DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 6-20 and 33-41 are rejected under 35 U.S.C. 103 as being unpatentable over Somberg et al. (US 10,512,620; hereinafter “Somberg”) in view of the FDA Label: Sotalol Hydrochloride Injection for Intravenous Use, (Label revised July 2009; hereinafter “FDA Label”) and Putman (US 6,944,638B1).
In relation to claim 6, claim 6 recites a method of initiating sotalol hydrochloride dosing for a patient, comprising: (a) measuring a creatinine clearance of the patient; (b) determining an amount
of an oral sotalol hydrochloride dose to administer to the patient; (c) inputting the patient's creatinine clearance and the amount of the oral sotalol dose into a treatment management application to provide an output comprising an amount of an intravenous (IV) dose of sotalol hydrochloride to administer to the patient; and (d) administering the IV dose to the patient over a period of one hour.
Somberg teaches a method of initiating sotalol therapy comprising administering an IV loading dose followed by an oral maintenance dose (Claim 1). Somberg teaches determining oral dose amounts of 80 mg or 120 mg and corresponding IV doses of 64 mg or 96 mg (specification). Somberg also mentions dose adjustments for renally impaired patients, implying the relevance of renal function (specification).
However, Somberg does not explicitly teach: (1) measuring and calculating creatinine clearance; (2) using a "treatment management application"; or (3) a specific one-hour infusion time. The FDA Label supplies the missing creatinine clearance element. The FDA Label explicitly states: "Measure serum creatinine and calculate an estimated creatinine clearance in order to establish the appropriate dosing interval for sotalol" (Page 3; Dosage and Administration). The FDA Label provides the Cockcroft-Gault formula for CrCl calculation and teaches IV-to-oral conversion ratios in Table 1: 80 mg oral = 75 mg IV; 120 mg oral = 112.5 mg IV (see page 3).
Putnam supplies the missing "treatment management application" element. Putnam teaches a medication dosage calculator that accepts input parameters such as prescribed dosage and patient characteristics, performs automated calculations, and provides calculated dosage output. Putnam teaches that the invention can be implemented as "a system, a device, a method, or a computer readable medium" (Abstract).
Based on the above supporting evidence, it would have been obvious to a person of ordinary skill in the art to combine Somberg, the FDA Label, and Putnam. The FDA Label is the official prescribing information that any physician implementing Somberg's method would necessarily consult for proper dosing guidance, including creatinine clearance calculations. Automating the manual calculations
taught by Somberg and the FDA Label using Putnam's calculator would reduce medication errors and improve clinical efficiency, which is a well-recognized benefit in the medical field. The combination would yield predictable results with no unexpected synergies. Regarding the one-hour infusion time, the FDA Label teaches a 5-hour infusion. The difference between 5 hours and 1 hour is a matter of routine clinical optimization. Infusion rates are commonly adjusted based on patient tolerance, clinical urgency, and institutional protocols. Selecting a faster infusion time within safe parameters would have been obvious and does not constitute an inventive step. Therefore, claim 6 is unpatentable under 35 U.S.C. § 103.
In relation to claim 7, claim 7 depends from claim 6 and further recites: (e) obtaining a baseline QTc interval for the patient; (f) obtaining one or more QTc intervals before, during or after administration of the IV dose; and (g) determining that at least one of the one or more QTc intervals is above 500 msec or more than 20% greater than the baseline QTc interval, and discontinuing
administering IV sotalol hydrochloride or discontinuing administering IV sotalol hydrochloride and administering oral sotalol hydrochloride to the patient.
