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 Claims
Claims 1-11 are pending.
Priority
Instant application 18/001,420, filed 12/09/2022 claims priority as follows:
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
All references from IDS(s) received 12/09/2022 have been considered unless marked with a strikethrough.
Response to Amendment/Arguments
The amendment filed 12/19/2025 has been entered. Applicant has amended claim 1.
In view of the amendment to claim 1, applicant has overcome the rejections previously raised in the Non-final rejection dated 08/20/2025. While the prior art and double patenting references previously identified disclosed treating FGFR3-related skeletal disease with an FGFR3 inhibitor, they do not teach or suggest the curative treatment of FGFR3-related cognitive deficit with an FGF3 inhibitor in a subject suffering from FGFR3-related skeletal disease. Therefore, the previous rejections are withdrawn.
Claim Rejections - 35 USC § 112 - New
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 1-11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter 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/or use the invention.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), the following factors are considered to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Breadth of the claims:
The claims are broadly directed to a method for the “curative treatment of FGFR3-related cognitive deficit in a subject suffering from FGFR3-related skeletal disease that has a FGFR3-related cognitive deficit, comprising administering a therapeutically effective amount of FGFR3 inhibitor. The amendment introducing “curative treatment” modifies the claim scope beyond mere amelioration of symptoms to require that the claimed method actually cure the cognitive deficit. The specification defines “treatment” broadly (page 7, line 22 to page 8, line 12) to include “curative” as well as prophylactic and disease-modifying treatment. Narrowing the claim to “curative treatment” requires that the FGFR3 inhibitor must cure the cognitive deficit, not merely improve it. The specification provides no evidence, in any species, that FGFR3 inhibition produces a cure of cognitive deficit. The mouse behavioral data show transient behavioral rescue during a short treatment window. No data on durability of effect, long-term outcomes, or permanent reversal of cognitive impairment is disclosed.
Nature of the invention:
The invention relates to treating cognitive deficits caused by FGFR3 over-activation in the brain (relating to symptoms such as depression, memory, perception, slowness, and difficulty solving problems) in patients with FGFR3-related skeletal diseases using FGFR3 inhibitors.
State of the prior art and predictability in the art:
At the time of filing, it was known that cognitive deficits in FGFR3-related craniosynostosis arise from multiple mechanisms, not solely from brain intrinsic FGFR3 overactivation. The prior art references HAYWARD (Journal of Neurosurgery: Pediatrics, vol. 18, no. 2, Aug. 2016, pp. 242–50) and MATHIJSSEN (Journal of Neurosurgery: Pediatrics, vol. 20, no. 5, Nov. 2017, pp. 498–502) reviewed the relationship between intracranial pressure and cognitive delay in craniosynostosis. MATHIJSSEN further discusses the complexity of cognitive impairment in syndromic craniosynostosis, noting that the rate of raised intracranial pressure varies by genetic abnormality (see page 1, Table 1). The prior art recognizes contributions from premature suture fusion, increased intracranial pressure, venous hypertension, hydrocephalus, and brain compression as independent mechanisms of cognitive injury. A person of skill in the art would understand that treating the FGFR3 signaling component alone would be insufficient to cure cognitive deficits that have structural and mechanical contributions.
The prior art identified structural brain malformations in the patient populations covered by the claims. LINNANKIVI (American Journal of Medical Genetics Part A, vol. 158A, no. 12, Dec. 2012, pp. 3119–25) assessed 13 HCH patients with the FGFR3 N540K mutation, and found that all 8 who underwent MRI had structural abnormalities consistent with temporal lobe dysgenesis. MANIKKAM (American Journal of Neuroradiology, vol. 39, no. 2, Feb. 2018, pp. 380–84) described temporal lobe malformations and hippocampal rotation in achondroplasia patients. For patients with confirmed cases of thanatophoric dysplasia, MANIKKAM discloses that temporal lobe megalocephaly was found in all patients. These are developmental structural abnormalities that would not be expected to be reversed, let alone cured, by postnatal pharmacological FGFR3 inhibition.
In view of the state of the art identified above, the skilled artisan could not predict whether addressing the molecular component alone would produce a curative outcome in a patient whose cognitive deficit has contributions from irreversible structural or mechanical contributions. Even where pharmacological intervention ameliorates a symptom, achieving a cure of a cognitive deficit that has developmental, structural, and functional components represents a qualitatively different outcome than symptom improvement.
Pharmacological activity in general is a very unpredictable area. Note also that in cases involving physiological activity, such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Moreover, the specification itself acknowledges the unpredictability of the claimed method, stating: “it is unclear how the antidepressant phenotype observed in FGFR3 A385E/+ mice and FGFR3 N534K/+ mice could be translated in human condition” (page 26, lines 10-12).
Level of ordinary skill in the art:
The person of ordinary skill would be a medical researcher or clinician with an M.D. and/or PhD in a relevant discipline (e.g. neuroscience, genetics, pharmacology), and possess several years of professional experience, with some familiarity for FGFR-related cognitive disorders. While this person would possess a high level of skill, they would face substantial uncertainty in predicting whether FGFR3 inhibition would produce a curative treatment of cognitive deficits in the diverse clinical contexts covered by the claims.
