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 May 11, 2026 in response to the Office Action of February 9, is acknowledged and has been entered. Claims 48-61, 64-76 are pending. Claims 1-47, 62 and 63 are canceled. Claims 48-51, 56-58, 60, 61, 65-68, 70 and 76 are amended. Claims 54, 56, 57, 60, 61, and 75 remain withdrawn as being drawn to non-elected species. Claims 48-53, 55, 58-59, 64-74 and 76 are currently under prosecution as drawn to the elected species of:
A. (iii) cell therapy that is T cells stimulated with APCs comprising (i) of claim 48;
B. (i) T cells are from the subject (autologous);
C. (i) administration of the checkpoint inhibitor is initiated before initiation of administration of the cell therapy (claims 53 and 69);
D. (ii) method not further administering additional agents; and
E. (i) the subject is suffering from neoplasia that is melanoma.
New Rejection
(necessitated by amendments)
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
2. Claim 53 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 53 depends from claim 48. Claim 48 is amended and now limited to administering cell therapy and checkpoint inhibitor on different days. Claim 53 recites administering the cell therapy and checkpoint inhibitor at the same time (on the same day): “(iv) administration of the checkpoint inhibitor is initiated simultaneously with the initiation of administration of the cell therapy”, therefore this limitation falls outside the scope of amended claim 48. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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) 48-53, 55, 58-59, 64-73 and 76 remain rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2011/0293637 (also issued as US Patent 9,115,402), Hacohen et al, published December 2011; in view of Mackensen et al (Journal of Clinical Oncology, 2006, 24:5060-5069); Verdegaal et al (Cancer Immunol Immunother, 2011, 60:953-963); Robbins et al (Nature Medicine, June 2013, 19:747-752); Overwijk et al (Journal for ImmunoTherapy of Cancer, 2013, 1:11, internet pages 1-4); Pilon-Thomas et al (Journal of Immunology, 2010, 184:3442-3449); Ott et al (Clinical Cancer Research, October 1, 2013, 19:5300-5309); Hamid et al (NEJM, July 2013, 369:134-144); and John et al (Clinical Cancer Research, October 2013, 19:5636-5646), as evidenced by Maeda et al (British Journal of Cancer, 2002, 87:796-804).
Hacohen teaches a method for treating cancer in a subject comprising administering to the subject:
(a) a composition comprising cytotoxic T lymphocyte precursor cells (CTLp), including CD8+ CTLp, stimulated ex vivo by antigen presenting cells (APCs), the APCs comprising a plurality of subject-specific neoantigenic peptide sequences; wherein each of the neoantigenic peptide sequences comprise a subject-specific mutation expressed in a cancer cell from the subject, wherein the mutation is not present in a normal cell of the subject, therefore is a cancer-specific mutation not present in non-cancer cells of the subject ([163-174]);
wherein the neoantigenic peptide sequences comprising subject-specific mutations are identified by comparing whole genome or whole exome sequencing of the subject’s tumor cells and non-cancer cells; wherein the peptide sequences are identified by computer algorithm to have an IC50 of less than 500 nM or 150 nM binding affinity to the subject’s HLA allele; wherein the mutations are non-silent mutations and more than 4 are identified ([6]; [8]; [23-31]; [47]; [50]; [52]; [72-162]; Figure 2; Examples 1-3 and 7; claims 1, 11-34, 39); and
(b) an anti-PD1 antibody to block immunosuppression and enhance the immune response to cancerous cells in the subject ([13]; [139]; Figure 2; claims 16, 21, and 26);
wherein 2, 3, 4, or more neoantigen peptides are from different proteins ([17-30]; [118-119]; [118-120]; Example 7; claim 36);
wherein the neoantigen peptides are about 8-50 amino acids long ([9]; [29-30]; [89-91]; [168]; claims 27-29);
wherein the T cells are administered intravenously by infusion and are comprised in a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient ([174]; [145]); and
wherein the subject has melanoma ([15]; [135]; claims 32-34); administering the compositions in excess to treat serious disease states, especially when cancer has metastasized ([143]).
Hacohen teaches using their method to identify and select tumor-specific neoantigen peptide sequences that bind to class I HLA protein and activate anti-tumor CD8+ T cells ([6-7]; [52]). Hacohen recognizes the importance of mutated antigens, neoantigens, or neoepitopes, in mounting immune responses, and teaches ([53]):
(a) mice and humans often mount T cell responses to mutated antigens (Parmiani et al., 2007; Sensi and Anichini, 2006); (b) mice can be protected from a tumor by immunization with a single mutated peptide that is present in the tumor (Mandelboim et al., 1995); (c) spontaneous or vaccine-mediated long-term melanoma survivors mount strong memory cytotoxic T cell (CTL) responses to mutated antigens (Huang et al., 2004; Lennerz et al., 2005; Zhou et al., 2005a); (d) finally, lymphoma patients show molecular remission when immunized with patient-specific mutated immunoglobulin proteins that are present in autologous tumor cells. (Baskar et al., 2004). Furthermore, the CTL responses in these patients are directed toward the mutated rather than shared regions of the immunoglobulin protein. Additionally, such mutated peptides have the potential to: (a) uniquely mark a tumor for recognition and destruction by the immune system, thus reducing the risk for autoimmunity; and (b) avoid central and peripheral T cell tolerance, allowing the antigen to be recognized by more effective, high avidity T cells receptors. (FIG. 1).
Hacohen does not teach the anti-PD1 antibody is pembrolizumab or nivolumab (claims 48, 72, and 73) and is administered intravenously (claim 71).
Hacohen suggests, but does not exemplify, treating metastatic melanoma with the claimed adoptive T cell therapy specific for neoantigens in combination with anti-PD-1 antibody, and wherein the adoptive T cell therapy is autologous (claims 48, 51, 58, 64).
