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 .
Election/Restrictions
Applicant’s election without traverse of Group (I) with the addition of urticaria as the elected disease species and 4-methyl glutamate as the elected GluR6 glutamate receptor agonist species in the reply filed on 06/09/2026 is acknowledged.
Claims 11-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/09/2026.
Priority
This application claims priority to United States Provisional Patent Application No. 63/458,450 filed April 11, 2023.
Claims Status
Claims 1-20 are pending. Claims 11-20 are withdrawn. Claims 1-10 are pending and examined in accordance to the elected species.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/11/2024 has been considered by the examiner.
Claim Objections
Claim 5 is objected to because of the following informalities: the recited list of diseases lacks proper punctuation, render the phrase “skin inflammation urticaria” unclear. Additionally, the list should be properly terminated with and appropriate punctuation (e.g., “or”) consistent with the recitation “one of.”. 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 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 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating contact dermatitis and urticaria using SYM2081 (i.e., (2S,4R)-4-Methylglutamic acid), does not reasonably provide enablement for full scope of GluR6 glutamate receptor agonist and the full scope of a disease associated with activation of mast cell in a patient. 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.
The claims encompass methods of treating diseases associated with mast cell activation by administering a GluR6 agonist. The specification defines GluR6 agonist broadly to encompass numerous compounds encompassed by Formula (I), stereoisomers, pharmaceutically acceptable salts, glutamate, kainic acid, domoic acid, and combinations thereof, administered through numerous dosage forms and administration routes for treatment of a broad spectrum of mast cell-associated diseases.
The disclosure, however, provides experimental support for only SYM2081 (2S,4R)-4-methylglutamic acid). Although the specification states that other GluR6 agonists “are expected to be useful,” no experimental evidence is provided demonstrating that compounds across the claimed genus possess the required therapeutic activity in the numerous diseases encompassed by the claims. Such statements constitute prophetic assertions rather than enabling disclosure.
The determination of whether undue experimentation would have been required is guided by the factors set forth in in re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400 (Fed. Cir. 1988).
(1) Breadth of the claims
This factor weighs strongly in favor of nonenablement.
The claims encompass an extraordinarily broad genus of GluR6 agonists, including compounds of Formula (I), stereoisomers, pharmaceutically acceptable salts, glutamate receptor agonists such as glutamate, kainic acid, domoic acid, and numerous pharmaceutical formulations and routes of administration. Additionally, the claims encompass treatment of numerous unrelated diseases associated with mast cell activation, including allergic disease, mastocytosis, mast cell activation syndrome, psoriasis, rosacea, eczema, inflammatory bowel disease, asthma, anaphylaxis, allergic rhinitis, foot allergy, Sjogren syndrome, cardiovascular disorder, cancer, Quilain-Bare syndrome, and numerous additional diseases. Accordingly, the breadth of the claimed invention greatly exceeds the scope of the enabling disclosure.
(2) Nature of the Invention
This factor weighs in favor of nonenablement
The invention concerns pharmacologic modulation of GluR6 receptors to therapeutically treat disease involving mast cell activation. Predicting in vivo therapeutic efficacy from receptor agonism across multiple structurally distinct agonists and across numerous unrelated diseases represent a complex and unpredictable field of pharmacologic and immunology.
(3) State of the prior art
This factor weighs in favor of nonenablement.
Although GluR6 receptors and certain agonists such as SYM2081 were known, the prior art did not establish that activation of GluR6 receptors generally would successfully treat the broad spectrum of mast cell-associated disease now claimed. Likewise, the art did not establish that all GluR6 agonists possess substantially equivalent pharmacological properties, receptor selectivity, potency, pharmacokinetics, toxicity, tissue penetration or therapeutic efficacy.
(4) Level of ordinary skill
This factor is neutral.
One of ordinary skill would possess expertise in immunology, pharmacology, medicinal chemistry, and drug development. However, even highly skilled artisans cannot predict in vivo therapeutic efficacy across an expansive chemical genus without experimental validation.
(5) Level of predictability
This factor weighs heavily in favor of nonenablement.
