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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 20 November 2025 has been entered.
Status of the Claims
Applicant’s submission filed 20 November 2025 has been entered. Claims 1-2, 4, 7-8, 23-24, 27, 31, and 58-60 are pending. Claims 4, 7-8, 23-24, and 27 have been amended, while claims 12, 14, 16, 20, and 34-35 have been cancelled without prejudice or disclaimer and claims 58-60 have been newly added. Therefore, prosecution on the merits continues for claims 1-2, 4, 7-8, and 58 as being drawn to the elected invention, with claims 23-24, 27, 31, and 59-60 withdrawn for reading on the non-elected invention. It is of note that new claims 59-60 are directed to methods of treating different types of cancers, and accordingly are encompassed by the invention of unelected Group III within the Restriction requirement filed 26 September 2024. 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 the drawings
The replacement drawings sheets filed 20 November 2025 are acknowledged and entered into
the application file. With that, the replacement drawing sheets are submitted in black and white, thus obviating the objection of record.
Therefore, the objection is withdrawn.
RE: Objection to the Specification
As indicated in the Office action filed 20 October 2025, the substitute Specification filed 29 September 2025 obviates the objection of record.
Therefore, the objection was withdrawn.
RE: Rejection of claims 1-2, 4, and 7-8 under 35 USC 102(a)(2) over Powell et al
As indicated in the Office action filed 20 October 2025, Powell et al is disqualified as prior art under 35 USC 102(b)(2)(C) since both Powell et al and the instant invention are both owned or subject to assignment of The Trustees of the University of Pennsylvania.
Therefore, the rejection was withdrawn.
RE: Rejection of claims 1-2, 4, and 7-8 under 35 USC 103 over June et al in view of Jeevan-Raj et al
Applicant's arguments filed 20 November 2025 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting in Pages 6-8 of the Remarks filed 20 November 2025 that June et al fail to teach, suggest, or motivate an ordinary artisan to utilize a transcription factor as the agent comprised within the second polynucleotide, and instead point to other CARs, checkpoint inhibitors, or cytokines. In response, the Examiner respectfully submits that June et al disclose that the agent comprised within the second polynucleotide activates the expression and/or secretion of a component that enhances the immune response or immune cell activation. See Paragraph [0216] of June et al. With that, Jeevan-Raj et al disclose that TCF7 enhances immune effector cell activation through the controlled expression of granzyme. Therefore, the ordinary artisan would have been motivated to utilize TCF7 as the inducible agent since it fits the description provided by June et al.
It is also of note that June et al further disclose that the second, inducible polynucleotide can comprise binding sites for transcription factors, and that transcription occurs in response to activation of the CAR molecule comprised within the first polynucleotide. See Paragraphs [0040], [0130], and [0185] of June et al. This therefore further supports the Examiner’s assertion, as the ordinary artisan would have recognized and been motivated to include transcription factors within the second polynucleotide given that the disclosure of June et al highlights their inducible interplay with the first polynucleotide, as well as their role in transcription.
Applicant has further traversed the rejection, asserting in Pages 9-10 that the ordinary artisan would not have had a reasonable expectation of success in generating the engineered cell as instantly claimed, as current CAR T therapy has thus far demonstrated limited success in the solid tumor setting due, in part, to T cell exhaustion. In response, the Examiner respectfully submits that the features upon which Applicant relies (i.e., T cells, solid tumor setting, cancer therapeutic, T cell exhaustion) are not recited in at least rejected claim 1. 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). Furthermore, it was well known in the art at the time of filing that TCF7 regulates memory-like states in CD8+ T cells and is required for reinvigorating CD8+ T cells. See Pages 1007 and 1010 of Sade-Feldman et al. Accordingly, the ordinary artisan would have recognized the potential of TCF7 in rescuing exhausted T cells, as well as the enhancement of CAR T cell activity by generating more memory-like cells. See Page 1010 of Sade-Feldman et al.
Therefore, the rejection is maintained.
RE: IDS size fee and assertion
Applicant has provided the size fee required under 37 CFR 1.17(v)(1) for the IDS filed 29 September 2025.
Therefore, the IDS has been considered.
New/Maintained Grounds of Rejection
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 1-2, 4, and 7-8 remain rejected under 35 U.S.C. 103 as being unpatentable over June et al (US 2018/0044424 A1, of record on the IDS filed 23 November 2022) in view of Jeevan-Raj et al (Cell Reports, 2017, of record).
June et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2), with a publication date of 15 February 2018. Jeevan-Raj et al is considered prior art under 35 USC 102(a)(1).
Regarding claims 1-2: June et al disclose immune effector cells engineered to constitutively express a chimeric antigen receptor (CAR) (referred to herein as a nonconditional CAR) and conditionally express an agent that enhances the immune effector response (Abstract; Paragraphs [0214]-[0215], [0219]). June et al further disclose that the agent that enhances the immune response is only substantially expressed when the non-conditional CAR-expressing cell is activated (Paragraphs [0215], [0219]).
June et al further disclose that the agent that enhances the immune response comprises an agent that activates the expression and/or secretion of a component that enhances immune response or immune effector cell activation (Paragraph [0216]).
