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 6-17 are rejected under 35 U.S.C. 103 as being unpatentable over TIKOSYN®
USPI [1] in view of Falk et al. [2], and further in view of Levy et al. [3] or Gupta et al. (US 9,069,887; hereinafter “Gupta”) [4].
In relation to claim 6, claim 6 recites a method of providing a dofetilide dosing regimen. The TIKOSYN® USPI [1] teaches key elements of this claim. Specifically, it discloses:
• (a) measuring a creatinine clearance of the patient: The USPI states, "The dose of
TIKOSYN must be individualized according to calculated creatinine clearance...
Calculation of creatinine clearance using the formula..." (Dosage and Administration).
• (b) determining an amount of an oral dofetilide dose: The USPI provides a clear
algorithm: The starting dose of TIKOSYN is based on the calculated creatinine
clearance: >60 mL/min: 500 mcg twice daily; 40 to 60 mL/min: 250 mcg twice daily; 20 to
<40 mL/min: 125 mcg twice daily (Dosage and Administration).
• (e, partially) administering the oral dofetilide dose... at a selected dosing interval:
The USPI specifies a twice-daily (BID) regimen, which corresponds to a 12-hour dosing
interval.
However, the TIKOSYN® USPI [1] only describes oral administration, and therefore, does not
teach administering an intravenous (IV) dose of dofetilide (element d), nor does it teach the
sequence of administering an IV dose followed by an oral dose (element e, sequence). It
also fails to teach a treatment management application for calculating an IV dose (element c).
Falk et al. [2] remedy the deficiency of IV administration by teaching the use of intravenous
dofetilide for terminating atrial fibrillation. Falk discloses that "The infusion of dofetilide
was administered as a 15-min infusion" (Methods, Protocol). Accordingly, an artisan skilled in the art seeking to achieve a more rapid therapeutic effect of dofetilide, would have found it obvious to combine the established oral dosing regimen of the TIKOSYN® USPI [1] with the IV administration method taught by Falk et al. [2]. IV administration provides immediate bioavailability, and it would be a logical and predictable step to initiate therapy with an IV loading dose to quickly achieve therapeutic plasma concentrations before transitioning to the oral maintenance schedule described in the USPI.
The combination of the TIKOSYN® USPI [1] and Falk et al. [2] still does not explicitly teach
element (c), a treatment management application that calculates an IV dose based on creatinine clearance and the oral dose. This final element is rendered obvious by either Levy et al. [3] or Gupta [4]. Levy et al. [3] teaches the application of machine learning and computational decision analysis specifically for dofetilide dose management, stating in the Conclusions section of the article that a reinforcement learning algorithm... was able to predict dosing decisions with 96.1% accuracy. Gupta [4] teaches a general "patient-specific dosing management system" that uses a processor to modify operating limit parameters for drug delivery based on patient-specific information.
An artisan skilled in the art, aware of the need to calculate a safe and effective IV loading dose that corresponds to the maintenance oral dose, would find it obvious to implement this calculation within a software application, as suggested by the computational approaches in Levy et al. [3] or the general system in Gupta [4]. Automating such calculations is a predictable use of modern computing to enhance the safety and efficiency of a known drug therapy regimen. Therefore, the combination of these references renders claim 6 obvious.
In relation to claim 7, Claim 7 adds steps for QTc monitoring and discontinuing administration if specific thresholds are met. The TIKOSYN® USPI [1] explicitly teaches these safety parameters for
oral dofetilide. It discloses:
(f) measuring a baseline QTc interval: "Prior to administration of the first dose, the
QTc or QT must be checked..." (Dosage and Administration).
(g) determining one or more QTc intervals after administration: After
administration, QTc or QT should be re-evaluated at 2–3 hours (Instructions, step 6).
(h) discontinuation criteria: If the QTc or QT has increased by greater than 15% or
exceeds 500 msec... subsequent doses should be adjusted accordingly (Instructions, step 5).
Based on the above evidence, it would have been entirely obvious to an artisan skilled in the art to apply these established, FDA-mandated safety protocols for dofetilide to any method of its administration, including the combined IV/oral regimen found obvious in the rejection of claim 6. The risk of QTc prolongation is an inherent property of dofetilide, and applying these known monitoring and discontinuation rules is a necessary and obvious step to ensure patient safety, regardless of the route of
administration.