Hacohen does not teach treating metastatic melanoma that is previously untreated (claim 65);
Hacohen does not teach the patient is not immuno-compromised by a previous cancer-directed therapy (claim 70);
Hacohen does not teach the checkpoint inhibitor nivolumab or pembrolizumab is administered prior to the cell therapy and on different days (claims 48, 53, and 69).
Hacohen does not teach the patient was previously treated with adoptive T cell therapy.
Mackensen teaches successfully clinically treating metastatic melanoma patients with adoptive transfer of autologous purified CD8+ peripheral blood lymphocytes that were stimulated ex vivo with autologous dendritic cells (APCs) pulsed with an HLA-A2 binding melan A peptide antigen, then intravenously administered to the patients. The administered Melan-A-specific CTLs successfully produced antitumor responses including a complete regression and partial regression. Mackensen teaches adoptive transfer of antigen-specific T cells in melanoma patients can induce clinical tumor-specific immune response without major adverse events. See entire abstract.
As evidenced by Maeda, peripheral blood lymphocytes or PBMCs from healthy and cancer patients, including melanoma patients, inherently comprise CTL-precursors (abstract; p. 796, col. 2 to p. 797, col. 2; p. 799, col. 1 to p. 803, col. 1; Tables 4 and 6). Therefore the melanoma patient CD8+ peripheral blood lymphocytes that were stimulated ex vivo with autologous dendritic cells (APCs) pulsed with an HLA-A2 binding melan A peptide antigen in the method of Mackensen inherently comprise CTLp.
Verdegaal teaches successfully treating previously treated/refractory metastatic melanoma patients clinically with adoptive transfer of autologous PBMC that were stimulated ex vivo with autologous tumor cells containing endogenous antigen, confirming the stimulated T cells specifically lyse the autologous tumor cells but not irrelevant cells and that they express activated T cell biomarkers such as CD45RA negative and CD137 positive; then infusing the patients with the stimulated/activated T cells (Patients and Methods, p. 954-955; Characteristics of infused cells, p. 958-959; Figures 3 and 4). Verdegaal teaches this method resulted in objective clinical responses, wherein one patient exhibited ongoing complete response with a duration of more than 45 months after two cycles of adoptive cell therapy; another patient experience complete regression of all but one mesenterial lesion, including a brain lesion, 4 skin lesions, and 4 LN-lesions; and another patient experienced an unexpected long survival (Clinical Response p. 956; Figure 1; Table 1). Verdegaal teaches that stimulation of patients’ PBMC with autologous tumor cells, expressing the full spectrum of relevant HLA molecules and tumor antigens, leads to expansion of polyclonal CD4+ as well as CD8+ T cells, which may contribute to the current success of the method (p. 961, col. 1-2).
Verdegaal noted that in their study, their results are in line with previous observations in the prior art, indicating that infusion of T cells that predominantly produce Th1 cytokines results in a better clinical outcome compared to infusion of T cells that produce mainly Th2 cytokines or no Th1/Th2 cytokines at all and that the presence of both tumor-specific Th1 cells and CTL mediates an effective anti-tumor response. Verdegaal teaches (p. 961, col. 2):
In summary, the adoptive transfer of polyclonal tumor-specific T cells obtained after stimulation of PBMC with autologous tumor cells in combination with low-dose IFN can result in durable clinical responses in stage IV melanoma patients supporting the idea to explore IFN as an alternative conditioning regimen and cytokine for ACT trials. Although the use of IFN also comes with some side effects, including the beneficial leukopenia and controllable psychological symptoms, it is far less toxic than high-dose IL-2, commonly used to support transferred T cells. The clinical responses reported here are associated with IFN-induced lympho- and neutropenia and the proliferative capacity as well as the Th1/Th2 cytokine profile of the T cells used for infusion, underscoring the importance of measuring parameters that are associated with clinical reactivity of the infused T-cell batches to fully appreciate their in vivo effectiveness. Eventual combination of this approach with other treatment options may even further enhance the clinical outcome. One possibility is the combined use of ACT/IFN with ipilimumab or negative immunoregulatory human cell surface receptor PD-1 (programmed death-1). These immune activating antibodies may result in further in vivo expansion of tumor-specific T cells and improved clinical effect after ACT/IFN.
Thus, Verdegaal suggests immune checkpoint inhibition therapy, such as immune-activating anti-PD-1 antibodies, should be combined with the adoptive cell transfer (ACT) to improve further in vivo expansion of tumor-specific T cells and improve clinical effect of ACT.
As evidenced by Maeda, peripheral blood lymphocytes or PBMCs from healthy and cancer patients, including melanoma patients, inherently comprise CTL-precursors (abstract; p. 796, col. 2 to p. 797, col. 2; p. 799, col. 1 to p. 803, col. 1; Tables 4 and 6). Therefore the melanoma patient PBMCs that were stimulated ex vivo with melanoma tumor antigen in the method of Verdegaal inherently comprise CTLp.
Robbins teaches substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs) in clinical trials (Abstract). Robbins teaches they developed whole-exome sequence data to identify mutated proteins expressed in patient tumors, then synthesized and evaluated candidate mutated T cell epitopes that were identified using MHC-binding algorithm for recognition by TILs. They identified mutated antigens expressed on autologous tumor cells that were recognized by three TIL lines from three melanoma patients that were associated with objective tumor regression following adoptive transfer (abstract; Online Methods). Robbins synthesized several tumor-specific neoantigen peptide epitopes from different tumor proteins, wherein epitopes were 9 (nonamer) or 10 (decamer) amino acids long, were recognized by MHC Class I alleles, and were recognized by melanoma patient TILs. Robbins determined the mutated epitopes had a higher affinity than the wild type epitopes for HLA binding (p. 748-750; Figures 1-4). Robbins teaches whole-exome sequencing of tumor cell DNA, followed by the use of MHC binding algorithms, has led to the identification of eight mutated epitopes recognized by four of the five melanoma TILs that have been evaluated to date. Mutated antigen identified using this approach can be used to carry out in vitro sensitization of cells from patient peripheral blood that can be further expanded in vitro for use in patient adoptive transfer protocols, as well as providing potential cancer vaccine targets (p. 751, col. 2).
