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 Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on 06/18/2026, wherein claim 2 is cancelled, claim 1 is amended to recite R1 selected from specific heteroaryl group.
Election/Restriction
Applicant elected, with traverse, Group I, subgenus of Formula I wherein R3 is C2-6 alkyl substituted with at least one of amino, C1-6 alkyl-amino, etc. and compound species, Example 10 having following structure, in the reply filed on 01/08/2026.
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Applicant elected the species with traverse. However, the shared common structure of instant claimed compound of Formula I is not novel in view of Slaugenhaupt’s 748. The Restriction/Election requirement is deemed proper and made final in the office action mailed on 03/26/2026.
The elected species is a compound of Formula I wherein
R1 is furanyl;
R2 is fluoro;
R3 is C2-6 alkyl substituted with amino;
R4 is H;
R5 is chloro.
Claims 1, 3-4 and 6-12 read on the elected species. Claim 5 directing to R-configuration is also considered/examined since isomers are construed as exhibiting similar activity in the absence of evidence to the contrary.
The elected species, Example 10 (CAS# 2477799-01-0, entered STN database on 09/11/2020) is disclosed by WO2020167624 A1(hereafter “Wang’624) which is prior art under 102(a)(2) based upon the earlier effectively filed date.
The examiner has expanded the search to non-elected species, wherein R1 is phenyl or heteroaryl (e.g. furanyl), R2 is H or C1-6 alkyl, R3 is C1-6 alkyl substituted with C1-6 alkyl-amino; R4 is H, C1-6 alkyl, R5 is H or halogen( e.g. chloro). The non-elected species remain rejected under the 103 rejections shown below. Other non-elected species are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Claims 1 and 3-12 remain rejected and the action is made final.
Status of Claims
Claims 1 and 3-12 are pending and currently under examination.
Priority
This instant application 18/264,183 filed 08/03/2023, is a 371 of PCT/US2022/014929 filed 02/02/2022, which claims benefit of US provisional application 63/146,139 filed on 02/05/2021.
Information Disclosure Statement
The information disclosure statements submitted on 05/28/2026 and 07/15/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the reference listed in IDS are being considered by the Examiner. Reference written in foreign language is considered to the degree of English abstract or patent family of foreign patent by Examiner.
Response to Arguments
Applicant's remarks filed 06/18/2026 have been fully considered. Any objection and rejection found in the previous Office Action and not repeated herein has been withdrawn in view of amendment and Applicant’s remarks .The text of those sections of Title 35 U.S. Code not included in this action can be found in a prior Office action.
NEW Rejections As Necessitated By Amendment
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.
Claims 1, 3-5, and 10-12 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 (newly reapplied as necessitated by amendment).
Claim 1 is amended to recite heteroaryl group selected from the group consisting of furanyl, thiophenyl, ... pyridazinyl, and a 5-8 membered monocyclic or a 5-8 membered bicyclic aromatic carbon atom ring structure radical containing 1-3 heteroatoms selected from N, O, and S. Please note “carbon atom ring structure radical” containing heteroatoms is not a standard or recognized chemical term for defining a heteroaryl group. A person of ordinary skilled in the art would not know whether the “1-3 heteroatoms” are included in the counting of the 5-8 members.
Further, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, 5-8 membered monocyclic aromatic carbon ring structure radical containing 1-3 heteroatoms is broad recitation of heteroaryl group while the specific furanyl, thiophenyl, etc. is the narrower statement/ limitation of the 5-8 membered heteroaryl groups. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims
Claims 3-5, and 10-12 are rejected due to dependency on amended claim 1.
Maintained/Modified Rejections
As Necessitated By Amendment
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.
Claims 1, and 3-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention (reapplied as necessitated by amendment).
Instant claims are to directed to “[a] method for treating spinocerebellar ataxia type 3 (SCA3) in a subject in need thereof, comprising administering to said subject an effective amount of a compound of Formula (I) … ”. The instant disclosure does not contain sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue experimentation in full scope upon consideration of the factors set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1998), as follows. See also MPEP § 2164.01(a) and § 2164.04.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). The determination that "undue experimentation" would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
As stated in the MPEP 2164.01(a), “There are many 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 is "undue." In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(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.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The Breadth of The Claims/ Nature of The Invention
Independent claim 1 is directed to a method of treating SCA3 by administering a large scope of compounds of Formula (I) comprising vast variety of R groups. Claims 6-9 recite compound species that are not tested or inactive in in-vitro assay. Instant specification defines the term “treating” as including “preventing”, “inhibiting”, and “ameliorating” (See PGPub US 20240041886 A1 [0160]).
