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 .
Response to Amendments
Applicant’s amendments to the claims of March 23, 2026, in response to the Office Action of October 23, 2025, are acknowledged. The examiner further acknowledges the filing and approval a Terminal Disclaimer on March 23, 2026.
Response to Arguments
Applicant argues that the dosing protocols are not taught by the cited prior art. The specific periods of time and rates and intervals between doses are not taught, according to Applicant. Applicant has also amended the claims to include outpatient cardiac monitoring procedures to ensure a safe rhythm.
The examiner notes that Ivaturi claims administration of 10-60 mg over 0.5-2 hours as a first IV administration and a second IV infusion over 0.5-2 hours, starting 0.5 hours after the first infusion starts in an amount of 10-40 mg. This includes an infusion over 1 hour and 1.5 hours of up to 100 mg. See prior art claims 4 and 7, e.g. Figure 4 describes a loading dose over 1 hour that is up to 80 mg. Further, a maintenance dose can start 12 hours after infusion. Figure 6 provides for oral maintenance doses to start as early as 2 hours after infusion and the oral doses are typically twice the dosage (i.e., increased) over the infusion dosage. Figure 8 provides additional scenarios wherein 60 mg is administered over 1-1.5 hours and wherein oral maintenance administration starts 12 hours after. Without a criticality of a claimed regimen, the claimed methods appear to fall within the breadth of that taught to be safe and effective by the cited prior art.
Similarly, Batul reference provides for a substantially more rapid infusion of sotalol as safe and effective.
The rate of administration claimed includes 80 mg over 1 hour intravenously followed by 160 mg 3-5 hours after the IV dosage. The prior art teaches 80 mg infusion over 1-1.5 hours, e.g., and also teaches oral doses to start as early as at the end of an infusion. See par. 61. This provides for a Cmax, ss to be reached within 4 hours after initiation of a first IV loading dose. Results were observed with 120 mg and 160 mg oral doses. See par. 61.
The totality of the teachings provide for IV administration on a rapid basis to be safe and includes similar doses to those claimed. Further, oral administration is commenced shortly after infusion and on an outpatient maintenance basis to provide for a rapid discharge from a hospital. The subjects are monitored for QTc prolongation and changes from baseline throughout administrations.
With respect to continued monitoring using mobile cardiac telemetry, the examiner cites: Zweibel, “The Use of Mobile Cardiac Telemetry to Improve Diagnostic Accuracy and Enable More Efficient Patient Care,” February 6, 2012 (Abstract). Zweibel explains that mobile cardiac telemetry provides a continuous monitoring of a patient’s rhythm, on an outpatient basis to provide immediate access to potentially dangerous cardiac rhythms. This “also allows them to determine the onset and offset of an arrhythmia, detect asymptomatic runs of arrhythmias such as AF, and enables physicians to read, sign, and file their patient’s loop tracings in an EMR with the click of a few computer keys. The creative fusion of technologies between MCT and AMS gives physicians the tools necessary for providing efficient, accurate, and safer outpatient cardiac monitoring to patients.” It would be obvious to provide this monitoring after dosages of sotalol are administered to determine how a subject is impacted by administrations. This would include 2.5 hours after a dose, among other times.
The examiner notes that Applicant has not provided a showing and allegation of unexpected results. The claimed agent is taught to be safe and effective and a specific motivation is taught to rapidly convert a subject from IV to oral sotalol to discharge them from a hospital or emergency facility. Additionally, QTc interval is taught to be monitored to ensure that the interval remains within a safe threshold and 20% of a baseline value. Moreover, in the claimed subject population, the use of outpatient monitoring to ensure that a subject’s cardiac rhythm is safe and effective as a tool to safely monitor a cardiac outpatient with claimed conditions. Advantages of MCT monitoring include an ability to detected AF episodes in asymptomatic and symptomatic subjects.
As such, the rejections of record are maintained.
Status of the Claims
Claims 1-15 and 18-24 are pending and examined.
Claim Rejections - 35 USC § 112
Claims 11-15, 18, 19, and 21-23 contain the trademark/trade name MCOT®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a mobile cardiac telemetry unit, one of which is MCOT®, which is a registered mark and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 103
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 1-15 and 18-24 are rejected under 35 U.S.C. 103 as being unpatentable over Ivaturi et al., (US2019/0307343) (cited in IDS), in view of Zweibel, “The Use of Mobile Cardiac Telemetry to Improve Diagnostic Accuracy and Enable More Efficient Patient Care,” February 6, 2012 (Abstract).
