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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/02/2026 has been entered.
The Amendment filed 03/02/2026, amended claims 1, 7, and 24, and cancelled claims 16-18.
Claims 1-3, 5-8, 12-15, and 21-24 are pending, and examined on the merits herein.
Priority
This application claims the following priority:
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REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
35 U.S.C. § 112(b) and (d)
Applicant’s amendment to claim 7 is sufficient to overcome these rejections.
NEW & MODIFIED REJECTIONS
Applicant’s amendment to independent claim 1 that amends a method of treating ataxia to a method of treating cerebellar ataxia, has resulted in the below new and modified rejections.
Claim Rejections - 35 USC § 112(a)-New Matter
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 1-3, 5-8, 12-15, and 21-24 are 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This is a new matter rejection.
The recitation of a method of treating “cerebellar ataxia” in claim 1, line 1, is new matter.
While Applicant states that support for this amendment can be found in [0002]-[0003] and [0089], of the instant specification, a careful review of these paragraphs does not provide support for this limitations.
[0002] and [0003] discuss the field of the invention. [0002] does not even mention “cerebellar ataxia,” in general. [0003] merely recites that episodic ataxias are characterized by recurrent episodes of a cerebellar ataxia.
[0089] does not mention “cerebellar ataxia,” but references ataxia in general, and specifically references spinocerebellar ataxia.
Thus, none of [0002], [0003], or [0089] provide support for a method of treating cerebellar ataxia by administering a combinations of acetyl-leucine and acetazolamide.
All other claims not specifically recited are rejected for depending from an indefinite claim and failing to cure the deficiency.
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 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.
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 1-3, 5-7, 12-15, 21-22, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Strupp 2 (Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series, J. Neurol., published 2013, IDS of 09/04/2025, NPL210) in view of Strupp (Episodic ataxia type 2, Springer Nature Link, published 2007, PTO-892 of 12/02/2025), Tomimitsu (Episodic ataxia type 2, published 2001, PTO-892), Pedroso (Acute cerebellar ataxia: differential diagnosis and clinical approach, published 2019), and WO 2021/048431 to McKnight (effectively filed 09/12/2019, PTO-892 of 06/04/2025), as evidenced by PubChem (“Acetylleucine,” PTO-892 of 06/04/2025).
Strupp 2 teaches the effects of acetyl-DL-leucine in patients with cerebellar ataxia (title).
Strupp 2 specifically teaches administering 5 g/day of acetyl-DL-leucine to patients with degenerative cerebellar ataxia. Strupp 2 teaches this treatment as causing a remarkable decrease in the Scale for the Rating and Assessment of Ataxia, a significant improvement in motor function, and an overall increase in quality of life, and teaches this treatment as having no reported side-effects. “In conclusion, acetyl-DL-leucine significantly improved ataxic symptoms without side effects and therefore showed a good risk-benefit profile” (abstract).
Regarding claim 1, while Strupp 2 teaches a method of treating cerebellar ataxia by administering acetyl-DL-leucine, it differs from that of instant claim 1 in that it does not teach the administration of acetazolamide.
Strupp teaches episodic ataxia type 2 (EA2) as a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage gated calcium channel. Strupp teaches that EA2 is caused most often by loss of function mutations of the calcium channel gene CACNA1A. Strupp teaches acetazolamide (ACTZ) as an effective treatment option for EA2 (Abstract, pgs. 268-269, “Clinical Features of Episodic Ataxia Type 2”).
Strupp teaches EA2 as a slow progression of cerebellar signs accompanied by atrophy of midline cerebellar structures (abstract). Strupp teaches that 5 of its 60 studied patients exhibit a combination of absence epilepsy and cerebellar ataxia, which is due to a mutation of the CACNA1A gene (pg. 269, Col. 1, 1st two paragraphs; Col. 2, 3rd-4th paragraphs). Strupp teaches ACTZ as improving interictal cerebellar signs (pg. 271, paragraph spanning Cols. 1-2).
Strupp teaches ACTZ as the drug of first choice for preventative treatment of EA with dosages of 250-1000 mg/day. ACTZ effectively prevents or attenuates the attacks in approximately 50-75% of all patients. ACTZ inhibits the carbonic anhydrase interconversion of CO2 + H20 ↔ H2CO3. It causes diuresis, initial kaliuresis, and metabolic acidosis. It lowers serum bicarbonate levels and reduces the amount of brain lactate and pyruvate, resulting in subsequent brain acidosis (pg. 270, “Treatment Options and Principles”). ACTZ additionally normalizes the abnormal intracellular pH levels in the cerebellum of patients, reducing potassium conductance of the cell membrane, and thus restoring the excitability and resting activity of neurons. Without ACTZ, Strupp teaches that attacks may be precipitated by exercise and stress (pg. 271).
