DETAILED ACTION
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 .
Applicant’s amendments, filed 4/08/2026, is acknowledged.
Claims 4-6 and 18 are cancelled.
Claims 1-3, 7-17, and 19 are currently pending.
Claim 1 is the only independent claim.
Claim 19 stands withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions and/or Species.
Claims 1-3 and 7-17 are under examination as reading on an engineered immune cell with at least one MHC and one NK activating receptor binding molecule is suppressed or silenced.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/08/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner in its entirety.
Terminal Disclaimer
Applicant has filed a terminal disclaimer for the following patents and applications:
Application 17/910,007
Application 18/034,177
Application 18/025,558
Application 18/254,037
Application 18/260,905
Application 17/456,436
Application 17/550,455
Application 18/263,439
Application 18/861,006
Application 18/861,000
Patent 11,203,758
Patent 12,029,760
Patent 11,896,620
Patent 12,344,843
Patent 11,208,661
The Non-Statutory Double Patenting rejections for these references are hereby withdrawn in light of the filing of the Terminal Disclaimers
In view of the amendments and remarks filed on 4/08/2026, the following rejections remain.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 16, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Bhattacharya et al. (WO 2018175390, in Office Action mailed 1/08/2026) in view of Banerjee et al. (J Virol. 2007 Sep;81(18):9707-17. doi: 10.1128/JVI.00887-07). This is a new grounds for rejection necessitated by Applicant’s amendments.
Bhattacharya et al. teaches development of “universal donor” embryonic cells that have HLA expression and NK ligand expression reduced to reduce the immunogenicity of the cells (pg. 52): “[u]niversal-donor hES cells are a goal of many fields, but the immunological barriers are substantial… the creation of 'universal' donor cell lines is proposed herein. These lines are genetically stripped of their immunogenicity, thereby allowing cells and tissues derived from a single line to be transplanted into any recipient. Removal of HLA expression has been shown to be a requirement for such a universal donor line, but mouse allograft studies have demonstrated that this alone is insufficient to prevent rejection.”
Bhattacharya et al. teaches human embryonic stem cells that have been genetically modified via CRISPR/Cas9 technology to have the B2M, TAP1, CD74, and CIITA (i.e., a “MHC related gene”) genes silenced (pg. 52 and 53): “Through CRISPR/Cas9-based targeted mutations, a karyotypically normal hES cell line that lacks HLA expression was generated. One clone carrying inactivating mutations in both alleles of B2M and TAP1 and one allele of CD74 was identified through MiSeq analysis of the targeted regions…[t]his HLA-I-deficient line subsequently re-targeted using CRISPR to ablate the remaining allele of CD74 and both alleles of CIITA, a transcription factor required for expression of HLA-II.”
Bhattacharya et al. teaches that this deletion reduced stem cell recognition by NK cells, further reducing immunogenicity of the stem cells, wherein these genes are targeted for deletion via CRISPR/Cas9 (pg. 54): “…the absence of HLA-I may render target cells susceptible to NK cell mediated cytolysis, NKG2D ligands are targeted through CRISPR/Cas9.”
Bhattacharya et al. further teaches that these human embryonic stem cells were further engineered via CRISPR to delete MICA and MICB (i.e., “at least one NK activating receptor binding molecule”; Bhattacharya et al. pg. 54 and 55): “This MICA/B fusion was retargeted with CRISPR/Cas9, to generate a clone with frameshift mutations in all 4 alleles of MICA and MICB (FIG. 118). This clone was validated for normal karyotype. HLA, MICA/B deficient hES cells will henceforth be referred to as HM-KO hES.”
Bhattacharya et al. teaches that this deletion reduced stem cell recognition by NK cells, further reducing immunogenicity of the stem cells, wherein these genes are targeted for deletion via CRISPR/Cas9 (pg. 54): “…the absence of HLA-I may render target cells susceptible to NK cell mediated cytolysis, NKG2D ligands are targeted through CRISPR/Cas9.”
Bhattacharya et al. additionally teaches differentiation of human embryonic stem cells, with and without gene deletion, into monocytes (i.e., B-cells or “immune cell”; Bhattacharya et al. pg. 54-55, Fig. 10 and claims 1 and 3): “A method of differentiating human embryonic stem cells (ES cells) into a plasma cell…”
Bhattacharya et al. teaches an engineered human embryonic stem cell with suppressed/silenced expression of at least B2M and MICA, and differentiated B-cells derived from the embryonic stem cells that have at least B2M and MICA expression silenced/suppressed.
