DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s preliminary amendments filed 10/26/2023 have been entered.
Claims 1-4, 6, 8, 10, 12-16, 19, 23, 32, 36, 42, 45, 49, 53, 54, 56, 57, 60, and 66 are pending.
At the outset, the instant invention is directed to the use of a combination of a BRAF inhibitor – Compound A (aka DAY101, MLN2480, BIIB024, TAK-580, and tovorafenib) with a MEK inhibitor such pimasertib. In the depending claims, the cancers being treated are having some forms of mutations or fusions.
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.
Claim(s) 1-4, 6, 8, 10, 12-16, 19, 23, 32, 36, 42, 45, 49, 53, 54, 56, 57, 60, and 66 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2019/207087 (‘087) in view of Zaman et al., Cancers 2019, 11, 1197 and Rasco et al., Journal of Clinical Oncology, Volume 31, Number 15 suppl, May 2013, Page: 2547.
‘087 teaches “One class of cancer compounds useful in the treatment of subjects afflicted with cancer include compounds involved in the mitogen activated protein kinase (MAPK) pathway, namely, inhibitors of said pathway offer promise for defined subsets of patients.” Also “The MAPK pathway rep- resents a signaling pathway mediating cellular responses to growth signals. The ultimate function of this is to link receptor activity at the same membrane with modifications of cytoplasmic or nuclear targets that govern cell proliferation, differentiation and survival. Mutations in various Ras GTPases and the B-Raf kinase have been identified that they can lead to sustained and constitutive activity of the MAPK path- way. The signaling pathways include the Ras-Raf-MEK-ERK-kinase pathway. These kinases then phosphorylate and activate the intracellular protein kinase MEK1 and MEK2. It is known that the MAPK pathway represents a suitable target for treatment of cancer including metastatic cancer. Various BRAF inhibitors and MEK inhibitors as well as ERK inhibitors are described in the art. However, the presence of metastases in particular brain metastases can compromise the structure and integral of the blood brain barrier hence, it is still a significant obstacle to efficient delivery of drugs including BRAF inhibitors. Further, cancer cells that have extravasated to the brain parenchyma may find protection within the microenvironment beyond the blood brain barrier, and be more prone to develop resistance due to subtherapeutic drug concentrations.” (see page 2, line 18 bridging page 3, line 4). ‘087 teaches “In recent years, it has been shown that several genetic and molecular drivers of melanoma modulate cellular metabolism in ways that are critical tumor development, metastases and drug resistance. Recently, a BRAF and MEK combination treatment received approval for the treatment of metastatic melanoma.” (see page 3, lines 10-13). ‘087 teaches the combination of BRAF inhibitors including compound A (TAK-580) and MEK inhibitors including pimasertib (see claim 1; page 3, line 26 bridging page 4, line 2). ‘087 teaches various cancers can be treated with the combination such as Thyroid carcinoma, BRAF-mutant melanoma, glioma, pediatric glioma, colorectal cancer (see page 23, lines 1-20; claim 2).
‘087 does not expressly teach the mutations or fusion of BRAF. ‘087 does not expressly teach the dosage of Compound A. ‘087 does not expressly teach the herein claimed age of the patients.
Zaman et al. teaches various BRAF gene mutations have been identified to be associated with various of cancer and those include V600E, K601E, G469V, G469R, G464V (see for example page 4 of 19, Table 1). Zaman et al. also teaches “Recent publications have also shown that oncogenic BRAF gene fusions can also activate BRAF in melanomas and other cancers. In these cases, the BRAF kinase domain is fused with N-terminal partner genes suchasSOX10, AGK,SEPT3. The fusions result in an alteration of the BRAF copy number and activity independent of common missense BRAF.” (see page 5 of 19, last paragraph).
Rasco et al. teaches a phase I clinical study on Compound A and the maximum dosage would be Q2D 200mg (see the abstract). The maximum weekly dosage would be 800mg, which means the compound is administered 4 times weekly.
It would have been obvious to one of ordinary skill in the art at the time of filing to employ the herein claimed combination of Compound A, in the herein claimed dosage, and a MEK inhibitor, such as pimasertib, in a method of treating BRAF mutation and/or fusion associated cancers such as melanoma.
One of ordinary skill in the art would have been motivated to employ the herein claimed combination of Compound A, in the herein claimed dosage, and a MEK inhibitor, such as pimasertib, in a method of treating BRAF mutation and/or fusion associated cancers such as melanoma. Since the BRAF mutation/fusion are associated with aberrated MARK pathway in cancer development, a combination of MEK inhibitor and BRAF inhibitors as well-known in the art would be used in treating cancer associated with the herein claimed V600E or non-V600E mutations associated cancers. Furthermore, the optimization of result effect parameters (dosage range, dosing regimens) is obvious as being within the skill of the artisan. The optimization of known effective amounts of known active agents to be administered, is considered well in the competence level of an ordinary skilled artisan in pharmaceutical science, involving merely routine skill in the art. It has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980). It is also noted 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). The dosage recited in the claims would be considered as obvious since it is within the dosage that minimize side effects and at the same time, maximize the therapeutic effects. As for the age of the patients, the herein claimed combination is well-known in treating pediatric glioma, as the name suggested, the age of patients would encompass the age recited in the claims.
