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 .
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 42 and 43 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077).
Regarding claim 42 and 43, Hu et. al. teach that B-cell lymphoma-2 (Bcl-2), an anti-apoptosis protein, is over expressed and leads to oncogenes is or drug resistance in various tumor types, including lymphoma and leukemia (Summary Section paragraph 1). Additionally, Hu et. al. teach that Bcl-2 is a well-validated target for B-cell malignancies as demonstrated by a Bcl-2 inhibitor venetoclax which was recently approved for the treatment of chronic lymphocytic leukemia (CLL) and is currently in phase III clinical development for other hematologic malignancies(Summary Section paragraph 1). Moreover, Hu et. al. teach that long term treatment, recurrent mutation G101V in Bcl-2 has been reported to mediate resistance to venetoclax in patients with CLL (Summary Section paragraph 1). Furthermore, Hu et.al. teach that BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, is a highly potent and selective Bcl-2 inhibitor against both wildtype and G101V-mutated Bcl-2 in Surface Plasmon Resonance (SPR) binding assay with KD of 0.035 and 0.28 nM, respectively (Summary Section paragraph 2).
Additionally, Hu et. al. teach that BGB-11417 demonstrated significantly greater efficacy than venetoclax in human acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) and DLBCL (diffuse large B-cell lymphoma) xenograft mouse models (claim 42) (Summary Section paragraph 2). Specifically, Hu et. al. teach that BGB-11417 when administered orally to RS4;11 ALL xenograft mice, DLBCL xenograft mice, and MAVER-1 MCL xenograft mice at 0, 5, 15 or 50 mg/kg QD (claim 43) performed significantly better mean tumor volumes as compared to venetoclax (Figure 3 - 5).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 44 – 46, and 58 – 60 are rejected under 35 U.S.C. 103 as being unpatentable over Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077) as applied to claims 42 and 43, above, and further in view of Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863).
The teachings of Hu et. al. as they relate to claim 42, from which claims 44 – 46, and 58 – 60, depend, are given previously in this office action and are fully incorporated here.
While Hu et. al. taught the oral administration of BGB-11417 to RS4;11 ALL xenograft mice, DLBCL xenograft mice, and MAVER-1 MCL xenograft mice at 0, 5, 15 or 50 mg/kg QD; Hu et. al. fail to teach the administration of the Bcl-2 inhibitor at a dose of 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg once per day (QD) (claim 44); at a dose of 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg twice per day (BID) (claim 45); and orally at 320 mg once per day (QD) (claim 46). Moreover, Hu et. al. fail to teach a method wherein the Bcl-2 inhibitor is administered according to a daily ramp-up schedule which is about 1 mg QD on Day 1, about 2 mg QD on Day 2, about 3 mg QD on Day 3, about 4 mg QD on Day 4, about 5 mg QD on Day 5, about 5 mg QD on Day 6, about 5 mg QD on Day 7, about 6 mg QD on Day 8, about 8 mg QD on Day 9, about 10 mg QD on Day 10, about 13 mg QD on Day 11, about 15 mg QD on Day 12, about 15 mg QD on Day 13, about 15 mg QD on Day 14, about 20 mg QD on Day 15, about 25 mg QD on Day 16, about 30 mg QD on Day 17, about 40 mg QD on Day 18, about 50 mg QD on Day 19, about 50 mg QD on Day 20, about 50 mg QD on Day 21, about 60 mg QD on Day 22, about 80 mg QD on Day 23, about 100 mg QD on Day 24, about 120 mg QD on Day 25, about 160 mg QD on Day 26, about 160 mg QD on Day 27, about 160 mg QD on Day 28, and about 320 mg QD on Day 29 (claim 58) or wherein the Bcl-2 inhibitor is administered according to a weekly ramp-up schedule which lasts for five, six, seven, eight, or nine weeks (claim 59) wherein the weekly ramp-up schedule is about 1 mg QD in Week 1, about 2 mg QD in Week 2, about 5 mg QD in Week 3, about 10 mg QD in Week 4, about 20 mg QD in Week 5, about 40 mg QD in Week 6, about 80 mg QD in Week 7, about 160 mg QD in Week 8, and about 320 mg QD in Week 9 (claim 60).
Nevertheless, Koenig et. al. teach that despite sustained disease control observed with B-cell receptor pathway inhibitors (BCRi’s), particularly Bruton tyrosine kinase inhibitors (BTKis), patients with chronic lymphocytic leukemia (CLL) who relapse after treatment with these agents often have rapidly progressive symptomatic disease (page 4860 paragraph 2). Moreover, Koenig et. al. teach that BCL-2 inhibitor venetoclax demonstrated an overall response rate of 65% and median progression-free survival (PFS) of 24 months in patients relapsing after ibrutinib in a phase 2 trial and is currently the most effective standard therapy in this patient population (page 4860 paragraph 2). Furthermore, Koenig et. al. teach that this study was performed in a high-risk patient population that was heavily pretreated, with a median of 4 prior therapies and that these patients also had a significant tumor lysis syndrome (TLS) risk (page 4860 paragraph 2). Additionally, Koenig et. al. teach that Venetoclax dose was increased in stepwise fashion from 20 to 400 mg in a rapid manner, based on patient tolerability and TLS, with close in-hospital monitoring (page 4861 column 1 paragraph 2). Moreover, Koenig et. al. teach that there were no standard criteria employed for when to increase the dose, but attempts were made by practitioners to escalate every 1 to 2 days if TLS did not occur (page 4861 column 1 paragraph 2).
Also Koenig et. al. teach that the most substantial risk with venetoclax is TLS with treatment initiation thus to mitigate this, a 5-week dose ramp-up (claim 59) to the target dose of 400 mg with close monitoring and prophylaxis demonstrated reduced incidence of TLS, from 18% to 1.7% (page 4860 paragraph 2). Specifically, Koenig et. al. teach that venetoclax was administered at 20 mg, 50 mg, 100 mg 200 mg, and 400 mg (page 4861 Table 2).
