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 .
DETAILED ACTION
Claims 25, 36-44 and 46 are pending in the instant application.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/12/2025 has been entered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e)
or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not
complied with one or more conditions for receiving the benefit of an earlier filing date
under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention
which is also disclosed in the prior application (the parent or original nonprovisional
application or provisional application). The disclosure of the invention in the parent
application and in the later-filed application must be sufficient to comply with the
requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112,
except for the best mode requirement. See Transco Products, Inc. v. Performance
Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The instant Application claims priority to five priority Applications, namely:
62/944,809 filed 12/6/2019;
63/023,198 filed 5/11/2020;
63/037,353 filed 6/10/2020;
63/094,833 filed 10/21/2020; and
EP20315186.5 filed 4/17/2020.
All priority Applications fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Claims 25, 36-44, and 46 contain subject matter introduced for the first time in application 63/094,833 and have a priority date of 10/21/2020. Specifically introduced subject matter is: complete renal response is first introduced in the specification of 63/094,833 on page 67 in paragraph 179.
Thus, instant claims 25, 36-44, and 46 have the priority date of 10/21/2020.
Claim Rejections Withdrawn
The rejections to claims 25, 36-44, and 46 under 35 USC §103 are withdrawn to add further clarity to the obvious rational.
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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 25, 36-37, 40, 43-44, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Martin TG et al. (Journal of Clinical Oncology 2018, 36(15) suppl TPS8060, reference of record) as evidenced by US 8153765 (Park PU et al., reference of record) and further in view of Dimopoulos MA et al. (Clinical Lymphoma Myeloma and Leukemia 19(10) Supplement, 2019, Page e254., reference of record) and Groen K et al. (Cancer Management and Research 2019:11 2663–2675, reference of record).
Martin taught a method for treating a human having multiple myeloma, comprising administering an effective amount of: the anti-CD38 antibody isatuximab (also known as SAR650984 or 38SB19) (10 mg/kg); carfilzomib (20 mg/m2 or 56 mg/m2); and dexamethasone (20 mg), wherein the individual received at least one prior therapy for multiple myeloma (patients received 1-3 prior lines of therapy)(page 2, Methods).
As evidenced by Park, isatuximab (also known as SAR650984 or 38SB19) of Martin is comprised of three sequential heavy chain CDRs of SEQ ID NO: 13, 81, and 15 (identical to instant SEQ ID NO:1-3), and three sequential light chain CDRs of SEQ ID NO: 16, 17, and 18 (identical to instant SEQ ID NO:4-6) (specification, column 10 lines 38-48).
As evidenced by Park, the 38SB19 antibody is comprised of a VH having the amino acid sequence of SEQ ID NO: 66 (identical to the VH of isatuximab and instant SEQ ID NO:7) and VL having the amino acid sequence of SEQ ID NO: 62 (identical to VL of isatuximab and instant SEQ ID NO:8) (claim 43).
Martin taught a method for multiple myeloma patients with revised international staging system at baseline of I-III and unknown, stratified as I or II vs III vs unknown (page 2, Methods). Martin taught carfilzomib-based treatments are a standard of care (page 2, background). Martin taught isatuximab has antitumor and immunomodulatory activities in preclinical models of multiple myeloma, has shown clinical activity as monotherapy and in combination with current standard of care in patients with relapsed/refractory multiple myeloma (page 2, background), which would expect the effect of the combination treatment method being more likely to be Minimal Residual Disease (MRD) negative at a threshold of 10-5 or less after the treatment of multiple myeloma with combination of isatuximab, carfilzomib and dexamethasone as compared to a treatment with the carfilzomib and dexamethasone and without the anti-CD38 antibody.
Martin is silent to achieving a complete renal response in an individual in need thereof, wherein the individual has multiple myeloma and renal impairment, but this deficiency is addressed in Dimopoulos and Groen.
Dimopoulos taught renal impairment (RI) is a common feature in multiple myeloma (MM) and an adverse predictor of survival (background). Dimopoulos taught anti-myeloma treatments that can also improve renal function in patients (pts) with MM are required (background). Dimopoulos taught the addition of the anti-CD38 monoclonal antibody isatuximab (Isa) at 10 mg/kg to combination treatment pomalidomide and dexamethasone (Pd) increased the number of patients with reversal of RI, sustained renal responses and improved progression free survival (PFS) and overall response rate (ORR) consistent with the benefit observed in the overall study population (conclusions). Dimopoulos taught complete renal response occurred in 71.9% pts in the Isa-Pd arm (23/32) and 38.1% (8/21) pts in the Pd arm and these were durable in 31.3% and 19.0% pts, respectively (results), wherein complete renal response was defined as improvement in eGFR from <50 mL/min/1.73m2 at baseline to ≥60 mL/min/1.73m2 (eGFR ≥60; no RI).
Groen taught the maximum tolerated dose (MTD) of carfilzomib was established at 56 mg/m2 (page 2667, left column, second to last paragraph). Groen taught carfilzomib (20 or 56 mg/m2) and dexamethasone (20 mg) treatment of patients with relapsed or refractory multiple myeloma where 55% had at least a partial response (page 2667, left column, second to last paragraph). Groen taught 55% of patients treated with carfilzomib for multiple myeloma showed an improved renal function of patients with baseline estimated glomerular filtration rate <60 mL/min/1.73 m2 (initially impaired renal (kidney) function) (page 2672, left column, paragraph 3).
Regarding claims 25, 37, and 43-44, it would have been obvious for a person having ordinary skill in the art to use the method of Martin for treating multiple myeloma with the anti-CD38 antibody isatuximab (also known as SAR650984 or 38SB19, same as instant antibody comprising VH SEQ NO: 7 and VL SEQ ID NO:8) (10 mg/kg); carfilzomib (20 mg/m2 or 56 mg/m2); and dexamethasone (20 mg), wherein the individual received 1-3 prior lines of therapy – and further use it to treat the cancer and achieve a complete renal response, wherein the complete renal response in the individual would naturally result in an improvement in estimated glomerular filtration rate (eGFR) from< 50 ml/min/1.73 m2 at baseline to ≥ 60 ml/min/1.73 m2.
This is obvious because: 1) Dimopoulos taught addition of 10 mg/kg isatuximab to multiple myeloma treatment regimens increased complete renal response, wherein complete renal response was defined as improvement in eGFR from <50 mL/min/1.73m2 at baseline to ≥60 mL/min/1.73m2 (eGFR ≥60; no RI) and was more durable and that anti-myeloma treatments that can also improve renal function in patients (pts) with multiple myeloma are required; and 2) Groen taught carfilzomib treatment of multiple myeloma patients improved renal function of patients with initially impaired renal (kidney) function.
This would produce a method of treating a patient with multiple myeloma and renal impairment for cancer and to achieve a complete renal response, wherein the complete renal response in the individual naturally results in an improvement in estimated glomerular filtration rate (eGFR) from< 50 ml/min/1.73 m2 at baseline to ≥ 60 ml/min/1.73 m2 comprising administering: the anti-CD38 antibody isatuximab (also known as SAR650984 or 38SB19) (10 mg/kg)(claim 44); carfilzomib (20 mg/m2 or 56 mg/m2); and dexamethasone (20 mg), wherein the individual received 1-3 prior lines of therapy (claim 37), wherein the individual is inherently more likely to achieve a complete renal response following treatment compared to carfilzomib and dexamethasone treatment without isatuximab (claim 25).
There is a reasonable expectation of success because: 1a) a method of isatuximab (10 mg/kg); carfilzomib (20 mg/m2 or 56 mg/m2); and dexamethasone (20 mg) for multiple myeloma treatment was known; 1b) isatuximab and combination carfilzomib and dexamethasone were known to have antitumor activity against multiple myeloma; 1c) addition of isatuximab to multiple myeloma treatment regimens increases complete renal response; and 2) carfilzomib improves renal function of patients with initially impaired renal (kidney) function.
