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 Status
Claims 1-24 are currently pending and subject to examination.
Claim Rejections - 35 USC § 112(d)- Withdrawn- Overcome by Amendment
The rejection of claims 24-25 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn.
The above rejection was overcome by Applicant’s amendment to the claims.
Claim Rejections - 35 USC § 112(b) – New Grounds of Rejection Necessitated by Amendment
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 24 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 24 is directed towards the method of claim 1, further comprising, after step (b) but before step (c), continuing the maintenance infusion until the patient has recovered from the termination of the arrhythmic storm and is able to take dofetilide orally, then stopping the IV maintenance infusion.
One of ordinary skill in the art cannot determine the metes and bounds of claim 24 because claim 24 requires, after step B, but before step (c) continuing the maintenance infusion until the patient has recovered from the termination of arrhythmic storm but (1) what if the patient never recovers from the arrhythmic storm or (2) the patient recovers during step (b). For (1) If the patient dies, remains critically ill, or never stabilizes, the condition precedent to step (c) is never satisfied. For (2) If the patient recovers for example, at hour 8 during step (b), then what exactly is being continued until?
Appropriate correction is required.
Claim Rejections - 35 USC § 103- Previously Presented
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.”
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
The rejection of claims 1-24 under 35 U.S.C. 103 as being unpatentable over Pinter (J Am Coll Cardiol., 2011 Jan, Vol. 57, No. 3, pages 380–381, published January 18, 2011) in view of Kashfian and Devlin (US20230172883A, filed August 22, 2022), Eifling et al. (Texas Heart Institute Journal, 2011; 38(2):111–121), and Kalus & Mauro (The Annals of Pharmacotherapy, 2000 January, Volume 34, p. 44-56) is maintained.
Response to Arguments
The Applicant argues that the USPTO has improperly considered the individual components of the claimed invention and of Kashfian rather than the invention as a whole (Remarks, p. 5). These arguments were fully considered but are not persuasive. The obviousness analysis did consider the invention as a whole and the Applicant mischaracterizes the rejection. Kashfian is not a random collection of possibilities as suggested by the Applicant. Kashfian is a structured disclosure teaching dofetilide administration with specific guidance on dose adjustment based on creatinine clearance and QTc monitoring. The 1B embodiments figure is misleading because the claims do not recite a single narrow embodiment. The claims recite ranges (450-500 micrograms loading dose, 30-60 minute administration, 2-6 hour delay, etc.) that substantially overlaps with Kashfian’s teachings. The question is not whether one specific combination was obvious, but whether the claimed ranges were obvious given the prior art. The evidence presented in the prior action clearly meets this standard.
The Applicant argues that Pinter and Eifling do not teach that arrhythmic storm is caused by implementation and testing of an ICD (Remarks, p. 6). These arguments were fully considered but are not persuasive. Eifling specifically teaches that ICD therapy delivery- which occurs during implementation and testing- can cause an electrical storm (Eifling p. 117-118, cited on p. 7 of the previous OA).One of ordinary skill in the art would understand that ICD implementation necessarily involves therapy delivery, which Eifling identifies as a potential electrical storm triggers. The Applicant’s distinction between storms cause “over time” versus caused by “implementation and testing” is not meaningful. The prior art establishes that ICDs can trigger arrhythmic storm and dofetilide is effective for treating such storms. An ordinary artisan would reasonably apply dofetilide to ICD-triggered storms regardless of whether they occurred during implementation or later.
The Applicant argues that Pinter and Kashfian do not teach claimed step (a) 450-500 micrograms IV loading dose over 30-60 minutes (Remarks, p. 7) These arguments were fully considered but are not persuasive. A loading dose of 450-500 micrograms (mcgs) is clearly contemplating by Kashfian, and falls within the ranges taught by Kashfian. As already cited, Kashfian teaches doses of 0.1-12 mcg/kg (Kashfian, Specification, paragraph 0040). For a typical adult patient (70 kg), this translates to doses ranging from 7 mcg to up to 840 mcg. The claimed 450-500 mcg range falls squarely within the disclosed range. Regarding the 30-60 minute administration, as already cited, Kashfian teaches administration over “5,10, 15, 20, 30, 45 or 60 minutes). The MPEP § 2144.05 states that a prima facie case of obviousness exists when claimed ranges overlap or lie inside the ranges taught by the prior art. The Applicant’s argument that fixed doses are not taught, only weight-based doses, is a distinction without patentable weight—converting between the two is routine arithmetic a clinician would perform in order to administer the drug.
