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 .
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to a method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel in a subject in need thereof, and the following species:
essential tremor (ET) as the elected species of disease or condition;
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as the elected species of compound of Formula (I) or a pharmaceutically acceptable salt thereof;
propranolol as the elected species of second compound or a pharmaceutically acceptable salt thereof; and
a subject refractory to propranolol as the elected species of subject
in the reply filed on August 10, 2026 is acknowledged.
Claims 3-6 and 21-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 10, 2026.
Please note applicant states claims 1-9, 11-12, 14, 16-21 are readable on the elected species; However, the Examiner determined that claims 3-6 and 21 do not read on the elected species. Specifically, claim 3 is drawn to HCl salt of Formula (I) and claim 5 is drawn to HCl salt of propranolol. It is respectfully noted that applicant does not elect a HCl salt of Formula (I) as the elected species of compound of Formula (I) or a pharmaceutically acceptable salt thereof; and does not elect HCl salt of propranolol as the elected species of second compound or a pharmaceutically acceptable salt thereof. Therefore, these two salt forms noted above are drawn to nonelected species; and therefore claims 4 and 6, which depend on a withdrawn claim, are also drawn to a nonelected species. Additionally, claim 21 is drawn to a deuterium-enriched compound of Formula (I) or pharmaceutically acceptable salt thereof, and that is a compound of Formula (II). While the compound of Formula (II) recites therein appears to embrace the compound of Formula (I), the compound of Formula (II) is a “deuterium-enriched” compound, which is materially different that the elected, non-deuterated compound of Formula (I). Therefore, the Examiner has reasonably construed that the “deuterium-enriched compound of Formula (I) or pharmaceutically acceptable salt thereof” recites therein as being drawn to a nonelected species.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on August 10, 2026, wherein claims 1, 14, and 21 are amended; claims 2-9, 11-12, 16-20, and 22-24 are unchanged; and claims 10, 13 and 15 are canceled. Specifically, applicant amends independent claim 1 by adding the new limitation of “, or a deuterium-enriched compound of Formula (I) or pharmaceutically acceptable salt thereof,” and further amended dependent claim 21 by reciting the new limitation of “a compound of Formula (II):
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or a pharmaceutically acceptable salt thereof…”.
Claims 1-9, 11-12, 14 and 16-24 are pending.
Claims 3-6 and 21-24 are withdrawn.
Claims 1-2, 7-9, 11-12, 14 and 16-20 are under examination in accordance with the elected species.
Priority
The instant application 18/834,466 filed on July 30, 2024 is a 371 of PCT/US2023/061973 filed on February 3, 2023, which claims priority to, and the benefits of U.S. Provisional Application No.
63/306,340 filed on February 3, 2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 2/11/2026 and 8/14/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Interpretation
The claimed term “treating”, when reasonably construed in view of the special definition provides in paragraph [044] of the specification shown below:
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, is taken to include prevention.
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 1-2, 7-9, 11-12, 14 and 16-20 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 essential tremor as the disease or condition to the extent that “treating” does not include preventing, does not reasonably provide enablement for treating the full scope of disease or condition relating to aberrant function or activity of a T-type calcium channel, including essential tremor, to the extent that “treating” includes preventing. 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.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and, (8) the quantity of experimentation necessary. All of the Wands factors have been considered and discussed below:
(1, 5) The breadth of the claims and the Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
Instant claims 1 recites “[a] method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel in a subject in need thereof, comprising administering to the subject a compound of Formula (I)…. in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof”.
The claimed term “treating”, when reasonably construed in light of the special definition provides in paragraph [044] of the specification:
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, is taken to include prevention.
The claimed term “a disease or condition relating to aberrant function or activity of a T-type calcium channel”, when given it broadest reasonable interpretation, is taken to include any disease or condition that involves the mechanism of “aberrant function or activity of a T-type calcium channel”.
Therefore, the breadth of the claims covers treating the entire scope of disease or condition relating to aberrant function or activity of a T-type calcium channel, including the essential tremor, and the term “treating” includes preventing.
(2, 3, 4) The state of the prior art, the level of skill in the art, and the predictability or lack
thereof in the art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.”
According to Snutch et al. (Br J Pharmacol, 2018. Vol. 175(12): 2375-2383), one skilled in the art would have known Cav3.2 T-type calcium channels are important regulators of pain signals in the afferent pain pathway, and their activities are dysregulated during various chronic pain states (see e.g., abstract); while it is reasonable to predict that inhibiting T-type calcium channels in dorsal root ganglion neurons and in the spinal dorsal horn can be targeted for pain relief (see e.g., abstract); however, ABT-639, a potent blocker of T-type calcium channels, did not perform better than placebo in trials assessing nociceptor activity and pain in diabetic patients nor was it effective when given orally to capsaicin-induced experimental pain in humans (see e.g., p. 2379, 1st paragraph). In other words, at the time the application was filed, the relative skill of those in the art with respect to treating the full scope of disease or condition relating to aberrant function or activity of a T-type calcium channel, including pain, would have been low, because T-type calcium channel blocker fails to treat chronic pain that involves the aberrant activity of T-type calcium channel.
According to LeWine (“Essential tremor” [Online]. Harvard Health Publishing: Harvard Medical School. Published online on November 5, 2024), “[n]o one knows what causes essential tremor. Therefore, there is no way to prevent it” (see e.g., “Preventing essential tremor” section). In other words, the cited reference demonstrates the relative skill of those in the art with respect to preventing the entire scope of disease or condition relating to aberrant function activity of a T-type calcium channel, including essential tremor, would have been low.
While essential tremor as the disease or condition relating to aberrant function or activity of a T-type calcium channel may be treated to the extent that the treatment does not include prevention, it is uncertain whether administering any amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a deuterium-enriched compound of Formula (I) or pharmaceutically acceptable salt thereof in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can successfully treat the entire scope of disease or condition relating to aberrant function or activity of a T-type calcium channel, such as chronic pain noted above, to the extent that the treatment includes prevention.
(6, 7, 8) The amount of guidance given, the presence of working example and the quantitation
of experimentation required:
In view of all the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the claimed invention. Although the instant specification generally assessed the efficacy of the HCl salt compound of Formula (I) in patients who had had signs and symptoms consistent with essential tremor (see e.g., [0113]), wherein some patients were on propranolol (see e.g., Table 5); as well as assessing the effect of the HCl salt of the compound of Formula (I) in combination with propranolol in rats with harmaline-induced tremor activity. However, their biological activities against other diseases or conditions relating to aberrant function or activity of a T-type calcium channel have not been disclosed. The specification also does not expressly demonstrate their preventive effect against any diseases or conditions relating to aberrant function or activity of a T-type calcium channel, including essential tremor. In this case, the breadth of the claim is substantial, and the quantity of experimentation required to identify suitable amount and dosage regimen for treating the full scope of disease or condition relating to aberrant function or activity of a T-type calcium channel, such that the term “treating” includes preventing, would be undue in view of the unpredictability surrounding the treatment and the prevention of the entire scope of disease or condition relating to aberrant function or activity of a T-type calcium channel noted above.