Regarding claims 36 and 43, it would have been obvious for a person having ordinary skill in the art to expect that patients with renal impairment treated with isatuximab and carfilzomib would be more likely to be MRD negative at a threshold of 10-5 or less after the treatment, as compared to a treatment with the carfilzomib and dexamethasone and without the anti-CD38 antibody.
This is obvious because Martin teaches that isatuximab has antitumor and immunomodulatory activities in preclinical models of multiple myeloma, has shown clinical activity as monotherapy and in combination with current standard of care in patients with relapsed/refractory multiple myeloma, which would indicate the effect of the combination treatment method would naturally be more likely to be Minimal Residual Disease (MRD) negative at a threshold of 10-5 or less after the treatment of multiple myeloma with combination of isatuximab, carfilzomib and dexamethasone as compared to a treatment with the carfilzomib and dexamethasone and without the anti-CD38 antibody.
There is a reasonable expectation of success because isatuximab and combination carfilzomib and dexamethasone were known to have antitumor activity against multiple myeloma and carfilzomib is known to increase renal function and is included in the combination treatment. As noted above, the isatuximab antibody used in the method of Martin is comprised of a VH having the amino acid sequence of instant SEQ ID NO:7 and VL having the amino acid sequence of instant SEQ ID NO:8)(claim 43).
Regarding claim 40, it would have been obvious for a person having ordinary skill in the art to modify the method of Martin, Dimopoulos and Groen of treating both multiple myeloma and to achieve a complete renal response in an individual in need comprised of administering the isatuximab, carfilzomib, and dexamethasone combination treatment above and: – to include myeloma patients with revised international staging system at baseline of I-III and unknown (claim 40).
This is obvious because: 1) Martin teaches administering the isatuximab, carfilzomib, and dexamethasone combination treatment to patients with multiple myeloma revised international staging system at baseline of I-III and unknown.
There is a reasonable expectation of success because: 1a) isatuximab and combination carfilzomib and dexamethasone were known to have antitumor activity against multiple myeloma; 1b) addition of isatuximab to multiple myeloma treatment regimens increases complete renal response; 1c) carfilzomib improves renal function of patients with initially impaired renal (kidney) function; and 1d) the patient population would be expected to be responsive to the combination treatment in both an anticancer and renal protective/regenerative capacity.
Regarding claim 46, because Dimopoulos taught the addition of 10 mg/kg isatuximab to a combination multiple myeloma treatment: 1) increased complete renal response, wherein complete renal response was defined as improvement in eGFR from <50 mL/min/1.73m2 at baseline to ≥60 mL/min/1.73m2 (eGFR ≥60; no RI) and 2) was more durable; the method of Martin, Dimopoulos, and Groen for treatment with isatuximab (10 mg/kg) carfilzomib (20 mg/m2 or 56 mg/m2); and dexamethasone (20 mg), would be expected with a reasonable expectation of success to naturally achieve a more durable complete renal response compared to treatment with carfilzomib and dexamethasone without isatuximab (claim 46).
Response to Applicant Arguments
1. Applicant argues the cited references do not specifically disclose the method recited in the claims can achieve a complete renal response. The cited references do not specifically disclose that the individual is more likely to achieve a complete renal response following the treatment, as compared to a treatment comprising the carfilzomib and the dexamethasone and without the anti-CD38 antibody, wherein the complete renal response in the individual is an improvement in estimated glomerular filtration rate (eGFR) from< 50 ml/min/1.73 rn2 at baseline to-?: 60 ml/min/l .73 m2 as recited in independent claim 25.
Martin does not specifically disclose the inclusion of patients with renal impairment in the IKEMA clinical trial described therein. Moreover, as acknowledged by the Examiner, Martin is silent about achieving a complete renal response in an individual in need thereof: wherein the individual has multiple myeloma and renal impairment, and wherein the complete renal response in the individual is an improvement in estimated glomerular filtration rate ( eGFR) from < 50 ml/min/J 73 m2 at baseline to > 60 ml/min/1. 73 m2, as recited in pending claim 25, and dependent claims thereof.
Park does not specifically point to an impact of the anti-CD38 antibodies described therein on the renal function of a patient with renal impairment, much less an impact wherein an individual is more likely to achieve a complete renal response, as recited in pending claim 25, and dependent claims 36-37, 40, and 44-46.
The Examiner further alleges that Dimopoulos teaches that "the addition of the antiCD38 monoclonal antibody isatuximab (Isa) at 10mg/kg to combination treatment pomalidomide and dexamethasone increased the number of patients with reversal of renal impaim1ent" Office Action, p. 7, first paragraph. However, the combination therapy taught by Dimopoulos is isatuximab, dexamethasone and pomalidomide and is different from the combination therapy recited in pending claim 25 and dependent claims 25, 36-37, 40, and 44-46.
The Examiner alleges that Groen teaches that ''55% of patients treated with carfilzomib for multiple myeloma showed an improved renal function of patients with baseline estimated glomerular filtration rate <60 mL/min/1.73 m2 (initially impaired renal (kidney) function)." Office Action, p. 7, first full paragraph. However, Groen is disclosing this information in the context of the administration of carfilzomib as a monotherapy, instead of a combination therapy, as recited in claim 25 and dependent claims 25, 36-37, 40, and 44-46. Groen does not disclose a method of achieving a complete renal response in an individual that has multiple myeloma and renal impairment with an anti-CD38 antibody, carfilzomib, and dexamethasone, much less a method wherein the individual is more likely to achieve a complete renal response following the treatment, as recited in claim 25, and dependent claims 25, 36-37, 40, and 44-46.
Accordingly, the cited references, alone or in combination, do not specifically disclose a method to achieve a complete renal response as recited in pending claim 25 and dependent claims 25, 36-37, 40, and 44-46.
In response, Applicant's arguments filed 9/12/2025 have been fully considered but they are not persuasive.
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).
Regarding Martin does not teach the inclusion of patients with renal impairment in the IKEMA clinical trial described therein and is silent about achieving a complete renal response in an individual in need thereof, wherein the individual has multiple myeloma and renal impairment, and wherein the complete renal response in the individual is an improvement in estimated glomerular filtration rate (eGFR) from < 50 ml/min/1.73 m2 at baseline to ≥ 60 ml/min/1.73 m2:
Martin taught an identical combination treatment for multiple myeloma, wherein the components were known to the art as renal protective as described in the obvious rational above;
Martin taught carfilzomib-based treatments are a standard of care and that isatuximab has antitumor and immunomodulatory activities in preclinical models of multiple myeloma, wherein isatuximab has shown clinical activity as monotherapy and in combination with current standard of care in patients with relapsed/refractory multiple myeloma;
Dimopoulos taught renal impairment (RI) is a common feature in multiple myeloma (MM) and an adverse predictor of survival;
Dimopoulos taught the addition of the anti-CD38 monoclonal antibody isatuximab (Isa) at 10 mg/kg to combination treatment pomalidomide and dexamethasone (Pd) increased the number of patients with reversal of RI, complete renal response, sustained renal responses and improved progression free survival (PFS) and overall response rate (ORR) consistent with the benefit observed in the overall study population, wherein complete renal response was defined as improvement in eGFR from <50 mL/min/1.73m2 at baseline to ≥60 mL/min/1.73m2 (eGFR ≥60; no RI).
Further, Groen taught 55% of patients treated with carfilzomib showed improved renal function in the context of the administration of carfilzomib as a monotherapy, Groen specifically recognizes the importance of carfilzomib for renal protection.
Thus, the method of multiple myeloma treatment of Martin for isatuximab, carfilzomib, and dexamethasone treatment at the concentrations taught by Martin would be obvious with a reasonable expectation of success for treating renal response in multiple myeloma because the method comprises known renal protection agents, wherein the combination therapy performs the function of both treating the multiple myeloma and achieving complete renal response.
Regarding Park, Park is relied upon to evidence the 38SB19 antibody is comprised of a VH having the amino acid sequence of SEQ ID NO: 66 (identical to the VH of isatuximab and instant SEQ ID NO:7) and VL having the amino acid sequence of SEQ ID NO: 62 (identical to VL of isatuximab and instant SEQ ID NO:8).
