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
Claims 1-2, 5-11, 13-18, 22, 30, 35-36 and 38-39 are pending in the application. Applicant’s election without traverse of Group II, Claims 35-36 and 38-39, in the reply filed on November 3, 2025 is acknowledged. Claims 1-2, 5-11, 13-18, 22, are 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 35-36 and 38-39 are under examination.
Information Disclosure Statement
The listing of references in the specification (pg. 66-67) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112 – Scope of Enablement
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 35-36 and 38-39 are rejected under 35 U.S.C. 112(a), first paragraph, because the specification, while being enabling for a method for treating or ameliorating temporal lobe epilepsy in a subject comprising administering to the subject the antisense oligonucleotide of Claim 1 (or expressions cassettes or vectors thereof), does not reasonably provide enablement for treating or ameliorating any disorder in a subject by administering the composition of Claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The present disclosure, while describing certain embodiments, does not enable the full scope of the claimed method “for treating or ameliorating a disorder in a subject” by administering the antisense oligonucleotide of Claim 1 (or expressions cassettes or vectors thereof), without undue experimentation. The disclosure provides ex vivo/in vitro data limited to temporal lobe epilepsy-related models and general construction/delivery guidance, but it does not reasonably enable the use of the claimed inventions to treat or ameliorate any disorder across the breadth of the claim. The enablement assessment below applies the In re Wands factors.
Claim Breadth
The breadth of Claim 35 encompasses treating or ameliorating “a disorder” generally, not limited to a specific disorder or even epilepsy etiology. Claim 36 encompasses epilepsy etiologies beyond temporal lobe epilepsy. The disclosure supports, at most, reducing GluK2 (Grik2) expression and epileptiform discharges in temporal epilepsy-related ex vivo models. The claimed scope far exceeds the enabled embodiments.
Direction and Working Examples Provided
The specification provides procedural guidance on constructing antisense/shRNA/miRNA/shmiRNA agents (e.g., miR-30 scaffolds), vector options (AAV/lentivirus), and promoter choices, and lists many known delivery chemistries and conjugates. However, therapeutic guidance is limited to epilepsy (particularly temporal lobe epilepsy) and to ex vivo slice models.
The working examples (Specification pg. 62-66) show: 1) reduction of GluK2 (Grik2) protein in rat primary neuronal cultures using LV constructs encoding SEQ ID NO: 14 (shRNA/miRNA), and 2) reduction of epileptiform discharge frequency in organotypic mouse hippocampal slices using LV shmiRNA/miRNA constructs and an AAV9 vector encoding the human-targeting guide (Tables 4–6; Figures 1–3).
There is no guidance on treating disorders outside of temporal lobe epilepsy, nor on clinically relevant dosing, safety, or efficacy endpoints in vivo for any other disorder. The disclosure does not provide disease-specific protocols across the breadth of any disorder.
State of the Art & Predictability
The claimed invention is drawn to a therapeutic method in living subjects using antisense/viral gene therapy to modulate gene expression. The art generally characterizes antisense technology as complex and unpredictable in nature, particularly with disorders affecting the central nervous system (CNS). Although not uniformly predictable, validation using disease-specific model organisms is essential for establishing potential therapeutic effect.
Across the spectrum of disease, practitioners wishing to develop successful RNAi therapeutics face significant challenges during target validation, in vitro screening, and preclinical model testing. Tang and Khvorova (RNAi-based drug design: considerations and future directions. Nat Rev Drug Discov. 2024 May;23(5):341-364) note the following:
Routine failure of gene knockdown targets to demonstrate therapeutic efficacy (see pg. 17).
Limited availability and complex handling procedures of cell lines suitable for in vitro testing (see pg. 19).
Lack of or limited availability of relevant animal models essential for evaluating potential efficacy (see pg. 19).
