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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/13/2026 has been entered.
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 40, 43-44, 46, 48-52 and 54 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 ALS or FTD in a subject wherein the ALS or FTD are characterized by having pathological accumulation of TDP-43 in neurons, the method comprising administering to a motor neuron in the brain of the subject an AAV9 comprising a nucleic acid construct encoding an cyclin F operably linked to a promoter wherein said administering increase the levels cyclin F one in motor neurons of the brain of the subject, enhances neuron survival, inhibits neuron degeneration, and inhibits pathological accumulation of TDP-43 in the neuron, does not reasonably provide enablement for the following:
1) treating any form of ALS or FTS other than one characterized by a pathological accumulation of TDP-43;
2) administering the gene therapy construct by any route of administration; and 3) treating any symptom in the subject.
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 use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is “undue”.
Nature of Invention: a therapeutic and preventative method for ALS of FTD associated with neuronal TDP proteinopathy.
Breadth of the claims: The breadth of the amended claims encompasses sporadic ALS, familial ALS, sporadic FTD, and familial FTD “associated with a neuronal TDP-43 proteinopathy”.
The breadth of “TDP-43 proteinopathy” encompasses an pathology involving TPD-34. This includes but is not limited to reduced expression or activity of TPD-34, increased expression or activity of TPF-34, an mutant form of the TPD-34 gene or protein that alters the function of TPD-34, accumulation of TPD-34 in neurons, among many other possibilities. As such, “TDP-43 proteinopathy” is a broad heterogenous genus of conditions.
The breadth of ALS or FTD “associated with neuronal TDP-43 proteinopathy” is a causal or significant direct or indirect co-incidence between ALS or FTD and neuronal TDP-43 proteinopathy”. The association is not required to be causative of symptoms of ALS or FTD. Further, the association can be one the generically coinciding with ALS or FTD. As such, the breadth of “associated with neuronal TDP-43 proteinopathy” is quite broad and not necessarily limiting to ALS or FTD.
The breadth encompasses “treating” encompasses alleviating/reducing at least one symptom of a ALS or FTD to curing.
The amendments narrow the agent to a construct comprising a nucleotide sequence encoding cyclin F operably linked to a promoter that is operably in the neuron. As such, the promoter is the broadest element including promoters that are only function in neurons (i.e. tissue specific) or promoters that drive expression in other tissue as well as neurons.
The breadth encompasses administering to the subject in vivo by any route of administration and treating any symptom of ALS or FTD.
Specification Guidance (see citations above and additional citations below):
[0017] Still another aspect of the present disclosure provides methods for treating a subject with a neurodegenerative condition or at risk of developing a neurodegenerative condition. These methods generally comprise, consist or consist essentially of increasing the level of cyclin F in a neuron (e.g., a motor neuron) of the subject regardless of the neuron's level or activity of endogenous cyclin F.
[0106] The present disclosure demonstrates for the first time that cyclin F localizes to the cytoplasm of neurons, including motor neuro, and selectively targets cytoplasmically localized, pathological insTDP-43 for proteolytic degradation, without significantly interfering with the cell cycle regulatory function of nuclear localized sTDP-43. This finding is significant because it extends the utility of cyclin F-enhancing agents to neurodegenerative diseases associated with neuronal TDP-43 proteinopathy, which were previously thought not be susceptible to treatment with such agents, including sporadic neurodegenerative diseases such as sporadic ALS, FTD and AD, which are not associated with neuronal cyclin F deficiency. Consistent with these findings, the present disclosure provides methods for enhancing neuron survival, inhibiting neuron degeneration, inhibiting abnormal protein accumulation in a neuron and/or treating neurodegenerative conditions (e.g., ALS, FTD, AD, etc.), suitably ones that are associated with neuronal TDP-43 proteinopathy, which comprise contacting the neuron with a cyclin F-enhancing agent that increases the level of cyclin F in the neuron, regardless of the neuron's level or activity of endogenous cyclin F, including embodiments in which the neuron does not have a reduced level or activity of endogenous cyclin F relative to a control.
