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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/28/2026 has been entered.
Claims 1-5, 7, 9, 11-13, 17, 19-20, 22-24, and 30-34, of record 8/28/2026, are pending and subject to prosecution. Claims 1-5, 7, 11-12, 17, 19, 22, and 24 are amended. Claims 14-16 are cancelled.
Status of Prior Rejections/Response to Arguments
RE: Objection to claims 1-5, 7, 12, 15, 17, 19, 22, and 24:
The cancellation of claim 15 renders the objection thereto moot.
The amendment to claims 1-5, 7, 12, 15, 17, 19, 22, and 24 is effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claims 1-5, 7, 9, 11-17, 19-20, 22-24, and 30-34 are rejected under 35 U.S.C. 112(b):
The cancellation of claims 14-16 renders the rejection thereto moot.
The amendment to claims 1-3 is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claims 1-2, 4-5, 7, 9, 12-13, 17, 19, and 31-34 under 35 U.S.C. 103 over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020), in view of Schumacher et al. (US 20210040558 A1) and Minagawa et al. (Cell Stem Cell, 2018):
RE: Rejection of claims 1-5, 7, 9, 11-13, 17, 19, and 31-34 under 35 U.S.C. 103 over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Schumacher et al. (US 20210040558 A1) and Minagawa et al. (Cell Stem Cell, 2018), further in view of Suzuki et al. (Cancer Science, 2011):
RE: Rejection of claims 1-2, 4-5, 7, 9, 12-14, 17, 19, and 31-34 under 35 U.S.C. 103 over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Schumacher et al. (US 20210040558 A1) and Minagawa et al. (Cell Stem Cell, 2018), further in view of Yelensky et al. (US 20200363414 A1):
RE: Rejection of claims 1-2, 4-5, 7, 9, 12-13, 15-17, 19, and 31-34 under 35 U.S.C. 103 over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Schumacher et al. (US 20210040558 A1) and Minagawa et al. (Cell Stem Cell, 2018), further in view of Nakauchi et al. (EP 2853590 B1):
RE: Rejection of claims 1-2, 4-5, 7, 9, 12-13, 17, 19-20, and 31-34 under 35 U.S.C. 103 over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Schumacher et al. (US 20210040558 A1) and Minagawa et al. (Cell Stem Cell, 2018), further in view of Giannoni et al. (Molecular Therapy, 2013) and Vodyanik et al. (Blood, 2006):
RE: Rejection of claims 1-2, 4-5, 7, 9, 12-13, 17, 19, 22-24, and 30-34 under 35 U.S.C. 103 over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Schumacher et al. (US 20210040558 A1) and Minagawa et al. (Cell Stem Cell, 2018), further in view of Healy et al. (Human Pluripotent Stem Cells, 2011):
The cancellation of claims 14-16 renders the rejections thereto moot.
The applicant asserts that the prior art does not make obvious the sorting and isolation of tumor-reactive T cells for CD3+/CD137+ cells, preparing cDNAs encoding TCRαβ chains, analyzing the cDNAs by expression in a TCR-deficient T cell line, and introducing the cDNAs into iPSC or iPSC-derived HSCs or immature or immature T cells (Applicant Remarks, page 12). The applicant asserts that Nagano et al. teach a process to make regenerated T cells that is “drastically different” from the claimed process and that Nagano et al. and Minagawa et al. do not teach the above active steps of claims 1-3 (Applicant Remarks, page 13).
