DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of (i) a hydroxyl methyl cellulose acetate succinate salt of 1-((1S,1aS,6bS)-5-((7-oxo- 5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-la,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)- 3-(2,4,5-trifluorophenyl)urea; (ii) non-small cell lung cancer as the solid tumor, and (iii) BRAF as the patient mutation as the elected species, in the reply filed on 10/23/2025 is acknowledged and maintained.
Priority
The present application claims priority to U.S. Provisional Application No. 63/379,617 filed October 14, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/05/2026 has been considered by the examiner.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on June 06, 2026. Claims 1-12 and 15-25 are pending. Claims 13-14 are canceled. Claims 17-21 are withdrawn. Claims 1-12, 15-16, and 22-25 are examined in accordance to the elected species.
Action Summary
Claims 1-12, 15-16, and 22-25 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, are withdrawn in light of the amendment incorporating therapeutic treatment.\
Claims 1-6, 8-12, 15-16, and 22-25 rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al (WO2014/206343 A1) in view of Luo et al (WO2020/202981 A1), are withdrawn in light of the claim amendment incorporating “the solid cancer is a lung cancer selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer” and “therapeutic treatment.”
Claim 7 rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al (WO2014/206343 A1) in view of Luo et al (WO2020/202981 A1) as applied to claims 1-6, 8-12, 15-16, and 22-25, in further view of Ueda et al (Journal of Pharmaceutical Sciences 109 (2020) 2464-2473 is withdrawn because the underlying rejection of claims 1-6, 8-12, 15-16, and 22-25 has been withdrawn in light of Applicant’s amendment incorporating the limitation that “the solid cancer is a lung cancer selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer” and “therapeutic treatment.”
Claims 1-12, 15-16 and 22-25 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 30, 31, and of copending Application No. 17/995,002 in view of Zhou et al (WO2014/206343 A1), Luo et al (WO2020/202981 A1), and Ueda et al (Journal of Pharmaceutical Sciences 109 (2020) 2464-2473, are withdrawn in light of the claim amendment incorporating “the solid cancer is a lung cancer selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer” and “therapeutic treatment.”
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 15 and 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 depends, directly or indirectly, from claim 1. Claim 1 recites a method of therapeutic treatment of a subject having a solid cancer wherein the solid cancer is a lung cancer selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer. However, claim 15 further recites treatment of non-small cell lung cancer (NSCLC) generally.
The recitation of NSCLC encompasses additional forms of NSCLC beyond those required by claim 1, including disease states that do not necessarily satisfy the limitation of claim 1. Accordingly, claim 15 appears to broaden, rather than further limit, the scope of claim 1. Because a dependent claim must further limit the subject matter of the claim from which it depends (35 U.S.C 112(d)), it is unclear whether claim 15 is intended to be limited to the specific disease recited in claim 1 or to encompass the broader recited disease. Therefore, the metes and bounds of claim 15 cannot be determined with reasonable certainty.
Claim 16 depends from claim 15 and therefore incorporates the same indefiniteness.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-6, 8-12, 15-16, and 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al (WO2014/206343 A1) in view of Luo et al (WO2020/202981 A1) and Zhou et al. (Chin J Cancer (2015) 34:31, cited herein as “Zhou-2.”)
Zhou teaches a method of treating cancer responsive to inhibition of Raf kinase and/or Raf kinase dimer comprising administering to a subject in recognized need thereof at least one compound of the formula (I)
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, or a pharmaceutically acceptable salt in an amount effective to inhibit said Raf kinase and/or Raf kinase dimer. (See claim 36 and claim 1.) Moreover, Zhou teaches one of the preferred compounds of the formula (I) includes compound 1.40
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. (See page 27.) Moreover, Zhou teaches the dosage administered is a preferred daily dose of 10-500 mg once or multiple times per day. (See lines 33-35 of page 42 bridging lines 1-2 of page 43.) Zhou teaches the compound of the formula (I) can be administered as the sole active ingredient or in combination with at least one second active ingredient useful for treating cancer and can be administered concomitantly, sequentially. (See lines 1-9 of page 45.) Zhou teaches when administered as a separate dosage form, the at least one other therapeutic agent may be administered prior to, at the same time as, or following administration of the at least one compound and /or at least one pharmaceutically acceptable salt thereof. (See lines 1-3 of page 38.) The separate administration contemplated both the same or different dosage forms. Zhou teaches the composition can be administered orally in the form of a tablet. (See lines 23-29 of page 41 Compounds 1.1-1.87 and 2.1-2.16 inhibited B-Raf (wild type, V60OE)/C-Raf with IC50 values ranging from 0.1 nM to 10 µM. (See lines 32-33 of page 114.) Furthermore, Zhou teaches the cancer can be non-small cell lung cancer. (See claim 37.)