The nature of the claimed invention is drawn to treating/preventing SCA3 by inducing exon 4 skipping in the ATXN3 pre-mRNA during splicing in a patient. To date there are no known disease-modifying therapies for SCA3 (Spec [0008]).
The State of the Prior Art and the Predictability or Lack Thereof in the Art
Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease (MJD), is an inherited neurodegenerative disorder and the most common form of autosomal dominant hereditary ataxia worldwide. The treatment of SCA3/MJD is highly unpredictable due to the complex nature of the disease, various etiology/mechanism, and the mode of action of treatment. There are many other factors contributing to the effectiveness/efficacy of compounds in treating SCA3/MJD disease, such as pharmacokinetic profile, bioavailability, administration route, dosage regimen, etc.
Wang (2018) reviews pathogenic mechanisms of SCA3/MJD and therapeutic strategies (See whole paper). Wang 2018 states: “Despite enormous progress toward elucidating the molecular pathogenesis of SCA3/MJD in the last 20 years, there is no cure available for SCA3/MJD patients” (See page 139, left column). “Pharmacological approaches for improving various symptoms have been developed and tested in clinical studies. However, most drug clinical trials for SCA3/MJD had negative or inconclusive results due to the multiple methodological issues of these studies” (See page 147, left column).
More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity (e.g., cancer prevention) is generally considered an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The Amount of Direction Present and Presence or Absence of Working Examples
The specification does not provide sufficient guidance/protocols for a skilled artisan to practice the claimed method of treating SCA3/MJD with compound of Formula I in its full scope.
Instant specification disclosed 62 compound species (See [0086]-[0088]), but only 12 compounds were tested in in-vitro assay with varied activity. Instant specification discloses endogenous total ATXN3 (tATXN3) protein assay, wherein 12 compounds were tested, three compounds are inactive and three compounds show IC50 >1.0uM (See Example 1, Table1). In instant RT-qPCR assay to quantify Exon 4 Skipping in ATXN3 Pre-mRNA in cells, 12 compounds were tested, three compounds are inactive and three compounds show IC50 >1.5uM (See Example 2, Table 2).
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It’s noted there is no apparent correlation between the structure of compounds that are indicated as “inactive” versus those with mM level of activity. There is no in-vivo assay or working example of compounds treating a subject associated with SCA3.
The guidance provided by the assay do not clearly describe how the results are correlated with an expectation of any therapeutic effect with spinocerebellar ataxia type 3 (SCA3). One of ordinary skilled in the art would not know if the assay examples would support instantly claimed method of treatment of (SCA3) in a subject. Regarding dosing and effective amounts, all of the guidance provided regarding dosing and effective amounts is completely generic without any specific dose related to response curves or any experimental data associated with spinocerebellar ataxia type 3 (SCA3).
The level of one of ordinary skill in the art
The level of skill required to make and/or use the instant invention would likely require many years of professional experience conducting research in the art (e.g., medicine, pharmaceutical science, biology, biochemistry, medicinal chemistry, and/or organic chemistry, etc.) as well as an advanced educational degree (e.g., M.D. and/or Ph.D.) commensurate in level with the advanced techniques involved in the preparation and/or use of the instant invention.
The quantity of experimentation needed
An unduly extensive amount of experimentation would be required for one of ordinary skill in the art to use the instantly claimed method The efficacy/ effectiveness of compound of Formula I needs to be evaluated/validated through in-vivo test/animal study to provide accurate evidence for effective treatment of SCA3 . Working examples would be needed to determine the therapeutically effective dose and administration route for different compound species due to the different activity. The therapeutically effective amount may vary depending on many factors, such the subjects being treated, the disease condition, intended outcome, patient response, etc. Thus, the skilled artisan would have to undergo exhaustive studies to evaluate each condition that falls under the umbrella compound of Formula I in order to be able to fully carry out the invention commensurate in scope with the claims.
Therefore, it would be a great burden for one of ordinary skill in the art to carry out undue experimentation to in full scope.
Conclusion
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562,27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here with respect to instantly claimed method of treating SCA3 in a subject with compound of Formula I , in view of the analysis above pursuant to In re Wands. In other words, one skilled in the art could not practice the claimed invention in full scope without undue experimentation.
Response to Arguments
Applicant argues they are not required to provide data showing activity for each and every possible compound falling under the scope of general Formula (I)... the claims should be interpreted in accordance with their full breadth and not confined to the disclosed embodiments (Remarks, page 19/38).
