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, 4, 10, 12, 15-19, 24-26, 28, 30, 36, 38, 40, 45, 50-51, 53-56, of record 9/30/2025, are pending and subject to prosecution. Claims 1, 12, 17-19, 25, 30, and 50-51 are amended. Claims 2-3, 5, and 11 are cancelled. Claims 54-56 are newly added.
Status of Prior Rejections/Response to Arguments
RE: Objection to the drawings:
The submission of replacement drawings is effective to obviate the objection. The objection is withdrawn.
RE: Objection to claim 25:
The amendment to claim 25 is effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claims 1, 3, 18-19, and 50-51 under 35 U.S.C. 112(b):
The cancellation of claim 3 renders the rejection thereto moot.
The amendment to claims 1, 18-19, and 50-51 is effective to obviate the rejection. The rejection is withdrawn.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 Kiertscher et al. (Journal of Leukocyte Biology, 1996):
RE: Rejection of claims 1-4, 11-12, 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 Kiertscher et al. (Journal of Leukocyte Biology, 1996), 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 Kiertscher et al. (Journal of Leukocyte Biology, 1996), 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, 50-51, and 53 under 35 U.S.C. 103 over Reisner et al. (US 20180193384 A1) in view of Kiertscher et al. (Journal of Leukocyte Biology, 1996), further in view of Aversa et al. (Blood Advances, 2017):
RE: Rejection of claims 1-3, 5, 11, 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 and 11773372:
RE: Rejection of claims 1-3, 5, 11-12, 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:
The cancellation of claims 2-3, 5, and 11 renders the rejections thereto moot.
The amendment to independent claim 1, wherein the method requires selection of CD14+ that does not comprise plastic adherence, is effective to obviate the rejections.
The rejections are withdrawn.
While the rejections of record are withdrawn in light of the applicant’s amendments to the claims, the arguments of record 9/30/25 are addressed below for completeness of record:
The applicant asserts that Reisner et al., in teaching selection based on plastic adherence, teach away from a method of producing dendritic cells from CD14+ cells that does not comprise a plastic adherence selection step (Applicant Remarks, page 11). The applicant asserts that selection of CD14+ cells without prior plastic adherence is thought to be described only by Elkord et al. prior to the effective filing date of the claimed invention, further underscoring the non-obviousness of the instant claims as Elkord et al. describe a distinct and inferior dendritic cell population resulting from selection with a CD14 antibody (Applicant Remarks, page 11-12). The applicant also asserts that the methods of Reisner et al. involves contacting a starting population of PBMCs with antigen, unlike the instant claims which comprise contacting memory T cells with antigen, which would yield different results compared to the claimed method (Applicant Remarks, page 12).
The applicant’s arguments have been fully considered but are not found persuasive. The teachings of Reisner et al. do not rise to the level of teaching away, as they do not proscribe or disparage the use of a selection step that does not include plastic adherence. Disclosed examples and preferred embodiments do not constitute a teaching away. See MPEP 2123(II). Further, Delirezh et al. also directly compare dendritic cells generated via plastic adherence and CD14 immunoselection and suggest that the latter have superior phagocytic activity (See page 222, col. 2, full ¶2 and fig. 3). In recommending MACS selection over plastic adherence, Delirezh et al. provide motivation for choosing immunoselection over plastic adherence, as well as a reasonable expectation of success in not only incorporating a step of CD14+ selection into methods of generating dendritic cells but also yielding highly-functional dendritic cells from doing so.
Additionally, the instant claims feature the transitional term “comprising”, which is inclusive or open-ended and does not exclude additional unrecited steps or elements, such as the contacting of PBMCs with antigen. See MPEP 2111.03(I). The limitations of instant claim 1 are therefore still taught by Reisner et al., with the exception of CD14+ cell selection by a method that omits plastic adherence.
New Rejections
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 18-19 and 55-56 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.
Claim 18 recites “wherein said viral peptides comprise at least one of… BKV LT, -BKV, -BKV, and BKV”. It is unclear which peptides are required by “-BKV” and “BKV”. The metes and bounds of the claim thus cannot be determined.
Claim 19 recites “EBV peptide”. It is unclear which peptide is required by the claim. The metes and bounds of the claim thus cannot be determined.
