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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/7/2026 has been entered.
Claims 1, 4, 10, 12, 15-19, 24-26, 28, 30, 36, 38, 40, 45, 50-51, 53, and 55-56, of record 2/24/2026, are pending and subject to prosecution. Claims 1, 10, 18-19, and 55-56 are amended. Claim 54 has been cancelled.
Status of Prior Rejections
RE: Rejection of claims 18-19 and 55-56 are rejected under 35 U.S.C. 112(b):
The amendment to claims 18-19 and 55-56 is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claims 1, 4, 12, 15-19, 24-26, 28, 30, 36, 38, 40, 45, and 53 under 35 U.S.C. 103 over Reisner et al. (US 20180193384 A1) in view of Delirezh et al. (Cell Journal (Yakhteh), 2013), further in view of Reisner et al. (WO 2018002924 A1):
RE: Rejection of claims 1, 4, 10, 12, 24-26, 28, 30, 36, 38, 40, 45, and 53 under 35 U.S.C. 103 over Reisner et al. (US 20180193384 A1) in view of Delirezh et al. (Cell Journal (Yakhteh), 2013), further in view of Märten et al. (Cancer Immunology, Immunotherapy, 2002), evidenced by ThermoFisher (Product webpage capture, 2018):
RE: Rejection of claims 1, 4, 12, 24-26, 28, 30, 36, 38, 40, 45, 53, and 55-56 under 35 U.S.C. 103 over Reisner et al. (US 20180193384 A1) in view of Delirezh et al. (Cell Journal (Yakhteh), 2013), further in view of Eljaafari et al. (Human Immunology, 1998):
The amendment to claim 1 to require the limitations of cancelled claim 54 is effective to obviate the rejections. The rejections are withdrawn.
RE: Rejection of claims 1, 4, 12, 24-26, 28, 30, 36, 38, 40, 45, and 53 under 35 U.S.C. 103 over Reisner et al. (US 20180193384 A1) in view of Delirezh et al. (Cell Journal (Yakhteh), 2013):
RE: Rejection of claims 1, 4, 12, 24-26, 28, 30, 36, 38, 40, 45, 50-51, and 53 under 35 U.S.C. 103 over Reisner et al. (US 20180193384 A1) in view of Delirezh et al. (Journal of Leukocyte Biology, 1996), further in view of Aversa et al. (Blood Advances, 2017):
Independent claim 1 has been amended to include the limitations of cancelled claim 54. The rejections over claims 1, 4, 10, 12, 15-19, and 55-56 are withdrawn.
Claims 24-26, 28, 30, 36, 38, 40, 45, 50-51, and 53, however, are directed to an isolated population of cells generated according to the method of claim 1 and methods of their use. The cells are described using product-by-process language. 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. See MPEP 2113. Because the instant does not demonstrate that the cells produced by the claimed method differ from any other non-GVHD inducing lymphocytes comprising a Tcm phenotype, which are tolerance inducing and/or endowed with anti-disease activity and capable of homing to the lymph nodes following transplantation, the cells and methods rendered obvious by the combined teachings of the prior art read on the claimed cells and claimed methods of their use. The rejections over claims 24-26, 28, 30, 36, 38, 40, 45, 50-51, and 53 are therefore maintained.
RE: Rejection of claims 1, 15-19, 24-26, 28, 36, and 38 on the ground of nonstatutory double patenting over claims 1-2, 4-5, 8-10, 18-24, 28, and 36-37 of U.S. Patent No. 10961504 in view of Delirezh et al. (Cell Journal (Yakhteh), 2013):
RE: Rejection of claims 1, 12, 15-19, 24-26, 28, 36, and 38 on the ground of nonstatutory double patenting over claims 1-4, 6-16, and 18-21 of U.S. Patent No. 11773372 in view of Delirezh et al. (Cell Journal (Yakhteh), 2013):
The amendment of claim 1 to recite culturing selected CD14+ cells in the presence of maturation factors comprising IL-4, GM-CSF, IFN- and LPS for 10-24 h to obtain mature dendritic cells is effective to obviate the rejections. The rejections are withdrawn.
