DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on September 9, 2025 has been entered.
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 .
Priority
This Application filed on 04/26/2024 is a continuation of 17/449,785 filed on 10/01/2021 which is a continuation of PAT 11135214 filed on 05/13/2019 , which has a PRO 62/670,253 filed on 05/11/2018.
Information Disclosure Statement
The information disclosure statement(s) (IDS) filed on 9/9/25 is in compliance with the provisions of S7 CFR 1.97. Accordingly, the IDS is being considered by the Examiner.
Response to Arguments
The arguments over the rejections of claims 117, 119-123, 126-136, 139-144 and 147-151 under 35 U.S.C. 103(a) as being unpatentable Vernier et al. ( US20110003850 A1) in view of CDER (Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2002) is not persuasive. The rejection is herewith maintained. Applicant points to US 2013/0131030 stating the food effect is somewhat unpredictable phenomenon, and can be negative or positive manifested as an increase in oral bioavailability or can be unaffected, therefore, are unpredictable. This unpredictability is further supported by many additional references. For example, in an article published in 2012, the state of the art relating to the predictability of food effects for drugs was described as: "Both physiochemical properties (dissolution rate and solubility) and physiological properties (gastric emptying time and pH changes) can influence the absorption of drugs, making interpretation of the effect of food on drug absorption complex and unpredictable." Pithavala, Y. K. et al. Cancer Chemother. Pharmacol. 2012, 70, 103-112. See, for example, paragraph [0043] of the present Application, and Heimbach, T. et al. AAPS J. 2013, 15(1), 143-158. Because the state of the art at the priority date, and even still today, understood food effects to be unpredictable, the person skilled in the art would not have understood whether a clinically meaningful food effect existed for Compound A, let alone the type of food effect for Compound A in the event a food effect were even to exist. Applicant argues Examiner’s CDER then recognizes the unpredictability in the presence of, type of, and magnitude of food effect for various biopharmaceutical classification system (BCS) classes, stating that "the relative direction and magnitude of food effects on formulation BA and the effects on the demonstration of BE are difficult, if not impossible, to predict without conducting a fed BE study." Id (emphasis added). As a result, the Final Office Action's conclusory allegation, in addition to failing as a matter of law, is also factually incorrect. Furthermore, Applicant argues as shown in FIG. 2 of the present application, the mean plasma concentration curves for the fed and fasted patient groups are substantially different, with the AUC and Cₘₐₓ being significantly larger in the fed group, thereby demonstrating a food effect. These results further confirm the unpredictability of both the existence of a food effect and also the type of food effect for Compound A.
The Examiner respectfully reiterates a human patient is in either fed or fasted condition. The food effect results in a change or no change on BA and BE. The prior art teaches to test and reference products in food-effect BA and fed BE studies: • Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t) • Peak exposure (Cmax) • Time to peak exposure (Tmax) • Lag-time (tlag) for modified-release products, if present • Terminal elimination half-life in order to see whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food. The Examiner points out that these effects are expected and not surprising or unexpected. Specifically, the prior art teaches to test food-effect BA and fed BE in order to see whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food. The Examiner’s contention is that Applicants must show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). Additionally, Applicant’s claims to administering a known drug, under a known route of administration - orally, for a known treatment in either a fed or fasted state is obvious over the teachings of the prior art. The route of administration taught by Vernier et al. is identical to the claims, and therefore, the limitation for oral administration under either ‘fed’ or ‘fasted’ conditions species is so small in number that one could readily envisage the claimed species. The claimed method is obvious and the argued food effect is an inherent property that does not render the claimed method nonobvious. To test and reference products in food-effect BA and fed BE studies is obvious over the teachings of CDER. Applicant’s arguments are not persuasive.
The arguments over the rejections of claims 145-146 under 35 U.S.C. 103(a) as being unpatentable Vernier et al. ( US20110003850 A1) and CDER (Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2002), as applied to claims 117, 119-123, 126-136, 139-144 and 147-151 above in view Johannessen et al. (Management of Focal-Onset Seizures. Qrugs, 2006, Volume 66, Number 13, Page 1704} is not persuasive. The rejection is herewith maintained. Applicant’s argument over claims 145-146 rejections depends on the validity of the previous arguments which were not found persuasive.
