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
This office action is being written to address an oversight in which the statement regarding the declaration did not have the accompanying signature of the primary examiner. This office action supersedes the office action of 05/29/2026.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/18/2026 has been entered.
Declaration Filed under 37 CFR 1.132
The declaration under 37 CFR 1.132 filed 05/18/2026 is sufficient to overcome the rejection of claims 245-250, 255-258, 263-265, 270 and 281-284 over PGPUB US 2024/0018524 to Crepel.
Election/Restrictions
Claim 245 is directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(B), claims 271-280, directed to the process of making or using an allowable product, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on 07/25/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim Rejections - 35 USC § 112(a) – 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.
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 276-280 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 a method of treating epilepsy comprising administering to the subject the polynucleotide of claim 245, an expression cassette comprising the polynucleotide, or a vector comprising the expression cassette, via intravascular, intra-arterial, or intrathecal injection, does not reasonably provide enablement for methods of treating disorders other than epilepsy via other routes of administration, such as oral delivery. 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention
The claims are drawn to a method of treating disorders. The invention is the class of invention that the CAFC has characterized as “the unpredictable arts such as chemistry and biology”. Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F. 3d 1316 (Fed. Cir. 2001).
The breadth of the claims
Claim 276, from which claims 277-280 depend, is drawn to a method of treating or ameliorating a generic disorder. The claim encompasses treating or ameliorating any disorder using any route of administration. Claims 277-280 limit the expression cassette to one having at least 85% sequence identity to SEQ ID NO: 256, but do not further limit the disorder or route of administration.
Guidance in the specification and working examples
The specification discloses that administration of AAV9 concatemer vectors #100 (SEQ ID NO: 256) and #101, via intracerebral injection, to mice which had been rendered epileptic (Example 8, pp. 165-66). Both constructs were effective in reducing the hyperlocomotion phenotype in vivo (p. 166 ln 28-29). The behaviors (nesting, shaking, hairs, handling and locomotion) of the animals also improved, with construct #100 showing the most dramatic effect (p. 166 ln 36-39). Construct #100 also proved effective in reducing both hyperlocomotion and reducing seizure activity in vivo (p. 167 ln 11-19).
The unpredictability of the art and the state of the prior art
The instantly rejected claims effectively encompass methods of treating any disorder for which a subject may be in need of treatment. This encompasses a vast array of disorders with significantly variability in symptoms, causes, and effective treatments, for which a reduction in Grik2 may or may not be appropriate. Prior to the filing date of the instant application, there was a well-known association between Grik2 (i.e., GluR-6 or GluK2) and neurological diseases such as epilepsy, or neurodevelopment disorders such as autism (Contractor et al., "Kainate receptors coming of age: milestones of two decades of research," Trends Neurosci. 34(3):154-63 (2011).; of record, cited on an IDS). There was also a known association between Grik2 overexpression and the maintenance of urothelial carcinoma stem-like cells (Inoue at al., "GRIK2 has a role in the maintenance of urothelial carcinoma stem-like cells, and its expression is associated with poorer prognosis." Oncotarget, 8(17);28826-28839. (March 2017).; of record, cited on an IDS). However, a search of the prior art did not find well-known associations between Grik2 and any other diseases or disorders.
Regarding the route of administration, since the claims are not particularly limited to a target tissue or route of administration, they encompass all tissues and modes of administration for all diseases. Certain organs are hard-to-reach with gene therapy vectors. For example, Bañuls notes, “the complexity of the lung structure places certain physical and chemical barriers to vector delivery, especially for viral vectors” (Bañuls et al. Gene Therapy in Rare Respiratory Diseases: What Have We Learned So Far? J Clin Med. 2020 Aug 8;9(8):2577.). Methods of treating cystic fibrosis which comprised administration of adeno-associated viral vectors have often failed to improve symptoms in clinical trials, despite previous positive results. For example, Bañuls notes that in one trial, “ In one maxillary sinus, AAV2-CFTR was administered…after 90 days, no significant differences were detected.” (p. 11). In another study, “After a phase I trial to prove the safety of one-dose nebulization of the vector…a phase II trial assessed the safety of repeated aerosolized doses in CF patients, showing a decrease in interleukin-8 (IL-8) and an improvement of Forced Expiratory Volume in the first second (FEV1) measurement…However, a phase IIb of this study with a higher number of participants did not prove any amelioration in CF patients, indicating that AAV2-CFTR did not improve lung function in the study conditions.” (pp. 11-12).
