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 .
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11 and 25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
In relation to claim 11, this claim recites: “[t]he method of claim 1, wherein the IV dosage of dofetilide is administered: in a first higher amount for the subject who is renally impaired; and in a
second lower amount for the subject who is non-renally impaired.
Claim 11 is rejected under 35 U.S.C. § 112(b) as being indefinite. The claim language recites administering a “first higher amount” to a subject who is renally impaired and a “second lower amount” to a subject who is nonrenally impaired. This language is medically counterintuitive and directly contrary to standard pharmacological principles for dofetilide, which is renally excreted. The FDA-approved prescribing information for dofetilide (Tikosyn) explicitly mandates lower doses for renally impaired patients to prevent toxic drug accumulation and fatal arrhythmias. Specifically, the FDA label states under “Step 3. Starting Dose”:
For Calculated Creatinine Clearance >60 mL/min (non-renally impaired): “500 mcg twice daily”
For Calculated Creatinine Clearance 40 to 60 mL/min (mildly impaired): “250 mcg twice daily”
For Calculated Creatinine Clearance 20 to <40 mL/min (moderately impaired): “125 mcg twice daily”
For Calculated Creatinine Clearance <20 mL/min (severely impaired): “Dofetilide is contraindicated”
Because the claim language explicitly contradicts established medical facts and the FDA-mandated dosing protocol regarding the drug’s administration, it is unclear whether the applicant intended to claim a novel (albeit dangerous) dosing regimen contrary to standard practice, or if this is a drafting error where “higher” and “lower” were inadvertently swapped. This ambiguity renders the scope of the claim indefinite.
In relation to claim 25, this claim recites the method of claim 16, wherein the IV dosage of dofetilide is administered: in a first higher amount for the subject with a CrCl of 20mL/min to <40mL/min; and in a second lower amount for the subject with a CrCl of 40mL/min or greater.
Claim 25 is rejected under 35 U.S.C. § 112(b) as being indefinite for the same reasons set forth regarding Claim 11. The claim explicitly recites administering a “higher amount” to subjects with severe renal impairment (CrCl 20 to <40 mL/min) and a “lower amount” to subjects with better renal function
(CrCl 40 mL/min or greater). This is directly contrary to the FDA-approved prescribing information for dofetilide (Tikosyn), which mandates the exact opposite dosing relationship for these specific creatinine clearance ranges. The FDA label explicitly states under “Step 3. Starting Dose”:
For Calculated Creatinine Clearance 40 to 60 mL/min: “250 mcg twice daily”
For Calculated Creatinine Clearance 20 to <40 mL/min: “125 mcg twice daily”
The FDA label requires a lower dose (125 mcg) for the 20-<40 mL/min range and a higher dose (250 mcg or 500 mcg) for the ≥40 mL/min range. Because the claim language contradicts established medical facts and the FDA-mandated dosing protocol regarding the drug’s safe administration, it is unclear whether the applicant intended to claim a novel dosing regimen contrary to standard practice, or if this is a drafting error where the amounts were inadvertently swapped. This ambiguity renders
the scope of the claim indefinite.
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.
Claims 1, 2, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 19, 21, 23, 24, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over the publication Falk et al. (“Intravenous Dofetilide, a Class III Antiarrhythmic Agent, for the Termination of Sustained Atrial Fibrillation or Flutter”; hereinafter “Falk”) in view of Ivaturi et al. (US 10,799,138B2; hereinafter “Ivaturi”) and the publication FDA Tikosyn Label.
Independent claim 1 recites a method of administering dofetilide comprising:
administering to a subject an intravenous (IV) dosage of dofetilide, wherein the subject is in a facility capable of providing cardiac resuscitation and continuous electrocardiographic monitoring, and wherein the IV dosage is administered:
(a) in an amount of about 62.5-187.5 μg;
(b) in an amount of about 125-375 μg; or
(c) in an amount of about 250-750 μg; and after completion of the administering of the IV dosage, administering a maintenance dose of dofetilide;
optionally administering a subsequent maintenance dose of dofetilide at least once at a selected interval, optionally after the subject is discharged from the facility capable of providing cardiac resuscitation and continuous electrocardiographic monitoring.
