DC Circuit Affirms MITIGARE 505(b)(2) NDA Approval, and Sidesteps COLCRYS Patent Certification Issue

By Kurt R. Karst –      

In a Per Curiam Judgment handed down last month, the U.S. Court of Appeals for the District of Columbia Circuit affirmed District Court Judge Ketanji Brown Jackson’s January 2015 ruling upholding FDA’s September 26, 2014 approval of a 505(b)(2) application (NDA 204820) submitted by Hikma Pharmaceuticals LLC (“Hikma”) and its U.S. partner West-Ward Pharmaceutical Corp. (“West-Ward”) for MITIGARE (colchicine) Capsules, 0.6 mg, for prophylaxis of gout flares. The DC Circuit also dismissed as moot and vacated the portion of Judge Jackson’s decision concerning Hatch-Waxman patent certification issues.

As we previously posted (, here, , and ), Takeda Pharmaceuticals U.S.A., Inc. (“Takeda”) is the holder of NDA 022352 for COLCRYS (colchicine) Tablets, 0.6 mg, which FDA approved to prevent and treat gout flares, and that is listed in the Orange Book with several unexpired patents. The MITIGARE 505(b)(2) NDA did not cite COLCRYS as a listed drug relied on for approval, but rather a different drug: COLBENEMID, a fixed-dose combination drug product containing probenecid (500 mg) and colchicine (0.5 mg) that FDA approved on July 27, 1961 (NDA 012383).  COLBENEMID is no longer marketed and there are no patents listed in the Orange Book for the drug product.  Takeda sued FDA in October 2014 alleging that the Agency’s approval of MITIGARE violates the FDC Act and the Administrative Procedure Act (“APA”) in several respects:

First, FDA acted arbitrarily and capriciously in approving Hikma’s Section 505(b)(2) application for Mitigare without requiring the label to contain critical safety information that FDA previously stated was necessary for single-ingredient oral colchicine products. Second, FDA’s approval of Hikma’s application for Mitigare was unlawful, arbitrary and capricious because, as approved, Mitigare is not safe in light of the defects in its label.  And third, FDA’s failure to require Hikma to reference Takeda’s own colchicine drug, Colcrys®, in its application interfered with Takeda’s rights to participate in the administrative process, including the Paragraph IV certification process under the Hatch-Waxman Act and the Citizen Petition process.  [(Emphasis in original)]

Later, Elliott Associates, L.P., Elliott International, L.P. and Knollwood Investments, L.P. (collectively “Elliott”), a hedge fund with investment interests in COLCRYS, filed a separate Complaint alleging that FDA’s approval of the MITIGARE 505(b)(2) NDA violated the FDC Act and the APA because Hikma was required to certify to patents listed in the Orange Book for COLCRYS. Both the Elliott and Takeda cases were subsequently consolidated.  

Meanwhile, during the course of the litigation with FDA, patent infringement litigation was ongoing in the U.S. District Court of Delaware. That litigation was initiated by Takeda outside of the Hatch-Waxman context after Takeda became aware of the MITIGARE 505(b)(2) approval.  In May 2016, the Delaware District Court dismissed Takeda’s patent infringement lawsuit after finding no infringement of Takeda’s patents.

In her January 2015 decision, Judge Jackson dismissed each of the allegations and ruled for FDA (and Intervenor-Defendants Hikma and West-Ward). “[T]his Court discerns no basis in law or fact for Plaintiffs’ insistence that FDA was legally required to force West-Ward to reference Colcrys and to certify to the Colcrys patents under the circumstances presented here,” wrote Judge Jackson.  Moving on to the Hatch-Waxman patent certification requirements, Judge Jackson found that “Congress’ intent regarding the scope of a Section 505(b)(2) applicant’s patent certification obligation is clear on the face of the statute: such applicant need only certify to the product patents or the method-of-use patents that are associated with the reference listed drug (i.e., the drug product on whose investigations the 505(b)(2) applicant relies).”  And with respect to Takeda’s allegation that FDA’s approval of MITIGARE with labeling that differs from COLCRYS with respect to certain drug-drug interactions was unauthorized, particularly in light of certain FDA statements in a May 2011 Citizen Petition response (Docket No. FDA-2010-P-0614), Judge Jackson found that “FDA’s conclusion that Mitigare did not need to include the same low-dose requirements as appear on Colcrys’s label was hardly a change of FDA’s position, much less an ‘arbitrary’ or ‘capricious’ deviation from its prior policy.”

On appeal to the DC Circuit, a three-judge panel (Judges Kavanaugh, Wilkins, and Silberman) concluded that as to the issue of whether or not Hikma should have certified to the COLCRYS patents listed in the Orange Book, the issue is moot because of the Delaware District Court’s decision resolving the issue of infringement in favor of Hikma:

Here, even if we were to hold that Hikma should have certified to Takeda’s patents, that decision would at most entitle Takeda to a stay of FDA’s approval of Mitigare pending a district court decision on the patent infringement suit. But there has already been a district court judgment on the patent infringement suit, so Takeda would not receive any stay of FDA’s approval of Mitigare.  Without the possibility of such a stay, Takeda’s and Elliott’s claims about Hikma’s failure to certify to the Colcrys patents are academic and  moot.

Moving on to Takeda’s allegation that the MITIGARE labeling omits critical safety information that FDA required of Takeda when approving COLCRYS, and that FDA violated the APA in taking such different positions, the Court deferred to FDA’s decision. “Here, FDA affirmatively chose to depart from some past statements it had made about the labeling of products for the prevention and treatment of acute gout flares. . . . FDA then adequately explained those decisions. . . .”  The APA, acknowledged the Court, requires nothing more.

In vacating the portion of Judge Jackson’s January 2015 decision concerning FDA’s decision to approve the MITIGARE 505(b)(2) NDA without patent certifications to COLCRYS (presumably pages 32-65 of Judge Jackson’s decision), the DC Circuit appears to have pulled back on some of the more controversial statements in that decision. For example, Judge Jackson stated that an NDA applicant’s “voluntary submission of its proprietary data to FDA waived any right that applicant may have had to prohibit FDA from ‘open[ing] th[e] locked file drawer’ to access the applicant’s data in the future.”  This statement, among others, upset some stakeholders in the pharmaceutical industry.