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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on July 14th, 2026, is acknowledged.
Applicant’s election without traverse of (a) a patient having multiple myeloma who has not received a stem cell transplant in the reply filed on July 14th, 2026, is also acknowledged. The search was expanded to (e) patients that are 75 years old or older that have not received a stem cell transplant, as the species was found in the same prior art references.
Claim 43 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 14th, 2026.
Claims 23 and 26-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 14th, 2026.
Priority
The instant application claims priority to 371 National Stage Application PCT/EP2022/068974, filed July 7th, 2022, and foreign applications GB2109894.2, filed July 8th, 2021, GB2112976.2, filed September 10th, 2021, under 35 U.S.C. 119(a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The priority date of July 8th, 2021 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) filed on April 5th, 2024is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is considered by the examiner.
Claims Status
The claim listing filed on September 12th, 2024 is pending. Claims 23, 26-27, and 43 are withdrawn from further consideration for the reasons set forth in the restriction requirement, 37 CFR 1.142(b). Claims 21-22, 24-25, and 28-42 are being examined on the merits in this office action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 28 and 30 are rejected 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.
Regarding claims 28 and 30, use of parentheses renders the claim indefinite because it is unclear whether the limitations following within the parentheses are part of the claimed invention or just optional.
The term “about” in claim 28 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
In determining the range encompassed by the term "about," one must consider the context of the term as it is used in the specification and claims of the application. Ortho-McNeil Pharm., Inc. v. Caraco Pharm. Labs., Ltd., 476 F.3d 1321, 1326, 81 USPQ2d 1427, 1432 [MPEP 2173.05 (b)]
The specification does not provide a standard for ascertaining the requisite degree, only certain embodiments are specified [0104]. Nor, would one of ordinary skill be apprised of the scope of the invention to treat multiple myeloma. Thus, claim 28 is indefinite.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 21-22, 28-33, 35, 37-39 and 42 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Richardson et al. (Richardson, P. G., Oriol, A., Larocca, A., Bladé, J., Cavo, M., Rodriguez-Otero, P., Leleu, X., Nadeem, O., Hiemenz, J. W., Hassoun, H., Touzeau, C., Alegre, A., Paner, A., Maisel, C., Mazumder, A., Raptis, A., Moreb, J. S., Anderson, K. C., Laubach, J. P., Thuresson, S., … HORIZON (OP-106) Investigators (2020). Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 39(7), 757–767.)
Richardson et al. evaluate the efficacy of melphalan flufenamide (melflufen) plus dexamethasone in relapsed and refractory multiple myeloma (RRMM) [pg 757 Abstract Purpose section]. Of all the 157 patients treated, 16 patients (10.2 %) had zero previous stem-cell transplants [pg 760 Table 1]. Richardson also performed a subgroup analysis of patients with triple-class–refractory MM (refractory to or intolerant of at least one immunomodulatory drug, at least one proteasome inhibitor, and at least one anti-CD38 monoclonal antibody) [pg 759 pgh 5 line 2]. Of all the 119 triple-class-refractory patients treated, 14 (11.7 %) patients had zero previous stem-cell transplants. Thus, Richardson et al. anticipate a method treating patients having multiple myeloma who have not received a stem cell transplant by administering melflufen.
Regarding claim 22 of the total patient population evaluated, 10.2% had not received a stem cell transplant. Of the triple-class-refractory patients treated, 11.7 % had not received a stem-cell transplant.
Regarding claim 28, Richardson’s patients received once-monthly 40 mg melflufen as a 30-minute central intravenous infusion on day 1 of each 28-day cycle in combination with oral dexamethasone 40 mg (20 mg for patients age ≥ 75 years) once-weekly administered on days 1, 8, 15, and 22 of each 28-day cycle until disease progression, unacceptable toxicity, or the patient or treating physician determined it was not in the patient’s best interest to continue [pg 758 pgh 3 line 21]. Therefore, Richardson anticipates a dose within the range of about 1 mg to 150 mg in a method of treating patients having multiple myeloma [MPEP 2144.05].
Regarding claim 29, Richardson’s patients received once-monthly 40 mg melflufen as a 30-minute central intravenous infusion on day 1 of each 28-day cycle in combination with oral dexamethasone 40 mg (20 mg for patients age ≥ 75 years) once-weekly administered on days 1, 8, 15, and 22 of each 28-day cycle until disease progression, unacceptable toxicity, or the patient or treating physician determined it was not in the patient’s best interest to continue [pg 758 pgh 3 line 21]. Therefore, Richardson anticipates a dose administered on day 1 of a cycle within the range of 1 to 42 days in a method of treating patients having multiple myeloma [MPEP 2144.05].
Regarding claim 30, patients received once-monthly 40 mg melflufen as a 30-minute central intravenous infusion on day 1 of each 28-day cycle [pg 758 pgh 3 line 21]. This translates the 1.3 mg/min, within the instant anticipated range of parenteral infusion rate [MPEP 2144.05].
