FDA Denies Petition on “Original NDA” Patent Certification Issue

By Kurt R. Karst –      

Is an ANDA applicant who cites a 505(b)(2) drug as the Reference Listed Drug (“RLD”) required to certify to Orange Book-listed patents covering the 505(b)(2) RLD drug as well as to Orange Book-listed patents covering the original listed drug approved under an NDA relied upon by the 505(b)(2) applicant for approval of its application?  No, according to FDA in a recent decision responding to a 2009 citizen petition submitted by Osmotica Pharmaceutical Corp. (“Osmotica”) involving Venlafaxine HCl Extended-Release Tablets. 

In May 2008, FDA approved Osmotica’s 505(b)(2) application for Venlafaxine HCl Extended-Release Tablets based on the Agency’s previous findings of safety and effectiveness for EFFEXOR XR Extended-Release Capsules and Osmotica’s bioequivalence data.  EFFEXOR XR and Osmotica’s Venlafaxine HCl Extended-Release Tablets share two common Orange Book patent listings; however, there are several other Orange Book-listed patents covering EFFEXOR XR that are not listed for Osmotica’s drug product.  At the time of approval of Osmotica’s drug product, there was a pending ANDA based on an approved suitability petition for Venlafaxine HCl Extended-Release Tablets.  As we previously reported, FDA determined in November 2008 (in response to a citizen petition) that Osmotica’s Venlafaxine HCl Extended-Release Tablets drug product became the RLD and that any generic applicant with a pending ANDA for Venlafaxine HCl Extended-Release Tablets would be required to identify Osmotica’s drug product as the RLD and to submit a new ANDA with appropriate bioequivalence information. 

In July 2009, Osmotica once again petitioned FDA requesting that the Agency, among other things:

Clarify that when an ANDA applicant relies on an RLD, the approval of which was pursuant to a [NDA] that is described in section 505(b)(2) of the Act . . . , and that 505(b)(2) application itself relied on an earlier approved NDA, the ANDA applicant must certify not only to the Orange Book-listed patents that cover the 505(b)(2) listed drug on which it directly relied, but also to the Orange Book-listed patents that cover the earlier approval on which the 505(b)(2) applicant relied.

By way of background, FDA’s long-standing policy has been to require that an ANDA that is submitted against another ANDA that was itself submitted and approved pursuant to a suitability petition contain an appropriate certification with respect to any Orange Book-listed patents covering the original RLD NDA relied on by the ANDA suitability petition applicant for approval. 

In 2002, FDA was first faced with the question of whether a generic applicant must certify to Orange Book-listed patents covering the  original NDA on which the approval of the generic applicant’s proposed RLD was based in the context of ANDA No. 75-250 for Prednisolone Sodium Phosphate Oral Solution.  In that case, FDA approved WE Pharmaceuticals, Inc.’s (“WE’s”) ANDA on January 4, 2002, but quickly rescinded that approval on January 17, 2002 “in light of the patent certification requirements of the [FDC] Act.”  According to FDA:

The ANDA submitted by [WE] does not meet the statutory requirements for approval, and did not do so at the time it was mistakenly approved by FDA.  The mistake arose from the status of the WE ANDA as a subsequent ANDA to that approved for Ascent Pharmaceuticals Orapred (ANDA 75-117).  Both your ANDA and the Ascent ANDA are for drug products for which a suitability petition was approved for a change to a listed drug (87P-0237/CP1).  The listed drug referenced in the approved suitability petition is Celltech Pharmaceuticals, USA’s (Celltech) Pediapred (NDA 19-157).  The listed drug product referenced in ANDA 75-250, by recent amendment, was Ascent’s Orapred, which has no listed patent protection.  Pediapred is subject to patent protection that expires on December 22, 2002: U.S. Patent No. 4,448,774 (the ‘774 patent).

Although the Agency considers Ascent’s Orapred to be the [RLD] for bioequivalence purposes, this does not obviate the need for WE to provide a patent certification and notification to the holder of the original listed drug upon which the approved suitability petition was based. [(emphasis added)] 

FDA later approved ANDA No. 75-250 after WE amended its pending ANDA to include a certification with respect to the Orange Book-listed patents covering Celltech’s PEDIAPRED and after WE and Celltech reached a settlement agreement concerning those patents.    

