FDA Grants Petition on Pioglitazone Split Certification Issue; It’s Caveat Utilitor on Old Orange Book Patent Listings

By Kurt R. Karst –      

FDA’s recent response to a 2009 citizen petition filed by Sandoz, Inc. concerning the appropriate certification to certain Orange Book-listed patents for Takeda’s ACTOS (pioglitazone HCI) Tablets and ACTOPLUS MET (pioglitazone HCl; metformin HCI) Tablets can be summed up in two (Latin) words: Caveat Utilitor (That is, let the user beware).  The cautionary note is to companies that plan to submit (or have already submitted) to FDA ANDAs for generic versions of reference listed drug products with old (i.e., pre-August 2003) Orange Book patent listings.

The Sandoz petition requested that FDA refuse to approve any ANDA for a generic version of ACTOS and/or ACTOPLUS MET if the ANDA includes a so-called “section viii statement” (for the omission of certain patent-protected information) with regard to U.S . Patent Nos. 5,965,584 (“the ‘584 patent”) and/or 6,329,404 (“the ‘404 patent”), but does not also include a Paragraph IV certification to the respective patent.  This is referred to as a split certification.  FDA has previously explained that although a Paragraph IV certification and a section viii statement “are not overlapping, and an applicant does not have the option of making a [Paragraph IV] certification . . . in lieu of, or in addition to, a [section viii] statement,” a split certification with respect to the same Orange Book-listed patent may be appropriate in certain instances:

If [] there are listed patents that present both a product and method of use claim, the applicant may file a paragraph IV certification with respect to the product patent or patent claim and a [section viii] statement that the product that is the subject of the application does not involve a patented method of use with respect to the method of use patent or patent claim.

Both the ‘584 and ‘404 patents were initially listed in the Orange Book prior to August 18, 2003 and were flagged with method-of-use claims.  August 18, 2003 is the date on which FDA’s June 2003 regulations implementing the FDC Act’s patent listing provisions went into effect, and when the Agency made a technological leap in identifying Orange Book-listed patents.  As FDA explains in the Sandoz petition response:

[A]t the time [the ‘584 and ‘404 patents] were submitted, FDA’s Orange Book database lacked the technological capacity to display a single patent as claiming more than one aspect of the drug.  At that time, FDA’s practice was to display a patent that had been submitted as claiming both a drug product and a method of use only for the method of use for which it had been submitted.  Thus, FDA's Orange Book lists each patent as claiming only a method of use and provides a use code for each patent to identify the use for which it was submitted by Takeda.  To alert users to the limitations of patent listings for patents submitted before August 2003, and make them aware that the Orange Book may not describe the complete universe of patent claims to which an ANDA applicant must certify, the Orange Book includes a notation that “[p]atents listed prior to August 18, 2003 are flagged with method-of-use claims only as applicable and submitted by the sponsor” and that “[t]hese patents may not be flagged with respect to other claims which may apply. . . .”

Patents submitted to FDA after August 18, 2003 may be identified in the Orange Book as covering the drug product, drug substance, and/or an approved method of use. 

Relying on statements in complaints filed by Takeda in patent infringement litigation against other generic applicants for allegedly infringing the ‘584 and/or ‘404 patents, Sandoz asserted that Takeda characterized both patents as including not only method-of-use claims, but drug product claims as well.  As such, Sandoz took the position that FDA could, of its own accord, flag the ‘584 and ‘404 patents in the Orange Book with drug product claims and require generic applicant to submit a split certification to both patents.   

In the meantime, Takeda notified FDA that when the company first submitted the  ‘584 and ‘404 patents to FDA for Orange Book listing, such patents were characterized as containing both method-of-use and drug product claims.

FDA, once again affirming the Agency’s ministerial role in Orange Book patent listing issues, and citing the Agency’s regulations at 21 C.F.R. § 314.53(f) for interested persons to challenge Orange Book patent listings, ruled that the Agency would not independently consider Sandoz’s assertions that statements in Takeda patent infringement complaints serve as evidence that the ‘584 and ‘404 patents cover both method-of-use and drug product claims.  Instead:

In keeping with our practice of relying solely on the NDA sponsor’s patent declaration describing relevant patent claims in Orange Book-listed patents, FDA will rely on Takeda’s patent declarations submitted to FDA.  We have evaluated our records and confirmed that Takeda’s original patent declaration to FDA for the ‘584 and ‘404 patents stated that the patents included drug product claims and method-of-use claims.

So, FDA granted the Sandoz petition and stated that the Agency would consider ANDAs that do not address the relevant drug product claims in the ‘584 and ‘404 patents to be ineligible for final approval. 

FDA also commented that:

Under the plain language of the statute, the patent certification requirement is not triggered by the publication in the Orange Book of patent information submitted to FDA.  Rather, . . . the statute requires certification where the patent (or patent claim) claims a listed drug, and where the NDA holder is required to submit and has submitted that patent information to FDA.  This obligation to certify attaches regardless of whether that submission is accurately reflected in the Orange Book.  Thus, the pre-2003 technological limitations that prevented our Orange Book listings from reflecting the fact that Takeda submitted the patents as claiming both a drug product and a method of using that drug product do not limit Takeda’s rights to receive patent certifications for the drug product claims in the ‘584 and ‘404 patents. . . .  Nor does the absence of the drug product information in the Orange Book deprive the eligible ANDA applicant with the first paragraph IV certification with respect to the patent of eligibility for a l80-day exclusivity period . . . . [(emphasis added; internal citations omitted)]

Thus, generic applicants that plan to submit, or that have pending at FDA, ANDAs for generic versions of drug products with pre-August 2003 Orange Book-listed patents would be wise to check that the appropriate certification was submitted to FDA, and, if there are questions about the accuracy of a particular patent listing, submit to FDA a 21 C.F.R. § 314.53(f) request.