DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/10/2026 has been entered.
Claims status
Claims 5-7 is/are cancelled. Claims 1, 4, 8-11, 14-22 is/are currently pending with claims 11, 14-21 is/are withdrawn. Claims 1, 4, 8-10, 22 is/are under examination.
Claim Interpretation
Claim 1 recites “An immunocompetent cell having decreased diacylglycerol kinase activity”, “wherein said cell is a T cell that is derived from an induced pluripotent stem cell (iPSC)”. The limitation “T cell that is derived from an induced pluripotent stem cell (iPSC)” is a product-by-process limitation. According to MPEP 2113, “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”. In the instant case, the process of obtaining a T cell such as by differentiation induction from a pluripotent stem cell such as iPSC as recited in the product-by-process limitation is not expected to alter the structure of the cell derived which is a T cell, especially in the absence of evidence to the contrary. Thus, prior art teaching a T cell meets the product-by-process limitation.
In the remarks filed 7/10/2026, Applicant allege that “iPSC-derived T cells possess distinct properties and exhibit markedly different biological performance compared to corresponding primary T-cell populations.” (page 4-5, bridge para). In support, Applicant do not point to any specific argument but only state “As discussed below” (page 4-5, bridge para). For the purpose of compact prosecution, it is assumed that Applicant intends to point to the alleged “unexpected and remarkable results” mentioned on page 8, para 2. Herein, Applicant state that “In particular, significant tumor regression and improved survival were observed in animals treated with DGK-dKO iCAR-TCTL mbIL15 cells. See Figs. 3C, 3E, 3H, 31, 4C, and 5B. These effects were not observed in the corresponding primary T cell-derived DGK-pKO pCAR-TCTL mbIL15 cells, despite the fact that those cells carried comparable genetic modifications.” (page 8, para 2).
In response, primary T cell-derived DGK-pKO pCAR-TCTL mbIL15 cells are not comparable to DGK-dKO iCAR-TCTL mbIL15 cells. While the iPSC derived DGK-dKO iCAR-TCTL mbIL15 cells have a double knockout of DGK alpha and zeta gene, primary T cell-derived DGK-pKO pCAR-TCTL mbIL15 cells merely comprise a partial deficiency. See para 69 in the instant specification identifying that “Primary T cells with partial deficiency of DGK were prepared by the following procedure (DGK-pKO pCAR-TCTL cells).”. Therefore, the data does not support that iPSC-derived T cells possess distinct properties and exhibit markedly different biological performance compared to corresponding primary T-cell populations. Furthermore, deriving T-cells from primary source or iPSC are obvious variants. Sabzevari (WO 2019236577 A2; ref of record) teaches these obvious variants stating that “[00249] Sources of immune effector cells can include both allogeneic and autologous sources. In some cases immune effector cells can be differentiated from stem cells or induced pluripotent stem cells (iPSCs ). Thus, cell for engineering according to the embodiments can be isolated from umbilical cord blood, peripheral blood, human embryonic stem cells, or iPSCs.” See also [0013], [0016] in the instant specification that identifies T-cells from primary source or iPSC are obvious variants. Thus, based on the inquiry from In re Thorpe noted by the Applicant i.e. “whether the claimed product is the same as or obvious from products disclosed in the prior art.” (emphasis added), prior art teaching T-cells derived from primary sources renders obvious T-cells derived from iPSC.
Claims 9-10 recite intended use of the pharmaceutical composition of claim 8 that comprises the cell of claim 1 without any additional elements. Th intended use is “for treatment of cancer” “wherein the cancer is solid cancer”. According to MPEP 2111.02, “During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim. See, e.g., In re Otto, 312 F.2d 937, 938, 136 USPQ 458, 459 (CCPA 1963) (The claims were directed to a core member for hair curlers and a process of making a core member for hair curlers. The court held that the intended use of hair curling was of no significance to the structure and process of making.)”. Only language that clearly defines structural limitations is considered with respect to patentability analysis. Therefore, in the instant claims, the intended use of the product of claim 1 and/or 8 for treatment of a solid cancer is not considered in analyzing the patentability of the cell of claims 9 and 10 since the pharmaceutical of claim 8 is the same the cell of claim 1 without any additional structure, especially in the absence of evidence to the contrary.
