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. Status of Claims Claims 1, 4-8, 10-18, 20-23, and 31 are currently pending. Claim Rejections - 35 USC § 112 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 appl icant regards as his invention. Claim s 1, 4-8, 10-18, 20-23, and 31 are rejected 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. In the context of instant claims 1 and 23 , a “dual targeting CAR” is indefinite because some skilled artisans would interpret the scope as requiring that two different antigens are targeted, while others would argue that “ a dual targeting CAR ” refers to a system of receptors comprising two individual CAR structures. Thus, some artisan would argue that the scope of claims 1 and 23 encompass targeting the same antigen with both the first and second CAR while other would argue that the claim requires targeting of two different antigens. Different skilled artisans would arrive at different interpretations “a CD8a stalk and transmembrane domain and… intracellular domain” as recited in instant claims 1 and 23. Some skilled artisan would interpret the limitations as requiring a CD8a stalk domain and CD8a transmembrane domain, however other skilled artisans would argue that the scope of claims 1 and 23 are generic with respect to the transmembrane domain. In other words, some of skill in the art would interpret the limitations as a CD8a stalk, any transmembrane domain, and the respective intracellular domain. The limitations of instant claim 1 in lines 7-8, and claim 23 in lines 8-9, are unclear. Some skilled artisan would argue that a “split costimulatory” signal should be interpreted congruent with and does not further limit the structures laid forth in lines 3-6, i.e. two CAR constructs each comprise a costimulatory signal, wherein an activating signaling domain of CD3z may be adjoined to one or the other or both. Other skilled artisan would argue that a “split costimulatory” signal should be interpreted as separating the costimulatory signal(s), i.e. CD28 and 4-1bb, and the activating signal, i.e. CD3z signal. Thus, some skilled artisan would argue that a “split costimulatory” further limits the structures laid forth in lines 3-6 because it requires an addition construct containing an activating signal through CD3z, which is structurally separate from the two CAR constructs comprising CD28 and 4-1bb costimulatory domains. The language of “a single CAR-CD3z domain” is equally vague. While the only reasonable interpretation dictates that a single CD3z domain is found in the entire dual CAR system, it would be unclear to the skilled artisan , in view of the foregoing lack of clarity, how the CD3z domain is part of the dual CAR system, i.e. does the claim language limit to having a single CD3z domain structural ly separated from the co-stimulatory domain-bearing CARs? Or may the CD3z domain be fused to one of the co-stimulatory domains? For the purpose of applying art, lines 7-8 claim 1 is interpreted with the scope of “wherein the dual targeting CAR further comprises a single CAR-CD3z domain which is fused to the CD28 or the 4-1BB co-stimulatory domain.” “…[T]he T cell exhibits killing activity and cytokine release of T-cells…” as recited in claim 5 is indefinite because different skilled artisans would arrive at different interpretations. Some skilled artisans would argue that “killing activity of T-cells” refers to the CAR T cells’ ability to kill other T-cells, therefore limiting the structure of the CAR T-cell to having an extracellular domain that recognizes an epitope expressed by T-cells. Other skilled artisan would argue that “of T cells” refers only the “cytokine release” and should be interpreted as “the T cell exhibits a) killing activity and b) cytokine release of T cells; wherein said killing activity and cytokine release are via the first CAR or the second CAR. Even so, the second interpretation is still unclear because “cytokine release of T cells” would not make sense to the skilled artisan because cytokines are intercellular signaling proteins, not cells and it is unclear what “cytokine release of T cells” refers to – e.g. does it refer to release of cytokines by the CAR or does the CAR induce release of cytokines from other T cells? To advance prosecution, claim 5 is interpreted as “the T cell exhibits killing activity and cytokine