While the prior art of Koenig et. al. discusses the administration of the Bcl-2 inhibitor venetoclax as taught by the prior art of Hu et. al. both the instant compound 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are both Bcl-2 inhibitor. Thus it would have been obvious to one or ordinary skill in the art to substitute the instant Bcl-2 for venetoclax. Moreover, as taught by Hu et. al. the instant compound 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide demonstrated significantly greater efficacy in human acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) and DLBCL (diffuse large B-cell lymphoma) xenograft mouse models when administered orally at 0, 5, 15 or 50 mg/kg QD. Furthermore, given that the prior art of Koenig et. al. teach that venetoclax was administered at 20 mg, 50 mg, 100 mg 200 mg, and 400 mg (page 4861 Table 2). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)(MPEP 2144.05(I)).
Moreover, given that the prior art of Koenig et. al. teach that venetoclax was administered at 20 mg, 50 mg, 100 mg 200 mg, and 400 mg (page 4861 Table 2), it would have been obvious to one of ordinary skill in the art to use the dosage ranges and frequencies of the prior art of Hu et. al. and Koenig et. al. as starting points to optimize for the recited dosage amounts and frequencies as recited in claims 44 – 46. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)(MPEP 2144.05 (II)A).
Additionally, while the prior art of Koenig et. al. taught that the Venetoclax dosage was increased in stepwise fashion from 20 to 400 mg in a rapid manner, with attempts made by practitioners to escalate every 1 to 2 days the prior art Koenig et. al. is silent on dosage regimen as recited in claims 58 or 60. Nevertheless, given that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)(MPEP 2144.05 (II)A). Thus to avoid the development of TLS one of ordinary skill in the art would optimize the dosage amount and dosage frequency.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to not only substitute 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, that is BGB-11417, as taught by Hu et. al. in view of Koenig et. al., that is for venetoclax and to administer 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide at a dose of 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg once per day (QD); at a dose of 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg twice per day (BID); and orally at 320 mg once per day (QD). One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Moreover, one of ordinary skill in the art would have had a reasonable expectation of success because BGB-11417 demonstrated significantly greater efficacy than venetoclax in human acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) and DLBCL (diffuse large B-cell lymphoma) xenograft mouse models.
Claims 47 – 48, 51 – 54, and 56 – 57 are rejected under 35 U.S.C. 103 as being unpatentable over Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077) and Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863) as applied to claims 44 – 46, and 58 – 60, above, and further in view of Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14).
The teachings of Hu et. al. and Koenig et. al. as they relate to claims 44 – 46, and 58 – 60, from which claims 47 – 48, 51 – 54, and 56 – 57, depend, are given previously in this office action and are fully incorporated here.
Regarding claim 47 – 48, 51 – 54, and 56 – 57, Hu et. al. teach that Bcl-2 is a well-validated target for B-cell malignancies as demonstrated by a Bcl-2 inhibitor venetoclax which was recently approved for the treatment of chronic lymphocytic leukemia (CLL) (claims 47 – 48) and is currently in phase III clinical development for other hematologic malignancies (Summary Section paragraph 1). Moreover, Hu et. al. teach that long term treatment, recurrent mutation G101V in Bcl-2 has been reported to mediate resistance to venetoclax in patients with CLL (claim 51) (Summary Section paragraph 1). Furthermore, Hu et.al. teach that BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, is a highly potent and selective Bcl-2 inhibitor against both wildtype and G101V-mutated Bcl-2 (claim 57) in Surface Plasmon Resonance (SPR) binding assay with KD of 0.035 and 0.28 nM, respectively (Summary Section paragraph 2). Additionally, Hu et. al. teach that BGB-11417 demonstrated significantly greater efficacy than venetoclax in human acute lymphoblastic leukemia (ALL) (claim 57), mantle cell lymphoma (MCL) (claim 54) and DLBCL (diffuse large B-cell lymphoma) xenograft mouse models (Summary Section paragraph 2). Specifically, Hu et. al. teach that BGB-11417 when administered orally to RS4;11 ALL xenograft mice, DLBCL xenograft mice, and MAVER-1 MCL xenograft mice at 0, 5, 15 or 50 mg/kg QD performed significantly better mean tumor volumes as compared to venetoclax (Figure 3 - 5).
Regarding claims 51 and 57, given that Hu e. al. suggest the need for a therapeutic that is effective against a recurrent mutation G101V in Bcl-2 that has shown resistance to venetoclax and given the development of resistance to BGB-11417 was effective against both wildtype and G101V-mutated Bcl-2 it would have been obvious to one of ordinary skill in the art to attempt to administer BGB-11417not only to a B-cell malignancy that has Bcl-2 Gly101Val mutation expression (claim 57) but also to patients previously treated with venetoclax (claim 51) as a way to increase efficacy in treating patients with CLL.
Moreover, Koenig et. al. teach that despite sustained disease control observed with B-cell receptor pathway inhibitors (BCRi’s), particularly Bruton tyrosine kinase inhibitors (BTKis), patients with chronic lymphocytic leukemia (CLL) who relapse after treatment with these agents often have rapidly progressive symptomatic disease (page 4860 paragraph 2). Moreover, Koenig et. al. teach that this study was performed in a high-risk patient population that was heavily pretreated, with a median of 4 prior therapies and that these patients also had a significant tumor lysis syndrome (TLS) risk (claim 56) (page 4860 paragraph 2). Additionally, Koenig et. al. teach that Venetoclax dose was increased in stepwise fashion from 20 to 400 mg in a rapid manner, based on patient tolerability and TLS, with close in-hospital monitoring (page 4861 column 1 paragraph 2). Moreover, Koenig et. al. teach that there were no standard criteria employed for when to increase the dose, but attempts were made by practitioners to escalate every 1 to 2 days if TLS did not occur (page 4861 column 1 paragraph 2).
