A New Variation on an Old Theme: FDA Refuses PTE Regulatory Review Period Revision Based on Filing Refusal Decision

By Kurt R. Karst –      

It’s been a long time since we last posted on a Patent Term Extension (“PTE”) controversy  – a little more than a year it seems (see here) – but that doesn’t mean we’re not keeping an eye on decisions coming out of FDA and the Patent and Trademark Office (“PTO”).  We still diligently track issues and cases of interest, whether with respect to so-called “reverse Photocure” issues (see our previous post here, and here for a recent FDA decision in Docket No. FDA-2014-E-0025), first permitted commercial marketing issues (see, e.g., here), or regulatory review period determination issues.  That last topic is the subject of today’s post.

Under 35 U.S.C. § 156, certain patents covering products regulated by FDA are eligible for a PTE if patent life was lost during a period when the product was undergoing regulatory review.  The “regulatory review period” is composed of a “testing phase” and a “review phase” (also referred to as an “approval phase”).  For drugs approved under the FDC Act, the “testing phase” begins on the effective date of an IND, and ends on the date an NDA (or BLA) is initially submitted to FDA.  The “review phase” is the period between the initial submission of the NDA (or BLA) and approval.  (The term of a patent may be extended for a period of time that is the sum of one-half of the time in the “testing phase,” plus all the time in the “review phase,” and minus any of the “regulatory review period” that occurs prior to the patent grant or where the sponsor did not act with due diligence.)   FDA’s regulations implementing the statute’s PTE provisions state that “[t]he approval phase begins on the date a marketing application under section 351 of the Public Health Service Act or section 505(b) of the Act is initially submitted to FDA . . . and ends on the date the application is approved” (21 C.F.R. § 60.22(a)(2) (emphasis added)), and that “[f]or purposes of determining the regulatory review period for any product, a marketing application . . . is initially submitted on the date it contains sufficient information to allow FDA to commence review of the application” (21 C.F.R. § 60.22(f) (emphasis added)). 

Over the years, questions have cropped up as to when the review phase begins – that is, when is an application considered initially submitted to FDA – in the context of “rolling” or modular submissions.  Insofar as NDA and BLA “fast track” submission are concerned, FDA has determined that receipt of the last module (or application component) makes the application complete, and thus “initially submitted” for PTE purposes.  This has been the topic of several letter decisions, including in Docket No. FDA-2005-E-0310 concerning KEPIVANCE, in Docket No. FDA-2009-E-0237 concerning DEXILANT, and in Docket No. FDA-2007-E-0278 concerning ZOLINZA.  FDA has come to a similar conclusion involving modular PMA (medical device) submissions (see our previous post here).

Perhaps most famously, both FDA and the PTO were sued over their determinations as to what it means for an animal drug application to be initially submitted to FDA.  In Wyeth Holdings Corp. v. Sebelius, Wyeth contended that a 16-day approval phase for a New Animal Drug Application reviewed under FDA’s Phased Data Review Policy and Administrative NADA process was unreasonable, and that the NADA was initially submitted to FDA when the company submitted the first technical section to its application.   In May 2010, the U.S. Court of Appeals for the Federal Circuit affirmed a March 2009 decision from the U.S. District Court for the District of Columbia granting summary judgment to FDA and the PTO (see our previous posts here and here). 

The case of U.S. Patent No. 6,087,380 (“the ‘380 patent) covering Boehringer Ingelheim Pharmaceuticals, Inc.’s (“BIPI’s”) PRADAXA (dabigatran etexilate) Capsules offers up a new twist on the question: “When is an NDA subject to a rolling review initially submitted to FDA?” 

PRADAXA is the subject of NDA 022512, which FDA approved on October 19, 2010, and for which the final “piece” of the submission arrived at FDA on December 15, 2009.  Almost two months after receiving that final NDA component, however, FDA, on February 12, 2010, issued a Refuse-to-File (“RTF”) letter refusing to file the December 15, 2009 submission for clinical reasons.  Nevertheless, FDA continued to review other parts of the application (e.g., Chemistry, Manufacturing, and Controls).  On April 19, 2010, BIPI resubmitted the NDA and the application was later accepted for review and approved.