Accordingly, one of ordinary skill in the art would be required to engage in substantial experimentation to identify amount and dosage regimen for treating and preventing the full scope of disease or condition relating to aberrant function or activity of a T-type calcium channel. Because the specification only provides guidance in treating essential tremor that does not include preventing, and does not teach other disease or condition relating to aberrant function or activity of a T-type calcium channel, the specification does not enable the full scope of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel to the extent that treating includes preventing. To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
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 8 is 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 8, the claim recites the limitation "the dosing regimen" in line 1. There is insufficient antecedent basis for this limitation in the claim, because “a” dosing regimen was not recited prior to said limitation. It is not clear what is being referred to therein as “the dosing regimen”.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 19 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding clam 19, the recitation of “as needed” in the phrase of “the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is administered as needed” is reasonably construed that the administration of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is optional, and therefore not required. However, said claim depends on claim 1 that requires the administration of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof; thus, the recitation of “as needed” fail to include all the limitations set forth in claim 1.
In order to advance prosecution, the Examiner is examining claim 19 to the extent that the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is administered.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 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, 2, 7-9, 11-12 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Reddy et al. (WO 2021/007487 A1; cited in the IDS filed on August 14, 2025), in view of Calzetti et al. (Journal of Neurology, Neurosurgery and Psychiatry, 1982. Vol. 45(10): 893–897).
Reddy et al. teaches a method of treating tremor (e.g., essential tremor) as the neurological disorder in a subject in need thereof, wherein the method comprises administering to the subject the oral dosage form (see e.g., claims 100 and 111); the oral dosage form comprising a compound of formula (I):
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, or a pharmaceutically acceptable salt or solvate thereof is useful for the modulation of T-type calcium channels (see e.g., p. 10, 5th to 6th paragraph; p. 7, last paragraph), e.g., Cav3.1, Cav3.2, and/or Cav3.3 (see e.g., p. 19, last line to p. 20, 1st line). Please note the compound of Formula (I) taught by Reddy et al. reading on the instant compound of Formula (I). Reddy et al. further teaches a dosage form comprising the compound of formula (I) may be administered in combination with another agent or therapy (see e.g., p. 41, “Combination Therapy”, 1st paragraph), and tremor medications includes, inter alia, propranolol (see e.g., p. 42, line 9-14). Reddy et al. further teaches an exemplary method of treating essential tremor as the neurological disorder in a subject in need thereof (see e.g., claims 100 and 111), which is a clinical study reported in Example 10 that enrolled patients who have been diagnosed with essential tremor (see e.g., Example 10). Reddy et al. further teaches in said study, the patient received a stable dose of 1 tremor medication throughout the clinical trial and received 20 mg of a compound of formula (I) orally once a daily for 7 days and then 40 mg of the compound of formula (I) orally once a day for 7 days; and the upper limb tremor score on The Essential Tremor Rating Assessment Scale (TETRAS) and TETRAS performance score were reduced as compared to baseline after administration of 20 mg for 7 days and further reduction were seen after administering 40 mg for an additional 7 days (see e.g., p. 63-64, “Example 10: Evaluation of efficacy, safety, tolerability and pharmacokinetics of the compound of formula (I) in essential tremor”).
While Reddy et al. teaches tremor medications includes propranolol (see e.g., p. 42, line 9-14), Reddy et al. does not expressly teach the compound of Formula (I) is administered in combination with propranolol.
Calzetti et al. teaches a double-blind crossover placebo-controlled study that assess the efficacy of propranolol (a non-selective [Symbol font/0x62]-adrenoceptor antagonist) and metoprolol ([Symbol font/0x62]1-selective adrenoceptor antagonist) in the treatment of essential tremor, wherein the propranolol was given for a period of 4 weeks at two different dosage regimens (120 and 240 mg daily for propranolol); and teaches the results demonstrated the lower dosage of propranolol was superior to placebo on the basis of performance test and patient’s self-assessment, and the higher dosage of propranolol was superior to placebo on all methods of assessment (see e.g., abstract). Calzetti et al. concludes propranolol represents a better choice in the treatment of patients with essential tremor (see e.g., abstract; p. 893, left column, 1st paragraph).
In this case, Reddy et al. clearly teaches a method of treating essential tremor in a subject in need thereof, comprising administering to the subject the compound of Formula (I) and 1 tremor medication, including propranolol. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of treating essential tremor taught by Reddy et al. to selectively choose to incorporate propranolol as the tremor medication, because Calzetti et al. teaches propranolol successfully improves essential tremor in the study, and concludes propranolol is a better choice in the treatment of essential tremor. One would have a reasonable expectation of success to arrive at the claimed invention, because Reddy et al. teaches a list of tremor medications, including propranolol, that may be administered in combination with the compound of formula (I). Accordingly, one would have reasonably expected that both agents, i.e., the compound of formula (I) of Reddy et al. and propranolol of Calzetti et al., taught to be useful separately for treating essential tremor would be expected to be similarly useful when used together. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Regarding the limitation of “wherein the subject was taking a dosing regimen of at least one of propranolol … prior to administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof” in claim 7, the instant situation is amenable to the type of analysis set forth in Ex parte Rubin , 128 USPQ 440 (Bd. App. 1959) and also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), where the court found that the selection of any order of performing process steps is prima facia obvious in the absence of new or unexpected results. As such, applying the same logic to the instant method claims, it would have been prima facie obvious to one of ordinary skill in the art the administer the propranolol in the method set forth above prior to administering the compound of formula (I). One would have a reasonable expectation that by administering a dosing regimen of the propranolol of Calzetti et al. prior to the compound of Formula (I) of Reddy et al. to the subject diagnosed with essential tremor would successfully treat the essential tremor.
Regarding the limitation of “wherein the dosing regimen of at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is not altered after administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, begins” in claim 8, Reddy et al. clearly teaches the patients were treated with a stable dose of 1 tremor medication throughout the clinical trial, and it silent that the tremor medication is altered. Given that Reddy et al. is silent regarding altering the dosing regimen of the tremor medication, it is reasonable to interpret the reference’s silence as teachings that the reference does not alter the stable dose of the tremor medication. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to not alter the dose of the tremor medication, including the propranolol of Calzetti et al., throughout the time that the compound of Formula (I) of Reddy et al. is being administered. One would have been motivated to do so with a reasonable expectation of success, because Reddy et al. teaches the patients diagnosed with essential tremor were on stable dose of 1 tremor medication.
Regarding the limitation of “wherein the subject is administered from about 5 mg to about 120 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily; or wherein the subject is administered from about 20 mg to about 80 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily” in claim 9, according to MPEP 2144.05, I, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In reWoodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Reddy et al. and Calzetti et al. set forth above by incorporating the dosing regimen of the compound of formula (I) taught by Reddy et al., i.e., 20 mg of the compound of formula (I) once a daily, to arrive at the claimed invention, because Reddy et al. teaches the patient diagnosed with essential tremor were treated with 20 mg of the compound of formula (I) once a daily, and the upper limb tremor score and TETRAS performance score were reduced. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering 20 mg of the compound of formula (I) of Reddy et al. in the method set forth above would have successfully treat the essential tremor. Regarding the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is titrated upward from a starting dose to a final dose during a course of administration” in claim 11, and the limitation of “wherein the starting dose of the
compound of Formula (I) or a pharmaceutically acceptable salt thereof is between about 10 mg to
about 40 mg once daily; or wherein the starting dose of the compound of Formula (I) or a
pharmaceutically acceptable salt thereof is about 20 mg once daily” in claim 12, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Reddy et al. and Calzetti et al. set forth above by starting the compound of Formula (I) at a dose of 20 mg, and then to 40 mg as taught by Reddy et al. to arrive at the claimed invention. One would have been motivated to do so, because Reddy et al. teaches the patients diagnosed with essential tremor received 20 mg of a compound of formula (I) orally once a daily for 7 days and then 40 mg of the compound of formula (I) orally once a day for 7 days, and reported the upper limb tremor score and TETRAS performance score were further reduced. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that administering the compound of formula (I) of Reddy et al. at a dose of 20 mg, and then 40 mg in the method set forth above would have successfully treat the essential tremor; and the 20 mg renders obvious the “starting dose” and the 40 mg renders obvious the “final dose” during a course of administration.