In relation to claim 8, claim 8 adds using the treatment management application to calculate an updated oral dose or interval based on QTc measurements. The TIKOSYN® USPI [1] teaches the underlying principle, stating that if QTc thresholds are exceeded, subsequent doses should be adjusted accordingly (Instructions, step 5). Levy et al. [3] teaches using computational systems for dofetilide dose adjustment decisions (column 15, starting in line 65 to column 16, line 11). Accordingly, it would have been obvious to an artisan skilled in the art to extend the functionality of the treatment management application of claim 6 to automate this dose adjustment process. Since the need for adjustment is known from the USPI [1] and the use of computational tools for this purpose is known from Levy et al. [3], integrating this feature into the application is a predictable design choice for improving the dosing method.
In relation to claim 9, claim 9 specifies that the dose adjustment involves lowering the dose or lengthening the interval. This is an obvious implementation of the instruction from the TIKOSYN® USPI [1] to "adjust" the dose. For an artisan skilled in the art, reducing drug exposure to mitigate toxicity (such as QTc prolongation) is a fundamental principle of pharmacology. The two most direct and obvious ways to achieve this are to either decrease the amount of the dose or increase the time between doses. Therefore, this claim recites nothing more than the obvious and expected implementation of the prior art's teaching.
In relation to claim 10, claim 10 specifies the exact dose reduction steps: 500 mcg to 250 mcg, and 250 mcg to 125 mcg. The TIKOSYN® USPI [1] explicitly lists 500 mcg, 250 mcg, and 125 mcg as the standard available dosage strengths, which are tied to different levels of renal function. When a dose
reduction is required, as taught by the prior art, it would be obvious for an artisan skilled in the art to select the next lowest standard dosage strength available. The claimed progression is the simple, logical, and predictable path of dose reduction based on the known dosages.
In relation to claim 11, claim 11 specifies lengthening the dosing interval from 12 hours to 24 hours for the 125 mcg dose. As stated in the rejection of claim 9, lengthening the interval is an obvious
alternative to lowering the dose amount. For the lowest available dose of 125 mcg, if a further reduction in daily drug exposure is needed, extending the interval from twice-daily (12 hours) to once-daily (24 hours) is a simple, conventional, and obvious modification for an artisan skilled in the art to make.
In relation to claims 12, 14, and 16, these claims recite specific combinations of creatinine clearance, oral dose, and IV dose ranges. The TIKOSYN® USPI [1] teaches the specific creatinine clearance ranges and the corresponding oral doses (e.g., >60 mL/min for 500 mcg, 40-60 mL/min for 250 mcg, etc.). The claims add specific IV dose ranges for each of these tiers. While the exact IV dose ranges
are not explicitly taught, the concept of an IV loading dose being proportional to the oral maintenance dose is a fundamental pharmacokinetic principle. An artisan skilled in the art would understand that the IV dose must be calculated to achieve a desired steady-state concentration that can be maintained by the subsequent oral doses. Determining the optimal IV dose range for a given oral dose and patient profile (like creatinine clearance) would be a matter of routine calculation, modeling, and optimization, not an inventive step. The claimed IV ranges appear to be simple pharmacokinetic equivalents or fractions of the established oral doses and would have been obvious to determine.
In relation to claim 13 and 15, these claims merely specify that the oral dofetilide dose is 250 mcg (claim 13) or 125 mcg (claim 15). The TIKOSYN® USPI [1] explicitly teaches these as standard dose levels for patients with corresponding levels of creatinine clearance. For an artisan skilled in the art, it would have been obvious to apply the general method of claim 6 to these known, standard doses of dofetilide.
In relation to claim 17, claim 17 adds inputting a projected IV start time into the treatment management application to calculate the start time for the subsequent oral doses. This is a simple
administrative calculation. Once the IV-to-oral dosing sequence is established as obvious, determining the timing of the first oral dose relative to the IV infusion is a matter of basic pharmacokinetic scheduling to ensure continuous therapeutic coverage. Automating this straightforward calculation within the treatment management application is an obvious feature to add for convenience and to reduce human error. It is a predictable extension of the application's core function of managing the dosing regimen.
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.
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Respectfully submitted,
/MANUEL A MENDEZ/ Primary Examiner, Art Unit 3783