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
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 October 9, 2025 has been entered.
2. Claims 1, 2, 11 and 13 were amended. Claims 4-10 were cancelled. New claim 21 was added.
3. Claims 1-3 and 11-21 are pending and under consideration.
New Grounds of Rejection
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.
4. Claim(s) 1-3, 11-17 and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0355776 A1 (Xiao et al. Dec. 14, 2017), “Xiao-776” in view of US 2018/0334490 A1 (Brogdon et al. Nov. 22, 2018, of record), “Brogdon” and in view of US 2022/0064599 (Spanholtz et al. Mar. 3, 2022, filed May 29, 2019, of record), “Spanholtz”.
Xiao-776 teaches compositions and methods for compositions, methods, and kits for treating cancer using chimeric antigen receptor (CAR) modified cells. See Abstract and ¶¶ 0005-0007.
Xiao-776 teaches administering to a subject an effective amount of a cell genetically modified to express a CAR. See ¶¶ 0011 and 0012.
Xiao-776 teaches intravenous administration, which would administer the CAR cells to the peripheral blood. See ¶¶ 0143, 0257, and 0261.
Xiao-776 teaches that the CAR cells can be T cells or NK cells. See 0094, 0192, and 0201.
Xiao-776 teaches the CAR can target GUCY2C or PAP. Xiao-776 teaches the GUCY2C CAR antigen binding domain comprises SEQ ID NO: 14. See ¶¶ 0016, 0033, 0051, 0061, 0177, and 0196-0201.
SEQ ID NO: 14 comprises the claimed SEQ ID NO: 11. See Appendix.
Xiao-776 teaches that CAR cells can be NK cells or T cells. See ¶¶ 0094, 0192, and 0201.
Xiao-776 teaches the CAR can target CD19. See ¶ 0178. The CD19 CAR would bind a granulocyte, monocyte, or a lymphocyte as claimed because the CD19 CAR has the same structure as claimed.
Xiao-776 teaches the CAR includes an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain. See ¶¶ 0006-0012.
Xiao-776 teaches the CAR includes a costimulatory signaling region that comprises the intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, and any combination thereof. See ¶ 0307 and Claims 1 and 6.
Xiao-776 teaches as set forth above, but does not teach administering NK cells comprising the GUCY2C CAR or PAP CAR with T or NK cells expressing a CD19 CAR.
Brogdon teaches methods and compositions for treating a disease associated with expression of a tumor antigen, e.g., a cancer, in a subject using a preconditioning agent (e.g., one or more therapies that target and/or inhibit B cells), to enhance a treatment, e.g., a treatment with an anti-cancer therapeutic agent. See ¶¶ 0005.
Brogdon teaches the anti-cancer therapeutic agent includes an immune effector cell, e.g., a T cell or an NK cell, that expresses a CAR that targets (e.g., binds to) a tumor antigen, referred to herein as a “treatment CAR cell” (“CAR-Tx”). Without wishing to be bound by theory, treatment with a preconditioning agent, e.g., CAR-Pc, is believed to improve the distribution and/or efficacy of an anti-cancer therapy (e.g., a CAR-Tx) in a subject, e.g., by one or more of: increasing one or more of proliferation, tumor infiltration, and/or persistence of the CAR-Tx, e.g., as compared to administering the CAR-Tx alone; modulating the tumor microenvironment; decreasing the level of B cells, e.g., B cell antigen-expressing cells; decrease the level of regulatory B cells (e.g., B regs) and/or regulatory T cells (T regs), e.g., in the tumor microenvironment; increasing the level of Th1 or Th17 cells; increasing the tolerance for the CAR-Tx; preventing or reducing an adverse response to the CAR-Tx; decreasing the likelihood of the subject's immune response to the CAR-Tx; or increasing anti-tumor activity of the CAR-Tx. See ¶¶ 0005-0006.
Brogdon teaches the CAR-Tx can target tumor antigens like PAP. See ¶¶ 0026.
Brogdon teaches the preconditioning agent includes an immune effector cell, e.g., a T cell or an NK cell, expressing a chimeric antigen receptor (CAR) molecule that targets B cells, e.g., binds to a B cell antigen. See ¶¶ 0005.
Brogdon teaches the preconditioning agent CAR (CAR-Pc) can bind CD19. See ¶¶ 0006-0012.
Brogdon teaches the CD19 CAR is a murine scFv domain that binds to human CD19, e.g., CTL019 (e.g., SEQ ID NO: 95). See ¶¶ 0021.
SEQ ID NO: 95 of Brogdon comprises the claimed SEQ ID NO: 6. See Appendix
Brogdon teaches that the cells expressing the CAR can express IL-6, which would be encoded by a polynucleotide. See ¶¶ 0537.