[0107] 3.1 Cyclin F-Enhancing Agents
[0108] The present disclosure contemplates any agent that enhances or increases the level or activity of cyclin F in a neuron (e.g., a motor neuron), to thereby promote neuron survival, inhibit neuron degeneration, and inhibit abnormal protein accumulation in the neuron. In some embodiments, an agent that enhances the level or activity of cyclin F increases the level or activity of cyclin F in the neuron by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% or at least 1, 2, 3, 5, 10, 20, 50, or 100-fold more relative to a control.
[0173] Those skilled in the art will also appreciate that the agents described herein can be used for inhibiting neuron degeneration or enhancing neuron survival, which can lead to treatment, inhibition of development or amelioration of a number of conditions characterized by neuron (e.g., motor neuron) degeneration.
[0174] In specific embodiments, the neuron degeneration comprises motor neuron degeneration. The motor neuron diseases (MND) are a group of neurodegenerative conditions that selectively affect motor neurons, the nerve cells that control voluntary muscle activity including speaking, walking, breathing, swallowing and general movement of the body. Skeletal muscles are innervated by a group of neurons (lower motor neurons) located in the ventral horns of the spinal cord which project out the ventral roots to the muscle cells. These nerve cells are themselves innervated by the corticospinal tract or upper motor neurons that project from the motor cortex of the brain. On macroscopic pathology, there is a degeneration of the ventral horns of the spinal cord, as well as atrophy of the ventral roots. In the brain, atrophy may be present in the frontal and temporal lobes. On microscopic examination, neurons may show spongiosis, the presence of activated astrocytes and microglia, and a number of inclusions including characteristic “skein-like” inclusions, bunina bodies, and vacuolization. Motor neuron diseases are varied and destructive in their effect. They commonly have distinctive differences in their origin and causation, but a similar result in their outcome for the patient: severe muscle weakness. Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy (SMA) and post-polio syndrome are all examples of MND. The major site of motor neuron degeneration classifies the neurodegenerative condition.
Working Examples:
Cyclin F Overexpression in Mice Leads to Enhanced Clearance of Insoluble TDP-43 Species
[0258] To determine the effect of cyclin F overexpression in the central nervous system of mice, AAV9-PHP.B was used to deliver expression of cyclin F or an empty vector control specifically in neurons (synapsin promotor) of wildtype mice over 8 months. Post-mortem motor cortex was obtained from these mice and the presence of RIPA-soluble and RIPA-insoluble TDP-43 were analyzed by immunoblotting. As seen in FIG. 5A, bands corresponding to TDP-43 were noted at 43 kDa as expected. In addition, higher molecular weight species were also detected, indicating the presence of ubiquitylated TDP-43 species. Densitometry analysis of immunoblots revealed that both monomeric and ubiquitylated TDP-43 was significantly reduced in mice overexpressing cyclin F, relative to the control.
Thus the specification and working examples, while generically contemplates the BRI, solely provides much narrow guidance to treating ALS or FTD characterized by accumulation of TDP-43 in motor neurons by administering to the motor cortex of a mouse model a AAV vector encoding cyclin F that increases cyclin F expression activity and inhibits pathological accumulation of TDP43 in motor neurons, inhibits neuron degeneration, and enhances neuron survival . The specification fails to provide specific guidance to the treatment of any other type of all forms of ALS and FTD associated in any with TDP-43 proteinopathy as claimed, fails to administer any other agent that increases F cyclin and treats ALS or FTD disease other than a F cyclin gene therapy, and fails to use any other administration other than directly to the motor cortex. As such, the specification fails to enable the BRI of the claims.
State of the Art:
As discussed above, the state of the art of treating neurodegenerative disease, particularly ALS is highly unpredictable. The cause of ALS is unknown and appears to be a heterogenous disease based upon the heterogenous display of symptoms among patients diagnosed with ALS. Only 10% of the cases of ALS have a genetic familial association to ALS. Further as discussed above in the written description rejection, it appears that only a fraction of the familial ALS has a nexus with mutations in F cyclin that leads to aberrant accumulation of TDP-43. As such, the breadth of treating any neurodegenerative disease by administering any agent that increase cyclin F is highly unpredictable because the art only describes a next of cyclin F and a few particular mutations in F cyclin in familial ALS.
