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
Claim 29 is pending.
Priority
Instant application 18/328,364, filed 06/02/2023 claims priority as follows:
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Information Disclosure Statement
All references from IDS(s) received 10/23/2023 have been considered unless marked with a strikethrough.
Election/Restrictions
Applicant’s election without traverse of Group III in the reply filed on 03/11/2026 is acknowledged.
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 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.
Claim 29 is 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 claim is broadly directed to a method for ameliorating and improving physiologic functions associated with Fyn kinase, said method comprising administering an effective amount of at least one compound, or pharmaceutically acceptable salt or solvate of the compound to a subject in need thereof, wherein the compound is 3,5-bis(3,4,5-trimethoxyphenyl)pyridine-2-amine.
The specification defines “physiologic function” as “the physiological activity of an organ, body part, or pathway within an animal” (para. [0092]). Fyn kinase is described in the specification as “ubiquitous in human cells” and playing “an important role in many physiologic processes” (para. [0003]). The specification itself identifies Fyn kinase as involved in: cellular metabolism and lipid utilization ([0004]-[0005]); glucose metabolism and insulin regulation/diabetes ([0006], [0040]); cellular growth, proliferation, morphogenesis, motility, and apoptosis ([0007]); oncogenesis in breast, prostate, pancreatic, liver, esophageal, gastric, cervical, and ovarian cancers ([0007]-[0008]); T-cell development and immune function ([0008]); dendritic maturation in the central nervous system ([0008]); neurodegenerative diseases including Multiple Sclerosis, Alzheimer’s disease, and Parkinson’s disease ([0008], [0042]); weight control, longevity, physical and mental well-being, exercise tolerance, and recovery from physical stress ([0040]); and neurological health and recovery from head or spinal trauma ([0042]). Because the claim is not limited to any specific physiologic function or disease, it covers the full breadth of every physiological process in which Fyn kinase participates.
The disease scope of claim 29 is extraordinarily broad.
Nature of the invention:
The claimed invention relates to a method for ameliorating and improving physiologic functions across multiple therapeutic areas (oncology, metabolic disease, immunology, neurology) by administering the claimed compound. The claim requires that administered compounds actually achieve therapeutic effects in a subject (i.e., in vivo) across a multiplicity of disparate disease states and physiological processes. The nature of the invention demands demonstration that the claimed compound is not merely an enzyme inhibitor in a test tube, but that it can produce meaningful physiological effects in living organisms for numerous conditions.
State of the prior art and predictability in the art:
The specification itself acknowledges that existing Fyn kinase inhibitors “all suffer from a lack of specificity” and “most significantly cross-react with other Src family enzymes” ([0012]). At the time of filing, there were no approved Fyn-specific kinase inhibitor therapeutics for any of the claimed indications. The known Fyn inhibitors (PP1, PP2, SU6656, staurosporine) were research tools, not drugs, and most data linking Fyn kinase to specific diseases came from knockout mouse studies and in vitro experiments rather than controlled therapeutic interventions.
See, for example, the prior art reference SCHENONE (“Fyn Kinase in Brain Diseases and Cancer: The Search for Inhibitors.” Current Medicinal Chemistry, vol. 18, no. 19, 2011, pp. 2921–42; cited in IDS). SCHENONE is a comprehensive review of Fyn kinase biology and the landscape of Fyn inhibitors. Fyn states (page 2937, 2nd para): “Unfortunately, no specific Fyn inhibitor has been reported to date, since all the reported compounds are also active on the other SFKs”. Fyn catalogs every known class of Fyn-active compounds (starting from page 2928, “Fyn Inhibitors”), and characterizes them all as either non-selective Src family inhibitors or broad-spectrum kinase inhibitors. Fyn additionally demonstrates that the evidence linking Fyn to diseases like Alzheimer’s, Parkinson’s, and cancer came from in vitro studies and genetic knockout experiments rather than from clinical or even preclinical therapeutic interventions with Fyn-selective agents. See the sections titled “Fyn and Brain Diseases” and “Fyn and Cancer”.
See also NYGAARD (Alzheimer’s Research & Therapy, vol. 6, no. 1, Feb. 2014, p. 8). NYGAARD represents the most advanced clinical effort involving Fyn inhibition as of the priority date. NYGAARD describes the rationale for repurposing saracatinib (AZD0530), a dual Src/Fyn inhibitor developed originally as an oncology compound, for Alzheimer’s disease. However, at the time of publication, the authors were only enrolling patients in a Phase Ib safety and tolerability study (abstract and page 6, 2nd para.). No efficacy data had been generated. Saracatinib itself is not Fyn-selective and had not been approved for any indication. NYGAARD demonstrates that even for the single best-developed Fyn-targeted therapeutic program in existence at the time of filing, the field was still at the earliest stage of clinical investigation, with no evidence yet that pharmacological Fyn inhibition produced any therapeutic benefit in any disease.
