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 .
Claims 1-28, of record 6/28/2023, are pending and subject to prosecution.
Priority
The instant application is a national stage entry of PCT/JP2021/049028 (filed 12/29/2021). Acknowledgement is made of the applicant’s claim for foreign priority to Japanese applications 2021-000176 (filed 1/4/2021) and 2021-070534 (filed 4/19/2021).
Drawings
The drawings are objected to because view number must be preceded by the abbreviation “FIG.” See 37 CFR 1.84(u). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
The limitation “regenerated T cells” is interpreted as referring to T cells that are derived from T cell-derived iPSCs and exhibit longer telomere length than non-regenerated T cells (See Iriguchi et al., page 18, col. 2, full ¶2 and page 19, col. 1, ¶1).
The limitation “high differentiation efficiency” is interpreted as requiring that the ratio of CD34/CD43 double-positive cells is 5 to 15% or more in the differentiation from iPS cells into hematopoietic stem cells, the ratio of CD4/CD8 double-positive cells or that of CD5 positive cells is 10% or more or 50% or more, respectively in the differentiation from hematopoietic stem cells into immature T cells, and the ratio of the cells wherein CD8 α chain, CD8 β chain, TCR α chain and TCR β chain are all positive is 50% or more in the differentiation from immature T cells into mature T cells, consistent with ¶0081 of the instant application’s PGPub.
In claims 17-18, the limitation “highly immunogenic” is interpreted as requiring a cancer wherein 1000 or more mutations are found per cancer cell, susceptibility to immune checkpoint inhibitors, and extensive infiltration by immune cells, consistent with ¶0137 of the instant application’s PG Pub.
Claim 28 recites regenerated T cells according to claim 1. The cells are defined using a product-by-process limitation. Product-by-process limitations are considered only in so far as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product as claimed is the same or obvious over a product of the prior art (i.e., is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. See MPEP 2113. In the instant application, because the method of claim 1 does not distinguish the differentiated cells structurally from regenerated T cells formed by other methods, the cells are interpreted as comprising any regenerated T cells.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 28 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating cancer, does not reasonably provide enablement for the prevention of cancer using the method claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claimed invention is drawn to a method of preventing or treating cancer using a pharmaceutical agent comprising regenerated T cells.
The prior art appears to be silent with regard to demonstrating prevention of any cancer using regenerated T cells. Furthermore, the instant specification fails to exemplify such prevention. While it may be argued that the scope of the term "preventative" or “preventing” embraces delaying the onset or reducing the severity of a cancer, the invention as claimed nevertheless also embraces full and complete prevention of any cancer using the recited steps. The full scope of the claim term "preventative" or “preventing” is thus not enabled as it regards prevention of cancer, since at best it would require undue trial and error experimentation, the outcome of which is highly unpredictable. Amendment to remove this term would be remedial.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 7-8 are drawn to methods of producing T cells from iPS cells, wherein the claims recite multiple instances of “a step for,” but do not recite actual active steps. A single claim which claims both an apparatus (i.e., a “step for”) and the method steps of making or using the apparatus is indefinite under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. See In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303, 1318, 97 USPQ2d 1737, 1748-49 (Fed. Cir. 2011). In Katz, a claim directed to "[a] system with an interface means for providing automated voice messages…to certain of said individual callers, wherein said certain of said individual callers digitally enter data" was determined to be indefinite because the italicized claim limitation is not directed to the system, but rather to actions of the individual callers, which creates confusion as to when direct infringement occurs. Katz, 639 F.3d at 1318, 97 USPQ2d at 1749 (citing IPXL Holdings v. Amazon.com, Inc., 430 F.3d 1377, 1384, 77 USPQ2d 1140, 1145 (Fed. Cir. 2005), in which a system claim that recited "an input means" and required a user to use the input means was found to be indefinite because it was unclear "whether infringement … occurs when one creates a system that allows the user [to use the input means], or whether infringement occurs when the user actually uses the input means."); Ex parte Lyell, 17 USPQ2d 1548 (Bd. Pat. App. & Inter. 1990). See MPEP 2173.05(p). Dependent claims 2-6 and 9-28 are included in the rejection.
Claim 6 recites the limitation “the subjects different from the subjects in step (1) and (2)”. There is insufficient antecedent basis for this limitation in the claim.
