Smarter than the Average Bear? Two Recent Lifecycle Management Strategies of Note

June 13, 2011

By Kurt R. Karst –      

Like Yogi Bear, who is always on the lookout for a better way to procure pic-i-nic baskets, we are always on the lookout for innovative strategies companies come up with to protect their market exclusivity.  Two strategies have recently come by our desks – one from a brand-name company related to New Chemical Entity (“NCE”) exclusivity covering INVEGA (paliperidone) Extended-release Tablets, and another from a generic manufacturer related to 180-day exclusivity for a generic version of GEMZAR (gemcitabine) for Injection.  Both companies appear to have successfully protected their  marketing exclusivities.  How did they do it?  Queue up the “How It’s Made” theme song . . . .


FDA approved INVEGA on December 19, 2006 under NDA No. 21-999 and granted the sponsor, Ortho-McNeil-Janssen Pharmaceuticals, Inc. (“Ortho”), a period of 5-year NCE exclusivity that expires on December 19, 2011.  Since then, FDA has granted Ortho several periods of 3-year new clinical investigation exclusivity for INVEGA in connection with NDA supplements, as well as a period of pediatric exclusivity earlier this year.  FDA’s grant of pediatric exclusivity extends by 6 months Orange Book-listed patent and non-patent exclusivities, and in particular, the period of NCE exclusivity for INVEGA until June 19, 2012. 

Shortly before the time FDA granted pediatric exclusivity (based on a pre-September 27, 2007 Pediatric Written Request), Ortho requested that FDA list U.S. Patent No. 5,158,952 (“the ‘952 Patent”) in the Orange Book for NDA No. 21-999, presumably because the ‘952 Patent “claims the drug for which the applicant submitted the [NDA] or which claims a method of using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture, use, or sale of the drug.”  FDC Act § 505(b)(1).  The ‘952 Patent, which is the only patent listed in the Orange Book for INVEGA, expires on April 9, 2012, but pediatric exclusivity would have been in effect until October 9, 2012 (or about four months after the pediatric extension on the NCE exclusivity period expires).  Would have been, you ask?  Yes, but we’ll get to that in a moment . . . .

Under the FDC Act, 5-year exclusivity prevents the submission of an ANDA (or a 505(b)(2) application) for 5 years, unless the applicant submits a Paragraph IV patent certification to an Orange Book-listed patent on the listed drug relied on for approval, in which case the ANDA (or 505(b)(2) application) can be submitted after four years.  Pediatric exclusivity granted under FDC Act § 505A extends the 5-year and 4-year periods out by an additional 6 months.  In the case of INVEGA, the 4-year ANDA/Paragraph IV certification period went from December 19, 2010, to June 19, 2011.

By submitting the ‘952 Patent to FDA for Orange Book listing, Ortho created the opportunity for an ANDA sponsor to submit an application containing a Paragraph IV certification to the ‘952 Patent beginning on June 19, 2011, instead of June 19, 2012.  So how do you prevent an ANDA sponsor from getting a 12-month head start on the review of its application based on a Paragraph IV certification to an early-expiring Orange Book-listed patent?  You disclaim the patent and dedicate the remaining term to the public and request that FDA remove the patent from the Orange Book.  That’s exactly what happened with the ‘952 Patent.  On June 1, 2011, Ortho dedicated the ‘952 Patent to the public, and on June 2, 2011 – a little more than two weeks before an ANDA could be submitted – Ortho requested that FDA delist the patent from the Orange Book.  


Under the FDC Act’s 180-day exclusivity failure-to-market forfeiture provisions (FDC Act § 505(j)(5)(D)(i)(I)), there must be two events (i.e., “bookends”) to calculate a “later of” event between items (aa) and (bb).  The first bookend date under item (aa) is the earlier of the date that is:

(AA) 75 days after the date on which the approval of the application of the first applicant is made effective under subparagraph (B)(iii); or

(BB) 30 months after the date of submission of the application of the first applicant

The (bb) part of the equation (i.e., the other bookend) provides that the (bb) date is “the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a [Paragraph IV] certification qualifying the first applicant for the 180-day exclusivity period,” one of three events occurs:

(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

(BB) In an infringement action or a declaratory judgment action described in [FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA)], a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

(CC) The patent information submitted under [FDC Act § 505(b) or (c)] is withdrawn by the holder of the application approved under subsection (b).

