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 .1
Status of Claims
Claims 1-3, 5-8, 12-16, 18-19, 21-25, 27-31 and 33-35 are pending. Claims 19, 21, 22 are under examination. Applicant’s election without traverse, of Group II, claims 19, 21 and 22, in the reply filed on June 2 2025 was acknowledged. Further, Applicant’s election of the species synucleozid 2 compound is acknowledged.
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Synucleozid is a compound of Formula I,
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wherein Y is CR1, R1 is hydrogen, X is NR2, R2 is hydrogen,
Z is
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, IM1 is guanidyl, and IM2 is guanidyl.
Claims 1-3, 5-8, 12-16, 18, 23-25, 27-31 and 33-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on Dec 22 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Response to Arguments
Applicant’s arguments, filed Dec 22 2025, with respect to the informality of claim 19 reciting “a synucleozid compound of Formula I of claim 1” has been fully considered and are persuasive. The objection of claim 19 has been withdrawn.
Applicant's arguments filed Dec 22 2025 regarding the obviousness rejection of claims 19, 21 and 22 have been fully considered but they are not persuasive. See below response to Attorney arguments.
Maintained Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 19, 21 and 22 remain rejected under 35 U.S.C. 103 as being unpatentable over WO 2016025692 A1 (WO 692) in view of Nuytemans et al. C9ORF72 Intermediate Repeat Copies Are a Significant Risk Factor for Parkinson Disease, Annals of Human Genetics Volume 77, Issue 5 pp. 351-363. WO 692 is listed on the IDS dated June 17 2022. Nuytemans was cited on the PTO-892 form.
Claim 19 is directed to the treatment of a synucleinopathy disease in a patient in need, having the disease, with a compound of formula I, inclusive of the elected species of compound synucleozid. Claims 21 and 22 recite the disease as Parkinson’s disease.
Regarding claim 19, WO 692 teaches synucleozid as elected, see below compound 2 in claim 1.
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As required by claim 19 and the treatment of a disease, WO 692 teaches treatment of disease (such as FTD/ALS, aka frontotemporal dementia/amyotrophic lateral sclerosis) with its claimed small molecules compounds, such as compound 2, synucleozid, by targeting a particular RNA sequence in the C90RF72 gene. See page 1, last paragraph. See also first paragraph of Summary, page 2, and disclosure of synucleozid, compound 2, below the first paragraph.
While WO 692 teaches the compound synucleozid administered to patients in need (diseases associated with the C90RF72 gene), it does not teach a subject patient in need suffering from the synucleinopathy disease, Parkinson’s disease as per claims 19, 21 and 22.
However, a person having ordinary skill in the art (PHOSITA) would look towards the teachings of WO 692, noting synucleozid capability to treat diseases via targeting the C90RF72 gene, where the C90RF72 gene is known in the prior art to be associated with Parkinson’s disease, as detailed below, per Nuytemans.
Further, with regard to the description of Parkinson’s disease as a synucleinopathy pathology in the patient in need, prior art noting the treatment of Parkinson’s disease (PD) with synucleozid will be relevant in the obviousness analysis. PD patients will require treatment of defective α-Synuclein proteins and synucleozid will necessarily treat defects/misfolds/oligomerization of the protein that result in fibrils that accumulate in Lewy bodies associated with PD pathology. (See paragraph, Background of specification noting the pathology of PD as it relates to α-Synuclein proteins).
Nuytemans teaches C90RF72 intermediate repeat copies are a significant risk factor for Parkinson’s disease (PD). See title and abstract. Similar to WO 692, Nuytemans teaches the strong association of C90RF72 with ALS and FTD. See Abstract. Nuytemans teaches that intermediate (> 20 to 30+) repeat copies of C90RF72 gene were significantly increased in PD and essential tremors plus Parkinson’s patients. See abstract. Nuytemans suggests, via its results, that intermediate copy numbers of the C9ORF72 repeat contribute to risk for PD and ETP, Id. Further, Nuytemans suggests that PD, ALS and FTD share some pathophysiological mechanisms of disease, Id.
To a person having ordinary skill in the art (PHOSITA), armed with the knowledge of WO 692 disclosing synucleozid is used to treat C90RF72 gene diseases such as ALS and FTD, it would have been prima facie obvious to combine this with the teachings of Nuytemans noting the association C90RF72 gene intermediate repeat copies with not only ALS/FTD but also Parkinson’s disease. The rationale to support the prima facie case are the prior art findings (C90RF72 gene associated with PD, as well as ALS/FTD) combined with a known method (treatment of C90RF72 gene disorders ALF/FTD with synucleozid) to predictably arrive at the claimed invention.
