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 .
DETAILED ACTION
1. Claims 2, 5-14, 19-21, 24-26, 28, 38-39 are pending in the current application.
2. This application is a 371 of PCT/US2022/024909 04/14/2022, which claims benefit of 63/175,513 04/15/2021.
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.
3. Claim(s) 2, 5-14, 19-21, 24-26, 28, 38-39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Online “https://ir.ideayabio.com/2020-08-12-IDEAYA-Biosciences-Inc-Reports-Second-Quarter-2020-Financial-Results-and-Provides-Business-Update” Aug. 12, 2020 accessed February 25, 2026 (IDEAYA I) and Online “https://media.ideayabio.com/2021-03-23-IDEAYA-Announces-Dose-Expansion-in-Phase-1-2-Study-of-IDE196-and-Binimetinib-Combination-in-Metastatic-Uveal-Melanoma-Based-on-Early-Clinical-Activity” March 23, 2021 accessed February 25, 2026 (IDEAYA 2), Porter US 9,446,043, Chen, X. “Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations.” Oncogene, 33(39), 4724-4734 2014, published online 21 October 2013 (cited on the IDS), and Cooke WO 2019053595 A1 (cited on the IDS). The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
IDEAYA 1 teaches the instant combination therapy with the two claimed compounds (compound 1 (IDE196)1 and compound 2 (Binimetinib )2) as reproduced here:
Combination Therapy
IDEAYA is enrolling MUM patients into a combination arm of the IDE196 Phase 1/2 clinical trial to evaluate safety and efficacy of IDE196 in combination with binimetinib, a MEK inhibitor. We may also evaluate IDE196 / binimetinib combination therapy in patients having other solid tumors with activating GNAQ/11 hotspot mutations, such as skin melanoma. The combination arm is being conducted under a clinical trial collaboration and supply agreement with Pfizer Inc., pursuant to which Pfizer supplies us with their MEK inhibitor, binimetinib; the companies established a Joint Development Committee with Pfizer to facilitate combination arm drug supply, trial initiation and ongoing development. Highlights:
First-Patient-In (FPI) of a MUM patient for IDE196 / binimetinib combination arm of the IDE196 clinical trial in June 2020;
Initiated dosing into a first cohort of the IDE196 / binimetinib dose escalation portion of combination arm; and
Interim data from evaluation of IDE196 / binimetinib combination therapy anticipated in late 2021 to early 2022.
IDEAYA 2 also teaches the same therapy, as discussed in the section below:
“Metastatic Uveal Melanoma is a high unmet medical need with no FDA approved therapies, and we are encouraged by the early clinical activity observed from the IDE196 and binimetinib combination," said Dr. Richard Carjaval, M.D., Director of Experimental Therapeutics and Director of the Melanoma Service, Columbia University Medical Center. "The Phase 1/2 dose expansion of the IDE196 and binimetinib combination study and the notice of allowance for the U.S. patent application directed to IDE196 and MEK combination therapy are important company milestones, and we look forward to further evaluating the clinical potential of this combination," said Yujiro S. Hata, Chief Executive Officer and President, IDEAYA Biosciences. The IDE196 and binimetinib combination initiated dose expansion based on early clinical activity, including percentage of patients with tumor reduction. The IDE196 and binimetinib combination arm will target to enroll approximately 40 patients in the Phase 1/2 study in MUM. IDEAYA received a Notice of Allowance of U.S. Patent Application No. 16/666,1083 covering methods of treating certain cancer types, including metastatic uveal melanoma, uveal melanoma and melanoma using a combination of IDE196 and a MEK inhibitor. Based on the preliminary IDE196 monotherapy clinical data and its mechanism of action, IDEAYA anticipates clinical activity independent of Human Leukocyte Antigen (HLA) status in GNAQ/11-mutation cancers. IDEAYA is targeting interim data from the IDE196 and binimetinib clinical combination arm in MUM and from the IDE196 monotherapy arm of the Phase 1/2 basket trial in MUM and GNAQ/11-mutation skin melanoma in 2021. As part of the IDE196 monotherapy clinical data update in 2021, IDEAYA is targeting to report tolerability and clinical efficacy, including survival data in MUM.
Chen explains that the combination of PKC inhibitors (compound 1) and MEK inhibitors (compound 2) reduce tumor size in UM synergistically, “[C]ombinations of PKC and MEK inhibition, using either PD0325901 or MEK162 [MEK 162 is the claimed compound 2 Binimetinib], led to sustained MAP-kinase pathway inhibition and showed a strong synergistic effect in halting proliferation and in inducing apoptosis in vitro. Furthermore, combining PKC and MEK inhibition was efficacious in vivo, causing marked tumor regression in a UM xenograft model. Our data identify PKC as a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations and demonstrate that combined MEK and PKC inhibition is synergistic, with superior efficacy compared to treatment with either approach alone.” [abstract] Over 95% of UM harbor mutually exclusive activating driver mutations in GNAQ or GNA11. GNAQ-mutant UM remain dependent on the initiating GNAQ mutations and appear to require PKC/MAPK signaling for survival. “We further show that MAP-kinase pathway activation occurs as a consequence of PKC activation and can be partially or temporarily suppressed by PKC inhibitors, slowing tumor growth. However, a significantly improved response can be obtained by combined PKC and MEK inhibition, which synergistically result in sustained growth inhibition and apoptosis in vitro and a markedly enhanced antitumoral response in vivo. We propose combinatorial inhibition of PKC and MAP-kinase signaling as a rational therapeutic approach for treating melanomas with GNAQ or GNA11 mutations.”
