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 .
Applicant’s remarks, filed 8/4/2026, are acknowledged and entered into the record. Applicants amended claims 1-2, 6, 10, 12, 19, 25, 33, 41, 57, 59, 85, 90, 110, 114 and 122; canceled claim 8; and added new claim 128, in the remarks of 8/4/2026.
Priority- Foreign
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(a)-(d) and (f) or under 35 U.S.C. 120, 121, 365(a) or (b), or 386(a) is acknowledged. The present application is drawn from PCT/CN2021/135295, filed 12/3/2021; and claims benefit under 35 U.S.C. 119(a)-(d) to foreign application PCT/CN2020/133598, filed 12/3/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of Claims
Claims 1-2, 6, 10, 12, 19, 25, 32-33, 41, 57, 59, 82, 84-85, 90, 110, 114, 122 and 128 are pending and are being examined on the merits.
Claim Rejections – Withdrawn
Claim Rejections - 35 USC § 112(b)
The rejection of claims 2, 6, 8, 10, 12, 19, 25, 33, 41, 57, 59, 90, 110, 114 and 122 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn. Applicants amended the claims to remove “optional” language, thus obviating the rejections for indefiniteness.
Claim Rejections – 35 U.S.C. 102(a)(1)
The rejection of claims 1-2, 10, 19, 32-33, 41, 57, 59, 82, 84-85, 90, 110, 114 and 122 under 35 U.S.C. 103 as being unpatentable over Fan et al., (from IDS, Cite No. B06; WO 2018028647; published 2/15/2018), is withdrawn. Applicants amended independent claims 1 and 85 to include new limitations, such that the methods are no longer anticipated by Fan et al.
Claim Rejections – Maintained, Amended
Applicant’s amended independent claims 1 and 85 to include new limitations. Thus, the rejections are maintained and amended to address the new limitations of the amended claims.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-2, 6, 10, 12, 19, 25, 32-33, 41, 57, 59, 82, 84-85, 90, 110, 114, 122 and 128 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fan et al., (from IDS, Cite No. B06; WO 2018028647; published 2/15/2018) and Raje et al., (New England Journal of Medicine; 2019, 380(18), Supplemental Protocol); as evidenced by San-Miguel et al., (New England Journal of Medicine, 2023).
Fan et al. teaches chimeric antigen receptors (CAR) targeting BCMA, wherein the CARs are multivalent, comprising one or more anti-BCMA single-domain antibodies, as well as engineered immune effector cells, such as T cells, comprising the CARs and methods of treating cancer (abstract).
Structurally, Fan teaches an exemplary multivalent BCMA CAR may be that of GSI5021, defined by SEQ ID NO: 300 (pg. 95-96, Table 5; pg. 9, para. 0024). Fan SEQ ID NO: 300 is 100% identical in amino acid sequence to instant SEQ ID NO: 17, of claim 85. It comprises a first anti-BCMA binding moiety of instant SEQ ID NO: 2 and a second anti-BCMA binding moiety of instant SEQ ID NO: 4 with 100% sequence identity for each (of claim 1); and which are encoded by the nucleic acid sequences of instant SEQ ID NOs: 10 and 12, respectively, (of claim 59) with 100% sequence identity. It comprises the linker of instant SEQ ID NO: 3, the signal peptide of instant SEQ ID NO: 1, the transmembrane domain of instant SEQ ID NO: 6, the intracellular signaling domain of instant SEQ ID NO: 8 and the hinge domain of instant SEQ ID NO: 5 (of claim 59), all with 100% sequence identity. Thus, the GSI15021 embodiment of the multivariant anti-BCMA CAR of Fan SEQ ID NO: 300 anticipates the exemplary embodiment of the multivariant anti-BCMA CAR of the instant claims; specifically, that encoded by instant SEQ ID NO: 17.
Fan teaches the CAR of SEQ ID NO: 300 may be used in generating engineered immune cells, including T cells, wherein the CAR comprises a first and a second BCMA binding moiety, a transmembrane domain and an intracellular signaling domain (pg. 114, paras. 0334-0335; para. 0336, pg. 118, last line). Fan teaches a method of treating cancer, such as multiple myeloma, in a human individual, comprising administering an effective amount of a pharmaceutical composition comprising an engineered T cell comprising any of the disclosed multivalent CARs (pgs. 134-135, paras. 0391-0392; pg. 146, para. 0405).
However, Fan does not teach single or double bags of CAR-T cells (re. claims 6 and 8), a lymphodepleting regimen (re. claim 12) or pre-infusion medication (re. claim 25).
Raje et al. teaches preclinical studies comprising administering bb2121, a CAR-T cell therapy that targets BCMA, for the treatment of multiple myeloma (abstract). In the Supplemental Data section, Raje provides Clinical Study Protocol CRB-401, describing a Phase 1 study of bb2121 in BCMA-Expression Multiple Myeloma (Supplemental Protocol, pg. 1).
In the supplemental protocol, Raje teaches that the primary objectives of the study are to determine the maximally tolerated dose of bb2121 in subjects with multiple myeloma whose tumors express BCMA (pg. 4, section 1.1). Raje teaches bb2121 is defined as autologous T cells transduced ex-vivo with anti-BCMA02 CAR lentiviral vector encoding the CAR targeted to human BCMA, suspended in cryopreservative solution (pg. 15, section 4.1).
Raje teaches infusion procedures and administration (pg. 19, section 4.5.3). Raje teaches the study protocol includes administering the bb2121, intravenously (IV), on Day 0. Raje teaches that pre-medication should occur approximately 30 minutes prior to the infusion and should include acetaminophen (i.e. a known antipyretic) and diphenhydramine (i.e. a known antihistamine), whereby the diphenhydramine is administered IV and the acetaminophen is administered orally. Raje teaches that the protocol includes a lymphodepletion treatment plan (pg. 18, section 4.5.2.2); whereby bb2121 is to be given on Day 0, after lymphodepletion on Days -5, -4 and -3 (section 4.5.3). Raje teaches the infusion procedures of anti-BCMA CAR-T therapy; specifically when the CAR-T cells are frozen (pg. 19, section 4.5.3). Raje teaches bb2121 must be delivered to the subject care unit, thawed at the infusion site in a 37°C water bath and infused immediately within 1 hour. If multiple drug product bags are to be administered to meet the protocol assigned dose, each bag will be thawed and administered 1 bag at a time within a maximum of 1 hour for each bag until the appropriate volume and corresponding CAR-T cell dose has been administered.
