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.
Claim 15 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites:
“wherein the IV dosage of dofetilide is administered: in a first higher amount for the subject with a CrCl of 20 ml/min to <40 ml/min; and in a second lower amount for the subject with a CrCl of 40 ml/min or greater.”
This claim language is indefinite because it recites a dosing regimen that is medically counterintuitive and directly contrary to the FDA-approved prescribing information for dofetilide, creating an irreconcilable ambiguity as to the intended scope of the claim. Specifically, the FDA Tikosyn Label (Instructions for Individualized Dose Initiation, Step 3) mandates the following starting doses based on creatinine clearance (CrCl):
>60 mL/min (non-renally impaired): 500 mcg twice daily
40-60 mL/min (mildly impaired): 250 mcg twice daily
20 to <40 mL/min (moderately impaired): 125 mcg twice daily
Because dofetilide is renally cleared, the FDA strictly mandates lower doses as renal impairment worsens to prevent drug accumulation and fatal arrhythmias (Torsades de Pointes). Claim 15 recites the exact opposite: a “higher amount” for patients with worse renal function (20 to <40 mL/min) and a “lower amount” for patients with better renal function (≥40 mL/min). It is unclear whether this is an intentional (but dangerous) departure from standard medical practice or a drafting error. Therefore, the claim fails to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
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.
Claim 1 is 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 10,799,138; hereinafter “Ivaturi”).
Independent claim 1 recites a method of intravenously administering dofetilide, comprising:
administering an IV dosage of dofetilide to a subject over a period of about 1 hour in the
range of ±50% of a target oral dose,
wherein the IV dosage is administered while the subject is in a facility capable of providing cardiac resuscitation and electrocardiographic monitoring.
In relation to independent claim 1, Falk discloses intravenous administration of dofetilide in a monitored clinical setting. Falk states:
"After a 30-min period of continuous ECG monitoring, patients received an infusion of randomly assigned therapy consisting of either 4.0 or 8.0 μg/kg body weight of dofetilide or placebo. The medication was administered as a 15-min infusion ... At the end of the infusion, subjects were continuously monitored for an additional 6 h ..." (Falk; page 386, col. I, Protocol).
Thus, Falk discloses IV dofetilide administration and electrocardiographic monitoring in a supervised facility. Falk does not expressly disclose that (1) the IV dosage is administered over about 1 hour, and (2) that the IV dosage is within ±50% of a target oral dose. However, Ivaturi discloses a one-hour IV loading regimen expressly tied to a target oral maintenance dose. Ivaturi explicitly states:
"The IV loading strategy begins with administering a first 40 mg IV loading dose for 1 hour, at which time the patient can be transitioned to 80 mg oral sotalol if an 80 mg BID oral maintenance dose is desired"
(Ivaturi, col. 10, lines 43-47).
The above teachings by Ivaturi demonstrate the conventionality of both, (1) the one-hour infusion feature and (2) a 50% IV-to-target-oral-dose relationship. Moreover, Ivaturi’s definition of "antiarrhythmic drug" expressly includes dofetilide (see Ivaturi, col. 11, lines 50-52).
Based on the above comments, a person of ordinary skill in the art would have been motivated to apply Ivaturi’s one-hour IV/switch dosing architecture to Falk’s monitored IV dofetilide administration in order to accelerate transition to a desired oral maintenance regimen while preserving monitored initiation of an antiarrhythmic drug associated with QT-related risk.
Claims 2, 3, 6, 7, 8, 16, 18, and 19 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 10,799,138; hereinafter “Ivaturi”), the publication Prystowsky et al. (Clinical experience with dofetilide in the treatment of patients with atrial fibrillation; hereinafter “Prystowsky”), the FDA-Tikosyn (dofetilide)-Label, and Somberg (US 2019/0388371A1).
