By Andrew Williams --
The pharmaceutical industry has been closing watching the proceedings at the Patent Trial and Appeal Board ("PTAB" or "Board") to see if inter partes review ("IPR") will be a viable option for generic drug companies seeking to challenge Orange-Book-listed patents. On December 9, 2014, the PTAB released two sets of decisions that handed major victories to pioneering pharmaceutical companies. In what is thought to be the first set of Final Written Decisions ("FWDs") of Orange-Book-listed patents, the PTAB ruled that three patents covering Galderma Laboratories's Oracea® drug product for the treatment of acne rosacea were not invalid as obvious in view of the cited art. Specifically, the Board concluded that the petitioner, Amneal Pharmaceuticals, LLC, had failed to show that the cited secondary reference disclosed the claim limitations. In the second set of decisions, the PTAB denied the institution of three IPR's for patents that cover Gilead Sciences, Inc.'s Viread® drug product for the treatment of HIV-1. A fourth IPR was also filed at the same time, but a decision on institution is forth-coming. In this post, we will review the Galderma FWDs, and the circumstances surrounding them. We will follow-up at a future date with a review of the decisions not to institute in the Gilead cases.
The active ingredient in Oracea® is doxycycline, an antibiotic tetracycline compound. The oral administration of the drug is done at sub-antibacterial dosages, which was found to be effective in treating acne rosacea without the known undesirable side effects accompanying antibacterial dosages. During development of the drug, scientists at Shire Laboratories Inc. developed a formulation using two different release profiles, an immediate release ("IR") and a delayed release ("DR"), which facilitated a once-daily dosing regimen. This formulation was first described and claimed in U.S. Patent No. 7,749,532 ("the '532 patent"), which had related continuations U.S. Patent Nos. 8,206,740 ("the '740 patent"), 8,394,405 ("the '405 patent"), and 8,394,406 ("the '406 patent"). These last three patents were the subject of the three IPRs at issue, IPR2013-00368, IPR2013-00371, and IPR2013-00372, respectively, (filed in June, 2013). The IPRs were entitled Amneal Pharmaceuticals, LLC v. Supernus Pharmaceuticals Inc. – Shire was the predecessor to Supernus. Representative claims of these three patents include:
1. An oral pharmaceutical composition of doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 µg/ml and a maximum of 1.0 µg/ml, the composition consisting of
(i) an immediate release (IR) portion comprising 30 mg doxycycline;
(ii) a delayed release (DR) portion comprising 10 mg doxycycline; and
optionally, (iii) one or more pharmaceutically acceptable excipients.
'740 Patent, claim 1;
1. An oral pharmaceutical composition comprising about 40 mg of total doxycycline, which at a once-daily dosage will give steady state blood levels of doxycycline of a minimum of 0.1 µg/ml and a maximum of 1.0 µg/ml, wherein the composition consists of 70 to 80 percent of the doxycycline formulated as an immediate release (IR) formulation and 20 to 30 percent of the doxycycline formulated as a delayed release (DR) formulation.
'405 Patent, claim 1; and
1. An oral pharmaceutical composition comprising less than 50 mg of total doxycycline, which at a once-daily dosage will give steady state blood levels of the doxycycline between 0.1 µg/ml and 1.0 µg/ml, and a Cmax of the doxycycline between 0.4 µg/ml and 0.8 µg/ml, the composition consisting of
(i) an immediate release (IR) formulation of the doxycycline,
(ii) a delayed release (DR) formulation of the doxycycline comprising at least one enteric polymer, and
(iii) one or more pharmaceutically acceptable excipients, wherein the doxycycline in the IR and DR formulations is in a ratio of 75:25.
'406 Patent, claim 1.
