Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
Claims 1, 4, 6-8, 10-14, 18-28, and 33-34 are pending.
Claims 26, 28, and 33-34 are withdrawn.
Claims 1, 4, 6-8, 10-14, 18-25, and 27 are examined on the merits herein.
Grounds of Rejection Withdrawn
All previous rejections of claims 9 and 15 are rendered moot by claim cancellation.
Previous rejection of claims 1, 4, and 12-14 under 35 U.S.C. 102 are withdrawn in view of claim amendments.
Previous rejections of claims 6-11, 15, 18-22, 24-25, and 27 under 35 U.S.C. 103 are withdrawn in view of claim amendments.
Claim Rejections - 35 USC § 103
New Rejection Necessitated by Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 4, 6-7, 10, 12-14, 18-24, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Kong (US 2021/0252069 A1; published 08/19/2021; cited in OA 01/13/2026) as evidenced by Wyman (US 2020/0397823 A1; cited in OA 01/13/2026) and Netsrithong (Front. Immunol. 12:759558; PTO-892).
Regarding claims 1 and 12, Kong teaches a polypeptide comprising a chimeric antigen receptor, which comprises an antigen binding domain; a hinge region; a transmembrane domain; a costimulatory domain; and a signaling domain, wherein the signaling domain comprises a CD3ζ domain (claim 1), which further comprises a wild-type TGF-βR2 (or TGF- βRII) exodomain and an IL18R endodomain, wherein an IL18R transmembrane domain is comprised between the TGF-βR2 exodomain and the IL18R endodomain (claim 18), wherein the TGF-βR2 exodomain, IL18R transmembrane domain, and IL18R endodomain, which is expressed in a T cell, is separated from the chimeric antigen receptor, and among these, the TGF-βR2 exodomain is exposed to the outside of the T cell, wherein the IL18R endodomain is activated by the linking of the TGF-β present outside of the T cell to the TGF-βR2 exodomain (claim 20). Kong further teaches that the chimeric switch receptor was introduced to convert the immunosuppressive signal in the hostile tumor microenvironment into an activation signal in CAR-T cells (para 0005).
Regarding claim 4, Kong teaches a chimeric switch receptor, which includes a TGF-βR2 exodomain (amino acid positions of 23 to 166; SEQ ID NO: 19), which is a receptor for binding to TGF-β (i.e., an immunosuppressive cytokine around solid cancer); and a transmembrane domain and an endodomain of IL-18R (amino acid positions of 323 to 541; SEQ ID NO: 20), which is a cytokine receptor (para 0040), SEQ ID NO: 20 has 100% sequence identity to the instant claimed SEQ ID NO: 5 and SEQ ID NO: 19 has 96.1% sequence identity to the instant claimed SEQ ID NO: 1.
As evidenced by Wyman, the extracellular ligand binding domain and transmembrane domain of the wild-type TGF-βRII is shown in the amino acid sequence of SEQ ID NO: 17 (para 0119), SEQ ID NO: 17 has 100% sequence identity to the instant claimed SEQ ID NO: 1, including 7 additional amino acid residues of the transmembrane domain compared to the sequence disclosed by Kong.
Regarding claims 12 and 14, Kong further teaches wherein the polypeptide further comprises a cytokine (claim 14), wherein the cytokine is IL-21 (claim 15), wherein the cytokine expressed in a T cell is separated from the chimeric antigen receptor and then released to the outside of the T cell (claim 17).
Regarding claim 13, Kong teaches wherein the antigen binding domain binds to an antigen selected from the group consisting of IL13Rα2, an antigen associated with an angiogenesis activity, EGFRvIII, EphA2, αVβ3, mesothelin, and glypican (claim 25).
Kong does not teach wherein the cell is an iPSC, a clonal iPSC or an iPS cell line cell; that the cells comprise an HLA deficiency; an exogenous CD16; an additional therapeutic; or TCR knockout.