Independent claim 2 recites a method of administering dofetilide, comprising the steps of:
administering an IV dosage of dofetilide to a subject in an amount of about 62.5-1000 μg,
wherein the IV dosage is administered while the subject is in a facility capable of providing cardiac resuscitation and electrocardiographic monitoring, and
after administering the IV dosage, and after discharging the subject from the facility, administering an oral dosage of dofetilide in an amount of 125 μg, 250 μg, or 500 μg.
In relation to independent claim 2, Falk discloses monitored IV dofetilide administration at 4.0 or 8.0 μg/kg body weight after continuous ECG monitoring (Falk; page 386, col. I, Protocol). Falk does not expressly disclose the later oral doses of 125 μg, 250 μg, or 500 μg, and Falk does not expressly disclose that oral dofetilide is administered after discharge. The FDA Tikosyn label discloses the exact oral strengths of 125 mcg, 250 mcg, and 500 mcg in the Description section, and the Clinical Studies section likewise states that both studies randomized patients to 125 mcg, 250 mcg, or 500 mcg twice a day. Moreover, Prystowsky states in the abstract, Methods and results section: “Sixty-nine patients ... were administered dofetilide in-hospital ... Fifty-eight patients were discharged receiving dofetilide treatment and were followed as outpatients”. Finally, Somberg further states at paragraph [0024] that the method includes “after completion of the intravenous administration, orally administering a first 500 μg dose of dofetilide” and “chronically administering 500 μg dofetilide orally, twice daily,” and paragraph [0037] explains that “chronically administering” refers to administration beyond the hospital setting.
Based on the above comments, a person of ordinary skill would have been motivated to combine Falk’s monitored IV initiation with the approved oral dose strengths in the FDA Tikosyn label and the known practice of discharging patients on continued dofetilide therapy shown by Prystowsky and Somberg in order to transition from acute monitored dosing to chronic outpatient maintenance.
Independent claim 7 recites the step of:
determining creatinine clearance before administering IV dofetilide and selecting the amount based on creatinine clearance.
In relation to independent claim 7, as discussed above, Falk discloses monitored IV dofetilide
Administration. Falk does not expressly disclose calculating creatinine clearance before the first dose or selecting dose based on creatinine clearance. However, the FDA Tikosyn label states in DOSAGE AND ADMINISTRATION, Step 2: “[p]rior to the administration of the first dose, the patient's creatinine clearance must be calculated.” The label’s Renal Impairment section further states that clearance of dofetilide decreases with decreasing creatinine clearance and that dosage adjustment based on calculated creatinine clearance is critically important. Ivaturi states in the detailed description that for patients with abnormal renal function, oral doses may be decreased, the time between IV and oral doses may be lengthened, and IV doses may be decreased in amount or strength to account for renal
impairment (Ivaturi; col. 5, lines 19-28).
Based on the above comments, a person of ordinary skill would have been motivated to
incorporate renal-function-based dose selection into IV dofetilide initiation because renal clearance is a known determinant of dofetilide exposure and proarrhythmic risk.
In relation to claim 3, as discussed above, Falk discloses IV dofetilide administration in monitored patients with sustained atrial fibrillation or flutter. Falk does not expressly disclose repeated
oral dofetilide administration after discharge. Prystowsky states in the Abstract, Methods and Results, that fifty-eight patients were discharged receiving dofetilide treatment and were followed as outpatients. The FDA Tikosyn label supplies repeated oral dosing by disclosing twice-daily dofetilide regimens in the Description and Clinical Studies sections. Somberg paragraph [0024] states that, after IV administration, the patient receives a first 500 μg oral dose and then is chronically administered 500 μg
dofetilide orally twice daily, and paragraph [0037] defines chronic dosing as dosing beyond the hospital setting.
Based on the above comments, a person of ordinary skill would have been motivated to continue antiarrhythmic therapy orally after monitored IV initiation in order to maintain rhythm
control outside the hospital under a known chronic dofetilide regimen.