Claims 55-56 recite the limitation "said culturing" in line 1. Because parent claim 1 recites culturing in multiple steps, it is unclear which step (or steps) requires the limitations of claims 55-56. The metes and bounds of the claim thus cannot be determined.
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, 4, 12, 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).
Regarding claims 1, 12, and 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). 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, or culturing with maturation factors prior to antigen loading.
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 (which read on “maturation factors”) 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.
Regarding claim 4: Following the discussion of claims 1, 12, and 24, Reisner et al. teach the PBMCs used for large-scale experiments were derived from a single batch of cryopreserved cells (which reads on “said first population of said PBMCs and said second population of said PBMCs are from the same batch”) (See ¶0323).
Regarding claims 25-26, 28, 30, 36, 38, and 40: Following the discussion of claims 1, 12, and 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 1, 4, 12, 15-19, 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), further in view of Reisner et al. (WO 2018002924 A1), 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 15-19: Following the discussion of claims 1, 4, 12, 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 but do not teach the peptides as derived from 4-10 viruses.
Reisner et al. (‘924) teach a method of generating non-GVHD-inducing Tcm cells by using a population of APCs, including dendritic cells (See Abstract and, page 7, line 1-7). The antigens can comprise four or more viral antigens and can comprise antigens from different viruses, such as BK polyoma virus, EBV, CMV, and adenovirus (See page 7, line 10-19; page 21, line 3-27; and page 26, line 10-20). The antigens can include CMV (which reads on “hCMV”) pp65 (See page 21, line 9-27). Reisner et al. (‘924) teach that antigenic peptides from viruses such as CMV, EBV, and adenovirus, displayed by dendritic cells could be used to deplete CD8+ T cells of GVHD reactivity (See page 16, line 3-8 and page 70, line 21-31).
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 Reisner et al., modified by Delirezh et al., to comprise peptides from multiple viruses, as taught by Reisner et al. (‘924). One would be motivated to make this modification because Reisner et al. (‘924) teach that the use of viral antigenic peptides could be used for decreasing GVHD reactivity in Tcm cells (See page 16, line 3-8 and page 70, line 21-31). There would be a reasonable expectation of success in doing so because the dendritic cells of Reisner et al. could be readily loaded with peptides derived from multiple viruses, which could readily encompass four or more viruses.
Claims 1, 4, 10, 12, 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), further in view of Märten et al. (Cancer Immunology, Immunotherapy, 2002), of record, evidenced by ThermoFisher (Product webpage capture, 2018), 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 claim 10: Following the discussion of claims 1, 4, 12, 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 in a T cell medium but do not teach co-culture in a medium comprising at least 50 mg/dl glucose (See ¶0269-0270).
Märten et al. teach the co-culture of antigen-loaded dendritic cells and CD8+ T cells in a medium comprising RPMI-1640 (See page 26, col. 1, full ¶4-5 and col. 2, ¶1).
ThermoFisher teaches that RPM-1640 contains 2000 mg/l D-glucose (which reads on “glucose to a concentration of at least 50 mg/dl”) (See product webpage capture).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the method of Reisner et al., modified by Delirezh et al., to substitute the RPMI-1640-based medium taught by Märten et al. in place of the T cell culture medium. Substitution of a known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predictable results.
Claims 1, 4, 12, 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) in view of Delirezh et al. (Journal of Leukocyte Biology, 1996), further in view of Aversa et al. (Blood Advances, 2017).
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 1, 4, 12, 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 teach administration of Tcm on day 6-9 post-transplantation, time of treatment is known to be a result-effective variable and administration on the claimed days would readily be achieved through routine optimization.
Claims 1, 4, 12, 24-26, 28, 30, 36, 38, 40, 45, 53, and 55-56 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), further in view of Eljaafari et al. (Human Immunology, 1998).
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 55-56: Following the discussion of claims 1, 4, 12, 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 but do not teach monitoring or adjusting pH levels.
Eljaafari et al. teach methods for generating monocyte-derived dendritic cells at different culture pH (See Abstract). Supernatant pH was monitored and supplemented throughout the culture period (See page 626, col. 2, full ¶1 and page 628, col. 2, ¶1). Dendritic cells produced by maintaining culture pH at 7.4 demonstrated greater maturity than cells cultured at pH 7 or 7.2 (See fig. 1-6).