release via activation of the first CAR and/or the second CAR.” Note well, "or" in the context of “the first CAR or second CAR” is interpreted congruent with specification pg. 40 in lines 3-5 as considered satisfied if one, more than one, or all of the group members are present employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. Claim 21 recites “CD27+/CD29+.” The use of a backslash in describing the claimed invention renders the interpretation indefinite because it is unclear whether the scope of the claim is limited to CD27- and CD29-positive T cells. Others of skill in the art would interpret the term “CD27+/CD29+” as “CD27+ and/or CD29+,” thus each of CD27 or CD29 alone may satisfy the limitations of the claimed invention. For the purpose of applying art, “CD27+/CD29+” is interpreted as “CD27+ and/or CD29+” . Claim 22 recites “GD2.28z.CAR/B7-H3.BB.CAR.” “GD2.28z.CAR/B7-H3.BB.CAR” is not a term of the art and the specification does not clearly define the metes and bounds of the term. Some skilled artisans would argue that “GD2.28z.CAR/B7-H3.BB.CAR” refers to a dual CAR system comprising an anti-GD2 CAR comprising a CD28 intracellular domain and a CD3z intracellular domain in addition to an anti-B7-H3 CAR comprising a 4-1BB intracellular domain. Other skilled artisans would interpret the scope of the term as an anti-GD2 CAR comprising a CD28 intracellular domain and/or a CD3z intracellular domain in addition to an anti-B7-H3 CAR comprising a 4-1BB intracellular domain. Still other skilled artisan would argue that the term refers to GD2 fused to CD28 fused to CD3z and/or B7-H3 fused to 4-1BB. Moreover, it is unclear in the context of the instant invention whether claim 22 is limited to a particular construct having a particular anti-GD2 / anti-B7-H3 binding domain and a particular stalk domain and a particular transmembrane domain, or whether the claim is generic with respect to these limitations and only requires the positively recited domains. The interpretation relevant to the prior art rejection below is “a dual CAR system comprising an anti-GD2 CAR only having a CD28 intracellular domain and a CD3z intracellular domain in addition to an anti-B7-H3 CAR only having a 4-1BB intracellular domain.” The binding domains, hinge / stalk domain, and transmembrane domain are interpreted as generic. The scope of claim 31 is unclear because “form a dimer” would be interpreted by some skilled artisans as only requiring that the structure of the CD8a stalk has the ability to form a dimer. However, other skilled artisans would argue that the scope of the claim is limited to the structure of dimer formed by a first CAR and a second CAR through their respective CD8a stalks. Claims 4, 6-8, 10-18, and 20 are rejected by virtue of their dependency. 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)(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, 4-6, 15, 23, and 31 are rejected under 35 U.S.C. 102 (a)(2) as being anticipated by Evans in WO 2021/211948 A1 effectively filed on April 17, 2020 . Figure 5A of Evans, shown below, teaches a dual CAR / CAR + chimeric costimulatory receptor (CCR) comprising an anti-BCMA CAR and an anti-EGFR CAR. The anti-BCMA CAR comprises a CD8a hinge, CD8a transmembrane domain, 4-1BB costimulatory domain, and a CD3z signaling domain. The anti-EGFR CAR comprises a CD8a hinge, CD8a transmembrane domain, and a CD28 cytoplasmic domain. Claim 62 of Evans also describes the above construct and claim 81 has the scope of a T-cell comprising the CAR + CCR. Example 4 (spanning pg. 114 and 115) also teaches that the construct of Figure 5A was expressed in T cells, anticipating instant claims 1 . In Example 5 constructs and controls were tested against tumor cells comprising EGFR alone (A549 or HT-1080) or having both EGFR and BCMA (A549.BCMA and HT-1080.BCMA). As demonstrated in Figures 7 and 8, the dual CAR transduced T cells exhibited dual antigen specificity and costimulation , as in instant claim 4 , and cytokine secretion and killing activity, even with only just the EGFR CAR and unmutated CD8 hinge, as in instant claim 5 . Figure 7 particularly shows increased IFN-y and IL-2 release compared to controls, as in instant claim 6 . Figure 8 particularly showed increased cytotoxicity compared to controls, teaching instant claim 15 . Claim 91 of Evan teaches treating cancer with a composition comprising the T cell comprising the dual CAR construct, as in instant claim 23 . Regarding claim 31, Example 4 teaches that the C1 variant comprises all CD8a hinge cysteines which Evans shows are critical for dimerization and activation of the CAR when there is only a CCR antigen present, anticipating instant claim 31 . 