Thus, Raje teaches the art on clinical trials involving administering anti-BCMA CAR-T cell therapy to patients with multiple myeloma. Raje teaches that a lymphodepleting regime, prior to infusion of the CAR-T cells, and a pre-medication administration of acetaminophen and diphenhydramine, are known regimens as part of a CAR-T cell therapy protocol. It therefore would have been obvious to a skilled artisan to include a lymphodepleting regimen and a pre-medication regimen in a clinical trial protocol for a method of administering anti-BCMA CAR-T cell therapy, with motivation and reasonable expectation for success provided by the Phase I clinical trial protocol of Raje et al. MPEP section 2143(I) provides examples of rationales that support a conclusion of obviousness, including (A)-combining prior art elements according to known methods to yield predictable results; (C)-use of a known technique to improve similar methods in the same way; and (D)-applying a known technique to a known method ready for improvement to yield predictable results. In this case, Raje teaches a method of administering anti-BCMA CAR-T cell therapy, whereby the method includes a lymphodepleting regimen and a pre-medication regimen. Therefore, it would have been obvious to modify the methods of administering anti-BCMA CAR-T cell therapy, of Fan, to further comprise a lymphodepleting regimen and the pre-medication regimen of Raje, to improve the cell therapy methods and yield predictable results.
Regarding claims 1 and 59; the combination methods of Fan and Raje make obvious administering an anti-BCMA CAR-T cell treatment regime for treating multiple myeloma, as described above. Fan teaches the method of treating multiple myeloma comprising administering a composition of genetically engineered T cells expressing the multivariant anti-BCMA CAR of GSI15021, which comprises a first BCMA binding moiety of instant SEQ ID NO: 2, a second BCMA binding moiety of instant SEQ ID NO: 4, a transmembrane domain and an intracellular domain, are taught by Fan. Further, Fan teaches the administration may be intravenous administration, and may be a single infusion over a period of time (pg. 134, para. 0387). Fan teaches a method of treating comprising administering CAR-T cells, via a single IV infusion, at a dose of 1 x 106 cells/kg (pg. 145, para. 0402). Fan teaches eligible patient criteria include wherein the patient has refractory multiple myeloma as defined by having received at least 3 prior treatment regimens, including bortezomib, which is a known PI (pg. 177, para. 0550). Raje teaches the CAR-T cells in a frozen product bag, whereby the bag is thawed and administered within a maximum of 1 hour after thawing (pg. 19, section 4.5.3). Raje teaches the pre-medication regime includes administering acetaminophen, which is a known antipyretic, and diphenhydramine, which is a known antihistamine, 30 minutes prior to infusion of the CAR-T cells (pg. 19, section 4.5.3). Thus the combination methods of Fan and Raje make obvious the methods of instant claim 1. Regarding claim 59, Fan teaches that anti-BCMA sdAb comprises a VHH domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 115-152 (pg. 139, para. 0393). Fan SEQ ID NO: 124 is 100% identical in amino acid sequence to instant SEQ ID NO: 2; and Fan SEQ ID NO: 117 is 100% identical in amino acid sequence to instant SEQ ID NO: 4. Also see pg. 96, Table 5, whereby GSI50 comprises the sdAb#1 of 269A37353 and the sdAb#2 of 269A37917; compared to pg. 35, Table 2, which teaches that 269A37353 is SEQ ID NO: 124 and 269A37917 is SEQ ID NO: 117. Thus, Fan teaches that the anti-BCMA binding domains of instant SEQ ID NOs: 2 and 4, which are comprised in the GSI15021 multivariant anti-BCMA CAR of Fan, are VHH domains. Thus, the combination of Fan and Raje make obvious instant claim 59.
Regarding claim 2; Fan teaches the engineered immune cells are administered at a dose of about 105 to about 107 cells/kg, such as about 3 x 105 cells/kg (pg. 139, para. 0393), or 7 x 105 cells/kg (pg. 145, para. 0402), which is equivalent to 0.7 x 106 cells. Thus, Fan makes obvious instant claim 2.
Regarding claim 6, the modified combination methods of Fan and Raje are described above. Raje teaches the CAR-T cells in a frozen product bag, whereby the bag is thawed and administered within a maximum of 1 hour after thawing. Raje also teaches that multiple drug product bags may be administered to meet the protocol assigned dose. Thus, Raje makes obvious administering the single IV infusion of CAR-T cells of Fan, by using CAR-T cells in a single bag, or multiple (i.e. two) bags. Therefore the combination of Fan and Raje make obvious instant claim 6.
Regarding claims 10 and 57, Fan teaches that the present application demonstrated the superior efficacy of bivalent bi-epitope CARs comprising two anti-BCMA sdAbs in treating multiple myeloma among human patients, including wherein patients remained free of minimal residual disease after more than a year of receiving the CAR-T treatment (pg. 13, para. 0054), with no detectable cancer cells in the bone marrow (pg. 178, para. 0553). Thus, Fan teaches that an alternative embodiment of the CAR-T cell therapy resulted in negative status of minimal residual disease, after treatment (re. claim 10) and over a year later (re. claim 57); and Fan teaches the GSI15021 embodiment of the CAR, which is 100% identical to the CAR of the instant claims, and thus possesses all the inherent properties of the CAR-T cells and methods of administering the CAR-T cells. Thus, the combination of Fan and Raje make obvious instant claims 10 and 57.
Regarding claim 12, Raje teaches the lymphodepleting regime occurs at days -5, -4 and -3 of the protocol, before the infusion of CAR-T cells on day 0. Further, Raje teaches the lymphodepletion treatment plan comprises administering cyclophosphamide (300 mg/m2; IV) and Fludarabine (30 mg/m2; IV), as described in Table 4-1 (pg. 19). Thus, the combination method of Fan and Raje makes obvious instant claim 12.
Regarding claim 19, Fan teaches that two patients experienced severe cytokine release syndrome (CRS), but recovered upon receiving tocilizumab, an inflammation-reducing treatment commonly used to manage CRS in clinical trials of CAR-T cell therapy, (pg. 178, para. 0554). Tocilizumab is an IL-6R inhibitor. Thus, as Fan teaches administering tocilizumab for treating CRS in response to the CAR-T therapy in multiple myeloma patients, and the combination of Fan and Raje make obvious instant claim 19.