Regarding claims 31, 35 and 37, Richardson’s patients received once-monthly melflufen 40 mg as a 30-minute central intravenous infusion on day 1 of each 28-day cycle in combination with oral dexamethasone 40 mg (20 mg for patients age ≥ 75 years) once-weekly administered on days 1, 8, 15, and 22 of each 28-day cycle until disease progression, unacceptable toxicity, or the patient or treating physician determined it was not in the patient’s best interest to continue [pg 758 pgh 3 line 21]. Therefore, Richardson anticipates a method of treating patients having multiple myeloma wherein the melflufen is administered simultaneously, sequentially or separately, with one or more further therapeutic agents, wherein the therapeutic agent is dexamethasone, because dexamethasone is also administered on day 1.
Regarding claim 38, Richardson’s patient population had received at least two prior lines of therapy, including an immunomodulatory agent and proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Therefore, Richardson anticipates a method of treating patients having multiple myeloma wherein the patient is (a), (d), (e), (g), (i), and (j) comprising melflufen.
Regarding claim 39, Richardson’s patient population had a median age of 65. [Table 1]. Thus, Richardson anticipates a method of treatment wherein the multiple myeloma patient is at least 65 years old.
Regarding claim 42, Richardson’s patient population had received at least two prior lines of therapy, including an immunomodulatory agent and proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Therefore, Richardson anticipates a method of treating patients having multiple myeloma that wherein the patient (a), (d), (e), (g), (i), and (j) comprising melflufen.
Claim 32 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Richardson et al., as evidenced by MedlinePlus (Dexamethasone: MedlinePlus Drug Information. (2018) MedlinePlus. https://medlineplus.gov/druginfo/meds/a682792.html).
Richardson et al. teach a method wherein dexamethasone os administered in combination with melflufen in patients who have not received a stem-cell transplant. Richardson does not teach that dexamethasone is a steroid.
MedlinePlus evidence that dexamethasone is a corticosteroid line 1]. Therefore, Richardson anticipates a method of treating patients having multiple myeloma who have not received a stem cell transplant comprising melflufen and a steroid.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 24-25 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Richardson et al. as applied to claim 21-22, 28-33, 35, 37-39, and 42 above.
Regarding claim 24 and 25 Richardson teaches a method of administering melflufen to patients with multiple myeloma. In Richardson et al’s study, 16 patients (10.2 %) had zero previous stem-cell transplants [pg 760 Table 1] and 25 patients were older than 75 years [pg 762 pgh 3 line 2]. Richardson does not detail the age of the patients who have not received stem transplants, only the age of the overall population. However, one of ordinary skill in the art would find it obvious to administer melflufen in patients who have not received a stem cell transplant and are 75 years old or older because Richardson demonstrates the method in both patient populations separately and there is a reasonable expectation that treating the overlapping patient population would be successful, as it is successful separately.
Regarding claim 41, of Richardson’s overall population, 59 of 157 patients had high-risk cytogenetics and 16 patients (10.2 %) had zero previous stem-cell transplants [pg 760 Table 1]. Of the Triple-Class Refractory Population, 41 of 119 patients had high-risk cytogenetics and 14 (11.7 %) patients had zero previous stem-cell transplants.. Richardson does not detail which patients with high risk cytogenetic had not received a stem-cell transplant, only the number of patients overall. However, one of ordinary skill in the art would find it obvious to administer melflufen in patients who have not received a stem cell transplant with high-risk cytogenetics because Richardson demonstrates the method in both patient populations separately and there is a highly reasonable expectation that treating the patient population overlap would be successful.
Claims 34 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Richardson et al. as applied to claim 21-22, 28-33, 35, 37-39, and 41-42 above in further view of Oriol et al. (Oriol, A., Larocca, A., Leleu, X., Hajek, R., Hassoun, H., Rodríguez-Otero, P., … Richardson, P. G. (2020). Melflufen for relapsed and refractory multiple myeloma. Expert Opinion on Investigational Drugs, 29(10), 1069–1078.).
Richardson’s patients received once-monthly melflufen 40 mg as a 30-minute central intravenous infusion on day 1 of each 28-day cycle in combination with oral dexamethasone 40 mg (20 mg for patients age ≥ 75 years) once-weekly administered on days 1, 8, 15, and 22 of each 28-day cycle until disease progression, unacceptable toxicity, or the patient or treating physician determined it was not in the patient’s best interest to continue [pg 758 pgh 3 line 21]. Richardson does not teach a method of treating multiple myeloma further comprising an inhibitor of nuclear export or B-cell maturation antigen (BCMA)-directed immunotherapies.
Oriol et al state that several novel drugs with new modes of action (MOA) have been approved or are in development for RRMM, including selective inhibitors of nuclear export (selinexor), B-cell maturation antigen (BCMA)-directed immunotherapies, and melflufen [pg 1070 pgh 3 line 4]. Selinexor, decabtagene vicleucel ,an investigational autologous BCMA chimeric antigen receptor (CAR)T-cell therapy, bb21217, a next-generation anti-BCMA CAR T–cell therapy, and belantamabmafodotin, an anti-BCMA antibody-drug conjugate, are all undergoing or have underwent clinical trials for RRMM.
