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 .1
Status of Claims
Claims 1-25 are pending.
Election/Restrictions
Applicant’s election without traverse of uveal melanoma in the reply filed on 8/8/2025 is acknowledged.
Claims 22 and 24-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/8/2025.
The claimed compound of the invention is the following:
PNG
media_image1.png
120
152
media_image1.png
Greyscale
3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide (aka Compound 1)
Compound 1 has been identified by the attached SciFinder search as CAS Registry Number: 1874276-76-22 Note that throughout this office action, the claimed compound will be referred to as Compound I, Compound 1, Darvobasertib or LXS196.
PNG
media_image2.png
188
268
media_image2.png
Greyscale
Information Disclosure Statement
The information disclosure statements (IDS)s submitted on 5/17/2022 (total of 2) and 9/8/2023 were filed are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 1-11, 18-21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/053595 (WO 595).
Claim 1 is a method of treating cancer mediated by protein kinase C comprising administering to a patient in need thereof, a therapeutically effective amount of 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide (Darovasertib, Compound (I)), or a pharmaceutically acceptable salt thereof, as a monotherapy, in a dosing regimen comprising a first dosing cycle comprising a first dosing series, followed by a second dosing series, wherein:
(a) the first dosing series comprises a dose of about 200 mg BID of compound (I), or a pharmaceutically acceptable salt thereof, and
(b) the second dosing series comprises a dose of about 400 mg BID of compound (I), or a pharmaceutically acceptable salt thereof.
Regarding a method of treating a PKC mediated cancer, WO 595 teaches elected species, uveal melanoma, comprising administering, 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6- (3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide (aka Darovasertib, Compound (I)) in doses of about 100 mg to about 1000 mg daily. See claim 1. More specifically, WO 595 teaches
Compound I can be administered (e.g., orally) at a lower starting dose (a "run-in" dose), e.g., 50 mg or higher BID (e.g., 50 mg BID, 75 mg BID, 100 mg BID, 200 mg BID or 300 mg BID) for a period of time (e.g., first 7 days of every 28 day cycle) while compound II is administered at a dose of 50 mg, 80 mg, 100 mg, 120 mg once weekly for 2 weeks followed by 2 weeks off, Compound I is then administered (e.g., orally) at a dose higher than the run-in dose, e.g., 75 mg or higher BID (e.g., 200 mg BID, 300 mg BID or 400 mg BID) for the rest of days in every 28 day cycle while Compound II is administered (e.g., orally) at a dose of 50 mg, 80 mg, 100 mg or 120 mg once weekly for 2 weeks followed by 2 weeks off (Day 1 and Day 8 of every 28 day cycle). See page 13, line 31 bridging to page 14, line 8.
It is noted that the passage above does not explicitly recite the monotherapy aspect of claim 1 with Compound I, but also includes an aspect of dosing a second compound, II.
Regarding the monotherapy aspect of examined claim 1, WO 595’s claim 1 suggests monotherapy of Compound I, aka Darovasertib, as it is the only compound administered to the uveal subject in need. See also claims 2-3, where the dose of about 100 mg to about 400 mg BID encompasses the doses of Compound I claimed.
In fact, WO 595 teaches that in previous trials at the time, “[p]reliminary data suggest encouraging clinical activity of LXS196 [Darovasertib] as monotherapy with manageable toxicities in pts with metastatic UM [uveal melanoma].” See page 23, lines 27-29. WO 595 teaches adjustment of dosages and treatment are known to a person having ordinary skill in the art (PHOSITA) as it teaches
A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease. Frequency of dosage may vary depending on the compound used and the particular condition to be treated or
prevented. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art. Page 17, lines 4-11.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of WO 595 at pages 13-14 to modify with the monotherapy taught at WO 595 claim 1, and page 23, in order to arrive at the monotherapy schedule as claimed. MPEP 2143.
The PHOSITA would have had a reasonable expectation of success because WO 595 teaches a schedule of dosing compound I at 200 mg BID initially in a first dosing cycle, followed by a second dosing series that comprises a dose of about 400 mg BID, where a suggestion of the safety and efficacy of Compound I/Darovasertib monotherapy is made.
Regarding claim 2 and the first dosing series lasting from 5 to 10 days, WO 595 identifies the first series dose as a “run-in” dose, that includes 200 mg BID for a period of 7 days. See page 13 line 33 to page 14, line 1.
Regarding claim 3 and the limitation wherein the length of the second dosing series is 18 to 23 days; provided the length of first dosing cycle comprising first dosing series and second dosing series is 28 days, WO 595 teaches “Compound I is then administered (e.g., orally) at a dose higher than the run-in dose, e.g., 75 mg or higher BID (e.g., 200 mg BID, 300 mg BID or 400 5 mg BID) for the rest of days in every 28 day cycle.” Page 14, lines 3-5.
