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
Claims 111, 114, 118-119, and 121-138 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
All previous rejections of claims 99-110, 112-113, 115-117, and 120 are rendered moot by claim cancellation.
Previous rejection of claims 111, 114, and 118-119 under 35 U.S.C. 102 is withdrawn in view of claim amendments.
Previous rejection of claims 111, 114, and 118-119 under 35 U.S.C. 103 is withdrawn in view of claim amendments.
Claim Objections
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
Misnumbered claims 127 (second)-137 have been renumbered 128-138.
Claim Rejections - 35 USC § 103
New Rejection Necessitated by Amendment
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.
Claims 111, 114, 118-119, 121, 124-126, and 129-138 are rejected under 35 U.S.C. 103 as being obvious over Trager (US 12,012,458 B2; cited in OA 10/21/2025), Whitlow (Protein Eng. 1993 Nov;6(8):989-95; cited in OA 10/21/2025), Costa (WO 2019/090202 A1; PTO-892), Arakawa (Sci Adv. 2016 Aug 24;2(8):e1600699; PTO-892) and (GenBank CISH mRNA; First publication reference 1995; PTO-892).
The applied reference has a common inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Regarding claim 111, 118, and 121, Trager teaches a population of genetically engineered natural killer (NK) cells, comprising a plurality of NK cells that have been expanded in culture, wherein the plurality of NK cells are engineered to express a chimeric antigen receptor (CAR) comprising a tumor binding domain that targets CD70, a transmembrane domain, and a cytotoxic signaling complex, wherein the immune cells are genetically edited at the endogenous CD70 gene to express a reduced level of CD70 protein as compared to an immune cell that has been expanded in culture and in which the endogenous CD70 gene has not been edited, wherein the immune cells are genetically edited at the endogenous CISH gene to express a reduced level of the cytokine-inducible SH2-containing (CIS) protein as compared to an immune cell in which the endogenous CISH gene has not been edited, and wherein the immune cells are genetically edited to express a reduced level of one or more of: Cbl proto-oncogene B (Cblb) protein (c) the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within the VH region amino acid sequence set forth in SEQ ID NO:943; and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within the VL region amino acid sequence set forth in SEQ ID NO:1017 or the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within the VH region amino acid sequence set forth in SEQ ID NO:956; and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within the VL region amino acid sequence set forth in SEQ ID NO:1030 (claims 1-3 an 6-7). Trager further teaches in several embodiments of these methods, the tumor binding domain comprises a single chain variable fragment (scFv) (col 3, lines 34-35). Trager further teaches a method of making a population of genetically engineered NK cells comprising expression of a CAR targeting CD70 wherein the immune cells are genetically edited to express reduced level of CD70 (col 2, lines 1-15) wherein the genetic editing to reduce expression is made using CRISPR-Cas system wherein the Cas is guided to the CD70 gene by one or more guide RNA (col 4, lines 20-30) and wherein the cells have been expanded in culture (claim 6) and cultured after genetic modification (figure 49A). Trager further teaches Table 1 with SEQ ID NO: 122 which has 100% sequence identity to the instant claimed SEQ ID NO: 180.
As seen in the alignment below SEQ ID NOs: 1017 and 943 comprise all of the scFv of the instant claimed SEQ ID NO: 51 except the linker. The same applies to SEQ ID NOs: 1030 and 956 comprise all of the scFv of the instant claimed SEQ ID NO: 52 except the linker.
Regarding claim 114, Trager teaches in several embodiments, the gene editing to reduce expression or the gene editing to induce expression is made using a CRISPR-Cas system (Col 6, lines 65-66), which inherently comprises an endonuclease mediated indel.
Regarding claims 119 and 129, Trager teaches there is provided a method of treating or preventing cancer or an infectious disease, comprising administering a therapeutically effective amount of natural killer (NK) cells expressing the cytotoxic receptor complex and/or a homing moiety as described herein (col 49, lines 44-47).
Regarding claim 124, Trager teaches wherein the transmembrane domain comprises a CD8alpha transmembrane region (claim 15).
