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 1-4, 6-8, 10-12, 14-21, and 23-30 are pending and examined on the merits herein.
Power of Attorney
It is noted that a Power of Attorney is not on record for the instant application. The Applicant is encouraged to file a Power of Attorney in the event that the Examiner needs to communicate with an authorized representative for the Applicant during the prosecution of the case.
Grounds of Objection/ Rejection Withdrawn
Previous objection to the drawings is withdrawn in view of amendment to the specification.
Previous objection to the specification regarding browser-executable code is withdrawn in view of amendment.
All previous rejections and objections of claims 5, 9, 13, and 22 are rendered moot by claim cancellation.
Previous rejection of claims 1, 15-16, and 23 under 35 U.S.C. 102 are withdrawn in view of claim amendments.
Previous rejection of claims 2, 6, 14, and 17-19 under 35 U.S.C. 103 are withdrawn in view of claim amendments.
Specification
Objection Maintained
The disclosure is objected to because of the following informalities:
The disclosure includes a reference to the sequence listing in kilobytes, but the size of the sequence listing must be disclosed in bytes.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
New Rejection Necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 29 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 29 recites a “the spacer domain comprises an amino acid domain selected from the group consisting of SEQ ID NO: 2-12” but claim 29 depends from claim 28 that recites “the spacer domain consists of an amino acid domain selected from the group consisting of SEQ ID NO: 2-12”, the same issue is perpetuated throughout the entirety of the claim. The language of claim 29 therefore broadens the scope of the claim from which it depends and is not further limiting.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1 and 4 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Junker (Hum Gene Ther. 1996 Oct 1;7(15):1861-9; PTO-892).
Regarding claims 1 and 4, Junker teaches expression of elF-5A mutant M13Δ via transduction in peripheral blood lymphocytes (PBLs) (abstract).
Claims 1-2 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bandyopadhyay (Mol Cell Biol. 2014 Jan;34(2):233-45; IDS entered 07/12/2024).
Regarding claims 1-2, Bandyopadhya teaches transduction of TH1 cells with retroviruses expressing GFP and Tle5 which is a shorter, 197-amino-acid, naturally occurring form of Tle4 that acts as a dominant negative protein by preventing Tle4 from undergoing multimerization (page 237, col 1, para 3).
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.
Claims 6, 15-16, 19, 23, 26, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Bandyopadhyay (Mol Cell Biol. 2014 Jan;34(2):233-45; IDS entered 07/12/2024) as applied to claims 1-2 above and further in view of Benson (US 2019/0284529 A1; cited in OA 04/01/2026) as evidenced by June (US 2013/0287748; PTO-892).
The teachings of Bandyopadhyay regarding claims 1-2 are detailed above.
Bandyopadhyay further teaches that anergy represents an intrinsic process of inactivation that occurs in T cells in response to suboptimal stimulation that renders them unable to respond to subsequent encounters with antigen and further that anergic T cells do not proliferate or produce cytokines when stimulated (discussion, para 1). Bandyopadhyay further teaches that the expression of Tle4, a member of the Groucho family of corepressors, was upregulated in anergic T cells in a calcium/ calcineurin/ NFAT1-dependent manner, which is then recruited to the IFN gamma upstream proximal promoter to repress transcription (page 243, col 2, para 2). Bandyopadhyay further teaches that overexpression of Tle5 a naturally occurring truncated form of Tle4 which acts as a dominant negative to Tle4 by blocking multimerization resulted in a partial reverse in the inhibition of IFN-γ production in anergic cells (2.5 fold) (page 237, col 1 last para – col 2 first para).
Bandyopadhyay does not teach use of CRISPR/ Cas system to modify Tle4 expression or that the T cell further comprise a CAR.
Benson teaches that there exists a need to improve the efficacy of adoptive transfer of modified immune cells in cancer treatment and that factors limiting the efficacy of genetically modified immune cells as cancer therapeutics include (1) cell proliferation (2) cell survival and (3) cell function (para 0005-6). Benson further teaches that the present disclosure provides immune cells comprising decreased expression and/or function of one or more endogenous target genes wherein the modified immune cells demonstrate an enhancement of one or more effector functions (para 0007). Benson teaches a modified immune effector cell comprising reduced expression or function of CBLB and BCOR (claim 296), further comprising reduced expression or function of one or more endogenous target genes (claim 297), wherein the immune effector cell is a lymphocyte selected from a T cell (claim 300), further comprising a CAR (claims 301-302).
Regarding claims 15-16 and 26, Benson teaches that said modified immune effector cells further comprising an engineered CAR construct displayed on the immune cell surface (para 0065). Benson teaches such CAR expression constructs comprising an scFv targeting CD19/ HER2/ EGFR, the human CD8a hinge as a transmembrane domain, the intracellular signaling domains of the CD3 zeta fused to the cytoplasmic end of the CD8a stalk (table 11, page 70). Benson further teaches in some embodiments, the intracellular signaling domain of a CAR further comprises a costimulatory domain, for example a 4-1BB, CD28, CD40, MyD88, or CD70 domain (para 0198). Figure 4D demonstrates that >30% were positive for the CD19 CAR after transduction.