Claims 13-14 contain the trademarks/trade names PiggyBac and RetroNectin, respectively. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademarks/trade names are used to identify/describe a cell editing reagent and a transduction reagent, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 27-28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Minagawa et al. (Cell Stem Cell, 2018), of record in IDS dated 2/5/2024.
Minagawa et al. teach T cells generated from T cell-derived iPSCs and their application in xenograft cancer models (See Summary).
Regarding claims 27-28: Minagawa et al. teach the isolation of GPC3-specific T cells and reprogramming to iPSCs (See page 851, col. 1, full ¶4). The iPSCs were differentiated to T cells (See fig. 1A). The regenerated T cells were administered to mice (which reads on “pharmaceutical composition”) injected with GPC3-positive tumor cells (See fig. 2 and 4).
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, 7-8, 10, 16-19, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Minagawa et al. (Cell Stem Cell, 2018), of record, Gros et al. (Journal of Clinical Investigation, 2014), and Jerby-Arnon et al. (US 20210130438 A1).
Regarding claims 1, 4, 10, 16-19, and 26-28: 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 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 teach the preparation of TCR cDNA from CD106+ T cells or its introduction into iPSCs generated from 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).
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 (which reads on “obtaining T cells from a subject, and preparing, from individual cells in T cell population that is reactive to a tumor-related antigen, cDNAs that code for TCR α chain and TCR β chain” and “virus 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 from each other and the subjects in step (2) are those to be prevented or treated of cancer”, “the subjects in step (1) or (2) are patients of hepatoma”, and “the subjects in step (1) or (2) are highly immunogenic cancer patients”) (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 852, col. 1, full ¶2).
Gros et al. teach that exhaustion markers can be used to identify and select tumor-reactive CD8+ TIL TCR clones (See Abstract and fig. 1-6).
Jerby-Arnon et al. teach VCAM1 (which reads on “CD106”) as surface protein that can be used to identify exhausted T cells (See ¶0319 and 0321).
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, as 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). It also would have been obvious to use GPC3-targeting T cells and TCRs, rather than MART-1-specific ones, for targeting other cancers, such as liver cancers. There would be a reasonable expectation of success in doing so because the iPSCs of Nagano et al. could be readily transduced with the TCR vectors taught by Minagawa et al.
It also would have been obvious to isolate TCR genes from CD8+ T cells expressing VCAM1 (which inherently reads on “CD3/CD106 double-positive”) for constructing the cDNA. One would have been motivated to make this modification because Jerby-Arnon et al. teach VCAM1 as marker of exhausted T cells (See ¶0319 and 0321) and because Gros et al. teach that exhaustion markers can be used to identify tumor-specific T cells (See Abstract and fig. 1-6). There would be a reasonable expectation of success in making this modification because T cells could be readily isolated on the basis of VCAM1 expression.
Regarding claim 2: Following the discussion of claims 1, 4, 10, 16-19, and 26-28, Nagano et al., modified by Minagawa et al., Gros et al., and Jerby-Arnon 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 5: Following the discussion of claims 1, 4, 10, 16-19, and 26-28, Nagano et al., modified by Minagawa et al., Gros et al., and Jerby-Arnon et al., do not expressly teach the TCR cDNA as isolated from a cancer patient, however, this would have been an obvious modification in order to isolate TCR clones reactive to that cancer.
Regarding claims 7-8: Following the discussion of claims 1, 4, 10, 16-19, and 26-28, Nagano et al. teach the assessment of alloreactivity in the regenerated T cells and selection of clones having TCRs with low alloreactivity (See fig. 4). Such a step could readily be included in the method of Nagano et al., modified by Minagawa et al., Gros et al., and Jerby-Arnon et al., for selecting allogeneic or autologous regenerated T cells to avoid an alloreactive response in subjects receiving the cells.
Claims 1-8, 10, 16-19, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Minagawa et al. (Cell Stem Cell, 2018), of record, Gros et al. (Journal of Clinical Investigation, 2014), and Jerby-Arnon et al. (US 20210130438 A1), further in view of Kasakovski et al. (Journal of Hematology & Oncology, 2018).
The teachings of Nagano et al., Minagawa et al., Gros et al., and Jerby-Arnon et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 3 and 6: Following the discussion of claims 1-2, 4-5, 7-8, 10, 16-19, and 26-28, Nagano et al., modified by Minagawa et al., Gros et al., and Jerby-Arnon et al., render obvious the generation of regenerated T cells comprising exogenous TCRs but do not teach the TCRs and regenerated T cells as being derived from the same person.
