FINAL 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 .
Status of Claims
Receipt is acknowledged of the claim amendments filed on 27 October 2025.
Claims 1 and 17-22 have been amended.
Claims 2-16 are cancelled.
Claims 1, 17-22 and 24-25 are presented for examination herein.
Information Disclosure Statement
The information disclosure statement (IDS) filed 10/27/2025 has been considered by the Examiner. A signed and initialed copy of the IDS is included with the instant Office Action.
Rejections Withdrawn
The rejection of claims 1 and 17-22 under U.S.C. 112(b), as being indefinite, is withdrawn in view of Applicant’s claim amendments.
Rejections Maintained and Modified as Necessitated by the Claim Amendments
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 17-22 and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over IVATURI (US 2019/0307343 A1, effective filing date of 05 April 2018) in view of KERIN (“The Efficacy of Sotalol in Preventing Postoperative Atrial Fibrillation: A Meta-Analysis”, The American Journal of Medicine, Volume 124, Number 9, pages 875.e1-e9, September 2011) as evidenced by the instant specification.
Ivaturi is primarily directed towards a method for determining an optimum dose of an antiarrhythmic drug for including sotalol (abstract).
Regarding instant claims 1, 17-19, 21 and 24-25, Ivaturi discloses that control of atrial fibrillation can be achieved with drugs including sotalol which can be used intravenously (paragraph [0003]). Ivaturi discloses a method including detecting a baseline QTc of a subject, administering a first dose of an antiarrhythmic drug via a first intravenous infusion for first duration of time, then determining the difference between the baseline QTc and a first QTc measured after the first intravenous infusion to detect a first delta QTc (paragraph [0006]). Ivaturi discloses that reference FDA recommended sotalol dosing regimens of 80, 120 and 160 mg BID given to a 70 kg patient (paragraph [0011]). Ivaturi discloses administration to a subject a drug including sotalol to treat atrial fibrillation and that the method involves titrating the dose of the drug gradually to determine the optimum plasma concentration for a patient (paragraph [0023]). Ivaturi discloses dosing the antiarrhythmic drug for accelerating achievement of steady-state maximum plasma concentration (Cmax,ss) of the therapeutic agent by intravenous administration (paragraph [0024]). Ivaturi discloses titration of the drug in order to safely increase the dose of the drug to reach a target maintenance dose in a shorter period of time (paragraph [0028]). Ivaturi discloses IV loading doses including 60, 70, 75 and 80 for a prior stable dose of 80 mg, an infusion time of including 1 hour, and maintenance dose initiation 12 hours after end of infusion (e.g., minimum delay to a first of the one or more subsequent doses) (Figure 4). Ivaturi teaches additional embodiments further include applying the IV loading strategy having progressively higher titrating doses including higher doses of 120 or 160 mg as target oral maintenance doses (e.g., higher than including 60, 70, 75 and 80 mg IV loading dose for 80 mg as prior stable dose in Figure 4) that is based on tolerability (paragraph [0048]). Further, an IV loading dose of including 80 mg disclosed by Ivaturi is close enough to the claimed range of “90-150mg”, “90-115mg”, and “90-105mg”, recited in claims 1 and 24-25, respectively. Pursuant to MPEP 2144.05(I) a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close, especially in the absence of any showing of unexpected results or criticality. As evidenced by the instant specification, about 82 mg to about 96 mg of intravenous sotalol hydrochloride administered over about 60 minutes can provide a steady state Cmax of between about 1000 ng/mL and about 1400 ng/mL (paragraph [0044] of the instant specification filed on 10/15/2025). Ivarturi discloses that an optimal dosing regimen achieved Cmax,ss as early as 4 hours after initiation of treatment on Day 1 (paragraph [0060]). Ivaturi discloses that Cmax,ss for 120 mg is around 1200 ng/mL and the Cmax,ss for 160 mg is around 1600 ng/mL (Figure 2, Figure 10 and Figure 11). Ivaturi discloses maintenance doses of including 160 mg and 120 mg if QTc is measured and is found to be not within an acceptable range (paragraph [0067]). Ivaturi discloses including providing a maintenance dose 12 hours (e.g., a minimum delay to a first of the one or more subsequent doses is 0.5-6 hours (e.g., at least 0.5-6 hours delay)) from including completion of the first IV infusion (paragraph [0067]).
Regarding claims 18 and 20, Ivaturi discloses that for patients with renal impairment or abnormal renal function, maintenance doses may be administered every 24 hours (e.g., minimum delay to the first of the one or more subsequent doses is 6 hours (e.g., at least 6 hours delay)) (paragraph [0031]).