Regarding claims 125-126, Trager further teaches wherein the cytotoxic signaling complex comprises an OX-40 subdomain and a CD3zeta subdomain (claim 8).
Regarding claim 130-138, Trager teaches a method of generating the gene edited NK cells in Figure 14F, including 7 day expansion (a), electroporation at Day 7 (b), and culturing for an additional 5 days at high IL-2 and 10 days in with low IL-2 (c) as well as Fig 28A where cells are electroporated at Day 0 with 2 gRNAs using CRISPR/ Cas (b) then expanded (c) before transduction of the CAR construct. Trager teaches editing of multiple genes in Example 3 including CD70 and CISH using the CRISPR/ Cas system (Fig 29B) and further that the CD70/CISH showed substantially more (about 30%) more proliferation than either the CD70 knockout or the CD70/TGFBR2 knockout (Fig 33A).
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Trager does not teach the full scFv sequence or the specific sequence of the CISH and CBLB gRNA.
Whitlow teaches an improved linker for scFv with reduced aggregation and enhanced proteolytic stability that demonstrated increased tumor uptake and decreased accumulation in the liver and spleen in mice (abstract).
Costa teaches a genome editing system comprising: a guide RNA (gRNA) comprising a targeting domain that is complementary with a target sequence of a Casitas B-lineage lymphoma proto-oncogene-b (CBLB) gene; and an RNA-guided nuclease (claim 1), wherein said targeting domain comprises a nucleotide sequence that is identical to, or differs by no more than 3 nucleotides from, a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1 to 14 (claim 9), wherein said cell is a T cell or a Natural Killer (NK) cell (claim 62). SEQ ID NO : 1 (para 0154) has 100% sequence identity to the instant claimed SEQ ID NO: 195. Costa further teaches that knocking out or knocking down the CBLB gene as described herein can: (1) improve T cell proliferation; (2) improve T cell survival; and/or (3) improve T cell function (para 0137).
Arakawa teaches a method to design gRNA for use in CRISPR/ Cas9 mediated editing of any organism by synthesizing complementary DNA from the mRNA sequence using semi-random primer containing a protospacer adjacent motif (PAM) complementary sequence and then cuts out the 20 mer adjacent to the PAM using type IIS and type III restriction enzymes to create a gRNA library (abstract). Arakawa further demonstrates successful generation of multiple guide sequences from the same gene (Fig 3) with functional validation (Fig. 4).
GenBank teaches the mRNA sequence of CISH variant 1 under NCBI reference NM_013324.7 has 100% sequence identity to the instant claimed SEQ ID NO: 191.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use the gRNA sequence for CBLB as taught by Costa, to design a gRNA for CISH as taught by Arakawa from the mRNA sequence from GenBank and to substitute the specific sequence of the linker as taught by Whitlow into the scFv and further into the anti-CD70 CAR with a flexible linker as taught by Trager. The ordinary artisan would have been motivated to do so as this is a simple substitution of the same element with known demonstrated improvements. Costa teaches that knocking out or knocking down the CBLB gene as described herein can: (1) improve T cell proliferation; (2) improve T cell survival; and/or (3) improve T cell function and Trager also demonstrated improved proliferation of immune cells with knockdown of CD70 and CISH. The ordinary artisan has a reasonable expectation of success to decrease the aggregation and enhance the stability of the anti-CD70 scFv to use in an anti-CD70 CAR with endogenous CD70, CISH and CBLB knockdown to improve immune cell proliferation and survival.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claims 123 and 128 are rejected under 35 U.S.C. 103 as being obvious over Trager (US 12,012,458 B2; cited in OA 10/21/2025), Whitlow (Protein Eng. 1993 Nov;6(8):989-95; cited in OA 10/21/2025), Costa (WO 2019/090202 A1; PTO-892), Arakawa (Sci Adv. 2016 Aug 24;2(8):e1600699; PTO-892) and (GenBank CISH mRNA; First publication reference 1995; PTO-892) as applied to claims 111, 114, 118-119, 121, 124-126, and 129-138 and further in view of Terrett (US 2019/0314413 A1; cited in OA 10/21/2025).