The applicant’s arguments have been fully considered but are not found persuasive. Regarding the assertion that the references do not teach the claimed active steps, prior art is not required to teach or suggest all claim limitations when a person of ordinary skill in the art would have understood them to be obvious. See MPEP 2141(III). Nagano et al. do not expressly teach any exogenous TCRs or the preparation of TCR cDNA and its introduction into T cell-derived iPSCs but suggest that the transduction of exogenous TCR genes may be beneficial (See page 132, col. 1, full ¶3). Minagawa et al., like Nagano et al., teach the production of regenerated T cells from antigen-specific T cell-derived iPSCs and suggest a benefit to the transduction of exogenous TCR genes, and they further teach antigen-specific T cells isolated from peptide-vaccinated cancer patients (See Abstract; page 851, col. 1, full ¶2 and 4; and fig. 3). Schumacher et al. teach methods for isolating antigen-specific TCR genes from cells identified on the basis of T cell markers (including CD137), generating cDNA, and evaluating specificity in TCR-null cells (See Abstract and ¶0008, 0010, 0016, 0129, 0246-0247, and 1051). One of ordinary skill in the art, who is able to devise and carry out methods for producing antigen-specific regenerated T cells from iPSCs, would have found the execution of the claimed active steps to have been an obvious, necessary, and relatively straightforward extension of the combined teachings of the prior art.
The rejections are therefore maintained.
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.
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 1-2, 4-5, 7, 9, 12-13, 17, 19, and 31-34 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020), of record, in view of Schumacher et al. (US 20210040558 A1), of record, and Minagawa et al. (Cell Stem Cell, 2018), of record.
Regarding claims 1, 5, 9, 12-13, 17, 19, and 31-34: Nagano et al. teach the production of T cells (which read on “regenerated T cells”) from T cell-derived iPSCs for (See Abstract). T cells were isolated from PBMCs obtained from a donor (See page 127, col. 1, full ¶1). The PBMCs were primed with a MART-1 peptide, and MART-1-tetramer-positive (which reads on “the T cell population in step (1) binds to MCH tetramer… that forms a complex with the tumor-related antigen peptide”) CD8 T cells were selected (See fig. 1). The T cells were transduced with Yamanaka factors to generate iPSCs (which reads on “initializing… T cells, to iPS cells”) (See page 133, col. 1, ¶1). Clones of iPSCs were induced for the T lineage, with all clonal lines yielding TCR-expressing T cells (which reads on “selecting… iPS cell clones that demonstrate high differentiation efficiency into T cells”) (See page 128, col. 1, v1). The iPSCs were differentiated to CD4+CD8+ T cells and expanded (which reads on “differentiating the iPSC cell clones… into mature T cells and proliferating the mature T cells”) (See page 133, col. 1, full ¶2).
Nagano et al. do not expressly teach the preparation of TCR cDNA or its introduction into iPSCs generated from antigen-specific T cells. However, Nagano et al. do note that TCR avidity of the clones varied widely and that the transduction of exogenous TCR genes may make it easier to produce a cell source for T cell therapy (See Abstract; page 129, col. 2, full ¶5; and page 132, col. 1, full ¶3).
Schumacher et al. teach methods for isolating antigen-specific and/or tumor-reactive TCR genes for immunotherapy (See Abstract and ¶0010, 0169, and 0179-0180). The T cells can be isolated from a subject, such as a patient with cancer (See ¶0010 and 0016). Cells can be separated on the basis of any CD marker or T cell activation marker or combinations of T cell activation markers, including CD137 (See ¶0010, 0246-0247, and 1150). Schumacher et al. teach isolation and activation of T cells using CD3/CD28 beads in one example (See ¶1051). TCR RNA can be isolated and converted to cDNA for preparation of an expression construct, which can be introduced into T cells by viral vectors or transposases (which read on “a transposon vector”) (See ¶0161-0163, 0819, and 0821). The TCRαβ gene products can be expressed in TCRαβ-null cells (which reads on “a TCR gene deficient T cell line”) to determine specificity to an antigen of interest following stimulation (which reads on “to select for cDNAs that exhibited significant reactivity”) (See ¶0008, 0016, 0129, and 0246-0247).