June et al further disclose that the constitutively-expressed CAR is encoded by a first polynucleotide and that the conditionally-expressed agent is encoded by a second polynucleotide, and that both polynucleotides are comprised within a single vector (Paragraphs [0042]-[0050], [0168], [0438]-[0439]).
June et al further disclose that the engineered immune effector cell is an NK cell (Abstract; Paragraphs [0065], [0154], [0273], [0423]).
June et al do not disclose that the agent that enhances the immune response is FOXO1-3A or TCF7, as required by instant claim 1.
Jeevan-Raj et al, however, disclose that Tcf1 – which is encoded by the Tcf7 gene – is essential for the development of NK cells, ensuring NK cell survival during maturation and following activation by preventing excessive granzyme expression (Abstract; Page 614, Column 1; Page 619; Page 621).
Therefore, it would have been prima facie obvious to have modified the engineered NK cell of June et al to comprise TCF7 as the inducible agent. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to have an induced expression of TCF7, as it enhances immune effector cell activation via the prevention of excessive granzyme expression according to Jeevan-Raj et al, and would have had a reasonable expectation of success based on the cell engineering protocols outline in the disclosure of June et al (Paragraphs [0042]-[0050], [0168], [0214]-[0215], [0219], [0438]-[0439]). See MPEP § 2143(I)(G).
Consequently, June et al as modified by Jeevan-Raj et al render obvious an engineered NK cell (claim 2) comprising (1) a first polynucleotide comprising a nucleic encoding a CAR that is operably linked to a constitutive promoter, and (2) a second polynucleotide comprising a nucleic acid encoding TCF7 that is operably linked to an inducible promoter, wherein the inducible promoter is induced when the CAR receives an activating signal. As the first polynucleotide and second polynucleotide are comprised within a single vector, this inherently indicates that the two polynucleotides are covalently linked to each other – see Figure 14 of the instant disclosure. This therefore renders obvious the engineered cell of instant claim 1.
Regarding claim 4: Following the discussion of claim 2, June et al further disclose that the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the intracellular signaling domain comprises an intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, LFA-1, CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83 (Paragraphs [0012], [0274], [0384], [0394], [0396], [0400]). This therefore reads on the engineered cell of the instant claim.
Regarding claim 7: Following the discussion of claim 2, June et al further disclose that an agent that enhances the immune response of an immune effector cell can also be an exogenous TCR or a TCR-based molecule, wherein the TCR comprises alpha and beta, or TCR gamma and delta chains (Paragraphs [0199], [0223]-[0237]).
Therefore, it would have been prima facie obvious to have substituted the first polynucleotide comprising a nucleic acid encoding a constitutively expressed CAR with a nucleic acid encoding a constitutively expressed TCR-based molecule, as doing so would have been a simple substitution of one known tumor-killing receptor for another. See MPEP § 2143(I)(B). One of ordinary skill before the effectively filing date of the invention would have recognized that the two receptors are functionally comparable, especially as the exogenous TCR-based molecule of June et al can be a fusion protein with a CAR (Paragraph [0223]), and thereby would have been able to substitute the receptors with predictable results.
Consequently, June et al as modified by Jeevan-Raj et al render obvious an engineered NK cell comprising a first polynucleotide comprising a nucleic encoding an exogenous TCR-based molecule that is operably linked to a constitutive promoter, wherein the TCR-based molecule comprises TCR alpha and beta chains, or TCR gamma and delta chains. This therefore renders obvious the engineered cell of the instant claim.
Regarding claim 8: Following the discussion of claim 1, June et al further disclose that the inducible promoter is an NFAT promoter or an NF-κB promoter (Paragraphs [0251]-[0254]). This therefore reads on the engineered cell of the instant claim.
Claims 1-2, 4, 7-8, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over June et al (US 2018/0044424 A1, of record on the IDS filed 23 November 2022) in view of Sade-Feldman et al (Cell, 2018).
June et al is considered prior art under 35 USC 102(a)(1) and 35 USC 102(a)(2), with a publication date of 15 February 2018. Sade-Feldman et al is considered prior art under 35 USC 102(a)(1).
Regarding claims 1-2: June et al disclose immune effector cells engineered to constitutively express a chimeric antigen receptor (CAR) (referred to herein as a nonconditional CAR) and conditionally express an agent that enhances the immune effector response (Abstract; Paragraphs [0214]-[0215], [0219]). June et al further disclose that the agent that enhances the immune response is only substantially expressed when the non-conditional CAR-expressing cell is activated (Paragraphs [0215], [0219]).
June et al further disclose that the agent that enhances the immune response comprises an agent that improves or enhances the efficacy of a CAR (Paragraphs [0004], [0212]).
June et al further disclose that the constitutively-expressed CAR is encoded by a first polynucleotide and that the conditionally-expressed agent is encoded by a second polynucleotide, and that both polynucleotides are comprised within a single vector (Paragraphs [0042]-[0050], [0168], [0438]-[0439]).