Regarding route of administration, the cite of action for treatment of neurodegeneration, such as seen in ALS, is the motor cortex. The prior art well establishes the limitation administering agent for delivery to the brain is hindered by the blood brain barrier and thus is highly unpredictable. Around the time of filing, Puhl (Puhl et al. Brain Res Bull 2019 August ; 150: 216–230. doi:10.1016/j.brainresbull.2019.05.024. Author Manuscript pp. 1-39) states, “Gene therapy is a promising form of treatment for those suffering from neurological disorders or central nervous system (CNS) injury, however, obstacles remain that limit its translational potential. The CNS is protected by the blood brain barrier, and this barrier blocks genes from traversing into the CNS if administered outside of the CNS. Viral and non-viral gene delivery vehicles, commonly referred to as vectors, are modified to enhance delivery efficiency to target locations in the CNS. Still, there are few gene therapy approaches approved by the FDA for CNS disease or injury treatment. The lack of viable clinical approaches is due, in part, to the unpredictable nature of many vector systems.” See abstract. Puhl further describes obstacles to gene constructs crossing the blood brain barrier, requiring the use of high doses, regardless of delivery in a viral vector or not, that results in toxicity, immune response, and decreased bioavailability of the intended gene therapeutic (see whole document). As such, Puhl demonstrates at the time of filing the instant application, route of administration was a source of a great deal of unpredictability in neuronal gene therapies.
Thus the art teaches that “treating” ALS or FTD in any form is highly unpredictable because the root cause is heterogeneous in nature and the genetic means of treating it are also highly unpredictable.
Overall the breadth of the claims lacks enable because the specification solely provide narrow guidance to a gene therapy that administers an AAV9 vector encoding a cyclin F gene that results in increased express of the cyclin F to treat a ALS preventing accumulation of TDP-43 in neurons. Further, the art teaches that not all forms of ALS or FTD “associated with TDP-43 proteinopathy” will be predictable treated by a cyclin F overexpression gene therapy. Further, neither the art nor the specification provide predictable guidance to a prevention method as the breadth of the claims embrace. Nor do they provide specification predictable guidance to the administering of any agent type to increase cyclin F and treat any ALS or FTD associated with a TDP-43 proteinopathy.
Response to Arguments
Applicant's arguments filed 1/13/2026 have been fully considered but they are not persuasive.
Applicant traverse many ground of the enablement rejection and then states to solely expedite prosecution the claims have been amended to specify particular limitations, such as ALS or FTD “associated with TDP-43 proteinopathy”. Applicant submits that those skilled in the art understand that abnormal cytoplasmic accumulation of TPD-43 occurs in a large number of ALS cases and also in FTD, citing the art of Aria et al 2006, Neumann et al 2006, and Ling et al.
In response, the amendments to the claims do not address all of the issues of enablement discussed in the previous office action and further introduces new issues of enablement. Particularly regarding ALS or FTD associated with TDP-43 proteinopathy, the breadth of the claims ALS or FTD would not need to be limited to familial or sporadic form with limitations that limit ALS or FTD having TDP-43 disfunction. However, as discussed above, reciting ALS or FTD “associated with TDP43 proteinopathy” is genus comprising a wide range of symptoms causally or non-causally coinciding with any type of pathology in TDP-43. As Applicant states in their remarks, many forms of ALS is characterized by having one specific species of TDP-43 proteinopathy, which is accumulation of TDP-43 in neurons. The specification teaches that their gene therapy uncovers a causal link between expression of cyclin F and TDP43 accumulation. However, the genus is much greater than this one species and given the great deal of unpredictability in treating ALS or FTD, neither the specification nor the art teach a means of overcoming the unpredictability of treating any symptoms of ALS or FTD associated in any way with any TDP-43 proteinopathy.