Leru et al. (Cureus 14(2): e22177, 2022) explains that mast cell disorders comprise a highly heterogenous group of diseases involving multiple organs systems, variable clinical manifestation, and differing pathologic mechanisms, making diagnosis and management particularly challenging. (See Abstract.) Leru further explains that mast cell disorders require individualized evaluation because of their biological and clinical complexity. (See fourth paragraph of page 4.) Leru also teaches patients with MCAS may have a variable clinical phenotype, affecting multiple organ systems but the key feature is recurrent episodes of severe symptoms (anaphylaxis), with concurrent involvement of a minimum of two organ systems and association with an acute increase of specific biologic mediator levels, considered biomarkers of MC activation, mainly the serum tryptase, rarely others (histamine, leukotrienes, prostaglandins). (See last paragraph of page 4.) Given this unpredictability, one of ordinary skill would not reasonably expect that every GluR6 agonist encompassed by the claims would effectively treat every mast cell-associated disease recited or encompassed by the claims.
(6) Amount of direction or guidance
This factor weights in favor of nonenablement.
Although the specification provides general dosage ranges, formulations, routes of administration, and identifies various GluR6 agonists, it provides little guidance regarding:
Selecting effective agonists from the claimed genus;
Predicting which agonists will possess suitable receptor selectivity;
Determining effective dosages for each disease;
Identifying compounds with acceptable toxicity profiles;
Determining whether structurally distinct agonists product comparable biological responses.
Instead, the specification repeatedly states that additional agonists are merely “expected”
to be useful.
(7) Presence of absence of working example
This factor weighs strongly in favor of nonenablement.
The specification provides working examp0les directed primarily to SYM2081 and
irritant dermatitis. No working example demonstrate therapeutic efficacy for:
Glutamate;
Kainic acid;
Domoic acid;
Additional Formula (I) compounds;
The numerous stereoisomers encompassed by the claims;
Pharmaceutically acceptable salts throughout the claimed scope; and
Combinations of GluR6 agonists.
Likewise, the examples focus principally on cutaneous mast cell model and do not demonstrate efficacy across the broad spectrum of disease encompassed by the claims.
(8) Quantity of experimentation
This factor weighs heavily in favor of nonenablement
To practice the full scope of the claims, one of ordinary skill would need to engage in substantial research to”
Synthesize or obtain numerous candidate GluR6 agonists;
Determine receptor affinity and selectivity;
Establish pharmacokinetics properties;
Evaluate toxicity;
Determine therapeutically effective doses;
Identify appropriate formulations; and
Perform efficacy studies across the numerous claimed diseases. Such
Experimentation would constitute a substantial research program rather than routine optimization.
Conclusion
Considering the Wands factors as a whole, particularly the exceptional breadth of the claims, the limited number of working examples, the highly unpredictable nature of mast cell biology and therapeutic pharmacology, the limited guidance provided by the specification, and the extensive experimentation require to practice the full scope of the claimed invention, the specification fails to enable one of ordinary skill in the art to make and use the claimed invention without undue experimentation.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims recite treatment of “a disease associated with mast cell activation.” This limitation fails to reasonably convey one of ordinary skill in the art of the metes and bounds of the claimed invention because the specification attributes mast cell activation to an exceptional broad heterogenous collection of diseases affecting numerous organs systems, including allergic disorders, autoimmune diseases, inflammatory disease, cardiovascular disorders, gastrointestinal disorders, neurologic disorder, type I diabetes, atherosclerosis, and others without identifying objective boundaries that distinguish diseases falling within the scope of the claims from disease that do not. Because mast cell activation may occur as a primary pathogenic mechanism, a secondary consequence, or merely an associated physiological finding, one of ordinary skill would be unable to determine with reasonable certainty whether a particular disease is encompassed by the claimed.
