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 May 15, 2026 with the Response to the non-final Office Action are acknowledged. Claims 3-4, 9, 11-20, and 22-48 are canceled. Claims 1-2, 5-8, 10, 49, 51, and 55 are amended. Claims 56-60 are newly added.
Claims 1-2, 5-8, 10, 21, and 49-60 are pending and under examination herein.
Notice Regarding Non-Compliant Claim Amendments
It is noted that claims 49 and 55 contain non-compliant amendments. Specifically, claim 49 is annotated as “Previously Presented” but contains annotated amendments at lines 8-9. Claim 55 is annotated as “Previously Presented” but contains amendments which are not properly annotated (i.e., updating the claim dependency from claim 48 to claim 49).
In the interest of compact prosecution, these claims will be examined herein. However, Applicant is advised to follow the rules set forth in MPEP § 714 in future amendment submissions.
WITHDRAWN REJECTIONS
All prior rejections of claims 22-23, 29, 31, 42-44, 46, and 48 are rendered moot by the cancelation of the claims.
The rejection of claims 2, 8, 10, and 51 under 35 U.S.C. § 112(b) is withdrawn in view of Applicant's amendments to said claims.
The rejection of claims 2 and 5-7 under 35 U.S.C. § 112(a) as failing to comply with the written description requirement is withdrawn in view of Applicant's amendments to said claims.
The rejection of claims 1-2, 5-8, 10, 21, and 49-55 under 35 U.S.C. § 102(a)(2) as being anticipated by Fan (WO 2021/170100 A1) is withdrawn in view of Applicant's declaration that, not later than the effective filing date of the instantly claimed invention, the subject matter disclosed in Fan and the claimed invention were subject to the exception under 35 U.S.C. § 102(b)(2)(C). See Remarks filed May 15, 2026, at page 9.
The rejection of claims 1-2, 5-8, 10, 21, and 49-55 under 35 U.S.C. § 103 as being unpatentable over Klingemann (US 2020/0038441 A1) in view of Ma (WO 2020/077356 A1) and Moelling (WO 2006/032525 A2), and as evidenced by Liu (Scientific Reports (2017) 7: Article 2193), is withdrawn in view of Applicant's claims amendments reciting that the immune effector cell and isolated nucleic acid of the invention do not comprise a IL-12 p35 subunit.
NEW OBJECTIONS AND MAINTAINED AND NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENT
Claim Objections (New)
Claims 1 and 49 are objected to because of the following informalities: The claims contain a premature period at the end of (iii)(c), prior to the end of the claim. As set forth in MPEP § 608.01(m), each claim should end with a period.
Appropriate correction is required.
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 1-2, 5-8, 10, 21, 49-58, and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Ma (Nature Biotechnology 38(4): 448-459; cited in IDS; hereafter “X. Ma”) in view of Lee (US 2021/0145879 A1; earliest priority date: November 20, 2020), and Moelling (WO 2006/032525 A2; cited in PTO-892). This is a new rejection necessitated by claim amendment.
X. Ma teaches that the suppressive tumor microenvironment in solid tumors usually hinders T cell expansion and persistence, hampering the effectiveness of genetically engineered CAR-T and TCR-T cells (e.g., Main). X. Ma further teaches that STAT3 signaling enhances CAR-T cell effector function in preclinical and clinical studies, and that IL-23 (which consists of IL-23α p19 and IL-12β p40 subunits), which is one of the STAT3-activating cytokines, promotes proliferation of memory T cells and T helper type 17 (Th17) cells expressing IL-23R (e.g., Main). Pertinent to claims 1-2, 8, 21, and 56-57, X. Ma augmented the anti-tumor activity of CAR-T cells by engineering CAR-T cells to express the human IL12p40 (IL12B) subunit (“p40-Td cells”), wherein the IL12B (accession NM_002187.3) shares 100% sequence identity to instant SEQ ID NO: 5 and is membrane-bound as verified by confocal microscopy (e.g., Abstract; Methods). Relevant to claim 10, Supplementary Figures 7-8 illustrate schematics showing that the CARs tested by X. Ma comprise a CD28 transmembrane domain and an intracellular co-stimulatory domain. Relevant to claims 49-52 and 55, X. Ma further discloses methods of generating the pd40-Td CAR-T cells by introducing vectors encoding nucleic acids encoding the IL12B subunit and CAR (e.g., Methods).