Applicant' s state that the provisional ODP rejection 18679045 be held in abeyance until patentable subject matter is determined. The rejection is herewith maintained.
The arguments over the ODP rejections of Applic. No. 17449785 is withdrawn in view of abandonment.
Applicant' s state that the ODP rejections over U.S. Applic. No. 17093183 or (US 12178811); 18921788; 18958937; 19008882 U.S. PAT. No. 11957675 U.S. Patent No. 11135214 U.S. Patent No. 11091441B2 be held in abeyance until patentable subject matter is determined. The rejection is herewith maintained.
The amended claims are now addressed in US Pat 19008882.
The following rejections are made:
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 117, 119-123, 126-136, 139-144 and 147-151 are rejected under 35 U.S.C. 103 as being unpatentable over Vernier et al. ( US20110003850 A1) in view of CDER (Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2002).
Vernier et al. teaches a method of treating or preventing a disease, disorder, or condition that is affected by modulation of at least one potassium ion channel selected from KCNQ2/3, KCNQ4, and KCNQ5, such as treating or preventing a seizure disorder in a patient comprising administering compound A:
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in an amount of from about 10 mg to about 2000 mg per day to a patient. [0337] Tests examples show oral administration of the compound. [0529]
While, Vernier et al. does not specify treatment under fed conditions,
CDER teaches food-effect bioavailability (BA) “studies may be exploratory and descriptive, or a sponsor may want to use a food effect BA study to make a label claim. The following exposure measures and pharmacokinetic parameters should be obtained from the resulting concentration-time curves for the test and reference products in food-effect BA and fed BE studies: • Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t) • Peak exposure (Cmax) • Time to peak exposure (Tmax) • Lag-time (tlag) for modified-release products, if present • Terminal elimination half-life • Other relevant pharmacokinetic parameters. Individual subject measurements, as well as summary statistics (e.g., group averages, standard deviations, coefficients of variation) should be reported. An equivalence approach is recommended for food-effect BA (to make a claim of no food effects) and fed BE studies, analyzing data using an average criterion. Log-transformation of exposure measurements (AUC and Cmax ) prior to analysis is recommended. The 90 percent CI for the ratio of population geometric means between test and reference products should be provided for AUC0-inf, AUC0-t, and Cmax.” “For IND or NDA food-effect BA studies, the fasted treatment serves as the reference. For ANDA fed BE studies, the RLD administered under fed condition serves as the reference treatment. The effect of food on the absorption and BA of a drug product should be described in the CLINICAL PHARMACOLOGY section of the labeling. In addition, the DOSAGE AND ADMINISTRATION section of the labeling should provide instructions for drug administration in relation to food based on clinical relevance (i.e., whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food).”
It would have been obvious to one of ordinary skill in the art at the time of filing to test a human subject under fasted or fed conditions. The motivation to test a human subject under fasted or fed conditions is because CDER teaches to test and reference products in food-effect BA and fed BE studies: • Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t) • Peak exposure (Cmax) • Time to peak exposure (Tmax) • Lag-time (tlag) for modified-release products, if present • Terminal elimination half-life in order to see whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food. Hence, a skilled artisan would have had reasonable expectation of successfully achieving similar results.
Furthermore, Applicant claims compound A administered under fed conditions. The Examiner points out a drug is administered to a human subject under fasted or fed conditions. The subject cannot be under any other state, in terms of feeding conditions. The recitation of administration “between about 30 minutes prior to consuming food to about 2 hours after consuming food”, consumption “concurrently” or “within 15 minutes” of a “standard meal,” or” high-fat and/or high calorie meal” of claims 120-123, 126, 133-136, and 139 is obvious. It would have been obvious to one having ordinary skill in the art at the time the invention was filed to modify the time and meal-type, since it has been held that consumption with food results in different safety or efficacy, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food, discovering the optimum time and meal-type involves only routine skill in the art.
Claims 145-146 are rejected under 35 U.S.C. 103 as being unpatentable over Vernier et al. ( US20110003850 A1) and CDER (Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2002), as applied to claims 117, 119-123, 126-136, 139-144 and 147-151 above in view Johannessen et al. (Management of Focal-Onset Seizures. Qrugs, 2006, Volume 66, Number 13, Page 1704}.