In relation to independent claim 1, Falk discloses:
administering to a subject an intravenous (IV) dosage of dofetilide:
“patients received an infusion of randomly assigned therapy consisting of either 4.0 or 8.0 μg/kg body weight of dofetilide” (Falk, Protocol, p. 386).
Falk discloses the subject is in a facility capable of providing cardiac resuscitation and continuous electrocardiographic monitoring: “After a 30-min period of continuous ECG monitoring … subjects were continuously monitored for an additional 6 h” (Falk, Protocol, p. 386).
Falk discloses the IV dosage in an amount of about 250-750 μg:
for a typical 70 kg patient, 4.0 μg/kg = 280 μg and 8.0 μg/kg = 560 μg, both falling within the claimed range of about 250-750 μg.
Falk further discloses that the IV dosage is administered in an amount of about 125-375 μg: for a typical 35-93 kg patient, 4.0 μg/kg = 140-372 μg, falling within the claimed range.
Falk does not disclose the steps of: (a) administering a maintenance dose of dofetilide after completion of the administering of the IV dosage and (b) optionally administering a subsequent maintenance dose of dofetilide at least once at a selected interval, optionally after the subject is discharged from the facility. However, Ivaturi discloses a method of administering a class III antiarrhythmic drug (sotalol) comprising: after completion of the IV dosage, administering a maintenance dose orally:
“discontinuing intravenous administration to the subject and administering at least one further dose orally” (Ivaturi, claim 1);
“a maintenance dose of at least 80 mg sotalol is orally administered 12 hours from initiation of the intravenous infusion, and every 12 hours thereafter” (Ivaturi, claim 5).
Ivaturi further discloses that this IV-to-oral switch method is designed to reduce the required 3-day hospital stay and allow earlier discharge:
“The dosing regimen… provides a titration of the drug in order to safely increase the dose of the drug to reach a target maintenance dose in a shorter period of time than the existing standard of care which includes a 3-day hospital stay” (Ivaturi, col. 11, lines 43-48).
Ivaturi explicitly identifies dofetilide as an antiarrhythmic drug to which the method is applicable:
“The term ‘antiarrhythmic drug’ as used herein, includes, sotalol, dofetilide, flecainide, propafenone, amiodarone, dronedarone, or ibutilide” (Ivaturi, col. 7, lines 51-53).
Moreover, the FDA Tikosyn Label discloses the standard of care for dofetilide, which requires continuous ECG monitoring in a facility capable of cardiac resuscitation for a minimum of 3 days during initiation (FDA Label, p. 18, Step 7), and establishes the standard oral maintenance doses of 125, 250, or 500 μg twice daily (FDA Label, p. 17, Step 3).
Based on the above comments, it would have been obvious to a person of ordinary skill in
the art at the time of filing to combine the IV dofetilide administration of Falk with the IV-to-oral maintenance dosing and early discharge protocol of Ivaturi, and the standard maintenance doses of the FDA Tikosyn Label. Both dofetilide and sotalol are class III antiarrhythmic drugs with similar mechanisms of action (Ikr blockade), similar risks of QTc prolongation, and similar FDA-mandated 3-day in-hospital
initiation requirements. Ivaturi explicitly identifies dofetilide as an antiarrhythmic drug to which the IV/switch method is applicable. Therefore, a person of ordinary skill would have been motivated to apply the accelerated IV-to-oral switch protocol developed for sotalol in Ivaturi to dofetilide (as taught by Falk and the FDA Label) in order to achieve steady state concentrations more rapidly and reduce the costly and burdensome 3-day hospital stay required for dofetilide initiation, while maintaining patient safety through QTc monitoring. The reasonable expectation of success is supported by the pharmacokinetic similarities between sotalol and dofetilide as class III antiarrhythmics.
Independent claim 16 recites a method of administering dofetilide, comprising:
(A) before administering an IV dosage of dofetilide to a subject, determining a creatinine
clearance (CrCl) of the subject, and selecting an amount of dofetilide to administer to the subject based on the creatinine clearance;
(B) administering to the subject the IV dosage of dofetilide comprising the selected amount of dofetilide based on the creatinine clearance and comprising an amount of dofetilide in the range of 0.1-12 μg/kg; and
(C) after the administering of the IV dosage, administering a first maintenance dose of dofetilide to the subject;
(D) optionally administering one or more subsequent maintenance doses of dofetilide at selected interval from the first maintenance dose.
