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 .
1. The Amendment filed March 31, 2026 in response to the Office Action of October 31, 2025, is acknowledged and has been entered. Claims 1-8, 10-12, 14-18, 20 are pending. Claim 20 is amended. Claims 4-8, 11, 12, 15-17 remain withdrawn. Claims 1-3, 10, 14, 18, and 20 are currently being examined as drawn to the elected species of:
A. (i) Chemotherapeutic (claims 2 and 3);
B. (iii) Further comprising administering an amino-bisphosphonate prior to the administration of the donor-derived allogeneic yδ-T cells (claims 9 and 10);
C. (iii) Further comprising culturing the yδ-T cells with one or more of agents listed in claim 18; and IL-15 or vitamin C; and
D. (i) Further comprising repeating steps (a) and (b) one or more times, wherein the donor-derived allogeneic yδ-T cells for each subsequent administration are from a different donor having a full HLA mismatch as compared to the subject and the previous donor(s) (claim 20).
Claim Interpretation
2. Claim 20 is amended to recite:
The method of claim 1, further comprising c) allowing immune function to recover in said subject to reject said donor-derived allogeneic γδ-T cells before repeating steps (a) - (c) one or more times, wherein the donor-derived allogeneic γδ- T cells for each subsequent administration are from a different donor having a full HLA mismatch as compared to the subject and the previous donor(s), and wherein the donor-derived allogeneic γδ-T cells for each subsequent administration are from a different donor that does not share any human leukocyte antigens with the subject and the previous donor(s).
Claim 20 now requires a step of: c) allowing immune function to recover in said subject to reject said donor-derived allogeneic γδ-T cells before any subsequent lymphodepletion and administration of donor-derived allogeneic γδ- T cells that are a full HLA mismatch. Claim 20 no longer recites and requires repeating lymphodepletion and administration of donor-derived allogeneic γδ-T cells. The claim only requires that the immune function is allowed to recover in the subject prior to any future repeat of steps (a)-(c) that have yet to occur.
Maintained Rejections
(amendments addressed)
Claim Rejections - 35 USC § 103
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.
3. Claim(s) 1-3, 10, 14, 18, and 20 remain rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2016/0256487, Cooper and Deniger, published September 2016, in view of Wilhelm et al (Journal of Translational Medicine, 2014, 12:45, internet pages 1-5); Zumwalde et al (JCI Insight, 2017, 2(13):e93179, internet pages 1-15); Handgretinger et al (Blood, March 2018, 131:1063-1072); Nicol et al (British Journal of Cancer, 2011, 105:778-786); Deniger et al (Frontiers in Immunology, 2014, 5:article 636; p. 1-10);Torikai et al (Molecular Therapy, 2016, 24:1178-1186); Salot et al (Journal of Immunological Methods, 2009, 347:12-18); Thedrez et al (Journal of Immunology, 2009, 182:3423-3431); and WO 2016/005752, Leek et al, published January 2016 (IDS).
Cooper and Deniger teach a method of treating cancer in a human subject, the method comprising:
administering at least one dose of donor-derived allogeneic yδ-T cells to the subject, wherein the yδ-T cells are expanded ex vivo by culturing the yδ-T cells with an amino-bisphosphonate (zoledronic acid) expansion compound prior to administration of the yδ-T cells to the subject;
wherein the treatment results in an anti-tumor response in the subject;
wherein the cancer subject and the donor of the donor-derived allogeneic yδ-T cells can have either partial HLA mismatch (haploidentical) or full HLA mismatch, wherein they do not share any human leukocyte antigens ([7-8]; [9-15]; [21-32]; [60-65]; [69-78]; Examples; claims 1-6, 33-46);
wherein the yδ-T cells include Vy9 and Vδ2 subsets ([7]; [10]; [61-62]; Examples; Figures);
wherein the yδ-T cells are cultured with IL-2 or IL-15 for expansion prior to administration ([70]);
wherein multiple doses and administrations of the yδ-T cells are given to achieve therapeutic efficacy (Figure 18; Examples; [55]; [76-79]; [138-139]; [158]).
