DETAILED ACTION
Claims 1-20, submitted on June 18, 2024, are pending in the application and are rejected for the reasons set forth below. No claim is allowed.
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 .
Claim Objections
Claims 1-3 are objected to because of the following informalities: In claim 1, “said subject” should instead be “a subject in need thereof.” Claims 2-3 are objected to because they do not end with a period. See MPEP 608.01(m), which states that “[e]ach claim begins with a capital letter and ends with a period.” Appropriate correction is required.
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 inven-tion, 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 inven-tion.
Claims 1-20 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a method of treating epilepsy or Huntington’s disease (see instant claims 12-15, 17-18, and 20) comprising administering compound 3 or compound 8 (see claim 6), does not reasonably provide enablement for the full scope of the claims. The specification does not enable any person 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 these claims.
The claimed invention is in a pharmaceutical arts. The independent claim is broadly drawn to a method of preventing or treating any and all neurological disorders comprising administering a compound of formula (I). Dependent claims are drawn to methods wherein the neurodegenerative disorder is epilepsy or Huntington’s disease (see claims 12-15, 17-18, and 20). The search of the prior art raises substantial questions about the ability of one of skill in the art to practice the invention commensurate in scope with the full scope of claimed subject matter. The state of the prior art is represented by the following references:
Cuny, “Neurodegenerative diseases: challenges and opportuni-ties,” Future Med. Chem. 2012;4(13):1647-49.
Guha et al., “Challenges in Drug Development for Neurological Disorders,” Chapter 2 (pp. 27-45) in “Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities,” Mishra et al. (Eds.), Springer (Singapore), copyright 2023.
Franco et al., “Challenges in the clinical development of new antiepileptic drugs,” Pharmacol. Res. 2016;103:95-104.
Travessa et al., “Fifteen Years of Clinical Trials in Huntington's Disease: A Very Low Clinical Drug Development Success Rate,” J. Huntington’s Dis. 2017;6(2):157-63.
The teachings of these references1 as they related to the instant claims are summarized below.
Cuny discloses (p. 1647) that “[n]eurodegenerative diseases encompass a broad array of conditions that involve progressive functional loss and neuron death within the CNS.” This reference outlines some of the notorious problems associated with this technology area:
Unfortunately, effective therapies are currently lacking for the vast majority of neurodegenerative diseases. For some conditions, such as Parkinson’s and Alzheimer’s diseases, therapeutic agents are available that provide symptomatic relief. However, the symptom alleviation is only temporary without significantly altering the underlying disease progression. Several impediments have hampered progress in the discovery and clinical development of drugs in the therapeutic arena of neurodegenerative diseases, including our rather rudimentary understanding of the CNS and the etiology of these diseases. This contributes to several practical issues that present significant challenges in both the discovery and clinical development phases of potential therapeutic agents. For example, it remains unclear if a single molecular target or pathway is vital for disease progression (even in those conditions with a genetic cause), and consequently if modulating that one molecular target or pathway will be sufficient to slow or stop disease progres-sion. To date, the reductionist strategy of drug discovery has not been successful for delivering effective disease-modifying treat-ments for neurodegenerative diseases. In addition, most success-ful drug discovery campaigns rely on animal models that adequately recapitulate the human disease. However, such animal models are lacking for most neurodegenerative diseases, even those with a genetic cause.
Cuny at pp. 1647-48. This reference further observes that the pathology of “neurodegenerative diseases is currently poorly understood” (p. 1647), and research in this area is characterized by “formidable challenges” (p. 1648). Cuny is evidence of the level of unpredictability in this tech-nology area.
Guha acknowledges (p. 28) “an unmet need to develop effective drugs for the treatment” of neurodegenerative disorders, but “[d]rug discovery is the lengthy, costly, and complex process of discovering and developing new chemical entities (NCEs) for curative, symptomatic, or diag-nostic therapeutic interventions for diseases.” Other difficulties include the following:
The complexity of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) system, difficulty in target identification and validation, an incomplete understanding of disease biology, impre-cise clinical outcome measures, shortage of trial-ready patients, variability in the clinical population, inferior reproducibility and predictive value of preclinical animal models, and lack of pharma-codynamic biomarkers and reliable target engagement are just some parameters to slow the progress of drug development in neurological disorders
Guha at p. 29. This reference summarizes the prior art relating to complexity of blood-brain and blood-spinal cord barrier (pp. 30-31), incomplete understanding of disease biology (pp. 31-32), inferior reproducibility and predictive value of preclinical animal models (pp. 33-34), lack of phar-macodynamic biomarkers and reliable target engagement (pp. 34-35), difficulty in target identi-fication and validation (pp. 35-36), imprecise clinical outcome measures (pp. 36-38), shortage of trial-ready patients and variability in the clinical population (pp. 38-39). Guha is further evidence of the low level of predictability in this technology area.