Kasakovski et al. review methods for reconstituting senescent and exhausted T cell pools and teach that reprogramming of exhausted T cells to iPSCs to regenerated T cells can occur autologously (See fig. 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., modified by Minagawa et al., Gros et al., and Jerby-Arnon et al., to comprise autologous regeneration of a cancer patient’s tumor-specific T cell pool. One would be motivated to make this modification because Kasakovski et al. teach that one’s own exhausted T cell pool can be restored in this manner, which could be readily done. Use of autologous TCR cDNA would also enable particular tumor-reactive clones to be expanded.
Claims 1-10, 16-19, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Minagawa et al. (Cell Stem Cell, 2018), of record, Gros et al. (Journal of Clinical Investigation, 2014), and Jerby-Arnon et al. (US 20210130438 A1), further in view of Kasakovski et al. (Journal of Hematology & Oncology, 2018), further in view of Kumagai-Takei et al. (American Journal of Respiratory Cell and Molecular Biology, 2013).
The teachings of Nagano et al., Minagawa et al., Gros et al., Jerby-Arnon et al., and Kasakovski et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 9: Following the discussion of claims 1-8, 10, 16-19, and 26-28, Nagano et al., modified by Minagawa et al., Gros et al., Jerby-Arnon et al., and Kasakovski et al., render obvious the generation of autologous regenerated T cells comprising exogenous TCRs but do not teach testing alloreactivity with PMBCs. Nagano et al. teach alloreactivity testing only with a lymphoblastoid cell line (See page 129, col. 2, full ¶2).
Kumagai-Takei et al. teach a mixed lymphocyte reaction assay using CD8+ T cells and autologous PBMCs (See Abstract and page 28, col. 2, full ¶2-3).
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 Minagawa et al., Gros et al., Jerby-Arnon et al., and Kasakovski et al., to substitute autologous PMBCs in place of a lymphoblastoid cell line for ensuring a lack of alloreactivity. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that he substitution yields more than predictable results. See MPEP 2143(I)(B).
Claims 1-2, 4-5, 7-8, 10-11, 16-19, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Minagawa et al. (Cell Stem Cell, 2018), of record, Gros et al. (Journal of Clinical Investigation, 2014), and Jerby-Arnon et al. (US 20210130438 A1), further in view of Vazquez-Lombardi et al. (bioRxiv, 2020).
The teachings of Nagano et al., Minagawa et al., Gros et al., and Jerby-Arnon et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 11: Following the discussion of claims 1-2, 4-5, 7-8, 10, 16-19, and 26-28, Nagano et al., modified by Minagawa et al., Gros et al., and Jerby-Arnon et al., render obvious the generation of regenerated T cells comprising exogenous TCRs but do not expressly teach introduction of the TCR cDNA using CRISPR.
Vazquez-Lombardi et al. teach a platform for the CRISPR-mediated insertion of transgenic TCR sequences into the endogenous TCRβ region (See Abstract and line 81-84). The platform promoted physiological TCR expression without the risks of random integration and display of multiple different TCRs by a single cell (See line 62-66 and 81-84).
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 Minagawa et al., Gros et al., and Jerby-Arnon et al., to comprise CRISPR-mediated TCR sequence insertion, as taught by Vazquez-Lombardi et al. One would be motivated to make this modification because Vasquez-Lombardi et al. teach that reduces the risks of random integration, constitutive expression, and multiple different TCR display associated with viral and plasmid vectors (See line 62-66). There would be a reasonable expectation of success because the platform of Vazquez-Lombardi et al. could be readily incorporated into the method of Nagano et al., modified by Minagawa et al., Gros et al., and Jerby-Arnon et al.
Claims 1-2, 4-5, 7-8, 10, 12-13, 16-19, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Minagawa et al. (Cell Stem Cell, 2018), of record, Gros et al. (Journal of Clinical Investigation, 2014), and Jerby-Arnon et al. (US 20210130438 A1), further in view of Yelensky et al. (US 20200363414 A1).