Cooper and Deniger recognize that human yδ-T cells have natural anti-tumor immunity and their utility in the clinic is restricted to one lineage, Vy9Vδ2, even though other Vδ-T cells can recognize and kill tumors. Polyclonal Vδ-T cells including Vy9Vδ2 lineage can be used to target multiple ligands on the tumor surface and maximize therapeutic efficacy ([60]). Adoptive transfer of Vy9Vδ2 T cells has already been demonstrated to yield objective clinical responses for investigational treatment of cancer ([7]). Cooper and Deniger teach that the T-cell receptor (TCR) on yδ-T cells recognizes antigen outside of the MHC restriction, therefore MHC mismatched yδ-T cells can be given to unrelated patients and serve as a universal source of tumor-reactive T cells. As such, yδ-T cells generated from one donor may be infused into one or more allogeneic recipients that may or may not share HLA with the donor. This provides an “off-the-shelf” therapy in which yδ-T cells can be both pre-prepared and infused on demand ([60]).
Cooper and Deniger demonstrate successfully lysing a wide variety of tumor cells with polyclonal yδ-T cells or Vδ2 T cell subsets, and establish Vδ2 cells as having the highest efficacy for lysing tumor cells compared to Vδ1 and Vδ1neg / Vδ2 neg cells (Examples, [60-62]; Figures 13-18; [134-139]). Human Vδ2 T cells and polyclonal yδ-T cells significantly reduced tumors in mice compared to controls (Figure 18; [55]; [139]). Cooper and Deniger suggest that a large bank of yδ-T cells can be manufactured and given to unrelated patients safely for the treatment of cancer ([63-64]).
Cooper and Deniger do not teach:
the method further comprises administering at least one lymphodepletion treatment to the subject before administration of yδ-T cells that comprises cyclophosphamide (claim 1);
administering an amino-bisphosphonate to the subject prior to the administration of the donor-derived yδ-T cells (claim 1);
the ex vivo expansion of yδ-T cells comprises synthetic phosphoantigen including C-HDMAPP (claim 1 and 14); and
following treatment, allowing immune function to recover in the subject to reject the donor-derived allogeneic T cells (claim 20).
Zumwalde teaches: “γδ T cells are attractive candidates for adoptive immunotherapy in human cancer patients because they mediate potent antitumor effects in an MHC-independent manner (1-4), and therefore they do not require HLA matching of donors and recipients” (Introduction p. 1). Zumwalde exemplifies successfully expanding human Vy9Vδ2-T cells ex vivo in the presence of zoledronic acid (Zometa) and IL-2 (p. 5), and administering them to an NSG mouse tumor model, wherein the adoptively transferred Vy9Vδ2-T cells persisted for at least 1 week (Figure 4), and wherein early treatment resulted in prevention of tumors (Figure 5; p. 7), and later treatment resulted in significantly reduced mass of established tumors (Figure 6; p. 7). Zumwalde cites Nicol (below) and other studies demonstrating clinical success of zoledronic acid (Zometa)-expanded γδ T cell therapy of cancers (p. 11). Zumwalde demonstrates the success of treating tumors in NSG mice (immunosuppressed environment) with human Vy9Vδ2-T cells that are a full HLA mismatch to mice.
Wilhelm teaches a method for treating cancer in a human subject, the method comprising:
(a) administering at least one lymphodepletion/immunosuppression treatment of fludarabine + cyclophosphamide to the subject;
(b) administering amino-bisphosphonate zolendronate (ZOL, zoledronic acid) and IL-2 to the subject intended for in vivo yδ-T cell expansion; and
(b) subsequently administering allogeneic donor HLA-mismatched yδ-T cells to the subject, wherein the donor allogeneic yδ-T cells are haploidentical, meaning partial HLA mismatch (Methods and Materials; Figure 1);
wherein the method resulted in an anti-tumor response in the subject including significant expansion of donor yδ-T cells, and complete remission (p. 2, “Engraftment and expansion of donor cells” col. 2 to p. 4, col. 1; and “Efficacy” p. 4, col. 2).
