Pediatric Exclusivity: Amazingly Powerful, Essentially Ironclad . . . and Often Overlooked

By Kurt R. Karst –      

One of the more memorable lines from the original Star Wars Trilogy is uttered in Return of the Jedi when Luke Skywalker surrenders himself to Darth Vader on the Forest Moon of Endor.  Luke tries to convince Vader to return to the Light Side of the Force, saying that he feels the “good” within Vader.  Vader, however, rebuffs the attempt at conversion, saying “You don’t know the power of the dark side!  I must obey my master.” 

Putting aside the light versus dark allegory, those lines sum up quite well the power of pediatric exclusivity (and its statutory master), particularly as it relates to Orange Book-listed patents.  And it’s a power that is often overlooked . . . at least initially, until the full force of pediatric exclusivity comes to bear on an ANDA or 505(b)(2) applicant.   Indeed, we’ve seen a few instances over the past year where pediatric exclusivity has crept up on an unsuspecting applicant to block final approval of an ANDA.  Consider, for example, the cascading periods of pediatric exclusivity applicable to various patents that were (and some that still are) listed in the Orange Book for NEXIUM (esomeprazole magnesium) Delayed-Release Capsules, 20 mg and 40 mg.  Although there is no 180-day exclusivity block on ANDA approval, only one ANDA sponsor, Ivax Pharmaceuticals, Inc., currently has approval of an application – ANDA 078003.  FDA approved that application after the sponsor obtained a waiver of pediatric exclusivity from the NDA sponsor, and which pediatric exclusivity became operative upon expiration of a patnet to which it attached (see our previous post here).   Other ANDA sponsor have apparently not been as fortunate. 

In light of this incident and others, we thought it would be a good time to review a couple of the ins and outs outs of pediatric exclusivity.  We also refer to several of our previous posts on some interesting pediatric exclusivity topics – here, here, and here. 

FDC Act § 505A provides an additional six months of patent and non-patent exclusivity to pharmaceutical manufacturers that conduct acceptable pediatric studies of new and currently-marketed drug products identified by FDA in a Written Request for which pediatric information would be beneficial.  Pediatric exclusivity extends all other types of Orange Book-listed patent and non-patent marketing exclusivity (e.g., five-year, three-year, and orphan drug exclusivity) an application holder may have under the FDC Act, provided that the exclusivity is granted with not less than nine months of term remaining.  Pediatric exclusivity does not extend the term of a patent itself, but only the period during which FDA cannot approve an ANDA or a 505(b)(2) application that includes a Paragraph II certification (patent has expired), a Paragraph III certification (date on which a patent will expire), or a Paragraph IV certification that concerns a patent that a court has determined is valid and would be infringed.
 
An important aspect of pediatric exclusivity is that it provides additional marketing exclusivity not just for the pediatric indications or formulations, but for all protected indications and formulations of that sponsor’s drug.  Thus, pediatric exclusivity attaches to the patent and non-patent marketing exclusivity for any of the sponsor’s approved drug products (including certain combination products) that contain the active moiety for which pediatric exclusivity was granted, and not to a specific drug product.  See National Pharmaceutical Alliance v. Henney, 47 F. Supp. 2d 37 (D.D.C. 1999) (here).

Where folks most often get tripped up with pediatric exclusivity is the applicability of the exclusivity after patent expiration (i.e., a Paragraph II certification).  A Paragraph II certification exists either because an applicant specifically certified as such, or because FDA has administratively converted a certification to a Paragraph II certification upon patent expiration.  FDA’s ability to make such conversion has been upheld in court.  See Mylan v. Thompson, 332 F. Supp. 2d 106 (D.D.C. 2004) (here), aff’d, 389 F.3d 1272 (D.C. Cir. 2004) (here); Ranbaxy Lab., Ltd. v. FDA, 307 F. Supp. 2d 15 (D.D.C. 2004) (here), aff’d 96 Fed. Appx. 1 (D.C. Cir. 2004).  Now add in 180-day exclusivity and things can really get complicated, particularly when 180-day exclusivity “overlaps” with patent expiration.  That is, when the period of 180-day exclusivity extends only to patent expiration (cutting that exclusivity short) and butts up against pediatric exclusivity applicable to a patent subject to a Paragraph II certification preventing subsequent ANDA applicants from obtaining final approval.  

FDA first encountered this fact pattern back in 2007 in the context of ANDA approval of generic versions of Pfizer’s NORVASC (amlodipine besylate) Tablets, and in light of pediatric exclusivity applicable to Orange Book-listed U.S. Patent No. 4,879,303 (“the ‘303 patent”).  It led to a flurry of activity, including litigation against FDA, citizen petitions, and more.  It was the first “big case” we covered on this blog (see our previous posts here, here, here, here, and here).  

In an April 18, 2007 Letter Decision (Docket No. FDA-2007-N-0090; Docket Legacy No. 2007N-0123), FDA laid out not only when a court decision becomes final in the context of a patent infringement action (i.e., upon issuance of the mandate), but what such a decision means in the context of the pediatric exclusivity statute.  In doing so, FDA explained how an ANDA applicant subject to pediatric exclusivity applicable to an expired patent can “beat” what is otherwise ironclad exclusivity.  You can read the opinion for greater context, but here’s the important part:

This is the first time that FDA has been called upon to determine whether an ANDA applicant is subject to the innovator’s pediatric exclusivity when the ANDA applicant has received a favorable court decision in its paragraph IV litigation but has not yet obtained final approval when the patent expires [(here, because of another applicant’s 180-day exclusivity)]. . . .

In considering [the Mylan and Ranbaxy decisions] regarding the switch to paragraph II certifications with today’s decision regarding the non-applicability of pediatric exclusivity to applicants who prevail in patent litigation, FDA determines as follows.  When the ‘303 patent expired on March 25, 2007, all of the unapproved ANDAs were required to change (or deemed to have changed) to paragraph II certifications and became subject to Pfizer’s pediatric exclusivity at that time.  That is their status during the period before the mandate issues.  However, FDA believes that the language of the statute manifests a clear Congressional intent that pediatric exclusivity not block the approval of an ANDA where the ANDA applicant has prevailed in the paragraph IV patent litigation and therefore creates an exception to the application of the Hatch-Waxman certification provisions.  Thus, if and when the mandate finalizing the panel’s March 22 decision issues in the Apotex case, Apotex’s ANDA will not be blocked by Pfizer’s pediatric exclusivity.

FDA followed up that initial Letter Decision with a couple of other letters (here and here) applying the Agency’s Letter Decision in light of developing facts.  Ultimately, the ‘303 patent was delisted from the Orange Book, thereby removing the pediatric exclusivity barrier to ANDA approval. 

So, at the end of the day, what are the options for an ANDA applicant to overcome pediatric exclusivity applicable to an expired patent that is blocking final approval?  There aren’t many options, and they can take some time to work through, but there are at least three: (1) obtain a wavier from the NDA sponsor; (2) obtain a final court decision of patent invalidity or non-infringement; or (3) successfully pursue Orange Book delisting of the blocking patent.