Fast-forward to May 2012, after BIPI timely requested a PTE for the ‘380 patent, and FDA’s publication of a notice in the Federal Register that the regulatory review period for PRADAXA is 2,633 days, of which 2,449 days occurred during the testing phase and only 184 days occurred during the approval phase.  The FDA notice states, in particular, with respect to the approval phase that:

The date the application was initially submitted with respect to the human drug product under section 505(b) of the FD&C Act: April 19, 2010.  The applicant claims December 15, 2009, as the date the new drug application (NDA) for PRADAXA (NDA 22–512) was initially submitted.  However, FDA records indicate that NDA 22–512, received December 15, 2009, was incomplete.  FDA refused to file this application and notified the applicant of this fact by letter dated February 12, 2010.  The completed NDA was then submitted on April 19, 2010, which is considered to be the NDA initially submitted date.

BIPI timely requested reconsideration of the regulatory review period determination asking that the initial submission date of NDA 022512 be corrected from April 19, 2010 to December 15, 2009.  According to BIPI, “[a]ll of the required elements of the NDA were submitted to FDA as of December 15, 2009,” and “[a]lthough FDA issued a [RTF] letter to BIPI on February 12, 2010, the agency continued to review the NDA.” 

FDA did not agree, however, that the continued review of NDA 022512 was material, and did not agree that the NDA could be considered initially submitted on December 15, 2009 as a result of the subsequent RTF determination.  In a Letter Decision that cites legislative history, a regulatory review period determination of a 1994 vintage, and (of course) the Federal Circuit’s Wyeth decision, FDA says:

For determining the regulatory review period, the application filing review provides a measure of whether an application contains all the information necessary for Agency review to begin.  If an application can be filed, then it is considered sufficiently complete.  If the application is sufficiently complete, then the end date of the testing phase of the regulatory review period and the beginning of the approval phase can be declared and the initially submitted date is the NDA receipt date.  However, if the application cannot be filed (RTF), then it is not sufficiently complete and the approval phase has not yet begun. . . .

FDA permitted BI to submit its application on a “rolling review” basis, so that segments of the application that would be reviewed by different disciplines within FDA could be submitted when they were ready.  It was clearly understood, however, including by BI, that the application itself would not be considered to be submitted to FDA until such time as the last segment of the application was submitted for FDA review so that the complete application was before the agency. . . .

Thus, the fact that BI had submitted, and FDA had begun to review, modules of the application —and continued to review them after the application was refused for filing based on the promise that the application would be resubmitted— has no effect on the date that the application is considered to have been “initially submitted” for purposes of 35 U.S.C. 156(g).  While, as the Wyeth court found, this statutory provision may be considered ambiguous, the FDA interpretation is clear, and it is binding here.  Accordingly, no application is considered to be “initially submitted” if it has not been found to be sufficiently complete to meet the filing requirement for an application.

Interestingly, FDA says that BIPI had the chance to secure a date earlier than April 19, 2010 as the date of initial submission, but lost it when the company decided not to raise the rarely used “filing over protest procedures” at 21 C.F.R. § 314.101(a)(3).  According to FDA:

While BI had an opportunity, under FDA regulations, to contest FDA’s position, assert that its application was in fact sufficiently complete to be reviewed, and ask FDA to file the application over protest, BI did not do so.  FDA accordingly refunded 75% of the user fee for this application and awaited submission of additional and corrected data that would permit the application to be considered suffrciently complete such that FDA review of the entire application could commence.  On April 19, 2010, BI submitted the necessary data to complete its application, together with a user fee required for the resubmission of a new drug application.

FDA’s RTF regulation provides that if the Agency issues a RTF decision, “the applicant may request in writing within 30 days of the date of the agency’s notification an informal conference with the agency about whether the agency should file the application,” and that “[i]f, following the informal conference, the applicant requests that FDA file the application (with or without amendments to correct the deficiencies), the agency will file the application over protest . . . , notify the applicant in writing, and review it as filed.”  In that case, “the date of filing will be the date 60 days after the date the applicant requested the informal conference.” 

Although it’s unlikely that FDA’s decision means that we’ll see a rush of “filing over protest” actions by NDA and BLA sponsors, it’s certainly a tool to keep in mind if the PTE calculus warrants such an action.