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 .
Application Status
Applicant's amendment and response, filed May 12, 2026, has been reviewed by the examiner and entered of record in the file.
3. Claim 11 is amended, and claim 21 is canceled.
4. Claims 1-10 remain withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, without traverse, there being no allowable generic or linking claim.
5. Applicant previously elected N546K as the species of amino acid mutation. Claims 15-19 remain withdrawn from consideration as directed to non-elected species.
6. Claims 11, 12, and 21-29 are under examination with the elected species and are the subject of this office action.
Information Disclosure Statement
7. The information disclosure statements (IDS) submitted on April 2, 2026 (five statements), and June 17, 2026, are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner, please refer to the signed copies of Applicant’s PTO-1449 forms, attached herewith.
Previous Claim Rejections - 35 USC § 112(a)
8. Claims 11, 12 and 22-29 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the FGFR inhibitor, (S)-1-(3 -(4-amino-3 -((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof, and its inhibitory effects on FGFR1 phosphorylation in human embryonic kidney cell line (HEK293T) having amino acid mutations N546K, N546D, K65E, K656D, K656N, K656M, R661P, or FGFR1-TACC1 (Specification at pages 18-19), does not reasonably provide enablement for treatment of all of the brain tumors embraced by the claims, comprising administering the claimed compound. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims.
9. This rejection has been modified as a result of Applicant’s amendment to the claims.
10. The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731,8 USPQ2d 1400 (Fed. Cir.,1988). The court in Wands states, "Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue', not 'experimentation'" (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations" (Wands, 8 USPQ2d 1404). The Wands factors are:
(1) the nature of the invention;
(2) the state of the prior art;
(3) the relative skill of those in the art;
(4) the predictability or unpredictability of the art;
(5) the breadth of the claims;
(6) the amount of direction or guidance presented;
(7) the presence or absence of working examples; and
(8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
11. The nature of the invention and the breadth of the claims: Instant claim 11 is directed to a method of treating a FGFR mutant positive brain tumor for an adult brain tumor patient who is FGFR1 mutant positive, the method comprising: administering an effective amount of (S)-1-(3 -(4-amino-3 -((3,5-dimethoxy-phenyl)ethynyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof to the adult brain tumor patient, wherein the adult patient has at least one amino acid mutation selected from the group consisting of N546K, N546D, K656E, K656D, K656N, K656M and R661P, or has a FGFR1 mutation having an FGFR1-TACC1 fusion protein or FGFR1-TACC1 fusion gene, and wherein the brain tumor is selected from the group consisting of glioblastoma, pilocytic astrocytoma, diffuse astrocytoma, rosette-forming glioneuronal tumor, ependymoma, and brainstem glioma.
Thus, claim 11 embraces a broad in scope in regards to the brain tumor to be treated.
12. The relative skill of those in the art: The relative skill of those in the pharmaceutical and medical arts is high, requiring advanced education and training.
13. State of the Art and Predictability of the Art: Hopkins Medicine teaches that the over 120 different types of brain tumors, lesions and cysts are differentiated by where they occur and what kinds of cells they are made of, wherein some arise from bone and others from types of tissues outside the brain and may also be called ‘skull base tumors.’ (page 1, first two paragraphs). Hopkins Medicine teaches that treatment is varied and dependent on tumor type/location, and may include a combination of surgery, radiation and chemotherapy (Hopkins Medicine, pages 1-9).
14. Ito et al. teach that Applicant’s recited compound, (S)-1-(3 -(4-amino-3 -((3,5-dimethoxy-phenyl)ethynyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (aka TAS-120, futibatinib) “is a potent and selective covalent inhibitor of FGFR1−4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR” that is currently in Phase I-III trials for patients with oncogenically driven FGFR genomic aberrations and in September 2022, the U.S.F.D.A. approved futibatinib for the treatment of previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement” (see abstract).
15. Despite the advanced training of those in the art, the art is highly unpredictable because the underlying mechanisms of distinct demyelinating disorders are not well known and the diseases are extraordinarily complex and difficult to diagnose, let alone treat. It is still not possible to predict the pharmacological activity or treatment efficacy of a compound based on the structure or based on the functionality alone. It is also not possible to predict the efficacy of a given class of compounds for the treatment of a particular disease absent a mechanistic link between the pharmacological activity of the class of agents and the etiology or pathophysiology of the disease. Typically, in order to verify that a compound will be effective in treating a disease, the compounds must be tested either directly in a patient or in a model that has been established as being predictive of treatment efficacy. Absent experimental tests verifying the efficacy of a compound or a strong nexus between the known pharmacological activity of a class of agents and the etiology and/or pathophysiology of the condition, it is impossible to predict whether the compound of claim 11 will be useful in treating all of the various brain tumors embraced by said claim.
16. The amount of guidance presented and the presence of working examples: It has been established that, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” In re Fisher, 427 F.2d 833, 839 166 USPQ 18, 24 (CCPA 1970). The specification provides experimental data demonstrating that
(S)-1-(3 -(4-amino-3 -((3,5-dimethoxy-phenyl)ethynyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one demonstrates inhibitory effects on FGFR1 phosphorylation in human embryonic kidney cell line (HEK293T) having amino acid mutations N546K, N546D, K65E, K656D, K656N, K656M, R661P, or FGFR1-TACC1 (Specification at pages 18-19).