Regarding claims 1 and 27, Netsrithong teaches that although CAR-T holds impressive clinical outcomes especially in patients that are refractory to other types of therapy but there are numerous challenges with CAR-T clinical application including insufficient number of autologous T cells from patients undergoing chemotherapy, long term ex vivo expansion can result in T cell exhaustion and batch to batch variation during production (abstract). Netsrithong further teaches that generation of universal off-the-shelf CAR T cells, which can be broadly given to any patient, prepared in advance and ready to use, would be ideal and more cost-effective through human induced pluripotent stem cells (iPSCs) that provide a renewable source of cells that can be genetically engineered and differentiated into immune cells with enhanced anti-tumor cytotoxicity (abstract). Netsrithong further teaches that IPSCs can be generated from various somatic cell sources, mainly skin fibroblasts and peripheral blood and further that iPSCs are amenable to genetic modification, so it is possible to engineer the cells to have enhanced specificity and effector functions (introduction, para 3).
Regarding claims 6-7, Netsrithong teaches that besides the risk of GvHD, graft rejection by the recipient’s immune cells is another concern which can be addressed by generating universal or hypoimmunogenic iPSC lines by eliminating HLA class Ia (HLA-A, -B, and -C) and class II molecules to avoid immune rejection by CD8 T cells and CD4 T cells, respectively, and introducing HLA class Ib (HLA-G or HLA-E) or immune checkpoint molecules (PD-L1 or CD47) to prevent NK cell-mediated lysis or phagocytosis by macrophages (page 10, col 2, para 3). Netsrithong further teaches that there is a demonstrated increase in persistence in CTLs generated from HLA-E-transduced, HLA-I- and HLA-II-null iPSCs with CD155 knocked out as well (page 11, col 1, para 1).
Regarding claims 10, 21-22, and 24, Netsrithong teaches the expression of a high-affinity, non-cleavable form of antibody receptor CD16 (hnCD16), which allows the scientists to adjust the specificity of the T cell killing through antibody-dependent cellular-cytotoxicity (ADCC) by adding a monoclonal antibody to target multiple cancer antigens; for example, the iPSC-derived CD19 CAR-hnCD16 T cells could efficiently recognize and kill both CD19+ CD20+ and CD19- CD20+ tumor cells when combined with anti-CD20 monoclonal antibody (Rituxan) (page 11, col 1, para 2).
Regarding claims 18-19, Netsrithong teaches that to broaden the applicability of CAR T cell therapy, many attempts have been made to generate allogeneic CAR T cells devoid of TCR to eliminate the risk of GvHD by employing genome editing technologies such as zinc finger nucleases, TALENs or CRISPR/Cas9 to disrupt TCR expression in primary T cells from healthy donors and introduce CAR specific to cancer antigens (page 4, col 2, para 2). Netsrithong further teaches that Fate Therapeutics has combined the iPSC technology with CAR to generate the iPSC-derived TCR-less CD19 1XX CAR T cell product “FT819” to treat B-ALL, which upon T cell differentiation, the iPSCs harboring TRAC CD19 1XX CAR could give rise to the highest CD4+ CD8+ DP population compared to other types of iPSC-derived CAR T cells (page 10, col 2, para 2).
Regarding claim 20, Netsrithong teaches a so-called “the first-of-kind off-the-shelf hiPSC-derived CAR19 T cell product FT819” was manufactured under the current Good Manufacturing Practice (cGMP) compliance and applied in the pre-clinical study (page 10, col 2, para 2).