It would have been obvious to one of ordinary skill in the art to combine prior art elements melflufen and an inhibitor of nuclear export or a BCMA-directed therapy according to their known methods in clinical trials prior to the effective filing date because the combined teachings yield the predictable result of treating multiple myeloma.
Regarding claim 36, Oriol et al state that several novel drugs with new MOAs have been approved or are in development for RRMM, including the selective inhibitor of nuclear export, selinexor [pg 1070 pgh 3 line 4].. Therefore, it would have been obvious to one of ordinary skill in the art to combine prior art elements melflufen and selinexor according to their known methods in clinical trials prior to the effective filing date because the combined teachings yield the predictable result of treating multiple myeloma.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Richardson et al. as applied to claim 21-22, 28-33, 35, 37-39, and 41-42 above in further view of Elnair et al. (Elniar et al. (Elnair, R., & Holstein, S. (2021). Treatment Considerations for Transplant-Ineligible Multiple Myeloma. Oncology (Williston Park, N.Y.), 35(4), 170–182).
Regarding claim 40, Richardson teaches that melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets amino peptidases and rapidly and selectively releases alkylating agents into tumor cells [Abstract purpose line 1]. Melflufen is used as a method of treating multiple myeloma in patients with zero previous stem cell transplants. Richardson does not teach that any of the patients with zero previous stem cell transplants are not suitable for a stem cell transplant.
Elnair summarizes the methods of the phrase 3 CLARION study in which newly diagnosed multiple myeloma patients who were transplant ineligible were administered either carfilzomib, melphalan, and prednisone (KMP) or bortezomib, melphalan, and prednisone [pg 178 pgh 2 line 1]. Melphalan is the drug portion of the peptide-drug conjugate melflufen (melphalan flufenamide). Thus, prior to the effective filing date, it was obvious to use melflufen in place of melphalan in patients who have not received a stem cell transplant and are transplant-ineligible because it constitutes simple substitution of one known element for another to obtain the predictable result of treating multiple myeloma.
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 21-22, 24-25, 28-33, 35, 37-39 and 41-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12396975 in view of Bahlis et al. (Bahlis, N. J., & Lazarus, H. M. (2006). Multiple myeloma-associated AL amyloidosis: is a distinctive therapeutic approach warranted?. Bone marrow transplantation, 38(1), 7–15) and Richardson et al. (Richardson, P. G., Oriol, A., Larocca, A., Bladé, J., Cavo, M., Rodriguez-Otero, P., Leleu, X., Nadeem, O., Hiemenz, J. W., Hassoun, H., Touzeau, C., Alegre, A., Paner, A., Maisel, C., Mazumder, A., Raptis, A., Moreb, J. S., Anderson, K. C., Laubach, J. P., Thuresson, S., … HORIZON (OP-106) Investigators (2020). Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 39(7), 757–767.)
‘975 claims a method for treating a patient having immunoglobulin light chain (AL) amyloidosis, comprising administering melflufen, or a salt thereof, to the patient wherein the melflufen, or a salt thereof, is administered at a dose of about 15 mg to 35 mg excluding the mass of any counterion [claim 1]. ‘975 does not claim a method of treating a patient with AL amyloidosis also having multiple myeloma (MM) who has not received a stem cell transplant.
Bahlis et al. teach that AL amyloidosis coexists in 12-30% of multiple myeloma patients [Abstract line 8]. This is because multiple myeloma is the malignancy of terminally differentiated B lymphocytes characterized by the expansion of clonal plasma cells in the bone marrow, often resulting from direct injury or accumulation of immunoglobulins (heavy or light chain) in various organs [pg 7 pgh 1]. Thus, Bahlis teaches there is an overlap between ‘975’s AL amyloidosis patient population and the instant multiple myeloma patient population. Bahlis does not teach the instant claim limitation of administering melflufen to patients who have not received a stem cell transplant.
Richardson et al. evaluate the efficacy of melphalan flufenamide (melflufen) plus dexamethasone in relapsed and refractory multiple myeloma (RRMM) [pg 757 Abstract Purpose section]. Of all the 157 patients treated, 16 patients (10.2 %) had zero previous stem-cell transplants [pg 760 Table 1]. Richardson also performed a subgroup analysis of patients with triple-class–refractory MM (refractory to or intolerant of at least one immunomodulatory drug, at least one proteasome inhibitor, and at least one anti-CD38 monoclonal antibody) [pg 759 pgh 5 line 2]. Of all the 119 triple-class-refractory patients treated, 14 (11.7 %) patients had zero previous stem-cell transplants.
Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant because there are patients with AL amyloidosis who also have multiple myeloma and melflufen can be administered to patients with MM who have not had a stem cell transplant.