17. The Specification does not provide any data or evidence of administering the compound of claim 11 to any in vitro or in vivo model of brain tumor(s) whatsoever. The specification fails to provide any evidence of treatment of any of the recited brain tumors of claim 11. There is no specific direction or guidance regarding a regimen or dosage effective treating a specific brain tumor. Thus, the Specification fails to demonstrate a representative number of types of brain tumor(s) to be treated.
18. The quantity of experimentation needed: In order to enable the instantly claimed methods commensurate with the entire scope, a large quantity of experimentation would be necessary. In order to practice the above claimed invention, one of ordinary skill in the art would have to first envision formulation, dosage, duration, route and, in the case of human treatment, an appropriate animal model system to test the claimed compounds in treating a neurological disorder with the agents as claimed. If unsuccessful, which is likely given the lack of significant guidance from the specification or prior art regarding the treatment of all neurological diseases one of ordinary skill in the art would have to envision a modification in the formulation, dosage, duration, route of administration etc. and appropriate animal model system, or envision an entirely new combination of the above and test the system again. With Applicants’ guidance provided in the specification and what is known in the prior art the person of ordinary skill in the art would have to conduct these experiments administering the compounds embraced by claim 11 in treating a variety of brain tumors, it would require undue, unpredictable experimentation to practice the claimed invention of treating every type and kind of brain tumor comprising administering the compounds claimed.
Thus, Applicant fails to provide information sufficient to practice the claimed invention, absent undue experimentation. Genetech, 108 F.3d at 1366 states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Response to Arguments
19. Applicant traverses the enablement rejection of claims 11, 12 and 22-29. Applicant argues that the claimed subject matter is drawn to FGFR mutations, and alleges that the Examples in the disclosure demonstrate that the instantly recited compound, (S)-1-(3-(4-amino-3-((3 ,5-dimethoxyphenyl)ethynyl)- 1H-pyrazolo [3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one, inhibits FGFR1 phosphorylation in human embryonic kidney cells (HEK293T) having specific mutations.
Applicant argues that: “the compound of claim 11 targets specific mutations, and one skilled in the relevant art would readily recognize that antitumor effects can be achieved when activity of the mutated protein is inhibited, regardless of the location of the tumor, whether it may be the kidney or the brain.”
Applicant references Table A of the previously cited U.S. Patent Application Publication No. 2017/0260168 ("Andrews"), which “provides that N546K is a point mutation in FGFR1 that is known in the art to cause brain tumors.” Applicant contends that “[a]ccordingly, if one can demonstrate FGFR1 inhibition in a kidney cell via targeting N546K, or any enumerated mutation in claim 11 that is known to cause brain tumors, it follows that one can also demonstrate FGFR1 inhibition in a brain cell via targeting N546K, or any enumerated mutation in claim 11 that is known to cause brain tumors.” (Applicant’s Remarks, page 10).
20. Applicant's arguments have been fully considered but they are not persuasive. Applicant provides just one in vitro ELISA assay demonstrating the ability of the instantly claimed compound to inhibit FGFR1 phosphorylation (IC50 value) in the 293T cell line (i.e., human embryonic kidney cells), see Tables 1 and 2 in the Specification (pages 18-29). However, one cannot extrapolate in vitro data demonstrating inhibition of FGFR1 in a kidney cell line via targeting N546K, to the treatment of any/ all of the brain tumors in adult brain tumor patients that are presently recited by claim 11. Those of skill in the art recognize that in vitro assays and/or cell-cultured based assays are generally useful to observe basic physiological and cellular phenomenon such as screening the effects of potential drugs. However, the greatly increased complexity of the in vivo environment as compared to the very narrowly defined and controlled conditions of an in vitro assay does not permit a single extrapolation of an in vitro assay in human embryonic kidney cells to efficacy in treating the recited scope of brain tumor(s) in adult patients with any reasonable degree of predictability. This lack of predictability is complicated by the challenge of limited drug exposure of FGFR1 inhibitors through the blood-brain barrier (BBB) when treating brain tumors such as glioma, for example (Han et al., Frontiers in Pharmacology 2026, see abstract).
Thus the data provided in the disclosure is insufficient evidence for the use of the recited compound for the treatment of all of the recited types of brain tumors. Applicant has not shown that the instant compound is beneficial for treating any/ all types of brain tumors encompassed by claim 11, which are extremely difficult to treat (given the challenge of crossing the BBB, for example) and have no known cure.
After applying the Wands factors and analysis to claim 11, in view of the Applicant’s entire disclosure and the state of the art, it is concluded that the practice of the invention as claimed in claim 11 would not be enabled by the written disclosure. Thus, the specification fails to provide sufficient support for the broad use of the compound of claim 11 for the treatment of any/ all claimed brain tumors.
It is suggested to limit the scope of the brain tumors to be treated to those that are enabled by Applicants' disclosure.
Conclusion
21. In conclusion, claims 1-12, 15-19, and 22-29 are present in the application. Claims 1-10 and 15-19 are presently withdrawn as directed to non-elected subject matter. Claims 11, 12 and 22-29 are rejected. No claim is currently allowable.
22. THIS ACTION IS MADE FINAL. 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.
23. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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