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. Claim s 1, 4-8, 10-18, 20, 23, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Evans in WO 2021/211948 A1 effectively filed on April 17, 2020 ; as evidenced by Murphy and Weaver. (2017). Chapter 7: Lymphocyte Receptor Signaling, § 7-7 through 7-17. Janeway ’s Immunobiology (pp.266-278). Taylor & Francis Group, LLC. (herein after referred to as “Janeway”). Evans anticipates claims 1, 4-6, 15, 23, and 31 , but insofar as one may argue that Evans does not anticipate each and every element of instant claims 7,8, 10-11, 14, 16-18, and 20 consider the following: Regarding instant claim s 7 , 8, 11 and 12 , on pg. 43 in lines 1-12, Evans teaches that TCR activation signaling is initiated through an activating signal, e.g. CD3z, and a co-stimulatory signal. Note well, the CAR and CCR described supra comprises both and the skilled artisan would understand from the basic biology of TCR activation that the signals of the CAR and CCR are transduced through phosphorylation of the CD3z chain and downstream signaling kinases which also results in glycolytic activity ( Janeway on pg. 266 in the last full ¶ through pg. 267 in the first ¶; see pg. 274 -275 regarding downstream signaling; see pg. 277 in the last ¶ regarding activation of glycolytic enzymes by downstream signaling activity ) . Regarding instant claim 10 , Evans teaches that immune effector cells comprising the CAR and CCR are activated and proliferate in vitro before genetic modifications (see pg. 90 in lines 28-29). Additionally and/or alternatively, pg. 42 in lines 13-19 teaches that the intracellular signaling domains initiate proliferation. Relating to instant claim 13 , Evans teaches that the CAR + CCR constructs are used to treat relapsed refractory DLBCL, which falls within the BRI of “tumor re-challenge.” Regarding instant claims 14 and 16 , in Example 2 Evans administered T cells with either a single anti-BCMA CAR or the anti-BCMA CAR + anti-EGFR CCR to mice with A549 grafte d tumor and only the anti-BCMA CAR + anti-EGFR CCR controlled tumor growth . The broadest reasonable interpretation of “stress conditions” includes the milieu factors that the T-cells are subject to when they are administered in vivo . Regarding instant claim 17 , at lines 11-13 on pg. 92, Evans teaches transducing human donor T-cells with the CAR + CCR constructs. In lines 14-15 on pg. 93, Evans teaches that the T-cells may be CD4+ and CD8+ T cells, relating to instant claim 20 . Relating to instant claim 18 , Evans teaches that suitable subjects for treatment include laboratory animals (mice, rats, rabbits, and guinea pigs), farm animals, and domestic animals or pets (cats or dogs) (pg. 105 in lines 13-22). It would have prima facie obvious to the skilled artisan to apply or extrapolate any one or more of the above to the exemplary embodiment of a T-cell comprising an anti-BCMA CAR comprises a CD8a hinge, CD8a transmembrane domain, 4-1BB costimulatory domain, and a CD3z signaling domain expressed in addition to an anti-EGFR CAR comprises a CD8a hinge, CD8a transmembrane domain, and a CD28 cytoplasmic domain. “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art .” Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989) . In the instant case the skilled artisan would be motivated by the explicit suggestions that the preferred embodiment can be used in any one or more the above described contexts. For example, regarding the intended outcomes, the skilled artisan, in view of the explicit teachings of Evans and foundational knowledge generally available to the skilled artisan regarding TCR / CAR activation as evidenced by Janeway, would have found the structure resulting in each intended outcome as prima facie obvious since the Evans clearly indicates that such outcomes are resultant from the structure of the CAR + CCR constructs. E.g., the costimulatory plus signaling domain activation results in intracellular signaling events leading to proliferation ( i.e. enriches cell cycle pathways) and