DETAILED ACTION
Priority
This application claims priority to U.S. provisional applications 63/322,868, filed on 23 March 2022, and 63/417,775, filed on 20 October 2022. The effective filing date is 23 March 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06 July 2023 is being considered by the examiner.
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 Application, Amendments, and/or Claims
Claims 1-6, 8-10, 12-25, 51, 52, 67, and 68 are pending and the subject of this office action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 19 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
“The purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
Claims 19 and 20 refer to the heavy and light chain variable regions of an anti-CD83 scFv present in the CAR of a genetically engineered T cell population. As disclosed in the claims, the scFv is comprised of a VH (SEQ ID No: 77) containing CDR1-CDR3 set forth as SEQ ID NOs: 71-73 and/or wherein the VL (SEQ ID No: 78) contains CDR1-CDR3 set forth as SEQ ID NOs: 74-76. The claims are written in the alternative and thus do not claim a scFv with both VH and VL chains. The specification reiterates the same teachings: “In some specific examples, the anti-CD83 antibody discloses herein may comprise the heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3 set forth as SEQ ID NOs: 71, 72 and 73, respectively, as determined by the Kabat method. Alternatively, or in addition, the anti- CD83 antibody discloses herein may comprise the light chain CDR1, light chain CDR2, and light chain CDR3 set forth as SEQ ID NOs: 74, 75 and 76, respectively, as determined by the Kabat method.”(page 32 lines 6-20)
The state of the art at the effective filing date of the claimed invention does not provide adequate support for the applicants claim of an anti-CD83 scFv comprised of VH (SEQ ID No: 77) that can maintain it biological activity when not paired with its VL (SEQ ID No: 78). Rather, the art demonstrates that antibody functionality was known to depend on the entire antibody structure, particularly a full complement of six CDRs. Chiu ML, et al. (2019) Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel). Dec 3;8(4):55 teaches that the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). Here, Chiu teaches that the interaction between the heavy and light chain variable domains effects the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably determine which amino acids in which CDR regions could be modified such that the antibody would still perform the function of selectively binding to chemerin and being able to treat a subject who has kidney cancer.
Additionally, Bendig (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest. This general strategy was still being used at the time of the claimed invention as evidenced by Khantasup et al. (Monoclonal Antibodies in Immunodiagnosis and Immunotherapy, 2015, 34(6): 404-417). Khantasup et al. teaches: “The standard method involves grafting mouse complementarity-determining regions (CDRs) onto human framework regions (FRs). The critical objective is to prevent loss of antigen-binding affinity due to loss of original CDR conformations after CDR grafting. Several factors play a role in preventing loss of affinity, including proper selection of human template, compatibility between mouse CDRs and human FRs, and retention or back mutation of mouse FR residues at positions that maintain original CDR conformation” (see page 405, paragraph 1 and page 407, column 2, paragraph 4). Murphy et al. (Journal of Immunological Methods, Vol. 463, Pg. 127-133, 2018), teach that altering amino acid D92 in the complementarity determining region light chain region 3 (CDRL3) of single chain fragment variable (scFv) 2G1 obliterates its capacity to bind to microcystin-leucine-arginine (Page 130, Section 3.2, paragraph 2) and changing phenylalanine at position 91 to tyrosine caused an increased in binding to MC-LR, compared to the parent clone (Page 131, Column 1, Paragraph 2). The alterations in binding that were observed in these two variants demonstrate the highly influential role of CDRL3 in binding MC-LR. Thus, the state of the art recognized that it would be highly unpredictable that a specific humanized antibody comprising less than all six CDRs of a parental antibody with a desired specificity would retain the antigen-binding function of the parental antibody. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of the parental donor antibody includes six CDRs (i.e. VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) from parental donor antibody in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function of the parental donor antibody. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification, limited to antibodies that comprise all six CDRs of a parental donor antibody that binds antigen to antibodies that comprise fewer than all six CDRs from the parental donor antibody, wherein the antibodies retain the antigen specificity of the parental donor antibody
Claims 19 and 20, written in the alternative do not provide for a definitive VH and VL for the scFv and allow for the interpretation that other heavy and light chains can be combined with those disclosed, potentially altering CD83 binding specificity. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification, limited to antibodies that comprise all six CDRs of a parental donor antibody that binds antigen to antibodies that comprise fewer than all six CDRs from the parental donor antibody, wherein the antibodies retain the antigen specificity of the parental donor antibody. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). One of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as is claimed. There is no disclosure of a correlation between structure and function that would allow those of skill in the art to recognize other members of the claimed genus from the disclosure.
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 1, 2, 13, 17-21, 23-25, 51, 52, 67, and 68 are rejected under 35 U.S.C. 103 as being unpatentable over US20200108098 A1 (herein Davila) in view of Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang).
In regard to claims 1, 2, 25, and 51, Davila teaches a method for creating a population of genetically modified CAR T cells expressing an extracellular antigen binding domain targeting CD83, comprised of a scFv, a co-stimulatory domain of 4-1BB, and a cytoplasmic signaling domain of CD3[Symbol font/0x7A] (figure 1A, [0231]). Davilla teaches that adaptive transfer of these engineered cells may be used to suppress alloreactive cells in a subject receiving transplant donor cells and prevent GVHD by depleting alloreactive CD4+ Tconv cells and mature inflammatory DCs, and enhancing the ratio of Treg to alloreactive Tconv cells ([0252], [0251], [0246], [0248], figure 15). Davila also teaches that these engineered T cells may be coupled with a second immune effector cell containing an additional CAR element targeted to additional antigens (e.g. CD19, CD70, BCMA, etc) (claims 6 and 19, [0013]).
Davila does not teach anti-CD83 CAR T cell populations with disrupted Reg1 and TGFBR2, genes. Zheng and Tang teach these deficiencies.
Zheng teaches that regnase-1 is an antigen-dependent regulator of CAR T cell fate, and directly interacts with TCF-1 to suppress long-term CAR T-mediated immunity (discussion paragraph 1). Zheng teaches that disrupting Reg1 in human CD19 CAR T cells leads to enhanced TCF-1 expression, which in turn results in enhanced CAR T cell expansion, CAR T cell persistence, as well as reduced tumor burden when compared to wild-type CD19 CAR T cells in a human xenograft B-ALL model (results: Regnase-1 deletion supports human CAR-T-cell expansion and function, figure 7). Zheng concludes the discussion by stating the following: “In summary, our findings provide new insight into the context-dependent control of CAR–T-cell memory and fate determination, and demonstrate how targeting Regnase-1 can improve the effectiveness of adoptive CAR-T immunotherapies.”
Tang teaches that the TGF-β signaling pathway acts as an important regulator of the tumor micro-environment, and when activated has an adverse effect on antitumor immunity and inhibits host tumor surveillance. Tang teaches that knocking out TGFBR2 in M28z CAR T cells allows these engineered cells to bypass TGF-β regulation, which in turn led to enhanced antitumor efficacy when compared to CAR T cells lacking the TGFB2 knock-out in a CDX model system (results: TGFBR2 editing enhanced tumor elimination efficacy in CDX models, figure 5). Zheng concludes the abstract by stating the following: “In conclusion, we greatly improved the in vitro and in vivo function of CAR T cells in TGF-β–rich tumor environments by knocking out endogenous TGFBR2 and propose a potentially new method to improve the efficacy of CAR T cell therapy for treating solid tumors.”