Vernier et al. and CEDR et al. fail to specify seizure focal onset.
Johannessen et al. teaches focal onset selzures are manifestations of abnormal epileptic firing of brain cells in a localized area or areas of the brain.
It would have been obvious to one of ordinary skill in the art at the time of the invention to treat focal onset seizures. The motivation comes from the general teaching that compound A is useful in treatment of seizure disorders. Hence, a skilled artisan would have reasonable expectation of successfully achieving similar efficacy and results.
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 117, 119-123, 126-136, 139-144 and 145-151 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 117, 124-135, and 143-146 of U.S. Applic. No. 18679045 in view of CDER (Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2002). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to a method of administering Compound A to a human in need thereof; wherein Compound A is N-[4-(6-fluoro-3,4-dihydro- 1 H-isoquinolin-2-yl)-2,6-dimethylpheny1]-3,3- dimethylbutanamide; the improvement comprising administering Compound A to the human without dose titration while the claims herein are drawn to in a method of orally administering Compound A to a human in need thereof, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro- 1 H-isoquinolin-2-yl)-2,6- dimethylphenyl]-3,3-dimethylbutanamide; the improvement comprising orally administering an amount of Compound A to the human under fed conditions.
While the claims do not specify treatment under fed conditions.
CDER teaches food-effect bioavailability (BA) “studies may be exploratory and descriptive, or a sponsor may want to use a food effect BA study to make a label claim. The following exposure measures and pharmacokinetic parameters should be obtained from the resulting concentration-time curves for the test and reference products in food-effect BA and fed BE studies: • Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t) • Peak exposure (Cmax) • Time to peak exposure (Tmax) • Lag-time (tlag) for modified-release products, if present • Terminal elimination half-life • Other relevant pharmacokinetic parameters. Individual subject measurements, as well as summary statistics (e.g., group averages, standard deviations, coefficients of variation) should be reported. An equivalence approach is recommended for food-effect BA (to make a claim of no food effects) and fed BE studies, analyzing data using an average criterion. Log-transformation of exposure measurements (AUC and Cmax ) prior to analysis is recommended. The 90 percent CI for the ratio of population geometric means between test and reference products should be provided for AUC0-inf, AUC0-t, and Cmax.” “For IND or NDA food-effect BA studies, the fasted treatment serves as the reference. For ANDA fed BE studies, the RLD administered under fed condition serves as the reference treatment. The effect of food on the absorption and BA of a drug product should be described in the CLINICAL PHARMACOLOGY section of the labeling. In addition, the DOSAGE AND ADMINISTRATION section of the labeling should provide instructions for drug administration in relation to food based on clinical relevance (i.e., whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food).”
It would have been obvious to one of ordinary skill in the art at the time of filing to test a human subject under fasted or fed conditions. The motivation to test a human subject under fasted or fed conditions is because CDER teaches to test and reference products in food-effect BA and fed BE studies: • Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t) • Peak exposure (Cmax) • Time to peak exposure (Tmax) • Lag-time (tlag) for modified-release products, if present • Terminal elimination half-life in order to see whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food. Hence, a skilled artisan would have had reasonable expectation of successfully achieving similar results.
Furthermore, Applicant claims compound A administered under fed conditions. The Examiner points out a drug is administered to a human subject under fasted or fed conditions. The subject cannot be under any other state, in terms of feeding conditions.
Claims 117, 119-123, 126-136, 139-144 and 145-151 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. 12178811. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to a method of treating a depressive disorder in a human in need thereof, comprising administering a therapeutically effective amount of Compound A to the human; wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2.6- dimethylphenyl]-3,3-dimethylbutanamide; wherein Compound A is orally administered to the human under fed conditions while the claims herein are drawn to in a method of orally administering Compound A to a human in need thereof, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro- 1 H-isoquinolin-2-yl)-2,6- dimethylphenyl]-3,3-dimethylbutanamide; the improvement comprising orally administering an amount of Compound A to the human under fed conditions.