Brogdon teaches the intracellular signaling domain comprises a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta. See ¶¶ 0039, 0092 and 0117.
Brogdon teaches that the CD19 CAR cells will be use to eradicate B cells and prevent humoral immunity against the additional CAR and target immunosuppressive B cells for elimination. See ¶¶ 0729, 0793 and 0830
Spanholtz teaches at paragraph [0012]:
CAR-NK cells are expected to have several advantages compared to CAR-T cells. In respect to the manufacturing, since NK-cells do not cause GvHD, they offer the opportunity to produce an off-the-shelf allogeneic product available for immediate clinical use. In addition, autologous and allogeneic NK cells have a limited in vivo persistence which makes the occurring of life threatening toxicities like cytokines release syndrome less likely. From an efficacy perspective, once engineered with CARs, NK cells should retain their native receptors thus allowing anti-tumour effect mediated by mechanisms others than those mediated by CAR specificity
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Xiao-776, Brogdon and Spanholtz and administer NK cells comprising the GUCY2C CAR or PAP CAR of Xiao-776 with T or NK cells expressing a CD19 CAR of because Brogdon teaches using CD19 CAR cells to enhance CAR T or NK cell therapy by suppressing immunosuppressive B cell activity and Spanholtz teaches the advantages of using NK cells. Thus one would have been motivated to enhance the activity of the NK CAR cells comprising the GUCY2C CAR or PAP CAR by reducing immunosuppressive B cell activity with the CD19 CAR cells of Brogdon.
5. Claim(s) 18 is rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0355776 A1 (Xiao et al. Dec. 14, 2017), “Xiao-776” in view of US 2018/0334490 A1 (Brogdon et al. Nov. 22, 2018, of record), “Brogdon” and in view of US 2022/0064599 (Spanholtz et al. Mar. 3, 2022, filed May 29, 2019, of record), “Spanholtz”, as applied to claims 1-3, 11-17 and 19-21 above, and further in view of US 2016/0256488 A1 (Wu, Z. Sep 8, 2016), Wu.
Xiao-776, Brogdon and Spanholtz teach as set forth above, but do not teach expressing a polynucleotide encoding a dominant negative form of PD-1 in the CAR cells.
Wu teaches compositions and methods for reducing immune tolerance associated with CAR T cell therapy. Embodiments of the present disclosure include isolated nucleic acid sequence comprising a nucleic acid sequence that encodes modified programmed cell death protein 1 (PD-1) and a nucleic acid sequence that encodes chimeric antigen receptor (CAR). See abstract and ¶¶ 0005-0014.
Wu teaches the CARs can target CD19 or PAP. See ¶¶ 0007 and 0105-0107.
Wu teaches the cells include T cells or NK cells. See ¶¶ 0013 and 0025.
Wu teaches that the modified PD-1 is a dominant negative PD-1 that inhibits wide-type PD-1 activity induced by PD-L1 of a tumor cell. See ¶¶ 0119.
Wu teaches that inhibition of cytotoxicity induced by PD-L1 decreases on T cells transduced with CAR and modified PD-1. See Example 5.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Xiao-776, Brogdon, Spanholtz and Wu and express a modified, dominant negative PD-1 in the NK or T CAR cells of Xiao-776, Brogdon, and Spanholtz because Wu teaches using dominant negative PD-1 for reducing immune tolerance associated with CAR T cell therapy. One would have been motivated to express a modified, dominant negative PD-1 in the NK or T CAR cells of Xiao-776, Brogdon, and Spanholtz because Wu teaches that inhibition of cytotoxicity induced by PD-L1 decreases on T cells transduced with a CAR and modified PD-1.
6. Claim(s) 14-17, 19 and 20 are alternatively rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0355776 A1 (Xiao et al. Dec. 14, 2017), “Xiao-776” in view of US 2018/0334490 A1 (Brogdon et al. Nov. 22, 2018, of record), “Brogdon” and in view of US 2022/0064599 (Spanholtz et al. Mar. 3, 2022, filed May 29, 2019, of record), “Spanholtz”, as applied to claims 1-3, 11-17 and 19-21 above, and further in view of US 2022/0056092 A1 (Lynn et al. Feb. 24, 2022, effectively filed June 12, 2019), “Lynn”.
Xiao-776, Brogdon and Spanholtz teach as set forth above, but do not teach expressing a polynucleotide encoding IL-12 in the CAR cells.
Lynn teaches the present disclosure include polypeptides of biocircuit systems, effector modules, stimulus response elements (SREs), polynucleotides encoding the same, vectors and cells containing the polypeptides and/or polynucleotides for use in cancer immunotherapy. In one embodiment, the compositions comprise a membrane-associated Interleukin 12 (IL12). See ¶¶ 0003, 0009, 0012.