Wilhelm teaches yδ-T cells can exert significant MHC-unrestricted activity against a broad spectrum of tumor cells in vitro, especially hematological neoplasia. It is known that Vy9Vδ2-T cells, which represent the vast majority of human circulating yδ-T cells, recognize aminobisphosphonates such as pamidronate or zoledronate (p. 2, col. 1). Wilhelm teaches they previously demonstrated successful in vivo activation and proliferation of autologous (self) yδ-T cells by prior in vivo administration of pamidronate or zoledronate and IL-2, for clinical treatment of cancer and this demonstrated anti-tumor activity (p. 2, col. 1). Wilhelm recognizes that a problem of autologous yδ-T cell-mediated tumor-immunotherapy is the frequent impaired function of yδ-T cells in up to 50-70% cancer patients. Wilhelm suggests the adoptive transfer of allogeneic donor haploidentical yδ-T cells for in vivo expansion of these innate effector cells for cancer treatment (p. 2, col. 1).
Wilhelm determined that selective stimulation of allogeneic yδ-T cells with aminobisphosphonate and IL-2 can be accompanied by activity in vivo without inducing graft-versus-host-disease (GVHD) (Conclusion on p. 4).
Wilhelm teaches the patients’ immune functions were allowed to recover, eventually rejecting the donor-derived allogeneic yδ-T cells, demonstrating decline in yδ-T cell levels (Figure 1; p. 4, col. 1).
Torikai teaches motivation to develop “off-the-shelf” T cell therapies and recognize that patients should avoid rejection of these allogeneic cell therapies (due to HLA mismatch) by suppressing the immune system through lymphodepletion by CY or fludarabine (p. 1179, col. 2; Figure 1; Table 3; p. 1184, col. 2).
Handgretinger teaches GVDH is caused by alloreactive T lymphocytes, which express the αβ T-cell receptor, whereas lymphocytes expressing the yδ T-cell receptor are not alloreactive and do not induce GVHD. Therefore, yδ T cells are becoming increasingly interesting in allogeneic hematopoietic stem cell transplantation (HCT), and clinical strategies to exploit the full function of these lymphocytes are being developed. Such strategies encompass in vivo or ex vivo expansion of yδ-T cells and adoptive transfer of ex vivo-activated yδ-T cells. The introduction of large-scale clinical methods to enrich, isolate, expand, and manipulate yδ-T cells will facilitate future clinical studies that aim to exploit the function of these beneficial nonalloreactive lymphocytes (abstract; Introduction p. 1063; Future perspectives p. 1066). Handgretinger teaches yδ-T cells can exert effective antitumor activity against various solid tumors and hematologic malignancies (p. 1063, col. 2). yδ-T cells can be expanded ex vivo by aminobisphosphonates such as zoledronate and with IL-2. In the absence of monocytes, IPPs or related phosphoantigens are necessary for yδ-T cell expansion. It has been demonstrated that IPP combined with IL-15 enhances the proliferation of purified yδ-T cells and the cells demonstrated an activated phenotype with increase cytotoxicity toward lymphoma and multiple myeloma targets, secreting high amounts of pro-inflammatory cytokines. Adding IL-15 to IL-2/zoledronate also boosted the expansion of yδ-T cell from PBMCs (p. 1065, col. 1-2). Handgretinger illustrates a method of expanding allogeneic donor yδ-T cells ex vivo and adoptively transferring yδ-T cells to patients (Figure 2). Handgretinger cites Wilhelm (above) for an example of clinical cancer treatment with adoptively transferred yδ-T cells from allogeneic haploidentical (partial HLA mismatch) donors into lymphodepleted recipients (p. 1065, col. 2).
Nicol demonstrates successfully combining steps of in vivo and ex vivo activation and expansion of yδ-T cells by exposure of yδ-T cells to aminobisphosphonate to treat cancer patients. Nicol teaches Vy9Vδ2-T cells have a unique capacity to recognize and be activated and expanded by non-peptide phosphoantigens and aminobisphosphonate drugs, such as zoledronate and pamidronate (p. 778, col. 1-2). Nicol teaches a method for treating cancer in a human subject, the method comprising:
(a) administering aminobisphosphonate zoledronate to the cancer patients (p. 779, col. 1 “Treatment protocols”);
(b) subsequently administering autologous Vy9Vδ2-T cells, wherein the autologous yδ-T cells were expanded/activated ex vivo by culturing with IL-2 and zoledronate (p. 780, col. 1, “Proliferation and preparation of Vy9Vδ2-T cells”);
wherein the method resulted in an anti-tumor response in the subject including complete and partial responses, particularly in the Group C patients that additionally received chemotherapy (Table I; p. 783, col. 1-2; “Clinical outcome of Vy9Vδ2-T cell administration” and “Treatment outcome”). Nicol suggests combining Vy9Vδ2-T cell immunotherapy with chemotherapy (p. 785, col. 2).
