The Oxaliplatin Controversy – a Tale of Intrigue, Secrecy, and Suspense

August 24, 2009

By Kurt R. Karst –      

The recent controversy over the approval of generic versions of  Sanofi-Aventis U.S. LLC’s (“Sanofi’s”) colon cancer drug ELOXATIN (oxaliplatin) is one for the books and will most certainly go down in Hatch-Waxman lore.  The story begins in 2007 with patent infringement lawsuits filed against several generic drug manufacturers – including  Sandoz, Inc., Mayne Pharma Inc., Teva Pharmaceutical Industries Ltd., and Hospira Inc. – stemming from their Paragraph IV certifications to U.S. Patent No. 5,338,874 (“the ‘874 patent”) listed in the Orange Book as covering ELOXATIN.  Fast forward to June 30, 2009, when the U.S. District Court for the District of New Jersey entered a judgment of non-infringement of the ‘874 patent (based on the court’s June 18, 2009 ruling), and then denied Sanofi’s request for a stay.  See Sanofi-Aventis, et al. v. Sandoz, et al., No. 3:07-cv-2762 (D.N.J. Jun 30, 2009).

Sanofi promptly appealed the decision to the U.S. Court of Appeals for the Federal Circuit, and on July 1, 2009, the Federal Circuit temporarily stayed the district court judgment, pending that court’s consideration of a petition for writ of mandamus and a motion for a stay pending appeal.  See Sanofi-Aventis v. Sandoz, et al., No. 2009-1427.  On July 10, 2009, the Federal Circuit granted Sanofi’s motion for a stay, pending appeal, of the district court’s judgment.

On July 16, 2009 Hospira and Teva submitted an emergency motion to the Federal Circuit seeking clarification of the July 10, 2009 stay order – specifically, whether the July 10th order was intended to: (1) enjoin FDA from granting final approval to their applications; or (2) to enjoin Mayne and Teva from launching their products upon FDA approval during the pendency of appeal, even though Sanofi did not request or obtain an injunction.  Hospira and Teva noted in their emergency motion papers that a stay of judgment is “ambiguous on these topics,” and that Sanofi had earlier stated that the company was seeking a writ of mandamus vacating the district court’s judgment of non-infringement because “a stay . . . may not result in maintaining the status quo.”  The emergency motion, which Sanofi did not oppose, also requested that if the court intended for the stay order to function as an injunction, then the matter should be remanded to the district court to fix an appropriate bond to compensate for delay in market entry.  On July 24, 2009, the Federal Circuit denied the motion for clarification and ordered that “the motion for a limited remand is deemed moot.”  The Federal Circuit did not explicitly clarify its intent regarding the effect of the stay of judgment on FDA approval of the pending applications or on Hospira’s/Teva’s ability to market any approved product.

Meanwhile, FDA was considering whether the district court’s entry of judgment that the ‘874 patent is not infringed permitted the Agency to approve applications pursuant to FDC Act § 505(j)(5)(B)(iii)(I) (ANDAs) and § 505(c)(3)(C)(i) (505(b)(2) applications) notwithstanding the Federal Circuit’s subsequent stay of the district court’s judgment.  Under these statutory provisions, which were enacted in 2003 by the Medicare Modernization Act (“MMA”), approval of an ANDA or 505(b)(2) application is made effective upon the expiration of the 30-month stay, except that “if before the expiration of such [30-month] period the district court decides that the patent is invalid or not infringed . . . the approval shall be made effective on (aa) the date on which the court enters judgment reflecting the decision. . . .” (emphasis added).  Pre-MMA, the comparable statutory provisions provided that “if before the expiration of such [30-month] period, the court decides that such patent is invalid or not infringed, the approval shall be made effective on the date of the court decision.” (emphasis added)

In a March 2000 guidance document interpreting the pre-MMA statute, FDA stated that the term “court” would mean “the first court that renders a decision finding the patent at issue invalid, unenforceable, or not infringed,” and that when the district court renders such a decision, “FDA may approve the ANDA as of the date the district court enters its decision.”  Importantly, the guidance document further states that:

Neither a stay nor a reversal of a district court decision finding the patent invalid, unenforceable, or not infringed will have an effect on the approval of the ANDA or on the beginning, or continued running, of exclusivity.  Should the NDA holder or patent owner wish to prevent an applicant with an approved ANDA from marketing its product during the course of an appeal, it must obtain an injunction from the court.