In addition to the teachings applied to claim 6, Somberg explicitly teaches all additional elements of claim 7. Somberg teaches the step of monitoring the patient's QTc interval, and if the QTc interval is greater than 500 msec or has increased by 20% or more from baseline, discontinuing sotalol therapy or reducing the dose [see column 1, starting in line 57 to column 2, line 20, and additionally, column 2, starting in line 58 to column 3, line 27]. This teaching encompasses obtaining a baseline QTc (element e), monitoring QTc intervals during treatment (element f), and discontinuing if QTc exceeds 500 ms or increases by 20% or more (element g). The FDA Label corroborates this teaching, stating: "If the QT interval prolongs to 500 ms or greater, reduce the dose, decrease the infusion rate, or discontinue the drug" (Page 3; Warning section). For the same reasons as claim 6, it would have been obvious to combine these references. Therefore, claim 7 is unpatentable under 35 U.S.C. § 103.
In relation to claim 8, claim 8 depends from claim 6 and further recites: the creatinine clearance of the patient is in the range of 60-90 ml/min or >90 ml/min; the IV dose is an amount in the range of 60 mg-125 mg; the amount of the oral sotalol hydrochloride dose is 80 mg or 120 mg; and the oral
sotalol hydrochloride dose is administered to the patient and the administration is repeated at a selected dosing interval, wherein the selected dosing interval is 12 hours from a previous oral sotalol hydrochloride dose.
In addition to the teachings applied to claim 6, Somberg teaches oral doses of 80 mg and
120 mg and IV doses of 64 mg and 96 mg, which fall within the claimed range of 60-125 mg
(specification). Somberg teaches twice-daily (BID) dosing, which corresponds to a 12-hour
interval (specification).
The FDA Label teaches: "Administer sotalol twice daily in patients with a creatinine
clearance >60 mL/min" (Page 3), which encompasses both the 60-90 ml/min and >90
ml/min ranges recited in the claim. The FDA Label also teaches IV doses of 75 mg and 112.5
mg, both within the claimed range (Table 1, Page 3). For the same reasons as claim 6, it would have been obvious to combine these references. Therefore, claim 8 is unpatentable under 35 U.S.C. § 103.
In relation to claim 9, claim 9 depends from claim 6 and further recites: administering the oral sotalol hydrochloride dose to the patient in an amount of 80 mg or 120 mg and at least six hours
after the IV dose has been administered. In addition to the teachings applied to claim 6, Somberg teaches oral doses of 80 mg or 120 mg administered about 2 to about 6 hours after completion of the IV loading dose (Claim 1). The claim recites "at least six hours," which is at the upper end of Somberg's taught range. A person of ordinary skill in the art would understand that selecting a specific timing
within or slightly beyond a taught range is routine optimization based on clinical judgment
and patient-specific factors. For the same reasons as claim 6, it would have been obvious to combine these references. Therefore, claim 9 is unpatentable under 35 U.S.C. § 103.
In relation to claim 10, claim 10 depends from claim 9 and further recites: the creatinine clearance of the patient is in the range of 30-60 ml/min; the IV dose is an amount in the range of 75 mg-112.5 mg; and the administering of the oral sotalol hydrochloride dose comprises repeating one or more
times the administering of the oral sotalol hydrochloride dose at a selected dosing interval, wherein the selected dosing interval is 12 hours from a previous oral sotalol dose.
In addition to the teachings applied to claims 6 and 9, the FDA Label teaches dose adjustments based on renal function. The FDA Label teaches: "Administer sotalol...once daily in patients with a creatinine clearance between 40 and 60 mL/min" (Page 3). The FDA Label also teaches IV doses of 75 mg and 112.5 mg (Table 1, Page 3), which define the exact range recited in the claim. While the FDA Label teaches once-daily (24-hour) dosing for CrCl 40-60 ml/min rather than 12-hour dosing, a person of ordinary skill in the art might select 12-hour dosing for this population based on clinical judgment, therapeutic goals, and patient-specific factors. The FDA Label teaches the principle of adjusting dosing intervals based on renal function, with more frequent dosing for better renal function. Selecting an alternative dosing frequency based on clinical goals and patient needs is within the ordinary skill of a physician. For the same reasons as claim 6, it would have been obvious to combine these references.
Therefore, claim 10 is unpatentable under 35 U.S.C. § 103.
