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 .
Claims status
Applicants reply filed 12/23/2025 is acknowledged.
Claims 2, 3 is/are cancelled and claims 22 is/are newly added. Claims 1, 4-11, 14-22 is/are currently pending with claims 11, 14-21 is/are withdrawn. Claims 1, 4-10, 22 is/are under examination.
Specification
Objection to the specification is withdrawn in light of amendment to the specification filed 12/23/2025.
Claim Rejections - 35 USC § 112(b) - Moot
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Rejection of Claim 2 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is moot due to claim cancellation.
Claim Interpretation – Updated in light of claim amendment
Claim 1 recites “An immunocompetent cell having decreased diacylglycerol kinase activity”, “wherein diacylglycerol kinase activity has been decreased by knocking out at least one diacylglycerol kinase gene or reducing expression of at least one diacylglycerol kinase gene” (emphasis added). Regarding “reducing expression of at least one diacylglycerol kinase gene”, this limitation embraces reduction in expression of any diacylglycerol kinase (DGK) gene by any means to any level for any duration. Of note, reduction in gene expression embraces reduction in transcription of the gene or translation of its mRNA product. Therefore, the claim embraces an immunocompetent cell wherein DGK activity of any of the member of the DGK protein family is decreased via reducing the expression of any DGK gene by any means, for any duration and to any amount.
Claim 6 recites “said cell is obtained by differentiation induction from a pluripotent stem cell” and Claim 7 recites “wherein the pluripotent stem cell is an induced pluripotent stem cell”. Regarding claim 6, it should be noted that all cells in an animal are derived from i.e. obtained from a pluripotent stem cell. Additionally, it should be noted that these limitations result in a product-by-process claim. 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 an immunocompetent cell by differentiation induction from a pluripotent stem cell or iPSC results in the immunocompetent cell of claim 1 and thus the cell of claim 6 or claim 7 is not patentably distinct from the cell of claim 1, especially in the absence of evidence to the contrary.
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 - New, necessitated by claim amendments
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) 1, 3-10 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 in light of claim amendments. New grounds of rejection below provide teachings from Hurton regarding reduction in DGK gene expression.
Rejection of Claim(s) 1, 3-10 is/are rejected 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 in light of claim amendments. New grounds of rejection below provide evidence from Hurton regarding reduction in DGK gene expression.
Claim(s) 1, 4-10 and 22 is/are rejected 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).
Regarding claims 1 and 5, Hurton discloses 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. Furthermore, Hurton shows that their mbIL15-CAR T cells have reduced expression of DGKA gene (Figure S4B).
Regarding claim 4, Hurton discloses 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).
Regarding claims 6 and 7, in disclosing an immunocompetent T-cell of claim 1, Hurton discloses the cell of claim 6 and 7 (see claim interpretation above).
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).
Regarding claims 9-10, in disclosing an immunocompetent T-cell of claim 1, Hurton discloses the cell of claim 9-10 (see claim interpretation above, also see figure 5 and 6 in Hurton).
Regarding claim 22, Hurton discloses knock down of DGK subtype a gene expression in their mbIL15-CAR (Figure S4B).
Therefore, Hurton anticipates the claimed invention.
Claim(s) 1, 4-10 and 22 is/are rejected 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).
Regarding claims 1 and 5, Sabzevari discloses 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. Furthermore, as evidenced by Hurton, mbIL-15 comprising CAR-T cells have reduced expression of DGKA gene (Figure S4B). Thus, Sabzevari’s mbIL15-CAR T cells have reduced expression of DGKA gene.
Regarding claim 4, Sabzevari discloses 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 6 and 7, in disclosing an immunocompetent T-cell of claim 1, Sabzevari discloses the cell of claim 6 and 7 (see claim interpretation above, also see [00249] in Sabzevari).
Regarding claims 8, 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, Sabzevari discloses the cell of claim 9-10 (see claim interpretation above, also see Example 10-12 in Sabzevari).
Regarding claim 22, Hurton evidences that Sabzevari’s mbIL15-CAR T cells have a knock down of DGK subtype a gene expression in their mbIL15-CAR (Figure S4B).
Therefore, Sabzevari anticipates the claimed invention.