Regarding claim 23, Netsrithong teaches that in solid tumors, the immunosuppressive tumor microenvironments (TME) represent a significant barrier that impairs the function of CAR T cells and that blocking antibodies such as anti-PD-1 scFv to inhibit immune checkpoints have been applied to alter the TME from immunosuppressive to pro-inflammatory (page 13, col 1, para 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add an HLA-I deficiency, TCR knockout, exogenous CD16 and additional therapeutic with a CD19 CAR in iPSC cells as taught by Netsrithong to the immune cells comprising a switch receptor and a CAR as taught by Kong. The ordinary artisan would have been motivated to do so because Netsrithong teaches that iPSCs provide a renewable source of cells that can be genetically engineered and differentiated into immune cells with enhanced anti-tumor cytotoxicity. Netsrithong further teaches that to broaden the applicability of CAR T cell therapy HLA-1 deficiency decreases the risk of GVHD for allogeneic cell transplant recipients; addition of a high-affinity, non-cleavable form of antibody receptor CD16 (hnCD16) allows adjustment to the specificity of the T cell killing through ADCC by adding a monoclonal antibody such as rituximab to target multiple cancer antigens. The ordinary artisan has a reasonable expectation of success to engineer iPSC with an exogenous CD16, knockout TCR, HLA deficiency and an additional monoclonal antibody to enhance cytotoxicity and persistence as well as generate a large cell bank for CAR-T therapy.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Kong (US 2021/0252069 A1; published 08/19/2021; cited in OA 01/13/2026) as evidenced by Wyman (US 2020/0397823 A1; cited in OA 01/13/2026) and Netsrithong (Front. Immunol. 12:759558; PTO-892) as applied to claims 1, 4, 6-7, 10, 12-14, 18-24, and 27 above, and further in view of Zhao (WO 2018/191490 A1; cited in OA
04/15/2025).
The teachings of Kong as evidenced by Wyman and Netsrithong as applied to claims 1, 4, 6-7, 10, 12-14, 18-24, and 27 are detailed above.
Kong and Netsrithong do not teach the wherein the immune cells further comprise the specific disruption to generate the HLA deficiency.
Regarding claim 8, Zhao teaches high gene disruption efficiency sgRNAs were selected for TRAC, TRBC, B2M, CIITA, and PD-1 (example 1). The disruption of B2M comprises an HLA-1 deficiency as recited in claim 8, and also comprises a safe harbor locus as recited in claim 19.
Zhao further teaches that T cells that have been genetically engineered to target CD19 have been used successfully in the clinic for the treatment of certain B cell leukemias but cell dysfunction that may arise from exposure to the immunosuppressive conditions of the tumor microenvironment (background of the invention). Zhao further teaches the use of allogeneic immune cells (e.g., chimeric antigen receptor (CAR) or T cell receptor (TCR) modified T cells) as universal effector cells provides an alternative to and potentially improves current cell therapy against cancers and infectious diseases, the endogenous TCR/CD3 complexes present on these immune cells may cause graft versus host disease (GVHD) if not depleted from the final T cell products but it is not possible to separate CD3+ T cells that express endogenous TCR (which can cause GVHD) from CD3+ T cells that express transferred TCR and CD3+ T cells that express both endogenous TCR and transgenic TCR (background of the invention).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use B2M disruption to generate an HLA-1 deficiency as taught by Zhao to the iPSC cells comprising a switch receptor and a CD19 CAR and HLA-I deficiency, TCR knockout, exogenous CD16 and additional therapeutic as taught by Kong and Netsrithong. The ordinary artisan would have been motivated to do so because Zhao teaches that the use of allogeneic cells in adoptive cell therapy can result in GVHD. Zhao teaches gene disruption that results in HLA-1 deficiency that would decrease the risk of GVHD for allogeneic cell transplant recipients and that CAR can be inserted to disrupt gene expression and specifically target B2M. The ordinary artisan has a reasonable expectation of success to target B2M to disrupt HLA-1 expression to lower the risk of GVHD in the engineered iPSCs.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Kong (US 2021/0252069 A1; published 08/19/2021; cited in OA 01/13/2026) as evidenced by Wyman (US 2020/0397823 A1; cited in OA 01/13/2026) and Netsrithong (Front. Immunol. 12:759558; PTO-892) as applied to claims 1, 4, 6-7, 10, 12-14, 18-24, and 27 above, and further in view of Zhao et al. (Hereafter “Xiong” for clarity; Cytotechnology, 2021, 73: 539–553; cited in OA 04/15/2025).