The Applicant argues that the combination of Pinter and Kashfian does not teach the presently claimed 2-6 hour delay in step (c) and that the USPTO is required to show a motivation to increase the delay of aspect 12 in Kashfian (Remarks, p. 7-8). These arguments were fully considered but are not persuasive. Under KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Court rejected the rigid teaching, suggestion, motivation (TSM) test. The examiner does not need to find explicit motivation in the prior art to make a specific modification. The examiner need only show a reason why a person of ordinary skill in the art would have been prompted to modify or combine the prior art references and a reasonable expectation of success in doing so (MPEP § 2143.02). When the general conditions of a claim are disclosed in the prior art, discovering the optimal or workable ranges involves only routine skill unless the applicant demonstrates criticality (MPEP § 2144.05.II (citing In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Timing and duration are a result-effective variables that one of ordinary skill in the art would optimize based on patient response and clinical judgement. The prior art establishes:
Loading doses precede maintenance doses
Maintenance infusions have variable duration
Oral dosing follows IV therapy
The patient is closely monitored via ECG and the timing and dosage adjusted based on side effects typically associated with dofetilide administration
One of ordinary skill in the art would understand that the IV duration and timing between doses directly affects:
Peak and trough drug concentrations
Risk of QTc prolongation
Therapeutic efficacy
Patient safety during transition.
For example, Kashfian teaches that: “First order kinetics with a linear dose plasma concentration relationship, and a linear relationship between plasma concentration and effect on QT interval during IV administration of dofetilide have been described. (Sedgwick et al., 1991). Such kinetics allows titration of an appropriate anti-arrhythmic therapeutic plasma concentration and effect.” (Kashfian, Specification, paragraph 0038). “Proper dosing for any of dofetilide,… can be ascertained by monitoring the QT interval, or the heart rate corrected QT (the QTc), during or after IV infusion of the loading and/or maintenance dose(s), and thus avoid the development of life-threatening ventricular tachycardias such as Torsades de Pointes. Patients can be monitored by electrocardiogram (ECG) and a baseline QTc can be measured.” (Kashfian, Specification, paragraph 0112). The Applicant is narrowly focused on Aspect 12-14’s listing of a 6 hour delay, but this ignores that Kashfian contemplates extended maintenance infusions, and explicitly teaches flexibility.
Furthermore, the Applicant would have a reasonable expectation of success in adjusting the protocol as claimed because the (1) pharmacokinetics of dofetilide are well characterized, (2) the mechanism is straight forward (IV infusion maintains blood levels, oral dosing continues maintenance after IV stops, extending the IV portion does not introduce any unpredictability), (3) ECG monitoring provides real time feedback (one of ordinary skill would know if the regimen causes problems because the prior art explicitly teaches monitoring and Kashfian also teaches that QTc is directly related to blood levels), (4) loading doses, maintenance infusions, oral dosing, time delays between transitions, and the combination thereof, are all well known in the art. Adjusting just one parameter, maintenance infusion duration, is a routine optimization that an ordinary artisan would carry out during a routine optimization with a full expectation of therapeutic success. The Applicant has not argued, let alone demonstrated, that the claimed protocol produces anything unexpected.
The Applicant again argues that Pinter and Kashfian do not teach the claimed amounts of dofetilide (Remarks, p. 8). These arguments were fully considered but are not persuasive. First, Kalus establishes that dofetilide treatment “up to 2 mg per day” are well known in the art. Moreover, Applicant’s own admissions establish that the prior art teaches doses in the relevant therapeutic ranges. Even if, in arguendo, the prior art teaches doses that are somewhat lower, this does not negate obviousness when they are close and optimization is routine (MPEP § 2144.05). Again, blood levels and therapeutic targets for dofetilide are well-characterized and routine as evidenced by the QTc monitoring requirements, making dose optimization a matter of routine skill rather than inventive contribution.
Rejection
Claims 1-25 are rejected under 35 U.S.C. 103 as being unpatentable over Pinter (J Am Coll Cardiol., 2011 Jan, Vol. 57, No. 3, pages 380–381, published January 18, 2011) in view of Kashfian and Devlin (US20230172883A, filed August 22, 2022), and Eifling et al. (Texas Heart Institute Journal, 2011; 38(2):111–121).
Claim 1 is directed towards:2883A1
PNG
media_image1.png
559
524
media_image1.png
Greyscale
PNG
media_image2.png
57
487
media_image2.png
Greyscale
Claim 1.
Pinter teaches dofetilide for the treatment of electrical storm (> 3 episodes of ventricular tachycardia or arrythmia in 24 hours) in patients with implantable defibrillators (ICDs):
“Many patients with an implantable cardioverter-defibrillator (ICD) require concomitant antiarrhythmic drug (AAD) therapy at some point. Sotalol and especially amiodarone have been shown to reduce the number of ventricular tachycardia (VT)/ventricular fibrillation (VF) episodes and high-energy shocks therapies delivered by the ICDs (1). However, these drugs are frequently not tolerated or are ineffective (2).
Dofetilide, a selective Ikr-blocking agent, was as efficacious as sotalol in preventing the induction of sustained VT in patients with ischemic heart disease in 1 study (3). Dofetilide appears to be safe, as the mortality rate was not increased with dofetilide in patients with recent myocardial infarction and impaired left ventricular function (4).
The aim of this cohort study was to assess the efficacy and tolerability of dofetilide in patients with ICDs who have frequent VT/VF and who either failed or did not tolerate conventional AAD therapy.