Overwijk teaches T cells can mediate remarkable tumor regression including complete cure in patients with metastatic cancer. Genetic alterations in an individual’s cancer cells (the mutanome) encode unique peptides (m-peptides) that can be targets for T cells. Next-generation sequencing and computation prediction allow for the rapid and affordable identification of m-peptides in individual patients (abstract). Mutanome-encoded peptides (m-peptides) evoke a more vigorous T cell response due to lack of thymic tolerance against them, and this immunity is restricted to tumors, since the mutated gene is only expressed in the tumors (p. 1, col. 2). Overwijk teaches there are remarkable clinical response rates to adoptively transferred T cells, and to CTLA-4 and/or PD(L)-1 checkpoint blockade, that are mediated in part, or even primarily, by m-peptide-specific T cells. Overwijk suggests m-peptides can be used for ex vivo expansion of patient-derived T cells (TIL or PBMCs) before adoptive T cell therapy. Overwijk teaches a prior study analyzed the mutanome of an immunogenic tumor by exome sequencing and MHC binding algorithms and identified point mutation in a gene that resulted in an m-peptide with greatly increased MHC Class I binding. This peptide proved to be a dominant tumor antigen that caused complete regression of this tumor in immunocompetent mice (p. 3, col. 2). Overwijk also cites the study of Robbins (above) as an example of how exome sequencing and computer algorithm-guided peptide epitope prediction identified MHC Class I-binding m-peptides that were processed and presented by tumor cells and recognized by tumor-specific T cells, validating this approach to identifying mutated tumor antigens recognized by tumor-reactive T cells (p. 3, col. 1-2).
Pilon-Thomas teaches blocking PD-1/PD-L1 signaling by administration of an anti-PD-L1 antibody for the treatment of melanoma enhanced the efficacy of adoptively transferred T cells in combination with dendritic cells (DCs) pulsed with tumor antigen peptide. Treatment resulted in higher numbers of CD8+ T cells infiltrating the tumor mass, increased activation of the T cells (increased IFNɣ production), and increased the persistence of adoptively transferred T cells (abstract; p. 3445, col. 1-2; Figures 5-6 and 8). Administration of a combination of anti-PD-L1 antibody, adoptively transferred T cells, and tumor antigen-pulsed DCs significantly reduced tumor volume in a mouse melanoma model compared to treatment with T cells + DCs and lacking PD-L1 antibody (Figure 8; p. 3448, col. 1). Pilon-Thomas explains that the expression of PD-L1 on DC and tumor cells limits the induction of robust antitumor T cell responses, where PD-L1 binds to PD-1 on activated T cells to induce and maintain peripheral tolerance (T cell anergy or immune suppression) (p. 3447, coo.2). Pilon-Thomas explains blocking PD-L1 signaling allows longer persistence and enhanced infiltration of T cells into PD-L1-expressing tumors, and suggests this is a valuable approach to enhance clinical responses in patients with melanoma (p. 3448, col. 1).
Ott suggests PD-1/PD-L1 inhibition in combination with other immunotherapeutic strategies in the treatment of melanoma. Ott explains that PD-1/PD-L1 signaling leads to downregulation of T-cell effector function in the tumor microenvironment. PD-L1 upregulation in metastatic melanoma was found to be colocalized with tumor infiltrating lymphocytes and IFNɣ production, suggesting a resistance mechanism by the tumor against endogenous immune response (p. 5304, col. 1; Figure 1 and 2). Ott summarizes known success of PD-1/PD-L1 blockade in treating patients with advanced (metastatic) melanoma (Table 1). Ott teaches nivolumab achieved objective responses in patients with advanced, previously treated melanoma, and a significant number of these objective responses were durable (p. 5304, col. 1). Another clinical trial treated previously treated melanoma patients with an anti-PD-L1 antibody and achieved objective responses with durable responses (p. 5304, col. 1). Ott cites Hamid (below) teaching that lambrolizumab (also known as pembrolizumab) treated advanced melanoma patients with durable responses (p. 5304, col. 2). Ott suggests complementary immune therapies to be combined with PD-1/PD-L1 blockade including adoptive T cell transfer (p. 5307, col. 1).
Hamid (cited by Ott above) demonstrates successfully treating advanced melanoma with intravenous lambrolizumab (also known as pembrolizumab and MK-3475) (abstract; Results; Figure 2). Hamid teaches their clinical study resulted in a 52% response rate with a median progression free survival (PFS) of greater than 7 months for those administered the highest dose (abstract; Discussion). Patients treated with 10 mg/kg of PD1 antibody every 2 weeks and previously treated with ipilimumab had a 62% objective response rate and patients with no prior ipilimumab therapy had a 49% objective response rate (Table 3). Hamid mentions phase I clinical studies with nivolumab demonstrated “significant antitumor activity” in patients with advanced melanoma and lung cancer (p. 135, col. 1). Hamid teaches treatment resulted in increased CD8+ T cell infiltration of tumor (Figure 2; Discussion). Hamid teaches their study confirms the importance of releasing inhibitory immune regulation by PD-1 for effective antitumor immunity (p. 143, col. 2).
John exemplifies success in treating a cancer by administering adoptively transferred tumor-specific T cells in combination with anti-PD-1 antibody, wherein PD-1 blockade resulted in enhanced proliferative and functional capacity of the tumor-specific T cells, enhanced regression of established tumors, and significantly increased survival compared to either agent alone (Figure 3 and 4; Results page 5639, col. 1 to p. 5640, col. 1).
