DETAILED ACTION
Claim Status
As of the Non-Final Office Action mailed 9/4/2025, claims 33-50 were pending.
In Applicant's Response filed on 3/4/2026, claims 33 and 45-50 were amended and claims 34-35 were canceled.
As such, claims 33 and 36-50 are pending and have been examined herein.
Withdrawn Objections/Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in this application. Any objections or rejections not specifically reiterated are hereby withdrawn.
Claim Rejections - 35 USC § 112(d)
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 44 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 44 recites, inter alia, “wherein the intracellular signaling domain further comprises a costimulatory domain comprising a functional signaling domain of a protein selected from the group consisting of . . . CD28”. This fails to further limit independent claim 33, which recites “an intracellular signaling domain of a Cluster of Differentiation 28 (CD28)” as a requirement for the CAR claimed in the instantly claimed immune cell. 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 – Necessitated by Amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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) 33, 36-37, 40, and 42-46 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Devine et al (WO2017053889A2, 9/23/2016; published 3/30/2017). Please note that this rejection is necessitated by amendments by Applicant made overcome posited 112(a) enablement rejection of record in the Non-Final Office action mailed 9/4/2025.
Devine teaches CAR cells targeting tumor necrosis therapy (abstract). The reference teaches a CAR comprising (a) an antigen binding domain of a FLT3 antibody; (b) a hinge domain; (c) a transmembrane domain; and (d) an intracellular domain. Further aspects of the disclosure relate to a chimeric antigen receptor (CAR) comprising: (a) an antigen binding domain of a FLT3 antibody; (b) a hinge domain; (c) a CD28 transmembrane domain; (d) one or more costimulatory regions selected from a CD28 costimulatory signaling region, a 4-1BB costimulatory signaling region, an ICOS costimulatory signaling region, and an OX40 costimulatory region; and (e) a CD3 zeta signaling domain (para 11) (“wherein the CAR comprises an extracellular antigen-binding domain” as in instant claim 42; “wherein the intracellular signaling domain further comprises a primary-signaling domain comprising a functional signaling domain of a protein selected from CD3 zeta” as in instant claim 43; “wherein the intracellular signaling domain further comprises a costimulatory domain comprising a functional signaling domain of a protein selected from the group consisting of . . . CD28, . . . , OX40, . . . , ICOS, and 4-1BB” as in instant claim 44). The reference teaches an isolated cell comprising the CAR wherein the cell is a eukaryotic cell such as a T cell, or NK cell (see claims 22 and 27 for Devine). An isolated nucleic acid sequence encodes that CAR and the reference teaches a vector or mRNA comprising the isolated nucleic acid sequence (see claim 10 and 19 of Devine) (“wherein the immune cell comprises a vector comprising a nucleic acid encoding the CAR” as in instant claim 40). T cells that can be used include T-cell lines such as J.Cam1.6 (i.e., LCK-deficient Jurkat cell) (“an immune cell expressing a chimeric antigen receptor, wherein the CAR comprises an intracellular signaling domain of a Cluster of Differentiation 28 (CD28) protein wherein expression of lymphocyte-specific protein tyrosine kinase (LCK) is disrupted in the immune cell, and the immune cell is a T cell or an NK cell.” as in instant claim 33; “an immune cell expressing a CAR, wherein the immune cell has been modified such that expression of the LCK gene has been disrupted, wherein the CAR comprises an intracellular signaling domain of a Cluster of Differentiation 28 (CD28) protein, wherein the immune cell is a T cell or an NK cell” as in instant claim 46).
Instant claims 36-37 recites, inter alia, “wherein the expression of LCK is disrupted using CRISPR editing, Meganuclease editing, TALEN editing, or zinc finger editing” and “wherein the expression of LCK is disrupted using a nucleic acid that inhibits gene expression of LCK”, respectively, which the examiner is interpreting as product-by-process limitations. Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)
Instant claim 45 recite, inter alia, “wherein the immune cell has reduced PD-1 expression as compared to a cell in which expression of LCK has not been disrupted”. The examiner notes that when the structure recited in the reference (in this case, lack of LCK expression) is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent (see MPEP 2112.01(I)). Moreover, if compositions are physically the same, it must have the same properties. “Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. (see MPEP 2112.01(II)).
Thus, absent evidence to the contrary, Devine anticipates the instant invention of claims 33, 36-37, 40, and 42-46.
Claim(s) 47-48 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Methi et al (J Immunol. 2005 Dec 1;175(11):7398-406. doi: 10.4049/jimmunol.175.11.7398).