Applicant traverse that the specification is not enabling for treatment by delivering the gene construct by any means. Applicant submits the claims now recite that the nucleotide is administered and is expressed in a motor neuron and this address Examiner’s concerns about route of administration.
In response, the breath of the claim encompasses administering the gene construct by any route of administration to impart the effect of expression of the construct in motor neurons. However, the vast majority of routes of administration encompassed by any route of administration will fail to predictably arrive at expression of motor neurons outside of direct administration to the brain (see modified rejection above for more detail).
Applicant submits that Maguire et al (2014; IDS 1/13/2026) teaches non-viral and viral route of administration for nervous system gene therapy were known in the prior art. As such, the route of administration that would arrive at expression in motor neurons is enabled.
In response, contrary to Applicants assertion Maguire teaches the same obstacles to nervous system gene therapy and also describe addition concerns. For examples, Maguire states, “The local at which a delivery vehicle is administered greatly impacts its ability to transfer its genetic payload to the CNS. Due to the constraints imposed by the blood brain barrier (BBB), the most common delivery route is direct injection into the target region in the brain, which bypass this barrier. Adeno-associated virus (AAV) vectors injected in the brain parenchyma primarily transduce neurons around the needs track…Similarly, other vectors, such as adenovirus (Ad)..., lentivirus…, and herpes simplex virus (HSV) exhibit local transduction around the needle with varying degrees of efficiency. Barrier to transport after direct injection into the brain include diffusion through the extracellular matrix…and availability of primary receptors of the virus…at the site of injection, which can limit diffusion and cell type entry…The systemic delivery route for gene therapy vehicles is very promising, but has major caveats..the BBB blocks transport of most delivery vehicles…and the filtration systems of the spleen and liver are efficient at removal of viruses and viral vectors from circulation before they can reach the brain…Other non-target organs, such as muscle and heart, will also be transduced with potential off-target toxicities... Innate immune cells…can eliminate vector from circulation; and cytotoxic T cells directed again viral antigens…or the transgene product…can eliminate transgene expression…The route of vector administration also impacts the level of the immune response on transgene expression in the CNS. For instance, vector administered via the bloodstream is most vulnerable to elimination by antibody neutralization and opsonization…AAV vectors have shown long-term transgene expression in the brain, but is has been reported recently that, at least in some instances, even this vector type can induce a cytotoxic T lymphocyte (CTL) response against vector-transduced cells expressing an antigenic transgene.” See page 818. In the section describing “New Strategies”, Maguire discussed AAV9 as an AAV vector capable of crossing the blood brain barrier. Maguire describes new approaches to select for viral vector with immune evasion phenotype, however, none of these approaches have been described as being delivered by any other route than direct delivery to the brain, with AAV9 being the exception (See p. 819-820). Maguire also discusses the development of non-viral vectors to overcome immune response known to occur with viral vectors. However, all of these non-viral approaches need direct delivery to the brain (p. 821). Thus while Maguire does describe the development of viral vector and non-viral vectors to overcome obstacles to predictable gene construct and delivery, Maguire teaches that these vehicles do not overcome the need for a direct route of administration to the brain, for the exception of AAV9.
In conclusion, the enablement rejection of record is maintained because Applicant’s arguments are not sufficient to demonstrate that the breadth of the claims can be predictable achieved in the face of an art that implies otherwise.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 46 and 50 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 46 recites, “the nucleotide sequence…a sequence encoding an amino acid sequence…or a sequence having at least 95% sequence identity thereto”. The recitation, “a sequence having at least 95% sequence identity thereto” lack sufficient antecedent bases because the claim comprises multiple sequences. As such, which previously recited sequence has at least 95% sequence identity thereto..the nucleotide sequence? The sequence encoding the amino acid sequence? Both?. The scope of the recitation is not apparent.
The term “normal” in claim 50 is a relative term which renders the claim indefinite. The term “normal” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The claim recites “a normal level or activity of endogenous cyclin F in the neuron relative to control”. In this instance the specification does not define the control from which to determine “normal” and the specification does not define a number or range that would be considered “normal”. As such, the metes and bound of the term “normal” are not apparent.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632