Claims 1 recites a disease associated with activation of mast cells in patient, “such as.” Likewise, claim 4 recites inflammatory bowel disease (IBD) “such as” and type I hypersensitivity reaction “(e.g., allergies).” The phrases “such as” and “e.g.” are exemplary languages and fail to positively recite the intended scope of the claimed patient and the claimed IBD. It is unclear whether claim 1 is intended to encompass any patient, only vertebrate patient, only mammalian patients, only human patients, or other unspecified patients. It is also unclear whether claim 4 is intended to encompass only IBD, Crohn’s disease only, ulcerative colitis only and whether the allergies are intended to be a structural feature or just an exemplary feature. The metes and bounds of the claims therefore are not set forth with reasonably certainty.
With respect to claim 10, the recitation that “the GluR6 glutamate receptor agonist is administered to a concentration ranging from 100 pM (picomolar) to 10 mM (millimolar)” without specifying the medium, formulation, biological compartment, or other environment to which the concentration pertains. Consequently, the scope of the claim cannot be determined with reasonable certainty because it is unclear whether the concentration refers to the pharmaceutical composition, administered dosage form, plasma concentration, tissue concentration, receptor-site concentration, or another concentration.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-5 and 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang. et al. (Cell 184, 2151–2166, April 15, 2021) in view of Donevan et al. (JPET Vol. 285, pages 539-545, 1998), Gu et al. (Bioorganic & Medicinal Chemistry Letters, Vol. 5, No. 17, pp. 1973-1976, 1995), and Zhou et al. (Review article, Front. Immunol., 30 May 2022).
Zhang teaches that agonism of the GluR6 glutamate receptor on mast cells represent a potential therapeutic approach for suppressing mast cell activation for human skin diseases. (See third paragraph of the right column of page 2163.) Thus, Zhang teaches therapeutic concept (mast-cell activation; GluR6 agonism as treatment.) Moreover, Zhang teaches mast-cell activation in multiple mammalian (mice) disease models. (See Abstract.)
Zhang does not specifically disclose the elected GluR6 agonist, SYM2081 ((2S,4R)-4-methylglutamic acid, nor does Zhang specifically disclose treatment of the elected dsease, urticaria. Zhang also does not expressly disclose administering the agonist at the concentration recited in claim 10.
Donevan teaches SYM2081 (4-methylglutamate) is a known, highly selective GluR6 agonist having high affinity for the receptor with EC50 values of 0.12 and 0.23 µM. (See Abstract.)
Gu teaches that SYM2081 is (2S,4R)-4-methylglutamic acid and how it is prepared. (See Abstract and Scheme 1.)
Zhou teaches that urticaria is a mast cell-mediated disease characterized by mast cell activation (See Abstract.)
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to substitute the known selective GluR6 agonist SYM2081, as taught by Donevan and Gu, for the generic GluR6 agonist proposed by Zhang in the treatment method disclosed by Zhang. Zhang expressly teaches that activation of the GluR6 receptor on mast cells suppresses mast cell activation and represent a promising therapeutic strategy for treating mast-cell-mediated disease in mammalian subjects. Zhou further teaches that urticaria is a mast cell-mediated disease characterized by mast cell activation. Therefore, one of ordinary skill in the art would have recognized urticaria as one of the diseases that would have benefited from Zhang’s therapeutic approach. Because Donevan teaches that SYM2081 is a potent and highly selective GluR6 agonist, and Gu teaches the identity and preparation of SYM2081. Accordingly, one of ordinary skill in the art would have been motivated to employ the known, highly selective GluR6 agonist SYM2081 in Zhang’s therapeutic method with a reasonable expectation of successfully activating the intended receptor and suppressing mast-cell activation in the treatment of urticaria.
Furthermore, Donevan teaches that SYM2081 activates the GluR6 receptor with an EC50 of approximately 0.12 µN and 0.23 µM (0.00012 mM and 0.00023 mM), concentrations falling within the presently claimed 100 pM to 10 mM. Because Donevan teaches that the elected agonist is pharmacologically effective within the claimed concentration range, and because optimization of an administered concentration to achieve the desired pharmacological response, constitutes routine optimization, it would have been obvious to administer the agonist at a concentration within the claimed range. See in re Aller, 220 F.2d 454 (CCPA 1955).
