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 .
Application Status
The amended claims filed February 25, 2026 are acknowledged. Claims 1-7, 10-19, 21, and 63 are amended. Claim 71 is newly added.
Claims 1-7, 10-19, 21, 63, and 71 are pending and under examination herein.
WITHDRAWN OBJECTIONS AND REJECTIONS
The objection to the specification is withdrawn in view of Applicant’s amendments to the title.
The rejection of claims 10-11 under 35 U.S.C. § 101 is withdrawn in view of Applicant's claim amendments to recite the engineered TfH-like tumor infiltrating cell of claim 2.
The rejection of claims 10-11 under 35 U.S.C. § 102 is withdrawn in view of Applicant's claim amendments to recite the engineered TfH-like tumor infiltrating cell of claim 2.
The rejection of claims 1, 3-7, 12, and 63 under 35 U.S.C. § 103 as being unpatentable over Kroenke (The Journal of Immunology (2012) 188(8): 3734-3744) in view of Du (J lmmunol Res Ther (2016) 1(1): 22-28), and of claims 13-19 and 21 further in view of Sahin (US 2018/0140634 A1) or Philip (/mmunobiology (2014) 124(8): 1277-1287), is withdrawn in view of Applicant's claim amendments.
The rejection of claims 1-7, 12, and 63 under 35 U.S.C. § 103 as being unpatentable over Kobayashi (European Journal of Immunology (2016) 46: 360-371) in view of Gu-Trantien '13 (The Journal of Clinical Investigation (2013) 123(7): 2873-2892), and of claim 17 further in view of Sahin (US 2018/0140634 A1), is withdrawn in view of Applicant's claim amendments.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENT
Claim Objections
Claim 2 is objected to for the following minor informalities: “proteinto” in line 2 should instead recite “protein to”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 10-11 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.
Claims 10-11 recite the limitation that the polynucleotide that encodes GZMB comprises a nucleic acid sequence of SEQ ID NO: 20 or an equivalent thereof. However, according to the CRF Sequence Listing and the specification (e.g., ¶ 0157), SEQ ID NO: 20 is an amino acid sequence, not a nucleotide sequence. Furthermore, it is not apparent from Applicant's disclosure that all possible nucleotide sequences having at least 90% sequence identity to instant SEQ ID NO: 19 or all possible amino acid sequences having at least 90% sequence identity to instant SEQ ID NO: 20 are sufficiently “equivalent” enough to encode and produce an engineered immune cell having increased GZMB expression as required by the claims. For example, which residues can be mutated (and which cannot) to reliably produce an immune cell that have increased exogenous GZMB expression? In view of these limitations, the claims are considered indefinite because one of ordinary skill in the art cannot readily determine what is considered “equivalent” as it relates to the instantly claimed invention.
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.
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.
(1)
Claims 1-7, 10-16, 18-19, 21, 63, and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Ostertag (US 2021/0130845 A1; earliest priority date: September 8, 2017) in view of Gu-Trantien ‘13 (The Journal of Clinical Investigation (2013) 123(7): 2873-2892; cited in PTO-892 mailed August 27, 2025), as evidenced by Seder (Nature Immunology (2003) 4: 835-842).
Ostertag discloses genetically modified T cells comprising (a) an inducible transgene construct and (b) a chimeric ligand receptor (CLR) construct such as a chimeric antigen receptor (CAR) (e.g., Abstract; ¶ 0005-0022; claims 133-142). The modified T cells of the disclosure can be selected from naïve T cells1 and others (e.g., ¶ 0261-0276). Pertinent to claim 1-3 and 10-12, T cells of the disclosure can be modified to express one or more therapeutic proteins and/or proteins that enhance CAR-T efficacy, including CD4, CD200, CXCL13, Granzyme B (GZMB), IL21, and TNFRSF18 (e.g., ¶ 0372; Table 1 at pages 82, 86, 95, 97, 118). The GZMB peptide sequence comprising SEQ ID NO: 6351 shares 100% sequence identity to instant SEQ ID NO: 20 (Table 1, page 95).
