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
Claims 1-15 are pending.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Instant application is a U.S. National Stage Entry of PCT/EP2022/063872, filed 05/23/2022. PCT/EP2022/063872 claims priority of foreign application EP21382472.5, filed 05/24/2021. Therefore, the effective filing date is 05/24/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/24/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Objections – Drawings
37 C.F.R. 1.84:
(u) Numbering of views.
(1) The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation "FIG." Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation "FIG." must not appear.
(2) Numbers and letters identifying the views must be simple and clear and must not be used in association with brackets, circles, or inverted commas. The view numbers must be larger than the numbers used for reference characters.
The drawings are objected to because the view numbers are not preceded by the abbreviation “FIG.”, and the view numbers are not larger than the text used in the figures.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1, 8, 9, and 11 are objected to because of the following informalities:
Claim 1 reads “…Ra, Rb, R2, R3, R4, R5, R6 are independently…” and should read “…Ra, Rb, R2, R3, R4, R5, and R6 are independently…” (emphasis added).
Claim 1 reads “…-COR7, -C(O)OR7, -C(O)NR7R8 -C=NR7, -CN, -OR7, -OC(O)R7, …”, and there should be a comma placed between “-C(O)NR7R8” and “-C=NR7”.
Claim 1 reads “…substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, halogen;…” and should read “…substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, or halogen;…” (emphasis added).
Claim 1 reads “…can form together a cyclic substituent,…” and for clarity should read “…can be taken together to form a cyclic substituent,…”.
Claims 8 and 9 read “…wherein R2, R3, R4, R5, R6 are…” and should read “…wherein R2, R3, R4, R5, and R6 are…” (emphasis added).
Claim 11 reads “…wherein the compound of formula (I) is selected from: … and their salts or solvates.” In order to be in the singular form, this claims should instead read “…wherein the compound of formula (I) is selected from: … or a salt or solvate thereof.”
Appropriate correction is required.
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-10 and 13-15 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 a method of treating LGMD comprising administering compounds of formula (I) where Ra, Rb, and R2 to R6 are H; and R1 is C1-3 alkyl, phenyl, naphthyl, or benzo[1,3]dioxolyl, wherein the C1-3 alkyl, phenyl, naphthyl, or benzo[1,3]dioxolyl is optionally further substituted with C1-5 alkyl, C1-3 alkoxy, phenoxy, or C0-3-alkyl-phenyl, does not reasonably provide enablement for a method of treating LGMD comprising administering compounds of formula (I). 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 the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application 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 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention
The nature of the invention relates to methods of treating LGMD comprising administering compounds of formula (I) in claim 1.
Predictability of the art
The hypothetical compounds in claim 1 would be unpredictable in terms of one skilled in the art being able to synthesize every possible compound claimed in instant claim 1. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Level of skill in the art
An ordinary artisan in the area of drug development would have experience in synthesizing and screening chemical compounds for particular activities, such as a medical doctor or chemist. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems.
4. The breadth of the claims
The scope of the claims involves compounds of formula (I), shown below.
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Claim 1 is very broad in the number of variables and the options of substituents for each variable. There is an infinite amount of hypothetical compounds included in claim 1, because each substituent may optionally be substituted with more substituents which are not limited by the claims or the specification.
5. The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary
The specification only provides the synthesis of 9 compounds. In all of the compounds synthesized, Ra, Rb, and R2 to R6 are H; and R1 is C1-2 alkyl, phenyl, naphthyl, or benzo[1,3]dioxolyl; and the C1-2 alkyl, phenyl, naphthyl, or benzo[1,3]dioxolyl are substituted with C1-4 alkyl, phenoxy, or C0-1-alkyl-phenyl. However, it would be assumed that the inventors are also enabled for R1 to be substituted with C1-5 alkyl, C1-3 alkoxy, phenoxy, or C0-3-alkyl-phenyl, since these substituents are similar in size and reactivity.