Bhattacharya et al. does not teach engineered immune cells with silenced/suppressed expression of ICAM2 (i.e., the limitations of instant claim 1).
Banerjee et al., in the same field of endeavor, teaches that the human T-cell leukemia virus type 1 can infect T-cells to lead to T-cell malignancy (Introduction). Banerjee et al. teaches that infected T-cells evade the immune system through downregulation of MHC-I expression (Introduction), and are also resistant to NK-mediated cell cytotoxicity (Results and Fig. 1).
Banerjee et al. further teaches that NK cells express LFA-1, which can bind to ICAM1 and ICAM2 on target cells, which is critical to NK mediated cytotoxicity (Introduction): “…[i]n addition to loss of inhibitory control through the altered expression of MHC-I, strong adhesion to the target cells, mediated by integrins such as leukocyte function antigen 1 (LFA-1) on NK cells, is critical in triggering NK cell cytotoxicity…” Banerjee et al. teaches that HTLV-1 infected T-cells also has downregulation of ICAM1 and ICAM2 (pg. 9710 and Fig. 3):
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Banerjee et al. teaches (Discussion): “[w]e found that HTLV-1 down- regulates ICAM-1 and -2 expression on primary CD4+ T cells… the ability of primary CD4+ T cells to adhere to autologous NK cells was significantly reduced after infection with HTLV-1… the downmodulation of ICAM-1 and -2 on HTLV-1-infected target cells may contribute to the reduced ability of NK cells to adhere to these infected target cells…[c]combined with the modulation of ICAM-1 and -2 and the lack of expression of NCR and NKG2D ligands, the present study indicates that the ligands on target cells that trigger the critical steps of NK cell cytotoxic response to target cells are either robustly down-regulated or not present on the HTLV-1-infected CD4+ T cells.”
Thus, Banerjee et al. demonstrates that down-regulation of ICAM1 and ICAM2 on cells, such as T-cells, leads to reduced adherence and cytotoxic killing by NK cells.
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have further modified the engineered cells of Bhattacharya et al. in view of Banerjee et al. to suppress or silence ICAM1 and ICAM2 in the engineered stem cells of Bhattacharya et al. (i.e., the limitations of instant claim 1) with a reasonable expectation of success, as Bhattacharya et al. teaches methods of silencing genes in cells (CRISPR/Cas9) that one with ordinary skill in the art would appreciate can be applied to other genes such as ICAM1 and ICAM2. One would have been motivated to make this change for the purposes of further reducing the immunogenicity of the engineered embryonic cells of Bhattacharya et al. to develop a “universal donor” embryonic stem cell.
Regarding claims 2 and 3, Bhattacharya et al. teaches deletion of B2M (supra), meeting the claim limitations.
Regarding claim 16, Bhattacharya et al. teaches engineered embryonic stem cells that differentiate into immune cells, meeting the claim limitations.
Regarding instant claim 17, Bhattacharya et al. teaches differentiation of the genetically modified human ESCs into myeloid cells (i.e., an “engineered immune cell”) in culture medium with GM-CSF (i.e., “a pharmaceutically acceptable excipient”; Bhattacharya et al. Figure 10), meeting the limitations of the claim.
Applicants arguments, filed 4/08/2026, have been rendered moot in light of this new rejection.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1-3, 7, 8, 10, 11, 13-15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Ren et al. (Clin Cancer Res. 2017 May 1;23(9):2255-2266. doi: 10.1158/1078-0432.CCR-16-1300. Epub 2016 Nov 4, in Office Action mailed on 1/08/2026) in view of Banerjee et al. (supra), as evidenced by Zhang et al. (Biomark Res. 2017 Jun 24;5:22. doi: 10.1186/s40364-017-0102-y, in Office Action mailed on 1/08/2026). This is a new grounds for rejection necessitated by Applicant’s amendments.