The teachings of Nagano et al., Minagawa et al., Gros et al., and Jerby-Arnon et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 12-13: Following the discussion of claims 1-2, 4-5, 7-8, 10, 16-19, and 26-28, Nagano et al., modified by Minagawa et al., Gros et al., and Jerby-Arnon et al., render obvious the generation of regenerated T cells comprising exogenous TCRs but do not expressly teach introduction of the TCR cDNA by transposon.
Yelensky et al. teach the PiggyBac transposon as an exemplary vector for introducing TCRs into cells (See ¶0641-0642).
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 Minagawa et al., Gros et al., and Jerby-Arnon et al., to comprise the use of a PiggyBac transposon for expressing exogenous TCRs in iPSCs. One would be motivated to make this modification because Yelensky et al. teach such a vector as exemplary for this purpose (See ¶0641-0642). There would be a reasonable expectation of success in doing so because a PiggyBac system could be readily used for the gene transfer.
Claims 1-2, 4-5, 7-8, 10, 15-19, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Minagawa et al. (Cell Stem Cell, 2018), of record, Gros et al. (Journal of Clinical Investigation, 2014), and Jerby-Arnon et al. (US 20210130438 A1), further in view of Nakauchi et al. (EP 2853590 B1).
The teachings of Nagano et al., Minagawa et al., Gros et al., and Jerby-Arnon et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 15: Following the discussion of claims 1-2, 4-5, 7-8, 10, 16-19, and 26-28, Nagano et al., modified by Minagawa et al., Gros et al., and Jerby-Arnon et al., render obvious the generation of regenerated T cells comprising exogenous TCRs but do not expressly teach differentiation of the iPSCs and expansion of the resulting T cells on PBMC feeder cells.
Nakauchi et al. teach methods for producing antigen-specific T cells from T cell-derived iPSCs (See ¶0001). The maturing T cells can be stimulated with one or more of PHA, an anti-CD3 antibody, and an anti-CD28 antibody and can be co-cultured with allogeneic or autologous PBMCs (which reads on “autologous or cross peripheral blood mononuclear cells”) (See ¶0056-0058, 0065, 0139-0140, and 0142 and fig. 24).
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 Minagawa et al., Gros et al., and Jerby-Arnon et al., to comprise differentiation and expansion of the iPSC-derived T cells using antibodies against CD3 and CD28 or PHA and PBMCs, as taught by Nakauchi et al. One would be motivated to make this modification because Nakauchi et al. teach these agents as suitable for stimulation of the differentiating T cells (See ¶0056-0058 and 0065). There would be a reasonable expectation of success in doing so because Nakauchi et al. demonstrate these discrete combinations as supporting T cell maturation and expansion (See ¶0139-0140 and 0142).
Claims 1-2, 4-5, 7-8, 10, 16-20, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Minagawa et al. (Cell Stem Cell, 2018), of record, Gros et al. (Journal of Clinical Investigation, 2014), and Jerby-Arnon et al. (US 20210130438 A1), further in view of Giannoni et al. (Molecular Therapy, 2013) and Vodyanik et al. (Blood, 2006).
The teachings of Nagano et al., Minagawa et al., Gros et al., and Jerby-Arnon et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claim 20: Following the discussion of claims 1-2, 4-5, 7-8, 10, 16-19, and 26-28, Nagano et al., modified by Minagawa et al., Gros et al., and Jerby-Arnon 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 Minagawa et al., Gros et al., and Jerby-Arnon 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, 7-8, 10, 16-19, and 22-28 are rejected under 35 U.S.C. 103 as being unpatentable over Nagano et al. (Molecular Therapy: Methods & Clinical Development, 2020) in view of Minagawa et al. (Cell Stem Cell, 2018), of record, Gros et al. (Journal of Clinical Investigation, 2014), and Jerby-Arnon et al. (US 20210130438 A1), further in view of Healy et al. (Human Pluripotent Stem Cells, 2011).