Regarding claim 22, ‘975 does not claim a method of treating multiple myeloma in a patient who has not received a stem cell transplant. Of the total patient population evaluated by Richardson, 10.2% had not received a stem cell transplant. Of the triple-class-refractory patients treated, 11.7 % had not received a stem-cell transplant. Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant because there are patients with AL amyloidosis who also have multiple myeloma and melflufen can be administered to patients with MM who have not had a stem cell transplant.
Regarding claim 24, ‘975 does not claim a method of administering melflufen to a patient 75 years old or older. In Richardson et al’s study, 25 patients were older than 75 years [pg 762 pgh 3 line 2]. Thus, it was obvious to claim a method of treating MM in a patient 75 years old or older prior to the effective filing date because there are patients with AL amyloidosis who also have multiple myeloma and Richardson demonstrates the method in a patient population 75 years or older.
Regarding claim 25, ‘975 does not claim a method of administering melflufen to a patient 75 years old or older who have not received a stem cell transplant. In Richardson et al’s study, 16 patients (10.2 %) had zero previous stem-cell transplants [pg 760 Table 1] and 25 patients were older than 75 years [pg 762 pgh 3 line 2]. Richardson does not detail the age of the patients who have not received stem transplants, only the age of the overall population. However, one of ordinary skill in the art would be motivated to administer melflufen in patients who have not received a stem cell transplant and are 75 years old or older because there are patients with AL amyloidosis who also have multiple myeloma and Richardson demonstrates the method in both patient populations separately, meaning that there is a reasonable expectation that treating the overlapping patient population would be successful. Therefore, prior to the effective filing date, it was obvious to claim a method of treating MM in a patient 75 years old or older and has not received a stem cell transplant because there are patients with AL amyloidosis who also have multiple myeloma.
Regarding claim 28, ‘975 claims method for treating a patient having immunoglobulin light chain (AL) amyloidosis, comprising administering melflufen, or a salt thereof, to the patient wherein the melflufen, or a salt thereof, is administered at a dose of about 15 mg to 35 mg excluding the mass of any counterion [claim 1]. Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering 1 mg to 150 mg of melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant because the dose encompasses ‘975’s range [MPEP 2144.05].
Regarding claim 29, ‘975 claims method for treating a patient having immunoglobulin light chain (AL) amyloidosis, comprising administering melflufen, or a salt thereof, to the patient wherein the melflufen, or a salt thereof, is administered at a dose of about 15 mg to 35 mg excluding the mass of any counterion, wherein a dose of melflufen, or a salt thereof, is administered on day 1 of a cycle of 21 days or a cycle of 28 days [claim 3]. Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein a dose of melflufen is administered on day 1 of a cycle of 1 to 42 days because the cycle encompasses ‘975’s range [MPEP 2144.05].
Regarding claim 30, ‘975 does not claim an infusion rate, Richardson’s patients received once-monthly 40 mg melflufen as a 30-minute central intravenous infusion on day 1 of each 28-day cycle [pg 758 pgh 3 line 21]. This translates the 1.3 mg/min, within the instant anticipated range of parenteral infusion rate [MPEP 2144.05]. Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant wherein a dose of melflufen is administered as a parenteral dosage at an infusion rate of 0.3 to 1.8 mg/min because there are patients with AL amyloidosis who also have multiple myeloma and melflufen can be administered to patients with MM who have not had a stem cell transplant, as taught by Richardson et al.
Regarding claim 31, ‘975 claims the method for treating a patient having immunoglobulin light chain (AL) amyloidosis further comprising administering to the patient simultaneously, sequentially or separately from melflufen, or a salt thereof, a steroid selected from the group consisting of prednisone, prednisolone and dexamethasone [claim 2]. Thus, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with one or more further therapeutic agent(s).
Regarding claim 32, ‘975 claims the method for treating a patient having immunoglobulin light chain (AL) amyloidosis further comprising administering to the patient simultaneously, sequentially or separately from melflufen, or a salt thereof, a steroid selected from the group consisting of prednisone, prednisolone and dexamethasone [claim 2]. Thus, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with a steroid.
Regarding claim 33, ‘975 claims the method for treating a patient having immunoglobulin light chain (AL) amyloidosis further comprising administering to the patient simultaneously, sequentially or separately from melflufen, or a salt thereof, a steroid selected from the group consisting of prednisone, prednisolone and dexamethasone [claim 2]. Thus, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with dexamethasone.
Regarding claim 35, ‘975 claims the method for treating a patient having immunoglobulin light chain (AL) amyloidosis further comprising administering to the patient simultaneously, sequentially or separately from melflufen, or a salt thereof, a steroid selected from the group consisting of prednisone, prednisolone and dexamethasone [claim 2]. Thus, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with dexamethasone.
Regarding claim 37, ‘975 claims the method for treating a patient having immunoglobulin light chain (AL) amyloidosis further comprising administering to the patient simultaneously, sequentially or separately from melflufen, or a salt thereof, a steroid selected from the group consisting of prednisone, prednisolone and dexamethasone [claim 2]. Thus, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with dexamethasone.