The teachings of Trager, Whitlow, Costa, Arakawa, and GenBank regarding claims 111, 114, 118-119, 121, 124-126, and 129-138 are detailed above.
Trager, Whitlow, Costa, Arakawa, and GenBank do not teach an scFv comprising SEQ ID NO: 53.
Regarding claims 123 and 128, Terrett teaches a population of T cells comprising an anti-CD70 CAR comprising an ectodomain with the anti-CD70 scFv comprising SEQ ID NO: 1499, a CD8 transmembrane domain and an endodomain that comprises a CD28 or 41BB costimulatory domain and a CD3z costimulatory domain (claim 195). SEQ ID NO: 1499 comprises 94.7% sequence identity to the SEQ ID NO: 53.
As seen in the alignment below the difference between the sequences comprises the linker of the scFv.
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute the anti-CD70 scFv as taught by Terrettt into the NK cell composition comprising an antiCD70-CAR with CD70, CISH and CBLB knockdown taught by Trager, Whitlow, Costa, Arakawa, and GenBank. The ordinary artisan would have been motivated to do so as this is a simple substitution of the same element in an analogous art. The ordinary artisan has a reasonable expectation of success to substitute the anti-CD70 scFv into the NK cell composition comprising an antiCD70-CAR with CD70, CISH and CBLB knockdown.
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 111, 114, 118, 121-122, and 124-127 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3 and 6-9 of U.S. Patent No. 12,012,458 B2 in view of Whitlow (Protein Eng. 1993 Nov;6(8):989-95; cited in OA 10/21/2025), Terrett (WO 2019/215500 A1; PTO-892), Costa (WO 2019/090202 A1; PTO-892), Arakawa (Sci Adv. 2016 Aug 24;2(8):e1600699; PTO-892), (GenBank CISH mRNA; First publication reference 1995; PTO-892) and Veluchamy JP et al. (Front Immunol. 2017; 8: 631; cited in OA 10/21/2025).
Regarding claims 111, 118, and 121-122, the patented claims teach a population of genetically engineered immune cells, comprising a plurality of immune cells that have been expanded in culture, wherein the plurality of immune cells are engineered to express a chimeric antigen receptor (CAR) comprising a tumor binding domain that targets CD70, a transmembrane domain, and a cytotoxic signaling complex, wherein the immune cells are genetically edited at the endogenous CD70 gene to express a reduced level of CD70 protein as compared to an immune cell that has been expanded in culture and in which the endogenous CD70 gene has not been edited, wherein the immune cells are genetically edited at the endogenous CISH gene to express a reduced level of the cytokine-inducible SH2-containing (CIS) protein as compared to an immune cell in which the endogenous CISH gene has not been edited, and wherein the immune cells are genetically edited to express a reduced level of one or more of: Cbl proto-oncogene B (Cblb) protein, as compared to a non-edited immune cell wherein (c) the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within the VH region amino acid sequence set forth in SEQ ID NO:943; and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within the VL region amino acid sequence set forth in SEQ ID NO:1017 or the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within the VH region amino acid sequence set forth in SEQ ID NO:956; and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within the VL region amino acid sequence set forth in SEQ ID NO:1030 (claims 1-3 an 6-7). The patented claims further teach wherein the population of immune cells comprises NK cells (claim 9). As seen in the alignment below SEQ ID NOs: 1017 and 943 comprise all of the scFv of the instant claimed SEQ ID NO: 51 except the linker. The same applies to SEQ ID NOs: 1030 and 956 which comprises all of the scFv of the instant claimed SEQ ID NO: 52 except the linker.
Regarding claim 124, the patented claims teach wherein the transmembrane domain comprises a CD8alpha transmembrane region (claim 15).
Regarding claims 125-127, the patented claims teach wherein the cytotoxic signaling complex comprises an OX-40 subdomain and a CD3zeta subdomain (claim 8)
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The patented claims do not teach the sequence of the linker in the scFv, the sequences of the gRNA targeting CD70, CISH and CBLB.
