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 4, 12, 14, and 17 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.
Claim 4 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. Claim 4 recites “the oral dosages”; however, no antecedent basis is provided for “the oral dosages.” The parent claims recite oral administration, but do not introduce “oral dosages” as claimed. Therefore, it is unclear what dosage(s) are being referenced.
Claim 12 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. The claim language of claim 12 is considered 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 (Section 2.2, Table 1) 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 12 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 14 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. Claim 14 recites “the target oral dose” while depending from claim 11, which does not provide antecedent basis for that term. Therefore, the scope of claim 14 is not reasonably certain.
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, 3, 5, 6, 7, 8, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Somberg (US 2019/0388371A1) in view of the publication Falk et al. (Intravenous Dofetilide, a Class III Antiarrhythmic Agent, for the Termination of Sustained Atrial Fibrillation or Flutter; hereinafter “Falk”) and the FDA Tikosyn Label.
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 10 minutes 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, Somberg discloses the 10-minute IV dofetilide administration and the target-oral-dose concept:
“Administering an IV infusion of dofetilide would achieve serum dofetilide concentration equivalent to that reached as steady state (Cmax ss) in one day under ECG observation.” (Somberg, ¶ [0015])
“a. infusing intravenously, to a patient in need thereof, dofetilide in an amount that achieves the predicted maximal serum concentration from 500 μg dofetilide orally administered”. (Somberg, ¶ [0024])
“In another aspect, dofetilide is infused over a period of 10 minutes.” (Somberg, ¶ [0033])
“The patient would be admitted to hospital, ECG continuously monitored, and an IV infusion of dofetilide administered at 2.4 μg/kg that is expected to achieve the predicted maximal serum concentration that one would expect from 500 μg dofetilide orally.” (Somberg, ¶ [0069])
Somberg does not disclose the claim’s exact “±50% of a target oral dose” formulation, and paragraph [0069] does not use the exact Tikosyn language requiring a facility capable of “cardiac resuscitation.” However, Falk discloses exact IV dofetilide dose magnitudes:
“Ninety-one patients with sustained atrial fibrillation (75 patients) or flutter (16 patients) were entered into a double-blind, randomized multicenter study of one of two doses of dofetilide (4 or 8 μg/kg body weight) or placebo.” (Falk, page 385, Methods)
“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...” (Falk, page 386, column I, Protocol)
The FDA Tikosyn label discloses the exact monitored-facility language and oral target-dose
strengths:
“To minimize the risk of induced arrhythmia, 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.” (Tikosyn Label, first page, label at top of page)
“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) ...” (Tikosyn Label, first page, Description)
Based on the above comments, it would have been obvious to use the monitored 10-minute IV
dofetilide loading method of Somberg together with Falk’s expressly disclosed IV dose magnitudes and the FDA Tikosyn Label oral-dose strengths and monitored-facility requirement in order to select a clinically useful IV loading dose relative to an intended oral dofetilide regimen while using the known safety conditions for dofetilide initiation.
Independent claim 2 recites a method of administering dofetilide, comprising:
administering an IV dosage of dofetilide to a subject over a period of about 10 minutes 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, administering an oral dosage of dofetilide to the subject in an amount of 125 μg, 250 μg or 500 μg.
In relation to independent claim 2, Somberg discloses:
“The patient would be admitted to hospital, ECG continuously monitored, and an IV infusion of dofetilide administered at 2.4 μg/kg that is expected to achieve the predicted maximal serum concentration that one would expect from 500 μg dofetilide orally.” (Somberg, ¶ [0069])
“A maintenance dose (500 μg dofetilide orally) would be administered approximately one hour after start of the IV infusion.” (Somberg, ¶ [0069])
“In another aspect, dofetilide is infused over a period of 10 minutes.” (Somberg, ¶ [0033])
Somberg does not use the exact Tikosyn language requiring a facility capable of “cardiac resuscitation,” and it does not itself list all three oral strengths “125 μg, 250 μg or 500 μg.” The FDA Tikosyn label discloses:
“To minimize the risk of induced arrhythmia, 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.” (Tikosyn Label, first page, label at top of page)
“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) ...” (Tikosyn Label, first page, Description)
Based on the above comments, A person of ordinary skill would have been motivated to implement the Somberg IV-to-oral dofetilide initiation method in the FDA-labeled monitored setting because the Tikosyn label provides the established safety conditions and oral dose strengths for dofetilide initiation.
