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 .
This application is the national stage entry of PCT/US2022/034872, filed 24 June 2022; and claims benefit of provisional application 63/214,587, filed 24 June 2021.
Claims 1-9 and 19-27 are pending in the current application. Claims 9, 23 and 27, drawn to non-elected species, are withdrawn. Claims 1-8, 19-22, and 24-26 are examined on the merits herein.
Election/Restrictions
Applicant's election with traverse of the species of compound I wherein R1 is H, also named as compound Ia, in the reply filed on 12 June 2026 is acknowledged. The traversal appears to be on the grounds that the common technical feature is not PRMT inhibition because the cited reference Hung et al. does not teach the features of the different species. This is not found persuasive because Applicant’s remarks appears to acknowledge that the different species are characterized by their own distinct special technical features such as their distinct chemical structures, rather than the technical feature that is in common with all the distinct species, namely the activity of PRMT inhibition. As detailed in the Restriction Requirement of record, the technical feature that is in common with all the distinct species is the activity of PRMT inhibition is taught by Hung et al., therefore this technical feature does not serve as the special technical feature of a single general inventive concept.
The requirement is still deemed proper and is therefore made FINAL.
Claims 9, 23 and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12 June 2026.
Specification
The disclosure is objected to because of the following informalities: the specification through contains missing text at the top right corner of each page. For example, see paragraph 4 at top of page 2:
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28
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and paragraph 28 at top of page 7:
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This missing text also occurs in the publication of PCT/US2022/034872. Provisional application 63/214,587 does not appear to include this typographical error and may provide descriptive support for corrections.
Appropriate correction is required.
Claim Rejections - 35 USC § 102/103
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
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.
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 1-5, 7, 19, 21, and 25 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over CN’002 (CN 110038002 A, published 23 July 2019, provided by Applicant in IDS filed 06 Sep 2024, Google Patents English machine translation cited in PTO-892) in view of Stouth et al. (Frontiers in Physiology, 2017, 8:870, 12 pages, cited in PTO-892) and Li et al. (Oncotarget, 2016, 7(15), p20236-20248, cited in PTO-892).
CN’002 discloses a preparation of salvianolic acid A for preventing, relieving and/or treating various causes, including diabetes and related diseases, heredity, muscular dystrophy and muscle atrophy, myopathy, musculoskeletal complications caused by neurological dysfunction and the same (page 1, paragraph 1 and 10), where the method of treating muscular dystrophy meets limitations of claims 4-5 and 19. Salvianolic acid A has the systematic chemical name (2R)-3-(3,4-hydroxyphenyl)-2-[(E)-3-[2-[(E)-2-(3,4 -Dihydroxyphenyl)vinyl]-3,4-dihydroxyphenyl]prop-2-enoyl]oxypropionic acid (page 1, paragraph 9), or the claimed compound Ia meeting limitations of claims 7, 21, and 25. The dosage of the pharmaceutical composition of the compound of the present invention may vary widely according to the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form. In general, a suitable daily dosage range of a compound of the invention is 0.001-150 mg/Kg body weight, most preferably 2-30 mg/Kg body weight (page 3, paragraph 4).
CN’002 does not specifically disclose the method of inhibiting arginine methylation of a double homeobox 4 (DUX4) protein in a cell (claim 1). CN’002 does not specifically disclose the method of decreasing double homeobox 4 (DUX4)-associated apoptotic cell death and/or decreasing DUX4 target gene activation in a cell (claim 2). CN’002 does not specifically disclose the method of treating a protein arginine methyl transferase (PRMT) disorder in a patient in need thereof (claim 3).
Stouth et al. teaches Protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze the methylation of arginine residues on target proteins, thereby mediating a diverse set of intracellular functions that are indispensable for survival. Indeed, full-body knockouts of specific PRMTs are lethal and PRMT dysregulation has been implicated in the most prevalent chronic disorders, such as cancers and cardiovascular disease (CVD). PRMTs are now emerging as important mediators of skeletal muscle phenotype and plasticity. Recent studies demonstrating that PRMT function is dysregulated in Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and amyotrophic lateral sclerosis (ALS) suggests that altering PRMT expression and/or activity may have therapeutic value for neuromuscular disorders (NMDs) (page 1, abstract).