Regarding claim 38, ‘975 does not claim the method, wherein the instant multiple myeloma patient is (a) to (g). Richardson’s patient population had received at least two prior lines of therapy, including an immunomodulatory agent and proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Therefore, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, wherein the multiple myeloma patient (a)-(g) because there are patients with AL amyloidosis who also have multiple myeloma and Richardson teaches that melflufen can be administered to patients with MM who have not had a stem cell transplant wherein the patient is (a), (d), (e), (g), (i), or (j).
Regarding claim 39, ‘975 does not claim the method wherein the instant multiple myeloma patient is at least 65 years old. Richardson’s patient population had a median age of 65. [Table 1]. Therefore, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, wherein the multiple myeloma patient is at least 65 years old because there are patients with AL amyloidosis who also have multiple myeloma and Richardson teaches that melflufen can be administered to patients with MM who have not had a stem cell transplant wherein the patient is 65 years old.
Regarding claim 41, ‘975 does not claim the method wherein the instant multiple myeloma patient is a high-risk patient in view of the patient’s cytogenetics. Of Richardson’s overall population, 59 of 157 patients had high-risk cytogenetics and 16 patients (10.2 %) had zero previous stem-cell transplants [pg 760 Table 1]. Of the Triple-Class Refractory Population, 41 of 119 patients had high-risk cytogenetics and 14 (11.7 %) patients had zero previous stem-cell transplants.. Richardson does not detail which patients with high risk cytogenetic had not received a stem-cell transplant, only the number of patients overall. However, one of ordinary skill in the art would be motivated administer melflufen in patients who have not received a stem cell transplant with high-risk cytogenetics because Richardson demonstrates the method in both patient populations separately and there is a highly reasonable expectation that treating the patient population overlap would be successful. Thus, it was obvious, prior to the effective filing date, to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, wherein the multiple myeloma patient is a high-risk patient in view of the patient’s cytogenetics.
Regarding claim 42, 975 does not claim the method, wherein the patient has received at least two previous lines of therapy. Richardson’s patient population had received at least two prior lines of therapy, including an immunomodulatory agent and proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Thus, it was obvious, prior to the effective filing date, to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, wherein the multiple myeloma patient has received at least two previous lines of therapy.
Claims 34 and 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 17-19 of U.S. Patent No. 12396975 in view of Bahlis et al and Richardson et al., as applied to claims 21-22, 24-25, 28-33, 35, 37-39 and 41-42 above, in further view of Oriol et al. (Oriol, A., Larocca, A., Leleu, X., Hajek, R., Hassoun, H., Rodríguez-Otero, P., … Richardson, P. G. (2020). Melflufen for relapsed and refractory multiple myeloma. Expert Opinion on Investigational Drugs, 29(10), 1069–1078.).
Regarding claim 34, ‘975, Richardson, and Bahlis do not claim or teach a method of treating multiple myeloma further comprising an inhibitor of nuclear export or B-cell maturation antigen (BCMA)-directed immunotherapies.
Oriol et al state that several novel drugs with new modes of action (MOA) have been approved or are in development for RRMM, including selective inhibitors of nuclear export (selinexor), B-cell maturation antigen (BCMA)-directed immunotherapies, and melflufen [pg 1070 pgh 3 line 4]. Selinexor, decabtagene vicleucel, an investigational autologous BCMA chimeric antigen receptor (CAR)T-cell therapy, bb21217, a next-generation anti-BCMA CAR T–cell therapy, and belantamabmafodotin, an anti-BCMA antibody-drug conjugate, are all undergoing or have undergone clinical trials for RRMM.
One of ordinary skill in the art would be motivated to combine prior art elements melflufen and an inhibitor of nuclear export or a BCMA-directed therapy according to their known methods in clinical trials, prior to the effective filing date, because the combined teachings yield the predictable result of treating multiple myeloma. Therefore, it was obvious to claim the method wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with an antibody against the B-cell maturation antigen, an inhibitor of nuclear export, an autologous chimeric antigen receptor (CAR) T-cell therapy directed against the B-cell maturation antigen, or a combination thereof.
Regarding claim 36, ‘975, Richardson, and Bahlis do not claim or teach a method of treating multiple myeloma further comprising selinexor.
Oriol et al state that several novel drugs with new MOAs have been approved or are in development for RRMM, including the selective inhibitor of nuclear export, selinexor [pg 1070 pgh 3 line 4]. One of ordinary skill in the art would be motivated to combine prior art elements melflufen and an inhibitor of nuclear export or a BCMA-directed therapy according to their known methods in clinical trials prior to the effective filing date because the combined teachings yield the predictable result of treating multiple myeloma. Therefore, it was obvious to claim the method wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with selinexor.