Also Koenig et. al. teach that the most substantial risk with venetoclax is TLS with treatment initiation thus to mitigate this, a 5-week dose ramp-up to the target dose of 400 mg with close monitoring and prophylaxis demonstrated reduced incidence of TLS, from 18% to 1.7% (page 4860 paragraph 2). Specifically, Koenig et. al. teach that venetoclax was administered at 20 mg, 50 mg, 100 mg 200 mg, and 400 mg (page 4861 Table 2). While the prior art of Koenig et. al. discusses the administration of the Bcl-2 inhibitor venetoclax as taught by the prior art of Hu et. al. both the instant compound 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are both Bcl-2 inhibitor. Thus it would have been obvious to one or ordinary skill in the art to substitute the instant Bcl-2 for venetoclax. Moreover, as taught by Hu et. al. the instant compound 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide demonstrated significantly greater efficacy in human acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) and DLBCL (diffuse large B-cell lymphoma) xenograft mouse models. Thus it would have been obvious before the effective filing date of the instant application to substitute BGB-11417 for venetoclax. Moreover, it would have been obvious to administer BGB-11417 for the treatment of a B-cell malignancy at a lower risk of TLS to reduce the risk of negative patient outcomes in already high risk CLL patients.
However, the prior art of Hu et. al. and Koenig et. al. fail to teach a method wherein chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL) included relapsed or refractory CLL/SLL (claim 52), treatment naïve (TN) CLL/SLL (claim 53).
Nevertheless, Lasica et. al. teach Venetoclax has changed the treatment paradigm of CLL and is of great interest in other hematological malignancies such as indolent Non-Hodgkin lymphoma (iNHL), MM and AML (page 2 paragraph 1). Furthermore, Lasica et. al. teach that in the first-in-human dose-escalation study of venetoclax monotherapy in relapsed and refractory (RR) CLL (claim 52) was enriched for patients with a high percentage (89%) of poor clinical and/or genetic prognostic features (page 2 paragraph 4). Moreover, Lasica et. al. teach that venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% (page 2 paragraph 4).
Additionally, Lasica et. al. teach that during the dose-finding phase of the first-in-human study, three patients experienced clinical tumor lysis syndrome (TLS) (claim 56), including one death (page 2 paragraph 4). Moreover, Lasica et. al. teach that the CLL14 study established the venetoclax-obinutuzumab combination as a fixed duration treatment option for patients with treatment-naïve (TN) CLL (claim 53) with co-morbidities had a median follow-up of 39.6 months with all patients being off therapy for at least 2 years, with the venetoclax-obinutuzumab cohort had a significantly longer PFS than the chlorambucil-obinutuzumab arm (HR 0.31, 95% CI 0.22–0.44, p < 0.0001) (page 3 paragraph 4).
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Kuoeng et. al. that is to substitute BGB-11417 for venetoclax in further view of Lasica et. al., that is to administer 2-((1H-pyrrolo[2,3-b] yrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) yrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide in a method of treating B-cell malignancy as recited in claim 47 – 48, and 52 – 53. One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% and the prior art taught that 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide was more effective.
Claims 49 – 50 are rejected under 35 U.S.C. 103 as being unpatentable over Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), and Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), as applied to claims 44 – 46, and 58 – 60, above, and further in view of Wierda et. al. ((2020), Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology, 18, 185 – 217).
The teachings of Hu et. al., Koenig et. al., and Lasica et. al. as they relate to claims 44 – 48, 51 – 54, and 56 – 60, from which claims 49 – 50, depend, are given previously in this office action and are fully incorporated here.
However, the prior art of Hu et. al., Koenig et. al., and Lasica et. al. fail to teach a method wherein chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL) includes CLL with low tumor burden (claim 49) and high tumor burden (claim 50).
Wierda et. al. teach that chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by a progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues (page 186 column 1 paragraph 1). Furthermore, Wierda et. al. teach that the Rai and Binet systems are the 2 staging systems currently used for the evaluation of patients with CLL, both in the routine practice and clinical trial settings (page 186 column 1 paragraph 2). Moreover, Wierda et. al. teach that both systems rely on physical evidence (i.e., presence of lymph node involvement, enlarged spleen and/or liver) and blood parameters (presence of anemia or thrombocytopenia) to assess the degree of tumor burden (page 186 column 2paragraph 2). Furthermore, Wierda et. al. teach that TLS was an important side effect of venetoclax therapy in early clinical trials and initiation at lower dose (20 mg for 1 week) and gradual step-wise ramp-up over 5 weeks to target dose (400 mg daily) along with prophylaxis for TLS is recommended to mitigate the risk and frequency of TLS in patients receiving venetoclax (page 210 column 2 paragraph 5). Additionally, Wierda et. al. teach that the initiation and accelerated escalation of venetoclax (20–400 mg over 3 weeks) with close inpatient monitoring for TLS can be performed to quickly regain disease control in a selected subgroup of patients with high tumor burden (claim 50 ), rapid disease progression, or disease elapse after treatment with BCRi therapy (page 210 column 2 paragraph 5). Moreover, Wierda et. al. teach recommendation for TLS prophylaxis based on tumor burden below (page 203).
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Thus Wierda et. al. suggest the administration of venetoclax for the treatment of CLL based on the tumor burden load as an indication of TLS risk.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Kuoeng et. al. that is to substitute BGB-11417 for venetoclax in view of Lasica et. al., that is to administer 2-((1H-pyrrolo[2,3-b] yrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) yrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide in a method of treating B-cell malignancy is CLL in further view of Wierda et. al., that is to treat CLL with low or high tumor burden. One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors and the TLS was an important side effect of venetoclax. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because initiation of venetoclax at lower dose (20 mg for 1 week) and in a gradual step-wise ramp-up over 5 weeks to target dose (400 mg daily) was recommended to mitigate the risk and frequency of TLS in patients.
Claims 55 is rejected under 35 U.S.C. 103 as being unpatentable over Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), and Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), as applied to claims 44 – 46, and 58 – 60, above, and further in view of Castillo et. al. ((2019), Multicenter prospective phase II study of venetoclax in patients with previously treated Waldenstrom macroglobulinemia), Clinical Lymphoma, Myeloma and Leukemia, 19, e39-40).
The teachings of Hu et. al., Koenig et. al., and Lasica et. al. as they relate to claims 44 – 48, 51 – 54, and 56 – 60, from which claim 55, depend, are given previously in this office action and are fully incorporated here.
However, the prior art of Hu et. al., Koenig et. al., and Lasica et. al. fail to teach a method wherein the B-cell malignancy is Waldenstrom macroglobulinemia (WM) (claim 55).
