DETAILED ACTION
This action is in reply to papers filed 1/13/2026. Claims 1-21 are pending and examined herein.
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
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230250452A1, Published 8/10/2023.
Withdrawn Rejection(s)
Applicant's arguments filed 1/13/2026, with respect to the 112(a) lack of enablement rejection of claims 1-19 has been fully considered. In view of the amendments made to independent claim 1, the rejection has been withdrawn.
Rejection Necessitated by Amendments
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 1-21 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 intracranially delivering a viral vector comprising a transgene to the brain of a subject, wherein the viral vector is an AAV2.5G9 vector and wherein CNS neurons in the brain lobes, cerebellum and spinal cord are transduced with a single site administration of said vector, does not reasonably provide enablement for treating a subject having a disease or disorder that is treatable by production of a therapeutic molecule in CNS cells by delivering an AAV2.5G9 vector comprising a transgene to the brain of a subject in need thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue.’ Not ‘experimentation;” (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
• (A) The breadth of the claims;
• (B) The nature of the invention;
• (C) The state of the prior art;
• (D) The level of one of ordinary skill;
• (E) The level of predictability in the art;
• (F) The amount of direction provided by the inventor;
• (G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
The Nature of the Invention: The inventive concept in the instant application is an adeno-associated virus (AAV) capsid protein that comprises an AAV2.5 VP 1 capsid protein, further comprising amino acid substitutions that introduce a galactose-binding site, wherein the amino acid substitutions comprise Q465V, A468P, D470N, I471M, R472A, D473V, S475G, Y501F, and S502A, wherein the amino acid sequence is SEQ ID NO:2.
Amount of Direction Provided by Inventor/Working Examples: The specification discloses four examples- none drawn to treating a disease or disorder that is treatable by production of a therapeutic molecule with said capsid protein. The first example (para. compares the safety, efficiency, and cell tropism of a naturally occurring AAV serotype (AAV9) with two novel chimeric AAV vectors (AAV2G9 and AAV2.5G9 (amino acid sequence of the capsid is show in SEQ ID NO:2)) following in utero intracranial administration into primates in the early second trimester under ultrasound guidance. At para. 227, the specification teaches all fetuses administered AAV vectors were observed with high levels of firefly luciferase expression within the cerebral hemispheres and primarily correlated with the side of vector administration (FIG. 2). At para. 229, the specification teaches the presence of the vector was detected in all AAV-treated brains (9/9) and in all regions of the spinal cord. The specification concludes that the chimeric vectors tested were shown to have robust transduction efficiency in all brain lobes, cerebellum, and spinal cord with single site administration. Example 2 is a prophetic example and teaches at para. 246 preliminary analysis shown in Example 1, indicating that the AAV2.5G9 chimera retains the various activities of the AAV2.5 will be confirmed by future experiments. Likewise, Examples 3 and 4 are prophetic examples, drawn to (1) demonstrating that the AAV2.5G9 A267 variant exhibits the muscle tropism of the 2.5 vector, and also preserves the loss of the liver specific tropism the 2.5 vector in turn lost when compared to the liver specific tropism characteristic of AAV2 and (2) comparing the transduction of the AAVrh10 with the AAV2.5G9 in various types of neuronal and glial cells.
At issue here is that no example (working or prophetic) is drawn to treating a single disease or disorder that is treatable by production of a therapeutic molecule with the capsid protein. And although the working example teaches robust transduction efficiency in all brain lobes, cerebellum, and spinal cord; the breadth of a disease or disorder affecting the brain lobes, cerebellum, and spinal cord is vast and no example (working or prophetic) is drawn to treating a disease or disorder that is treatable by production of a therapeutic molecule affecting the brain lobes, cerebellum, and spinal cord. The delivery of a transgene in vivo is not -absent a therapeutic outcome facilitated by the delivery- equivalent to a method of treating in vivo. It is further noted that that the examples do not show delivery of a therapeutic polypeptide. A firefly luciferase gene is a widely used bioluminescent reporter that quantifies gene expression- it does not provide treatment.
Prior Art: Tsai et al. (Neurobiol Dis. 2012 Jan;45(1):272-9.) teach insulin-like growth factor-1 (IGF-1) is a neurotrophic factor that modulates multiple fundamental cellular processes, such as cellular growth, proliferation, differentiation, and survival. IGF-1 treatment has been shown to improve disease phenotypes in several rodent models of motor neuron diseases such as amyotrophic lateral sclerosis (ALS), spinal and bulbar muscular atrophy (SBMA) and SMA. Tsai notes that a potential approach to achieve widespread IGF delivery to the spinal cord is to inject the deep cerebellar nucleus (DCN) of the cerebellum as there are abundant retrograde and anterograde axonal connections between the DCN and the rostrocaudal axis of the spinal cord. In a recent study, stereotaxic injection of an adeno-associated virus (AAV) vector encoding IGF-1 to the DCN led to reduced neuropathology and improved muscle strength in ALS mice. Here, Tsai and colleagues injected an AAV vector encoding human IGF-1 (AAV2/1-hIGF-1) into the DCN of a type III SMA mouse model. Expression of IGF-1 was observed in the spinal cord that correlated with a significant reduction in motor neuron cell death. However, the increased number of motor neurons in the spinal cord of treated SMA mice did not result in correction of muscle pathology or preserved motor function (Abstract).