Regarding the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof are each administered daily” in claim 18, and the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered daily and the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is administered as needed” in claim 19, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of Reddy et al. and Calzetti et al. set forth above by administering the compound of Formula (I) of Reddy et al. and the propranolol of Calzetti et al. daily. One would have been motivated to do so, because each is taught by the prior art to administered daily. One would have a reasonable expectation of success to arrive at the claimed invention, because Reddy et al. demonstrates once daily administration of compound of formula (I) to patients diagnosed with essential tremor and Calzetti et al. also demonstrates daily administration of propranolol to the same patient population. Accordingly, one would have reasonably expected that both agents would be similarly useful when administered each of them daily. Please note while claim 19 recites “the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is administered as needed”, said claim has been reasonably construed by the Examiner in view of claim 1, which it depends upon, as the required feature of the claim; and therefore, “daily” administration of propanol renders obvious the claimed limitation.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed.
Claims 1-2, 7-9, 11-12, 14 and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Reddy et al. (WO 2021/007487 A1), in view of Calzetti et al. (Journal of Neurology, Neurosurgery and Psychiatry, 1982. Vol. 45(10): 893–897) as applied to claims 1, 2, 7-9, 11-12 and 18-19 above, and further in view of Lee et al. (WO 2020/072773 A1).
The teachings of Reddy et al. and Calzetti et al. are set forth above and applied as before.
While Reddy et al. teaches the effective amount of the compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject (see e.g., p. 8, line 2-5), Reddy et al. and Calzetti et al. does not expressly teach the final dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is from about 80 mg once daily to about 120 mg once daily, or wherein the final dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is about 120 mg once daily as claimed in claim 14. Reddy et al. and Calzetti et al. also does not teach at least one intermediate dose of the compound Formula (I) or a pharmaceutically acceptable salt thereof between the starting dose and the final dose as claimed in claim 16. Reddy et al. and Calzetti et al. also does not teach the subject is refractory to at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof as claimed in claim 17. Reddy et al. and Calzetti et al. also does not teach wherein the dose of propranolol, primidone, topiramate is about 5% to 90% lower than the dose of propranolol, primidone, topiramate that the subject received prior to administration the compound of Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 20.
Lee et al. further teaches a dose titration study, also referred to therein as “T-CALM”, that assess the efficacy and safety of CX-8998, a selective modulator of the T-Type calcium channel (see e.g., p. 126, line 24-25), in doses titrated up to 10 mg BID for reducing the severity of tremor associated with essential tremor (see e.g., p. 241, last paragraph to p. 242, 1st paragraph; p.118, line 6-8); and the results demonstrated that CX-8998 reduced tremor severity and had a favorable safety and tolerability profile (see e.g., p. 127, 2nd paragraph). Lee et al. further teaches majority of patients in the study were also taking concomitant anti-tremor medications (see e.g., p. 10, line14-18); and non-selective beta-blockers, such as propranolol, were the most frequently used anti-tremor medications in both CX-8998 and placebo group (see e.g., p. 135, line 19-21). Lee et al. further teaches enrolled patients also include those who were not taking essential tremor (ET) medication were refractory to or intolerant of first and second line ET therapies (see e.g., p. 10, line14-18); and 11 of these patients (12%) were reported by investigational sites as having tried and discontinued standard-of-care medications (propranolol, primidone, or both) for either efficacy or tolerability reasons (see e.g., p., 135, line 21-24). Lee et al. further teaches doses of 20 and 24 mg were less well tolerated (see e.g., p. 220, last paragraph) in the phase 1 studies in healthy subjects; However, T-CALM employed the following dose titration scheme: Week 1 at 4 mg BID (8 mg/day), Week 2 at 8 mg BID (16 mg/day) and Weeks 3 & 4 at 10 mg BID (20 mg/day); adverse events reports decrease after the first week of dosing despite the fact that dose was being increased at the beginning of Weeks 2 and 3, and this shows that patients tolerate quickly to CX-8998 related CNS and psychiatric adverse events (see e.g., p. 102, line 4-8). Lee et al. further teaches in some cases, the dose can depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration; in some cases, the dose can be increased over time, e.g., a dose can be titrated up to a final dose over a period of time (e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks); and in some cases, the dose can be decreased over time, e.g., a dose can be decreased to a maintenance dose after one or more symptoms have been reduced or eliminated (see e.g., p. 60, line 22-29).
Regarding the limitation of “wherein the subject is refractory to at least one of propranolol…” in claim 17, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method set forth above by incorporating the subject is refractory to at least one of propranolol to arrive at the claimed invention, because Lee et al. et al. demonstrates selective modulator of the T-Type calcium channel CX-8998 reduces tremor severity in patients who were refractory to standard-of-care medications, including propranolol. While the CX-8998 of Lee et al. is not the compound of Formula (I) taught by Reddy et al., said CX-8998 and compound of Formula (I) both selectively modulate T-type calcium channel for treating essential tremor. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound of Formula (I) of Reddy et al. would have exhibits the same or substantially similar modulating effect on T-type calcium channel as the CX-8998 of Lee et al. in treating patients who were refractory to propranolol.
Regarding the limitation of “wherein the dose of propranolol … is about 5% to 90% lower than the dose of propranolol … that the subject received prior to administration the compound of Formula (I) or a pharmaceutically acceptable salt thereof” in claim 20, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to decrease the dose of propranolol in the method set forth above through routine optimization, because Lee et al. teaches the dose can be decreased over time, e.g., a dose can be decreased to a maintenance dose after one or more symptoms have been reduced or eliminated. In other words, decreasing the dose of anti-tremor medications, including propranolol, after symptoms have been reduced or eliminated is well-known and routine in the art. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed reduction percentages, because one would have reasonably expected that the dose of propranolol can be reduced based on the severity of symptoms. Regarding the limitation of “wherein the final dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is from about 80 mg once daily to about 120 mg once daily; or wherein the final dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is about 120 mg once daily” in claim 14, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to increase the dose of compound of Formula (I) of Reddy et al. in the method set forth above through routine optimization, because Reddy et al. teaches the effective amount of the compound may vary based on factors, such as the condition of the subject, and further teaches the patients who received 40 mg of compound of Formula (I), which is higher than 20 mg, has further reduction in upper limb tremor score and TETRAS performance score; and Lee et al. teaches in some cases, the dose can be increased over time, e.g., a dose can be titrated up to a final dose over a period of time (e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks). Accordingly, the dose of the compound of Formula (I) is a result-effective variable, and adjusting or optimizing said dose would have been an obvious matter or routine optimization. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed final dose, because one would have reasonably expected that the dose of compound of Formula (I) of Reddy et al. can be increased starting from 40 mg to improve the treatment of essential tremor.
