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 .
Status of the Claims
The status of the claims are as follows:
Claims 1-9 are pending.
Claims 1 and 5-9 are rejected.
Claims 2-4 are objected to.
Priority
Acknowledgement is made that Instant Application 18/849,105, filed on 09/20/2024, is a national stage entry of PCT/JP2023/010944, filed on 03/20/2023, which claims foreign priority from JP2022-045440, filed on 03/22/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/20/2024 and 04/29/2025 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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, 6-7 and 9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating CMT and/or promoting MFN1 gene expression in a mammal by administering a compound of Formula I or methylergonovine, it does not reasonably provide enablement for:
preventing CMT in a mammal by administering a compound of either Formula I or Formula II; and
treating CMT and/or promoting MFN1 gene expression in a mammal by administering a compound of Formula II.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 8 USPQ 2nd 1400 (Fed. Cir. 1988) as to undue experimentation. The factors include: (a) The nature of the invention; (b) The breadth of the claims; (c) The relative skill of those in the art; (d) Status of the prior art/predictability or unpredictability of the art (e) The amount of direction or guidance presented; (f) The presence or absence of working examples and (g) The quantity of experimentation necessary. Each factor is addressed below on the basis of comparison of the disclosure, the claims and the state of the art in the assessment of undue experimentation.
The nature of the invention: The invention is directed to drugs of Formula I or Formula II to treat or prevent Charcot-Marie-Tooth disease and/or promoting mitofusin 1 gene expression.
The breadth of the claim: The scope of the claims includes administering to a subject a compound of Formula I or Formula II to treat or prevent CMT and/or promote mitofusin 1 gene expression.
The relative skill of those in the art: The level of skill is high comparable to that of an M.D. or Ph.D.
Status of the prior art/predictability or unpredictability of the art: It is known in the art that a Charcot-Marie-Tooth disease is a complex inherited neuromuscular neuropathy, caused by genetic mutation (see Laurá. Charcot-Marie-Tooth Disease and Related Disorders: An Evolving Landscape. Curr. Opin. Neurol., 2019, 32(5), 641-650. Doi doi: 10.1097/WCO.0000000000000735). Recent advances in genetic sequencing techniques are still uncovering novel genetic causes in CMT, including the identification of recessive genes that cause late-onset inherited motor and sensory neuropathies. For example, the result of a large collaborative study with data sharing from more than 20 CMT research groups identified mutations in the ATP1A1 gene, encoding the alpha-1 subunit of the NA+/K+-ATPase, as a cause of autosomal dominant CMT2. Other genes known to be associated with CMT are shown in Table 1, of which there are at least 20. Accordingly, one of ordinary skill in the art could not reasonably prevent CMT, which is caused by many distinct genetic mutations, by administering a compound of either Formula I or Formula II.
Furthermore, the art recognizes that compounds to modulate mitofusin 1 (MFN1) expression levels can be unpredictable. For example, Rocha (MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A. Science, 2018, 360, 336-341. Doi: 10.1126/science.aao1785) teaches three-dimensional representations of hypothetical minipeptide conformations driven by Ser378 phosphorylation states (page 338, Fig 2A). Compound A is shown to preferentially bind to the pSer378 while compound B is shown to preferentially bind to unphosphorylated Ser378. A chimera compound formed from the combination A-B is shown to have greater activity than either compounds A or B. While this example is shown for mitofusin 2, MFN2 shares 60% identity with MFN1 (see Omim. https://omim.org/entry/608507). Therefore, one or ordinary skill in the art would reasonably expect MFN1 modulators to also be unpredictably affected by e.g., phosphorylation states.
The amount of direction or guidance presented: The specification does not provide any guidance in terms of preventing CMT using a compound of either Formula I or Formula II. Moreover, the specification does not provide any guidance in terms of treating CMT and/or promoting MFN1 gene expression by administering a compound of Formula II. The specification further does not provide any references to indicate such an effect is possible. It is known in the art that As such, one of ordinary skill wouldn’t anticipate a synergetic effect provided by caffeine would result in the same synergetic effect provided by hydrogen peroxide.
The present or absence of working examples: No working examples are provided for preventing CMT using a compound of either Formula I or Formula II, and no working examples are provided to treat CMT and/or promote MFN gene expression using a compound of Formula II, for example, in a patient in the specification. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved." See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The quantity of experimentation necessary: The quantity of experimentation would be an undue burden to one of ordinary skill in the art. Thus, factors such as “sufficient working examples,” “the level of skill in the art" and "predictability," etc. have been demonstrated to be sufficiently lacking in the instant case for the instant method claim”. In view of the breadth of the claims, the chemical nature for the instant claims and unpredictability of treating/preventing genetic mutations and promoting specific gene expression, and the lack of working examples regarding the activity as claimed, one skilled in the art would have to undergo an undue amount of experimentation to use the instantly claimed invention commensurate in scope with the claims.