Relevant to claims 53-54 and 60, X. Ma used murine tumor models and treated mice with CAR.p40-Td cells (e.g., Results; Figure 3). X. Ma observed that the CAR.p40-Td cells “showed superior initial expansion (day 10) in vivo in peripheral blood, spleen and liver (Fig. 3l) and prolonged persistence in the same organs ... (Fig. 3m)”, promoted tumor regression, and had enhanced anti-tumor activity (e.g., Results; Figures 3-5; Supplementary Figures 6-8). X. Ma concludes, “we have demonstrated that providing the p40 subunit of IL-23 to tumor-specific T cells is sufficient to cause the production and release of IL-23. Furthermore, IL-23 exerts its function exclusively through activated T cells because both IL-23 production and IL-23R expression occur following T cell activation. This tightly regulated IL-23–IL-23R-engineered pathway is further controlled by an autocrine mode of action of the secreted IL-23 that prevents cytokine usage by other bystander immune cells” (Discussion; see also Figure 6).
However, X. Ma does not teach further expressing exogenous human CCL19 or human CCL21 in the engineered CAR-T cells.
Lee describes recombinant T cell or natural killer (NK) cell compositions transfected with a nucleic acid encoding (i) a homing receptor, (ii) a chimeric antigen receptor that specifically binds a target antigen, (iii) an Fc receptor, and/or (iv) a secreted immune modulator selected from a TGF-β inhibitor and/or IL-12 and uses thereof in immunotherapy for cancer and tumors (e.g., Abstract; ¶ 0003). Relevant to claims 5-7, Lee teaches that the homing receptor is a receptor that activates a cellular pathway that results directly or indirectly in the cell migrating toward a target cell or tissue and may be a chemokine receptor such as a CCL19 comprising the amino acid sequence of SEQ ID NO: 45 (which shares 100% sequence identity to instant SEQ ID NO: 6) or a CCL21 comprising the amino acid sequence of SEQ ID NO: 46 (which shares 100% sequence identity to instant SEQ ID NO: 22) (e.g., ¶ 0019, 0051-0052).
Moelling teaches that CCL19 and CCL21 are both ligands of the CCR7 receptor, which is expressed on naïve T cells and dendritic cells (page 3). Moelling discloses that CCL19 and CCL21 act as chemo-attractants for naïve T cells and dendritic cells, and demonstrate anti-tumor activity (e.g., page 3; Examples). Moelling further discloses that the combinations of IL-12 (which comprises the IL-12p40 subunit) with CCL19 and IL-12 with CCL21 produce a synergistic effect (e.g., pages 3, 9; Examples). As illustrated in Figures 1-3, intratumoral combination treatments of IL-12/CCL19 and IL-12/CCL21 in murine cancer models decreased mean tumor volume and prolonged survival relative to monotherapy regimens comprising the same.
In view of these teachings, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the CAR.p40-Td cells described by X. Ma by further introducing exogenous CCL19 or CCL21 based on the further teachings of Lee and Moelling. The skilled artisan would have been motivated to do so because Lee and Moelling set forth that CCL19 and CCL21 are homing receptors that act as chemo-attractants for naïve T cells and dendritic cells, and expression of either of these chemokine receptors would serve to attract T cells to the site of the tumor microenvironment to further the anti-tumor activity of the engineered immune cells. There would have been a reasonable expectation of success because those of ordinary skill in the art would recognize that CARs, IL-12p40, and CCL19/CCL21 each have utility in the treatment of cancer, and, as noted in MPEP § 2144.06(1): '"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art.' In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)". Furthermore, Lee and Moelling provide a proof-of-concept that a polypeptide having multi-gene co-expression (i.e., expressing a CAR, a cytokine, and a chemokine), as well as immune effector cells comprising said polypeptide, can be generated and used in a method of treatment by a skilled artisan.