Combination of PD-1 antibody nivolumab or pembrolizumab with adoptive T cell therapy to treat melanoma or metastatic melanoma (claims 48, 51, 64):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat melanoma (including metastatic) by administering the adoptively transferred autologous T cells specific for tumor antigen neoepitopes of Hacohen in combination with nivolumab or pembrolizumab. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Hacohen suggests doing so; (2) Verdegaal demonstrates successfully treating metastatic melanoma by administering autologous PBMC CD3/CD4+ and CD3/CD8+ cells that were stimulated and activated ex vivo with autologous tumor antigen, resulting in complete regressions including an unexpected long survival; and Verdegaal suggests immune checkpoint inhibition therapy, such as immune-activating anti-PD-1 antibodies, should be combined with the adoptive cell transfer (ACT) to improve further in vivo expansion of tumor-specific T cells and improve clinical effect of ACT; (3) Mackensen demonstrates successfully clinically treating metastatic melanoma patients with adoptive transfer of autologous purified CD8+ peripheral blood lymphocytes that were stimulated ex vivo with autologous dendritic cells (APCs) pulsed with an HLA-A2 binding melan A peptide antigen, then intravenously administered to the patients; (4) Robbins teaches substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs), Robbins demonstrates that melanoma patient CTLs recognize mutant peptide epitopes expressed by their tumor, and Robbins suggests treating melanoma with adoptively transferred CTLs that recognize mutant epitopes expressed by the tumor; (5) Pilon-Thomas teaches administration of a combination of anti-PD-L1 antibody, adoptively transferred T cells, and tumor antigen-pulsed DCs significantly reduced tumor volume in a mouse melanoma model compared to treatment with T cells + DCs and lacking PD-L1 antibody, Pilon-Thomas teaches blocking PD-L1 signaling allows longer persistence and enhanced infiltration of T cells into PD-L1-expressing tumors and suggests this is a valuable approach to enhance clinical responses in patients with melanoma; (6) Ott teaches known success of PD-1/PD-L1 blockade in treating patients with advanced (metastatic) melanoma including with anti-PD-1 antibody nivolumab, and suggests combining with PD-1/PD-L1 blockade with adoptive T cell transfer as a complementary immune therapy; (7) Hamid teaches nivolumab demonstrated “significant antitumor activity” in patients with advanced melanoma, and demonstrates successfully treating advanced melanoma with intravenous lambrolizumab (pembrolizumab); and (8) John exemplifies success in treating a cancer by administering adoptively transferred tumor-specific T cells in combination with anti-PD-1 antibody, wherein PD-1 blockade resulted in enhanced proliferative and functional capacity of the tumor-specific T cells, enhanced regression of established tumors, and significant increase in survival compared to either agent alone.
Intravenous administration of nivolumab or pembrolizumab as the anti-PD-1 antibody (claim 48):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to intravenously administer nivolumab or pembrolizumab as the anti-PD-1 antibody in combination with the adoptively transferred autologous T cells specific for tumor antigen neoepitopes in the method of Hacohen. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Hacohen suggests co-administering an anti-PD-1 antibody to block immunosuppression and enhance the immune response to cancerous cells; (2) Overwijk recognizes there are remarkable clinical response rates to adoptively transferred T cells, and to PD(L)-1 checkpoint blockade, that are mediated in part, or even primarily, by mutant peptide-specific T cells; (3) Pilon-Thomas teaches blocking PD-1/PD-L1 signaling by administration of an anti-PD-L1 antibody for the treatment of melanoma enhanced the efficacy of adoptively transferred T cells in combination with dendritic cells (DCs) pulsed with tumor antigen peptide, wherein treatment resulted in higher numbers of CD8+ T cells infiltrating the tumor mass, increased activation of the T cells (increased IFNɣ production), and increased the persistence of adoptively transferred T cells; (4) Ott suggests complementary immune therapies to be combined with PD-1/PD-L1 blockade including adoptive T cell transfer, and teach nivolumab and pembrolizumab have been clinically used to successfully treat melanoma; (5) Hamid demonstrates successfully treating advanced melanoma with intravenous administration of lambrolizumab (pembrolizumab); (6) John exemplified that the combination of anti-PD-1 antibody and adoptively transferred tumor-specific T cells is successful in cancer treatment; and (7) all of Hacohen, Overwijk, Pilon-Thomas, Ott, Hamid and John explain the known, expected function of PD-1/PD-L1 blockade by antibodies and how they enhance tumor immunity, activate CD8+ T cell responses, and enhance T-cell tumor infiltration.
Metastatic melanoma patient is not previously treated (claim 65):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat metastatic melanoma patients that are not previously treated. One would have been motivated to, and have a reasonable expectation of success to, because all of the cited references recognize that metastatic melanoma patients are in need of cancer treatment, regardless of previous treatment status, and provide a reasonable expectation of success or treat advanced, or metastatic, melanoma for the reasons stated above.
Patient is not immuno-compromised by a previous cancer-directed therapy (claim 70):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat patients that are not immuno-compromised by a previous cancer therapy in the method of Hacohen. One would have been motivated to, and have a reasonable expectation of success to, because all of the cited references recognize that cancer patients are in need of treatment, and recognize and explain how the transferred tumor-specific T cells and PD-1 antibody blockade require the immune system to function in mounting and enhancing an anti-tumor immune response to effectively treat cancer.
Checkpoint inhibitor nivolumab or pembrolizumab is administered prior to the cell therapy and not on the same day (claims 48, 53 and 69):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer checkpoint inhibitor therapy prior to the cell therapy and on a different day. One would have been motivated to, and have a reasonable expectation of success to, because the cited references teach or demonstrate that each of the agents separately successfully treat melanoma, and teach the known mechanisms of how the agents act together to enhance antitumor immunity for treatment, providing a reasonable expectation of success for treating melanoma regardless of which agent is administered prior to the other and regardless if administered on separate days.
Treating melanoma patients previously treated with adoptive T cell therapy (claim 76):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the cell therapy of Hacohen + nivolumab or pembrolizumab to melanoma patients that previously received adoptive T cell therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the cited references recognize that patients diagnosed with melanoma are in need of treatment regardless of previous treatment, (2) the cited references demonstrate melanoma is successfully treated with antigen-specific autologous T cells produced ex vivo by stimulation with APCs or tumor antigen, as well as with nivolumab or pembrolizumab, (3) Mackensen and Verdegaal teach that the adoptive T cell therapy can be administered repeatedly, resulting in improved response, thereby demonstrating administering the T cell therapy after adoptive T cell therapy was previously administered; and (4) Verdegaal teaches and demonstrates successfully treating previously treated/refractory melanoma patients.