In consideration of the Wands factors, it is apparent that there is undue experimentation because of variability in prediction of outcome that is not addressed by the present application disclosure, examples, teaching and guidance presented. Absent factual data to the contrary, the amount and level of experimentation needed is undue.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 6 recites the limitation the method according to claim 1, wherein R3 and R4 in the Formula II are each independently a hydrogen atom. There is insufficient antecedent basis for this limitation in the claim because Formula II does not allow for R4 to be hydrogen.
Claim 7 recites the limitation the method according to claim 1, wherein the Formula II
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is represented by
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. There is insufficient antecedent basis for this limitation in the claim because Formula II does not permit R4 to be hydrogen.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1 and 5-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cohen (WO 2009/068668 A1. Published 06/04/2009) in view of Grill (WO 2022/008627 A2. Published 01/13/2022) and in view of Vallera (Uterotonic Medications Oxytocin, Methleygonovine, Carboprost, Misoprostol. Anesthesiol. Clin., 2017, 207-219. Doi: 10.1016/j.anclin.2017.01.007).
Claim 1 is directed to a method for treating or preventing Charcot-Marie-Tooth disease (CMT) in a mammal, comprising in part, administering to the mammal an effective amount of a compound represented by Formula II, shown below.
Cohen teaches new therapeutic methods for treating CMT and related disorders (title). One disclosed embodiment relates to the use of methylergonovine (CAS 113-42-8 and CAS 57432-61-8 corresponding to the maleate salt) and its possible salts and derivatives (page 5, lines 3-4) for the (manufacture of a medicament for the) treatment of CMT or a related disorder (page 6, lines 25-26).
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Methylergonovine reads on Instant Formula II when:
R1 is C1 aliphatic group;
R2 is not present;
The double bond is present;
R3 is C2 aliphatic group;
n is 1;
X is CZ, where Z is a hydrogen atom; and
The difference between the above teaching and the Instant Application is that Cohen teaches the use of methylergonovine to treat CMT, however methylergonovine is not a compound of Formula II because Formula II does not allow R4 = H. Therefore, Cohen fails to teach where R4 is selected from the group consisting of C1-C6 aliphatic groups and C3-C7 alicyclic hydrocarbon groups.
However, Grill teaches novel derivatives of lysergic acid diethylamide (LSD) (abstract). Specifically, Grill discloses compound I and compound II (page 15):
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Compound I is shown to have strong ligand-receptor interactions at all tested serotonin and dopamine isoforms (page 39, Table 1, “compound 3”). While the binding affinity of compound II is not disclosed, the properties of both compounds are linked by a common genus. Therefore, one of ordinary skill in the art would know compound II would exhibit similar activity.
Said artisan would have been motivated to combine the above teachings because they both teach derivatives of ergot alkaloids. Vallera teaches methylergonovine is a semisynthetic amide ergot derivative (page 4, paragraph 4), that is a known serotonergic receptor agonist in smooth muscle and a weak antagonist of dopaminergic receptors and partial agonist of α-adrenergic receptors (page 5, paragraph 2). One would have had a reasonable expectation of success to use the teachings of Grill to modify methylergonovine by alkylating the amide with, for example, CH3, while maintaining similar properties.
Claim 5 is directed to the method of claim 1 wherein X in the Formula II is CZ, where Z represented a hydrogen atom, a halogen atom, or CN.
The N-alkylated methylergonovine derivative from the combined teachings comprises X is selected as CZ, where Z is hydrogen.
Claim 6 is directed to the method of claim 1 wherein R3 and R4 in Formula II are each independently a hydrogen atom or a C1-C3 aliphatic group, in which each hydrogen atom may be substituted.
The N-alkylated methylergonovine derivative from the combined teachings comprises R3 is C2 aliphatic group and R4 is at least C1 aliphatic group.
Claim 7 is directed to the method of claim 1 wherein Formula II is represented by the compound of Formula II-I:
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Instant Formula II-I is the compound methylergonovine, as taught by Cohen to treat CMT.
Claim 8 is directed to the method of claim 1, wherein the CMT disease is CMT disease type 2.
In a preferred embodiment disclosed by Cohen, the related disorders treated by e.g. methylergonovine include CMT2A, CMT2B, CMT2D, CMT2E, and CMT2-P0 (page 12, lines 18-21). One of ordinary skill in the art would have had a reasonable expectation of success in treating the same disorders using the N-alkylated methylergonovine derivative from the combined teachings of Cohen in view of Grill in view of Vallera.
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Starovlah (Reduced Spermatozoa Functionality During Stress if the Consequence of Adrenergic-Mediated Disturbance of Mitochondrial Dynamics Markers. Sci. Rep., 2020, 10:16813. Doi: 10.1038/s41598-020-73630-y) in view of Vallera in view of Grill.