In relation to claim 3, Somberg discloses:
“c. after completion of the intravenous administration, orally administering a first 500 μg dose of dofetilide; d. chronically administering 500 μg dofetilide orally, twice daily” (Somberg, ¶ [0024])
“Chronic dosing or chronically administering refers to administration of dofetilide beyond the hospital setting (e.g., daily administration until the patient is advised otherwise).” (Somberg, ¶ [0037])
Somberg does not itself use the exact Tikosyn boxed-warning monitored-facility language carried into claim 3 through claim 1. However, the FDA Tikosyn Label discloses:
“To minimize the risk of induced arrhythmia, 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.” (Tikosyn Label, first page, label at top of page)
Based on the above comments, a person of ordinary skill would have been motivated to continue the oral dofetilide regimen after the monitored IV initiation of Somberg in the FDA labeled initiation setting because the Tikosyn label provides the established monitored facility safeguards for dofetilide loading.
In relation to claim 5, Somberg discloses:
“A 70 kg patient with a calculated GFR (glomerular filtration rate) of greater than 60 mL/min presents with intermittent atrial fibrillation (AF) and the physician decides to treat the patient with dofetilide.” (Somberg, ¶ [0069])
Somberg does not disclose the broader cardiovascular conditions list as written, and it does not use the exact Tikosyn language requiring “cardiac resuscitation.” However, Falk discloses atrial fibrillation and flutter:
“Objectives. This study sought to determine the safety and efficacy of a single bolus of intravenous dofetilide ... for the termination of sustained atrial fibrillation or flutter.” (Falk source page, Abstract)
“Ninety-one patients with sustained atrial fibrillation (75 patients) or flutter (16 patients) ...” (Falk source page, Methods)
Moreover, the FDA Tikosyn label discloses the exact monitored-facility language:
“To minimize the risk of induced arrhythmia, 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.” (Tikosyn Label, first page, label at top of page)
Based on the above comments, it would have been obvious to apply the Somberg dofetilide initiation method to patients with atrial fibrillation or flutter because both Somberg and Falk expressly address dofetilide use in atrial fibrillation.
In relation to claim 6, Somberg discloses:
“A 70 kg patient ... presents with intermittent atrial fibrillation (AF) and the physician
decides to treat the patient with dofetilide.” (Somberg, ¶ [0069])
Somberg does not disclose that the subject is “not in sinus rhythm before” IV administration, and it does not use the exact Tikosyn “cardiac resuscitation” language. However, Falk discloses treatment of sustained atrial fibrillation or flutter and conversion to sinus rhythm:
“A positive response to therapy was defined as conversion to normal sinus rhythm.”
(Falk, page 386, Protocol)
“Intravenous dofetilide can convert sustained atrial fibrillation or flutter to sinus rhythm.” (Falk, page 385, Conclusions)
Moreover, as discussed above, the FDA Tikosyn label discloses the monitored-facility language. Therefore, it would have been obvious to use IV dofetilide in patients who were not already in sinus rhythm because Falk expressly uses intravenous dofetilide to convert atrial fibrillation or flutter to sinus rhythm.
In relation to claim 7, Somberg discloses:
“A 70 kg patient ... presents with intermittent atrial fibrillation (AF) and the physician decides to treat the patient with dofetilide.” (Somberg, ¶ [0069])
Somberg does not disclose that the subject “has been converted to sinus rhythm,” and it does not use the exact Tikosyn facility language. However, Falk states:
“A positive response to therapy was defined as conversion to normal sinus rhythm.”
(Falk, page 386, Protocol)
“Intravenous dofetilide can convert sustained atrial fibrillation or flutter to sinus rhythm.” (Falk, page 385, Conclusions)
Moreover, as discussed above, the FDA Tikosyn label discloses the monitored-facility language.
Based on the above comments, it would have been obvious to use the Somberg monitored IV dofetilide method in a conversion-to-sinus-rhythm setting because Falk expressly teaches that “Intravenous dofetilide can convert sustained atrial fibrillation or flutter to sinus rhythm.”