Nevertheless, Castillo et. al. teach that Venetoclax was given in the outpatient setting to patients with Waldenstrom macroglobulinemia (WM) and followed a ramp-up of 200 mg daily days 1-7, 400 mg daily days 8-14, then 800 mg daily thereafter, for maximum of 2 years, for the first 6 patients and for the following 24 patients, venetoclax was given at 400 mg daily days 1- 7, then 800 mg daily thereafter, for maximum of 2 years (page e39 column 2 paragraph 2). Furthermore, Castillo et. al. teach that a very good partial response (VGPR) was attained in 6 patients (19%), PR in 19 (61%), minor response in 2 (6%), stable disease in 3 (10%) and no response in 1 (3%), for overall response rate of 87% and major response rate of 81% (page e40 column 1 paragraph 1). Thus, Castillo et. al. teach that Venetoclax is a safe and effective treatment option for patients with symptomatic, previously treated WM (page e40 column 1 paragraph 1).
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Kuoeng et. al. that is to substitute BGB-11417 for venetoclax in view of Lasica et. al., that is to administer 2-((1H-pyrrolo[2,3-b] yrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) yrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide in a method of treating B-cell malignancy in further view of Castillo et. al., that is to Waldenstrom macroglobulinemia (WM). One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because treatment with venetoclax attained a VGFR in 6 patients (19%), PR in 19 (61%), minor response in 2 (6%), stable disease in 3 (10%) and no response in 1 (3%), for overall response rate of 87% and major response rate of 81%.
Claims 61 – 63 are rejected under 35 U.S.C. 103 as being unpatentable over Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077) as applied to claims 42 and 43, above, and further in view of International Publication Number WO 2019/108795 A1 to Hilger et. al. (herein after Hilger’795; cited on the IDS dated March 13th, 2024).
The teachings of Hu et. al. as they relate to claims 42, from which claims 61 – 63 depend, are given previously in this office action and are fully incorporated here.
However, Hu et. al. fail to teach a method further comprising administering to the patient a therapeutically effective amount of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B)(claim 61) wherein (S)-7-( l -acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[l,5-a]pyrimidine-3-carboxamide (Compound B) or a pharmaceutically acceptable salt thereof is administered at a dose of 160 mg twice daily or 320 mg once daily (claim 62) and wherein (S)-7-(1 -acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[l,5-a]pyrimidine-3-carboxamide (Compound B) or a pharmaceutically acceptable salt thereof is administered for 8 weeks to 12 weeks before the BCL-2 inhibitor is administered (claim 63).
Nevertheless, Hilger’795 teach compound 1 of structure
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of the chemical name (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (claims 61) as a BtK inhibitor in methods for the prevention, delay or progression or treatment of indolent or aggressive B-cell lymphomas in an individual (page 3 paragraph 0010). Furthermore, Hilger’795 teach embodiments wherein indolent or aggressive B-cell lymphomas are B-cell lymphomas is indolent or aggressive chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), Hairy cell leukemia (HCL), Burkitt's-like leukemia (BL), B cell prolymphocytic leukemia (B-PLL), diffuse large B cell lymphoma (DLBCL), germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL), non-germinal center Bcell diffuse large B-cell lymphoma (non-GCB DLBCL), DLBCL with undetermined subtype, primary central nervous system lymphoma (PCNSL), secondary central nervous system lymphoma (SCNSL) of breast or testicular origin, transformed lymphoma, multiple myeloma, extra nodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, or a combination thereof (page 4 paragraph 0015). Moreover, Hilger’795 teach embodiments wherein Btk inhibitors of the disclosure, which include compound 1, can be is administered once a day (once daily, QD), two times per day (twice daily, BID), three times per day (Q3D), four times per day (Q4D), or five times per day (Q5D), and is administered at a dosage of about 80 mg/day to about 640 mg/day with a preferred embodiment, the BTK inhibitor is administered at a dose of 320 mg QD or 160 mg BID (claim 62). Furthermore, Hilger’795 teach example study 2 wherein compound 1 was administrated orally every day (320 mg QD or 160 mg BID) with or without food in a dose escalation study wherein cycle 1 included 28 days and all other cycles included 21 days (page 38 paragraphs 0128 – 0129). Furthermore, Hilger’795 teach out of the 25 patients with WM 33.3 % had an overall response rate to the treatment (page 42 paragraph 0146).
While the prior art of Hilger’795 is silent about the administration of compound 1 as delineated in claim 63, Hilger’795 does teach and embodiment wherein compound 1 was administered for at least 2 cycles (28 days + 21 days) or about 7 weeks. Thus, given that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)(MPEP 2144.05 (II)A). Therefore, in order to increase the drug efficacy for the patient one of ordinary skill in the art would optimize the dosage amount and dosage frequency.
Moreover, it would have been obvious to combine the compound 1 of Hilger’795 with BGB-11417 of Hu et. al. since both compounds are effective in treating B-cell lymphomas. Thus there would be a reasonable expectation that a method comprising both compound 1 of Hilger’795 with BGB-11417 of Hu et. al. would be as effective as a monotherapy comprising either compound 1 of Hilger’795 or BGB-11417 of Hu et. al.. Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Hilger’795, that is, to include (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B). One of ordinary skill in the art would have been motivated to make this modification because for the prevention, delay or progression or treatment of indolent or aggressive B-cell lymphomas. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because patients with an indolent or aggressive B-cell lymphomas had an 33.3 % overall response rate to the treatment.
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 42 – 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. App. 18/938467 to Simpson (herein after Simpson’467) in view of International Publication Number WO 2019/210828 A1 to Guo et. al. (herein after Guo’828; cited on the IDS dated March 13th, 2024).
Simpson’467 recite a method of treating myeloid malignancy in a subject, the method comprising administering to the subject a therapeutically effective amount of a Bcl-2 inhibitor, in combination with a therapeutic effective amount of azacitidine, wherein the myeloid malignancy is acute myeloid leukemia (AML) (reference claim 14), myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN); and the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b] yrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) yrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (reference claim 1; instant claim 42). Moreover, Simpson’467 recite a method comprising orally administering once daily the Bcl-2 inhibitor to the patient in escalating doses comprises an initial dose of 5, 10, 20, or 40 mg of the Bcl-2 inhibitor per day (reference claim 4; instant claims 43 – 44).
