).
Gschweng et al and Cooper et al are each considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2).
Regarding claims 5-7: The instant claims comprise product-by-process language. The effect of the product-by-process language is discussed above – see Claim Interpretation -– and included herein.
Accordingly, Gschweng et al disclose modified T cells that are generated from engineered stem cells for use in an autologous or allogeneic setting for engineered immunotherapy (Abstract).
As such, Gschweng et al disclose that the modified T cells are produced from induced pluripotent stem cells (iPSCs) derived from T cells that 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, wherein the modified cytotoxic T cells retain antigen specificity (Paragraphs [0060], [0063]-[0064], [0117], [0124], [0247]-[0248]).
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, as required by instant claim 5.
Cooper et al, however, disclose the generation of universal T cells that comprise an HLA-E molecule and a non-classical HLA molecule to enforce the expression of the HLA-E molecule, including HLA-A2 (Abstract; Paragraphs [0035], [0075]). Cooper et al further disclose that the chimeric HLA-E and HLA-A2 construct is introduced into a universal T cell expressing an HLA-A2-restricted TCR (Paragraphs [0073]-[0077]). Cooper et al further disclose that the co-expression of HLA-E and HLA-A2 on the universal T cell allows the universal T cell to avoid NK cell mediated targeting (Paragraph [0074]).
Therefore, it would have been prima facie obvious to have modified the cytotoxic T cells of Gschweng et al such that the final engineered cytotoxic T cells comprise an exogenous HLA-E molecule and supporting HLA-A2 molecule, wherein the exogenous HLA-A2 molecule matches the MHC-restricted TCR of the cytotoxic T cell, as detailed in Cooper et al. One of ordinary skill in the art would have been motivated to enhance the surface expression of HLA-E via the co-expression with HLA-A2, as it allows the cell to avoid NK mediated targeting (Cooper et al: Paragraph [0074]), and would have had a reasonable expectation of success given the disclosures of Gschweng et al and Cooper et al are both concerned with the generation of universal T cells that comprise MHC class I-restricted TCRs. See MPEP § 2143(I)(G).
Consequently, Gschweng et al as modified by Cooper et al render obvious the generation of modified cytotoxic T cells comprising an exogenous HLA-A2-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 exogenous HLA-E and HLA-A2 (claims 6-7) molecules, and then differentiated into cytotoxic T cells. As the exogenous HLA-A2 matches the HLA-restricted TCR of the cytotoxic T cell, and the co-expression of HLA-A2 with HLA-E allows for the cytotoxic T cell to avoid NK mediated targeting and subsequent elimination, this therefore renders obvious the method of instant claim 5.
Regarding claims 8-10: 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, as required by instant claim 8.
Cooper et al, however, disclose the generation of universal T cells that comprise an HLA-E molecule and a non-classical HLA molecule to enforce the expression of the HLA-E molecule, including HLA-A2 (Abstract; Paragraphs [0035], [0075]). Cooper et al further disclose that the chimeric HLA-E and HLA-A2 construct is introduced into a universal T cell expressing an HLA-A2-restricted TCR (Paragraphs [0073]-[0077]).
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 supporting HLA-A2 molecule, wherein the exogenous HLA-A2 molecule matches the MHC-restricted TCR of the cytotoxic T cell, as detailed in Cooper et al. One of ordinary skill in the art would have been motivated to enhance the surface expression of HLA-E via the co-expression with HLA-A2, as it allows the cell to avoid NK mediated targeting (Cooper et al: Paragraph [0074]), and would have had a reasonable expectation of success given the disclosures of Gschweng et al and Cooper et al are both concerned with the generation of universal T cells that comprise MHC class I-restricted TCRs. See MPEP § 2143(I)(G).
Consequently, Gschweng et al as modified by Cooper et al render obvious a method of generating a modified cytotoxic T cell comprising an exogenous HLA-A2-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 exogenous HLA-E and HLA-A2 (claims 9-10) molecules, and then differentiated into cytotoxic T cells. As the exogenous HLA-A2 matches the HLA-restricted TCR of the cytotoxic T cell, this therefore renders obvious the method of instant claim 8.
Conclusion
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