Minagawa et al. teach “rejuvenated” T cells produced from T cell-derived iPSCs and the transduction of TCR genes into non-T cell-derived iPSCs using a lentiviral vector (See Abstract and fig. 3). TCR genes were specific for WT-1 or the GPC3298-306 peptide (See page 854, col. 2, ¶1). GPC3 is overexpressed in cancers such as hepatocellular carcinoma, and iPSCs were generated from GPC3 peptide-vaccinated hepatocellular carcinoma patients (which reads on “the subjects in steps (1) and (2) are separate individuals and the subject in step (2) is a subject for cancer treatment” and “the subject in step (2) is a patient with hepatoma”) (See page 851, col. 1, full ¶4). The regenerated T cells reduced tumor size and increased survival in mice (which reads on “therapeutic agent for cancer”), “pharmaceutical composition”, and “method for… treating cancer”) (See fig. 4). Minagawa et al. also teach that exogenous gene transduction in iPSCs could prevent undesirable TCR rearrangement for obtaining antigen-specific T cells (See page 851, col. 1, full ¶2).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Nagano et al. to comprise transduction of the T cell-derived iPSC with exogenous TCR cDNA, such as that taught by Schumacher et al. and Minagawa et al., in the manner taught by Minagawa et al. One would be motivated to make this modification because Nagano et al. and Minagawa et al. suggest that transduction of T cell-derived iPSCs to express an exogenous TCR may improve the resulting regenerated T cells (See Nagano et al., page 132, col. 1, full ¶3 and Minagawa et al., page 852, col. 1, full ¶2). There would be a reasonable expectation of success in doing so because the iPSCs of Nagano et al. could be readily transduced with TCRαβ cDNA obtained from T cells positive for activation markers such as CD3 and CD137 and analyzed as taught by Schumacher et al.
Regarding claim 2: Following the discussion of claims 1, 5, 9, 12-13, 17, 19, and 31-34, Nagano et al., Schumacher et al., and Minagawa et al. do not expressly teach the TCR cDNA as derived from T cells contacted with a tumor-associated antigen after isolation. However, Schumacher et al. teach that TCRαβ pairs can be selected from reporter T cells modified to express the TCRs by stimulation with an antigen of interest (See ¶0010 and 0272).
It would have therefore been obvious to further modify the method of Nagano et al., modified by Schumacher et al. and Minagawa et al., to comprise contacting of T cells with an antigen post-isolation. The selection of any order of performing process steps is considered to be prima facie obvious in the absence of new or unexpected results. See MPEP 2144.04(IV)(C).
Regarding claim 4: Following the discussion of claims 1, 5, 9, 12-13, 17, 19, and 31-34, Nagano et al., modified by Schumacher et al. and Minagawa et al., render obvious the generation of regenerated T cells comprising exogenous TCRs but do not expressly teach preparation of the cDNA after or in parallel with initialization to iPSCs and selection of clones. However, the selection of any order of performing process steps is considered to be prima facie obvious in the absence of new or unexpected results. See MPEP 2144.04(IV)(C).
Regarding claim 7: following the discussion of claims 1, 5, 9, 12-13, 17, 19, and 31-34, Nagano et al. teach the assessment of alloreactivity in the regenerated T cells and selection of clones with low alloreactivity (See fig. 4). Such a step could readily be included in the method of Nagano et al., modified by Schumacher et al. and Minagawa et al., for selecting allogeneic or autologous regenerated T cells to avoid an alloreactive response in subjects receiving the cells.
Claims 1-5, 7, 9, 11-13, 17, 19, and 31-34 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020), of record, in view of Schumacher et al. (US 20210040558 A1), of record, and Minagawa et al. (Cell Stem Cell, 2018), of record, further in view of Suzuki et al. (Cancer Science, 2011), of record.
The teachings of Nagano et al., Schumacher et al., and Minagawa et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 3 and 11: Following the discussion of claims 1-2, 4-5, 7, 9, 12-13, 17, 19, and 31-34, Nagano et al., modified by Schumacher et al. and Minagawa et al., render obvious the generation of regenerated T cells comprising exogenous TCRs but do not expressly teach isolation of T cell TCR genes from a subject administered a tumor-related antigen.