Lynn teaches that IL-12 is type 1 cytokine that acts on natural killer (NK) cells, macrophages, CD8+ Cytotoxic T cells, and CD4+ T helper cells through STAT4 pathway to induce IFN-γ production in these effector immune cells. IL12 can promote the cytotoxic activity of NK cells and CD8+ T cells, therefore has anti-tumor function as well as promote T cell persistence in vivo. Lynn teaches that IL-12 has been used as an adjuvant to enhance cytotoxic immunity using a melanoma antigen vaccine and to promote NK cell activity in breast cancer with trastuzumab treatment. Local delivery of IL12 to the tumor microenvironment promotes tumor regression in several tumor models. These studies all indicate that locally increased IL12 level can promote anti-tumor immunity. See ¶¶ 0326.
Lynn teaches that the expressing IL-12 from nucleic acid vectors in CAR T cells increased the efficacy of the CAR-T cells and increased survival in tumor bearing animals treated with the IL-12 expressing CAR T cells. See Examples 9 and 10.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Xiao-776, Brogdon, Spanholtz and Lynn and express IL-12 in the NK or T CAR cells of Xiao-776, Brogdon, and Spanholtz because Lynn teaches that IL12 is known to have anti-tumor activity. One would have been motivated to express IL-12 in the NK or T CAR cells of Xiao-776, Brogdon, and Spanholtz because Lynn teaches that the expressing IL-12 from nucleic acid vectors in CAR T cells increased the efficacy of the CAR-T cells and increased survival in tumor bearing animals treated with the IL-12 expressing CAR T cells.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
7. Claims 1-3, 11-14 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-22 of co-pending Application No. 16/999,357 (published as US 2021/0100841, of record), in view of US 2017/0355776 A1 (Xiao et al. Dec. 14, 2017), “Xiao-776”. in view of US 2018/0334490 A1 (Brogdon et al. Nov. 22, 2018, of record), “Brogdon” and in view of US 2022/0064599 (Spanholtz et al. Mar. 3, 2022, filed May 29, 2019, of record), “Spanholtz”.
The ‘357 claims are drawn to:
1. (Currently Amended) A method of expanding lymphocytes or enhancing expansion of lymphocytes, the method comprising:
administering an effective amount of lymphocytes to a subject having a solid tumor; and administering an effective amount of an agent to the subject, wherein the agent stimulates or activates antigen presenting cells (APCs) of the subject, and wherein the agent comprises a CAR T cell binding a B cell, a bispecific antibody binding a B cell and a T cell, an antibody binding a B cell, or a combination thereof; and allowing the lymphocytes to expand in the subject.
4. (Original) The method of claim 1, wherein the allowing the lymphocytes to expand comprises allowing the lymphocytes to expand before contacting the lymphocytes with an antigen that the lymphocytes bind.
7. (Original) The method of claim 1, wherein the agent comprises a scFv binding a B cell.
8. (Original) The method of claim 1, wherein the lymphocytes comprise T cells or NK cells, or a combination thereof.
9 (Original) The method of claim 1, wherein the agent binds a B cell antigen.
10. (Original) The method of claim 9, wherein the B cell antigen comprises CD19, CD20, CD22, CD53, CD138, BCMA, CD38, FCRL5, or a combination thereof
4. (Currently Amended) The method of claim 1, wherein the lymphocytes comprises comprise a CAR or TCR.
15. (Original) The method of claim 14, wherein the CAR comprises an antigen- binding domain, a transmembrane domain, and an intracellular signaling domain.
16. (Original) The method of claim 15, wherein the antigen-binding domain binds a tumor antigen comprising MUC1 (tMUC1), PRLR, CLCA1, MUC12, GUCY2C, GPR35, CR1L, MUC 17, TMPRSS11B, MUC21, TMPRSS11E, CD207, SLC30A8, CFC1, SLC12A3, SSTR1, GPR27, FZD10, TSHR, SIGLEC15, SLC6A3, CLDN 18.2, KISS1R, QRFPR, GPR119, CLDN6, UPK2, ADAM12, SLC45A3, ACPP, MUC21, MUC16, MS4A12, ALPP, CEA, EphA2, FAP, GPC3, IL13-Ra2, Mesothelin, PSMA, ROR1, VEGFR-II, GD2, FR-a, ErbB2, EpCAM, EGFRvIII, MAGE A4, EGFR, or a combination thereof.