Regarding the limitation of “further comprising administering at least one intermediate dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, between the starting dose and the final dose, wherein the amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the intermediate dose is greater than the amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the starting dose but less than the amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the final dose” in claim 16, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to increase the dose of compound of Formula (I) of Reddy et al. over time in the method set forth above through routine optimization, because Reddy et al. teaches the effective amount of the compound may vary based on factors, such as the condition of the subject, and further teaches the patients who received 40 mg of compound of Formula (I), which is higher than 20 mg, has further reduction in upper limb tremor score and TETRAS performance score; and Lee et al. teaches in some cases, the dose can be increased over time, e.g., a dose can be titrated up to a final dose over a period of time (e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks); and further teaches dose titration (Week 1 at 4 mg BID; Week 2 at 8 mg BID; and Weeks 3 & 4 at 10 mg BID) decrease adverse events despite the fact that dose was being increased. Accordingly, titrating the dose of the compound of Formula (I) over a period of time, which includes a dose that falls between the starting and the final dose, is well-known and routine technique in the art to decrease adverse events. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed intermediate dose, because one would have reasonably expected that the dose of compound of Formula (I) of Reddy et al. can be increased over period of time, e.g., 1 week, 2 weeks, 3 weeks, to reduce adverse events by employing the routine dose titration technique.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 7-9, 11-12, 14 and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 131-134 and 138-165 of copending Application No. 18/746,428 (reference application), in view of Calzetti et al. (Journal of Neurology, Neurosurgery and Psychiatry, 1982. Vol. 45(10): 893–897) and Lee et al. (WO 2020/072773 A1).
In summary, the claims of the reference application are drawn to a method of treating an essential tremor in a patient in need thereof, comprising administering to the patient a sufficient amount of the compound of formula (I):
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or a pharmaceutically acceptable salt thereof.
The claims of the reference application do not teach the elected propranolol. The claims of the reference application also do not teach the dosing regimen of compound of formula (I) and the dosing regimen of the elected propranolol instantly claimed. The claims also do not teach the subject is refractory to at least one propranolol.
Calzetti et al. teaches a double-blind crossover placebo-controlled study that assess the efficacy of propranolol (a non-selective [Symbol font/0x62]-adrenoceptor antagonist) and metoprolol ([Symbol font/0x62]1-selective adrenoceptor antagonist) in the treatment of essential tremor, wherein the propranolol was given for a period of 4 weeks at two different dosage regimens (120 and 240 mg daily for propranolol); and teaches the results demonstrated the lower dosage of propranolol was superior to placebo on the basis of performance test and patient’s self-assessment, and the higher dosage of propranolol was superior to placebo on all methods of assessment (see e.g., abstract). Calzetti et al. concludes propranolol represents a better choice in the treatment of patients with essential tremor (see e.g., abstract; p. 893, left column, 1st paragraph).
Lee et al. further teaches currently, propranolol is the only medication approved for the treatment of essential tremor in the United States (see e.g., p. 4, line 8-9). Lee et al. further teaches a dose titration study, also referred to therein as “T-CALM”, that assess the efficacy and safety of CX-8998, a selective modulator of the T-Type calcium channel (see e.g., p. 126, line 24-25), in doses titrated up to 10 mg BID for reducing the severity of tremor associated with essential tremor (see e.g., p. 241, last paragraph to p. 242, 1st paragraph; p.118, line 6-8); and the results demonstrated that CX-8998 reduced tremor severity and had a favorable safety and tolerability profile (see e.g., p. 127, 2nd paragraph). Lee et al. further teaches majority of patients in the study were also taking concomitant anti-tremor medications (see e.g., p. 10, line14-18); and non-selective beta-blockers, such as propranolol, were the most frequently used anti-tremor medications in both CX-8998 and placebo group (see e.g., p. 135, line 19-21). Lee et al. further teaches enrolled patients also include those who were not taking essential tremor (ET) medication were refractory to or intolerant of first and second line ET therapies (see e.g., p. 10, line14-18); and 11 of these patients (12%) were reported by investigational sites as having tried and discontinued standard-of-care medications (propranolol, primidone, or both) for either efficacy or tolerability reasons (see e.g., p., 135, line 21-24). Lee et al. further teaches doses of 20 and 24 mg were less well tolerated (see e.g., p. 220, last paragraph) in the phase 1 studies in healthy subjects; However, T-CALM employed the following dose titration scheme: Week 1 at 4 mg BID (8 mg/day), Week 2 at 8 mg BID (16 mg/day) and Weeks 3 & 4 at 10 mg BID (20 mg/day); adverse events reports decrease after the first week of dosing despite the fact that dose was being increased at the beginning of Weeks 2 and 3, and this shows that patients tolerate quickly to CX-8998 related CNS and psychiatric adverse events (see e.g., p. 102, line 4-8). Lee et al. further teaches in some cases, the dose can depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration; in some cases, the dose can be increased over time, e.g., a dose can be titrated up to a final dose over a period of time (e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks); and in some cases, the dose can be decreased over time, e.g., a dose can be decreased to a maintenance dose after one or more symptoms have been reduced or eliminated (see e.g., p. 60, line 22-29). Lee et al. further teaches in some cases, the dose can be administered once daily (see e.g., p. 61, line 1-2); For example, a unit dosage can contain from about 0.5 mg to about 1,000 mg (1 g) of one or more T-type calcium channel antagonists per day (e.g., from about 5 mg to about 25 mg, or from about 40 mg to about 150 mg per day)(see e.g., p. 32, line 6-21).
In this case, the difference between the method of reference application and the claimed invention is that the reference application is silent about propranolol. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of treating essential tremor taught by the reference application to combine with propranolol as the tremor medication, because Calzetti et al. teaches propranolol successfully improves essential tremor in the study, and concludes propranolol is a better choice in the treatment of essential tremor. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that both agents, i.e., the compound of formula (I) of reference application and propranolol of Calzetti et al., taught to be useful separately for treating essential tremor would be expected to be similarly useful when used together. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Regarding the limitation of “wherein the subject was taking a dosing regimen of at least one of propranolol … prior to administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof” in claim 7, the instant situation is amenable to the type of analysis set forth in Ex parte Rubin , 128 USPQ 440 (Bd. App. 1959) and also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), where the court found that the selection of any order of performing process steps is prima facia obvious in the absence of new or unexpected results. As such, applying the same logic to the instant method claims, it would have been prima facie obvious to one of ordinary skill in the art the administer the propranolol in the method set forth above prior to administering the compound of formula (I). One would have a reasonable expectation that by administering a dosing regimen of the propranolol of Calzetti et al. prior to the compound of Formula (I) of reference application to the subject diagnosed with essential tremor would successfully treat the essential tremor.
Regarding the limitation of “wherein the dosing regimen of at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is not altered after administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, begins” in claim 8, Calzetti et al. clearly teaches the patients were treated with 120 or 240 mg of propranolol throughout the study, and it silent that the dose is altered during the treatment. Given that Calzetti et al. is silent regarding altering the dosing regimen of propranolol, it is reasonable to interpret the reference’s silence as teachings that the reference does not alter the dose of propranolol. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to not alter the dose of propranolol of Calzetti et al. throughout the time that the compound of Formula (I) of reference application is being administered. One would have been motivated to do so with a reasonable expectation of success, because Calzetti et al. teaches the patients who received 120 or 240 mg of propranolol experienced improvement in performance; and therefore, by administering the amount taught by Calzetti et al. without altering would be expected to be useful for treating the essential tremor.