Following FDA’s determination, the Agency amended the Orange Book Preface in 2003 to include the following passage:

Patent Certification(s) Reference Listed Drug based upon a suitability petition.  An [ANDA] that refers to a [RLD] approved pursuant to a suitability petition must demonstrate that the proposed product is bioequivalent to the RLD, and it must include appropriate patent certification(s) and an exclusivity statement with respect to the listed drug which served as the basis for the approved suitability petition. [(emphasis added)]

Subsequent editions of the Orange Book have included this statement.  And in the 28th edition (2008), the statement was expanded to state:

Patent Certification(s) Reference Listed Drug based upon a suitability petition.  An [ANDA] that refers to a [RLD] approved pursuant to a suitability petition must demonstrate that the proposed product is bioequivalent to the RLD, and it must include appropriate patent certification(s) and an exclusivity statement with respect to the listed drug which served as the basis for the approved suitability petition.  This concept also applies to an ANDA applicant that cites a RLD that was based upon an NDA that is still covered by patent(s) and/or exclusivity, e.g. a second RLD that was selected when the in vivo determination of bioequivalence of the original RLD is self evident and the waiver of the in vivo determination of bioequivalence may be granted. [(emphasis added)]

Citing a 2004 FDA citizen petition response concerning Fenofibrate, Osmotica argued that FDA applies an analogous requirement with respect to a 505(b)(2) applicant who seeks to rely on the Agency’s findings of safety or effectiveness for a listed drug that is a 505(b)(2) application that itself relied on a previous 505(b)(1) NDA for approval.  Specifically, FDA stated in 2004 that:

Where a 505(b)(2) application seeks to rely on the finding of safety or effectiveness for a listed drug that is a 505(b)(2) NDA which, itself, relied on a previous finding of safety and effectiveness, the 505(b)(2) applicant should certify to the patents of the 505(b)(2) NDA relied on, as well as to the patents of any underlying NDA on which that approved 505(b)(2) NDA relied for approval. [(emphasis added)]

Given these precedents, Osmotica argued that:

FDA should announce and apply a similar policy here, where the ANDA applicant . . . relies on FDA’s previous findings of safety and effectiveness of a listed drug (Osmotica’s venlafaxine product) that was the subject of  a 505(b)2) application which, itself, relied on a previous finding of safety and effectiveness, namely FDA’s finding of safety and effectiveness of Effexor XR Capsules.

FDA determined otherwise, however, stating that “[t]here is no basis in the Hatch-Waxman statutory scheme and our implementing regulations for requiring an ANDA applicant seeking approval of a ‘duplicate’ of the RLD to provide a patent certification or statement with respect to any patents other than those filed by the NDA holder for the RLD for listing in the Orange Book.”  With respect to FDA’s policy that an ANDA that is submitted against another ANDA that was itself submitted and approved pursuant to a suitability petition must contain an appropriate certification with respect to any Orange Book-listed patents covering the original RLD NDA relied on by the ANDA suitability petition applicant for approval, FDA commented that:

There is a clear regulatory distinction between reliance on an RLD approved for safety and effectiveness under section 505(c) of the Act (i.e., a stand-alone NDA or a 505(b)(2) application) and reference to a petitioned ANDA designated as the RLD for bioequivalence testing. . . .  unlike a 505(b)(2) applicant, an ANDA applicant is not required (or permitted) by statute to file patent information with FDA for listing in the Orange Book.  Thus, a subsequent ANDA applicant that refers to a petitioned ANDA is required to submit an appropriate patent certification or statement for the listed drug identified in the suitability petition upon which the ANDA necessarily relies.  In the absence of this patent certification requirement, a subsequent ANDA applicant could circumvent the patent certification process by submitting an ANDA that references another ANDA and for which no patents can be listed . . . .

And with respect to FDA’s 2004 statement concerning 505(b)(2) applicants, FDA provided a hypothetical situation and commented that:

Although we noted in the Fenofibrate Petition Response that a 505(b)(2) applicant seeking approval for a drug product that relies upon FDA’s finding of safety and/or effectiveness for a drug product approved through the 505(b)(2) pathway ‘should certify to the patents of the 505(b)(2) NDA relied on, as well as to the patents of any underlying NDA on which that approved 505(b)(2) NDA relied for approval’ . . . this was not the situation at issue in the Fenofibrate Petition.  We subsequently have required an appropriate patent certification or statement to an ‘underlying NDA’ only if the subsequent 505(b)(2) applicant specifically relied for approval on the drug product approved in the underlying NDA. . . .” (italics in original; bold italics added).