June et al further disclose that the second polynucleotide can comprise binding sites for transcription factors (Paragraphs [0040], [0130], [0185]).
June et al further disclose that the engineered immune effector cell is a CD8+ T cell (Abstract; Paragraphs [0064], [0154], [0174], [0273], [0423], [0524], [0562]).
June et al further disclose that the engineered immune effector cell is utilized in the treatment of melanoma (Paragraphs [0067], [620]-[0621], [0633], [0638]-[0639], [0665], [0730]).
June et al do not disclose that the agent that enhances the immune response is FOXO1-3A or TCF7, as required by instant claim 1.
Sade-Feldman et al, however, disclose that expression of TCF7 within CD8+ T cells allows for a positive clinical outcome in melanoma patients (Page 998). As such, Sade-Feldman et al disclose that TCF7 regulates memory-like states in CD8+ T cells and is required for reinvigorating CD8+ T cells (Pages 1007, 1010). Sade-Feldman et al further disclose that CAR T cell therapy is enhanced by generating more memory-like cells (Page 1010).
Therefore, it would have been prima facie obvious to have modified the engineered CD8+ T cell of June et al to comprise TCF7 as the inducible agent. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to have an induced expression of TCF7, as it enhances the efficacy of CAR T cell therapy via the generation of memory-like cells and leads to a better outcome (Sade-Feldman et al: Pages 1007, 1010), and would have had a reasonable expectation of success based on the cell engineering protocols outline in the disclosure of June et al that allow for the incorporation of transcription factors within the inducible second polynucleotide (Paragraphs [0042]-[0050], [0168], [0214]-[0215], [0219], [0438]-[0439]). See MPEP § 2143(I)(G).
Consequently, June et al as modified by Sade-Feldman et al render obvious an engineered T cell (claim 2) comprising (1) a first polynucleotide comprising a nucleic encoding a CAR that is operably linked to a constitutive promoter, and (2) a second polynucleotide comprising a nucleic acid encoding TCF7 that is operably linked to an inducible promoter, wherein the inducible promoter is induced when the CAR receives an activating signal. As the first polynucleotide and second polynucleotide are comprised within a single vector, this inherently indicates that the two polynucleotides are covalently linked to each other – see Figure 14 of the instant disclosure. This therefore renders obvious the engineered cell of instant claim 1.
Regarding claim 4: Following the discussion of claim 2, June et al further disclose that the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the intracellular signaling domain comprises an intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, LFA-1, CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83 (Paragraphs [0012], [0274], [0384], [0394], [0396], [0400]). This therefore reads on the engineered cell of the instant claim.
Regarding claim 7: Following the discussion of claim 2, June et al further disclose that an agent that enhances the immune response of an immune effector cell can also be an exogenous TCR or a TCR-based molecule, wherein the TCR comprises alpha and beta, or TCR gamma and delta chains (Paragraphs [0199], [0223]-[0237]).
Therefore, it would have been prima facie obvious to have substituted the first polynucleotide comprising a nucleic acid encoding a constitutively expressed CAR with a nucleic acid encoding a constitutively expressed TCR-based molecule, as doing so would have been a simple substitution of one known tumor-killing receptor for another. See MPEP § 2143(I)(B). One of ordinary skill before the effectively filing date of the invention would have recognized that the two receptors are functionally comparable, especially as the exogenous TCR-based molecule of June et al can be a fusion protein with a CAR (Paragraph [0223]), and thereby would have been able to substitute the receptors with predictable results.
Consequently, June et al as modified by Jeevan-Raj et al render obvious an engineered NK cell comprising a first polynucleotide comprising a nucleic encoding an exogenous TCR-based molecule that is operably linked to a constitutive promoter, wherein the TCR-based molecule comprises TCR alpha and beta chains, or TCR gamma and delta chains. This therefore renders obvious the engineered cell of the instant claim.
Regarding claim 8: Following the discussion of claim 1, June et al further disclose that the inducible promoter is an NFAT promoter or an NF-κB promoter (Paragraphs [0251]-[0254]). This therefore reads on the engineered cell of the instant claim.
Regarding claim 58: As aforementioned in the discussion of claims 1 and 8, June et al as modified by Sade-Feldman et al render obvious an engineered T cell comprising (1) a first polynucleotide comprising a nucleic encoding a CAR that is operably linked to a constitutive promoter, and (2) a second polynucleotide comprising a nucleic acid encoding TCF7 that is operably linked to an NFAT-inducible promoter, wherein the inducible promoter is induced when the CAR receives an activating signal, and wherein the first polynucleotide and second polynucleotide are covalently linked.
June et al further disclose that the CAR comprises an antigen binding domain that specifically binds to Her2 or CD20, a hinge region and transmembrane domain from human CD8, an intracellular costimulatory signaling domain from human 4-1BB, and an intracellular signaling domain of human CD3 zeta (Paragraphs [0023], [0028]-[0034], [0066], [0261], [0264]-[0267], [0270]-[0271], [0386], [0403]-[0404], [0446]).
This therefore renders obvious the engineered human T cell of the instant claim for the same reasons as discussed in the rejection of instant claim 1 above.
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