Interestingly, the '532 patent was involved in a Hatch-Waxman-type litigation in the U.S. District Court for the District of Delaware. We reported at the time on the Federal Circuit appeal of the outcome of that case (see "Research Foundation of State University of New York v. Mylan Pharmaceuticals Inc. (Fed. Cir. 2013)"). The Delaware District Court had held that the '532 patent (the patent not subject to an IPR) was not invalid as obvious, and the appeals court affirmed. In addition to the Research Foundation of State University of New York v. Mylan Pharmaceuticals Inc. case, there have been several litigations involving the Orange Book patent covering Oracea®, including Galderma Labs. v. Amneal Pharms. in the Delaware District Court. Only the '740 patent was in common between the IPRs and the Amneal case.
The three IPRS were virtually identical, so this post will focus on IPR2013-00368 as representative. The Board first construed the claim term "delayed release." Oddly, even though neither party proposed a construction for this term, the Board appeared to request one during oral argument. Everyone was in agreement that the term means "release of a drug at a time other than immediately following oral administration." However, there was disagreement whether the broadest reasonable construction required that there be no substantial release in the stomach. Supernus argued that the patent described this term as allowing "no substantial release of doxycycline in the acidic stomach environment of approximately below pH 4.5." Amneal, on the other hand, argued that this construction was too narrow, and that the delay should only include drug release after a time lag, irrespective of whether there is release in the stomach. The Board agreed with Amneal and chose not to read the limitation form an embodiment into the claim term.
All three IPRs were instituted with only one ground of rejection, that the claims at issue were obvious in view of Ashley '932 (WO 02/080932 AI), which incorporated by reference provisional application No. 60/281,854, and Sheth (U.S. Patent No. 5,348,748). According to the FWDs, "Ashley '932 discloses administering a tetracycline compound, e.g., doxycxline or minocycline, in sub-antibacterial doses to treat acne, including acne rosacea." The provisional application disclosed controlled release of the drug product in order to reach a sub-antibacterial serum level of 0.4 to 0.8 µg/ml. This reference was, however, missing the once daily dosage utilizing an IR and DR formulation, and it ratio. Amneal argued that Sheth provided the additional limitations, and that one of skill in the art would have combined the two references together. The FWD describes Sheth as disclosing "a once-daily formation of minocycline that provides an antibacterial total daily dose." This is accomplished using quick-release pellets and a secondary loading component of slow-release pellets. The issue came down to whether these slow-release pellets provided "delayed release." The Patent Owner took the position that the secondary loading portions were not delayed because they begin release "in the stomach promptly after administration." The petitioner, on the other hand, argued that there was a "lag" before release. In fact, they cited testimony of Supernus's expert, who said: "Again, you're over simplifying the question. I think there would be some lag between when the polymer hydrated and the drug diffused through, but you wouldn't consider that a delay." The Board agreed that Sheth did not describe a "delayed release," noting that the lag time to wet the material would not be considered a "delay." The Board also indicated that Amneal had failed to explain how there would be an appreciable delay "once water in the patient's saliva or gastric fluid has begun to solubilize the pH-insensitive polymer in the coating." Finally, the Board concluded that petitioner's "argument that Sheth discloses the claimed IR:DR ratio (or makes the claimed ratio reachable through routine experimentation) thus becomes untenable." Without this evidence, the challenge failed.
It goes without saying that it will be interesting to see how the other Orange-Book-listed patents fare in the other IPRs that are currently ongoing. It will also be informative to find out if patents (or related patents) that have also been unsuccessfully challenged in district court will be more likely to be upheld by the PTAB. Patent-owning practitioners often contemplate whether the filing of a Patent Owner Response is the best course of action. It can essentially "tip you hand" as to your arguments, providing the petitioner with an additional opportunity to respond. However, it is also considered advisable to prevent institution in the first place, which may only be possible in some cases with the filing of a response. In this case, Supernus did file such a response. Nevertheless, as explained above, even though the IPR was instituted, the Board did not follow-through, but instead found the patent to not be invalid. On the other hand, we will explore in a future post the Gilead case, in which institution of an IPR for pharmaceutical patent was successfully defended against.