Ivaturi teaches sotalol is used to treat ventricular arrhythmia and atrial fibrillation (AF) or flutter. See par. 3. It can be used for maintenance of normal sinus rhythm as well as acute management of ventricular arrhythmias. Ivaturi teaches administering sotalol in a manner that allows for intravenous sotalol administered and conversion to oral sotalol to increase hospital flexibility, convenience, and to save money, regardless of whether they have normal or abnormal renal function. See par. 27 and par. 33. Typically a subject is required to stay at a hospital for three days prior to discharge. See par. 35. Ivaturi teaches monitoring maximum QTc prolongation and changes in prolongation relative to a baseline measurement. The provisional application also teaches that the relationship between sotalol concentration and QTc is linear and enables a reliable prediction of QTc prolongation using a baseline QTc value. In view of the teachings as a whole, when QTc changes too much from a baseline value, infusions can cease any point. See p7. Further, a specific risk is taught to be calculated based on a calculated relationship relative to a subject’s baseline. Alternatively, if there is no change (i.e., 0% from baseline), a POSA would understand that this indicates the subject is tolerating sotalol well. QTc is measured after each first and second IV dose, e.g., to confirm that it is safe and has not deviated 20% or more from a baseline measurement. See prior art claims 1-3.
If a first dose is administered and the QTc is not acceptable, the subject will be switch to oral sotalol. Thus, they will only be administered a single IV dosage. This is consistent with claim 1. The examiner also notes that there is not much practical difference between an single infusion over 1 hour and a diffusion over 1.5 or 2 hours of a similar dosage.
A patient can be treated whether they have normal or abnormal renal function. See par. 31. The instant claims require a creatinine clearance that is greater than 60 mL/min. This includes subjects that have normal kidney function of a CrCl of greater than 90 mL/min. There is no claim that requires a CrCl of less than 90 mL/min. A subject will be administered a lower dosage or a less frequent dosage if they are known to have renal impairment, such as every 24 hours with impairment rather than every 12 hours, e.g. The methods described allow for a reduction of a hospital stay to 24 hours by accelerating parameters, such as Cmax. See par. 44. Further, after surgery re-initiation of sotalol can re-stabilize Cmax. See par. 47. QTc interval is able to be kept below 500 msec throughout this process. See par. 49. In an example, oral sotalol was administered at a dosage of 80, 120, and 160 mg twice daily. See par. 5 and Figure 2. Further, embodiments include administering an intravenous dosage initially over a period of 30 minutes to 2 hours. See par. 7. Sotalol hydrochloride is a form prescribed for injection. See par. 5. Further, IV loading doses are shown in Figure 4 to be 1-3 hours and include a dose of up to 80 mg in a subject that was on a prior stable dose of 80 mg. Figure 8 provides additional examples in which a target oral maintenance dose can range from 80 mg to 160 mg. Further, dose titration includes administering an IV dose of about 80 mg over 2 hour prior to a 160 mg oral dose; 60 mg infusion over 1.5 hours prior to a 120 mg oral dose; or a 40 mg infusion over 1 hour prior to a 80 mg oral dose. These examples include sotalol naïve subjects.
Ivaturi teaches a mixed dose method wherein a single IV dose is immediately followed by an oral administration. Immediately after is considered similar to or the same as administration about 1 hour after completion of a single dose of IV sotalol. It is abundantly clear that dose titration is taught and conveys to a POSA that is should be done and appears to be required to be guided by clinical response. As such, if a subjects requires an increase in dosage, they could be administered IV sotalol under QTc monitoring and have their Cmax, ss achieved rapidly to ensure the dose is safe. At that time, they could be transitioned to oral maintenance dosing as taught by Ivaturi. This would impart the benefits taught by Ivaturi to include a shorter hospital stay and a cost savings, among others.
This is particularly the case given the predictability of pharmacokinetic parameters, including Cmax, ss, and Tmax, the known bioavailability of oral compared to IV sotalol, and the known QTc-concentration relationship, among others.