17. (Currently Amended) The method claim 15, wherein the CAR that comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain, and the intracellular signaling domain comprises a co-stimulatory signaling domain, or a primary signaling domain and a co-stimulatory signaling domain, wherein the signaling domain and co-stimulatory signaling domain comprises comprise a functional signaling domain of a protein comprising CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1,CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1,CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, NKp44, NKp30, NKp46, NKG2D, or a combination thereof.
20. A method of expanding T cells or enhancing expansion of T cells, the method comprising: administering an effective amount of T cells to a subject having solid tumor: administering an effective amount of an agent to the subject, wherein the agent stimulates or activates B cells of the subject, and wherein the agent comprises a CAR T cell binding a B cell, a bispecific antibody binding a B cell and a T cell, an antibody binding a B cell, or a combination thereof: and allowing the T cells to expand in the subject.
21. The method of claim 20, wherein the agent stimulates or activates the B cells to differentiate into plasma cells or to up-regulate CCL17 and CCL22.
22. The method of claim 20, wherein the agent comprises an antibody binding a B cell.
The ‘357 claims teach as set forth above, but do not teach expanding in peripheral blood an NK cell comprising SEQ ID NO: 11 or a CAR comprising SEQ ID NO: 6.
Xiao-776, Brogdon, and Spanholtz teach as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘357 claims, Xiao-776, Brogdon and Spanholtz and administer an NK cell expressing a CAR comprising SEQ ID NO: 11 and administer white blood cell, like a NK cell or T cell, comprising a CD19 binding CAR comprising SEQ ID NO: 6 to enhance the expansion of NK cells in peripheral blood because the ‘357 claims teach expanding NK cells expressing CARs to GUCY2C with CAR T or NK cells expressing CD19, Xiao-776 teaches the GUCY2C CAR antigen binding domain comprises SEQ ID NO: 14 , which comprises SEQ ID NO: 11, and using NK cells for cancer therapy, Brogdon teaches using CD19 CAR cells comprising SEQ ID NO: 6 to enhance CAR T or NK cell therapy by suppressing immunosuppressive B cell activity and Spanholtz teaches the advantages of using NK cells. Thus one would have been motivated to combine the teachings of the ‘357 claims, Xiao-776, Brogdon and Spanholtz and administer an NK cell expressing a CAR comprising SEQ ID NO: 11 and administer white blood cell, like a NK cell or T cell, comprising a CD19 binding CAR comprising SEQ ID NO: 6 to enhance the expansion of NK cells in peripheral blood given the guidance and advantages taught by the Xiao-776, Brogdon and Spanholtz.
This is a provisional nonstatutory double patenting rejection.
8. Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-22 of co-pending Application No. 16/999,357 (published as US 2021/0100841), in view of US 2017/0355776 A1 (Xiao et al. Dec. 14, 2017), “Xiao-776”. in view of US 2018/0334490 A1 (Brogdon et al. Nov. 22, 2018, of record), “Brogdon” and in view of US 2022/0064599 (Spanholtz et al. Mar. 3, 2022, filed May 29, 2019, of record), “Spanholtz” as applied to claims 1-3, 11-14 and 21 above and further in view of US 2016/0256488 A1 (Wu, Z. Sep 8, 2016), Wu.
The ‘357 claims, Xiao-776, Brogdon and Spanholtz teach as set forth above, but do not teach expressing a polynucleotide encoding a dominant negative form of PD-1 in the CAR cells.
Wu teaches as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘357 claims Xiao-776, Brogdon, Spanholtz and Wu and express a modified, dominant negative PD-1 in the NK or T CAR cells of the ‘357 claims, Xiao-776, Brogdon, and Spanholtz because Wu teaches using dominant negative PD-1 for reducing immune tolerance associated with CAR T cell therapy. One would have been motivated to express a modified, dominant negative PD-1 in the NK or T CAR cells of the ‘357 claims, Xiao-776, Brogdon, and Spanholtz because Wu teaches that inhibition of cytotoxicity induced by PD-L1 decreases on T cells transduced with a CAR and modified PD-1.
9. Claims 14-17, 19 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-22 of co-pending Application No. 16/999,357 (published as US 2021/0100841), in view of US 2017/0355776 A1 (Xiao et al. Dec. 14, 2017), “Xiao-776”. in view of US 2018/0334490 A1 (Brogdon et al. Nov. 22, 2018, of record), “Brogdon” and in view of US 2022/0064599 (Spanholtz et al. Mar. 3, 2022, filed May 29, 2019, of record), “Spanholtz” as applied to claims 1-3, 11-14 and 21 above and further in view of US 2022/0056092 (Lynn et al. Feb. 24, 2022, effectively filed June 12, 2019), “Lynn”.
