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 .
Priority
U.S. Appln. Ser. No. 17/603.994, Filed: October 15, 2021, is a 371 Nat.’l Stage entry of WO 2020/215094 A1 Appln. (i.e. PCT/US2020/029021, Intern.’ l Filing Date: April 20, 2020; Intern.’l Pub Date: April 20, 2020), which is a Continuation of PCT/US2020/028869, Filed: April 17, 2020, which claims priority respectively from U.S. Prov. Appln. 62/835,652, Filed: April 18, 2019 and U.S. Prov. Appln. 62/835,649, Filed: April 18, 2019.
Status of the Claims
This FINAL Action is responsive to October 14, 2025 Amendment and Request for Reconsideration After Non-Final Rejection and corresponding documents.
Claims 1 to 30 and 32-33 are pending, claims 1-15, 21-23, 25, and 28 are amended, claims 16, 18-19, 24, 26-27 and 29-30 are previously presented, claim 20 is original and claim 31 is newly added in the above-identified application .
Information Disclosure Statement
The October 14, 2025 Information Disclosure Statement (IDS) is in compliance with the provisions of 37 CFR 1.97 and has been considered by the Examiner.
WITHDRAWN OBJECTIONS/REJECTIONS
[1] Claims 1 to 15 of the present invention are objected to, because of inadvertent typographical, grammatical and punctuation errors and/or unclear use of the English language terms defined therein, now is withdrawn; and
[2] Claims 1-15, 21, 23, 25 and 28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd para. for failure to particularly point out and distinctly claim the subject matter. U.S.C. 112, the Applicants), regards as the invention is withdrawn.
[3] Claims 1-19, 25 and 29-31 under 35 U.S.C. 103 for being unpatentable and obvious over by WO 2016/057522 A1 to Flatley Discovery Lab (i.e., Intern.’l Filing Date: 6 October 6, 2015; Intern.’l Pub. Date: April 14, 2016; “WO ‘522 Appln.”) is withdrawn.
[I] REJECTIONS UNDER 35 USC § 112(a) MAINTAINED
a. The Rejection
Rejection of claims 1 to 30 and 32-33, respectively, are rejected under 35 U.S.C.112(a) is maintained, because specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims; and
the specification, while being enabling for:
substituted 2-amino-pyrazolyl-[1,2,4]triazolo[1,5a]pyridine derivatives) compounds of Formula (I) (i.e., e.g., which inc.: Formulas (I), (I-C), (I-D), (II), (II-E), (II-F), (II-G)) or pharmaceutically acceptable salts thereof (i.e., claims 1 to 15);
corresponding pharmaceutical compositions thereof (i.e., claims 16-18; esp. those directed to ocular formulations); and
methods directed to treatment of:
optic nerve damage injury or optic nerve crush injury (i.e., synonymous terms); or
glaucoma,
which comprises administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof (i.e., claims 19-31);
(i.e., based solely on general RGC data and optic nerve crush models where broad list of systemic neurodegenerative diseases is not enabled without further, specific supporting data).
DOES NOT reasonably provide enablement for:
ANY or ALL solvate(s) thereof (i.e., as defined in claims 1 to 15);
ANY or ALL methods for treating:
ANY or ALL of neurodegenerative diseases, ophthalmological neurodegenerative disease or disorders, optic neuropathies (i.e., as defined in claims 19-30 and 31)
b. APPLICANTS ARGUMENTS TO REJECTION AND EXAMINER’S RESPONSE
[1] Regarding solvates and solvates of the salts thereof
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In response, the Examiner disagrees and maintains that it is conventionally understood in the chemical arts that:
formation of solvates is unpredictable or not always successful;
solvates" as a broad class is not supported without representative examples showing their successful preparation and efficacy;
instant specification does not demonstrate that "biological activity is not impacted by solvation."
an ordinary artisan cannot predict which solvates will form or if they will indeed revert to the free base in vivo, the claim may not be enabled examples showing their successful preparation and efficacy.
Claiming a compound or its solvates without exemplified solvates requires undue experimentation.
This concept is understood in the chemical arts (i.e., see generally Healy et al. “Pharmaceutical Solvates, Hydrates And Amorphous Forms: A Special Emphasis On Cocrystals”, ”Adv Drug Deliv Rev., 2017 Aug 1:117:25-46; and Braun et al. “Unraveling Complexity in the Solid Form Screening of a Pharmaceutical Salt: Why so Many Forms? Why so Few?”, Cryst. Growth Des. 2017, 17, 10, 5349–5365)
Amendment of the claims to delete the term “or solvates thereof” is required.