Claim 40 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 17-19 of U.S. Patent No. 12396975 in view of Bahlis et al and Richardson et al., as applied to claims 21-22, 24-25, 28-33, 35, 37-39 and 41-42 above, in further view of Elnair et al. (Elniar et al. (Elnair, R., & Holstein, S. (2021). Treatment Considerations for Transplant-Ineligible Multiple Myeloma. Oncology (Williston Park, N.Y.), 35(4), 170–182).
Richardson does not teach that any of the patients with zero previous stem cell transplants are not suitable for a stem cell transplant.
Elnair summarizes the methods of the phrase 3 CLARION study in which newly diagnosed multiple myeloma patients who were transplant ineligible were administered either carfilzomib, melphalan, and prednisone (KMP) or bortezomib, melphalan, and prednisone [pg 178 pgh 2 line 1]. Melphalan is the drug portion of the peptide-drug conjugate melflufen (melphalan flufenamide). One of ordinary skill in the art would be motivated to use melflufen in place of melphalan in patients who have not received a stem cell transplant and are transplant-ineligible because it constitutes simple substitution of one known element for another to obtain the predictable result of treating multiple myeloma. Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant and is not suitable for a stem cell transplant.
Claims 21-22, 24-25, 28-33, 35, 37-39 and 41-42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-14, 19-36 of copending Application No. 19280683 in view of Bahlis et al. (Bahlis, N. J., & Lazarus, H. M. (2006). Multiple myeloma-associated AL amyloidosis: is a distinctive therapeutic approach warranted?. Bone marrow transplantation, 38(1), 7–15) and Richardson et al. (Richardson, P. G., Oriol, A., Larocca, A., Bladé, J., Cavo, M., Rodriguez-Otero, P., Leleu, X., Nadeem, O., Hiemenz, J. W., Hassoun, H., Touzeau, C., Alegre, A., Paner, A., Maisel, C., Mazumder, A., Raptis, A., Moreb, J. S., Anderson, K. C., Laubach, J. P., Thuresson, S., … HORIZON (OP-106) Investigators (2020). Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 39(7), 757–767.)
‘683 claims a method for treating a patient having immunoglobulin light chain (AL) amyloidosis, comprising administering melflufen, or a salt thereof, to the patient [claim 13]. ‘683 does not claim to be a method of treating a patient with AL amyloidosis also having multiple myeloma (MM) who has not received a stem cell transplant.
Bahlis et al. teach that AL amyloidosis coexists in 12-30% of multiple myeloma patients [Abstract line 8]. This is because multiple myeloma is the malignancy of terminally differentiated B lymphocytes characterized by the expansion of clonal plasma cells in the bone marrow, often resulting from direct injury or accumulation of immunoglobulins (heavy or light chain) in various organs [pg 7 pgh 1]. Thus, Bahlis teaches there is an overlap between ‘683’s AL amyloidosis patient population and the instant multiple myeloma patient population. Bahlis does not teach the instant claim limitation of administering melflufen to patients who have not received a stem cell transplant.
Richardson et al. evaluate the efficacy of melphalan flufenamide (melflufen) plus dexamethasone in relapsed and refractory multiple myeloma (RRMM) [pg 757 Abstract Purpose section]. Of all the 157 patients treated, 16 patients (10.2 %) had zero previous stem-cell transplants [pg 760 Table 1]. Richardson also performed a subgroup analysis of patients with triple-class–refractory MM (refractory to or intolerant of at least one immunomodulatory drug, at least one proteasome inhibitor, and at least one anti-CD38 monoclonal antibody) [pg 759 pgh 5 line 2]. Of all the 119 triple-class-refractory patients treated, 14 (11.7 %) patients had zero previous stem-cell transplants.
Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant because there are patients with AL amyloidosis who also have multiple myeloma and melflufen can be administered to patients with MM who have not had a stem cell transplant.
Regarding claim 22, ‘683 does not claim a method of treating multiple myeloma in a patient who has not received a stem cell transplant. Of the total patient population evaluated by Richardson, 10.2% had not received a stem cell transplant. Of the triple-class-refractory patients treated, 11.7 % had not received a stem-cell transplant. Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant because there are patients with AL amyloidosis who also have multiple myeloma and melflufen can be administered to patients with MM who have not had a stem cell transplant.
Regarding claim 24, ‘683 does not claim a method of administering melflufen to a patient 75 years old or older. In Richardson et al’s study, 25 patients were older than 75 years [pg 762 pgh 3 line 2]. Thus, it was obvious to claim a method of treating MM in a patient 75 years old or older prior to the effective filing date because there are patients with AL amyloidosis who also have multiple myeloma and Richardson demonstrates the method in a patient population 75 years or older.