In relation to claim 8, Somberg discloses:
“a. infusing intravenously, to a patient in need thereof, dofetilide in an amount that
achieves the predicted maximal serum concentration from 500 μg dofetilide orally
administered” (Somberg, ¶ [0024])
“A maintenance dose (500 μg dofetilide orally) would be administered approximately one hour after start of the IV infusion.” (Somberg, ¶ [0069])
Somberg does not disclose the claim’s exact alternative IV amount bands. However, Falk states:
“one of two doses of dofetilide (4 or 8 μg/kg body weight)” (Falk, page 385, Methods)
“either 4.0 or 8.0 μg/kg body weight of dofetilide” (Falk, page 386, Protocol)
Moreover, the FDA Tikosyn label states:
“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) ...” (Tikosyn label, first page, Description)
Based on the above comments, it would have been obvious to pair Falk’s known IV dofetilide dose magnitudes with the known Tikosyn oral maintenance strengths in the IV-to-oral framework of Somberg. The claim in question [Claim 8] is written in alternatives, and the 500 μg oral branch is expressly supported by Somberg and the FDA Tikosyn label.
In relation to claim 20, Somberg discloses:
“If Cmax ss, the maximal concentration obtained at steady state, can be achieved in less
than 24 hrs., the maximum QTc will be obtained in the 24-hr. period...” (Somberg, ¶ [0008])
“Thus, if a single dose reaches 70% of predicted steady state, at steady state, one can estimate Cmax ss to be 2.7 ng/mL, if 500 μg/mL was administered twice daily for at least 5 doses.” (Somberg, ¶ [0015])
“if a single dose reaches 70% of predicted steady state ... a dose of 2.4 μg/kg ... would reach a peak concentration of 2.7 ng/mL, exposing the patient to the peak serum concentration predicted for steady state...” (Somberg, ¶ [0015])
Somberg does not disclose all three oral dosing protocols of 125 μg, 250 μg, or 500 μg in the same 70%-of-steady-state-Cmax sentence. However, the FDA Tikosyn Label states:
“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) ...” (Tikosyn label, first page, Description)
Moreover, Falk discloses:
“either 4.0 or 8.0 μg/kg body weight of dofetilide” (Falk, page 386, Protocol)
Based on the above comments, it would have been obvious to administer IV dofetilide in an amount that reaches at least about 70% of steady-state Cmax for a selected oral dofetilide regimen because Somberg expressly states that objective, the FDA Tikosyn label expressly identifies the approved oral dose levels, and Falk expressly provides known IV dofetilide dose magnitudes.
Claims 9, 10, 11, 12, 14, 16, 17, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Somberg (US 2019/0388371A1) in view of the publication Falk et al. (Intravenous Dofetilide, a Class III Antiarrhythmic Agent, for the Termination of Sustained Atrial Fibrillation or Flutter; hereinafter “Falk”) and the FDA Tikosyn Label, as discussed above, and in further view of Ivaturi et al. (US 10,799,138B2; hereinafter “Ivaturi”).
Independent claim 9 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 comprising the selected amount of dofetilide based on the CrCl, wherein the IV dosage is administered over a period of about 10 minutes and is administered to the subject in a facility capable of providing cardiac resuscitation and continuous electrocardiographic monitoring.
In relation to independent claim 9, Somberg discloses:
“When administering dofetilide, a physician first assesses the QTc interval.”