The ‘357 claims, Xiao-776, Brogdon and Spanholtz teach as set forth above, but do not teach expressing a polynucleotide encoding IL-12 in the CAR cells.
Lynn teaches as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘357 claims, Xiao-776, Brogdon, Spanholtz and Lynn and express IL-12 in the NK or T CAR cells of Xiao-776, Brogdon, and Spanholtz because Lynn teaches that IL12 is known to have anti-tumor activity. One would have been motivated to express IL-12 in the NK or T CAR cells of the ‘357 claims, Xiao-776, Brogdon, and Spanholtz because Lynn teaches that the expressing IL-12 from nucleic acid vectors in CAR T cells increased the efficacy of the CAR-T cells and increased survival in tumor bearing animals treated with the IL-12 expressing CAR T cells.
10. Claims 1-3, 11-17 and 19-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-16, 18-24, and 26, of co-pending Application No. 17/123,732 in view of US 2017/0355776 A1 (Xiao et al. Dec. 14, 2017), “Xiao-776”, in view of US 2018/0334490 A1 (Brogdon et al. Nov. 22, 2018, of record), “Brogdon” and in view of US 2022/0064599 (Spanholtz et al. Mar. 3, 2022, filed May 29, 2019, of record), “Spanholtz”.
The ‘732 claims are drawn to:
1. A method of enhancing anti-tumor activities of modified cells, the method comprising: administering an effective amount of the modified cells to a subject having a solid tumor, the modified cells comprising chimeric antigen receptor (CAR) CAR T cells targeting a solid tumor antigen; and administering an effective amount of granulocyte colony-stimulating factor (G-CSF) to the subject on the same day (Day 0) as administering the modified cells; wherein the modified cells inhibit growth of the solid tumor in the subject, wherein the G-CSF enhances anti-tumor activities and the anti-tumor activities in the subject are greater than those in a subject that is administered with an effective amount of modified cells but without G-CSF, and wherein the anti-tumor activities comprise expansion of the modified cells, proliferation of NK cells, and/or release of cytokines.
4. The method of claim- 1, wherein the solid tumor antigen comprises tumor associated MUC1 (tMUC1), PRLR, CLCA1, MUC12, GUCY2C, GPR35, CR1L, MUC 17, TMPRSS11B, MUC21, TMPRSS11E, CD207, SLC30A8, CFC1, SLC12A3, SSTR1, GPR27, FZD10, TSHR, SIGLEC15, SLC6A3, KISS1R, CLDN18.2, QRFPR, GPR119, CLDN6, UPK2, ADAM12, SLC45A3, ACPP, MUC21, MUC16, MS4A12, ALPP, CEA, EphA2, FAP, GPC3, IL13-Ra2, Mesothelin, PSMA, ROR1, VEGFR-II, GD2, FR-a, ErbB2, EpCAM, EGFRvIII, B7-H3, MAGE A4, EGFR, or a combination thereof
5. The method of claim 1, wherein the solid tumor antigen comprises tMUC1, ACPP, TSHR, GUCY2C, UPK2, CLDN18.2, PSMA, DPEP3, CXCR5, B7-H3, MUC16, SIGLEC-15, CLDN6, Muc17, PRLR, MAGE A4, FZD10, or a combination thereof.
6. The method of claim 1, wherein the solid tumor antigen comprises tMUC1, ACPP, TSHR, GUCY2C, UPK2, MAGE A4, CLDN18.2, or a combination thereof.
7. The method of claim 1, wherein the CAR comprises an antigen binding domain, a transmembrane domain, a co-stimulatory domain, and a CD3 zeta domain.
8. The method of claim 7, wherein the co-stimulatory domain comprises the intracellular domain of CD27, CD28, 4-1 BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, or a combination thereof.
9. The method of claim 1, wherein the modified cells comprise a first population of cells comprising a first CAR binding a first antigen, and a second population of cells comprising a second CAR binding a second antigen, and wherein the second antigen is different from the first antigen.
10. The method of claim 9, wherein the first antigen comprises a cell surface molecule of a white blood cell (WBC).
11. The method of claim 10, wherein the WBC comprises a granulocyte, a monocyte, a lymphocyte, or a combination thereof.
12. The method of claim 10, wherein the WBC is a B cell
13. The method of claim 10, wherein the cell surface molecule of the WBC comprises CD19, CD22, CD20, BCMA, CD5, CD7, CD2, CD16, CD56, CD30, CD14, CD68, CD11b, CD18, CD169, CD1c, CD33, CD38, CD138, CD13, or a combination thereof.
14. The method of claim 10, wherein the cell surface molecule of the WBC comprises CD19, CD20, CD22, BCMA, or a combination thereof.