Regarding claims 4-6 and the limitation wherein the first dosing series has compound I administered on days 1 to 5, 1 to 5 or 1 to 7, consecutively, WO 595 teaches Compound I is administered alone for a period of time of 1, 2, 3, 4, 5, 6 , 7, 8 , 9, 10, 11, 12, 13, 14 days. See page 7 lines 15-20. Also noted is the teaching of WO 595 that allows a physician of skill in the art to adjust dosing as necessary to best treat the patient, where it states “A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.” Page 17, lines 4-11. It would be routine for one of ordinary skill in the art to optimize dosing as claimed to best treat the patient.
Regarding claims 8-9 and the limitation where the first dosing cycle’s second dosing series where Compound I is administered on days 7 to 28 or 8 to 28 consecutively, WO 595 discloses a second dosing series, “Compound I is then administered (e.g., orally) at a dose higher than the run-in dose, e.g., 75 mg or higher BID (e.g., 200 mg BID, 300 mg BID or 400 mg BID) for the rest of days in every 28 day cycle.” See page 14, lines 3-5. Note that WO 595 teaches dose adjustment of up to 14 days, as an example (See page 7 lines 15-20), but also notes “A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.” Page 17, lines 4-11. . It would be routine for one of ordinary skill in the art to optimize dosing as claimed to best treat the patient.
Regarding claim 10 wherein the dosing regimen comprises one or more additional dosing cycles of second dosing series wherein each additional dosing cycle is 28 days, it is noted that with regard to dosing compound I in a 28 day cycle, WO 595 explicitly states that Compound I is orally administered at a dose higher than the run-in dose . . . for the rest of days in every 28 cycle. See page 14, lines 3-5. The recitation of “every 28 day cycle” explicitly teaches additional dosing cycles to be administered to the subject in need.
Regarding claim 11 wherein compound (I) is administered consecutively for 28 days of each additional dosing cycle, while there is no explicit teaching that compound I is administered for 28 days consecutively for each additional dosing cycle, WO 595 nonetheless teaches “A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.” Page 17, lines 4-11. WO 595 also teaches that compound I is administered at a dose from about 100 mg to about 1000 mg daily, i.e., leading to a suggestion that compound I be administered daily and consecutively for a 28 day cycle. It would be routine for one of ordinary skill in the art to optimize dosing as claimed to best treat the patient.
Regarding claim 18 and the limitation wherein the patient is administered 200 mg BID in the first series and 400 mg in the second series, WO 595 teaches this limitation as discussed above. See page 13, line 31 bridging to page 14, line 8.
Regarding claims 19-21 and the limitation of elected species of cancer, uveal melanoma (UM), including metastatic UM, WO 595 teaches treatment of uveal melanoma in claim 1 with Compound 1. See also claim 7 wherein the subjected treated suffers from metastatic uveal melanoma.
Regarding claim 23 and the mutation limitation therein, WO 595 teaches the treated subject’s uveal melanoma or metastatic uveal melanoma is characterized by mutation of guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) gene or guanine nucleotide binding protein G(q) subunit 11 (GNA 11) gene. See claim 20.
Claims 1-21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/053595 (WO 595) in view of Vincente et al. Uveal melanoma: Clinical characteristics, treatment and survival in a series of 500 patients, ARCH SOC ESP OFTALMOL . 2013; 88(11):433–438 .
WO 595 teaches the claimed invention of claims 1-11, 18-21 and 23 as discussed above, a method treating uveal melanoma in a subject in need comprising administering Compound 1 in a two series dosing as noted above. It is noted that WO 595 does not teach the particular species of the claimed invention of claims 12-17, where the number of additional dosing cycles of second dosing series is at least 4, is at least 8, is at least 10, is at least 12, is at least 16 or is at least 24.
Regarding claims 12-17, it is known in the art where Vincente teaches determining clinical characteristics, treatment and survival of 500 uveal melanoma patients, where the overall melanoma-related mortality rate of said patients as 11.6% and 14.8% at 5 and 10 years respectively. See Results section of Abstract. Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference WO 595 to treat uveal melanoma patients with monotherapy of Compound I to modify the treatment with those teachings of Vincente, noting the long term melanoma mortality of at least 5 or 10 years in these patients.
The PHOSITA would have had a reasonable expectation of success because Vincente teaches long term mortality of uveal melanoma patients (5 or 10 years), where it would be obvious to dose and apply at least 4, 8, 10, 12, 16 or at least 24 additional cycles (where the dose cycles are 28 days) of second dosing series as claimed.
Conclusion
No claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 CONTINUING DATA
This application is a 371 of PCT/US2020/061065 11/18/2020
PCT/US2020/061065 has PRO 62/988,483 03/12/2020
PCT/US2020/061065 has PRO 62/936,993 11/18/2019
2 3-Amino-N-[3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinyl]-6-[3-(trifluoromethyl)-2-pyridinyl]-2-pyrazinecarboxamide (ACI)
3-Amino-N-[3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl]-6-[3-(trifluoromethyl)pyridin-2-yl]pyrazine-2-carboxamide
Darovasertib
IDE 196
LXS 196
NVP-LXS 196