DETAILED ACTION
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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 .
Priority
This application is a continuation application of PCT/US2024/052155, filed October 19, 2024, which claims priority to, and the benefit of U.S. Provisional Application No. 63/545,126, filed October 20, 2023.
Status of Claims
Claims 1-24, 29, and 42-44 are canceled. Claims 25-28 and 30-41 are pending and under examination. Acknowledgement is made of the receipt and entry of the amendment to the claims filed on August 11, 2026.
Action Summary
Claims 25-28 and 30-41 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in view of the claim amendments.
Claims 25-28 and 30-41 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, has been withdrawn in view of the claim amendments.
Claims 25-28 and 30-41 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 treating fascioscapulohumeral muscular dystrophy to the extent treatment is defined in the specification at paragraph [0085], has been withdrawn in view of the amendment limiting the claimed treatment to a disease or disorder characterized by DUX4 misexpression or FSHD.
Claim 27 rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Wang et al. (US4,692,533), cited in the IDS of 02/11/2026, is withdrawn in view of the claim amendment limiting R10 to C6-10aryl.
Claims 25-28 and 30-31 rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US4,692,533, cited in the IDS of 02/11/2026) in view of Kaminski et al. (Current Topic in Medicinal Chemistry, 2017, 17, 858-874, cited in the IDS of 02/11/2026) and Kaminski et al. (WO2020/214043A1, cited as “Kaminski-WO”), are maintained.
Claims 32-36 rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US4,692,533, cited in the IDS of 02/11/2026) in view of Kaminski et al. (Current Topic in Medicinal Chemistry, 2017, 17, 858-874, cited in the IDS of 02/11/2026) as applied to claims 25-31 in further view of Kaminski et al. (WO2020/214043A1, cited as “Kaminski-WO”), are maintained.
Claims 37-41 rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US4,692,533, cited in the IDS of 02/11/2026) in view of Kaminski et al. (Current Topic in Medicinal Chemistry, 2017, 17, 858-874, cited in the IDS of 02/11/2026) and Kaminski et al. (WO2020/214043A1, cited as “Kaminski-WO”) as applied to claims 25-36, in further view of Mathews (Pain Management inf FSHD, The Science and psychology of managing chronic pain, May 2022), are maintained, but modified and revisited in light of the claim amendment.
Affidavit
The Declaration by Ali OZes under 37 CFR 1.132 filed August 11, 2026, is insufficient to overcome the rejection of claims 25-29 and 30-41 based upon the rejections that have not been overcome as set forth in the last Office action because of the reasons set forth in the Declaration and Applicant’s arguments section below.
Response to Arguments
Applicant’s arguments filed August 11, 2026, have been fully considered but they are not persuasive for the reasons set forth in the Declaration and Applicant’s arguments section below.
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 25-28 and 30-31 remain rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US4,692,533, cited in the IDS of 02/11/2026) in view of Kaminski et al. (Current Topic in Medicinal Chemistry, 2017, 17, 858-874, cited in the IDS of 02/11/2026) and Kaminski et al. (WO2020/214043A1, cited as “Kaminski-WO”).
Wang teaches aminoalkyl imide compounds comprising succinimide/pyrrolidine-2,5-dione cores; aminoalkyl linkers; amide linkages; and aryl substituents including compound 6
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. (See col. 1, lines 7-12; col. 2, lines 1-15; Table 1, and Examples 1-8.) Wang further teaches such compounds are useful intermediates for preparing valuable organic compounds. (See col. 2, lines 10-15.) The disclosed compounds are prepared reaction products and isolated compounds, rather than merely speculative intermediates.
Wang does not teach a compound
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.
Kaminski teaches pyrrolidine-2,5-dione scaffolds containing aminoalkyl substituted imidides, aromatic and phenyl-substituted moieties, and medicinal chemistry optimization of such scaffolds through incorporation of substituted aryl groups has having anticonvulsant/antinociceptive structure-activity relationship. (See Title, Abstract; Figures, and Tables.) Moreover, Kaminski teaches some of these compounds are orally and intraperitoneally administered. (See left col., third paragraph of page 859; left col., of last paragraph of page 862.) Kaminski further teaches that incorporation of aromatic phenyl-containing substituents into pyrrolidine-2.5-dione systems was known to impart desirable neurological and pharmacological properties. (See figures and Tables.)
It would have been prima facie to one of ordinary skill in the art at the time the invention was filed to modify the aminoalkyl imide compound 6 taught by Wang to include the aromatic susbstitution patterns taught by Kaminski because Kaminski teaches that such aryl-substituted pyrrolidine-2,5-dione derivatives possess useful neurological and anticonvulsant properties. A person of ordinary skill in the art would have reasonably expect that incorporation of known aryl substitution motifs into the Wang scaffold would provide structurally related compound possessing biological properties. The modification merely involves predictable substitution of known aromatic substituents into known aminoalkyl imide scaffold are represents no more than routine medicinal chemistry optimization.