Strupp teaches that side effects of ACTZ are dose related. Strupp teaches that even with adverse side effects, ACTZ is the drug of first choice (pg. 271).
Tomimitsu teaches EA2 as an autosomal dominant cerebellar ataxia, caused by mutations in the CACNA1A gene (abstract).
Pedroso teaches episodic ataxias as causing cerebellar ataxia, and teaches episodic ataxia 1 and 2 as causing recurrent symptoms of acute cerebellar ataxia (pg. 185, Table 1; pg. 191, Col. 1).
As evidenced by [0003], Specification, episodic ataxias are characterized by recurrent episodes of a cerebellar ataxia.
McKnight teaches combining active ingredients for the treatment of ataxia, wherein the combined preparation is for simultaneous, separated or sequential use (pg. 1, lines 31-32; pg. 5, lines 6-9, 25-31; pg. 20, lines 1-9; pgs. 32-34, claims 9-10, 14).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add acetazolamide to the method of treating cerebellar ataxia taught by Strupp 2, to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Strupp specifically teaches a method of treating EA2, wherein EA2 is a slow progression of cerebellar signs accompanied by atrophy of midline cerebellar structures,
-Tomimitsu teaches EA2 as a type of cerebellar ataxia,
-as evidenced by the instant Specification, episodic ataxias are characterized by recurrent episodes of a cerebellar ataxia,
-Pedroso teaches episodic ataxias as causing cerebellar ataxia, and teaches episodic ataxia 1 and 2 as causing recurrent symptoms of acute cerebellar ataxia,
-Strupp teaches ACTZ as an effective and first choice of treatment for EA2,
-Strupp teaches ACTZ as improving cerebellar symptoms,
-Strupp specifically teaches ACTZ as normalizing the abnormal intracellular pH levels in the cerebellum of patients, reducing potassium conductance of the cell membrane, and thus restoring the excitability and resting activity of neurons,
-McKnight teaches combining active ingredients for the treatment of ataxia, and
-"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980), see MPEP 2144.06.
As such, an artisan having ordinary skill in the art would have been motivated to make such an addition to predictably arrive at a more therapeutically effectively method of treating cerebellar ataxia that improves a patient’s cerebellar symptoms, and thus, quality of life.
Regarding claims 2-3 and 24, since McKnight teaches the combined preparation for simultaneous, separated or sequential use (pg. 1, lines 31-32; pg. 5, lines 6-9, 25-31; pg. 20, lines 1-9; pgs. 32-34, claims 9-10, 14), an ordinary skilled artisan would have been motivated to combine the acetyl-DL-leucine and ACTZ in a single composition in the combined method of Strupp 2, Strupp, Tomimitsu, and Pedroso, and McKnight, to predictably arrive at a method of simultaneous administration of the active ingredients. Since a single formulation must be contained, the limitations of claim 24 are met.
Regarding claims 5 and 24, since McKnight teaches sequential administration, an ordinary skilled artisan would have been motivated to sequentially administer the acetyl-DL-leucine and ACTZ, in the combined method of Strupp 2, Strupp, Tomimitsu, and Pedroso, and McKnight, to predictably arrive at a method of sequential administration of the active ingredients. Since each formulation is contained, the limitations of claim 24 are met.
Regarding claims 6-7, while the combination of Strupp 2, Strupp, Tomimitsu, and Pedroso, and McKnight does not teach which compound to administer first in the sequential administration, an artisan having ordinary skill in the art would have been motivated to modify the sequence of administration, to achieve an optimized therapeutic dosage regimen; "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" (MPEP 2144.05(II)).
Regarding claims 12-13, Strupp teaches administration of ACTZ daily (pg. 272, Col. 1) and Strupp 2 teaches daily administration of acetyl-DL-leucine (pg. 2557, Col. 2). An artisan having ordinary skill in the art would have been motivated to modify the times per day the active ingredients are administered to predictably arrive at a dosage regimen that is optimized for therapeutic effect and minimized for negative side-effects; "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" (MPEP 2144.05(II)).
Regarding claim 14, Strupp 2 teaches administration of 5g/day acetyl-DL-leucine (pg. 2557, Col. 2); in the case where the claimed ranges “overlap or lie inside ranges disclosed in the prior art” a prima facie case of obviousness exists. See MPEP 2144.05.