Nicol teaches adoptive transfer of Vy9Vδ2-T cells as a therapeutic modality has a number of distinct advantages over active immune therapy with vaccines and direct stimulation of Vy9Vδ2-T cells in vivo with pharmaceutical agents or vaccines, but can also be seen as an additional mode of therapy with its own unique set of roles, rather than simply as an alternative to active immunotherapy (p. 779, col. 1).
Nicol recognized that patients need higher Vy9Vδ2-T cell doses for clinical benefit, and there were problems achieving a high enough dose from in vitro expansion of autologous cancer patient Vy9Vδ2-T cells (p. 784, col. 1). Nicol teaches that healthy donor Vy9Vδ2-T cells expand massively when stimulated in vitro by IL-2 in combination with phosphoantigens or bisphosphoates, however Vy9Vδ2-T cells from patients with cancer seem less reproducible (p. 779, col. 1).
Deniger summarizes known studies clinically treating cancer patients with ex vivo expanded yδ-T cells that were cultured with phosphoantigen (BrHPP, 2M3BIPP) and/or zoledronate (Table 1). Deniger teach that yδ-T cells are unlikely to cause GVHD due to their ligands not being MHC restricted, and suggest yδ-T cell therapy could be generated from healthy donors in a third part manufacturing facility, and administered in the allogeneic setting as an “off-the-shelf” therapeutic. Deniger recognizes there are cases where T cells are difficult to manufacture due to high tumor burden, and the production and administration of third party “off-the-shelf” allogeneic yδ-T cells can be a solution. Deniger also recognizes that third party “off-the-shelf” allogeneic yδ T cells would need to be administered while the patient is immunosuppressed so that they do not reject the adoptive therapy (p. 6, col. 2). Deniger concludes (p. 7, col. 1): “Given the development of aminobisphosphonates, synthetic phosphoantigens, immobilized antigens, antibodies, and designer clinical-grade aAPC, it now appears practical to sculpt and expand yδ T cells to achieve a therapeutic effect.”
Salot also recognizes that yδ-T cells respond to non-processed and non-peptidic phosphoantigens in an MHC-unrestricted manner (p. 12, col. 1). Salot teaches expanding yδ-T cells ex vivo with phosphopantigen for clinical cell therapies (p. 12, col. 2). Salot teaches a successful protocol for large scale production/expansion of purified Vy9Vδ2-T cells from donor PBMCs utilizing ex vivo culture with phosphoantigen (BrHPP or C-HDMAPP) (section 3 and 4.3). Salot suggest cell manufacturing units use their protocol to obtain a yδ-T cell therapy product (p. 17, col. 1).
Thedrez teaches it is known that phosphoantigens or aminobisphosphonates together with IL-2 trigger selective outgrowth of Vy9Vδ2-T cells in vitro and in vivo in cancer patients (p. 3423, col. 2). Thedrez exemplifies successful ex vivo expansion/activation of healthy donor Vy9Vδ2-T cells by culturing with phosphoantigen C-HDMAPP (p. 3424, col. 1 “Expansion of human Vy9Vδ2 PBL”; Figures 1 and 2).
Leek teaches producing allogeneic yδ-T cell compositions for the treatment of cancer. Leek, like the combined references, recognizes that allogeneic yδ-T cell therapy is feasible because the cells are capable of targeting cancer cells for cytolysis independently of MHC-haplotype, and GVHD risk is minimal. Leek also recognizes that there is a low risk of cell graft rejection in immunocompromised patients (“Summary of the Invention”). Leek teaches culturing donor PBMCs with zoledronic acid and IL-2 to activate and proliferate the yδ-T cells prior to administration. Leek teach it is known that ex vivo expansion of donor yδ-T cells form PBMCs gives rise to Vy9Vδ2 phenotype when activated with phosphoantigen or aminobisphosphonate (p. 2-5). Leek teaches expansion of yδ-T cells by culturing the yδ-T cells with either aminobisphosphonate (p. 7-8) or synthetic phosphoantigen such as IPP, BtHPP, HMBPP (p. 9). Leek further teaches the yδ-T cells can be cultured with factors that encourage proliferation of yδ-T cells and maintenance of cellular phenotype, such factors including IL-2 and IL-15 (p. 11-12).