The study included all defibrillator patients from our center who were placed on dofetilide for frequent VT/VF defined as either electrical storm (≥3 episodes of VT/VF within 24 h) or an average ≥1 symptomatic episodes of VT/VF or appropriate shock per month. These patients did not tolerate or failed a mean number of 2.7 ± 1.0 AADs (range 2 to 5) alone or in combination, including amiodarone in all but 1 patient.
The primary end point was the total number of VT/VF episodes. Secondary end points were mortality, number of total shocks, appropriate shocks, electrical storm, hospitalization, and drug discontinuation. The patients served as their own controls: the “on dofetilide” treatment period was compared with an equivalent duration of a “pre-dofetilide” treatment period just prior to initiating dofetilide, when the patient had been treated with other AADs…
In the subgroup of the 9 responders, the number of VT/VF episodes, total shocks, appropriate shocks, appropriate antitachycardia pacing, electrical storm, and hospitalizations were significantly reduced both during short-term and medium-term follow-up.
Dofetilide-based antiarrhythmic therapy was well tolerated and moderately effective for electrical storm and/or frequent VT/VF in patients who did not tolerate or failed amiodarone-based antiarrhythmic therapy”
Pinter, page 380 (emphasis added).
As shown above, Pinter teaches that patients with ICDs often require anti-arrhythmic drug therapy and many do not tolerate amiodarone or sotalol. Pinter teaches that dofetilide can terminate arrhythmic storm in patients with ICDs. Therefore, one of ordinary skill in the art would have a reasonable expectation of success to terminate arrhythmic storm in a patient with an ICD. While Pinter does not teach that the ICD is the cause of the arrhythmic storm, one of ordinary skill in the art would have a reasonable expectation of success to terminate arrhythmic storm cause by the ICD because Pinter teaches dofetilide to terminate arrhythmic storm in patients with ICDs and because it is well known that the ICD can be a cause of the arrhythmic storm. For example, Eifling teaches that ICD therapy can cause electrical storm and that these patients may require anti-arrhythmic therapy:
An ICD storm may result from appropriate therapy (antitachycardia pacing, cardioversion, or defibrillation), inappropriate therapy (shocks without evidence of an arrhythmia), or phantom shocks (Fig. 2). (These last 2 conditions are not considered to be true electrical storm.) In cases of ongoing arrhythmia with hemodynamic compromise, the arrhythmia should be corrected immediately. Interrogating the device helps to distinguish appropriate from inappropriate therapy. If the device reveals appropriate termination of VT or VF, a search should begin for ischemia, electrolyte imbalances, worsening heart failure, and other causes. Transient ST-segment changes and mildly elevated cardiac troponin levels are common after multiple shocks. Shocks without evidence of an arrhythmia indicate device malfunction, such as the sensing of electrical noise from a fractured lead. In such cases, the patient should be hospitalized and observed by means of telemetry with the ICD programmed to “off.” (The nursing staff should be apprised that the ICD is turned off.) Rapid SVT or atrial fibrillation may result in inappropriate shocks, in which case a magnet can be placed over the ICD to inhibit sensing and treatment of the arrhythmia. If the patient develops a ventricular arrhythmia, removing the magnet enables the delivery of therapy. Applying a magnet does not alter the pacing ability of the ICD…
Antiarrhythmic medications can reduce the frequency of ICD shocks.
Eifling p. 117-118.
While Pinter does not teach the exact dosing regimen as claimed, one of ordinary skill in the art would have a reasonable expectation of success to administer the dosage regimen as claimed because they are known in the art. For example, Kashfian and Devlin teach the claimed dosing regimen for the treatment of ventricular tachycardia and arrythmia (loading dose 450-500 mcg (about 6 mcg/kg) administered up to 60 minutes, maintenance dose administered 0-4 hours after loading dose for over one hour, orally administering a maintenance dose every 12 hours based on the CrCl and adjusting dose based on QTc):
“[0039]
According to embodiments, Aspect 1 is a method comprising: administering an anti-arrhythmic, such as dofetilide, to a patient, wherein the anti-arrhythmic or dofetilide is administered intravenously over a duration of at least 1 hour and in an amount effective for treating or preventing a cardiovascular condition of the patient.
[0040]
Aspect 2 is a method, comprising: administering an anti-arrhythmic or dofetilide to a patient; wherein the anti-arrhythmic or dofetilide is administered: as a loading dose intravenously, optionally over a duration of up to 60 minutes, and in an amount ranging from 0.1 to 12 μg/kg bodyweight; and/or as a maintenance dose intravenously, optionally over a duration of at least 1 hour, and in an amount ranging from 0.1 to 10 μg/kg/hr, optionally alternatively or in addition wherein the amount of the IV loading dose is in the range of about ±50% of the IV maintenance dose.
[0041]
Aspect 3 is the method of Aspect 1 or 2, wherein: the cardiovascular condition is selected from atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation, paroxysmal supraventricular tachycardia, heart failure, coronary artery disease, and pulmonary artery hypertension.
