False Friends: FDA’s “Gift” on NESINA – Present or Poison? It May Depend on Which Hatch-Waxman Language is Spoken

By Kurt R. Karst –      

Frau Rommelfanger’s seventh grade German class: that’s where we first learned to appreciate “false friends,” which are pairs of words or phrases in two languages that look or sound alike, but differ significantly in meaning.  Never write the word “gift” on a package to Germany, said Frau Rommelfanger, because while in English it means “present,” in German it means “poison.” 

That memory was triggered earlier this week when we read an article from Mike McCaughan over at the RPM Report, titled “Which Came First?  Alogliptin Avoids Possible Exclusivity Dispute.”  In his article, Mr. McCaughan discusses a “favor” FDA did for Takeda Pharmaceuticals U.S.A., Inc. (“Takeda”) when approving NDA No. 022271 for NESINA (alogliptin) Tablets as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.  The January 25, 2013 NESINA approval letter, signed on the same day FDA approved Takeda’s NDA No. 203414 for KAZANO (alogliptin and metformin HCl) Tablets and NDA No. 022426 for OSENI (alogliptin and pioglitazone) Tablets, also for type 2 diabetes mellitus, incudes a curious statement after the electronic signature of FDA Office of Drug Evaluation II Director Curtis Rosebraugh: “I am approving the single-entity alogliptin first, before approving the combination products containing alogliptin.”

Why would Dr. Rosebraugh include such a statement?  As Mr. McCaughan points out, “the explicit declaration that single-agent alogliptan was approved first [] should ensure that Takeda does not face any future challenges to the five-year new chemical entity exclusivity associated with the brand.” 

As readers of this blog know, timing really counts in the Hatch-Waxman world.  This is true regardless of whether we are talking about Orange Book patent listings and non-patent marketing exclusivity under Title I, or Patent Term Extensions (“PTEs”) under Title II of Hatch-Waxman (notwithstanding one exception).  Consider, for example, the order of NDA approval.  FDA’s long-standing position has been that in order for a fixed-dose combination drug to be eligible for 5-year New Chemical Entity (“NCE”) exclusivity, each of the active moieties in the drug product must be new (i.e., not previously approved).  That means in order for a company to to obtain NCE exclusivity for a combination drug containing new and old actives, the NCE component must be approved first, followed by the combination drug.  In that case, NCE exclusivity granted with respect to the single entity approval would apply to the combination drug under FDA’s so-called “umbrella policy.”  In the case of alogliptin, that means to get NCE exclusivity FDA needed to approve the alogliptin single-entity NDA first, because FDA has previously approved drug products containing metformin and pioglitazone.  And, in fact, FDA’s Orange Book shows a period of 5-year NCE exclusivity for each of the NESINA, KAZANO, and OSENI NDAs expiring on January 25, 2018.  (As we previously reported, two citizen petitions were recently submitted to FDA challenging the Agency’s interpretation and application of the FDC Act to deny 5-year NCE exclusivity for a combination drug containing new and previously approved moieties.  FDA has not substantively responded to either petition.)

But what helps under Title I of Hatch-Waxman may hinder under Title II of Hatch-Waxman.  That is, what appears to be an attempt by FDA to avoid controversy with respect to NCE exclusivity might raise raise controversy with respect to PTE.  Indeed, FDA and the courts have long recognized that the law that applies under Title I may not apply under Title II – see, e.g., the Federal Circuit’s May 10, 2010 decision in Photocure v. Kappos, 603 F.3d 1372 (Fed. Cir. 2010) and FDA’s May 29, 2012 Letter Decision concerning TORISEL (temsirolimus) Injection exclusivity.

The same day approvals of the NESINA, KAZANO, and OSENI NDAs raises the possibility of multiple PTE applications and the granting of multiple PTEs for different patents covering the drug products.  Indeed, several patents are listed in the Orange Book for each of the three drug products, including U.S. Patent Nos. 6,150,383, 6,211,205, 6,303,640, 6,303,661, 6,329,404, 6,890,898, 7,078,381, 7,459,428, 7,807,689, 8,173,663, and 8288539 for NESINA, and the same patents plus U.S. Patent Nos. 5,965,584, 6,150,384, 6,166,042, 6,166,043, 6,172,090, and 6,211,205 for KAZANO and OSENI, and all of the same patents plus U.S. Patent No. 6,271,243 for OSENI.  It is well after the 60-day statutory deadline for submitting PTE applications, and it seems highly likely that PTE applications have been submitted with respect to each NDA (although Public PAIR has not yet been updated with this information).