Applicants’ specification itself acknowledges recognized challenges and unpredictability in RNAi therapeutics (particularly in the CNS), including delivery across the blood-brain barrier, dosage toxicity, and potential model inconsistency. Applicants cite Boudreau et al. (RNAi medicine for the brain: progresses and challenges. Hum Mol Genet. 2011 Apr 15;20(R1):R21-7), which notes the following:
Delivery of RNAi through the blood-brain barrier represents a formidable task (see pg. R24, col. 2).
Severe dosage toxicity and the requirement for model systems to establish potency correlations (see pg. R23, col. 1).
Inconsistent results from model organisms (Parkinson’s disease) for unknown reasons (see pg. 23, col. 2).
Regarding the GluK2 (Grik2) target specifically, state of the art results provide little indication that RNAi would likely be a successful candidate therapy over a range of potentially associated disease states. For example, Inoue et al. (GRIK2 has a role in the maintenance of urothelial carcinoma stem-like cells, and its expression is associated with poorer prognosis. Oncotarget. 2017 Apr 25;8(17):28826-28839) performed siRNA-mediated knockdown analysis of GluK2 (Grik2) of urothelial cancer (UC) cells but merely concluded that target expression in patients with UC could be a prognostic factor after nephroureterectomy (see pg. 28828-35; Fig 3. Furthermore, in a recent study, Webb et al. (Pathological gain-of-function human variants in the GRIK2 kainate receptor gene cause wide-ranging behavioral dysfunction and seizures in mouse models. Neurobiol Dis. 2025 Dec 13;218:107226) reported that two mouse models of GluK2 (Grik2) variants (gain-of-function) exhibited wide-ranging behavioral dysfunction. Their results, “reinforce the importance of variant-specific knock-in models for understanding GRIK2-linked pathophysiology.”
Taken together, these references support that RNAi therapeutics have unpredictable efficacy, and that outcomes are highly context dependent on disease, target, delivery, and dosing.
Quantity of Experimentation
The broadest claim covers treating or ameliorating any disorder using any of the three administration formats (antisense oligo itself, expression cassette, or vector), for any subject. To practice the claim across its full scope, a skilled artisan would need to determine, among other aspects:
Whether Grik2/GluK2 biology is implicated in the pathogenesis of the particular disorder and whether knockdown would be therapeutic rather than harmful.
Appropriate target tissue(s), route(s) of administration, vector, dosage, etc.
The specification does not provide therapeutic data in animal models demonstrating seizure reduction or clinical endpoints; it reports ex vivo slice reductions in epileptiform discharges and in vitro protein knockdown in cultured neurons. Transitioning from such results to any disorder would require extensive, iterative experimentation that is non-routine in this field, particularly for CNS delivery and therapeutic outcomes.
Conclusion
Summarily, available evidence suggests that designing functional RNAi for treatment of disorders requires more effort than routine, predictable extrapolation of available data. To successfully determine if a potential RNAi product may be used to treat a disorder, one must, among other efforts, engage in extensive testing with an acceptable animal model that mimics the pathogenesis of the particular disorder. The specification contains experimental results using specific RNAi compounds (claimed SEQ ID NOs) with a specific animal model (confined to temporal lobe epilepsy). A preponderance of evidence tends to show that the exemplified embodiments and supporting disclosure do not enable a skilled artisan to practice the claimed invention beyond such embodiments without undue experimentation.
Prior Art Search
A search of the prior art revealed no reference teaching or fairly suggesting antisense RNA comprising SEQ ID NOs: 14, 15, 18, or 19 (or at least 85% sequence identity thereof) in the context of treating temporal lobe epilepsy. The closest prior art found appeared to be Applicants’ own work, Crepe et al. (US 2016/0228439; published 8/11/2016). While this reference generally teaches treatment of temporal lobe epilepsy with siRNA compounds targeted to GluK2 (Grik2) , it does not teach or fairly suggest antisense RNA comprising SEQ ID NOs: 14, 15, 18, or 19 nor reduce any specific RNAi compound to practice.
Conclusion
No claims are allowed.
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/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633