New/Maintained Objections/Rejections
Claim Objections
Claim 1 is objected to because of the following informalities:
In line 4 of claim 1, “the” should be deleted in front of “lymph nodes”; “the following steps” should be inserted after “comprising” in line 5; “CD14+ expressing” should be inserted after “selected” in line 10; “comprising memory T cells expressing a CD45RA-CD8+ phenotype” should be inserted after “cells” in line 19; and “expressing a CD45RA-CD8+ phenotype” should be inserted in front of “with” in line 20.
Appropriate correction is required.
Claim Interpretation
Claims 24 recites an isolated population of non-GVHD-inducing cells comprising cells having a central memory T-lymphocyte phenotype, said cells being tolerance-inducing and/or endowed with anti-disease activity and capable of homing to the lymph nodes following transplantation, generated according to the method of claim 1 and methods of their use. The cells are described using product-by-process language. 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 cells from Tcm cells generated by other methods, the cells are interpreted as comprising any viral peptide-reactive non-GVHD-inducing Tcm that are tolerance inducing cells and/or endowed with anti-disease activity and capable of homing to the lymph nodes following transplantation.
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 24-26, 28, 30, 36, 38, 40, 45, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Reisner et al. (US 20180193384 A1), of record, in view of Delirezh et al. (Cell Journal (Yakhteh), 2013), of record.
Regarding claim 24: Reisner et al. teach methods for generating an isolated population of Tcm cells that are tolerance-inducing (which reads on “non-GVHD inducing cells ”) and capable of homing to lymph nodes following transplantation (See Abstract). PBMCs are contacted with antigens in the presence of IL-21 to allow enrichment of antigen-reactive cells, and the antigen-reactive cells are cultured in the presence of IL-21, IL-15, and IL-7 to enable proliferation of Tcm cells (See ¶0016 and 0119). The PBMC population for generating TCM cells is depleted of CD4+ and CD56+ cells prior to co-culture with APCs, which can be dendritic cells (See fig. 3A). The Tcm cells can further have a CD8+/CD45RA- signature, and in an embodiment, at least 50% (which reads on “at least 40%”) of the isolated population of Tcm cells comprise a CD3+/CD8+/CD62L+/CD45RA-/CD45RO+ phenotype (which reads on “CD45RA-CD8+ phenotype”) (See ¶0019 and 0053). Antigens can be viral-derived peptides and can be presented by dendritic cells (which reads on loading… antigen presenting cells with viral peptides”) (See ¶0029, 0032, 0135, and 0143 and fig. 3A). The APC can be autologous (which reads on “same donor” and “same donor subject”) (See ¶0031). Immature dendritic cells can be matured in medium comprising IL-4, GM-CSF, IFN-γ, and LPS (See ¶0147). Reisner et al. do not teach dendritic cell generation by the selection of CD14+ cells from PBMCs, wherein the selection is not performed by plastic adherence.
Delirezh et al. teach the generation of dendritic cells from PBMCs, wherein monocytes are isolated from the PBMCs on the basis of plastic adherence or immunomagnetic sorting for CD14+ cells (See Abstract and page 219, col. 2, full ¶2-3 and page 220, col. 1, ¶1). The isolated cells were cultured with GM-CSF and IL-4 prior to exposure to tumor cell antigens (See page 220, col. 1, full ¶1). Delirezh et al. teach that the dendritic cells generated by immunomagnetic selection yielded a lower percentage of phagocytic cells but that those cells had higher phagocytic capacity (See fig. 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 methods of Reisner et al. to comprise selection of CD14+ cells from PBMCs with an anti-CD14 antibody and maturation to dendritic cells, as taught by Delirezh et al. One would be motivated to make this modification because Delirezh et al. teach that dendritic cells generated in this manner exhibited higher phagocytic capacity, which could result in greater antigen loading (See page 222, col. 2, full ¶2 and fig. 3). There would be a reasonable expectation of success in doing so because the PBMCs of Reisner et al. could be readily selected for CD14 expression and matured into a population comprising dendritic cells, which would then read on the claimed population.
Regarding claims 25-26, 28, 30, 36, 38, and 40: Following the discussion of claim 24, Reisner et al. teach that the Tcm cells can be administered to a subject with or sequentially with a cell or tissue transplant and can be transplanted via intravenous infusion (which necessarily reads on “a pharmaceutical acceptable carrier”) in a therapeutically effective amount for reducing graft rejection and GVHD (See ¶0233-0238). A subject can receive transplanted cells or tissues, such as immature hematopoietic cells, prior to the Tcm cells (See ¶0196). The transplanted cells or tissue can be non-syngeneic with the subject (See ¶0197). The subject can be administered 1 × 106 cells/kg to 1 × 107 or 1 × 108 cells/kg body weight (which reads on “at least 2.5 x 106 CD8+ cells per kg ideal body weight”) (See ¶0239).