The amount of direction provided:
The specification identifies the FGFR3 inhibitor BGJ398, describes two routes of administration (intracerebroventricular, and subcutaneous), and provides a general dosing range (page 11 line 30 to page 12, line 15). It also describes the rationale for the therapeutic hypothesis, which is that FGFR3 gain-of-function mutations affect hippocampal neurogenesis and that FGFR3 inhibition may reverse cognitive deficits.
However, the specification does not provide any direction on how to achieve a curative treatment in the claimed patient population. The behavioral rescue shown in the examples was measured during or immediately after a 6-7 day treatment course; no follow up data is presented to establish whether the behavioral improvements persist. The specification provides no direction on treating the cognitive deficits having structural brain malformation components (temporal lobe dysgenesis, hippocampal malformation) that the prior art discloses in, for example, HCH, ACH, and TD patients. The specification provides no direction for treating cognitive deficits in the context of elevated intracranial pressure or craniosynostosis.
The specification itself acknowledges that the mouse model “showed an absence of craniosynostosis and normal craniocerebral proportion” (page 3, lines 2-4) and that the CAN mutation “expressed in osteoblasts was not active and consequently did not affect craniofacial development” (page 19, lines 16-18). The specification therefore provides no direction for treating patients whose cognitive deficits arise in the context of the skeletal disease, which is the patient population required by every claim.
Existence of working examples:
The specification provides two working examples which are both in mice.
Example 1 (CAN mouse model FGFR3A385E/+) discloses that behavioral tests showed memory deficits and altered stress coping behavior in mutant mice. Intracerebroventricular injection of BGJ398 for seven days rescued performance (see e.g. FIG 2B and 2D). The mouse model did not exhibit craniosynostosis, had no limb shortening, normal craniofacial features, normal coronal structures, and no acanthosis nigricans (pages 18-19, section titled “Skeletal phenotype is mildly affected in CAN mouse model”). The model therefore does not recapitulate the hallmark skeletal features of human CAN, despite a requirement for FGFR3-related skeletal disease recited in the claims.
Example 2 (HCH mouse model FGFR3N534K/+) discloses that behavioral tests showed episodic and spatial memory deficits. Subcutaneous injection of BGJ398 restored performance. While the HCH model displays some skeletal features of HCH, the behavioral rescue was assessed during treatment, with no data on durability.
Neither example demonstrates curative treatment. Both examples show transient behavioral rescue measured during or immediately after a short (6-7 day) treatment course. A “curative treatment” requires, at minimum, a lasting resolution of the condition being treated. The examples demonstrate pharmacological modulation of behavioral endpoints, but do not demonstrate a cure.
The examples do not address the claimed patient population. The claims require the subject to suffer from an FGFR3-related skeletal disease. The primary mouse model (Example 1) lacks the skeletal disease entirely. In the human subjects covered by the claims, cognitive deficits arise in a pathophysiological context that includes craniosynostosis, elevated intracranial pressure, structural brain malformations, and other mechanical consequences of the skeletal disease. The mouse model example eliminates one of the critical features that define the claimed patient population.
The specification provides no working examples using mouse models of achondroplasia, thanatophoric dysplasia, dwarfism, or craniosynostosis (claim 4) for cognitive endpoints. These diseases involve different FGFR3 mutations with different levels of constitutive activation and different pathophysiological contexts for cognitive deficit. A person of ordinary skill cannot extrapolate from the CAN and HCH models to these other conditions without undue experimentation, particularly when the claims require curative treatment.
See also MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art”).
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. To practice the claimed method for curative treatment of FGF3-related cognitive deficits in human patients with FGFR3-related skeletal diseases, a person of ordinary skill would need to identify how the phenotypes observed in the two example mouse models actually translate to cognitive deficits in humans. This would involve testing whether the FGFR3 inhibition produces cognitive improvement in subjects where the cognitive deficit has both brain intrinsic and mechanical/ structural components; establish dose response relationships for cognitive endpoints; determine whether any cognitive improvements persist after cessation of treatment (as required by the limitation “curative treatment”); determine whether pharmacological FGFR3 inhibition can reverse or cure cognitive deficits that have structural brain malformation components, which are documented in e.g. HCH, TD, and ACH patients; and ultimately conduct human clinical trials to establish that the method achieves curative treatment of cognitive deficits in the claimed patient populations.
Each of these steps represents substantial, unpredictable experimentation. Collectively, they constitute an extensive research program that goes well beyond reasonable experimentation.
Therefore, in view of the factors discussed above, claims 1-11 are rejected as failing to comply with the enablement requirement. Consistent with MPEP 2164.04 and in the interest of compact prosecution, the examiner notes that the specification may enable a narrower claim directed to:
A method for improving hippocampal-dependent memory in a subject suffering from an FGFR3 gain-of-function mutation in need thereof, comprising administering to the subject an FGFR3 inhibitor, wherein the FGFR3 inhibitor is a tyrosine kinase inhibitor (TKI).
Conclusion
Claims 1-11 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
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, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621