DETAILED ACTION
Claims 344-363 are currently pending in the instant application and are rejected.
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 .
Notice of Non-Compliant Amendment
The amendment document filed on 8/1/2024 is considered non-compliant because it has failed to meet the requirements of 37 CFR 1.121 or 1.4. In order for the amendment document to be compliant, correction of the following item(s) is required.
Claims 334-343 are not present in the claim amendment filed 1 August 2024. Claims 1-333 are indicated as canceled in the claim amendment filed 1 August 2024 and claims 344-363 are provided as “(New).”
The remarks filed 1 August 2024 indicate that Claims 1-343 have been canceled and claims 344-363 have been added.
As such, a complete listing of all the claims is not present.
A response should include a proper claim set providing claims 1-343 canceled as such:
1.-343. (Canceled)
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) 344-356, 359, and 360 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 8,987,267 By Reddy et al. (herein referred to as “Reddy et al.”) in view of Reddy et al. J. Med. Chem. 2014, 57, 578-599 (herein referred to as “Reddy et al. (2014)”) and in further view of Colon-Otero et al. ESMO Open, 2020, 5, e000926.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Reddy et al. teach compounds (abstract) “as anti-proliferative agents and kinases” having the following general formula or pharmaceutically acceptable salts thereof (column 29):
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The prior art particularly teaches 8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically acceptable salt thereof in claim 13 of the patent (column 30).
Regarding utilities, Reddy et al. teaches the treatment of gynecological cancers including cancers of the uterus, e.g. endometrial carcinoma (column 14) with claim 18 providing wherein the tumor cells are uterine.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art generally teaches the application of 8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically acceptable salt thereof in gynecological cancers including cancers of the uterus, e.g. endometrial carcinoma, but does not particularly teach application in hormone receptor positive endometrial cancer. Additional limitations of dependent claims are addressed below.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2141.02)
Regarding specific properties, Reddy et al. (2014) teach on page 588: ”Compound 7x, with a 4-(4-methyl-piperazin-1-yl) phenylamine group at C-2 position, cyano group at C-6 position, and cyclopentyl at N-8 position showed optimum biological activity. The biochemical and biological studies presented here show that this compound is a potent inhibitor of CDK4 and CDK6 kinases and in this aspect is comparable to PD-0332991, a dual CDK4/6 inhibitor that is currently in clinical trials.” Compound 7x is depicted in the abstract of Reddy et al. (2014) and is 8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidine-6-carbonitrile.
Colon-Otero et al. teach a study involving ribociclib and letrozole and the following result (Conclusion section of the abstract): “Ribociclib and letrozole have promising clinical activity in relapsed ER-positive OC and EC, particularly in LGSOC and relapsed ER-positive grade 1 and 2 EC.” Colon-Otero et al. further teach that ribociclib and palbociclib belong to the same class of inhibitors on page 2: “CDK inhibitors (palbociclib, ribociclib and abemaciclib) have been developed and shown on clinical trials to significantly prolong PFS (palbociclib, ribociclib and abemaciclib) and overall survival (OS) (ribociclib and abemaciclib) when combined with AIs or
fulvestrant in the treatment of metastatic ER-positive breast cancer, leading to approval by the Food and Drug Administration.16–18” Page 2 provides in the abstract that 2.5mg of oral letrozole is administered daily.
Since Colon-Otero et al. teach the useful of a CDK4/6 inhibitor in treating relapsed oestrogen receptor (ER)-positive endometrial cancer and Reddy et al. demonstrate 8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidine-6-carbonitrile has similar properties, a person having ordinary skill in the art would have reasonably expected 8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidine-6-carbonitrile to be similarly useful in treating hormone receptor positive endometrial cancer, particularly ER positive endometrial cancer. In the interest of determining which particular CDK4/6 inhibitor would provide best therapeutic results, a person having ordinary skill in the art would have been motivated to test known CDK4/6 inhibitors in treating ER positive endometrial cancer with letrozole. Such as approach would meet the limitations of instant claims 344, 348, 351-356, 359, and 360. Please see paragraph [0066] of the instant specification which provides that letrozole as an estrogen receptor blocker and an aromatase inhibitor: “in combination with an estrogen receptor blocker, e.g., an aromatase inhibitor such as letrozole.”. Instant specification paragraph [0068] provides letrozole as an estrogen receptor blocker.
Regarding instant claims 346, 347, and 349, Colon-Otero et al. teach the use of 400 mg of oral ribociclib. At least in the interest of comparing the instantly claimed combination, a person having ordinary skill in the art would have been motivated to apply analogous dosing. Furthermore and regarding instant claim 350, Reddy et al. teach modes of administration in column 18 including oral and intravenous. A person having ordinary skill in the art seeking to optimize delivery would have been motivated to test the administration routes taught by Reddy et al. for 8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidine-6-carbonitrile. Reddy et al. further teach a dosage range of about 1 to about 500 mg in column 16, lines 62 and 63, preferably about 10 to about 100mg.
Regarding instant claim 345, Reddy et al. teach pharmaceutically acceptable salts in column 15, lines 29-67 including the use of lactic acid as an acid in line 49. A person having ordinary skill in the art in seeking to determine an optimum formulation would have at least been motivated to test the explicit acids taught by the prior art in various ratios.
Claim(s) 357, 358, and 361-363 is/are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 8,987,267 By Reddy et al. (referred to as “Reddy et al.”) in view of Reddy et al. J. Med. Chem. 2014, 57, 578-599 (referred to as “Reddy et al. (2014)”) and in further view of Colon-Otero et al. ESMO Open, 2020, 5, e000926, as applied to claims 445-452, 454-456, 459 and 460 above, and in further view of A.L. Covens et al. (Gynocologic Oncology 120, (2011) 185-188 and/or MacKay et al. Gynecological Cancer, 2020 ASCO Educational Book 245-255.
The first rationale above does not address the presence of the additional compounds of instant claims 357, 358, and 361-363. A.L. Covens et al. teaches the use of fulvestrant, (a selective estrogen receptor degrader as embraced by claim 361), in ER postivie patients with the median progession free survival and overall survival in the ER positive patients 10 and 26 months, as compared to 2 and 3 months in the ER negative patients (abstract). A.L. Covens et al. also provides on page 188 that the standard hormonal therapy for ER/PR positive patients remain megestrol acetate +/- tamoxifen. Megestrol acetate is a progestin as embraced by claims 357 and 358 MacKay et al. provides the use of CDK4/6 inhibitors on page 248 referenceing ribociclib and letrozole in ER+ endometrial cancer. Page 248 provides the use of tamoxifen and fulvestrant, Figure 2. Page 247 provides PI3K/AKT pathway inhibitors and includes discussion on megestrol acetate and tamoxifen. Page 249 provides additional PI3K/AKT pathway targeting. Page 250 provides aflibercept and bevacizumab (acting on the VEGF receptor as embraced by instant claim 362). The instant claims place no limitation on the order of administration or any particular overlap and would encompass administration of the discussed additional second agents and 8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidine-6-carbonitrile, which would be suggested by a person having ordinary skill in the art seeking to study the effect of the combination of 8-cyclopentyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidine-6-carbonitrile and a secondary agent.. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Thus, the skilled artisan would reasonably expect success in this combination.
Conclusion
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/REBECCA L ANDERSON/Primary Examiner, Art Unit 1626 ____________________ 17 August 2026
Rebecca Anderson
Primary Examiner
Art Unit 1626, Group 1620
Technology Center 1600
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