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 § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Pool et al. (“Effects of intravenous dofetilide in patients with frequent premature ventricular contractions: A clinical trial”, hereinafter “Pool”).
In relation to claim 1, claim 1 recites: "A method of administering dofetilide, comprising: administering an IV dosage of dofetilide to a subject over a period of time in the range of about 1-5 hours." Pool discloses a method of administering dofetilide intravenously to human subjects (Summary: "Subjects received...an infusion of dofetilide"). Pool specifically teaches in the Methods section of the article, administering the IV dosage over a total period of 75 minutes (1.25 hours), which falls within the claimed range of "about 1-5 hours" (Methods: "a 15-min loading infusion of 4 µg/kg followed by a 60-min maintenance infusion of 3.5 µg/kg"). The total infusion time is 15 minutes + 60 minutes = 75 minutes = 1.25 hours. Pool thus anticipates all elements of claim 1:
"A method of administering dofetilide" - Pool, Summary and Methods
"administering an IV dosage of dofetilide" - Pool, Summary and Methods
"to a subject" - Pool, Methods (human subjects)
"over a period of time in the range of about 1-5 hours" - Pool, Methods (1.25 hours)
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 2-22 are rejected under 35 U.S.C. 103 as being unpatentable over Pool et al. (“Effects of intravenous dofetilide in patients with frequent premature ventricular contractions: A clinical trial”, hereinafter “Pool”) in view of TIKOSYN® (dofetilide) Capsules, U.S. Prescribing Information, Pfizer Inc.; hereinafter “TIKOSYN label”).
In relation to claim 2, Pool teaches all elements of claim 1 (as established in the § 102 rejection above). Pool further teaches administering an IV loading dose followed by an IV maintenance dose (Methods: "a 15-min loading infusion...followed by a 60-min maintenance infusion"). Pool does not explicitly teach (1) the specific dosing amount of "up to 1000 μg" as Pool uses body weight-based dosing in μg/kg, and (2) the option of administering an oral maintenance dose. However, the TIKOSYN Label teaches specific dofetilide doses of 125 mcg, 250 mcg, and 500 mcg (Description: "TIKOSYN is supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg)...250 mcg (0.25 mg)...and 500 mcg (0.5 mg)"). The TIKOSYN Label further teaches oral maintenance dosing administered every 12 hours for long-term therapy (Dosage and Administration: "500 mcg BID").
Based on the above comments, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify Pool's IV administration method to include the specific dosing amounts and oral maintenance dosing taught by the TIKOSYN Label. The motivation to combine arises from the fact that the TIKOSYN Label represents the FDA-approved prescribing information for
dofetilide and establishes the standard therapeutic doses. A person of ordinary skill developing an IV method would naturally reference the approved oral doses to establish bioequivalent IV doses. Furthermore, it is standard medical practice to transition patients from IV loading doses to oral maintenance therapy for convenience and long-term management. The combination would yield predictable results, as the pharmacological properties of dofetilide are well-characterized. The claim limitation "up to 1000 μg" is a reasonable design choice encompassing the standard 500 mcg dose and allowing for dose adjustments.
In relation to claim 3, claim 3 recites: "[t]he method of claim 2, wherein the one or more oral maintenance dose comprises an amount selected from the group consisting of: 125 μg, 250 μg, and 500 μg." As established for claim 2, Pool teaches IV administration and the TIKOSYN Label teaches oral maintenance dosing. The TIKOSYN Label explicitly teaches the three specific oral maintenance doses recited in claim 3 (Description: "TIKOSYN is supplied for oral administration in three dosage strengths: 125 mcg...250 mcg...and 500 mcg"). Accordingly, it would have been obvious to one of ordinary skill in the art to use the FDA-approved oral doses (125, 250, and 500 μg) when transitioning a patient from IV to oral therapy as taught by Pool and the TIKOSYN Label. These are the only commercially available oral
formulations and represent clinically validated therapeutic doses.
In relation to claim 4, Pool teaches IV administration with electrocardiographic monitoring.
In the Methods section the study describes "2-hour telemetric electrocardiogram" monitoring. Pool does not explicitly teach administration in a facility with cardiac resuscitation capability or that maintenance doses are administered before discharge. However, the TIKOSYN Label teaches that dofetilide therapy must be initiated in a monitored facility with cardiac resuscitation capability and a minimum 3-day hospitalization. In the Dosage and Administration section the label states: "[t]herapy with TIKOSYN must be initiated...in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular
arrhythmias. Patients should continue to be monitored in this way for a minimum of three days."