In relation to independent claim 16, Falk discloses administering an IV dosage of dofetilide in an amount of 4.0 or 8.0 μg/kg:
“patients received an infusion of randomly assigned therapy consisting of either 4.0 or 8.0 μg/kg body weight of dofetilide” (Falk, Protocol, p. 386), which falls squarely within the claimed range of 0.1-12 μg/kg.
Falk does not explicitly disclose the steps of: (1) determining CrCl before IV administration, (2) selecting the IV dose based on CrCl, or (3) administering subsequent maintenance doses. However, the FDA Tikosyn Label explicitly discloses:
“Step 2. Calculation of creatinine clearance: Prior to the administration of the first dose, the patient’s creatinine clearance must be calculated using the following formula: creatinine clearance (male) = (140-age) × actual body weight in kg / 72 × serum creatinine (mg/dL) … Step 3. Starting Dose: The starting dose of TIKOSYN is determined as follows: [CrCl-based dosing table]” (FDA Label, p. 17).
Moreover, Ivaturi discloses a method of administering a class III antiarrhythmic drug comprising: administering an IV loading dose followed by administering a maintenance dose orally (Ivaturi, claim 1), and administering subsequent maintenance doses at selected intervals (Ivaturi, claim 5). Ivaturi also discloses adjusting the IV and oral doses based on renal function (Ivaturi, claims 2, 4, 5, 6). Ivaturi explicitly identifies dofetilide as an antiarrhythmic drug to which the method is applicable (Ivaturi, col. 11, lines 51-54).
Based on the above comments, it would have been obvious to a person of ordinary skill in the art to combine the IV dofetilide administration of Falk with the mandatory pre-dose creatinine clearance calculation and dose selection of the FDA Tikosyn Label, and the IV-to-oral maintenance dosing protocol of Ivaturi. Because dofetilide is renally excreted and has a narrow therapeutic index, calculating CrCl before the first dose is an absolute safety requirement established by the FDA. Furthermore, applying the IV to oral switch protocol of Ivaturi would be obvious to rapidly achieve steady-state concentrations and reduce the required 3-day hospital stay.
In relation to claim 2, Falk discloses administering the IV dosage in a monitored facility (Falk, p. 386). Falk does not disclose the specific discharge timing relative to maintenance doses. Ivaturi discloses administering the initial IV dose and first maintenance dose in the hospital, followed by discharge and subsequent maintenance doses at home, to reduce the standard 3-day hospital stay:
“The dosing regimen… provides a titration of the drug in order to safely increase the dose of the drug to reach a target maintenance dose in a shorter period of time than the existing standard of care which includes a 3-day hospital stay” (Ivaturi, col. 4, lines 43-47).
The FDA Tikosyn Label discloses the requirement for a facility capable of providing cardiac resuscitation and continuous ECG monitoring (FDA Label, Step 7). Accordingly, it would have been obvious to apply the early discharge protocol of Ivaturi to the dofetilide administration of Falk and the FDA Label. The motivation would be to safely initiate dofetilide therapy while reducing the standard 3-day hospitalization requirement, by monitoring the patient during the IV loading dose and first maintenance dose to ensure QTc stability, and then discharging the patient for subsequent maintenance doses once steady-state is rapidly achieved, as explicitly taught by Ivaturi for the analogous drug sotalol.
In relation to claim 6, as discussed above, Falk discloses IV dofetilide dosages of 4.0 or 8.0 μg/kg (approx. 280 μg or 560 μg for a 70 kg patient). The FDA Tikosyn Label discloses standard oral maintenance doses of 125, 250, or 500 μg. If a patient receives the 4.0 μg/kg (280 μg) IV dose of Falk and a 500 μg maintenance dose from the FDA Label, the IV dosage is 56% of the maintenance dose, which falls squarely within the claimed range of 50% to 110%. Accordingly, it would have been obvious to combine the IV dosages of Falk with the standard maintenance doses of the FDA Label. The resulting mathematical relationship between the doses (50% to 110%) is an inherent result of combining these
known, safe, and effective doses for dofetilide.