(Somberg, ¶ [0005])
“The physician then calculates the patient's creatinine clearance employing the following formulas” (Somberg, ¶ [0005])
“Following calculation of creatinine clearance, the starting dose of dofetilide is determined as:”
(Somberg, ¶ [0006])
“The patient would be admitted to hospital, ECG continuously monitored, and an IV infusion of dofetilide administered at 2.4 μg/kg...” (Somberg, ¶ [0069])
“In another aspect, dofetilide is infused over a period of 10 minutes.” (Somberg, ¶ [0033])
Somberg does not disclose that (1) the IV dosage comprising the selected amount is selected based on CrCl before IV administration, and (2) Somberg (paragraph [0069]) does not use the exact Tikosyn “cardiac resuscitation” phrase. However, the FDA Tikosyn label discloses:
“Step 2. Calculation of creatinine clearance: Prior to the administration of the first dose, the patient's creatinine clearance must be calculated...” (Tikosyn label, Instructions for Individualized Dose Initiation, Initiation of TIKOSYN Therapy)
“Step 3. Starting Dose: The starting dose of TIKOSYN is determined as follows:” (Tikosyn label, Instructions for Individualized Dose Initiation, Initiation of TIKOSYN Therapy)
“To minimize the risk of induced arrhythmia, 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.” (Tikosyn label, first page, top of page)
Moreover, Ivaturi discloses:
“Embodiments of the invention are broadly drawn to methods for determining an optimum dose of an antiarrhythmic drug, for example sotalol. In particular, the method involves titrating the dose of the drug gradually to determine the optimum plasma concentration for a patient, whether the patient has normal or abnormal renal function.” (Ivaturi, Abstract)
“In some instances, with patients having abnormal renal function, the IV doses administered may be decreased in amount or strength to account for any renal impairment.” (Ivaturi, col. 5, lines 25-28)
Based on the above comments, it would have been obvious to use creatinine-clearance-based IV dofetilide selection in the monitored IV dofetilide method of Somberg because both the FDA Tikosyn label and Ivaturi expressly tie antiarrhythmic dose selection to renal function.
In relation to claim 10, Somberg discloses:
“Administering an IV infusion of dofetilide would achieve serum dofetilide concentration equivalent to that reached as steady state (Cmax ss) in one day under ECG observation.” (Somberg, ¶ [0015])
“a. infusing intravenously, to a patient in need thereof, dofetilide in an amount that achieves the predicted maximal serum concentration from 500 μg dofetilide orally administered” (Somberg, ¶ [0024])
“The patient would be admitted to hospital, ECG continuously monitored, and an IV infusion of
dofetilide administered at 2.4 μg/kg that is expected to achieve the predicted maximal serum concentration that one would expect from 500 μg dofetilide orally.” (Somberg, ¶ [0069])
Somberg does not disclose the monitored-facility and renal-adjusted framework recited through claim 9. However, as discussed above, the FDA Tikosyn label and Ivaturi disclose the creatinine-clearance and renal-function framework quoted in claim 9 above. Therefore, it would have been obvious to select the IV dofetilide amount with reference both to the target oral dofetilide dose and to renal function, because Somberg expressly ties IV loading to the predicted oral exposure and the secondary references [FDA Tikosyn label and Ivaturi] expressly require renal-based dose determination.
In relation to claim 11, Somberg discloses:
“If Cmax ss, the maximal concentration obtained at steady state, can be achieved in less
than 24 hrs., the maximum QTc will be obtained in the 24-hr. period...” (Somberg, ¶ [0008])
“Administering an IV infusion of dofetilide would achieve serum dofetilide concentration equivalent to that reached as steady state (Cmax ss) in one day under ECG observation.” (Somberg, ¶ [0015])
“if a single dose reaches 70% of predicted steady state, at steady state, one can estimate Cmax ss to be 2.7 ng/mL...” (Somberg, ¶ [0015])
“The peak concentration will typically be reached at termination of infusion (typically a 10-minute infusion).” (Somber, ¶ [0069])
Somberg does not disclose all of the express renal-selection and monitored-facility language carried through claim 9. However, as discussed above, the FDA Tikosyn label and Ivaturi disclose the renal selection and monitored-initiation framework quoted under claim 9. Therefore, it would have been obvious to use the renal-adjusted, monitored IV dofetilide initiation method while selecting an IV regimen that reaches the predicted steady-state Cmax rapidly, because Somberg expressly states that the purpose of the IV loading method is to achieve “Cmax ss” and the FDA Tikosyn label provides the renal-adjusted safety framework.
In relation to claim 12, Somberg discloses:
“[i]f patients present with a lower than normal GFR, the initial target concentration would be the same, but the maintenance dose administered would be lower; 250 μg or 125 μg b.i.d” (Somberg, ¶ [0071])
Somberg does not disclose the literal claim wording requiring a higher amount for the more renally impaired patient. However, it should be noted that this claim recites a dosing regimen that is medically counterintuitive and directly contrary to the FDA-approved prescribing information for dofetilide, which mandates lower doses for patients with worse renal function. Therefore, a person of ordinary skill in the art would have modified the dose within the approved limitations of the FDA. This claim is also subject to a § 112(b) rejection for indefiniteness.