Based on the above comments, it would have been obvious to one of ordinary skill in the art to administer IV dofetilide in a facility capable of cardiac resuscitation and ECG monitoring, as taught by the TIKOSYN Label. This is a critical safety requirement due to the risk of QT prolongation and Torsade dePointes, and therefore, it would also be obvious to administer the first maintenance dose before discharge to ensure the patient tolerates the transition and to verify appropriate QT/QTc response. This is standard medical practice for medications requiring careful monitoring during initiation.
In relation to claim 5, as established for claim 4, Pool teaches IV administration with ECG monitoring and the TIKOSYN Label teaches administration in a monitored facility. The TIKOSYN Label teaches long-term oral maintenance therapy extending for months to years. Therefore, it would have been obvious to one of ordinary skill in the art that oral maintenance dosing would continue after discharge from the facility, as this is the fundamental purpose of maintenance therapy—to sustain therapeutic benefit in the outpatient setting. The TIKOSYN Label describes clinical outcomes at 6 and 12 months, demonstrating long-term outpatient therapy.
In relation to claim 6, Pool teaches treating premature ventricular contractions (Title and Summary: "Effects of intravenous dofetilide in patients with frequent premature ventricular contractions"). The TIKOSYN Label teaches treating atrial fibrillation and atrial flutter (Indications: conversion and maintenance of normal sinus rhythm in patients with atrial fibrillation/flutter). The TIKOSYN Label also discusses ventricular tachycardia, ventricular fibrillation, and supraventricular arrhythmias in the Clinical Studies and Warnings sections. Therefore, it would have been obvious to one of ordinary skill in the art that the IV administration method taught by Pool could be applied to any of the cardiovascular conditions for which dofetilide is therapeutically indicated. Dofetilide is a well-known Class III antiarrhythmic agent with established efficacy for various cardiac arrhythmias as taught by the TIKOSYN Label.
In relation to claim 7, Pool teaches IV dofetilide administration using body weight-based dosing (4 μg/kg loading dose). Pool does not explicitly teach the specific IV dose ranges correlated with specific oral maintenance doses as recited in claim 7. However, TIKOSYN Label teaches in the Description the three specific oral maintenance doses: "TIKOSYN is supplied for oral administration in three dosage strengths: 125 mcg...250 mcg...and 500 mcg." Additionally, the TIKOSYN Label provides data on
plasma concentrations achieved with oral dosing, which would inform selection of bioequivalent IV doses. Based on the above evidence, it would have been obvious to one of ordinary skill in the art to select IV doses that are proportional to the target oral maintenance doses to achieve therapeutic plasma concentrations. The specific ranges in claim 7 represent routine optimization based on:
1. Bioavailability differences: IV administration has 100% bioavailability while oral
dofetilide has >90% bioavailability (per TIKOSYN Label). A person of ordinary skill would
adjust IV doses accordingly;
2. Pharmacokinetic principles: The goal of an IV loading dose is to rapidly achieve plasma concentrations equivalent to those at steady state with oral dosing. The TIKOSYN Label provides the pharmacokinetic data needed to calculate appropriate IV doses; and
3. Dose proportionality: The claimed ranges (62.5-187.5 μg for 125 μg oral, 125-375 μg for
250 μg oral, 250-1000 μg for 500 μg oral) represent approximately 0.5-1.5x, 0.5-1.5x, and
0.5-2x the oral doses, respectively. These are routine variations within the skill of the art.
For example, for a 70 kg patient, Pool's 4 μg/kg loading dose equals 280 μg, which falls within the range of claim 7(c) for a 500 μg oral maintenance dose.
In relation to claim 8, Pool teaches IV administration with a loading dose followed by maintenance dose(s) using body weight-based dosing. In the Summary section, Pool discloses: "[s]ubjects received...an infusion of dofetilide (a 15-min loading infusion of 4 g/kg followed by a 60-min maintenance infusion of 3.5 g/kg)." Pool does not explicitly teach the specific amounts "up to 1000 μg" for both the IV dosage and IV maintenance dose(s). However, the TIKOSYN Label teaches specific dofetilide doses of 125, 250, and 500 μg. Therefore, it would have been obvious to one of ordinary skill in the art to express Pool's body weight-based doses in absolute micrograms and to select doses up to 1000 μg. For a typical adult patient (70 kg), Pool's loading dose (4 μg/kg) equals 280 μg and maintenance dose (3.5 μg/kg) equals 245 μg, both well within the claimed "up to 1000 μg" range. The upper limit
of 1000 μg represents a reasonable design choice allowing for larger patients or dose adjustments while remaining within safe therapeutic ranges established by the TIKOSYN Label.