Regarding claim 25, Raje teaches the pre-medication regime includes administering acetaminophen (at 650 mg, orally), which is a known antipyretic, and diphenhydramine (at 25 to 50 mg, orally) , which is a known antihistamine, 30 minutes prior to infusion of the CAR-T cells (pg. 19, section 4.5.3). Thus, the combination method of Fan and Raje makes obvious instant claim 25.
Regarding claim 32, Fan teaches appropriate excipients include dextran (pg. 133, para. 0383). Further, Fan teaches that the T cells may be frozen and that a solution comprising 20% DMSO or 10% Dextran 40 may be particularly suitable for a cell freezing media (pg. 127, para. 0367). Thus, Fan and Raje make obvious instant claim 32.
Regarding claim 33, Fan teaches eligible patient criteria include wherein the patient has refractory multiple myeloma as defined by having received at least 3 prior treatment regimens, or has relapsed multiple myeloma (pg. 177, para. 0550). Thus, the combination of Fan and Raje make obvious instant claim 33.
Regarding claim 41, Fan teaches that an interim analysis of 35 patients with refractory multiple myeloma showed an overall objective response rate was 100% and 33/35 (94%) patients had an evident clinical remission of myeloma (pg. 178, para. 0552). Thus, the combination of Fan and Raje make obvious instant claim 41.
Regarding claims 82 and 84; Fan teaches the engineered immune effector cells, for use in a method of treating cancer in an individual, may be autologous or allogenic immune effector cells (pg. 10, para. 0029). Further, Fan teaches the individual is a human (pg. 30, para. 0109; pg. 13, para. 0054).
Regarding claim 85; as described above, Fan teaches the embodiment of the multivariant anti-BCMA CAR of species GSI15021, which is 100% identical in amino acid sequence to instant SEQ ID NO: 17. Fan teaches a method of treating comprising administering CAR-T cells, via a single IV infusion, at a dose of about 3 x 105 to about 7 x 106 cells/kg (pg. 135, para. 0392, last line), or 1 x 106 (pg. 145, para. 0402), and wherein the method is effective in obtaining minimal residual disease negative status over 12 months following infusion. Fan teaches eligible patient criteria include wherein the patient has refractory multiple myeloma as defined by having received at least 3 prior treatment regimens, including bortezomib, which is a known PI (pg. 177, para. 0550). Raje teaches the CAR-T cells in a frozen product bag, whereby the bag is thawed and administered within a maximum of 1 hour after thawing (pg. 19, section 4.5.3). Raje teaches the pre-medication regime includes administering acetaminophen, which is a known antipyretic, and diphenhydramine, which is a known antihistamine, 30 minutes prior to infusion of the CAR-T cells (pg. 19, section 4.5.3). Thus the combination methods of Fan and Raje make obvious the methods of instant claim 85.
Regarding claims 90 and 110, Fan teaches the primary outcome of the study includes efficacy objectives such as the pathological Complete Response proportion (re. claim 90) and 3-year Progression Free Survival (re. claim 110; pg. 177, para. 0549). Fan teaches that in a study comprising administering an alternative embodiment of the CAR of the invention, of 19 patients, 14 have reached stringent complete response criteria, 1 patient has reached partial response, and 4 patients have achieved very good partial remission criteria in efficacy (pg. 2, para. 0008); and that patients who reached Stringent Complete Response criteria remained free of minimal residual disease after more than a year of receiving the CAR-T treatment (pg. 13, para. 0054). Thus, Fan teaches that stringent complete response criteria and progression-free survival are common parameters for use in a method of treating cancer using CAR-T cell therapy; and Fan teaches an embodiment of the multivalent anti-BCMA CAR of GSI15021, which is identical to the CAR of instant SEQ ID NO: 17 and the CAR-T cells of the instant invention, and thus possesses all the inherent properties of the CAR-T cells and methods of administering the CAR-T cells. Thus, the combination of Fan and Raje make obvious instant claims 90 and 110.
Regarding the limitation of “more than 1 day” (re. clam 114) or “more than 3 days following infusion” (re. claim 19); it is obvious for a skilled artisan to optimize known protocols (see MPEP 2144.05(II)), whereby if the CRS is detected more than 1 day or more than 3 days following infusion, and administering tocilizumab for treating CRS is common in the art, as taught by Fan, then the tocilizumab would be administered at the appropriate time relative to the onset of CRS. Thus, the combination of Fan and Raje make obvious treating CRS more than 1 day after infusion of CAR-T cells, and thus make obvious instant claim 114.
Regarding claim 122, Fan teaches in some embodiments the amount of the pharmaceutical composition is effective to prevent relapse or disease progression of the cancer in the individual, and that the relapse or disease progression is prevented for at least about 6 months, 1 year, 2 years or more (pg. 147, para. 0407). As Fan also teaches that efficacy objectives of the study include Complete Response proportion and 3-year Progression Free Survival, as described above (pg. 177, para. 0550), Fan contemplates that the method is effective in maintaining a response in the subject at a follow-up time, approximately 180 days after infusion of CAR-T cells. Thus, the combination of Fan and Raje make obvious instant claim 122.
Regarding claim 128; the combination methods of Fan and Raje are described above. Specifically, Fan teaches the anti-BCMA CAR of GSI15021, which is identical to the CAR of instant SEQ ID NO: 17 and the CAR-T cells of the instant invention, and thus possesses all the inherent properties of the CAR-T cells and methods of administering the CAR-T cells. The instant specifications describe the anti-BCMA CAR of instant SEQ ID NO: 17 as “Ciltacabtagene autoleucel” or “Cilta-cel” (specs., pg. 22, para. 1). San-Miguel discloses cilta-cel directed CAR T-cell therapy is effective in patients with relapsed or refractory multiple myeloma (abstract). San-Miguel discloses patients having no MRD (i.e. MRD negative) was 60.6% in the cilta-cel group (pg. 343, Table 2). San-Miguel discloses the MRD was assessed on bone marrow samples at a sensitivity of 1 x 10-5 (pg. 337, col. 1, para. 2); and MRD negativity was determined at any time during the trial (pg. 342, col. 1, para. 2). Thus, Fan teaches the identical Cilta-cel CAR-T cell treatment for multiple myeloma of San-Miguel, encompassing the same treatment parameters of instant claims 1 and 10 (see above), and San-Miguel provides evidence that 60.6% of subjects obtain MRD negative status. Thus instant claim 128 is made obvious over the combination of Fan and Raje, whereby it is an inherent property of the Cilta-cel treatment to result in a MRD negative status as recited in instant claim 128, as evidenced by San-Miguel.