In relation to claim 7, Falk discloses the IV dosage. The FDA Tikosyn Label explicitly discloses oral
maintenance doses of dofetilide in amounts of 125 μg, 250 μg, or 500 μg: “500 mcg twice daily… 250 mcg twice daily… 125 mcg twice daily” (FDA Label, Step 3). Accordingly, it would have been obvious to use the specific oral maintenance doses of 125, 250, or 500 μg following the IV administration of Falk, as these are the exact FDA-approved, standard-of-care maintenance doses for dofetilide. A person of ordinary skill would naturally select these proven doses for maintenance therapy.
In relation to claim 10, Falk discloses measuring baseline QTc and monitoring QTc during and after IV dofetilide infusion (Falk, p. 387, Table 2). The FDA Tikosyn Label explicitly discloses the exact claimed QTc monitoring and dose adjustment protocol for dofetilide: “Step 1. … the QTc or QT must be checked [before first dose] … Step 5. At 2-3 hours after administering the first dose of dofetilide, determine the QTc or QT… If the QTc or QT has increased by greater than 15% compared to the baseline… OR if the QTc or QT is greater than 500 msec… subsequent dosing should be adjusted… NOTE: If at any time after the second dose of dofetilide is given the QTc or QT is greater than 500 msec… Tikosyn should be discontinued” (FDA Label, steps 1, 5, and 6). Ivaturi discloses applying strict QTc monitoring protocols during IV-to-oral switch of antiarrhythmic drugs, including discontinuing IV administration if delta QTc is unacceptable (Ivaturi, claim 1).
Based on the above comments, it would have been obvious to apply the exact FDA mandated
QTc monitoring and discontinuation protocol (FDA Label) to the IV dofetilide administration of Falk. Because dofetilide is known to cause dose-dependent QTc prolongation and torsade de pointes, a person of ordinary skill would strictly adhere to the FDA-approved safety parameters (discontinuation if QTc > 500 msec or increases > 15%) regardless of whether the drug is administered orally or intravenously.
In relation to claim 11, Falk discloses IV dofetilide dosages but does not disclose adjusting the IV dosage based on renal impairment. The FDA Tikosyn Label explicitly discloses adjusting dofetilide doses based on renal impairment (creatinine clearance) (FDA Label, Step 3). Ivaturi discloses adjusting IV antiarrhythmic drug dosages based on whether the subject has normal or abnormal renal function (Ivaturi, claims 2, 4, 5, 6). Importantly, the claim as written recites a “higher amount for the subject who is renally impaired” and a “lower amount for the subject who is non-renally impaired,” which is medically counterintuitive and contrary to the FDA label. The FDA label mandates lower doses for renally impaired patients to prevent toxic drug accumulation. However, regardless of this apparent error, adjusting doses based on renal function is a standard practice taught by the prior art.
Based on the above comments, it would have been obvious to adjust the IV dosage of
dofetilide based on the subject’s renal function, as explicitly taught by the FDA Tikosyn Label and Ivaturi. Because dofetilide is primarily eliminated by the kidneys, adjusting the dose based on renal impairment is a fundamental requirement for safe administration of this drug, regardless of the route of administration.
In relation to claim 12, Falk discloses IV dofetilide dosages of 4.0 or 8.0 μg/kg. The FDA Tikosyn Label discloses standard oral maintenance doses of 125 μg (FDA Label, p. 2). For a typical 70 kg patient, a 125 μg dose equals approximately 1.78 μg/kg, which is below the claimed 1.8 μg/kg threshold. For a 100 kg patient, a 125 μg dose equals 1.25 μg/kg. Therefore, it would have been obvious to administer a maintenance dose below 1.8 μg/kg, as the FDA-approved 125 μg dose inherently falls below this threshold for most adult patients. The selection of this specific dose is dictated by the patient’s creatinine clearance as required by the FDA Label.
