DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 24, 2025 has been entered.
Claims 48-61, 64-76 are now pending. Claims 72-76 are new. Claims 48, 51, 52, 57-61 are amended. Claims 54, 56, 57, 60, 61, and 75 remain/are withdrawn as being drawn to non-elected species.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.
Maintained Rejections
(amendments addressed and additional references added)
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.
2. Claim(s) 48-53, 55, 58-59, 64-73 and 76 remain/are 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 (claims 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 (claims 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. 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.
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.
Response to Arguments
3. Applicants argue that the cited references do not present any clinical data demonstrating that the claimed cell therapy is safe to administer to human subjects with melanoma or that it is effective to treat melanoma.
4. The arguments have been considered but are not persuasive. References Mackensen et al (Journal of Clinical Oncology, 2006, 24:5060-5069) and Verdegaal et al (Cancer Immunol Immunother, 2011, 60:953-963) were added to the rejection demonstrating an expected clinical success to treat melanoma patients. Both references demonstrate clinical success of administering autologous patient PBMCs or CD8+ PBLs stimulated with either autologous tumor cells/antigen or with APCs loaded with a tumor antigen, and treating metastatic melanoma patients, wherein PBMCs and PBLs inherently comprise CTLp (as evidenced by Maeda). Further, Verdegaal teaches treatment 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 experienced 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. Hamid demonstrated successfully clinically treating advanced melanoma with intravenous lambrolizumab (also known as pembrolizumab and MK-3475). Hamid teaches phase I clinical studies with nivolumab demonstrated “significant antitumor activity” in patients with advanced melanoma and lung cancer, treatment resulted in increased CD8+ T cell infiltration of tumor, and the importance of releasing inhibitory immune regulation by PD-1 for effective antitumor immunity. Those three references alone provide a reasonable expectation of success to treat melanoma and metastatic melanoma with either adoptive cell transfer method of Hacohen or anti-PD-1 antibody nivolumab or pembrolizumab therapy.
It is noted that the instant specification does not provide a working example or clinical data for treating melanoma patients with the claimed cell therapy or in combination with nivolumab or pembrolizumab.
5. Applicants argue that the cited references do not provide motivation to combine nivolumab or pembrolizumab with the claimed cell therapy. Applicants argue that Hacohen does not exemplify or provide data for combining pembrolizumab or nivolumab with the cell therapy.
6. The arguments have been considered but are not persuasive. Contrary to arguments, several of the cited references provide motivation to add anti-PD-1 immune checkpoint inhibition therapy to adoptive cell therapies, including known anti-PD-1 antibodies pembrolizumab and nivolumab. One would have been motivated to, and have a reasonable expectation of success to combine the anti-PD-1 antibodies with the cell therapy of Hacohen to treat melanoma, 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) 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; (4) 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; (5) Hamid teaches nivolumab demonstrated “significant antitumor activity” in patients with advanced melanoma, and demonstrates successfully treating advanced melanoma with intravenous lambrolizumab (pembrolizumab); and (6) 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.
It is noted that the instant specification does not provide a working example or clinical data for treating melanoma patients with the claimed cell therapy or in combination with nivolumab or pembrolizumab.
7. Applicants argue that Robbins is directed to administering tumor infiltrating lymphocytes (TILs) to treat melanoma and not to administering T lymphocytes that were activated by stimulating ex vivo with APCs loaded with neoantigen epitopes as claimed. Applicants argue that the TILs of Robbins were already specific to a tumor antigen.
8. The arguments have been considered but are not persuasive. Robbins demonstrates successful treatment of melanoma clinically by administering TILs that are T cells already specific for melanoma tumor antigens because they were activated in vivo naturally with APCs and tumor antigen. The instantly claimed method also administers T cells that are already specific for melanoma tumor antigen, however, the claimed T cells were activated ex vivo with specific tumor antigens presented by APCs. Applicants have not persuasively argued that the successful results of administering tumor-specific T cells (TILs) to treat melanoma would not be reasonably or predictably extrapolated to the treatment results of the tumor-specific T cells administered in the method of Hacohen.