Regarding the combination therapy taught by Dimopoulos is isatuximab, dexamethasone and pomalidomide and is different from the combination therapy recited in pending claim 25 and dependent claims, Dimopoulos taught the addition of isatuximab to pomalidomide and dexamethasone increased the number of patients with reversal of renal impairment, sustained renal responses and improved PFS and ORR consistent with the benefit observed in the overall study population. Thus, Dimopoulos specifically recognizes the importance of isatuximab in the combination for achieving complete renal response.
Regarding Groen, Groen specifically recognizes the importance of carfilzomib for renal protection. The renal protection capabilities of carfilzomib would be obvious with a reasonable expectation of success to occur in the combination treatment with another known renal protection agent isatuximab, wherein the combination therapy performs the function of both treating the multiple myeloma and achieving complete renal response.
Regarding the references combined do not specifically disclose a method to achieve a complete renal response as recited in pending claim 25 and dependent claims 25, 36-37, 40, and 44-46, the obvious rational is above. Using a known combination of therapeutics: 1) known to be effective in patients with multiple myeloma, wherein carfilzomib-based treatments are a standard of care and isatuximab has shown clinical activity with current standard of care in patients with multiple myeloma; 2) wherein the components are known to effectively improve renal response and achieve complete renal response; and 3) wherein renal impairment of multiple myeloma patients is a known complication, would be obvious with a reasonable expectation of success. Further, the inclusion of isatuximab, which is a known effective treatment of multiple myeloma, in the combination treatment would make patients more likely to be MRD negative. Additionally, 10 mg/kg isatuximab increased complete renal response, wherein complete renal response was defined as improvement in eGFR from <50 mL/min/1.73m2 at baseline to ≥60 mL/min/1.73m2 (eGFR ≥60; no RI) and 2) was more durable.
2. Applicant argues the present invention provides unexpected results that fully rebut any prima facie case of obviousness. Applicant respectfully submits that the specification has shown the claimed methods have unexpected effects in support of non-obviousness. In the present invention, the Applicant unexpectedly found that treatment with the combination recited in pending claim 25, and dependent claims 25, 36-37, 40, and 44-46, improves renal function in individuals ,who had received at least one prior therapy for multiple myeloma and who had renal impairment at the start of treatment. Briefly, patients who had received at least one prior therapy for multiple myeloma and who also had renal impairment (i.e., eGFR < 60 ml/min/1.73 m2) at baseline were randomly assigned to receive either (a) isatuximab, carfilzomib, and dexamethasone ("IKd" arm), or (b) carfilzomib and dexamethasone ("Kd" arm).
See Example 1E, Table J, and paragraph [0180] of the present application. Complete renal response (i.e., an improvement in eGFR from< 50 ml/min/1.73 m2 at baseline to~ 60 ml/min/1.73 m2) occurred in 52% of patients in the IKd arm, compared to 30.8% of patients in the Kd arm. The complete renal response was durable (i.e., maintained for~ 60 days) in 32% of the patients in the IKd arm versus 7.7% of the patients in the Kd arm. See paragraph [0184] of the present application. Given that renal impairment is a common complication of multiple myeloma known to increase in frequency with the progression of disease, with recovery of renal function becoming less likely as patients progress through lines of therapy, Applicant's results are particularly significant.
In response, Applicant's arguments filed 9/12/2025 have been fully considered but they are not persuasive.
Regarding the unexpected results, Martin taught a method for treating a human having multiple myeloma, comprising administering an effective amount of: the anti-CD38 antibody isatuximab (also known as SAR650984 or 38SB19) (10 mg/kg); carfilzomib (20 mg/m2 or 56 mg/ m2); and dexamethasone (20 mg), wherein the individual received at least one prior therapy for multiple myeloma (patients received 1-3 prior lines of therapy)(page 2, Methods), the combination therapy was already known as a treatment for multiple myeloma. The renal protective effects of carfilzomib was previously taught by Groen, wherein 55% of patients treated with carfilzomib for multiple myeloma showed an improved renal function of patients with baseline estimated glomerular filtration rate <60 mL/min/1.73 m2 (initially impaired renal (kidney) function) (page 2672, left column, paragraph 3). Further, Dimopoulos taught complete renal response occurred in 71.9% pts in the Isa-Pd arm (23/32) and 38.1% (8/21) pts in the Pd arm and these were durable in 31.3% and 19.0% pts, respectively. Thus, isatuximab and dexamethasone combinations with pomalidomide were known to be renal protective for the percentage of patients in this range. Additionally, the results of Dimopoulos taught the inclusion of isatuximab increased renal response rates about 1.9-fold (71.9%/38.1% ~ 1.9). This is about the same effect seen in the instant results of the current study wherein complete renal response (i.e., an improvement in eGFR from< 50 ml/min/1.73 m2 at baseline to~ 60 ml/min/1.73 m2) occurred in 52% of patients in the IKd arm, compared to 30.8% of patients in the Kd arm, wherein 52%/30.8% is about a 1.7-fold difference in the number of patients that achieved a complete renal response with the addition of isatuximab. Thus, using a known combination of therapeutics: 1) known to be effective in patients with multiple myeloma, wherein carfilzomib-based treatments are a standard of care and isatuximab has shown clinical activity with current standard of care in patients with multiple myeloma; 2) wherein the components are known to effectively improve renal response and achieve complete renal response; and 3) wherein renal impairment of multiple myeloma patients is a known complication, would be obvious with a reasonable expectation of success.
The method of Martin does not require exchange of any of the combination treatment drugs in the treatment method. The method of Martin is only further being extended to achieve a complete renal response, wherein the components of the combination treatment drugs are known renal protection agents at the concentrations claimed. Thus, a method of treating multiple myeloma and achieving a complete renal response in a patient by administering 10 mg/kg isatuximab, 20 mg/ m2 or 56 mg/ m2 carfilzomib, and 20 mg dexamethasone is obvious with a reasonable expectation of success and the percentage of patients that achieved a complete renal response in the instant application is not surprising wherein the complete renal response in the individual is an improvement in estimated glomerular filtration rate (eGFR) from < 50 ml/min/1.73 m2 at baseline to ≥ 60 ml/min/1.73 m2.
Claims 25, 36-37, 40, 43-44, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Martin TG et al. (Journal of Clinical Oncology 2018, 36(15) suppl TPS8060, reference of record) as evidenced by US 8153765 (Park PU et al., reference of record) and further in view of Monge J et al. (Blood (2019) 134 (Supplement_1): 5563, November 13 2019, reference of record) and Groen K et al. (Cancer Management and Research 2019:11 2663–2675, reference of record) and evidenced by Chng W-J et al. (Leukemia 2017 31(6):1368-1374, reference of record).
Martin taught a method for treating a human having multiple myeloma, comprising administering an effective amount of: the anti-CD38 antibody isatuximab (also known as SAR650984 or 38SB19) (10 mg/kg); carfilzomib (20 mg/ m2 or 56 mg/ m2); and dexamethasone (20 mg), wherein the individual received at least one prior therapy for multiple myeloma (patients received 1-3 prior lines of therapy)(page 2, Methods).
As evidenced by Park, isatuximab (also known as SAR650984 or 38SB19) of Martin is comprised of three sequential heavy chain CDRs of SEQ ID NO: 13, 81, and 15 (identical to instant SEQ ID NO:1-3), and three sequential light chain CDRs of SEQ ID NO: 16, 17, and 18 (identical to instant SEQ ID NO:4-6) (specification, column 10 lines 38-48).
As evidenced by Park, the 38SB19 antibody is comprised of a VH having the amino acid sequence of SEQ ID NO: 66 (identical to the VH of isatuximab and instant SEQ ID NO:7) and VL having the amino acid sequence of SEQ ID NO: 62 (identical to VL of isatuximab and instant SEQ ID NO:8) (claim 43).
