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 Application
Claims 1-12 are pending in the application as of the preliminary amendment submitted 10/20/2023. Claim 13 is cancelled. Claims 1-12 are examined herein.
Priority
This application is a 371 of PCT/EP22/60445 filed 04/20/2022 and claims foreign priority to FRANCE 2104119 filed 04/20/2021.
It is noted that Applicants have not provided an English translation of the certified copy of the foreign priority application as required by 35 U.S.C. 119(b). Without the English translation, one cannot ascertain if the instant invention is supported in the French application. Therefore, art prior to the PCT date, but not before the date of the French application may be cited against the claims. Accordingly, claims 1-12 have been afforded an effective filing date of 04/20/2022, the filing date of the PCT application.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statement submitted on 10/20/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings Objected To
The drawings are objected to for the following reasons:
37 CFR 1.84(u)(1) states “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”. The examiner suggests that the drawing should be properly labeled simply as: The Figure.
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 Rejections - 35 USC § 112 - Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 1-12 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 reducing methionine sulfoximine (MSO)-induced hyperammonemia and/or convulsions by the administration of stiripentol, does not reasonably provide enablement for a method of preventing or treating hyperammonemia in an individual thereof comprising administering a compound 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 use the invention commensurate in scope with these claims.
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 re Wands, 8 USPQe2d 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/The nature of the invention
The claims recite a method for preventing or treating hyperammonemia in an individual, comprising administering a compound of the following formula (I), with variables as defined in instant claim 1. The nature of the invention is the provision of pharmaceutical compounds in the prevention and treatment of hyperammonemia, particularly drug-induced hyperammonemia.
The state of the prior art/The level of predictability in the art
Savy et al. (Acute pediatric hyperammonemia: current diagnosis and management strategies, 12 September 2018, hereinafter Savy); Tseng et al. (Risk Factors of Hyperammonemia in Patients With Epilepsy Under Valproic Acid Therapy, September 2014, hereinafter Tseng) and Ali et al. (Starting stiripentol in adults with Dravet syndrome? Watch for ammonia and carnitine, 21 October 2020, hereinafter Ali, in the IDS).
Savy teaches acute hyperammonemia has varied etiology triggered by protein catabolism caused by prolonged fasting, fever, infections, gastrointestinal bleeding, dehydration, high protein intake, anesthesia, and surgery (Pg. 106, second column, last paragraph). Savy teaches the clinical symptoms are numerous including digestive symptoms (nausea, vomiting, anorexia, abdominal pain, and failure to thrive) and neuropsychiatric symptoms (headaches, ataxia, dysarthria, behavioral modifications, neurodevelopmental delay, and hypotonia) and, in severe cases, seizures, alteration of consciousness, and central hyperventilation (Pg. 107, first column, continued paragraph). Savy teaches the clinical symptoms may be non-specific in neonates (Pg. 107, first column, continued paragraph). Savy teaches having a reliable plasma ammonia level remains a challenge (Pg. 107, first column, first full paragraph – second full paragraph). Savy teaches a complex diagnostic algorithm for diagnosing hyperammonemia due to the varied etiology (Pg. 107, second column, fourth full paragraph; Figure 2). Savy teaches rapid diagnosis and management are primordial to reduce the risk of irreversible brain damage (Pg. 111, second column, continued paragraph; Figure 4). Savy teaches management of hyperammonemia in children may require a multidisciplinary approach with the involvement of geneticists/metabolicians, nephrologists, intensivists, neurologists, pharmacists, and nutritionists (Pg. 114, first column, third full paragraph).
Tseng teaches hyperammonemia in epileptic patients who receive valproic acid (VPA) therapy (Abstract). Tseng teaches most patients with VPA-induced hyperammonemia were asymptomatic (Abstract; Pg. 5, first column, first full paragraph). Tseng teaches in patients with severe and symptomatic hyperammonemia, the most effective treatment may be to decrease the VPA dosage or to discontinue the drug completely (Pg. 5, first column, last paragraph – second column, continued paragraph). Tseng teaches the reported prevalence of hyperammonemia under VPA therapy is highly variable, ranging from 2% to 80% (Pg. 5, first column, second full paragraph).