Methi teaches the effects of acute elimination of Lck in Jurkat TAg and primary T cells using RNA interference mediated by short-interfering RNAs (“a method of manufacturing the immune cell of claim 33, the method comprising disrupting expression of LCK” as in instant claim 47; “wherein the expression of LCK is disrupted using a nucleic acid that inhibits gene expression of LCK” as in instant claim 48). They observed sustained and elevated phosphorylation of ERK1/2 in Lck kd cells 30 min to 2 h after stimulation. Downstream effects on immune function as determined by activation of a NFAT-AP-1 reporter, and TCR/CD28-stimulated IL-2 secretion were strongly augmented in Jurkat and primary T cells, respectively. Downstream effects on immune function as determined by activation of a NFAT-AP-1 reporter, and TCR/CD28-stimulated IL-2 secretion were strongly augmented in Jurkat and primary T cells, respectively (Discussion para 2). Lck knockdown exhibited elevated and prolonged phosphorylation of the MAPKs ERK1/2, the activation of an NFAT-AP-1 reporter was strongly augmented, and likewise secretion of IL-2 (same para). This suggests the following: 1) parallel pathways of T cell activation after engagement of the TCR are in operation, a notion that has been proposed by others; and 2) Lck plays a dual role in TCR signaling, being important for transferring classical TCR-induced signaling and suppressing the very same signal by initiating one or more negative feedback loops (same para). Importantly, there are some discrepancies between Lck-deficient JCAM1/Jcam1.6 clones and Lck-/- cells. T cell activation may indeed occur in the absence of Lck, and such T cells are hyperactivated after stimulation of the TCR (Discussion para 3). A possible explanation for the discrepancy between the results presented in this study and similar experiments conducted with T cells from the Lck-deficient JCAM1 clone, which is defective in IL-2 production, may be the large difference in duration under which the cells have endured their respective deficiencies. JCAM1 cells and T cells from Lck−/− mice have been without Lck for long periods of time, during which compensatory and interfering mechanisms may have developed as opposed to cells with acute siRNA-mediated kd. The most potent kd of Lck using siRNA-mediated RNAi still rendered an endogenous pool of Lck left in the cell that could potentially produce incomplete phosphorylation of CD3-ζ and weak mobilization of intracellular Ca2+. Lck knockdown cells displayed a phenotype with diminished proximal response.
Thus, absent evidence to the contrary, Methi anticipates the instant invention of claims 47-48.
Claim(s) 47-49 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wan et al (Cell Mol Immunol. 2020 Feb;17(2):143-152. Epub 2018 Dec 6).
Wan teaches that LCK association underlies bystander and costimulatory ICOS signaling. A subline of Jurkat cells that performs well in electroporation was used to create Lck-deficient Jurkat cells (Lck-deficient Jurkat cells, para 1). The cells were electroporated with MSCV-based GFP-tagged vectors that express Cas9 and Lck-targeting guide RNAs (same para). Single GFP+ Jurkat cells were cloned by sorting and were genotyped by PCR. Two Jurkat clones (clone 1 and clone 16) that lacked the guide RNA-targeted fragment from exon 2 to exon 9 were selected for subsequent experiments after validation by Western blotting (see Figure S5 for details) (same para). For experiments involving ICOS stimulation or immunoprecipitation in the absence of Lck, these Lck-deficient Jurkat cells and corresponding wild-type control cells were further transduced with ICOS-expressing constructs (same para). This shows that LCK can be successfully disrupted via CRISPR editing a method of manufacturing the immune cell of claim 33, the method comprising disrupting expression of LCK” as in instant claim 47; “wherein the expression of LCK is disrupted using a nucleic acid that inhibits gene expression of LCK” as in instant claim 48; “wherein the expression of LCK is disrupted using a CRISPT editing” as in instant claim 49).
Thus, absent evidence to the contrary, Wan anticipates the instant invention of claims 47-49.
Claim Rejections - 35 USC § 103 – Necessitated by Amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 ordina ry skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 38-39 and 41 is/are rejected under 35 U.S.C. 103 as being unpatentable over Devine as applied to claims 33, 36-37, 40, and 42-46 above, and further in view of Methi et al (J Immunol. 2005 Dec 1;175(11):7398-406. doi: 10.4049/jimmunol.175.11.7398).
The teachings of Devine were recited in the above 35 U.S.C. 102 rejection as applied to claim 33 of which claims 37-39 depend.
Regarding claim 41, Devine teaches “a T cell comprising a nucleic acid encoding the CAR” (see 102 rejection above; renders prima facie obvious instant claim 41 in-part).
The difference between the teachings and the invention as instantly claimed is that it does not teach that the nucleic acid molecule that inhibits gene expression of LCK is selected from antisense RNA, antagomir RNA, siRNA, and shRNA (instant claims 38 and 41 in-part) or that the immune cell comprises a vector comprising the nucleic acid that inhibits gene expression (claim 39).
