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 .
Priority
This application is a Continuation of 16/963,075 filed on 07/17/2020 now abandoned, which is a national stage entry of PCT/US2019/014153 filed on 01/18/2019, which claims priority from U.S. Provisional No. 62/679,477 filed on 06/01/2018; U.S. Provisional No. 62/647,282 filed on 03/23/2018; and U.S. Provisional No. 62/619,210 filed on 01/19/2018.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-10 and new claims 19-20) drawn to a composition comprising an androgen receptor antagonist and a kinase inhibitor, and darolutamide as a species of an androgen receptor antagonist and Lenvatinib as a species of a kinase inhibitor in the reply filed on May 20, 2026 is acknowledged.
Claims 5-9 and 11-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species or group, there being no allowable generic or linking claim.
Claims 1-4, 10, 19 and 20 are currently being examined as they read on the elected species.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Haendler WO 2019/002068 A1.
Claims 1-3 of the instant application claim a composition comprising an androgen receptor antagonist and a kinase inhibitor.
Haendler teaches a combination of a PI3K-inhibitor and an androgen receptor antagonist (title). Specifically, Haendler teaches combinations of a component A which is a PI3K kinase inhibitor, such as copanlisib and a component B which is an androgen receptor antagonist, such as darolutamide or enzalutamide (abstract and page 1 lines 3-10). Haendler teaches that components A and B are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously for the treatment or prophylaxis of prostate cancer (page 1 lines 12-19). Haendler further teaches compositions containing the combination together with pharmaceutically acceptable ingredients (page 1 lines 23-24).
Haendler teaches that it was observed that by administering copanlisib or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, in combination with darolutamide or enzalutamide, a synergistic anti-proliferative effect could be achieved in cell lines representing human prostate cancer (page 4 lines 5-10).
Claim 22 of Haendler claims a composition comprising a combination of a PI3K kinase inhibitor, such as copanlisib, and a component B which is an androgen receptor antagonist, such as darolutamide or enzalutamide together, with pharmaceutically acceptable ingredients (page 82).
Thus the cited claims of the instant application are anticipated since Haendler teaches a composition comprising an androgen receptor antagonist which is darolutamide or enzalutamide and a kinase inhibitor which is copanlisib, a Phosphoinositide 3-kinase (PI3K) inhibitor, which is a lipid kinase inhibitor.
Claims 1-4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sweeney et al. WO 2014/165779 A1 (Provided on IDS).
Claims 1-4 of the instant application claim a composition comprising an androgen receptor antagonist and a kinase inhibitor.
Sweeney et al. teaches the combination of cabozantinib and abiraterone to treat cancer, particularly castration resistant prostate cancer (abstract). Sweeney et al. specifically teaches the combination of 1000 mg abiraterone and 60 mg cabozantinib, 1 g abiraterone and 40 mg cabozantinib, and 1 g abiraterone and 20 mg cabozantinib (pages 53-55).
Thus the cited claims of the instant application are anticipated since Sweeney et al. teaches a combination of an androgen receptor antagonist which is abiraterone and a kinase inhibitor which is cabozantinib, a receptor tyrosine kinase inhibitor.
Claims 1-4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al. U.S. Publication No. 2014/0199236 A1.
Claims 1-4 of the instant application claim a composition comprising an androgen receptor antagonist and a kinase inhibitor.
Chen et al. teaches an androgen receptor modulator of formula (I) having the following structure:
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which is apalutamide, in the treatment of prostate cancer in combination with other therapeutic options and in the treatment of diseases or conditions that are amenable to treatment with the androgen receptor modulator, as well as pharmaceutical compositions and medicaments that include such compound (abstract).
Chen et al. teaches in one aspect, described therein is a method of treating prostate cancer in a male human comprising administering apalutamide at a dose of about 30 mg per day to about 480 mg per day to a male human with metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer or high-risk localized prostate cancer in combination with a phosphoinositide 3-kinase (PI3K) inhibitor, TORC inhibitor, or dual PI3K/TORC inhibitor [0015]. Chen et al. teaches the phosphoinositide 3-kinase (PI3K) inhibitor, TORC inhibitor, or dual PI3K/TORC inhibitor is everolimus, administered at a dose of about 5 mg per day to about 20 mg per day or at a dose of about 5 mg per day or about 10 mg per day [0015].