15. The method of claim 10, wherein the cell surface molecule of the WBC comprises CD19 or BCMA.
16. The method of claim 1, wherein the modified cells comprise a vector encoding at least one or more of IL-6, IL-12, IL-15, IL-7, TNF- a, or IFN-g.
24. The method of claim 9, wherein the first CAR comprises a scFv binding CD19, and an intracellular domain of 4-1BB or CD28, and CD3 zeta domain, and the second CAR comprises a scFv binding tMUC1, ACPP, TSHR, GUCY2C, or CLDN18.2, and an intracellular domain of 4-1BB or CD28, and CD3 zeta domain.
26. The method of claim 1, wherein the cytokines comprise IL-6, IFN-g, and GZMB.
The ‘732 claims teach as set forth above, but do not teach expanding in peripheral blood an NK cell comprising SEQ ID NO: 11 or a CAR comprising SEQ ID NO: 6.
Xiao-776, Brogdon, and Spanholtz teach as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘732 claims, Xiao-776, Brogdon and Spanholtz and administer an NK cell expressing a CAR comprising SEQ ID NO: 11 and administer white blood cell, like a NK cell or T cell, comprising a CD19 binding CAR comprising SEQ ID NO: 6 to enhance the expansion of NK cells in peripheral blood because the ‘732 claims teach administering T cells expressing CARs to GUCY2C with CAR T cells expressing CD19, Xiao-776 teaches the GUCY2C CAR antigen binding domain comprises SEQ ID NO: 14 , which comprises SEQ ID NO: 11, and using NK cells for cancer therapy, Brogdon teaches using CD19 CAR cells comprising SEQ ID NO: 6 to enhance CAR T or NK cell therapy by suppressing immunosuppressive B cell activity and Spanholtz teaches the advantages of using NK cells. Thus one would have been motivated to combine the teachings of the ‘732 claims, Xiao-776, Brogdon and Spanholtz and administer an NK cell expressing a CAR comprising SEQ ID NO: 11 and administer white blood cell, like a NK cell or T cell, comprising a CD19 binding CAR comprising SEQ ID NO: 6 to enhance the expansion of NK cells in peripheral blood given the guidance and advantages taught by the Xiao-776, Brogdon and Spanholtz.
This is a provisional nonstatutory double patenting rejection.
11. Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-16, 18-24, and 26, of co-pending Application No. 17/123,732, in view of US 2017/0355776 A1 (Xiao et al. Dec. 14, 2017), “Xiao-776”, in view of US 2018/0334490 A1 (Brogdon et al. Nov. 22, 2018, of record), “Brogdon” and in view of US 2022/0064599 (Spanholtz et al. Mar. 3, 2022, filed May 29, 2019, of record), “Spanholtz” as applied to claims 1-3, 11-17 and 19-21 above and further in view of US 2016/0256488 A1 (Wu, Z. Sep 8, 2016), Wu.
The ‘732 claims, Xiao-776, Brogdon and Spanholtz teach as set forth above, but do not teach expressing a polynucleotide encoding a dominant negative form of PD-1 in the CAR cells.
Wu teaches as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘732claims Xiao-776, Brogdon, Spanholtz and Wu and express a modified, dominant negative PD-1 in the NK or T CAR cells of the ‘732 claims, Xiao-776, Brogdon, and Spanholtz because Wu teaches using dominant negative PD-1 for reducing immune tolerance associated with CAR T cell therapy. One would have been motivated to express a modified, dominant negative PD-1 in the NK or T CAR cells of the ‘732 claims, Xiao-776, Brogdon, and Spanholtz because Wu teaches that inhibition of cytotoxicity induced by PD-L1 decreases on T cells transduced with a CAR and modified PD-1.
12. Claims 1-3 and 11-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-13, 15, 18, 19, 20, 23, 24, 26 and 27 of U.S. Patent No. 10,869,888 B2 (Xiao et al. Dec. 22, 2020, of record) in view of in view of US 2022/0064599 (Spanholtz et al. Mar. 3, 2022, filed May 29, 2019, of record), “Spanholtz”.
The ‘888 claims teach:
1. A method of enhancing expansion of cells in a subject, the method comprising: administering an effective amount of a composition to the subject having a form of cancer expressing a tumor antigen, wherein the composition comprises a first population of cells comprising a first chimeric antigen receptor (CAR) binding a first antigen, and a second population of cells comprising a second CAR binding a second antigen, the first and second population of cells comprising T cells, the first and second CAR comprising an antigen binding domain, a transmembrane domain, a costimulatory domain, and a CD3 zeta domain, and the first antigen comprising CD19 or BCMA and the second antigen comprising a solid tumor antigen; and allowing the first and second population of cells to expand, wherein expansion of the second population of cells in the subject is enhanced as compared to a subject administered a composition comprising the second population of cells without the first population of cells.