Martin taught a method for multiple myeloma patients with revised international staging system at baseline of I-III and unknown, stratified as I or II vs III vs unknown (page 2, Methods). Martin taught carfilzomib-based treatments are a standard of care (page 2, background). Martin taught isatuximab has antitumor and immunomodulatory activities in preclinical models of multiple myeloma, has shown clinical activity as monotherapy and in combination with current standard of care in patients with relapsed/refractory multiple myeloma (page 2, background), which would expect the effect of the combination treatment method being more likely to be Minimal Residual Disease (MRD) negative at a threshold of 10-5 or less after the treatment of multiple myeloma with combination of isatuximab, carfilzomib and dexamethasone as compared to a treatment with the carfilzomib and dexamethasone and without the anti-CD38 antibody.
Martin is silent to achieving a complete renal response in an individual in need thereof, wherein the individual has multiple myeloma and renal impairment, but this is deficiency is addressed in Monge and Groen.
Monge taught renal impairment is a frequent complication of multiple myeloma (MM) associated with poor prognosis and decreased overall survival (abstract). Monge taught the CD38 antibody inhibitor daratumumab is a treatment for multiple myeloma (abstract). Monge taught a retrospective, single-center analysis of patients with relapsed/refractory MM treated with the CD38 antibody inhibitor daratumumab with impaired renal function indicated by an eGFR of 30-59 ml/min/1.73 m2 or <30 ml/min/1.73 m2 where renal response was measured before and following treatment (abstract). Renal response was defined as an eGFR >= 60 in two consecutive visits for patients with baseline renal impairment (abstract). The table shows 41% of multiple myeloma patients with an eGFR of 30-59 ml/min/1.73 m2 achieved a complete response, while 0% of multiple myeloma patients with an eGFR of <30 ml/min/1.73 m2 (Table, Renal Response). Monge taught when compared to patients with chronic renal impairment, those with acute renal impairment were more likely to achieve a renal response (80% vs 21%, p=0.02). Monge taught the high renal response rate (29%) seen, as compared to the one in the subgroup analysis of ENDEAVOR (15%), highlights the utility of daratumumab in reversing renal end-organ damage in patients with relapsed/refractory MM without an increase in adverse events compared to patients with preserved renal function (abstract).
Chng evidences the ENDEAVOR trial compares carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma (abstract).
Groen taught the maximum tolerated dose (MTD) of carfilzomib was established at 56 mg/ m2 (page 2667, left column, second to last paragraph). Groen taught carfilzomib (20 or 56 mg/ m2) and dexamethasone (20 mg) treatment of patients with relapsed or refractory multiple myeloma where 55% had at least a partial response (page 2667, left column, second to last paragraph). Groen taught 55% of patients treated with carfilzomib for multiple myeloma showed an improved renal function of patients with baseline estimated glomerular filtration rate <60 mL/min/1.73 m2 (initially impaired renal (kidney) function) (page 2672, left column, paragraph 3).
Regarding claims 25, 37, and 43-44, it would have been obvious for a person having ordinary skill in the art to use the method of Martin for treating multiple myeloma with the anti-CD38 antibody isatuximab (also known as SAR650984 or 38SB19, same as instant antibody comprising VH SEQ NO: 7 and VL SEQ ID NO:8) (10 mg/kg); carfilzomib (20 mg/ m2 or 56 mg/ m2); and dexamethasone (20 mg), wherein the individual received 1-3 prior lines of therapy – and further use it to treat the cancer and achieve a complete renal response, wherein the complete renal response is an improvement in multiple myeloma patients with eGFR from <50 mL/min/1.73 m2 at baseline to ≥60 mL/min/1.73 m2 (eGFR ≥60).
This is obvious because: 1) Monge taught treatment that included a therapeutic anti-CD38 antibody inhibitor for multiple myeloma patients with impaired kidney function with an eGFR from 30-59 mL/min/1.73 m2 at baseline to ≥60 mL/min/1.73 m2 (eGFR ≥60) – and <50 overlaps with 30-59 mL/min/1.73 m2 increased complete renal response and was also a treatment for multiple myeloma; and 2) Groen taught carfilzomib treatment of multiple myeloma patients improved renal function of patients with initially impaired renal (kidney) function. Further, while Monge taught a different CD38 antibody inhibitor, daratumumab instead of isatuximab, both antibodies target CD38 and would be expected to perform similarly because they target the same protein.
This would produce a method of treating a patient with multiple myeloma and renal impairment for cancer and to achieve a complete renal response, wherein the complete renal response is naturally an improvement in multiple myeloma patients with eGFR from 30-59 mL/min/1.73 m2 at baseline to ≥60 mL/min/1.73 m2 (eGFR ≥60), which overlaps with 30-59 mL/min/1.73 m2, comprising administering: the anti-CD38 antibody isatuximab (also known as SAR650984 or 38SB19 and the same as instant antibody comprising VH SEQ NO: 7 and VL SEQ ID NO:8) (10 mg/kg)(claim 44); carfilzomib (20 mg/ m2 or 56 mg/ m2); and dexamethasone (20 mg), wherein the individual received 1-3 prior lines of therapy (claim 37), wherein the individual is naturally more likely to achieve a complete renal response following treatment compared to carfilzomib and dexamethasone treatment without isatuximab (claim 25).
There is a reasonable expectation of success because a method of isatuximab (10 mg/kg); carfilzomib (20 mg/ m2 or 56 mg/ m2); and dexamethasone (20 mg) for multiple myeloma treatment was known and isatuximab and combination carfilzomib and dexamethasone were known to have antitumor activity against multiple myeloma; – and
1) there is an overlap of the claimed eGFR value of <50 mL/min/1.73 m2 and the range of eGFR from 30-59 mL/min/1.73 m2 that achieved complete renal response in multiple myeloma patients treated with a therapeutic anti-CD38 antibody. Further, Monge taught the high renal response rate (29%) seen, as compared to the one in the subgroup analysis of a trial without a CD38 inhibitor ENDEAVOR (15%), highlights the utility of the therapeutic anti-CD38 antibody in reversing renal end-organ damage in patients with relapsed/refractory MM without an increase in adverse events compared to patients with preserved renal function. Isatuximab is also a therapeutic anti-CD38 antibody an would be expected to perform similarly because it has the same target; and addition of a therapeutic anti-CD38 inhibitor to multiple myeloma treatment regimens increases complete renal response; and
2) carfilzomib improves renal function of patients with initially impaired renal (kidney) function.
Regarding claims 36 and 43, it would have been obvious for a person having ordinary skill in the art to expect that patients with renal impairment treated with isatuximab and carfilzomib would naturally be more likely to be MRD negative at a threshold of 10-5 or less after the treatment, as compared to a treatment with the carfilzomib and dexamethasone and without the anti-CD38 antibody.
This is obvious because: 1) Martin teaches that isatuximab: i) has antitumor and immunomodulatory activities in preclinical models of multiple myeloma, and ii) has shown clinical activity as monotherapy and in combination with current standard of care in patients with relapsed/refractory multiple myeloma – which would indicate the effect of the combination treatment method being naturally more likely to be Minimal Residual Disease (MRD) negative at a threshold of 10-5 or less after the treatment of multiple myeloma with combination of isatuximab, carfilzomib and dexamethasone as compared to a treatment with the carfilzomib and dexamethasone and without the anti-CD38 antibody (claim 36).
There is a reasonable expectation of success because: 1) Martin teaches that isatuximab: i) has antitumor and immunomodulatory activities in preclinical models of multiple myeloma, and ii) has shown clinical activity as monotherapy and in combination with current standard of care in patients with relapsed/refractory multiple myeloma; and 2) carfilzomib is known to increase renal function and is included in the combination treatment. As noted above, the isatuximab antibody used in the method of Martin is comprised of a VH having the amino acid sequence of instant SEQ ID NO:7 and VL having the amino acid sequence of instant SEQ ID NO:8)(claim 43).