Regarding the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof are each administered daily” in claim 18, and the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered daily and the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is administered as needed” in claim 19, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of reference application and Calzetti et al. set forth above by administering the compound of Formula (I) of reference application and the propranolol of Calzetti et al. daily. One would have been motivated to do so, because Calzetti et al. teaches propranolol is administered daily; and Lee et al. teaches in some cases, the dose of T-Type calcium channel modulator, which is taught to be useful for treating essential tremor, can be administered once daily. One would have a reasonable expectation of success to arrive at the claimed invention, because the compound of Lee et al. and the compound of formula (I) of reference application are each taught to be useful for treating essential tremor and T-type calcium channel modulator. Accordingly, one would have reasonably expected that substituting one art recognized T-Type calcium channel modulator for another in the dosing frequency of once daily taught by Lee et al. would have reasonably expected to obtain predictable results in treating essential tremor.
Regarding the limitation of “wherein the subject is administered from about 5 mg to about 120 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily; or wherein the subject is administered from about 20 mg to about 80 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily” in claim 9, the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is titrated upward from a starting dose to a final dose during a course of administration” in claim 11, the limitation of “wherein the starting dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is between about 10 mg to about 40 mg once daily; or wherein the starting dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is about 20 mg once daily” in claim 12, and the limitation of “wherein the final dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is from about 80 mg once daily to about 120 mg once daily; or wherein the final dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is about 120 mg once daily” in claim 14, according to MPEP 2144.05, I, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In reWoodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of reference application and Calzetti et al. set forth above by incorporating the dosing regimen of CX-8998, a selective modulator of the T-Type calcium channel, taught by Lee et al. to arrive at the claimed invention through routine optimization, because each is taught by the reference to be a compound that modulates T-type calcium channel for treating essential tremor; and Lee et al. expressly teaches the dose depend on the overall health status of the particular patient. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed amount, because Lee et al. teaches the unit dosage containing the T-type calcium channel antagonist can be in the amount from about 0.5 mg to about 1,000 mg per day, including from about 40 mg to about 150 mg per day, for treating essential tremor. Accordingly, one would have reasonably expected that substituting one art recognized T-Type calcium channel modulator for another in the same dosing regimen taught by Lee et al., including from about 40 mg to about 150 mg per day, would have reasonably expected to obtain predictable results in treating essential tremor. Regarding the limitation of “wherein the subject is refractory to at least one of propranolol…” in claim 17, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method set forth above by incorporating the subject is refractory to at least one of propranolol to arrive at the claimed invention, because Lee et al. et al. demonstrates selective modulator of the T-Type calcium channel CX-8998 reduces tremor severity in patients who were refractory to standard-of-care medications, including propranolol. While the CX-8998 of Lee et al. is not the compound of Formula (I) taught by reference application, said CX-8998 and compound of Formula (I) both selectively modulate T-type calcium channel for treating essential tremor. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound of Formula (I) of reference application would have exhibits the same or substantially similar effect as the CX-8998 of Lee et al. in treating patients who were refractory to propranolol.
Regarding the limitation of “wherein the dose of propranolol … is about 5% to 90% lower than the dose of propranolol … that the subject received prior to administration the compound of Formula (I) or a pharmaceutically acceptable salt thereof” in claim 20, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to decrease the dose of propranolol in the method set forth above through routine optimization, because Lee et al. teaches the dose can be decreased over time, e.g., a dose can be decreased to a maintenance dose after one or more symptoms have been reduced or eliminated. In other words, decreasing the dose of anti-tremor medications, including propranolol, after symptoms have been reduced or eliminated is well-known and routine in the art. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed reduction percentages, because one would have reasonably expected that the dose of propranolol can be reduced based on the severity of symptoms.
Regarding the limitation of “further comprising administering at least one intermediate dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, between the starting dose and the final dose, wherein the amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the intermediate dose is greater than the amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the starting dose but less than the amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the final dose” in claim 16, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to increase the dose of compound of Formula (I) of reference application over time in the method set forth above through routine optimization, because Lee et al. teaches in some cases, the dose can be increased over time, e.g., a dose can be titrated up to a final dose over a period of time (e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks); and further teaches dose titration (Week 1 at 4 mg BID; Week 2 at 8 mg BID; and Weeks 3 & 4 at 10 mg BID) decrease adverse events despite the fact that dose was being increased. Accordingly, titrating the dose of the compound of Formula (I) over a period of time, which includes a dose that falls between the starting and the final dose, is well-known and routine technique in the art to decrease adverse events. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed intermediate dose, because one would have reasonably expected that the dose of compound of Formula (I) of reference application can be increased over period of time, e.g., 1 week, 2 weeks, 3 weeks, to reduce adverse events by employing the routine dose titration technique.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 7-9, 11-12, 14 and 16-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,427,540 B2; over claims 1-35 of US 12,077,502 B2 in view of Calzetti et al. (Journal of Neurology, Neurosurgery and Psychiatry, 1982. Vol. 45(10): 893–897), and Lee et al. (WO 2020/072773 A1).
The claims of the reference patents, ‘540 and ‘502 patent, are drawn to a method of treating an essential tremor in a subject in need thereof, comprising administering to the subject an effective amount of the anhydrous crystalline Form C hydrochloride of Formula (II)
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. Please note said anhydrous crystalline Form C contains the chemical structure of
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, reading on the compound of Formula (I) instantly claimed.
The claims of the reference application do not teach the elected propranolol. The claims of the reference application also do not teach the dosing regimen of compound of formula (I) and the dosing regimen of the elected propranolol instantly claimed. The claims also do not teach the subject is refractory to at least one propranolol.
Calzetti et al. teaches a double-blind crossover placebo-controlled study that assess the efficacy of propranolol (a non-selective [Symbol font/0x62]-adrenoceptor antagonist) and metoprolol ([Symbol font/0x62]1-selective adrenoceptor antagonist) in the treatment of essential tremor, wherein the propranolol was given for a period of 4 weeks at two different dosage regimens (120 and 240 mg daily for propranolol); and teaches the results demonstrated the lower dosage of propranolol was superior to placebo on the basis of performance test and patient’s self-assessment, and the higher dosage of propranolol was superior to placebo on all methods of assessment (see e.g., abstract). Calzetti et al. concludes propranolol represents a better choice in the treatment of patients with essential tremor (see e.g., abstract; p. 893, left column, 1st paragraph).