The state of the art had not established that pharmacological inhibition of Fyn kinase can safely and effectively treat any of the myriad conditions recited by the claim.
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). A compounds IC50 against purified Fyn kinase does not predict bioavailability, metabolic stability, tissue distribution, toxicity, or therapeutic efficacy in a living organism. Whether inhibiting Fyn kinase will produce a therapeutic benefit for any particular disease (let alone all of the myriad diseases covered by the claim) depends on complex, disease-specific biology that cannot be predicted from enzyme inhibition data alone. The relationship between Fyn kinase and each claimed physiologic function involves different signaling contexts, cell types, and pathophysiological mechanisms. Note also that the specification relies heavily on speculative language: compounds “may be effective” ([0042]), and “may improve exercise tolerance” ([0040]).
Level of ordinary skill in the art:
The person of ordinary skill would hold a Ph.D. or equivalent advanced degree in medicinal chemistry, pharmacology, biochemistry, or a related discipline, and possess several years of professional experience, with some familiarity for kinase-targeted drug discovery. While this person would possess a high level of skill, that skill does not overcome the fundamental gaps in the disclosure. A highly skilled artisan would known that in vitro kinase inhibition data cannot be reliably extrapolated to in vivo therapeutic efficacy without extensive additional experimentation. Indeed, the high skill level means the ordinary artisan would be acutely aware of the high failure rate in translating kinase inhibitor leads to effective therapies.
The amount of direction provided:
The specification provides a background discussion of the role of Fyn kinase in various diseases. However, the direction provided is limited to teaching that certain compounds can inhibit Fyn kinase in vitro. No evidence or direction is provided to bridge the gap between in vitro inhibition to an actual therapeutic benefit in any of the myriad diseases encompassed by the claim.
Existence of working examples:
The specification provides in vitro enzyme assay procedures and IC50 data for approximately 600 compounds screened against purified recombinant Fyn kinase (Table 3), with selected compounds further characterized (Table 4).
The specification does not provide any dosage information, dosing regimen, or route of administration, any formulation guidance. The specification provides no working examples demonstrating inhibition of Fyn kinase in a cellular context (the cell-based assays in [0110]-[0112] are prophetic), any therapeutic effect in any animal model, amelioration or improvement of any physiologic function in any living organism, bioavailability, pharmacokinetics, or metabolic stability of any compound, or safety or tolerability of any compound in any subject.
The gap between an in vitro IC50 value and a demonstrated therapeutic benefit in a living organism is one of the most significant and unpredictable gaps in drug development.
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 full scope of claim 29, the skilled artisan would need to develop and conduct cell-based assays for each of the many physiologic functions encompassed by the claim to determine whether Fyn kinase inhibition translates to cellular effects; perform pharmacokinetic and ADMET studies for the claimed compound, since no such data are provided and these properties are unpredictable from structure alone; design and conduct in vivo efficacy studies in appropriate animal models for each of the numerous disease indications and physiological functions encompassed by the claims (diabetes, multiple cancers, MS, Alzheimer’s, Parkinson’s, immune function, weight control, exercise tolerance, recovery from trauma, longevity, etc.); and determine appropriate dosages, routes of administration, and formulations for each compound-indication pair.
This cumulative experimentation would require years of research and development at enormous expense, with no guarantee of success, before a skilled artisan could practice the full scope of the claim.
Accordingly, claim 29 is rejected as failing to comply with the enablement requirement.
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 possible 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 provisions 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 accompanied 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.
Claim 29 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 11,701,353 (“the ‘353 patent”). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘353 patent recites a method which anticipates instant claim 29. See the comparison below:
11,701,353
18/328,364
1. A composition comprising 3,5-bis(3,4,5-trimethoxyphenyl)pyridin-2-amine or a pharmaceutically acceptable salt or solvate thereof.
N/A
2. A method of treating, or slowing progression of, a disease associated with Fyn kinase activity in a subject in need thereof, comprising administering a therapeutically effective amount of the composition of claim 1 to the subject, wherein the disease associated with Fyn kinase activity is selected from the group consisting of type II diabetes, breast cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, liver cancer, multiple sclerosis, Alzheimer's disease, and Parkinson's disease.
29. A method for ameliorating and improving physiologic functions associated with Fyn kinase, said method comprising administering an effective amount of at least one compound, or pharmaceutically acceptable salt or solvate of the compound to a subject in need thereof, wherein the compound is 3,5-bis(3,4,5-trimethoxyphenyl)pyridin-2-amine.
The phrase “Improving physiologic functions associated with Fyn kinase” is being interpreted as encompassing treating a disease associated with Fyn kinase activity. Accordingly, claim 29 is unpatentable over the claims of the ‘353 patent.
Conclusion
Claim 29 is rejected.
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.
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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
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