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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 16, 2025 has been entered.
Application Status
Claims 1, 4, 6-15, 18-28, and 33-34 are pending.
Claims 26, 28, and 33-34 are withdrawn.
Claims 1, 4, 6-15, 18-25, and 27 are examined on the merits herein.
Grounds of Rejection Withdrawn
All previous rejections of claims 2-3 and 29-30 are rendered moot by claim cancellation.
Previous rejection of claims 1, 4, 13, and 20 under 35 U.S.C. 102 are withdrawn in view of claim amendments.
Previous rejection of claims 6-12, 14-15, 18-19, 21-25, and 27 under 35 U.S.C. 103 are withdrawn in view of claim amendments.
Previous rejection of claims 1, 4, 6-15, 18-19, 20-25, and 27 under non-statutory double patenting over US 12,203,098 B2 and copending application 18/702,764 are withdrawn in view of the terminal disclaimer filed and approved December 4, 2025.
Claim Rejections - 35 USC § 102
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, and 12-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kong (US 2021/0252069 A1; published 08/19/2021; PTO-892) as evidenced by Wyman (US 2020/0397823 A1; 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 which 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).
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 6-9, 15, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Kong (US 2021/0252069 A1; published 08/19/2021; PTO-892) as evidenced by Wyman (US 2020/0397823 A1; PTO-892) as applied to claims 1, 4, and 12-14 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 as applied to claims 1, 4, and 12-14 are detailed above.
Kong does not teach the wherein the immune cells further comprise a gene disruption, an HLA-I deficiency, the type of derivative cell, the type of CAR, or disruption of a safe harbor locus/ loci.
Regarding claims 6-8 and 18-19, 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.
Regarding claims 9 and 15, Zhao teaches wherein the cell is an allogeneic cell (claim 31) and further that in some embodiments, the host cell an immune cell or precursor thereof, e.g., a T cell, an NK cell, or an NKT cell (page 80, lines 32-33). The cells for engineering as described may be isolated from a sample, such as a biological sample, e.g., one obtained from or derived from a subject (page 96, lines 2-3), therefore derivative cells. The introduction of the exogenous polynucleotide switch receptor would result in the engineered NK or T cell reducing tumor immunosuppression.
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 add a gene disruption, an HLA-I deficiency, disruption of a safe harbor locus/ loci and to specify the type of derivative cell as taught by Zhao 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 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. The ordinary artisan has a reasonable expectation of success to lower the risk of GVHD by genetic gene disruption that results in HLA-1 deficiency in the engineered immune effector cells.
Claims 10, 20-22, 24, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Kong (US 2021/0252069 A1; published 08/19/2021; PTO-892) as evidenced by Wyman (US 2020/0397823 A1; PTO-892) as applied to claims 1, 4, and 12-14 above, and further in view of Goodridge (Blood, 2019, Volume 134, Supplement 1, Page 301; cited in OA 04/15/2025).
The teachings of Kong as evidenced by Wyman as applied to claims 1, 4, and 12-14 are detailed above.
Kong does not teach the composition further comprises an exogenous CD16, the composition further comprising an antibody, or the composition of the cytokine signaling complex.
Regarding claims 10, 20-22, 24, and 27, Goodridge teaches FT596 is consistently manufactured from a master iPSC line engineered to uniformly express an NK cell-calibrated CD19-targeting CAR (CD19-CAR), an enhanced functioning high-affinity, non-cleavable CD16 (hnCD16) and a recombinant fusion of IL-15 and IL-15 receptor alpha (IL-15RF) for cytokine-autonomous persistence (page 1) resulting in specific in vitro recognition of CD19+ B cell lymphoma cells in short-term and long-term NK cytotoxicity assays (page 2, paragraph 1). The functionality of the CD19-CAR was further enhanced in combination with autonomous IL-15 signaling. Introduction of the IL-15RF enabled expansion of iNK cells without addition of soluble cytokine and greatly improved longevity and functional persistence of iNK cells both in vitro and in animal models. Goodridge further teaches iNK cells modified with IL-15RF showed enhanced functional maturation, including upregulated expression of effector molecules such as granzyme B (page 2, paragraph 2). Goodridge further teaches that in combination with hnCD16, co-expression of CD19-CAR and IL15-RF culminates in iNK cells capable of dual-specificity through combinatorial use with monoclonal antibodies to tackle antigen escape (page 2, paragraph 3). Goodridge further teaches that when targeting CD19- CD20+ B lymphoblast target cells and used in combination with rituximab (which targets CD20), only FT596 was able to effectively eliminate the CD19 antigen escaped target cell (page 2, paragraph 3). Goodridge further teaches that FT596 provides a multi-antigen targeting, potent and persistent engineered immune cell that is derived from a master iPSC line which utilizes the intrinsic versatility of NK cells to enable a highly effective combination therapy in a single, standardized, scalable, off-the-shelf platform (page 2, paragraph 4).