Ivaturi explains that the rapid infusion of sotalol is known to be safe. Ivaturi explains that IV infusions as rapid as 5 minutes have been without incident. In examples, Ivaturi teaches administration of an IV infusion of 40 mg, followed by an IV infusion of 20 mg, and followed by an IV infusion of 20 mg. This is an 80 mg infusion, e.g., over a period of 2 hours. Ivaturi explains a goal to accelerate dosing of Cmax, ss to as early as 1 day. In some embodiment, Cmax, ss is achieved within 4 hours of initiation of treatment (i.e., 2 hours after completion of a 2 hour IV regimen) in a method wherein one IV infusion or more are followed by oral administration. See par. 61. In some cases, an oral dose can immediately follow IV administration (i.e., a mixed dosing regimen is also contemplated). In other embodiments, at the end of a 2-hour infusion, an 80 mg dose can be administered followed by another 80 mg dose 12 hours after the initiation of infusion. Similar achievement for 120 mg and 160 mg oral doses can also be achieved through such regimen. Thus, regardless of the ultimate maintenance dosage desired, the ability administer rapid IV sotalol followed by oral sotalol is predictable. Cmax is known to be a function of length of infusion and dose-proportionate linear pharmacokinetics for sotalol. Treatment of naïve patients is also contemplated. See par.’s 44, 47, 49, and others.
Ivaturi also teaches a first infusion of 10 mg to 60 mg over 0.5 hours. See prior art claim 4. Then, a second infusion can be over 0.5 hours after the start of the first infusion. This second infusion is 10 to 40 mg. This equates to 100 mg over 1 hour and falls within the scope of the instant claims. Further, a third infusion of 10 mg to 30 mg starting 0.5 hours after the start of the second infusion is claimed. See prior art claims 12 and 13, e.g. Thus, Ivaturi claims administering 100 mg over 1 hour and 130 mg over 1.5 hours.
Ivaturi teaches in the background section that standard prescribing information for sotalol injection includes a 5 hours infusion to mimic the PK of oral therapy. As such, administration over 5 hours could be a starting point for treatment. Further, a previous standard for AF included titration of 80 mg BID to a titration of up to 360 mg/day. The bioavailability is similar for oral and IV sotalol. See par. 5.
Zweibel explains that mobile cardiac telemetry provides a continuous monitoring of a patient’s rhythm, on an outpatient basis to provide immediate access to potentially dangerous cardiac rhythms. This “also allows them to determine the onset and offset of an arrhythmia, detect asymptomatic runs of arrhythmias such as AF, and enables physicians to read, sign, and file their patient’s loop tracings in an EMR with the click of a few computer keys. The creative fusion of technologies between MCT and AMS gives physicians the tools necessary for providing efficient, accurate, and safer outpatient cardiac monitoring to patients.” It would be obvious to provide this monitoring after dosages of sotalol are administered to determine how a subject is impacted by administrations. This would include 2.5 hours after a dose, among other times.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. ‘[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Optimizing a dosage of a known-result effective variable with predictable trends in pharmacokinetic parameters would require nothing more than routine experimentation, including in those subjects with varying degrees of renal function, as explicitly taught by Ivaturi. Thus, while examples provided by Ivaturi generally show a lower IV dose followed by a higher oral dose, these are examples that can be modified as needed. Further, instant claim 1 includes administration of an IV dosage that is 60 mg, followed by a 120 mg oral dose. This is exactly what Ivaturi teaches in an example. Ivaturi also teaches that a steady state can be achieved within 4 and 7 hours for re-stabilized subjects. See Figures 6 and 7.
Instant claims 1 and 8 provide for 60 mg to be administered over about 1 hour followed by 120 mg orally. Ivaturi teaches and claims 60 mg over 1.5 hours followed by 120 mg orally. This dosage is almost anticipated by the prior art in Figure 8 and the claims.
The notion of administering an IV dose over one hour to a few hours prior to switching to an oral dose that is equal to or less than double the dose of the single IV administered dose is shown in examples provided by Ivaturi to be acceptable. Additionally, titrating an oral dose up to 240 mg/day or 360 mg/day is obvious in view of the cited prior art. This is the case based on specific examples and the predictability of PK parameters taught by the prior art. In light thereof and without an allegation nor showing of unexpected results, it would appear that the claims are drawn to specific yet optimizable doses of sotalol designed to achieve a rapid and safe Cmax and ss while keeping a subject’s QTc monitored and below an acceptable threshold.