In relation to claim 6, as discussed above, Falk discloses IV dofetilide administration at
“either 4.0 or 8.0 μg/kg body weight” in monitored patients. The FDA Tikosyn label discloses oral dofetilide strengths of 125 mcg, 250 mcg, and 500 mcg in the Description section and Clinical Studies
section. Falk and the Tikosyn label do not, by themselves, expressly disclose the pairing of an IV dose administered over about 1 hour with one of the three recited IV/oral combinations, nor do they expressly disclose the carried-forward post-discharge oral transition of claim 2.
Ivaturi states that a first antiarrhythmic dose may be given by “a first intravenous infusion, infused for a 0.5 hour-2-hour time period” (Ivaturi; col. 2, lines 49-52). Somberg paragraph [0069] gives a dofetilide-specific example in which a 70 kg patient receives an IV infusion of dofetilide at 2.4 μg/kg to reach the predicted maximal serum concentration expected from 500 μg dofetilide orally, and the same paragraph states that a maintenance dose of 500 μg dofetilide orally is administered approximately one hour after start of the IV infusion. Using the express 70 kg patient example in paragraph [0069], Falk’s 4.0 μg/kg and 8.0 μg/kg IV doses correspond to 280 μg and 560 μg, which fall within claim 6’s third alternative of about 250-1000 μg IV paired with 500 μg oral. Prystowsky further supports the carried forward transition to oral outpatient treatment by stating in the Abstract, Methods and Results, that fifty-eight patients were discharged receiving dofetilide treatment.
Based on the above comments, a person of ordinary skill would have been motivated to combine Falk’s weight-based IV dofetilide dosing, the Tikosyn oral maintenance strengths, Ivaturi’s 0.5- 2-hour infusion framework, and the dofetilide-specific 70 kg oral-targeting example in Somberg paragraph [0069] in order to select an IV dofetilide amount and infusion period that transition a monitored patient to a desired chronic oral regimen.
In relation to claim 8, as discussed above, Falk discloses a monitored IV dofetilide setting,
including continuous ECG monitoring before and after infusion. Falk does not use the full claim language requiring a facility capable of both cardiac resuscitation and continuous electrocardiographic monitoring. However, the FDA Tikosyn label boxed warning states: “patients initiated or re-initiated on TIKOSYN should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation.”
Based on the above comments, person of ordinary skill would have been motivated to use those
safeguards during dofetilide initiation because they directly address initiation-related arrhythmic risk.
In relation to claim 16, as discussed above, Falk discloses monitored IV dofetilide treatment. Falk does not disclose discharge with continuing oral dofetilide instructions or a dosing interval within the claimed 12-to-48-hour range. Prystowsky states in the Abstract, Methods and Results, that fifty-eight patients were discharged receiving dofetilide treatment. The Tikosyn label discloses twice-daily oral dosing in the Description and Clinical Studies sections, which corresponds to a 12-hour interval. Ivaturi states that, for patients with renal impairment, oral maintenance doses may be administered every 24 hours instead of every 12 hours (Ivaturi; col. 5, lines 19-28). Somberg paragraph [0037]
explains that chronic dosing is beyond the hospital setting.
Based on the above comments, a person of ordinary skill would have been motivated to discharge the patient on continued oral dofetilide after successful monitored initiation and to choose
a dosing interval within the claimed 12-to-48-hour range according to the known maintenance regimen and renal-function considerations.
In relation to claim 18, as discussed above, Falk discloses IV dofetilide administration but not the specific 70%-of-steady-state-Cmax concept. Somberg paragraph [0015] expressly states: “[t]hus, if a single dose reaches 70% of predicted steady state, at steady state, one can estimate Cmax ss to be 2.7 ng/mL ...” The same paragraph explains that a 2.4 μg/kg IV dose would reach the peak concentration predicted for steady state.
Based on the above comments, a person of ordinary skill would have been motivated to select an IV loading regimen that exposes the patient to a known fraction of chronic steady-state peak concentration while the patient remains under monitoring, thereby allowing prompt assessment of maximal QT response.
