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 .
Current Status of 17/791,680
This Office Action is responsive to the amended claims and Applicant remarks of 12/12/2025. Claims 1, 3-12, and 14-20 are pending in the application and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/CN2021/077394, international filing date 02/23/2021, which claims priority to Chinese Patent Application No. 202010112976.3, filed 02/24/2020.
Response to Arguments
The Applicant arguments of 12/12/2025 have been fully considered but are not persuasive.
In section I of the arguments, Applicants do not address the teachings of the primary reference Wu, nor do they rebut the reference’s teachings. Accordingly, the examiner maintains the rejection for reasons set forth in the previous action.
The arguments presented in section II are unpersuasive because the examples relied upon to allege unexpected superiority compare the claimed compounds to general chemotherapeutic agents rather than other FGFR inhibitors. As the closest prior art comprises FGFR inhibitors, any showing of unexpected results must be demonstrated relative to other FGFR inhibitors. Accordingly, the comparisons relied upon do not substantiate the asserted unexpected results.
The arguments presented in section III are unpersuasive because they rely on the teachings of an exhibit submitted in a previous Office action. Applicants allege that the poster contains a direct comparison between the claimed FGFR inhibitor and other FGFR inhibitors. However, Figure 1 of the exhibit is illegible, and the alleged comparison cannot be determined. Accordingly, the exhibit does not provide persuasive evidence of the asserted unexpected clinical benefit. While Applicants may submit a legible exhibit demonstrating such a comparison, the arguments as presented fail to overcome the outstanding rejections.
Claim Rejections - 35 USC § 103 - Maintained
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.
Claims 1, 3-12, and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over Wu (WO 2018108079, publication date 21 June 2018) in view of Mahipal ("FGFR2 genomic aberrations: Achilles heel in the management of advanced cholangiocarcinoma." Cancer treatment reviews 78 (2019): 1-7.).
For ease of examination, the Examiner relied upon US Patent 10,208,042 B2 as an equivalent English translation of the Chinese WO 2018108079 publication. All citations henceforth to Wu are locations in the US Patent.
Determining the scope of the prior art:
Wu teaches:
A compound of formula (III),
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(Col 22, lines 15-25), reading on claims 1, and 3-5, which pertains to the claimed formula (I) wherein Y is CH, P is CR4, wherein R4 is
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and n=0; W is N and Ar is a phenyl substituted with one halogen.
A class of compounds (multi-kinases inhibitors) shown in formulas (I) and (II), or pharmaceutically acceptable salts and stereoisomers thereof, capable of regulating and/or modulating the activity of one or more protein kinases (Col 2, lines 34-38).
A crystal form I of the compound show in formula (III); and pharmaceutical formulation and pharmaceutical composition comprising the above compounds and/or the crystal form I, for use in treating diseases mediated by these kinase abnormalities, particularly cancer related diseases (Col 2, lines 39-44).
Methods for using the compounds, crystal form, pharmaceutical formulation and/or pharmaceutical composition to treat the above-described diseases in mammals, particularly humans (Col 2, lines 45-48), reading on instant claims 16 and 17.
A pharmaceutical formulation comprising the compounds of formula (I) or II), pharmaceutically acceptable salts or stereoisomers thereof, and/or comprising the crystal form I of the compound of formula (III) (Col 26, lines 16-20), reading on claim 15.
In one specific embodiment of the present invention, the composition may be used in a combined administration, in a “therapeutically effective amount”, of the aforementioned compound of formula (I) or (II) or pharmaceutically acceptable salts or stereoisomers thereof, and/or the aforementioned crystal form I of the compound of formula (III), along with one or more second therapeutic active agents, such as sequential administration, simultaneous administration, alternatively, the therapeutically active ingredients are formulated into a compound formulation for administration (Col 26 lines 61-67 and Col 27 lines 1-3), reading on claim 15.
The pharmaceutical formulations may further comprise one or more second therapeutic agents, which are antimetabolites, growth factor inhibitors, mitosis inhibitors, antineoplastic hormones, alkylating agents, metals, topoisomerase inhibitors, hormone drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoints or tumor immunotherapy-related antibodies or small molecular drugs (Col 26, lines 45-53), reading on claim 14.
