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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 27, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Restriction/ Election -- Claim Status
Claims 1-18 are currently pending. Applicant’s election without traverse of
PNG
media_image1.png
123
120
media_image1.png
Greyscale
in the reply filed on Oct. 1, 2025 is acknowledged.1 Claims 1-10 and 12-18 read on the elected species. Claims 11 is withdrawn. Claims 1-10 and 12-18 are active and subject to examination.
Claim Rejections - 35 USC § 112(b)
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 10 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 10 is directed towards the compound of claim 1, wherein the compound has the structure:
PNG
media_image2.png
202
474
media_image2.png
Greyscale
One of ordinary skill in the art cannot determine the metes and bounds of the claim because is unclear how the retention times under these conditions are further limiting to the compound. The retention time is just an inherent property of the compound and does not further limit the compound’s structure or attributes. Appropriate correction is required.
Claim 16 recites the limitation "the mutant RAS" in line 1. There is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
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.
Claim(s) 1-10 and 12-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fell et al. (Journal of Medicinal Chemistry, Vol. 63, Issue 13, April 6, 2020, p. 6679-6693) in view of Wang et al. (US 2023/0072276 A1; published Mar. 9, 2023; filed Dec. 15, 2021).
Claim 1 is directed towards a compound of formula
PNG
media_image3.png
151
130
media_image3.png
Greyscale
, which are useful as inhibitors of KRAS for the treatment of cancer. For example, the Applicant elected the compound
PNG
media_image4.png
141
139
media_image4.png
Greyscale
(claim 8).
Fell teaches the clinical development candidate MRTX849, which is a potent and selective inhibitor of mutant KRAS:
PNG
media_image5.png
320
1209
media_image5.png
Greyscale
Fell, Abstract;
PNG
media_image6.png
340
307
media_image6.png
Greyscale
Fell, Fig. 1, p. 6680.
While MRTX849 differs from the compound of formula I in that there is a substituted piperazine attached to the core instead of naphthyridine, one of ordinary skill in the art would have a reasonable expectation of success to exchange piperazine for naphthyridine because KRAS inhibitors with such fused ring systems are commonly known in the art.
For example, Wang teaches a similar KRAS inhibitor:
PNG
media_image7.png
201
269
media_image7.png
Greyscale
(Wang, Specification, Example 246, paragraph 1311). This compound is so similar to the compounds of formula I that one of ordinary skill in the art would expect them to have similar properties. While this inhibitor differs from formula 1 in that the fused ring system is pyridoazepine instead of pyridopiperidine, Wang also teaches that this group could be pyridopiperidine:
PNG
media_image8.png
183
336
media_image8.png
Greyscale
PNG
media_image9.png
119
184
media_image9.png
Greyscale
PNG
media_image10.png
217
299
media_image10.png
Greyscale
PNG
media_image11.png
128
299
media_image11.png
Greyscale
PNG
media_image12.png
59
304
media_image12.png
Greyscale
PNG
media_image13.png
59
301
media_image13.png
Greyscale
PNG
media_image14.png
17
92
media_image14.png
Greyscale
Wang, Specification, paragraphs 0086-0112.
As shown in the paragraphs above, Wang also teaches that the pyridopiperidine can be substituted with methyl and fluoro as in the claimed compound.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claims 2-10 read on the claimed compound and as such were prima facie obvious for the reasons given in the rejection of claim 1.
Claim 12 is directed towards a pharmaceutical composition comprising the compound of claim 1 and a pharmaceutical adjuvant.
One of ordinary skill in the art would have a reasonable expectation of success to formulate a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable adjuvant because similar compositions are commonly known in the art.
For example, Fell teaches pharmaceutical compositions comprising the similar compound MRTX849 in a vehicle of Captisol and 50 mM citrate buffer pH 5.0 (Fell, col. 1, p. 6690).
Therefore, claim 12 was prima facie obvious at the time of filing.
Claim 13 is directed towards a method of inhibiting RAS in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of formula I to a subject in need thereof, and the RAS is wild type RAS or mutant RAS and the mutant RAS is KRAS, HRAS, or NRAS. Claim 14 is directed towards the method of claim 13, wherein the KRAS mutation is a G12 mutation.
One of ordinary skill in the art would have a reasonable expectation of success to inhibit mutant G12 KRAS in a subject in need thereof because similar compounds are commonly known in the art to inhibit mutant RAS. For example, as shown in the rejection of claim 1, Fell teaches that the similar compound MRTX849 is a potent inhibitor of mutant KRASG12C.
Therefore, claims 13-14 were prima facie obvious at the time of filing.
Claim 15 is directed towards a method for treating or preventing a RAS related disease in a subject in need thereof comprising administering a therapeutically effective amount of the compound of formula I. Claim 16 is directed towards the method of claim 15, wherein the mutant RAS is a KRAS wherein the KRAS mutation is KRAS G12C and/or the RAS-related disease is a cancer selected from the group consisting of colon cancer, appendiceal cancer, pancreatic cancer, MYH-related polyposis, hematologic cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma. Claim 17 is directed towards a method for treating or preventing cancer in a subject in need thereof, comprising administering an effective amount a compound of formula I. Claim 18 is directed towards the method of claim 17, wherein the cancer is selected from the group consisting of colon cancer, appendiceal cancer, pancreatic cancer, MYH-related polyposis, hematologic cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.