4. Claim(s) 74 remains rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2011/0293637 (also issued as US Patent 9,115,402), Hacohen et al, published December 2011; Mackensen et al (Journal of Clinical Oncology, 2006, 24:5060-5069); Verdegaal et al (Cancer Immunol Immunother, 2011, 60:953-963); Robbins et al (Nature Medicine, June 2013, 19:747-752); Overwijk et al (Journal for ImmunoTherapy of Cancer, 2013, 1:11, internet pages 1-4); Pilon-Thomas et al (Journal of Immunology, 2010, 184:3442-3449); Ott et al (Clinical Cancer Research, October 1, 2013, 19:5300-5309); Hamid et al (NEJM, July 2013, 369:134-144); and John et al (Clinical Cancer Research, October 2013, 19:5636-5646) as evidenced by Maeda et al (British Journal of Cancer, 2002, 87:796-804); as applied to claims 48-53, 55, 58-59, 64-73, and 76 above, and further in view of Anichini et al (Mol. Cancer Ther., November 1, 2013; 12(11_Supplement):A89).
Hacohen; Mackensen; Verdegaal; Robbins; Overwijk; Pilon-Thomas; Ott; Hamid; and John (the combined references) teach as set forth above.
The combined references do not teach the melanoma patient is refractory to an immune checkpoint inhibitor therapy.
Anichini teaches that melanoma patients can develop resistance to immune checkpoint inhibition (see entire abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the cell therapy of Hacohen + nivolumab or pembrolizumab to melanoma patients that are refractory to prior checkpoint inhibition therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the cited combined references recognize that patients diagnosed with melanoma are in need of treatment regardless of previous treatment, (2) Anchini demonstrates melanoma patients include those refractory to immune checkpoint therapy; (3) the cited references demonstrate melanoma is successfully treated with antigen-specific autologous T cells produced ex vivo by stimulation with APCs or tumor antigen, as well as with nivolumab or pembrolizumab, and combining T cell therapy with anti-PD-1 antibody treatment significantly improves tumor treatment, and (4) Verdegaal teaches and demonstrates successfully treating previously treated/refractory melanoma patients.
Response to Arguments
5. Applicants argue that Hacohen and the combined references do not teach or suggest the checkpoint inhibitor and cell therapy are not administered on the same day, as required by amended claim 48. Applicants provide their own summary of each reference to argue none of the cited references teach all of the limitations of treating melanoma by administering CTLp cells stimulated with peptide antigens on a different day than a checkpoint inhibitor. Applicants argue that Maeda does not remedy the deficiencies of Hacohen and the secondary references because Maeda does not teach CTLp that are stimulated ex vivo with APC comprising the claimed polypeptides or polynucleotides encoding different peptide sequences.
6. The arguments have been considered but are not persuasive. The amendment to claim 48 regarding not administering the checkpoint inhibitor and CTL therapy on the same day was addressed in the rejections above:
Checkpoint inhibitor nivolumab or pembrolizumab is administered prior to the cell therapy and not on the same day (claims 48, 53 and 69):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer checkpoint inhibitor therapy prior to the cell therapy and on a different day. One would have been motivated to, and have a reasonable expectation of success to, because the cited references teach or demonstrate that each of the agents separately successfully treat melanoma, and teach the known mechanisms of how the agents act together to enhance antitumor immunity for treatment, providing a reasonable expectation of success for treating melanoma regardless of which agent is administered prior to the other and regardless if administered on separate days.
In other words, the cited prior art teaches that each of the agents: (a) pCTL that recognize cancer-specific antigens and were stimulated with APC presenting the cancer-specific antigens, and (b) immune checkpoint inhibitors, such as nivolumab or pembrolizumab; have the known, established function of treating cancer and melanoma independently of each other and are reasonably expected to treat melanoma regardless of which sperate days and which order they are administered. MPEP 2144.06 states:
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
In the instant case, the cited prior art provides both motivation and reasonable expectation of success for the two agents: tumor-specific CTLp and checkpoint inhibitor, to be used for the same purpose of treating melanoma. The cited prior art does NOT teach that the two agents need to be administered on the same day in order to operate as taught.
Further, the cited prior art suggests the combination of PD-1/PD-L1 blockade and T cell therapy, and teaches and demonstrates the advantages for adding PD-1/PD-L1 blockade therapy to enhance T cell therapy of cancers. As stated in the rejection:
Combination of PD-1 antibody nivolumab or pembrolizumab with adoptive T cell therapy to treat melanoma or metastatic melanoma (claims 48, 51, 64):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat melanoma (including metastatic) by administering the adoptively transferred autologous T cells specific for tumor antigen neoepitopes of Hacohen in combination with nivolumab or pembrolizumab. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Hacohen suggests doing so; (2) Verdegaal demonstrates successfully treating metastatic melanoma by administering autologous PBMC CD3/CD4+ and CD3/CD8+ cells that were stimulated and activated ex vivo with autologous tumor antigen, resulting in complete regressions including an unexpected long survival; and Verdegaal suggests immune checkpoint inhibition therapy, such as immune-activating anti-PD-1 antibodies, should be combined with the adoptive cell transfer (ACT) to improve further in vivo expansion of tumor-specific T cells and improve clinical effect of ACT; (3) Mackensen demonstrates successfully clinically treating metastatic melanoma patients with adoptive transfer of autologous purified CD8+ peripheral blood lymphocytes that were stimulated ex vivo with autologous dendritic cells (APCs) pulsed with an HLA-A2 binding melan A peptide antigen, then intravenously administered to the patients; (4) Robbins teaches substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs), Robbins demonstrates that melanoma patient CTLs recognize mutant peptide epitopes expressed by their tumor, and Robbins suggests treating melanoma with adoptively transferred CTLs that recognize mutant epitopes expressed by the tumor; (5) Pilon-Thomas teaches administration of a combination of anti-PD-L1 antibody, adoptively transferred T cells, and tumor antigen-pulsed DCs significantly reduced tumor volume in a mouse melanoma model compared to treatment with T cells + DCs and lacking PD-L1 antibody, Pilon-Thomas teaches blocking PD-L1 signaling allows longer persistence and enhanced infiltration of T cells into PD-L1-expressing tumors and suggests this is a valuable approach to enhance clinical responses in patients with melanoma; (6) Ott teaches known success of PD-1/PD-L1 blockade in treating patients with advanced (metastatic) melanoma including with anti-PD-1 antibody nivolumab, and suggests combining with PD-1/PD-L1 blockade with adoptive T cell transfer as a complementary immune therapy; (7) Hamid teaches nivolumab demonstrated “significant antitumor activity” in patients with advanced melanoma, and demonstrates successfully treating advanced melanoma with intravenous lambrolizumab (pembrolizumab); and (8) John exemplifies success in treating a cancer by administering adoptively transferred tumor-specific T cells in combination with anti-PD-1 antibody, wherein PD-1 blockade resulted in enhanced proliferative and functional capacity of the tumor-specific T cells, enhanced regression of established tumors, and significant increase in survival compared to either agent alone.
