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 .
The examination of this case was initiated by an Examiner PhD and JD degree in Art Unit different from that of instant Examiner.
Election/Restrictions
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Claims 6-8, 51-53, 96-99, 123-126 and 131 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/25/2026.
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.
Claim(s) 13-21, 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lu, The Journal of Immunology, Volume 194, Issue 4, February 2015, Pages 2011–202; Gardner; Blood (2017), 129(25), 3322-3331; Wang, Clinical Cancer Research (2017), 23(5), 1156-1166; Kochenderfer, Journal of Clinical Oncology (2015), 33(6), 540-549 and Korell, Cells 2020, 9, 1225; 1-17.
Base Claim 13: A method of treating a tumor or a cancer in a subject in need thereof, wherein the subject has been administered an alkylating agent, comprising administering to the subject T cells expressing a chimeric antigen receptor (CAR T cells) manufactured from a sample comprising peripheral blood mononuclear cells PBMCs isolated from the subject, wherein at the time the PBMCs are isolated, the subject has last received the alkylating agent at least about six (6) months prior to the time the PBMCs are isolated.
Gardner titled “Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults” teaches that transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled patients. The maximum tolerated dose was 106 CAR T cells per kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat minimal residual disease–negative (MRD−) remission rate for this phase 1 study was 89%. The MRD− remission rate was 93% in patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine and cyclophosphamide lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome and/or reversible severe neurotoxicity. These data demonstrate that manufacturing a defined-composition CD19 CAR T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect profile in a cohort of patients with an otherwise poor prognosis.
Lu teaches that Alkylating Agent Melphalan Augments the Efficacy of Adoptive Immunotherapy Using Tumor-Specific CD4+ T Cells.
In recent years, the immune-potentiating effects of some widely used chemotherapeutic agents have been increasingly appreciated. This provides a rationale for combining conventional chemotherapy with immunotherapy strategies to achieve durable therapeutic benefits. Previous studies have implicated the immunomodulatory effects of melphalan, an alkylating agent commonly used to treat multiple myeloma, but the underlying mechanisms remain obscure. In the present study, we investigated the impact of melphalan on endogenous immune cells as well as adoptively transferred tumor-specific CD4+ T cells in tumor-bearing mice. We showed that melphalan treatment resulted in a rapid burst of inflammatory cytokines and chemokines during the cellular recovery phase after melphalan-induced myelodepletion and leukodepletion. After melphalan treatment, tumor cells exhibited characteristics of immunogenic cell death, including membrane translocation of the endoplasmic reticulum–resident calreticulin and extracellular release of high-mobility group box 1. Additionally, there was enhanced tumor Ag uptake by dendritic cells in the tumor-draining lymph node. Consistent with these immunomodulatory effects, melphalan treatment of tumor-bearing mice led to the activation of the endogenous CD8+ T cells and, more importantly, effectively drove the clonal expansion and effector differentiation of adoptively transferred tumor-specific CD4+ T cells. Notably, the combination of melphalan and CD4+ T cell adoptive cell therapy was more efficacious than either treatment alone in prolonging the survival of mice with advanced B cell lymphomas or colorectal tumors. These findings provide mechanistic insights into melphalan’s immunostimulatory effects and demonstrate the therapeutic potential of combining melphalan with adoptive cell therapy utilizing antitumor CD4+ T cells.
Chun-Meng Wang (Abstract) teaches that relapsed or refractory Hodgkin lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin lymphoma. Patients with relapsed or refractory Hodgkin lymphoma received a conditioning chemotherapy followed by the CART-30 cell infusion. The level of CAR transgenes in peripheral blood and biopsied tumor tissues was measured periodically according to an assigned protocol by quantitative PCR (qPCR).Eighteen patients were enrolled; most of whom had a heavy treatment history or multiple tumor lesions and received a mean of 1.56 × 107 CAR-positive T cell per kg (SD, 0.25; range, 1.1–2.1) in total during infusion. CART-30 cell infusion was tolerated, with grade ≥3 toxicities occurring only in two of 18 patients. Of 18 patients, seven achieved partial remission and six achieved stable disease. An inconsistent response of lymphoma was observed: lymph nodes presented a better response than extranodal lesions and the response of lung lesions seemed to be relatively poor. Lymphocyte recovery accompanied by an increase of circulating CAR T cells (peaking between 3 and 9 days after infusion) is a probable indictor of clinical response. Analysis of biopsied tissues by qPCR and immunohistochemistry revealed the trafficking of CAR T cells into the targeted sites and reduction of the expression of CD30 in tumors.