9. Applicants argue that Pilon-Thomas teaches data indicating that an anti-PD-L1 antibody + melanoma peptide-pulsed DC resulted in a higher number of melanoma peptide-specific CD8+ T cells but the combination was insufficient to delay tumor growth of established B16 melanoma model. Applicants argue that based on their data, one would not expect combining nivolumab or pembrolizumab with the cell therapy of Hacohen would treat melanoma.
10. The arguments have been considered but are not persuasive. Contrary to arguments, Pilon-Thomas does not teach away from the invention and Applicants have taken a quote from Pilon-Thomas out of context. The full abstract of Pilon-Thomas states:
Inhibition of antitumor T cell responses can be mediated by the productive interaction between the programmed death-1 (PD-1) receptor on T cells and its ligand PD-L1. PD-L1 is highly expressed on both murine bone marrow-derived dendritic cells (DCs) and B16 melanoma. In this study, in vitro blockade of PD-L1 interaction on DCs led to enhanced IFN-g production and cytotoxicity by Ag-specific T cells. In vivo, the systemic administration of anti–PD-L1 Ab plus melanoma peptide-pulsed DCs resulted in a higher number of melanoma peptide-specific CD8+ T cells, but this combination was insufficient to delay the growth of established B16 melanoma. Although the addition of 600 rad of total body irradiation delayed tumor growth, further adoptive transfer of Ag-specific CD8+ T cells was needed to achieve tumor regression and long-term survival of the treated mice. Lymphopenic mice treated with anti–PD-L1 Ab demonstrated increased activation and persistence of adoptively transferred T cells, including a higher number of CD8+ T cells infiltrating the tumor mass. Together, these studies support the blocking of PD-L1 signaling as a means to enhance combined immunotherapy approaches against melanoma.
Pilon-Thomas teaches (p. 3448, col. 1):
“Combination therapy with anti–PD-L1 Ab and peptide-pulsed DC immunizations resulted in a significant delay in B16 tumor growth. The addition of adoptively transferred, tumor-specific T cells enhanced this effect and led to an improved survival in mice bearing either B16 or the M05 melanoma.”
“Collectively, our studies support the addition of anti–PD-L1 Ab to immunotherapeutic approaches that employ the adoptive transfer of T cells and active vaccination, particularly in the setting of lymphopenia. Blocking PD-L1 signaling allows longer persistence and enhanced infiltration of T cells into PD-L1–expressing tumor. This approach may be valuable as a means to enhance clinical responses in patients with melanoma.”
Pilon-Thomas provides motivation and reasonable expectation of success to add PD-L1/PD-1 blockade to adoptive transfer of T cells in order to treat melanoma and enhance persistence and tumor infiltration of T cells.
11. Applicants argue that Overwijk does not teach data from treating melanoma patients. Applicants argue Overwijk teaches administering a peptide and not CTLp cells stimulated ex vivo with APCs.
12. The arguments have been considered but are not persuasive. Overwijk is a review article summarizing the known success in the art for T cells that can “mediate remarkable tumor regressions including complete cure in patients with metastatic cancer” (abstract). The additional disclosure of vaccinating with unique mutantome peptides (m-peptides) does not teach away from the success of adoptive T cell therapy taught by Overwijk. As stated in the rejection of record, 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.
13. Applicants argue that Ott does not remedy the deficiencies of Hacohen, Robbins, Pilon-Thomas, and Overwijk. Applicants argue that Ott suggests complementary immunotherapies to be combined with PD-1/PD-L1 blockade including adoptive T cell transfer but does not teach the T cells transferred are CTLp cells stimulated ex vivo with APCs. Applicants argue that Ott teaches checkpoint inhibitor therapy is safe and efficacious without the use in combination with cell therapy. Applicants argue that because Ott teaches a phase I combination trial of anti-CTL-4 antibody ipilimumab and vemurafenib (BRAF kinase inhibitor) and nivolumab was halted due to grade 3 or 4 toxicity that one of skill in the art would understand that therapeutic combination clinical trials are unpredictable.