RESPONSE: Applicant's arguments have been fully considered but they are not persuasive. To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. As shown in instant Table 1 and Table 2, different compound species exhibit different activity and some compounds encompassed by instant compound of Formula I are inactive. Applicant has not provided a representative number of working examples to show that all of the claimed compounds comprising vast variety of R groups are effective for treating spinocerebellar ataxia type 3 (SCA3). Instant specification does not support the full scope of compound of Formula I genus are active for treating spinocerebellar ataxia type 3 (SCA3). Furthermore, Applicant has not sufficiently limited the compound species in claim 6-9 to what has been demonstrated active in the specification.
As disclosed by Wang (2018) and confirmed by instant disclosure, there is currently no cure or disease-modifying treatment to slow the progression of spinocerebellar ataxia type 3 (SCA3)/ Machado-Joseph disease (MJD). The treatment of spinocerebellar ataxia type 3 is highly unpredictable. Therefore, the rejection is maintained for the reasons of record and the reasons set forth above.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 3-12 are rejected under 35 U.S.C. 103 as being unpatentable over Slaugenhaupt et al. (WO 2016/115434, hereafter “Slaugenhaupt’ 434”, Applicant’s IDS dated 11/26/2024 ), in view of Wang (Neuroscience 2018, Vol. 371, pp 138-154, https://doi.org/10.1016/j.neuroscience.2017.11.051, Experimental and Clinical Strategies for Treating Spinocerebellar Ataxia Type 3) (reiterated as necessitated by amendment).
Slaugenhaupt’ 434 teaches compound of Formula I, II, Ia, Ib, Ic, etc. or salt thereof, and composition comprising aforementioned compounds for treating diseases of central nervous system (e.g. familial dysautonomia, Fragile X tremor/ataxia, etc. ) by improving mRNA splicing in genes (See abstract, page 2, lines 10-25; page 3-7; page 20-26; page 27-32, lines 1-25; Table A; Examples claims 1-70).
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Slaugenhaupt’ 434 teaches compound species that are encompassed by or very similar to instant claimed compound of Formula I , e.g. compound 177-181, 206, 225, etc. (See Table A; Examples )
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Slaugenhaupt’ 434 compounds read on instant compound of Formula, wherein R1 is phenyl or heteroaryl (e.g. furanyl), R2 is H or C1-6 alkyl, R3 is C1-6 alkyl substituted with C1-6 alkyl-amino; R4 is H, C1-6 alkyl, R5 is H or halogen (e.g. chloro).
Slaugenhaupt’ 434 teaches primary splicing assay in different gene and efficacy thereof (See Example 44, page 261; Table 3-5). Slaugenhaupt’ 434 also teaches in vivo familial dysautonomia mouse model (See Example 46, page 271). Slaugenhaupt’ 434 teaches variety of disease associated with one or more mRNA splicing defects (e.g. familial dysautonomia, Fragile X tremor/ataxia, etc. ) (See page 196, lines 15-25; Table 1; page 197-200). Slaugenhaupt’ 434 teaches method of treating diseases of central nervous system by improving mRNA splicing in genes comprising improving exon inclusion ending in the nucleotide sequence(See abstract, page 199, lines 28-30; Table 1; page 206-207).
Slaugenhaupt’ 434 collectively teaches a method of treating neurological/neurodegenerative disease with pyrrolopyrimidine compounds that could improve mRNA splicing/ improving exon inclusion in the nucleotide sequence. According to MPEP § 2144.09, A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). Please note prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979). Further, a claimed compound may be obvious because it was suggested by, or structurally similar to, a prior art compound even though a particular benefit of the claimed compound asserted by patentee is not expressly disclosed in the prior art. It is the differences in fact in their respective properties which are determinative of non-obviousness.
Slaugenhaupt’ 434 is silent about treating SCA3/MJD associated with mutant ATXN3 (mATXN3) mRNA. Please note biological activity is the property of compound. Instantly recited limitation wherein compound of claim 1 induces exon skipping are considered to simply express the intended result of the process step of administering compound of Formula I, which does not necessarily contribute to patentable weight. See MPEP 2111.04: In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Wang 2018 reviews pathogenic mechanisms of SCA3/MJD and therapeutic strategies for treating SCA3/MJD (See whole paper). Wang 2018 and its incorporated reference teach therapeutic interventions focus on directly targeting the mutant protein or attenuating the mutant atx-3-induced cellular toxicity, e.g. gene silencing or mutant protein clearance, mutant polyQ protein modification, etc.( See page 139, Table 1).