The crystal form I of the compound of formula (III) has good inhibitory activity against a variety of kinases, indicating the compounds have a good clinical application potential in the treatment of diseases mediated by abnormal expression of various kinases such as Aurora, VEGFR2 (KDR), FGFR, FLT, and JAK (Col 76, lines 13-20, Table 6), reading on claim 7.
Mahipal teaches:
Cholangiocarcinomas is the most common aggressive biliary tract malignancy with dismal prognosis (Abstract, page 1), reading on claims 1 and 6
Depending upon the molecular structure and mechanisms of action, FGFR inhibitors are broadly classified into various classes such as- small molecule selective tyrosine kinase inhibitors (small molecule TKIs), non-selective small molecule TKIs, heat shock protein inhibitors, and FGFR monoclonal antibodies (Page 3)
Small molecule TKI suppressed the FGFR fusion oncogenic activity and inhibited the downstream MAPK signaling pathway. Since then, small molecule TKIs – Infigratinib (BGJ398) and Derazantinib (ARQ 087) have been well-explored with specificity against FGFRs (page 3),
Patients with tumors harboring FGFR2 translocations had a better prognosis as compared to that of patients without such translocations (page 3),
FGFR genetic aberrations were more commonly seen in in younger patients, tumors presented at early states, and were associated with longer overall survival (page 3),
Tumors are broadly classified into intrahepatic, perihilar and distal cholangiocarcinomas based on their anatomical location (page 1), reading on claim 12
FGFs are broadly classified into endocrine FGFs and paracrine/canonical FGFs. Endocrine FGFs play a key role in metabolism and bile acid, and mineral-phosphate homeostasis, whereas paracrine FGFs regulate cell cycle differentiation, proliferation and survival. FGFs are also known to play an essential role in the regulation of tissue fibrosis, cardioprotection following an ischemic injury, and epithelial/wound repair. Given this pervasive role of FGFs in various metabolic and cell survival pathways, any aberrations in the FGF-FGFR signaling may potentially lead to tumorigenesis (page 2),
Aberrations in FGF-FGFR pathway lead to tumorigenesis by effecting cell survival/apoptosis, proliferation, migration, and angiogenesis. This oncogenic potential of FGF pathway aberrations can be attributed to chromosomal translocations leading to FGFR auto-dimerization and activation; interaction of FGFs with vascular endothelial growth factors (VEGFs) promoting angiogenesis; and lastly, chromosomal aberrations leading to ligand-dependent and independent tumor formation and proliferation (page 2),
Fusion aberrations are commonly encountered in intrahepatic cholangiocarcinoma (FGFR2 fusions) (page 2),
Genomic studies have shown that FGFR2 fusion aberrations are implicated in approximately 15% of intrahepatic cholangiocarcinomas (page 2), reading on claim 20
FGFR inhibitors have demonstrated clinically meaningful responses in phase II trials. However, majority of patients with FGFR fusions did not achieve overall response. Moreover, the median duration of response is only 5-6 months (page 6), reading on claim 11
FGFR inhibitors have distinctive capabilities to incapacitate the newly developed resistant FGFR point mutations (page 6), reading on claim 11
Ascertaining the differences between the prior art and the claims at issue:
Wu does not explicitly teach biliary cancer or cholangiocarcinoma as species of cancer treated with compound of formula (I). Wu broadly teaches the genus of metals as an additional therapeutically active agent.
Mahipal does not teach the compound of formula (I) as a small molecule treatment of biliary cancer or cholangiocarcinoma.
Resolving the level of ordinary skill in the pertinent art:
Those of relevant skill in the art are those with the level of skill of the inventors of the references cited to support the Examiner’s positions.
Considering objective evidence present in the application indicating obviousness or nonobviousness:
The instant claims 1, 3-12 and 14-20 are prima facie obvious in view of the combined teachings of Wu and Mahipal.