One of ordinary skill in the art would also have had a reasonably expectation of success because Zhang had already established activation of the GluR6 receptor suppresses mast cell activation in mammalian disease models. Donevan teaches that SYM2081 effectively activates the same receptor with high potency and selectivity, while Gu provides the identity and synthesis of the elected agonist. Zhou confirms that urticaria is a mast-cell-mediated disease involving activation and degranulation of mast cells. Accordingly, the combined teachings of the references would have reasonably suggested using the known GluR6 agonist SYM2081 to treat urticaria by suppressing mast cell activation.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang. et al. (Cell 184, 2151–2166, April 15, 2021) in view of Donevan et al. (JPET Vol. 285, pages 539-545, 1998), Gu et al. (Bioorganic & Medicinal Chemistry Letters, Vol. 5, No. 17, pp. 1973-1976, 1995), and Zhou et al. (Review article, Front. Immunol., 30 May 2022) as applied to claims 1-5 and 7-10 above, and further view of Choudhury et al. (Journal of Pharmaceutical Sciences, Volume 106, Issue 7, July 2017, Pages 1736-1751). Donevan can be found in the IDS.
The teachings of Zhang, Donevan, Gu, and Zhou have been discussed supra.
Zhang, Donevan, Gu, and Zhou collectively do not teach formulating the GluR6 agonist for topical administration.
Choudhury teaches being an emerging transdermal delivery tool, nanoemulgel, has proved to show surprising upshots for the lipophilic drugs over other formulations. This lipophilic nature of majority of the newer drugs developed in this modern era resulting in poor oral bioavailability, erratic absorption, and pharmacokinetic variations. Therefore, this novel transdermal delivery system has been proved to be advantageous over other oral and topical drug delivery to avoid such disturbances. These nanoemulgels are basically oil-in-water nanoemulsions gelled with the use of some gelling agent in it. This gel phase in the formulation is nongreasy, which favors user compliance and stabilizes the formulation through reduction in surface as well as interfacial tension. Simultaneously, it can be targeted more specifically to the site of action and can avoid first-pass metabolism and relieve the user from gastric/systemic incompatibilities. This brief review is focused on nanoemulgel as a better topical drug delivery system including its components screening, formulation method, and recent pharmacokinetic and pharmacodynamic advancement in research studies carried out by the scientists all over the world. Therefore, at the end of this survey it could be inferred that nanoemulgel can be a better and effective drug delivery tool for the topical system.
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to formulate and administer the known selective GluR6 agonist SYM2081 taught by Donevan and Gu as a topical composition such as a nanoemulgel taught by Choudhury for use in the treatment of method disclosed by Zhang. Zhang expressly teaches that activation of the GluR6 receptor suppresses mast cell activation in the skin and proposed GluR6 agonism as a therapeutic strategy for treating mast cell-mediated skin diseases. Choudhury teaches that nanoemulgels are advantageous topical drug delivery systems because they provide localized delivery to the site of action, avoid first-pass metabolism, minimize systemic exposure, improve patient compliance, and are particularly suitable for topical administration of therapeutic agents. Accordingly, one of ordinary skill in the art would have been motivated to formulate the known GluR6 agonist SYM2081 in Choudhury’s topical nanoemulgel delivery system in order to deliver the agonist directly to the affected skin tissue where mast cell activation occurs, thereby achieving the therapeutic objective taught by Zhang.
One of ordinary skill in the art would have had a reasonable expectation of success because Zhang had already identified GluR6 activation as the therapeutic mechanism for suppressing mast cell activation in skin disease, Donevan demonstrated that SYM2081 is a potent and selective GluR6 agonist capable of activating that receptor, Gu identified and enabled preparation of the elected compound, and Choudhury taught established topical nanoemulgel formulation for localized dermal drug delivery. The combination merely employs a known drug, a known route of administration, and a known delivery vehicle for their expected functions to achieve the predictable result of delivering GluR6 agonist to the site of mast cell-mediated skin disease.
Conclusion
Claims 1-10 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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