Li et al. teaches investigation into whether protein arginine methyl transferase 1 (PRMT1) is involved in PXR-activated overexpression of MDR1 during acquired multidrug resistance. 136 candidate compounds were screened for PRMT1 inhibition. Five compounds including rutin, isoquercitrin, salvianolic acid A, naproxen, and felodipline were identified to be PRMT1 inhibitors (page 20236, abstract; page 20241, figure 4).
Regarding the rejection under 35 U.S.C. 102(a)(1), while CN’002 is silent as to the mechanism of inhibiting arginine methylation of a double homeobox 4 (DUX4) protein in a cell, decreasing double homeobox 4 (DUX4)-associated apoptotic cell death and/or decreasing DUX4 target gene activation in a cell, or treating a protein arginine methyl transferase (PRMT) disorder in a patient in need thereof. MPEP 2112.01 especially at I. citing In re Best, 562 F.2d 1252, 195 USPQ 430 (C.C.P.A. 1977) and In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly recited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to show the products of the applicant and the prior art are not the same or that the prior art products do not necessarily possess the characteristics of the claimed product. In this CN’002 discloses the method of treating muscular dystrophy comprising administering an effective amount of salvianolic acid A, most preferably 2-30 mg/Kg body weight. The examined application describes the administration of salvianolic acid A, but is silent as to the specific dosage is administered, generally describing the effective dose in terms of the results achieved at paragraph 97 spanning pages 23-24 of the specification. Further, CN’002 discloses treatment of musculoskeletal complications caused by neurological dysfunction, Stouth et al. teaches PRMT function is dysregulated in Duchenne muscular dystrophy and that altering PRMT expression and/or activity may have therapeutic value for neuromuscular disorders, and Li et al. teaches salvianolic acid A is known to be a PRMT1 inhibitor. Therefore there is reason to believe the method of treating muscular dystrophy comprising administering an effective amount of salvianolic acid A, most preferably 2-30 mg/Kg body weight disclosed in CN’002 inherently includes functions that are newly recited.
Regarding the rejection under 35 U.S.C. 103, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine CN’002 in view of Stouth et al. and Li et al. to make obvious the treatment of muscular dystrophy disclosed in CN’002 to be a PRMT disorder. One of ordinary skill in the art would have been motivated to combine CN’002 in view of Stouth et al. and Li et al. with a reasonable expectation of success because CN’002 discloses a method of treating muscular dystrophy comprising administering an effective amount of salvianolic acid A, most preferably 2-30 mg/Kg body weight, CN’002 teaches the same treatment of musculoskeletal complications caused by neurological dysfunction, Stouth et al. teaches PRMT function is dysregulated in Duchenne muscular dystrophy and that altering PRMT expression and/or activity may have therapeutic value for neuromuscular disorders, and Li et al. teaches salvianolic acid A is known to be a PRMT1 inhibitor, suggesting it would have been obvious to one of ordinary skill in the art to determine that the active agent of salvianolic acid A disclosed by CN’002 has PRMT1 inhibitor activity that is a mechanism of action for treatment of neuromuscular disorders such as the muscular dystrophy disclosed by CN’002. Regarding the mechanism of inhibiting arginine methylation of a double homeobox 4 (DUX4) protein in a cell, decreasing double homeobox 4 (DUX4)-associated apoptotic cell death and/or decreasing DUX4 target gene activation in a cell, as detailed above, there is reason to believe the method taught in the prior art inherently possesses the functions that are newly recited. See MPEP 2112 providing ““The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995)”
Claim Rejections - 35 USC § 103
Claims 8, 22, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over CN’002 (CN 110038002 A, published 23 July 2019, provided by Applicant in IDS filed 06 Sep 2024, Google Patents English machine translation cited in PTO-892) in view of Stouth et al. (Frontiers in Physiology, 2017, 8:870, 12 pages, cited in PTO-892) and Li et al. (Oncotarget, 2016, 7(15), p20236-20248, cited in PTO-892) as applied to claim 1-5, 7, 19, 21, and 25 above, and further in view of Tian et al. (Journal of Pharmacy and Pharmacology, 2010, 62, p1534-1546, cited in PTO-892).
CN’002 in view of Stouth et al. and Li et al. discloses or teaches as above.
CN’002 in view of Stouth et al. and Li et al. does not specifically teach the compound Ia is a hydrate (claims 8, 22, and 26).