Regarding claim 40, it would have been obvious for a person having ordinary skill in the art to modify the method of Martin, Monge and Groen of treating both multiple myeloma and to achieve a complete renal response in an individual in need comprised of administering the isatuximab, carfilzomib, and dexamethasone combination treatment above: and – to include myeloma patients with revised international staging system at baseline of I-III and unknown (claim 40).
This is obvious because: 1) Martin teaches administering the isatuximab, carfilzomib, and dexamethasone combination treatment to patients with multiple myeloma revised international staging system at baseline of I-III and unknown; and 2) Martin teaches that isatuximab: i) has antitumor and immunomodulatory activities in preclinical models of multiple myeloma, and ii) has shown clinical activity as monotherapy and in combination with current standard of care in patients with relapsed/refractory multiple myeloma; and 1c) carfilzomib improves renal function of patients with initially impaired renal (kidney) function.
There is a reasonable expectation of success because the patient population would be expected to be responsive to the combination treatment in both an anticancer and renal protective/regenerative capacity.
Regarding claim 46, it would have been obvious for a person of ordinary skill in the art to expect the complete renal response to be more durable than an individual treated with carfilzomib and dexamethasone and without the CD38 antibody because Monge taught a higher renal response rate (29%) seen with a therapeutic anti-CD38 antibody, as compared to the one in the subgroup analysis of a trial without a CD38 inhibitor ENDEAVOR (15%) that treats with carfilzomib and dexamethasone indicates treatment with a CD38 inhibitor yields better renal response rates. Durability of the response is further expected because renal values of ≥60 mL/min/1.73 m2 (eGFR ≥60) were seen in two separate office visits and thus not a single value.
There is a reasonable expectation of success because Monge taught the high renal response rate (29%) seen, as compared to the one in the subgroup analysis of a trial without a CD38 inhibitor ENDEAVOR (15%), highlights the utility of the therapeutic anti-CD38 antibody in reversing renal end-organ damage in patients with relapsed/refractory MM without an increase in adverse events compared to patients with preserved renal function. Isatuximab is also a therapeutic anti-CD38 antibody an would be expected to perform similarly because it has the same target.
Response to Applicant Arguments
Applicant argues none of the cited references specifically discloses a method to achieve a complete renal response in an individual in need thereof wherein the individual has multiple myeloma and renal impairment, and wherein the individual is more likely to achieve a complete renal response following the treatment, as compared to a treatment comprising the carfilzomib and the dexamethasone without the anti-CD38 antibody, wherein the complete renal response in the individual is an improvement in estimated glomerular filtration rate (eGFR) from< 50 ml/min/1. 73 m2 at baseline to > 60 ml/min/173 m2, as recited in pending claim 25, and dependent claims 36-37, 40, and 44-46
Martin is silent about achieving a complete renal response in an individual in need thereof, wherein the individual has multiple myeloma and renal impairment. This deficiency is not cured by Park, Monge, Groen, or Chng.
The Examiner alleges that Monge teaches that "the CD38 antibody inhibitor
daratumumab is a treatment for multiple myeloma" and further teaches "the utility of
daratumumab in reversing renal end-organ damage in patients with relapsed/refractory MM." Office Action, p. 25, last paragraph. However, daratumumab is a different antibody from isatuximab. Nowhere does Monge teach that isatuximab in a combination therapy would achieve a complete renal response, let alone that the combination therapy comprises isatuximab, carfilzomib and dexamethasone.
The Examiner alleges that Chng "evidences the ENDEAVOR trial compares carfilzomib dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma. "Office Action, p. 26, first full paragraph. Chng does not teach or suggest a therapy comprising an anti-CD38 antibody, and more specifically isatuximab, in combination with carfilzomib and dexamethasone, to achieve a complete renal response. as recited in claim 25, and dependent claims 36-37, 40, and 44-46.
Accordingly, the cited references, alone or in combination, do not specifically disclose a method to achieve a complete renal response in an individual in need thereof ,wherein the individual has multiple myeloma and renal impairment, comprising administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone, ,wherein the individual is more likely to achieve a complete renal response following the treatment, as compared to a treatment comprising the carfilzomib and the dexamethasone and without the anti-CD38 antibody, and wherein the complete renal response in the individual is an improvement in estimated glomerular filtration rate (eGFR) from < 50 ml/min/1.73 m 2 at baseline to > 60 ml/min/L 73 m2, as recited in pending claim 25 and dependent claims 36-3 7, 40, and 44-46.
In response, Applicant's arguments filed 9/12/2025 have been fully considered but they are not persuasive.
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).
Regarding Martin and Monge:
Martin taught an identical combination treatment for multiple myeloma, wherein the components were known to the art as renal protective as described in the obvious rational above;
Martin taught carfilzomib-based treatments are a standard of care and that isatuximab has antitumor and immunomodulatory activities in preclinical models of multiple myeloma, wherein isatuximab has shown clinical activity as monotherapy and in combination with current standard of care in patients with relapsed/refractory multiple myeloma;
Monge taught renal impairment is a frequent complication of multiple myeloma (MM) associated with poor prognosis and decreased overall survival and that the CD38 antibody inhibitor daratumumab is a treatment for multiple myeloma.
Monge taught treatment that included a therapeutic anti-CD38 antibody inhibitor to multiple myeloma patients with impaired kidney function with an eGFR from 30-59 mL/min/1.73 m2 at baseline to ≥60 mL/min/1.73 m2 (eGFR ≥60) – and <50 overlaps with 30-59 mL/min/1.73 m2 and was also a treatment for multiple myeloma; Further, while Monge taught a different CD38 antibody inhibitor, daratumumab instead of isatuximab, both antibodies target CD38 and would be expected to perform similarly because they target the same protein.
Further, Groen taught 55% of patients treated with carfilzomib showed improved renal function in the context of the administration of carfilzomib as a monotherapy, Groen specifically recognizes the importance of carfilzomib for renal protection.
Thus, the method of multiple myeloma treatment of Martin for isatuximab, carfilzomib, and dexamethasone treatment at the concentrations taught by Martin would be obvious with a reasonable expectation of success for treating renal response in multiple myeloma patients because the method comprises known renal protection agents, wherein the combination therapy performs the function of both treating the multiple myeloma and naturally achieving complete renal response, wherein the estimated glomerular filtration rate (eGFR) from < 50 ml/min/1.73 m2 at baseline to ≥ 60 ml/min/1.73 m2. No changes are made to the method of Martin and the complete renal response would be naturally expected based on the known renal protective effects of carfilzomib and anti-CD38 inhibitors.
Regarding daratumumab is a different antibody from isatuximab, both antibodies are therapeutic CD38 antibodies used to treat multiple myeloma and would be expected to perform similarly because the therapeutic antibodies target the same protein. Monge taught treatment that included a therapeutic anti-CD38 antibody inhibitor to multiple myeloma patients with impaired kidney function (between 30-59 ml/min/1.73 m2) increased complete renal response and was also a treatment for multiple myeloma. Monge taught the high renal response rate (29%) seen, as compared to the one in the subgroup analysis of ENDEAVOR (15%), highlights the utility of daratumumab in reversing renal end-organ damage in patients with relapsed/refractory MM without an increase in adverse events compared to patients with preserved renal function (abstract). Thus, the known method of combination treatment of multiple myeloma of Martin would be expected to also provide complete renal response when combined with carfilzomib, and dexamethasone, wherein the estimated glomerular filtration rate (eGFR) from < 50 ml/min/1.73 m2 at baseline to ≥ 60 ml/min/1.73 m2.
Regarding Chng, Chng is relied upon to evidence the ENDEAVOR trial compares carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma.