Response to Arguments
Applicant's arguments filed 8/4/2026 have been fully considered but they are not persuasive. Applicants contend that neither of the cited references, alone or in combination, teach the claimed treatment method, as Fan does not disclose the specific methods of CARVYKTI (remarks, pg. 20, section III), and Raje does not resolve the deficiencies of Fan (pg. 21, para. 2). Applicants contend reliance on Faje is misplaced because Raje concerns a different CAR construct and Raje’s treatment protocol differs from the claimed treatment method. Specifically, Raje requires administration within 1 hour of thawing and the instant claims require administration within 3 hours; and that Raje does not teach the specific dose range of CAR-T cells. Further, that the fact that the CAR is recited in the art and other treatment methods are recited in the art, does not suggest the claimed treatment method, and does not provide a reasonable expectation for success (pg. 21, para. 4); particularly the treatment results achieved as described (pg. 22, para. 1).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In this case, Fan teaches the identical anti-BCMA CAR-T cells, the cilta-cel CAR, as a treatment option for refractory multiple myeloma. Thus, Fan discloses the principle component of the methods of the instant claims, the CAR-T cells and their use in treating multiple myeloma. Raje teaches alternative aspects of providing anti-BCMA CAR-T cell therapies, including various parameters, such as thawing a frozen bag comprising the CAR-T cells before administration. The parameters of the methods of Raje are disclosed in the art, and it is obvious for a skilled artisan to incorporate one or more of said parameters into the methods of Fan, the motivation for doing so is inherent in the desire to optimize the treatment protocol of Fan. MPEP section 2143(I) teaches examples of rationales that may support a conclusion of obviousness, including, for example, (C)- use of known techniques to improve similar methods in the same way. Thus, Fan does not need to disclose the parameters of Raje, and Raje does not need to disclose the cilta-cel CAR constructs of Fan. As both teach methods of administering anti-BCMA CAR-T cells in a method of treating refractory multiple myeloma, one reference may inform the other. Importantly, each reference discloses the subject matter in the public domain, prior to the filing of the instant claims. Thus, the various parameters claimed, and made obvious over Fan and Raje, are not novel, and do not provide a novel technical advantage to the instant invention. Rather, they are a combination of parameters that were each disclosed in the prior art, and are incorporated for the same reasons as they were taught in the art, thus it is obvious to combine them into a single method. Similarly, all such “effects obtained” claim limitations are properties of the methods, and not novel active steps to the methods; thus all properties are inherent to the methods of Fan and Raje. Applicants arguments against the references individually are not found persuasive.
Regarding applicant’s contention that Raje requires administration within 1 hour of thawing and the instant claims require administration within 3 hours; administering the thawed CAR-T cells of Raje, within 1 hour of each bag being thawed, is encompassed by a limitation that comprises wherein administration is completed no later than 3 hours following thawing of the T cells.
Regarding applicant’s contention that there would not be a reasonable expectation for success to achieve the balanced efficacy and safety profile as demonstrated in the described results (remarks, pg. 21, bottom – pg. 22, top); the examiner highlights that these results are properties of the method and not novel active steps to the method. As Fan teaches the identical CAR-T cells for use in methods of treating multiple myeloma, and Raje teaches the same methodological parameters in methods of treating multiple myeloma with alternative species of anti-BCMA CAR-T cells, it is obvious to combine the teachings of Fan and Raje, and have a reasonable expectation for success in the treatment efficacy against multiple myeloma. The degree of success, such as the response rate properties outlined by applicant, are inherent in the treatment by Fan, which utilized the identical CAR-T cells, at the identical doses. If applicants are implying that a particular property of the treatment is unexpectedly better than the obvious combination treatment of Fan and Raje, whereby the unexpected result is due to a particular parameter of the treatment method, then applicants should provide a comparative study which identifies and demonstrates which parameter of the instant claim limitations provided the unexpected technological advantage, as compared to the closest prior art (i.e. the same methods without the single parameter). Instead the examiner maintains that the CAR-T cells (Cilta-cel) were known in the art as a treatment for multiple myeloma, as taught by Fan, and the various parameters of the treatment methodology, such as patient inclusion/exclusion criteria, handling and administration of frozen bags of CAR-T cells, pre-treatment and post-treatment regimens, and measuring post-treatment responses in the subjects, were described by either Fan or Raje, in the prior art, and thus are obvious alternative parameters to include or to optimize, in the method of treating refractory multiple myeloma with cilta-cel, of Fan et al. That is, the inclusion of known methodological parameters of similar treatments, into a known treatment regimen, does not provide a patentable point of novelty to the treatment. These are obvious attempts to optimize treatment protocols to generate better outcomes, and not a novel invention. Applicants arguments are not found persuasive and the rejections are maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 10, 33, 41, 57, 59, 82, 84-85, 90, 110, 122 and 128 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-62 of U.S. Patent No. 12,522,645. Although the claims at issue are not identical, they are not patentably distinct from each other because the scope of the claims of US Patent ‘645 anticipate that of the instant claims.
US ‘645 claims a method of treating a subject who has cancer comprising administering a dose of cells comprising a CAR, wherein the CAR has a first BCMA binding moiety of SEQ ID NO: 1 and a second BCMA binding moiety of SEQ ID NO: 3, wherein the CAR has a transmembrane domain and a intracellular domain, wherein the cancer is refractory multiple myeloma, wherein the dose is 5 x 105 to 1 x 106 cells, wherein the cells are T cells, whereby the cells are administered as a single dose, and whereby the patient has received multiple lines of therapy comprising a proteasome inhibitor, and immunomodulatory agent and an anti-CD38 monoclonal antibody (claim 1). US ‘645 also claims wherein the anti-BCMA binding moieties have the nucleic acid sequence of SEQ ID NOs: 2 and 4 (claims 33-34); a linker of SEQ ID NO: 5 (claims 35-36), a signal peptide of SEQ ID NO: 6 (claims 37-40), a transmembrane domain of SEQ ID NO: 8 (claims 41-42), a primary intracellular signaling domain derived from CD3ζ (claims 43-44), a costimulatory signaling domain of SEQ ID NOs: 10 or 12 (claims 45-49), a hinge domain of SEQ ID NO: 15 (claims 50-52).