Lee et al. further teaches currently, propranolol is the only medication approved for the treatment of essential tremor in the United States (see e.g., p. 4, line 8-9). Lee et al. further teaches a dose titration study, also referred to therein as “T-CALM”, that assess the efficacy and safety of CX-8998, a selective modulator of the T-Type calcium channel (see e.g., p. 126, line 24-25), in doses titrated up to 10 mg BID for reducing the severity of tremor associated with essential tremor (see e.g., p. 241, last paragraph to p. 242, 1st paragraph; p.118, line 6-8); and the results demonstrated that CX-8998 reduced tremor severity and had a favorable safety and tolerability profile (see e.g., p. 127, 2nd paragraph). Lee et al. further teaches majority of patients in the study were also taking concomitant anti-tremor medications (see e.g., p. 10, line14-18); and non-selective beta-blockers, such as propranolol, were the most frequently used anti-tremor medications in both CX-8998 and placebo group (see e.g., p. 135, line 19-21). Lee et al. further teaches enrolled patients also include those who were not taking essential tremor (ET) medication were refractory to or intolerant of first and second line ET therapies (see e.g., p. 10, line14-18); and 11 of these patients (12%) were reported by investigational sites as having tried and discontinued standard-of-care medications (propranolol, primidone, or both) for either efficacy or tolerability reasons (see e.g., p., 135, line 21-24). Lee et al. further teaches doses of 20 and 24 mg were less well tolerated (see e.g., p. 220, last paragraph) in the phase 1 studies in healthy subjects; However, T-CALM employed the following dose titration scheme: Week 1 at 4 mg BID (8 mg/day), Week 2 at 8 mg BID (16 mg/day) and Weeks 3 & 4 at 10 mg BID (20 mg/day); adverse events reports decrease after the first week of dosing despite the fact that dose was being increased at the beginning of Weeks 2 and 3, and this shows that patients tolerate quickly to CX-8998 related CNS and psychiatric adverse events (see e.g., p. 102, line 4-8). Lee et al. further teaches in some cases, the dose can depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration; in some cases, the dose can be increased over time, e.g., a dose can be titrated up to a final dose over a period of time (e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks); and in some cases, the dose can be decreased over time, e.g., a dose can be decreased to a maintenance dose after one or more symptoms have been reduced or eliminated (see e.g., p. 60, line 22-29). Lee et al. further teaches in some cases, the dose can be administered once daily (see e.g., p. 61, line 1-2); For example, a unit dosage can contain from about 0.5 mg to about 1,000 mg (1 g) of one or more T-type calcium channel antagonists per day (e.g., from about 5 mg to about 25 mg, or from about 40 mg to about 150 mg per day)(see e.g., p. 32, line 6-21).
In this case, the difference between the method of reference patent and the claimed invention is that the reference patent is silent about propranolol. It would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to modify the method of treating essential tremor taught by the reference patent to combine with propranolol as the tremor medication, because Calzetti et al. teaches propranolol successfully improves essential tremor in the study, and concludes propranolol is a better choice in the treatment of essential tremor. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that both agents, i.e., the compound of formula (I) of reference patent and propranolol of Calzetti et al., taught to be useful separately for treating essential tremor would be expected to be similarly useful when used together. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Regarding the limitation of “wherein the subject was taking a dosing regimen of at least one of propranolol … prior to administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof” in claim 7, the instant situation is amenable to the type of analysis set forth in Ex parte Rubin , 128 USPQ 440 (Bd. App. 1959) and also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), where the court found that the selection of any order of performing process steps is prima facia obvious in the absence of new or unexpected results. As such, applying the same logic to the instant method claims, it would have been prima facie obvious to one of ordinary skill in the art the administer the propranolol in the method set forth above prior to administering the compound of formula (I). One would have a reasonable expectation that by administering a dosing regimen of the propranolol of Calzetti et al. prior to the compound of Formula (I) of reference patent to the subject diagnosed with essential tremor would successfully treat the essential tremor.
Regarding the limitation of “wherein the dosing regimen of at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is not altered after administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, begins” in claim 8, Calzetti et al. clearly teaches the patients were treated with 120 or 240 mg of propranolol throughout the study, and it silent that the dose is altered during the treatment. Given that Calzetti et al. is silent regarding altering the dosing regimen of propranolol, it is reasonable to interpret the reference’s silence as teachings that the reference does not alter the dose of propranolol. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to not alter the dose of propranolol of Calzetti et al. throughout the time that the compound of Formula (I) of reference patent is being administered. One would have been motivated to do so with a reasonable expectation of success, because Calzetti et al. teaches the patients who received 120 or 240 mg of propranolol experienced improvement in performance; and therefore, by administering the amount taught by Calzetti et al. without altering would be expected to be useful for treating the essential tremor.
Regarding the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof are each administered daily” in claim 18, and the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered daily and the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is administered as needed” in claim 19, it would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to modify the method of reference patent and Calzetti et al. set forth above by administering the compound of Formula (I) of reference patent and the propranolol of Calzetti et al. daily. One would have been motivated to do so, because Calzetti et al. teaches propranolol is administered daily; and Lee et al. teaches in some cases, the dose of T-Type calcium channel modulator, which is taught to be useful for treating essential tremor, can be administered once daily. One would have a reasonable expectation of success to arrive at the claimed invention, because the compound of Lee et al. and the compound of formula (I) of reference patent are each taught to be useful for treating essential tremor and T-type calcium channel modulator. Accordingly, one would have reasonably expected that substituting one art recognized T-Type calcium channel modulator for another in the dosing frequency of once daily taught by Lee et al. would have reasonably expected to obtain predictable results in treating essential tremor.
Regarding the limitation of “wherein the subject is administered from about 5 mg to about 120 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily; or wherein the subject is administered from about 20 mg to about 80 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof daily” in claim 9, the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is titrated upward from a starting dose to a final dose during a course of administration” in claim 11, the limitation of “wherein the starting dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is between about 10 mg to about 40 mg once daily; or wherein the starting dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is about 20 mg once daily” in claim 12, and the limitation of “wherein the final dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is from about 80 mg once daily to about 120 mg once daily; or wherein the final dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is about 120 mg once daily” in claim 14, according to MPEP 2144.05, I, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In reWoodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. It would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to modify the method of reference patent and Calzetti et al. set forth above by incorporating the dosing regimen of CX-8998, a selective modulator of the T-Type calcium channel, taught by Lee et al. to arrive at the claimed invention through routine optimization, because each is taught by the reference to be a compound that modulates T-type calcium channel for treating essential tremor; and Lee et al. expressly teaches the dose depend on the overall health status of the particular patient. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed amount, because Lee et al. teaches the unit dosage containing the T-type calcium channel antagonist can be in the amount from about 0.5 mg to about 1,000 mg per day, including from about 40 mg to about 150 mg per day, for treating essential tremor. Accordingly, one would have reasonably expected that substituting one art recognized T-Type calcium channel modulator for another in the same dosing regimen taught by Lee et al., including from about 40 mg to about 150 mg per day, would have reasonably expected to obtain predictable results in treating essential tremor. Regarding the limitation of “wherein the subject is refractory to at least one of propranolol…” in claim 17, it would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to modify the method set forth above by incorporating the subject is refractory to at least one of propranolol to arrive at the claimed invention, because Lee et al. et al. demonstrates selective modulator of the T-Type calcium channel CX-8998 reduces tremor severity in patients who were refractory to standard-of-care medications, including propranolol. While the CX-8998 of Lee et al. is not the compound of Formula (I) taught by reference patent, said CX-8998 and compound of Formula (I) both selectively modulate T-type calcium channel for treating essential tremor. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound of Formula (I) of reference patent would have exhibits the same or substantially similar effect as the CX-8998 of Lee et al. in treating patients who were refractory to propranolol.
Regarding the limitation of “wherein the dose of propranolol … is about 5% to 90% lower than the dose of propranolol … that the subject received prior to administration the compound of Formula (I) or a pharmaceutically acceptable salt thereof” in claim 20, it would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to decrease the dose of propranolol in the method set forth above through routine optimization, because Lee et al. teaches the dose can be decreased over time, e.g., a dose can be decreased to a maintenance dose after one or more symptoms have been reduced or eliminated. In other words, decreasing the dose of anti-tremor medications, including propranolol, after symptoms have been reduced or eliminated is well-known and routine in the art. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed reduction percentages, because one would have reasonably expected that the dose of propranolol can be reduced based on the severity of symptoms.