Zhou does not teach mirdametinib administered twice a day in the amount claimed and two equal doses and does not further teach lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer. Moreover, Zhou does not teach 28-day dosing cycle that is repeated up to a total of 24 consecutive 28-day dosing cycles.
Luo teaches a method of treating a patient having a solid tumor comprising administering twice daily 4 mg Compound A as free base and once d acceptable salt thereof. (See claim 292.) Compound A is mirdametinib. (See paragraph [0002].) Moreover, Luo teaches compound A is administered before, concomitantly, or subsequently to the administering of Compound B, or a pharmaceutically acceptable salt form thereof. (See claim 304.) The dosage form of compound A is an oral capsule. (See claims 306 and 307.) Luo also teaches the patient has a confirmed mutation of BRAF and has non-small cell lung cancer. (See claims 309 and 313.) BRAF encompasses BRAF Class II/III fusion mutation. Additionally, Luo teaches the amount of Compound A, or a pharmaceutically acceptable salt thereof, administered in the lead-in period is the same as the amount of Compound A, or a pharmaceutically acceptable salt thereof, administered during the first 28-day dosing cycle. (See claim 195.) Luo teaches
the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles. (See paragraph [0535].) Furthermore, Luo teaches compound A free based is divided over two doses per day. (See paragraph [0144].) Two divided doses contemplate two equal doses.
Zhou-2 teaches non-small cell lung cancer (NSCLC) is divided into squamous and non-squamous subtypes based on histologic features. With a growing number of oncogenic drivers being identified in squamous and non-squamous NSCLC, this malignancy has been recently divided into several distinct subtypes according to the specific molecular alterations. (See Abstract.) Moreover, Zhou-2 teaches in a retrospective analysis of 1,046 NSCLC patients in Caucasian population, BRAF mutations were pre sent in 4.9% (36/739) of lung adenocarcinoma and 0.3% (1/307) of squamous cell carcinoma (SqCC). V600E BRAF mutation, a domain subtype of BRAF mutations, was significantly more common in females and was identified in 8.6% of female patients with adenocarcinoma, which is helpful to identify the enriched patient population for treatment with BRAF inhibitors. Dabrafenib is a potent and selective inhibitor of BRAF kinase activity. In interim analysis of a single-arm, phase II study, 17 pretreated NSCLC patients carrying V600E BARF mutations were treated with dabrafenib. The results were encouraging, with an ORR of 54% (7 patients with partial response) (Table 2). Dramatic response was also observed in several case reports of NSCLC patients harboring activating V600E BRAF mutations treated with vemurafenib, another inhibitor of BRAF kinase. (See last line of the left column bridging the first paragraph of the right column of page 6.)
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was made to combine the method disclosed by Zhou that includes the claimed effective amount with the method set forth by Luo because each is taught by the prior art to be useful for the same purpose (i.e., treating BRAF-driven non-small cell lung cancer, including lung adenocarcinoma, and squamous cell carcinoma). See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Further, a person of ordinary skill in the art would reasonably have expected to be successful because both compositions were shown to be useful separately for the exact same purpose and thus would be expected to be similarly useful when used together.
It would have been further obvious to one of ordinary skill in the art at the time the invention was filed to select the compound I.40 taught by Zhou in combination with merdametinib taught by Luo to arrive at the presently claimed method. One of ordinary skill in the art would have been motivated to select compound I.40 from Zhou because Zhou expressly teaches compound 1.40 as a preferred BRAF inhibitor useful for treating cancers response to BRAF inhibition, including non-small lung cancer. Luo independently teaches that mirdametinib is advantageously administered in combination with a RAF-inhibitor to treat patient having BRAF-mutant non-small lung cancer. Zhou-2 further establishes that BRAF mutations are recognized oncogenic drivers in non-small cell lung cancer, including adenocarcinoma and squamous cell carcinoma, and that BRAF inhibitors were an established targeted therapeutic approach for such patients. Accordingly, one of ordinary skill in the art would have had a reason to substitute the preferred BRAF inhibitor of Zhou for the RAF inhibitor employed in Luo’s combination regimen with a reasonable expectation of success because both references are directed because both references are directed to inhibiting the same oncogenic BRAF-signaling pathway for the treatment of the same patient population.