Methi teaches the effects of acute elimination of Lck in Jurkat TAg and primary T cells using RNA interference mediated by short-interfering RNAs (“nucleic acid molecule that inhibits gene expression of LCK is selected from . . . , siRNA” as in instant claim 38). Jurkat TAg T cells were cotransfected with 2 μg of pMACS Kk.II selection vector encoding a truncated murine H-2Kk surface marker, siRNA (100 nM) and NFAT-AP-1 luciferase construct (10 μg), and subjected to a MACSelection procedure (Selection of transfected cells, para 1) (“the immune cell comprises a vector comprising the nucleic acid that inhibits gene expression” as in instant claim 39). They observed sustained and elevated phosphorylation of ERK1/2 in Lck kd cells 30 min to 2 h after stimulation. Downstream effects on immune function as determined by activation of a NFAT-AP-1 reporter, and TCR/CD28-stimulated IL-2 secretion were strongly augmented in Jurkat and primary T cells, respectively (Discussion para 2). Lck knockdown exhibited elevated and prolonged phosphorylation of the MAPKs ERK1/2, the activation of an NFAT-AP-1 reporter was strongly augmented, and likewise secretion of IL-2 (same para). This suggests the following: 1) parallel pathways of T cell activation after engagement of the TCR are in operation, a notion that has been proposed by others; and 2) Lck plays a dual role in TCR signaling, being important for transferring classical TCR-induced signaling and suppressing the very same signal by initiating one or more negative feedback loops (same para). Importantly, there are some discrepancies between Lck-deficient JCAM1/Jcam1.6 clones and Lck-/- cells. T cell activation may indeed occur in the absence of Lck, and such T cells are hyperactivated after stimulation of the TCR (Discussion para 3). A possible explanation for the discrepancy between the results presented in this study and similar experiments conducted with T cells from the Lck-deficient JCAM1 clone, which is defective in IL-2 production, may be the large difference in duration under which the cells have endured their respective deficiencies. JCAM1 cells and T cells from Lck−/− mice have been without Lck for long periods of time, during which compensatory and interfering mechanisms may have developed as opposed to cells with acute siRNA-mediated kd. The most potent kd of Lck using siRNA-mediated RNAi still rendered an endogenous pool of Lck left in the cell that could potentially produce incomplete phosphorylation of CD3-ζ and weak mobilization of intracellular Ca2+. Lck knockdown cells displayed a phenotype with diminished proximal response to TCR stimulation, whereas downstream T cell effector functions were paradoxically enhanced.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a CAR expressing T cell that is also LCK-deficient as taught by Devine, where the LCK expression is knocked down via siRNA as taught by Methi, to arrive at the instantly claimed invention. As Methi shows LCK can be knocked down in immune cell with siRNA, one of ordinary skill would have been motivated to simply substitute one known element [JCAM1 cell of Devine] for another [T cell with siRNA LCK knockdown] to obtain the predictable result of a Lck-deficient T cell expressing a CAR with a reasonable expectation of advantageously having a T cell that maintains and has enhanced downstream T cell effector functions not seen in JCAM1 cells as taught by the prior art.
Claim(s) 50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Methi as applied to claims 47-48 above, and further in view of Gulati et al (Clinical Cancer Research 24(16):3981-3993; 10 May 2018; Ref. 1 of Non-Patent Literature in IDS filed 8/26/2021).
The teachings of Methi were recited in the above 35 U.S.C. 102 rejection as applied to claim 47 of which claim 50 depends.
The difference between the teachings and the invention as instantly claimed is that it does not teach introducing a nucleic acid encoding a CAR into the immune cell.
Gulati teaches that aberrant Lck signal via CD28 co-stimulation augments antigen-specific functionality and tumor control. The reference teaches that delta-CD28 CAR carries a deletion in the lck binding domain, and mediates superior in vitro functionality, showed enhanced metabolism, activation after cognate antigen encounter, and mediated better tumor control in combination with PD-1 blockade in humanized mice. Δ-CD28/CD3ζ CAR-T cells revealed maximum antigen-specific IFNγ release (Fig. 3E). Thus, our data demonstrate that T cells redirected with Δ-CD28/CD3ζ show less antigen-independent proliferation with similar antigen-specific proliferation, similar killing to CD28, and enhanced IFNγ, but reduced IL2 release.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a LCK-deficient T cell as taught by Methi, where a CAR is introduced into the cell as taught by Gulati, to arrive at the instantly claimed invention. As Gulati shows aberrant LCK signaling in CAR containing T cells mediates superior in vitro functionality, showed enhanced metabolism, activation after cognate antigen encounter, one of ordinary skill would have been motivated to modify the method of Methi to include introducing a CAR containing CD28 into the LCK-deficient T cell with a reasonable expectation of advantageously having augmented antigen-specific functionality and better tumor control as taught by the prior art.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GILLIAN C REGLAS whose telephone number is (571)270-0320. The examiner can normally be reached M-F 9-5.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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