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 .
Status of the Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on February 8,2024, wherein claims 1-6 are cancelled; claims 11-18 are newly added.
Claims 7-18 are currently pending and under examination.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. CN2021/111878, filed on Aug. 10 2021. As such, the effective filling date of claims is Aug. 10 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/08/2024 and 09/16/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 7-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while enabling treatment of only lung cancer and stomach cancer carrying MET exon 14 skipping mutation administering to a subject in need a therapeutically effective amount of ensartinib or a salt, does not reasonably provide enablement for the full scope of the claim. The claim contains subject which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with the claim.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG V. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
the nature of the invention
the state of the prior art
the predictability of the art
the amount of direction or guidance provided
the presence or absence of working examples
the breadth of the claims
the quantity of experimentation necessary
the relative skill of those in the art
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
I. The nature of the invention – The invention is directed to a method of treating diseases carrying a MET exon 14 skipping mutation in a subject by administering a compound of Formula I, i.e., ensartinib or a salt thereof. The claimed invention is not limited to a single cancer type, but instead encompasses treatment of multiple cancers or diseases carrying MET exon 14 skipping mutation.
II. The state of the art – The art supports MET exon 14-targeted treatment primarily in lung cancer/NSCLC, not across the full scope of cancers recited or encompassed by the instant claims. For example, Paik et al. (NEJM 2020 383(10) 931-943) teaches that MET exon 14 skipping occurs in 3–4% of NSCLC patients and that tepotinib is a highly selective MET inhibitor(see e.g. p.931, Abstract/Background); Paik et al. administered tepotinib 500 mg once daily to patients with advanced or metastatic NSCLC having confirmed MET exon 14 skipping mutation(see e.g. p.931, Methods); and Paik et al. reports a 46% independent-review response rate and conclude that tepotinib was associated with partial response in approximately half of such patients (see e.g. p,931, Results/Conclusions).
Paik et al. further teaches that MET exon 14 skipping alterations are primary oncogenic drivers in NSCLC and that MET inhibitors being evaluated for this population include crizotinib, tepotinib, savolitinib, and capmatinib(see e.g. p. 932 col. 1 ). Paik et al. also teaches in the Discussion that tepotinib showed durable antitumor activity in advanced NSCLC with MET exon 14 skipping mutations and compare tepotinib results with crizotinib and capmatinib studies in NSCLC with MET exon 14 skipping mutations (see e.g. p. 937, col. 2 discussion).
Yang et al. ( J. Thorac oncol. 2021, 16(3):e17-e19) teaches in the case report/results section that a patient with lung adenocarcinoma had a novel MET exon 14 skipping variant, was treated with crizotinib 250 mg twice daily, and after 1.5 months showed reduced chest and brain lesions with clinical evaluation of partial response (see e.g. p. e18 col. 1). Yang et al. further conclude in the summary that the lung adenocarcinoma patient with the novel MET exon 14 skipping variant was sensitive to crizotinib(see e.g. p. e18 col. 1).
The FDA approved capmatinib and tepotinib on May 6, 2020, and February 3, 2021, respectively. Capmatinib is indicated for patients with metastatic non–small cell lung cancer (mNSCLC) whose tumors have a mutation leading to mesenchymal–epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. Tepotinib is indicated for mNSCLC harboring MET exon 14 skipping alterations.
Thus, the art provides support for treatment of MET exon 14-altered lung cancer/NSCLC with MET inhibitors, including tepotinib, capmatinib, and crizotinib. However, the art does not provide comparable evidence or guidance for treating the full range of additional cancers encompassed by the instant claims.
III. The predictability or unpredictability of the art – The pharmaceutical and oncology arts are unpredictable. The instant specification itself acknowledges that different targeted drugs may show promising therapeutic effects against cancers caused by specific mutations, but the efficacy against cancers caused by other gene mutations remains unpredictable. Accordingly, a showing that a MET inhibitor treats one MET exon 14-altered cancer type does not, without more, establish that ensartinib would treat every cancer type recited or encompassed by the claims.