Method further comprises administering at least one lymphodepletion treatment to the subject before administration of yδ-T cells that comprises cyclophosphamide;
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer a lymphodepleting agent, cyclophosphamide, to the subject prior to administration of yδ T cells in the method of Cooper and Deniger. One would have been motivated to and have a reasonable expectation of success to because: (1) Cooper and Deniger and all of the cited references teach administration of yδ-T cells for the same function of treating cancer and teach the known success of yδ-T cells in the treatment of cancer; (2) Wilhelm teaches administering at least one lymphodepletion/immunosuppression treatment of fludarabine + cyclophosphamide to the subject prior to administration of yδ-T cells and the method successfully resulted in an anti-tumor response and cancer treatment; (3) Zumwalde demonstrates successfully treating tumors in an immunosuppressed environment by administration of full HLA mismatched donor yδ-T cells; (4) Nicol demonstrates administering aminobisphosphonate zoledronate to the cancer patients prior to administering ex vivo expanded Vy9Vδ2-T cells, wherein the method resulted in an anti-tumor response in the subject, including complete and partial responses, particularly in the patients that additionally received chemotherapy; (6) Deniger recognizes that third party “off-the-shelf” donor allogeneic yδ T cells would need to be administered while the patient is immunosuppressed (lymphodepletion) so that they do not reject the adoptive therapy; and (6) Torikai recognizes that patients should avoid rejection of “off the shelf” allogeneic cell therapies (due to HLA mismatch) by suppressing the immune system through lymphodepletion by CY or fludarabine.
Method further comprises administering an amino-bisphosphonate to the subject prior to the administration of the donor-derived yδ-T cells:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer an amino-bisphosphonate (zoledronic acid) to the subject prior to the administration of the donor-derived yδ-T cells in the method of Cooper and Deniger. One would have been motivated to and have a reasonable expectation of success to because: (1) Cooper and Deniger and all of the cited references teach administration of yδ-T cells for the same function of treating cancer, and recognize the need to expand the cells ex vivo and/or in vivo for therapeutic effectiveness, and Cooper and Deniger teach using zoledronic acid to expand the yδ-T cells; (2) Wilhelm suggests the adoptive transfer of allogeneic donor haploidentical yδ-T cells for in vivo expansion of these innate effector cells for cancer treatment and teaches administering an amino-bisphosphonate, zolendronate, to the subject prior to the administration of the donor-derived yδ-T cells; (3) Wilhelm teaches the method successfully resulted in an anti-tumor response in the subject including significant expansion of donor yδ-T cells, and complete remission; (4) Handgretinger teaches yδ-T cells can be expanded in vitro or in vivo for cancer therapy; and (5) Nicol demonstrates successfully combining steps of in vivo and ex vivo activation and expansion, and demonstrate administering aminobisphosphonate zoledronate to the cancer patients prior to administering ex vivo expanded Vy9Vδ2-T cells, wherein the method resulted in an anti-tumor response in the subject, including complete and partial responses, particularly in the patients that additionally received chemotherapy,
Ex vivo expansion of yδ-T cells with using synthetic phosphoantigen including C-HDMAPP:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to expand the yδ-T cells ex vivo by stimulation with a phosphoantigen, such as C-HDMAPP, prior to administering in the method of Cooper and Deniger. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Cooper and Deniger and the cited prior art recognize that the yδ-T cells require expansion and activation for therapeutic success and recognize yδ-T cells require phosphoantigen for activation; (2) Cooper and Deniger demonstrate expanding yδ-T cells ex vivo prior to administration; (3) Zumwalde, Handgretinger, Nicol, and Deniger all teach or demonstrate successfully expanding yδ-T cells ex vivo prior to administration in order to produce sufficient numbers of cells for effective dosing; (4) Nicol teaches that healthy donor Vy9Vδ2 T cells expand massively when stimulated in vitro by IL-2 in combination with phosphoantigens or bisphosphoates; (5) Deniger teaches several known studies clinically treating cancer patients with ex vivo expanded yδ-T cells that were cultured with phosphoantigen (BrHPP, 2M3BIPP) and/or zoledronate prior to administration; (6) Salot teaches and successfully demonstrates a protocol for large scale production/expansion of purified yδ-T cells for clinical therapy that comprises culturing donor yδ-T cells with a phosphoantigen, and Salot suggests known phosphoantigens BrHPP or C-HDMAPP in the protocol; (7) Thedrez teaches it is known that either phosphoantigens or aminobisphosphonates with IL-2 expand Vy9Vδ2-T cells ex vivo/ in vitro, and Thedrez demonstrates successful ex vivo expansion/activation of donor Vy9Vδ2-T cells by culturing with phosphoantigen C-HDMAPP; and (8) Leek teaches the expansion of yδ-T cells can be accomplished by culturing the yδ-T cells with either aminobisphosphonate or synthetic phosphoantigen such as IPP, BtHPP, HMBPP. Therefore, it is well established in the prior to take the step of expanding yδ-T cells ex vivo prior to administration and to use synthetic phosphoantigen including C-HDMAPP for expansion.