In relation to claim 13, Falk explicitly discloses administering IV dofetilide in amounts of 4.0 μg/kg and 8.0 μg/kg: “patients received an infusion of randomly assigned therapy consisting of
either 4.0 or 8.0 μg/kg body weight of dofetilide” (Falk, p. 386). Both of these doses are explicitly above the claimed 3 μg/kg threshold. Accordingly, in view of the conventionality of this enhancement, it implementation in the invention of this application would have been considered an obvious alternative in the design of the methodology.
In relation to claim 14, Falk discloses IV dofetilide dosages. The FDA Tikosyn Label explicitly discloses standard oral maintenance doses of 125 μg, 250 μg, and 500 μg (FDA Label, p. 17, Step 3). The
125 μg dose falls squarely within the claimed range of 90-150 μg. The 250 μg dose falls squarely within the claimed range of 190-300 μg. The 500 μg dose falls squarely within the claimed range of 425-550 μg.
Accordingly, it would have been obvious to administer maintenance doses in the claimed ranges, as the exact FDA-approved standard-of-care doses (125, 250, 500 μg) fall squarely within these ranges.
In relation to claim 15, Falk discloses IV dofetilide dosages. The FDA Tikosyn Label explicitly discloses determining the dose of dofetilide based on the creatinine clearance of the subject, providing a specific table mapping CrCl ranges (>60, 40-60, 20-<40, <20 mL/min) to specific dofetilide doses (500, 250, 125 mcg): "Step 2. Calculation of creatinine clearance: Prior to the administration of the first dose, the patient's creatinine clearance must be calculated... Step 3. Starting Dose: The starting dose of TIKOSYN is determined as follows: [CrCl >60 mL/min → 500 mcg twice daily; CrCl 40 to 60 mL/min
→ 250 mcg twice daily; CrCl 20 to <40 mL/min → 125 mcg twice daily]” (FDA Tikosyn Label). Ivaturi discloses adjusting IV antiarrhythmic drug dosages based on whether the subject has normal or abnormal renal function (Ivaturi, claims 2, 4, 5, 6).
Based on the above comments, it would have been obvious to base the IV dosage of dofetilide on the subject’s creatinine clearance, using the exact ranges established by the FDA Tikosyn Label. Because dofetilide is primarily eliminated by the kidneys, adjusting the dose based on creatinine clearance is a fundamental, FDA-mandated requirement for safe administration of this drug to prevent toxic accumulation and fatal arrhythmias.
In relation to claim 17, Falk discloses administering the IV dosage in a monitored facility (Falk, p. 386). The FDA Tikosyn Label discloses the requirement for a facility capable of providing cardiac resuscitation and continuous ECG monitoring (FDA Tikosyn Label, Step 7). Ivaturi discloses administering the initial IV dose and first maintenance dose in the hospital, followed by discharge and subsequent maintenance doses at home, to reduce the standard 3-day hospital stay (Ivaturi, col. 4, lines 43-47).
Based on the above comments, it would have been obvious to apply the early discharge
protocol of Ivaturi to the dofetilide administration of Falk and the FDA Label. The motivation would be to safely initiate dofetilide therapy while reducing the standard 3-day hospitalization requirement, by monitoring the patient during the IV loading dose and first maintenance dose to ensure QTc stability, and then discharging the patient for subsequent maintenance doses once steady-state is rapidly achieved.
In relation to claim 19, Falk discloses an IV dosage of 4.0 μg/kg (approx. 280 μg for a 70 kg patient). The FDA Tikosyn Label discloses oral maintenance doses of 500 μg (FDA Label). For a
patient receiving the 4.0 μg/kg (280 μg) IV dose of Falk, a standard maintenance dose of 500 μg would be a higher dose than the IV dosage. Accordingly, it would have been obvious to administer a maintenance dose that is higher than the IV dosage, as this is an inherent mathematical result of
combining the known, safe 4.0 μg/kg IV dose of Falk with the known, safe 500 μg oral maintenance dose of the FDA Label for a patient with normal renal function.
In relation to claim 21, Falk discloses IV dofetilide dosages of 4.0 or 8.0 μg/kg (approx. 280 μg or 560 μg for a 70 kg patient). The FDA Tikosyn Label discloses standard oral maintenance doses of 125, 250, or 500 μg. If a patient receives the 8.0 μg/kg (560 μg) IV dose of Falk and a 500 μg maintenance dose from the FDA Label, the IV dosage is 112% of the maintenance dose (which is within +50% of the maintenance dose, i.e., 150% of 500 μg = 750 μg). If a patient receives the 4.0 μg/kg (280 μg) IV dose and a 250 μg maintenance dose, the IV dosage is 112% of the maintenance dose, also within +50%.