Wang 2018 and its incorporated reference teach antisense oligonucleotide (AON)-mediated
exon skipping targeting exons 9 and 10 of atx-3 has several advantages that maintain normal atx-3 function and can be applied in all SCA3/MJD patients . AON-based therapy targeting atx-3 exon 10
reduced insoluble atx-3 and inhibited the nuclear localization of atx-3 in SCA3/MJD mice. Moreover, AON activity can last for at least 2.5 months(See page 139, right column).
It is a common practice in the pharmaceutical industry to repurpose and/or explore different disease treatment with known active agent/ drug. It would have been prima facie obvious to one of the ordinary skilled in the art before the effective filling date of instant invention to further explore/ expand Slaugenhaupt’ 434 compounds for treating other neurological/neurodegenerative disease (e.g. SCA3/MJD) based on the combined teachings of Slaugenhaupt’ 434, Wang and general knowledge of structure similarity/ bioisosteric modification/ SAR study for treating neurological/neurodegenerative disease. At the time of instant invention was made, it was already known that Slaugenhaupt’ 434 compound could be used for treating neurological/neurodegenerative disease by improving mRNA splicing/ improving exon inclusion ending in nucleotide sequence. It was also known SCA3/MJD is neurological/neurodegenerative disease associated with mutant ATXN3 (mATXN3) RNA with expanded polyQ as taught by Wang. In searching for alternative treatment of SCA3/MJD, a skilled artisan would be motivated to further explore Slaugenhaupt’ 434 compound for treating SCA3/MJD and reasonably expect improving mRNA splicing might benefit treatment of SCA3/MJD in a subject.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of structure similarity/ bioisosteric modification/ SAR study for treating neurological/neurodegenerative disease/gene therapy. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues about the difference of Slaugenhaupt '434 compounds, Slaugenhaupt '434 does not contain any mention or discussion at all of treating spinocerebellar ataxia type 3 (SCA3)... Wang does not contain any teaching, suggestion, or motivation to modify those 2 selected compounds for the purpose of treating spinocerebellar ataxia type 3 (SCA3) (Remarks, page 23-27/38).
RESPONSE: Applicant’s argument has been fully considered, but NOT persuasive. Slaugenhaupt '434 teaches compounds that are very similar to instant compound of Formula I, with difference of one or two carbon length as illustrated by Cpd 177, 181, 193, 206, etc. Please note prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979). Further, a claimed compound may be obvious because it was suggested by, or structurally similar to, a prior art compound even though a particular benefit of the claimed compound asserted by patentee is not expressly disclosed in the prior art. Instant claims. As such, instant claimed compound of Formula I as a whole is obvious over Slaugenhaupt '434.
Regarding the method of treatment, Slaugenhaupt’ 434 collectively teaches a method of treating variety of neurodegenerative disease associated with mRNA splicing defects with pyrrolopyrimidine compounds that could improve mRNA splicing/ improving exon inclusion in the nucleotide sequence. Thus, Slaugenhaupt’ 434 provides a technical rationale for exploring pyrrolopyrimidine compounds that modulate RNA splicing for treating different generic neurodegenerative disease. Wang’2018 and its incorporated reference teach treatment strategy for SCA3, e.g. exon skipping targeting at ATX3 ( which is a form of RNA splicing), has several advantages that maintain normal atx-3 function and can be applied in all SCA3/MJD patients (See page 139, right column). Accordingly, the use of pyrrolopyrimidine compounds for treating SCAs is not arbitrary selection of compounds for unrelated disease, but a logical application of known splicing modulating approach to another disease in which splicing is implicated as a therapeutic strategy.
Please note the reasonable expectation of success for obviousness is not absolute expectation of therapeutic success. As MPEP 2143.02.I. stated : “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute"))”. Further, instant specification does not support the full scope of compound of Formula I genus are active for treating spinocerebellar ataxia type 3 (SCA3).
Claims 1, and 3-12 are rejected under 35 U.S.C. 103 as being obvious over Wang’624 (WO2020167624 A1, family member of US 12398140 B2, Applicant’s IDS dated 11/26/2024) in view of Wang (Neuroscience 2018, Vol. 371, pp 138-154, https://doi.org/10.1016/j.neuroscience.2017.11.051, Experimental and Clinical Strategies for Treating Spinocerebellar Ataxia Type 3).