Ren et al. teaches use of genetically modified allogenic T cells to be used in CAR-T therapy to treat cancer (Abstract). Ren et al. teaches CRISPR/Cas9 can be used to delete TCR genes such as TRAC and MHC genes such as B2M from T-cells to reduce alloreactivity in patients (pg. 7-8, “Results” section): “An initial experiment targeting the TCR α constant region (TRAC) or β constant region (TRBC) with single electroporation resulted in 7.51% and 12% CD3-negative (CD3neg) T cells, respectively…Since disrupting either TCR α or β is sufficient to ablate TCR/CD3 expression and B2M is essential for the assembly and expression of HLA-I complex…, TCR and B2M double disruption was developed to generate gene-disrupted T cells…Four of the five mice infused with non-manipulated lymphocytes developed lethal xenogeneic graft-versus-host disease (GVHD) within 2 month after the infusion. GVHD was also evidenced by elevated number of CD8 positive cell infiltrating in different organs, as well as elevated CD45 positive cell counts in the peripheral blood. (Supplementary Figure 5a,b,c), whereas none of the mice receiving TCR single or TCR/HLA-I double ablated cells (n = 5, per group) developed GVHD (Fig. 3d,e).”
Ren et al. further teaches these genetically engineered T-cells can be induced to express an anti-CD19 CAR and retains antitumor efficacy (pg. 9, “Gene-disrupted CART cells retain antitumor efficacy” section): “Gene-disrupted CD19 CART cells were generated by combing CD19 CAR lentiviral transduction with the RNA electroporation of Cas9/gRNAs…Mice treated with CART cells with a disrupted endogenous TCR (LV-CD19 CAR TCRneg) or with a simultaneous disruption of TCR and HLA-I (LV-CD19 CAR TCR/HLA-Ineg) exhibited similar survival rates to that of mice treated with wild-type CD19 CART cells (LV-CD19 CAR) (Figure 4h). The numbers of human T cells in the peripheral blood of the Nalm6-bearing mice treated with TCRneg or TCR/HLA-Ineg were comparable to mice treated with wild type CD19 CART cells (Figure 4i), suggesting that the disruption of TCR alone or together with B2M does not significantly affect CART cell engraftment, in vivo proliferation and anti-tumor activity”
Given that Ren et al. teaches that either TRAC or TRBC can be ablated to reduce TCR/CD3 expression via CRISPR/Cas9, Ren et al. teaches engineered T-cells (i.e. “immune cell”) that has silenced expression of TRAC and B2M, as well as anti-CD19 CAR-T cells lacking TRAC and B2. Ren et al. further teaches the T-cells are CD4+/CD8+ (“Materials and Methods” section): “[p]rimary human CD4 and CD8 T cells were isolated from healthy volunteer donors”.
Ren additionally teaches mixtures (i.e., “a pharmaceutical composition”) comprising the CAR-T cells in R10 medium (i.e., “one or more pharmaceutically acceptable excipients).
Ren et al. does not teach engineered T-cells that have silenced or suppressed TRAC, B2M, and a NK activating receptor such as ICAM2 (i.e., the limitations of instant claim 1).
Banerjee et al., in the same field of endeavor, teaches that the human T-cell leukemia virus type 1 can infect T-cells to lead to T-cell malignancy (Introduction). Banerjee et al. teaches that infected T-cells evade the immune system through downregulation of MHC-I expression (Introduction), and are also resistant to NK-mediated cell cytotoxicity (Results and Fig. 1).
Banerjee et al. further teaches that NK cells express LFA-1, which can bind to ICAM1 and ICAM2 on target cells, which is critical to NK mediated cytotoxicity (Introduction): “…[i]n addition to loss of inhibitory control through the altered expression of MHC-I, strong adhesion to the target cells, mediated by integrins such as leukocyte function antigen 1 (LFA-1) on NK cells, is critical in triggering NK cell cytotoxicity…” Banerjee et al. teaches that HTLV-1 infected T-cells also has downregulation of ICAM1 and ICAM2 (pg. 9710 and Fig. 3).
Banerjee et al. teaches (Discussion): “[w]e found that HTLV-1 down- regulates ICAM-1 and -2 expression on primary CD4+ T cells… the ability of primary CD4+ T cells to adhere to autologous NK cells was significantly reduced after infection with HTLV-1… the downmodulation of ICAM-1 and -2 on HTLV-1-infected target cells may contribute to the reduced ability of NK cells to adhere to these infected target cells…[c]ombined with the modulation of ICAM-1 and -2 and the lack of expression of NCR and NKG2D ligands, the present study indicates that the ligands on target cells that trigger the critical steps of NK cell cytotoxic response to target cells are either robustly down-regulated or not present on the HTLV-1-infected CD4+ T cells.”