Regarding claim 25, ‘683 does not claim a method of administering melflufen to a patient 75 years old or older who have not received a stem cell transplant. In Richardson et al’s study, 16 patients (10.2 %) had zero previous stem-cell transplants [pg 760 Table 1] and 25 patients were older than 75 years [pg 762 pgh 3 line 2]. Richardson does not detail the age of the patients who have not received stem transplants, only the age of the overall population. However, one of ordinary skill in the art would be motivated to administer melflufen in patients who have not received a stem cell transplant and are 75 years old or older because there are patients with AL amyloidosis who also have multiple myeloma and Richardson demonstrates the method in both patient populations separately, meaning that there is a reasonable expectation that treating the overlapping patient population would be successful. Therefore, prior to the effective filing date, it was obvious to claim a method of treating MM in a patient 75 years old or older and has not received a stem cell transplant because there are patients with AL amyloidosis who also have multiple myeloma.
Regarding claim 28, ‘683 claims method for treating a patient having immunoglobulin light chain (AL) amyloidosis, comprising administering melflufen, or a salt thereof, to the patient wherein the melflufen, or a salt thereof, is administered at a dose of about 15 mg to 150 mg excluding the mass of any counterion [claim 19]. Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering 1 mg to 150 mg of melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant because the dose matches ‘683’s range [MPEP 2144.05].
Regarding claim 29, ‘683 claims method for treating a patient having immunoglobulin light chain (AL) amyloidosis, comprising administering melflufen, or a salt thereof, to the patient wherein the melflufen, or a salt thereof, wherein a dose of melflufen, or a salt thereof, is administered on day 1 of a cycle of 21 days or a cycle of 28 days [claim 22]. Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein a dose of melflufen is administered on day 1 of a cycle of 1 to 42 days because the cycle encompasses ‘683’s range [MPEP 2144.05].
Regarding claim 30, ‘683 does not claim an infusion rate. Richardson’s patients received once-monthly 40 mg melflufen as a 30-minute central intravenous infusion on day 1 of each 28-day cycle [pg 758 pgh 3 line 21]. This translates the 1.3 mg/min, within the instant anticipated range of parenteral infusion rate [MPEP 2144.05]. Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant wherein a dose of melflufen is administered as a parenteral dosage at an infusion rate of 0.3 to 1.8 mg/min because there are patients with AL amyloidosis who also have multiple myeloma and melflufen can be administered to patients with MM who have not had a stem cell transplant, as taught by Richardson et al.
Regarding claim 31, ‘683 claims the method for treating a patient having immunoglobulin light chain (AL) amyloidosis further comprising administering to the patient simultaneously, sequentially or separately from melflufen, or a salt thereof one or more further therapeutic agent(s). [claim 25]. Thus, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with one or more further therapeutic agent(s).
Regarding claim 32, ‘683 claims the method for treating a patient having immunoglobulin light chain (AL) amyloidosis further comprising administering to the patient simultaneously, sequentially or separately from melflufen, or a salt thereof, a steroid selected from the group consisting of prednisone, prednisolone and dexamethasone [claim 14]. Thus, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with a steroid.
Regarding claim 33, ‘683 claims the method for treating a patient having immunoglobulin light chain (AL) amyloidosis further comprising administering to the patient simultaneously, sequentially or separately from melflufen, or a salt thereof, a steroid selected from the group consisting of prednisone, prednisolone and dexamethasone [claim 14]. Thus, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with dexamethasone.
Regarding claim 35, ‘683 claims the method for treating a patient having immunoglobulin light chain (AL) amyloidosis further comprising administering to the patient simultaneously, sequentially or separately from melflufen, or a salt thereof, a steroid selected from the group consisting of prednisone, prednisolone and dexamethasone [claim 14]. Thus, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with dexamethasone.
Regarding claim 37, ‘683 claims the method for treating a patient having immunoglobulin light chain (AL) amyloidosis further comprising administering to the patient simultaneously, sequentially or separately from melflufen, or a salt thereof, a steroid selected from the group consisting of prednisone, prednisolone and dexamethasone [claim 14]. Thus, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant, wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with dexamethasone.
Regarding claim 38, ‘683 does not claim the method, wherein the instant multiple myeloma patient is (a) to (g). Richardson’s patient population had received at least two prior lines of therapy, including an immunomodulatory agent and proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Therefore, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, wherein the multiple myeloma patient (a)-(g) because there are patients with AL amyloidosis who also have multiple myeloma and Richardson teaches that melflufen can be administered to patients with MM who have not had a stem cell transplant wherein the patient is (a), (d), (e), (g), (i), or (j).
Regarding claim 39, ‘683 does not claim the method wherein the instant multiple myeloma patient is at least 65 years old. Richardson’s patient population had a median age of 65. [Table 1]. Therefore, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, wherein the multiple myeloma patient is at least 65 years old because there are patients with AL amyloidosis who also have multiple myeloma and Richardson teaches that melflufen can be administered to patients with MM who have not had a stem cell transplant wherein the patient is 65 years old.