14. The arguments have been considered but are not persuasive. Hacohen, Robbins, Pilon-Thomas, and Overwijk do not have the deficiencies argued by Applicants, therefore Ott does not need to remedy the argued deficiencies. Ott does not need to teach the adoptive T cell therapy is CTLp cells stimulated ex vivo with APCs because Hacohen met that limitation. Contrary to arguments, a disclosure that checkpoint inhibitor therapy is safe and efficacious without the combination of cell therapy, provides further reasonable expectation of success for administering checkpoint inhibitor therapy for efficacious and successful treatment of melanoma. Finally, contrary to arguments, Ott does not teach away from the combination therapy of adoptive T cell transfer and immune checkpoint inhibition, nor does Ott teach it is unpredictable. The title of the Ott reference is: “CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients”. Ott concludes increasing the number of patients with melanoma to benefit from durable responses with immune checkpoint blockade by concurrent or sequenced CTLA-4 and PD-1/PD-L1 inhibition and combination with other immunotherapeutic strategies (abstract), wherein complementary immunotherapeutic strategies include adoptive T cell transfer (p. 5307, col. 1).
15. Applicants argue that Hamid does not remedy the deficiencies of the prior references. Applicants argue that Hamid only teaches the safety of anti-PD1 monotherapy pembrolizumab in melanoma patients, citing clinical trial data. Applicants argue the clinical trial cited by Hamid demonstrates high disease progression, indicating unpredictability in the art.
16. The arguments have been considered but are not persuasive. The prior cited references do not have the deficiencies argued by Applicants, therefore Hamid does not need to remedy the argued deficiencies. Contrary to arguments, Hamid’s conclusion identifies the predictable success of treating melanoma with pembrolizumab (lambrolizumab): “In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.)”
17. Applicants argue that John does not remedy the deficiencies of the prior cited art. Applicants argue that John teaches combining anti-PD-L1 antibody with CAR T cell therapy and none of the data is directed at treating melanoma with CTLp cells stimulated in vitro with APCs. Applicants argue the data in John does not provide a reasonable expectation of success to arrive at the claimed invention.
18. The arguments have been considered but are not persuasive. The prior cited references do not have the deficiencies argued by Applicants, therefore John does not need to remedy the argued deficiencies. Contrary to arguments, John demonstrates that adding PD-1 blockade to tumor-specific T cell therapy successfully enhances tumor-specific T cell therapy by significantly improving tumor growth inhibition and increase the function of the tumor specific T cells, providing motivation and reasonable expectation of success to add PD-1 blockade to the tumor-specific T cell therapy of Hacohen and improve T cell function and significantly improve tumor inhibition. John does not teach that the effects of PD-1 blockade on improving T cell therapy they observed is unique or limited to CAR T cells or to a specific cancer.
19. Applicants argue there is a long felt need in the art to treat melanoma that the instant invention has satisfied. Applicants argue they are conducting clinical trials with the claimed combination treatment for melanoma, citing Borgers (2025). Applicants argue the reference describes a clinical trial for treating melanoma with NEO-PTC-01 autologous personalized T cell product for adoptive therapy that is manufactured ex vivo and targets neoantigens displayed on the patient’s tumor and tumor microenvironment, in combination with anti-PD-1 inhibitors. Applicants argue the results suggest there is room for improvement with the caveat that increasing the number of T cells per dose can often be difficult to achieve for further improving the clinical efficacy, and that there is a necessity for additional therapeutic approaches. In this context, it was observed that T cells remained functional and expressed PD-1, which indicated that such cells have the potential and receptivity to an anti-PD-1 therapy for a heightened immune response within safety limits.