Claim Rejections - 35 USC § 103 - New, necessitated by claim amendments
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) 2 under 35 U.S.C. 103 as being unpatentable over Hurton as applied to claim1 above and alternatively as being unpatentable over Sabzevari as applied to claim 1 above, and further in view of Loew et al (US 20170335281 A1, Published 2017-11-23; IDS 11/6/2024) is moot due to claim cancellation.
Claim(s) 1, 4-10 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 claims 1 and 22, as detailed in the U.S.C. 102 rejection of these claims above, both Hurton and Sabzevari teach the CAR- T-cell expressing a transmembrane mbIL-15 fusion protein comprising IL-15 and IL-15 receptor alpha subunit. Furthermore, as evidenced by Hurton, both Hurton and Sabzevari’s mbIL15-CAR T cells have a reduced expression of DGKA gene.
Regarding claim 4, as detailed in the U.S.C. 102 rejection of these claims above, both Hurton and Sabzevari teach 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 6 and 7, as detailed in the U.S.C. 102 rejection of these claims above, in disclosing an immunocompetent T-cell of claim 1, both Hurton and Sabzevari teach discloses the cell of claim 6 and 7 (see claim interpretation above, also see [00249] in Sabzevari).
Regarding claims 8, as detailed in the U.S.C. 102 rejection of these claims above, 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, as detailed in the U.S.C. 102 rejection of these claims above, 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 the alternate limitation recited in claim 1 and 22 regarding knocking out of at least one DGK gene in their a mbIL-15 CAR-T cells wherein the DGK gene is DGKa or DGKz.
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].
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
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, 3-10 on the ground of nonstatutory double patenting as being unpatentable over claim 7 of copending Application No. 19/266,860 (reference application) as evidenced by CD5 Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) and CD8b Antibodies (Thermo Fischer Scientific Primary Antibodies, PTO-892) is withdrawn in light of cancellation of claim 7 in `860.
Rejection of Claims 1, 3-10 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) is withdrawn to address new claim limitations. Hurton is provided as additional evidentiary reference.
Claims 1, 4-10 and 22 are 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.
Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 7 of `956 is directed to a method that generates an immunocompetent T-cell comprising a CAR (recited in claim 5 that claim 7 depends from) and a fusion protein comprising IL-15 and IL-15Ra (recited in claim 7). Hurton evidences that mbIL15-CAR T cells have reduced DGKA gene expression under some circumstances (Figure S4B). Thus the method of claim 7 that generates mbIL15-CAR T has reduced DGKA gene expression under some circumstances. Thus the method of claim 7 generates the cell identical to the cell claimed in claims 1, 4-10, 22 based on claim interpretation presented above and evidence from Hurton, CD5 Antibodies and CD8b antibodies.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Rejection of Claims 1, 3-10 on the ground of nonstatutory double patenting as being unpatentable over claim 7 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) is withdrawn due to claim amendments in `773.
Claims 1, 4-10 and 22 are 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.
Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 27 of `773 is directed to a method that generates an immunocompetent T-cell comprising a CAR (recited in claim 25 that claim 27 depends from) and a fusion protein comprising IL-15 and IL-15Ra (recited in claim 27). Hurton evidences that mbIL15-CAR T cells have reduced DGKA gene expression under some circumstances (Figure S4B). Thus the method of claim 27 that generates mbIL15-CAR T has reduced DGKA gene expression under some circumstances. Thus the method of claim 27 generates the cell identical to the cell claimed in claims 1, 4-10, 22 based on claim interpretation presented above and evidence from Hurton, CD5 Antibodies and CD8b antibodies.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Rejection of Claims 1, 3-10 on the ground of nonstatutory double patenting as being unpatentable over claim 7 of copending Application No. 17/259,736 in view of claim 5 of copending Application No. 17/259,736 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 `736 is now issued as a patent US 12391739 B2.
Claima 1, 4-10, 22 are rejected 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).
Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 6 of `739 is directed to a method that generates an immunocompetent T-cell (recited in claim 1 that claim 6 depends from) comprising a fusion protein comprising IL-15 and IL-15Ra. Further, claim 4 teaches that the T-cell of claim 1 further comprises a CAR.