In relation to claim 9, Pool teaches a 15-minute loading infusion and a 60-minute (1 hour) maintenance infusion. In the Methods section, Pool states: "a 15-min loading infusion of 4 g/kg followed by a 60-min maintenance infusion of 3.5 g/kg." Pool does not explicitly teach a 1-hour IV dosage (loading dose) or a 5-hour IV maintenance dose. However, it would have been obvious to one of ordinary skill in the art to extend Pool's 15-minute loading infusion to about 1 hour to reduce infusion-related side effects or to better control the rate of drug delivery. Similarly, extending the maintenance infusion from 1 hour to 5 hours would be an obvious variation to maintain steady plasma concentrations over a longer period. Adjusting infusion times for intravenous medications is a routine optimization within the skill of the art to balance efficacy, safety, and patient comfort.
In relation to claim 10, Pool teaches IV loading and maintenance dosing. As established for claim 9, the doses can be expressed in absolute micrograms. For a 70 kg patient, Pool's doses (280 μg loading, 245 μg maintenance) fall within the claimed 250-500 μg range. Pool does not explicitly teach administering the first IV maintenance dose 6-12 hours after initiation of the IV dosage. However, it would have been obvious to one of ordinary skill in the art to administer a subsequent IV maintenance dose 6-12 hours after the initial IV dosage to maintain therapeutic plasma concentrations. This timing is based on the pharmacokinetics of dofetilide. The TIKOSYN Label teaches that oral dofetilide is administered every 12 hours (BID), indicating that therapeutic levels need to be maintained at approximately 12-hour intervals. A person of ordinary skill would apply this same principle to IV maintenance dosing.
In relation to claim 11, Pool teaches IV infusions over shorter periods (15 minutes and 60 minutes). Therefore, it would have been obvious to one of ordinary skill in the art to extend both the IV dosage and IV maintenance dose infusions to about 5 hours to maintain steady plasma concentrations, reduce peak concentrations, and minimize infusion-related adverse effects. This is a routine optimization of infusion parameters.
In relation to claim 12, as established for claims 10 and 11, Pool teaches IV loading and maintenance dosing in amounts that can be expressed as 250-500 μg for a typical adult. Pool does not explicitly teach administering the first IV maintenance dose 2-12 hours after initiation of the IV dosage. However, it would have been obvious to one of ordinary skill in the art to administer the first IV maintenance dose 2-12 hours after initiation of the IV dosage to maintain therapeutic plasma concentrations. This timing range is based on the pharmacokinetics of dofetilide and represents routine optimization. The TIKOSYN Label's 12-hour dosing interval for oral therapy provides guidance on the appropriate timing for maintenance dosing.
In relation to claim 13, Pool teaches IV dofetilide administration over 1.25 hours (within the claimed 1-5 hour range) with electrocardiographic monitoring. In the Methods section, Pool discloses a total infusion time of 75 minutes with "2-hour telemetric electrocardiogram" monitoring. Pool does not explicitly teach (1) determining creatinine clearance before dosing, (2) selecting dose based on CrCl, or (3) administration in a facility with cardiac resuscitation capability. However, the TIKOSYN Label explicitly teaches all missing elements: (a) TIKOSYN Label, Dosage Administration, Step 2: Prior to the administration of the first dose, the patient's creatinine clearance must be calculated using the Cockcroft-Gault equation [see TIKOSYN Label male/female calculation in the step 2 section], (b) TIKOSYN Label, Dosage and Administration, Step 3 (Dosing Table):
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and finally, (c) in Dosage and Administration section, TIKOSYN discloses "Therapy with TIKOSYN must be
initiated...in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias." Accordingly,
it would have been obvious to one of ordinary skill in the art to incorporate CrCl-based dosing and administration in a monitored facility with resuscitation capability into Pool's IV dofetilide method. The TIKOSYN Label provides explicit and compelling rationale in the section titled “Pharmacokinetics in Special Populations”:
"In volunteers with varying degrees of renal impairment and patients with arrhythmias, the clearance of dofetilide decreases with decreasing creatinine clearance...Because increase in QT interval and the
risk of ventricular arrhythmias are directly related to plasma concentrations of dofetilide, dosage adjustment based on calculated creatinine clearance is critically important."