Regarding claim 15, Strupp teaches administration of 250-1000mg/day of ACTZ (pg. 270, Col. 2); in the case where the claimed ranges “overlap or lie inside ranges disclosed in the prior art” a prima facie case of obviousness exists. See MPEP 2144.05.
Regarding claim 21, Strupp 2 teaches acetyl-DL-leucine. As evidenced by PubChem (“Acetylleucine,” PTO-892), acetyl-DL-leucine is N-acetyl-DL-leucine (pg. 1).
Regarding claim 22, “A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. . .Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus). . .are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties,” see MPEP 2144.09. As such, an artisan have ordinary skill in the art would have been motivated to substitute the N-acetyl-DL-leucine with N-acetyl-L-leucine, to predictably arrive at a compound with similar activity to N-acetyl-DL-leucine, that is effective in treating cerebellar ataxia.
(Modified) Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Strupp 2 (Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series, J Neurol, published 2013, IDS of 09/04/2025, NPL210), Strupp (Episodic ataxia type 2, Springer Nature Link, published 2007, PTO-892 of 12/02/2025), Tomimitsu (Episodic ataxia type 2, published 2001, PTO-892), Pedroso (Acute cerebellar ataxia: differential diagnosis and clinical approach, published 2019, PTO-892), and WO 2021/048431 to McKnight (effectively filed 09/12/2019, PTO-892 of 06/04/2025), as evidenced by PubChem (“Acetylleucine,” PTO-892 of 06/04/2025), as applied to claims 1-3, 5-7, 12-15, 21-22, and 24 above, and further in view of Fang (“Dose staggering as a strategy to reduce drug-drug interactions due to reversible enzyme inhibition between orally administered drugs with high first pass effect: a computer simulation study,” Biopharm. Drug. Dispos., published 2000, PTO-892 of 06/04/2025).
Strupp 2, Strupp, Tomimitsu, Pedroso, McKnight, and PubChem are applied as discussed above and incorporated herein.
Regarding claim 8, while the combination of Strupp 2, Strupp, Tomimitsu, Pedroso, and McKnight, teaches a method of treating cerebellar ataxia by administering a combination of acetyl-DL-leucine and acetazolamide, it differs from that of the instantly claimed invention in that it does no teach administration of acetyl-DL-leucine and acetazolamide about 1 minute to about 6 hours apart.
Fang teaches that a physiological computer model was designed to simulate the metabolic drug-drug interactions between two orally co-administered drugs due to reversible enzyme inhibition using drug concentrations in the portal vein. It was demonstrated that the extent of the interactions can be strongly affected by a time interval between the two drug administrations. By delaying the administration of the inhibitor until after the absorption phase of the substrate, one can significantly reduce the extent of the drug-drug interactions. This is because drug concentrations in the portal vein and the liver are much higher than that in the systemic circulation during the absorption phase. The model showed that interactions involving substrates with a high extraction ratio, i.e. drugs with higher first-pass effect, can be more strongly affect by dose staggering. This observation suggests dose staggering as a simple and cost-effective way to reduce the extent of unwanted drug-drug interactions in clinical practice (abstract).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select administration of the acetyl-DL-leucine and acetazolamide in the combined method of Strupp 2, Strupp, Tomimitsu, Pedroso, and McKnight, as about 1 minute to about 6 hours apart, to arrive at instant claim 8. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-McKnight teaches sequential administration, and
-Fang teaches that dose staggering is a simple and cost-effective way to reduce the extent of unwanted drug-drug interactions in clinical practice, and
- "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." MPEP 2144.05(II).
As such, an ordinary skilled artisan would have been motivated to make such a selection to arrive at an optimized dosage regimen that reduces unwanted drug-drug interactions and optimizes therapeutic effectiveness.
(Modified) Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Strupp 2 (Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series, J Neurol, published 2013, IDS of 09/04/2025, NPL210), Strupp (Episodic ataxia type 2, Springer Nature Link, published 2007, PTO-892 of 12/02/2025), Tomimitsu (Episodic ataxia type 2, published 2001, PTO-892), Pedroso (Acute cerebellar ataxia: differential diagnosis and clinical approach, published 2019, PTO-892), and WO 2021/048431 to McKnight (effectively filed 09/12/2019, PTO-892 of 06/04/2025 of 06/04/2025), as evidenced by PubChem (“Acetylleucine,” PTO-892 of 06/04/2025), as applied to claims 1-3, 5-7, 12-15, 21-22, and 24 above, and further in view of Kim (Episodic Ataxia Type 2 due to a Deletion Mutation in the CACNA1A Gene in a Korean Family, published 2006, PTO-892 of 06/04/2025).