The applied reference has a common inventor and applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Wang’624 disclosed pyrrolo[2,3-d]pyrimidine compound of Formula I or a form thereof, and a method for treating familial dysautonomia (See abstract, page 2, lines 1-25; claims 1 -11).
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Wang’624 disclosed compound species that are encompassed by instant compound of Formula I, and compound species as recited in instant claims 6-9, including instant elected species (See page 8-18, claims 6-7).
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Wang’624 disclosed IKBKAP-HTRF Assay (See Example 1) and a method of treating familial dysautonomia (FD) by targeting pre-mRNA splicing mechanisms (See abstract, page 1, lines 14-28; claim 8).
Wang’624 is silent about treating SCA3/MJD with pyrrolo[2,3-d]pyrimidine compound of Formula I. The collective teachings of Wang (2018) is elaborated in preceding 103 rejection and applied as before. Wang 2018 reviews pathogenic mechanisms of SCA3/MJD and therapeutic strategies for treating SCA3/MJD (See whole paper).
It is a common practice in the pharmaceutical industry to repurpose and/or explore different disease treatment with known active agent/ drug. It would have been prima facie obvious to one of the ordinary skilled in the art before the effective filling date of instant invention to further explore/ expand Wang’624 compounds for treating other neurological/neurodegenerative disease (e.g. SCA3/MJD) based on the combined teachings of Wang’624 and Wang 2018. In searching for alternative treatment of SCA3/MJD, a skilled artisan would be motivated to further explore Wang’624 compound for treating SCA3/MJD and reasonably expect improving mRNA splicing might benefit treatment of SCA3/MJD in a subject.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of structure similarity/ bioisosteric modification of SAR study for treating neurological/neurodegenerative disease/gene therapy. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues Wang '624 does not contain any mention or discussion all of treating spinocerebellar ataxia type 3 (SCA3)... one with ordinary skill in the art would not have any motivation
whatsoever to use the compounds of Wang '624 to treat spinocerebellar ataxia type 3 (SCA3)... One with ordinary skill in the art in view of Wang '624 in view of Wang, would not have any expectation that the compounds of Wang '624 could be used to treat spinocerebellar ataxia type 3 (SCA3), an entirely different disease to the indication of Wang '624 (Remarks, 28/38).
RESPONSE: Applicant’s argument has been fully considered, but NOT persuasive. Wang '624 teaches instant claimed compounds including the elected species for treating nervous system disease associated with one or more pre-mRNA splicing defects (e.g. familial dysautonomia FD) by targeting pre-mRNA splicing. Thus, Wang '624 provides a technical rationale for exploring pyrrolopyrimidine compounds that modulate RNA splicing for treating different generic nervous system disease. Wang’2018 and its incorporated reference teach treatment strategy for SCA3, e.g. exon skipping targeting at ATX3 ( which is a form of RNA splicing), has several advantages that maintain normal atx-3 function and can be applied in all SCA3/MJD patients . Accordingly, the use of Wang '624 compound for treating SCAs is not arbitrary selection of compounds for unrelated disease, but a logical application of known splicing modulating approach to another disease in which splicing is implicated as a therapeutic strategy.
Please note the reasonable expectation of success for obviousness is not absolute expectation of therapeutic success. As MPEP 2143.02.I. stated : “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019). Most importantly, the biological activity is the property of compound. Instant specification does not support the full scope of compound of Formula I genus are active for treating spinocerebellar ataxia type 3 (SCA3).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 and 3-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1- 13 of U.S. Patent No. 12398140 B2, in view of Wang (Neuroscience 2018, Vol. 371, pp 138-154, https://doi.org/10.1016/j.neuroscience.2017.11.051, Experimental and Clinical Strategies for Treating Spinocerebellar Ataxia Type 3).
Reference claims are directed to compound formula I with the same core structure. Reference claims 8-11 recite compound species that read on instant claims 6-9. Reference claims 7 and 13 recite treating familial dysautonomia in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of reference compounds.
Reference claims are silent about treating spinocerebellar ataxia type 3 (SCA3).
The collective teachings of Wang (2018) is elaborated in preceding 103 rejection and applied as before. Wang 2018 reviews pathogenic mechanisms of SCA3/MJD and therapeutic strategies for treating SCA3/MJD (See whole paper).
It is a common practice in the pharmaceutical industry to repurpose and/or explore different disease treatment with known active agent/ drug. It would have been prima facie obvious to one of the ordinary skilled in the art to further explore/ expand reference compounds for treating other neurological/neurodegenerative disease (e.g. SCA3/MJD) based on the combined teachings of reference claims and Wang 2018.