Regarding claim 41, ‘683 does not claim the method wherein the instant multiple myeloma patient is a high-risk patient in view of the patient’s cytogenetics. Of Richardson’s overall population, 59 of 157 patients had high-risk cytogenetics and 16 patients (10.2 %) had zero previous stem-cell transplants [pg 760 Table 1]. Of the Triple-Class Refractory Population, 41 of 119 patients had high-risk cytogenetics and 14 (11.7 %) patients had zero previous stem-cell transplants.. Richardson does not detail which patients with high risk cytogenetic had not received a stem-cell transplant, only the number of patients overall. However, one of ordinary skill in the art would be motivated administer melflufen in patients who have not received a stem cell transplant with high-risk cytogenetics because Richardson demonstrates the method in both patient populations separately and there is a highly reasonable expectation that treating the patient population overlap would be successful. Thus, it was obvious, prior to the effective filing date, to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, wherein the multiple myeloma patient is a high-risk patient in view of the patient’s cytogenetics.
Regarding claim 42, 975 does not claim the method, wherein the patient has received at least two previous lines of therapy. Richardson’s patient population had received at least two prior lines of therapy, including an immunomodulatory agent and proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Thus, it was obvious, prior to the effective filing date, to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, wherein the multiple myeloma patient has received at least two previous lines of therapy.
This is a provisional nonstatutory double patenting rejection.
Claims 34 and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-14, 19-36 of copending Application No. 19280683 in view of Bahlis et al and Richardson et al., as applied to claims 21-22, 24-25, 28-33, 35, 37-39 and 41-42 above, in further view of Oriol et al. (Oriol, A., Larocca, A., Leleu, X., Hajek, R., Hassoun, H., Rodríguez-Otero, P., … Richardson, P. G. (2020). Melflufen for relapsed and refractory multiple myeloma. Expert Opinion on Investigational Drugs, 29(10), 1069–1078.).
Regarding claim 34, ‘683, Richardson, and Bahlis do not claim or teach a method of treating multiple myeloma further comprising an inhibitor of nuclear export or B-cell maturation antigen (BCMA)-directed immunotherapies.
Oriol et al state that several novel drugs with new modes of action (MOA) have been approved or are in development for RRMM, including selective inhibitors of nuclear export (selinexor), B-cell maturation antigen (BCMA)-directed immunotherapies, and melflufen [pg 1070 pgh 3 line 4]. Selinexor, decabtagene vicleucel, an investigational autologous BCMA chimeric antigen receptor (CAR)T-cell therapy, bb21217, a next-generation anti-BCMA CAR T–cell therapy, and belantamabmafodotin, an anti-BCMA antibody-drug conjugate, are all undergoing or have undergone clinical trials for RRMM.
One of ordinary skill in the art would be motivated to combine prior art elements melflufen and an inhibitor of nuclear export or a BCMA-directed therapy according to their known methods in clinical trials, prior to the effective filing date, because the combined teachings yield the predictable result of treating multiple myeloma. Therefore, it was obvious to claim the method wherein the melflufen, or salt thereof, is administered simultaneously, sequentially or separately with an antibody against the B-cell maturation antigen, an inhibitor of nuclear export, an autologous chimeric antigen receptor (CAR) T-cell therapy directed against the B-cell maturation antigen, or a combination thereof.
This is a provisional nonstatutory double patenting rejection.
Claim 40 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-14, 19-36 of copending Application No. 19280683 in view of Bahlis et al and Richardson et al., as applied to claims 21-22, 24-25, 28-33, 35, 37-39 and 41-42 above, in further view of Elnair et al. (Elniar et al. (Elnair, R., & Holstein, S. (2021). Treatment Considerations for Transplant-Ineligible Multiple Myeloma. Oncology (Williston Park, N.Y.), 35(4), 170–182).
Richardson does not teach that any of the patients with zero previous stem cell transplants are not suitable for a stem cell transplant.
Elnair summarizes the methods of the phrase 3 CLARION study in which newly diagnosed multiple myeloma patients who were transplant ineligible were administered either carfilzomib, melphalan, and prednisone (KMP) or bortezomib, melphalan, and prednisone [pg 178 pgh 2 line 1]. Melphalan is the drug portion of the peptide-drug conjugate melflufen (melphalan flufenamide). One of ordinary skill in the art would be motivated to use melflufen in place of melphalan in patients who have not received a stem cell transplant and are transplant-ineligible because it constitutes simple substitution of one known element for another to obtain the predictable result of treating multiple myeloma. Therefore, prior to the effective filing date, it was obvious to claim a method for the treatment of multiple myeloma, comprising administering melflufen, or a salt thereof, to a patient having multiple myeloma who has not received a stem cell transplant and is not suitable for a stem cell transplant.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 28 and 30 are rejected under 35 U.S.C. 112(b). Claims 21-22, 28-33, 35, 37-39 and 42 are rejected under 35 U.S.C. 102. Claims 24-25, 34, 36, and 40-41 are rejected under 35 U.S.C. 103. Claims 21-22, 24-25, and 28-42 are rejected on the ground of nonstatutory double patenting. Claims 21-22, 24-25, and 28-42 are rejected on the ground of provisional nonstatutory double patenting.
Correspondence
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/SACHI JAUHARI/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
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