The fact that Zhou discloses additional BRAF inhibitor compounds does not detract from the obviousness of selecting compound I.40. A prior art reference is not limited to its most preferred embodiment, and the disclosure of preferred or more potent alternatives does not constitute a teaching away from other expressly disclosed embodiments. Zhou specifically identifies compound I.40 as a preferred compound and teaches its utility as a BRAF inhibitor for treating cancer. Therefore, the selection of compound I.40 from the finite number of expressly disclosed preferred compounds would have been an obvious design choice for one of ordinary skill in the art.
Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on June 06, 2026.
Applicant first argues that amendment of claim 1 to recite “therapeutic treatment” and to incorporate the limitation that the solid cancer is a lung cancer selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer overcome the prior rejections.
This argument is persuasive with respect to the enablement rejection. Accordingly, the rejection under 35 U.S.C. 112(a) has been withdrawn.
However, the amendment does not overcome the rejection under 35 U.S.C. 103.
As set forth in the present Office Action, Zhou teaches methods of therapeutically treating cancers responsive to inhibition of RAF kinase by administering a compound of Formula (I)(, including preferred compound I.40, while Luo teaches therapeutic treatment of patients having solid tumors by administering mirdametinib in combination with another therapeutic agent. Additionally, Zhou-2 expressly teaches that BRAF mutations occur in lung adenocarcinoma and squamous non-small cell lung cancer and further teaches that patient harboring such BRAF motions benefit from treatment with BRAF inhibitor, including dabrafenib and vemurafenib. Zhou-2 therefore provides additional evidence that BRAF-mutated lung cancers were recognized in the art as appropriate targets for BRAF inhibition. Consequently, the newly added disease limitations do not patentably distinguish the claimed method from the combined teachings of Zhou, Luo, and Zhou-2.
Applicant further argues that Zhou discloses numerous RAF kinase inhibitors and that one of ordinary skill in the art would have had no motivation to select compound I.40 because other compounds, including compound I.22, allegedly possess greater potency.
This argument is not persuasive. The rejection is not predicated upon compound I.40 being the most potent compound disclosed by Zhou. Rather, Zhou expressly identifies compounds and teaches that preferred compounds of Formula (I), including compound I.40, are useful for treating RAF-kinase-dependent cancers, including non-small cell lung cancer. The mere disclosure of additional compounds having different biological potency does not constitute a teaching away from the expressly preferred compound selected by the Office. Obviousness does not require selection of the single potent embodiment disclosed by a reference, particularly where the reference affirmatively identifies the selected compound as a preferred embodiment useful for the same therapeutic purpose.
Applicant next argues that Zhou does not disclose treatment using mirdametinib and that Luo does not disclose the combination therapy employing compound I.40. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the present case, the rejection does not rely upon either Zhou or Luo individually to disclose every limitation of the claims. Rather, the rejection relies upon Zhou for treating administration of the claimed BRAF inhibitor, Luo for teaching therapeutic administration of mirdametinib in combination with another therapeutic agent, and Zhou-2 for further demonstrating that BRAF-mutant lung cancer, including lung adenocarcinoma and squamous NSCLC, were recognized therapeutic targets for BRAF inhibitors. Therefore, Applicant’s arguments attacking Zhou and Luo individually do not rebut the articulated rationale supporting the proposed combination.
Applicant additionally, argue that Luo teaches combination therapy specifically with lifirafenib and therefore provides not motivation to substitute another RAF inhibitor.
This argument is not persuasive. Luo teaches the therapeutic benefit of combining mirdametinib with inhibition of the RAF signaling pathway. Zhou independently teaches that compound I.40 is an effective RAF kinase inhibitor useful for treating RAF-driven cancers. Furthermore, Zhou-2 demonstrates that BRAF-mutated non-small cell lung cancers were recognized as suitable candidates for treatment of BRAF inhibitors. Accordingly, one of ordinary skill in the art would have reasonably expected that another therapeutically useful RAF inhibitor, such as Zhou’s preferred compound I.40, could likewise be employed in combination with mirdametinib to treat BRAF-drive lung cancers. The office does not rely upon lifirafenib and compound I.40 being structurally identical or possessing identical kinase selectivity. Rather, both references therapeutically useful RAF kinase inhibition for treatment of RAF-driven malignancies. Where prior art teaches multiple compounds situatable for achieving the same therapeutic objective, substitution of one known therapeutic agent for another constitutes no mor than the predictable use of prior art elements according to their established functions.