Although the post-MMA statutory provisions cited above are silent as to the effect of a stay or appeal of a district court’s judgment on the timing of approval of an ANDA or 505(b)(2) application, we understand that FDA, consistent with its pre-MMA statutory interpretation, determined that nothing in the text or structure of the FDC Act suggests that a stay of the district court’s decision finding the patent invalid or not infringed requires that the Agency delay approving an otherwise approvable ANDA or 505(b)(2) application until the stay is lifted or until there is additional finality to the district court's decision regarding invalidity or non-infringement.  As such, on Friday, August 7, 2009, FDA approved several applications for generic ELOXATIN.

On Monday, August 10, 2009, Sanofi filed an emergency motion with the Federal Circuit to enforce the court’s July 10, 2009 stay order, arguing that FDA lacked the legal authority to lift the 30-month stay and approve generic applications in light of the Federal Circuit’s stay of the New Jersey district court’s judgment giving FDA approval authority.  On that same day, Sanofi filed a complaint (under seal) in the U.S. District Court for the District of Columbia against FDA seeking a Temporary Restraining Order (“TRO”) and a Preliminary Injunction (“PI”) that would require FDA to rescind generic ELOXATIN approvals.  See Sanofi-Aventis et al. v. Food & Drug Admin. et al, No. 2009-1495.  As with its emergency motion filed with the Federal Circuit, Sanofi argued that FDA should not have approved any generic applications because the 30-month stay was still in effect.  The district court denied Sanofi’s motions from the bench during an emergency hearing held on the same day the complaint was filed, and later issued a memorandum opinion explaining its ruling.  Sanofi appealed the decision to the U.S. Court of Appeals for the District of Columbia Circuit (again, in a case under seal).  See Sanofi-Aventis et al. v. Food & Drug Admin. et al, No. 2009-5278. 

On August 11th, the Federal Circuit denied Sanofi’s August 10th emergency motion.  Sanofi moved for panel review and for reconsideration of that order, and on August 13th, the court issued an order granting panel review, but denying the motion for reconsideration.  Circuit Judge Moore, in his concurrence in the denial of reconsideration took issue with FDA’s decision to approve generic applications in light of the Federal Circuit’s stay, stating that “FDA’s position is dubious at best,” but also stating that despite this “our inability to rectify the problem is due to Sanofi’s failure to file for a preliminary injunction against the generics seeking to prevent them from entering the market.”  Oral argument in the Federal Circuit is scheduled for September 2, 2009.

Meanwhile, in Sanofi’s lawsuit against FDA, the D.C. Circuit issued an order on August 13th suspending the approvals of generic ELOXATIN.  According to the court order, “[t]he purpose of this administrative injunction is to give the court sufficient opportunity to consider the merits of the motion for injunctive relief pending appeal . . . .”  Accordingly, we understand that FDA issued letters formally suspending application approvals and removed the drugs from from the Orange Book.

Finally, on August 18th, the D.C. Circuit ruled that Sanofi et al. “have not demonstrated the requisite likelihood of success on the merits to warrant either injunctive relief pending appeals or expedition, . . . nor have they shown that summary reversal is warranted” and  denied Sanofi’s emergency motion for an injunction and ordered the dissolution of the court’s August 13th administrative injunction suspending the approvals of generic ELOXATIN.  FDA promptly reinstated the approvals. 

So for now, it appears that this saga over FDA approvals is effectively over.  But who knows what surprises the coming weeks might bring . . . . 

Categories: Hatch-Waxman