Regarding the cited references in combination do not disclose the method to achieve complete renal response, the obvious rational is above. Thus, using a known combination of therapeutics at a known concentration in a known method of treatment of multiple myeloma : 1) known to be effective in patients with multiple myeloma wherein carfilzomib-based treatments are a standard of care and isatuximab has shown clinical activity with current standard of care in patients with multiple myeloma; 2) wherein the components of a therapeutic CD38 antibody and carfilzomib are known to effectively improve renal response and achieve complete renal response; and 3) wherein renal impairment of multiple myeloma patients is a known complication, would be obvious with a reasonable expectation of success. The known method of combination treatment of multiple myeloma of Martin would be reasonably expected to also provide complete renal response when combined with carfilzomib, and dexamethasone, wherein the estimated glomerular filtration rate (eGFR) from < 50 ml/min/1.73 m2 at baseline to ≥ 60 ml/min/1.73 m2.
Claims 25, 36-40, 42-44, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Martin TG et al. (Journal of Clinical Oncology 2018, 36(15) suppl TPS8060, reference of record), Dimopoulos MA et al. (Clinical Lymphoma Myeloma and Leukemia 19(10) Supplement, 2019, Page e254., reference of record) and Groen K et al. (Cancer Management and Research 2019:11 2663–2675, reference of record) as applied to claims 25, 36-37, 40, 43-44, and 46 and further in view of, Chari A et al. (Journal of Clinical Oncology 2018 36, no. 15_suppl 8014-8014, reference of record).
Martin, Dimopoulos, and Groen are described above.
Martin, Dimopoulos, and Groen are silent to the individual receiving treatment having: 1) more than three prior therapies for multiple myeloma; 2) prior therapy with a proteasome inhibitor and/or an immunomodulatory agent; and 3) an age of 65 to 75 or 75 or older at the start of treatment, but these deficiencies are addressed by Chari.
Chari taught a Phase Ib study of treatment of multiple myeloma with isatuximab (includes 10 mg/kg dosage) and carfilzomib (includes greater than 20 mg/ m2 dosage) is safe with encouraging anti-cancer activity against multiple myeloma with a 66% overall response rate at all dose levels (page 2-3, methods and conclusions). The combination appeared safe and effective in patients that were up to 79 years old with 2-8 prior lines of therapy that included previous treatment with immunomodulatory agents (IMed) and proteasomal inhibitors (PI) (page 2-3, results and conclusions). Chari taught that the dosing from the Phase Ib trial informed the IKEMA:NCT03275285 trial (identical clinical trial of Martin isatuximab, carfilzomib, and dexamethasone combination therapy above) (page 3, conclusion).
Regarding claims 38-39 and 42, it would have been obvious for a person having ordinary skill in the art to modify the method of Martin, Dimopoulos and Groen of treating both multiple myeloma and to achieve a complete renal response in an individual in need comprised of administering the isatuximab, carfilzomib, and dexamethasone combination treatment above, wherein the complete renal response in the individual is an improvement in estimated glomerular filtration rate (eGFR) from< 50 ml/min/1.73 m2 at baseline to ≥ 60 ml/min/1.73 m2 – to include the teachings of Chari for populations of patients to be treated from the Phase Ib trial of combination isatuximab and carfilzomib treatment for multiple myeloma for individuals that: 1) received more than three prior therapies for multiple myeloma (claim 38); 2) received prior therapy with a proteasome inhibitor and/or an immunomodulatory agent (claim 39); and 3) are 75 years of age or older (claim 42).
This is obvious because all three of the population identifiers above received isatuximab and carfilzomib combination treatment previously and the combination was safe and effective. Isatuximab and carfilzomib were also known to allow patients to achieve a complete renal response. It would be further obvious that the inclusion of the dexamethasone was not an issue because Chari taught that results of the dosing from the Phase Ib trial informed the IKEMA:NCT03275285 trial of Martin above, which is the same combination treatment dosing and drugs.
There is a reasonable expectation of success because isatuximab (includes 10 mg/kg dosage) and carfilzomib (includes greater than 20 mg/ m2 dosage) combination treatment was safe with encouraging anti-cancer activity against multiple myeloma with a 66% overall response rate at all dose levels. Further, Isatuximab and carfilzomib were also known to allow patients to achieve a complete renal response. Thus, there is a reasonable expectation that the population that would be effectively treated for multiple myeloma and achieve a complete renal response.
Response to Applicant Arguments
Chari does not cure the deficiencies of Martin, Dimopoulos, and Groen. Chari does not teach or suggest the inclusion of patients with renal impairment, the improvement of renal impairment, or the achievement of a complete renal response in patients with renal impairment. Accordingly, the cited references, alone or in combination, do not teach a method to achieve a complete renal response in an individual in need thereof, as recited in claims 38-39 and 42.
In response, Applicant's arguments filed 9/12/2025 have been fully considered but they are not persuasive.
Martin, Dimopoulos and Groen are described above. The obvious rational above describes the combination of the references. Chari taught a method of treatment of multiple myeloma with isatuximab and carfilzomib was safe and effective in patients that had: 1) 2-8 prior lines of therapy (as recited in claim 38); 2) received prior therapy with a proteasome inhibitor and/or an immunomodulatory agent, (as recited in claim 39); and 3) up to 79 years old (as recited in claim 42). Further, Chari taught that the dosing from the Phase Ib trial informed the IKEMA:NCT03275285 trial (identical clinical trial of Martin isatuximab, carfilzomib, and dexamethasone combination therapy above), so the inclusion of dexamethasone was obvious because it taught the clinical trial what to use. Martin, Dimopoulos, and Groen taught the method would be effective and achieve complete renal response as indicated above. Chari demonstrates that it is obvious with a reasonable expectation of success that populations of patients treated with 2-8 prior lines of therapy, received prior therapy with a proteasome inhibitor and/or an immunomodulatory agent and up to 79 years old would be obvious to treat for multiple myeloma with a reasonable expectation of success, wherein complete renal response wherein the complete renal response in the individual is an improvement in estimated glomerular filtration rate (eGFR) from< 50 ml/min/1.73 m2 at baseline to ≥ 60 ml/min/1.73 m2 would also be obvious with a reasonable expectation of success because isatuximab and carfilzomib were also known to allow patients to achieve a complete renal response. Thus, treating this patient population with the combination of isatuximab, carfilzomib, and dexamethasone for multiple myeloma and to achieve a complete renal response would be obvious with a reasonable expectation of success.
Claims 25, 36-40, 42-44, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Martin TG et al. (Journal of Clinical Oncology 2018, 36(15) suppl TPS8060, reference of record), Monge J et al. (Blood (2019) 134 (Supplement_1): 5563, November 13 2019, reference of record) and Groen K et al. (Cancer Management and Research 2019:11 2663–2675, reference of record) as applied to claims 25, 36-37, 40, 43-44, and 46 and further in view of, Chari A et al. (Journal of Clinical Oncology 2018 36, no. 15_suppl 8014-8014, reference of record).
Martin, Monge, Groen are described above.
Martin, Monge, and Groen are silent to the individual receiving treatment having: 1) more than three prior therapies for multiple myeloma; 2) prior therapy with a proteasome inhibitor and/or an immunomodulatory agent; and 3) an age of 65 to 75 or 75 or older at the start of treatment, but these deficiencies are addressed by Chari.
Chari taught a Phase Ib study of treatment of multiple myeloma with isatuximab (includes 10 mg/kg dosage) and carfilzomib (includes greater than 20 mg/ m2 dosage) is safe with encouraging anti-cancer activity against multiple myeloma with a 66% overall response rate at all dose levels (page 2-3, methods and conclusions). The combination appeared safe and effective in patients that were up to 79 years old with 2-8 prior lines of therapy that included previous treatment with immunomodulatory agents (IMed) and proteasomal inhibitors (PI) (page 2-3, results and conclusions). Chari taught that the dosing from the Phase Ib trial informed the IKEMA:NCT03275285 trial (identical clinical trial of Martin isatuximab, carfilzomib, and dexamethasone combination therapy above) (page 3, conclusion).