It would have been obvious to one skilled in the art to combine the teachings of Tang and Zheng (TGFBR2 and Reg1 disruption, respectively) with the anti-CD83 CAR T cells taught by Davila. One of ordinary skill in the art at the time of filing would have been motivated to incorporate the disruption of the TGFBR2 and Reg1 genes with the recognized benefit of knocking out either or both of these genes in a population of CAR T cells (i.e. enhanced proliferation, persistence, and overall efficacy compared to similar CAR T cell populations lacking gene(s) disruption). Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
In regard to claim 13, Davila, Zheng, and Tang teach anti-CD83 CAR T cell populations with disrupted Reg1 and TGFBR2 genes as discussed for claims 1 and 2.
Davila further teaches the integration of the anti-CD83 CAR into the T-cell genome using a retroviral delivery system ([0212]).
In regard to claim 17-21, Davila, Zheng, and Tang teach anti-CD83 CAR T cell populations with disrupted Reg1 and TGFBR2 genes as discussed for claims 1 and 2.
Davila further teaches that the CAR is comprised of an extracellular antigen binding domain targeting CD83, a co-stimulatory domain of 4-1BB, and a cytoplasmic signaling domain of CD3[Symbol font/0x7A] (figure 1A, [0231]). The antigen binding domain of the CAR contains a scFv comprised of a variable heavy and light chains, that share 100% sequence identity to SEQ ID NOs: 77 and 78 of the instant application, as shown below:
VH Alignment
Ref QVQLKESGPGLVKPSQSLSLTCSVTGFSITTGGYWWTWIRQFPGQKLEWMGYIFSSGNTN 60 (Ref SEQID 19)
#77 QVQLKESGPGLVKPSQSLSLTCSVTGFSITTGGYWWTWIRQFPGQKLEWMGYIFSSGNTN 60 (SEQ ID 77)
************************************************************
Ref YNPSIKSRISITRDTSKNQFFLQLNSVTTEGDTARYYCARAYGKLGFDYWGQGTLVTVSS 120 (Ref SEQID 19)
#77 YNPSIKSRISITRDTSKNQFFLQLNSVTTEGDTARYYCARAYGKLGFDYWGQGTLVTVS- 119 (SEQ ID 77)
***********************************************************
VL Alignment:
Ref QPVLTQSPSASASLGNSVKITCTLSSQHSTYTIGWYQQHPDKAPKYVMYVNSDGSHSKGD 60 (Ref SEQID 20)
#78 QPVLTQSPSASASLGNSVKITCTLSSQHSTYTIGWYQQHPDKAPKYVMYVNSDGSHSKGD 60 (SEQ ID 78)
************************************************************
Ref GIPDRFSGSSSGAHRYLSISNIQPEDEADYFCGSSDSSGYVFGSGTQLTVL 111 (Ref SEQID 20)
#78 GIPDRFSGSSSGAHRYLSISNIQPEDEADYFCGSSDSSGYVFGSGTQLTVL 111 (SEQ ID 78)
***************************************************
Consequently, the CDRs (SEQ ID NO: 71-73 and 74-76) claimed within claim 19 also share 100% sequence identity with the CDRs of the scFv taught by Davila. Furthermore, the entirety of the scFv claimed by the applicant in claim 21 shares 100% sequence identity with the scFv taught by Davila as illustrated in the following alignment:
Ref QVQLKESGPGLVKPSQSLSLTCSVTGFSITTGGYWWTWIRQFPGQKLEWMGYIFSSGNTN 60 (Ref SEQID 71)
SEQ QVQLKESGPGLVKPSQSLSLTCSVTGFSITTGGYWWTWIRQFPGQKLEWMGYIFSSGNTN 60 (SEQ ID 79)
************************************************************
Ref YNPSIKSRISITRDTSKNQFFLQLNSVTTEGDTARYYCARAYGKLGFDYWGQGTLVTVSS 120 (Ref SEQID 71)
SEQ YNPSIKSRISITRDTSKNQFFLQLNSVTTEGDTARYYCARAYGKLGFDYWGQGTLVTVSS 120 (SEQ ID 79)
************************************************************
Ref GGGGSGGGGSGGGGSQPVLTQSPSASASLGNSVKITCTLSSQHSTYTIGWYQQHPDKAPK 180 (Ref SEQID 71)
SEQ GGGGSGGGGSGGGGSQPVLTQSPSASASLGNSVKITCTLSSQHSTYTIGWYQQHPDKAPK 180 (SEQ ID 79)
************************************************************
Ref YVMYVNSDGSHSKGDGIPDRFSGSSSGAHRYLSISNIQPEDEADYFCGSSDSSGYVFGSG 240 (Ref SEQID 71)
SEQ YVMYVNSDGSHSKGDGIPDRFSGSSSGAHRYLSISNIQPEDEADYFCGSSDSSGYVFGSG 240 (SEQ ID 79)
************************************************************
Ref TQLTVL 246 (Ref SEQID 71)
SEQ TQLTVL 246 (SEQ ID 79)
******
In regard to claim 23, Davila, Zheng, and Tang teach anti-CD83 CAR T cell populations with disrupted Reg1 and TGFBR2 genes as discussed for claims 1 and 2.
Davila further teaches a population of engineered anti-CD83 CAR T cells that were derived from human leukocytes collected from a donor ([0212]).
In regard to claims 24, 67, and 68, Davila, Zheng, and Tang teach anti-CD83 CAR T cell populations with disrupted Reg1 and TGFBR2 genes as discussed for claims 1 and 2.
Davilla teaches that the population of engineered T cells, containing anti-CD83 CAR T cells, that also contain additional T cells expressing an additional CAR element that targets tumor antigens (e.g. CD19, CD70, BCMA, etc) (claims 6 and 19, [0012]).
In regard to claim 52, Davila, Zheng, and Tang teach anti-CD83 CAR T cell populations with disrupted Reg1 and TGFBR2 genes as discussed for claim 1.
Davilla further teaches that the population of engineered anti-CD83 CAR T cells provide a method of for eliminating undesired cells in a subject, such as alloreactive CD83-expressing T cells [0265]).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over US20200108098 A1 (herein Davila), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang) as applied to claim 1 above and further in view of in view of Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper).
As discussed for claim 1, Davila, Zheng, and Tang teach anti-CD83 CAR T cell populations with disrupted Reg1 and TGFBR2 genes.
Davila, Tang, and Zheng do not teach anti-CD83 CAR T cell populations with disrupted Reg1, TGFBR2, and CD83 genes.