Suzuki et al. teach the generation of antigen specific T cell clones from which TCR cDNA was prepared (See page 1622, col. 2, full ¶1). Hepatocellular carcinoma patients were vaccinated with a GPC3 peptide, and cytotoxic T cells were isolated from patient PBMCs (which reads on “T cells obtained from a subject to whom a tumor-related antigen has been administered”) (See page 1622, col. 2, full ¶1). Suzuki et al. teach that the GPC3 peptide comprises the sequence FVGEFFTDV, which is identical to instant SEQ ID NO 2 (See page 1622, col. 1, ¶3 and alignment below).
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It would have been obvious to one having ordinary skill in the art to modify the method rendered obvious by Nagano et al., Schumacher et al., and Minagawa et al. to comprise isolation of TCR genes from cancer patients vaccinated with an HLA-restricted antigenic peptide, as taught by Suzuki et al. One would have been motivated to make this modification because Suzuki et al. teach that peptide-specific CTL clones could recognize and were active against GPC3-expressing cancer cell lines (See Abstract and fig. 1-2). There would be a reasonable expectation of success in doing so because TCR genes could be readily isolated from T cells of liver cancer patients vaccinated in such a manner.
Claims 1-2, 4-5, 7, 9, 12-13, 17, 19-20, and 31-34 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020), of record, in view of Schumacher et al. (US 20210040558 A1), of record, and Minagawa et al. (Cell Stem Cell, 2018), of record, further in view of Giannoni et al. (Molecular Therapy, 2013), of record, and Vodyanik et al. (Blood, 2006), of record.
The teachings of Nagano et al., Schumacher et al., and Minagawa et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 20: Following the discussion of claims 1-2, 4-5, 7, 9, 12-13, 17, 19, and 31-34, Nagano et al., modified by Schumacher et al. and Minagawa et al., render obvious the generation of regenerated T cells comprising exogenous TCRs but do not expressly teach transduction of the TCRs into CD34+/CD43+ hematopoietic stem cells.
Giannoni et al. teach the transduction of TCR genes into Human hematopoietic stem/progenitor cells for generating transgenic T cells (See Abstract and fig. 1).
Vodyanik et al. teach that CD34 and CD43 are early markers of hematopoietic progenitors (See Abstract and fig. 1 and 3).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Nagano et al., modified by Schumacher et al. and Minagawa et al., to comprise transduction of the TCRs into CD34+/CD43+ hematopoietic stem cells differentiated from the iPSCs. One would be motivated to make this modification because Giannoni et al. demonstrate that TCR cDNA can be successfully introduced into hematopoietic stem cells for the generation of mature, antigen-specific T cells (See Abstract). One would also be motivated to use CD34+/CD43+ cells because Vodyanik teach those markers as indicative of hematopoietic progenitor cells (See Abstract). Such a modification could be readily made.
Claims 1-2, 4-5, 7, 9, 12-13, 17, 19, 22-24, and 30-34 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020), of record, in view of Schumacher et al. (US 20210040558 A1), of record, and Minagawa et al. (Cell Stem Cell, 2018), of record, further in view of Healy et al. (Human Pluripotent Stem Cells, 2011), of record.
The teachings of Nagano et al., Schumacher et al., and Minagawa et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 22-24 and 30: Following the discussion of claims 1-2, 4-5, 7, 9, 12-13, 17, 19, and 31-34, Nagano et al., modified by Schumacher et al. and Minagawa et al., render obvious the generation of regenerated T cells comprising exogenous TCRs but do not expressly teach the construction of a master cell bank.
Healy et al. teach that the establishment of a cryopreserved master cell bank is a key part of assuring well-characterized, high-quality cells for research and industry (See page 17, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Nagano et al, modified by Schumacher et al. and Minagawa et al., to comprise the cryopreservation of at least some of the iPSC clones and/or regenerated T cells. One would be motivated to make this modification because Healy et al. teach the creation of a master cell bank to be good practice for cell culture applications (See page 17, full ¶1). There would be a reasonable expectation of success in doing so because the cells could be readily cryopreserved and stored for later differentiation and/or expansion.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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/JENNIFER S SPENCE/Examiner, Art Unit 1633