Allowing subject’s immune function to recover and reject donor-derived allogeneic yδ-T cells:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to allow the subject’s immune function to recover and reject the donor-derived allogeneic yδ-T cells in the method of Cooper and Deniger. One would have been motivated to, and have a reasonable expectation of success to, because Wilhelm successfully demonstrates this is the natural course of a subject’s immune system after administration of mismatched donor-derived allogeneic yδ-T cells.
Response to Arguments
4. Applicants argue that Cooper and Deniger do not teach administering fully mismatched donor-derived allogeneic yδ-T cells. Applicants argue that although Cooper and Deniger teach administering donor-derived allogeneic yδ-T cells that may or may not share HLA with the patient, Applicants argue that Cooper and Deniger are referring to HLA mismatch in terms of the yδ-T cells functional requirement to kill tumor cells, and not in terms of the need or function to clear the donor yδ-T cells from the patient’s immune system. Applicants are arguing that Cooper and Deniger teach HLA mismatched donor-derived allogeneic yδ-T cells can be administered to patients because the cancer-treating effects of the yδ-T cells are not functionally dependent on HLA molecules and are not reliant upon matching patient HLA. Applicants argue that Cooper and Deniger are concerned with producing off-the-shelf universal donor yδ-T cells without regard to patient-donor HLA matching. Applicants argue they have invented a method requiring fully mismatched HLA donor yδ-T cells to be administered so the cells are cleared/rejected from the patient’s immune system after their immune system recovers from immunodepletion, and Cooper and Deniger do not teach this function or step.
Applicants argue that Cooper and Deniger and Zumwalde utilize tumor xenograft models which is not the same immune environment as a subject receiving lymphodepletion and donor yδ-T cells, and the donor yδ-T cells are not expected to be cleared by NSG mice lacking functional T cells, B cells, and NK cells.
Applicants argue that they are first to discover there exists a functional window of time from administration of the donor-derived fully mismatched yδ-T cells, until the immune system of the subject recovers from the lymphodepletion in which the yδ-T cells can exert measurable antitumor effects. Applicants argue data to support the statement in the instant application regarding this functional window are provided in Item 8 of the Lopez Declaration under 37 CFR 1.132 filed August 13, 2025. Applicants argue that without the knowledge of this functional window, one of ordinary skill in the art would not have believed there to be a reasonable expectation of success in treating cancer in a subject with fully mismatched yδ-T cells. Applicants point to Item 9 of the Lopez Declaration arguing an unmet need for off-the-shelf donor yδ-T cells, where fully mismatched yδ-T cells can mount an effective antitumor response within hours of administration despite the expectation that they will be cleared more quickly than partially mismatched yδ-T cells by the patient’s recovering immune response.
5. The arguments have been carefully considered but are not persuasive. Contrary to arguments, the donor yδ-T cells taught by Cooper and Deniger encompass yδ-T cells that do not share (or match) any HLA with the receiving patient. Donor yδ-T cells fully mismatched are encompassed by the yδ-T cells that “may not share HLA with the patient” as taught by Cooper and Deniger. Cooper and Deniger teach:
[0028] In one aspect, the cell composition may be allogeneic to the patient. In various aspects, an allogeneic cell composition may or may not share HLA with the patient. In another aspect, the cell composition may be autologous to the patient.