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 monitoring and adjusting the dendritic cell maturation medium to pH 7.4. One would be motivated to make this modification because Eljaafari et al. teach that maintaining a pH of 7.4 improves dendritic cell maturation (See Abstract). There would be a reasonable expectation of success in doing so because the culture pH could be readily measured and adjusted.
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, 15-19, 24-26, 28, 36, and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable 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).
Regarding claims 1, 15-19, 24-26, 28, 36, and 38: Patented claim 1 recites a method of generating an isolated population of non graft versus host disease (GvHD) inducing anti-viral, anti-bacterial and/or anti-tumor cells comprising a central memory T-lymphocyte (Tcm) phenotype, said cells being tolerance inducing cells and/or endowed with anti-viral, anti-bacterial and/or anti-tumor activity, and capable of homing to the lymph nodes following transplantation, the method comprising: (a) providing a population of T cells comprising at least 50% memory T cells; (b) contacting said population of T cells with a viral, bacterial and/or tumor antigen or antigens in the presence of IL-21 so as to allow enrichment of antigen reactive cells; and (c) culturing said cells resulting from step (b) in the presence of any of IL-21, IL-15 and/or IL 7 so as to allow proliferation of cells comprising said Tcm phenotype. Patented claim 2 recites the method of patented claim 1, wherein said memory T cells: are depleted of CD45RA+ cells; and/or are depleted of CD4+ and/or CD56+ cells. Patented claim 4 recites the method of patented claim 1, wherein said population of T cells comprising said at least 50% memory T cells are enriched towards said viral, bacterial and/or tumor antigen or antigens. Patented claim 5 recites a method of generating an isolated population of non-GvHD inducing anti-viral, anti-bacterial and/or anti-tumor cells comprising a central memory T-lymphocyte (Tcm) phenotype, said cells being tolerance inducing cells and/or endowed with anti-viral, anti-bacterial and/or anti-tumor activity, and capable of homing to the lymph nodes following transplantation, the method comprising: (a) treating peripheral blood mononuclear cells (PBMCs) with an agent capable of depleting CD4+, CD56+ and CD45RA+ cells, or with an agent capable of selecting CD45RO+, CD8+ cells, so as to obtain a population of cells enriched of memory T cells comprising a CD45RO+CD45RA−CD8+ phenotype; (b) contacting said population of cells enriched of memory T cells with aft viral, bacterial and/or tumor antigen or antigens in the presence of IL-21 so as to allow enrichment of antigen reactive cells; and (c) culturing said cells resulting from step (b) in the presence of IL-21, IL-15 and/or IL-7 so as to allow proliferation of cells comprising said Tcm phenotype. Patented claim 8 recites the method of patented claim 1, wherein said viral antigen or antigens comprises two or more viral peptides. Patented claim 9 recites the method of patented claim 1, wherein said viral antigen or antigens comprises an EBV peptide, a CMV peptide, an Adenovirus (Adv) peptide, and/or a BK virus peptide. Patented claim 10 recites the method of patented claim 1, wherein said viral antigen or antigens: is selected from the group consisting of EBV-LMP2, EBV-BZLF1, EBV-EBNA1, CMV-pp65, CMV-IE-1, Adv-penton and Adv-hexon; and/or comprises two or more of EBV-LMP2, EBV-BZLF1, EBV-EBNA1, CMV-pp65, CMV-IE-1, Adv-penton and Adv-hexon. Patented claim 18 recites the method of patented claim 1, wherein said cells having said Tcm phenotype comprise a CD3+, CD8+, CD62L−, CD45RA−, CD45RO+ signature. Patented claim 19 recites an isolated population of non-GvHD inducing anti-cells comprising cells having a central memory T-lymphocyte (Tcm) phenotype, said cells being tolerance inducing cells and/or endowed with anti-viral, anti-bacterial and/or anti-tumor activity, and capable of homing to the lymph nodes following transplantation, generated according to the method of patented claim 1. Patented claim 20 recites a pharmaceutical composition comprising as an active ingredient the isolated population of non-GvHD inducing anti-viral, anti-bacterial and/or anti-tumor cells of patented claim 19 and a pharmaceutical acceptable carrier. Patented claim 21 recites a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the isolated population of non-GvHD inducing anti-viral, anti-bacterial and/or anti-tumor cells of patented claim 19, thereby treating the disease in the subject. Patented claim 23 recites method of