The BCMA binding domain of US ‘645 SEQ ID NOs: 1 and 3 are 100% identical to that of instant SEQ ID NOs: 2 and 4, respectively. The nucleic acid sequences of US ‘645 SEQ ID NOs: 2 and 4 are 100% identical that that of instant SEQ ID NOs: 10 and 12, respectively. The linker of US ‘645 SEQ ID NO: 5 is identical to that of instant SEQ ID NO: 3. The signal peptide of US ‘645 SEQ ID NO: 6 is identical to that of instant SEQ ID NO: 1. The transmembrane domain of US ‘645 SEQ ID NO: 8 is identical to that of instant SEQ ID NO: 6. The co-stimulatory signaling domains of US ‘645 SEQ ID NOs: 10 and 12 are identical to instant SEQ ID NOs: 8 and 7, respectively. The hinge domain of US ‘645 SEQ ID NO: 15 is identical to that of SEQ ID NO: 5. Further, all of the above components of the CAR are comprised in the single embodiment of the CAR of instant SEQ ID NO: 17.
US ‘645 also claims wherein the cells are expanded prior to infusion (claim 2), wherein the T cells are heterologous T cells (claim 3), wherein the dose is 5.5 x 105 to 8 x 105 kg/mass (claim 4), 7.5 x 105 (claim 5), 1 x 106 to 1 x 108 (claim 6), 2 x 107 to 8 x 108 (claim 7), 5.25 x 107 (claim 8), 5 x 105 to 1 x 106 (claim 9), 5.5 x 105 to 8 x 105 (claim 10), 7.5 x 105 (claim 11), 1 x 106 to 1 x 108 (claim 12), 2 x 107 to 8 x 107 (claim 13), 5.25 x 107 (claim 14). US ‘645 claims whereby the cells are administered IV (claim 15). US ‘645 claims whereby the T cells are a mix of CD4+ and CD8+ T cells with varying ratios (claims 16-30 and 56), or wherein the T cells expressing the CAR comprise a predominant phenotype in varying levels (claims 57-62). US ‘645 also claims wherein the first and/or second BCMA binding moiety is a sdAb (claims 31-32). US ‘645 claims wherein the T cells are autologous (claim 53), allogenic (claim 54), and whereby the subject is human (claim 55).
The structure of the CAR of US ‘645 anticipates the structure of the CAR the instant claims; and the methods of treating a cancer, or refractory multiple myeloma, comprising administering a composition of genetically engineered T cells expressing the CAR of US ‘645 are the same as the methods of the instant claims, including wherein the subject has at least 3 prior lines of treatment. Therefore, US ‘645 claims 1-62 anticipate instant claims 1, 2, 33, 59, 82, and 84-85. Further, as the CAR of US ‘645 is the same structure as that of instant SEQ ID NO: 17, and the methods of treating comprise the same active steps of administering the same doses of CAR-T cells, then the effects of the treatment (i.e. wherein the method is effective in obtaining…, or effective in maintaining…) are inherent properties of the structure/method. Therefore, US ‘645 claims 1-62 also anticipate instant claims 10, 41, 57, 90, 110, 122 and 128.
Claims 1-2, 6, 10, 12, 19, 32-33, 41, 57, 59, 82, 84-85, 90, 110, 114, 122 and 128 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-62 of U.S. Patent No. 12,522,645 in view of Raje et al., (New England Journal of Medicine; 2019, 380(18), Supplemental Protocol).
The reasons why claims 1-2, 10, 33, 41, 59, 82, 84-85, 90, 110, 122 and 128 are anticipated by US ‘645 are described above. However, US ‘645 does not claim wherein the method comprises using one or two bags of CAR-T cells (re. claims 6 and 8), a lymphodepleting regimen (re. claim 12), a step of treating a subject for CRS (re. claims 19 and 114), a pre-infusion medication (re. claim 25), or the excipient of the composition (re. claim 32).
Raje et al. teaches preclinical studies comprising administering bb2121, a CAR-T cell therapy that targets BCMA, for the treatment of multiple myeloma, as described above. In the Supplemental Data section, Raje provides Clinical Study Protocol CRB-401, describing a Phase 1 study of bb2121 in BCMA-Expression Multiple Myeloma (Supplemental Protocol, pg. 1).
It would have been obvious to one of skill in the art to incorporate aspects of the protocol for administering anti-BCMA CAR-T cell therapy in patients with multiple myeloma, of Raje et al., into the method for treating multiple myeloma of US ‘645. One would have been motivated to do so in order to optimize the therapeutic effect of administering CAR-T cell therapy. There would have been a reasonable expectation for success given that the protocol of Raje is a preclinical study protocol for administering anti-BCMA CAR-T cell therapy in patients with multiple myeloma. Thus, inclusion of the additional protocol aspects of Raje was prima facie obvious to one of skill in the art at the time the invention was made.
Raje teaches the CAR-T cells in a frozen product bag, whereby the bag is thawed and administered within a maximum of 1 hour after thawing. Raje also teaches that multiple drug product bags may be administered to meet the protocol assigned dose. Thus, Raje makes obvious wherein the single IV infusion of US ‘645 is administered using a single or two bags of said CAR-T cells. Thus, the combination method of US ‘645 and Raje make obvious instant claim 6.
Raje teaches the protocol may include a lymphodepleting regimen that precedes the infusion of CAR-T cells. Raje teaches the lymphodepleting regime occurs as days -5, -4 and -3 of the protocol, before the infusion of CAR-T cells on day 0. Thus, the combination method of US ‘645 and Raje makes obvious instant claim 12.
Raje teaches the CAR-T therapy for B cell malignancy includes treating and management of CRS (pg. 19, section 2.5; pg. 90, section 8), which includes administering tocilizumab, and IL-6R inhibitor (pg. 59, para. 2). Raje teaches the CRS treatment scheme in Figure 8-1 (pg. 60). Raje teaches First Line treatment of CRS with tocilizumab may occur after rapid onset of CRS (i.e. ≤ 72 hours after infusion) or after slow onset (≥ 72 hours after infusion). Thus Raje teaches the protocol may include treatment of CRS, with tocilizumab, more than 1 day, or more than 3 days after infusion of the CAR-T cells. Thus, the combination of US ‘645 and Raje make obvious instant claims 19 and 114.