Applicant argues that lifirafenib is a reversible pan-RAF/EGFR inhibitor whereas compound I.40 is a selective BRAF inhibitor and therefore, one would not reasonably expect the same synergy.
This argument is not persuasive. The claims do not require any degree of synergy, enhanced efficacy, or unexpected therapeutic interaction between mirdametinib and the claimed BRAF inhibitor. Rather, the claims merely require co-administration of therapeutically effective amounts of the two compounds. Absent a claim limitation directed to synergistic activity or other unexpected property, alleged differences in the kinase activity do not distinguish the claimed subject matter from the combination suggested by the prior art. The rejection relies upon the known therapeutic utility of each agent for treatment of BRAF-driven cancers, and the reasonable expectation that their combined administration would have been useful for the same therapeutic purpose. Moreover, Zhou-2 provides additional evidence that selective BRAF inhibition itself was recognized as an effective therapeutic strategy in BRAF-mutated lung cancers through the successful clinical use of selective BRAF inhibitors such as dabrafenib and vemurafenib. Thus, Zhou-2 further supports the reasonable expectation of success in employing another known BRAF inhibitor, namely Zhou’s preferred compound I.40, in treating the claimed lung cancers.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al (WO2014/206343 A1) in view of Luo et al (WO2020/202981 A1) and Zhou et al. (Chin J Cancer (2015) 34:31, cited herein as “Zhou-2.”) as applied to claims 1-6, 8-12, 15-16, and 22-25, in further view of Ueda et al (Journal of Pharmaceutical Sciences 109 (2020) 2464-2473.
The teachings of Zhou, Luo, and Zhou-2 have been discussed supra.
Zhou, Luo, and Zhou-2 collectively do not teach hydroxypropyl methyl cellulose acetate succinate salt of compound I.40 as claimed in claim 7.)
Ueda evaluates the effect of polymer substituent type on drug amorphous solubility as well as drug membrane transport rate. Two grades of hypromellose acetate succinate (HPMCAS), AS-LF and AS-HF, were studied with 4 model drugs. (See Abstract.) Moreover, Ueda teaches these polymers can improve the transport of drug to the vicinity of the epithelial cells, resulting in further enhancements in drug absorption. (See Conclusion Section and last paragraph of the right column of page 2464.) While Ueda does not teach HPMCAS is a pharmaceutically acceptable salt, the instant specification and the election of HPMCAS as the elected pharmaceutically acceptable salt are taken as evidentiary that HPMCAS as the elected pharmaceutically acceptable salt. A chemical compound and its properties are considered inseparable because a specific chemical structure inherently possesses its physical and chemical properties. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method taught by Zhou as modified by Luo and Zhou-2 to include the HPMCAS as taught by Ueda to give Applicant’s claimed invention. One would have been motivated to do so, because Ueda teaches HPMCAS can improve the transport of drug to the vicinity of the epithelial cells, resulting in further enhancements in drug absorption. One would reasonably expect the inclusion of HPMCAS to improve the transport of the drugs taught by Zhou as modified by Luo and Zhou-2 in order to effectively treat NSCLC harboring BRAF mutation.
Applicant argues that Ueda does not remedy the alleged deficiencies of Zhou and Luo.
This argument is not persuasive. The rejection does not rely upon Ueda to teach mirdametinib or compound I.40. Rather, Ueda is relied upon for the additional limitation of the hydroxypropyl methylcellulose acetate succinate salt. Accordingly, Applicant’s argument directed to Ueda’s failure to disclose the claimed combination of therapeutic agents do not address the actual basis of the rejection.
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 1-2, 15-16 and 22-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 30, 31, and of copending Application No. 17/995,002 in view of Zhou et al (WO2014/206343 A1), Luo et al (WO2020/202981 A1), and Ueda et al (Journal of Pharmaceutical Sciences 109 (2020) 2464-2473) and Zhou et al. (Chin J Cancer (2015) 34:31, cited herein as “Zhou-2.”)
The copending claims teach a method of treating a patient having a solid tumor comprising administering a therapeutically effective amount of mirdametinib and a therapeutically effective amount of lifirafenib. (See claim 2) Moreover, the copending claims teach mirdametinib is the amount of 1 mg to about 5 mg per day and administered once per day. (See claims 30 and 31.) The solid tumor can include non-small cell lung cancer. (See claim 37.)