Tian et al. teaches a hydrate is the most commonly identified solvate within small organic drug molecules. It has been estimated that at least every third drug compound can form a hydrate. Hydrate formation or dehydration of a given hydrate may affect the performance of the final medicinal product. The bioavailability of a poorly water soluble compound is affected due to the difference in solubility and dissolution rate between the anhydrate and hydrate forms (page 1534, paragraph 1). Crystallization of an anhydrate/hydrate system from aqueous solution is common in industry for various reasons. For the compounds that have significant temperature-dependent solubility, the final crystal product yield of a cooling crystallization can be increased by using a mixture of water and an organic solvent (page 1537, right column, paragraph 1). Another typical occasion for the crystallization of the anhydrate/hydrate system from aqueous solutions is the antisolvent crystallization, which is commonly used for compounds having high but weakly temperature dependent solubility in a given solvent (water or an organic solvent) (page 1538, right column, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine CN’002 in view of Stouth et al. and Li et al. further in view of Tian et al. in order to formulate the salvianolic acid A of CN’002 as a hydrate. One of ordinary skill in the art would have been motivated to combine CN’002 in view of Stouth et al. and Li et al. further in view of Tian et al. with a reasonable expectation of success because Tian et al. teaches a hydrate is the most commonly identified solvate within small organic drug molecules, it has been estimated that at least every third drug compound can form a hydrate, and that hydrate formation can affect the performance of the final medicinal product such as by improving bioavailability. Therefore it would have been obvious to try to formulate the salvianolic acid A of CN’002 as a hydrate in order to improve the medicinal product in the same way because the hydrate is the most commonly identified solvate.
Claims 6, 20, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over CN’002 (CN 110038002 A, published 23 July 2019, provided by Applicant in IDS filed 06 Sep 2024, Google Patents English machine translation cited in PTO-892) in view of Stouth et al. (Frontiers in Physiology, 2017, 8:870, 12 pages, cited in PTO-892) and Li et al. (Oncotarget, 2016, 7(15), p20236-20248, cited in PTO-892) as applied to claim 1-5, 7, 19, 21, and 25 above, and further in view of Jones et al. (US 2019/0343865, published 14 Nov 2019, cited in PTO-892).
CN’002 in view of Stouth et al. and Li et al. discloses or teaches as above.
CN’002 in view of Stouth et al. and Li et al. does not specifically teach the method wherein the muscular dystrophy is a facioscapulohumeral muscular dystrophy (FSHD) (claims 6, 20, and 24).
Jones et al. teaches methods and compositions for regulating expression of DUX4, useful for treating a disease associated with aberrant DUX4 expression (e.g. facioscapulohumeral muscular dystrophy (FSHD)) (abstract). In some embodiments, reduction of DUX4 expression by epigenetic modulators (e.g. selective inhibitors) in subjects having diseases characterized by aberrant expression of DUX4 (e.g. FSHD) (page 1, paragraph 5). The term “facioscapulohumeral muscular dystrophy” or “FSHD” refers to a muscular dystrophy involving progressive loss of skeletal muscle mass and/or function, in which muscles of the face, shoulder blades and upper arms are among the most affected. FSHD is associated with aberrant expression of DUX4. In certain embodiments, FSHD results from transcriptional activation of a DUX4 gene (page 4, paragraph 65). The term "epigenetic modulator" refers to an agent that alters the transcriptional activity of a gene (e.g. DUX4), e.g. by affecting the chromatin state of that gene (page 5, paragraph 69). In some embodiments, the epigenetic modulator of DUX4 is an inhibitor of a methyltransferase enzyme. In some embodiments, the epigenetic modulator is an inhibitor of an arginine-specific methyltransferase, also referred to as PRMTs (page 1, paragraph 13; page 6, paragraph 78).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine CN’002 in view of Stouth et al. and Li et al. further in view of Jones et al. in order to select the muscular dystrophy treated to be FSHD. One of ordinary skill in the art would have been motivated to combine CN’002 in view of Stouth et al. and Li et al. further in view of Jones et al. with a reasonable expectation of success because CN’002 broadly teaches a method of treating muscular dystrophy comprising administering an effective amount of salvianolic acid A, Li et al. teaches salvianolic acid A is known to be a PRMT1 inhibitor, and Jones et al. provides guidance for selecting treatment of specifically the muscular dystrophy FSHD comprising administering an inhibitor of PRMT in order to decrease DUX4 target gene activation.
Conclusion
No claim is found to be allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan S Lau whose telephone number is (571)270-3531. The examiner can normally be reached Monday-Friday 9a-5p Eastern.
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/JONATHAN S LAU/ Primary Examiner, Art Unit 1693
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