Claims 32-36 remain rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US4,692,533, cited in the IDS of 02/11/2026) in view of Kaminski et al. (Current Topic in Medicinal Chemistry, 2017, 17, 858-874, cited in the IDS of 02/11/2026) as applied to claims 25-31 in further view of Kaminski et al. (WO2020/214043A1, cited as “Kaminski-WO”).
The teachings of Wang and Kaminski have been discussed above.
Wang and Kaminski collectively do not teach a pharmaceutical composition comprising the modified compound and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is a solid, liquid. Wang does not further teach the compound is an amorphous solid.
Kaminski-WO teaches pyrrolidine-2,5-dion aminoalkyl derivatives
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useful as anticonvulsant, analgesic, antidepressant, anxyolytic, and neuroprotective agents. (See Abstract; pages 1-10.) Moreover, Kaminski-WO teaches pyrrolidine-2,5-dione aminoalkyl derivatives can be formulated with a pharmaceutically acceptable carrier at a dose of 0.1-1000 mg in single or divided doses, in the form of a tablet (solid), granules, solution (liquid). (See last paragraph of page 9.) Kaminski-WO additionally teaches analgesic and pain-related therapeutic utility for structurally similar pyrrolidine-2,5-dione aminoalkyl compounds, including antinoniceptive activity in recognized pain models. (See Figures and page 10.)
It would have been obvious to one of ordinary skill in the art to formulate the compounds taught resulting from the Wang/Kaminski combination into a pharmaceutical composition comprising pharmaceutically acceptable carriers, excipients/diluents as taught by Kaminski-WO because formulation of biologically active small molecules into oral pharmaceutical dosage forms represent routine practice in the pharmaceutical arts. Likewise, it would have been obvious to provide tablet (solid dosage forms) or solution (liquid dosage forms) because Kaminski-WO expressly teaches such conventional pharmaceutical parameters for structural similar pyrrolidine-2,5-dione aminoalkyl compounds.
With respect to the amorphous limitation. Kaminski-WO teaches the same type of solid pharmaceutical compositions comprising structurally similar compounds. The amorphous character of a solid pharmaceutical composition is an inherent solid-state property that results from conventional preparation and processing methods, including drying, precipitation, milling, solvent extraction, spray drying or related formulation operations routinely employed in the pharmaceutical arts. Moreover, Applicant does not recite any specific structural or analytical parameters distinguishing the claimed amorphous form from the prior art solid compositions, such as a particular XRDP patterns, glass transition temperature, DSC thermogram, or degree of crushability. Accordingly, the claimed amorphous limitation merely reflects an inherent or otherwise routise solid-state characteristic of the prior art compositions. Alternatively, even if not identically produced in every instance, selection or production of an amorphous form would have constituted routine optimization of a known pharmaceutical solid-state property.
Claims 37-41 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US4,692,533, cited in the IDS of 02/11/2026) in view of Kaminski et al. (Current Topic in Medicinal Chemistry, 2017, 17, 858-874, cited in the IDS of 02/11/2026) and Kaminski et al. (WO2020/214043A1, cited as “Kaminski-WO”) as applied to claims 25-36, in further view of Mathews (Pain Management inf FSHD, The Science and psychology of managing chronic pain, May 2022).
The teachings of Wang, Kaminski, and Kaminski-WO have been discussed in the first and second rejections set forth above.
Wang, Kaminski, and Kaminski-WO collectively do not teach facioscapulohumeral muscular dystrophy. However, as highlighted above, Wang teaches the claimed aminoalkyl imide scaffold. Kaminski discloses therapeutic pyrrolidine-2,5-dione derivatives possessing neurological and antinociceptive activities. Kaminski-WO asserts that analgesic and neurological therapeutic utility, pharmaceutical formulations, and dosing regimens for structurally similar compounds.
Mathews teaches that facioscapulohumeral muscular dystrophy (FSHD) patients commonly experience substantial pain symptoms and that pain management is an important aspect of treatment. (See Whole document.)
The specification at Paragraph [0085] states that “Treating” or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In certain embodiments, “treating” or “treatment” includes modulating the disease or disorder, physically (e.g., stabilization of a discernible symptom). Thus, treating a symptom of FSHD can satisfy claim 37 under Applicant’s own express definition.