Chen et al. further teaches in one aspect, described therein is a method of treating prostate cancer in a male human comprising administering apalutamide at a dose of about 30 mg per day to about 480 mg per day to a male human with post-abiraterone acetate treated metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer or high-risk localized prostate cancer in combination with a kinase inhibitor [0022]. Chen et al. teaches that the kinase inhibitor targets angiogenesis or bone metastases and the kinase inhibitor is a MET or VEGFR kinase inhibitor such as Cabozantinib (XL184), PF-2341066 (Crizotinib), ARQ-197 (Tivantinib), MK-2461, JNJ-38877605, MK-8033, INCB-28060, BMS-777607, AMG-208, LY-2801653, EMD-1214063, EMD-1204831, AMG-337, HMPL-504 (Volitinib), SAR-125844, LY2875358, ABR-215050 (Tasquinimod), CHIR-258 (Dovitinib), EXEL-7647, OSI-930, BIBF-1120, BAY-73-4506 (Regorafenib), BMS-582664 (Brivanib), JNJ-26483327, AZD-2171 (Cediranib), Sorafenib, Aflibercept, Enzastaurin, AG-013736 (Axitinib), OSI-632, or GSK-786034 (Pazopanib) [0022]. Chen et al. teaches that preferably, the kinase inhibitor is Cabozantinib administered orally at a dose of about 40 mg per day to about 100 mg per day [0022]. Chen et al. further teaches the kinase inhibitor may be selected as Erlotinib, Cetuximab, Gefitinib, Canertinib, Panitumumab, Nimotuzumab, Lapatinib, Vandetanib, Afatinib, MP-412, AEE-788, Neratinib, XL-647, AC-480, Dacomitinib, AZD-8931, CUDC-101, AP-26113, CO-1686, Trametinib, Selumetinib, MEK-162, Refametinib, TAK-733, RO-5126766, BI-847325, AZD6244, GSK1120212, PF-5208763 (Bosutinib), or AZD-0530 (Saracatinib) [0022]. Preferably the kinase inhibitor is Erlotinib administered orally at a dose of about 100 mg to about 150 mg, or Gefitinib administered orally at a dose of about 250 mg [0022].
Chen et al. specifically teaches a combination of apalutamide with a kinase inhibitor wherein the kinase inhibitor is cabozantinib, erlotinib or gefitinib [0231] [0233] [0234] [0235] [0237]-[0240]. Chen et al. specifically teaches treating patients with the combination of apalutamide and cabozantinib [0508].
Thus the cited claims of the instant application are anticipated since Chen et al. teaches a combination of an androgen receptor antagonist which is apalutamide and a receptor tyrosine kinase inhibitor such as cabozantinib, erlotinib or gefitinib.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-4, 10, 19 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bold et al. U.S. Publication No. 2008/0085902 A1 in view of Aragon-Ching et al. (Curr Mol Pharmacol. 2009 June 1; 2(2): 161–168), Yamamoto et al. (Vascular Cell 2014, 6:18) and Shore (EXPERT OPINION ON PHARMACOTHERAPY, 2017 VOL. 18, NO. 9, 945–952 ).
Bold et al. teaches a combination therapy for treating patients suffering from proliferative diseases or diseases associated with persistent angiogenesis comprising a VEGF inhibitor compound; and one or more chemotherapeutic agents (abstract and [0001]).
Bold et al. teaches that VEGF receptors are transmembranous receptor tyrosine kinases characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain [0014]. Various types of VEGF receptor are known, e.g., VEGFR-1, VEGFR-2 and VEGFR-3 [0014]. Bold et al. teaches that VEGF is an angiogenic compound and a large number of tumors express high levels of VEGFR and its receptors [0013]-[0015]. Bold et al. teaches that angiogenesis is regarded as an absolute prerequisite for those tumors which grow beyond a maximum diameter of about 1-2 mm; up to this limit, oxygen and nutrients may be supplied to the tumor cells by diffusion [0016]. Every tumor, regardless of its origin and its cause, is thus dependent on angiogenesis for its growth after it has reached a certain size [0016]. Thus Bold et al. teaches the combination of chemotherapeutic agents and a VEGF inhibitor to inhibit angiogenesis in the tumor to provide both synergistic and additive advantages both for efficacy and safety ([0017]-[0019])
Bold et al. teaches pharmaceutical compositions comprising: (a) a VEGF inhibitor; (b) one or more chemotherapeutic agents; and (c) a pharmaceutically acceptable carrier ([0004]- [0007] and [0022]-[0028]). Bold et al. teaches the combination partners (a) and (b) can be administered together, one after the other, or separately, in one combined unit dosage form or in two separate unit dosage forms, and the unit dosage form may also be a fixed combination [0011].