[0060] Human γδ T cells have natural anti-tumor immunity, but their utility in the clinic is restricted to one lineage (Vγ9Vδ2) even though other γδ T-cell lineages can recognize and kill tumors. A polyclonal approach to γδ T-cell immunotherapy could target multiple ligands on the tumor surface and maximize therapeutic efficacy. However, a clinically-relevant expansion of polyclonal γδ T cells has yet to be achieved. Recognition of multiple ligands on the tumor surface is mediated by the T cell receptor (TCR) expressed on the γδ T cell surface, which is composed of a heterodimer of δ and γ TCR chains. Moreover, γδ T-cell TCR recognizes antigens outside of major histocompatibility complex (MHC) restriction, which is in contrast to αβ T cells that do recognize their antigens in the context of MHC. Therefore, MHC mis-matched γδ T cells could be given to un-related patients and serve as a universal source of tumor-reactive T cells. As such, γδ T cells generated from one donor may be infused into one or more allogeneic recipients that may or may not share HLA with the donor. This provides an “off-the-shelf” therapy in which γδ T cells can be both pre-prepared and infused on demand.
[0064] The present invention results in cell therapy products for adoptive T cell therapies and has at least four potential uses. First, polyclonal γδ T cells can be used as a universal source of tumor reactive T cells that can be given to unrelated individuals. This has commercialization appeal as a universal source of T cells could decrease the costs associated with generating autologous T cells for each patient to be treated. Second, polyclonal γδ T cells can be further manipulated to increase their tumor reactivity, e.g., through introduction of a chimeric antigen receptor (CAR) that targets a specific tumor antigen. Third, polyclonal γδ T cells also have anti-viral activity (cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human immunodeficiency virus (HIV)) and can be used as direct immunotherapies for viral infection and/or protection of opportunistic infections in immunocompromised patients, e.g., cancer patients receiving hematopoietic stem cell transplant (HSCT). Fourth, transplant of a universal set of polyclonal γδ T cells may be used in the control of bacterial infection and sepsis.
Therefore, Cooper and Deniger meet the claim limitation of administering fully HLA mismatched donor γδ T-cells, and explain why they are expected to be successful as a universal off-the-shelf donor γδ T-cell therapy, therefore meet the need of universal off-the-shelf donor γδ T-cell therapy.
Contrary to arguments, the motivation provided by the cited combined references to administer fully mismatched donor γδ T-cells is not required to be the same as Applicant’s motivation. MPEP 2144 states:
The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon,, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
In the instant case, Cooper and Deniger teach producing and administering a universal off-the-shelf donor γδ T-cell without the need to match HLA to patients for effectiveness. Cooper and Deniger and secondary references do not need to teach or provide the same motivation argued by Applicants for administering fully mismatched HLA donor γδ T-cells in order for the γδ T-cells to be cleared after the subject’s immune function recovers.
Contrary to arguments, Cooper and Deniger provide a reasonable expectation of success for the full HLA mismatched donor γδ T-cells to provide antitumor immune function in recipients, teaching that the γδ T-cells’ anticancer function is not dependent upon HLA or HLA matching.
Contrary to arguments, the cited references recognize the advantage of lymphodepletion prior to infusion of HLA mismatched donor γδ T-cells, especially to allow the donor γδ T-cells to engraft and function in anti-tumor immunity without the patient’s immune system rejecting the foreign γδ T-cells, as stated in the rejection. Therefore, the cited references do teach a window of therapeutic opportunity for the donor γδ T-cells is required and permitted by lymphodepletion.
Applicants argue the success demonstrated by Cooper and Deniger and Zumwalde is not persuasive because they used an NSG immunodeficient NSG mouse model that allows the full HLA mismatched yδ-T cells to persist longer due to the lack of functional T cells, B cells, and NK cells, and do not demonstrate the immune system recovering to clear the yδ-T cells. The arguments are not persuasive because the cited prior art in the rejection of record provides motivation and reasonable expectation of success to add the claimed step of lymphodepletion to immunosuppress the cancer patient prior to yδ-T cells administration in order to allow the yδ-T cells to expand and function. Zumwalde demonstrated the success of treating tumors in NSG mice (immunosuppressed environment) with human Vy9Vδ2-T cells that are a full HLA mismatch to mice. Therefore, an immunosuppressed environment is taught by the cited prior art (by immunodeficient mice or by lymphodepletion through chemotherapy) and the cited art provides a reasonable expectation of success for full HLA mismatch “off-the-shelf” donor yδ-T cells to provide an anti-tumor response and treat cancer in the immunosuppressed environment, as required by the claims.