Therefore, it would have been obvious to combine the IV dosages of Falk with the standard maintenance doses of the FDA Label. The resulting mathematical relationship between the doses (±50%) is an inherent result of combining these known, safe, and effective doses for dofetilide.
In relation to claim 23, Falk discloses administering an IV dosage of dofetilide. The FDA Tikosyn Label discloses that dofetilide normally takes 2-3 days to reach steady state with oral dosing (FDA Label, p. 2, Step 7). Ivaturi discloses a method of administering a class III antiarrhythmic drug comprising an IV loading dose followed by an oral maintenance dose, specifically designed to accelerate the achievement of steady-state maximum plasma concentration (Cmax,ss): “Methods are described for dosing the antiarrhythmic drug for accelerating achievement of steady-state maximum plasma concentration (Cmax,ss) of the therapeutic agent by intravenous administration or a combination of intravenous and oral administration” (Ivaturi, col. 3, lines 42-46). Ivaturi explicitly discloses that this method achieves Cmax,ss within 4 to 8 hours: “optimal dosing regimen(s) achieved Cmax,ss as early as 4 hours after initiation of treatment on Day 1” (Ivaturi, col. 9, lines 65-67). Therefore, it would have been obvious to apply the accelerated IV-to-oral switch protocol of Ivaturi to the dofetilide administration of Falk and the FDA Label. The motivation would have been to rapidly achieve steady-state concentrations (Cmax,ss) within 8 hours, thereby reducing the costly and burdensome 3-day hospital stay required for dofetilide initiation, while maintaining patient safety through QTc monitoring. The achievement of Cmax,ss within 8 hours is an inherent pharmacokinetic result of administering an appropriate IV loading dose followed by maintenance dosing, as taught by Ivaturi.
In relation to claim 24, Falk discloses administering an IV dosage of dofetilide. The FDA Tikosyn Label discloses the standard oral dosing protocols of 125 μg, 250 μg, or 500 μg dofetilide (FDA Label). Ivaturi discloses administering an IV loading dose of an antiarrhythmic drug in an amount and over a period of time designed to rapidly achieve concentrations approaching the steady-state Cmax (Cmax,ss) of the target oral maintenance dose: “optimal dosing regimen(s) achieved Cmax, ss as early as 4 hours
after initiation of treatment on Day 1” (Ivaturi, col. 9, lines 65-67), and FIGS. 9-11 showing IV loading concentrations rapidly approaching the final steady-state concentrations. Therefore, it would have been obvious to administer the IV dosage of Falk in an amount and over a period of time sufficient to reach at least 70% of the steady-state Cmax for the standard oral dosing protocols of the FDA Label. The entire
purpose of an IV loading dose, as taught by Ivaturi, is to rapidly achieve plasma concentrations near the target steady-state Cmax, thereby avoiding the 3-day delay associated with oral-only initiation. Achieving at least 70% of the target Cmax is an inherent and intended pharmacokinetic result of a properly calculated loading dose.
In relation to claim 25, Falk discloses IV dofetilide dosages but does not disclose adjusting the IV dosage based on specific creatinine clearance ranges. The FDA Tikosyn Label explicitly discloses adjusting dofetilide doses based on specific creatinine clearance ranges, including the exact ranges claimed: “40 to 60 mL/min → 250 mcg twice daily” and “20 to <40 mL/min → 125 mcg twice daily” (FDA Label, p. 2, Step 3). Ivaturi discloses adjusting IV antiarrhythmic drug dosages based on whether the subject has normal or abnormal renal function (Ivaturi, claims 2, 4, 5, 6). Importantly, as with Claim 11, the claim as written recites a “higher amount for the subject with a CrCl of 20 mL/min to <40 mL/min" and a "lower amount for the subject with a CrCl of 40 mL/min or greater," which is medically counterintuitive and contrary to the FDA label. The FDA label mandates *lower* doses for patients with CrCl 20-<40 mL/min (125 μg) and *higher* doses for patients with CrCl >40 mL/min (250-500 μg), because dofetilide is renally excreted and accumulates to toxic levels in renally impaired patients. However, regardless of this apparent error, adjusting doses based on these specific CrCl ranges is a standard practice taught by the prior art.