The limitation “admitted to a facility capable of providing cardiac resuscitation and continuous electrographic monitoring” is interpreted to include facilities such as a hospital, as described in paragraph 85 of the instant Specification. Ivaturi teaches treating a subject in a hospital. See par. 5. Standard treatment is recommended to be at a hospital and monitoring is recommended until steady state is achieved. See par. 5.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to arrive at the claimed invention in view of Ivaturi. One would be motivated to do so because Ivaturi teaches advantages of converting a subject from IV sotalol to oral sotalol in a manner that reduces hospital stay, increases convenience and reduces cost. This is done safely and effectively by allow a patient to be monitored for QTc prolongation three times within a short period of time so that conversion can be rapid. This is taught to be possible regardless of renal abnormality. A single IV dose is contemplated and there does not appear to be a distinction over a single dose as compared to multiple doses in rapid succession wherein the multiple doses are similar and/or of an optimizable strength based on predictable PK. Further, Ivaturi explains that as renal function decreases, the dose of sotalol and/or the frequency of administration of sotalol must be decreased. Ivaturi teaches the safety of broad dosage ranges and the ability to provide infusions over longer periods of time or rapidly. Administration prior to the Ivaturi’s teachings include a 5 hours infusion. Ivaturi teaches rapid infusions over 1-3 hours, although rapid infusions over 5 minutes has also been shown to be safe. Thus, slower and more rapid infusions have been shown to be acceptable. However, a shorter infusion can allow for faster stabilization for patient release from a facility or hospital. Typically, the dosages taught by Ivaturi include a 40, 60 or 80 mg infusion over a couple of hours followed by oral maintenance dosage of 80, 120, or 160 mg up to twice daily that can be titrated up. These are the standard doses known to be used in the field. Using higher or lower loading doses and/or maintenance doses would appear to include optimizable doses based on patient tolerability, weight, agent, renal function, and other result-effective parameters. While many dosage regimens are safe with predictable PK, Ivaturi provides examples in which an IV dose is approximately 50% lower than the oral dose to be titrated to. Ivaturi teaches broad ranges for IV dosage administration over the first couple of hours to be later converted to an oral dose that can be administered periodically and also outside of a hospital facility. As such, there is a reasonable and predictable expectation of success in arriving at the claimed methods in view of Ivaturi.
Claims 1-15 and 18-24 are rejected under 35 U.S.C. 103 as being unpatentable over Batul et al., “Intravenous Sotalol- Reintroducing a Forgotten Agent to the Electrophysiology Therapeutic Arsenal,” Journal of Atrial Fibrillation, Feb-Mar 2017, Vol 9, Issue 5 (cited in IDS), in view of Li et al., “Efficacy of Intravenous Sotalol for Treatment of Incessant Tacharrhythmias in Children,” Am J Cardiol 2017; 119:1366-1370 (cited in IDS), in view of Somberg et al., “Developing a safe intravenous sotalol dosing regimen,” Am J Ther, 2010 Jul-Aug; 17(4): 365-72 (cited in IDS), in view of Saul et al., “Pharmacokinetics and pharmacodynamics of sotalol in a pediatric population with superventricular and ventricular tacharrhythmia,” Clinical Pharmacology and Therapeutics, March 2001 (cited in IDS), and in view of Ivaturi et al., (US2019/0307343) (cited in IDS), in view of Zweibel, “The Use of Mobile Cardiac Telemetry to Improve Diagnostic Accuracy and Enable More Efficient Patient Care,” February 6, 2012 (Abstract).
Batul teaches sotalol for treatment of atrial fibrillation (AF) and atrial flutter (AFL). Batul explains that the safety principles applicable to oral sotalol are valid for intravenous sotalol as well. The bioavailability of oral sotalol is 93% with peak plasma concentrations in 2.5 to 4 hrs. Batul indicates that IV sotalol dosage includes administering 1-1.5 mg/kg over 5-30 minutes. In a 30 kg pediatric subject, this would include 30-45 mg over 5-30 minutes, and in a 70 kg human, this would include 70-105 mg over 5-30 minutes. This rate of infusion is substantially more rapid than claimed and well under a 1 hour infusion time. Batul explains that risk increases when QTc is above 500 msec and shows a linear correlation to sotalol blood levels. See p2, 5th full par. High dose rapid therapy was shown to be safe and efficacious in suppressing SVT in 90% of patients aged 7 to 728 days, with no proarrhythmic effect or QTc prolongation observed. See p4. Further, it has an elimination half-life of 12-16 hours. See p3, 3rd full par. Further, Table 1 below explains the dose conversion for oral and intravenous forms.
