DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/21/2026 has been entered.
Applicant’s amendment, filed 04/21/2026, has been entered.
Claims 1-89 have been canceled.
Claims 90-119 are pending and currently under examination as they read on a method comprising providing a subject genetically engineered T cells and RNA encoding IL-2 in a particle comprising at least one lipid.
The previous Written Description Rejection under 35 USC 112(a) has been withdrawn in view of Applicant’s remarks and amendment, filed 04/21/2026.
The previous Rejection under 35 USC 102(a)(2) as being anticipated by Xiao et al. has been withdrawn in view of Applicant’s amendment, filed 04/21/2026.
The previous rejection under 35 USC 103 as being unpatentable over Xiao et al. in view of Zhu et al. has been withdrawn in view of Applicant’s amendment, filed 04/21/2026.
New Grounds of 103 Rejection and NSDP rejection are set forth.
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.
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.
Claims 90-119 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Oncotarget 2016 7(50):82354-82368) in view of Sahin et al. (US 2016/0250323 A1, “Sahin’323”), Sahin et al. (WO 2016/180467 “Sahin’467”; cited in IDS) and Zhu et al. (Cancer Cell 2015 27:489-501; reference of record).
The present claims are directed to a method for enhancing CAR-T cells expansion in vivo in a subject comprising providing:
the CAR-T cell,
RNA encoding IL-2 in a lipid containing particle, and
an antigen that CAR specifically binds or RNA encoding the antigen.
Xu et al. teaches methods of treating cancer using genetically engineered T cells expression CAR (see entire documents). Xu teaches that cytokines, including IL-2, IL-7, IL-15 and IL-21, support proliferation, persistence, and function of the CAR-T cells. Xu further demonstrates that IL-2 and IL-7 promote CAR-T cell expansion and evaluates administration of cytokines in conjunction with CAR-T therapy to improve anti-tumor activity (see Results). Together, Xu teaches engineered T cells expressing a CAR, administration of the CAR-T cells to a subject; enhancement of CAR-T cell expansion and persistence through cytokine support, specifically, IL-2, IL-7, IL-15 and IL-21; and treatment of cancer using CAR-T cells.
Xu does not teach administering RNA encoding IL-2 in a lipid-containing particle. However, it would have been obvious to one of ordinary skill in the art to deliver IL-2-encoding RNA via a lipid-containing particle because such practice was well known in the art before the effective filing date of the claimed invention. For example, Sahin’323 teaches administration of RNA molecules encoding cytokines, specifically IL-2, IL-7, IL-15 and IL-21, for enhancing T cell development, priming, expansion, differentiation and/or survival (see entire document, in particular, see, e.g., paragraph 0134). Moreover, Sahin’323 teaches lipid-based RNA delivery system (e.g., lipoplex particle comprising DOTMA and DOPE) and in vivo expression of cytokines following administration of the RNA using the lipid particle RNA delivery system (see, e.g., paragraphs 0033-0034).
Given that Xu taught the desirability of administering IL-2 to enhance CAR-T expansion and persistence; and that Sahin’323 teaches administering RNA encoding IL-2 in a lipid particle to promote T-cell expansion; it would have been obvious to use the IL-2 RNA delivery system of Sahin’323 in the CAR-T methods of Xu to achieve the known benefit of IL-2-mediated enhancement of CAR-T expansion and persistence.
It would have been obvious to substitute the cytokine administration taught by Xu with the cytokine-encoding RNA delivery system taught by Sahin’323 because the secondary reference merely provides a known alternative means of delivering the same biologically active cytokines to achieve the same recognized objective of enhancing T-cell expansion and persistence. Such substitution represents the predictable use of known element according to its established function. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417(2007).
Xu identified IL-2, IL-7, and IL-21 as useful cytokines for supporting CAR-T cell expansion and function. Sahin’323 identifies the same cytokines as suitable RNA payloads for enhancing T-cell development, expansion, differentiation and survival. Faced with the recognized need to improve CAR-T persistence and expansion, a skilled artisan would have had a finite number of identified and predictable cytokine choices and delivery approaches from which to select. Therefore, selecting IL-2, IL-7 or IL-21 RNA form the expressly disclosed cytokines would have been no more than the predictable use of prior art elements according to their established function. KSR, 550 U.S. at 421.
Moreover, a person of ordinary skill in the art would have reasonable expectation of success because Xu establishes that IL-2, IL-7, and IL-21 exert beneficial effects on CAR-T cells, while Sahin’323 teaches that RNA encoding those same cytokines can be delivered using lipic particles to induce cytokine expression and promote T-cell expansion and survival. Since both references rely on the same cytokine signaling pathways to enhance T-cell response, combining the teachings would have predictably resulted in enhanced expansion and persistence of CAR-T cells.