Raje teaches the therapeutic protocol may include a pre-medication regime (pg. 19, section 4.5.3, para. 2), and the pre-medication regime includes administering acetaminophen, which is a known antipyretic, and diphenhydramine, which is a known antihistamine, 30 minutes prior to infusion of the CAR-T cells. Thus, the combination method of US ‘645 and Raje makes obvious instant claim 25.
Raje teaches the drug product, autologous T cells genetically modified to express the anti-BCMA CAR, is cryopreserved in a final 5% dimethylsulfoxide (i.e. DMSO) dolution until disposition for infusion (pg. 16, section 4.2, para. 2). Thus, the combination of US ‘645 and Raje make obvious instant claim 32.
Claims 1-2, 10, 19, 32-33, 41, 57, 59, 82, 84-85, 90, 110, 114, 122 and 128 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-19 of U.S. Patent No. 10,934,363 in view of Fan et al., (from IDS, Cite No. B06; WO 2018028647; published 2/15/2018).
US Patent ‘363 claims an anti-BCMA CAR comprising a polypeptide comprising an extracellular binding domain comprising a first and second single domain antibody VHH domain, wherein the first VHH comprises SEQ ID NO: 87 and the second VHH comprises SEQ ID NO: 80; wherein the CAR further comprises a transmembrane domain and an intracellular signaling domain (claims 1 and 13-14).
US ‘363 also claims wherein the CAR further comprises a hinge domain (claim 2), wherein the CAR comprises a signal peptide (claim 3), wherein the first and second sdAbs are fused to each other via a peptide linker (claim 5), wherein the peptide linker comprises no more than 50 residues (claim 6), wherein the CAR comprises the amino acid sequence of SEQ ID NO: 265 (claim 7). US ‘363 also claims nucleic acids encoding the CAR (claim 8) and vectors comprising the nucleic acids (claim 9). US ‘363 claims an engineered immune effector cell comprising the CAR (claim 10), wherein the immune cell is a T cell (claim 11), and a pharmaceutical composition comprising the engineered immune cells (claim 12). US ‘363 claims the transmembrane domain is derived from CD8α (claim 15), the intracellular signaling domain is a primary intracellular signaling domain of an immune cell (claim 16), which may be CD3ζ (claim 17), whereby the intracellular singling domain comprises a co-stimulatory signaling domain (claim 18), which may be derived from CD137 (claim 19).
The first and second sdAb VHH domains of US ‘363 SEQ ID NOs: 87 and 80 are 100% identical to instant SEQ ID NOs: 2 and 4, respectively. The CAR construct of US ‘363 SEQ ID NO: 265 is 100% identical in amino acid sequence to the CAR of instant SEQ ID NO: 17. Thus, US ‘363 claims an identical CAR construct and identical genetically engineered T cells expressing the CAR construct as the instant claims. However, US ‘363 does not claim methods of treating multiple myeloma comprising administering the engineered T cells, and the accompanying limitations related to the method of treatment of the instant claims.
Fan et al. teaches a multivalent anti-BCMA CAR construct of GSI5021, defined by SEQ ID NO: 300 (pg. 95-96, Table 5; pg. 9, para. 0024), which is 100% identical in amino acid sequence to instant SEQ ID NO: 17, as well as to the CAR of US ‘363 SEQ ID NO: 265; and thereby also comprise a first and second anti-BCMA binding moiety of instant SEQ ID NOs: 2 and 4, respectively, and that of US ‘363 SEQ ID NOs: 87 and 80, respectively. The CAR of Fan SEQ ID NO: 300 also comprises the linker of instant SEQ ID NO: 3, the signal peptide of instant SEQ ID NO: 1, the transmembrane domain of instant SEQ ID NO: 6, the intracellular signaling domain of instant SEQ ID NO: 8 and the hinge domain of instant SEQ ID NO: 5, all with 100% sequence identity, and all of which correspond equally to that of US ‘363 claims 3, 6, 7 and 15-19. Thus, Fan teaches the identical multivalent anti-BCMA CAR construct of the instant claims as well as that claimed in US ‘363.
Fan teaches the CAR of SEQ ID NO: 300 may be used in generating engineered immune cells, including T cells, wherein the CAR comprises a first and a second BCMA binding moiety, a transmembrane domain and an intracellular signaling domain (pg. 114, paras. 0334-0335; para. 0336, pg. 118, last line). Fan teaches a method of treating cancer, such as multiple myeloma, in a human individual, comprising administering an effective amount of a pharmaceutical composition comprising an engineered T cell comprising any of the disclosed multivalent CARs (pgs. 134-135, paras. 0391-0392; pg. 146, para. 0405).
It would have been obvious to one of skill in the art to utilize the multivalent anti-BCMA CAR of US ‘363, as well as genetically engineered T cells expressing the CAR, and to administer a composition of the engineered T cells in a method of treating an individual with multiple myeloma. One would have been motivated to do so in order to find a therapeutic strategy for treating multiple myeloma, as taught by Fan. There would have been a reasonable expectation for success given that the CAR of GSI15021 is an exemplary embodiment of a multivariant anti-BCMA CAR for use in generating genetically engineered T cells for use in a method for treating multiple myeloma, as taught by Fan et al., and that the CAR of US ‘363 SEQ ID NO: 265 is identical to the GSI15021 construct of Fan et al. Thus, the CAR construct of US ‘363, used in the method of treating multiple myeloma, of Fan, was prima facie obvious to one of skill in the art at the time the invention was made, and arrives at the methods of the instant invention.
Fan makes obvious the limitations of each of instant claims 1-2, 10, 19, 32-33, 41, 57, 59, 82, 84-85, 90, 110, 114, 122 and 128, as detailed and described above. Therefore, the CAR of US ‘363, claims 1-3 and 5-19, over the methods of Fan, make obvious instant claims 1-2, 10, 19, 32-33, 41, 57, 59, 82, 84-85, 90, 110, 114, 122 and 128.
Claims 1-2, 6, 8, 10, 12, 19, 32-33, 41, 57, 59, 82, 84-85, 90, 110, 114, 122 and 128 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-19 of U.S. Patent No. 10,934,363 in view of Fan et al., (from IDS, Cite No. B06; WO 2018028647; published 2/15/2018) and Raje et al., (New England Journal of Medicine; 2019, 380(18), Supplemental Protocol).