In this report, although Tsai observed expression of IGF-1 in the spinal cord, said expression did not result in the correction of muscle pathology or preserved motor function~ treatment. Again, it is emphasized that Applicant is not claiming a method of delivery and/or expression. Rather, Applicant claims a method of treatment. Tsai’s teachings are instructive as it teaches expression ≠ treatment.
Kambey et al. (Front Aging Neurosci. 2021 Feb 24;13:645583.) teach in prior clinical trials, GDNF was injected into the brain in the form of protein. The idea came that why should it not be used in the form of a gene; the endpoint would probably have been promising. As most neurotrophic factors are labile agents that do not successfully pass the blood-brain barrier readily, viral vectors have a possible means of transmitting GDNF to degenerating dopaminergic neurons. Previous experiments using adenoviral and adeno-associated viral vectors (AAV) have shown that transmission of the GDNF gene to the nigrostriatal system before a 6-OHDA lesion protects against dopaminergic neuron death in rats. When all these GDNF clinical trials were going on, other members of the GDNF neurotrophic factor family were being studied in Parkinson’s models especially Neurturin in the context of gene therapy. The first phase of the clinical trial was reported and the findings showed that the procedure was safe and well-accepted, so the company launched a Phase II clinical trial (NCT00400634), and the results were released in 2010. In this study, 58 patients from nine sites in the USA participated in the trial between December 2006 and November 2008. In patients treated with AAV2-neurturin, there was no substantial change in the primary endpoint. In 13 out of 38 patients infected with AAV2-neurturin and four out of 20 control subjects, severe adverse effects occurred. Three patients developed tumors in the AAV2-neurturin group and two in the sham surgery group. In 2015, a longer-term follow-up series of findings was released, with 51 patients involved in the study. No substantial variation was observed in the primary endpoint classes or in the majority of secondary endpoints. Two participants encountered cerebral hemorrhages with intermittent signs. AAV2-neurturin was not linked to any potentially relevant adverse events. In conclusion, Kambey teaches, in this study, the transmission of AAV2-neurturin bilaterally in PD to the putamen and substantia nigra was not superior to sham surgery (paragraph bridging Pg. 3 and Pg. 4).
In this report, Kambey and colleagues detail the tolerability of the AAV- neurturin therapy. Nevertheless, tolerability did not lead to a therapeutic effect as the transmission of AAV2-neurturin bilaterally in PD to the putamen and substantia nigra was not superior to sham surgery. Again, it is emphasized that Applicant is not claiming a method of delivery and/or expression. Rather, Applicant claims a method of treatment. Kambey’s teachings are instructive as it teaches expression ≠ treatment.
Xu et al. (Mol Ther Nucleic Acids. 2024 Mar 25;35(2):102176.) teach retinal neovascularization (RNV) is primarily driven by vascular endothelial growth factor (VEGF). However, current anti-VEGF therapies are limited by short half-lives and repeated injections, which reduce patient quality of life and increase medical risks. In this study, Xu and colleagues constructed a recombinant adeno-associated virus (AAV), AAV2-SPLTH, which encodes an anti-VEGF antibody similar to bevacizumab, and assessed its effects in a doxycycline-induced Tet-opsin-VEGFA mouse model of RNV. AAV2-SPLTH effectively inhibited retinal leakage, RNV progression, and photoreceptor apoptosis in a Tet-opsin-VEGF mouse model. However, proteomic sequencing showed that AAV2-SPLTH failed to rescue the expression of phototransduction-related genes, which corresponded to reduced photoreceptor cell numbers. This study suggests that anti-VEGF monotherapy can significantly inhibit RNV to some extent but may not be enough to save visual function in the long term (Abstract).
Xu et al. highlights a particular problem found in gene therapy- the inability of a delivered genetic payload to produce therapeutic levels of a protein such that the disease phenotype is altered. As also found in Kambey, the tolerability of the payload of Xu was not a harbinger for the payload’s therapeutic ability. The issue of therapeutic ability of the expressed gene is exacerbated by the fact that the instant working examples do not use a therapeutic gene. Rather, a reporter gene is used.
The level of Predictability in the Art/Conclusion: The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. Due to the large quantity of experimentation necessary to establish the claimed invention of treatment with a AAV2.5G9 vector, the state of the art which establishes safety and tolerability of a gene therapy vector is not indicative of its therapeutic ability, the lack of guidance or evidence in the specification regarding treatment with the AAV2.5G9, it would have required undue experimentation for one skilled in the art at the time of the invention to practice over the full scope of the invention claimed. Thus, limiting the claimed invention to the scope above would be proper.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. 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 extension fee 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 date of this final action.
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/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632