The (AA) and (BB) court decision events under item (bb) can be triggered in patent infringement litigation by “the first applicant or any other applicant (which other applicant has received tentative approval),” while the (CC) event would occur as the result of the NDA sponsor requesting that FDA delist Orange Book-listed patents. 

In the case of a generic version of Lilly’s GEMZAR (gemcitabine) for Injection, 200 mg/vial and 1 gram/vial, TEVA Parenteral Medicines, Inc. (“Teva”) submitted the first ANDA to FDA containing a Paragraph IV certification, thereby qualifying the company as a first applicant eligible for 180-day exclusivity.  That ANDA, ANDA No. 77-983, was submitted to FDA in November 2005.  Several other generic drug manufacturers submitted ANDAs to FDA containing Paragraph IV certifications to Orange Book-listed patents on GEMZAR, including APP Pharmaceuticals, Inc. (“APP”) and Sun Pharmaceuticals (“Sun”); however, all of these applicants submitted their applications subsequent to Teva’s ANDA submission.  As such, final approval for these ANDAs is prevented until Teva’s 180-day exclusivity has been triggered and run or is forfeited. 

FDA tentatively approved APP’s ANDA No. 90-242 on September 24, 2009.  FDA tentatively approved Sun’s ANDA No. 78-433 on March 4, 2008.  Sun was involved in patent infringement litigation with Lilly with respect to a patent on which Teva qualified for 180-day exclusivity.  The district court ruled in Sun’s favor, and Lilly appealed to the U.S. Court of Appeals for the Federal Circuit.  In July 2010, a panel of Federal Circuit judges affirmed the district court decision.  Lilly petitioned the Court for a panel rehearing/rehearing en banc, which the Court denied on November 1, 2010.  On November 12, 2010, the Federal Circuit issued its mandate. 

FDA considered the date of issuance of the mandate to be a final court decision for purposes of triggering the 75-day clock under FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA).  The date that is 75 days after November 12, 2010, and that is the item (bb) bookend date for a forfeiture calculation, was January 26, 2011.  The item (aa) bookend date (i.e., the date that is 30 months after the date of submission of Teva’s application) was in May 2008.  The later of the item (aa) and item (bb) dates, and the date on which a forfeiture of 180-day exclusivity would have occurred was January 26, 2011.  However, FDA approved ANDA No. 77-983 on January 25, 2011, just one day short of the forfeiture date for 180-day exclusivity eligibility. 

From what we can surmise, unresolved manufacturing issues probably meant that ANDA No. 77-983 was not in an approvable position, thereby placing the company at risk of a forfeiture of 180-day exclusivity as a result of the November 12, 2010 discussed above.  According to a Teva press release, Teva entered into a “commercialization, manufacture and supply agreement” with APP (which already held a tentative approval for the company’s ANDA No. 90-242), under which “APP will manufacture Gemcitabine HCI for Injection and will receive a license from Teva to market the product within Teva’s 180-day exclusivity.”  What we infer from this is that Teva and APP reached an agreement under which Teva was able to use/transfer information from the tentatively approved APP ANDA and include that information in Teva’s ANDA, thereby placing Teva’s ANDA in an approvable position.  Although longstanding FDA policy requires ANDA sponsors to recertify to Orange Book-listed patents when submitting an amendment for a formulation change, such a recertification would not be triggered when two formulations are quantitatively and qualitatively (“Q1/Q2”) the same.  If the APP and Teva gemcitabine formulations were Q1/Q2 the same, which was presumably the case, then FDA would not have required Teva to recertify to any GEMZAR patents.