Therefore, it would be obvious to an ordinary artisan to generate an immunocompetent T-cell comprising a fusion protein comprising IL-15 and IL-15Ra of claim 6 of `739, further comprising a CAR, as taught in claim 4 of `739. The method of claim 6 of `739 in combination with claim 4 of `739 generates an immunocompetent T-cell comprising a CAR and a fusion protein comprising IL-15 and IL-15Ra. Hurton evidences that mbIL15-CAR T cells have reduced DGKA gene expression under some circumstances (Figure S4B). Thus the method of claim 6 and claim 4 together generate mbIL15-CAR T that has reduced DGKA gene expression under some circumstances. Thus the methods of claim 6 and 4 generates the cell identical to the cell claimed in claims 1, 4-10, 22 based on claim interpretation presented above and evidence from Hurton, CD5 Antibodies and CD8b antibodies.
Response to Declaration by Dr. Kaneko filed 12/23/2025
The Declaration by Dr. Kaneko under 37 CFR 1.132 filed 12/23/2025 is insufficient to overcome the U.S.C. 102 rejection of claims 1, 4-10 based upon Hurton or Sabzevari as set forth in the last or the instant Office action since no opinion or argument is presented regarding these rejections.
Per #4 in the declaration, the opinions and arguments presented are regarding the U.S.C. 103 rejection of the now cancelled claim 2 as being unpatentable over Huron in view of Loew. Since claim 2 is cancelled, arguments pertaining to this rejection are moot.
However, in the interest of compact prosecution, arguments relevant to the instant U.S.C. 103 rejection of claims 1, 4-10 and 22 as being unpatentable over Huron in view of Loew are addressed below.
First, Dr. Kaneko present their opinions regarding Hurton and Loew in #7 and #8. Based on these, Dr. Kaneko allege that “A POSITA would understand that combining a mechanism for hyper-activation (DGK knockout) with a mechanism for continuous maintenance signaling (mblL15) poses a severe risk of chronic over-stimulation. It is well-established in immunology that chronic, high intensity stimulation leads to rapid T cell exhaustion and apoptosis (activation-induced cell death). Therefore, the hyper-active nature of the cells taught by Loew would act as a disincentive (teaching away) for a POSITA to incorporate the continuous signaling strategy of Hurton, as doing so would likely destroy the long-term persistence benefit Hurton seeks to achieve” (#9).
This argument is not persuasive because no evidence is provided that an ordinary or a skilled artisan has any reason to believe that a combination of DGK-knockout with mbIL15 expression would result in “high intensity stimulation” leading to “T cell exhaustion and apoptosis”. The stimulation leading to T cell exhaustion is due to antigen-CAR interaction and not IL15 signaling, which provides pro-survival signal to T-cells (see Hurton Introduction para 3). No evidence is provided that increased efficacy of DGK-knockout CAR-T cells of Loew is “hyper-activation” that would alone or in combination with a pro-survival signal like mbIL-15 would result in T cell exhaustion. No evidence is provided that an ordinary artisan observed T cell exhaustion when combining methods that increase CAR-T cytotoxic efficacy with pro-survival signal like mbIL-15. No evidence is provided that an ordinary artisan using Huron’s mbIL-15 CART cells that have improved persistence even in low antigen environment, even after tumor clearance (Figure 5 and 6) would not attempt to further improve its cytotoxic response in the presence of antigen. In fact, Hurton “hypothesized that mbIL15 can continue to support CAR T-cell persistence and act additively with an improved CAR design to augment antitumor efficacy further.” (page E7793, col. 2, last para). Then Hurton modifies their first iteration of mbIL-15 CAR-T cells by substituting the CAR with a CAR* that has improved anti-tumor activity and show that mbIL-15 CAR*-T cells have much improved tumor activity and survival (Figure 6).
Furthermore, as taught by both Hurton and Loew, inclusion of IL-15 along with CAR-T therapy is well known due to IL-15’s pro-survival effects (see also Example 10 in Loew). Hurton shows that mbIL15 is an improvement over soluble IL15 because avoids the increased proliferation phase of IL15-induced CAR-T but maintains CAR-T cell numbers. Hurton state that “Thus, it appears that mbIL15 mimics the transpresentation of endogenous IL-15, signaling via STAT5, without leading to aberrant proliferation.” (page e7794, col. 2, para 1 and “Thus, it appears that coordinated signaling with mbIL15 and CAR provides a pathway to improving antitumor effects across a spectrum of tumor burden. The approach of combining signals 1 and 2 via CAR with signal 3 from mbIL15 may be preferred to coinfusing CAR T cells with soluble recombinant IL-15 due to toxicity (50).” (emphasis added; page e7795, col.1, para 1). Hurton also provides teachings regarding T-cell exhaustion, specifically based on the data from their antigen-withdrawal experiments on CAR T and mbIL15-CAR T cells, it appears that mbIL15 may also blocks T cell exhaustion (page e7795, col. 2, para 1).