The art shows that MET exon 14 skipping can be an actionable driver in NSCLC, and that several MET inhibitors have clinical activity in NSCLC. However, that does not make it predictable that ensartinib would treat all other claimed cancers carrying MET exon 14 skipping mutation, including cancers arising from different tissues and having different tumor biology, co-mutation profiles, pharmacologic sensitivities, and clinical treatment standards.
IV. The amount of direction or guidance presented – The instant specification provides guidance only for a narrow portion of the claimed scope. The specification states that ensartinib or a salt thereof can significantly inhibit MET exon 14 skipping mutation kinase activity, inhibit proliferation of human gastric cancer Hs746T cells carrying MET exon 14 skipping mutation, and show anti-tumor activity in a xenograft tumor model carrying MET exon 14 skipping mutation. The specification further describes Hs746T human gastric cancer cells carrying MET exon 14 skipping mutation and reports that ensartinib dose-dependently inhibited proliferation of Hs746T cells with an IC50 of 31 nM. The specification also describes an Hs746T xenograft model using Hs746T cells carrying MET exon 14 skipping mutation and administration of ensartinib hydrochloride.
Therefore, the specification provides direct experimental guidance for gastric cancer models carrying MET exon 14 skipping mutation. The art provides additional guidance for lung cancer/NSCLC settings, as discussed above. However, neither the specification nor the art provides sufficient guidance showing that ensartinib would be effective for the full scope of other claimed cancers.
V. The presence or absence of working examples – The specification provides working examples for MET exon 14-altered gastric cancer models, including Hs746T cell proliferation and Hs746T xenograft tumor studies. The art provides clinical support for MET exon 14-altered NSCLC/lung adenocarcinoma, including tepotinib-treated NSCLC in Paik et al., crizotinib-treated lung adenocarcinoma in Yang et al.
However, the specification does not provide working examples for the additional cancers recited or encompassed by the claims, such as colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, skin cancer, bone cancer, glioma, papillary renal cell carcinoma, or head and neck squamous cell carcinoma. The prior art also does not provide compensatory guidance sufficient to enable treatment of those additional cancers with ensartinib.
VI. The breadth of the claims – The claims are broad because they encompass treatment of many different cancers or diseases merely because they carry a MET exon 14 skipping mutation. The specification lists diseases carrying MET exon 14 skipping mutation including lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, gastric cancer, skin cancer, bone cancer, glioma, papillary renal cell carcinoma, and squamous cell carcinoma of the head and neck. These cancers arise from different tissues, involve different tumor microenvironments and co-mutation patterns, and are treated with different clinical regimens. The disclosure is not commensurate with this breadth.
VII. The quantity of experimentation necessary – The amount of experimentation required would not be reasonable because a skilled artisan would need to determine, for each additional claimed cancer type, whether ensartinib is effective, whether the tumor is sufficiently dependent on MET exon 14 signaling, what dose and schedule would be effective, whether the compound reaches the relevant tumor site, and whether co-occurring alterations confer resistance. This would require substantial cancer-by-cancer experimentation, including in vitro testing, in vivo models, pharmacologic evaluation, and clinical investigation. Such work would go beyond routine optimization because the specification and the art provide support only for gastric cancer models and lung/NSCLC clinical settings.
VIII. The level of skill in the art – The level of ordinary skill in the art may be found by inquiring into: (1) the type of problems encountered in the art; (2) prior art solutions to those problems; (3) the rapidity with which innovations are made; (4) the sophistication of the technology; and (5) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962 (Fed. Cir. 1986). Based on the typical education level of active workers in the pharmaceutical and oncology arts, as well as the high degree of sophistication required to solve problems encountered in targeted cancer therapy, the Examiner finds that a person of ordinary skill in the art would have at least a college degree in a field related to medicine, oncology, pharmaceutical science, or medicinal chemistry, and at least several years of relevant experience, such as a masters or doctorate level scientist/clinician.
Although the level of skill in the art is high, the breadth of the claims, the unpredictability of oncology treatment, the limited guidance in the specification, and the limited prior-art support do not enable the full scope of the claims.