TCR activation ( e.g. ITAM phosphorylation and signaling pathway enrichment). Moreover, regarding instant claim 18, the skilled artisan would have found it prima facie obvious to treat a non-human animal as suggested by Evans with a matching non-human cell transduced with a CAR + CCR construct to, e.g. , avoid host vs. graft effects. In performing each of the suggested , one of ordinary skill would have arrived at the instantly claimed invention from following the suggestions of Evans and done so with a reasonable expectation of success in view of the level of ordinary skill and experimental evidence present by Evans. Therefore, by preponderance of the evidence the instantly claimed invention as whole would have been prima facie obvious to a person having ordinary skill in the art. Claims 1, 4-8, 10-11, 14-18, 20, 22 - 23, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Evans in WO 2021/211948 A1 effectively filed on April 17, 2020; as evidenced by Murphy and Weaver. (2017). Chapter 7: Lymphocyte Receptor Signaling, § 7-7 through 7-17. Janeway’s Immunobiology (pp.266-278). Taylor & Francis Group, LLC. (herein after referred to as “Janeway”); as applied to claim s 1, 4-8, 10-11, 14-18, 20, 23, and 31 above, and further in view of Hernandez et al . J Nucl Med . May 2020. 61(Supplement 1):376 ; further evidenced by Majzner et al. Transl Cancer Mech Ther . April 15, 2019. 25(8):2560-2574. Evans on pg. 6 in the last ¶ spanning pg. 7 teaches that the first and/or second antibody is selected from a group comprising about 80 antigens including B7-H3 and GD2. Given the two-receptor system suggested by Evans, the total possible number of combinations is about 3,160. On pg. 46 in lines 6-10, Evans teaches that the CAR comprises a CD8a hinge, CD8a transmembrane, CD28 co-stimulatory domain and a CD3z signaling domain. Evans also suggests that the CCR may have a 4-1BB co-stimulatory domain (see pg. 8 in lines 21-29). While Evans teaches GD2 and B7-H3 are targets for a CAR + CCR system , a CAR comprising CD8ahinge-CD8aTM-CD28-CD3z, and a CCR comprising, inter alia , a 4-1BB, Evans does not disclose in a single embodiment all the elements as arranged in instant claim 22. Hernandez teaches that targeting GD2 and B7-H3 concomitantly overcomes toxicity related to targeting GD2 alone in glioblastoma. “ Despite high-expression in tumor cells, GD2 is also present in peripheral nerves , leading to substantial, at times dose-limiting, neuropathic-pain in many treated patients. Another molecular target B7-H3 (CD276), is also overexpressed in many cancers including neuroblastoma, but not on nerves. ” (see Objectives on pg. 1). “ We successfully generated bs- mAbs with high tumor avidity to GD2/B7-H3cells and limited off-target binding to GD2/B7-H3 cells. ” (Conclusions on pg. 2). It would have been prima facie obvious to the skilled artisan to select GD2 and B7-H3 as targets for the CAR + CCR construct of Evans in view of Hernandez’s teachings that targeting GD2 and B7-H3 at the same time with immunotherapeutics can limit off-target toxicity in treating neuroblastoma. In view of Hernandez’s teachings, the person having ordinary skill in the art would have expected an advantage of reducing off-target toxicity by dual targeting of GD2 and B7-H3 in treating neuroblastoma for a CAR + CCR system taught by Evans. “The expectation of some advantage is the strongest rationale for combining references.” ( see MPEP 2144 II.). CAR T-cells were known to cause neurotoxicity (see pg. 2 in lines 7-8 of Evans), and in the case of targeting GD2, a first-line tumor target for neuroblastoma, Evans evidences that the neurotoxicity may be due to off-target affects on non-tumorous nerves. Evans presents the solution of targeting GD2 and B7-H3, which is not expressed on nerves, and shows that off-target toxicity is effectively limited by doing so. Thus, the skilled artisan would have understood that the solution of Evans could also apply to the known problem of targeting GD2 with CARs. (see also Majzner in the second col. on pg. 494: “[T] he E101K-CAR induced neurotoxicity through on-target recognition of GD2 … ‘ GD2 may be a difficult target antigen for CAR T-cell therapy without additional strategies that can control CAR T-cell function within the CNS. ’”). In view of the experimental evidence presented by Evans and the level of ordinary