Strupp 2, Strupp, Tomimitsu, Pedroso, and McKnight, and PubChem are applied as discussed above and incorporated herein.
Regarding claim 23, while the combination of Strupp 2, Strupp, Tomimitsu, Pedroso, and McKnight, teaches a method of treating cerebellar ataxia by administering a combination of acetyl-DL-leucine and acetazolamide, it differs from that of the instantly claimed invention in that it does not teach deletion of cytosine and thymidine at position 2070-2071 in exon 16 of the CACNA1A gene.
Strupp teaches EA2 and cerebellar ataxia as due to a mutation of the CACNA1A gene (pg. 269, Col. 1, 1st two paragraphs; Col. 2, 3rd-4th paragraphs).
Kim teaches that the underlying cause of EA2 is a genetic alteration of the voltage dependent calcium channel (CACNA1A), and specifically teaches this deletion mutation in exon 16 (pg. 268; pg. 269, Fig. 2; pg. 270, Col. 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select a patient with a deletion mutation in exon 16 of the CACNA1A gene, to arrive at instant claim 23. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Strupp teaches that 60% of patients with EA2 have a CACNA1A gene mutation, and
-Kim teaches that the underlying cause of EA2 is a generic alteration of CACNA1A and further teaches this mutation in exon 16 of the CACNA1A gene.
As such, an artisan having ordinary skill would have been motivated to make such a selection to predictably identify and treat a patient with cerebellar ataxia and EA2. While the combination of Strupp 2, Strupp, Tomimitsu, Pedroso, McKnight, and Kim do not expressly teach the deletion of cytosine and thymidine at position 2070-2071, a skilled artisan would be motivated to select such a specific mutation since it is known in the art that mutations in exon 16 of CACNA1A gene are the underlying cause of EA2.
Response to Arguments
The prior art rejections have been modified in view of the amendments to the claims that limit the ataxia treated to cerebellar ataxia. As such, only arguments pertinent to the modified rejections are addressed below.
On pg. 6, Remarks, Applicant argues that an ordinary skilled artisan would not have selected acetazolamide to treat cerebellar ataxia because Strupp is silent regarding treating cerebellar ataxia.
This argument has been fully considered, but is not found persuasive. As discussed in the above rejection:
-Strupp specifically teaches a method of treating EA2, wherein EA2 is a slow progression of cerebellar signs accompanied by atrophy of midline cerebellar structures,
-Tomimitsu teaches EA2 as a type of cerebellar ataxia,
-as evidenced by the instant Specification, episodic ataxias are characterized by recurrent episodes of a cerebellar ataxia,
-Pedroso teaches episodic ataxias as causing cerebellar ataxia, and teaches episodic ataxia 1 and 2 as causing recurrent symptoms of ACA
-Strupp teaches ACTZ as improving cerebellar symptoms,
-Strupp specifically teaches ACTZ as normalizing the abnormal intracellular pH levels in the cerebellum of patients, reducing potassium conductance of the cell membrane, and thus restoring the excitability and resting activity of neurons.
As such, an artisan having ordinary skill in the art would reasonably expected acetazolamide as useful to treat cerebellar ataxia for improving patients’ cerebellar symptoms, and thus, qualities of life.
On pg. 6, Remarks, Applicant further argues that acetazolamide is not indicated to treat cerebellar ataxia.
This argument has been fully considered, but is not found persuasive. For the reasons stated above, an ordinary skilled artisan would have been motivated to select acetazolamide to treat cerebellar ataxia. Applicant is respectfully reminded that obviousness does not require absolute predictability, but a reasonable expectation of success, MPEP 2143.02.
Regarding the teachings of the Farzam publication, referenced on pg. 6, Remarks, it is respectfully pointed out that FDA status is not a condition for patentability.
On pgs. 6-7, Remarks, Applicant argues that Strupp 2 is silent with regard to administering acetazolamide to treat cerebellar ataxia.
This argument has been fully considered, but is not found persuasive. The examiner agrees that Strupp 2 does not teach administering acetazolamide to treat cerebellar ataxia. It is respectfully pointed out that Strupp 2 is not relied upon as an anticipatory reference, but is relied upon in an obviousness rejection, combined with other prior art references, to arrive at instant claim 1.
For these reasons, Applicant’s arguments are not persuasive to overcome the rejections of record.
Conclusion
No claims are allowed.
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/LAUREN WELLS/Examiner, Art Unit 1622
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