Claim Rejections - 35 USC § 102 – Moot/Withdrawn
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Rejection of Claim(s) 5-7 under 35 U.S.C. 102(a)(a) as being anticipated by Hurton et al (PNAS, Vol. 113, e7788-e7797, 2016; IDS 12/15/2022) as evidenced by CD5 Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) and CD8b Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) is moot due to claim cancellation.
Rejection of Claim(s) 1, 4, 8-10 and 22 under 35 U.S.C. 102(a)(a) as being anticipated by Hurton et al (PNAS, Vol. 113, e7788-e7797, 2016; IDS 12/15/2022) as evidenced by CD5 Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) and CD8b Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) is withdrawn because Hurton does not teach knocking out a DGK gene.
Rejection of Claim(s) 5-7 under 35 U.S.C. 102(a)(a) as being anticipated by Sabzevari et al (WO 2019236577 A2, Published 2019-12-12) as evidenced by Hurton, CD5 Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) and CD8b Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) is moot due to claim cancellation..
Rejection of Claim(s) 1, 4, 8-10 and 22 under 35 U.S.C. 102(a)(a) as being anticipated by Sabzevari et al (WO 2019236577 A2, Published 2019-12-12) as evidenced by Hurton, CD5 Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) and CD8b Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892). is withdrawn because Sabzevari does not teach knocking out a DGK gene.
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.
Rejection of Claim(s) 5-7 under 35 U.S.C. 103 as being unpatentable over Hurton and alternatively as being unpatentable over Sabzevari in view of Loew et al (US 20170335281 A1, Published 2017-11-23; ref of record) as evidenced by CD5 Antibodies (Thermo Fischer Scientific Primary Antibodies, ref of record) and CD8b Antibodies (Thermo Fischer Scientific Primary Antibodies, ref of record) is moot due to claim cancellation.
Rejection of Claim(s) 1, 4, 8-10 and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hurton and alternatively as being unpatentable over Sabzevari in view of Loew et al (US 20170335281 A1, Published 2017-11-23; ref of record) as evidenced by CD5 Antibodies (Thermo Fischer Scientific Primary Antibodies, ref of record) and CD8b Antibodies (Thermo Fischer Scientific Primary Antibodies, ref of record) is withdrawn in favor of the rejection below that address claim amendments.
Claim(s) 1, 4, 8-10 and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hurton and alternatively as being unpatentable over Sabzevari in view of Loew et al (US 20170335281 A1, Published 2017-11-23; ref of record) as evidenced by CD5 Antibodies (Thermo Fischer Scientific Primary Antibodies, ref of record) and CD8b Antibodies (Thermo Fischer Scientific Primary Antibodies, ref of record).
Regarding claim 1, Hurton teaches a T-cell (=immunocompetent cell) expressing a membrane-bound fusion-protein comprising IL-15 and IL-15 receptor alpha subunit (mbIL15) and a CD19 CAR (Figure 1, T cells stably coexpressing mbIL15 and CAR wherein mbIL15 is the fusion protein shown in Figure 1A). The IL-15 receptor alpha subunit portion of mbIL15 provides the transmembrane portion of the fusion protein. See SI Appendix Materials and Methods: Plasmid Design. mbIL15 that discloses that the fusion protein comprises the full-length IL-15Ra cDNA sequence i.e. it includes the transmembrane region of the IL-15Ra.
