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 .
Examiner’s note
The Examiner initiated an interview on 9/17/2026 regarding an allowance of claims 1-3 and 10 with an examiner’s amendment (See ‘Interview Summary’ and ‘Free of Prior Art” section below for Proposed Amendments that were discussed). In response to Examiner’s initiated interview, applicant’s request for a written correspondence/ office action is acknowledged.
Status of Claims
Claims 1-13 are pending. Applicant amended claims 1-3, 8, and 10-13. There are no new or withdrawn claims.
Claims 1-13 are under consideration in the instant office action and will be examined on the merits.
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 1-13 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 certain specifically exemplified compounds, compositions of claims 1-3 and 10 (excluding duplicate structures), does not reasonably provide enablement for a person of ordinary skill in the art to practice the full scope of the claimed method of treating “a disease or condition, at least in part by NLRP3,” across plethora of diseases listed in claims 5-13 and “or prodrug of” without undue experimentation.
Additionally, the specification does not reasonably provide enablement for particular dosage amounts, administration routes, and pharmacokinetic properties. 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.
Independent claim 1 is understood to encompass administering the claimed compounds or compositions to treat any disease or condition for which NLRP3 contributes “at least in part” to disease biology. Dependent claims 4, 5, 6–9, and 11–13 further purport to encompass a broad and heterogeneous universe of disease states, including, inter alia, inflammatory, autoimmune, autoinflammatory, neurodegenerative, cardiovascular, metabolic, pulmonary, dermatologic, infectious, oncologic, and/or organ-specific disorders. The claims are therefore not limited to a particular disease, patient subpopulation, disease phenotype, validated NLRP3-dependent mechanism, target tissue, dosing regimen, pharmacokinetic exposure, biomarker, route of administration, or demonstrated therapeutic endpoint.
The disclosure does not provide a representative number of working examples, a predictive structure–activity relationship applicable across the claimed compounds and indications, or a teaching that permits the skilled artisan to identify, without undue experimentation, which claimed compounds will safely and effectively treat each recited disease or condition. Rather, the skilled artisan would be required to undertake an extensive, disease-by-disease research program—including target-validation studies, compound-selection studies, pharmacology and exposure studies, dose-ranging, toxicology, model selection, efficacy testing, and ultimately human clinical investigation—to determine whether the claimed method works for each disease and condition within the claims’ scope.
The fact that NLRP3 may be implicated in, associated with, activated in, or otherwise contribute “at least in part” to a disease does not, without more, establish that pharmacologic inhibition or modulation of NLRP3 by every claimed compound will safely and effectively treat that disease. The instant specification fails to provide information that would allow the skilled artisan to practice the instant invention. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
Nature of the Invention:
The nature of the invention is therapeutic intervention in complex biological diseases by pharmacologically modulating NLRP3. Such subject matter is inherently unpredictable because it requires translating a molecular mechanism, biomarker association, or preclinical inflammatory signal into safe and efficacious treatment in a human disease. This is especially true where NLRP3 functions in innate immune defense, cytokine maturation, pyroptosis, tissue repair, and host responses to pathogens and cellular injury.
Kang et al. explains that inflammasomes mediate host immune responses to pathogen infection and tissue repair and that NLRP3 activation results in IL-1β and IL-18 maturation, secretion, and pyroptosis. Kang et al., 44 Arch. Pharm. Res. at 16–17, Abstract and Introduction, paragraph 1–2 (Seok, J.K., Kang, H.C., Cho, YY. et al. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch. Pharm. Res. 44, 16–35 (2021). Swanson et al. similarly states that NLRP3 detects microbial motifs, endogenous danger signals, and environmental irritants, and that assembly of the inflammasome causes caspase-1-dependent cytokine release and gasdermin D-mediated pyroptosis. (Swanson, Karen V et al. “The NLRP3 inflammasome: molecular activation and regulation to therapeutics.” Nature reviews. Immunology vol. 19,8 (2019): 477-489 at 477, Abstract, lines 1–10). Because NLRP3 signaling is involved in both protective host responses and disease-associated inflammation, therapeutic modulation cannot be presumed to be beneficial across all diseases and patient settings. The invention’s nature therefore requires indication-specific demonstration and guidance that are not supplied by the specification.
The State of the Prior Art:
The pre-filing state of the art did not establish a predictable, generally applicable therapeutic relationship between NLRP3 modulation and successful treatment of all diseases or conditions in which NLRP3 was implicated. Rather, the art characterized NLRP3 as a broadly responsive sensor activated by unrelated stimuli and acknowledged unresolved mechanistic questions.
