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 December 18, 2025, in response to the Office Action of August 19, 2025, are acknowledged.
Response to Arguments
The Double Patenting Rejections are withdrawn in view of the filing and approval of a Terminal Disclaimer on December 18, 2025.
Applicant argues that the claims have been amended to recite a specific subject population have GFR rate of 45 to 60 mL/min and a single IV dose of 82 to 96 mg administered over a period of 1 hour to provide a Cmax of 750-850 ng/mL.
The examiner notes that Ivaturi teaches treating the same subject population with abnormal or normal renal function and/or teaches treating a subject that is naïve to sotalol. Ivaturi explains that doses and/or frequency between IV and oral doses as well as between subsequent maintenance doses can be lengthened to account for abnormal renal function. This is not required but is discretionary and is optimizable in view of patient response and monitoring. Further, Ivaturi explains that doses for those that are naïve to sotalol can be titrated up to 120 mg or 160 mg. Thus, using a dose that is lower, including 82 mg or 80 mg could be a proper dose adjustment for those with abnormal renal function. Further, administering 80 mg BID could also be a sufficient lengthening of time between doses to account for a renal abnormality.
Prior art claims 4 and 5 provide for administration of up to 60 mg to a subject over 0.5 hours including for those with abnormal renal function. Similarly, claim 7 provides for a second IV dose of up to 40 mg administered over 0.5 hours, starting 0.5 hours after the first infusion. Thus, these claims provide for up to 100 mg over 1.5 hours to a subject that has abnormal renal function. Even further, a subject can receive a dose of 120 mg administered orally (after a second infusion) if the QTc is not acceptable. This dosage could be adjusted lower for abnormal renal function as described above.
Further, Ivaturi taches, e.g., when a subject has a GFR of 45 to 60, administering an oral maintenance dose over a longer interval. For example a once daily 160 mg oral dose can be administered, e.g., twice daily of 80 mg. Further, an IV dose is taught to yield a Cmax between 750 ng/ml and 850 ng/ml. See Examples 44 and 53.
In Example 3, a subject that is naïve to sotalol is going to be adjusted to a sotalol dosage of 80 mg orally twice daily. He is initially administered 55 mg over 1 hour. In this case if a second dose is administered via IV administration in a range of 25 to 40 mg, this would yield a method that is almost identical to the instant claims.
In totality, Ivaturi teaches administration of a similar dose over 1.5 hours rather than 1 hour and an oral maintenance dose that is higher and can be adjusted to account to any renal abnormality is taught. Without any allegation or showing of an unexpected results and the well-established safety of higher and more rapid doses, the instant claims appears optimizable in view of the cited prior art. Moreover, other prior art references teach safety and efficacy of sotalol administered faster than that claimed by Ivaturi. A roadmap for the optimization of sotalol in a subject having a monitored QTc is established. The claimed dosages are each similar to those taught to be administered by the prior art and the timing and dose adjustment, if necessary, is also taught. Such adjustments can be to account for abnormal renal function and/or QTc level relative to a baseline. Further, independent claim 8 provides for administration of an oral dose. Claim 8 does not require timing for this oral dose. Dependent claim 38 provides for administration of an oral dose 4-6 hours after completion of an IV dose. Thus, if a subject is initiated on an IV dose of 80 mg with a goal of administering 160 mg orally, such adjustment to 80 mg BID schedule starting hours after IV administration would appear to be a reasonable way to spread out timing of dosages to account for any renal abnormality. The specifics of any regimen would be optimizable in view of the known correlations/relationships among QTc level, renal impairment, dosage, and timing of administrations.
As such, without an allegation and showing of unexpected results a prima facie showing is established for the record. The initial IV dose overlaps a claimed amount. Further, a dose of 80 mg or 160 mg orally at a period after the IV administration ends also overlaps the claimed amounts. Even further, a Cmax of 750 to 850 ng/mL is taught as a goal in one embodiment.
Status of the Claims
Claims 8, 30, 36, 38, 40, 43-45 are pending and examined.
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 8, 30, 36, 38, 40, 43-45 are rejected under 35 U.S.C. 103 as being unpatentable over Ivaturi et al., (US2019/0307343) (cited in IDS).
Ivaturi teaches administering sotalol in a manner that allows for intravenous sotalol administered and a patient can be converted 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 baseline QTc. In view of the teachings as a whole in the provisional application, whether a threshold of 20% or another threshold is used, when QTc changes too much, 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. The claims merely require ceasing infusions if QTc differs by more than 20%. This includes the most obvious and drastic of scenarios. For example, if QTc changes 80%, infusions would cease. Alternatively, if there is no change (i.e., 0% from baseline), a POSA would understand that this indicates the subject is tolerating sotalol well.
Further, a patient can be treated whether they have normal or abnormal renal function. See par. 31. More specifically, 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. In other words, a subject with impaired renal function will receive a lower dose or receive administration less frequently. 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.
Ivaturi teaches a mixed dose methods wherein a single IV dose is immediately followed by an oral administration. 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 through 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 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. While these administration may not be in a “single” IV dosage, the dosing regimen overlaps.
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. Further, Ivaturi explains that as renal function decreases, the dose of sotalol and/or the frequency of administration of sotalol must be decreased. Ivaturi even provides an example that indicates that abnormal renal function may require administration once daily rather than twice daily. Given the optimizable nature of dosage and the trend to administer a lower amount to a subject as renal impairment increases, it would require nothing more than routine optimization to arrive at the claimed dosage. Further, discharging a subject after 2-4 dosages does not appear to conflict with the dosage trend and intent of Ivaturi.
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.
Claims 8, 30, 36, 38, 40, 43-45 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).
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 administering sotalol in a manner that allows for intravenous sotalol administered and a patient can be converted 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 baseline QTc. In view of the teachings as a whole in the provisional application, whether a threshold of 20% or another threshold is used, when QTc changes too much, 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. The claims merely require ceasing infusions if QTc differs by more than 20%. This includes the most obvious and drastic of scenarios. For example, if QTc changes 80%, infusions would cease. Alternatively, if there is no change (i.e., 0% from baseline), a POSA would understand that this indicates the subject is tolerating sotalol well.
Further, a patient can be treated whether they have normal or abnormal renal function. See par. 31. More specifically, 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. In other words, a subject with impaired renal function will receive a lower dose or receive administration less frequently. 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.
Ivaturi teaches a mixed dose methods wherein a single IV dose is immediately followed by an oral administration. 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 through 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 and secondary references cited below 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 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.
Ivaturi 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. While these administration may not be in a “single” IV dosage, the dosing regimen overlaps. Treatment of naïve patients is also contemplated. See par.’s 44, 47, 49, and others.
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, and Ivaturi 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628