FDA Grants Petition Requesting a “Superseding” 30-Month Stay for Generic HECTOROL

By Kurt R. Karst –      

FDA’s recent decision to grant an April 27, 2010 citizen petition submitted on behalf of Genzyme Corporation (“Genzyme”) concerning the Agency’s ability to approve Cobrek Pharmaceuticals, Inc.’s (“Cobrek’s”) pending ANDA for a generic version of HECTOROL (doxercalciferol) Injection sheds some light on the circumstances in which a second 30-month stay (or “superseding stay” as FDA terms it in this case) could arise as a result of a Paragraph IV certification to an Orange Book-listed patent – regardless of whether the patent was listed prior to or after the December 8, 2003 enactment of the Medicare Modernization Act (“MMA”), which generally limits ANDA applicants to a single 30-month stay of ANDA approval.  Genzyme’s petition requested that FDA not approve Cobrek’s ANDA No. 90-040 until the expiration of a second 30-month stay, or 30 months from November 24, 2009, when Genzyme received a second notice of a Paragraph IV certification from Cobrek regarding U.S. Patent No. 5,602,116 (“the ‘116 patent”), a method-of-use patent covering HECTOROL.  The initial 30-month stay reportedly expired in early July 2010.

FDA approved HECTOROL (2 mcg/mL, 2 mL) in an ampule presentation under NDA No. 21-027 in April 2000 for the treatment for secondary hyperparathyroidism in patients with end stage renal disease.  The ‘116 patent, as well as other patents, were submitted to FDA for Orange Book listing.  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in July 2010, FDA determined in response to a citizen petition – FDA-2009-P-0088 – that the ampule presentation was not withdrawn from the market for safety or effectiveness reasons, thereby clearing the way for ANDA approval, and that the ampule and vial formulations would be considered therapeutic equivalents.)  Pursuant to 21 C.F.R. § 314.53(d)(2)(i), Genzyme resubmitted the ‘116 patent to FDA for Orange Book listing for the new vial product formulation, as well as U.S. Patent No. 7,148,211 (“the ‘211 patent”), a formulation (drug product) patent.

Cobrek submitted ANDA No. 90-040 to FDA on October 13, 2007 containing a Paragraph IV certification to the ‘116 patent (based solely on invalidity), among other 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, thus seemingly making Cobrek’s submission subject to the MMA, although the possibility of an “MMA straddle” situation exists.)  Genzyme timely asserted the ‘116 patent in infringement litigation and triggered a 30-month stay of approval on Cobrek’s ANDA.  While ANDA No. 90-040 was under review, and after FDA approved the new HECTOROL vial formulation in December 2008 and the ‘211 patent was timely listed in the Orange Book, 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.”

All seemed in order until FDA 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 the company the option to request whether the old HECTOROL formulation had been withdrawn for safety or effectiveness reasons (which, as mentioned above, FDA recently ruled on) and continue on without new certifications.  Cobrek decided not to take that path, and instead continued on with its reformulated drug product and in late November 2009 certified to the ‘116 and ‘211 patents.  In January 2010, Genzyme sued for patent infringement with respect to both patents. 

About three months after initiating patent infringement litigation, Genzyme submitted a citizen petition to FDA arguing that the FDC Act “requires a separate 30-month-stay analysis for ‘each certification’ to a patent that claims the drug at issue[, and that in] this case, analysis of a second certification to the ‘116 patent requires a second 30-month stay.”  Genzyme also argued that FDA should grant the company’s request for a second 30-month stay regardless of whether the post-MMA version of the FDC Act applies, and further, that the MMA’s provisions generally prohibiting more than a single 30-month stay are inapplicable in this case because the ‘116 patent was listed in the Orange Book for HECTOROL prior to August 18, 2003 and prior to the submission of ANDA No. 90-040. 

As FDA explains in a draft October 2004 guidance document interpreting the MMA’s provisions:

The relevant provisions of the MMA apply to patents submitted to FDA on or after August 18, 2003.  For ANDAs and 505(b)(2) applications with paragraph IV certifications to a patent submitted to FDA on or after August 18, 2003, the MMA provides that a 30-month stay may be available for litigation related to that patent only if the patent was submitted to FDA before the date that the ANDA or 505(b)(2) application (excluding an amendment or supplement) was submitted.  In other words, the MMA precludes 30-month stays for later listed patents, that is, those patents submitted to FDA on or after the date the ANDA or 505(b)(2) application was submitted. Because of this limitation, in most cases, ANDAs and 505(b)(2) applications will be subject to no more than one 30-month stay.

FDA also notes in the draft guidance, however, that:

Multiple 30-month stays . . . still may be possible in certain cases.  For instance, an ANDA or 505(b)(2) application may contain a paragraph IV certification to a patent at the time of first submission that gives rise to one 30-month stay.  If the same application also contains a paragraph III certification to a different patent that was submitted to FDA (1) on or after August 18, 2003, and (2) before the ANDA or 505(b)(2) application was submitted, and the applicant subsequently converts this certification to a paragraph IV certification, a second 30-month stay could be possible.  This is because the new paragraph IV certification is subject to the MMA and references a patent submitted to FDA before the applicant’s ANDA was submitted.

Cobrek, argued in the company’s comments submitted to FDA in response to the Genzyme petition that the MMA applies in this case “because patent information on the ‘116 patent was submitted a second time with respect to the amendment covering the reformulation of this drug on December 26, 2008, after the August 18,2003 effective date of the MMA with respect to submission of patent information.”  Thus, according to Cobrek, only a single 30-month stay applies in this case.

Although FDA notes in the Agency’s petition response that “[d]etermination of whether or not the MMA applies thus depends on whether one concludes that the operative submission of patent information was [pre- or post-MMA],” such a determination is not, according to FDA, necessary “[b]ecause we conclude that the relief requested in your petition must be granted” regardless of whether or not the MMA applies.  Specifically, FDA ruled that:

Genzyme is entitled to a 30-month stay stemming from Cobrek’s paragraph IV certification made in connection with the reformulated product and Genzyme’s resulting patent infringement. . . .  Once Cobrek made the paragraph IV certification, and Genzyme subsequently sued Cobrek for infringing the ‘116 patent, the statutory requirements for a 30-month stay with respect to this paragraph IV certification were met, as the information concerning the ‘116 patent was submitted to FDA before either the original submission of the ANDA to FDA in October 2007, or the submission of the ANDA amendment in 2009.  We reach this conclusion regardless of whether the MMA applies to the facts at hand.

Although Cobrek argues in the company’s comments to FDA that Cobrek should not have been required to submit a second Paragraph IV certification in connection with the its new formulation amendment (and should be permitted to withdraw that certification), FDA declined to comment on this point, stating that such an argument is not appropriate for a petition comment and that the time for Cobrek to make that argument had passed.  That would have been an interesting to point to argue.  FDA has long been of the opinion that ANDA drug product formulation changes made in an amendment to a pending application (or a supplement to an approved application) require a new certification, but has never (to our knowledge) been challenged on the issue.  FDA stated this policy at least as far back as an October 1986 “dear applicant” letter, and most recently (to our knowledge) in the preamble to the Agency’s 1999 proposed rule that was later withdrawn.