In relation to claim 11, claim 11 recites administering oral sotalol at least 12 hours after IV administration, which represents routine optimization of the timing taught by Somberg (2-6 hours) based on patient-specific factors and clinical judgment.
In relation to claim 12, claim 12 recites dosing for patients with CrCl 10-30 ml/min with 48-hour intervals. While the FDA Label contraindicates sotalol for CrCl <40 ml/min, the FDA Label teaches the principle of extending dosing intervals for patients with impaired renal function. The progression
from BID (>60 ml/min) to QD (40-60 ml/min) suggests that further extension to every 48 hours for severe renal impairment would be an obvious extrapolation of the same principle.
In relation to claims 13 and 14, claims 13 and 14 recite calculating start times for subsequent doses based on projected start times for initial doses. These are straightforward temporal calculations that would obviously be implemented in Putnam's calculator given the timing relationships taught by
Somberg and the FDA Label. Accordingly, for an artisan skilled in the art, the implementation of this enhancement would have been considered an obvious alternative in the design of the process.
In relation to claim 15, Claim 15 recites a method of increasing sotalol hydrochloride dosing, comprising: (a) measuring a creatinine clearance of the patient; (b) determining an amount of an oral
sotalol hydrochloride dose to administer to the patient that is an increased amount above an amount the patient is currently being administered; (c) inputting the patient's creatinine clearance and the amount of the increased oral sotalol dose into a treatment management application to provide an output comprising an amount of an intravenous (IV) dose of sotalol hydrochloride to administer to the patient; and (d) administering the IV dose to the patient over a period of one hour.
Somberg's title is "Method of initiating and escalating sotalol hydrochloride dosing" (emphasis added). Somberg explicitly teaches dose escalation methods, including increasing from initial doses to higher doses. Somberg teaches oral doses of 80 mg and 120 mg, implying escalation from 80 to 120 mg, with corresponding IV doses (specification). The FDA Label teaches: "The dose can be up-titrated to maximal dose of 150 mg twice daily" (Page 3). The FDA Label's Table 1 shows higher dose conversions, including 160 mg oral = 150 mg IV.
Claim 15 is essentially the same as claim 6, but applied to dose escalation rather than initiation. Since Somberg explicitly teaches both initiation and escalation, and the FDA Label teaches dose escalation with corresponding IV doses, all elements of claim 15 are taught by the same combination as claim 6. For the same reasons as claim 6, it would have been obvious to combine these references.
Therefore, claim 15 is unpatentable under 35 U.S.C. § 103.
In relation to claims 16-20, claim 16 adds QTc monitoring elements (same as claim 7). Claims 17-19 specify various CrCl ranges, dose ranges, and dosing intervals (similar to claims 8, 10, and 12). Claim 20 adds temporal calculation functionality (similar to claim 13). All of these elements are taught by the combination of Somberg, FDA Label, and Putnam for the same reasons discussed above. Accordingly, for an artisan skilled in the art, the implementation of these enhancements would have been considered obvious alternatives in the design of the process.
In relation to claim 33, claim 33 recites a method of initiating creatinine clearance-based dosing of a selected drug for a patient, comprising: (a) measuring a creatinine clearance of the patient; (b)
determining an amount of an oral dosage of a selected drug to administer to the patient; (c) inputting the patient's creatinine clearance and the amount of the oral dosage into a treatment management application to provide an output comprising an amount of an intravenous (IV) dose of the selected drug to administer to the patient based on the creatinine clearance; and (d) administering the IV dose to the patient over a selected period of time.