Relevant to claim 2, 10-11, and 71, Ostertag discloses that genetically modified T cells of the invention which have been modified to enhance their therapeutic potential comprise an exogenous sequence encoding the therapeutic protein(s) (e.g., ¶ 0550-0551). Ostertag discloses the modification of immune cells of the invention by introducing a vector comprising a nucleotide sequence (e.g., ¶ 0316-0335).
Pertinent to claims 13-16, 18-19, and 21, the CLR is a chimeric antigen receptor that binds to a tumor-associated antigen (e.g., PSMA) and comprises an ectodomain comprising a ligand recognition region, a transmembrane domain, and an endodomain comprising at least one co-stimulatory domain (e.g., claims 133-136).
Relevant to claim 63, Ostertag discloses a method of treating cancer that comprises administering a population of the genetically modified cells of the invention (e.g., claims 151-152).
However, Ostertag does not expressly recite that the engineered T cells are Tfh-like cells.
Gu-Trantien ’13 teaches that various CD4+ Th subsets have important functions in both pro-tumor and anti-tumor immunity, and that CD4+ Th17 have been shown to produce effective anti-tumor responses (e.g., page 2873). Gu-Trantien ’13 performed comprehensive molecular profiles of infiltrating CD4+ T cells isolated from untreated invasive primary breast cancer tumors (e.g., Abstract). Gu-Trantien ’13 disclose that comparisons between TILs from extensively infiltrated breast cancer tumors revealed a distinct skew to gene expression of Tfh-related factors (e.g., CD200, CXCL13, IL-21) and Th1-related factors (e.g., IFNG, GZMB) relative to minimally infiltrated tumors (e.g., pages 2875-2879; Figure 3, 6I), relevant to claims 1, 3, and 12. Gu-Trantien ’13 further investigated whether these data suggested that extensively infiltrated tumors were characterized by higher T cell activation by treating CD4+ CD45RO+ (memory) T cells from donor peripheral blood with supernatant (SN) retained from fresh primary tumor homogenates, with or without stimulation (S) (e.g., page 2881). Treatment with SN reduced expression of CXCR5 (e.g., page 2881), pertinent to claim 7.
Gene expression profiles of TILs from extensively infiltrated breast cancer tumors further showed that a variety of immune response genes (e.g., TNFRSF4 (LIGHT), TNFRSF18 (GITR), SH2D1A (SAP), CD200, and CXCL13) have increased expression relative to those from minimally infiltrated tumors, with CXCL13 from CD4+ TIL being the most consistently increased (e.g., page 2882; Figure 7), further relevant to claim 12. Gu-Trantien ’13 notes that CXCL13 mRNA expression has been shown to predict survival in breast cancer patients (page 2882). Upon further analysis, Gu-Trantien ’13 determined that the principal CXCL13-producing cells in extensively infiltrated tumors were Tfh cells high in CD200 and PD-1 expression (e.g., page 2885; Figure 9B), and that expression of CXCL13 and IFNG in CD4+ TILs was significantly correlated with CD8+ T cell marker expression in the non-CD4+ tumor fraction (page 2885). Gu-Trantien ’13 also evaluated the association of an 8-gene Tfh signature comprising CXCL13, CD200, SH2D1A, and PDCD1 with disease-free survival (DFS) in systematically untreated primary BC and with pathological complete response (pCR) in a BC cohort treated with preoperative chemotherapy. Gu-Trantien ’13 observed that the 8-gene signature was consistently prognostic, which Gu-Trantien ’13 suggests supports the hypothesis that CXCL13-producing Tfh cells produce antitumor immune responses associated with improved clinical outcomes (e.g., page 2887; Figure 11; Supplemental Table 7B).