Regarding claims 38-39 and 42, it would have been obvious for a person having ordinary skill in the art to modify the method of Martin, Monge and Groen of treating both multiple myeloma and to achieve a complete renal response in an individual in need comprised of administering the isatuximab, carfilzomib, and dexamethasone combination treatment above – to include the teachings of Chari for populations of patients to be treated from the Phase Ib trial of combination isatuximab and carfilzomib treatment for multiple myeloma for individuals that: 1) received more than three prior therapies for multiple myeloma (claim 38); 2) received prior therapy with a proteasome inhibitor and/or an immunomodulatory agent (claim 39); and 3) are 75 years of age or older (claim 42).
This is obvious because all three of the population identifiers above received isatuximab and carfilzomib combination treatment previously and the combination was safe and effective. A therapeutic CD38 antibody and carfilzomib were also known to allow patients to achieve a complete renal response. It would be further obvious that the inclusion of the dexamethasone was not an issue because Chari taught that results of the dosing from the Phase Ib trial informed the IKEMA:NCT03275285 trial of Martin above, which is the same combination treatment dosing and drugs.
There is a reasonable expectation of success because isatuximab (includes 10 mg/kg dosage) and carfilzomib (includes greater than 20 mg/ m2 dosage) combination treatment was safe with encouraging anti-cancer activity against multiple myeloma with a 66% overall response rate at all dose levels. Further, a therapeutic CD38 antibody and carfilzomib were also known to allow patients to achieve a complete renal response. Thus, there is a reasonable expectation that the population that would be effectively treated for multiple myeloma and achieve a complete renal response.
Response to Applicant Arguments
Applicant argues none of the cited references teach or suggest a method to achieve a complete renal response in an individual in need thereof, wherein the individual has multiple myeloma and renal impairment, comprising administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone, wherein the individual received at least one prior therapy for multiple myeloma, wherein the individual: 1) received more than three prior therapies for multiple myeloma, as recited in claim 38; 2) received prior therapy with a proteasome inhibitor and/or an immunomodulatory agent, as recited in claim 39; or 3) (a) 65 to less than 75 years of age at the start of treatment or (b) 75 years of age or older at the start of treatment, as recited in claim 42.
Accordingly, the cited references, alone or in combination, do not teach a method to achieve a complete renal response in an individual in need thereof, as recited in claims 38-39 and 42.
In response, Applicant's arguments filed 9/12/2025 have been fully considered but they are not persuasive.
Martin, Monge, and Groen are described above. The obvious rational above describes the combination of the references. Chari taught a method of treatment of multiple myeloma with isatuximab and carfilzomib was safe and effective in patients that had: 1) 2-8 prior lines of therapy (as recited in claim 38); 2) received prior therapy with a proteasome inhibitor and/or an immunomodulatory agent, (as recited in claim 39); and 3) up to 79 years old (as recited in claim 42). Further, Chari taught that the dosing from the Phase Ib trial informed the IKEMA:NCT03275285 trial (identical clinical trial of Martin isatuximab, carfilzomib, and dexamethasone combination therapy above), so the inclusion of dexamethasone was obvious because it taught the clinical trial what to use. Martin, Monge, and Groen taught the method would be effective and achieve complete renal response as indicated above. Chari demonstrates that it is obvious with a reasonable expectation of success that populations of patients treated with 2-8 prior lines of therapy, received prior therapy with a proteasome inhibitor and/or an immunomodulatory agent and up to 79 years old would be obvious to treat for multiple myeloma with a reasonable expectation of success, wherein complete renal response wherein the complete renal response in the individual is an improvement in estimated glomerular filtration rate (eGFR) from< 50 ml/min/1.73 m2 at baseline to ≥ 60 ml/min/1.73 m2 would also be obvious with a reasonable expectation of success because isatuximab and carfilzomib were also known to allow patients to achieve a complete renal response. Thus, treating this patient population with the combination of isatuximab, carfilzomib, and dexamethasone for multiple myeloma and to achieve a complete renal response would be obvious with a reasonable expectation of success.
Claims 25, 36-37, 40-41, 43-44, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Martin TG et al. (Journal of Clinical Oncology 2018, 36(15) suppl TPS8060, reference of record), Dimopoulos MA et al. (Clinical Lymphoma Myeloma and Leukemia 19(10) Supplement, 2019, Page e254., reference of record), and Groen K et al. (Cancer Management and Research 2019:11 2663–2675, reference of record) as applied to claims 25, 36-37, 40, 43-44, and 46 and further in view of, US 20190127479 (Ahmadi T et al., reference of record) and Chim CS et al. (Leukemia. 2018 Feb; 32(2): 252–262, reference of record).
Martin, Dimopoulos, and Groen are described above.
Martin, Dimopoulos, and Groen are silent to the inclusion of patients with multiple myeloma containing the del(17p) cytogenetic abnormality, but this is addressed in Ahmadi and Chim.
Ahmadi taught a method of achieving negative minimal residual disease status in a subject having multiple myeloma comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody (as isatuximab (specification, page 7, paragraph 81) at a dose of 10 mg/kg (specification, page 10, paragraph 115)), a corticosteroid (as dexamethasone (specification, page 18, paragraph 299) at a dose of 20 mg (specification, page 10, paragraph 115)), and a non-corticosteroid chemotherapeutic agent (as carfilzomib (specification, page 11, paragraph 124), but silent as to the dose) for a time sufficient to achieve negative minimal residual disease status (page 1, paragraph 9). Ahmadi taught the negative minimal residual disease status can be determined at a sensitivity of 0.001% (10−5)(specification, page 11, paragraph 139). Ahmadi taught the anti-CD38 antibody can induce killing of CD38-expressing cells by antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and apoptosis (specification, page 8, paragraph 104). Ahmadi taught the patients being treated can have the del(17p) cytogenetic abnormality (specification, page 12, paragraph 149).
Chim taught combination carfilzomib (proteasomal inhibitor) and dexamethasone treatment is a superior treatment of multiple myeloma in humans compared to bortezomib (proteasomal inhibitor) and dexamethasone (page 253 last paragraph and 255, left column, first paragraph). Chim taught patients with high-risk multiple myeloma harboring cytogenetic aberrations of t(4;14), t(14;16) or del(17p) had improved treatment outcomes regardless of cytogenetic status when administered a CD38 antibody (daratumumab), a proteasomal inhibitor (bortezomib) and dexamethasone (page 256 last paragraph and 257, left column, first paragraph). Chim taught isatuximab has been used as a treatment in multiple myeloma patients with high risk cytogenetics (257, left column, second paragraph).
Regarding claim 41, it would have been obvious for a person having ordinary skill in the art to modify the method of Martin, Dimopoulos and Groen of treating both multiple myeloma and to achieve a complete renal response in an individual in need comprised of administering the isatuximab, carfilzomib, and dexamethasone combination treatment above – to include patients with multiple myeloma containing the del(17p) cytogenetic abnormality – of Ahmadi, because Ahmadi taught patients with this abnormality can be treated with combination isatuximab, carfilzomib, and dexamethasone.
There is a reasonable expectation of success because Chim taught administration of a CD38 antibody (daratumumab), a proteasomal inhibitor (bortezomib) and dexamethasone had improved treatment outcomes of multiple myeloma patients with t(4;14), t(14;16) or del(17p) cytogenetic abnormalities. Because Chim also taught: 1) that carfilzomib and dexamethasone treatment is a superior treatment of multiple myeloma in humans compared to bortezomib and dexamethasone; and 2) that isatuximab has been used as a treatment in multiple myeloma patients with high risk cytogenetics, it is reasonable to assume a CD38 antibody of isatuximab in combination with the proteasomal inhibitor carfilzomib and dexamethasone would be an appropriate or superior treatment. Further, isatuximab and carfilzomib were also known to allow patients to achieve a complete renal response. Thus, there is a reasonable expectation that the population that would be effectively treated for multiple myeloma and achieve a complete renal response.
Response to Applicant Arguments
Applicant argues none of the cited references teach or suggest a method to achieve a complete renal response in an individual in need thereof, wherein the individual has multiple myeloma and renal impairment, comprising administering to the individual an antiCD38 antibody, carfilzomib, and dexamethasone, and wherein the individual has one or more cytogenetic abnormalities selected from the group consisting of: del(l 7p ), t( 4; 14), t(l 4; 16) and gain(lq21), as recited in claim 41.