These are critical safety requirements driven by:
1. Pharmacokinetic necessity: Dofetilide is primarily eliminated renally (>80% unchanged in urine per TIKOSYN Label). Renal function directly affects drug clearance regardless of route of administration;
2. Safety imperative: The risk of life-threatening arrhythmias (Torsade de Pointes) is directly related to plasma concentrations, which are affected by renal function; and
3. Regulatory guidance: The FDA-mandated CrCl-based dosing reflects a critical safety requirement.
A person of ordinary skill would be compelled to apply these safety measures to IV administration.
In relation to claim 14, the TIKOSYN Label teaches specific oral doses (125, 250, 500 μg) selected based on creatinine clearance. Accordingly, it would have been obvious to one of ordinary skill in the art to base the IV dose on the target oral maintenance dose to ensure therapeutic equivalence and smooth transition from IV to oral therapy. This is standard practice in pharmaceutical development—IV loading doses are designed to achieve plasma concentrations equivalent to those achieved with oral maintenance dosing. The TIKOSYN Label provides the pharmacokinetic data needed to establish this relationship.
In relation to claim 15, the TIKOSYN Label teaches CrCl-based dosing with specific doses for different CrCl ranges. In the Dosage administration section, Step 3, TIKOSYN Label discloses:
CrCl >60 mL/min: 500 mcg BID
CrCl 40-60 mL/min: 250 mcg BID
CrCl 20 to <40 mL/min: 125 mcg BID
The TIKOSYN Label teaches lower doses for lower CrCl, not higher doses as recited in claim 15. However, in paragraph [0120], the specification of this application explains that in some cases, patients with lower CrCl may receive higher loading doses than patients with higher CrCl to compensate for reduced clearance and achieve target plasma concentrations more rapidly. Paragraph [0120] states:
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While the TIKOSYN Label teaches lower oral maintenance doses for patients with lower CrCl, it would have been obvious to one of ordinary skill in the art that IV loading doses might need to be higher for patients with lower CrCl to achieve target plasma concentrations more rapidly. This is because patients with impaired renal function have reduced drug clearance and may require a higher initial dose to reach therapeutic levels, after which lower maintenance doses are used. This represents a routine pharmacokinetic optimization based on the known relationship between CrCl and dofetilide clearance
taught by the TIKOSYN Label.
In relation to claim 16, Pool teaches IV maintenance dosing after the IV loading dose. The TIKOSYN Label teaches oral maintenance dosing. Accordingly, it would have been obvious to one of ordinary skill in the art to administer IV or oral maintenance doses after the IV dosage to maintain therapeutic plasma concentrations, as taught by Pool and the TIKOSYN Label.
In relation to claim 17, Pool teaches IV dofetilide administration. The TIKOSYN Label teaches CrCl-based oral dosing (125, 250, 500 μg) and provides pharmacokinetic data. Neither Pool nor TIKOSYN Label explicitly teach the specific IV dose ranges in the Table [part of claim 17] correlated with CrCl ranges and target oral doses. It would have been obvious to one of ordinary skill in the art to select the specific IV dose ranges in the Table based on:
1. Pharmacokinetic principles: The TIKOSYN Label provides pharmacokinetic data
showing that dofetilide clearance decreases with decreasing CrCl. A person of ordinary
skill would use this data to calculate appropriate IV doses to achieve target plasma
concentrations equivalent to oral steady-state levels;
2. Bioavailability adjustment: The TIKOSYN Label teaches that oral dofetilide has >90%
bioavailability. IV doses would be adjusted accordingly (slightly lower than oral doses
for equivalent exposure);
3. Dose proportionality: The IV dose ranges in the Table are generally proportional to
(approximately 0.4-2x) the target oral maintenance doses, representing routine optimization; and
4. CrCl-based adjustment: The table shows that for a given target oral dose, patients with
lower CrCl receive higher IV doses (e.g., for 500 μg oral target: 300-800 μg IV for CrCl >60,
400-1000 μg IV for CrCl 40-60). This reflects the teaching in the specification [0120] that
patients with lower CrCl may require higher loading doses to achieve target concentrations.
Accordingly, for an artisan skilled in the art, the specific dose ranges represent routine optimization based on well-established pharmacokinetic principles and the data provided in the TIKOSYN Label.