In relation to claim 14, Somberg discloses:
“The physician then calculates the patient's creatinine clearance...”
(Somberg, ¶ [0005])
“Following calculation of creatinine clearance, the starting dose of dofetilide is determined as:” (Somberg, ¶ [0006])
“60 mL/min 500 μg bid / 40-60 mL/min 250 μg bid / 20-40 mL/min 125 μg bid / <20 mL/min Dofetilide not indicated” (Somberg, ¶ [0006])
“if a single dose reaches 70% of predicted steady state ... one can estimate Cmax ss to be 2.7 ng/mL...” (Somberg, ¶ [0015])
“The patient would be admitted to hospital, ECG continuously monitored, and an IV infusion of dofetilide administered at 2.4 μg/kg that is expected to achieve the predicted maximal serum concentration that one would expect from 500 μg dofetilide orally.” (Somberg, ¶ [0069])
Somberg does not disclose the exact dosage matrix disclosed in claim 14. However, the FDA Tikosyn label supplies the renal categories and maintenance-dose anchors:
“Step 3. Starting Dose: The starting dose of TIKOSYN is determined as follows:” (FDA Tikosyn label, Instructions for Individualized Dose Initiation, step 3)
“500 mcg twice daily” / “250 mcg twice daily” / “125 mcg twice daily” (Tikosyn label, FDA Tikosyn label, Instructions for Individualized Dose Initiation, step 3)
Falk supplies IV dose magnitudes:
“one of two doses of dofetilide (4 or 8 μg/kg body weight)” (Falk, page 385, Methods)
“either 4.0 or 8.0 μg/kg body weight of dofetilide” (Falk, page 386, Protocol)
Ivaturi discloses the renal adjustment principle for IV dosing:
“In some instances, with patients having abnormal renal function, the IV doses administered may be decreased in amount or strength to account for any renal impairment.” (Ivaturi; col. 5, lines 25-28)
Based on the above arguments, it would have been obvious to implement a renal-adjusted IV
dosing table keyed to oral maintenance-dose targets because Somberg and the FDA Tikosyn label expressly tie dofetilide dose selection to creatinine clearance and oral dose level, Falk supplies concrete IV dofetilide dose magnitudes, and Ivaturi expressly states that IV antiarrhythmic doses may be decreased for renal impairment.
In relation to claim 16, Somberg discloses:
“When administering dofetilide, a physician first assesses the QTc interval.”
(Somberg, ¶ [0005])
“The patient would be admitted to hospital, ECG continuously monitored...” (Somberg, ¶ [0069])
“QTc would be measured every 30 mins.” (Somberg, ¶ [0069])
“A maintenance dose (500 μg dofetilide orally) would be administered approximately one hour after start of the IV infusion.” (Somberg, ¶ [0069])
Somberg does not disclose a QT or QTc interval during or after administering the IV dosage is less than a 15% increase from the QT or QTc interval before administering the IV dosage. However, Ivaturi discloses:
“a method including detecting a baseline QTc of a subject, administering a first dose of an antiarrhythmic drug via a first intravenous infusion ... then determining the difference between the baseline QTc and a first QTc measured after the first intravenous infusion to detect a first delta QTc.” (Ivaturi, col. 2, lines 36-42)
Moreover, the FDA Tikosyn label discloses:
“Step 5. At 2–3 hours after administering the first dose of Tikosyn, determine the QTc or QT ... If the QTc or QT has increased by greater than 15% compared to the baseline established in Step 1 ... subsequent dosing should be adjusted...” (Tikosyn label, Instructions for Individualized Dose Initiation, Step 5)
Based on the above comments, it would have been obvious to use baseline and post-IV QT/QTc
assessment in the monitored IV dofetilide method because Somberg expressly measures QTc around the IV infusion, Ivaturi expressly compares baseline QTc to post infusion QTc, and the Tikosyn label expressly uses a “greater than 15%” QT/QTc threshold.