patented claim 21, further comprising transplanting a cell or tissue transplant into the subject. Patented claim 24 recites a method of treating a subject in need of a cell or tissue transplantation, the method comprising: (a) transplanting a cell or tissue transplant into the subject; and (b) administering to the subject a therapeutically effective amount of the isolated population of non-GvHD inducing anti-viral, anti-bacterial and/or anti-tumor cells of patented claim 19, thereby treating the subject in need of the cell or tissue transplantation. Patented claim 28 recites the method of patented claim 24, wherein said cell or tissue transplant is non-syngeneic with the subject. Patented claim 36 recites the method of patented claim 1, wherein said population of T cells is obtained by treating peripheral blood mononuclear cells (PBMCs) with an agent capable of depleting CD4+, CD56+ and CD45RA+ cells, or with an agent capable of selecting CD45RO+, CD8+ cells. Patented claim 37 recites the method of patented claim 5, wherein said population of cells enriched of memory T cells are depleted of CD4+ T cells, CD56+NK cells and/or CD45RA+naïve T cells.
The patented claims do not teach selection of CD14+ cells by a method that does not comprise 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 (which read on “maturation factors”) (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 patented method 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 the patented claims could be readily selected for CD14 expression and matured into a population comprising dendritic cells.
Claims 1, 12, 15-19, 24-26, 28, 36, and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable 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). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
Regarding claims 1, 12, 15-19, 24-26, 28, 36, and 38: Patented claim 1 recites a method of generating an isolated population of non graft versus host disease (GvHD) inducing cells comprising a central memory T-lymphocyte (Tcm) phenotype, said cells being tolerance inducing cells and/or endowed with anti-disease activity, and capable of homing to the lymph nodes following transplantation, the method comprising: (a) providing a population of T cells comprising at least 70% memory T cells; (b) contacting said population of T cells with an antigen or antigens so as to allow enrichment of antigen reactive cells; and (c) culturing said cells resulting from step (b) in the presence of cytokines in an antigen free environment so as to allow proliferation of cells comprising said Tcm phenotype, thereby generating the isolated population of non-GvHD inducing cells. Patented claim 2 recites the method of patented claim 1, wherein said memory T cells: are depleted of CD45RA+ cells; and/or are depleted of CD4+ and/or CD56+ cells. Patented claim 3 recites the method of patented claim 1, wherein said contacting said population of T cells with an antigen or antigens occurs in the presence of IL-21. Patented claim 4 recites the method of patented claim 1, wherein said culturing said cells resulting from step (b) in the presence of cytokines comprises culturing said cells in the presence of any of IL-21, IL-15 and/or IL-7. Patented claim 6 recites the method of patented claim 1, wherein said antigen or antigens is selected from the group consisting of a viral antigen or antigens, a bacterial antigen or antigens, a tumor antigen or antigens, an autoimmune disease related antigen or antigens, a protein extract, a purified protein and a synthetic peptide. Patented claim 7 recites the method of patented claim 6, wherein said viral antigen or antigens are obtained from a virus selected from the group consisting of an Epstein-Barr virus (EBV), an Adenovirus (Adv), a cytomegalovirus (CMV), a BK virus, a Hepatitis virus, a Herpes simplex virus, a Human immunodeficiency virus (HIV), an Influenza virus, a Japanese encephalitis virus, a Polio virus, a Rabies virus, a Respiratory syncytial virus (RSV), a Rubella virus, a Smallpox virus, a Varicella zoster virus, a Rotavirus, a West Nile virus and a Zika virus. Patented claim 8 recites the method of patented claim 1, wherein said antigen or antigens is presented by antigen presenting cells. Patented claim 9 recites the method of patented claim 1, wherein said antigen or antigens is presented by autologous antigen presenting cells, non-autologous antigen presenting cells, artificial vehicles or artificial antigen presenting cells. Patented claim 10 recites the method of patented claim 1, wherein said antigen or antigens is presented by antigen presenting cells of the same origin as said memory T cells. Patented claim 11 recites