Furthermore, Applicant claims compound A administered under fed conditions. The Examiner points out a drug is administered to a human subject under fasted or fed conditions. The subject cannot be under any other state, in terms of feeding conditions.
Claims 117, 119-123, 126-136, 139-144 and 145-151 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 8-21, 24, 35 of U.S. Applic. No. 18921788 – claims filed on 2/28/25; IDS filed 1/23/25. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to a method of enhancing the opening of a Kv7 potassium channel in a human, comprising administering an effective amount of Compound A to the human; wherein Compound A is N-[4-(6-fluoro-3,4-dihydro- 1 H-isoquinolin-2-yl)-2,6- dimethylpheny1]-3,3-dimethylbutanamide; and wherein the human is suffering from anhedonia while the claims herein are drawn to in a method of orally administering Compound A to a human in need thereof, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro- 1 H-isoquinolin-2-yl)-2,6- dimethylphenyl]-3,3-dimethylbutanamide; the improvement comprising orally administering an amount of Compound A to the human under fed conditions.
While the claims do not specify treatment under fed conditions.
CDER teaches food-effect bioavailability (BA) “studies may be exploratory and descriptive, or a sponsor may want to use a food effect BA study to make a label claim. The following exposure measures and pharmacokinetic parameters should be obtained from the resulting concentration-time curves for the test and reference products in food-effect BA and fed BE studies: • Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t) • Peak exposure (Cmax) • Time to peak exposure (Tmax) • Lag-time (tlag) for modified-release products, if present • Terminal elimination half-life • Other relevant pharmacokinetic parameters. Individual subject measurements, as well as summary statistics (e.g., group averages, standard deviations, coefficients of variation) should be reported. An equivalence approach is recommended for food-effect BA (to make a claim of no food effects) and fed BE studies, analyzing data using an average criterion. Log-transformation of exposure measurements (AUC and Cmax ) prior to analysis is recommended. The 90 percent CI for the ratio of population geometric means between test and reference products should be provided for AUC0-inf, AUC0-t, and Cmax.” “For IND or NDA food-effect BA studies, the fasted treatment serves as the reference. For ANDA fed BE studies, the RLD administered under fed condition serves as the reference treatment. The effect of food on the absorption and BA of a drug product should be described in the CLINICAL PHARMACOLOGY section of the labeling. In addition, the DOSAGE AND ADMINISTRATION section of the labeling should provide instructions for drug administration in relation to food based on clinical relevance (i.e., whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food).”
It would have been obvious to one of ordinary skill in the art at the time of filing to test a human subject under fasted or fed conditions. The motivation to test a human subject under fasted or fed conditions is because CDER teaches to test and reference products in food-effect BA and fed BE studies: • Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t) • Peak exposure (Cmax) • Time to peak exposure (Tmax) • Lag-time (tlag) for modified-release products, if present • Terminal elimination half-life in order to see whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food. Hence, a skilled artisan would have had reasonable expectation of successfully achieving similar results.
Furthermore, Applicant claims compound A administered under fed conditions. The Examiner points out a drug is administered to a human subject under fasted or fed conditions. The subject cannot be under any other state, in terms of feeding conditions.
Claims 117, 119-123, 126-136, 139-144 and 145-151 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Applic. No. 18958937– claims filed on 11/25/24; IDS filed 1/23/25. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to a method of treating one or more somatic symptoms of a depressive disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of azetukalneror a pharmaceutically acceptable salt thereofwhile the claims herein are drawn to in a method of orally administering Compound A to a human in need thereof, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro- 1 H-isoquinolin-2-yl)-2,6- dimethylphenyl]-3,3-dimethylbutanamide; the improvement comprising orally administering an amount of Compound A to the human under fed conditions.
While the claims do not specify treatment under fed conditions.