2. The method of claim 1, wherein the solid tumor antigen is tMUC 1, PRLR, CLCA1, MUC12, GUCY2C, GPR35, CR1L, MUC 17, TMPRSS11B, MUC21, TMPRSS11E, CD207, SLC30A8, CFC1, SLC12A3, SSTR1, GPR27, FZD10, TSHR, SIGLEC15, SLC6A3, KISS1R, QRFPR, GPR119, CLDN6, UPK2, ADAM12, SLC45A3, ACPP, MUC21, MUC16, MS4A12, ALPP, CEA, EphA2, FAP, GPC3, IL13-Rα2, Mesothelin, PSMA, ROR1, VEGFR-II, GD2, FR-α, ErbB2, EpCAM, EGFRvIII, B7-H3, or EGFR.
4. The method of claim 1, wherein the co-stimulatory domain comprises the intracellular domain of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that binds CD83, or a combination thereof.
5. The method of claim 1, wherein the first CAR comprises a scFv binding CD19, an intracellular domain of 4-1BB or CD28, and a CD3 zeta domain, and the second CAR comprises a scFv binding tMUC1, an intracellular domain of 4-1BB or CD28, and a CD3 zeta domain.
6. The method of claim 1, wherein the antigen binding domain of the first CAR comprises amino acid sequence SEQ ID NO: 5 or 6 and the antigen binding domain of the second CAR comprises amino acid sequence SEQ ID NO: 8, 11, 70, or 439.
7. The method of claim 1, wherein the second population of cells comprises a lentiviral vector encoding the second CAR and a dominant negative form of PD-1.
8. The method of claim 1, wherein the first population of cells comprises a lentiviral vector encoding the first CAR and a therapeutic agent.
9. The method of claim 8, wherein the therapeutic agent comprises a cytokine.
10. The method of claim 9, wherein the cytokine is IL6 and/or IFN-γ.
11. The method of claim 9, wherein the cytokine is at least one of IL6, IL12, TNF-α, or IFN-γ.
12. The method of claim 1, wherein the method further comprises treating the subject having solid tumor cancer.
13. The method of claim 12, wherein the solid tumor cancer is cholangiocarcinoma, pancreatic cancer, breast cancer, colorectal cancer, thyroid cancer, or prostate cancer.
15. The method of claim 1, wherein the solid tumor antigen is GUCY2C.
18. The method of claim 1, wherein the solid tumor antigen is ACPP.
19. The method of claim 1, wherein the first CAR comprises amino acid sequence SEQ ID NO: 5.
20. The method of claim 1, wherein the first CAR comprises amino acid sequence encoded by nucleic acid sequence SEQ ID NO: 28 (CD19 CAR, See Table 4).
23. The method of claim 1, wherein the second CAR comprises amino acid sequence SEQ ID NO: 11.
24. The method of claim 1, wherein the antigen binding domain of the first CAR comprises amino acid sequence SEQ ID NO: 5, and the solid tumor antigen comprises GUCY2C.
26. The method of claim 1, wherein the antigen binding domain of the first CAR comprises amino acid sequence SEQ ID NO: 5, and the solid tumor antigen comprises ACPP.
27. The method of claim 1, wherein the antigen binding domain of the first CAR comprises amino acid sequence SEQ ID NO: 5, and the antigen binding domain of the second CAR comprises amino acid sequence SEQ ID NO: 11.
SEQ ID NOs: 5 and 11 of the ‘888 claims are the same as the claimed SEQ ID NOs: 5 and 11. See Appendix.
The ‘888 claims teach as set forth above, but do not teach using NK-cells.
Spanholtz teaches as set forth above.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of the ‘888 claims and Spanholtz and use NK-cells in the methods of the ‘888 claims because Spanholtz teaches CAR-NK cells are expected to have several advantages compared to CAR-T cells such as because NK-cells do not cause GvHD, they offer the opportunity to produce an off-the-shelf allogeneic product available for immediate clinical use. In addition, autologous and allogeneic NK cells have a limited in vivo persistence which makes the occurring of life threatening toxicities like cytokines release syndrome less likely. Thus given the advantages of CAR-NK cells taught by Spanholtz one would have been motivated with a reasonable expectation of success to NK cells in place of T cells of the ‘888 claims
Conclusion
13. All other objections and rejections recited in the Office Action of May 09, 2025 are withdrawn in view of Applicant’s amendments and arguments..