The copending claims do not teach 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl) oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl) urea, or a pharmaceutically acceptable salt thereof in the amount claimed, oral capsule administration. Moreover, the copending claims do not teach 28-day dosing cycle that is repeated up to a total of 24 consecutive 28-day dosing cycles.
Zhou teaches a method of treating cancer responsive to inhibition of Raf kinase and/or Raf kinase dimer including lung adenocarcinoma and squamous non-small cell lung cancer comprising administering to a subject in recognized need thereof at least one compound of the formula (I)
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, or a pharmaceutically acceptable salt in an amount effective to inhibit said Raf kinase and/or Raf kinase dimer. (See claim 36 and claim 1.) Moreover, Zhou teaches one of the preferred compounds of the formula (I) includes compound 1.40
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. (See page 27.) Moreover, Zhou teaches the dosage administered is a preferred daily dose of 10-500 mg once or multiple times per day. (See lines 33-35 of page 42 bridging lines 1-2 of page 43.) Zhou teaches the compound of the formula (I) can be administered as the sole active ingredient or in combination with at least one second active ingredient useful for treating cancer and can be administered concomitantly, sequentially. (See lines 1-9 of page 45.) Zhou teaches when administered as a separate dosage form, the at least one other therapeutic agent may be administered prior to, at the same time as, or following administration of the at least one compound and /or at least one pharmaceutically acceptable salt thereof. (See lines 1-3 of page 38.) The separate administration contemplated both the same or different dosage forms. Zhou teaches the composition can be administered orally in the form of a tablet. (See lines 23-29 of page 41 Compounds 1.1-1.87 and 2.1-2.16 inhibited B-Raf (wild type, V60OE)/C-Raf with IC50 values ranging from 0.1 nM to 10 µM. (See lines 32-33 of page 114.) Furthermore, Zhou teaches the cancer can be non-small cell lung cancer. (See claim 37.)
Luo teaches a method of treating a patient having a solid tumor comprising administering twice daily 4 mg Compound A as free base and once d acceptable salt thereof. (See claim 292.) Compound A is mirdametinib. (See paragraph [0002].) Moreover, Luo teaches compound A is administered before, concomitantly, or subsequently to the administering of Compound B, or a pharmaceutically acceptable salt form thereof. (See claim 304.) The dosage form of compound A is an oral capsule. (See claims 306 and 307.) Luo also teaches the patient has a confirmed mutation of BRAF and has non-small cell lung cancer. (See claims 309 and 313.) BRAF encompasses BRAF Class II/III fusion mutation. Additionally, Luo teaches the amount of Compound A, or a pharmaceutically acceptable salt thereof, administered in the lead-in period is the same as the amount of Compound A, or a pharmaceutically acceptable salt thereof, administered during the first 28-day dosing cycle. (See claim 195.) Luo teaches
the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles. (See paragraph [0535].) Furthermore, Luo teaches compound A free based is divided over two doses per day. (See paragraph [0144].) Two divided doses contemplate two equal doses.
Zhou-2 teaches non-small cell lung cancer (NSCLC) is divided into squamous and non-squamous subtypes based on histologic features. With a growing number of oncogenic drivers being identified in squamous and non-squamous NSCLC, this malignancy has been recently divided into several distinct subtypes according to the specific molecular alterations. (See Abstract.) Moreover, Zhou-2 teaches in a retrospective analysis of 1,046 NSCLC patients in Caucasian population, BRAF mutations were pre sent in 4.9% (36/739) of lung adenocarcinoma and 0.3% (1/307) of squamous cell carcinoma (SqCC). V600E BRAF mutation, a domain subtype of BRAF mutations, was significantly more common in females and was identified in 8.6% of female patients with adenocarcinoma, which is helpful to identify the enriched patient population for treatment with BRAF inhibitors. Dabrafenib is a potent and selective inhibitor of BRAF kinase activity. In interim analysis of a single-arm, phase II study, 17 pretreated NSCLC patients carrying V600E BARF mutations were treated with dabrafenib. The results were encouraging, with an ORR of 54% (7 patients with partial response) (Table 2). Dramatic response was also observed in several case reports of NSCLC patients harboring activating V600E BRAF mutations treated with vemurafenib, another inhibitor of BRAF kinase. (See last line of the left column bridging the first paragraph of the right column of page 6.)