Swanson et al. reports that NLRP3 is activated by bacterial, viral, and fungal infection; sterile inflammation involving endogenous danger signals; and environmental irritants. (Swanson, Karen V et al. “The NLRP3 inflammasome: molecular activation and regulation to therapeutics.” Nature reviews. Immunology vol. 19,8 (2019): 477-489 at 481, “NLRP3 activation,” para. 1, lines 1–13). The same reference states that the exact mechanism by which NLRP3 senses cellular stress and the pathways culminating in NLRP3 activation remained to be fully elucidated. Id. at p. 481 para. 2, lines 1–21. The state of the art also recognized conflicting data about particular mechanisms. For example, Swanson et al. describes contradictory evidence as to whether calcium flux is critical for some forms of NLRP3 activation and describe conflicting results concerning the contribution of mitochondrial pathways. Id. at pp. 482–84, respectively, “Ca2+ flux,” final paragraph, and “Mitochondria,” final paragraph. Such uncertainty demonstrates that a person of ordinary skill would not have had a reliable, established roadmap for extending a generalized NLRP3-targeting concept across the full disease scope now claimed.
The Relative Skill of those in the Art:
The level of skill in the art is a neuro-oncologist or clinician with a Ph.D., and/or an M.D.
The Predictability or Lack thereof in the Art:
The art was unpredictable with respect to whether NLRP3 modulation would be therapeutically beneficial in all diseases claimed. The record shows that NLRP3 can promote pathology in certain settings but can also have protective, disease-limiting, or context-dependent functions. This lack of consistent directionality precludes a reasonable expectation that administering a claimed NLRP3 modulator will treat every condition encompassed by claims 4, 5, 6–9, and 11–13.
For example, Kang et al. reports that the role of NLRP3 in cancer “remains controversial depending on types and stages of cancer.” Kang et al., 44 Arch. Pharm. Res. at 24, “Cancer,” para. 1. The reference specifically reports that studies of colitis-associated colorectal cancer suggested a protective role for NLRP3 mediated by IL-18, while NLRP3, IL-1β, and IL-18 were reported to promote tumor growth, proliferation, invasion, and metastasis in lung, prostate, breast, and head-and-neck cancers. Id. at p. 24, “Cancer,” para. 1, sentences 2–5 (Seok, J.K., Kang, H.C., Cho, YY. et al. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch. Pharm. Res. 44, 16–35 (2021). Similarly, with respect to systemic lupus erythematosus, Kang et al. describe reports of NLRP3 overactivation and increased NLRP3 expression in which NLRP3 downregulation correlated with disease incidence and activation of NLRP3 decreased lupus development in mice. “Systemic lupus erythematosus (SLE),” p. 23, para. 1, sentences 1–6. For atopic dermatitis, the article reports that NLRP3 may have detrimental roles in one setting, but impaired activity may increase vulnerability to Staphylococcus aureus-mediated inflammation, concluding that its role depends on context. p. 28–29, “Atopic dermatitis,” final paragraph, Seok, J.K., Kang, H.C., Cho, YY. et al. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch. Pharm. Res. 44, 16–35 (2021).These examples establish that the direction and value of NLRP3 modulation cannot be predictably extrapolated across the broad disease categories recited in the claims.
The Breadth of the Claims:
The claims are exceptionally broad because they cover treatment of diseases or conditions “at least in part” involving NLRP3, rather than a defined condition, mechanistic subtype, biomarker-positive subgroup, treatment regimen, or demonstrated clinical setting. Claims 4, 5, 6–9, and 11–13 accordingly encompass numerous unrelated diseases spanning multiple organ systems and pathophysiological pathways.
The breadth is magnified by the phrase “at least in part by NLRP3,” which encompasses diseases in which NLRP3 plays any partial, indirect, downstream, transient, correlative, or context-dependent role. Such language extends beyond diseases in which NLRP3 has been established as a necessary and therapeutically actionable driver. The claims thus include diseases in which NLRP3 activation may be pathogenic, neutral, compensatory, protective, or dependent on disease stage, tissue, and patient characteristics.
The breadth of the claimed disease universe is illustrated by the pre-filing literature’s disease-by-disease discussion of neurologic, autoimmune, autoinflammatory, oncologic, cardiovascular, metabolic, pulmonary, and dermatologic conditions Seok, J.K., Kang, H.C., Cho, YY. et al. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch. Pharm. Res. 44, 16–35 (2021).at 21–29, “NLRP3 inflammasome-associated diseases.” A broad catalog of diseases associated with a target does not render treatment of every such disease predictable or enabled. Rather, it demonstrates that the claims sweep far beyond the limited range of conditions, models, compounds, and treatment outcomes that may be actually supported by the disclosure (Seok, J.K., Kang, H.C., Cho, YY. et al. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch. Pharm. Res. 44, 16–35 (2021)).
The Presence or Absence of Working Examples and Quantity of Experimentation:
The specification lacks working examples commensurate with the breadth of the therapeutic claims. In particular, it does not provide a representative number of examples showing that claimed compounds effectively treat the full range of diseases and conditions recited in claims 4, 5, 6–9, and 11–13. Even if the specification contains biochemical, cellular, pharmacokinetic, or selected animal-model data, such data do not demonstrate treatment across the broad heterogeneous set of claimed diseases.