In relation to claim 17, Somberg discloses:
“QTc would be measured every 30 mins.” (Somberg, ¶ [0069])
“A maintenance dose (500 μg dofetilide orally) would be administered approximately one
hour after start of the IV infusion.” (Somberg, ¶ [0069])
“After the infusion and oral dose of dofetilide, the peak concentration will be reached in 4 h and then at 8 h a trough concentration will be reached, and a second oral dose can be administered.” (US20190388371A1, ¶ [0069])
Somberg does not explicitly disclose the claim’s exact before-first-oral-dose QT/QTc comparison language. However, Ivaturi states:
“detecting a baseline QTc of a subject ... then determining the difference between the baseline QTc and a first QTc measured after the first intravenous infusion to detect a first delta QTc.” (Ivaturi, col. 2, lines 37-42)
Additionally, the FDA Tikosyn label discloses:
“If the QTc or QT has increased by greater than 15% compared to the baseline established in Step 1 ... subsequent dosing should be adjusted...” (Tikosyn label, Instructions for Individualized Dose Initiation, Step 5)
Based on the above comments, it would have been obvious to make a QT/QTc reassessment before proceeding to the first oral dofetilide dose because Somberg expressly transitions from monitored IV dosing to oral dosing, Ivaturi expressly uses a post-infusion delta-QTc decision point, and the FDA Tikosyn label expressly uses the 15% QT/QTc threshold to guide subsequent dosing.
In relation to claim 18, Somberg discloses:
“c. after completion of the intravenous administration, orally administering a first 500 μg dose of dofetilide; d. chronically administering 500 μg dofetilide orally, twice daily” (Somberg, ¶ [0024])
Somberg also discloses:
“After the infusion and oral dose of dofetilide ... a second oral dose can be administered.” (Somberg, ¶ [0069])
Somberg does not disclose the precise QT/QTc decision framework carried through claim 17. However, as discussed above, Ivaturi and the FDA Tikosyn label disclose the post-infusion QT/QTc decision framework quoted under claims 16 and 17. Therefore, it would have been obvious to administer the first and subsequent oral doses after acceptable QT/QTc reassessment because Somberg expressly states the first and second oral doses, while Ivaturi and the FDA Tikosyn label expressly teach post-infusion QT/QTc-based dosing decisions.
Claims 4 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Somberg (US 2019/0388371A1) in view of the publication Falk et al. (Intravenous Dofetilide, a Class III Antiarrhythmic Agent, for the Termination of Sustained Atrial Fibrillation or Flutter; hereinafter “Falk”) and the FDA Tikosyn Label, as discussed above, and in further view of the publication Prystowsky et al. (Clinical Experience with Dofetilide in the Treatment of Patients with Atrial Fibrillation; hereinafter “Prystowsky”).
In relation to claim 4, Somberg discloses:
“Chronic dosing or chronically administering refers to administration of dofetilide beyond the hospital setting (e.g., daily administration until the patient is advised otherwise).” (Somberg, ¶ [0037])
“the patient could still be discharged in 24 hrs.” (Somberg, ¶ [0072])
Somberg does not expressly state that oral dosing is performed “before or after” discharge from the monitored facility, and it does not use the exact Tikosyn boxed-warning language for that facility. However, Prystowsky discloses:
“Fifty-eight patients were discharged receiving dofetilide treatment and were followed as outpatients for 21 +/- 7 months.” (Prystowsky Abstract, Methods and Results, page S287)
“To minimize the risk of induced arrhythmia, 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.” (Tikosyn label, first page, top of the page)
Based on the above comments, it would have been obvious to continue oral dofetilide after
discharge from the monitored initiation facility because Somberg expressly contemplates chronic dosing beyond the hospital setting and Prystowsky expressly states that patients were “discharged receiving dofetilide treatment.”
In relation to claim 19, Somberg discloses:
“c. after completion of the intravenous administration, orally administering a first 500
μg dose of dofetilide; d. chronically administering 500 μg dofetilide orally, twice daily;
provided that if the patient's QTc has increased by 15% over baseline QTc or if the QTc
greater than 500 msec ... the chronic oral dosages of dofetilide are reduced to 250 μg.”