Therefore, the cited prior art teaches both motivation and reasonable expectation of success to treat melanoma with tumor antigen-specific pCTL and immune checkpoint inhibition PD-1/PD-L1 blockade, and the advantageous anti-cancer effects of combining the two therapies. Given the teaching of the prior art and the expected anti-cancer effects of administering both tumor antigen-specific pCTL and immune checkpoint inhibition PD-1/PD-L1 blockade, it is well within the level of the ordinary skilled artisan to administer both tumor antigen-specific pCTL and immune checkpoint inhibition PD-1/PD-L1 blockade, whether it be on the same day or different days, and whether one is administered before the other, and reasonably expect the advantages and anti-cancer benefits of the combination therapy.
The cell therapy administered in step (A) of claim 48 is a product-by-process, wherein the “cell therapy” administered in step (A) can be made by CTLp cells stimulated ex vivo with APCs comprising polypeptides comprising different tumor-specific peptide sequences having an affinity to an HLA of the subject with an IC50 of less than 500 nM. Hacohen addressed this limitation for the reasons stated in the rejection. Mackensen, Verdegaal, Robbins, and Overwijk provide a reasonable expectation of success for the tumor-specific cell therapy (CTLp cells) of Hacohen to successful treat previously treated/refractory metastatic melanoma for the reasons of record.
Contrary to arguments, Maeda was provided as evidence to demonstrate the peripheral blood lymphocytes or PBMCs from healthy and cancer patients, including melanoma patients, inherently comprise CTL-precursors (CTLp). As stated in the rejection, based on the evidence of Maeda: (1) the melanoma patient CD8+ peripheral blood lymphocytes (PBMCs) that were stimulated ex vivo with autologous dendritic cells (APCs) pulsed with an HLA-A2 binding melan A peptide antigen in the method of Mackensen inherently comprise CTLp; and (2) the melanoma patient PBMCs that were stimulated ex vivo with melanoma tumor antigen in the method of Verdegaal inherently comprise CTLp. Therefore, contrary to arguments, Maeda is not required to teach administering CTLp stimulated ex vivo with APCs comprising the claimed tumor-specific peptide sequences.
7. Applicants argue that Examiner relied upon impermissible hindsight reasoning to arrive at the claimed invention.
8. The arguments have been considered but are not persuasive. It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In the instant case, it is clear in the rejection of record that the combined references teach not only the suggestion but also the means and motivation to treat melanoma with neoantigen-specific T cell therapy and immune checkpoint inhibition for the reasons of record.
9. Applicants argue that they previously submitted Borgers clinical trial data that demonstrates the infusion of antigen-specific T cells resulted in their expression of PD-1, providing clinical rationale for PD-1 inhibition. Applicants argue that these clinical observations provide motivation for Applicants to arrive at their invention of combined therapy, and this therapy was not obvious over the cited prior art.
10. The arguments have been considered but are not persuasive. Examiner points Applicants to Examiner’s response to the Borgers arguments in the office action mailed February 9, 2026, section 20. Examiner further notes that the prior art’s motivation to arrive at the claimed invention need not be the same as Applicant’s to obviate the invention. 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).
Although Applicants argue that Borgers, published in 2025 well after the effective filing date in 2013, discloses an observation that T cell therapy expresses PD-1 after infusion and there is a need to inhibit PD-1, this motivation to arrive at the claimed invention is not required to be recognized by the cited prior art in order to obviate the invention. As stated in the rejection of record and responses above, the cited prior art suggests the combination neoantigen-specific T cell and checkpoint inhibition therapy for melanoma, and provides a reasonable expectation of success for the two therapies to treat melanoma both separately and together.
Maintained Rejection
(amendments addressed)
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.
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11. Claims 48-53, 55, 58-59, 64-74 and 76 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 49-51, 58, 60-69, 71, 72, and 75 of copending Application No. 17/089,408 in view of US Patent Application Publication 2011/0293637 (also issued as US Patent 9,115,402), Hacohen et al, published December 2011; Mackensen et al (Journal of Clinical Oncology, 2006, 24:5060-5069); Verdegaal et al (Cancer Immunol Immunother, 2011, 60:953-963); Robbins et al (Nature Medicine, June 2013, 19:747-752); Overwijk et al (Journal for ImmunoTherapy of Cancer, 2013, 1:11, internet pages 1-4); Pilon-Thomas et al (Journal of Immunology, 2010, 184:3442-3449); Ott et al (Clinical Cancer Research, October 1, 2013, 19:5300-5309); Hamid et al (NEJM, July 2013, 369:134-144); John et al (Clinical Cancer Research, October 2013, 19:5636-5646), as evidenced by Maeda et al (British Journal of Cancer, 2002, 87:796-804); and Anichini et al (Mol. Cancer Ther., November 1, 2013; 12(11_Supplement):A89).