Considered together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to engineer a T cell according to the methods of Ostertag which is modeled from the naturally-occurring Tfh-like cells in the tumor microenvironment described by Gu-Trantien ’13 (i.e., Tfh-like cells expressing at least CD4, CXCL13, and GZMB). The skilled artisan would have been motivated to do so because Gu-Trantien ’13 teaches that naturally-occurring Tfh-like cells in the tumor microenvironment produce anti-tumor immune responses associated with improved clinical response to cancer. By applying the methods of Ostertag to engineer a T cell having essentially identical characteristics, one could generate a more effective anti-tumor therapy that can be administered to patients. Furthermore, Ostertag teaches that modifying the T cells of the invention to express one or more of CD4, CXCL13, GZMB, IL21, etc., increases their efficacy for CAR-T cell therapy. One of ordinary skill in the art could have generated such an engineered Tfh-like cell with a reasonable expectation of success because the production of genetic modified T cells as described by Ostertag can be carried out using well-understood, routine, and conventional activities that are known in the relevant art (i.e., introducing expression vectors encoding nucleotide sequences into a cell to induce expression of one or more genes).
Regarding claims 4-7, an engineered Tfh-like cell having essentially the same composition as set forth in the instant claims (i.e., expressing the cell surface markers of CD4 and CXCL13 and further expressing exogenous GZMB) – generated according to the methods of Ostertag based on the further teachings of Gu-Trantien ‘13 – would be expected to have the functional properties of activating a CD8+ cytotoxic T lymphocyte (CTL) response and a CD8+ tissue resident memory (TRM) response in a tumor microenvironment as evidenced by Applicant's disclosure.
(2)
Claims 1 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Ostertag (US 2021/0130845 A1; supra) in view of Gu-Trantien ‘13 (The Journal of Clinical Investigation (2013) 123(7): 2873-2892; supra), as evidenced by Seder (Nature Immunology (2003) 4: 835-842; supra), as applied to claims 1-7, 10-16, 18-19, 21, 63, and 71 above, further in view of Philip (Immunobiology (2014) 124(8): 1277-1287; cited in PTO-892 mailed December 30, 2024).
The teachings of Ostertag are discussed in the 35 U.S.C. § 103 rejection above. In addition, further relevant to claim 17, Ostertag teaches that the expression vectors comprised in the genetically modified cells of the disclosure will preferably include a selectable cell surface marker for isolation of the cells modified by the methods of the disclosure, e.g., the suicide gene marker RQR8 (e.g., ¶ 0394-0398, 0453).
However, Ostertag does not expressly recite that the engineered T cells of the invention are Tfh-like cells further comprising a suicide gene.
The teachings of Gu-Trantien ’13 are recited above.
Philip teaches that suicide genes have considerable practical utility in T-cell cancer gene therapy as they allow selective deletion of administered engineered T cells in the face of toxicity (Abstract; Introduction). Philip generated a highly compact marker/suicide gene for T cells ("RQR8") that binds rituximab, a therapeutic monoclonal antibody used to treat certain types of lymphoma and leukemia, resulting in selective deletion of transgene-expressing cells. Philip predicts that RQR8 will make T-cell gene therapy both safer and cheaper (Abstract).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to further engineer a Tfh-like cell such as that based on the collective teachings of Ostertag and Gu-Trantien ’13, to additionally express a suicide gene, based on the further teachings of Philip. The skilled artisan would have been motivated to do so because suicide genes allow for the selective deletion of engineered T cells administered during the course of T cell cancer therapy in the event that the engineered T cells are toxic to the host. There would have been a reasonable expectation of success in producing such an engineered cell because methods of introducing suicide genes into T cells intended for use in T cell cancer gene therapies are routine and conventional for those of ordinary skill in the art.
Conclusion
No claims are allowed.
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.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
1 As evidenced by Seder (e.g., pages 835-836; Figure 1), naïve T cells can be CD4+ or CD8+.
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