Wang concludes CART-30 cell therapy was safe, feasible, and efficient in relapsed or refractory lymphoma and guarantees a large-scale patient recruitment.
Kochenderfer also teaches successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.
T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19 B-cell malignancies. 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell
lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. Results Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/ L.
Korell titled ‘Current Challenges in Providing Good Leukapheresis Products for Manufacturing of CAR-T Cells for Patients with Relapsed/Refractory NHL or ALL’
Korell teaches an analysis of the leukapheresis products used to produce CART cells in pretreated cancer patients (abstract). The apheresis products are analyzed for CD3+/CD45+ T cells and total nucleated cells (TNCs; item 2.3, on p. 4). The characteristics of the leukapheresis products are detailed in Table 4. As can be seen from Table 4, the ratio of CD3+ cells is on average above 20% of all the nucleated cells. The patients either have lymphoma, chronic lymphocytic leukemia or acute lymphoblastic leukemia (Table 4), most of them with diffuse large B-cell lymphoma (Table 5). Some of the patients have been treated with the alkylating agent bendamustine (Table 5). Statistical analysis yielded cut-off values for apheresis products of: 1.2 x 1as CD3+ T cell count, 2.8 x 1as TNC count, and 51.0 x 1as platelet count (item 3.8, p. 11 and 12). The CD19 CAR used is scFv based (item 2.4 on p. 4).
Karell teaches recommendations for stopping different ongoing therapies prior to apheresis and the manufacture of CART cells (Fig. 7 and p. 12, last paragraph - p. 14, paragraph 2). Korell defines cut-off criteria for the apheresis product as : 1.2 x 1as CD3+ T cell count, 2.8 x 1as TNC count, and 51.0 x 1as platelet count to achieve best response. D2 (WO2019108900) recommends a 2 week washout period between previous therapies (including cyclophosphamide) and apheresis to manufacture BCMA CART cells (p. 302, I. 25-35 and Table 32).
The teachings of Lu, Gardner, Wang, Kochenderfer, Korell show the successful treatment of tumor or a cancer with CAR T-cells in subjects previously treated with alkylating agents. Dependent claim 14 relates to the ‘relapsed time’ before the administration of the CAR T cells, claims 15-19 (cancer being treated), and claims 21, 23 (the alkylating agents) all found in the teaching of Lu, Gardner, Wang, Kochenderfer and Korell.
As such there is nothing unobvious in these claims.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Feins, An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer Am J Hematol. 2019;94:S3–S9.
Wang, Combining chemotherapy with CAR-T cell therapy in treating solid tumors, Front Immunol. 2023 Mar 6;14:1140541.
Rytlewski, Effects of Prior Alkylating Therapies on Preinfusion Patient Characteristics and Starting Material for CAR T Cell Product Manufacturing in Late-Line Multiple Myeloma, Blood, vol. 136, no. Supplement 1, 5, 11-05-2020, pages 7-8.
(Note instant provisional priority 11-04/-2020).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim(s) 13-21, 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 14 of copending Application No. 18864469 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claim contains overlapping subject matter.
18864469:
14. (Currently Amended) A method of treating a tumor or a cancer in a subject in need thereof, comprising administering to a subject T cells manufactured from peripheral blood mononuclear cells (PBMCs) isolated from the patient subject, wherein: the subject has been administered a prior therapy selected from a topoisomerase inhibitor therapy or a proteasome inhibitor therapy; and at the time the PBMCs are isolated, the subject has last received the prior therapy at least about six (6) months prior to the time the PBMCs are isolated.
Instant Base claim 13:
13: A method of treating a tumor or a cancer in a subject in need thereof, wherein the subject has been administered an alkylating agent, comprising administering to the subject T cells expressing a chimeric antigen receptor (CAR T cells) manufactured from a sample comprising peripheral blood mononuclear cells PBMCs isolated from the subject, wherein at the time the PBMCs are isolated, the subject has last received the alkylating agent at least about six (6) months prior to the time the PBMCs are isolated.
The difference is the prior chemotherapy in the conflicting claim. The method is same in both cases and administered agent in the treatment method in both cases is the same: Chimeric Antigen Receptor (CAR) T-cell therapy, a personalized immunotherapy that genetically modifies a patient's own T-cells to detect and destroy cancer cells, primarily treating relapsed or refractory blood cancers like leukemia, lymphoma, and myeloma. For example, topoisomerase inhibitors are key agents in multiple myeloma (MM) treatment, targeting enzymes responsible for DNA replication and repair.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625
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