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was made to combine the method disclosed by Zhou that includes the compound taught by the copending claims with the method set forth by Luo because each is taught by the prior art to be useful for the same purpose (i.e., treating BRAF-driven non-small cell lung cancer, including lung adenocarcinoma, and squamous cell carcinoma). See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Further, a person of ordinary skill in the art would reasonably have expected to be successful because both compositions were shown to be useful separately for the exact same purpose and thus would be expected to be similarly useful when used together.
It would have been further obvious to one of ordinary skill in the art at the time the invention was filed to select the compound I.40 taught by Zhou in combination with merdametinib taught by the copending claims and Luo and the copending claims to arrive at the presently claimed method. One of ordinary skill in the art would have been motivated to select compound I.40 from Zhou because Zhou expressly teaches compound 1.40 as a preferred BRAF inhibitor useful for treating cancers response to BRAF inhibition, including non-small lung cancer. Luo and the copending claims independently teaches that mirdametinib is advantageously administered in combination with a RAF-inhibitor to treat patient having BRAF-mutant non-small lung cancer. Zhou-2 further establishes that BRAF mutations are recognized oncogenic drivers in non-small cell lung cancer, including adenocarcinoma and squamous cell carcinoma, and that BRAF inhibitors were an established targeted therapeutic approach for such patients. Accordingly, one of ordinary skill in the art would have had a reason to substitute the preferred BRAF inhibitor of Zhou for the RAF inhibitor employed in Luo’s and the copending claims’ combination regimen with a reasonable expectation of success because both references are directed because both references are directed to inhibiting the same oncogenic BRAF-signaling pathway for the treatment of the same patient population.
The fact that Zhou discloses additional BRAF inhibitor compounds does not detract from the obviousness of selecting compound I.40. A prior art reference is not limited to its most preferred embodiment, and the disclosure of preferred or more potent alternatives does not constitute a teaching away from other expressly disclosed embodiments. Zhou specifically identifies compound I.40 as a preferred compound and teaches its utility as a BRAF inhibitor for treating cancer. Therefore, the selection of compound I.40 from the finite number of expressly disclosed preferred compounds would have been an obvious design choice for one of ordinary skill in the art.
The copending claims do not further teach hydroxypropyl methyl cellulose acetate succinate salt of compound I.40 as claimed in claim 7.)
Ueda evaluates the effect of polymer substituent type on drug amorphous solubility as well as drug membrane transport rate. Two grades of hypromellose acetate succinate (HPMCAS), AS-LF and AS-HF, were studied with 4 model drugs. (See Abstract.) Moreover, Ueda teaches these polymers can improve the transport of drug to the vicinity of the epithelial cells, resulting in further enhancements in drug absorption. (See Conclusion Section and last paragraph of the right column of page 2464.) While Ueda does not teach HPMCAS is a pharmaceutically acceptable salt, the instant specification and the election of HPMCAS as the elected pharmaceutically acceptable salt are taken as evidentiary that HPMCAS as the elected pharmaceutically acceptable salt. A chemical compound and its properties are considered inseparable because a specific chemical structure inherently possesses its physical and chemical properties. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method taught by the copending claims, Zhou and Luo to include the HPMCAS as taught by Ueda to give Applicant’s claimed invention. One would have been motivated to do so, because Ueda teaches HPMCAS can improve the transport of drug to the vicinity of the epithelial cells, resulting in further enhancements in drug absorption. One would reasonably expect the inclusion of HPMCAS to improve the transport of the drugs taught by Zhou and Luo in order to effectively treat NSCLC harboring BRAF mutation.
This is a provisional nonstatutory double patenting rejection.
Applicant traverses the provisional obviousness type double patenting rejection on the basis that the copending application claims lifirafenib rather than the presently claimed BRAF inhibitor.
This argument is not persuasive. The provisional obviousness-type double patenting rejection is based upon the claims of the copending application in view of the teachings of Zou. Luo, and Zhou-2. As explained in the rejection under 35 U.S.C. 103, it would have been obvious to substitute Zhou’s preferred BRAF inhibitor for the lifirafenib recited in the copending claims because each reference teaches therapeutically useful RAF inhibition for treatment of BRAF-driven cancers, and Zhou-2 further establishes that BRAF-mutated lung cancers were recognized therapeutic targets for BRAF inhibitors. Therefore, the claimed subject matter is not patentably distinct from the claims of the copending application.
Conclusion
Claims 1-12, 15-16 and 22-25 are not allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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