In relation to claim 18, Pool teaches IV loading and maintenance dosing. The TIKOSYN Label teaches CrCl-based dosing. Neither Pool nor TIKOSYN explicitly teach the specific IV and IV maintenance dose ranges in the Table correlated with CrCl ranges, or that IV maintenance doses can be administered
outside a monitored facility. Accordingly, it would have been obvious to one of ordinary skill in the art to select CrCl-based IV and IV maintenance doses as shown in the Table for the same pharmacokinetic reasons articulated for claim 17. The dose ranges represent routine optimization based on the relationship between CrCl and dofetilide clearance taught by the TIKOSYN Label. Additionally, it would be obvious that IV maintenance doses could be administered outside a monitored facility (e.g., in a home healthcare setting or outpatient infusion center) once the patient has been stabilized and shown to tolerate dofetilide without excessive QT prolongation. This is standard medical practice for transitioning stable patients to less intensive monitoring settings.
In relation to claim 19, Pool teaches IV dofetilide administration. Pool does not explicitly teach discharging the subject with instructions to self-administer oral doses. However, the TIKOSYN Label teaches oral dofetilide administration every 12 hours (BID) for long-term maintenance therapy. In the Dosage and Administration section, the TIKOSYN Label discloses "[t]he usual recommended dose of
TIKOSYN is 500 mcg BID...". The TIKOSYN Label also includes extensive patient information and instructions. Accordingly, it would have been obvious to one of ordinary skill in the art to discharge a patient with instructions to self-administer oral dofetilide every 12 to 48 hours following IV loading. The 12-hour interval is explicitly taught by the TIKOSYN Label (BID dosing). The extended interval up to 48 hours represents an obvious variation for patients requiring less frequent dosing or dose adjustments. Instructing patients on self-administration of oral medications is standard medical practice and an inherent component of discharge planning for long-term oral therapy.
In relation to claim 20, Pool teaches IV dofetilide administration with electrocardiographic monitoring: "2-hour telemetric electrocardiogram" monitoring. Pool does not explicitly teach (1) obtaining specific QT/QTc interval measurements before and after dosing, (2) the 15% threshold for QT/QTc increase, or (3) the decision algorithm based on QT/QTc changes. However, the TIKOSYN Label explicitly teaches all missing elements:
"Prior to administration of the first dose, the QTc or QT must be checked using an average of 5–10 beats. If the QTc or QT is greater than 440 msec (500 msec in patients with ventricular conduction abnormalities), TIKOSYN is contraindicated..." [see Dosage and Administration; step 1];
"At 2–3 hours after administering the first dose...determine the QTc or QT. If the QTc or QT has increased by greater than 15% compared to the baseline...subsequent dosing should be adjusted..." [see Dosage and Administration, step 5].
Accordingly, it would have been obvious to one of ordinary skill in the art to apply the QT/QTc
monitoring protocol from the TIKOSYN Label to Pool's IV dofetilide administration. The
motivation arises from:
1. Known risk of Torsade de Pointes: Dofetilide carries a well-known risk of QT
prolongation and Torsade de Pointes, a potentially fatal arrhythmia. This risk is
independent of route of administration.
2. FDA-mandated safety protocol: The 15% threshold is an FDA-mandated safety
protocol established through clinical trials and regulatory review.
3. Pharmacodynamic equivalence: The pharmacodynamic effects of dofetilide (QT
prolongation) occur regardless of whether the drug is administered orally or
intravenously.
4. Standard of care: A person of ordinary skill would recognize that the same safety
monitoring required for oral dofetilide would be equally, if not more, important for IV
administration, where plasma concentrations may rise more rapidly.
In relation to claim 21, as established for claim 20, the TIKOSYN Label teaches QT/QTc monitoring with a 15% threshold and dose adjustment based on QT/QTc changes:
"If the QTc or QT has increased by greater than 15% compared to the baseline...subsequent dosing should be adjusted..." [see Dosage and Administration, step 5].
The TIKOSYN Label further teaches ongoing monitoring during dofetilide therapy and dose reduction if QT/QTc increases excessively. Accordingly, it would have been obvious to one of ordinary skill in the art to continue applying the same 15% threshold safety protocol to subsequent maintenance doses. Claim 21 simply extends the monitoring and dose adjustment algorithm from claim 20 to the second maintenance dose:
• If QT/QTc increase is <15%, continue with the same dose (safe to proceed), or
• If QT/QTc increase is >15%, reduce the dose (dose adjustment for safety).
This is a straightforward extension of the monitoring protocol taught by the TIKOSYN Label
and represents standard medical practice for dose titration based on safety parameters.