The teachings of Kong and Netsrithong as applied to claims 1, 4, 6-7, 10, 12-14, 18-24, and 27 are detailed above.
Kong and Netsrithong do not teach the exogenous CD16 comprises a non-native transmembrane domain or intracellular signaling domain.
Xiong teaches use of a recombinant CD16 in comparison to a CD16/CAR with a CD8 hinge and transmembrane domain and 41BB and CD3 intracellular domains (figure 1a) in NK-92 cells (abstract). Xiong further teaches that NK92 cells modified with the CD16/CAR gene had a higher efficiency, specific tumor cell killing activity and higher antibody affinity than NK92 cells (page 551, col 2, para 3). Xiong further teaches the ADCC receptor protein CD16 intracellular signal region was replaced with the intracellular signal region of the CAR structure, utilizing the advantages of ADCC and CAR effects to generate an efficient, specific antitumor cell line (page 551, col 1, last para- col 2, 1st para).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the teachings of Xiong to modify the exogenous CD16 to a CD16/CAR in the iPSC cells comprising a switch receptor and a CD19-CAR and HLA-I deficiency, TCR knockout, exogenous CD16 and additional therapeutic as taught by Kong and Netsrithong. The ordinary artisan would have been motivated to do so because as Xiong teaches modifying the CD16 to comprise an CD16/CAR allows generation of an efficient, specific antitumor cell line with higher efficiency, specific tumor cell killing activity and higher antibody affinity. The ordinary artisan has a reasonable expectation of success to generate and implement the modified CD16-CAR into the iPSC cells as these are analogous arts and the transmembrane/ intracellular components of the CAR structure are already known from the prior art teachings of Kong and Netsrithong.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Kong (US 2021/0252069 A1; published 08/19/2021; cited in OA 01/13/2026) as evidenced by Wyman (US 2020/0397823 A1; cited in OA 01/13/2026) and Netsrithong (Front. Immunol. 12:759558; PTO-892) as applied to claims 1, 4, 6-7, 10, 12-14, 18-22, 24, and 27 above, and further in view of Smits (J Clin Oncol, 2016, 34(10): 1131-3; cited in OA 04/15/2025).
The teachings of Kong as evidenced by Wyman and Netsrithong as applied to claims 1, 4, 6-7, 10, 12-14, 18-22, 24, and 27 are detailed above.
Kong and Netsrithong do not teach the wherein the composition comprises an engager.
Smits teaches a bispecific T-cell engager (BiTE) is a unique BsAb that has two linked, single-chain variable fragments constructed to be flexible and have a 1 + 1 antigen-binding valency (page 1131, col 1, para 3) that bring together T cells and tumor cells together and only trigger T-cell cytotoxicity and cytokine production when both binding sites are occupied (page 1131, col 2, para 1). Smits further teaches that the BiTE blinatumomab has demonstrated clinical responses at very low doses in patients with non-Hodgkin lymphoma at very low dose with a high response rate (page 1131, col 2, para 2) and provides a novel therapeutic option for patients with relapsed/ refractory B-cell acute lymphoblastic leukemia (page 1132, col 2, para 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to apply the teachings of Smits to add a BiTE in the iPSC cells comprising a switch receptor and a CD19-CAR and HLA-I deficiency, TCR knockout, exogenous CD16 and additional therapeutic as taught by Kong and Netsrithong. The ordinary artisan would have been motivated to do so because Smits teaches that BiTEs allow low dosing with high efficacy in non-Hodgkin lymphoma by bringing together T cells and tumor cells together and only trigger T-cell cytotoxicity and cytokine production when both binding sites are occupied. The ordinary artisan has a reasonable expectation of success at adding a BiTE to the composition as blinatumomab has already demonstrated clinical efficacy and provides a benefit to the population with relapsed/ refractory B-cell acute lymphoblastic leukemia.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1, 4, 6-15, 18-25, and 27 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AMBER K FAUST/ Examiner, Art Unit 1643
/GARY B NICKOL/ Primary Examiner, Art Unit 1643
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