One of ordinary skill in the art would have a reasonable expectation of success to treat a cancer patient, wherein the cancer patient has, for example, lung cancer with a KRASG12C mutation because similar compounds are commonly known in the art to inhibit mutant RAS to treat cancers such as lung cancer.
For example, Fell teaches that MRTX849 inhibits mutant KRASG12C for the treatment of cancers such as lung cancer:
KRAS is the single most frequently mutated oncogene and the first of more than 700 genes to be causally implicated in human cancer (COSMIC). (1) Mutations in KRAS are prevalent amongst the top three most deadly cancer types in the United States: pancreatic (95%), colorectal (45%), and lung (35%). (2) Its frequent mutation across a spectrum of aggressive cancers has stimulated an intensive drug discovery effort to develop therapeutic strategies that block KRAS function for cancer treatment. Despite nearly four decades of research, a clinically viable KRAS cancer therapy has remained elusive largely because of its high affinity for GTP and lack of a well-defined binding pocket. (3−6) However, recent findings have stimulated a new wave of activities to develop KRAS-targeted therapies.
Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target’s resurgence. (7,8) Central to this renewal is a single mutation: KRASG12C, a well-validated driver mutation and the most frequent individual KRAS mutation in lung cancer. (4) Associated with poor prognosis and resistance to treatment, KRASG12C represents both an extraordinary unmet clinical need and opportunity. This mutation has a causal role in 14% of lung adenocarcinomas (∼14,000 new US cases annually) and 5% of colorectal adenocarcinomas (∼5000 new US cases annually) and is present in smaller fractions of other cancers. Collectively, KRASG12C mutations comprise a patient population with a worldwide annual incidence of greater than 100,000 individuals. A novel scientific basis for targeting KRASG12C was recently described in a breakthrough article by Shokat and Wells, in which they identified a previously unknown allosteric pocket near the nucleotide binding site. (9) Small molecules binding to this pocket can inhibit signaling through KRAS by locking the protein in its inactive GDP-bound state. (10−13) Although targeting this site with covalent, small-molecule inhibitors was a clear advancement, it was also evident that the molecules identified required significant optimization to achieve drug-like potency and pharmaceutical properties.
As previously reported, compound 1 (Figure1) is an irreversible covalent inhibitor of KRASG12C that binds in the switch-II pocket of KRAS and makes a covalent bond to cysteine 12. (14) Inhibitor 1 showed robust target engagement in a PK/PD experiment using MIA PaCa-2 tumor bearing mice when dosed IP. In a related tumor growth inhibition (TGI) experiment, compound 1 demonstrated rapid regressions with cures when dosed as low as 30 mg/kg IP once a day. While providing a valuable tool compound, inhibitor 1 demonstrated clearance (CL) of 46 mL/min/kg following a 3 mg/kg IV dose to CD-1 mice and oral bioavailability of 2.4% with a 100 mg/kg PO dose. The pharmacokinetic limitations of 1 necessitated several iterations of optimization to identify a tractable clinical candidate. Described in this paper are the insights that led to the discovery of the clinical candidate MRTX849.
Fell, p. 6679-6680.
Therefore, claims 15-18 were prima facie obvious at the time of filing.
Nonstatutory 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.
Claim 1-10 and 12-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of of copending Application No. 18/249,993 (reference application) in view of Wang et al. (US 2023/0072276 A1; published Mar. 9, 2023; filed Dec. 15, 2021). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application and the reference application are directed towards patentably indistinct KRAS inhibitors which differ only by the fused ring system which is taught by Wang.
The claims of the instant application read on the compound:
PNG
media_image1.png
123
120
media_image1.png
Greyscale
. The copending application claims the compound:
PNG
media_image15.png
148
150
media_image15.png
Greyscale
. These compounds differ by only two atoms. The claimed compound has a pyridopiperidine instead of pyrazolopiperidine. One of ordinary skill in the art would have a reasonable expectation that these highly similar compounds would have similar properties because Wang teaches that the piperidine can be fused with a heteroaryl (A heteroaryl preferably has 5, 6, 9 or 10 ring atoms (Wang, Specification, paragraph 0081)):
PNG
media_image8.png
183
336
media_image8.png
Greyscale
PNG
media_image9.png
119
184
media_image9.png
Greyscale
PNG
media_image10.png
217
299
media_image10.png
Greyscale
PNG
media_image11.png
128
299
media_image11.png
Greyscale
PNG
media_image12.png
59
304
media_image12.png
Greyscale
PNG
media_image13.png
59
301
media_image13.png
Greyscale
PNG
media_image14.png
17
92
media_image14.png
Greyscale
Wang, Specification, paragraphs 0086-0112.
Claims 1-10 read on the compound shown above.
Therefore, claims 1-10 are provisionally rejected on the grounds of nonstatutory double patenting.
Claims 12-18 read on the same compositions and methods of treatment as in claims 14-17 of the reference application and are therefore provisionally rejected on the ground of nonstatutory double patenting.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is found to be allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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, Jeffrey Lundgren can be reached on (571) 272-5541. 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 86-217-9197 (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.
/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).