Cooper teaches a strategy for preventing unintended CAR T fratricide, which involves using CRISPR/Cas9 gene-editing to knockout the endogenous gene encoding the target of the CAR, within a population of CAR T cells. The example provided is a population of anti-CD7 CAR T cells, which have had the CD7 gene knocked out (abstract). This population of CAR T cells showed enhanced persistence and anti-tumor activity when compared to similar CAR T cells with a functional CD7 gene (results: CD7[Symbol font/0x44]CART7 prevents fratricide and kill T-ALL in vitro and in vivo, figure 2).
It would have been obvious to one skilled in the art to combine the teachings of Cooper with the anti-CD83 CAR T cells taught by Davila, Tang, and Zheng. One of ordinary skill in the art at the time of filing would have recognized the benefit of knocking out the gene encoding the target of the CAR in a population of CAR T cells. Target-driven T cell fratricide is a well-documented issue in T cell therapy. As taught by Cooper, the shared expression of target antigens between T effector cells and malignant cells expressing the target antigen results in self-killing of CAR T cells (introduction paragraph 2). A person of ordinary skill in the art would have known that knocking out the gene encoding the shared antigen, CD83, one could eliminate/limit T cell fratricide, thus allowing for increased proliferation, persistence, and efficacy of the T cell therapy. By combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over US20200108098 A1 (herein Davila), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang) as applied to claims 1, 17-21 above and further in view of WO2018161026 A1 (herein Suri).
Davila, Zheng, and Tang teach anti-CD83 CAR T cell populations with disrupted Reg1 and TGFBR2 genes. Davila further teaches that the CAR is comprised of an extracellular antigen binding domain targeting CD83, a co-stimulatory domain of 4-1BB, and a cytoplasmic signaling domain of CD3[Symbol font/0x7A] (figure 1A, [0231]). The antigen binding domain of the CAR contains a scFv comprised of a variable heavy and light chains, that share 100% sequence identity to SEQ ID NOs: 77 and 78 of the instant application, as discussed above.
Davilla does not teach a CAR element comprised of SEQ ID: 80 or 81. Although, Davilla teaches a CAR element containing a co-stimulatory domain of 4-1BB, and a cytoplasmic signaling domain of CD3[Symbol font/0x7A] (figure 1A, [0231]), the particular sequence used varies from the claimed invention, sequence 80 and 81. Suri teaches this deficiency.
The work of Suri et al involves numerous methods and compositions for immunotherapy, but what is pertinent to the instant application is the defined amino acid for a CD8 transmembrane domain-CD137 (4-1BB) signaling domain and CD3 zeta signaling domain, corresponding to SEQ ID NO: 107 in the reference, and intended for use in CAR element design (page 39 table 5). This defined domain is 100% identical to the corresponding sequence in the CAR element defined in SEQ ID NO: 80 and 81 of the instant application. As shown below the applicants scFv is fused to this element:
scFv QVQLKESGPGLVKPSQSLSLTCSVTGFSITTGGYWWTWIRQFPGQKLEWMGYIFSSGNTN 60(SEQ ID NO:79)
CAR QVQLKESGPGLVKPSQSLSLTCSVTGFSITTGGYWWTWIRQFPGQKLEWMGYIFSSGNTN 60(SEQ ID NO:81)
Ref ------------------------------------------------------------ 0(Ref SEQ ID NO:107)
scFv YNPSIKSRISITRDTSKNQFFLQLNSVTTEGDTARYYCARAYGKLGFDYWGQGTLVTVSS 120(SEQ ID NO:79
CAR YNPSIKSRISITRDTSKNQFFLQLNSVTTEGDTARYYCARAYGKLGFDYWGQGTLVTVSS 120(SEQ ID NO:81)
Ref ------------------------------------------------------------ 0(Ref SEQ ID NO:107)
scFv GGGGSGGGGSGGGGSQPVLTQSPSASASLGNSVKITCTLSSQHSTYTIGWYQQHPDKAPK 180(SEQ ID NO:79)
CAR GGGGSGGGGSGGGGSQPVLTQSPSASASLGNSVKITCTLSSQHSTYTIGWYQQHPDKAPK 180(SEQ ID NO:81)
Ref ------------------------------------------------------------ 0(Ref SEQ ID NO:107)
scFv YVMYVNSDGSHSKGDGIPDRFSGSSSGAHRYLSISNIQPEDEADYFCGSSDSSGYVFGSG 240(SEQ ID NO:79)
CAR YVMYVNSDGSHSKGDGIPDRFSGSSSGAHRYLSISNIQPEDEADYFCGSSDSSGYVFGSG 240(SEQ ID NO:81)
Ref ------------------------------------------------------------ 0(Ref SEQ ID NO:107)
scFv TQLTVL------------------------------------------------------ 246(SEQ ID NO:79)
CAR TQLTVLRAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWA 300(SEQ ID NO:81)
Ref -------AAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWA 53(Ref SEQ ID NO:107)
scFv ------------------------------------------------------------ 246(SEQ ID NO:79)
CAR PLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCE 360(SEQ ID NO:81)
Ref PLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCE 113(Ref SEQ ID NO:107)
scFv ------------------------------------------------------------ 246(SEQ ID NO:79)
CAR LRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY 420(SEQ ID NO:81)
Ref LRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY 173(Ref SEQ ID NO:107)
scFv ----------------------------------------------------- 246(SEQ ID NO:79)
CAR NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 473(SEQ ID NO:81)
Ref NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 226(Ref SEQ ID NO:107)
Additionally, Suri teaches the CD8 leader, reference SEQ ID NO: 105, that is used in the CAR element described in the instant claim in regard to SEQ ID: 80 (page 38 table 5).
It would have been obvious to one skilled in the art to combine the teachings of Suri with the anti-CD83 CAR T cells taught by Davila, Tang, Zheng, and Cooper. There is clear motivation to use a predefined and functional sequence, as it would limit design time necessary to enact the intended invention. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over US20200108098 A1 (herein Davila), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang), and Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper) as applied to claims 1 and 3 above and further in view of in view of Ren J, et al (2017) Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res, May 01; 23(9): 2255-2266 (herein Ren).
As discussed for claim 3, Davila, Zheng, Tang, and Cooper teach anti-CD83 CAR T cell populations with disrupted Reg1, TGFBR2, and CD83 genes.
Davila, Zheng, Tang, and Cooper do not teach anti-CD83 CAR T cell populations with disrupted Reg1, TGFBR2, CD83, TRAC, and β2M genes.
Ren teaches the use of CRISPR/Cas9-mediated multiplex gene editing for producing a β2M /TRBC double knock-out in allogenic T cells for CAR-T cell therapy. Ren teaches that disrupting β2M prevents the expression of functional MHC-1 and disruption of either TRAC or TRBC result in a lack of functional TCR, it was hypothesized that disrupting these two genes would reduce the alloreactivity of the modified CAR T cells compared to unmodified CAR T cells. Ren teaches that disruption of these two genes does in fact lead to a dramatic reduction in alloreactivity compared to non-modified lymphocytes when injected into NSG mice, as shown by a 0% and 80% mortality rate, respectively (Results: Reduced alloreactivity of TCR and B2M double-disrupted T cells, and figure 3). Ren also teaches that the double knock-out cells retain antitumor efficacy in both in vitro and in vivo, when compared to wild-type anti-CD19 CAR T cells (Results: Gene-disrupted CART cells retain antitumor efficacy and figure 4). Ren states the following in the discussion section: “In summary, clinical-scale gene-disrupted CAR T cells with potent anti-tumor activity and reduced alloreactivity can be efficiently generated using multiplex CRISPR technology and potentially could be used as off-the-self universal T cells.”