(2)
Claims 1 and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over X. Ma (Nature Biotechnology 38(4): 448-459; supra) in view of Lee (US 2021/0145879 A1; supra) and Moelling (WO 2006/032525 A2; supra) as applied to claims 1-2, 5-8, 10, 21, 49-58, and 60 above, further in view of Ma (WO 2020/077356 A1; cited in IDS; hereafter “Y. Ma”) and Alabanza (Molecular Therapy (2017) 25(11): 2452-2465). This is a new rejection necessitated by claim amendment.
The teachings of X. Ma are recited in the 35 U.S.C. § 103 rejection above.
However, X. Ma does not recite that the membrane-bound p40 comprises p40, a CD8α hinge, and a CD8α transmembrane domain.
The teachings of Lee and Moelling are set forth in the 35 U.S.C. § 103 rejection above.
Y. Ma describes engineered cells having at least one CAR polypeptide and at least one of a cytokine and chemokine (Abstract). Y. Ma discloses an engineered cell (e.g., T cell, natural killer (NK) cell) comprising (i) a CAR polypeptide, (ii) at least one heterologously expressed cytokine, and (iii) at least one heterologously expressed chemokine such as CCL19 or CCL21 (e.g., claims 1-14; ¶ 0013-0023, 0302-0333). Y. Ma illustrates that the heterologously expressed cytokines (e.g., IL-18 or IL-21) may be anchored to the T or NK cells via a linkage with the CD8 hinge region and CD8 transmembrane domain (e.g., Figures 25, 27, 34, 36, and 60, and in-text descriptions thereof).
Alabanza investigated the role of CD8α vs. CD28 hinge and transmembrane domains on the in vivo efficacy and activity of anti-CD19 CARs (Abstract). Alabanza discloses, “Compared with T cells expressing CARs with CD28 hinge and transmembrane domains, T cells expressing CARs with CD8α hinge and transmembrane domains produced lower levels of cytokines and exhibited lower levels of activation-induced cell death (AICD). Importantly, CARs with hinge and transmembrane regions from either CD8α or CD28 had similar abilities to eliminate established tumors in mice” (Abstract).
Based on the further teachings of Y. Ma and Alabanza, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute a CD8α hinge and CD8α transmembrane domain as the membrane-bound anchor for the exogenously expressed IL-12p40 in CAR-T cells described by X. Ma. The skilled artisan would have been motivated to do so because, as shown by Y. Ma, the CD8α hinge and transmembrane domain are suitable for anchoring exogenous cytokines to the cell membrane in engineered CAR-T cells. Furthermore, Alabanza teaches that the CD8α hinge and transmembrane domain may have the advantage of eliciting less cytokine release (IFN-γ and TNF-α) and AICD. There would have been a reasonable expectation of success because Y. Ma provides a proof-of-concept that CD8α hinge/transmembrane domain can be successfully incorporated into a CAR-T cell as a means of anchoring an exogenously expressed cytokine to the cell membrane.
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.
(1)
Claims 1, 8, and 53-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 9-14, 18, 29-30, 32, 35, 43-45, and 50-53 of co-pending Application No. 17/798,541 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention. This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
Regarding claims 1 and 8, co-pending claims 1, 18 and 43 recite an immune effector cell expression the CAR of co-pending claim 18, an exogenously introduced p40 subunit, and exogenously introduced CCL-19.
Regarding claim 53, co-pending claim 44 recites a pharmaceutical composition comprising the immune effector cell of co-pending claim 43. Regarding claim 54, co-pending claim 45 recites a method of treating a patient having a GPC3-expressing cancer by administering said pharmaceutical composition.
(2)
Claims 1-2, 5-8, 10, 21, 49-58, and 60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 9-14, 18, 29-30, 32, 35, 43-45, and 50-53 of co-pending Application No. 17/798,541 as applied to claims 1, 8, and 53-54 above, further in view of X. Ma (Nature Biotechnology 38(4): 448-459; supra), Lee (US 2021/0145879 A1; supra), and Moelling (WO 2006/032525 A2; supra). This is a new rejection necessitated by claim amendment.
The teachings of the co-pending reference application as they relate to instant claims 1, 8, and 53-54 are described above.
In addition, relevant to claims 49-50, 55, and 60, co-pending claims 50-52 recite a cell and a vector comprising a nucleic acid comprising a sequence encoding the CAR of co-pending claim 18.