Whitlow teaches an improved linker for scFv with reduced aggregation and enhanced proteolytic stability that demonstrated increased tumor uptake and decreased accumulation in the liver and spleen in mice (abstract) with 100% sequence identity to the instant claimed SEQ ID NO: 51.
Regarding claims 111 and 114, Terrett teaches an engineered T cell comprising a disrupted CD70 gene (claim 1), wherein the CD70 gene is disrupted by CRISPR/Cas gene editing (claim 159), wherein the gRNA targeting the CD70 gene comprises the nucleotide sequence of SEQ ID NOS: 94 or 95 (claim 120), wherein the engineered T cells: (a) exhibit increased cellular proliferative capacity; (b) exhibit increased cell lysis; (c) exhibit reduced cellular exhaustion; (d) maintain cytokine-dependent proliferation; (e) exhibit increased cytokine secretion; or (f) any combination of (a) - (e), relative to control T cells, wherein control T cells express endogenous CD70 protein (claim 96). SEQ ID NO: 94 has 100% sequence identity to the instant claimed SEQ ID NO: 180.
Costa teaches a genome editing system comprising: a guide RNA (gRNA) comprising a targeting domain that is complementary with a target sequence of a Casitas B-lineage lymphoma proto-oncogene-b (CBLB) gene; and an RNA-guided nuclease (claim 1), wherein said targeting domain comprises a nucleotide sequence that is identical to, or differs by no more than 3 nucleotides from, a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1 to 14 (claim 9), wherein said cell is a T cell or a Natural Killer (NK) cell (claim 62). SEQ ID NO : 1 (para 0154) has 100% sequence identity to the instant claimed SEQ ID NO: 195. Costa further teaches that knocking out or knocking down the CBLB gene as described herein can: (1) improve T cell proliferation; (2) improve T cell survival; and/or (3) improve T cell function (para 0137).
Arakawa teaches a method to design gRNA for use in CRISPR/ Cas9 mediated editing of any organism by synthesizing complementary DNA from the mRNA sequence using semi-random primer containing a protospacer adjacent motif (PAM) complementary sequence and then cuts out the 20 mer adjacent to the PAM using type IIS and type III restriction enzymes to create a gRNA library (abstract). Arakawa further demonstrates successful generation of multiple guide sequences from the same gene (Fig 3) with functional validation (Fig. 4).
GenBank teaches the mRNA sequence of CISH variant 1 under NCBI reference NM_013324.7 has 100% sequence identity to the instant claimed SEQ ID NO: 191.
Veluchamy taught NK cell tumor targeting can be made more specific by employing chimeric antigen receptors (CARs) as demonstrated for T cell adoptive transfer strategies (page 11, right column, last paragraph) and have shown efficacy in preclinical studies as cancer treatments (page 14, left column, first paragraph). Veluchamy taught gene editing is widely used to overexpress or knock out genes of interest to augment NK cell function (page 14, left column, paragraph 3) and CIS knockout is a strategy to augment NK cell function (Figure 2). Veluchamy taught in vivo studies in mice with Cish−/− knockout NK cells showed that loss of CIS led to prolonged IL-15 signaling, resulting in an increased proliferation (same as enhanced expansion capability), survival, and functionality of NK cells (page 14, left column, paragraph 3). Veluchamy taught to improve the antitumor activity of autologous NK cells, systemic administration of single chain IL-15 (scIL-15) has been used following NK cell-adoptive transfer in cancer patients (page 14, right column, last paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use the gRNA sequence for CISH as taught by Terrett, CBLB as taught by Costa, to design a gRNA for CISH as taught by Arakawa from the mRNA sequence from GenBank and to substitute the specific sequence of the linker as taught by Whitlow into the scFv and further into the anti-CD70 CAR in NK cells as taught by the patented claims. The ordinary artisan would have been motivated to do so as this is a simple substitution of the same element with known demonstrated improvements for the scFv linker. Costa teaches that knocking out or knocking down the CBLB gene as described herein can: (1) improve T cell proliferation; (2) improve T cell survival; and/or (3) improve T cell function and Terrett teaches the same for CD70. Veluchamy teaches that CIS knockout is a strategy to augment NK cell function resulting in an increased proliferation (same as enhanced expansion capability), survival, and functionality. The ordinary artisan has a reasonable expectation of success to decrease the aggregation and enhance the stability of the anti-CD70 scFv to use in an anti-CD70 CAR with endogenous CD70, CISH and CBLB knockdown to improve immune cell proliferation and survival.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claims 111, 114, 118-119, 121-122, 125-127, and 129 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 10, 12, 14-18, 21-25, and 28-29 of copending Application No. 18/657,550 in view of Whitlow (Protein Eng. 1993 Nov;6(8):989-95; cited in OA 10/21/2025), Terrett (WO 2019/215500 A1; PTO-892), Costa (WO 2019/090202 A1; PTO-892), Arakawa (Sci Adv. 2016 Aug 24;2(8):e1600699; PTO-892), (GenBank CISH mRNA; First publication reference 1995; PTO-892) and Veluchamy JP et al. (Front Immunol. 2017; 8: 631; cited in OA 10/21/2025).
