FDA Determines that Cobalt Forfeited 180-Day Exclusivity for Generic PRECOSE; Agency is Sued Yet Another Time

May 11, 2008

We previously reported (here and here) on FDA’s efforts to resolve 180-day exclusivity forfeiture issues concerning generic versions of Bayer Pharmaceuticals’ (“Bayer’s”) diabetes drug PRECOSE (acarbose) Tablets by establishing a public docket.  (FDA has also taken similar actions to resolve 180-day exclusivity issues concerning ramipril and granisetron.)  Under changes made to the Federal Food, Drug, and Cosmetic Act (“FDC Act”) by the 2003 Medicare Modernization Act (“MMA”), generic applicants that are “first applicants” are eligible for 180-day exclusivity, unless such eligibility is forfeited.  A “first applicant” eligible for 180-day exclusivity is defined in FDC Act § 505(j)(5)(B)(iv)(II)(bb) to mean “an applicant that, on the first day on which a substantially complete [ANDA] containing a [Paragraph IV certification] is submitted for approval of a drug, submits a substantially complete [ANDA] that contains and lawfully maintains a [Paragraph IV certification].”  Forfeiture of 180-day exclusivity eligibility can occur under several statutory provisions.   

In September 2007, FDA issued a letter soliciting public comment on whether the “first applicant” to submit an ANDA for generic PRECOSE Tablets was eligible for 180-day exclusivity, or whether such eligibility was forfeited.  Specifically, FDA’s September 2007 letter identifies the following facts and requested comment on the following forfeiture issues:

As of the date of this letter, which is more than 30 months from March 22, 2005 [when the first ANDA was submitted], no first applicant’s ANDA has been approved.  Also, on April 16, 2007, Bayer requested that [U.S. patent #4,904,769 (“the ‘769 patent”] be “delisted” as to Precose, i.e., they withdrew the patent information.  On September 26, 2007, FDA indicated in [the Orange Book] that the request to delist this patent had been submitted on April 16, 2007.

To determine whether any ANDA referencing Precose is eligible for final approval, the agency must consider how the 180-day generic drug exclusivity forfeiture provisions at section 505(j)(5)(D) of the [FDC Act] apply to this set of facts.  As part of the process for making such a determination, we are seeking your views regarding the applicability of sections 505(j)(5)(D)(i)(IV) — failure to obtain tentative approval within 30 months — and 505(j)(5)(D)(i)(I)(aa)(BB) — failure to market by 30 months. We also are interested in your views regarding the applicability of section 505(j)(5)(D)(i)(I)(bb)(CC) — relating to the delisting of a patent.

The “first applicant” eligible for 180-day exclusivity was later revealed to be Cobalt Pharmaceuticals, Inc. (“Cobalt”) when the company submitted an Emergency Petition for Stay of Action to FDA on October 24, 2007 requesting that the Agency stay the approval of all subsequent acarbose tablets ANDAs until Cobalt’s 180-day exclusivity period expires.  Sixteen days later, Cobalt submitted a Citizen Petition and another Emergency Petition for Stay of Action to FDA challenging the Agency’s bioequivalence recommendations for generic PRECOSE Tablets. 

Cobalt submitted ANDA #77-532 to FDA in January 2005 containing a Paragraph IV certification to the ‘769 patent; however, after initially reviewing the application, FDA refused to receive the ANDA.  FDA later received the application on March 22, 2005, and Cobalt provided the required notice of the Paragraph IV certification to Bayer.  Bayer did not sue Cobalt.  In October 2007, Cobalt filed an action for declaratory judgment of non-infringement and invalidity of the ‘769 patent.  The case was later voluntarily dismissed without prejudice. 

On May 7, 2008, FDA issued a Letter Decision in which the Agency determined that Cobalt forfeited 180-day exclusivity eligibility on September 22, 2007 under the “failure to market” forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I) because the company did not begin to market its drug product by that date.  (FDA also simultaneously denied Cobalt’s October 2007 Emergency Petition for Stay of Action.) According to FDA’s calculations, September 22, 2007 is the “earlier of” date between March 22, 2005 (i.e., the date that is 30 months from the date on which Cobalt submitted a substantially complete ANDA #77-532 containing a Paragraph IV certification to the ‘769 patent) and July 21, 2008 (i.e., the date that is 75 days after FDA approved ANDA #77-532 on May 7, 2008).  September 22, 2007 is also the “later of” date that is 75 days after April 16, 2007, when Bayer withdrew the ‘769 patent from the Orange Book (i.e., June 30, 2007). 