The prior art reflects the disease-specific character of evidence needed for therapeutic utility. For instance, with respect to Alzheimer’s disease, Kang et al. discuss findings based on APP/PS1 mice, streptozotocin-induced sporadic Alzheimer’s disease models, and CRND8 transgenic mice, with selected compounds tested in those distinct models. Seok, J.K., Kang, H.C., Cho, YY. et al. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch. Pharm. Res. 44, 16–35 (2021). at 21–22, “Alzheimer’s disease,” para. 1–4. With respect to gout, the literature identifies monosodium urate crystals as known NLRP3 activators and reports attenuation in NLRP3-deficient mice in an MSU-injection model. Seok, J.K., Kang, H.C., Cho, YY. et al. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch. Pharm. Res. 44, 16–35 (2021). p. 27, “Gout,” para. 1. These are disease- and model-specific findings, not a generalized teaching that NLRP3 modulation treats all diseases claimed. Likewise, the disclosure of activity in one disease model, one class of disease, or one assay cannot reasonably establish therapeutic efficacy in unrelated conditions such as neurodegeneration, cancer, cardiovascular injury, autoimmune disease, metabolic disease, pulmonary fibrosis, dermatologic disease, and infectious disease. The absence of representative working examples across the claimed scope weighs strongly against enablement.
Furthermore, the quantity of experimentation required to determine whether the claimed compounds can treat each disease or condition in claims 4, 5, 6–9, and 11–13 would be extensive and undue. For each claimed indication, the skilled artisan would need to determine whether NLRP3 is a causal, therapeutically actionable driver rather than a downstream marker or context-dependent participant; select an appropriate in vitro and/or in vivo disease model; establish target engagement; determine pharmacologically effective systemic and tissue exposures; establish dose and route; identify therapeutic endpoints; and assess disease-specific toxicity.
The prior art establishes that NLRP3 activation itself can proceed through multiple mechanisms—including ion flux, lysosomal disruption, mitochondrial dysfunction, reactive oxygen species, oxidized mitochondrial DNA, and trans-Golgi-network events—and that these mechanisms are interconnected and not mutually exclusive. Seok, J.K., Kang, H.C., Cho, YY. et al. Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch. Pharm. Res. 44, 16–35 (2021). at 18–20, “Upstream and intracellular events that activate the NLRP3 inflammasome,” para. 1–5, including the discussion that activation pathways “are not mutually exclusive,” are interconnected, and “remain to be defined in detail.” The requirement to resolve those mechanistic and pharmacologic issues across each disparate disease constitutes a substantial research program, not routine optimization. Swanson et al. further explains that the upstream pathways are overlapping, data are sometimes conflicting, and no consensus activation model existed (Swanson, Karen V et al. “The NLRP3 inflammasome: molecular activation and regulation to therapeutics.” Nature reviews. Immunology vol. 19,8 (2019): 477-489.at 481, para 2, lines 8–21; p. 485, para 3, lines 1–12). Thus, the needed experimentation would not merely confirm a predictable result; it would determine whether the claimed treatment works at all in a given disease context.
For the foregoing reasons, claims 1–13 are not enabled across their full scope. The specification does not provide sufficient representative working examples, disease-specific efficacy data, predictive correlation, or practical guidance to permit a person of ordinary skill in the art to practice the full genus of claimed therapeutic methods without undue experimentation. The claims require the skilled artisan to conduct an extensive and unpredictable research program to determine:
• Which diseases or patient subgroups are therapeutically responsive to NLRP3 modulation.
• Whether NLRP3 has a pathogenic, protective, or context-dependent role in the claimed disease.
• Which claimed compound is appropriate for a particular indication.
• What mechanism of action, exposure, dose, schedule, route, and treatment duration is required.
• Whether a claimed compound provides a clinically meaningful therapeutic benefit; and
•Whether modulation of NLRP3 produces acceptable safety in view of its role in host defense, inflammatory signaling, and tissue response.
Note that lack of a working example is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164. Genentech, Inc. v. Novo Nordisk, 108 F.3d at 1366, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable". Therefore, in view of the Wands factors, e.g., the amount of direction or guidance provided, absence of working examples, and the predictability of the art discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation in order to practice invention based on the details provided and scope of invention defined in claims 1-13.
Consequently, 1-13 are rejected for lacking scope of enablement.
Free of Prior Art
With regards to the applicant’s compounds of claim 1-2 (without the duplicates), the examiner has determined that there is no prior art that is either anticipatory or rendered obvious of these compounds. Claims 1-3 and 10 are in condition for an allowance with the examiner’s suggested amendments. As discussed over the telephonic interview, the duplicate structures are as follows and only one of the two similar structures would need to be deleted in order to make the claims 1-3 and 10 in condition for an allowance:
In claim 1, compound structures 7 or 8, 9 or 10, 13 or 14, 17 or 18, 19 or 20, 21 or 22, 25 or 26 and 35 or 36.
In claims 1-3, delete “or prodrug thereof”.
In claim 10, delete “or prodrug thereof, for use in therapy”.
Conclusion
Claims 1-13 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHAR INAM whose telephone number is (571)272-0821. The examiner can normally be reached 7:30 am-5:00 pm EST.
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, James H Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAHAR INAM/
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