Thus, Banerjee et al. demonstrates that down-regulation of ICAM1 and ICAM2 on cells, such as T-cells, leads to reduced adherence and cytotoxic killing by NK cells.
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have further modified the engineered T-cells of Ren et al. in view of Banerjee et al. to suppress or silence ICAM1 and ICAM2 in the engineered T-cells Ren et al. (i.e., the limitations of instant claim 1) with a reasonable expectation of success, as Ren et al. teaches methods of silencing genes in cells (CRISPR/Cas9) that one with ordinary skill in the art would appreciate can be applied to other genes such as ICAM1 and ICAM2. One would have been motivated to make this change for the purposes of further reducing the immunogenicity of the engineered CAR-T cells of Ren et al. that have suppressed ICAM1 and ICAM2 and less NK-mediated cell cytotoxicity, leading to decreased immunogenicity of the CAR-T cells to develop a cell that can be more universally applied to patients in need.
Regarding claims 2 and 3, Ren et al. teaches deletion of the B2M gene (supra), meeting the claim limitations.
Regarding claims 7 and 8, the combined references teach an engineered T-cell with reduced expression of TRAC, B2M, ICAM1, and ICAM2, meeting the claim limitations.
Regarding claim 10 and 11, Ren et al. teaches engineered CAR-T cells. Zhang et al. is provided as an evidentiary reference to teach that chimeric antigen receptors comprise at least an antigen recognition domain (i.e., “a ligand binding domain”), a transmembrane domain, and an intracellular domain (Fig. 2, cropped below, the extracellular portion of the CARs is a scFv):
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Therefore, the anti-CD19 CAR taught by Ren et al. is considered to inherently have at least a ligand binding domain, a transmembrane domain, and an intracellular signaling domain, meeting the limitations of instant claims 10 and 11.
Regarding claims 13-15, Ren et al. teaches anti-CD19 CAR-T cells that can be CD4+/CD8+ cells (supra), meeting the claim limitations.
Regarding claim 17, Ren et al. teaches pharmaceutical compositions comprising the CAR-T cells and an acceptable excipient (supra), meeting the claim limitations.
Applicants arguments, filed 4/08/2026, have been fully considered, but have been found to be not convincing.
Applicant argues that the amendments to the claim obviate the previous rejection, however this has been rendered moot by the new grounds of rejection necessitated by the amendment.
Applicant further argues (Remarks pg. 11):
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However, Ren et al. teaches that knockout of TCR/B2M reduces graft-vs-host disease, as well as reducing a T-cell response against the engineered cells, however it does not reduce NK cell killing, which was still active (pg. 8): “…we found that the TCR and B2M double-knockout T cells abrogated the allogeneic killing of HLA unmatched tumor cell lines…[w]e did not observe any response when these cells were challenged by allogeneic whole-blood irradiated PBMCs…ablation of HLA-I molecules also sharply reduced the alloreactivity, as confirmed by co-culture of allogenic PBMCs with irradiated B2M-disrupted cells the ability of HLA-I negative T cells to stimulate an allogenic PBMC response caused by T cell was markedly reduced, it was not completely diminished, probably due to the activation of NK cells within the PBMCs, which was supported by the finding that allogeneic T cells activation was completely abrogated as long as the HLA-I of stimulating gene-disrupted T was ablated when the purified CD4 and CD8 T cells, instead of PBMCs, were used as allogeneic effectors…”
Thus, the expected result of silencing/suppressing a gene such as ICAM2 would reduce NK-cell killing, as is demonstrated in the instant specification in Figure 2. In absence of evidence to the contrary, the reduced NK cell killing is the expected result of ablating the genes in Fig. 2.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Ren et al. (supra) in view of Banerjee et al. (supra), as evidenced by Zhang et al. (supra) as applied to claims 1-3, 7, 8, 10, 11, 13-15, and 17 above, and further in view of Graham et al. (Blood (2019) 134 (Supplement_1): 3228. doi: 10.1182/blood-2019-123018, in Office Action mailed on 1/08/2026). This is a new grounds for rejection necessitated by Applicant’s amendments.