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 exogenous CD16 and an additional antibody therapeutic as taught by Goodridge to the immune cells comprising a switch receptor, an exogenous IL-21, and a CAR as taught by Kong. The ordinary artisan would have been motivated to do so because as Goodridge teaches the non-cleavable, high affinity CD16 results in enhanced function, the IL-15RF showed enhanced functional maturation, including upregulated expression of effector molecules; and the combination of these elements results a multi-antigen targeting, potent and persistent engineered immune cell that is derived from a master iPSC line which utilizes the intrinsic versatility of NK cells to enable a highly effective combination therapy in a single, standardized, scalable, off-the-shelf platform. Goodridge further teaches that in combination with hnCD16, co-expression of CD19-CAR and IL15-RF culminates in iNK cells capable of dual-specificity through combinatorial use with monoclonal antibodies to tackle antigen escape. The ordinary artisan has a reasonable expectation of success to enhance the function of the immune effector cells by adding an exogenous high affinity CD16, a cytokine signaling complex and an additional therapeutic antibody to overcome antigen escape.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Kong (US 2021/0252069 A1; published 08/19/2021; PTO-892) as evidenced by Wyman (US 2020/0397823 A1; PTO-892) and Goodridge (Blood, 2019, Volume 134, Supplement 1, Page 301; cited in OA 04/15/2025) as applied to claims 1, 4, 10, 12-14, 20-22, 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 Goodridge as applied to claims 1, 4, 10, 12-14, 20-22, 24, and 27 are detailed above.
Li and Goodridge 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 immune cells comprising an exogenous CD16, a cytokine signaling complex of IL-15, with a CAR that specifically targets CD19, and additional antibody therapeutic as taught by Kong and Goodridge. 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 NK 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 Goodridge.
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; PTO-892) as evidenced by Wyman (US 2020/0397823 A1; PTO-892) and Goodridge (Blood, 2019, Volume 134, Supplement 1, Page 301; cited in OA 04/15/2025) as applied to claims 1, 4, 10, 12-14, 20-22, 24, and 27 above and further in view of Shin (Immune Netw, 2020, 20(2):e14; cited in OA 04/15/2025).
The teachings of Kong and Goodridge as applied to claims 1, 4, 10, 12-14, 20-22, 24, and 27 are detailed above.
Kong and Goodridge do not teach wherein the composition comprises a checkpoint inhibitor.
Shin teaches that Immune checkpoint inhibitors are Abs blocking the PD-1:PD-L1 and CTLA-4 (page 16, para 3) and that checkpoint inhibitors have been reported to improve overall survival and the survival rate of many cancer patients and promote immune responses and tumor regression by reducing the immune suppressive mechanisms in many cancer patients (page 17, para 1). Shin further teaches that despite the efficacy of allogeneic NK cells in hematological malignancies, the function of NK cells is often impaired in solid tumors and combination therapy with checkpoint inhibitors is being tested to improve the effectiveness in solid tumors as well as hematological malignancies (page 9, para 2; Table 2).
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 Shin to add a checkpoint inhibitor to the derived immune cells comprising a switch receptor, a CD19-CAR, and gene disruption as taught by Kong and Goodridge. The ordinary artisan would have been motivated to do so because Shin teaches that checkpoint inhibitors have been reported to improve overall survival and the survival rate of many cancer patients and promote immune responses and tumor regression by reducing the immune suppressive mechanisms in many cancer patients and that combination therapy with checkpoint inhibitors and NK cell immunotherapy would improve the effectiveness of treatment therefore providing a benefit to patients. Therefore the ordinary artisan has a reasonable expectation of success at adding a checkpoint inhibitor to the treatment composition of Kong and Goodridge.
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; PTO-892) as evidenced by Wyman (US 2020/0397823 A1; PTO-892) and Goodridge (Blood, 2019, Volume 134, Supplement 1, Page 301; cited in OA 04/15/2025) as applied to claims 1, 4, 10, 12-14, 20-22, 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 and Goodridge as applied to claims 1, 4, 10, 12-14, 20-22, 24, and 27 are detailed above.
Kong and Goodridge do not teach 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 to the derived immune cells comprising a switch receptor, a CD19-CAR, and gene disruption as taught by Kong and Goodridge. The ordinary artisan would have been motivated to do so because Smits teaches that BiTEs allows 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
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/AMBER K FAUST/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643