Porter on column 2 line 10-11, teaches the use of PKC inhibitors generally (compound A) and Binimetinib (compound B) as a combined treatment for uveal melanoma as suggested by Chen,
The present inventors have now found that inhibition of the signaling cascade downstream of these G proteins may be useful for the treatment of a proliferative disease such as cancer, e.g. a tumor with a Ga mutation (GNA11/GNAQ), and in particular, uveal melanoma, metastatic uveal melanoma, and GNAQ or GNA11 mutant uveal melanoma. It has now been found that a combination of a protein kinase C (PKC) inhibitor compound and a MEK inhibitor compound is effective for the delay of progression or treatment of a proliferative disease, especially uveal melanoma, metastatic uveal melanoma, and GNAQ or GNA11 mutant uveal melanoma. It has now been surprisingly discovered that the combination of an effective amount of a protein kinase C (PKC) inhibitor, e.g. 3-(1H-indol-3-yl)-4-2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl)-1H-pyrrole-2,5-dione, or a pharmaceutically acceptable salt thereof, e.g. the acetate thereof, with an effective amount of at least one MEK inhibitor compound, e.g. 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide.
Compound A is the PKC inhibitor, and compound B is the MEK inhibitor. On page 11 the doses claimed are given as a range by Porter:
[0133] The PKC inhibitor compound COMPOUND A may be administered to a suitable subject daily in single or divided doses at an effective dosage in the range of about 0.05 to about 50 mg per kg body weight per day, preferably about 0.1-25 mg/kg/day, more preferably from about 0.5-10 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to a preferable dosage range of about 35-700 mg per day.
[0134] The MEK inhibitor compound COMPOUND B may be administered to a suitable Subject daily in single or divided doses at an effective dosage in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to a preferable dosage range of about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day.
Porter further explains that finding the right dosage is simply routine optimization:
[0136] The optimal dosage of each combination partner for treatment of a proliferative disease can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art.
[0137] The amount of each combination partner that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration. In some embodiments the unit dosage forms containing the combination of agents as described herein will contain the amounts of each agent of the combination that are typically administered when the agents are administered alone.
Cooke explains that IDE196 can be administered in the dose of claim 1, i.e. 400 mg to 600 mg daily at in a related combination therapy for UM at page 6 lines 4-13. Both 400 and 600 mg doses are listed in line 12-13. The BID doses in claims 5-6 are also listed in the same section. Claim 3 and 6 have the same doses. Weekly doses are described on page 18 lines 12-30.
Ascertainment of the difference between the prior art and the claims
The only point of novelty of the instant claims is the dose of the combination claimed. The doses are taught in the references.
Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to optimize the dose of the known drug combination of IDE196 and binimetinib to produce the instant invention. The doses of the individual drugs were already known in the ranges claimed in the combinations of Porter and Cooke. Chen explains that “The data provided indicate that the combination may allow reducing the doses of the individual compounds, which is expected to improve the tolerability of the drugs.” [Chen conclusions]. The fact that the combination has entered a clinical trial is strong evidence of the seriousness of the approach and the fundamental belief by those in the art that this is an effective therapy. “Metastatic Uveal Melanoma is a high unmet medical need with no FDA approved therapies, and we are encouraged by the early clinical activity observed from the IDE196 and binimetinib combination," said Dr. Richard Carjaval, as quoted above. MPEP 2107.03 IV states, “[A]s a general rule, if an applicant has initiated human clinical trials for a therapeutic product or process, Office personnel should presume that the applicant has established that the subject matter of that trial is reasonably predictive of having the asserted therapeutic utility." This is because “Before a drug can enter human clinical trials, the sponsor, often the applicant, must provide a convincing rationale to those especially skilled in the art (e.g., the Food and Drug Administration (FDA)) that the investigation may be successful. Such a rationale would provide a basis for the sponsor’s expectation that the investigation may be successful.” There is a reasonable expectation of success of producing the claimed invention from the prior art.
Conclusion
4. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/ Primary Examiner, Art Unit 1621
1 Compound 1, CAS # 1874276-76-2, 3-Amino-N-[3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinyl]-6-[3-(trifluoromethyl)-2-pyridinyl]-2-pyrazinecarboxamide, AKA Darovasertib, LXS 196, NVP-LXS 196, IDE196 (Knox WO 2020146355 A1, cited on the IDS, shows that IDE196 was a known synonym for compound 1 at the time the invention was made, see page 31, [0094] “This example describes the phase 1/2 study of compound of Formula (III) above, ("IDE196")”, Formula III is defined on page 20 at paragraph [0072] as compound 1. Compound 1 will be referred to as IDE196 henceforth.
2 Compound 2, CAS # 606143-89-9, 5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide AKA 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide, ARRY 162, ARRY 438162, Binimetinib, MEK 162
Mektovi Binimetinib. Compound 2 will be referred to as Binimetinib henceforth.
3 The 16/666,108 application is not commonly assigned to IDEAYA. The application is assigned to Novartis AG, Reel frame number 55446/0806, which does not appear to have changed. US 2020/0262814 A1 is the PGPub and the resultant patent is US 11,059,804.