Somberg teaches a method of initiating sotalol therapy comprising administering an IV loading dose followed by an oral maintenance dose (Claim 1). Somberg teaches determining oral dose amounts and corresponding IV doses (specification). Somberg also mentions dose adjustments for renally impaired patients, implying the relevance of renal function (specification). Somberg does not explicitly teach: (1) measuring and calculating creatinine clearance; or (2) using a "treatment management application." The FDA Label supplies the missing creatinine clearance element. The FDA Label explicitly
states: "Measure serum creatinine and calculate an estimated creatinine clearance in order to establish the appropriate dosing interval for sotalol" (Page 3). The FDA Label provides the Cockcroft-Gault formula for CrCl calculation and teaches IV-to-oral conversion ratios (Table 1, Page 3). Moreover, Putnam supplies the missing "treatment management application" element. Putnam teaches a medication dosage calculator that accepts input parameters such as prescribed dosage and patient characteristics, performs automated calculations, and provides calculated dosage output. Accordingly, it would have been obvious to a person of ordinary skill in the art to combine Somberg, the FDA Label, and Putnam. The FDA Label is the official prescribing information that any physician implementing Somberg's method would necessarily consult for proper dosing guidance. Automating the manual calculations taught by Somberg and the FDA Label using Putnam's calculator would reduce medication errors and improve clinical efficiency. The combination would yield predictable results with no unexpected synergies. Therefore, claim 33 is unpatentable under 35 U.S.C. § 103.
In relation to claim 34, claim 34 recites a method of initiating sotalol hydrochloride dosing for a patient, comprising: (a) measuring a creatinine clearance and an initial QT interval of the patient; (b)
selecting a target oral sotalol hydrochloride dose to administer to the patient; (c) based on
the patient's creatinine clearance and the target oral sotalol hydrochloride dose,
determining an amount of an intravenous (IV) dose of sotalol hydrochloride to administer
to the patient; (d) administering the IV dose to the patient; (e) determining one or more
subsequent QT interval(s) of the patient; and (f) administering one or more oral dose of
sotalol hydrochloride to the patient.
Somberg teaches a method of initiating sotalol therapy comprising administering an IV
loading dose followed by an oral maintenance dose (Claim 1). Somberg teaches determining oral dose amounts and corresponding IV doses (specification). Somberg also teaches monitoring the patient's QTc interval, including obtaining a baseline QTc and monitoring subsequent QTc intervals (Claim 1). The FDA Label teaches measuring creatinine clearance (Page 3) and provides IV-to-oral conversion ratios (Table 1, Page 3). Putnam teaches a treatment management application for automating dosage calculations. For the same reasons as claim 33, it would have been obvious to a person of ordinary skill in the art to combine these references to arrive at the invention of claim 34. Therefore, claim 34 is unpatentable under 35 U.S.C. § 103.
In relation to claim 35, claim 35 depends from claim 34 and further recites: one or more of the subsequent QT interval(s) is above 500 msec or is more than 20% greater than the initial QT interval; the target oral dose of sotalol hydrochloride is 120 mg; and the one or more oral dose of sotalol hydrochloride administered to the patient is 80 mg.
Somberg teaches discontinuing sotalol therapy or reducing the dose if the QTc interval is
greater than 500 msec or has increased by 20% or more from baseline (specification). Somberg also teaches oral doses of 80 mg and 120 mg (specification). The FDA Label teaches a 120 mg oral dose corresponds to a 112.5 mg IV dose (Table 1, Page 3). Accordingly, it would have been obvious to a person of ordinary skill in the art to start with a target oral dose of 120 mg, and upon determining that the QTc interval exceeded the safety threshold, reduce the dose to 80 mg, as taught by Somberg. Therefore, claim 35 is unpatentable under 35 U.S.C. § 103.
In relation to claim 36, claim 36 depends from claim 33 and further recites: the selected drug is a drug for which dosing is based on renal function. Sotalol, the drug in Somberg and the FDA Label, is a drug for which dosing is based on renal function, as explicitly taught by the FDA Label (Page 3). Accordingly, for an artisan skilled in the art, the implementation of this enhancement would have been considered an obvious alternative in the design of the system.
In relation to claim 37, claim 37 depends from claim 33 and further recites: the selected drug is an anti-arrhythmic drug. Sotalol, the drug in Somberg and the FDA Label, is an anti-arrhythmic drug.