In view of the combined teachings of the references, one of ordinary skill in the art would have been to administer the compounds resulting from the Wang/Kaminski combination to subjects suffering from FSDH and related symptoms, including pain. One of ordinary skill in the art would have motivated to administer a pharmaceutical composition comprising the compound resulting from the Wang/Kaminski combination to a subject suffering from facioscapulohumeral muscular dystrophy (FSHD) for treatment of pain associated with FSHD. Kaminski-WO teaches and demonstrates analgesic/antinociceptive activity of structurally similar pyrrolidine-2,5-dione-containing compounds, while Mattews teaches that pain is a common and clinically significant manifestation of FSHD and that pharmacological therapy, including anticonvulsant agents, is employed in the management of pain in patients with FSHD. Thus, one of ordinary skill seeking to treat an FSHD patient experiencing pain would have had a reasonable expectation of success to administer the pharmacological active compound resulting from Wang/Kaminski combination, formulated as taught by Kaminski-WO, to ameliorate or stabilize the patient’s pain. Such symptomatic treatment falls within the scope of claim 37 because the instant specification expressly defines “treating” or “treatment” to include ameliorating a disease or disorder, ameliorating at least one physical parameter, and physically modulating the disease or disorder, including stabilization of discernible symptom.” (See paragraph [0085].)
Declaration of Ali Ozes and Applicant’s arguments
Applicant’s arguments concerning the rejection under 35 U.S.C. 103 and the Declaration of Ali Ozes submitted in support thereof are addressed together below. The Declaration provides evidentiary support for Applicant’s arguments concerning the alleged lack of a reasonable expectation of success, the alleged unexpected DUX/MBD3L2 inhibitory activity of the claimed compounds, and the asserted low toxicity profiled. Because Applicant’s remarks and the Declaration raise substantially the same substantive issues and rely upon the same comparative evidence, they are considered together to avoid unnecessary duplication. The Examiner has nevertheless fully considered both Applicant’s arguments and all evidence presented in the Declaration in determining whether the evidence of nonobviousness, when weighed together with the evidence supporting the prima facie case of obviousness, is sufficient to overcome the rejections. For the reasons discussed below, the arguments and evidence are not persuasive of patentability.
Applicant argues that the proposed modification of Wang Compound 6 in view of Kaminski would not have provided a reasonable expectation of obtaining a compound capable of inhibiting DUX4 and treating (FSHD). Applicant further relies upon the Ozes Declaration as evidence of unexpected results. In particular, the Declaration reports that Compound 1, corresponding to the compound of claim 31, exhibited 85% MBD3L2 inhibition, whereas comparative Compounds 100 and 101 exhibited 26% and 0% MBD3L2 inhibition, respectively. Applicant contends that these data demonstrate that the aryl substitution of the claimed provides an unexpected improvement over the modification of Wang suggested by Kaminski.
In response, these arguments and evidence are not persuasive for the following reasons:
First, the comparative compounds relied upon in the Declaration do not reasonable correspond to the structural modification forming the basis of the rejection. The ejection does not propose modification of Wang Compound 6 by incorporation of a heteroaryl substituent. Rather, Wang is relied upon for the aminoalkyl pyrrolidine-2,5-dione scaffold, and Kaminski is relied upon for its teaching of incorporation of an additional aryl, particularly phenyl moiety into structurally related pyrrolidine-2,5-dione compounds having useful pharmacological activity. The proposed modification therefore concerns incorporation of an aryl phenyl substituent of the type taught by Kaminski.
This distinction is particularly relevant in view of the presently amended claims. Independent claim 27 expressly requires R10 to be a C6-10 aryl, and the specific compound of claim 31 contains an additional phenyl group. In contrast, comparative Compounds 100 and 101 presented in the Ozes Declaration contain heteroaryl substituents. Thus, Compounds 100 and 101 do not represent the aryl/phenyl modification relied upon in the rejection and do not fall within the presently claimed C6-10 aryl limitation.
Accordingly, the reported 20% and 0% MBD3L2 inhibition for comparative Compounds 100 and 101 establishes, at most, that the particular heteroaryl-substituted compounds tested exhibit lower MBD3L2 inhibition than Compound 1. The evidence does not establish that the claimed aryl/phenyl modification itself provide an unexpected result relative to the structural modification suggested by the combined teachings of Wang and Kaminski.
The Examiner has also considered declarant’s statement that “it matters which aryl groups are used and where they are positioned.” However, the comparative data does not establish that proposition with respect to the claimed aryl genus. Compounds 100 and 101 do not merely vary the identity or position of C6-10 aryl substituent relative to Compound 1; rather, the comparative compounds employ chemically different heteroaryl substituents. Thus, the evidence does not isolate the claimed aryl substitution or its position as the variable responsible for the reported difference in MDL3L2 inhibition. Consequently, the evidence does not establish criticality of the particular aryl substitution relied upon by Applicant.