Thus, contrary to Dr. Kaneko’s allegation, sufficient motivation to combine Hurton with Loew was available to an ordinary artisan. Such a combination was expected to have improved CAR-T cell efficacy due reduced feedback inhibition of antigen-induced CAR activation due to DGK KO and also improved persistence without soluble-IL15-associated aberrant proliferation as well as potentially reduced exhaustion due mbIL15 expression.
Next, Dr. Kaneko references “Examiner's observation that IL-15 can cause expansion” without identifying where this observation was mentioned. Dr. Kaneko allege that “Hurton provides experimental evidence demonstrating that mblL15 functions distinctly from soluble IL-15 or soluble IL-15/IL-15R complexes.” (emphasis added, #10). and that “Hurton's mbIL15 provides a qualitative signal distinct from the "expansion stimulus" provided by soluble forms. Hurton explicitly utilizes mbIL15 for the purpose of "maintenance/survival" to preserve a stem-like phenotype. If Hurton had intended to promote "expansion," they would have likely utilized the soluble complex format or a different signaling domain. The selection of mbIL15 was a deliberate choice to avoid the rapid proliferation and subsequent differentiation associated with strong cytokine stimulation.” (#12).
In response, Hurton does not show that that mblL15 functions distinctly from soluble IL-15 or soluble IL-15/IL-15R complexes or that it provides a qualitatively distinct signal. Hurton shows that IL15 - both soluble and membrane-bound, function via the same downstream effector pSTAT5 (Figure 1E). Hurton shows that in comparison to soluble IL15 which results in stronger downstream IL15R activation (see pSTAT5 levels in Figure 1E) and thus rapid, yet short-lived increase in CAR-T cell proliferation which stabilizes in 15-30 days (Figure S3B), mbIL15 provides a weaker downstream IL15R activation (see pSTAT5 levels in Figure 1E) and maintains the number of CAR-T cells without the proliferative phase. Both soluble and membrane bound IL15 are useful for maintenance as well as survival of CAR-T cells, however indeed soluble IL15 results in an initial proliferative phase. In agreement with Dr. Kaneko, Hurton indeed shows key differences in mbIL15 CAR-T cells and CAR-T cells with soluble IL-15, especially regarding emergence of CCR7+ T cells (T-memory stem cells) after antigen-withdrawal (Figure S5). As noted above, Hurton also expands on potential benefits of using mbIL15 which results in lower pSTAT5 expression over using a soluble IL15 stating “we provide an alternative to IL-15 hyperstimulation. We demonstrated that mbIL15-CAR T cells had submaximal pSTAT5 levels relative to control CAR T cells stimulated with exogenous IL-15 and that these cells attained a desired less differentiated phenotype.” (e7796, col.1-2 bridging para).
Response to Arguments
Applicant’s arguments with respect to U.S.C. 102 rejection of claim(s) 1, 3-10 over Hurton or Sabzevari have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Arguments pertinent to instant U.S.C. 102 rejection of claim(s) 1, 4-10 over Hurton or Sabzevari are addressed below.
Applicant argue that “claim 1 is amended to explicitly require that the DGK activity has been decreased by a specific structural modification, i.e., "by knocking out at least one diacylglycerol kinase gene or reducing expression of at least one diacylglycerol kinase gene", similar to the structural modification previously recited in claim 2”. (page 9, last para)
This is not persuasive because amendment to claim 1 embraces a cell wherein DGK gene expression is reduced by any means, at any level and for any duration. This feature is anticipated by a mbIL15-CAR T cells, such as of Hurton and Sabzevari because Hurton teaches mbIL15-CAR T cells have DGKA gene expression after 4xantigen-stimulation in comparison to 65 days post antigen-withdrawal (Figure S4B). The limitation in now cancelled claim 2 specifically required genetic mutation in DGK genes, this is significantly narrower than “reducing expression of at least one diacylglycerol kinase gene”.
Applicant’s arguments with respect to U.S.C. 103 rejection of claim(s) 2 over Hurton or Sabzevari in Loew have been considered but are moot because claim 2 is cancelled.