Regarding claim 23, Benson further teaches a gene-regulating system capable of reducing the expression or function of CBLB and BCOR in a cell comprising: (i) one or more nucleic acid molecules selected from an siRNA, an shRNA, a microRNA (miR), an antagomiR, or an antisense RNA; (ii) one or more enzymatic proteins selected from a zinc finger nuclease and a transcription-activator-like effector nuclease (TALEN); or
(iii) one or more guide RNAs (gRNAs) and a Cas endonuclease (claim 321), wherein the one or more gRNAs comprise a targeting domain sequence that is complementary to a target DNA sequence defined by a set of genomic coordinates selected from those in Table 5A and Table 5B (claim 328), a modified immune effector cell comprising the gene-regulating system of claim 321 (claim 332), a method of producing a modified immune effector cell, comprising introducing the gene-regulating system of claim 321 into the immune effector cell (claim 333). Benson further teaches wherein the modified immune effector cells are allogenic to a subject (claim 312). Benson further teaches the CAR construct was inserted into a plasmid with a SFFV promoter which further comprised a U6 promoter driving expression of one or more sgRNAs (para 0516). T cell isolation and activation from human PBMCs (para 0518) followed by lentiviral transduction (para 0524-5) or electroporation (para 0526-7) followed by purification and characterization (para 0530-1).
Regarding claims 28-29, Benson teaches an exemplary CAR construct in SEQ ID NO: 26 (para 0511). SEQ ID NO: 26 has 100% sequence identity to the instant claimed SEQ ID NO: 8, 17, and 21. Benson further teaches that exemplary CAR structures and intracellular signaling domains are known in the art See US 2013/0287748 (para 0198).
As evidenced by June (US 2013/0287748) an exemplary CAR with a costimulatory domain comprises SEQ ID NO: 12 (claims 1-2). SEQ ID NO: 12 has 100% sequence identity to the instant claimed SEQ ID NO: 24.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to disrupt gene expression of TLE4 to counter T cell anergy as taught by Bandyopadhyay using CRISPR/Cas in combination with a CAR as taught by Benson. The ordinary artisan would have been motivated to do so because Benson teaches that there exists a need to improve the efficacy of adoptive transfer of modified immune cells in cancer treatment and that this can be achieved by targeted decreased expression of genes that results in improved effector function. Bandyopadhyay teaches that anergic T cells are unable to proliferate or produce cytokines when stimulated and that Tle4 mediates this response through suppression of IFN gamma which can be rescued by targeted inhibition of Tle4 expression. The ordinary artisan has a reasonable expectation of success to increase T cell effector cytokine production by repression of TLE4 in CAR-T cells.
Claims 14, 26, 27, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Bandyopadhyay (Mol Cell Biol. 2014 Jan;34(2):233-45; IDS entered 07/12/2024) and Benson (US 2019/0284529 A1; cited in OA 04/01/2026) as evidenced by June (US 2013/0287748; PTO-892) as applied to claims 1-2, 6, 15-16, 19, 23, 26, and 28-29 above, and further in view of MacLeod (Molecular Therapy, 2017; 25, 949-961; cited in OA 04/01/2026).
The teachings of Bandyopadhyay and Benson regarding claims 1-2, 6, 15-16, 19, 23, 26, and 28-29 are detailed above.
Bandyopadhyay and Benson do not teach wherein the one or more genes is disrupted by a nucleic acid encoding a chimeric antigen receptor.
MacLeod teaches streamlines strategy for CAR T cell production with gene disruption by targeting the insertion of a CAR transgene, by using an engineered homing endonuclease and an AAV donor template (abstract). MacLeod further teaches that to achieve CAR expression, the majority of studies have utilized lentiviral or γ-retroviral vectors to stably insert a CAR expression cassette into the T cell genome, resulting in semi-random integration, variable copy number, heterogeneous expression, and the potential for insertional mutagenesis but by exploiting cellular homology-directed repair (HDR) mechanisms to “knock in” a CAR transgene to a defined location in the genome to yield a more consistent and safe product (page 950, col 1, para 1). MacLeod further demonstrated targeted insertion of a CAR expression cassette with simultaneous knockout of the native TCR by targeting the TRAC locus using an engineered homing endonuclease with over 30% of the cells testing positive for the CAR and negative for the targeted TCR (Fig 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to disrupt gene expression by targeted insertion of the CAR as taught by MacLeod in the CAR-T with disrupted TLE4 expression as taught by Benson and Bandyopadhyay. The ordinary artisan would have been motivated to do so because MacLeod teaches that using lentivirus for CAR expression results in semi-random integration, variable copy number, heterogeneous expression, and the potential for insertional mutagenesis but by exploiting cellular homology-directed repair (HDR) mechanisms to “knock in” a CAR transgene to a defined location in the genome to yield a more consistent and safe product, as well as streamlined strategy for CAR T cell production with gene disruption. The ordinary artisan has a reasonable expectation of success to target the CAR insertion to disrupt TLE4 gene expression to streamline CAR-T production.