CDER teaches food-effect bioavailability (BA) “studies may be exploratory and descriptive, or a sponsor may want to use a food effect BA study to make a label claim. The following exposure measures and pharmacokinetic parameters should be obtained from the resulting concentration-time curves for the test and reference products in food-effect BA and fed BE studies: • Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t) • Peak exposure (Cmax) • Time to peak exposure (Tmax) • Lag-time (tlag) for modified-release products, if present • Terminal elimination half-life • Other relevant pharmacokinetic parameters. Individual subject measurements, as well as summary statistics (e.g., group averages, standard deviations, coefficients of variation) should be reported. An equivalence approach is recommended for food-effect BA (to make a claim of no food effects) and fed BE studies, analyzing data using an average criterion. Log-transformation of exposure measurements (AUC and Cmax ) prior to analysis is recommended. The 90 percent CI for the ratio of population geometric means between test and reference products should be provided for AUC0-inf, AUC0-t, and Cmax.” “For IND or NDA food-effect BA studies, the fasted treatment serves as the reference. For ANDA fed BE studies, the RLD administered under fed condition serves as the reference treatment. The effect of food on the absorption and BA of a drug product should be described in the CLINICAL PHARMACOLOGY section of the labeling. In addition, the DOSAGE AND ADMINISTRATION section of the labeling should provide instructions for drug administration in relation to food based on clinical relevance (i.e., whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food).”
It would have been obvious to one of ordinary skill in the art at the time of filing to test a human subject under fasted or fed conditions. The motivation to test a human subject under fasted or fed conditions is because CDER teaches to test and reference products in food-effect BA and fed BE studies: • Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t) • Peak exposure (Cmax) • Time to peak exposure (Tmax) • Lag-time (tlag) for modified-release products, if present • Terminal elimination half-life in order to see whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food. Hence, a skilled artisan would have had reasonable expectation of successfully achieving similar results.
Furthermore, Applicant claims compound A administered under fed conditions. The Examiner points out a drug is administered to a human subject under fasted or fed conditions. The subject cannot be under any other state, in terms of feeding conditions.
Claims 117, 119-123, 126-136, 139-144 and 145-151 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 117-136 of U.S. Applic. No. 19008882– claims filed on 1/3/25; IDS filed 1/23/25. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to a method of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a human in need thereof, comprising orally administering a therapeutically effective amount of Compound A to the human under fed conditions; wherein Compound A is V N-[4-(6-fluoro-3,4-dihydro- 1 H-isoquinolin-2-yl)-2,6- dimethylphenyl]-3,3-dimethylbutanamide while the claims herein are drawn to in a method of orally administering Compound A to a human in need thereof, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro- 1 H-isoquinolin-2-yl)-2,6- dimethylphenyl]-3,3-dimethylbutanamide; the improvement comprising orally administering an amount of Compound A to the human under fed conditions.
While the claims do not specify treatment under fed conditions.
CDER teaches food-effect bioavailability (BA) “studies may be exploratory and descriptive, or a sponsor may want to use a food effect BA study to make a label claim. The following exposure measures and pharmacokinetic parameters should be obtained from the resulting concentration-time curves for the test and reference products in food-effect BA and fed BE studies: • Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t) • Peak exposure (Cmax) • Time to peak exposure (Tmax) • Lag-time (tlag) for modified-release products, if present • Terminal elimination half-life • Other relevant pharmacokinetic parameters. Individual subject measurements, as well as summary statistics (e.g., group averages, standard deviations, coefficients of variation) should be reported. An equivalence approach is recommended for food-effect BA (to make a claim of no food effects) and fed BE studies, analyzing data using an average criterion. Log-transformation of exposure measurements (AUC and Cmax ) prior to analysis is recommended. The 90 percent CI for the ratio of population geometric means between test and reference products should be provided for AUC0-inf, AUC0-t, and Cmax.” “For IND or NDA food-effect BA studies, the fasted treatment serves as the reference. For ANDA fed BE studies, the RLD administered under fed condition serves as the reference treatment. The effect of food on the absorption and BA of a drug product should be described in the CLINICAL PHARMACOLOGY section of the labeling. In addition, the DOSAGE AND ADMINISTRATION section of the labeling should provide instructions for drug administration in relation to food based on clinical relevance (i.e., whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food).”