[0042]
Aspect 4 is the method of any of Aspects 1-3, further comprising measuring a QT interval of the patient before, during, and/or after the administering, and selecting or adjusting the effective amount, the loading dose and/or the maintenance dose based on the QT interval.
[0043]
Aspect 5 is the method of any of Aspects 1-4, further comprising measuring a creatinine clearance of the patient before the administering, and selecting or adjusting the effective amount, the loading dose and/or the maintenance dose based on the creatinine clearance.
[0044]
Aspect 6 is a method of administering an anti-arrhythmic or dofetilide to a patient, comprising: (A) determining a creatinine clearance of the patient; (B) administering to the patient an IV loading dose of the anti-arrhythmic or dofetilide selected from an amount ranging from 0.1-12 μg/kg; (C) administering to the patient one or more IV maintenance dose of the anti-arrhythmic or dofetilide selected from an amount ranging from 0.1-10 μg/kg; and (D) optionally alternatively or in addition wherein the amount of the IV loading dose is in the range of about ±50% of the IV maintenance dose.
[0045]
Aspect 7 is the method of any of Aspects 1-6, wherein the IV loading dose is 0.1 μg/kg, 0.5 μg/kg, 0.8 μg/kg, 1.5 μg/kg, 3.5 μg/kg, 4.5 μg/kg, 5.5 μg/kg, 6 μg/kg, 6.5 μg/kg, 7 μg/kg, 7.5 μg/kg, 8.5 μg/kg, 9 μg/kg, 9.5 μg/kg, 10.5 μg/kg, 11 μg/kg, or 11.5 μg/kg.
[0046]
Aspect 8 is the method of any of Aspects 1-7, wherein the IV maintenance dose is 0.1 μg/kg, 0.5 μg/kg, 0.8 μg/kg, 1.5 μg/kg, 3.5 μg/kg, 4.5 μg/kg, 5.5 μg/kg, 6 μg/kg, 6.5 μg/kg, 7 μg/kg, 7.5 μg/kg, 8.5 μg/kg, 9 μg/kg, 9.5 μg/kg.
[0047]
Aspect 9 is the method of any of Aspects 1-8, wherein the IV maintenance dose is lower than the IV loading dose.
[0048]
Aspect 10 is the method of any of Aspects 1-8, wherein the IV maintenance dose is higher than the IV loading dose.
[0049]
Aspect 11 is the method of any of Aspects 1-10, further comprising administering one or more oral dose of the anti-arrhythmic or dofetilide to the patient.
[0050]
Aspect 12 is the method of any of Aspects 1-11, further comprising a time delay between completion of the administering of the IV loading dose and administering the one or more IV maintenance dose to the patient and/or administering the one or more oral dose to the patient.
[0051]
Aspect 13 is the method of Aspect 12, wherein the time delay is less than 1 hour.
[0052]
Aspect 14 is the method of Aspect 12, wherein the time delay is 1, 2, 3, 4, 5, or 6 hours.
[0053]
Aspect 15 is the method of any of Aspects 1-8, wherein the IV maintenance dose is the same as the IV loading dose.
[0054]
Aspect 16 is the method of Aspect 12, wherein the time delay is less than 30 minutes.
[0055]
Aspect 17 is the method of any of Aspects 1-16, wherein the patient is being treated for atrial fibrillation and/or atrial flutter.
[0056]
Aspect 18 is a method of administering an anti-arrhythmic or dofetilide to a patient, comprising: (A) determining a creatinine clearance of the patient; (B) administering to the patient an IV loading dose of the anti-arrhythmic or dofetilide selected from an amount ranging from 0.1-12 μg/kg; (C) administering to the patient (i) one or more IV maintenance dose of the anti-arrhythmic or dofetilide selected from an amount ranging from 0.1-10 μg/kg and/or (ii) one or more oral maintenance dose of the anti-arrhythmic or dofetilide selected from an amount ranging from 125 μg to 500 such as 125 μg, 250 μg, or 500 μg; and (D) optionally alternatively or in addition wherein the amount of the IV loading dose is in the range of about ±50% of the oral dose and/or the IV maintenance dose.
[0057]
Aspect 19 is the method of Aspect 18, wherein the creatinine clearance of the patient is >60 mL/min and the oral maintenance dose is 500 μg.
[0058]
Aspect 20 is the method of Aspect 18, wherein the creatinine clearance of the patient is 40-60 mL/min and the oral maintenance dose is 250 μg.
[0059]
Aspect 21 is the method of Aspect 18, wherein the creatinine clearance of the patient is 20-40 mL/min and the oral maintenance dose is 125 μg.[0060]
Aspect 22 is the method of Aspect 18, wherein the creatinine clearance of the patient is 20-60 mL/min and the IV loading dose is 3.5 μg/kg.