Similarly, regarding claim 1, Sabzevari teach a T-cell (=immunocompetent cell) expressing a fusion protein comprising IL-15 and IL-15 receptor alpha subunit and a CAR ([0024-0025], [0174-00177], Example 1, Figures 1 and 2 shows constructs with CAR and mbIL15 wherein mbIL15 is the fusion protein, Figure 4, 8 shows using T-cells expressing the constructs). Sabzevari discloses the fusion protein is a transmembrane protein ([00174], references Hurton et al (as above) as the source of the mbIL-15 which as discussed above discloses mbIL-15 as a transmembrane fusion protein.
Thus, both Hurton and Sabzevari teach a CAR- T-cell expressing a transmembrane mbIL-15 fusion protein comprising IL-15 and IL-15 receptor alpha subunit.
Regarding the product-by-process limitation wherein T-cell is derived from iPSC, Sabzevari teaches that T-cells in their disclosure can be derived from iPSC [0249].
Regarding claim 4, Hurton teaches mbIL15-CAR T-cells as CD8 positive (Figure 1F). Additionally T-cells are inherently CD5 and CD8b positive, as evidenced by basic information available regarding CD5 Antibodies and CD8b Antibodies from Thermo Fischer Scientific that evidences that “CD5 is present on all mature T-lymphocytes” (see Target Information in CD5 Antibodies) and “The CD8B antigen is a cell surface glycoprotein found on most cytotoxic T lymphocytes” (see Target Information in CD8b Antibodies).
Similarly, regarding claim 4, Sabzevari teaches T-cells that are inherently CD5 and CD8b positive, as evidenced by basic information available regarding CD5 Antibodies and CD8b Antibodies from Thermo Fischer Scientific that evidences that “CD5 is present on all mature T-lymphocytes” (see Target Information in CD5 Antibodies) and “The CD8B antigen is a cell surface glycoprotein found on most cytotoxic T lymphocytes” (see Target Information in CD8b Antibodies).
Regarding claims 8, Hurton delivers the cell of claim 1 to animal model of cancer thus disclosing a pharmaceutical composition comprising the cell (see figure 5 and 6 in Hurton) and Sabzevari delivers the cell of claim 1 to animal model of cancer thus disclosing a pharmaceutical composition comprising the cell (see Example 10-12 in Sabzevari).
Regarding claims 9-10, in disclosing an immunocompetent T-cell of claim 1, both Hurton and Sabzevari teach the cell of claim 9-10 (see claim interpretation above, also see figure 5 and 6 in Hurton and Example 10-12 in Sabzevari).
Hurton and Sabzevari do not teach knocking out of at least one DGK gene in their a mbIL-15 CAR-T cells wherein the DGK gene is DGKa or DGKz, as recited in claim 22.
Loew teaches CAR-T cells derived from mice with a deletion of DGKa and DGKz genes i.e. knockout of DGKa and DGKz gene [1213]; as required by claim 1 and 22.
Loew teaches that “Previous studies, for example, the experiments discussed in Example 6, have suggested that CAR T cells lose efficacy over time in vivo” [1211] and “Inhibitory mechanisms that possibly explain the decrease in CAR T cell activity in vivo over time include […] DGK” and “Previous studies have shown that mice deficient in DGKa or DGKz; results in CD4 T cells that demonstrate enhanced signal transduction and appear more resistant to anergy-inducing stimuli” [1212]. To overcome the loss of efficacy in CAR-T cells, Loew teaches that “deletion of DGKs markedly enhanced effector function of CAR T cells, especially at low effector: target ratios” and in vivo(Figure 68, 72, Example 11). Furthermore, Loew also teaches that cytokines such as IL-15 and fusion polypeptides of IL15-IL15Ra increase the therapeutic efficacy and/or proliferation of CAR-T cells ([0081, 0088, 0093, 724, 725, 0955], example 10).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to delete the DGKa and DGKz genes in the CAR-T cells of Hurton, and alternatively in the CAR-T cells of Sabzevari. An ordinary artisan would be motivated to delete these genes in the CAR-T cells of Hurton, and alternatively Sabzevari, because Loew teaches that deletion of DGKa and DGKz genes in the CAR-T cells enhance their therapeutic efficacy. An ordinary artisan would reasonably expect to produce a CAR-T cells of Hurton, and alternatively Sabzevari, further comprising deletion of DGKa and DGKz genes by using the method taught by Loew [1213].