Therefore, claims 7–18 are rejected because the Wands factors suggest a conclusion that the skilled artisan would not be able to make and use the full scope of the claimed invention without undue experimentation. The specification provides experimental support for gastric cancer models carrying MET exon 14 skipping mutation, and the prior art provides clinical support for lung/NSCLC settings using MET inhibitors such as tepotinib, capmatinib, and crizotinib. However, the claims are broader than those supported embodiments and encompass numerous additional cancers for which neither the specification nor the art provides sufficient guidance or working examples. Accordingly, the specification enables, at most, the limited disease scope demonstrated in the examples and supported by the art, but does not enable the full breadth of claims 7–18.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 7 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xia et al. (Xia et al. A single-arm, multicenter phase II clinical study to evaluate the efficacy of Ensartinib in patients with advanced or metastatic non-small cell lung cancer harboring MET 14 exon skipping mutation, ChiCTR2100048767, https://www.chictr.org.cn/showprojEN.html?proj=130131 July 16 2021).
Xia et al. discloses a Phase II clinical trial, single-arm, multicenter phase II clinical study to evaluate the efficacy of ensartinib in patients with advanced or metastatic non-small cell lung cancer harboring MET 14 exon skipping mutation, to evaluate the ORR of ensatinib in the treatment of NSCLC patients with MET exon 14 skipping mutation ( See, https://www.chictr.org.cn/showprojEN.html?proj=130131 line 5, trial title, line 34, Objectives of Study). Xia et al. teaches a method of treating disease carrying MET exon 14 skipping mutation, comprising administering to a subject in need thereof a therapeutically effective amount of ensartinib. The patients of Xia et al. are subjects in need thereof, the disclosed NSCLC harboring MET exon 14 skipping mutation is a disease carrying MET exon 14 skipping mutation as recited in the claim 7.
Therefore, the claimed invention is being anticipated by Xia et al.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 7-18 are rejected under 35 U.S.C. 103 as being unpatentable over Drilon et al. (Nature medicine 26, 47-51 2020) in view of Horn et al. (Clinical Cancer Research 24(12) 2771-2779 2018) and further in view of Bibulic et al. (WO2022031636A1).
Drilon et al. teaches crizotinib is a multi-tyrosine kinase inhibitor that is approved for the treatment of ALK- or ROS1-rearranged advanced NSCLCs. Apart from its activity against ALK and ROS1, it has potent activity against MET and low nanomolar potency in cell lines that harbor MET exon 14 alterations(See e. g. p. 47, col 2, line 1). Drilon et al. further teaches the first cases of response to crizotinib in patients with MET exon 14-altered lung cancers in a small retrospective series, and the antitumor activity of crizotinib in MET exon 14-altered advanced NSCLCs in an expansion cohort of the PROFILE 1001 trial(See e.g. p. 49 col 1, line 11).
Drilon et al. does not teach ensartinib.
Horn et al. teaches ensartinib is a novel, aminopyridazine-based small molecule that potently inhibits ALK (See e.g. p. 2772 col. 1 line 6). Horn et al. further teaches that ensartinib is 10-fold more potent than crizotinib at inhibiting the growth of ALK-positive lung cancer cell lines(See e.g. p. 2772 col. 1 line 8). Ensartinib potently inhibited all evaluated ALK variants, with in vitro IC50 <4 nM. At higher concentrations (IC50: 1-10 nM) kinases inhibited by ensartinib are EphA2, EphA1, EphB1 and c-MET (See e.g. p. 2773, col. 1-2 Results). Thus, Horn et al. teaches that ensartinib is a clinically administered small-molecule kinase inhibitor and provides a workable human dosing regimen. Horn et al. further teaches (See e.g. p. 2772 Abstract, Patients and Methods) ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion phase, patients with advanced ALK-positive NSCLC were administered 225 mg once daily (See e. g. p2774, figure 1).
Regarding claim 7, Drilon et al. teaches treatment of advanced NSCLC harboring MET exon 14 alterations with crizotinib(See e. g. p. 47, col 2, line 1), thereby teaching that NSCLC bearing MET exon 14 skipping/alteration is responsive to treatment with a MET-targeting small-molecule kinase inhibitor. Horn et al. teaches ensartinib as a clinically administered small-molecule kinase inhibitor in NSCLC patients(See e.g. p. 2776 col.1 line 5). Thus, the combination teaches the claimed method of treating NSCLC bearing MET exon 14 skipping mutation by administering ensartinib.