As we discussed several years ago, the PTE statute states (at 35 U.S.C. § 156(c)(4)) that “in no event shall more than one patent be extended . . . for the same regulatory review period for any product.”  The U.S. Patent and Trademark Office (“PTO”) interprets 35 U.S.C. § 156(c)(4) to permit multiple PTEs under certain circumstances – specifically, for a drug product covered by several patents the PTO may extend a different patent for each NDA approved on the same first day (even when multiple NDAs share common “testing phase” and a “review phase” dates).  That is, the PTO considers each NDA “regulatory review period” to be distinct and for which a PTE is available.  There is only a handful of cases in which the PTO has granted, or companies have been eligible for and pursued, multiple PTEs for different patents covering the same product approved under separate NDAs on the same first day.  Specifically, the ones we know of are:

• OMNICEF (cefdinir):  Approved on December 4, 1997 under NDA Nos. 050739 and 050749.  One PTE was granted for U.S. Patent No. 4,559,334 with respect to NDA No. 050739, and another PTE was granted for U.S. Patent No. 4,935,507 with respect to NDA No. 050749.  In this case, FDA approved both NDAs simultaneously under a single approval letter that does not reflect a date/time-stamp.

• LYRICA (pregabalin):  Approved on December 30, 2004 under NDA Nos. 021446 and 021723.  One PTE was granted for U.S. Patent No. 6,001,876 with respect to NDA No. 021723, and another for U.S. Patent No. 6,197,819 with respect to NDA No. 021446.  As opposed to the opther multiple PTE precedents, FDA separately approved each NDA.  The approval letter for NDA No. 021446 is date/time stamped “12/30/04 04:33:10 PM ,” while the approval letter for NDA No. 021723 is date/time-stamped “12/30/04 04:36:18 PM.”

• MYCAMINE (micafungin sodium):  Approved on March 16, 2005 under NDA Nos. 021506 and 021754.  In this case, the NDA sponsor applied for two PTEs based on both approvals – one for either U.S. Patent Nos. 5,376,634, 6,265,536, or 6,107,458 for NDA No. 021506, and one for either of these same patents for NDA No. 021754 – but ultimately decided not to elect a second PTE.  The PTO granted a PTE for U.S. Patent No. 6,107,458 with respect to NDA No. 021506.  FDA approved both NDAs simultaneously under a single approval letter date/time-stamped “3/16/05 12:54:49 PM.”

• VIMPAT (lacosamide):  Approved on October 28, 2008 under NDA Nos. 022253 and 022254.  In this case, the NDA sponsor applied for two PTEs based on both approvals – one for either U.S. Patent Nos. 5,654,301 or RE38,551 for NDA No. 022253, and one for either of these same patents for NDA No. 022254.  The NDA sponsor ultimately elected a single PTE – for U.S. Patent No. RE38,551 with respect to NDA No. 022253 – and withdrew its PTE applications with respect to NDA No. 022254.  FDA approved both NDAs simultaneously under a single approval letter date/time-stamped “10/28/2008 08:00:13 PM.”

None of these precedents involve multiple NDAs where one application is for a single entity NCE and another is for a combination of that single entity with a previously approved drug.  In 2004, the Federal Circuit stated in its decision in Arnold Partnership v. Dudas, 362 F.3d 1338 (Fed. Cir. 2004), which concerned the availability of a PTE for a combination drug, that “the [PTE] statute places a drug product with two active ingredients, A and B, in the same category as a drug product with a single ingredient . . . .  To extend the term of a patent claiming a composition comprising A and B, either A or B must not have been previously marketed.”  Thus, a patent on a combination drug may be eligible for a PTE.  But the issue raised by FDA’s alogliptin NDA approvals, which Dr. Rosebraugh’s statement – “I am approving the single-entity alogliptin first, before approving the combination products containing alogliptin” – calls out is different.  The issue is whether the time of day counts for purposes of determining PTE eligibility and whether the first single-entity NDA approval precludes PTE eligibility for patents covering the combination drugs approved later (perhaps only seconds or minutes later) the same day.

In one sense, the three alogliptin NDA approvals are similar to those for OMNICEF.  In both cases, the NDA approval letters do not include a time-stamp, just a date-stamp.  But there are differences.  In the case of OMNICEF, although there is not a time-stamp, both NDAs were approved simultaneously on the same day under the same approval letter.  Simultaneous approvals under a single approval letter (and, therefore, the same date/time stamp) also show up in the MYCAMINE and VIMPAT PTE cases.  In the case of  alogliptin, however, three different NDA approval letters were issued, with the first NDA for NESINA specifically identified as the first approval. 

That leads us to LYRICA.  In that case, FDA issued two approval letters: one date/time-stamped “12/30/04 04:33:10 PM ” (NDA No. 021446) and the other date/time-stamped “12/30/04 04:36:18 PM” (NDA No. 021723).  Although minutes separated the NDA approvals, the PTO nevertheless granted PTEs for different patents vis-à-vis the different NDA approvals.  Thus, LYRICA may be most applicable to alogliptin if multiple PTEs have been requested on different patents vis-à-vis the different NDA approvals.  But one questions remains . . . . did the PTO ever consider the date/time-stamp when considering the PTE applications for LYRICA?  And, if not, will the Office do so here in light of Dr. Rosebraugh’s statement?