In relation to claim 19, as discussed above, Falk discloses ECG monitoring during IV dofetilide
Treatment. Falk does not expressly disclose the specific baseline-versus-post-IV QT/QTc comparison and 15% threshold. Ivaturi states in the Summary of the Invention and the detailed description that the method includes detecting a baseline QTc, administering a first IV infusion, then determining the difference between baseline QTc and a first QTc measured after the first IV infusion, and proceeding only if the delta QTc is within an acceptable range (Ivaturi; col. 2, lines 36-48). The FDA Tikosyn label states in DOSAGE AND ADMINISTRATION Step 5 that, if QTc or QT has increased by greater than 15% compared to baseline, subsequent dosing should be adjusted.
Based on the above comments, a person of ordinary skill would have been motivated to structure IV initiation and later dosing around established QT-safety criteria in order to reduce
proarrhythmic risk.
Claims 4, 5, and 20 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 10,799,138; hereinafter “Ivaturi”), and Pool et al. (Effects of intravenous dofetilide in patients with frequent premature ventricular contractions: A clinical trial; hereinafter “Pool”).
In relation to claim 4, Falk states in the Methods portion of the source page that ninety-one patients with sustained atrial fibrillation or flutter were entered into the study. Falk does not disclose each condition recited in claim 4, including premature ventricular contractions. Pool states in the Summary, Hypothesis sentence: “[t]his study was undertaken to determine whether intravenous (IV) dofetilide has the ability to suppress PVCs in patients who have frequent occurrences”.
Based on the above comments, a person of ordinary skill would have been motivated to look to
both Falk and Pool because both concern IV dofetilide in clinically significant arrhythmias and together show use of IV dofetilide across multiple expressly recited cardiovascular conditions.
In relation to claim 5, Falk states that “[a] positive response to therapy was defined as conversion to normal sinus rhythm,” and the results text states that patients receiving dofetilide converted to sinus rhythm (Falk; column I, page 386, Protocol, second paragraph). Accordingly, in view of the demonstrated conventionality of this enhancement, its implementation in the invention would have been considered an obvious alternative in the design of the methodology.
In relation to claim 20, Falk studies patients with sustained atrial fibrillation or flutter and states in the Conclusions text on the source page that intravenous dofetilide can convert sustained atrial fibrillation or flutter to sinus rhythm. That disclosure necessarily concerns subjects who are not already in sinus rhythm at the time treatment is undertaken. Therefore, the treatment of a subject not in sinus rhythm would have been an obvious alternative in the application of the methodology.
Claim 9, 11, 17, 12, 13, 14, and 15 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 10,799,138; hereinafter “Ivaturi”) and the FDA-Tikosyn (dofetilide)-Label, and in further view of Somberg (US 2019/0388371A1).
In relation to claim 9, as discussed above, Falk discloses IV dofetilide administration in a monitored facility. Falk does not disclose that the IV dosage is selected based on a target oral dose or that oral doses are administered outside the monitored facility. Somberg paragraph [0024] recites a method in which dofetilide is infused intravenously in an amount that achieves the predicted maximal serum concentration from 500 μg dofetilide orally administered, followed by a first 500 μg oral dose and chronic oral dosing twice daily. Paragraph [0037] defines chronic dosing as administration of dofetilide beyond the hospital setting.
Based on the above comments, a person of ordinary skill would have been motivated to use an IV dose selected with reference to the intended oral maintenance regimen and then continue oral dosing beyond the monitored facility to maintain therapy after safe monitored initiation.
In relation to claim 11, as discussed above, Falk discloses IV dofetilide administration. Falk does not disclose oral dofetilide administration before or after IV administration. Somberg paragraph [0024] states that after completion of the intravenous administration, a first 500 μg oral dose of dofetilide is administered, followed by chronic twice-daily oral dosing. Therefore, a person of ordinary skill would have been motivated to transition from IV initiation to oral maintenance dosing once monitored assessment of QT response had been performed.
