DETAILED ACTION
Claims 1, 5-6, 9, 16, 20, 24, 67, 83-86, 88, 90, 95, and 99-105, submitted on September 29, 2023, 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 Rejections – 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 84 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. In claim 84, the first row of each Table includes chemical structures that are illegible.
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.
Claims 86, 88, 90, and 95 are rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The claims contain 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 use the invention.
The claimed invention is in the pharmaceutical arts. The independent claim is directed to a method of treating “cancer, an immunological disorder, a central nervous system disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease.” See claim 86. Dependent claims are drawn to more specific diseases, including rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes mellitus, arthritis, psoriasis, spondylitis, parodontitits, or an inflammatory neuropathy, among other things. See claims 87, 89, and 95. Applicant’s specification (see, e.g., p. 95) explains that the compounds at issue function by blocking Kv1.3 potassium channels. The following is a summary of the state of the art as it pertains to drug discovery in general, and drugs targeting ion channels in particular. These three references are representative of the prior art:
Arun B (2009) Challenges in Drug discovery: Can We Improve Drug Development. J Bioanal Biomed 1: 050-053.
Van et al. Challenges in the Therapeutic Targeting of KCa Channels: From Basic Physiology to Clinical Applications. Int. J. Mol. Sci. 2024, 25, 2965.
Bagal et al., Ion Channels as Therapeutic Targets: A Drug Discovery Perspective, Journal of Medicinal Chemistry 2013 56 (3), 593-624
Arun discloses that “finding a novel drug for a disease is always a challenge. Following the path from discovery of a molecule through the road of development is complex and involves time, money and multiple disciplines to move it ahead” (p. 050). This reference highlights some of the difficulties encountered when trying to predict whether a drug candidate will ultimately be clinically useful:
All the high end predictions of the molecule based on various approaches from Chemo informatics modeling and wet lab target specific approaches like target based drug design, identifying new targets and applying new targets and identifying novel molecules from diverse sources both through the synthetic route and by scanning the biodiversity for novel molecules all appear to be failing at some level. The drop out of molecules when moved through the development chain, despite showing very promising activities in the invitro models is high.
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Predicting human clinical efficacy is a complex challenge and can be addressed if the mechanism of action of the drug and the target can be validated. The novel approaches available today can be exploited to study the compound action. Between 1991 to 2001, the failure in drug discovery has been attributed to pharmacokinet-ics reasons, absorption, and destruction of tissue, localization, duration of action and excretion problems. The current reasons of drug failures are mainly due to toxicology and clinical safety, even target-based discovery approaches do[] not seem to have eased the solution. Thus, pharmaceutical industry faces unprecedented challenges, as number of new molecule entities approved by FDA has stagnated during this period.
See Arun at pp. 051 and 052 (internal citations omitted). One would therefore understand that the level of predictability in the pharmaceutical arts is generally low.
The development of drugs that targeting ion channels is also known in the prior art to be encumbered by numerous challenges. Van, for example, discloses that “KCa [potassium-calcium] channels are widely distributed in the body and play various physiological and pathological roles. Numerous studies on KCa channel activators and inhibitors have been conducted in vitro, in vivo, and in clinical trials to identify novel pharmaceutical therapies. However, endeavors to develop KCa channel-targeting drugs have not yet translated to the widespread clinical application of KCa channel modulators.” See Van at p. 21. This reference offers several reasons for why only a few ion channel modulators have been introduced in the pharmaceutical market. First, some of them “have not demonstrated significant efficacy in clinical treatment.” Van at p. 21. “Secondly, due to their potent pharmacological properties[they] can pose serious risks to patients.” Van at p. 22. Such problems have
… hindered investigators and physicians from using these substances clinically. Researchers have made efforts to synthesize small-molecule substances that are both highly selective and have low toxicity based on the structures of these modulators. How-ever, the lack of three-dimensional structural information on these modulators in the resting and active states, along with structural changes upon interactions with other molecules, pose significant challenges to the design of novel modulators. Finally, several modulators may exhibit unintended effects. For example, modula-tors could induce off-target effects, leading to serious adverse events.
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KCa channels are potential therapeutic targets due to their diverse and essential roles in various pathological conditions. Therefore, KCa channel modulators have been extensively studied despite the challenges in their clinical implementation. Over the past two decades, remarkable advancements have been made in the devel-opment of compounds targeting KCa channels for treatment. However, more efforts are still needed to bring KCa channel modulators into clinical practices.