The artisan would recognize the example compounds 22, 29, and 33-51 of Table 1 of Wu as compounds encompassed by the instant compound of formula (I). Based on the teachings of Mahipal, the specified compounds of Wu would be expected to be able to treat cholangiocarcinomas. The artisan would expect that the demonstrated ability of compound (III) to inhibit the activity of the FGFR kinase would be effective in inhibiting the same FGFR kinase pathway in cholangiocarcinomas. The artisan would also expect that compound (III) would modulate the activity of other protein kinases, such as Aurora kinase and VEGFR kinase, which are likely to be up-regulated in cholangiocarcinomas, reading on claim 7. This teaches claims 1, and 3-7.
Regarding claims 8, 18, 19, and 20, the artisan would have been further motivated to use the compounds of Wu for the treatment of cholangiocarcinoma with FGRF aberrations because cholangiocarcinoma bearing these aberrations are identified in the earlier stages of the cancer, resulting in better prognosis and longer overall survival of patients (Mahipal, page 2 and 3). Regarding claim 9-10, the artisan would have been motivated to specifically target FGFR2 fusion mutations as they are implicated in 15% of intrahepatic cholangiocarcinomas (Mahipal, page 2). The artisan would recognize that intrahepatic, perihilar, and distal cholangiocarcinomas are the broad classifications of the cancer based on its anatomical location (Mahipal, page 1). The artisan would expect that the multi-kinase inhibitor of compound (III) would be able to target overexpression of not just FGFR kinases, but in Aurora kinases and VEGFR kinases. The artisan would recognize that overexpression of these kinases is a hallmark of intrahepatic, perihilar, and distal cholangiocarcinomas and would expect that a multi-kinase inhibitor that affects these kinases would be effective in treating the types of cholangiocarcinomas previously listed, reading on claim 12. The artisan would expect that cholangiocarcinomas being treated with FGFR inhibitors would develop resistance to the treatment (Mahipal, page 6) and that FGFR inhibitors are capable of combatting the newly developed resistances (Mahipal, page 6), reading on claim 11. The artisan would have expected that targeting the FGFR2 fusion aberration with the kinase inhibitor of Wu would result in improved prognosis, earlier detection, and higher survival for patients as this is the most prevalent aberration of FGFR. This teaches claims 8-12 and 18-20.
The artisan would have been motivated to use the compounds of general formula (I) or the pharmaceutically acceptable salt, the stereoisomer and the crystal form thereof with one or more therapeutic active agents (Col 26, lines 45-53) as part of a treatment for cholangiocarcinoma in a human patient, reading on instant claims 16-17. The artisan would recognize that anti-neoplastic hormones are a species of the genus of anti-tumor hormones, and similarly recognize that metallic platinum is a species of the genus of metals, reading on claim 14. Wu is silent on the species. The artisan would be motivated to use a platinum metal as part of the treatment of cholangiocarcinoma because systemic therapy with gemcitabine and cisplatin is the gold standard therapeutic option for treatment of the disease (Mahipal, page 1), reading on claim 14. The artisan would expect that the combination therapy using the compounds of Wu with a platinum metal agent, such as cisplatin, would result in improved prognosis/patient outcomes. The artisan would be motivated to use compound (III), in the form of a pharmaceutically acceptable salt, stereoisomers of the compound or its crystal form in combination with an additional therapeutic agent in the method of treatment (Wu, Col 26 lines 61-67 and Col 27 lines 1-3). The artisan would expect that the administration of (III) in any of these forms in combination with the administration of an additional therapeutic agent sequentially, simultaneously, or in combination would provide effective therapeutic intervention, reading on claim 15. This teaches claims 14-17.
Double Patenting – Maintained Rejection
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.
Claims 1, 3-12 and 14-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 10,208,042 in view of WO 2018108079 in view of Mahipal. The instant claims of 07/08/2022 were used to write this rejection.
Although the claims at issue are not identical, they are not patentably distinct from each other because the combined teachings of the references above make obvious the instant claims. US 10,208,042 teaches compound of Formula (III), reading on compound 29 of claims 1-5. US 10,208,042 does not teach the claimed method of treating biliary tract cancer.
The teachings of WO’079 and Mahipal are discussed above and are incorporated into this rejection.
It would have been obvious to use the compound of US 10,208.042 to treat biliary tract cancer for the same reasons discussed in the above rejection.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625