Ali teaches the initiation of stiripentol (STP) in adult STP-naïve Dravet syndrome (DS) patients led to hyperammonemic encephalopathy (Abstract). Ali teaches STP can increase serum levels of other drugs commonly used in DS such as valproate and clobazam (Pg. 2439, second column, third full paragraph). Ali teaches hyperammonemia in 77% of the adult STP-naïve patients who were on valproate and clobazam, despite dose reduction of the latter drugs (Abstract; Pg. 2439, second column, third full paragraph). Ali teaches the mean final daily STP dose in the adult STP -naïve patients was only 14.89 ± 8.72 mg/kg/d which is much lower than the recommended dose of 50 mg/kg/d in children (Pg. 2439, second column, last paragraph). Ali concludes that the role of stiripentol with regard to hyperammonemia remains unclear (Pg. 2440, second column, continued paragraph).
Therefore, the state of the prior art teaches varied etiology with respect to the development of hyperammonemia. The state of the prior art teaches challenges with respect to diagnosing hyperammonemia and obtaining a reliable plasma ammonia level. The state of the prior art teaches hyperammonemia as a recognized complication of antiseizure treatment. The state of the prior art teaches stiripentol (the compound of instant claim 3) induces hyperammonemia in DS patients who are on other antiepileptic drugs, such as valproate and clobazam. The scope of the instant compounds extends beyond stiripentol in the treatment of hyperammonemia.
Furthermore, it is noted that the state of the art with regard to pharmacology is generally unpredictable. The field of pharmacology involves screening compounds both in vitro and in vivo to determine lead compounds that exhibit the desired pharmacological activity. According to MPEP 2164.03, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).”, with physiological activity being considered to be an unpredictable factor.
Therefore, in consideration of the various challenges and the high level of unpredictability with regard to treating hyperammonemia, it is unclear how the instant invention is enabled for not only treating hyperammonemia in an individual, comprising administering the genus of compounds of formula (I), but also preventing hyperammonemia in an individual.
The level of one of ordinary skill in the art
The relative level of skill in the art is high, including healthcare professionals with multidisciplinary backgrounds, such as geneticists/metabolicians, nephrologists, intensivists, neurologists, pharmacists, and nutritionists with advanced educational degrees (e.g., M.D. and/or Ph.D.). Additionally there is significant unpredictability in the field of hyperammonemia treatments.
The amount of direction provided by the inventor/The existence of working examples
Applicants have provided guidance for reducing convulsion rate and hyperammonemia in a model of MSO-induced hyperammonemia. Pages 18-20 of the instant specification disclose 300 mg/kg stiripentol administered just prior to MSO and 30 minutes prior to MSO significantly reduced the convulsion rate and hyperammonemia in mice. There is lack of further direction or guidance regarding making and using the full scope of compounds of formula (I) being claimed for broadly preventing and treating hyperammonemia in an individual.
The quantity of experimentation needed
Considering the state of the art as discussed in the references above, high degree of unpredictability in the field diagnosing and treating hyperammonemia, and lack of sufficient guidance in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in scope with the claims.
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.
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 2 and 11-12 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.
Regarding claim 2, the claim depends from claim 1 and recites “wherein the compound of formula (I) is of the following formula (II)”.
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However, the compound of formula (I) only allows for one R1 group in the compound.
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There is insufficient antecedent basis for this grouping having three R1 groups in the claim.
For the purpose of applying prior art, claim 2 has been interpreted to have the grouping
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as in claim 1, to provide sufficient antecedent basis.
Regarding claims 11-12, the claims recite “A pharmaceutical composition comprising as an active substance at least one compound of formula (I) of claim 1”. However, claim 1 is drawn to a method. This poses some clarity issues regarding the statutory basis of the claim.
For the purpose of applying prior art, claims 11-12 have been treated as independent claims without reference to claim 1.
Conclusion
Claims 1-12 are rejected.
No claims are allowed.
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/PADMAJA S RAO/Examiner, Art Unit 1627