However, the co-pending reference application does not expressly teach that the p40 is a human IL-12 p40 comprising the amino acid sequence of instant SEQ ID NO: 5 and that the CCL-19 is a human CCL-19 comprising the amino acid sequence of instant SEQ ID NO: 6 (as set forth in claims 2 and 5-7), or that the CAR comprises a transmembrane domain, intracellular signaling domain, hinge, and/or signal peptide (as set forth in claims 8, 10, 29, and 31), or that the immune effector cell expressing said CAR is a T cell (as recited in claim 21), or a method of making said immune cell (as set forth in claims 51-52).
These deficiencies are remedied by the teachings of X. Ma, Lee, and Moelling, which are summarized in the 35 U.S.C. § 103 rejections above.
Based on the further teachings of X. Ma, Lee, and Moelling, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to co-express an exogenous membrane-bound human IL-12p40 subunit comprising the amino acid sequence of instant SEQ ID NO: 5 and one of a human CCL19 peptide comprising the amino acid sequence of instant SEQ ID NO: 6 or a human CCL21 peptide comprising the amino acid sequence of instant SEQ ID NO: 22, alongside a CAR (e.g., a CAR comprising the components set forth in claim 10) in an immune effector cell (e.g., a T cell). The skilled artisan would have been motivated to do so because X. Ma teaches that CAR-T cells expressing IL-12p40 show enhanced proliferation and anti-tumor activity, and because Lee and Moelling set forth that the additional expression of one of the homing receptors CCL19 or CCL21 acts as a chemo-attractant for T cells in the tumor microenvironment, further enhancing anti-tumor activity. There would have been a reasonable expectation of success because those of ordinary skill in the art would recognize that CARs, IL-12p40, and CCL19/CCL21 each have utility in the treatment of cancer, and, as noted in MPEP § 2144.06(I): “‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. Furthermore, Lee and Moelling provides a proof-of-concept that a polypeptide having multi-gene co-expression (i.e., expressing a CAR, a cytokine, and a chemokine), as well as immune effector cells comprising said polypeptide, can be generated and used in a method of treatment by a skilled artisan.
(3)
Claims 1 and 58-59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 9-14, 18, 29-30, 32, 35, 43-45, and 50-53 of co-pending Application No. 17/798,541 as applied to claims 1, 8, and 53-54 above, further in view of X. Ma (Nature Biotechnology 38(4): 448-459; supra), Y. Ma (WO 2020/077356 A1; supra), and Alabanza (Molecular Therapy (2017) 25(11): 2452-2465; supra). This is a new rejection necessitated by claim amendment.
The teachings of the co-pending reference application are recited in the provisional non-statutory double patenting rejections above.
However, the co-pending claims do not recite that the p40 is a membrane-bound p40 comprising p40, a CD8α hinge, and a CD8α transmembrane domain.
These deficiencies are remedied by the further teachings of X. Ma, Y. Ma, and Alabanza as set forth in the 35 U.S.C. § 103 rejections above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to express the p40 subunit in the CAR-T cell of the co-pending claims as a membrane-bound p40 comprising p40, a CD8α hinge, and a CD8α transmembrane domain based on the further teachings of X. Ma, Y. Ma, and Alabanza. The skilled artisan would have been motivated to do so because, as shown by Y. Ma, the CD8α hinge and transmembrane domain are suitable for anchoring exogenous cytokines to the cell membrane in engineered CAR-T cells. Furthermore, Alabanza teaches that the CD8α hinge and transmembrane domain may have the advantage of eliciting less cytokine release (IFN-γ and TNF-α) and AICD. There would have been a reasonable expectation of success because Y. Ma provides a proof-of-concept that CD8α hinge/transmembrane domain can be successfully incorporated into a CAR-T cell as a means of anchoring an exogenously expressed cytokine to the cell membrane, and because it was routine and conventional in the prior art to tether an exogenous cytokine to the cell membrane of CAR-T cells (e.g., via NGFR as originally described by X. Ma or via a CD8α hinge/transmembrane domain as shown by Y. Ma).
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
/Brad Duffy/Primary Examiner, Art Unit 1643
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