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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/01/2025 has been entered.
Current Status of 18/138,545
The rejections of record have been withdrawn below.
This Office Action is responsive to the amended claims of 10/01/2025.
Claims 1-14 and new claim 16 are examined on the merits. Claim 15 is still withdrawn.
Priority
This application claims priority to U.S. Patent 11633401, which is a national stage entry of PCT/US2019/040647, which claims priority to 62/694,519.
The instant claims find support from 62/694,519. Therefore, the effective filing date is 7/6/2018.
Response to Arguments
Applicants’ claim amendments and Remarks of 10/01/2025 are acknowledged and have been considered.
Any rejection and/or objection not specifically addressed or modified below is herein withdrawn.
In regard to the 112(a) rejection, this rejection is withdrawn. Applicants submit that preventing metastases in pancreatic cancer is not unpredictable. Applicants submit Figure 5(B) and Figure 28(I) which the use of trametinib and palbociclib inhibited the formation lung metastases in a mouse model for metastatic pancreatic cancer. After a review of these figures, Examiner agrees.
In regard to the obviousness rejection, this rejection is withdrawn. Applicants remarks with Examiner’s reply are summarized below:
Applicants submit that none of the art relates to methods of preventing lung metastases. Infante expressly teaches that the combination did not improve overall survival, progression free survival, overall response rate, and duration of response in subjects with previously untreated metastatic cancers cancer.
NIH does not have any clinical results for the treatment cohorts.
Applicants submit unexpected, synergistic effects of MEK/CDK4/6 inhibitor combination therapy in the treatment of pancreatic cancer that is resistant to chemotherapeutic agents.
Figures 3A-3B from the instant application show that the combination therapy with trametinib and palbociclib significantly increased survival and reduced tumor progression in an animal model known to be resistant to gemcitabine.
Applicants respond to Examiner’s comments from the last Office Action. Agents were administered at the same dosage in the single and combination treatment groups.
Palbociclib alone did not increase percent survival over vehicle, whereas trametinib monotherapy led to a modest increase in survival.
With Applicants added explanation and details, examiner understands that the combination of trametinib and palbociclib significantly increased survival by approximately 43% and 57% (synergistic effect).
While Applicants submit unexpected results for trametinib and palbociclib, there are not unexpected results for the whole scope of base claims 1 and 16. This still leaves other obviousness rejections to be considered.
Response to Amendment
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.
Claim(s) 1-7, 9, 12-14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Franco (Franco et al., “CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer”, Oncotarget, August 15, 2014) as evidenced by Sharaite (Sharaite et al., “Anticancer Activity of Sunitinib Analogues in Human Pancreatic Cancer Cell Cultures under Normoxia and Hypoxia”, International Journal of Molecule Sciences, March 12, 2023) and in view of ONCOLINK (“Pancreatic Cancer”, Oncolink, March 26, 2006, previously cited).
Franco teaches that MEK inhibitors potently cooperated with CDK4/6 inhibition and that these agents were synergistic with CDK4/6 inhibition, and yielded potent inhibition of Pancreatic ductal adenocarcinoma (PDA) tumor cell growth (abstract). PDA is a pancreatic cancer of claim 6.
Franco teaches “MEK inhibitors also had additive effects in concert with CDK4/6 suppression” (page 6520). Franco teaches this combination in Figure 4B middle and Figure 6 E. This teaches PD-0332991(palbociclib, as a species of CDK4/6 inhibitor) and AZD6244 (selumetinib, as a species of MEK inhibitor), of claims 2-3.
Franco uses Human pancreatic cancer cell lines PL45, MIAPACA-2, PANC1, CAPAN2, BXPC3, HS 766T, ASPC1, PL5 (page 6521).
Sharaite is relied upon for the beneficial teaching that PANC1 is a cell line known to be resistance to chemotherapy (page 2). This teaches claim 4.
ONCOLINK teaches that exocrine pancreatic cancer is 90-95% of all pancreatic cancers and it arises from exocrine cells that secrete digestive enzymes (page 5). This helps teach claim 5.
Franco teaches that these cell lines carried KRAS mutation (page 6513). This teaches claim 7.
The artisan would have expected the pharmaceutical composition to treat Pancreatic ductal adenocarcinoma (PDA) in a subject because the pharmaceutical composition is effective in the in vitro model (Franco Abstract). This teaches claims 1-4, 6-7, and 12.
It is obvious to administer to any pancreatic cancer patient, including a sub-population of exocrine pancreatic cancer patients and pancreatic ductal adenocarcinoma. Without evidence to the contrary, nothing precludes exocrine pancreatic cancer patients from the combined treatment. This teaches claims 5, and 13-14.
The artisan would be motivated to administer the combined treatment of a MEK inhibitor and CDK4/6 inhibitor simultaneously, sequentially, and separately. The artisan would expect to combination Franco treatment to be administered simultaneously since simultaneous administration is one of two ways that a combination of compounds can be administered to a subject. Furthermore, the artisan would be motivated to administer Franco’s combination treatment sequentially and separately, because these ways of administration are the other way to administer compounds to subjects. Therefore, the artisan would naturally come to the conclusion to administer the combined treatment separately, sequentially, or simultaneously. This teaches claim 9.
The artisan would also expect that Franco’s combination treatment given to the same patient population would prevent lung metastases. It is obvious to administer the combination treatment to any pancreatic cancer patient, including that sub-population, because nothing precludes them from the treatment. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Chemical properties are inherent to their compounds. See MPEP 2112 (II). Products of identical chemical composition can not have mutually exclusive properties. A chemical composition, trametinib and palbociclib, and its properties, preventing lung metastases, are inseparable. See MPEP 2112.01 (II). This rejects claim 16.
Claim(s) 1-14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Franco (Franco et al., “CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer”, Oncotarget, August 15, 2014) as evidenced by Sharaite (Sharaite et al., “Anticancer Activity of Sunitinib Analogues in Human Pancreatic Cancer Cell Cultures under Normoxia and Hypoxia”, International Journal of Molecule Sciences, March 12, 2023) and in view of Magliano (Magliano et al., “Roles for KRAS in Pancreatic Tumor Development and Progression”, Gastroenterology, Jan 27, 2014), in view of FDA (“Palbociclib (IBRANCE)”, FDA, March 2017) and in view of Dombi (Dombi et al., “Activity of Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas”, The New England Journal of Medicine, December 29, 2016).
Claim(s) 1-7, 9, 12-14, and 16 are taught above.
The Kras gene is mutated to an oncogenic form in most pancreatic tumors, specifically Kras G12D is common (Magliano abstract). This teaches claim 8.
It is obvious to administer to any pancreatic cancer with a KRAS mutation, including a sub-population of KRAS G12D mutations. Without evidence to the contrary, nothing precludes claim 8’s specific KRAS mutations in pancreatic cancer patients from the combined treatment. This teaches claim 8.
FDA teaches that Palbociclib is known to be administered orally (page 1).
Dombi teaches that Selumetinib is known to be administered orally (Methods).
This teaches PD-0332991(palbociclib, as a species of CDK4/6 inhibitor) and AZD6244 (selumetinib, as a species of MEK inhibitor), of claims 2-3.
Because these compounds are known to be administered orally, the artisan would be motivated to administer the combined treatment of selumetinib and palbociclib (of Franco) by oral administration. This teaches claims 10-11.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GILLIAN A HUTTER whose telephone number is (571)272-6323. The examiner can normally be reached M-F 7:30-5.
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/G.A.H./ Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625