Bold et al. teaches the chemotherapeutic agent may be selected as an anti-androgen (especially in the case of prostate cancer) ([0030] [0032]). Bold et al. teaches the term "anti-androgen", as used therein, relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX) [0061]. Bold et al. teaches VEGF inhibitors are especially compounds, proteins or antibodies which inhibit at least one VEGF receptor tyrosine kinase [0116].
Claim 10 of Bold et al. specifically claims a pharmaceutical composition comprising: (a) a VEGF inhibitor compound; and (b) one or more chemotherapeutic agents such as an anti-androgen (especially in the case of prostate cancer).
Bold et al. does not specifically exemplify combining a VEGF inhibitor compound with an anti-androgen. Bold et al. does not teach combining darolutamide and Lenvatinib specifically.
However, Bold et al. teaches throughout that a suitable combination is a VEGF inhibitor compound; and (b) one or more chemotherapeutic agents such as an anti-androgen (especially in the case of prostate cancer). Thus an ordinary skilled artisan would have been motivated to combine a VEGF inhibitor compound; and an anti-androgen, especially in the case of prostate cancer, as taught in Bold et al. with a reasonable expectation of similar success as all the other combinations taught therein. Thus although Bold et al. includes an anti-androgen on a list that includes other chemotherapeutic agents, a prima facie case of obviousness can still be established since picking one of a finite number of known solutions to a known problem is prima facie obvious. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
In addition, Aragon-Ching et al. teaches a role for VEGF inhibitors in prostate cancer therapy (see title). Aragon-Ching et al. teaches that prostate cancer remains the most common non-cutaneous malignancy among American men, and while the majority of men are diagnosed in early stages, a subset will develop recurrence and eventually, metastatic disease (abstract and page 1). Aragon-Ching et al. teaches that angiogenesis has been shown to play an important role in tumorigenesis, proliferation and metastasis in prostate cancer, and VEGF is a major angiogenic signaling pathway involved in prostate cancer progression (abstract and page 1). Aragon-Ching et al. discusses several clinical trials administering VEGFR inhibitors for the treatment of prostate cancer including sorafenib and cediranib (pages 2-7). Aragon-Ching et al. teaches that it is likely that combination of anti-angiogenic agents with conventional cytotoxic therapy will yield better clinical responses compared to either agent alone (page 7).
In addition, prior to the effective filing date of the claimed invention Lenvatinib was known in the art as an oral inhibitor of multiple receptor tyrosine kinases (RTKs) targeting vascular endothelial growth factor receptor (VEGFR1-3) and as an anti-angiogenesis agent (Yamamoto et al. abstract). Yamamoto et al. teaches that angiogenesis is the formation of new blood vessels, and RTK signaling pathways have been identified as crucial regulators of angiogenesis, including the signaling pathways of VEGFR, FGFR, HGFR, PDGFR, TIE2 and EPH expressed in endothelial or vascular mural cells (page 2). The VEGF-signaling pathway is the key regulator of tumor growth and metastasis and consists of five ligands (VEGFA-D and placental growth factor (PlGF)) and three RTKs (VEGFR1, VEGFR2, VEGFR3) (page 2). Yamamoto et al. teaches VEGFR2 induces major phenotypic changes of endothelial cells in angiogenesis, including proliferation, migration, survival, and tube formation and several small-molecule inhibitors of VEGFR2 kinase have been approved for treatments of multiple cancer types, such as sunitinib (page 2). Yamamoto et al. teaches Lenvatinib (E7080) is a novel multi-targeted VEGFR2 TKI (page 2). Yamamoto et al. demonstrates that Lenvatinib strongly inhibited VEGFR 1, 2, 3 RTK (Ki =1.3, 0.74, 0.71nM, respectively) (page 5). Yamamoto et al. further demonstrates that Lenvatinib inhibits VEGFR activated angiogenesis (page 5). Yamamoto et al. further demonstrates that Lenvatinib at doses of 10 and 30 mg/kg significantly inhibited in vivo angiogenesis (page 5). Yamamoto et al. further demonstrates that treatment with Lenvatinib at doses of 1 to 100 mg/kg resulted in a dose-dependent inhibition of tumor growth of prostate tumor xenograft model (page 6). Thus Yamamoto et al. teaches that Lenvatinib is an angiogenesis inhibitor targeting VEGFR2 and FGFR and shows antitumor activity in a broad spectrum of tumor xenograft models (page 11).
