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
The listing of claims filed 04 April 2024 has been examined.
Claims 1-16 are pending.
Priority
The instant application was received 04 April 2024; it is a continuation of PCT/EP2022/077524, filed 04 October 2022, which claims foreign priority to EP21201281.9, filed 06 October 2021. Acknowledgment is made of Applicant’s claim for foreign priority and a certified copy of the priority document has been received.
Claim Rejections - 35 USC § 112(a)
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 15-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 15, upon which claim 16 depends, recites, “A method for treating or preventing acute neurological disorders, chronic neurological disorders and/or cognitive disorders in a subject, said method comprising administering an effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, to the subject.” These are broad genera and, according to their broadest reasonable interpretation, include any neurological/cognitive disorder. While the specification, in view of the prior art, reasonably provides enablement for the treatment of GABAA ᵞ1 receptor-related acute neurological disorders, chronic neurological disorders, and/or cognitive disorders, it does not reasonably provide enablement for prevention of the disorders recited in claims 15-16 or the treatment or prevention of all acute neurological disorders, chronic neurological disorders, and/or cognitive disorders encompassed by claim 15.
MPEP § 2164.01(a) explains how enablement for the claimed invention can be analyzed:
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In view of the Wands factors, which are discussed individually below, the specification fails to provide adequate enablement for the full scope of the claimed method and one skilled in the art could not practice the invention without undue experimentation.
The breadth of the claims and b) the nature of the invention. The claims are directed to a method for treating or preventing acute neurological disorders, chronic neurological disorders, and/or cognitive neurological disorders in a subject, said method comprising administering an effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.
The range of disorders that can be associated with the terms “acute neurological disorders, and/or cognitive disorders” are extensive and could, for example, include injury-related conditions such as Traumatic Brain Injury (TBI). As such, the scope of the claim is broad.
The state of the prior art. Cook (US 10,259,815 B2) discloses α3 or α2 or α2/α3 GABAergic receptor subtype selective ligands (Claim 1, Formula 1), pharmaceutical compositions, and methods of use of such ligands and compositions in treatment of anxiety disorders, epilepsy, and schizophrenia with reduced sedative and ataxic side effects.
As previously stated, the range of disorders from the instant claims that can be associated with the terms “acute neurological disorders, chronic neurological disorders, and/or cognitive disorders” are extensive and could, for example, include injury-related conditions such as Traumatic Brain Injury (TBI).
Treatment is defined per the Specification (p. 8, Line 32 – p. 9, Line 3) as “(1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms).” While treating symptoms of a TBI may be possible, prevention, which is defined by the Specification (p. 9, Lines 7-11) as “preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition,” is not.
In addition, the “subject,” defined per the Specification (p. 9, Lines 12-14), “includes both humans and non-humans and includes but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines,” but does not define the life-cycle or developmental stage of the mammal (i.e., infant, child, adolescent, or adult), which can impact the dosage and/or efficacy of the method of treatment.
Khanna (Khanna et al., “Limitations of current GABA agonists in neonatal seizures: toward GABA modulation via the targeting of neuronal Cl- transport,” (2013), Frontiers in Neurology, 4(78), p. 1-8.) reveals that “current GABA agonists and prodrugs (Benzodiazepines and Barbiturates) are inadequate in the treatment of neonatal seizures” (Col. 1, Title).
The level of one of ordinary skill. One of ordinary skill in the art is a person having advanced training or other significant relevant experience in medicine, pharmacology, chemistry, or another related technical discipline.
The level of predictability in the art. Pharmacology is quite unpredictable (See In re Marzocchi and Horton 169 USPQ at 367 CJ ¶3). Similarly, it is well established that [T]he scope of enablement varies inversely with the degree of unpredictability of the factors involved, and physiological activity is generally considered to be an unpredictable factor {See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970)}. Indeed, Applicant admits that, “No approved pharmacological treatment exists for core symptoms of social deficits and restricted/repetitive behaviour of ASD, while only inadequate therapeutic options are available for most of ASD’s affective and physiological co-morbidities” (Specification, p. 2, Lines 20-22). In addition, “very narrow therapeutic margins were observed due to sedation mediated by the GABAA aly2 subtype” (Specification, p. 3, Lines 20-21). Also mentioned, “[t]he dosage can vary in wide limits…” (Specification, p. 37, Line 27).
Furthermore, Khanna reveals that, “First-line treatments targeting GABAA receptors, like barbiturates and benzodiazepines, are limited in their efficacy and carry significant risks to the developing brain.” (Abstract, Sentence 3).
Thus, it is evident that pharmacology is quite unpredictable.