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215
822
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Batul explains IV sotalol can be a substitute for oral medication, such as for post-operative and critically ill subjects, especially when they have reduced GI permeability and absorption for oral administrations to reach effective serum concentrations. See p3, 1st full par. In other instances, IV forms provide advantages as compared to oral forms because it reaches therapeutic levels quicker and could be used in hospitals to facilitate a transition to oral forms.
Li teaches treating patients with IV sotalol and those subjects that maintained sinus rhythm were transitioned to oral therapy. See p1367, par. 7. Subjects that were treated have AVRT, AT, Aflutter, AF, and VT. See Table 1. Any patient with a QTc above 480 was converted to oral sotalol therapy. See p1367, par. 4. Li used a loading dose of 1 mg/kg over 10 minutes and then 4.5 mg/kg/day. See p1369, last full par. Thus, Li shows a reasons that subjects taking IV will be transitioned to oral sotalol.
Li explains that for patients with atrioventricular reentrant tachycardia who converted to sinus rhythm on sotalol within 2 hours, IV sotalol was continued for another 1 to 24 hours and then transitioned to oral therapy. See p1367, 1st par. In other words, patients were converted to oral therapy in as few as 3 hours after starting the IV dose.
Further, Somberg teaches Cmax is known to be a function of length of infusion, wherein increasing duration of infusion decreases Cmax.
Saul teaches, “An examination of the individual data of the smallest patients did not indicate any deviation from dose-proportionate linear pharmacokinetics for sotalol.” P150, 1st full par. These data are shown below in Table III. QTc interval was dose dependent. The steady state pharmacokinetics of sotalol was dose proportionate. See Abstract. A dose of 30 mg/m2 yielded a SS Cmax of 851 +/- 185.
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568
1546
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The pediatric patients receiving multiple doses of sotalol achieved ideally small fluctuation factor values between peak and steady state and experienced a dose-proportionate response. Further, there were linear correlations between drug concentration and pharmacological activity on the QTcB interval. See p155, last par.
Ivaturi teaches sotalol is used to treat ventricular arrhythmia and atrial fibrillation (AF) or flutter. See par. 3. It can be used for maintenance of normal sinus rhythm as well as acute management of ventricular arrhythmias. Ivaturi teaches administering sotalol in a manner that allows for intravenous sotalol administered and conversion to oral sotalol to increase hospital flexibility, convenience, and to save money, regardless of whether they have normal or abnormal renal function. See par. 27 and par. 33. Typically a subject is required to stay at a hospital for three days prior to discharge. See par. 35. Ivaturi teaches monitoring maximum QTc prolongation and changes in prolongation relative to a baseline measurement. The provisional application also teaches that the relationship between sotalol concentration and QTc is linear and enables a reliable prediction of QTc prolongation using a baseline QTc value. In view of the teachings as a whole, when QTc changes too much from a baseline value, infusions can cease any point. See p7. Further, a specific risk is taught to be calculated based on a calculated relationship relative to a subject’s baseline. Alternatively, if there is no change (i.e., 0% from baseline), a POSA would understand that this indicates the subject is tolerating sotalol well. QTc is measured after each first and second IV dose, e.g., to confirm that it is safe and has not deviated 20% or more from a baseline measurement. See prior art claims 1-3.
If a first dose is administered and the QTc is not acceptable, the subject will be switch to oral sotalol. Thus, they will only be administered a single IV dosage. This is consistent with claim 1. The examiner also notes that there is not much practical difference between an single infusion over 1 hour and a diffusion over 1.5 or 2 hours of a similar dosage.