It would have been obvious to one skilled in the art to combine the teachings of Ren (TRAC and β2M disruption) with the anti-CD83 CAR T cells taught by Davila, Tang, Zheng, and Cooper. The benefit of knocking out either or both of these genes in a population of CAR T cells (i.e. enhanced persistence, and overall efficacy compared to similar CAR T cell populations lacking gene(s) disruption while having decreased alloreactivity) would have been a clear motivation for the combination. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
Claims 6, 8-10, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over US20200108098 A1 (herein Davila), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), and Ren J, et al (2017) Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res, May 01; 23(9): 2255-2266 (herein Ren) as applied to claims 1, 3, and 4 above and further in view of in view of WO2016160721 A1 (herein Meissner), WO2019051541 A1 (herein Hart), US20190284553 A1 (herein Benson), and US20210228630 A1 (herein Lee).
In regard to claims 6, 8-10, and 12, as discussed for claim 4, Davila, Zheng, Tang, Cooper, and Ren teach anti-CD83 CAR T cell populations with disrupted Reg1, TGFBR2, CD83, TRAC, and β2M genes. Zheng also teaches the use of gRNA targeting exon 4 of Reg1, sgRNA-1, as method for CRISPR/Cas-9 gene editing (supplemental methods: sgRNA sequences).
Davila, Zheng, Tang, Cooper, and Ren do not teach detailed strategies (i.e. gRNA sequences/exon targeting) for the editing of TGFBR2, CD83, TRAC, and β2M genes. These deficiencies are taught by Meissner, Hart, Benson, and Lee as described below:
-Benson teaches the disruption of Reg1 in CAR T cells using CRISPR/cas-mediated gene editing and teaches Reg1-targeted gRNA (ref SEQ ID NO: 1467) that is targeted to exon 4 and is identical to the instant sequence: SEQ ID NO: 37 ([0008][0026]).
Benson acgacgcgtgggtggcaagc 20 (REF SEQ ID NO: 1467)
Instant acgacgcgtgggtggcaagc 20 (SEQ ID NO: 37)
********************
-Meissner teaches the disruption of TRAC in CAR T cells using CRISPR/cas-mediated gene editing and teaches TRAC-targeted gRNA (ref SEQ ID NO: 550) that is identical to the instant sequences: SEQ ID NO: 7 and 4 (page 62 lines 7-24).
Meissner agagcaacagtgctgtggcc (REF SEQ ID NO: 550)
Instant agagcaacagtgctgtggcc (SEQ ID NO: 4 and 7)
********************
- Meissner teaches the disruption of β2M in CAR T cells using CRISPR/cas-mediated gene editing and teaches β2M-targeted gRNA (ref SEQ ID NO: 778) that is identical to the instant sequences: SEQ ID NO: 13 and 10 (page 62 line 25 - page 63 line 2).
Meissner GCTACTCTCTCTTTCTGGCC (REF SEQ ID NO: 778)
Instant gctactctctctttctggcc (SEQ ID NO: 10 and 13)
********************
-Hart teaches an oligonucleotide, SEQ ID NO: 101, directed towards exon 2 of the CD83 gene, “human CD83 exon 2 forward primer 5”, with a sequence identical to that of instant sequence, SEQ ID NO: 101 (page 39 line 3).
Hart AGGTTCCCTACACGGTCTCC
Instant aggttccctacacggtctcc (SEQ ID NO: 98 and 101)
********************
- Lee teaches the disruption of TGFBR2 in CAR T cells using CRISPR/cas-mediated gene editing targeted to exon 4 and teaches a gRNA (ref SEQ ID NO: 1) that is identical to the instant sequences: SEQ ID NO: 28 and 31 (table 1 and [0134].
Lee CCCCTACCATGACTTTATTC 20 (REF SEQ ID NO:1)
Instant cccctaccatgactttattc 20 (SEQ ID NO: 28 and 31)
********************
It would have been obvious to one skilled in the art to combine the teachings of Lee, Hart, Meissner with the anti-CD83 CAR T cells taught by Davila, Tang, Zheng, and Cooper. The teachings provide a protocol for implementing the teachings of Davilla, Tang, Zheng, and Cooper and would have been proven effective prior to the submission of the instant application. This provides a clear motivation, which would have been obvious to those skilled in the art, to incorporate these teachings into the instant invention. Furthermore, it would have been clear that utilization of these teachings would have yielded predictable results.
Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over US20200108098 A1 (herein Davila), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), and Ren J, et al (2017) Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res, May 01; 23(9): 2255-2266 (herein Ren) as applied to claims 1 and 13 above and further in view of Eyquem J, et al (2017) Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumor rejection. Nature, 543, 113–117 (herein Eyquem) and WO2021044378 A1 (herein Terrett).
As discussed for claim 4, Davila, Zheng, Tang, Cooper, and Ren teach anti-CD83 CAR T cell populations with disrupted Reg1, TGFBR2, CD83, TRAC, and β2M genes. What is not taught for claim 4 is the insertion of the CD83 CAR into the disrupted CD83, TRAC, TGFBR2, or β2M gene. These deficiencies are taught by Eyquem and Terrett.
Eyquem teaches the insertion of an anti-CD19 CAR into the TRAC locus of a T cell genome using an AAV delivery method and a gRNA targeting the first exon of TRAC (second paragraph). Eyquem shows that this method effectively performs a 2-1 knockout, of TRAC, and knock-in of the CAR element under the control of the TRAC locus (second paragraph). Additionally, it is shown that targeting the CAR element to the TRAC locus provides a number of benefits such as uniform CAR expression in peripheral blood T cell, enhanced T cell potency, aversion of tonic CAR signaling, effective internalization and re-expression upon single or repeated exposure to antigen (abstract). The authors summarize their work with the following quote: “The targeting of CARs to a TCR locus may thus provide a safer therapeutic T cell (by minimizing the risks of insertional oncogenesis and TCR-induced autoimmunity and alloreactivity), a better-defined T-cell product (by yielding constant CAR expression and avoiding position-effect variegation and vector copy number variation) and a more potent T cell (by reducing constitutive signaling and delaying T-cell exhaustion).”
Terrett also teaches the targeting of the TRAC gene for disruption and replacement with a CAR element (page 45 lines 16-21). Additionally, Terrett teaches the use of a gRNA (SEQ ID NO: 146) that is identical to the sequence referenced in claim 16 (SEQ ID NO: 7).