However, Simpson’467 is silent about whether a myeloid malignancy is a b-cell malignancy (instant claim 42).
Nevertheless, Guo’848 teach that Bcl-2 overexpression is frequently found in acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), relapsed/refractory chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), non-Hodgkin lymphoma (NHL) and solid tumors such as pancreatic, prostate, breast, and small cell and non-small cell lung cancers (page 2 paragraph 0005). Moreover, Guo’848 teach that novel Gly101Val mutation in BCL2 was identified after the patients were treated with the Bcl-2 inhibitor venetoclax (ABT-199) for 19 to 42 months and that this mutation dramatically reduced the binding affinity of Bcl-2 for Venetoclax (ABT-199) by about 180-fold in cell based assay (page 2 paragraph 0005). Additionally, Guo’848 teach example F43 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (claim 42) of structure
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(page 309-310 paragraph 1513).
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of copending Simpson’467 comprising the administration of the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b] yrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) yrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide in view of Guo’828 that is for a method for treating a B-cell malignancy. One of ordinary skill in the art would have been motivated to make this modification because Bcl-2 overexpression is frequently found in acute myeloid leukemia (AML). Additionally one of ordinary skill in the art would have had a reasonable expectation of success because as taught by Guo’828, venetoclax, is an alternative Bcl-2 inhibitor.
This is a provisional nonstatutory double patenting rejection.
Claims 42 – 48, 51 – 54, and 56 – 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 7, and 9 – 10 of copending Application No. 19/030242 to Li et. al. (herein after Li’242) in view of Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), and International Publication Number WO 2019/108795 A1 to Hilger et. al. (herein after Hilger’795; cited on the IDS dated March 13th, 2024).
Li’242 recite a method of treating multiple myeloma in a subject, the method comprising administering to the subject a therapeutically effective amount of a Bcl-2 inhibitor, in combination with a therapeutically effective amount of dexamethasone, wherein the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b] yrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) yrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (reference claim 2; instant claim 42). Additionally, Li’242 recite a method wherein the Bcl-2 inhibitor is orally administered (reference claim 7) at a dose of 40 to 640 mg once daily (reference claims 9 – 10; instant claims 43 – 44, and 46).
However, Li’242 is silent about whether a multiple myeloma is a B-cell malignancy (instant claim 42). Moreover, Li’242 is silent about the administration of 2-((1H-pyrrolo[2,3-b] yrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl) yrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide as recited in instant claims 58 – 60 or the inclusion of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (instant claims 61).
The teachings of prior art of Hu et. al., Koenig et. al., Lasica et. al., and Hilger’795 as they relate to the prior art rejections of claims 42 – 48, 51 – 54, and 56 – 63, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to use the compound of copending Li’242, for a method of inhibiting Bcl-2 protein in view of Hu et. al. for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view further of Kuoeng et. al. and Lasica et. al., that is to substitute BGB-11417 for venetoclax and in further view of Hilger’795, that is, to include (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B).
One of ordinary skill in the art would have been motivated to make this modification to combine the compound of copending Li’242 with prior art Hilger’795 since both compounds are effective in treating B-cell lymphomas. Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Hilger’795, that is, to include (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B). Additionally one of ordinary skill in the art would have had a reasonable expectation of success because patients with an indolent or aggressive B-cell lymphomas had an 33.3 % overall response rate to the treatment.
One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% and the prior art taught that 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide was more effective.
This is a provisional nonstatutory double patenting rejection.
Claims 42 – 48, 51 – 54, and 56 – 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3 – 4, and 7 of U.S. Patent No. US 11786529 B2 to Hilger et. al. (herein after Hilger’529) in view of Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), and International Publication Number WO 2019/108795 A1 to Hilger et. al. (herein after Hilger’795; cited on the IDS dated March 13th, 2024).
Hilger’529 recite a method for the delay of progression or treatment of an indolent or aggressive B-cell lymphoma in a human in need thereof, comprising administering to the human a therapeutically effective amount of a BTK inhibitor, in combination with a therapeutically effective amount of an anti-PD-I antibody or an antigen-binding fragment thereof, wherein the BTK inhibitor is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (instant claim 61), or a pharmaceutically acceptable salt thereof; and the anti-PD-I antibody or fragment comprises a heavy chain variable region (Vh) amino acid sequence of SEQ ID NO:24 and a light chain variable region (VI) amino acid sequence of SEQ ID NO:26 (reference claim 1); wherein the indolent or aggressive B-cell lymphoma is indolent or aggressive Hodgkin's B-cell lymphoma, or indolent or aggressive nonHodgkin's B-cell lymphoma (reference claim 3); wherein the B-cell lymphoma is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), non-germinal center B-cell diffuse large B-cell lymphoma (nonGCB DLBCL), germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL) or DLBCL with undetermined subtype, follicular lymphoma (FL) or transformed FL, marginal zone lymphoma (MZL), Hairy cell leukemia (HCL), Richter' s transformation, primary central nervous system lymphoma (PCNSL), secondary central nervous system lymphoma (SCNSL) of breast or testicular origin, transformed lymphoma, or a combination of two or more thereof (reference claim 4); wherein the BTK inhibitor is administered orally at a dose of 320 mg QD or 1 60 mg BID (reference claim 7; instant claim 62).
However, Hilger’529 fails to recite a method comprising administering a therapeutically effective amount of a Bcl-2 inhibitor, wherein the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((lr,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-l-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (instant claim 42). Additionally, Hilger’529 fails to recite the administration of Zanubrutinib as recited in instant claim 63.
The teachings of prior art of Hu et. al., Koenig et. al., Lasica et. al., and Hilger’795 as they relate to the prior art rejections of claims 42 – 48, 51 – 54, and 56 – 63, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of copending, Hilger’529 for a method for treating B-cell proliferative disorders using (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide in view of Hu et. al. for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view further of Kuoeng et. al. and Lasica et. al., that is to substitute BGB-11417 for venetoclax and in further view of Hilger’795, that is, to include (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B).