Regarding claims 111, 118-119, 121-122, and 129, the copending claims teach a method of treating a CD70-expressing cancer in a subject comprising administering to the subject a population of genetically engineered immune cells expressing an anti-CD70 chimeric antigen receptor (CAR) comprising an anti-CD70 binding domain comprising a heavy chain variable (VH) region and a light chain variable (VL) region; a transmembrane domain; and a cytotoxic signaling complex, wherein: (c) the VH region comprises a CDR-Hl, a CDR-H2, and a CDR-H3 contained within the VH region amino acid sequence set forth in SEQ ID NO:943; and the VL region comprises a CDRL1, a CDR-L2, and a CDR-L3 contained within the VL region amino acid sequence set forth in SEQ ID NO:1017 or the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within the VH region amino acid sequence set forth in SEQ ID NO:956; and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within the VL region amino acid sequence set forth in SEQ ID NO:1030 (claim 1-3, 18 and 25), wherein anti-CD70 binding is a single-chain variable fragment (scFv) (claim 10), wherein the genetically engineered immune cells are genetically edited to reduce expression of CD70 protein (claim 14) and wherein the genetically engineered immune cells are genetically edited to reduce expression of cytokine-inducible SH2-containing (CIS) protein (claim 15 and 21), wherein the genetically engineered immune cells are genetically edited to reduce expression of one or more of: a Cbl proto-oncogene B (Cblb) protein (claim 16, 22, and 28), wherein the population of genetically engineered immune cells comprises natural killer (NK) cells (claim 17 and 24). As seen in the alignment below SEQ ID NOs: 1017 and 943 comprise all of the scFv of the instant claimed SEQ ID NO: 51 except the linker. The same applies to SEQ ID NOs: 1030 and 956 which comprises all of the scFv of the instant claimed SEQ ID NO: 52 except the linker.
Regarding claims 125-127, the copending claims teach wherein the cytotoxic signaling complex comprises an OX-40 subdomain and a CD3zeta subdomain (claim 12, 23, and 29).
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The copending claims do not teach the sequence of the linker in the scFv, the sequences of the gRNA targeting CD70, CISH and CBLB.
Whitlow teaches an improved linker for scFv with reduced aggregation and enhanced proteolytic stability that demonstrated increased tumor uptake and decreased accumulation in the liver and spleen in mice (abstract) with 100% sequence identity to the instant claimed SEQ ID NO: 51.
Regarding claims 111 and 114, Terrett teaches an engineered T cell comprising a disrupted CD70 gene (claim 1), wherein the CD70 gene is disrupted by CRISPR/Cas gene editing (claim 159), wherein the gRNA targeting the CD70 gene comprises the nucleotide sequence of SEQ ID NOS: 94 or 95 (claim 120), wherein the engineered T cells: (a) exhibit increased cellular proliferative capacity; (b) exhibit increased cell lysis; (c) exhibit reduced cellular exhaustion; (d) maintain cytokine-dependent proliferation; (e) exhibit increased cytokine secretion; or (f) any combination of (a) - (e), relative to control T cells, wherein control T cells express endogenous CD70 protein (claim 96). SEQ ID NO: 94 has 100% sequence identity to the instant claimed SEQ ID NO: 180.