Claim 9 is directed to a method of promoting mitofusin-1 gene expression in a subject, comprising administering to the subject a compound represented by either Formula I or Formula II
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Starovlah teaches the stress-signaling responsible for the effects of acute/repeated psychological stresses on spermatozoa number and functionality, as well as the transcriptional profile of mitochondrial dynamics markers (abstract). Rats immobilized once for 3 h and immobilized for 3 h for 10 consecutive days experienced higher serum levels of stress hormones adrenaline and cortisol, lower serum levels of androgens testosterone + dihydrotestosterone, and lower levels of spermatozoa (page 3, Fig 1). Undisturbed rats were also treated with adrenaline as an α1-adrenergic receptor agonist, and the resultant isolated spermatozoa had a significantly higher expression of MFN1 compared to basal levels (page 6, Fig 4a). Undisturbed rats were also treated with a combination α1-adrenergic receptor agonist/antagonist (adrenaline/prazosin) and the resultant isolated spermatozoa had a significantly lower expression of MFN1 compared to basal levels (page 6, Fig4a). Therefore, Starovlah teaches α1-adrenergic receptor agonists promoted MFN1 expression levels.
The difference between the teaching of Starovlah and the Instant Application is that Starovlah fails to teach the use of a compound of Formula I or of Formula II.
However, Vallera teaches methylergonovine is a partial agonist of α-adrenergic receptors (page 5, paragraph 2).
One of ordinary skill in the art would have been motivated to combine the above teachings because they are both in the same field of endeavor of α-adrenergic receptor agonists. Said artisan would have had a reasonable expectation of success in promoting MFN1 expression by substituting adrenaline for any other known α-adrenergic receptor, i.e., methylergonovine.
The difference between the combined teachings above and the Instant Application is that Starovlah in view of Vallera teach the use of methylergonovine to promote MFN1 gene expression, however methylergonovine is not a compound of Formula II because Formula II does not allow R4 = H. Therefore, Starovlah in view of Vallera fails to teach where R4 is selected from the group consisting of C1-C6 aliphatic groups and C3-C7 alicyclic hydrocarbon groups.
However, Grill teaches compounds I and II as derivatives of LSD (page 15).
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As discussed above, the tertiary amide of compound II is linked as having similar properties as the secondary amide of compound I through a common genus.
Grill further teaches LSD has non-specific binding to e.g. adrenoceptors, which causes numerous side effects and therefore prohibits a broader use of LSD-based pharmaceuticals (page 1, lines 38-40). As such, one of ordinary skill in the art would have known that compounds I and II would have a reasonable expectation of success in similar adrenoceptor binding.
Said artisan would have been motivated to combine the teaching of Grill with Starovlah in view of Vallera because they teach the same field of endeavor of α-adrenergic receptor agonists. Routine optimization of methylergonovine, as guided by the teaching of Grill, would have included tertiary amides as part of a standard structure-activity-relationship analysis to determine the effect of compounds of Formula II on MFN1 gene expression levels.
Claim Objections
Claims 2-4 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The claims are directed to the use of clofazimine and derivatives thereof for the treatment of Charcot-Marie-Tooth disease (CMT) in a mammal.
Zhou (Restoring Mitodusin Balance Prevents Axonal Degeneration in a Charcot-Marie-Tooth Type 2A Model. The Journal of Clinical Investigation, 2019, 129(4), 1756-1771. Doi: 10.1172/JCI124194) teaches mitrofusin-2 (MFN2) is a mitochondrial outer-membrane protein that plays a pivotal role in mitochondrial dynamics, such as regulation of mitochondrial fusion, transport, mitophagy, mtDNA stability, and mitochondria-ER interactions (page 1756, left column, paragraph 1). Disruption of natural mitochondrial dynamics has been linked to a diverse spectrum of neurological conditions (page 1756, left column, paragraph 1). CMT is one of the most common inherited neurological disorders, and MFN2 mutations are the most frequently identified cause of axonal CMT (CMT type 2A) (page 1756, right column, paragraph 1).
Baik (Molecular Imagining of Intracellular Drug-Membrane Aggregate Formation. Mol Pharm. 2011, 8(5) 1742-1749. Doi: 10.1021/mp200101b) teaches how clofazimine accumulates inside cells in the presence of supersaturating, extracellular concentrations of the drug (in the range of physiological drug concentrations) (abstract). It was revealed that clofazimine first accumulated in the mitochondria, with ensuring changes in mitochondrial structure and function (abstract).
However, despite recognizing that clofazimine accumulates in the mitochondria, the prior art is silent on the effects of clofazimine on mitochondrial dynamics, MFN2 expression, and/or CMT pathogenesis. Accordingly, claims 2-4 comprise an inventive concept.
Conclusions
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/P.A./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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