[0061]
Aspect 23 is a method of initiating anti-arrhythmic or dofetilide treatment in a patient, comprising: (A) determining a creatinine clearance of the patient; (B) determining a QT interval of the patient; (C) administering to the patient an IV loading dose of an anti-arrhythmic or dofetilide selected from an amount ranging from 0.1-12 μg/kg; and (D) determining a second QT interval of the patient; (E) optionally administering one or more subsequent IV and/or oral doses of the anti-arrhythmic or dofetilide to the patient; (F) optionally alternatively or in addition wherein the amount of the IV loading dose is in the range of about ±50% of the subsequent IV dose and/or oral dose; and (G) optionally determining one or more subsequent QT interval of the patient between one or more of the subsequent IV and/or oral doses.
[0062]
Aspect 24 is the method of Aspect 23, further comprising: determining a change in QT interval of the patient; and if the second QT interval has increased less than 15% over the first QT interval, then administering to the patient one or more IV maintenance dose selected from an amount ranging from 0.1-10 μg/kg and/or one or more oral maintenance dose selected from an amount of 125 μg, 250 μg, or 500 μg.”
Kashifan and Devlin, Specification, paragraphs 0039-0062;
Furthermore, Kalus teaches that dofetilide treatment up to 2 mg per day is well known in the art for treating ventricular tachycardia, and that it is well known to adjust for CrCl and QT prolongation:
PNG
media_image3.png
477
848
media_image3.png
Greyscale
Kalus, p. 51;
PNG
media_image4.png
223
424
media_image4.png
Greyscale
Kalus, p. 53.
Given the above teachings, the claimed invention is well within the level of ordinary skill.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 2 recites:
“The method of Claim 1, further comprising: measuring the QTc of the patient prior to the IV loading dose of dofetilide to establish a baseline QTc and then measuring the QTc about every 15-30 minutes thereafter for 60 min and prior to the IV maintenance infusion and before each oral dose.”
Claim 2.
Pinter teaches that excessive QTc prolongation may necessitate dose reduction: “No patient required a reduction of the dofetilide dose due to side effect or excessive QTc prolongation” (Pinter, page 380). While Pinter does not teach how to measure QTc prolongation, Kashifan and Devlin teach measuring QTc at baseline and at intervals of 15, 30 and 60 minutes:
“Proper dosing for any of dofetilide, sotalol, amiodarone, ibutilide, dronedarone, procainamide, flecainide, or propafenone can be ascertained by monitoring the QT interval, or the heart rate corrected QT (the QTc), during or after IV infusion of the loading and/or maintenance dose(s), and thus avoid the development of life-threatening ventricular tachycardias such as Torsades de Pointes. Patients can be monitored by electrocardiogram (ECG) and a baseline QTc can be measured. A baseline QTc exceeding a certain threshold, such as 440 msec, may exclude some patients from dofetilide treatment (see US Patent Application Publication No. 20190388371A1). For patients that qualify for treatment, the QTc can be monitored during infusion of the loading and/or maintenance dose, and such dose can be adjusted downward or ceased if the patient's QTc becomes too high, either over a QTc threshold or a change exceeding a patient's baseline QTc. In one implementation, the QTc threshold is 500 msec. In various implementations, the change exceeding baseline QTc can be 5, 10, 15, or 20% over baseline QTc. The QTc can be measured at regular intervals, such as every 10, 15, 20, 30, 45, or 60 minutes during treatment. In some situations, such as if the patient's heart rate is less than 60 bpm, the uncorrected QT interval can be used. Remote ECG monitoring, such as Holter monitoring or event monitoring, may be indicated for long term monitoring of QT or QTc.”
Kashifan and Devlin, Specification, paragraph 0112;
The patient's QT or QTc is monitored every hour during the administration of the IV maintenance dose. If during or after the IV maintenance dose the patient's QT or QTc is greater than 550 msec or if the QT or QTc increases by greater than 20% of the patient's baseline QT or QTc, then the IV maintenance dose is reduced and subsequent IV maintenance doses are delivered at approximately 1.25 μg/kg over up to 5 hours.
Kashifan and Devlin, Specification, paragraph 0127.
Therefore, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to administer dofetilide while “measuring the QTc of the patient prior to the IV loading dose of dofetilide to establish a baseline QTc and then measuring the QTc about every 15-30 minutes thereafter for 60 min and prior to the IV maintenance infusion and before each oral dose.”
Thus, claim 2 was prima facie obvious at the time of filing.
Claims 3-8 specify loading doses of 450, 460, 470, 480, 490, and 500 mcg of dofetilide respectively. As shown above, while Pinter does not teach the loading protocol, Kashifan and Devlin teach loading doses of 5.5 μg/kg, 6 μg/kg, 6.5 μg/kg (Kashifan and Devlin, Specification, paragraph 0045). Taking the average body weight of 80 kg, this corresponds to doses between 440 and 520 μg/kg. “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists” (MPEP § 2144.05 [R-07.2022]).
Thus, claims 3-8 were prima facie obvious at the time of filing.
Claims 9-12 specify loading doses administered over 30, 40, 50, and 60 minutes respectively. While Pinter does not teach a loading dose protocol, Kashifan and Devlin teach: “the IV loading dose is administered over 5, 10, 15, 20, 30, 45, or 60 minutes” (Kashifan and Devil, Specification, paragraph 64). Therefore, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to administer the loading dose over 30, 40, 50, or 60 minutes.