Costa teaches a genome editing system comprising: a guide RNA (gRNA) comprising a targeting domain that is complementary with a target sequence of a Casitas B-lineage lymphoma proto-oncogene-b (CBLB) gene; and an RNA-guided nuclease (claim 1), wherein said targeting domain comprises a nucleotide sequence that is identical to, or differs by no more than 3 nucleotides from, a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1 to 14 (claim 9), wherein said cell is a T cell or a Natural Killer (NK) cell (claim 62). SEQ ID NO : 1 (para 0154) has 100% sequence identity to the instant claimed SEQ ID NO: 195. Costa further teaches that knocking out or knocking down the CBLB gene as described herein can: (1) improve T cell proliferation; (2) improve T cell survival; and/or (3) improve T cell function (para 0137).
Arakawa teaches a method to design gRNA for use in CRISPR/ Cas9 mediated editing of any organism by synthesizing complementary DNA from the mRNA sequence using semi-random primer containing a protospacer adjacent motif (PAM) complementary sequence and then cuts out the 20 mer adjacent to the PAM using type IIS and type III restriction enzymes to create a gRNA library (abstract). Arakawa further demonstrates successful generation of multiple guide sequences from the same gene (Fig 3) with functional validation (Fig. 4).
GenBank teaches the mRNA sequence of CISH variant 1 under NCBI reference NM_013324.7 has 100% sequence identity to the instant claimed SEQ ID NO: 191.
Veluchamy taught NK cell tumor targeting can be made more specific by employing chimeric antigen receptors (CARs) as demonstrated for T cell adoptive transfer strategies (page 11, right column, last paragraph) and have shown efficacy in preclinical studies as cancer treatments (page 14, left column, first paragraph). Veluchamy taught gene editing is widely used to overexpress or knock out genes of interest to augment NK cell function (page 14, left column, paragraph 3) and CIS knockout is a strategy to augment NK cell function (Figure 2). Veluchamy taught in vivo studies in mice with Cish−/− knockout NK cells showed that loss of CIS led to prolonged IL-15 signaling, resulting in an increased proliferation (same as enhanced expansion capability), survival, and functionality of NK cells (page 14, left column, paragraph 3). Veluchamy taught to improve the antitumor activity of autologous NK cells, systemic administration of single chain IL-15 (scIL-15) has been used following NK cell-adoptive transfer in cancer patients (page 14, right column, last paragraph).
It would have been obvious to one of ordinary skill in the art to use the gRNA sequence for CISH as taught by Terrett, CBLB as taught by Costa, to design a gRNA for CISH as taught by Arakawa from the mRNA sequence from GenBank and to substitute the specific sequence of the linker as taught by Whitlow into the scFv and further into the anti-CD70 CAR in NK cells as taught by the copending claims. The ordinary artisan would have been motivated to do so as this is a simple substitution of the same element with known demonstrated improvements for the scFv linker. Costa teaches that knocking out or knocking down the CBLB gene as described herein can: (1) improve T cell proliferation; (2) improve T cell survival; and/or (3) improve T cell function and Terrett teaches the same for CD70. Veluchamy teaches that CIS knockout is a strategy to augment NK cell function resulting in an increased proliferation (same as enhanced expansion capability), survival, and functionality. The ordinary artisan has a reasonable expectation of success to decrease the aggregation and enhance the stability of the anti-CD70 scFv to use in an anti-CD70 CAR with endogenous CD70, CISH and CBLB knockdown to improve immune cell proliferation and survival.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims 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 AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMBER K FAUST/ Examiner, Art Unit 1643
/SEAN E AEDER/ Primary Examiner, Art Unit 1642
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