[2] Regarding Breadth of Neurodegenerative Diseases and Disorders:
Examples and Data in Specification
[a] Applicants Arguments
Applicants arguments are reiterated below, which states compounds of the claimed invention are DLK or LZK inhibitors and discusses why experimental examples and data in the specification are predictive of potential applications to neurodegenerative diseases and disorders.
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[b] Examiner’s Response
Standard
Under 35 U.S.C. § 112 (Enablement), the present invention must be supported by sufficient data to convince a person of ordinary skill in the art (PHOSITA) that the claimed invention will work as described. In this regard, these critical elements were considered:
to support claims for disease treatment, the patent application must provide data demonstrating that the claimed compounds would be effective for treating a specific condition, not just generally useful for an unspecified outcome.
The data must establish a "nexus" between the compounds and a "specific, substantial, and credible" utility, showing actual effectiveness for the listed diseases
The data must specifically indicate that the compounds are effective treatments for a particular disease, not just suggest a general mechanism. The data needs to provide a credible basis for a person skilled in the art to believe the treatment would work in a human for the claimed disease
Review of the Information Set Forth in the Specification
Without reiterating Applicants’ arguments, Examiner maintains that based on specification examples, it appears that the specification discloses and teaches use of preliminary model systems; i.e., which serve as robust in vitro (cell culture) and in vivo (animal) models to investigate disease mechanisms and test potential therapeutic agents.
In the instant case, there is no direct nexus or correlation and/or insufficient support to demonstrate that the claimed treat the wide range of neurodegenerative or neurological diseases or disorders indicated; i.e., which include:
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Specification Data from Target Engagement and Optic Nerve Crush (ONC)
Presenting results from target engagement assays and optic nerve crush (ONC) models using DLK and LXK inhibitors suggests treatments for diseases involving neuronal death and axonal degeneration. DLK (Dual Leucine Zipper Kinase) is a key regulator of the stress response in neurons; its inhibition is primarily linked to neuroprotective effects in:
Glaucoma: Where RGC death follows axonal injury.
Acute Nerve Injury: The ONC model is a standard surrogate for traumatic optic neuropathy and axonal stress.
Compounds of the present invention appear to be enabled for treatment of glaucoma or optic nerve injury.
RGC Cells in Disease Testing
The conventional art teaches and suggests that ability of DLK/LXK inhibition to block the toxic effects of these compounds highlights the potential of developing specific pharmacologic inhibitors targeting this pathway as a neuroprotective strategy for human RGC degenerations and other neurodegenerative conditions (i.e., see generally Zhang et al., ARVO Annual Meeting Abstract, July 2018, Vol. 59, Issue 9)
However, the conventional art teaches that Retinal Ganglion Cells (RGCs) are a standard model in the art for studying optic neuropathies, most notably glaucoma. RGCs can also be used in preclinical studies to screen for other conditions affecting the optic nerve and retina, such as:
Optic neuritis
Ischemia affecting the retina
Certain types of traumatic optic neuropathy
Neuroprotection strategies for a range of retinal and optic nerve disorders [1]
Glaucoma: They are the primary cell type that degenerates in this disease.
Optic Neuropathies: Various conditions leading to irreversible vision loss due to nerve damage.
Neuroprotection and Regeneration: Assessing the ability of compounds to prevent cell death or promote axonal regrowth.
There is no direct correlation taught in the specification to indicated that compounds of the present invention may be used in the treatment of the above diseases, except for glaucoma.
Comparison with Rotenone and Colchicine with Compound I-81
A comparison of DLK and LXK inhibitors (compound I-81) against rotenone and colchicine would indicate how the inhibitors perform against known toxic agents used to induce specific cellular damage.
Rotenone is a mitochondrial complex I inhibitor and is often used in research to induce models of Parkinson's disease and other mitochondrial dysfunction disorders due to its ability to generate oxidative stress and cause cell death [1].
Colchicine is an anti-mitotic agent that disrupts microtubule formation. It is used in research to study inflammation (it is an established treatment for gout) and can be used to induce models of peripheral neuropathy or disrupt cellular transport systems [1].
A comparison would likely show whether the DLK/LXK inhibitors can mitigate the specific toxic effects caused by these compounds, providing data relevant to treating conditions involving mitochondrial dysfunction or microtubule disruption.
Comparing DLK/LXK inhibitors to rotenone and colchicine typically indicates the compound's ability to protect against specific types of cellular stress:
Rotenone: A mitochondrial toxin used to model Parkinson's Disease by inducing dopaminergic neuron death.
Colchicine: A microtubule-disrupting agent used clinically for gout and familial Mediterranean fever. In research, it models axonal transport failure and inflammatory responses.