RESPONSE TO ATTORNEY ARGUMENTS:
While PD and ALS share an underlying mechanism of sharing C90RF72 repeats so to treat with synucleozid3, the Attorney’s rebuttal of the prima facie case of obvious is summarized as follows:
per Nuytemans large C90RF72 expansions do not contribute to Parkinson's disease ("PD") risk, instead increased intermediate expansions were observed in Parkinson's cases relative to controls; while PD and ALS same some pathophysiological disease mechanisms, further studies are necessary.4
the expanded GGGGCC repeat in the C9ORF72 gene is the most common genetic cause of ALS/FTD, where per WO ‘692, Ash and Mori references, compounds that bind repeat sequence decrease abnormal, non-canonical RNA translation and treat ALS.
in contrast, synucleinopathy diseases were understood to implicate standard, canonical RNA translation that results in expression or over-expression of a-synuclein protein, i.e. an entirely different mechanism and etiology,
that different structures and locations (start codon vs. intron 1) of the a-synuclein Iron-Responsive-Element ("IRE") and r(GGGGCC)exp supports understanding in the art that ALS and PD have entirely different mechanisms and etiologies, (citation to Cahill, Olivares, Su and Zamiri)
while Nuytemans cites studies that implicate RAN translation in ALS, Nuytemans does not teach or suggest that this mechanism is implicated in synucleinopathy diseases, such as PD, where the Attorney states such theory is still within its infancy with respect to PD and C9ORF72 repeats are not associated with stringently selected autopsy confirmed PD..
The Attorney response states, the Office Action fails to explain why a skilled person would be motivated to treat a disease implicating a different canonical translation mechanism, and why a PHOSITA would disregard the lack of similarity between codon/intron structures. The response states the Examiner fails explaining why a skilled person would have reasonably expected that a small molecule that binds the repeat expansion in PD would also bind the IRE and mitigate synucleinopathy disease pathologies.
In response, as detailed above, a PHOSITA, armed with the knowledge of WO 692 disclosing synucleozid is used to treat C90RF72 gene diseases such as ALS and FTD, it would have been prima facie obvious to combine this with the teachings of Nuytemans noting the association C90RF72 gene intermediate repeat copies with not only ALS/FTD but also Parkinson’s disease. The rationale to support the prima facie case are the prior art findings (C90RF72 gene associated with PD, as well as ALS/FTD) combined with a known method (treatment of C90RF72 gene disorders ALF/FTD with synucleozid) to predictably arrive at the claimed invention.
Furthermore, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
Note MPEP 2145, Example 1, citing to PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 83 USPQ2d 1289 (Fed. Cir. 2007). There had been ample suggestion in the prior art that the claimed method would have worked, Id. Absolute predictability is not a necessary prerequisite to a case of obviousness, Id. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient, Id. The Federal Circuit concluded that “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304. See MPEP 2145, citing to PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 83 USPQ2d 1289 (Fed. Cir. 2007).
While the Attorney response notes various mechanisms and theories behind the claimed method of treatment, the alternate basis of the prima facie case of obviousness remains so long as there is not a stronger basis to criticize, discredit or otherwise discourage the solution claimed.
Claim 19’s method of treatment is broadly directed to treatment of synucleinopathy disease (i.e., PD) in a patient having the disease with an effective amount of a compound of formula I. In support of claim 19, it is noted that the specification details the propensity and selectivity of Synucleozid for regions of SNCA, starting at paragraph 221 and Figures 1A-1D and Figures S2-S16A/S16B (for example specifically, the SNCA IRE A bulge per Figures 3A-3C. See also Figures 6A-6C noting first potential mode of action of Synucleozid. See also Figures 7A-7B noting second and third potential mode of action of Synucleozid). However, the claimed method is broader in scope than any of the experimental details of the specification noted above.
Amendment of the examined claims so that they are in line not only with any experimental data with unexpected results over the cited prior art, possibly in-line with the Attorney response rebuttal statements, will overcome the cited prior art.
Conclusion and Correspondence
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 WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 CONTINUING DATA
This application is a 371 of PCT/US2020/065901 12/18/2020
PCT/US2020/065901 has PRO 62/950,267 12/19/2019
2 CAS No. : 502139-01-7
Synucleozid (NSC 377363) is a potent inhibitor of the SNCA mRNA that encodes α-synuclein protein. https://www.medchemexpress.com/synucleozid.html?srsltid=AfmBOoqoGD1CP2en_0wdrqg93xjEpoqk0TajzaVhfZvammfFaaq4ddA2
3 In summary, the response notes '692 PCT Publication discloses that a repeat expansion in C90RF72 causes frontotemporal dementia ("FTD") and amyotrophic lateral sclerosis ("ALS") and discloses small molecule inhibitors that bind r(GGGGCC)exp, where Nuytemans discloses increased intermediate expansions of C90RF72 gene expression were observed in Parkinson’s disease.
4 In summary, the response notes Nuytemans discloses that, while large C90RF72 expansions do not contribute to Parkinson's disease ("PD") risk, increased intermediate expansions were observed in Parkinson's cases relative to controls, noting further studies are necessary to understand the contribution of C90RF72 with regard to PD and AL sharing some pathophysiological mechanisms of disease.