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 .
Withdrawn Rejection
The rejection of claim 46 and 50, 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn. The amendments to the claims overcome this rejection.
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, as amended or previously presented, 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 directly administering to a motor neuron in the brain of the subject a nucleic acid construct encoding an cyclin F operably linked to a promoter or (ii) administering an AAV 9 vector 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 4/28/2026 have been fully considered but they are not persuasive.
Applicant submits that the amendments to the claims address the issues of enablement. In response, the amendments still do not address the enablement issues regarding routine of administration and treating any symptom of ALS or FTS, as the breadth of the claims still embrace.
The remainder of the remarks in the response reiterate the topic of delivery and route of administration that takes specifically from the declaration provided by Applicant. In considering the Declaration, Examiner felt it was necessary to broaden the scope of the route of administration to include localized direct administration to the brain in addition to the stated AAV9 viral vector delivery because direct and localized delivery is an enabled route of administration for gene therapy. As such, the scope deemed enabled in the rejection of record has been modified to include direct administration. However, the overall breadth of the route of administration embrace by the claims still remains an issue of enablement and will be addressed in more detail below. The substance of the declaration will be addressed separately below. As such, Applicant is referred below for the response to remarks regarding route of administration.
Response to Declaration
The Declaration under 37 CFR 1.132 filed 4/28/2026 is insufficient to overcome the rejection of claims 40, 43-44, 46, 48-52 and 54 based upon 35 U.S.C 112(a) as set forth in the last Office action because: The Declaration does not provide sufficient evidence that specifically demonstrate additional means of predictably administer the active construct to motor neurons in a therapeutic amount to effectively treating any or all symptoms of ALS or FTD characterized by cytoplasmic accumulation of TDP-43 other than via direct deliver or AAV9 delivery.
The declaration mostly provide prior art as evidence of multiple known ways delivery the genetic construct of the claimed gene therapy. However the neither the declaration nor the remarks address the cited art by the rejection that specifically teaches that the particulars of delivering a gene construct in a manner that it arrives in a specific part of the brain is highly unpredictable, hindered by the blood brain barrier, for the exception of direct administration to the brain or delivery via an AAV9 vector.
The declaration states that other AAV based gene therapies were well know prior to 2019. Applicant refers to Glybera, Luxturna, Zolgensma (see item 9 of declaration). In response, Glybera is an AAV-1 vector with a target organ being the pancreas, not the brain or a motor neuron. It does not have the issues of traversing the blood brain barrier has is the case for the instantly claimed gene therapy. Luxutra target is the retina and is delivered by local administration by subretinal administration. As such, it does not address the unpredictable factor patterns of a gene therapy with the target site being a motor neuron. Zolgensma is an AAV-9 vector which the rejection of record already states is enabled.
The declaration refers to the prior art of Wang, particularly Table 1 and states that multiple AAV vectors were in human clinical trials for treating CNS disease. Thus providing a feasible AAV capsid options as vehicles for gene therapies in neurons (10 of the declaration). In response, Table 1 provide a generic description of AAV vectors in clinical trials, it does not describe the route of administration and does not provide any evidence that the pre-clinical trials successfully overcome the unpredictabilites described in the prior art as discussed in the rejection of record. Further, Wang details key challenges (i.e obstacles and unpredictability) to AAV-base gene therapy (see pages 14-17).
The declaration refers to Shi et al provides a detailed overview of the landscape of options including inorganic nanoparticles that have the advantage of being relatively easy to manufacture and highly customizable with targeting ligands and other functional properties. (See 12 of the declaration.) In response, Shi et al does not address the particular needs for administration and successful delivery to motor neurons as detailed in the rejection of record. Shi et al generical addresses DNA-based gene therapies and the use of multifunctional polymeric DNA carriers. Shi et al concludes, “recent advances in multifunctional polymeric DNA deliver system based on “off-the-shelf” polycations including PEI, PLL and Chitosan were comprehensively reviewed. Unfortunately, although a growing number of multifunctional polymeric DNA delivery systems have been successfully developed and demonstrate great promise in in vitro and in vivo preclinical evaluations, none of them show satisfactory performance in clinical trails.” See Wang et al (paragraph bridging p. 2241 and 2242).
The declaration refers to Mead et al as an example of a nanoparticles containing DNA cargo together with focused ultrasound that transiently opened the BBB to allow nanoparticle entry into the CNS. The declaration submits that this has since become a mainstream therapeutic option. In response, Mead et al does provide a species of nanoparticle coupled with ultrasound opening of the BBB that overcomes the unpredictabilites of delivering and even expressing a transgene in the CNS. However, it fall short of demonstrating delivery of a therapeutic dose which is also described as a hinderance to a CNS therapeutic gene therapy. Further, Mead et al teaches that targeting is not limited to neurons but resulted in wide-spread expression in multiple brain cells types. As such, specificity of expression and controlled targeted delivery and expression in neurons that results in a therapeutic effect are not demonstrated by Mead et al.
The declaration generically discussed retroviruses are being used for gene therapy and cites Dunbar et al (see 15 of declaration). In response, Examiner cannot speak to the merits of Dunbar et al because the reference has not been provided. The rejection of record describes the unpredictabilites of viral vector gene therapy specifically for targeting neurons in the brain, which this generic discussion does not address.
The declaration refers to Pinyon et al demonstrating electroporation used to transiently open cell membrane to allow direct transfer of DNA cargo. In response, Pinyon et al. is providing localized delivery of cochlear genes in cochlea with a cochlea implant comprising electrodes that can provide electroporation. This constitutes a localized and direct administration, methods known to be the most predictable means of delivering a gene therapy to a target site and is considered enable. However, this does not address delivery to neurons in the CNS impacted in ALS and FTD which is required by the claimed methods.
16-18 of the declaration address known means of direct route of administration to the brain which is the long standing means of exacting gene therapy. In response, localized and means of direct route of administration to the brain are enabled routes of administration. As such, the scope of enablement has been modified to include direct routes of administration. See modified scope deemed enabled above.
Thus overall, for the exception of direct routes of administration, the declaration does not provide sufficient evidence of enablement for other routes of administration and delivery methods. The declaration mostly relies on cited art that generically describe additional means of administration and delivery that are being developed but fall short of demonstrating enablement for the fact patterns specific to CNS gene therapy requires specific delivery and expression to impacted neurons in a therapeutic dose to impart a therapeutic phenotype. As such, the rejection of record is maintained.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 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
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