Sandoz Requests 180-Day Exclusivity Forfeiture Decision for Generic HECTOROL

By Kurt R. Karst –

In a recent citizen petition submitted to FDA, Sandoz Inc. (“Sandoz”) requests from the Agency a written decision that Cobrek Pharmaceuticals, Inc. (“Cobrek”), the alleged “first applicant” for a generic version of HECTOROL (doxercalciferol) Injection, has forfeited 180-day exclusivity eligibility.  The Sandoz petition follows another citizen petition, submitted on behalf of Genzyme Corporation (“Genzyme”), concerning the Agency’s ability to approve Cobrek’s pending ANDA No. 90-040 for Doxercalciferol Injection.  Genzyme’s petition requested that FDA not approve Cobrek’s ANDA until the expiration of a second, superseding 30-month stay.  FDA granted the petition in October.  Although the Sandoz petition raises a different set of issues than the Genzyme petition, they arise from the same factual circumstances,  and FDA’s reasoning for granting Genzyme’s petition is relevant to Sandoz’s request. 

As we previously noted, FDA approved HECTOROL (2 mcg/mL, 2 mL) in April 2000 in an ampule presentation under NDA No. 21-027.  In December 2008, FDA approved an NDA supplement for HECTOROL for a new injectable formulation (and packaging configuration) in a vial presentation.  (The old ampule product is no longer being manufactured and in July 2010, FDA determined that the ampule presentation was not withdrawn from the market for safety or effectiveness reasons.)  There are currently three unexpired patents listed in the Orange Book for HECTOROL: U.S. Patent No. 5,602,116 (“the ‘116 patent”), a method-of-use patent, U.S. Patent No. 7,148,211 (“the ‘211 patent”), a formulation (drug product) patent, and U.S. Patent No. 6,903,083 (“the ‘083 patent”), a patent with drug product and drug substance claims, and for which a request for delisting has been submitted to FDA. 

Cobrek submitted ANDA No. 90-040 to FDA on October 13, 2007 (a Saturday) containing a Paragraph IV certification to the ‘116 and ‘083 patents.  According to FDA’s Paragraph IV Certification List, the first ANDA containing a Paragraph IV certification to an Orange Book-listed patent for HECTOROL, 2 mcg/mL, 2 mL ampules, was submitted to FDA on October 15, 2007 (a Monday), thus seemingly making Cobrek a first applicant eligible for 180-day exclusivity.  Genzyme timely asserted the ‘116 patent in infringement litigation and triggered a 30-month stay of approval on Cobrek’s ANDA.  The  ‘211 patent was not listed in the Orange Book for HECTOROL when Cobrek initially submitted its ANDA.  Rather, the ‘211 patent was added to the Orange Book after the December 2008 approval of HECTOROL in a vial presentation.

While Cobrek’s ANDA was under review, and after the new vial presentation approval, Cobrek amended its application to include a Paragraph IV certification to the ‘211 patent.  Genzyme did not sue Cobrek for patent infringement because the company “believed that Cobrek’s ampule formulation for which it was seeking approval at the time would not infringe the ‘211 patent claims.”

FDA eventually informed Cobrek that the Agency could not approve ANDA No. 90-040 because the ampule formulation was not quantitatively and qualitatively (“Q1/Q2”) the same as the new HECTOROL vial drug product.  Instead, FDA recommended that Cobrek reformulate to a Q1/Q2 formulation.  Cobrek reformulated its drug product and amended its application in 2009, but without new patent certifications.  FDA refused to accept the ANDA amendment without new certifications to both the ‘116 and ‘211 patents, but did give Cobrek the option to request whether the old HECTOROL formulation had been withdrawn for safety or effectiveness reasons and continue on without new certifications.  Cobrek decided not to take that path, but instead continued on with its reformulated drug product and in late November 2009 certified to the ‘116 and ‘211 patents.  Genzyme then sued Cobrek for infringement with respect to both patents, according to Sandoz, and FDA determined that a second, superseding 30-month stay applied.  (It is unclear whether Cobrek also submitted a new certification with respect to the ‘083 patent.)