The teachings of Nagano et al., Minagawa et al., Gros et al., and Jerby-Arnon et al., are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 22-25: Following the discussion of claims 1-2, 4-5, 7-8, 10, 16-19, and 26-28, Nagano et al., modified by Minagawa et al., Gros et al., and Jerby-Arnon et al., render obvious the generation of regenerated T cells from iPSCs 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 Minagawa et al., Gros et al., and Jerby-Arnon 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4, 7-8, 10, 12-18, and 20-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7, 12-17, 20, 22-24, 30-31, and 33-34 of co-pending Application No. 17/924480 (reference application) in view of Gros et al. (Journal of Clinical Investigation, 2014) and Jerby-Arnon et al. (US 20210130438 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
Regarding claims 1 and 19: Co-pending claim 1 recites a method for producing regenerated T cells via iPS cells, comprising: (1) a step for obtaining T cells from a subject, and preparing, from individual cells in T cell population that is reactive to a tumor-related antigen, cDNAs that code for TCR α chain and TCR β chain; (2) a step for initializing a subject-derived peripheral blood mononuclear cells from which B cells and T cells have been removed, or T cells, to iPS cells, and selecting, from the iPS cells thus obtained, iPS cell clones that demonstrate high differentiation efficiency into T cells; (3) a step for introducing the cDNAs into the iPS cell clones, into hematopoietic stem cells differentiated from the iPS cell clones, into immature T cells differentiated from the hematopoietic stem cells, or into mature T cells differentiated from the immature T cells; and (4) a step for differentiating the iPS cell clones, the hematopoietic stem cells or the immature T cells, which are obtained in step (3) and into which the cDNAs have been introduced, into mature T cells and proliferating the mature T cells. Co-pending claim 2 recites a method for producing regenerated T cells via iPS cells, comprising: (1) a step for contacting T cells obtained from a subject with a tumor-related antigen, and preparing, from individual cells in T cell population that is reactive to the tumor-related antigen, cDNAs that code for TCR α chain and TCR β chain; (2) a step for initializing a subject-derived peripheral blood mononuclear cells from which B cells and T cells have been removed, or T cells, to iPS cells, and selecting, from the iPS cells thus obtained, iPS cell clones that demonstrate high differentiation efficiency into T cells; (3) a step for introducing the cDNAs into the iPS cell clones, into hematopoietic stem cells differentiated from the iPS cell clones, into immature T cells differentiated from the hematopoietic stem cells, or into mature T cells differentiated from the immature T cells; and (4) a step for differentiating the iPS cell clones, the hematopoietic stem cells or the immature T cells, which are obtained in step (3) and into which the cDNAs have been introduced, into mature T cells and proliferating the mature T cells. Co-pending claim 3 recites a method for producing regenerated T cells via iPS cells, comprising: (1) a step for contacting T cells obtained from a subject to whom a tumor-related antigen has been administered with the tumor-related antigen, and preparing, from individual cells in T cell population that is reactive to the tumor-related antigen, cDNAs that code for TCR α chain and TCR β chain; (2) a step for initializing a subject-derived peripheral blood mononuclear cells from which B cells and T cells have been removed, or T cells, to iPS cells, and selecting, from the iPS cells thus obtained, iPS cell clones that demonstrate high differentiation efficiency into T cells; (3) a step for introducing the cDNAs into the iPS cell clones, into hematopoietic stem cells differentiated from the iPS cell clones, into immature T cells differentiated from the hematopoietic stem cells, or into mature T cells differentiated from the immature T cells; and (4) a step for differentiating the iPS cell clones, the hematopoietic stem cells or the immature T cells, which are obtained in step (3) and into which the cDNAs have been introduced, into mature T cells and proliferating the mature T cells. The co-pending claims do not teach the TCR chains as derived from a CD106+ T cell population.
Gros et al. teach that exhaustion markers can be used to identify and select tumor-reactive CD8+ TIL TCR clones (See Abstract and fig. 1-6).
Jerby-Arnon et al. teach VCAM1 (which reads on “CD106”) as surface protein that can be used to identify exhausted T cells (See ¶0319 and 0321).
It would have been obvious to isolate TCR genes from CD8+ T cells expressing VCAM1 (which inherently reads on “CD3/CD106 double-positive”) for constructing the cDNA. One would have been motivated to make this modification because Jerby-Arnon et al. teach VCAM1 as marker of exhausted T cells (See ¶0319 and 0321) and because Gros et al. teach that exhaustion markers can be used to identify tumor-specific T cells (See Abstract and fig. 1-6). There would be a reasonable expectation of success in making this modification because T cells could be readily isolated on the basis of VCAM1 expression.
Regarding claim 2: Following the discussion of claims 1 and 19, co-pending claim 4 recites the method according to co-pending claim 3, wherein the step (2) is carried out prior to or in parallel with of step (1).
