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 1-23 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. Drawings The description of the drawings for Figures 6, 7, 9, 10 and 13 includes reference to figures in color that are not discernible in grayscale. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO p atent e lectronic f iling s ystem or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO p atent e lectronic f iling s ystem , and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification: The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2). Specification 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. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 23 and 27- 29 . Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. 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. (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. Claim s 1, 5, 15-16, 22, and 23 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Benson (US 2019/0284529 A1; PTO-892) . Regarding claims 1 and 5, 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 IKAROS family zinc finger 2 ( IKZF2 ) (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, Benson teaches said modified immune effector cells with reduced expression of IKZF2 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, t he human CD8a hinge as a transmembrane domain , t he intracellular signaling domains of the CD3 zeta fused to the cytoplasmic end of the CD8a stalk (table 11, page 70). Benson further teaches i n 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 22, Benson teaches wherein the expression or function of the one or more endogenous target genes is reduced by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% compared to an un-modified or control immune effector cell (claim 299). 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 (which includes IKZF2) 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). Claim Rejections - 35 USC § 103 The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. Claims 2, 6, 9, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Benson (US 2019/0284529 A1; PTO-892) as applied to claim s 1, 5, 15-16, 22, and 23 above, and further in view of Bandyopadhyay ( Mol Cell Biol. 2014 Jan;34(2):233-45 ; IDS entered 07/12/2024). The teachings of Benson regarding claims 1, 5, 15-16, 22, and 23 are detailed above. Benson does not teach wherein the one or more targeted gene (s) comprises TLE4. Bandyopadhyay 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 c alcium/ 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 i n anergic T cells, the transcription factor Ikaros is a critical regulator of the expression of the IL-2 gene through the induction of suppressive chromatin modifications at the IL-2 promoter ( page 242, last para-page 243, 1st para ). Bandyopadhyay further teaches that when Tle4-induced repression of Ifng transcription was blocked , there was only a partial reverse in the inhibition of IFN-γ production in anergic cells (almost 3 fold) and this indicates the coexistence of several signaling blocks that determine the capacity of anergic cells to produce cytokines (page 244, col 1, 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 disrupt gene expression of TLE4 to counter T cell anergy as taught by Bandyopadhyay in the CD19-CAR-T with disrupted IKZR2 expression as taught by Benson. The ordinary artisan would have been motivated to do so because 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. The ordinary artisan has a reasonable expectation of success to increase proliferation and cytokine production by repression of TLE4 or IKZF2 and TLE4 in the population of CAR-T cells. Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Benson (US 2019/0284529 A1; PTO-892) as applied to claim s 1, 5, 15-16, 22, and 23 above, and further in view of MacLeod ( Molecular Therapy, 2017; 25, 949-961 ; PTO-892). The teachings of Benson regarding claims 1, 5, 15-16, 22, and 23 are detailed above. Benson does 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 t o 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 e xploiting 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 CD19-CAR-T with disrupted IKZR2 expression as taught by Benson. 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 e xploiting 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 IKZR2 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 Benson (US 2019/0284529 A1; PTO-892) as applied to claim s 1, 5, 15-16, 22, and 23 above, and further in view of Abate- Daga ( Oncolytics , 2016, 3 :16014; PTO-892). The teachings of Benson regarding claims 1, 5, 15-16, 22, and 23 are detailed above. Benson does 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 redirect s 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 IKZR2 expression as taught by Benson. 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 Benson (US 2019/0284529 A1; PTO-892) as applied to claim s 1, 5, 15-16, 22, and 23 above, and further in view of Schlake ( Cell. Mol. Life Sci. 76 , 301–328 (2019) ; The teachings of Benson regarding claims 1, 5, 15-16, 22, and 23 are detailed above. Benson does 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 IKZF2 expression as taught by Benson. 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. Allowable Subject Matter Claim s 3 -4 , 7- 8, 10- 11, 12- 13, 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 Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT AMBER K FAUST whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (703)756-1661 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT 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, FILLIN "SPE Name?" \* MERGEFORMAT Julie Wu can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 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