The teachings of Ren et al. in view of Banerjee et al., as evidenced by Zhang et al. have been discussed supra. The combined teachings do not teach engineered immune cells that further has CD52 silenced (i.e., the limitations of instant claim 9).
Graham et al., in the same field of endeavor, teaches the CD52 gene can be genetically deleted from T-cells to make them resistant to lymphodepletion with an anti-CD52 antibody (pg. 1): “CAR T cell product expressing a second generation anti-CD19 CAR with TALEN®-mediated gene knockouts of T cell receptor alpha chain (TRAC) and CD52 to prevent graft versus host disease and to render them resistant to anti-CD52 antibody used for lymphodepletion”.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have modified the CAR-T cell taught by Ren et al. in view of Banerjee et al., as evidenced by Zhang et al., further in view of Graham et al. to delete the CD52 gene from the CAR-T cell with a reasonable expectation of success, as the references all concern engineering of CAR-T cells that one with ordinary skill would be able to apply to other CAR-T cells. One would have been motivated to make this change for the purposes of rendering the CAR-T cells of Ren et al. in view of Banerjee et al., as evidenced by Zhang et al. resistant to anti-CD52 antibody based lymphodepletion.
Applicants arguments, filed 4/08/2026, have been rendered moot in light of this new rejection.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Ren et al. (supra) in view of Banerjee et al. (supra), as evidenced by Zhang et al. (supra) as applied to claims 1-3, 7, 8, 10, 11, 13-15, and 17 above, and further in view of Ghorashian et al. (Nat Med. 2019 Sept;25:1408-1414 doi: 10.1038/s41591-019-0549-5, in Office Action mailed on 1/08/2026). This is a new grounds for rejection necessitated by Applicant’s amendments.
The teachings of Ren et al. in view of Banerjee et al., as evidenced by Zhang et al. have been discussed supra. The combined teachings do not teach a specific anti-CD19 CAR structure that comprises an antigen recognition domain, a TM domain, an intracellular signaling domain, and a co-stimulatory domain (i.e., the limitations of instant claim 12).
Ghorashian et al., in the same field of endeavor, teaches an anti-CD19 CAR that is improved over previous anti-CD19 CARs in that it caused increased proliferation an in vivo antitumor activity against ALL compared to other CARs, and the reason for this was the use of a low-affinity anti-CD19 scFv (Abstract). Ghorashian et al. further teaches the anti-CD19 CAR contains a CAT scFv, a CD8 TM domain, a 4-1BB co-stimulatory domain, and a CD3ζ intracellular domain (i.e., the limitations of instant claim 12; Ghorashian et al. Introduction): “We compared the function of T cells that were lentivirally transduced with either FMC63 or CAT in identical second-generation CAR formats. These cells had a CD8-derived stalk/transmembrane region, a 4-1BB co-stimulatory domain and a CD3ζ chain”.
Ghorashian et al. further teaches that T-cells expressing the anti-CD19 CAR with the low-affinity CAT scFv clone had a significant reduction in tumor burden when compared with an anti-CD19 CAR comprising the high-affinity FMC63 scFv in a mouse Nalm6 ALL xenograft model (Fig. 2B, cropped below):
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Ghorashian et al. teaches (Discussion): “…we report on a new, low-affinity CD19 CAR incorporating a CD19-specific scFv with a faster off-rate than the FMC63 CD19 binder used in many clinical studies. T cells expressing our low-affinity CAT CAR showed greater cytotoxic and proliferative responses in vitro. These data were supported by enhanced CAR T cell proliferation and antileukemic activity with our low-affinity CAT CAR in a xenogeneic model of ALL”.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have modified the anti-CD19 CAR taught by Ren et al. in view of Banerjee et al., as evidenced by Zhang et al., further in view of Ghorashian et al. to try and use the CAT anti-CD19 CAR in place of the anti-CD19 CAR taught by Ren et al. with a reasonable expectation of success, as the references all concern CARs and CAR-T therapy that one with ordinary skill in the art would be able to apply to other CARs and CAR-T cells. One would have been motivated to make this change for the purposes of using an anti-CD19 CAR with increased potency to treat ALL in patients.