In relation to claim 22, Pool teaches IV dofetilide administration. The TIKOSYN Label provides steady-state plasma concentration data for oral dofetilide [the label provides pharmacokinetic parameters including Cmax at steady state for oral dosing]. Accordingly, it would have been obvious to one of ordinary skill in the art that the goal of an IV loading dose is to rapidly achieve therapeutic plasma concentrations equivalent to those achieved at steady state with oral maintenance dosing. This is a fundamental principle of pharmacokinetics and loading dose design. The claim limitation does not recite a specific method step but rather describes the expected pharmacokinetic result of proper IV dose
selection. This represents the inherent and obvious objective of developing an IV loading dose regimen. A person of ordinary skill could have used the steady state Cmax data from the TIKOSYN Label to design an IV regimen that achieves equivalent plasma concentrations.
Claims 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Pool et al. (“Effects of intravenous dofetilide in patients with frequent premature ventricular contractions: A clinical trial”, hereinafter “Pool”) in view of TIKOSYN® (dofetilide) Capsules, U.S. Prescribing Information, Pfizer Inc.; hereinafter “TIKOSYN label”) and Falk et al. (“Intravenous Dofetilide, a Class III Antiarrhythmic Agent, for the Termination of Sustained Atrial Fibrillation or Flutter”; hereinafter “Falk”).
In relation to claim 23, Pool teaches IV dofetilide administration over 1.25 hours with ECG monitoring. Pool does not explicitly teach (1) the specific dose of 500 μg, (2) the specific infusion time of 2.5 hours, (3) treating atrial fibrillation/flutter, (4) the specific timing of oral maintenance doses, or (5) the 12-hour oral dosing interval.
The TIKOSYN Label teaches: (a) 500 μg dose (the highest standard dose), (b) oral maintenance dosing every 12 hours (BID), (c) treatment of atrial fibrillation and atrial flutter, (d) QT/QTc monitoring during therapy, (d) administration in a facility with cardiac resuscitation and ECG monitoring, and (e) restoration and maintenance of normal sinus rhythm.
Falk teaches IV dofetilide for atrial fibrillation and atrial flutter. Based on the above teachings, it would have been obvious to one of ordinary skill in the art to combine the teachings of Pool, the TIKOSYN Label, and Falk to arrive at the method of claim 23:
1. 500 μg IV dose over 2.5 hours: Pool teaches IV administration over 1.25 hours. The TIKOSYN Label teaches the 500 μg dose. Extending the infusion to 2.5 hours is a routine optimization (approximately 2x Pool's time). For a 70 kg patient, Pool's dose would be 280 μg; scaling to 500 μg is an obvious variation based on the TIKOSYN Label's standard dose.
2. Treating atrial fibrillation/flutter: Falk and the TIKOSYN Label explicitly teach this
indication.
3. Multiple QT/QTc measurements during IV administration: The TIKOSYN Label teaches QT/QTc monitoring, and Pool teaches ECG monitoring during IV infusion. Obtaining multiple measurements during a 2.5-hour infusion is obvious for safety.
4. First oral dose 4 hours after IV completion: This timing allows for assessment of the patient's response to the IV dose before transitioning to oral therapy. It is a routine optimization based on the pharmacokinetics of dofetilide (half-life ~10 hours per TIKOSYN Label).
5. 12-hour oral dosing interval: Explicitly taught by the TIKOSYN Label (BID dosing).
6. QT/QTc monitoring between oral doses: Explicitly taught by the TIKOSYN Label's dose
adjustment protocol.
7. Restoring/maintaining normal sinus rhythm: Explicitly taught as the therapeutic goal
by the TIKOSYN Label and Falk.
The combination represents a straightforward application of the known teachings of the cited references to develop a specific IV-to-oral transition protocol for atrial fibrillation/flutter patients.
In relation to claim 24, The TIKOSYN Label teaches a minimum 3-day hospitalization for dofetilide initiation: "Patients should continue to be monitored in this way for a minimum of three days" [see TIKOSYN Label, Dosage and Administration]. Accordingly, it would have been obvious to one of ordinary skill in the art to administer the first and second oral maintenance doses before discharge to ensure the patient tolerates the transition to oral therapy and to verify appropriate QT/QTc response during the required 3-day hospitalization. Subsequent oral doses would naturally be administered after discharge for long-term outpatient maintenance therapy. This is standard medical practice for medications requiring careful monitoring during initiation.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MANUEL A MENDEZ whose telephone number is (571)272-4962. The examiner can normally be reached Mon-Fri 7:00 AM-5:00 PM.
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Respectfully submitted,
/MANUEL A MENDEZ/ Primary Examiner, Art Unit 3783