The reasons why the combination of US ‘363 claims 1-3 and 5-19, and Fan et al., make obvious claims 1-2, 10, 19, 32-33, 41, 57, 59, 82, 84-85, 90, 110, 114, 122 and 128 are described above. However, the combination of US ‘363 and Fan does not teach wherein the method comprises using one or two bags of CAR-T cells (re. claims 6 and 8), a lymphodepleting regimen (re. claim 12), or a pre-infusion medication (re. claim 25).
Raje et al. teaches preclinical studies comprising administering bb2121, a CAR-T cell therapy that targets BCMA, for the treatment of multiple myeloma, as described above. In the Supplemental Data section, Raje provides Clinical Study Protocol CRB-401, describing a Phase 1 study of bb2121 in BCMA-Expression Multiple Myeloma (Supplemental Protocol, pg. 1).
It would have been obvious to one of skill in the art to incorporate aspects of the protocol for administering anti-BCMA CAR-T cell therapy in patients with multiple myeloma, of Raje et al., into the method for treating multiple myeloma of the combination of US ‘363 and Fan et al. One would have been motivated to do so in order to optimize the therapeutic effect of administering CAR-T cell therapy. There would have been a reasonable expectation for success given that the protocol of Raje is a preclinical study protocol for administering anti-BCMA CAR-T cell therapy in patients with multiple myeloma. Thus, inclusion of the additional protocol aspects of Raje was prima facie obvious to one of skill in the art at the time the invention was made.
Raje teaches the CAR-T cells in a frozen product bag, whereby the bag is thawed and administered within a maximum of 1 hour after thawing. Raje also teaches that multiple drug product bags may be administered to meet the protocol assigned dose. Thus, Raje makes obvious wherein the single IV infusion of the combination of US ‘363 and Fan is administered using a single or two bags of said CAR-T cells. Thus, the combination method of US ‘363, Fan and Raje make obvious instant claims 6 and 8.
Raje teaches the protocol may include a lymphodepleting regimen that precedes the infusion of CAR-T cells. Raje teaches the lymphodepleting regime occurs as days -5, -4 and -3 of the protocol, before the infusion of CAR-T cells on day 0. Thus, the combination method of US ‘363, Fan and Raje makes obvious instant claim 12.
Raje teaches the therapeutic protocol may include a pre-medication regime (pg. 19, section 4.5.3, para. 2), and the pre-medication regime includes administering acetaminophen, which is a known antipyretic, and diphenhydramine, which is a known antihistamine, 30 minutes prior to infusion of the CAR-T cells. Thus, the combination method of US ‘363, Fan and Raje makes obvious instant claim 25.
Claims 1-2, 6, 8, 10, 12, 19, 32-33, 41, 57, 59, 82, 84-85, 90, 110, 114, 122 and 128 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 8, 12-24, 26-32, 35-39, 46 and 82-94 of copending Application No. 17/540,736 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the scope of the claims of application ‘736 anticipate that of the instant claims.
Application ‘736 claims a method of treating a subject who has multiple myeloma comprising administering to the subject a dose of T cells comprising a CAR comprising the amino acid sequence of SEQ ID NO: 17, wherein the does comprises 0.5 x 106 to 1.0 x 106 cells/mass, wherein the method comprises administering the T cells no later than 3 hours following thawing of the T cells, wherein the subject has received prior treatment with at least three prior lines of treatment, and wherein the subject has received an anti-pyretic and an antihistamine up to about 1 hour prior to infusion of the dose of CAR-T cells (claim 1), or whereby the dose of CAR-T cells is administered via a single IV infusion (claim 85).
The CAR of application ‘736 SEQ ID NO: 17 is 100% identical to the CAR of instant SEQ ID NO: 17. Therefore the CAR of application ‘736 SEQ ID NO: 17 comprises the sdAb VHH domains of instant SEQ ID NOs: 2 and 4, or polypeptides encoded by the nucleic acid sequences of instant SEQ ID NOs: 10 and 13. The CAR of ‘736 also comprises the linker of instant SEQ ID NO: 3, the signal peptide of instant SEQ ID NO: 1, the transmembrane domain of instant SEQ ID NO: 6, the co-stimulatory signaling domains of both of instant SEQ ID NOs: 7 and 8, and the hinge domain of instant SEQ ID NO: 5; all with 100% sequence identity.
Application ‘736 also claims wherein the dose of CAR-T cells is 0.75 x 106 (claims 4 and 93), or 1.0 x 108 (claims 5 and 94); wherein the cells are administered, and contained in, a single cryopreserved bag (claim 6), or two cryopreserved bags (claim 8). App ‘736 claims wherein the method comprises administering a lymphodepleting regimen prior to administering the CAR-T cells (claim 12), including administering cyclophosphamide (claim 13), wherein the lymphodepleting regimen is administered IV (claim 14), whereby the lymphodepleting regimen is administered 5 to 7 days prior to the CAR-T cell infusion (claim 15), administering cyclophosphamide and fludarabine 5 to 7 days prior to CAR-T infusion (claim 16), wherein the cyclophosphamide is IV at 300 mg/m2 (claim 17), the fludarabine is administered IV at 30 mg/m2 (claim 18). App ‘736 also claims treating the subject for CRS more than 3 days following the infusion of CAR-T cells (claim 19), wherein the treatment for CRS comprises administering an IL-6R inhibitor (claim 20), which may be an antibody (claim 21), whereby the antibody inhibits IL-6R by binding its extracellular domain (claim 22), and prevents binding of IL-6 to IL-6R (claim 23), wherein the inhibitor is tocilizumab (claim 24); wherein the antipyretic comprises acetaminophen (claim 26), wherein the antipyretic is administered orally or IV (claim 27), whereby the acetaminophen is administered at a dose between 650 mg and 1000 mg (claim 28), wherein the antihistamine is diphenhydramine (claim 29), whereby the diphenhydramine is administered orally or IV (claim 30), at a dose between 25 mg and 50 mg (claim 31). App ‘736 claims wherein the CAR-T cells comprise an excipient of DMSO or dextran-40 (claim 32). App ‘736 claims wherein the subject has relapsed after at least 3 prior lines of treatment (claim 35), wherein the multiple myeloma is refractory to at least two medicaments following the at least 3 prior lines of treatment (claim 36), wherein the two medicaments comprise a PI and an IMiB (claim 37), wherein the multiple myeloma is refractory to at least 3 medicaments (claim 38), or at least four or five medicaments (claim 39). App ‘736 also claims wherein the method comprises assessing the overall response rage at a median follow-up time of at least 12 months (claim 46). App ‘736 claims wherein the T cells are autologous (claim 82), allogeneic (claim 83), wherein the subject is human (claim 84), wherein the antihistamine is administered orally, or IV, 15-45 min or 45-60 min prior to the CAR-T cells (claims 86 and 89-91), wherein the antipyretic is administered orally, or IV, 15-45 min prior to the CAR-T cells (claims 87 and 92), wherein the subject has not received a corticosteroid prior to administering the CAR-T cells (claim 88).