Applicants arguments, filed 4/08/2026, have been rendered moot in light of this new rejection.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Ren et al. (supra) in view of Banerjee et al. (supra), as evidenced by Zhang et al. (supra) as applied to claims 1-3, 7, 8, 10, 11, 13-15, and 17 above, and further in view of Lee (Int J Mol Sci. 2019 Apr 12;20(8):1825. doi: 10.3390/ijms20081825, in Office Action mailed on 1/08/2026). This is a new grounds for rejection necessitated by Applicant’s amendments.
The teachings of Ren et al. in view of Banerjee et al., as evidenced by Zhang et al. have been discussed supra. The combined teachings do not teach engineered immune cells that are derived from embryonic stem cells (i.e., the limitations of instant claim 16).
Lee, in the same field of endeavor, teaches (Abstract): “Pluripotent stem cell-derived immune cells such as natural killer cells, macrophages, and lymphoid cells, especially T cells, can be used in immune cell therapy to treat incurable cancers. Moreover, since the advent of chimeric antigen receptor (CAR) technology, the success of CAR-T cells in the clinic has galvanized new efforts to harness the power of CAR technology to generate CAR-engineered immune cells from pluripotent stem cells”.
Lee further teaches that primary immune cells (i.e., fully differentiated immune cells such as T-cells) have disadvantages over stem cells (Introduction): “primary immune cells are refractory to gene editing procedures and such cells have limited proliferation activity, which hinders clonal selection. Therefore, with their capacity for indefinite proliferation and their pluripotent character, human pluripotent stem cells could be a perfect alternative for generating an unlimited number of improved immune cells through gene modification and clonal selection”.
Lee teaches there are at least three different protocols to generate T-cells from pluripotent stem cells (i.e., embryonic stem cells), including the use of the OP9 cell line genetically modified to express DLL-1 or DLL-4, or using an organoid culture (section 2.2 and Figure 1): “Using the OP9-DL1 cell line, human pluripotent stem cells were differentiated into T cells… The protocol generated functionally mature CD4+ and CD8+ TCR αβ T cells. Recently, T cell differentiation using DLL-4 instead of Dll-1 was reported. Montel-Hagen et al., showed conventional T cell differentiation from human pluripotent stem cells using organoid”.
Lee further teaches that there are efforts to generate CAR-T cells from human embryonic stem cells, and induced pluripotent stem cells have been successfully differentiated into CAR-T cells (section 4, final ¶): “Human iPS-derived CAR-NK cells showed in vivo cytotoxic activity toward tumor cells comparable to CAR-T cells, but with less overall toxicity…These results indicate that CAR-NK cells derived from human pluripotent stem cells could be a valuable method for generating “off-the-shelf” allogeneic therapeutics”.
Lee provides motivation for one with ordinary skill in the art to make CAR-T cells from embryonic stem cells (Conclusion): “A recent paper showed that TALEN-mediated genetic
ablation of the gene encoding GM-CSF in CAR-T cells can prevent CRS…These results could be applied to human pluripotent stem cells to generate cells that were less prone to causing CRS using CRISPR/Cas9, after which the engineered cells could be clonally selected and differentiated into CAR-T cells. Therefore, through the deployment of CRISPR/Cas9 technology and fourth generation CARs, human pluripotent stem cells could enhance next generation immune cell therapy in terms of safety, cost, and activity… The resulting next generation
immune cell therapy may solve limitations of current therapies by achieving improvements such as off-the-shelf availability, increased potency, increased cost-effectiveness, and increased precision of anti-tumor activity”. Furthermore, Lee provides an example of a method of generating such CAR-T-cells (Figure 3):
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It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have modified the CAR-T cell taught by Ren et al. in view of Banerjee et al., as evidenced by Zhang et al., further in view Lee to derive the T-cells from embryonic stem cells with a reasonable expectation of success, as Lee provides an example of such an experiment, and teaches multiple methods of differentiating T-cells from human embryonic stem cells. One would have been motivated to make this change for the purposes of generating CAR-T cells with off-the-shelf capability, increased potency, increased cost-effectiveness, and increased anti-tumor precision, as taught by Lee.
Applicants arguments, filed 4/08/2026, have been rendered moot in light of this new rejection.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEC JON PETERS whose telephone number is (703)756-5794. The examiner can normally be reached Monday-Friday 8:30am - 6:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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