As for the patient population of whether they previously received the cytochrome P450 substrates, the skilled artisans would be charged to know the drug-drug interactions between the agents administered, and adjusted the dosage or dosing regimen accordingly.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 6, 8, 10, 12-16, 19, 23, 32, 36, 42, 45, 49, 53, 54, 56, 57, 60, and 66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 63-91 of copending Application No. 18/035,478 (‘478) in view of ‘087 and Zaman et al. ‘478 teaches a method of treating pediatric low grade glioma using Compound A, in the dosage as claimed, to the patients with age from 6 months to 25 years (see claim 63). ‘478 teaches the cancer is associated with V600 BRAF mutations and fusions (see claim 68 for example).
‘478 does not expressly teach the specific BRAF mutations or fusions. It does not expressly teach the use of MEK inhibitors such as pimasertib.
‘087 teaches the use of a combination of BRAF inhibitors (including Compound A) and a MEK inhibitor including pimasertib to treat low grade glioma (see claims 1 and 2).
Zaman et al. teaches various BRAF gene mutations have been identified to be associated with various of cancer and those include V600E, K601E, G469V, G469R, G464V (see for example page 4 of 19, Table 1). Zaman et al. also teaches “Recent publications have also shown that oncogenic BRAF gene fusions can also activate BRAF in melanomas and other cancers. In these cases, the BRAF kinase domain is fused with N-terminal partner genes suchasSOX10, AGK,SEPT3. The fusions result in an alteration of the BRAF copy number and activity independent of common missense BRAF.” (see page 5 of 19, last paragraph).
It would have been obvious to one of ordinary skill in the art at the time of filing to employ the herein claimed combination in the method of treating BRAF mutations/fusion associated low grade glioma.
One of ordinary skill in the art would have been motivated to employ the herein claimed combination in the method of treating BRAF mutations/fusion associated low grade glioma. The examiner notes that the herein claimed BRAF mutations and/or fusions affect the MARK pathway that will result in the promoting cancer development. Therefore, using more than one agents (the combination is known to be effective) to prevent resistance and enhance therapeutic effect in treating these BRAF mutation associated cancer would be reasonably expected to be effective.
Claims 1-4, 6, 8, 10, 12-16, 19, 23, 32, 36, 42, 45, 49, 53, 54, 56, 57, 60, and 66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 15, 17-19, 23, 24, 26, 28-33, 44 of copending Application No. 18/696942 (‘942) in view of ‘087, Zaman et al., and Rasco et al.
‘942 teaches a method of treating cancer associated with BRAF fusions using Compound A (see claim 1 and 15 for example).
‘942 does not expressly teach the dosage, the BRAF mutations associated with cancers. ‘942 does not expressly teach the use of combination with MEK inhibitors such as pimasertib.
‘087 teaches the use of a combination of BRAF inhibitors (including Compound A) and a MEK inhibitor including pimasertib to treat melanoma and pediatric glioma (see claims 1 and 2).
Zaman et al. teaches various BRAF gene mutations have been identified to be associated with various of cancer and those include V600E, K601E, G469V, G469R, G464V (see for example page 4 of 19, Table 1). Zaman et al. also teaches “Recent publications have also shown that oncogenic BRAF gene fusions can also activate BRAF in melanomas and other cancers. In these cases, the BRAF kinase domain is fused with N-terminal partner genes suchasSOX10, AGK,SEPT3. The fusions result in an alteration of the BRAF copy number and activity independent of common missense BRAF.” (see page 5 of 19, last paragraph).
Rasco et al. teaches a phase I clinical study on Compound A and the maximum dosage would be Q2D 200mg (see the abstract). The maximum weekly dosage would be 800mg, which means the compound is administered 4 times weekly.
It would have been obvious to one of ordinary skill in the art at the time of filing to employ the herein claimed combination in the method of treating BRAF mutations/fusion associated low grade glioma.
One of ordinary skill in the art would have been motivated to employ the herein claimed combination in the method of treating BRAF mutations/fusion associated low grade glioma. The examiner notes that the herein claimed BRAF mutations and/or fusions affect the MARK pathway that will result in the promoting cancer development. Therefore, using more than one agents (the combination is known to be effective) to prevent resistance and enhance therapeutic effect in treating these BRAF mutation associated cancer would be reasonably expected to be effective.
This is a provisional nonstatutory double patenting rejection.
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/SAN MING R HUI/ Primary Examiner, Art Unit 1627