Martin, Dimopoulos, and Groen are discussed above. Ahmadi and Chim do not remedy the deficiencies of Martin, Dimopoulos, and Groen. Neither Ahmadi nor Chim teach or suggest the treatment of patients with renal impairment, the improvement of renal impairment, or the achievement of a complete renal response in patients with renal impairment.
Accordingly, the cited references, alone or in combination, do not teach a method to achieve a complete renal response in an individual in need thereof, wherein the individual has multiple myeloma and renal impairment, comprising administering to the individual an anti-CD38 antibody, carfilzomib, and dexamethasone, and wherein the individual has one or more cytogenetic abnormalities selected from the group consisting of: del(l 7p ), t( 4; 14), t(l 4; 16) and gain(lq21), as recited in claim 41.
In response, Applicant's arguments filed 9/12/2025 have been fully considered but they are not persuasive.
Martin, Dimopoulos and Groen are described above. The obvious rational above describes the combination of the references. Ahmadi taught patients with the del(17p) cytogenetic abnormality can be treated with combination isatuximab, carfilzomib, and dexamethasone. There is a reasonable expectation of success because Chim taught administration of a CD38 antibody (daratumumab), a proteasomal inhibitor (bortezomib) and dexamethasone had improved treatment outcomes of multiple myeloma patients with t(4;14), t(14;16) or del(17p) cytogenetic abnormalities. Because Chim also taught: 1) that carfilzomib and dexamethasone treatment is a superior treatment of multiple myeloma in humans compared to bortezomib and dexamethasone; and 2) that isatuximab has been used as a treatment in multiple myeloma patients with high risk cytogenetics, it is reasonable to assume a CD38 antibody of isatuximab in combination with the proteasomal inhibitor carfilzomib and dexamethasone would be an appropriate or superior treatment. Further, isatuximab and carfilzomib were also known to allow patients to achieve a complete renal response. Thus, treating this patient population with the combination of isatuximab, carfilzomib, and dexamethasone for multiple myeloma and to achieve a complete renal response would be obvious with a reasonable expectation of success.
Claims 25, 36-37, 40-41, 43-44, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Martin TG et al. (Journal of Clinical Oncology 2018, 36(15) suppl TPS8060, reference of record), Monge J et al. (Blood (2019) 134 (Supplement_1): 5563, November 13 2019, reference of record), and Groen K et al. (Cancer Management and Research 2019:11 2663–2675, reference of record) as applied to claims 25, 36-37, 40, 43-44, and 46 and further in view of, US 20190127479 (Ahmadi T et al., reference of record) and Chim CS et al. (Leukemia. 2018 Feb; 32(2): 252–262, reference of record).
Martin, Monge, and Groen are described above.
Martin, Monge, and Groen are silent to the inclusion of patients with multiple myeloma containing the del(17p) cytogenetic abnormality, but this is addressed in Ahmadi and Chim.
Ahmadi taught a method of achieving negative minimal residual disease status in a subject having multiple myeloma comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody (as isatuximab (specification, page 7, paragraph 81) at a dose of 10 mg/kg (specification, page 10, paragraph 115)), a corticosteroid (as dexamethasone (specification, page 18, paragraph 299) at a dose of 20 mg (specification, page 10, paragraph 115)), and a non-corticosteroid chemotherapeutic agent (as carfilzomib (specification, page 11, paragraph 124), but silent as to the dose) for a time sufficient to achieve negative minimal residual disease status (page 1, paragraph 9). Ahmadi taught the negative minimal residual disease status can be determined at a sensitivity of 0.001% (10−5)(specification, page 11, paragraph 139). Ahmadi taught the anti-CD38 antibody can induce killing of CD38-expressing cells by antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and apoptosis (specification, page 8, paragraph 104). Ahmadi taught the patients being treated can have the del(17p) cytogenetic abnormality (specification, page 12, paragraph 149).
Chim taught combination carfilzomib (proteasomal inhibitor) and dexamethasone treatment is a superior treatment of multiple myeloma in humans compared to bortezomib (proteasomal inhibitor) and dexamethasone (page 253 last paragraph and 255, left column, first paragraph). Chim taught patients with high-risk multiple myeloma harboring cytogenetic aberrations of t(4;14), t(14;16) or del(17p) had improved treatment outcomes regardless of cytogenetic status when administered a CD38 antibody (daratumumab), a proteasomal inhibitor (bortezomib) and dexamethasone (page 256 last paragraph and 257, left column, first paragraph). Chim taught isatuximab has been used as a treatment in multiple myeloma patients with high risk cytogenetics (257, left column, second paragraph).
Regarding claim 41, it would have been obvious for a person having ordinary skill in the art to modify the method of Martin, Monge and Groen of treating both multiple myeloma and to achieve a complete renal response in an individual in need comprised of administering the isatuximab, carfilzomib, and dexamethasone combination treatment above – to include patients with multiple myeloma containing the del(17p) cytogenetic abnormality – of Ahmadi, because Ahmadi taught patients with this abnormality can be treated with combination isatuximab, carfilzomib, and dexamethasone.
There is a reasonable expectation of success because Chim taught administration of a CD38 antibody (daratumumab), a proteasomal inhibitor (bortezomib) and dexamethasone had improved treatment outcomes of multiple myeloma patients with t(4;14), t(14;16) or del(17p) cytogenetic abnormalities. Because Chim also taught: 1) that carfilzomib and dexamethasone treatment is a superior treatment of multiple myeloma in humans compared to bortezomib and dexamethasone; and 2) that isatuximab has been used as a treatment in multiple myeloma patients with high risk cytogenetics, it is reasonable to assume a CD38 antibody of isatuximab in combination with the proteasomal inhibitor carfilzomib and dexamethasone would be an appropriate or superior treatment. Further, a therapeutic CD38 antibody and carfilzomib were also known to allow patients to achieve a complete renal response. Thus, there is a reasonable expectation that the population that would be effectively treated for multiple myeloma and achieve a complete renal response.
Response to Applicant Arguments
Applicant argues none of the cited references teach or suggest a method to achieve a complete renal response in an individual in need thereof, wherein the individual has multiple myeloma and renal impairment, comprising administering to the individual an antiCD38 antibody, carfilzomib, and dexamethasone, and wherein the individual has one or more cytogenetic abnormalities selected from the group consisting of: del(l 7p ), t( 4; 14), t(l 4; 16) and gain(lq21), as recited in claim 41.
A skilled person in the art, seeking to achieve such an effect, would have no
motivation to combine Martin, Monge, Groen, Ahmadi, and Chim.
In response, Applicant's arguments filed 9/12/2025 have been fully considered but they are not persuasive.
Martin, Monge, and Groen are described above. The obvious rational above describes the combination of the references. Ahmadi taught patients with the del(17p) cytogenetic abnormality can be treated with combination isatuximab, carfilzomib, and dexamethasone. There is a reasonable expectation of success because Chim taught administration of a CD38 antibody (daratumumab), a proteasomal inhibitor (bortezomib) and dexamethasone had improved treatment outcomes of multiple myeloma patients with t(4;14), t(14;16) or del(17p) cytogenetic abnormalities. Because Chim also taught: 1) that carfilzomib and dexamethasone treatment is a superior treatment of multiple myeloma in humans compared to bortezomib and dexamethasone; and 2) that isatuximab has been used as a treatment in multiple myeloma patients with high risk cytogenetics, it is reasonable to assume a CD38 antibody of isatuximab in combination with the proteasomal inhibitor carfilzomib and dexamethasone would be an appropriate or superior treatment. Further, isatuximab and carfilzomib were also known to allow patients to achieve a complete renal response. Thus, treating this patient population with the combination of isatuximab, carfilzomib, and dexamethasone for multiple myeloma and to achieve a complete renal response would be obvious with a reasonable expectation of success.
Conclusion
No claims are allowable.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643