Putting the Genie Back in the Bottle – Apotex Petitions FDA to Recognize Remaining 180-Day Exclusivity for Generic PLAVIX Launched At-Risk

February 21, 2008

Last week, Apotex Inc. submitted an interesting Petition for Stay of Action to FDA requesting that the Agency recognize the company’s remaining 180-day exclusivity for its generic version of Sanofi-Synthelabo’s PLAVIX (clopidogrel bisulfate) by staying the effective date of final approval of other ANDAs (and in particular Dr. Reddy’s Laboratories, Inc.’s ANDA #76-273 approved on January 14, 2008) containing a paragraph IV patent certification with respect to U.S. patent #4,847,265 (“the ‘265 patent”).  The ‘265 patent is listed in the Orange Book with other patent and non-patent market exclusivities as covering PLAVIX.  Specifically, Apotex requests that FDA stay the effective date of final approval of competitor applications until the earlier of either: (1) 156 days after the August 31, 2006 permanent injunction issued by the U.S. District Court for the Southern District of New York barring Apotex from marketing clopidogrel bisulfate is lifted; or (2) the expiration of the ‘265 patent on November 17, 2011.  Apotex also requests that FDA, at a minimum, stay the effectiveness of final approvals of competitor ANDAs until the injunction is lifted, provided the U.S. Court of Appeals for the Federal Circuit finds the ‘265 patent invalid.  Any other decision, contends Apotex, “will result in the anomaly that Apotex, the first to file a paragraph IV certification challenging the validity or enforceability of the ‘265 patent . . . may be the last to market.” 

Apotex submitted ANDA #76-274 to FDA in 2001, prior to the enactment of the Medicare Modernization Act (“MMA”).  The application contained a paragraph IV certification to the ‘265 patent that made Apotex eligible for 180-day exclusivity.  Such exclusivity (in a pre-MMA case like this) is triggered by either the first commercial marketing of the drug approved under ANDA #76-274, or a court of appeals decision that the ‘265 patent is invalid, not infringed, or unenforceable.  In March 2002, Sanofi sued Apotex for infringement of the ‘265 patent in the U.S. District Court for the Southern District of New York, thereby triggering a 30-month stay of approval of ANDA #76-274.  FDA approved ANDA #76-274 on January 20, 2006, after the 30-month stay expired in May 2005 without a relevant court decision.  Almost six months later, on August 8, 2006, Apotex began commercially marketing its generic clopidogrel bisulfate drug product at-risk of an adverse court decision, thereby triggering the company’s 180-day exclusivity.  Sanofi quickly sought a permanent injunction barring Apotex from further marketing the drug product, and on August 31, 2006, the district court granted the injunction pending the outcome of the case.  Meanwhile, Apotex’s 180-day exclusivity was ticking away, notwithstanding that marketing of the generic drug was enjoined 24 days after such exclusivity was triggered. 

Apotex appealed the decision to the U.S. Court of Appeals for the Federal Circuit, where the case is pending.  Oral arguments in the case are scheduled for March 3, 2008.  If the Federal Circuit issues a mandate requiring the district court to lift the injunction, then Apotex could resume marketing the drug product approved under ANDA #76-274.  The timing of a decision by the Federal Circuit is unclear, as the issuance of the mandate could be delayed if Apotex is initially successful in the Federal Circuit, but Sanofi then timely requests a rehearing and/or a rehearing en banc. 

The Federal Circuit’s decision will also affect generic clopidogrel bisulfate patent infringement litigation between Sanofi and generic applicants Teva Pharmaceuticals, Cobalt Pharmaceuticals, and Dr. Reddy’s.  In the Teva and Cobalt cases, which are also before the Federal Circuit and concern later-filed ANDAs with paragraph IV certifications to the ‘265 patent, decisions on the permanent injunctions have been stayed pending the outcome of Apotex’s appeal.  In the case involving Dr. Reddy’s, in which a permanent injunction was not entered, Sanofi and Dr. Reddy’s entered into an agreement permitting Dr. Reddy’s to, among other things, import clopidogrel bisulfate into the U.S. for sale if Apotex obtains a favorable result in the Federal Circuit. 

During the pendency of the ‘265 patent litigation, Apotex’s 180-day exclusivity would have naturally expired on February 4, 2007.  Nevertheless, Apotex argues in the company’s Petition for Stay of Action that the language, intent, and policy goals of the Hatch-Waxman Act would be frustrated if FDA does not recognize the remaining 156 days of that exclusivity period (provided, of course, that Apotex is ultimately successful in the company’s pending patent infringement litigation).  “The wording of the [FDC Act] makes clear that later-filed applications cannot be approved until at least 180 days after the first filer has begun commercial marketing – it does not, however, require FDA woodenly to approve such applications on the 181st day after such marketing begins,” states the petition (emphasis in original).  Apotex contends that:

Certainly, nothing in the language of the statute prohibits a first filer who risks coming to market prior to an operative court decision and who successfully overturns an improvidently granted injunction from enjoying the full benefit of the 180-days of exclusivity granted by Congress.  Rather, the “not earlier than” language [in FDC Act § 505(j)(5)(B)(iv) (2002)] gives FDA discretion to delay the effective date of approval of ANDAs submitted by subsequent filers to ensure that the first filer who has undertaken the risk of opening up the market for a particular drug product to generic competition can reap the full benefit of Congress’s 180-days of marketing exclusivity.

Moreover, Apotex argues that FDA’s decision to recognize the remaining 156 days of generic exclusivity “would best effectuate Congress’s intent and policy animating the Hatch-Waxman Amendments in general and the exclusivity provision in particular” by encouraging generic companies to continue to challenge questionable Orange Book-listed patents and by preserving the meaningfulness of 180-day exclusivity. 

Whether FDA will ultimately recognize any remaining 180-day exclusivity is uncertain.  Apotex requests that FDA respond to the petition no later than March 15, 2008.

By Kurt R. Karst    

Categories: Hatch-Waxman