Xu did not teach administering an antigen or an RNA encoding the antigen.
Sahin’467 teaches administration of an antigen or a nucleic acid encoding the antigen in conjuction with adoptive CAR-T cell therapy. Specifically, Sahin’467 teaches administering RNA encoding a target antigen such that the antigen is expressed in vivo and presented to the transferred CAR-T cells, thereby stimulating, activating, and expanding the antigen-specific CAR-T cell population. Sahin’467 further teaches that such antigen-RNA vaccination may be employed to increase the number, persistence, and therapeutic activity of CAR-T cells following administration to a subject.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the antigen-RNA administration strategy of Sahin’467 in the the CAR-T treatment methods of Xu as modified by Sahin’323. Xu teaches that cytokines such as IL-, IL-7 and IL-21 enhance CAR-T cell expansion, persistence and function. Sahin’323 teaches administration of lipid particle-associated RNA encoding the same cytokines to promote T cell development, priming, expansion, differentiation, and survival. Sahin’467 teaches that administration of antigen encoding RNA stimulates and expands antigen-specific CAR T cell in vivo.
One of ordinary skill in the art would have recognized that cytokine-mediated stimulation and antigen-mediated stimulation are complementary mechanisms for enhancing the efficacy of adoptively transferred CAR-T cells. The combination of the references merely employs known methods to improve expansion and persistence of the CAR-T cells through both cytokine support and antigen-specific stimulation. A skilled artisan would have reasonable expectation of success that providing both cytokine stimulation and antigen-driven activation would increase the number and persistence of functional CAR-T cells and thereby improve therapeutic efficacy. Combining known prior-art elements according to known methods to yield predictable results is a proper basis for a conclusion of obviousness. KSR, 550 U.S. at 421.
With respect to extended pharmacokinetic (PK) IL2 or other cytokine, the following is noted:
Moreover, Xu did not teach extended PK IL-2 or IL-7. However, it would have been obvious to one of ordinary skill in the art to use extended PK cytokines as they were well known in the art before the effective filing date of the claimed invention. For example, Zhu et al. taught an extended PK IL-2 with extended serum half-life induced an anti-tumor T cell response when administered in a combination therapy (see entire document). In particular, Zhu taught a fusion protein comprising IL-2 and Fc that had an increase in serum duration. The serum half-life extension of Fc/IL-2 afforded a synergistic efficacy against tumor when administered with anti-TYRP antibody TA99 (see Results page 490). Upon reading the teachings, one of ordinary skill in the art would have been motivated to make an IL-2/Fc or IL-7/Fc fusion protein to prolong the serum half-life in the method taught by Xiao.
The rationale to support a conclusion that the claims would have been obvious is that all the claimed elements (e.g., inducing an immune response comprising administering a CAR T cell and IL-2, IL-7 and IL-21 / extended PK IL-2, IL-7 and IL-21) were known in the prior art and one of ordinary skill in the art could have arrived at the claimed invention by using known methods with no change in their respective functions and the combination would have yielded nothing more than predictable results of inducing an immune response comprising administering a CAR T cell, extended PK IL-2, IL-7 and IL-21.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art, before the effective filing of the claimed invention as evidenced by the reference, especially in the absence of evidence to the contrary.
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.
Claims 90-119 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent 10,799,534 and claims 1-29 of U.S. Patent 12,186,275 in view of Xu et al. (Oncotarget 2016 7(50):82354-82368), Sahin et al. (US 2016/0250323 A1, “Sahin’323”) and Zhu et al. (Cancer Cell 2015 27:489-501).
The patent claims disclosed a method for stimulating an immune response in a mammal comprising administering CAR-T cells targeting to an antigen and administering an RNA encoding the antigen carried in a liposome comprising DOTMA and DOPE. Although the patent claims did not disclose administering cytokines, it would have been obvious to administering RNA-encoded cytokines as recited in the present claims in view of the teachings by Xu et al., Sahin’323 and Zhu et al. for reasons discussed above (see 103).
Claims 90-119 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10, 12-13, 26, 35-49 of copending Application No. 17757195 in view of Xu et al. (Oncotarget 2016 7(50):82354-82368), Sahin et al. (US 2016/0250323 A1, “Sahin’323”), Sahin et al. (WO 2016/180467 “Sahin’467”; cited in IDS) and Zhu et al. (Cancer Cell 2015 27:489-501).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the co-pending application disclosed a method of treatment of cancer comprising administering a CAR T cell. Although the claims did not disclose administering IL-2 and IL-7, it would have been obvious in view of Xu, Sahin’323, Sahin’467 and Zhu discussed above (see 103). Therefore, the co-pending claims render obvious of the present claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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/SHARON X WEN/Primary Examiner, Art Unit 1641
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