Arguments pertinent to instant U.S.C. 103 rejection of claim(s) 1, 4-10 over Hurton or Sabzevari in view of Loew are addressed below.
First, applicant argue that “Modifying the primary references as suggested would render them unsuitable for their intended purpose”. Regarding Hurton, Applicant allege that “The express purpose is to avoid the terminal differentiation and exhaustion associated with strong activation signals. Hurton' s goal is to maintain T-cells in a more quiescent, self-renewing state”. (page 10, para 3). Regarding Loew, Applicant allege that “Loew is directed to the problem of maximizing immediate effector function and overcoming T-cell anergy. Loew's solution is to knock out DGK genes, which are critical negative regulators of T-cell activation. This modification renders the T-cells hyperresponsive to TCR stimulation, significantly enhancing their cytolytic activity. The objective of Loew is to create a "hyper-activated" T-cell, not a quiescent, persistent memory cell”. Regarding the combination, Applicant allege that “A person of ordinary skill in the art would have recognized that these two approaches are fundamentally at odds. Indeed, one having ordinary skill in the art would expect that modifying the teachings of the primary reference to include Loew's DGK knockout would result in the teachings of these references unsuitable for their intended purpose of maintaining T-cells in a quiescent state.” (page 10, para 4).
In response, there is no evidence that Hurton’s goal is to “maintain T-cells in a more quiescent, self-renewing state”. Additionally, there is no evidence that Loew’s cells are hyperresponsive. Thus, there is no evidence that an ordinary artisan would consider Hurtons’ mbIL15 CAR T cells uncombinable with DGK KO or unsuitable for their intended purpose.
Hurton uses their mbIL15-CAR-T cells for tumor suppression i.e. CAR-antigen-induced activation (Figures 4-6). In fact, Hurton further increases the tumor killing efficacy of their mbIL15-CAR-T cells by substituting the CAR with a more potent CAR* (Figure 6). Thus, Hurton does not intend to maintain their T cells as quiescent or self-renewing state.
Furthermore, the stimulation leading to T cell activation such as in Loew’s is due to antigen-CAR interaction and this is distinct from IL15 signaling, which provides a distinct pro-survival signal to T-cells (see Hurton Introduction para 3). Thus, there is no evidence that an ordinary artisan would consider these two approaches at odds
Next, Applicant argue that “The Combination Would Have Been Dissuaded by the Expectation of Premature T-Cell Exhaustion”. In support, applicant allege without evidence that “A person of ordinary skill in the art would have reasonably predicted that combining the continuous, pro-survival/pro-memory signal of Hurton's mbIL15 with the hyper-activation phenotype of Loew's DGK-deficient cells would subject the T-cells to chronic, over-stimulating signaling. This state of constant stimulation would be expected to drive the T-cells rapidly towards exhaustion and terminal differentiation, thereby shortening, not lengthening, their functional lifespan in vivo.” and “The teaching of Loew, when applied to Hurton's system, would be expected to destroy the primary benefit sought by Hurton” (page 11, para 2,3).
In response, at first it should be noted, it is unclear what Applicant means by “state of constant stimulation”. IL15 provides a pro-survival signal to T cells and Hurton suggests that IL15 signaling may even block exhaustion (e7795, col.2, para 1). This is of course distinct from CAR activation is response to antigen presentation. A cell, including T-cell, is expected to have more than one signaling cascade active at any given time.
No evidence is provided that increased efficacy of DGK-knockout CAR-T cells of Loew is “hyper-activation” that would alone or in combination with a pro-survival signal like mbIL-15 would result in T cell exhaustion or even differentiation. No evidence is provided that an ordinary artisan observed T cell exhaustion when combining methods that increase CAR-T cytotoxic efficacy with pro-survival signal like mbIL-15. No evidence is provided that an ordinary artisan using Huron’s mbIL-15 CART cells that have improved persistence even in low antigen environment, even after tumor clearance (Figure 5 and 6) would not attempt to further improve its cytotoxic response in the presence of antigen. In fact, Hurton “hypothesized that mbIL15 can continue to support CAR T-cell persistence and act additively with an improved CAR design to augment antitumor efficacy further.” (page E7793, col. 2, last para). Then Hurton modifies their first iteration of mbIL-15 CAR-T cells by substituting the CAR with a CAR* that has improved anti-tumor activity and show that mbIL-15 CAR*-T cells have much improved tumor activity and survival (Figure 6).