Shore teaches that Darolutamide (ODM-201, BAY-1841788) is a novel, oral, next-generation AR antagonist with a high affinity for the AR receptor (page 950). A second-generation AR antagonist is enzalutamide; and an androgen synthesis inhibitor, is abiraterone (page 945). Shore teaches that Darolutamide binds to the AR with high affinity, and impairs subsequent androgen-induced nuclear translocation of AR and transcription of AR gene targets (page 946). Darolutamide and ORM-15341 have demonstrated retention of full AR-antagonist properties against known clinically relevant AR mutants that confer resistance to other antiandrogens (page 946).
Shore teaches in the phase I dose-escalation part (n = 24), where darolutamide doses of 200–1800 mg daily (100-mg capsules) were administered, after a median 25 months on treatment, PSA responses (≥50% PSA decrease from baseline) occurred in 17 of 21evaluable patients who received darolutamide across all doses (page 946). In the phase II part, patients were randomized to receive darolutamide 200, 400, or 1400 mg daily; the primary end point was PSA response at week 12 (page 946).
Shore teaches that in contrast to current second-generation AR antagonists, darolutamide also inhibited AR mutants in preclinical models that have been implicated in conferring treatment resistance to CRPC therapies (page 950). Moreover, darolutamide has demonstrated negligible blood–brain barrier penetration, which may lead to an enhanced safety and tolerability profile (page 950). Consistent with preclinical findings, there have been no reports from clinical trials of any increased risk of seizures, even in patients with a history or at increased risk of seizures, as these patients have not been excluded in trials to date (pages 950-951).
Accordingly, prior to the effective filing date of the claimed invention, it would have been prima facie obvious to combine the teachings of Bold et al. which teaches the combination of a VEGF inhibitor compound; and (b) one or more chemotherapeutic agents such as an anti-androgen (especially in the case of prostate cancer); with the teachings of Aragon-Ching et al. which teaches that angiogenesis has been shown to play an important role in tumorigenesis, proliferation and metastasis in prostate cancer, and VEGF is a major angiogenic signaling pathway involved in prostate cancer progression; and with the teachings of Yamamoto et al. which teaches that Lenvatinib is an angiogenesis inhibitor targeting VEGFR2 and shows antitumor activity in a broad spectrum of tumor xenograft models including prostate tumor model; and with the teachings of Shore which teaches that Darolutamide (ODM-201, BAY-1841788) is a novel, oral, next-generation AR antagonist with a high affinity for the AR receptor useful for the treatment of prostate cancer. Thus since angiogenesis has been shown to play an important role in tumorigenesis, proliferation and metastasis in prostate cancer, and VEGF is a major angiogenic signaling pathway involved in prostate cancer progression, an ordinary skilled artisan would have been specifically motivated to treat prostate cancer according to the teachings of Bold et al. by combining a VEGF inhibitor compound to inhibit angiogenesis and an anti-androgen compound with a reasonable expectation of improving the treatment for prostate cancer by creating an additive or synergistic combination. Furthermore, an ordinary skilled artisan would have been motivated to specifically select darolutamide as a suitable anti-androgen compound for use in the method of Bold et al. since Shore teaches that darolutamide is a next-generation AR antagonist with a high affinity for the AR receptor with improved properties as compared to other second-generation AR antagonists. In addition, an ordinary skilled artisan would have been motivated to specifically select Lenvatinib as a suitable VEGFR inhibitor for use in the method of Bold et al. in treating prostate cancer since Yamamoto et al. demonstrates that Lenvatinib inhibits VEGFR activated angiogenesis and further demonstrates that treatment with Lenvatinib at doses of 1 to 100 mg/kg resulted in a dose-dependent inhibition of tumor growth of prostate tumor xenograft model (page 6). Therefore since Bold et al. teaches combining a VEGF inhibitor compound and an anti-androgen compound for the treatment of prostate cancer, and the prior art as detailed above teach the use of both Lenvatinib and darolutamide in the treatment of prostate cancer, combining said compounds would have been seen as an obvious substitution of equivalent alternatives to yield predictable results.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 5-9 and 11-18 are withdrawn. Claims 1-4, 10, 19 and 20 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA R. MCMILLIAN whose telephone number is (571)270-5236. The examiner can normally be reached Tuesday-Friday 12:00 PM-6:00 PM.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM
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