20. The arguments have been considered but are not persuasive. Borgers (2025). discloses (abstract):
We designed BNT221, a personalized, neoantigen-specific autologous T cell product derived from peripheral blood, and tested this in a 3 + 3 dose-finding study with two dose levels (DLs) in patients with locally advanced or metastatic melanoma, disease progression after ICB, measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1) and, where appropriate, BRAF-targeted therapy. Primary and secondary objectives were evaluation of safety, highest tolerated dose and anti-tumor activity. We report here the non-pre-specified, final results of the completed monotherapy arm consisting of nine patients: three at DL1 (1 × 108 –1 × 109 cells) and six at DL2 (2 × 109 –1 × 1010 cells). Drug products (DPs) were generated for all enrolled patients. BNT221 was well tolerated across both DLs, with no dose-limiting toxicities of grade 3 or higher attributed to the T cell product observed. Specifically, no cytokine release, immune effector cell-associated neurotoxicity or macrophage activation syndromes were reported. A dose of 5.0 × 108 –1.0 × 1010 cells was identified for further study conduct. Six patients showed stable disease as best overall response, and tumor reductions (≤20%) were reported for four of these patients. In exploratory analyses, multiple mutant-specific CD4+ and CD8+ T cell responses were generated in each DP. These were cytotoxic, polyfunctional and expressed T cell receptors with broad functional avidities. Neoantigen-specific clonotypes were detected after treatment in blood and tumor. Our results provide key insights into this neoantigen-specific adoptive T cell therapy and demonstrate proof of concept for this new therapeutic approach.
The study in Borgers does not teach or demonstrate adding nivolumab or pembrolizumab to the autologous T cell therapy, which is required by the instant claims.
As evidenced by the cited prior art references in the rejection of record, the cited prior art also recognized the need to treat melanoma and demonstrated success doing so with either tumor-specific T cell adoptive therapy (whether it is TILs, or T cells in PBMC stimulated ex vivo with APCs or tumor antigen), or PD-1 antibody nivolumab or pembrolizumab, and the cited prior art suggested and demonstrated combination T cell therapy with PD-1 blockade provides improved cancer treatment. Further, as stated in the rejection, Hacohen and Verdegaal specifically suggest and recognize the need to add anti-PD-1 therapy to the adoptive T cell therapy, where Verdegaal teaches the addition will improve further in vivo expansion of tumor-specific T cells and improve clinical effect of adoptive cell transfer. Applicants have not shown how the long-felt need for treatment of melanoma was not solved previously or by the teaching of the cited combined references. In addition, there is no evidence that if persons skilled in the art who were presumably working on the problem knew of the teachings of the above cited references, would still be unable to solve the problem. See MPEP §716.04.
New Rejection
(necessitated by amendments)
Claim Rejections - 35 USC § 103
21. Claim(s) 74 is 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.
Maintained Rejection
(amendments addressed and additional references added)
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).
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22. Claims 48-53, 55, 58-59, 64-74 and 76 remain/are 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.
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:
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. 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.
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
23. Applicants argue that the copending application claims do not render obvious the instant method. Applicants argue the copending claims do not recite administering the same cell therapy with nivolumab or pembrolizumab to teat melanoma.
24. The arguments have been considered but are not persuasive. Contrary to arguments, the copending application claims treating a subject having cancer that is specifically melanoma (claim 66), by administering a subject-specific composition comprising autologous T cells stimulated ex vivo with APCs comprising a mutant neoantigenic epitopes identified by the same criteria instantly claimed; wherein the T cells are from PBMCs of the subject (comprising naïve cells); and administering the cells in combination with anti-PD-1 antibody. The secondary references cited render obvious utilizing CTLp as the T cell for APC/antigen stimulation ex vivo and utilizing nivolumab and pembrolizumab as the anti-PD-1 antibodies for combination therapy, as well as additional limitations stated in the rejection of record.
25. Conclusion: No claim is allowed.
26. 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