Regarding the limitation of “further comprising administering at least one intermediate dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, between the starting dose and the final dose, wherein the amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the intermediate dose is greater than the amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the starting dose but less than the amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the final dose” in claim 16, it would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to increase the dose of compound of Formula (I) of reference patent over time in the method set forth above through routine optimization, because Lee et al. teaches in some cases, the dose can be increased over time, e.g., a dose can be titrated up to a final dose over a period of time (e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks); and further teaches dose titration (Week 1 at 4 mg BID; Week 2 at 8 mg BID; and Weeks 3 & 4 at 10 mg BID) decrease adverse events despite the fact that dose was being increased. Accordingly, titrating the dose of the compound of Formula (I) over a period of time, which includes a dose that falls between the starting and the final dose, is well-known and routine technique in the art to decrease adverse events. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed intermediate dose, because one would have reasonably expected that the dose of compound of Formula (I) of reference patent can be increased over period of time, e.g., 1 week, 2 weeks, 3 weeks, to reduce adverse events by employing the routine dose titration technique.
Claims 1-2, 7-9, 11-12, 14 and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41-63 of copending Application No. 18/864,098 in view of Calzetti et al. (Journal of Neurology, Neurosurgery and Psychiatry, 1982. Vol. 45(10): 893–897) and Lee et al. (WO 2020/072773 A1).
In summary, the claims of the reference application is drawn to a method of treating essential tremor in a subject in need thereof, said method comprising administering to said subject a compound of formula (I), or a pharmaceutically acceptable salt thereof:
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, wherein the compound of formula (I) is administered to said subject at a daily dose of about 20 mg for at least 7 days (see e.g., claim 1), followed by administering to said subject the compound of formula (I) or a pharmaceutically acceptable salt thereof at a daily dose of about 40 mg for 7 days (see e.g., claim 44). The claims of the reference application is also drawn to a method of treating essential tremor in a subject in need thereof, said method comprising administering to said subject the same compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said method comprises administering to said subject for a first time period a first dose of about 20 mg to about 40 mg per day of the compound of formula (I), or a pharmaceutically acceptable salt thereof; increasing the first dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and administering one or more increased doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the subject to arrive at a maximum titrated dose of about 80 mg to about 120 mg per day; and administering the maximum titrated dose to the subject once daily (see e.g., claim 47).
The claims of the reference application do not teach propranolol. The claims of the reference application also do not teach the dosing regimen of elected propranolol instantly claimed. The claims also do not teach the subject is refractory to at least one propranolol.
Calzetti et al. teaches a double-blind crossover placebo-controlled study that assess the efficacy of propranolol (a non-selective [Symbol font/0x62]-adrenoceptor antagonist) and metoprolol ([Symbol font/0x62]1-selective adrenoceptor antagonist) in the treatment of essential tremor, wherein the propranolol was given for a period of 4 weeks at two different dosage regimens (120 and 240 mg daily for propranolol); and teaches the results demonstrated the lower dosage of propranolol was superior to placebo on the basis of performance test and patient’s self-assessment, and the higher dosage of propranolol was superior to placebo on all methods of assessment (see e.g., abstract). Calzetti et al. concludes propranolol represents a better choice in the treatment of patients with essential tremor (see e.g., abstract; p. 893, left column, 1st paragraph).
Lee et al. further teaches currently, propranolol is the only medication approved for the treatment of essential tremor in the United States (see e.g., p. 4, line 8-9). Lee et al. further teaches a dose titration study, also referred to therein as “T-CALM”, that assess the efficacy and safety of CX-8998, a selective modulator of the T-Type calcium channel (see e.g., p. 126, line 24-25), in doses titrated up to 10 mg BID for reducing the severity of tremor associated with essential tremor (see e.g., p. 241, last paragraph to p. 242, 1st paragraph; p.118, line 6-8); and the results demonstrated that CX-8998 reduced tremor severity and had a favorable safety and tolerability profile (see e.g., p. 127, 2nd paragraph). Lee et al. further teaches majority of patients in the study were also taking concomitant anti-tremor medications (see e.g., p. 10, line14-18); and non-selective beta-blockers, such as propranolol, were the most frequently used anti-tremor medications in both CX-8998 and placebo group (see e.g., p. 135, line 19-21). Lee et al. further teaches enrolled patients also include those who were not taking essential tremor (ET) medication were refractory to or intolerant of first and second line ET therapies (see e.g., p. 10, line14-18); and 11 of these patients (12%) were reported by investigational sites as having tried and discontinued standard-of-care medications (propranolol, primidone, or both) for either efficacy or tolerability reasons (see e.g., p., 135, line 21-24). Lee et al. further teaches doses of 20 and 24 mg were less well tolerated (see e.g., p. 220, last paragraph) in the phase 1 studies in healthy subjects; However, T-CALM employed the following dose titration scheme: Week 1 at 4 mg BID (8 mg/day), Week 2 at 8 mg BID (16 mg/day) and Weeks 3 & 4 at 10 mg BID (20 mg/day); adverse events reports decrease after the first week of dosing despite the fact that dose was being increased at the beginning of Weeks 2 and 3, and this shows that patients tolerate quickly to CX-8998 related CNS and psychiatric adverse events (see e.g., p. 102, line 4-8). Lee et al. further teaches in some cases, the dose can depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration; in some cases, the dose can be increased over time, e.g., a dose can be titrated up to a final dose over a period of time (e.g., 1 week, 2 weeks, 3 weeks, or 4 weeks); and in some cases, the dose can be decreased over time, e.g., a dose can be decreased to a maintenance dose after one or more symptoms have been reduced or eliminated (see e.g., p. 60, line 22-29). Lee et al. further teaches in some cases, the dose can be administered once daily (see e.g., p. 61, line 1-2); For example, a unit dosage can contain from about 0.5 mg to about 1,000 mg (1 g) of one or more T-type calcium channel antagonists per day (e.g., from about 5 mg to about 25 mg, or from about 40 mg to about 150 mg per day)(see e.g., p. 32, line 6-21).
In this case, the difference between the method of reference application and the claimed invention is that the reference application is silent about propranolol. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of treating essential tremor taught by the reference application to combine with propranolol as the tremor medication, because Calzetti et al. teaches propranolol successfully improves essential tremor in the study, and concludes propranolol is a better choice in the treatment of essential tremor. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that both agents, i.e., the compound of formula (I) of reference application and propranolol of Calzetti et al., taught to be useful separately for treating essential tremor would be expected to be similarly useful when used together. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Regarding the limitation of “wherein the subject was taking a dosing regimen of at least one of propranolol … prior to administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof” in claim 7, the instant situation is amenable to the type of analysis set forth in Ex parte Rubin , 128 USPQ 440 (Bd. App. 1959) and also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), where the court found that the selection of any order of performing process steps is prima facia obvious in the absence of new or unexpected results. As such, applying the same logic to the instant method claims, it would have been prima facie obvious to one of ordinary skill in the art the administer the propranolol in the method set forth above prior to administering the compound of formula (I). One would have a reasonable expectation that by administering a dosing regimen of the propranolol of Calzetti et al. prior to the compound of Formula (I) of reference application to the subject diagnosed with essential tremor would successfully treat the essential tremor.