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Double Patenting - Withdrawn
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.
Rejection of Claims 1, 4-10 and 22 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 7 of copending Application No. 19/266,956 (reference application) as evidenced by CD5 Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) and CD8b Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) and Hurton is withdrawn in light of claim amendment requiring knockout of a DGK gene.
Rejection of Claims 1, 4-10 and 22 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 27 of copending Application No. 19/266,773 (reference application) as evidenced by CD5 Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) and CD8b Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) and Hurton is withdrawn in light of claim amendment requiring knockout of a DGK gene.
Rejection of Claims 1, 4-10, 22 on the ground of nonstatutory double patenting as being unpatentable over claims 4 and 6 of U.S. Patent No. US 12391739 B2 as evidenced by Hurton, CD5 Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) and CD8b Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) is withdrawn in light of claim amendment requiring knockout of a DGK gene.
Response to Arguments
Applicant’s arguments with respect to U.S.C. 102 rejection of claim(s) 1, 4-10, 22 over Hurton or Sabzevari have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Applicant’s arguments with respect to U.S.C. 103 rejection of claim(s) 1, 4-10, 22 over Hurton or Sabzevari in Loew have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Arguments pertinent to instant U.S.C. 103 rejection of claim(s) 1, 4-10, 22 over Hurton or Sabzevari in view of Loew are addressed below.
Applicant argue that “ Neither Hurton, Sabzevari, nor Loew discloses or suggests an iPSC-derived T cell.” and “the claimed combination produces unexpected and remarkable results that would not have been predicted from the cited references.”. In support, Applicant allege that “significant tumor regression and improved survival were observed in animals treated with DGK-dKO iCAR-TCTL mbIL15 cells. See Figs. 3C, 3E, 3H, 31, 4C, and 5B. These effects were not observed in the corresponding primary T cell-derived DGK-pKO pCAR-TCTL mbIL15 cells, despite the fact that those cells carried comparable genetic modifications.” and “The
dramatic superiority exhibited by the claimed DGK-dKO iCAR-TcTL mbIL15 cells therefore
constitutes strong objective evidence of nonobviousness” (page 8, para 1-3).
In response, Sabzevari teaches an iPSC-derived T cell [0249].
Regarding unexpected and superior results, at first it must be noted that the results referred to do not compare cells that are genetically comparable. While the iPSC derived DGK-dKO iCAR-TCTL mbIL15 cells have a double knockout of DGK alpha and zeta gene, primary T cell-derived DGK-pKO pCAR-TCTL mbIL15 cells merely comprise a partial deficiency. See para 69 in the instant specification identifying that “Primary T cells with partial deficiency of DGK were prepared by the following procedure (DGK-pKO pCAR-TCTL cells).”. Thus, it cannot be concluded that any difference in the iPSC derived DGK-dKO iCAR-TCTL mbIL15 cells in comparison to primary T cell-derived DGK-pKO pCAR-TCTL mbIL15 is because the T-cells in the prior are derived from iPSCs. Furthermore, the claimed immunocompetent cell is not limited to a iPSC derived DGK-dKO iCAR-TCTL mbIL15 since it can comprise a knockout in any DGK gene or any one of DGKa or DGKz gene. The results presented are specifically for a double knockout and there is no evidence that a similar result would produced if any DGK gene, such as any one of DGKa and DGKz, is knocked out. Therefore, arguments pertaining to unexpected and superior results are unpersuasive.
Conclusion
No claim is allowed.
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/MATASHA DHAR/Examiner, Art Unit 1632
Prosecution Insights