Enter Sandoz, which has ANDAs pending at FDA for generic versions of both the ampule and vial presentations of HECTOROL . . . . and the approval of which FDA presumably could determine would be held up by any 180-day exclusivity associated with Cobrek’s ANDA No. 90-040.  Sandoz argues in its petition that:

Cobrek has forfeited its 180-day exclusivity rights for a generic version Hectorol® Injection for (at least) two independent reasons.  First, Cobrek has amended or withdrawn the Paragraph IV certifications that form the basis for its 180-day exclusivity rights, leading to forfeiture under condition (III).  Second and independently, Cobrek has failed to receive tentative approval within 30 months after submission of its ANDA, leading to forfeiture under condition (IV). 

The references to “(III)” and “(IV)” above are to FDC Act § 505(j)(5)(D)(i)(III) and (IV), which provide that a first applicant forfeits 180-day exclusivity eligibility under the following circumstances:

(III)  Amendment of certification.  The first applicant amends or withdraws the certification for all of the patents with respect to which that applicant submitted a certification qualifying the applicant for the 180-day exclusivity period.

(IV)  Failure to obtain tentative approval.  The 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.

With respect to FDC Act § 505(j)(5)(D)(i)(III), Sandoz argues that as a result of FDA’s regulation at 21 C.F.R. § 314.94(a)(12)(viii), which requires ANDA sponsors to maintain accurate patent certifications and to amend a certification if it is no longer accurate, and Cobrek’s “new” certifications to the ‘116 patent and the ‘083 patent (insofar as the ‘083 patent is relevant to 180-day exclusivity in this case), 180-day exclusivity has been forfeited.  According to Sandoz:

Under the plain language of § 314.94(a)(12)(viii), once a Paragraph IV certification that had provided a basis for 180-day exclusivity rights is “amended,” 180-day exclusivity rights for that applicant, based on that patent in that certification, no longer exists.  Even if the original Paragraph IV certification is amended to another Paragraph IV certification, the pending ANDA “will no longer considered to contain the prior [Paragraph IV] certification” (21 C.F.R. § 314.94(a)(12)(viii)) that provided the basis for the 180-day exclusivity.

In other words, according to Sandoz, the “new” Paragraph IV certification does not relate back to the original Paragraph IV certification that formed the basis for a claim to 180-day exclusivity; instead, it supplants the original certification and makes the original certification (and any related claim to 180-day exclusivity) a nullity.  It’s an interesting argument, and one that FDA has not yet, to our knowledge, publicly addressed. 

With respect to FDC Act § 505(j)(5)(D)(i)(IV), Sandoz argues that Cobrek failed to obtain tentative approval within 30 months of ANDA submission (i.e., about April 2010), and that “[n]othing indicates that there was ever any ‘change in or a review of the requirements for [ANDA] approval’ (21 U.S.C. § 355(j)(5)(D)(i)(IV) of a generic ampule version of Hectorol® Injection for which Cobrek submitted its original ANDA,” or for the vial version for which Cobrek is currently seeking ANDA approval.  “[I]f anything,” according to Sandoz, “Cobrek’s delay in receiving tentative approval is attributed to its voluntary decision to seek approval for a generic vial version of Hectorol® Injection” (emphasis in original).  The three precedents Sandoz identifies in its petition where FDA has identified the exception clause in FDC Act § 505(j)(5)(D)(i)(IV) (i.e., Metaxalone, Imiquimod, and Acarbose) do not provide “any support for the conclusion that an ANDA sponsor’s voluntary decision to reformulate its proposed ANDA product should excuse its failure to obtain tentative approval within 30 months” (emphasis in original), according to the company.  More recently, as noted in our 180-Day Exclusivity Tracker, FDA has applied the exception provision in FDC Act § 505(j)(5)(D)(i)(IV) to Zolpidem Tartrate, and to Levocetirizine Dihydrochloride, where FDA determined that “the labeling of the RLD changed after submission of the ANDA” and that “this change was the cause of [ANDA applicant] not obtaining tentative approval of the ANDA within 30 months after the date on which it was filed.”

Sandoz also argues that the Genzyme petition does not excuse Cobrek’s failure to obtain tentative approval, because the petition “has no bearing on Cobrek’s eligibility for tentative approval” (emphasis in original), and could affect only Cobrek’s eligibility for final ANDA approval.  By way of background, the 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, 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)).