Furthermore, as taught by both Hurton and Loew, inclusion of IL-15 along with CAR-T therapy is well known due to IL-15’s pro-survival effects (see also Example 10 in Loew). Hurton shows that mbIL15 is an improvement over soluble IL15 because it avoids the increased proliferation phase of IL15-induced CAR-T but maintains CAR-T cell numbers. Hurton state that “Thus, it appears that mbIL15 mimics the transpresentation of endogenous IL-15, signaling via STAT5, without leading to aberrant proliferation.” (page e7794, col. 2, para 1 and “Thus, it appears that coordinated signaling with mbIL15 and CAR provides a pathway to improving antitumor effects across a spectrum of tumor burden. The approach of combining signals 1 and 2 via CAR with signal 3 from mbIL15 may be preferred to coinfusing CAR T cells with soluble recombinant IL-15 due to toxicity (50).” (emphasis added; page e7795, col.1, para 1). Hurton also provides teachings regarding T-cell exhaustion, specifically based on the data from their antigen-withdrawal experiments on CAR T and mbIL15-CAR T cells, it appears that mbIL15 may also blocks T cell exhaustion (page e7795, col. 2, para 1).
Thus, contrary to Applicants allegation, sufficient motivation to combine Hurton with Loew was available to an ordinary artisan. Such a combination was expected to have improved CAR-T cell efficacy due reduced feedback inhibition of antigen-induced CAR activation due to DGK KO and also improved persistence without soluble-IL15-associated aberrant proliferation as well as potentially reduced exhaustion due mbIL15 expression.
Next, Applicant argue that “Loew's General Mention of IL-15 Does Not Motivate the Claimed Combination.” In support, Applicant argue that “Loew mentions IL-15 as one of many possible agents to improve CAR-T therapy but provides no teaching or suggestion to combine it with DGK deficiency. Loew presents these as separate, independent strategies. Moreover, Loew suggests that an agent such as IL-15 can increase T-cell activity, which would render the teachings of the primary references unsuitable for their intended purpose” (page 11, para 4).
In response, Hurton and Sabzevari are the primary reference teaching mbIL15-CAR-T cells. Loew is relied upon for its teachings regarding improved efficacy of DGK KO CAR-T cells. 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.
Of note, Loew teaches in example 10 that “mice treated with IL-15 presented highest
T cell number in the tumor, followed by IL-21, IL-2, IL-7, PBS and IL-18” (Figure 64), thus providing a specific IL-15 related teaching.
Finally, there is no evidence that Loew’s suggestion that an agent such as IL-15 can increase T-cell activity means that IL-15 would render the teachings of the primary references unsuitable for their intended purpose. Detail reasoning why an ordinary artisan is motivated to combine mbIL15 and DGK KO is provided above, including reasonable expectation.
Finally, Applicant point to Dr. Kaneko’s declaration and more or less repeat the declaration (page12-para 1 to page 13-para3).
In response, arguments raised by Dr. Kaneko are addressed above and were not persuasive.
Regarding Dependent claims, Applicant argue that they “do not necessarily agree with the characterization and assessments of the dependent claims made by the Examiner, and Applicant believes that each claim is patentable on its own merits”. (page 13, last para )
In response, Applicant do not identify the distinct patentable features of these dependent claim that are novel or non-obvious over the applied art. Arguments pertaining to independent claim were not persuasive.
Regarding the NSDP rejections, Applicant argue that amendment to claim 1, which in their opinion incorporates limitation of claim 2, overcome the NSDP rejections. (page 14, para 2).
This is not persuasive because amendment to claim 1 embraces a cell wherein DGK gene expression is reduced by any means, at any level and for any duration. This feature is anticipated by a mbIL15-CAR T cells, of the copending application and now issued patent, because Hurton teaches mbIL15-CAR T cells have DGKA gene expression after 4xantigen-stimulation in comparison to 65 days post antigen-withdrawal (Figure S4B). The limitation in now cancelled claim 2 specifically required genetic mutation in DGK genes, this is significantly narrower than “reducing expression of at least one diacylglycerol kinase gene”.
Conclusion
No claim is 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.
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/MATASHA DHAR/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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