In relation to claim 17, Falk does not disclose varying oral dofetilide amounts over time. However, the FDA Tikosyn label states in DOSAGE AND ADMINISTRATION Step 5 that, 2-3 hours after the first dose, if QTc or QT has increased by greater than 15% compared to baseline or exceeds the listed threshold, “subsequent dosing should be adjusted as follows.” The same Step 5 adjustment scheme changes later doses from 500 mcg twice daily to 250 mcg twice daily, from 250 mcg twice daily to 125 mcg twice daily, and from 125 mcg twice daily to 125 mcg once daily. Therefore, a person of ordinary skill would have been motivated to apply this QT-based down-titration logic to reduce proarrhythmic risk while maintaining therapy.
In relation to claim 12, Falk does not disclose a 1-5 hour infusion period. Ivaturi states that a first antiarrhythmic dose may be administered via a first IV infusion “for a 0.5 hour-2 hour time period” (Somberg; col. 2, lines 49-54). That disclosed range overlaps the lower end of claim 12’s 1-5 hour range. Therefore, a person of ordinary skill would have been motivated to use a longer infusion period to align IV initiation with a controlled IV-to-oral antiarrhythmic loading strategy.
In relation to claim 13, as discussed above, Falk discloses IV dofetilide dosages in monitored patients. The Falk source-page protocol states that, after continuous ECG monitoring, patients received “either 4.0 or 8.0 μg/kg body weight of dofetilide,” administered as a 15-minute infusion. Falk does not expressly disclose determining the IV dose based on the subject’s creatinine clearance. However, the FDA Tikosyn label expressly discloses creatinine-clearance-based dofetilide dose selection. In DOSAGE AND ADMINISTRATION, Step 2, the label states: “[p]rior to the administration of the first dose, the patient's creatinine clearance must be calculated.” In Step 3, the label provides the starting-dose table using the exact renal brackets greater than 60 mL/min, 40 to 60 mL/min, and 20 to less than 40 mL/min, with corresponding dofetilide doses of 500 mcg twice daily, 250 mcg twice daily, and 125 mcg twice daily. The label’s Renal Impairment section further explains that dofetilide clearance decreases with decreasing creatinine clearance and that dosage adjustment based on calculated creatinine clearance is critically important. Ivaturi then teaches that IV antiarrhythmic dosing also should be adjusted for renal function, stating that, for patients with abnormal renal function, oral doses may be decreased, the time between IV and oral doses may be lengthened, and “the IV doses administered may be decreased in amount or strength to account for any renal impairment” (Ivaturi; col. 5, lines 26-28). Somberg reinforces the same dofetilide-specific renal-adjusted framework. Paragraph [0069] discloses a 70 kg patient with GFR greater than 60 mL/min receiving 2.4 μg/kg IV dofetilide to correspond to a 500 μg oral regimen, and paragraph [0071] states that patients with lower-than-normal GFR receive lower maintenance doses of 250 μg or 125 μg twice daily.
Based on the above comments, a person of ordinary skill would have been motivated to base the IV dosage of dofetilide on the subject’s creatinine clearance using the exact renal categories established in the FDA Tikosyn label, while also adjusting the IV regimen for renal function as taught by Ivaturi and reinforced by Somberg, because dofetilide is primarily renally eliminated and the verified label states that dosage adjustment based on calculated creatinine clearance is critically important to control plasma concentration and related arrhythmic risk. In view of Falk’s express IV dofetilide dosing, the FDA Tikosyn label’s exact creatinine-clearance brackets and dose-selection logic, and Ivaturi’s teaching that IV antiarrhythmic doses may be decreased for renal impairment, the claim 13 dosage matrix would have been an obvious renal-adjusted IV implementation of known dofetilide dosing principles.