Based on the above comments, it would have been obvious to adjust the IV dosage of
dofetilide based on the subject’s specific creatinine clearance ranges (20-<40 mL/min and >40 mL/min), as explicitly taught by the FDA Tikosyn Label and Ivaturi. Because dofetilide is primarily eliminated by the kidneys, adjusting the dose based on these exact FDA-mandated CrCl ranges is a fundamental requirement for safe administration of this drug, regardless of the route of administration.
Claims 3, 4, 5, 8, 9, 18, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over the publication Falk et al. (“Intravenous Dofetilide, a Class III Antiarrhythmic Agent, for the Termination of Sustained Atrial Fibrillation or Flutter”; hereinafter “Falk”) in view of Ivaturi et al. (US 10,799,138B2; hereinafter “Ivaturi”), the publication FDA Tikosyn Label, as discussed above, and in further view of the publication Pool et al. (“Effects of Intravenous Dofetilide in Patients with Frequent Premature Ventricular Contractions: A Clinical Trial.”; hereinafter “Pool”).
In relation to claim 3, Falk discloses a single IV dosage of dofetilide over 15 minutes (Falk, p. 386). Falk does not disclose the 1-5 hour infusion time or the maintenance dose timing. Pool discloses administering IV dofetilide as a 15-min loading infusion followed by a 60-min maintenance infusion, for a total infusion time of 75 minutes (1.25 hours), which falls within the claimed 1-5 hour range:
“a 15-min loading infusion of 4 μg/kg followed by a 60-min maintenance infusion of 3.5 μg/kg, for a total dose of 7.5 μg/kg” (Pool, Summary, Methods, p. 415).
Ivaturi discloses administering an IV infusion of an antiarrhythmic drug over 0.5 to 2 hours (Ivaturi, claim 3), and administering the oral maintenance dose 0.5 to 2 hours after the start of the IV infusion (Ivaturi, claim 4). Based on the above comments, it would have been obvious to modify the 15-minute infusion of Falk to a longer 1–5-hour infusion as taught by Pool and Ivaturi. The motivation would have been to avoid rapid peak plasma concentrations that could cause excessive QTc prolongation, as longer infusions are known to be safer for class III antiarrhythmics. Furthermore, it would have been obvious to administer the maintenance dose after the IV dosage is complete to maintain therapeutic plasma levels, as taught by Ivaturi.
In relation to claim 4, Falk discloses the initial IV dosage. Pool discloses an intravenous maintenance dose of dofetilide: “a 60-min maintenance infusion of 3.5 μg/kg” (Pool, p. 415). Ivaturi discloses an oral maintenance dose of an antiarrhythmic drug following IV loading (Ivaturi, claim 1). The FDA Tikosyn Label discloses standard oral maintenance doses of dofetilide (125, 250, or 500 μg) (FDA Label). Accordingly, it would have been obvious to utilize either an IV maintenance dose (as taught by Pool) or an oral maintenance dose (as taught by Ivaturi and the FDA Label) following the initial IV loading dose of Falk. The choice between IV and oral maintenance dosing is a simple design choice based on patient status (e.g., ability to swallow) and clinical setting, with both routes being well-known in the art for antiarrhythmic therapy.
In relation to claim 5, Falk discloses an IV dosage of 8.0 μg/kg (approx. 560 μg for a 70 kg patient). Pool discloses an IV loading dosage of 4.0 μg/kg followed by a maintenance dose of 3.5 μg/kg, where the maintenance dose is less than the IV loading dosage: “a 15-min loading infusion of 4 μg/kg followed by a 60-min maintenance infusion of 3.5 μg/kg” (Pool, p. 415). The FDA Tikosyn Label discloses oral maintenance doses of 125, 250, or 500 μg (FDA Label), all of which are less than the 560 μg IV dose of Falk. Therefore, it would have been obvious to administer a maintenance dose that is less than the IV loading dosage. The purpose of a loading dose is to rapidly achieve therapeutic steady-state concentrations, which inherently requires a larger initial dose, while the maintenance dose only needs to replace the drug eliminated during the dosing interval. This pharmacokinetic principle is standard in the art and explicitly demonstrated for dofetilide by Pool.