Regarding claim 4: Following the discussion of claims 1 and 19, co-pending claim 5 recites the method according to co-pending claim 1, wherein the subjects in steps (1) and (2) are the same individual; or wherein the subject in steps (1) and (2) are separate individuals and the subject in step (2) is a subject for cancer prevention or treatment.
Regarding claims 7-8: Following the discussion of claims 1 and 19, co-pending claim 7 recites the method according to co-pending claim 5, further comprising a step for selecting, from the T cells introduced with the cDNAs obtained in step (4), the T cells that do not exhibit an alloreaction to the cells derived from the subject in step (2); or further comprising a step for selecting, from the cDNAs prepared in step (1), cDNAs that code for a TCR that does not induce an alloreaction to the cells derived from the subject in step (2).
Regarding claim 10: Following the discussion of claims 1 and 19, co-pending claim 12 recites the method according to co-pending claim 1, wherein the introduction of the cDNAs into the iPS cell clones, into the hematopoietic stem cells differentiated from the iPS cell clones, into the immature T cells differentiated from the hematopoietic stem cells, or into mature T cells differentiated from the immature T cells in step (3) uses a virus vector, a non-viral vector, or a genome editing technique.
Regarding claim 12: Following the discussion of claims 1, 10, and 19, co-pending claim 13 recites the method according to co-pending claim 12, wherein the non-viral vector is a transposon vector.
Regarding claim 13: Following the discussion of claims 1, 12, and 19, co-pending claim 14 recites the method according to co-pending claim 13, wherein the transposon vector is piggyBac® vector.
Regarding claim 14: Following the discussion of claims 1 and 19, co-pending claim 15 recites the method according to co-pending claim 1, wherein the step (4) for differentiating the iPS cell clones, the hematopoietic stem cells or the immature T cells, into which the cDNAs have been introduced, into mature T cells and proliferating the mature T cells is carried out in the presence of feeder cells and PHA, in the presence of RetroNectin® and anti-CD3 antibodies, or in the presence of anti-CD3 antibodies and anti-CD28 antibodies.
Regarding claim 15: Following the discussion of claims 1, 14, and 19, co-pending claim 16 recites the method according to co-pending claim 15, wherein the feeder cells are autologous or cross peripheral blood mononuclear cells.
Regarding claims 16-18: Following the discussion of claims 1 and 19, co-pending claim 17 recites the method according to co-pending claim 1, wherein the subject in step (2) is a patient with hepatoma or hepatoblastoma.
Regarding claims 20-21: Following the discussion of claims 1 and 19, co-pending claim 20 recites the method according to co-pending claim 1, wherein the hematopoietic stem cells are CD34/CD43 double-positive; and/or wherein the immature T cells are CD8 α chain/β chain double-positive.
Regarding claim 22: Following the discussion of claims 1 and 19, co-pending claim 22 recites the method according to co-pending claim 1, wherein the iPS cell clones selected in step (2), the hematopoietic stem cells differentiated from the iPS cell clones, the immature T cells differentiated from the hematopoietic stem cells, or the mature T cells differentiated from the immature T cells are preserved to construct a master cell bank.
Regarding claim 23: Following the discussion of claims 1, 19, and 22, co-pending claim 23 recites the method according to co-pending claim 22, wherein the preservation is cryopreservation.
Regarding claim 24: Following the discussion of claims 1, 19, and 22, co-pending claim 24 recites the method according to co-pending claim 22, wherein steps (3) and (4) are performed on the iPS cell clones, the hematopoietic stem cells, the immature T cells, or the mature T cells preserved in the master cell bank.
Regarding claim 25: Following the discussion of claims 1, 19, and 22, co-pending claim 30 recites the master cell bank according to co-pending claim 22, comprising the iPS cell clones, the hematopoietic stem cells, the immature T cells, or the mature T cells.
Regarding claim 26: Following the discussion of claims 1 and 19, co-pending claim 31 recites regenerated T cells produced by the method according to co-pending claim 1.
Regarding claim 27: Following the discussion of claims 1, 19, and 26, co-pending claim 33 recites a pharmaceutical composition, comprising the regenerated T cells according to co-pending claim 31.
Regarding claim 28: Following the discussion of claims 1, 19, and 26-27, co-pending claim 34 recites a method for preventing or treating cancer using the pharmaceutical composition according to claim co-pending 33.
Conclusion
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633