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 .
Detailed Action
Response to Amendments
The amendments made to the claims 03/30/2026 have been entered.
Status of claims
Claims currently pending are claims 1-6 and 11-20.
Claims currently withdrawn are claims 1-6, 11-12, and 16-20.
Claims currently under examination are claims 13-15.
Claim Interpretation
Claim 13 has been amended to include “VPS35/VPS29 retromer dysfunction”. There is not an explicit definition of this term. However, the specification on p. 2 states “An in silico screen recently targeted retromer stabilizers binding at the interface between VPS35 and VPS29. The thiophene-connected bis-isothiourea R55 (1) was identified as a pharmacological chaperone being able to bind at the VPS35-VPS29 interface.”
The term “VPS35/VPS29” is understood to mean the combination of VPS35 and VPS29.
New Claim Objection
Claim 13 is objected to for the following informality:
The wherein clause that states “wherein the mammal has a reduced expression of VPS35 and/or a VPS35/VPS29 retromer dysfunction” interrupts the sentence “a compound of Formula (I) and its salts and solvates”.
The wherein clause can be moved to the end of the claim and maintain its meaning.
Maintained Rejections
Claim Rejections - 35 USC § 112(a)
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.
Maintained Rejection
Claims 13-15 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 the treatment of Parkinson’s disease (PD), Alzheimer’s Disease (AD), and Amyotrophic Lateral Sclerosis (ALS) with the VPS35-D620N mutation, does not reasonably provide enablement for all neurological diseases and prevention of PD, AD, and ALS. 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.
The following Wands factors have been considered if not explicitly stated:
(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.
Breadth of the claims
Claim 13 states “A method for treatment and/or prevention of a neurological disease, the method comprising administering to a mammal in need thereof an effective amount of a compound of Formula (I), wherein the mammal has a reduced expression of VPS35 and/or a VPS35/VPS29 retromer dysfunction…”.
Claim 14 specifies that the neurological disease is ALS, Alzheimer’s disease, Parkinson’s disease, or Charcot-Marie Tooth Disease.
Formula I
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Critically, “neurological diseases” is not explicitly defined within the specification. The specification discusses Parkinson’s disease and Alzheimer’s disease. The specification also discusses the use of G93A mice in its testing. G93A mice are a murine model of amyotrophic lateral sclerosis (ALS). However, because the term “neurological disease” is not defined and because claim 13 simply states “neurological disease”, the broadest reasonable interpretation is all neurological diseases, including undiscovered neurological diseases or neurological diseases in which a connection to VPS35 has not been elucidated.
Nature of the invention
The invention is drawn to a clinical method of treating a neurological disease.
State of the prior art
There closest art is found in Stein-Garlach (WO 03/006426). Stein-Garlach teaches a compound of the following structure which is effective in reducing the amount of PrPSc in prion infected cells.”
Stein-Garlach compound
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The instant claims exclude compounds wherein R3 is NHCOR8. Therefore, Stein-Garlach does not read on the instant claims.
Additionally, prions are not affected by the VPS35-620N gene mutation.
The art does affirm a connection between at least the VPS35 gene to Parkinson’s disease and Alzheimer’s Disease. As affirmed in Jang (Biodesign, Vol. 5, No. 3, 2017) on p. 91, sec. Correlation between retromer and Alzheimer’s Neurological Disorders states “Numerous studies showed that the retromer plays a pathogenic role in Alzheimer’s when defects occur in the endosomal trafficking pathway involving the retromer Jang also indicates that, there are several units within this retromer in Table 1. The units are VPS26, VPS29, VPS35, SNX dimer, and WASH complex.
Regarding Parkinson’s disease, Jang connects mutations in VPS35 to Parkinson’s on p. 93, sec. Correlation between retromer and other neurological disease.
However, Jang does not significantly support a connection between the VPS35 gene mutation and ALS or Charcot-Marie tooth disease and a search of the art did not result in any references that would strongly support a connection.
Direction provided and working examples
The figures are largely drawn to cell assays that show efficacy of the Formula I compound against motor neuron degeneration. Under discussion of figures 8 and 9, the specification discusses a mouse modal of ALS showing improvements where it states “Figure 8 shows the ability of 2a to counteract motor neurons degeneration in G93A mice” and “Figure 9 shows that 2a protects G93A mice from nerve degeneration.”
Level of Predictability
There exists a number of neurological diseases. While the specification discusses and provides examples for ALS and the art enables the instant disclosure for PD and AD, the specification and art do not link VPS35 to Charcot-Marie Tooth disease or other neurological diseases not affected by VPS35. One of ordinary skill in the art would find a significant amount of unpredictability in attempting to practice the claimed method towards treatment and/or prevention of neurological diseases outside of AD, PD, and ALS.
Applicant may overcome this rejection by amending claim 13 to specify AD, PD, and ALS.
Response to Arguments
Applicant argues that the specification is enabling and points to the specification for synthesis of the molecules claimed and methods for testing molecules for treating diseases.
Applicant discusses a neuroprotective retromer related to PD, AD, and ALS. As stated in the prior office action, applicant is enabled for treatment of ALS, PD, and AD in subjects where VPS35 expression is reduced and/or have a VPS35/VPS29 retromer dysfunction. However, claim 13 is still drawn to broadly to all neurological diseases, including those not affected by VPS35.
Regarding prevention, the arguments provided have been considered but are not persuasive. The remarks submitted 03/30/2026, on p. 3 state “In view of the requirements, the application as filed illustrates preventative methods by testing compounds prior to behavioral or histopathological abnormalities are yet detectable in a variety of situations.” The remarks continue “The examples of the specification once a biomarker is identified, but generally before any behavioral or histopathological abnormalities are detected, the model (or animal) is administered a compound of the invention, and when compared to the wild type result invariable returns to an improved subject as compared to the wild type. This is true in Parkinson’s disease models, ALS models, and AD models, among others. The ‘extensive and potentially open-ended clinical research’ suggested by the examiner…is unreasonable, given that the prevention would be subjects desiring testing as noted in the application, prevention is not read out of context of the specification.”
First, “prevention” is not explicitly defined within the specification. Therefore, “prevention” is not limited to “subjects desiring testing”. Additionally, the claim does not make this distinction. Claim 13 reads “mammal in need thereof”.
Secondly, the remarks summarized above and the conclusion discussed in the specification describe the reduction of VPS35 expression more as a symptom of the neurodegenerative disease, even if the symptom is one that is shared amongst PD, AD, and ALS. The specification, p. 44 states “Using G93A transgenic mice we observed that CRC protein levels are substantially reduced in ALS motor neurons, Interestingly, such reduction occurs before the appearance of any signs of the disease and, above all before motor neurons degeneration. Parallel experiments performed on post mortem SCs from ALS patients further indicate the reduction of VPS35 and VPS26 levels in ventral horn bona fide motor neurons. These results suggest that retromer failure can anticipate the degeneration of these ells and therefor strategies fostering retromer stabilization can be neuroprotective in ALS.”
Essentially, for the instant application to be enabled for “prevention”, the data provided would require that administration of compound 2a can prevent the reduction in VPS35 expression and can prevent VPS35/VPS29 retromer dysfunction.
Conclusion
No claims 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.
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/L.G./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
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