One of ordinary skill in the art would have been motivated to make this modification to combine the compound Hilger’529 with BGB-11417 of Hu et. al. since both compounds are effective in treating B-cell lymphomas. Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Hilger’795, that is, to administration of Zanubrutinib as recited in instant claim 63. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because patients with an indolent or aggressive B-cell lymphomas had an 33.3 % overall response rate to the treatment.
One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% and the prior art taught that 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide was more effective.
This is a provisional nonstatutory double patenting rejection.
Claim42 – 48, 51 – 54, and 56 – 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 15 of U.S. Patent No. US 10570139 B2 to Wang et. al. (herein after Wang’139) in view of Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), and International Publication Number WO 2019/108795 A1 to Hilger et. al. (herein after Hilger’795; cited on the IDS dated March 13th, 2024).
Wang’139 recite a method for modulating Bruton’s tyrosine kinase activity in a patient suffering from a B-cell proliferative disorder, comprising administering to the patient a therapeutically effective amount of a compound of formula (I)
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(reference claim 1). More specifically, Wang’139 recite a method of (reference) claim 1 wherein the compound is
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that is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (reference claim 2 – 15; instant claim 61).
However, Wang’139 fails to recite a method for treating a B-cell malignancy comprising administering 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (instant claim 42).
The teachings of prior art of Hu et. al., Koenig et. al., Lasica et. al., and Hilger’795 as they relate to the prior art rejections of claims 42 – 48, 51 – 54, and 56 – 63, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the invention of Wang’139 for a method for treating B-cell proliferative disorders using (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide in view of Hu et. al. for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view further of Kuoeng et. al. and Lasica et. al., that is to substitute BGB-11417 for venetoclax and in further view of Hilger’795, that is, to administer (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B) as recited in instant claims 62 – 63.
One of ordinary skill in the art would have been motivated to make this modification to combine the compound Wang’139 with BGB-11417 of Hu et. al. since both compounds are effective in treating B-cell lymphomas. Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Hilger’795, that is, to administration of Zanubrutinib as recited in instant claim 63. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because patients with an indolent or aggressive B-cell lymphomas had an 33.3 % overall response rate to the treatment.
One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% and the prior art taught that 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide was more effective.
Claims 42 – 48, 51 – 54, and 56 – 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 7, 9 – 11, and 13 – 18 of copending Application No. 18/712682 to Liu et. al. (herein after Liu’682) in view of Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), and International Publication Number WO 2019/108795 A1 to Hilger et. al. (herein after Hilger’795; cited on the IDS dated March 13th, 2024).
Liu’682 recite a compound, having a structure of general formula (I),
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(reference claim 1) selected from the following compounds which includes
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(reference claims 2 – 7, 9 – 11, and 13; instant claim 42). Additionally, Liu’682 recite a use of the compound according to (reference) claim 1 in a preparation of a drug for treating a disease, disorder or condition that benefits from inhibition of BCL-2 activity, either alone or in combination with other drugs (reference claim 15; instant claim 42 and 61) wherein the other drugs are selected from a group that includes BTK inhibitors (instant claim 61). Moreover, Liu’682 recite a use of the compound according to (reference) claim 1 wherein the disease is a hematological disease preferably acute lymphoblastic leukemia (ALL), diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL) (instant claim 48), mantle cell lymphoma (MCL) (instant claim 54), or Waldenstrom macroglobulinemia (WM) (instant claim 55) (reference claims 17 – 18; instant claims 42 and 47).
However, Liu’682 fails to recite a method for treating a B-cell malignancy wherein the dosages and treatment regimen as recited in instant claims 43 – 46 and 58 – 60. Moreover, Liu’682 fails to recite a method wherein the method further comprises the administration of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (instant claim 61) at the dosages and regimen as recited in instant claims 62 – 63.
The teachings of prior art of Hu et. al., Koenig et. al., Lasica et. al., and Hilger’795 as they relate to the prior art rejections of claims 42 – 48, 51 – 54, and 56 – 63, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to use the compound of copending Liu’682, for a method of inhibiting Bcl-2 protein in view of Hu et. al. for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view further of Kuoeng et. al. and Lasica et. al., that is to substitute BGB-11417 for venetoclax and in further view of Hilger’795, that is, to include (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B).
One of ordinary skill in the art would have been motivated to make this modification to combine the compound of copending Liu’682 with prior art Hilger’795 since both compounds are effective in treating B-cell lymphomas. Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Hilger’795, that is, to include (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B). Additionally one of ordinary skill in the art would have had a reasonable expectation of success because patients with an indolent or aggressive B-cell lymphomas had an 33.3 % overall response rate to the treatment.
One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% and the prior art taught that 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide was more effective.
This is a provisional nonstatutory double patenting rejection.
Claims 42 – 48, 51 – 54, and 56 – 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/541928 to Paik et . al. (herein after Paik’928) in view of Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), and International Publication Number WO 2019/108795 A1 to Hilger et. al. (herein after Hilger’795; cited on the IDS dated March 13th, 2024).
Paik’928 recite a method of mitigating the diarrhea of a patient having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the method comprising orally administering to the patient Zanubrutinib, that is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (instant claim 61), or a pharmaceutically acceptable salt thereof at a dose of 160 mg of Zanubrutinib twice a day or 320 mg of Zanubrutinib once a day (instant claim 62) , wherein the administration mitigates the diarrhea of the patient as compared to the diarrhea of a comparable patient orally administered with ibritonib at a dose of 420 mg once a day (reference claim 1).
However, Paik’928 fails to recite a method for treating a patient with CLL comprising 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (instant claim 42). Additionally, Paik’386 fails to recite the administration of Zanubrutinib as recited in instant claim 63.
The teachings of prior art of Hu et. al., Koenig et. al., Lasica et. al., and Hilger’795 as they relate to the prior art rejections of claims 42 – 48, 51 – 54, and 56 – 63, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to apply the compound of copending Paik’928 for a method for treating B-cell proliferative disorders using Zanubrutinib that is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide in view of Hu et. al. for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view further of Kuoeng et. al. and Lasica et. al., that is to substitute BGB-11417 for venetoclax and in further view of Hilger’795, that is, to administer (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B) as recited in instant claims 62 – 63.