Terrett AGAGCAACAGTGCTGTGGCC 20 (REF SEQ ID NO: 146)
SEQ agagcaacagtgctgtggcc 20 (SEQ ID NO: 7)
********************
It would have been obvious to one skilled in the art to combine the teachings of Eyquem and Terret (inserting the CAR element into a disrupted TRAC gene) with the anti-CD83 CAR T cells taught by Davila, Tang, Zheng, and Cooper. The benefits as stated by Eyquem include: constant and uniform CAR expression, reduced risk of insertional oncogenesis, and most importantly enhanced T cell proficiency. These benefits provide clear motivation for the incorporation of these teachings into the instant application, and there is no evidence that this combination of previously known elements yielded results that were not predictable.
Double Patenting
The non-statutory 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 non-statutory 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 non-statutory 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 non-statutory 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 1, 2, 4-6, 10, 12, 13-16, 25, and 51 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 9, 14, 15, 16, and 18 of co-pending Application No. 18/069693 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), and Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper).
Application 18/069693, claim 9 teaches genetically engineered CAR T cells, in which Reg1, TRAC, β2M, and TGFBR2 genes are disrupted, which has relevance to instant claims 1, 2, 4, 5, 25, 51. Claims 15 describes T cells designed in such a way that the CAR element is inserted into the disrupted TRAC gene, which has relevance to instant claims 13-15. Additionally, claim 18 of application 18/069693 provides gRNA sequences, targeting Reg1 (Ref SEQ ID NO:337, Instant SEQ ID NO: 37), TRAC (Ref SEQ ID NO:3 and 14, Instant SEQ ID NO: 7), β2M (Ref SEQ ID NO:7, Instant SEQ ID NO: 13), and TGFBR2 (Ref SEQ ID NO:393, Instant SEQ ID NO: 31), which are identical to those disclosed in the instant claims 10 and 12 and meet the limitations established in instant claims 6 and 16.
Application 18/069693 does not teach the use of an anti-CD83 CAR to produce anti-CD83 CAR T cells. 17/81430 also does not teach the disruption of the CD83 gene in a population of anti-CD83 CAR T cells. As described above in the 103 section (claims 3, 8, 13, 17-24, 52, 67, and 68) Davila, Cooper, Suri, and Hart teach these deficiencies.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Davila, Cooper, and Hart with the method described in claims 9, 14, 15, 16, and 18 of application 18/069693. An ordinarily skilled artisan would have been motivated to combine disruptions of Reg1, TGFBR2, TRAC, and β2M, which have been shown to enhance proliferation and persistence, reduce alloreactivity, and increase overall efficacy of engineered T cell populations, with the insertion of an anti-CD83 CAR, which has been shown to be deplete various alloreactive immune cells associated with GVHD. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 4-6, 10, 12, 13-16, 25, and 51 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 1, 7, and 19 of co-pending Application No. 18/188436 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), and Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper).
Application 18/188436, claims 1 and 19 disclose genetically engineered CAR T cells, in which Reg1, TRAC, β2M, and TGFBR2 genes are disrupted, which has relevance to instant claims 1, 2, 4, 5, 25, 51. Claims 7 describes T cells designed in such a way that the CAR element is inserted into the disrupted TRAC gene, which has relevance to instant claims 13-15. Additionally, claim 7 of application 18/188436 provides the gRNA sequences targeting TRAC (Ref SEQ ID NO:18, Instant SEQ ID NO: 7) which is identical to those described instant claims 10 and 12, and meet the limitations established in instant claim 16.
Application 18/188436 does not teach the use of an anti-CD83 CAR to produce anti-CD83 CAR T cells. 17/81430 also does not teach the disruption of the CD83 gene in a population of anti-CD83 CAR T cells. As described above in the 103 section (claims 3, 8, 13, 17-24, 52, 67, and 68) Davila, Cooper, Suri, and Hart teach these deficiencies.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Davila, Cooper, and Hart with the method described in claims 1, 7, and 19 of application 18/188436. An ordinarily skilled artisan would have been motivated to combine disruptions of Reg1, TGFBR2, TRAC, and β2M, which have been shown to enhance proliferation and persistence, reduce alloreactivity, and increase overall efficacy of engineered T cell populations, with the insertion of an anti-CD83 CAR, which has been shown to be deplete various alloreactive immune cells associated with GVHD. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
Claims 1, 2, 4, 5, 13-15, and 51 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claim 1 of co-pending Application No. 18/482752 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), and Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper).
Application 18/482752, claim 1, teaches genetically engineered CAR T cells, in which Reg1, TRAC, β2M, and TGFBR2 genes are disrupted, which has relevance to instant claims 1, 2, 4, 5, 25, 51. The described T cells are designed in such a way that the CAR element is inserted into the disrupted TRAC gene, which has relevance to instant claims 13-15.
Application 18/482752 does not teach the use of an anti-CD83 CAR to produce anti-CD83 CAR T cells. 17/81430 also does not teach the disruption of the CD83 gene in a population of anti-CD83 CAR T cells. As described above in the 103 section (claims 3, 8, 13, 17-24, 52, 67, and 68) Davila, Cooper, Suri, and Hart teach these deficiencies.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Davila, Cooper, and Hart with the method described in claim 1 of application 18/482752. An ordinarily skilled artisan would have been motivated to combine disruptions of Reg1, TGFBR2, TRAC, and β2M, which have been shown to enhance proliferation and persistence, reduce alloreactivity, and increase overall efficacy of engineered T cell populations, with the insertion of an anti-CD83 CAR, which has been shown to be deplete various alloreactive immune cells associated with GVHD. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 4-6, 9, 10, 12-15, 16, and 51 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 1 and 88 of co-pending Application No. 17/814930 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), and Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper).
Application 17/814930, claim 1, describes a method for genetically engineering T cells, in which Cas9 enzymes are coupled with gRNAs targeting the Reg1, TRAC, β2M, and TGFBR2 genes to disrupt the targeted genes, which has relevance to instant claims 1, 2, 4, 5, and 9, 25, 51. The described method produces T cells containing a CAR element inserted into one of the disrupted genes, which has relevance to instant claims 13-15. Additionally, claim 88 of application 17/814930 provides gRNA sequences, targeting Reg1, TRAC, β2M, and TGFBR2, which are identical to those contained in the instant claims 10 and 12 and meet the limitations established in instant claims 6 and 16.
Application 17/814930 does not teach the use of an anti-CD83 CAR to produce anti-CD83 CAR T cells. 17/81430 also does not teach the disruption of the CD83 gene in a population of anti-CD83 CAR T cells. As described above in the 103 section (claims 3, 8, 13, 17-24, 52, 67, and 68) Davila, Cooper, Suri, and Hart teach these deficiencies.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Davila, Cooper, and Hart with the method described in claims 1 and 88 of application 17/814930. An ordinarily skilled artisan would have been motivated to combine disruptions of Reg1, TGFBR2, TRAC, and β2M, which have been shown to enhance proliferation and persistence, reduce alloreactivity, and increase overall efficacy of engineered T cell populations, with the insertion of an anti-CD83 CAR, which has been shown to be deplete various alloreactive immune cells associated with GVHD. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 4-5, 9, 10, 12, 13-16, 25, and 51 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 35 and 44 of U.S. Patent No. 10857184 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang).