The co-pending application 17/089,408 claims a method for treating a subject diagnosed has having neoplasia with a subject-specific composition comprising:
(a) identifying a plurality of sequences comprising missense and/or neoORF mutations in the neoplasia;
(b) ranking neo-antigenic epitopes encoded by the plurality of sequences comprising the mutations which include epitopes that bind to an HLA of the subject with a Kd of ≤500 nM or ≤150 nM;
(c) administering a subject-specific composition that comprises either (i) APCs comprising one or more polypeptides comprising at least 2 of the neoantigen epitopes or (ii) T cells stimulated with the APCs of (i);
wherein the neoantigen epitope is from 5 to 50 amino acids in length or from 15 to 35 amino acids in length;
wherein the T cells are autologous, from the subject;
further comprising administering additional therapeutic agents;
further comprising administering a PD-1 antibody that is an anti-immunosuppressive/immunostimulatory agent;
wherein the neoplasia is melanoma;
wherein the method results in induction of anti-tumor CTL response.
Application 17/089,408 does not claim the T cells are CTLp. Application 17/089,408 does not claim the PD-1 antibody is nivolumab or pembrolizumab, the melanoma is metastatic, intravenous administration, patient is previously untreated, patient is not immuno-compromised by prior therapy, or administering the PD-1 antibody before cell therapy and on a different day.
Hacohen; Mackensen; Verdegaal; Robbins; Overwijk; Pilon-Thomas; Ott; Hamid; John; Maeda; and Anichini (the combined references) teach as set forth above.
Utilizing CTLp as the T cell and utilizing nivolumab or pembrolizumab as the anti-PD-1 antibody:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize CTLp as the T cells stimulated ex vivo with APCs/antigen and to intravenously administer nivolumab or pembrolizumab as the anti-PD-1 antibody in combination with the neoantigen-specific CTL in the claimed method of the copending application. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the copending application claims utilizing T cells for ex vivo stimulation to produce tumor-specific CTLs and claims additionally administering anti-immunosuppressive/immunostimulatory agent PD-1 antibody; (2) Hacohen suggests utilizing CTLp as the T cell for ex vivo stimulation with APCs/antigen to produce tumor-specific CTL therapy and teaches co-administering an anti-PD-1 antibody with the T cell therapy to block immunosuppression and enhance the immune response to cancerous cells; (3) Verdegaal demonstrates successfully treating metastatic melanoma by administering autologous PBMC CD3/CD4+ and CD3/CD8+ cells that were stimulated and activated ex vivo with autologous tumor antigen, resulting in complete regressions including an unexpected long survival; and Verdegaal suggests immune checkpoint inhibition therapy, such as immune-activating anti-PD-1 antibodies, should be combined with the adoptive cell transfer (ACT) to improve further in vivo expansion of tumor-specific T cells and improve clinical effect of ACT; (4) Mackensen demonstrates successfully clinically treating metastatic melanoma patients with adoptive transfer of autologous purified CD8+ peripheral blood lymphocytes that were stimulated ex vivo with autologous dendritic cells (APCs) pulsed with an HLA-A2 binding melan A peptide antigen, then intravenously administered to the patients; (5) Robbins teaches substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs), Robbins demonstrates that melanoma patient CTLs recognize mutant peptide epitopes expressed by their tumor, and Robbins suggests treating melanoma with adoptively transferred CTLs that recognize mutant epitopes expressed by the tumor; (6) Pilon-Thomas teaches administration of a combination of anti-PD-L1 antibody, adoptively transferred T cells, and tumor antigen-pulsed DCs significantly reduced tumor volume in a mouse melanoma model compared to treatment with T cells + DCs and lacking PD-L1 antibody, Pilon-Thomas teaches blocking PD-L1 signaling allows longer persistence and enhanced infiltration of T cells into PD-L1-expressing tumors and suggests this is a valuable approach to enhance clinical responses in patients with melanoma; (7) Overwijk recognizes there are remarkable clinical response rates to adoptively transferred T cells, and to PD(L)-1 checkpoint blockade, that are mediated in part, or even primarily, by mutant peptide-specific T cells; (4) Pilon-Thomas teaches blocking PD-1/PD-L1 signaling by administration of an anti-PD-L1 antibody for the treatment of melanoma enhanced the efficacy of adoptively transferred T cells in combination with dendritic cells (DCs) pulsed with tumor antigen peptide, wherein treatment resulted in higher numbers of CD8+ T cells infiltrating the tumor mass, increased activation of the T cells (increased IFNɣ production), and increased the persistence of adoptively transferred T cells; (8) Ott suggests complementary immune therapies to be combined with PD-1/PD-L1 blockade including adoptive T cell transfer, and teach nivolumab and pembrolizumab have been clinically used to successfully treat melanoma; (9) Hamid demonstrates successfully treating advanced melanoma with intravenous administration of lambrolizumab (pembrolizumab); (10) John exemplified that the combination of anti-PD-1 antibody and adoptively transferred tumor-specific T cells is successful in cancer treatment; and (11) all of Hacohen, Overwijk, Pilon-Thomas, Ott, Hamid and John explain the known, expected function of antigen-specific T cell therapy and PD-1/PD-L1 blockade by antibodies and how they enhance tumor immunity, activate CD8+ T cell responses, and enhance T-cell tumor infiltration.