skill in the art, a person having ordinary skill would have had a reasonable expectation of success in targeting GD2 and B7-H3 with the CAR + CCR of Evans. R egarding the arrangement of intracellular co-stimulatory and signaling domains, the person having ordinary skill in the art would have found GD2-CD28-CD3z with B7-H3-4-1BB prima facie obvious in view of Evans’ teaching that the CAR component may have CD28-CD3z. The skilled artisan would reasonably infer that a CD28-CD3z CAR W ould be paired with a 4-1BB CCR , i.e. merely switching the co-stimulatory domains of the exemplary arrangement, and result in the same result of activation of TCR signaling pathways by either the CAR, the CCR, or both together. When the position of a component does not modify the operation of a construct, the courts have held that mere design choice does not render a claimed invention patentable over the prior art. (see In re Japikse , 181 F.2d 1019, 86 USPQ 70 (CCPA 1950) and In re Kuhle , 526 F.2d 553, 188 USPQ 7 (CCPA 1975) as cited in MPEP 2144.04 VI. C). In view of the explicit disclosure of Evans and ordinary skill in the art, on would have had a reasonable expectation of success in doing so. Therefore, the invention as set forth in claim 22 as a whole would have been prima facie obvious to the skilled artisan by preponderance of the evidence. Claims 1, 4-8, 10-11, 14-18, 20, 21 , 23, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Evans in WO 2021/211948 A1 effectively filed on April 17, 2020; as evidenced by Murphy and Weaver. (2017). Chapter 7: Lymphocyte Receptor Signaling, § 7-7 through 7-17. Janeway’s Immunobiology (pp.266-278). Taylor & Francis Group, LLC. (herein after referred to as “Janeway”); as applied to claim s 1, 4-8, 10-11, 14-18, 20, 23, and 31 above, and further in view of Wang et al. Cancer Res . 2019. 79(12_Supplement):2321. See discussion of Evans as applied to claim s 1, 4-8, 10-11, 14-18, 20, 23, and 31 above . While Evans teaches a population of CD4+ and CD8+ T cells comprising first CAR comprising CD8a stalk, CD8a transmembrane domain, CD28 intracellular domain and second CAR comprising CD8a stalk, CD8a transmembrane domain, a 4-1BB costimulatory domain, and a CD3z signaling domain; Evans does not teach that the T-cells are enriched in CD27+/CD29+ cells in both the CD4+ and CD8+ T cells. However, Wang investigated the function of CD27+ CARs compared to CD27- CAR T cells and found that CD27+ CAR T-cells induced long-term tumor eradication, were less exhausted, and were sensitized to target low-antigen expressing tumors. Particularly, enriched CD27+ CAR T cells resulted in enhanced antitumor potency, whereas constitutive expression impaired CAR T cell function. It would have been prima facie obvious to a person of ordinary skill in the art to use CD4+ and CD8+ CAR + CCR T cells taught by Evans that are enriched for CD27 expression, as taught by Wang. The advantage of enhanced antitumor potency with enriched CD27 expression would have motivated the skilled artisan to do so. “The expectation of some advantage is the strongest rationale for combining references.” ( see MPEP 2144 II.). In view of the experimental evidence described by the references and level of ordinary skill, the person having ordinary skill would have had a reasonable expectation of success in doing so. Therefore, the population of CD4+ and CD8+ T cells enriched for CD27 as set forth in claim 21 would have been obvious to the person of ordinary skill. Conclusion The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Orentas in WO 2018/045325 A1 published on March 8, 2018 . Orentas teaches a DuoCAR comprising two CAR constructs, wherein one construct comprises an intracellular 4-1BB co-stimulatory domain fused to a CD3z signaling domain and the other car comprises a CD28 co-stimulatory domain without a CD3z signaling domain (see Fig. 5E). Maher in WO 2021/038036 A1 effectively filed on August 28, 2019 teaches parallel CARs having split co-stimulatory domains and a single CD3z domain as well as a CD8a hinge domain. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT BRIANNA K SWARTWOUT whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (703)756-4672 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday-Friday 8-5 . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. 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