The instant application shares at least one common inventor /applicant with the reference patent. Furthermore, the instant application is not related to the reference patent based on the record, thus no 35 USC 121 shield exists.
Response to Arguments
Applicant argues one with ordinary skill in the art in view of claims 1-13 of the' 140 patent in view of Wang, would not have any expectation that the compounds of the '140 patent could be used to treat spinocerebellar ataxia type 3 (SCA3 ), an entirely different disease to the indication of the '140 patent (Remarks, page 29/38)
RESPONSE: Applicant’s argument is similar to 35 USC 103 rejection over Wang '624 in view of Wang 2018. As elaborated above, the use of reference compound/ Wang '624 for treating SCAs is not arbitrary selection of compounds for unrelated disease, but a logical application of known splicing modulating approach to another disease in which splicing is implicated as a therapeutic strategy. Again, reasonable expectation of success for obviousness is not absolute expectation of therapeutic success.
Claims 1, 3-5 and 10-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U S patent No. 12723049 (corresponding to US application No. 18/264,189 ), in view of Patani et al. (Chemical Reviews, 1996. Vol. 96, 8: 3147-3176) (newly reiterated as necessitated by amendment and change of reference application).
Reference claims are directed to method for inhibiting or ameliorating spinocerebellar ataxia type 3 (SCA3) in a subject in need thereof, comprising administering to said subject an effective amount of a compound of Formula (I). Reference claims 14-15 recite inducing exon skipping that read on instant claims 10 and 11.
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The difference of reference compounds and instant claimed compound of Formula I is thiophene ring vs pyrrole ring. Patani teaches S, O, N and CH are classical bioisosteres that could be used within ring system as ring equivalents (See page 3158). A skilled artisan would have known S, O, N and CH are classical bioisosteres which is also illustrated by R1 reciting phenyl and heteroaryl comprising heteroatoms N, O and S.
According to MPEP § 2144.09, A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
The instant application shares at least one common inventor /applicant with the reference patent. Furthermore, the instant application is not related to the reference patent based on the record, thus no 35 USC 121 shield exists.
Response to Arguments
Applicant argues it is not possible to accurately predict what effect such a replacement would have on the activity of a compound... the substitution or modified placement of a single substituent will result in a specific, unpredictable activity... one having ordinary skill in the art would not have any expectation of successfully arriving at Applicant's claimed invention (Remarks, page 30-34/38).
RESPONSE: The examiner dose not dispute reference compounds comprising different substituents have different activities. Please note this double-patenting rejection is based on the bioisosteric replacement of compound of formula I genus, not against individual compound species. As elaborated above, the reasonable expectation of success for obviousness is not absolute expectation of therapeutic success.
Claims 1, 3-5 and 10-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of copending Application No. 18/264,187 (reference application), in view of Patani et al. (Chemical Reviews, 1996. Vol. 96, 8: 3147-3176) (reapplied as necessitated by amendment). NOA of application No. 18/264,187 is mailed on 07/30/2026.
Reference claims are directed to method for inhibiting or ameliorating spinocerebellar ataxia type 3 (SCA3) in a subject in need thereof, comprising administering to said subject an effective amount of a compound of Formula (I). Reference claims 11-12 recite inducing exon skipping that read on instant claims 10 and 11.
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The difference of reference compounds and instant claimed compound of Formula I are the heteroatoms on the ring. A skilled artisan would have known S, O, N and CH are classical bioisosteres as taught by Patani, which is also illustrated by R1 reciting phenyl and heteroaryl comprising heteroatoms N, O and S.
According to MPEP § 2144.09, A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
The instant application shares at least one common inventor /applicant with the reference patent. Furthermore, the instant application is not related to the reference patent based on the record, thus no 35 USC 121 shield exists.
Response to Arguments
Applicant argues it is not possible to accurately predict what effect such a replacement would have on the activity of a compound... because the change in activities is not predictable, one having ordinary skill in the art would not have any expectation of successfully arriving at Applicant's claimed invention (Remarks, page 34-38/38).
RESPONSE: The examiner dose not dispute reference compounds comprising different substituents have different activities. Please note this double-patenting rejection is based on the bioisosteric replacement of compound of formula I genus, not against individual compound species. As elaborated above, the reasonable expectation of success for obviousness is not absolute expectation of therapeutic success.
Conclusion
NO claims are 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 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 LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on (571)272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LIYUAN MOU/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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