Treating melanoma that is metastatic:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat metastatic melanoma by administering a combination of the adoptively transferred autologous T cells specific for tumor antigen neoepitopes with nivolumab or pembrolizumab. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the copending application claims treating melanoma with the tumor antigen-specific T cell composition and anti-immunosuppressive/immunomodulatory PD-1 antibody; (2) Hacohen suggests treating metastatic melanoma with the T cell therapy and a PD-1 antibody; (3) Verdegaal demonstrates successfully treating metastatic melanoma by administering autologous PBMC CD3/CD4+ and CD3/CD8+ cells that were stimulated and activated ex vivo with autologous tumor antigen, resulting in complete regressions including an unexpected long survival; and Verdegaal suggests immune checkpoint inhibition therapy, such as immune-activating anti-PD-1 antibodies, should be combined with the adoptive cell transfer (ACT) to improve further in vivo expansion of tumor-specific T cells and improve clinical effect of ACT; (4) Mackensen demonstrates successfully clinically treating metastatic melanoma patients with adoptive transfer of autologous purified CD8+ peripheral blood lymphocytes that were stimulated ex vivo with autologous dendritic cells (APCs) pulsed with an HLA-A2 binding melan A peptide antigen, then intravenously administered to the patients; (5) Robbins teaches substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs), Robbins demonstrates that melanoma patient CTLs recognize mutant peptide epitopes expressed by their tumor, and Robbins suggests treating melanoma with adoptively transferred CTLs that recognize mutant epitopes expressed by the tumor; (6) Pilon-Thomas teaches administration of a combination of anti-PD-L1 antibody, adoptively transferred T cells, and tumor antigen-pulsed DCs significantly reduced tumor volume in a mouse melanoma model compared to treatment with T cells + DCs and lacking PD-L1 antibody, Pilon-Thomas teaches blocking PD-L1 signaling allows longer persistence and enhanced infiltration of T cells into PD-L1-expressing tumors and suggests this is a valuable approach to enhance clinical responses in patients with melanoma; (7) Ott teaches known success of PD-1/PD-L1 blockade in treating patients with advanced (metastatic) melanoma including with anti-PD-1 antibody nivolumab, and suggests combining with PD-1/PD-L1 blockade with adoptive T cell transfer as a complementary immune therapy; (8) Hamid teaches nivolumab demonstrated “significant antitumor activity” in patients with advanced melanoma, and demonstrates successfully treating advanced melanoma with intravenous lambrolizumab (pembrolizumab); and (9) John exemplifies success in treating a cancer by administering adoptively transferred tumor-specific T cells in combination with anti-PD-1 antibody, wherein PD-1 blockade resulted in enhanced proliferative and functional capacity of the tumor-specific T cells, enhanced regression of established tumors, and significant increase in survival compared to either agent alone.
Melanoma patient is not previously treated:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat metastatic melanoma patients that are not previously treated in the method claimed by the copending application. One would have been motivated to, and have a reasonable expectation of success to, because all of the cited combined references and copending application claims recognize that melanoma patients are in need of cancer treatment, regardless of previous treatment status, and the cited combined references provide a reasonable expectation of success or treat melanoma for the reasons stated above.
Patient is not immuno-compromised by a previous cancer-directed therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat patients that are not immuno-compromised by a previous cancer therapy in the method of the copending application. One would have been motivated to, and have a reasonable expectation of success to, because all of the cited combined references and copending application claims recognize that cancer patients are in need of treatment with the T cell therapy and/or PD-1 antibody, the copending application claims the PD-1 therapy is an anti-immunosuppressive/immunomodulatory agent, and the combined references recognize and explain how the transferred tumor-specific T cells and PD-1 antibody blockade require the immune system to function in mounting and enhancing an anti-tumor immune response to effectively treat cancer.
Checkpoint inhibitor nivolumab or pembrolizumab is administered prior to the cell therapy and on a different day:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer checkpoint inhibitor PD-1 antibody therapy prior to the cell therapy and on a different day. One would have been motivated to, and have a reasonable expectation of success to, because the cited combined references teach or demonstrate that each of the agents separately successfully treat melanoma, and teach the known mechanisms of how the agents act together to enhance antitumor immunity for treatment, providing a reasonable expectation of success for treating melanoma regardless of which agent is administered prior to the other and regardless if administered on separate days.
Treating melanoma patients previously treated with adoptive T cell therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the cell therapy + nivolumab or pembrolizumab to melanoma patients that previously received adoptive T cell therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the copending application claims and the cited combined references recognize that patients diagnosed with melanoma are in need of treatment regardless of previous treatment, (2) the cited combined references demonstrate melanoma is successfully treated with antigen-specific autologous T cells produced ex vivo by stimulation with APCs or tumor antigen, as well as with nivolumab or pembrolizumab, (3) Mackensen and Verdegaal teach that the adoptive T cell therapy can be administered repeatedly, resulting in improved response, thereby demonstrating administering the T cell therapy after adoptive T cell therapy was previously administered; and (4) Verdegaal teaches and demonstrates successfully treating previously treated/refractory melanoma patients.
Treating melanoma patients refractory to immune checkpoint inhibition therapy:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the cell therapy + nivolumab or pembrolizumab to melanoma patients that are refractory to prior checkpoint inhibition therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) the copending application claims and the cited combined references recognize that patients diagnosed with melanoma are in need of treatment regardless of previous treatment, (2) Anchini demonstrates melanoma patients include those refractory to immune checkpoint therapy; (3) the cited combined references demonstrate melanoma is successfully treated with antigen-specific autologous T cells produced ex vivo by stimulation with APCs or tumor antigen, as well as with nivolumab or pembrolizumab, and combining T cell therapy with anti-PD-1 antibody treatment significantly improves tumor treatment, and (4) Verdegaal teaches and demonstrates successfully treating previously treated/refractory melanoma patients.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
12. Applicants point to the arguments above regarding 35 USC 103 and state that none of the cited prior art teach the claim limitations, and the copending application does not claim the instant limitations. There is no motivation or reasonable expectation of success to treat melanoma by administering the claimed T cell therapy and immune checkpoint inhibition on different days.
13. The arguments have been considered but are not found persuasive for the same reasons stated above in response to the arguments regarding the rejection of claims under 35 USC 103(a).
14. Conclusion: No claim is allowed.
Conclusion
15. 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.
16. 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
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