Indication: A "better" result than these agents suggests the new inhibitors may possess superior neuroprotective properties or target a more specific pathway (like DLK/LXK) compared to general toxins.
Preclinical Studies and Breadth of Claims
The tests described (target engagement, RGC assays, optic nerve crush model, comparison with toxins) in the specification and via arguments are generally used in preclinical studies. The tests described (ONC models, RGC assays) are standard preclinical studies used to suggest therapeutic potential. However, to cover the extensive list of neurodegenerative disorders you mentioned (ALS, Parkinson’s, Huntington’s, MS, etc.), the USPTO typically requires:
In vivo data or highly relevant animal models for a representative sample of those specific diseases.
Evidence of shared pathology: Showing that the DLK pathway is the primary driver of neuronal death across all those conditions. Without this, claims for the entire list may be considered overly broad.
To indicate that the compounds are effective for the treatment of a wide range of neurodegenerative ophthalmological and neurological disorders listed (e.g., glaucoma, AMD, ALS, Alzheimer's, Parkinson's), the patent application would require:
Relevant animal models for each major disease category claimed (e.g., a specific Alzheimer's model, a Parkinson's model, an ALS model, a glaucoma model) [1].
Data demonstrating statistically significant efficacy in these models [1].
Dose-response data and evidence of a therapeutic effect beyond just in vitro activity
No Nexus Regarding Variety of Neurodegenerative or Neurological Diseases or Disorders and Conclusion Requirements
If the patent application only shows that the compounds are active in RGC cell models (which are conventionally used to screen for glaucoma/optic neuropathies) but provides no nexus or further data to support treating other conditions like Alzheimer's disease, ALS, etc., the claims for those other diseases will likely be rejected for lack of enablement and lack of a "specific, substantial, and credible" utility [1].
The patent office requires data that allows a person skilled in the art to reasonably conclude that the claimed compounds actually work for the specific diseases listed in the claim [1]. RGC data alone does not support the breadth of the list you provided.
If there is no nexus (link) between the data (e.g., RGC cell survival) and a specific disease (e.g., Alzheimer’s), the patent claims for that disease may be rejected for lack of enablement.
RGC cells are conventionally used for glaucoma and ocular nerve damage.
To claim treatment for non-ophthalmological diseases (e.g., ALS, Alzheimer's, stroke), an applicant must provide a clear scientific conclusion or additional data showing the mechanism (DLK/LXK inhibition) is applicable to those distinct pathologies.
Regarding “Substantial Literature Evidence: Neuroprotective Small Molecule DLK Inhibitors; Retinal RGCs; Table 1 Of Amendment
Applicants assert that:
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While the Examiner appreciates the fact that many general literature references or examples teaching DLK and/or LXK inhibitors defined by different compounds with chemical structures, characterized by corresponding unique chemical/physical properties/activities exist, it does not necessarily translate or correlate to compounds of the present invention which would likely demonstrate unique chemical and/or physical characteristics with "specific, substantial, and credible" utility for the treatment of specific diseases different than what is taught in art references.
In particular, from each of the target engagement assays (such as those involving DLK and LXK inhibitors) and an optic nerve crush model alone essentially would provide enablement for methods directed to treatment of:
optic nerve damage injury or optic nerve crush injury (i.e., synonymous terms); or
glaucoma,
In summary, the instant application fails to satisfy the enablement requirement of 35 U.S.C. § 112(a), because the specification does not provide an adequate teaching for one of ordinary skill in the art to practice the full scope of the claimed invention without undue experimentation.
The claimed invention is directed to a broad compound genus scope or pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions and treatment methods directed to all neurological or psychiatric disorders, while the specification only teaches and supports compounds directed to a limited subgenus of compounds of Formulas (IIA) and (IIB) or pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions thereof, and methods for treating optic nerve damage injury or optic nerve crush injury (i.e., synonymous terms) (i.e., as described supra). The burden is on the applicant to show that the disclosure is enabling for the full scope of the claimed invention.
Accordingly, above-identified claims of the instant invention are non-enabled under 35 U.S.C. § 112(a) and appropriate correction or amendment is required.
REJECTION OF RECORD REITERATED IN ENTIRETY
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CONCLUSION
Applicants amendment necessitated the new ground(s) of rejection presented in this Office action. There will be no rejoinder and examination of withdrawn claims in the instant matter. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to GRACE C HSU whose telephone number is (571) 270-1689. The Examiner can normally be reached Monday-Friday 7:30 am - 6 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicants 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, Jeffrey Murray can be reached on 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/G.C.H./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624