FDA's Request for Comments on Ramipril 180-day Exclusivity Draws Letters from Eight Generic Companies

King Pharmaceuticals markets Altace (ramipril), a treatment for high blood pressure with nearly $1 billion in annual U.S. sales.  U.S. Patent No. 5,061,722, owned by Aventis and licensed to King, is listed in the Orange Book for Altace.

Cobalt Pharmaceuticals submitted the first ANDA with a paragraph IV certification to the '722 patent in 2002, thereby earning 180-day exclusivity for ramipril (and thereby establishing this as a "pre-MMA" case).  In 2005, Lupin Pharmaceuticals submitted the second ANDA with a paragraph IV certification to the '722 patent.  Aventis and King sued both companies.  In 2006, Aventis and King settled with Cobalt.  On September 11, 2007, the Federal Circuit reversed a district court decision in the Lupin case and invalidated the claims of the '722 patent (see this post).

According to the FDA website, five companies have received tentative approval to market generic ramipril: Dr. Reddy's; Purepac; Roxane; Sandoz; and Teva (see this web page).  Shortly after the Federal Circuit decision, one of those five companies and Lupin submitted letters to FDA urging that final approval of their ANDAs should not be held up by Cobalt's 180-day exclusivity (see this post).  In response, FDA requested comments from other interested parties.  To date, FDA has received comments from eight generic drug companies and three PBM companies (all may be found here).  The comments fall into three categories.

Lupin (with support from the three PBMs)

Besides accusing King of settling with the first ANDA filer to deliberately create a "bottleneck" to generic competition from subsequent ANDA filers, Lupin presents three main arguments : (1) Cobalt is no longer entitled to 180-day exclusivity because Cobalt stipulated to infringement of the '722 patent in its settlement with King, which caused Cobalt's paragraph IV certification to be converted into a paragraph III certification; (2) Lupin should be permitted to amend its ANDA to remove its paragraph IV certification because the '722 patent was invalidated (such an amendment would mean Lupin's approval would not be affected by any exclusivity Cobalt might have); and (3) Lupin is entitled to immediate approval of its ANDA--without waiting for the Federal Circuit to issue a mandate from its Sept. 11 decision (such immediate approval would give Lupin a head start in marketing ramipril before other generic competitors).

Anonymous tentatively approved filer (with support from Sandoz and Apotex)

The law firm of Hyman, Phelps & McNamara ("HPM") submitted a letter "on behalf of a company with a tentatively approved ANDA" for ramipril.  The letters from Sandoz and Apotex essentially mirror HPM's letter.  The letters make two main arguments: (1) Cobalt is no longer eligible for 180-day exclusivity, for the same reasons as those put forward by Lupin; and (2) once the Federal Circuit issues its mandate, FDA should deem the '722 patent to be de-listed from the Orange Book, which will then free FDA to grant final approval to all tentatively approved ramipril ANDAs.  In support of the second argument, Sandoz cites FDA's April 18, 2007 amlodipine decision.

Cobalt (with support from Barr, Ranbaxy, and URL Mutual)

Cobalt's letter makes three main points: (1) contrary to the allegations of Lupin, HPM and others, this is not a case where 180-day exclusivity has been "parked" indefinitely--rather, Cobalt's exclusivity period will be triggered when the Federal Circuit issues its mandate, and will terminate 180 days later; (2) the statute is unambiguous--no subsequent ANDA may be approved until the expiration of Cobalt's 180-day exclusivity; (3) there is no statute, regulation or case under which Cobalt may be found to have forfeited its exclusivity.  Cobalt makes what seems to be a very important point in that last argument: the admission of infringement that Cobalt made in the settlement of its litigation with King was made "without prejudice to Cobalt's allegations that the claims of the '722 patent are invalid and unenforceable."  Thus, Cobalt argues that it has not admitted the validity or enforceability of the '722 patent, and therefore its paragraph IV certification with respect to the '722 patent remains valid.  Barr and Ranbaxy echo this point in their letters.

Finally, Cobalt correctly notes that the impact of FDA's decision in this case will likely be limited, since there are only a handful of remaining cases governed by the pre-MMA version of the statute.  Nonetheless, it will be interesting to see how the FDA resolves this situation.