Synthesis methods are not taught in the specification to provide for the aforementioned variables to include all of the possible substituents listed in the claims. It would be expected that the variations of possible substituents (e.g., R1 being any aryl or alkyl-aryl group which may then be further substituted, and Ra, Rb, and R2 to R6 being any alkyl, cyclic group, -COR7, -C(O)OR7, -C(O)NR7R8, -C=NR7, -CN, -OR7, -OC(O)R7, -S(O)t-R7 , -NR7R8, - NR7C(O)Rs, -NO2, -N=CR7R8 or halogen which may then be further substituted) would change the reactivity of the compounds, and therefore would require alternate synthesis methods. It could also be possible that some combinations of compounds may not be able to be synthesized due to their instability (e.g., where Ra, Rb, and R1 to R6 are all polycyclic groups). It would require one skilled in the art, such as a chemist, to perform an infinite number of reactions to determine which compounds of formula (I) can be prepared and would likely require synthesis methods other than those provided in the specification. One would then have to determine which of the infinite number of compounds is capable of treating LGMD through clinical trials or in vitro or in vivo studies. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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.
Claims 1-10 and 13-15 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.
Regarding claim 1, 2, and 8, the phrase "substituted" renders the claims indefinite because the claims include elements not actually disclosed (those encompassed by "substituted"), thereby rendering the scope of the claims unascertainable. The claims do not define the optional substituents, and the specification, on page 7, provides non-limiting examples of optional substituents, using the phrase “such as”. Therefore, there are an indefinite number of compounds encompassed by the instant claims.
Claims 3-7, 9, 10, and 13-15, are rejected as being dependent upon a rejected claim and failing to define all optional substituents. This rejection would be overcome by including a definition of optional substituents.
Claim Rejections - 35 USC § 103
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 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Snape (WO 2022243973 A1), with an effective filing date of 21 May 2021, further in view of Magdinier et al. (WO 2021233810 A1), with an effectively filed date of 19 May 2020.
Snape teaches, in claims 1 and 8, a method of treating a disease associated with a RNA molecule having an abnormal repeat sequence in a subject, comprising administering a compound of Formula I, shown below.
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Claim 16 teaches a method of treating muscular dystrophy type 1 in a subject comprising administering 4-benzyl-2-naphthalen-1-yl-[1,2,4]thiadiazolidine-3,5-dione, shown below, as in instant claims 1-12. It is taught, in claim 14, that the method comprises an additional adjuvant, as in instant claim 15.
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Snape teaches, on page 10, that the disease being treated “includes, but is not limited, to myotonic dystrophy type 1 (DM1), also known as Steinherfs Disease, whether of Congenital, Childhood or Adult Onset sub-type DM1, as well as Fuchs endothelial corneal dystrophy”.
Snape fails to teach a specific embodiment where the muscular dystrophy being treated is limb girdle muscular dystrophy R1 calpain 3-related, as in instant claims 13 and 14.
However, Magdinier et al. teaches, on page 14 lines 31-35, a method comprising “the treatment of the muscle fibers innervated by motor neurons according to the invention with a test compound”. The method of treating the skeletal muscle fibers is taught, in claim 2, to comprise administering TDZD-8, shown below.
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It is taught, in claim 13, that the neuromuscular disease is type 2A Limb-Girdle Muscular Dystrophy (LGMD2A).
Therefore, it would be prima facie obvious to one of ordinary skill in the art to extend the method of treating muscular dystrophy taught by Snape to include the treatment of LGMD, and specific types of LGMD, since a similar compound is taught by Magdinier et al. to be used in the treatment of LGMD, and since Snape teaches that the compounds may be used in the treatment of other endothelial muscular dystrophies.
One of ordinary skill in the art would have a reasonable expectation of success using compounds known to treat myotonic and endothelial muscular dystrophies for the treatment of the specific muscular dystrophies listed in instant claims 13 and 14, since the same compounds are taught to treat similar muscular dystrophies in the prior art. Even though the specific type of LGMD of instant claims 13 and 14 is not taught by the prior art, it would be routine procedure for one of ordinary skill in the art to use a known method to treat these types of LGMD, and one would have a reasonable expectation of success in doing so.
Conclusion
Claims 1-15 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RILLA M SAMSELL whose telephone number is (703)756-5841. The examiner can normally be reached Monday-Friday, 7-3.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/R.M.S./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624