Accordingly, for an artisan skilled in the art, the implementation of this enhancement would have been considered an obvious alternative in the design of the system.
In relation to claim 38, claim 38 depends from claim 33 and further recites: the selected drug is one or more of sotalol, dofetilide, amiodarone, ibutilide, dronedarone, procainamide, flecainide, and/or
propafenone. The method of claim 33 is a general method for initiating creatinine clearance-based dosing of a selected drug. The prior art teaches this method for sotalol. It would have been obvious
to a person of ordinary skill in the art to apply this general method to other anti-arrhythmic drugs for which dosing is based on renal function, such as those listed in the claim. Therefore, claim 38 is unpatentable under 35 U.S.C. § 103.
In relation to claim 39, claim 39 depends from claim 33 and further recites: the selected drug is sotalol. Somberg and the FDA Label explicitly teach the use of sotalol. Accordingly, for an artisan skilled in the art, the implementation of this enhancement would have been considered an obvious alternative in the design of the system.
In relation to claim 40, claim 40 depends from claim 33 and further recites: the selected drug is dofetilide. Dofetilide is an anti-arrhythmic drug for which dosing is based on renal function. For the
same reasons as claim 38, it would have been obvious to a person of ordinary skill in the art to apply the general method of claim 33 to dofetilide. Therefore, claim 40 is unpatentable under 35 U.S.C. § 103.
In relation to claim 41, claim 41 depends from claim 33 and further recites: the selected drug is procainamide. Procainamide is an anti-arrhythmic drug for which dosing is based on renal function. For
the same reasons as claim 38, it would have been obvious to a person of ordinary skill in the art to apply the general method of claim 33 to procainamide. Therefore, claim 41 is unpatentable under 35 U.S.C. § 103.
Response to Arguments
Applicant’s arguments with respect to the pending claims have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Allowable Subject Matter
Independent claims 21 and 27 are allowable over the prior art of record. The following is an examiner’s statement of reasons for allowance:
in relation to independent claim 21, the prior art of record does not disclose or suggest, in combination and sequence, a method of maintaining sinus rhythm in a patient aged 18 or less who is currently in sinus rhythm, comprising of:
a. determining whether the patient has normal or impaired renal function and (i) the patient’s age and the patient’s weight, or (ii) the patient’s body surface area;
b. inputting the patient’s renal function and (i) the patient’s age and the patient’s weight, or (ii) the patient’s body surface area into a treatment management application to provide an output comprising an amount of an intravenous (IV) dose of sotalol hydrochloride to be administered to the patient based on the patient’s renal function, age and weight or the patient’s renal function and body surface area; and
c. administering the IV dose of sotalol hydrochloride to the patient over a selected period of time.
in relation to independent claim 27, the prior art of record does not disclose or suggest, in combination and sequence, a method of substituting oral sotalol with intravenous sotalol hydrochloride, comprising:
a. determining an amount of an oral dose of sotalol hydrochloride for a patient;
b. inputting the amount of the patient’s oral sotalol hydrochloride dose into a treatment management application to provide an output comprising an amount of an intravenous (IV) dose of sotalol hydrochloride to be administered to the patient as a substitute for the oral sotalol hydrochloride dose;
c. administering the substitute IV dose to the patient over a selected period of time, and administering one or more subsequent substitute IV dose(s) at a selected dosing interval; and
d. inputting a projected start time for the substitute IV dose into the treatment management application to provide an output comprising a start time for one or more of the subsequent substitute IV dose(s).
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MANUEL A MENDEZ whose telephone number is (571)272-4962. The examiner can normally be reached Mon-Fri 7:00 AM-5:00 PM.
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, Bhisma Mehta can be reached at 571-272-3383. 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 866-217-9197 (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.
Respectfully submitted,
/MANUEL A MENDEZ/ Primary Examiner, Art Unit 3783