As such, claims 9-12 were prima facie obvious at the time of filing.
Claims 13-17 specify that the maintenance infusion is started about 0, 1, 2, 3 and 4 hours after completion of the loading dose respectively. While Pinter does not teach a loading and maintenance infusion protocol, Kashifan and Devlin teach starting the maintenance infusion immediately after, and less than 1 hour or at 1, 2, 3, and 4 hours following the loading infusion:
“[0050]
Aspect 12 is the method of any of Aspects 1-11, further comprising a time delay between completion of the administering of the IV loading dose and administering the one or more IV maintenance dose to the patient and/or administering the one or more oral dose to the patient.
[0051]
Aspect 13 is the method of Aspect 12, wherein the time delay is less than 1 hour.
[0052]
Aspect 14 is the method of Aspect 12, wherein the time delay is 1, 2, 3, 4, 5, or 6 hours.
[0053]
Aspect 15 is the method of any of Aspects 1-8, wherein the IV maintenance dose is the same as the IV loading dose.
[0054]
Aspect 16 is the method of Aspect 12, wherein the time delay is less than 30 minutes.”
Kashifan and Devlin, Specification, paragraphs 0050-0054;
The maintenance dose can be initiated immediately after completion of the loading dose, or can be initiated after a delay of 0.5 hours to 6 hours, such as a delay of from 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, or 5.5 hours after completion of the loading dose.
Kashifan and Devlin, Specification, paragraph 0109.
As such, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to administer the maintenance dose at 0, 1, 2, 3, or 4 hours following the loading dose.
Therefore, claims 13-17 were prima facie obvious at the time of filing.
Claim 18 recites: “The method of Claim 1, wherein the patient has a CrCl of >60 mL/min, the IV maintenance infusion is about 450-500 µg given over about 12 h and the oral doses are 500 µg.” While Pinter does not explicitely teach dose adjustment based on CrCl, Kashifan and Devlin teach adjusting the dose based on CrCl and a dose of 500 mcg for patients with CrCl over 60 mL/min:
“[0056]
Aspect 18 is a method of administering an anti-arrhythmic or dofetilide to a patient, comprising: (A) determining a creatinine clearance of the patient; (B) administering to the patient an IV loading dose of the anti-arrhythmic or dofetilide selected from an amount ranging from 0.1-12 μg/kg; (C) administering to the patient (i) one or more IV maintenance dose of the anti-arrhythmic or dofetilide selected from an amount ranging from 0.1-10 μg/kg and/or (ii) one or more oral maintenance dose of the anti-arrhythmic or dofetilide selected from an amount ranging from 125 μg to 500 such as 125 μg, 250 μg, or 500 μg; and (D) optionally alternatively or in addition wherein the amount of the IV loading dose is in the range of about ±50% of the oral dose and/or the IV maintenance dose.
[0057]
Aspect 19 is the method of Aspect 18, wherein the creatinine clearance of the patient is >60 mL/min and the oral maintenance dose is 500 μg.”
Kashifan and Devlin, Specification, paragraphs 0056-0057.
They also teach administering the IV maintenance infusion for over 1 hour, for example 6 hours:
“Aspect 36 is the method of any of Aspects 1-35, wherein the anti-arrhythmic or dofetilide, and/or the IV loading dose, and/or one or more subsequent IV doses, and/or one or more of the IV maintenance doses is administered over 5, 10, 15, 20, 30, 45, or 60 minutes, is administered for up to 60 minutes, is administered over a time period of at least 1 hour, is administered over 0.5, 1, 2, 3, 4, 5, or 6 hours, or is administered for a duration of at least 1 hour, and/or optionally is administered by way of several IV doses.”
Kashifan and Devlin, Specification, paragraph 0074.
While they do not explicitly teach 12 hours, this difference amounts to nothing more than a routine optimization in light of the prior art. Thus, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to administer the IV maintenance infusion of 450-500 µg over about 12 h and oral doses of 500 µg to a patient with a CrCl > 60 mL/min.
Therefore, claim 18 was prima facie obvious at the time of filing.
Claim 19 recites: “The method of Claim 18, wherein the oral doses are reduced to 250 µg due to a QTc that increased by 15% over baseline QTc or if the QTc is measured at >500 msec or >550 msec if the patient has a ventricular conduction abnormality.” While Pinter does not explicitly teach how to adjust the dose for QTc, Kashifan and Devlin teach reducing the dose to 250 mcg if the change in QTc exceeds 15-20% or if the QTc is greater than 500-550 msec:
“For patients that qualify for treatment, the QTc can be monitored during infusion of the loading and/or maintenance dose, and such dose can be adjusted downward or ceased if the patient's QTc becomes too high, either over a QTc threshold or a change exceeding a patient's baseline QTc. In one implementation, the QTc threshold is 500 msec. In various implementations, the change exceeding baseline QTc can be 5, 10, 15, or 20% over baseline QTc. The QTc can be measured at regular intervals, such as every 10, 15, 20, 30, 45, or 60 minutes during treatment.”