(Somberg, ¶¶ [0024-0028])
“If the QTc has increased by 15% over baseline QTc ... subsequent oral doses would be reducted to 250 μg b.i.d.” (Somberg, ¶ [0070])
Somberg does not expressly provide the full set of alternative later oral-dose adjustments reflected in the FDA label. The FDA Tikosyn label discloses:
“If the QTc or QT has increased by greater than 15% compared to the baseline established in Step 1 ... subsequent dosing should be adjusted as follows:” (Tikosyn label, Instructions for Individualized Dose Initiation, Step 5)
“500 mcg twice daily ... 250 mcg twice daily / 250 mcg twice daily ... 125 mcg twice daily / 125 mcg twice daily ... 125 mcg once a day” (Tikosyn label, Instructions for Individualized Dose Initiation, Step 5)
Additionally, Prystowsky discloses:
“Reductions in subsequent dosage occurred in 12 patients, 4 for QT prolongation.” (Prystowsky Abstract, Methods and Results, page S287)
Based on the above comments, it would have been obvious to make one or more subsequent oral doses different from the first oral dose because Somberg, the FDA Tikosyn label, and Prystowsky each expressly disclose QT-based reduction of later oral dofetilide dosing.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Somberg (US 2019/0388371A1) in view of the publication Falk et al. (Intravenous Dofetilide, a Class III Antiarrhythmic Agent, for the Termination of Sustained Atrial Fibrillation or Flutter; hereinafter “Falk”) and the FDA Tikosyn Label, as discussed above, and in further view of Ivaturi et al. (US 10,799,138B2; hereinafter “Ivaturi”) and Prystowsky et al. (Clinical Experience with Dofetilide in the Treatment of Patients with Atrial Fibrillation; hereinafter “Prystowsky”).
In relation to claim 15, Somberg discloses:
“Chronic dosing or chronically administering refers to administration of dofetilide
beyond the hospital setting...” (Somberg, ¶ [0037])
“the patient could still be discharged in 24 hrs.” (Somberg, ¶ [0072])
Somberg does not disclose discharge with instructions to self-administer oral doses “every 12 to 48 hours.” However, Prystowsky discloses:
“Fifty-eight patients were discharged receiving dofetilide treatment and were followed as outpatients...” (Prystowsky Abstract, Methods and Results, page S287)
Additionally, Ivaturi discloses:
“the oral maintenance doses may be administered every 24 hours instead of every 12 hours for patients with renal impairment or abnormal renal function.” (Ivaturi, col. 5, lines 23-25)
Also, the FDA Tikosyn label discloses:
“TIKOSYN is supplied for oral administration in three dosage strengths...” (Tikosyn label, Description)
Based on the above comments, it would have been obvious to discharge the patient with
continued oral dofetilide instructions after successful monitored IV initiation because Somberg expressly contemplates chronic dosing beyond the hospital setting, Prystowsky expressly states that patients were “discharged receiving dofetilide treatment,” and Ivaturi expressly states that oral maintenance doses may be given “every 24 hours instead of every 12 hours,” which falls within the claimed “every 12 to 48 hours” range.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Somberg (US 2019/0388371A1) in view of the publication Falk et al. (Intravenous Dofetilide, a Class III Antiarrhythmic Agent, for the Termination of Sustained Atrial Fibrillation or Flutter; hereinafter “Falk”) and the FDA Tikosyn Label, as discussed above, and in further view of Ivaturi et al. (US 10,799,138B2; 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 13, Somberg discloses:
“c. after completion of the intravenous administration, orally administering a first 500 μg dose of dofetilide; d. chronically administering 500 μg dofetilide orally, twice daily” (Somberg, ¶ [0024])
Somberg does not disclose an IV maintenance infusion after the initial IV dosage. However, Ivaturi discloses a maintenance-dose definition:
“maintenance dose” is “an oral or IV dose given following IV titration/loading.” (Somberg, Table 1, col. 4)
Pool discloses an IV loading-plus-maintenance regimen:
“Subjects received a single-blind, IV infusion of placebo and were randomized (3:1) to receive a double-blind second infusion of placebo or 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, for a total dose of 7.5 g/kg).” (Pool, Summary, page 415)
Based on the above comments, it would have been obvious to use either oral maintenance dosing after IV dofetilide loading, as expressly stated in Somberg, or an IV maintenance infusion following an IV loading infusion, as expressly stated in Pool and Ivaturi’s maintenance-dose terminology. In view of the conventionality of this enhancement in the art, its implementation in the invention would have been considered an obvious alternative in the design of the method.
Conclusion
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Respectfully submitted,
/MANUEL A MENDEZ/ Primary Examiner, Art Unit 3783
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