A patient can be treated whether they have normal or abnormal renal function. See par. 31. The instant claims require a creatinine clearance that is greater than 60 mL/min. This includes subjects that have normal kidney function of a CrCl of greater than 90 mL/min. There is no claim that requires a CrCl of less than 90 mL/min. A subject will be administered a lower dosage or a less frequent dosage if they are known to have renal impairment, such as every 24 hours with impairment rather than every 12 hours, e.g. The methods described allow for a reduction of a hospital stay to 24 hours by accelerating parameters, such as Cmax. See par. 44. Further, after surgery re-initiation of sotalol can re-stabilize Cmax. See par. 47. QTc interval is able to be kept below 500 msec throughout this process. See par. 49. In an example, oral sotalol was administered at a dosage of 80, 120, and 160 mg twice daily. See par. 5 and Figure 2. Further, embodiments include administering an intravenous dosage initially over a period of 30 minutes to 2 hours. See par. 7. Sotalol hydrochloride is a form prescribed for injection. See par. 5. Further, IV loading doses are shown in Figure 4 to be 1-3 hours and include a dose of up to 80 mg in a subject that was on a prior stable dose of 80 mg. Figure 8 provides additional examples in which a target oral maintenance dose can range from 80 mg to 160 mg. Further, dose titration includes administering an IV dose of about 80 mg over 2 hour prior to a 160 mg oral dose; 60 mg infusion over 1.5 hours prior to a 120 mg oral dose; or a 40 mg infusion over 1 hour prior to a 80 mg oral dose. These examples include sotalol naïve subjects.
Ivaturi teaches a mixed dose method wherein a single IV dose is immediately followed by an oral administration. Immediately after is considered similar to or the same as administration about 1 hour after completion of a single dose of IV sotalol. It is abundantly clear that dose titration is taught and conveys to a POSA that is should be done and appears to be required to be guided by clinical response. As such, if a subjects requires an increase in dosage, they could be administered IV sotalol under QTc monitoring and have their Cmax, ss achieved rapidly to ensure the dose is safe. At that time, they could be transitioned to oral maintenance dosing as taught by Ivaturi. This would impart the benefits taught by Ivaturi to include a shorter hospital stay and a cost savings, among others.
This is particularly the case given the predictability of pharmacokinetic parameters, including Cmax, ss, and Tmax, the known bioavailability of oral compared to IV sotalol, and the known QTc-concentration relationship, among others.
Ivaturi explains that the rapid infusion of sotalol is known to be safe. Ivaturi explains that IV infusions as rapid as 5 minutes have been without incident. In examples, Ivaturi teaches administration of an IV infusion of 40 mg, followed by an IV infusion of 20 mg, and followed by an IV infusion of 20 mg. This is an 80 mg infusion, e.g., over a period of 2 hours. Ivaturi explains a goal to accelerate dosing of Cmax, ss to as early as 1 day. In some embodiment, Cmax, ss is achieved within 4 hours of initiation of treatment (i.e., 2 hours after completion of a 2 hour IV regimen) in a method wherein one IV infusion or more are followed by oral administration. See par. 61. In some cases, an oral dose can immediately follow IV administration (i.e., a mixed dosing regimen is also contemplated). In other embodiments, at the end of a 2-hour infusion, an 80 mg dose can be administered followed by another 80 mg dose 12 hours after the initiation of infusion. Similar achievement for 120 mg and 160 mg oral doses can also be achieved through such regimen. Thus, regardless of the ultimate maintenance dosage desired, the ability administer rapid IV sotalol followed by oral sotalol is predictable. Cmax is known to be a function of length of infusion and dose-proportionate linear pharmacokinetics for sotalol. Treatment of naïve patients is also contemplated. See par.’s 44, 47, 49, and others.
Ivaturi also teaches a first infusion of 10 mg to 60 mg over 0.5 hours. See prior art claim 4. Then, a second infusion can be over 0.5 hours after the start of the first infusion. This second infusion is 10 to 40 mg. This equates to 100 mg over 1 hour and falls within the scope of the instant claims. Further, a third infusion of 10 mg to 30 mg starting 0.5 hours after the start of the second infusion is claimed. See prior art claims 12 and 13, e.g. Thus, Ivaturi claims administering 100 mg over 1 hour and 130 mg over 1.5 hours.
Ivaturi teaches in the background section that standard prescribing information for sotalol injection includes a 5 hours infusion to mimic the PK of oral therapy. As such, administration over 5 hours could be a starting point for treatment. Further, a previous standard for AF included titration of 80 mg BID to a titration of up to 360 mg/day. The bioavailability is similar for oral and IV sotalol. See par. 5.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. ‘[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Optimizing a dosage of a known-result effective variable with predictable trends in pharmacokinetic parameters would require nothing more than routine experimentation, including in those subjects with varying degrees of renal function, as explicitly taught by Ivaturi. Thus, while examples provided by Ivaturi generally show a lower IV dose followed by a higher oral dose, these are examples that can be modified as needed. Further, instant claim 1 includes administration of an IV dosage that is 60 mg, followed by a 120 mg oral dose. This is exactly what Ivaturi teaches in an example. Ivaturi also teaches that a steady state can be achieved within 4 and 7 hours for re-stabilized subjects. See Figures 6 and 7.