Regarding the limitation of “wherein the dosing regimen of at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is not altered after administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, begins” in claim 8, Calzetti et al. clearly teaches the patients were treated with 120 or 240 mg of propranolol throughout the study, and it silent that the dose is altered during the treatment. Given that Calzetti et al. is silent regarding altering the dosing regimen of propranolol, it is reasonable to interpret the reference’s silence as teachings that the reference does not alter the dose of propranolol. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to not alter the dose of propranolol of Calzetti et al. throughout the time that the compound of Formula (I) of reference application is being administered. One would have been motivated to do so with a reasonable expectation of success, because Calzetti et al. teaches the patients who received 120 or 240 mg of propranolol experienced improvement in performance; and therefore, by administering the amount taught by Calzetti et al. without altering would be expected to be useful for treating the essential tremor.
Regarding the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof are each administered daily” in claim 18, and the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered daily and the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is administered as needed” in claim 19, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of reference application and Calzetti et al. set forth above by administering the propranolol of Calzetti et al. daily. One would have been motivated to do so, because Calzetti et al. teaches propranolol is administered daily for treating essential tremor. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that once daily administration of propranolol in the method set forth above would have reasonably expected to obtain predictable results in treating essential tremor. Regarding the limitation of “wherein the subject is refractory to at least one of propranolol…” in claim 17, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method set forth above by incorporating the subject is refractory to at least one of propranolol to arrive at the claimed invention, because Lee et al. et al. demonstrates selective modulator of the T-Type calcium channel CX-8998 reduces tremor severity in patients who were refractory to standard-of-care medications, including propranolol. While the CX-8998 of Lee et al. is not the compound of Formula (I) taught by reference application, said CX-8998 and compound of Formula (I) both selectively modulate T-type calcium channel for treating essential tremor. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound of Formula (I) of reference application would have exhibits the same or substantially similar effect as the CX-8998 of Lee et al. in treating patients who were refractory to propranolol.
Regarding the limitation of “wherein the dose of propranolol … is about 5% to 90% lower than the dose of propranolol … that the subject received prior to administration the compound of Formula (I) or a pharmaceutically acceptable salt thereof” in claim 20, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to decrease the dose of propranolol in the method set forth above through routine optimization, because Lee et al. teaches the dose can be decreased over time, e.g., a dose can be decreased to a maintenance dose after one or more symptoms have been reduced or eliminated. In other words, decreasing the dose of anti-tremor medications, including propranolol, after symptoms have been reduced or eliminated is well-known and routine in the art. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed reduction percentages, because one would have reasonably expected that the dose of propranolol can be reduced based on the severity of symptoms.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 7-9, 11-12, 14 and 16-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 12,697,331 B2 in view of Calzetti et al. (Journal of Neurology, Neurosurgery and Psychiatry, 1982. Vol. 45(10): 893–897) and Lee et al. (WO 2020/072773 A1).
In Summary, the claims of the reference patent is drawn to a method of treating a subject suffering from essential tremor, the method comprising administering to said subject a titrated dose of a compound of formula (I):
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or a pharmaceutically acceptable salt thereof, wherein administering the titrated dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprises: (a) administering to said subject a first dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, of about 5 mg to about 40 mg per day for a first period of time; (b) administering to said subject one or more increased doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the one or
more increased doses are increased relative to the first dose, to arrive at a maximum titrated dose of about 20 mg to about 120 mg per day; and (c) administering the maximum titrated dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the subject (see e.g., claim 1), including (a) administering to the subject a first dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, of about 20 mg to about 40 mg per day for a first period of time; (b) administering to the subject a second dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, of about 40 mg to about 80 mg per day for a second period of time; and (c) administering to the subject a third dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, of about 60 mg to about 120 mg for a third period of time (see e.g., claim 20).
In this case, the difference between the method of reference patent and the claimed invention is that the reference patent is silent about propranolol. It would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to modify the method of treating essential tremor taught by the reference patent to combine with propranolol as the tremor medication, because Calzetti et al. teaches propranolol successfully improves essential tremor in the study, and concludes propranolol is a better choice in the treatment of essential tremor. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that both agents, i.e., the compound of formula (I) of reference patent and propranolol of Calzetti et al., taught to be useful separately for treating essential tremor would be expected to be similarly useful when used together. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Regarding the limitation of “wherein the subject was taking a dosing regimen of at least one of propranolol … prior to administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof” in claim 7, the instant situation is amenable to the type of analysis set forth in Ex parte Rubin , 128 USPQ 440 (Bd. App. 1959) and also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), where the court found that the selection of any order of performing process steps is prima facia obvious in the absence of new or unexpected results. As such, applying the same logic to the instant method claims, it would have been prima facie obvious to one of ordinary skill in the art the administer the propranolol in the method set forth above prior to administering the compound of formula (I). One would have a reasonable expectation that by administering a dosing regimen of the propranolol of Calzetti et al. prior to the compound of Formula (I) of reference patent to the subject diagnosed with essential tremor would successfully treat the essential tremor.
Regarding the limitation of “wherein the dosing regimen of at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is not altered after administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, begins” in claim 8, Calzetti et al. clearly teaches the patients were treated with 120 or 240 mg of propranolol throughout the study, and it silent that the dose is altered during the treatment. Given that Calzetti et al. is silent regarding altering the dosing regimen of propranolol, it is reasonable to interpret the reference’s silence as teachings that the reference does not alter the dose of propranolol. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to not alter the dose of propranolol of Calzetti et al. throughout the time that the compound of Formula (I) of reference patent is being administered. One would have been motivated to do so with a reasonable expectation of success, because Calzetti et al. teaches the patients who received 120 or 240 mg of propranolol experienced improvement in performance; and therefore, by administering the amount taught by Calzetti et al. without altering would be expected to be useful for treating the essential tremor.
Regarding the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof are each administered daily” in claim 18, and the limitation of “wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered daily and the at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is administered as needed” in claim 19, it would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to modify the method of reference patent and Calzetti et al. set forth above by administering the propranolol of Calzetti et al. daily. One would have been motivated to do so, because Calzetti et al. teaches propranolol is administered daily for treating essential tremor. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that once daily administration of propranolol in the method set forth above would have reasonably expected to obtain predictable results in treating essential tremor. Regarding the limitation of “wherein the subject is refractory to at least one of propranolol…” in claim 17, it would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to modify the method set forth above by incorporating the subject is refractory to at least one of propranolol to arrive at the claimed invention, because Lee et al. et al. demonstrates selective modulator of the T-Type calcium channel CX-8998 reduces tremor severity in patients who were refractory to standard-of-care medications, including propranolol. While the CX-8998 of Lee et al. is not the compound of Formula (I) taught by reference patent, said CX-8998 and compound of Formula (I) both selectively modulate T-type calcium channel for treating essential tremor. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound of Formula (I) of reference patent would have exhibits the same or substantially similar effect as the CX-8998 of Lee et al. in treating patients who were refractory to propranolol.
Regarding the limitation of “wherein the dose of propranolol … is about 5% to 90% lower than the dose of propranolol … that the subject received prior to administration the compound of Formula (I) or a pharmaceutically acceptable salt thereof” in claim 20, it would have been prima facie obvious to one of ordinary skill in the art at the time the patent was filed to decrease the dose of propranolol in the method set forth above through routine optimization, because Lee et al. teaches the dose can be decreased over time, e.g., a dose can be decreased to a maintenance dose after one or more symptoms have been reduced or eliminated. In other words, decreasing the dose of anti-tremor medications, including propranolol, after symptoms have been reduced or eliminated is well-known and routine in the art. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed reduction percentages, because one would have reasonably expected that the dose of propranolol can be reduced based on the severity of symptoms.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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