In relation to claim 8, Falk discloses the initial IV dosage. Pool discloses an intravenous maintenance dose of dofetilide of 3.5 μg/kg: “a 60-min maintenance infusion of 3.5 μg/kg” (Pool, p. 415). For a typical adult patient weighing 50-100 kg, this results in an absolute dose of 175 μg to
350 μg, which falls squarely within the claimed range of 62.5 μg-750 μg. Therefore, it would have been obvious to use the IV maintenance dose taught by Pool following an initial IV loading dose. Pool demonstrates that this specific IV maintenance dosing regimen is safe and effective for suppressing arrhythmias.
In relation to claim 9, Falk explicitly discloses administering IV dofetilide to subjects having atrial fibrillation and atrial flutter: “Intravenous Dofetilide… for the Termination of Sustained Atrial Fibrillation or Flutter” (Falk, Title). Pool explicitly discloses administering IV dofetilide to subjects having premature ventricular contractions (PVCs): “Effects of Intravenous Dofetilide in Patients with Frequent Premature Ventricular Contractions” (Pool, Title). Therefore, the claim recites a Markush group of conditions. Falk and Pool explicitly disclose treating at least three of the claimed conditions (atrial fibrillation, atrial flutter, and PVCs) with IV dofetilide. No further motivation is required as the primary references explicitly disclose the claimed conditions.
In relation to claim 18, Falk discloses the initial IV dosage. Pool discloses an intravenous maintenance dose of dofetilide: “a 60-min maintenance infusion of 3.5 μg/kg” (Pool, p. 415). Ivaturi
discloses an oral maintenance dose of an antiarrhythmic drug following IV loading (Ivaturi, claim 1).
Therefore, it would have been obvious to utilize either an IV maintenance dose (as taught by Pool) or an oral maintenance dose (as taught by Ivaturi) following the initial IV loading dose of Falk. The choice between IV and oral maintenance dosing is a simple design choice based on patient status and clinical
setting.
In relation to claim 20, Falk discloses an IV dosage of 8.0 μg/kg (approx. 560 μg for a 70 kg patient). Pool discloses an IV loading dosage of 4.0 μg/kg followed by a maintenance dose of 3.5
μg/kg, where the maintenance dose is lower than the IV loading dosage (Pool, p. 415). The FDA Tikosyn Label discloses oral maintenance doses of 125, 250, or 500 μg (FDA Label), all of which are less than the 560 μg IV dose of Falk. Therefore, it would have been obvious to administer a maintenance dose that is lower than the IV loading dosage. The purpose of a loading dose is to rapidly achieve therapeutic steady-state concentrations, which inherently requires a larger initial dose, while the maintenance dose only needs to replace the drug eliminated during the dosing interval. This pharmacokinetic principle is standard in the art and explicitly demonstrated for dofetilide by Pool.
In relation to claim 22, Falk discloses a single IV dosage of dofetilide over 15 minutes (Falk, p. 386). Pool discloses administering IV dofetilide as a 15-min loading infusion followed by a 60-min maintenance infusion (Pool, p. 415). Ivaturi discloses administering an IV infusion of an antiarrhythmic drug over 0.5 to 2 hours (Ivaturi, claim 3), and explicitly discloses a 1-hour (60-minute) IV infusion: “a 40 mg Sotalol IV infusion for one hour” (Ivaturi, col. 9, lines 32-33). Therefore, it would have been obvious to modify the 15-minute infusion of Falk to a 60-minute infusion as taught by Pool and Ivaturi. The motivation would have been to avoid rapid peak plasma concentrations that could cause excessive QTc
prolongation, as longer infusions (such as 60 minutes) are known to be safer for class III antiarrhythmics and are explicitly taught by Ivaturi for the analogous drug sotalol.
Conclusion
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Respectfully submitted,
/MANUEL A MENDEZ/ Primary Examiner, Art Unit 3783
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