Therefore, as the CAR of app ‘736 SEQ ID NO: 17 anticipates that of the instant claims with 100% identity, the methods of app 736 claims 1, 4-5, 85 and 93-94 anticipate instant claims 1-2, 25, 33, 59 and 85; and inherently anticipate the effective result limitations of claims 10, 41, 57, 90, 110, 122 and 128 by virtue of inherent properties of identical structures/methods. App ‘736 claims 6 and 8 anticipate instant claims 6 and 8; app ‘736 claims 12-18 anticipate the lymphodepleting regimen of instant claim 12; app ‘736 claims 19-24 anticipate the CRS treatment of instant claims 19 and 114; app ‘736 claims 26-31 and 86-92 anticipate the pre-infusion medication of instant claim 25; app ‘736 claim 32 anticipates instant claim 32; app ‘736 claims 35-39 anticipate instant claim 33; app ‘736 claim 46 anticipates instant claim 41; app ‘736 claims 82-84 anticipate instant claims 82 and 84.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 6, 8, 10, 12, 19, 32-33, 41, 57, 59, 82, 84-85, 90, 110, 114, 122 and 128 are rejected (in the case of issued patents), or provisionally rejected (in the case of pending applications) over the listed claims of the following U.S. Patents and pending applications, in view of Fan et al., (from IDS, Cite No. B06; WO 2018028647; published 2/15/2018) and Raje et al., (New England Journal of Medicine; 2019, 380(18), Supplemental Protocol).
Below is a Table listing patents and/or co-pending applications, which name a common inventor, and which claim a multivariant anti-BCMA CAR, or method of treating comprising administering engineered immune effector cells expressing the CAR, whereby the claims would make obvious, over Fan and Raje, instant claims 1 and 85, and all dependent claims, for the same reasons why Fan and Raje make obvious the instant claims as described above. Specifically, as Fan and Raje make obvious a method of treating multiple myeloma comprising administering anti-BCMA CAR-T cells, any patent or co-pending application that claims an anti-BCMA CAR having the anti-BCMA binding moieties of instant SEQ ID NOs: 2 and 4, or the full CAR construct of instant SEQ ID NO: 17, will be made obvious in a method of treating multiple myeloma as taught by Fan and Raje, and whereby the responses and effects obtained by the treatment are inherent properties of practicing the same methods with the identical anti-BCMA CAR-T cells.
U.S. Patent or co-pending U.S. application
Claims
Comment
11186647
1-21
‘647 SEQ NOs: 124, 117 = instant SEQ NOs: 2, 4
12351638
1,2, 8
‘638 SEQ NOs: 124, 117 = instant SEQ NOs: 2, 4; and corresponding nucleic acid (n.a.) sequence 338.
17/164125
44-49, 58, 60-62, 64-72 and 75-77
Generic multivariant anti-BCMA CAR with two anti-BCMA binding domains, immune cells and compositions.
18/052349
1-4, 11, 18-19, 38, 58, 67, 87, 104, 116, 151, 189, 217, 220-225
‘349 SEQ NOs: 2, 4 (claims 189, 221) = instant SEQ NOs: 2, 4 (claim 1); and comprise ‘349 CDR SEQ NOs: 18-23 (claims 1-3)
‘349 SEQ: 17 (claim 189) = instant SEQ 17 (claim 85)
18/175347
1-9, 11-14, 19-21, 24-28
‘347 SEQ: 17 (claim 1) = instant SEQ: 17, comprises instant SEQs: 2 and 4
18/499720
1-4, 6, 8, 13, 17-18, 22, 25, 28-30, 32-37
‘720 SEQs: 2, 4 (claim 1, 3) = instant SEQs: 2, 4
‘720 SEQ: 17 (claim 17) = instant SEQ: 17
18/592234
1, 3-4, 6, 17, 23, 26-27, 34, 37, 39-40, 62-64, 67, 78, 87-89
‘234 SEQs: 2, 4, 17 (claim 40) = instant SEQs: 2, 4, 17
18/639682
1, 3-4, 6, 17, 23, 26-27, 34, 37, 39-40, 62-64, 67, 78, 87-89
‘682 SEQs: 2, 4, 17 (claim 40) = instant SEQs: 2, 4, 17
19/045247
1-2, 12, 14, 31, 33-34, 39-40, 45, 47, 49, 76, 81, 86, 88, 94-96, 99, 103, 107, 109, 114-119
‘247 SEQs: 2, 4, 17 (claims 1, 116) = instant SEQs: 2, 4, 17
19/076517
1-21
Specs. (pg. 9, para. 0037), teach “Ciltacabtagene autoleucel” (claim 1) is CAR of SEQ ID NO: 17.
‘517 SEQ: 17 = instant SEQ: 17, comprises instant SEQs: 2 and 4
19/409583
1-65
‘409 SEQs: 1, 3 (claims 41, 43) = instant SEQs: 2, 4
‘409 n.a. SEQs 2, 4 (claims 42, 44) = instant SEQs: 10, 12
Response to Arguments
Applicant's arguments filed 8/4/2026 have been fully considered but they are not persuasive. Applicants request that the nonstatuatory double patenting rejections be held in abeyance until the indication of allowable subject matter (remarks, pgs. 22-25).
The Office does not hold double patenting rejections in abeyance for any reason. The examiner has not indicated that the claims contain allowable subject matter. Thus the rejections for double patenting are maintained.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normally be reached M-F 8:00-5:00 CST.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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