method of generating an isolated population of non-GvHD inducing cells comprising a central memory T-lymphocyte (Tcm) phenotype, said cells being tolerance inducing cells and/or endowed with anti-disease activity, and capable of homing to the lymph nodes following transplantation, the method comprising: (a) treating peripheral blood mononuclear cells (PBMCs) with an agent capable of depleting CD4+, CD56+ and CD45RA+ cells, or with an agent capable of selecting CD45RO+, CD8+ cells, so as to obtain a population of cells comprising T cells enriched in memory T cells comprising a CD45RO+CD45RA−CD8+ phenotype; (b) contacting said population of cells resulting from step (a) with an antigen or antigens in the presence of IL-21 so as to allow enrichment of antigen reactive cells; and (c) culturing said cells resulting from step (b) in the presence of IL-21, IL-15 and/or IL-7 in an antigen free environment so as to allow proliferation of cells comprising said Tcm phenotype, thereby generating the isolated population of non-GvHD inducing cells. Patented claim 12 recites a method of generating an isolated population of non-GvHD inducing cells comprising a central memory T-lymphocyte (Tcm) phenotype, said cells being tolerance inducing cells and/or endowed with anti-disease activity, and capable of homing to the lymph nodes following transplantation, the method comprising: (a) treating peripheral blood mononuclear cells (PBMCs) with an agent capable of depleting CD4+, CD56+ and CD45RA+ cells, or with an agent capable of selecting CD45RO+, CD8+ cells, so as to obtain a population of cells comprising T cells enriched in memory T cells comprising a CD45RO+CD45RA−CD8+ phenotype; (b) contacting said population of cells resulting from step (a) with a viral antigen or antigens in the presence of IL-21 so as to allow enrichment of antigen reactive cells; and (c) culturing said cells resulting from step (b) in the presence of IL-21, IL-15 and/or IL-7 in an antigen free environment so as to allow proliferation of cells comprising said Tcm phenotype, thereby generating the isolated population of non-GvHD inducing cell. Patented claim 13 recites the method of patented claim 12, wherein said viral antigen or antigens comprises an EBV peptide, a CMV peptide, an Adenovirus (Adv) peptide, and/or a BK virus peptide. Patented claim 14 recites an isolated population of non-GvHD inducing cells generated according to the method of patented claim 1. Patented claim 15 recites a pharmaceutical composition comprising as an active ingredient the isolated population of non-GvHD inducing cells of patented claim 14 and a pharmaceutical acceptable carrier. Patented claim 16 recites a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the isolated population of non-GvHD inducing cells of patented claim 14, thereby treating the disease in the subject. Patented claim 18 recites a method of treating a subject in need of a cell or tissue transplantation, the method comprising: (a) transplanting a cell or tissue transplant into the subject; and (b) administering to the subject a therapeutically effective amount of the isolated population of non-GvHD inducing cells of patented claim 14, thereby treating the subject in need of the cell or tissue transplantation. Patented claim 19 recites the method of patented claim 12, wherein said viral antigen or antigens comprises three EBV peptides, two CMV peptides and two Adenovirus (Adv) peptides. Patented claim 20 recites the method of patented claim 12, wherein said viral antigen or antigens is/are selected from the group consisting of EBV-LNP2, EBV-BZLF1, EBV-EBNA1, CMV-pp65, CMV-IE-1, Adv-penton, and/or Adv-hexon. Patented claim 21 recites the method of patented claim 12, wherein said viral antigen or antigens comprises two or more of EBV-LMP2, EBV-BZLF1, EBV-EBNA1, CMV-pp65, CMV-IE-1, Adv-penton and Adv-hexon.
The patented claims do not teach selection of CD14+ cells by a method that does not comprise 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 (which read on “maturation factors”) (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 patented method 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 the patented claims could be readily selected for CD14 expression and matured into a population comprising dendritic cells.
Allowable Subject Matter
Claim 54 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
The prior art does not teach or suggest the generation of mature dendritic cells from PBMC-derived CD14+ cells in 24h or less.
Conclusion
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.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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