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.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Bandyopadhyay (Mol Cell Biol. 2014 Jan;34(2):233-45; IDS entered 07/12/2024) and Benson (US 2019/0284529 A1; cited in OA 04/01/2026) as evidenced by June (US 2013/0287748; PTO-892) as applied to claims 1-2, 6, 15-16, 19, 23, 26, and 28-29 above, and further in view of Abate-Daga (Oncolytics, 2016, 3:16014; cited in OA 04/01/2026).
The teachings of Bandyopadhyay and Benson regarding claims 1-2, 6, 15-16, 19, 23, 26, and 28-29 are detailed above.
Bandyopadhyay and Benson do not teach wherein the targeting domain of the CAR comprises a ligand for a cell surface receptor.
Abate-Daga teaches that to increase safety the scFv portion of the CAR can be replaced with a ligand for a tumor marker to create a ligand-based CAR or universal CAR, such as a ligand for the IL13 receptor that redirects T cells to the IL13R which is highly specific for glioblastoma which has already demonstrated in vivo efficacy (page 3, col 2, para 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to replace the scFv of the CAR with a ligand as taught by Agate-Daga in the CD19-CAR-T with disrupted TLE4 expression as taught by Benson and Bandyopadhyay. The ordinary artisan would have been motivated to do so because Abate-Daga teaches that to increase safety the scFv portion of the CAR can be replaced with a ligand for a tumor marker to create a ligand-based CAR. The ordinary artisan has a reasonable expectation of success to replace the scFv of the CAR with a tumor marker ligand in the population of CAR-T cells with gene disruption.
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.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Bandyopadhyay (Mol Cell Biol. 2014 Jan;34(2):233-45; IDS entered 07/12/2024) and Benson (US 2019/0284529 A1; cited in OA 04/01/2026) as evidenced by June (US 2013/0287748; PTO-892) as applied to claims 1-2, 6, 15-16, 19, 23, 26, and 28-29 above, and further in view of Schlake (Cell. Mol. Life Sci. 76, 301–328 (2019); cited in OA 04/01/2026).
The teachings of Bandyopadhyay and Benson regarding claims 1-2, 6, 15-16, 19, 23, 26, and 28-29 are detailed above.
Bandyopadhyay and Benson do not teach wherein the nucleic acid encoding the CAR is an mRNA.
Schlake teaches that the most common techniques for generating TCR- or CAR-engineered T cells utilize viral gene transduction with retro- or lentiviral vectors but permanent expression of the transgenic receptor mediated by this efficient technology can be disadvantageous due to insertional mutagenesis, off-target toxicity, cytokine release syndrome (page 306, col 2, para 1). Schlake further teaches that therapeutic application of mRNA combines several advantages including no risk of induced genomic changes and transient toxicity (abstract). Schlake further teaches that in vitro testing of an mRNA based for a CD19-CAR yielded surface expression and cytotoxic function (page 312, col 1, para 2). Schlake further teaches that in vivo testing of CAR-T cells generated with mRNA encoding a CD19-CAR prolonged survival and reduced tumor burden (page 312, col 2, para 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use mRNA for the CAR expression as taught by Schlake in the CD19-CAR-T with disrupted TLE4 expression as taught by Benson and Bandyopadhyay. The ordinary artisan would have been motivated to do so because Schlake teaches that therapeutic application of mRNA combines several advantages including no risk of induced genomic changes and transient toxicity and has demonstrated in vitro and in vivo efficacy. The ordinary artisan has a reasonable expectation of success to generate a population of CAR-T cells using mRNA to express the CAR with safety advantages.
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.
Response to Arguments
Applicant's arguments filed 07/01/2026 have been fully considered but they are not persuasive.
Applicant submits: Neither Benson nor any of the other cited references cited in the rejections under 35 U.S.C. § 103 disclose or suggest human T cells having a disrupted Transducin-Like Enhancer of Split 4 (TLE4) gene, a disrupted Transmembrane Protein 184B (MEM 184B) gene, or a disrupted Eukaryotic Translation Initiation Factor SA-1 (EIFSA) gene, much less disruption of combinations of these genes. Thus, none of the combinations of cited references can render any of the claims obvious.
In Response: Applicant should submit an argument under the heading “Remarks” pointing out disagreements with the examiner’s contentions. Applicant must also discuss the references applied against the claims, explaining how the claims avoid the references or distinguish from them.
The updated 103 rejection detailed above discloses that it is obvious to disrupt TLE4 in view of the teachings of Bandyopadhyay. Bandyopadhyay teaches that anergic T cells are unable to proliferate or produce cytokines when stimulated and that TLE4 mediates part of this response through suppression of IFN gamma. Bandyopadhyay also teaches that Ikaros is a critical regulator of IL-2 expression that is also upregulated in anergy so that it would be obvious to repress expression of both Ikaros (IKZF2) and TLE4.
Allowable Subject Matter
Claims 3, 7-8, 10-12, and 20-21 are objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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.
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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