10857184, claim 35, describes a method for genetically engineering T cells, in which gRNAs targeting the TRAC and β2M genes disrupt the targeted genes, which has relevance to instant claims 4 and 5. The described method produces T cells containing a CAR element inserted into one of the disrupted genes, which has relevance to instant claims 13-15. Claim 51 describes this method, in which Cas9 nucleases are used, which is relevant to instant claim 9. Additionally, claim 44 of 10857184 provides gRNA sequences, targeting TRAC (reference SEQ ID NO: 76, corresponding to instant SEQ ID NO: 7) and β2M (reference SEQ ID NO: 417, corresponding to instant SEQ ID NO: 13 and 10), which are identical to those contained in the instant claims 10 and 12 and meet the limitations established in instant claim 6.
However, 10857184 does not indicate anti-CD83 in the CAR construct and that the Reg1 and TGFBRII gene were disrupted. Regarding anti-CD83, Davila teaches anti-CD83 in CAR T constructs for the prevention of GVHD, which may be paired with additional CAR T elements ([0252], [0251], [0246], [0248], figure 15, claims 6 and 19, [0013]). Further teaching regarding the implementation of anti-CD83 CAR T cells are provided by Cooper and Hart, who teach disruption of the gene encoding the antigen targeted by the CAR and a means for targeting the CD83 gene, respectively. Zheng and Tang provide the guidance that disrupting these genes lead to expansion of T cells (Zheng: (Results: Regnase-1 deletion supports human CAR-T-cell expansion and function, and figure 7), Tang: (Results: TGFBR2 editing enhanced tumor elimination efficacy in CDX models, and figure 5)). Thus, one would have been motivated to include disruptions in Reg1 and TGFBRII in order to arrive at an expanded population of CAR T cells. One would also have been motivated to make anti-CD83 CAR T constructs to reduce GVHD in patients. There would have been reasonable expectation of success based on the prior art describing each element individually.
Claims 4-5, 10, 12, 13-16, 25, and 51 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 187, 193-195, 202-204, 211, 212, and 216 of U.S. Patent No. 10881689 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang).
10881689, claim 187, describes a population of genetically engineering T cells, in which TRAC and β2M genes are disrupted, which has relevance to instant claims 4 and 5. Claim 216 described a method for producing T cells, in which TRAC and β2M are targeted by gRNA, containing a CAR element inserted into one of the disrupted genes, which has relevance to instant claims 13-15. Additionally, claims 195, 204, and 216) of 10881689 provides target sequences for TRAC gRNA (reference SEQ ID NO: 76, corresponding to instant SEQ ID NO: 7), which are identical to those contained in the instant claims 10 and 12, and when coupled with TRAC gRNA targets meet the limitations established in instant claim 16. Additionally, in claims 194, 203, and 212, the β2M sequence targeted, reference SEQ ID NO: 1561, contains the gRNA described in the instant claims 10 and 12, SEQ ID NO: 13 and 10.
However, 10881689 does not indicate anti-CD83 in the CAR construct and that the Reg1 and TGFBRII gene were disrupted. Regarding anti-CD83, Davila teaches anti-CD83 in CAR T constructs for the prevention of GVHD, which may be paired with additional CAR T elements ([0252], [0251], [0246], [0248], figure 15, claims 6 and 19, [0013]). Further teaching regarding the implementation of anti-CD83 CAR T cells are provided by Cooper and Hart, who teach disruption of the gene encoding the antigen targeted by the CAR and a means for targeting the CD83 gene, respectively. Zheng and Tang provide the guidance that disrupting these genes lead to expansion of T cells (Zheng: (Results: Regnase-1 deletion supports human CAR-T-cell expansion and function, and figure 7), Tang: (Results: TGFBR2 editing enhanced tumor elimination efficacy in CDX models, and figure 5)). Thus, one would have been motivated to include disruptions in Reg1 and TGFBRII in order to arrive at an expanded population of CAR T cells. One would also have been motivated to make anti-CD83 CAR T constructs to reduce GVHD in patients. There would have been reasonable expectation of success based on the prior art describing each element individually.
Claims 4-5, 10, 12, 13-16, 25, and 51 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 187, 196, 203, and 205 of U.S. Patent No. 11071755 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang).
11071755, claim 187, describes a population of genetically engineering T cells, in which TRAC and β2M genes are disrupted and a CAR element is inserted into the disrupted TRAC gene, which has relevance to instant claims 4, 5, 13-15. Claim 216 described a method for producing T cells, in which TRAC and β2M are targeted by gRNA, containing a CAR element inserted into one of the disrupted genes, which has relevance to instant claims 13-15. Additionally, claims 196 and 205 of 11071755 provides target sequences for TRAC gRNA (reference SEQ ID NO: 76, corresponding to instant SEQ ID NO: 7), which are identical to those contained in the instant claims 10 and 12, and meet the limitations established in instant claim 16.
However, 11071755 does not indicate anti-CD83 in the CAR construct and that the Reg1 and TGFBRII gene were disrupted. Regarding anti-CD83, Davila teaches anti-CD83 in CAR T constructs for the prevention of GVHD, which may be paired with additional CAR T elements ([0252], [0251], [0246], [0248], figure 15, claims 6 and 19, [0013]). Further teaching regarding the implementation of anti-CD83 CAR T cells are provided by Cooper and Hart, who teach disruption of the gene encoding the antigen targeted by the CAR and a means for targeting the CD83 gene, respectively. Zheng and Tang provide the guidance that disrupting these genes lead to expansion of T cells (Zheng: (Results: Regnase-1 deletion supports human CAR-T-cell expansion and function, and figure 7), Tang: (Results: TGFBR2 editing enhanced tumor elimination efficacy in CDX models, and figure 5)). Thus, one would have been motivated to include disruptions in Reg1 and TGFBRII in order to arrive at an expanded population of CAR T cells. One would also have been motivated to make anti-CD83 CAR T constructs to reduce GVHD in patients. There would have been reasonable expectation of success based on the prior art describing each element individually.
Claims 4-5, 10, 12, 13-16, 25, and 51 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 187, 196-198, 200, 201, and 203 of U.S. Patent No. 11135247 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang).
11135247, claim 187, describes a method for producing genetically engineering T cells, in which TRAC and β2M genes are disrupted, which has relevance to instant claims 4 and 5. Claim 196 described a method for producing T cells, in which TRAC and β2M are targeted by gRNA, containing a CAR element inserted into one of the disrupted genes, which has relevance to instant claims 13-15. Claim 203 describes this method, in which Cas9 nucleases are used, which is relevant to instant claim 9. Additionally, claims 197 and 200 of 11135247 provides target sequences for TRAC gRNA (reference SEQ ID NO: 76, corresponding to instant SEQ ID NO: 7) and β2M gRNA (reference SEQ ID NO: 417 and 466, corresponding to instant SEQ ID NO: 10 and 13), which are identical to those contained in the instant claims 10 and 12, and meet the limitations established in instant claim 16.