14 No claims allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Janet L Epps-Smith can be reached at 571-272-0757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PETER J REDDIG/Primary Examiner, Art Unit 1646
APPENDIX
Alignment of SEQ ID NO: 11 with SEQ ID NO: 14 of Xiao-776
Sequence 14, US/15685670
Publication No. US20170355776A1
GENERAL INFORMATION
APPLICANT: Innovative Cellular Therapeutics CO., LTD.
TITLE OF INVENTION: Use of chimeric antigen receptor modified cells to treat cancer
FILE REFERENCE: SDS1.0028US1
CURRENT APPLICATION NUMBER: US/15/685,670
CURRENT FILING DATE: 2017-08-24
PRIOR APPLICATION NUMBER: PCT/CN2017/078740
PRIOR FILING DATE: 2017-03-30
PRIOR APPLICATION NUMBER: US62/317261
PRIOR FILING DATE: 2016-04-01
NUMBER OF SEQ ID NOS: 45
SEQ ID NO 14
LENGTH: 241
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: synthetic
Query Match 100.0%; Score 1283; Length 241;
Best Local Similarity 100.0%;
Matches 241; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIYGASTRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIYGASTRATGIPA 60
Qy 61 RFSGSGSGTEFTLTIGSLQSEDFAVYYCQQYKTWPRTFGQGTNVEIKGGGGSGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTEFTLTIGSLQSEDFAVYYCQQYKTWPRTFGQGTNVEIKGGGGSGGGGSGGG 120
Qy 121 GSQVQLQQWGAGLLKPSETLSLTCAVFGGSFSGYYWSWIRQPPGKGLEWIGEINHRGNTN 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSQVQLQQWGAGLLKPSETLSLTCAVFGGSFSGYYWSWIRQPPGKGLEWIGEINHRGNTN 180
Qy 181 DNPSLKSRVTISVDTSKNQFALKLSSVTAADTAVYYCARERGYTYGNFDHWGQGTLVTVS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DNPSLKSRVTISVDTSKNQFALKLSSVTAADTAVYYCARERGYTYGNFDHWGQGTLVTVS 240
Qy 241 S 241
|
Db 241 S 241
Alignment of SEQ ID NO: 6 with SEQ ID NO: 95 of Xiao-776
ALIGNMENT:
Query Match 100.0%; Score 1279; Length 242;
Best Local Similarity 100.0%;
Matches 242; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPS 60
Qy 61 RFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGG 120
Qy 121 GSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTY 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTY 180
Qy 181 YNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 YNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTV 240
Qy 241 SS 242
||
Db 241 SS 242
Alignment of SEQ ID NO: 11 with SEQ ID NO: 11 of US 10,869,888
ALIGNMENT:
Query Match 100.0%; Score 1283; Length 241;
Best Local Similarity 100.0%;
Matches 241; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIYGASTRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIYGASTRATGIPA 60
Qy 61 RFSGSGSGTEFTLTIGSLQSEDFAVYYCQQYKTWPRTFGQGTNVEIKGGGGSGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTEFTLTIGSLQSEDFAVYYCQQYKTWPRTFGQGTNVEIKGGGGSGGGGSGGG 120
Qy 121 GSQVQLQQWGAGLLKPSETLSLTCAVFGGSFSGYYWSWIRQPPGKGLEWIGEINHRGNTN 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSQVQLQQWGAGLLKPSETLSLTCAVFGGSFSGYYWSWIRQPPGKGLEWIGEINHRGNTN 180
Qy 181 DNPSLKSRVTISVDTSKNQFALKLSSVTAADTAVYYCARERGYTYGNFDHWGQGTLVTVS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DNPSLKSRVTISVDTSKNQFALKLSSVTAADTAVYYCARERGYTYGNFDHWGQGTLVTVS 240
Qy 241 S 241
|
Db 241 S 241
Alignment of SEQ ID NO: 5 with SEQ ID NO: 5 of US 10,869,888
ALIGNMENT:
Query Match 100.0%; Score 1283; Length 242;
Best Local Similarity 100.0%;
Matches 242; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDISKYLNWYQQKPGKAPKLLIYHTSRLHSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGQGTKVEIKGGGGSGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPYTFGQGTKVEIKGGGGSGGGGSGGG 120
Qy 121 GSEVQLVESGGGLVQPGGSLRLSCAASGVSLPDYGVSWVRQAPGKGLEWVSVIWGSETTY 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSEVQLVESGGGLVQPGGSLRLSCAASGVSLPDYGVSWVRQAPGKGLEWVSVIWGSETTY 180
Qy 181 YNSALKSRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKHYYYGGSYAMDYWGQGTLVTV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 YNSALKSRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKHYYYGGSYAMDYWGQGTLVTV 240
Qy 241 SS 242
||
Db 241 SS 242