Regarding claim 45: Following the discussion of claims 1, 12, 24-26, 28, 30, 36, 38, and 40, Reisner et al. teach that the subject can be conditioned with an immunosuppressive regimen prior to, concomitantly with, or following transplantation (See ¶0228). The regimen can include cyclophosphamide (which reads on “non-myeloablative”) (See ¶0232).
Regarding claim 53: Following the discussion of claims 1, 12, 24-26, 28, 30, 36, 38, 40, and 45, Reisner et al. do not list corticosteroids among the immunosuppressive agents that may be used in conjunction with the Tcm cells (which reads on “wherein corticosteroids are not administered”) (See ¶0232).
Claims 24-26, 28, 30, 36, 38, 40, 45, 50-51, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Reisner et al. (US 20180193384 A1), of record, in view of Delirezh et al. (Journal of Leukocyte Biology, 1996), of record, further in view of Aversa et al. (Blood Advances, 2017), of record.
The teachings of Reisner et al. and Delirezh et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 50-51: Following the discussion of claims 24-26, 28, 30, 36, 38, 40, 45, and 53, Reisner et al., modified by Delirezh et al., render obvious the generation of Tcm cells using viral peptide-loaded dendritic cells. Reisner et al. teach that subjects can be administered cyclophosphamide but do not teach the timing or dosage.
Aversa et al. teach a protocol for the transplantation of hematopoietic stem cells in multiple myeloma patients (which read on “subject in need”) (See Abstract). Subjects receive thymoglobulin (days -9 and -7) and fludarabine (days -6 through -2) (which read on “chemotherapeutic agent” and “administered on days -7 to -1”) and total body irradiation (day -1) (See fig. 4). CD3/CD19-depleted CD34+ cells are administered at day 0 at a dosage of 10 × 106 cells (which reads on at least 5 × 106 CD34+ cells per kilogram ideal body weight”) (See fig. 4). The dosage for one subject contained 1.17 × 105 CD3+ T cells/kg (which reads on “less than 5 x 105 CD3+ T cells per kilogram ideal body weight”) and 15.5 × 106 CD34 cells/kg (See page 2169, col. 2, full ¶1). Cyclophosphamide is administered at days 3 and 4 at 50 mg/kg post-transplant (which reads on “two doses one on day 3… and the other on day 4” and “25-200 mg cyclophosphamide per kilogram ideal body weight”) (See fig. 4). Engraftment and complete remission was achieved in one subject (which reads on “therapeutically effective amount”) (See page 2172, col. 1, ¶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 methods of Reisner et al., modified by Delirezh et al., to comprise the complete hematopoietic stem cell transplant protocol taught by Aversa et al. One would be motivated to make this modification for maximizing immune tolerance following cell transplantation for disease treatment (See Aversa et al., Abstract). There would be a reasonable expectation of success in doing so because Reisner et al. teach that administration of Tcm cells can follow transplantation and immunosuppressive therapy (See ¶0067, 0073, and 0228-0229). While Reisner et al. do not expressly teach administration of Tcm on day 6-9 post-transplantation, they teach administration of a therapeutically effective amount of Tcm cells (See ¶0022), which may encompass additional doses on additional days. Timing of treatment is known to be a result-effective variable, and administration on the claimed days would readily be achieved through routine optimization.
Allowable Subject Matter
Claims 1, 4, 10, 12, 15-19, and 55-56 are allowed.
The following is an examiner’s statement of reasons for allowance:
The prior art does not teach or suggest a method of generating an isolated population of non-GVHD inducing cells comprising a Tcm phenotype using viral peptide-loaded dendritic cells produced by contacting a first population of PBMCs from a donor subject with a CD14 antibody for selecting CD14+ expressing cells and culturing the selected cells in the presence of maturation factors comprising IL-4, GM-CSF, IFN-γ, and LPS for 10-24 h to obtain mature dendritic cells.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M Babic, can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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