In relation to claim 14, Falk does not expressly disclose achieving, or being capable of achieving, steady-state-equivalent dofetilide Cmax within about 2 hours of IV administration. However, Somberg paragraph [0015] states that administering an IV infusion of dofetilide would achieve serum dofetilide concentration equivalent to that reached as steady state in one day under ECG observation, and further states that a 2.4 μg/kg IV dose would reach the peak concentration predicted for steady state in a short period of time. Paragraph [0069] states that the peak concentration is typically reached at termination of infusion and describes an IV-plus-oral sequence beginning approximately one hour after start of the IV infusion. Therefore, a person of ordinary skill would have been motivated to select an IV dofetilide loading regimen that rapidly reaches the predicted chronic steady-state peak under monitored conditions so that maximal QT response can be evaluated promptly and safely.
In relation to claim 15, as discussed above, Falk discloses IV dofetilide dosages in monitored patients. The Falk source-page protocol states that, after continuous ECG monitoring, patients received “either 4.0 or 8.0 μg/kg body weight of dofetilide” administered as a 15-minute infusion. Falk does not expressly disclose adjusting the IV dosage based on renal impairment or creatinine clearance, and Falk does not expressly disclose any renal-function-based dose-selection framework for IV dofetilide. However, the FDA Tikosyn label expressly discloses adjusting dofetilide dose based on renal impairment. In DOSAGE AND ADMINISTRATION Step 3, the label assigns 500 mcg twice daily for creatinine clearance greater than 60 mL/min, 250 mcg twice daily for creatinine clearance 40 to 60 mL/min, and 125 mcg twice daily for creatinine clearance 20 to less than 40 mL/min. The label’s Renal Impairment section further explains that dofetilide clearance decreases with decreasing creatinine clearance and that dosage adjustment based on calculated creatinine clearance is critically important. Ivaturi teaches that IV antiarrhythmic doses also may be adjusted for renal function, stating that, for patients with abnormal renal function, oral doses may be decreased, the time between IV and oral doses may be lengthened, and “the IV doses administered may be decreased in amount or strength to account for any renal impairment” (Ivaturi; col. 5, lines 26-28). Somberg paragraph [0071] reinforces the same principle by stating that, if patients present with lower-than-normal GFR, the maintenance dose administered would be lower, specifically 250 μg or 125 μg twice daily.
Based on the above comments, a person of ordinary skill would have been motivated to adjust the IV dosage of dofetilide based on the subject’s renal function, as taught by the Tikosyn label and Ivaturi, because dofetilide is primarily eliminated by the kidneys and renal-function-based dose adjustment is a fundamental safety requirement to avoid excessive plasma accumulation and arrhythmic risk. As an additional observation, the claim as written recites a “higher amount” for the renally impaired subject and a “lower amount” for the non-renally impaired subject, which is medically counterintuitive and contrary to the dose direction stated in the Tikosyn label. Nevertheless, the prior art clearly teaches the general concept of adjusting dofetilide dosage based on renal function, regardless of route of administration.
Claim 10 is 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 10,799,138; hereinafter “Ivaturi”) and the FDA-Tikosyn (dofetilide)-Label, and in further view of Pool et al. (Effects of intravenous dofetilide in patients with frequent premature ventricular contractions: A clinical trial; hereinafter “Pool”).
In relation to claim 10, Falk does not expressly disclose an IV maintenance dose after an initial IV dose. However, Pool states in the Summary, Methods, that subjects received “an infusion of dofetilide (a 15-min loading infusion ... followed by a 60-min maintenance infusion ...).” The language in the Methods section expressly teaches a loading infusion followed by a maintenance infusion. Accordingly, a person of ordinary skill would have been motivated to use a loading-plus-maintenance infusion strategy to achieve therapeutic concentration rapidly and then maintain exposure during the monitored period.
Conclusion
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Respectfully submitted,
/MANUEL A MENDEZ/ Primary Examiner, Art Unit 3783
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