Instant claims 1 and 8 provide for 60 mg to be administered over about 1 hour followed by 120 mg orally. Ivaturi teaches and claims 60 mg over 1.5 hours followed by 120 mg orally. This dosage is almost anticipated by the prior art in Figure 8 and the claims.
The notion of administering an IV dose over one hour to a few hours prior to switching to an oral dose that is equal to or less than double the dose of the single IV administered dose is shown in examples provided by Ivaturi to be acceptable. Additionally, titrating an oral dose up to 240 mg/day or 360 mg/day is obvious in view of the cited prior art. This is the case based on specific examples and the predictability of PK parameters taught by the prior art. In light thereof and without an allegation nor showing of unexpected results, it would appear that the claims are drawn to specific yet optimizable doses of sotalol designed to achieve a rapid and safe Cmax and ss while keeping a subject’s QTc monitored and below an acceptable threshold.
The limitation “admitted to a facility capable of providing cardiac resuscitation and continuous electrographic monitoring” is interpreted to include facilities such as a hospital, as described in paragraph 85 of the instant Specification. Ivaturi teaches treating a subject in a hospital. See par. 5. Standard treatment is recommended to be at a hospital and monitoring is recommended until steady state is achieved. See par. 5.
Zweibel explains that mobile cardiac telemetry provides a continuous monitoring of a patient’s rhythm, on an outpatient basis to provide immediate access to potentially dangerous cardiac rhythms. This “also allows them to determine the onset and offset of an arrhythmia, detect asymptomatic runs of arrhythmias such as AF, and enables physicians to read, sign, and file their patient’s loop tracings in an EMR with the click of a few computer keys. The creative fusion of technologies between MCT and AMS gives physicians the tools necessary for providing efficient, accurate, and safer outpatient cardiac monitoring to patients.” It would be obvious to provide this monitoring after dosages of sotalol are administered to determine how a subject is impacted by administrations. This would include 2.5 hours after a dose, among other times.
It would have been prima facie obvious to a person of ordinary skill in the art prior the filing of the instant application to combine the teachings of Batul, Li, Somberg, Saul, Ivaturi, and Zweibel to arrive at the instantly claimed methods. One would have been motivated to do so because Ivaturi provides a motivation to expeditiously arrive at an oral dosage after IV therapy, and provides a strong correlation to assist a POSA to arrive at a proper dosage in a subject with renal impairment. Dosage must decrease in amount and/or frequency of administrations as renal impairment increases. Further, the claimed dosage baselines are taught. Batul explains that IV sotalol dosage includes administering 1-1.5 mg/kg over 5-30 minutes. In a 30 kg pediatric subject, this would include 30-45 mg over 5-30 minutes, and in a 70 kg human, this would include 70-105 mg over 5-30 minutes. These rates are consistent with the rapid rates of infusion claimed and in some cases are even faster than the rapid infusion rates claimed. Moreover, Batul explicitly states that such rapid IV administration can be used in a hospital setting to transition a subject to oral therapy. Li explains that subjects that are administered IV sotalol and converted to a normal sinus rhythm were transitioned to oral sotalol. For example, patients with atrioventricular reentrant tachycardia who converted to sinus rhythm were transitioned to oral therapy in as few as 3 hours after starting IV sotalol. See p1367, 1st par. Somberg and Saul are cited merely to show the known predictability of sotalol pharmacokinetic data. For example, Cmax is known to be a function of length of infusion, wherein increasing duration of infusion decreases Cmax, and even pediatric patients show a dose-proportionate linear pharmacokinetic profile. As such, as person of ordinary skill in the art would understand how to obtain a desired Cmax by altering length of infusion and dosage, e.g. The prior art shows that the IV and oral dosage equivalents, which for the oral dosage include a range of 80 mg to 160 mg, which is the same range presently claimed. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. ‘[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Optimizing a dosage of a known-result effective variable with predictable trends in pharmacokinetic parameters would require nothing more than routine experimentation, including in those subjects with varying degrees of renal function, as explicitly taught by Ivaturi.
As such, no claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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 mailing date of this final action.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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