Regarding claims 9 and 11, Horn et al. teaches once-daily ensartinib dosing in human patients and dose escalation from 25 mg to 250 mg once daily in patients with advanced solid tumors, with 225 mg once daily used in the NSCLC dose-expansion setting(See e. g. p. 2773, col. 2 line 29). The recited dosage ranges of 5–500 mg/day and 10–400 mg/day encompass or overlap the clinically administered ensartinib doses taught by Horn et al.; therefore, the claimed dosage ranges would have been obvious as routine optimization of a result-effective variable. As stated in MPEP 2144.05.II.A, "it is not inventive to discover the optimum or workable ranges by routine experimentation." Absent evidence of criticality or unexpected results, the claimed numerical ranges would have been obvious as result-effective variables.
In instant application, the inventor identifies a preferred dosage of 225 mg/day (spec. p13 line 21) which is the same dosage disclosed by Horn et al. for treatment of advanced ALK-positive NSCLC, Horn et al. further teach ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors(See e. g. p. 2773, col. 2 line 29).; which encompasses the dosage recited in claim 12.
Regarding Claims 8, 10 and 13-17, these claims further limit the known compound ensartinib to pharmaceutically acceptable conventional salt forms and/or conventional modes of administration. Bibulic et al. teaches solid state forms of ensartinib and ensartinib salts, pharmaceutical compositions thereof, and methods of treating cancer including NSCLC, by administering a therapeutically effective amount of ensartinib and/or ensartinib salts( see. e.g. p.1 [0001]-[0003], p.3 [0009]-[0016] and p. 14 [0089]-[0092] ). Bibulic et al. further specifically teaches ensartinib hydrochloride salt Form T1, as well as crystalline forms of ensartinib dihydrochloride with maleic acid, L-tartaric acid and succinic acid(See e. g. p. 4 [0020]-[0024]). Horn et al. teaches oral administration of ensartinib to human patients(See e.g. p. 2772, study design), and the use of pharmaceutically acceptable salts and routine dosage forms for kinase inhibitors was well known in the art. Accordingly, the recited salt forms of ensartinib were taught in the art, and it would have been obvious to prepare and administer ensartinib in such pharmaceutically acceptable salt forms in a pharmaceutical composition and by the recited conventional route without inventive effort.
Regarding claim 18, to the extent the claim further recites administration of ensartinib or a pharmaceutically acceptable salt thereof in a pharmaceutical composition for treating cancer/NSCLC, Bibulic et al. teaches methods of treating cancer, including NSCLC, by administrating a therapeutically effective amount of ensartinib and/or ensartinib salts, or a pharmaceutical composition thereof, to a subject in need of treatment( See e.g. p. 3 [0015]-[0016]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention, to substitute ensartinib, as taught by Horn et al., for crizotinib, as taught by Drilon et al., for the treatment of NSCLC bearing MET exon 14 skipping mutants. Because Drilon et al. teaches that MET exon 14-altered NSCLC responds to treatment with crizotinib, and Horn et.al teaches ensartinib as a clinically administered kinase inhibitor with a once -daily oral regimen, including 225 mg once daily in NSCLC patients. Both references concern closely related small-molecular kinase inhibitor therapy in NSCLC. Bibulic et al. further teaches pharmaceutically acceptable ensartinib salt forms and pharmaceutical compositions useful for treating cancer including NSCLC.
A person of ordinary skill in the art would have been motivated to use ensartinib in place of crizotinib because both references concern small-molecule kinase inhibitor therapy in NSCLC, and Drilon et al. establish that the claimed MET exon 14-altered NSCLC disease subtype is susceptible to treatment with a MET-active kinase inhibitor. A person of ordinary skill would have had a reasonable expectation of success because Horn et al. provide a clinically tested human dosing regimen for ensartinib, and Bibulic et al. provide ensartinib salt forms and pharmaceutical compositions suitable for administration.
Accordingly, the subject matter of claims 7–18 would have been obvious.
Conclusion
No claims are allowed.
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/G.S./Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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