Regarding claim 22, Ivaturi discloses a method including detecting a baseline QTc of a subject, administering a first dose of an antiarrhythmic drug via a first intravenous infusion for first duration of time, then determining the difference between the baseline QTc and a first QTc measured after the first intravenous infusion to detect a first delta QTc to see if the first delta QTc is in an acceptable range of less than 20% from the baseline (e.g., QTc of the patient measured prior to administration of the loading dose) or <500 msec (paragraphs [0006] and [0049]).
Ivaturi does not specifically teach that the patient is a patient who is currently in sinus rhythm. The deficiency is made up for by the teachings of Kerin.
Kerin is primarily directed towards the effectiveness of sotalol in preventing supraventricular tachyarrhythmia after cardiac surgery (abstract).
Regarding claim 1, Kerin teaches that supraventricular tachyarrhythmias are common and troubling complications after cardiac surgery. Kerin teaches that the reported incidence ranges from 15% to 50%, with atrial fibrillation and atrial flutter being the most common (page 875.e1, paragraph in first column). Kerin teaches that sotalol is more effective in the prevention of postoperative atrial fibrillation and other forms of supraventricular tachyarrhythmias than placebo or beta-blockers (page 875.e8, second column, fourth paragraph).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to prevent atrial fibrillation in a patient that had cardiac surgery (e.g., includes patients who have not experienced or will not experience atrial fibrillation (e.g., abnormal sinus rhythm) after the cardiac surgery (e.g., who is currently in sinus rhythm)) by performing a method comprising detecting a baseline QTc of the patient, administering an intravenous loading dose for a target dose of 120 mg or 160 mg of sotalol which is higher than doses of including 60, 70, 75 and 80 mg that are used for a target dose of 80 mg, determining the difference between the baseline QTc and a first QTc measured after the intravenous loading dose to detect the first delta QTc to see if the first delta QTc is in an acceptable range of less than 20% from the baseline, administration of an oral maintenance dose (e.g., one or more subsequent oral doses) of 120 mg or 160 mg of sotalol; where the intravenous loading dose is an intravenous infusion of including for 1 hour; wherein the administration of the oral maintenance dose of 120 mg or 160 mg of sotalol is provided every 12 hours or 24 hours if the patient has renal impairment or abnormal renal function; and wherein the Cmax,ss is achieved as early as 4 hours and Cmax,ss for 120 mg is around 1200 ng/mL and the Cmax,ss for 160 mg is around 1600 ng/mL. The person of ordinary skill in the art would have been motivated to make to modifications to provide prevention of atrial fibrillation in a patient that had cardiac surgery, because Kerin teaches that sotalol can be used for prevention of postoperative atrial fibrillation and other forms of supraventricular tachyarrhythmias than placebo or beta-blockers. The person of ordinary skill in the art would have expected success because Ivaturi discloses administration to a subject a drug including sotalol to treat atrial fibrillation and that the method involves titrating the dose of the drug gradually to determine the optimum plasma concentration for a patient (paragraph [0023]). Ivaturi discloses dosing the antiarrhythmic drug for accelerating achievement of steady-state maximum plasma concentration (Cmax,ss) of the therapeutic agent by intravenous administration (paragraph [0024]). Ivaturi discloses IV loading doses including 60, 70, 75 and 80 mg for a prior stable dose of 80 mg, an infusion time of including 1 hour, and maintenance dose initiation 12 hours after end of infusion (e.g., minimum delay to a first of the one or more subsequent doses) (Figure 4). Ivaturi discloses titrating doses including higher doses of 120 or 160 mg (e.g., target maintenance doses) (paragraph [0048]). Kerin teaches that supraventricular tachyarrhythmias are common and troubling complications after cardiac surgery. Kerin teaches that the reported incidence ranges from 15% to 50%, with atrial fibrillation and atrial flutter being the most common (page 875.e1, paragraph in first column). Kerin teaches that sotalol is more effective in the prevention of postoperative atrial fibrillation and other forms of supraventricular tachyarrhythmias than placebo or beta-blockers (page 875.e8, second column, fourth paragraph).