The amount of direction provided by the inventor and g) the existence of working examples. The amount of guidance 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. The less predictable the nature of the invention, the more information needs to be explicitly stated in the specification. See MPEP 2164.03.
The Specification does provide some direction related to possible pharmaceutical compositions (e.g., oral, nasal, and rectal preparations) (p. 37, Lines 3-9), excipients, and dosage amounts (e.g., 0.1-20 mg per kg body weight) (p. 37, Lines 27-30) as well as working examples related to synthesis methods for compounds of formula (I) and the compounds’ GABA binding affinity (p. 136). There are no working examples demonstrating the in vivo activity of the claimed compounds of formula (I) or their efficacy in treating and/or preventing neurological/cognitive disorders in a subject. The instant specification indicates GABAA ᵞ1 positive allosteric modulators (PAMs) may be effective in treating various psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, and metabolic disorders (p. 2, Lines 1-7) and GABAergic signaling is altered in autism spectrum disorder (p. 2, Lines 28-33).
However, there is no detail nor experimental results, either in the application itself or in any other evidence of record, to support the notion that these compounds are useful for treating or preventing all of the extraordinarily large range of diseases or disorders within the scope of this claim. More specifically, there are no examples that in any way suggest that compounds of formula (I) are useful in preventing a Traumatic Brain Injury. Additionally, the Specification does not provide any direction or teaching for how to treat or prevent seizures in a subject. Furthermore, the Specification does not provide any direction or teaching for how to treat or prevent seizures in a non-adult subject, i.e., neo-natal seizures (Khanna).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure. The treatment or prevention of acute neurological disorders, chronic neurological disorders, and/or cognitive disorders would depend at the very least on the cause of said disorder (e.g., chemical or physical) and the developmental stage of the subject (e.g., infant, adult, etc.). The prior art demonstrates that it is not possible for a single pharmaceutical product (and its analogs) to treat or prevent all neurological and cognitive disorders.
In order to practice the invention commensurate with the full scope of the claim, the skilled artisan would need to undertake experiments in order to determine (1) whether the compound is, in fact, clinically useful for the treatment or prevention of the claimed diseases or conditions; (2) the amount of compound that is to be administered; (3) the frequency of dosing and the manner in which the compound is to be administered; (4) the likely side effects and how they should be mitigated; and (5) the pharmaceutical formulation that is suitable for administration to a patient.
Scope of Enablement Conclusion
While the state of the art does agree that GABAA-related treatments have been effective in a wide range of neurological and cognitive impairments, claims 15-16, as written, capture too broad a scope. Given the level of unpredictability in this technology area, and the relative lack of working examples of other specific guidance or teachings by Applicant, Examiner concludes that one skilled in the art would be burdened with undue experimentation when attempting to practice the full scope of the invention as claimed. Deleting the word “preventing” from claim 15 and limiting the disorders treated to those recited in claim 16 would overcome the rejection.
Allowable Subject Matter
Claims 1-14 are allowed. None of the prior art of record nor a search in the pertinent art area teaches the compounds of formula (I) or compositions comprising the compounds of formula (I) as claimed herein.
The following is a statement of reasons for the indication of allowable subject matter:
The closest prior art is Weber (DE3724031A1) and Moriwaki (WO9422872A1). An example structure disclosed by Weber and Moriwaki is shown below, alongside a generic and an exemplary instantly claimed compound of formula (I).
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Weber
CAS RN: 114777-43-4
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293
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Moriwaki
CAS RN: 166880-95-1
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214
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250
271
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Instant Application
The instantly claimed compounds of formula (I) differ from Weber and Moriwaki in the following respects:
In the instantly claimed compounds, the phenyl group has two halogen substitutions, F and R3, wherein R3 is Cl or F. However, in the compounds disclosed by Weber and Moriwaki, the phenyl group only has one halogen substitution, which is Cl.
In the instantly claimed compounds, R2 is either H or C1-C6 alkyl. However, Moriwaki discloses a substituent containing O and N as well as an aromatic ring.
In the instantly claimed compounds, Y1-Y5 can all be CH2 and, in addition to H, R4-R5 could also be deuterium, halogen or hydroxy. However, Weber discloses a carboxylate substitution at Y4.
Thus, while Weber’s and Moriwaki’s compounds share a similar core structure to the instantly claimed compounds of formula (I), a skilled artisan would not have been motivated to make the aforementioned changes as a whole to the core structure which would have resulted in the instantly claimed compounds of formula (I).
Conclusion
Claims 1-14 are allowed.
Claims 15-16 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANNA L BAUER whose telephone number is (571)272-5752. The examiner can normally be reached 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, ADAM C MILLIGAN can be reached at (571)270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/B.L.B./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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