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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 18, 2025 has been reviewed by the examiner and entered of record in the file.
3. Claims 11, 12, 15-19 and 21 are amended.
4. Claims 1-10 (Group I, drawn to a composition) remain withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, without traverse, there being no allowable generic or linking claim.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 Claims 15-19 remain withdrawn as directed to non-elected species.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 July 22, 2025, September 12, 2025, October 9, 2025, and December 4, 2025, 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 § 103
8. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
9. Claims 11, 12, 21, 22, 23 (in part), and 27-29 were previously rejected under 35 U.S.C. 103 as being unpatentable over Ali et al., (WO 2015066452 A2), as evidenced by the webpage printout of Yale Medicine (https://www.yalemedicine.org/clinical-keywords/central-nervous-system-neuroblastoma#:~:text=Definition,spread%20and%20improve%20patient%20outcomes), in view of Andrews et al., (U.S. 2017/0260168 A1).
10. In view of Applicant’s amendments to the claims to limit the patient population to an adult brain tumor patient who is FGFR1 mutant-positive, the previous obviousness rejection is overcome and is withdrawn.
New Claim Rejections - 35 USC § 112(a)
11. Claims 11, 12 and 21-29 are 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 brain tumors, or all of the brain tumors embraced by claim 21, 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.
12. 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.
13. 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.
Claim 11 is very broad in scope in regards to the brain tumor to be treated. The term " brain tumor" covers a broad scope of more than 120 different types of brain tumors, lesions, and cysts, and can be benign or malignant, including a diverse array of tumors including glioblastoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, gangliocytoma, ganglioglioma, anaplastic ganglioglioma, rosette-forming glioneuronal tumor, ependymoma, medulloblastoma, brainstem glioma, craniopharyngioma, anterior pituitary tumor, pheochromocytoma, chordoma, spongioblastoma, head and neck tumor, choroid plexus papilloma, choroid plexus carcinoma, oligodendroglioma, and anaplastic oligodendroglioma (as recited by claim 21).
14. 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.
15. State of the Art and Predictability of the Art: Hopkins Medicine teaches that there are more than 120 different types of brain tumors, lesions and cysts, which are differentiated by where they occur and what kinds of cells they are made of. Certain types of tumors are typically benign (noncancerous), while others are typically malignant (cancerous). Some… arise from the bone or other types of tissues outside the brain and may also be called ‘skull base tumors.’ However, their proximity to the brain makes them likely to affect structures of the brain,” (page 1, first two paragraphs). Hopkins Medicine teaches typically benign brain tumors including meningioma, pituitary adenoma, craniopharyngioma, schwannoma, nasopharyngeal angiofibroma, choroid plexus tumors, dysembryoplastic neuroepithelial tumors, neurofibromas, hemangioblastomas, chrondroma, giant cell tumor, osteoma, arachnoid cyst, colloid cyst, dermoid or epidermoid cyst, encephalocele, fibrous dysplasia, rathke’s cleft cyst,
Petrous apex lesion; as well as typically malignant tumors including glioma, ependymal tumors, hemangiopericytomas, germ cell tumors, pineal tumors, chordoma, chondrosarcoma, medulloblastoma, olfactory neuroblastoma, lymphoma, gliosarcoma, rhabdomyosarcoma, paranasal sinus cancer, and Atypical Teratoid/Rhabdoid Tumor (AT/RT). Treatment is varied and dependent on tumor type/location, and may include a combination of surgery, radiation and chemotherapy (Hopkins Medicine, pages 1-9).
16. 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).
17. Despite the advance 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 the various brain tumors embraced by said claim.
18. 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).
19. 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 21, let alone the full scope of brain tumors embraced by claim 11 (see paragraph 15, above). 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.
20. 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”.
Conclusion
21. In conclusion, claims 1-12, 15-19, and 21-29 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 20-29 are rejected. No claim is currently allowable.
22. 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
/JARED BARSKY/Primary Examiner, Art Unit 1628