With regard to claim 20, and contrary to arguments, Wilhem does teach HLA-mismatched donor yδ-T cells are cleared as a patient’s immune system recovers. Wilhelm demonstrates that patients’ immune functions were allowed to recover after receiving partially HLA mismatched donor yδ-T cells, eventually rejecting the donor-derived allogeneic yδ-T cells, and demonstrating decline in yδ-T cell levels (Figure 1; p. 4, col. 1). Therefore, the cited prior art recognizes the rejection of HLA mismatched donor yδ-T cells is a natural process and is expected to occur with full HLA-mismatched yδ-T cells.
The Lopez declaration argues demonstrating antitumor effects for the administration of full HLA mismatch yδ-T cells to mice in a lymphodepletion model. The Lopez declaration states that although fully HLA- mismatched donor yδ-T cells persist only transiently in a lymphodepleted murine model, these cells are still able to kill tumors within hours of administration before eventual rejection when the host’s immune function recovers. Applicants argue the lymphodepletion by cyclophosphamide allows for a window of opportunity for the donor yδ-T cells to function before the mouse immune system is restored. The Lopez declaration points to Figure 2 to demonstrate that fully HLA-mismatched donor yδ-T cells administered after lymphodepletion with cyclophosphamide resulted in substantially less tumor compared to control mice receiving cyclophosphamide but no yδ-T cells. Examiner asserts this result is expected based upon the teaching and demonstrated results of the cited prior art for the reasons stated above.
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.
6. Claims 1-3, 10, 14, 18, and 20 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16, 18-21 of copending Application No. 18/553,947 in view of US Patent Application Publication 2016/0256487, Cooper and Deniger, published September 2016, Wilhelm et al (Journal of Translational Medicine, 2014, 12:45, internet pages 1-5); Zumwalde et al (JCI Insight, 2017, 2(13):e93179, internet pages 1-15); Handgretinger et al (Blood, March 2018, 131:1063-1072); Nicol et al (British Journal of Cancer, 2011, 105:778-786); Deniger et al (Frontiers in Immunology, 2014, 5:article 636; p. 1-10);Torikai et al (Molecular Therapy, 2016, 24:1178-1186); Salot et al (Journal of Immunological Methods, 2009, 347:12-18); Thedrez et al (Journal of Immunology, 2009, 182:3423-3431); and WO 2016/005752, Leek et al, published January 2016 (IDS).
This is a provisional nonstatutory double patenting rejection.
The copending application claims a method of treating cancer in a human subject, the method comprising administering a therapeutically effective amount of yδ-T cells, wherein the yδ-T cells are derived form a donor that is a full HLA mismatch to the subject, further comprising treating the subject with amin-bisphosphonate prior to administration of said yδ-T cells, and further comprising administering a lymphodepletion treatment to said subject prior to administration of said yδ-T cells.
The copending application does not exemplify practicing the method, does not teach the amin-bisphosphonate is zoledronic acid, the lymphodepletion is accomplished with cyclophosphamide, the method further comprises ex vivo expansion of yδ-T cells with synthetic phosphoantigen including C-HDMAPP, or repeating steps of lymphodepletion and yδ-T cell administration sourced from different donors that do not share HLA antigens with previous donors.
Cooper and Deniger; Wilhelm; Zumwalde; Handgretinger; Nicol; Deniger; Torikai; Salot; Thedrez; and Leek teach as set forth above, and render obvious the above limitations for the reasons stated in the rejection under 35 USC 103.
Response to Arguments
7. Applicants reiterate arguments from the rejection under 35 USC 103 above given the same references are cited.
8. The arguments have been considered but are not persuasive for the reasons stated above in response to 35 USC 103 arguments.
9. Conclusion: No claim is allowed.
Conclusion
10. THIS ACTION IS MADE FINAL. 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.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
Prosecution Insights