In what will likely be a surprise to those following 180-day exclusivity issues (and could have significant implications on some currently pending ANDAs otherwise eligible for 180-day exclusivity), FDA notes that the U.S. Court of Appeals for the District of Columbia Circuit’s 2006 decision in Ranbaxy Labs. Ltd. v. Leavitt holding that FDA may not condition the delisting of a patent on the existence of patent litigation and deprive an ANDA applicant eligible for 180-day exclusivity of such exclusivity does not apply to the version of the FDC Act amended by the MMA.  FDA’s Decision Letter states:

[T]he Ranbaxy court noted that the decisions rendered by the FDA and the district court had been made pursuant to the Act “as it stood before the MMA and, because the MMA was not made retroactive . . . this decision is also geared to the Act pre-MMA” (469 F.3d at 122). Therefore, the court did not purport to render a decision on patent delisting and exclusivity under the MMA. The effect of patent delisting on eligibility for 180-day exclusivity is expressly addressed by the plain language of section 505(j)(5)(D)(i)(I) of the Act. . . .  FDA reads the plain language of 505(j)(5)(D)(i)(I)(bb)(CC) to apply whenever a patent is withdrawn (or requested to be “delisted”) by the NDA holder.

FDA’s Decision Letter also addresses the forfeiture of exclusivity under FDC Act § 505(j)(5)(D)(i)(IV), which states that 180-day exclusivity eligibility is forfeited when “[t]he first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.”  (FDA has previously made determinations under this forfeiture provision – see FDA Law Blog post here – but has not, until now, substantively discussed the provision.) FDA states that “[t]o calculate the start of the 30-month period under this forfeiture provision, it is reasonable to use the date that qualifies the applicant as a first applicant for 180-day exclusivity purposes: the date the ANDA is sufficiently complete to permit a substantive review,” and further notes that:

[I]n contrast, the failure to market provision at section 505(j)(5)(D)(i)(I)(aa)(BB) of the Act calculates the 30-month period from the date of “submission,” rather than the date the application is “filed.”  The exclusivity provisions appear to use the terms “submit” and “file” interchangeably; there is no evidence that Congress intended a difference in meaning between these latter two terms.  Because both terms are used in the context of “first applicant” status, we will interpret the terms to refer to the time that the agency has determined [an] ANDA to be sufficiently complete to permit substantive review.  If we interpreted the term “submission” in this context to mean the date the ANDA is date-stamped by FDA, regardless of whether the application is found to have been reviewable, an applicant whose ANDA cannot be reviewed without the submission of additional information would find its failure to market period under section 505(j)(5)(D)(i)(I)(aa)(BB) to have begun to run even before the agency could begin a substantive review of the application.

In the context of Cobalt’s ANDA #77-532, FDA notes that the application “was sufficiently complete to permit review and was received on March 22, 2005, and that the 30-month period beginning on this date ended on September 22, 2007.  As of that date FDA had not granted tentative or final approval.  However, because FDA’s May 7, 2008 decision with respect to Cobalt’s November 2007 Citizen Petition and Emergency Petition for Stay of Action changed certain bioequivalence requirements, and as a result of a new provision added to the FDC Act at § 505(q)(1)(G) by the FDA Amendments Act permitting the extension of this 30-month period if “approval of the application was delayed because of a petition,” FDA determined that Cobalt did not forfeit exclusivity for failing to obtain tentative approval by September 22, 2007.   

FDA’s May 2008 Letter Decision also addresses the Agency’s interpretation of the beginning of the two 30-month periods described in the “failure to market” and “failure to obtain tentative approval” forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I) and § 505(j)(5)(D)(IV), respectively.  Cobalt had argued that “FDA must interpret the two 30-month periods described in the MMA forfeiture provisions as beginning not from the date the application is submitted or filed, but rather from the date the NDA holder and patent owner receive the first applicant’s notice of paragraph IV certification.”  FDA disagreed, and referring back to a passage quoted above, states that “although there is some ambiguity created by the use of the term ‘submission’ in section 505(j)(5)(D)(i)(I)(aa)(BB) and ‘filed’ in section 505(j)(5)(D)(i)(IV) to identify what appears to have been intended to be the same event, that ambiguity can be easily resolved in a manner that is both consistent with the agency’s use of these terms in the review of ANDAs and with the statutory scheme.”

Dissatisfied with FDA’s decision, Cobalt sued FDA in the U.S. District Court for the District of Columbia on May 8, 2008 seeking declaratory and injunctive relief.  A copy of Cobalt’s Complaint, Cobalt’s Motion for Temporary Restraining Order, FDA’s Opposition Memorandum, and Cobalt’s Supplemental Memorandum are available via the hyperlinked text.  We understand that on May 9th the court denied Cobalt’s motion for a temporary restraining order.  Roxane Laboratories has also filed a Motion to Intervene in the case.  We understand that the court granted Roxane’s motion.  The lawsuit is the latest in a recent spat of cases concerning Hatch-Waxman issues, including controversies over generic PLAVIX (clopidogrel bilsulfate), generic DEPAKOTE (divalproex sodium), and generic RISPERDAL (risperidone) Tablets

By Kurt R. Karst   

Categories: Hatch-Waxman