Regarding the ranges of 90-150 mg IV loading dose and 120 or 160 mg oral dose (e.g., claim 1), IV loading dose is 90-115 mg, the one or more subsequent oral doses comprises 120 mg (e.g., claim 24), IV loading dose is 90-105, and the one or more subsequent oral doses comprises 160 mg (e.g., claim 25), Ivaturi discloses IV loading doses including 60, 70, 75 and 80 mg for a prior stable dose of 80 mg, an infusion time of including 1 hour, and maintenance dose initiation 12 hours after end of infusion (e.g., minimum delay to a first of the one or more subsequent doses) (Figure 4). Ivaturi discloses titrating doses that are progressively higher for higher doses of 120 or 160 mg (e.g., target maintenance doses) (paragraph [0048]). It would have been prima facie obvious for one of ordinary skill in the art to pick doses higher than including 60, 70, 75 and 80 mg, in Figure 4 of Ivaturi, as the loading dose for target maintenance doses of 120 mg or 160 mg. It is prima facie obvious for one of ordinary skill in the art to determine the optimum loading doses to administer as the first dose in order accelerate reaching Cmax,ss, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
Response to Arguments
Applicant argues on page 6 that in all of Ivaturi’s examples the IV dose amount does not exceed half the target oral dose and thus results in a different concentration of sotalol than the claimed methods. Applicant points to Figure 11 and paragraph [0058] of Ivaturi to show that 80 mg by IV over 2 hours did not reach a concentration of 1000 ng/mL but only after an oral 160 mg dose of sotalol is administered the sotalol concentration increases to over 1000 ng/mL. Applicant argues that the claimed method enables the patient to approach/reach Cmax,ss after the IV dose alone.
Applicant's arguments filed on 27 October 2025 have been fully considered but they are not persuasive. In response, Ivaturi teaches additional embodiments further include applying the IV loading strategy having progressively higher titrating doses including higher doses of 120 or 160 mg as target oral maintenance doses (e.g., higher than including 60, 70, 75 and 80 mg IV loading dose for 80 mg as prior stable dose in Figure 4) that is based on tolerability (paragraph [0048]). Ivarturi discloses that an optimal dosing regimen achieved Cmax,ss as early as 4 hours after initiation of treatment on Day 1 (paragraph [0060]). Ivaturi discloses that Cmax,ss for 120 mg is around 1200 ng/mL and the Cmax,ss for 160 mg is around 1600 ng/mL (Figure 2, Figure 10 and Figure 11). One of ordinary skill in the art would select doses including higher than 80 mg for target oral maintenance doses of 120 mg or 160 mg. As evidenced by the instant specification, about 82 mg to about 96 mg of intravenous sotalol hydrochloride administered over about 60 minutes can provide a steady state Cmax of between about 1000 ng/mL and about 1400 ng/mL (paragraph [0044] of the instant specification filed on 10/15/2025).
Further, the recitation of “whereby the patient achieves a concentration of sotalol of between 1000 ng/mL and 1800 ng/mL” in its broadest reasonable interpretation reads on the patient achieving a concentration of sotalol of between 1000 ng/mL and 1800 ng/mL anytime during the method including after an oral administration.
Applicant argues that it is unexpected that a single IV dose can be used as a reliable indicator of patient tolerance to sotalol, thus allowing for a broader population of patients to be treated and providing a more accurate test that increased confidence that subsequent oral dosing will be safe.
In response, Ivaturi discloses a method including detecting a baseline QTc of a subject, administering a first dose of an antiarrhythmic drug via a first intravenous infusion for first duration of time, then determining the difference between the baseline QTc and a first QTc measured after the first intravenous infusion to detect a first delta QTc (paragraph [0006]). Ivaturi discloses a method including detecting a baseline QTc of a subject, administering a first dose of an antiarrhythmic drug via a first intravenous infusion for first duration of time, then determining the difference between the baseline QTc and a first QTc measured after the first intravenous infusion to detect a first delta QTc to see if the first delta QTc is in an acceptable range of less than 20% from the baseline (e.g., QTc of the patient measured prior to administration of the loading dose) or <500 msec (paragraphs [0006] and [0049]). Ivaturi discloses maintenance doses of including 160 mg and 120 mg if QTc is measured and is found to be not within an acceptable range (paragraph [0067]). Therefore, from the disclosure of Ivaturi, it is expected that single IV dose can be used to indicate tolerance of a patient to sotalol using first delta QTc.
Thus, for the reasons of record and for the reasons presented above claims 1, 17-22 and 24-25 are rejected under 35 U.S.C. 103(a).
Conclusion and Correspondence
No claims are allowed.
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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN P NGUYEN whose telephone number is (571)270-5877. The examiner can normally be reached Monday-Friday 10am-6pm EST.
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/JOHN P NGUYEN/
Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600