Another hard-to-reach system is the gastrointestinal tract. Gombash reviews AAV-delivery to the enteric nervous system, stating, “Oral administration is an attractive option for AAV delivery because it is non-invasive, can potentially transduce the entire length of the GI tract, and can elevate serum levels of a desired protein. Rectal administration by enema is also relatively non-invasive and is advantageous if only colonic transduction is desired. However both routes of delivery are particularly challenging for ENS transduction due to the thick epithelial barrier, acidic pH of the stomach, and digestive mucous and other fluids limiting the stability of AAV particles and accessibility to the deeply embedded ENS cells.” (Adeno-Associated Viral Vector Delivery to the Enteric Nervous System: A Review. Postdoc J. 2015 August ; 3(8): 1–12.)(p. 3). Gombash discloses that other routes of administration are more effective, such as direct (p. 3) and systemic (p. 4) injection both of which have successfully transduced the ENS.
Even when considering only delivery to the brain, given Grik2’s role in neurological disorders, it is not clear that certain routes of administration encompassed by the claims would allow the method to be practiced as claimed. Fischell reviewed the approaches for AAV delivery to the brain, noting, “the blood–brain barrier (BBB) makes IV delivery of AAVs, to the brain highly inefficient. At IV doses capable of widespread expression in the brain, there is a significant risk of severe immune-mediated toxicity. Direct intracerebral injection of vectors is being attempted. However, this method is invasive, and only provides localized delivery for diseases known to afflict the brain globally. More advanced methods for AAV delivery will likely be required for safe and effective gene therapy to the brain.” (Abstract)(A Multifaceted Approach to Optimizing AAV Delivery to the Brain for the Treatment of Neurodegenerative Diseases. Front. Neurosci. 2021. 15:747726.). Fischell writes shortly after the filing date of the instant invention, which indicates that even at that time, the development of safe and effective AAV delivery methods to the brain was a problem that the art had not yet solved. Some routes are ineffective in humans, such as direct intracerebral delivery: “studies investigating dIC injection for the delivery of gene therapy in humans have been universally unsuccessful, citing inadequate distribution volume as a major limitation” (p. 4).
In summary, the claims encompass a wide variety of diseases and routes of administration, and given the unpredictability and the failures in the art of safe and effective delivery of AAV vectors to different organs, the ordinary artisan would not have reasonably expected to be able to effectively treat the full scope of diseases claimed with a vector comprising the claimed polynucleotide.
The quantity of experimentation
To practice the method to the full scope as claimed, the ordinary artisan would have to test administration of the claimed polynucleotide for the full range of any disorder, via various routes of administration for delivery to any organ or tissue. Considering that for some of the embodiments encompassed by the claims (e.g., treating a human subject with epilepsy via administration of the claimed polynucleotide via oral delivery or direct intracerebral injection), the additional experimentation would require de novo experimentation without a guarantee of success, and further considering that any positive results would amount to a significant advancement in the state of the art, the additional experimentation required is considered undue.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue amount experimentation would be required to make and use the invention as claimed.
Subject Matter Free of the Prior Art
The prior art does not teach or suggest an isolated polynucleotide that specifically binds a Grik2 mRNA comprising a guide strand sequence comprising the nucleic acid sequence of SEQ ID NO: 19 and/or 141, or an RNA thereof. The prior art also does not teach or suggest an expression cassette comprising SEQ ID NO: 256, as recited in claim 263, which comprises the recited guide RNA sequences.
The closest art is Crepel, as described in the office actions of 02/20/2026 and 10/23/2025. However, the declaration filed 05/18/2026 shows that the subject matter disclosed in Crepel was obtained directly from the inventor or joint inventor of this application, and thus disqualifies Crepel as prior art.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 245-250, 255-258, 263-265, 270-275, and 281-284 are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
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