Outstanding Pre-FDAAA Citizen Petition Causes FDA to Rule Against 180-Day Exclusivity Forfeiture for Generic SKELAXIN

By Kurt R. Karst –   

FDA’s recent decision to approve Sandoz Inc.’s (“Sandoz’s”) ANDA No. 40-445 for a generic version of King Pharmaceuticals, Inc.’s (“King’s”) SKELAXIN (metaxalone) Tablets, 800 mg, with a period of 180-day exclusivity is one of the few cases in which the Agency has ruled that a forfeiture of exclusivity did not occur even though the application sponsor failed to obtain tentative approval within 30 months of ANDA submission.  But the story does not end there.  As with so many Hatch-Waxman 180-day exclusivity cases, it’s complicated.  And this case is no exception.  It is a story of exclusivity gained, exclusivity lost, exclusivity regained, exclusivity lost again, and regained yet again.

As we recently discussed, FDC Act § 505(j)(5)(D)(i)(IV) – “Failure to obtain tentative approval” – is one of the six 180-day exclusivity provisions added to the FDC Act by Title XI of the Medicare Modernization Act (“MMA”) and provides that 180-day exclusivity eligibility is forfeited if “[t]he first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed. . . .”  The provision also contains a saving clause, however, stating that failure to obtain tentative approval within 30 months of ANDA submission will not result in a forfeiture of 180-day exclusivity if “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.”  In addition, the 2007 FDA Amendments Act (“FDAAA”) clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition [subject to FDC Act § 505(q)], the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .” (FDC Act § 505(q)(1)(G)). 

SKELAXIN was first approved (based on safety) on August 13, 1962 under NDA No. 13-217 and was reviewed under the Drug Efficacy Study Implementation program.  See 39 Fed. Reg. 29,396 (Aug. 15, 1974).  Under that review, FDA determined SKELAXIN to be effective for the relief of painful musculoskeletal conditions. 

In the case of ANDA No. 40-445, FDA received an amendment to Sandoz’s pending application as of November 4, 2004 for Metaxalone Tablets, 800 mg, containing a Paragraph IV Certification to the two Orange Book-listed patents covering the Reference Listed Drug (“RLD”), SKELAXIN – U.S. Patent Nos. 6,407,128 (“the ‘128 patent”) and 6,683,102 (“the ‘102 patent”).  (ANDA No. 40-445 was initially submitted to FDA on August 31, 2001 for a 400 mg strength, which was later withdrawn.)  Both of the patents are directed to methods of informing patients about and administering metaxalone with food and are listed in the Orange Book with a “U-189” patent use code, defined as “ENHANCEMENT OF THE BIOAVAILABILITY OF THE DRUG SUBSTANCE.”  U.S. Patent No. 7,122,566 (“the ‘566 patent”), a method-of-use patent covering the treatment of musculoskeletal conditions, was later added to the Orange Book for SKELAXIN, and Sandoz amended its pending application to include a Paragraph IV Certification to that patent as well. 

King timely sued Sandoz for infringement of the ‘128 and ‘102 patents in the U.S. District Court for the Eastern District of New York (King Pharmaceuticals, Inc. v.Eon Labs, Inc., Civil Action No. 04-5540), triggering a 30-month stay of ANDA approval.  King also timely sued Sandoz for infringement of the ‘566 patent in the U.S. District Court for the District of New Jersey (King Pharmaceuticals Inc., King Pharmaceuticals Research and Development Inc., Pharmaceutical IP Holding Inc. v. Sandoz Inc., Civil Action No. 08-CV-05974-GEB-JJH); however, that lawsuit did not result in a separate 30-month stay under provisions added to the FDC Act by the MMA that except amendments adding a Paragraph IV Certification from a new 30-month stay.  In January 2009, the U.S. District Court for the Eastern District of New York ruled that the ‘128 and ‘102 patents are invalid.  King has appealed that decision to the Federal Circuit (Case Nos. 09-1437 & 09-1438).  Litigation on the ‘566 patent is also ongoing. . . . but more on that later.

As the first applicant to submit an ANDA containing a Paragraph IV Certification to the 800 mg strength of SKELAXIN, Sandoz became eligible for 180-day exclusivity.  But Sandoz failed to obtain tentative approval within 30 months of ANDA submission (i.e., May 4, 2007), thereby setting the stage for a forfeiture of exclusivity.  Nevertheless, FDA determined that the failure:

was caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application was filed.  Namely, Sandoz submitted its amendment for the 800 mg strength on November 4, 2004, and during the entire time the ANDA was under review, the agency had pending before it a citizen petition that created a review of the appropriate labeling for generic metaxalone in light of certain patent-protected language in the labeling of the RLD.

The citizen petition identified by FDA in the Sandoz ANDA approval letter was submitted to the Agency in March 2004 (FDA Docket No. FDA-2004-P-0426) and requests that FDA rescind a March 1, 2004 “Dear Applicant” Letter in which the Agency invited generic SKELAXIN applicants to submit a “section (viii)” statement to carve out of their proposed labeling “information on fed-state bioavailability claimed by the ‘128 patent because metaxalone products with such labeling will be no less safe or effective for all of the remaining conditions of use,” require generic applicants to certify to the ‘128 patent, and prohibit the carve out of certain pharmacokinetic information from the SKELAXIN labeling.  FDA never substantively responded to the petition . . . allowing it to effectively die on the vine and become moot once the U.S. District Court for the Eastern District of New York ruled that the ‘128 and ‘102 patents are invalid.  (FDA’s failure to substantively respond to the petition presumably means that the Agency had some concerns with permitting a labeling carve-out.)

The March 2004 petition is the one in a line of citizen petitions (not all of which have been substantively responded to) concerning various issues about generic SKELAXIN approval requirements.  The petitions include FDA-2003-P-0081, FDA Docket No. 2001P-0117, FDA Docket No. 2001P-0481, and FDA-2009-P-0223.  Because the March 2004 petition is a pre-FDAAA petition (and therefore not a 505(q) petition), FDC Act § 505(q)(1)(G), which extends the 30-month tentative approval forfeiture provision under FDC Act § 505(j)(5)(D)(i)(IV), did not come into play.  Instead, FDA’s decision of a non-forfeiture appears to be based solely on its review of generic SKELAXIN approval requirements raised in the March 2004 petition and made moot by the New Jersey district court’s patent invalidity decision. 

The story does not end there, however.  Despite having been saved from a forfeiture of 180-day exclusivity, Sandoz “lost” its exclusivity again in the ongoing ‘566 patent infringement litigation, but then quickly “regained” it. 

In early April 2010, shortly after FDA approved Sandoz’s ANDA No. 40-445 and after the company triggered its 180-day exclusivity with an at-risk launch, King sought and obtained a Temporary Restraining Order (“TRO”) in the ‘566 patent infringement litigation.  FDA’s longstanding statutory interpretation is that once 180-day exclusivity is triggered, it “will continue to run during the pendency of a stay or injunction.”  (A few years ago, Apotex challenged this interpretation at FDA and in court, but the issue was eventually dropped without a decision.)  Thus, once the TRO was entered, Sandoz was unable to take advantage of its 180-day exclusivity and had effectively lost it.  But the TRO was quickly vacated, effectively restoring Sandoz’s 180-day exclusivity.  (Meanwhile, King is litigating another dispute over the marketing of an authorized generic version of SKELAXIN – King Pharmaceuticals Inc., et al v. CorePharma LLC, Civil Action No. 10-CV-01878-GEB-DEA.)