However, 11135247 does not indicate anti-CD83 in the CAR construct and that the Reg1 and TGFBRII gene were disrupted. Regarding anti-CD83, Davila teaches anti-CD83 in CAR T constructs for the prevention of GVHD, which may be paired with additional CAR T elements ([0252], [0251], [0246], [0248], figure 15, claims 6 and 19, [0013]). Further teaching regarding the implementation of anti-CD83 CAR T cells are provided by Cooper and Hart, who teach disruption of the gene encoding the antigen targeted by the CAR and a means for targeting the CD83 gene, respectively. Zheng and Tang provide the guidance that disrupting these genes lead to expansion of T cells (Zheng: (Results: Regnase-1 deletion supports human CAR-T-cell expansion and function, and figure 7), Tang: (Results: TGFBR2 editing enhanced tumor elimination efficacy in CDX models, and figure 5)). Thus, one would have been motivated to include disruptions in Reg1 and TGFBRII in order to arrive at an expanded population of CAR T cells. One would also have been motivated to make anti-CD83 CAR T constructs to reduce GVHD in patients. There would have been reasonable expectation of success based on the prior art describing each element individually.
Claims 4-5, 10, 12, 13-16, 25, and 51 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 187, 189, 191, 193, and 202 of U.S. Patent No. 11191783 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang).
11191783, claim 187, describes a method for producing genetically engineering T cells, in which TRAC and β2M genes are disrupted, which has relevance to instant claims 4 and 5. Claim 187 described a method for producing T cells, in which TRAC and β2M are targeted by gRNA, containing a CAR element inserted into the disrupted TRAC gene, which has relevance to instant claims 13-15. Claim 202 describes this method, in which Cas9 nucleases are used, which is relevant to instant claim 9. Additionally, claims 187 and 192 of 11191783 provides target sequences for TRAC gRNA (reference SEQ ID NO: 76, corresponding to instant SEQ ID NO: 7) and β2M gRNA (reference SEQ ID NO: 417 and 466, corresponding to instant SEQ ID NO: 10 and 13), which are identical to those contained in the instant claims 10 and 12 and meet the limitations established in instant claim 16.
However, 11191783 does not indicate anti-CD83 in the CAR construct and that the Reg1 and TGFBRII gene were disrupted. Regarding anti-CD83, Davila teaches anti-CD83 in CAR T constructs for the prevention of GVHD, which may be paired with additional CAR T elements ([0252], [0251], [0246], [0248], figure 15, claims 6 and 19, [0013]). Further teaching regarding the implementation of anti-CD83 CAR T cells are provided by Cooper and Hart, who teach disruption of the gene encoding the antigen targeted by the CAR and a means for targeting the CD83 gene, respectively. Zheng and Tang provide the guidance that disrupting these genes lead to expansion of T cells (Zheng: (Results: Regnase-1 deletion supports human CAR-T-cell expansion and function, and figure 7), Tang: (Results: TGFBR2 editing enhanced tumor elimination efficacy in CDX models, and figure 5)). Thus, one would have been motivated to include disruptions in Reg1 and TGFBRII in order to arrive at an expanded population of CAR T cells. One would also have been motivated to make anti-CD83 CAR T constructs to reduce GVHD in patients. There would have been reasonable expectation of success based on the prior art describing each element individually.
Claims 4-5, 13-15, and 51 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 11202802 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang).
11202802, claim 1, describes a method for treating cancer comprising the administration of genetically engineered CAR T cells, in which TRAC and β2M genes are disrupted, which has relevance to instant claims 4 and 5. The T cells are engineered in such a way that the CAR element is inserted into the disrupted TRAC gene, which has relevance to instant claims 13-15.
However, 11202802 does not indicate anti-CD83 in the CAR construct and that the Reg1 and TGFBRII gene were disrupted. Regarding anti-CD83, Davila teaches anti-CD83 in CAR T constructs for the prevention of GVHD, which may be paired with additional CAR T elements ([0252], [0251], [0246], [0248], figure 15, claims 6 and 19, [0013]). Further teaching regarding the implementation of anti-CD83 CAR T cells are provided by Cooper and Hart, who teach disruption of the gene encoding the antigen targeted by the CAR and a means for targeting the CD83 gene, respectively. Zheng and Tang provide the guidance that disrupting these genes lead to expansion of T cells (Zheng: (Results: Regnase-1 deletion supports human CAR-T-cell expansion and function, and figure 7), Tang: (Results: TGFBR2 editing enhanced tumor elimination efficacy in CDX models, and figure 5)). Thus, one would have been motivated to include disruptions in Reg1 and TGFBRII in order to arrive at an expanded population of CAR T cells. One would also have been motivated to make anti-CD83 CAR T constructs to reduce GVHD in patients. There would have been reasonable expectation of success based on the prior art describing each element individually.
Claims 4-5, 13-15, and 51 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 11207351 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang).
11207351, claim 1, describes a method for treating cancer comprising the administration of genetically engineered CAR T cells, in which TRAC and β2M genes are disrupted, which has relevance to instant claims 4 and 5. The T cells are engineered in such a way that the CAR element is inserted into the disrupted TRAC gene, which has relevance to instant claims 13-15.
However, 11207351 does not indicate anti-CD83 in the CAR construct and that the Reg1 and TGFBRII gene were disrupted. Regarding anti-CD83, Davila teaches anti-CD83 in CAR T constructs for the prevention of GVHD, which may be paired with additional CAR T elements ([0252], [0251], [0246], [0248], figure 15, claims 6 and 19, [0013]). Further teaching regarding the implementation of anti-CD83 CAR T cells are provided by Cooper and Hart, who teach disruption of the gene encoding the antigen targeted by the CAR and a means for targeting the CD83 gene, respectively. Zheng and Tang provide the guidance that disrupting these genes lead to expansion of T cells (Zheng: (Results: Regnase-1 deletion supports human CAR-T-cell expansion and function, and figure 7), Tang: (Results: TGFBR2 editing enhanced tumor elimination efficacy in CDX models, and figure 5)). Thus, one would have been motivated to include disruptions in Reg1 and TGFBRII in order to arrive at an expanded population of CAR T cells. One would also have been motivated to make anti-CD83 CAR T constructs to reduce GVHD in patients. There would have been reasonable expectation of success based on the prior art describing each element individually.
Claims 4-5, 13-15, and 51 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 10, 13, and 16 of U.S. Patent No. 11298378 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang).
11298378, claim 10, describes a method for treating cancer comprising the administration of genetically engineered CAR T cells, in which TRAC and β2M genes are disrupted, which has relevance to instant claims 4 and 5. Claim 10 notes that the cells are engineered in such a way that the CAR element is inserted into the disrupted TRAC gene, which has relevance to instant claims 13-15.
However, 11298378 does not indicate anti-CD83 in the CAR construct and that the Reg1 and TGFBRII gene were disrupted. Regarding anti-CD83, Davila teaches anti-CD83 in CAR T constructs for the prevention of GVHD, which may be paired with additional CAR T elements ([0252], [0251], [0246], [0248], figure 15, claims 6 and 19, [0013]). Further teaching regarding the implementation of anti-CD83 CAR T cells are provided by Cooper and Hart, who teach disruption of the gene encoding the antigen targeted by the CAR and a means for targeting the CD83 gene, respectively. Zheng and Tang provide the guidance that disrupting these genes lead to expansion of T cells (Zheng: (Results: Regnase-1 deletion supports human CAR-T-cell expansion and function, and figure 7), Tang: (Results: TGFBR2 editing enhanced tumor elimination efficacy in CDX models, and figure 5)). Thus, one would have been motivated to include disruptions in Reg1 and TGFBRII in order to arrive at an expanded population of CAR T cells. One would also have been motivated to make anti-CD83 CAR T constructs to reduce GVHD in patients. There would have been reasonable expectation of success based on the prior art describing each element individually.