With respect to methods of treating epilepsy, Franco states that “[e]pilepsy is a highly heterogeneous disease, which implies that a single drug is unlikely to benefit broadly all patients” (p. 96). This statement alone calls into question the very premise of applicant’s invention, namely, that all of the compounds of formula (I) would be broadly useful for preventing or treat-ing all neurological disorders.
With respect to methods of treating Huntington’s disease, Travessa similarly discloses that research into drugs for the treatment of this disease “has faced significant obstacles: several therapies have failed to demonstrate efficacy or were associated with significant toxicity” (p. 158). Travessa explains that “some of these reasons are the strength and quality of target validation, the design of early exploratory trials, the true lack of efficacy of compounds, their tolerability and safety related to the administered doses, the inadequate selection of treatment indications, the target population of patients” (p. 162).
It is implicit that one of ordinary skill in the art is a person who can read and understand these references, as well as applicant’s own specification. Such a person would have advanced training or significant professional experience in pharmacology, medicine as it relates to neuro-logical disorders, or a related technical discipline. Even though a person of ordinary skill in the art is quite sophisticated, the prior art indicates that this person would nevertheless be presented with numerous technical challenges when attempting to make and use the claimed invention.
In light of the foregoing technical problems known to exist in the development of drugs for preventing and treating neurological disorders, one of skill in the art would look to applicant’s own specification for information about how the claimed methods are performed in actual practice. 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. The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See MPEP 2164.03 (relationship of predictability of the art and the enablement requirement).
Applicant’s specification (pp. 47-129) includes detailed information about the synthesis of numerous compounds according to formula (I). The specification (pp. 130-37) also includes an in vitro comparison of mTOR binging of several compounds of formula (I) in comparison with similar compounds in the prior art. However, only two of them, namely, Compound 3 (pp. 48 and 98) and Compound 8 (pp. 49 and 100) appear to have been reduced to practice with working examples providing evidence of their utility in the treatment of epilepsy and Huntington’s disease. Example 3 and Example 4 in applicant’s specification (pp. 137-40) describe the maximal tolerated dose and pharmacokinetics is Compound 3 and Compound 8 in laboratory animals. Example 5 (pp. 140- 41) is evidence that these two compounds are found “in brain and thigh muscle after a single oral administration to mice.” Example 7 (pp. 143-47) and Example 12 (pp. 153-56) in the specification include evidence that Compound 3 and Compound 8 inhibit seizures in the maximal electroshock seizure threshold test, which is a mouse epilepsy model. The examiner therefore acknowledges that the specification includes evidence predictive that these two compounds have utility in the treatment of epilepsy. Example 13 and Example 14 in the specification (pp. 156-59) include evidence that Compound 3 and Compound 8 have utility in the treatment of Huntington’s disease. Importantly, the examiner observes that there is no evidence whatsoever that any compound is useful in the prevention of any neurological disorder.
In view of the foregoing, the examiner concludes that there is evidence of enablement of a method of treating epilepsy or Huntington’s disease (see instant claims 12-15, 17-18, and 20) comprising administering compound 3 or compound 8 (see claim 6). However, when attempting to make and use the broader aspects of the claimed invention, one of skill in the art would be burdened with undue experimentation.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possi-ble harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provi-sions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompa-nied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10,640,516 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. The ‘516 Patent claims the same compounds of the instant claims. The specification (see, e.g., col. 1, l. 56) discloses that these compounds are useful in treating neuropathy, which appears to be a neurological disorder within the scope of at least instant claim 1.
Claims 1-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,186,591 B2. Although the claims at issue are not identical, they are not patentably distinct from each other for substantially the same reasons discussed immediately above. Note that the ‘591 Patent is a division of the ‘516 Patent.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,878,972 B2. Although the claims at issue are not identical, they are not patentably distinct from each other. The instant application is a continuation of the ‘972 Patent, so they share the same specification. Claim 1 of the ‘972 Patent claims a method of preventing or treating a neurological disorder in a subject comprising admin-istering an effective amount of a compound of formula (I) to said subject, wherein formula (I) is substantially the same as that of the instant claims. Dependent claims 10-20 of the ‘972 Patent are drawn to methods of treating diseases within the scope of instant claims 10-20. As such, the claims of the ‘972 Patent would anticipate the instant claims, so the examiner concludes that they are not patentably distinct.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Theodore R. Howell whose telephone number is (571)270-5993. The exam-iner can normally be reached Monday - Thursday, 8:00 am - 7:00 pm (Eastern Time). 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, Amy L. Clark can be reached at (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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THEODORE R. HOWELL
Primary Examiner
Art Unit 1628
/THEODORE R. HOWELL/Primary Examiner, Art Unit 1628
March 16, 2026
1 Internal citations in the quotations to the references discussed in this action are omitted to improve readability.