Kashifan and Devlin, Specification, paragraph 0112;
“During or following administration of the IV loading dose, the patient's QT interval is determined to be not greater than 550 msec, but the ΔQTc is greater than 20% of the patient's initial QTc. A maintenance dose is administered to the patient in a reduced amount as an oral dose of 250 The patient's QT interval is monitored following administration of the first oral maintenance dose. The patient's QT interval still does not exceed 550 msec and the ΔQTc is no longer greater than 20% of the patient's initial QTc. Subsequent oral maintenance doses of 250 μg are given every 12 to 48 hours.”
Kashifan and Devlin, Specification, paragraph 140.
Therefore, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to reduce the dose due to a QTc that increased by 15% over baseline QTc or if the QTc is measured at >500 msec or >550 msec if the patient has a ventricular conduction abnormality.
Thus, claim 19 was prima facie obvious at the time of filing.
Claim 20 recites: “The method of Claim 1, wherein the patient has a CrCl of 40<60 mL/min, the IV maintenance infusion is about 225-250 µg given over about 12 h and the oral doses are 250 µg.” While Pinter does not explicitly teach dose adjustment for CrCl, Kashifan and Pinter teach 250 mcg maintenance doses for patients with CrCl between 40 and 60 mL/min:
“Aspect 20 is the method of Aspect 18, wherein the creatinine clearance of the patient is 40-60 mL/min and the oral maintenance dose is 250 μg.”
Kashifan and Devlin, Specification, paragraph 58.
They also teach administering the IV maintenance infusion for over 1 hour, for example 6 hours:
“Aspect 36 is the method of any of Aspects 1-35, wherein the anti-arrhythmic or dofetilide, and/or the IV loading dose, and/or one or more subsequent IV doses, and/or one or more of the IV maintenance doses is administered over 5, 10, 15, 20, 30, 45, or 60 minutes, is administered for up to 60 minutes, is administered over a time period of at least 1 hour, is administered over 0.5, 1, 2, 3, 4, 5, or 6 hours, or is administered for a duration of at least 1 hour, and/or optionally is administered by way of several IV doses.”
Kashifan and Devlin, Specification, paragraph 0074.
While they do not explicitly teach 12 hours, this difference amounts to nothing more than a routine optimization in light of the prior art.
Therefore, one of ordinary skill in the art would have a reasonable expectation of success to administer a maintenance infusion of about 225-250 mcg over 12 hours and oral maintenance doses of 250 mcg to a patient with CrCl between 40 and 60 mL/min.
Thus, claim 20 was prima facie obvious at the time of filing.
Claim 21 recites: “The method of Claim 20, wherein the oral doses are reduced to 125 µg due to a QTc that increased by 15% over baseline QTc or if the QTc is measured at >500 msec or >550 msec if the patient has a ventricular conduction abnormality.”
While Pinter does not explicitly teach how to reduce the dose based on elongated QTc, Kashifan and Devlin teach a dose reduction to 125 mcg in a patient with a ventricular conduction abnormality and CrCl between 40 and 60 mL/min:
“[0129]
An example anti-arrhythmic, such as dofetilide, treatment protocol for a patient experiencing a ventricular conduction abnormality, such as atrial flutter, is described herein. The male patient, age 60, is admitted to the hospital to initiate treatment. The patient's creatinine clearance is determined to be between 40 and 60 mL/min. The patient is connected to an electrocardiograph, and an initial (or baseline) QT interval is determined to be not greater than 500 msec. Treatment is initiated with an IV loading dose of up to 1.6 μg/kg infused over up to 1 hour. The loading dose may be administered by way of several smaller IV doses. The patient's QT interval is measured every 15 minutes during the IV loading dose administration along with HR and BP.
[0130]
During or following administration of the IV loading dose, the patient's QT interval is determined to be greater than 550 msec. A reduced maintenance dose is administered to the patient up to 6 hours after completion of the IV loading dose or dofetilide administration is discontinued. The reduced maintenance dose is administered as an oral dose of 125 μg. The patient's QT interval is monitored following administration of the oral maintenance dose. The patient's QT interval no longer exceeds 550 msec and the ΔQTc is not greater than 20% of the patient's initial QTc. Subsequent oral maintenance doses of 125 μg are given every 12 to 48 hours.”
Kashifan and Delvin, Specification, paragraphs 0129-0130.
Therefore, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to give a 125 mcg oral dose to a patient with a ventricular conduction abnormality and CrCl between 40 and 60 mL/min when the QTc interval exceeds 550 msec.
Thus, claim 21 was prima facie obvious at the time of filing.