One of ordinary skill in the art would have been motivated to make this modification to combine the Zanubrutinib of Paik’928 with BGB-11417 of Hu et. al. since both compounds are effective in treating B-cell lymphomas. Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Hilger’795, that is, to administration of Zanubrutinib as recited in instant claim 63. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because patients with an indolent or aggressive B-cell lymphomas had an 33.3 % overall response rate to the treatment.
One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% and the prior art taught that 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide was more effective.
This is a provisional nonstatutory double patenting rejection.
Claims 42 – 48, 51 – 54, and 56 – 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 7, and 9 of U.S. Patent No. US 11786531 B2 to Paik et. al. (herein after Paik’531) in view of Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), and International Publication Number WO 2019/108795 A1 to Hilger et. al. (herein after Hilger’795; cited on the IDS dated March 13th, 2024).
Paik’531 recites a method of treating or delaying progression of a B-cell proliferative disorder in in a patient receiving a moderate CYP3A inducer, the method comprising concomitantly administering to the patient Zanubrutinib (instant claim 61), or a pharmaceutically acceptable salt thereof, at a total daily dose of about 640 mg, and the moderate CYP3A inducer, the method wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL) (reference claim 3, 13, and 23) , small lymphocytic lymphoma (SLL) (reference claim 4, 14, and 24), Waldenström macroglobulinemia (WM) (reference claim 5, 15, and 25), mantle cell lymphoma (MCL)(reference claim 6, 16, and 26), marginal zone lymphoma (MZL)(reference claim 7, 17, and 27), or follicular lymphoma (FL); and the moderate CYP3A inducer is rifabutin, bosentan, efavirenz, etravirine, modafinil, phenobarbital or nafcillin (reference claim 1, 11, and 21). Furthermore, Paik’531 recites a method wherein Zanubrutinib is administered at a dose of about 320 mg twice a day (reference claims 2, 12, and 22; instant claim 62).
However, Paik’531 fails to recite a method for treating a B-cell malignancy comprising 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (instant claim 42). Additionally, Paik’386 fails to recite the administration of Zanubrutinib as recited in instant claim 63.
The teachings of prior art of Hu et. al., Koenig et. al., Lasica et. al., and Hilger’795 as they relate to the prior art rejections of claims 42 – 48, 51 – 54, and 56 – 63, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to apply the invention of, Paik’531 for a method for treating B-cell proliferative disorders using Zanubrutinib that is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide in view of Hu et. al. for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view further of Kuoeng et. al. and Lasica et. al., that is to substitute BGB-11417 for venetoclax and in further view of Hilger’795, that is, to administer (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B) as recited in instant claims 62 – 63.
One of ordinary skill in the art would have been motivated to make this modification to combine the Zanubrutinib of Paik’531 with BGB-11417 of Hu et. al. since both compounds are effective in treating B-cell lymphomas. Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Hilger’795, that is, to administration of Zanubrutinib as recited in instant claim 63. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because patients with an indolent or aggressive B-cell lymphomas had an 33.3 % overall response rate to the treatment.
One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% and the prior art taught that 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide was more effective.
Claims 42 – 48, 51 – 54, and 56 – 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 7, 9, 11 – 17, 19, 21 – 27, and 29 of U.S. Patent No. US 11911386 B2 to Paik et. al. (herein after Paik’386) in view of Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), and International Publication Number WO 2019/108795 A1 to Hilger et. al. (herein after Hilger’795; cited on the IDS dated March 13th, 2024).
Paik’596 recites a method of treating or delaying progression of a B-cell proliferative disorder in a patient comprising administering to the patient Zanubrutinib (instant claim 61), or a pharmaceutically acceptable salt thereof, at a total daily dose of 640 mg twice a day or 320 mg twice daily (reference claim 11 and 21; instant claim 62), and the moderate CYP3A inducer, wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL) (reference claim 3, 13, and 23) , small lymphocytic lymphoma (SLL) (reference claim 4, 14, and 24), Waldenström macroglobulinemia (WM) (reference claim 6, 15, and 25), mantle cell lymphoma (MCL)(reference claim 6, 16, and 26), marginal zone lymphoma (MZL)(reference claim 7, 17, and 27), or follicular lymphoma (FL); and the moderate CYP3A inducer is rifabutin, bosentan, efavirenz, etravirine, modafinil, phenobarbital or nafcillin (reference claim 1) or diffuse large B-cell lymphoma (DLBCL) (reference claim 11 and 21 – 22).
However, Paik’386 fails to recite a method for treating a B-cell malignancy comprising 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (instant claim 42). Additionally, Paik’386 fails to recite the administration of Zanubrutinib as recited in instant claim 62 – 63.
The teachings of prior art of Hu et. al., Koenig et. al., Lasica et. al., and Hilger’795 as they relate to the prior art rejections of claims 42 – 48, 51 – 54, and 56 – 63, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to apply the invention of, Paik’386 for a method for treating B-cell proliferative disorders using Zanubrutinib that is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide in view of Hu et. al. for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view further of Kuoeng et. al. and Lasica et. al., that is to substitute BGB-11417 for venetoclax and in further view of Hilger’795, that is, to administer (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B) as recited in instant claims 62 – 63.
One of ordinary skill in the art would have been motivated to make this modification to combine the Zanubrutinib of Paik’386 with BGB-11417 of Hu et. al. since both compounds are effective in treating B-cell lymphomas. Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Hilger’795, that is, to administration of Zanubrutinib as recited in instant claim 63. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because patients with an indolent or aggressive B-cell lymphomas had an 33.3 % overall response rate to the treatment.
One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% and the prior art taught that 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide was more effective.
Claim42 – 48, 51 – 54, and 56 – 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 7, 9 – 16, 18 – 23, and 27 – 28 of U.S. Patent No. U.S. Patent No. US 11896596 B2 to Paik et. al. (herein after Paik’596) in view of Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), and International Publication Number WO 2019/108795 A1 to Hilger et. al. (herein after Hilger’795; cited on the IDS dated March 13th, 2024).