Claims 4-5, 10, 12, 13-16, 25, and 51 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1, 5-8, 19, and 20 of U.S. Patent No. 11471491 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang).
11471491, claim 1, describes a method for treating cancer comprising the administration of genetically engineering T cells, in which TRAC and β2M genes are disrupted, which has relevance to instant claims 4 and 5. Claim 19 describes the population of genetically engineered cells, and claim 20 describes the method for preparing the population of engineered cells. Claim 1, 7, 8, 19, and 20 described a method for producing T cells, in which TRAC and β2M are targeted by gRNA, containing a CAR element inserted into the disrupted TRAC gene (exon 1), which has relevance to instant claims 13-16. Claims 5 and 6 describe this method, in which Cas9 nucleases are used, which is relevant to instant claim 9.
However, 11471491 does not indicate anti-CD83 in the CAR construct and that the Reg1 and TGFBRII gene were disrupted. Regarding anti-CD83, Davila teaches anti-CD83 in CAR T constructs for the prevention of GVHD, which may be paired with additional CAR T elements ([0252], [0251], [0246], [0248], figure 15, claims 6 and 19, [0013]). Further teaching regarding the implementation of anti-CD83 CAR T cells are provided by Cooper and Hart, who teach disruption of the gene encoding the antigen targeted by the CAR and a means for targeting the CD83 gene, respectively. Zheng and Tang provide the guidance that disrupting these genes lead to expansion of T cells (Zheng: (Results: Regnase-1 deletion supports human CAR-T-cell expansion and function, and figure 7), Tang: (Results: TGFBR2 editing enhanced tumor elimination efficacy in CDX models, and figure 5)). Thus, one would have been motivated to include disruptions in Reg1 and TGFBRII in order to arrive at an expanded population of CAR T cells. One would also have been motivated to make anti-CD83 CAR T constructs to reduce GVHD in patients. There would have been reasonable expectation of success based on the prior art describing each element individually.
Claims 4-5, 10, 12, 13-16, 25, and 51 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 61-64, 188- 194, 198-200, 202, and 206 of U.S. Patent No. 11622977 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper), Zheng W, et al (2021) Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood. Jul 15;138(2):122-135 (herein Zheng), and Tang N, et al (2020) TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. Feb 27;5(4):e133977 (herein Tang).
11622977, claim 62, describes a genetically engineered CAR T cells, in which TRAC and β2M genes are disrupted, which has relevance to instant claims 4, 5. Claim 63 describes a method for producing these cells. a method for producing T cells. Claims 188-194 describe a population of cells, containing disrupted TRAC and β2M genes, and containing a CAR element inserted into the disrupted TRAC gene, which has relevance to instant claims 13-15. Claim 202 describes this method, in which Cas9 nucleases are used, which is relevant to instant claim 9. Additionally, claims 199 and 200 of 11622977 provides gRNA and/or target sequences for TRAC gRNA (reference SEQ ID NO: 152/76, corresponding to instant SEQ ID NO: 7) and β2M (reference SEQ ID NO: 459, corresponding to instant SEQ ID NO: 16), which are identical to those contained in the instant claims 10 and 12, and meet the limitations established in instant claim 16.
However, 11622977 does not indicate anti-CD83 in the CAR construct and that the Reg1 and TGFBRII gene were disrupted. Regarding anti-CD83, Davila teaches anti-CD83 in CAR T constructs for the prevention of GVHD, which may be paired with additional CAR T elements ([0252], [0251], [0246], [0248], figure 15, claims 6 and 19, [0013]). Further teaching regarding the implementation of anti-CD83 CAR T cells are provided by Cooper and Hart, who teach disruption of the gene encoding the antigen targeted by the CAR and a means for targeting the CD83 gene, respectively. Zheng and Tang provide the guidance that disrupting these genes lead to expansion of T cells (Zheng: (Results: Regnase-1 deletion supports human CAR-T-cell expansion and function, and figure 7), Tang: (Results: TGFBR2 editing enhanced tumor elimination efficacy in CDX models, and figure 5)). Thus, one would have been motivated to include disruptions in Reg1 and TGFBRII in order to arrive at an expanded population of CAR T cells. One would also have been motivated to make anti-CD83 CAR T constructs to reduce GVHD in patients. There would have been reasonable expectation of success based on the prior art describing each element individually.
Claims 1, 2, 4-6, 10, 12, 13-15, 25, and 51 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-6, 8, and 9 of U.S. Patent No. 11497773 in view of US20200108098 A1 (herein Davila), WO2019051541 A1 (herein Hart), WO2018161026 A1 (herein Suri), and Cooper ML, et al (2018). An "off-the-shelf" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. Sep;32(9):1970-1983 (herein Cooper).
U.S. Patent No. 11497773, claims 1 and 6 teaches genetically engineered CAR T cells, in which Reg1, TRAC, β2M, and TGFBR2 genes are disrupted, which has relevance to instant claims 1, 2, 4, 5, 25, 51. Claims 9 describes T cells designed in such a way that the CAR element is inserted into the disrupted TRAC gene, which has relevance to instant claims 13-15. Additionally, claim 4 of U.S. Patent No. 11497773 provides gRNA sequences, targeting Reg1 (Ref SEQ ID NO:327, Instant SEQ ID NO: 37) and TGFBR2 (Ref SEQ ID NO:317, Instant SEQ ID NO: 31), which are identical to those disclosed in the instant claims 10 and 12 and meet the limitations established in instant claim 6.
U.S. Patent No. 11497773 does not teach the use of an anti-CD83 CAR to produce anti-CD83 CAR T cells. 17/81430 also does not teach the disruption of the CD83 gene in a population of anti-CD83 CAR T cells. As described above in the 103 section (claims 3, 8, 13, 17-24, 52, 67, and 68) Davila, Cooper, Suri, and Hart teach these deficiencies.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Davila, Cooper, and Hart with the method described in claims 1-6, 8, and 9 of U.S. Patent No. 11497773. An ordinarily skilled artisan would have been motivated to combine disruptions of Reg1, TGFBR2, TRAC, and β2M, which have been shown to enhance proliferation and persistence, reduce alloreactivity, and increase overall efficacy of engineered T cell populations, with the insertion of an anti-CD83 CAR, which has been shown to be deplete various alloreactive immune cells associated with GVHD. Furthermore, by combining these pre-existing elements, the instant application discloses a claimed invention that behaves in a predictable manner, based on the prior art describing each element individually.
Conclusion
All claims are rejected.
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/MATTHEW CURRAN METCALF/ Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647