Claim 22 recites: “The method of Claim 1, wherein the patient has a CrCl of 20<40 mL/min, the IV maintenance infusion is about 100-125 µg given over about 12 h and the oral doses are 125 µg.” While Pinter does not explicitly teach dose adjustment for CrCl, Kashifan and Devlin teach maintenance doses of 125 micrograms for patients with CrCl between 20 and 40 mL/min:
“[0056]
Aspect 18 is a method of administering an anti-arrhythmic or dofetilide to a patient, comprising: (A) determining a creatinine clearance of the patient; (B) administering to the patient an IV loading dose of the anti-arrhythmic or dofetilide selected from an amount ranging from 0.1-12 μg/kg; (C) administering to the patient (i) one or more IV maintenance dose of the anti-arrhythmic or dofetilide selected from an amount ranging from 0.1-10 μg/kg and/or (ii) one or more oral maintenance dose of the anti-arrhythmic or dofetilide selected from an amount ranging from 125 μg to 500 such as 125 μg, 250 μg, or 500 μg; and (D) optionally alternatively or in addition wherein the amount of the IV loading dose is in the range of about ±50% of the oral dose and/or the IV maintenance dose…
[0059]
Aspect 21 is the method of Aspect 18, wherein the creatinine clearance of the patient is 20-40 mL/min and the oral maintenance dose is 125 μg.”
Kashifan and Devlin, Specification, paragraphs 0056 and 0059.
They also teach administering the IV maintenance infusion for over 1 hour, for example 6 hours:
“Aspect 36 is the method of any of Aspects 1-35, wherein the anti-arrhythmic or dofetilide, and/or the IV loading dose, and/or one or more subsequent IV doses, and/or one or more of the IV maintenance doses is administered over 5, 10, 15, 20, 30, 45, or 60 minutes, is administered for up to 60 minutes, is administered over a time period of at least 1 hour, is administered over 0.5, 1, 2, 3, 4, 5, or 6 hours, or is administered for a duration of at least 1 hour, and/or optionally is administered by way of several IV doses.”
Kashifan and Devlin, Specification, paragraph 0074.
While they do not explicitly teach 12 hours, this difference amounts to nothing more than a routine optimization in light of the prior art.
Therefore, one of ordinary skill in the art would have a reasonable expectation of success to administer a maintenance infusion of about 100-125 mcg over 12 hours and oral maintenance doses of 125 mcg to a patient with CrCl between 20 and 40 mL/min.
Therefore, claim 22 was prima facie obvious at the time of filing.
Claim 23 recites: “The method of Claim 22, wherein the oral doses are discontinued due to a QTc that increased by 15% over baseline QTc or if the QTc is measured at >500 msec is observed or >550 msec if the patient has a ventricular conduction abnormality.” While Pinter does not explicitly teach how to adjust or discontinue treatment for QTc, Kashifan and Devlin teach discontinuing therapy for QTc increases greater than 20% from baseline or QTc greater 550 msec:
“The patient's QTc is calculated from the QT measurement. If the patient's baseline (i.e., prior to dofetilide administration) QT interval or baseline QTc is greater than 500 msec (in patients with ventricular conduction abnormalities), then dofetilide is contraindicated. Measure every 15 min. during the IV loading dose, and if the QT or QTc increases by greater than 20% of the patient's baseline QT or baseline QTc (or is greater than 550 msec), then the IV dofetilide is discontinued or a subsequent lower dose is considered or administered. If after any subsequent IV or oral dose the QT or QTc increases to greater than 550 msec, then dofetilide is discontinued”
Kashifan and Devlin, Specification, paragraph 0126.
They also teach that the relevant QTc increase for dose adjustment can be 15% from baseline or QTc threshold of 500 msec:
“For patients that qualify for treatment, the QTc can be monitored during infusion of the loading and/or maintenance dose, and such dose can be adjusted downward or ceased if the patient's QTc becomes too high, either over a QTc threshold or a change exceeding a patient's baseline QTc. In one implementation, the QTc threshold is 500 msec. In various implementations, the change exceeding baseline QTc can be 5, 10, 15, or 20% over baseline QTc. The QTc can be measured at regular intervals, such as every 10, 15, 20, 30, 45, or 60 minutes during treatment.”
Kashifan and Devlin, Specification, paragraph 0112.
Therefore, one of ordinary skill in the art would be motivated and have a reasonable expectation of success to discontinue therapy due to a QTc that increased by 15% over baseline QTc or if the QTc is measured at >500 msec is observed or >550 msec if the patient has a ventricular conduction abnormality.
Thus, claim 23 was prima facie obvious at the time of filing.
Claim 24 is directed towards the method of claim 1, further comprising after step (b) but before step (c), continuing the maintenance infusion until the patient has recovered to take dofetilide orally, then stopping the maintenance infusion. One of ordinary skill in the art would have a reasonable expectation of success to stop the maintenance infusion once the patient has recovered to take dofetilide orally, because as shown above, it is well known in the art to administer an infusion when the patient is experienced an acute heart event and then stopping the maintenance infusion and administering dofetilide orally when the patient has recovered. For example, see Kashfian.
Therefore, claim 24 was prima facie obvious at the time of filing.
In light of the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 86-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
Prosecution Insights