See Van at pp. 22 and 23. Bagal discusses similar problems known in the art with respect to drugs that target ion channels.
A cursory glance over approved drugs would suggest that the ion channel family has yielded a significant number of important drugs across several subfamilies. … the number of discrete channels that has been successfully drugged is relatively small, and drugs for cardiac, neurophysiological, or local anesthetic application are most common. It is also notable how few drugs have gained approval in the past decade, a likely consequence of clinical failures due to efficacy and safety issues and the apparent difficulty in iden-tifying clinical candidate quality chemical matter across the ion channel family.
See Bagal at p. 597. This reference concludes that “the structural knowledge of ion channels is still at such an early stage that we have not noted any truly predictive methods that can be applied to any chemotype to increase selectivity against a particular channel.”
The level of ordinary skill in the art would be a person who can read and understand applicant’s specification, as well as the references discussed above. It is the examiner’s impres-sion that such a person would have advanced training or significant professional experience in pharmacology, clinical medicine, or a related technical discipline. Even though the level of ordinary skill in the art is high, Arun, Van, and Bagal are evidence that this technology area is unpredictable and requires a large amount of technical skill.
One of skill in the art would therefore look to applicant’s specification for information about how the invention is used in actual practice. The specification (pp. 139-149) includes an example in which CHO-K1 cells that express Kv1.3 and hERG (both of which are potassium ion channels) were grown in cell culture. The specification also includes evidence that the compounds at issue are effective at inhibiting these potassium ion channels. See Table 7 in the specification at pp. 143-149. There is no evidence whatsoever that the compounds are actually useful in the treatment of any human disease. The examiner therefore concludes that one of skill in the art would be burdened with undue experimentation when attempting to perform the treatment method as claimed.
Claims 1, 5-6, 9, 16, 20, 24, 67, 84-86, 88, 90, and 95 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for the subject matter of claims 83 and 99-105, does not reasonably provide enablement for the full scope of claimed compounds. 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.
As explained above, the claimed invention is in the pharmaceutical arts. The observations and conclusions in the rejection above are reiterated and incorporated herein by reference. The particular claims at issue are drawn to chemical compounds that are not described in the prior art. In order to make and use the invention commensurate in scope with the claims, one of skill in the art would first need to obtain the compounds or figure out a way of making them. The general level of predictability in the prior art as it pertains to the synthesis of new chemical compounds is discussed in Blakemore et al., “Organic synthesis provides opportunities to transform drug discovery,” Nat. Chem. 2018;10(4):383-94. According to this reference,
synthetic methodology still limits the compounds that medicinal chemists can design and make experimentally. The timelines required by industry for compound delivery determine whether synthetically complex compounds are practically accessible. Organic synthesis is certainly not a solved problem as many significant challenges remain. Furthermore, experimental synthesis represents the most time-consuming aspect of medicinal chemistry so improvements there, along with in silico predictions and compound design, have great potential to increase efficiency and reduce the cost of preparing novel molecules.
See Blakeman at p. 383. See also “Box 1” at p. 384 and the discussion thereof. One would therefore understand that the synthesis of the new chemical compounds within the scope of the instant claims to require substantial work and entail high levels of unpredictability. The examiner therefore concludes that one of skill in the art would be burdened with undue experimentation when attempting to make and use the invention commensurate in scope with the claims.
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 rejec-tion 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, 5-6, 9, 16, 20, 24, 67, 83-86, 88, 90, 95, and 99-105 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 35-36 and 70-82 of copending Application No. 17/766,832 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. Claims 35-36 of the ‘832 are directed to compounds having the following chemical structures:
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These compounds are within the scope of instant claims 1 and 5-6 when m is zero. Dependent claims 70-82 of the ‘382 Application are drawn to methods of treating various diseases within the scope of instant claims 86, 88, 90, and 95. The examiner therefore concludes that the instant claims are drawn to subject matter that is not patentably distinct from the claims of the ‘382 Application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Background Prior Art
The prior art made of record (see attached form PTO-892) and not relied upon is consid-ered pertinent to applicant’s disclosure. Specifically, WO 2021/071802 A1 discloses certain aryl heterocyclic compounds as kv1.3 potassium shaker channel blockers. This reference, however, does not name another inventor within the meaning of 35 U.S.C. 102(a)(2) and is therefore not citable against the instant claims.
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 examiner can normally be reached Monday - Thursday, 8:00 am - 7:00 pm (Eastern Time). Exam-iner 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
February 2, 2026(revised February 17, 2026)