It would have been obvious to one of ordinary skill in the art at the time of filing to test a human subject under fasted or fed conditions. The motivation to test a human subject under fasted or fed conditions is because CDER teaches to test and reference products in food-effect BA and fed BE studies: • Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t) • Peak exposure (Cmax) • Time to peak exposure (Tmax) • Lag-time (tlag) for modified-release products, if present • Terminal elimination half-life in order to see whether or not the changes in systemic exposure caused by co-administration with food results in safety or efficacy concerns, or when there is no important change in systemic exposure but there is a possibility that the drug substance causes GI irritation when taken without food. Hence, a skilled artisan would have had reasonable expectation of successfully achieving similar results.
Furthermore, Applicant claims compound A administered under fed conditions. The Examiner points out a drug is administered to a human subject under fasted or fed conditions. The subject cannot be under any other state, in terms of feeding conditions.
Claims 117, 119-123, 126-136, 139-144 and 145-151 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 19-34 of U.S. PAT. No. 11957675. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to a Method of treating anhedonia, comprising administering a therapeutically effective amount of Compound A to a human in need thereof; wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, wherein Compound A is orally administered to the human from between about 30 minutes before to about 2 hours after eating a meal and Compound A is administered at a dose of 5-150 mg per day to the human , while the claims herein are drawn to in a method of orally administering Compound A to a human in need thereof, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro- 1 H-isoquinolin-2-yl)-2,6- dimethylphenyl]-3,3-dimethylbutanamide; the improvement comprising orally administering an amount of Compound A to the human under fed conditions.
Furthermore, Applicant claims compound A administered under fed conditions. The Examiner points out a drug is administered to a human subject under fasted or fed conditions. The subject cannot be under any other state, in terms of feeding conditions.
Claims 117, 119-123, 126-136, 139-144 and 145-151 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 11135214. Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patented claims are drawn to a method of orally administering Compound A to a human in need thereof, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H- isoquinolin-2-yl)-2,6-dimethylphenyl]-3 ,3-dimethyloutanamide; wherein the improvement comprises orally administering an amount of Compound A to the human from between 30 minutes prior to consuming food until 2 hours after consuming food while the claims herein are drawn to method of increasing one or more of the Cmax, AUCinf, Tmax, or t1/2 of Compound A in a human receiving an oral administration of Compound A, comprising orally administering an amount of Compound A to the human under fed conditions; wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6- dimethylpheny|]-3,3-dimethyloutanamide; and wherein the method increases the one or more of Cmax, AUCinf, Tmax, or t1/2 as compared to when the same amount of Compound A is orally administered to the human under fasted conditions. The difference being the specific hours of the fed state. The specification herein describes “under fed conditions’ refers to the condition of having consumed food during the time period between from about 4 hours prior to the oral administration of an effective amount (e.g., within the therapeutically effective dose range) of Compound A to about 4 hours after the administration of Compound A while the prior art claims between 30 minutes prior to consuming food until 2 hours after consuming food. The claims are rendered obvious.
Claims 117, 119-123, 126-136, 139-144 and 145-151 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-22 of U.S. Patent No. 11091441B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patented claims are drawn to method of preparing the pharmaceutical composition of claim 7, the method comprising combining the crystalline form of Compound A with the pharmaceutical excipient, carrier, and/or diluent to form the pharmaceutical composition wherein the crystalline form is administered to the human from between 30 minutes before to 2 hours after eating a meal while the claims herein are drawn to method of increasing one or more of the Cmax, AUCinf, Tmax, or t’2 Az of Compound A in a human receiving an oral administration of Compound A, comprising orally administering an amount of Compound A to the human under fed conditions; wherein Compound A is N-[4-(6-fluoro-3,4-dihydro- 1 H-isoquinolin-2-yl)-2,6- dimethylpheny|]-3,3-dimethyloutanamide; and wherein the method increases the one or more of Cmax, AUCinf, Tmax, or t/2 as compared to when the same amount of Compound A is orally administered to the human under fasted conditions. The difference being the specific hours of the fed state. The specification herein describes “under fed conditions’ refers to the condition of having consumed food during the time period between from about 4 hours prior to the oral administration of an effective amount (e.g., within the therapeutically effective dose range) of Compound A to about 4 hours after the administration of Compound A while the prior art between 30 minutes before to 2 hours after eating a meal. The claims are rendered obvious.
Conclusion
No claims are allowed.
Correspondence
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/LAYLA SOROUSH/