Paik’596 recites a method of treating or delaying progression of a B-cell proliferative disorder in a patient receiving a moderate CYP3A inducer, the method comprising concomitantly administering to the patient Zanubrutinib (instant claim 61), or a pharmaceutically acceptable salt thereof, at a dose 60 of about 320 mg twice a day (instant claim 62) , and the moderate CYP3A inducer, wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL) (reference claim 2, 10, and 19) , small lymphocytic lymphoma (SLL) (reference claim 4, 11, and 20), Waldenström macroglobulinemia (WM) (reference claim 5, 12, and 21) , mantle cell lymphoma (MCL)(reference claim 6, 13, and 22), marginal zone lymphoma (MZL)(reference claim 7, 14, and 23), or follicular lymphoma (FL); and the moderate CYP3A inducer is rifabutin, bosentan, efavirenz, etravirine, modafinil, phenobarbital or nafcillin (reference claim 1) or diffuse large B-cell lymphoma (DLBCL) (reference claim 9 and 18).
However, Paik’596 fails to recite a method for treating a B-cell malignancy comprising 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (instant claim 42). Additionally, Paik’596 fails to recite the administration of Zanubrutinib as recited in instant claim 63.
The teachings of prior art of Hu et. al., Koenig et. al., Lasica et. al., and Hilger’795 as they relate to the prior art rejections of claims 42 – 48, 51 – 54, and 56 – 63, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to apply the invention of, Paik’596 for a method for treating B-cell proliferative disorders using Zanubrutinib that is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide in view of Hu et. al. for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view further of Kuoeng et. al. and Lasica et. al., that is to substitute BGB-11417 for venetoclax and in further view of Hilger’795, that is, to administer (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B) as recited in instant claims 62 – 63.
One of ordinary skill in the art would have been motivated to make this modification to combine the compound 1 of Paik’596 with BGB-11417 of Hu et. al. since both compounds are effective in treating B-cell lymphomas. Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Hilger’795, that is, to administration of Zanubrutinib as recited in instant claim 63. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because patients with an indolent or aggressive B-cell lymphomas had an 33.3 % overall response rate to the treatment.
One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% and the prior art taught that 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide was more effective.
Claims 42 – 48, 51 – 54, and 56 – 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 15, 20 – 27, and 31 of U.S. Patent No. U.S. Patent No. US 11420968 B2 to Guo et. al. (herein after Guo’968; cited on the IDS dated March 13th, 2024) in view of in view of Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), and International Publication Number WO 2019/108795 A1 to Hilger et. al. (herein after Hilger’795; cited on the IDS dated March 13th, 2024).
Guo’968 recite a compound of formula (II)
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(reference claim 1). More specifically, Guo’968 recite a compound is selected from a group including 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (reference claim 2 – 15, 20 – 27, and 31; instant claim 42).
However, Guo’968 fails to recite a method for treating a B-cell malignancy (instant claim 42).
The teachings of prior art of Hu et. al., Koenig et. al., Lasica et. al., and Hilger’795 as they relate to the prior art rejections of claims 42 – 48, 51 – 54, and 56 – 63, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to apply the invention of, Guo’968, for the compound 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide in view of Hu et. al. for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view further of Kuoeng et. al. and Lasica et. al., that is to substitute BGB-11417 for venetoclax and in further view of Hilger’795, that is, to include (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B).
One of ordinary skill in the art would have been motivated to make this modification to combine the compound 1 of Hilger’795 with BGB-11417 of Guo’968 since both compounds are effective in treating B-cell lymphomas. Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Hilger’795, that is, to include (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B). Additionally one of ordinary skill in the art would have had a reasonable expectation of success because patients with an indolent or aggressive B-cell lymphomas had an 33.3 % overall response rate to the treatment.
One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% and the prior art taught that 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide was more effective.
Claims 42 – 48, 51 – 54, and 56 – 63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 16, and 22 of U.S. Patent No. U.S. Patent No. US 12077536 B2 to Guo et. al. (herein after Guo’536) in view of Hu et. al. ((2020), Preclinical characterization of BGB-11417, a potent and selective Bcl-2 inhibitor with superior antitumor activities in hematological tumor models. Cancer Res, 80(suppl 16), 3077), Koenig et. al. ((2020), Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists, Blood Advances, 4, 4860 – 4863), Lasica et. al. ((May 2021), Review of Venetoclax in CLL, AML and Multiple Myeloma, J. Pers. Med., 11, 1-14), and International Publication Number WO 2019/108795 A1 to Hilger et. al. (herein after Hilger’795; cited on the IDS dated March 13th, 2024).
Guo’536 recite a method for inhibiting Bcl-2 proteins in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II)
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(reference claim 1). More specifically, Guo’536 recite a method wherein the compound is selected from a group including 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (reference claim 2 – 16, and 22; instant claim 42).
However, Guo’536 fails to recite a method for treating a B-cell malignancy (instant claim 42).
The teachings of prior art of Hu et. al., Koenig et. al., Lasica et. al., and Hilger’795 as they relate to the prior art rejections of claims 42 – 48, 51 – 54, and 56 – 63, are given previously in this office action and are fully incorporated here.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the invention of, Guo’536, for a method of inhibiting Bcl-2 protein in view of Hu et. al. for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view further of Kuoeng et. al. and Lasica et. al., that is to substitute BGB-11417 for venetoclax and in further view of Hilger’795, that is, to include (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B).
One of ordinary skill in the art would have been motivated to make this modification to combine the compound 1 of Hilger’795 with BGB-11417 of Guo’536 since both compounds are effective in treating B-cell lymphomas. Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Hu et. al, that is for a method of treating a B-cell malignancy comprising administering BGB-11417, that is 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide, in view of Hilger’795, that is, to include (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B). Additionally one of ordinary skill in the art would have had a reasonable expectation of success because patients with an indolent or aggressive B-cell lymphomas had an 33.3 % overall response rate to the treatment.
One of ordinary skill in the art would have been motivated to make this modification because both 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide and venetoclax are Bcl-2 inhibitors. Additionally one of ordinary skill in the art would have had a reasonable expectation of success because venetoclax demonstrated promising efficacy at 400 mg dose with overall response rate (ORR) of 79 % complete response (CR) 20%, undetectable minimal residual disease (uMRD) 15% and 15-month progression free survival (PFS) of 69% and the prior art taught that 2-((1H-pyrrolo[2,3-b]pyrrolid-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide was more effective.
Conclusion
Claims 42 – 63 are rejected.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627