The Examiner does not dispute the reported 80% and 0% MDB3L2 inhibition of Compound 1. Nor does the Examiner dispute that this activity constitutes a property of the compound that must be considered in determining obviousness. Applicant’s reliance upon in re Papesch, 315 F2.d 381, 137 USPQ 43 (CCPA 1963), has therefore been considered. However, consideration of a compound together with all of its properties does not mean that evidence of a newly demonstrated property automatically establishes nonobviousness. The evidence must be weighed against the evidence supporting the prima facie case, including whether the asserted result has been shown to be unexpected relative to the closest prior art and whether a nexus exists between the asserted result and the feature distinguishing the claimed invention from the prior art.
Here, the Declaration does not provide a comparison demonstrating that the aryl/phenyl-substituted modification actually relied upon in the rejection produces an unexpectedly superior result. Rather, Applicant compares the claimed phenyl-containing compound with compounds having materially different heteroaryl substituents. The comparative data therefore do not establish that the difference relied upon by the Examiner-incorporation of the additionally aryl/phenyl group suggested by Kaminski-is responsible for an unexpected improvement over the prior art. The comparative data supported by the heteroaryl-containing Compounds 101 and 100 is outside the scope of the claim because the heteroaryl substituents are not recited in the claims as amended.
Moreover, with respect to the broader genus claims, the evidence is not reasonably commensurate in scope with the claims. The Declaration provides MBD3L2 inhibition data for the single Compound 1, whereas claims 25-28 and 30 encompass genera permitting additional structural variation. The Declaration does not establish that compounds throughout the scope of these general possess the asserted degree of MBD3L2 inhibition, nor does it provide a structure-activity relationship or other evidentiary bases from which the result obtained for Compound 1 reasonably mya be extrapolated throughout the scope of these claims. See MPEP 716.02(d). Thus, even assuming the comparative evidence were otherwise persuasive as to Compound 1, the showing would not establish unexpected results commensurate in scope with the broader claimed genera.
Applicant additionally that there would have been no reasonable expectation that modification of Wang Compound 6 in accordance with Kaminski would result in DUX4 inhibition.
In response, this argument is not persuasive. This argument does not address the rationale actually relied upon in the rejection. The rejection does require that one of ordinary skill has predicted DUX inhibition before making the proposed compound. Wang provides the closely related aminoalkyl pyrrolidine-2,5-dione derivatives and associates such structural modifications with used pharmacological, including anticonvulsant/antinociceptive, activity. Thus, Kaminski provides both a reason for making the proposed aryl modification and a reasonable expectation of obtaining a structural related compound having the type of useful pharmacological activity taught therein. Obviousness does not require that every property subsequently discovered for the resulting compound has been predictable beforehand.
The Declaration’s demonstration that heteroaryl-substituted Compounds 100 and 101 possess lower MBD3L2 activity does not negate that rationale because those compounds do not represent the aryl/phenyl modification proposed in the rejection. Rather, the results demonstrate that clinically different substituents may produce different biological effects, which does not establish that one of ordinary skill would have lacked a reason or reasonable expectation of success in making the specific aryl modification taught by Kaminski.
Applicant further asserts the compounds possess an unexpectedly low toxicity profile.
In response, this argument is likewise not persuasive. The fact that toxicity may not have been predictable does not itself establish unexpectedly superior toxicity profile. Applicant has not provided comparative toxicity data demonstration that the claimed compounds exhibit a significant improvement relative to Wang Compound 6 or otherwise appropriate prior-art compound. Accordingly, the evidence does not establish that the alleged low toxicity represents an unexpected attributable to the structural distinction relied upon in the rejection.
After considering the totality of the evidence, including Ozes Declaration and the objective evidence of alleged unexpected results, the evidence of non-obviousness does not outweigh the evidence supporting the prima facie case. The Declaration does not provide a comparison corresponding to the aryl/phenyl modification actually suggested by the applied prior art, does not establish that the claimed aryl substitution is responsible for the asserted improvement, and with respect to the broader genus claims, is not reasonably commensurate in scope with the claims.
Accordingly, Applicant’s argument and the Ozes Declaration are not persuasive, and the rejection under 35 U.S.C. 103 is maintained.
With respect to amended claim 37, Applicant’s argument concerning DUX4 misexpression does not overcome the ejection. Claim 37 recites, in the alternative, that the dise4ase or disorder is (i) characterized by DUX misexpression or (ii) facioscapulohumeral muscular dystrophy (FSDH). Thus, satisfaction of the expressly recited FSDH alternative is sufficient to meet the disease limitation; the applied prior art need not additionally have recognized FSDH as being characterized by DUX misexpression.
Conclusion
Claims 25-28 and 30-41 are not 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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/JEAN P CORNET/ Primary Examiner, Art Unit 1628
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