January 26, 2016
AIPLA Chemical Practice Chronicles Newsletter
By Leslie A. McDonell; Clara N. Jiménez; Nicholas E. Bencivenga
On December 9, 2014, the PTAB issued its Final Written Decision in each of the three separate, but related, Inter Parte Review proceedings1, captioned as Amneal Pharmaceuticals, LLC ("Amneal") v. Supernus Pharmaceuticals, Inc. ("Supernus"). The Final Written Decisions, finding each challenged claim not unpatentable on the instituted grounds, represent more than just a win for patentee Supernus—they represent the first successfully defended IPR proceedings of Orange Book listed patents.
Oracea® was developed as a treatment for rosacea, also known as acne rosacea, which is a chronic disorder of the skin characterized by inflammatory lesions and dilation of cutaneous blood vessels.2Doxycycline, the active ingredient of Oracea®, is a member of the tetracycline family. The invention was based upon the realization that Periostat®, a twice-daily, 20 mg dose of doxycycline hyclate for the treatment of periodontitis, may be used for the treatment of acne and rosacea.3In order to achieve a blood concentration of doxycycline at a level high enough to be effective against acne and rosacea, but low enough to avoid the side effects associated with antibacterial dosages of doxycycline, the inventors sought to develop new formulations.4After many failed development attempts, a formulation with two different release profiles—immediate release and delayed release, each with an optimal doxycycline dosage at each level—was developed.5The challenged patents generally relate to the once daily, sub-antibacterial dosage formulations of doxycycline used for the inhibition of collagen destroying enzymes that lead to acne and rosacea.6Because of the similarity between the three challenged patents, only the ’740 patent and its IPR proceeding will be discussed in detail in this article.
As of the date of this article, there are eleven Orange Book listed patents covering Oracea®. When the aforementioned IPR petitions were filed, five of the Orange Book listed patents were the subject of at least one district court litigation and/or appeal to the Federal Circuit.7Indeed, the parent patent, U.S. Patent No. 7,749,532 ("’532 patent"), was found to be not invalid at the district court level, and that holding was affirmed on appeal.8The ’740 patent is a continuation application of the ’532 patent, and the ’405 and ’406 patents are continuation applications of the ’740 patent.
Claim 1 of the ’740 patent is a representative claim:
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.
Amneal’s petition challenged the validity of the ’740 patent on four obviousness grounds.9One ground alleged obviousness over International Patent Application Publication No. WO 02/080932 to Ashley ("Ashley"); and the other three grounds alleged obviousness over Ashley in combination with one or more of U.S. Patent No. 5,348,748 to Sheth ("Sheth"), International Patent Application Publication No. WO 02/083106 ("Ashley 2"), and "Treatment of Rosacea" (an article published by G.F. Webster). Supernus filed a Patent Owner Preliminary Response highlighting the fact that the parent of the ’740 patent had essentially survived the same challenges raised by Amneal in IPR during district court litigation and at the Federal Circuit.10Further, Supernus cited to trial testimony of Robert Ashley, the inventor of the primary prior art reference, and of Guy Webster, the author of another asserted reference.11During trial, Ashley testified that he, “had no idea how to create any formulations that met the steady state blood levels claimed [in the ’532 patent],” and Webster testified that, "they [doctors] didn’t think it [Webster’s disclosure] would work."12Additionally, Supernus noted that all of the asserted references were considered during the prosecution of the ’740 patent.13
The PTAB instituted review of the ’740 patent, but only on one ground: obviousness over Ashley in view of Sheth.14The PTAB adopted the construction proposed by the parties for the terms "about," "immediate release" and "steady state blood level(s)."15The Board also construed the term "pellets, " adopting its ordinary and customary meaning.16
In its Patent Owner Response, Supernus advanced, among other things, the new argument that Ashley fails to disclose the particular ratio of 30 mg doxycycline in the immediate-release portion and 10 mg doxycycline in the delayed-release portion, and that Sheth fails to cure such deficiency.17Supernus argued that Sheth describes formulations consisting of two components—an initial loading portion of "quick release granules" and a secondary loading portion using a modified coating system for controlled release—both portions containing minocycline (not doxycycline).18Because the secondary loading portion of Sheth is made of a blend of water-soluble polymers and pH-sensitive polymers, it is expected that it would begin to release the drug promptly after administration upon reaching the stomach.19Because of this (nearly) immediate release profile, Supernus argued, Sheth does not teach a "delayed release" portion at all, and therefore, cannot cure the deficiency in Ashley.20
In its Final Written Decisions, the Board found that the challenged claims of the ’740 patent were not determined to be unpatentable.21In reaching its decision, the Board construed the term "delayed release" to mean "release of a drug at a time other than immediately following oral administration."22While neither the parties nor the Board had indicated that this term needed construction at institution, during the oral hearing the Board asked the parties to provide proposed constructions for the term.23In reaching this construction, the term rejected the narrower construction proposed by Supernus which would have required “no substantial release of doxycycline in the acidic stomach environment of approximately below pH 4.5.”24
Addressing the obviousness challenge, the Board found that Sheth discloses "a oncedaily formation of minocycline that provides an antibacterial total daily dose." The Board further found that the formulation in Sheth includes an initial loading component of quickrelease pellets and a secondary loading component of slow-release pellets.25Thus, the Board focused on whether the slow-release pellets in Sheth constituted or provided a "delayed release" portion under the Board’s construction. Supernus argued that the slow-release pellets in Sheth were not delayed but rather "a 'modified sustained release' that begins slowly but promptly in the stomach, followed by rapid release in the intestine."26Amneal, on the other hand, argued that there was a "delay" before release from the slow-release pellets.27
The Board agreed with Supernus, crediting the declaration testimony of Supernus’s expert witness for the proposition that "inclusion of a water soluble polymer in the coating of Sheth’s slow-release pellets results in release of drug promptly after administration."28The Board further agreed with Supernus’s expert on the point that the "lag" required for dissolution of the polymer coating the slow-release pellets would not be considered a "delay."29According to the Board, Amneal failed to appropriately rebut this testimony and 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."30Accordingly, the Board found that Sheth does not disclose a “delayed release portion” as recited in the challenged claims. Based on this conclusion, the Board also rejected Amneal's argument that Sheth discloses the claimed ratio of doxycycline in the immediate-release portion of the oral dosage to doxycycline in the delayed-release portion of the oral dosage.31On that point, the Board noted that Amneal’s expert evidence concerning ratio’s in Sheth was premised in the improper assumption that Sheth disclosed a delayed-release portion.32
This decision reiterates to practitioners that the Board is not obligated to follow the holdings of any related litigation. In the instant case, the Board instituted IPR on grounds and references nearly identical to those unsuccessfully asserted during district court litigation, forcing the patentee to develop new—and eventually successful—arguments.
Also of note is the fact that Supernus did not attempt to amend the claims during IPR. One can speculate that this approach was adopted because the patentee still had pending applications where it could more freely to pursue the claim scope of its choosing, in a manner of its choosing.
As time passes, it will be interesting to see how many Orange Book listed patents are challenged in this forum. We will follow up, as appropriate, with developments in this area.
Endnotes
1The IPR proceedings are: IPR2013-00368, challenging U.S. Patent No. 8,206,740 ("’740 patent"); IPR2013-00371, challenging U.S. Patent No. 8,394,405 ("’405 patent"); and IPR2013- 00372, challenging U.S. Patent No. 8,394,406 ("’406 patent").
2Patent Owner Preliminary Response, IPR2013-00368, Paper 6 at 3.
3Id.
4Id. At 5.
5Id. at 6.
6Final Written Decision, IPR2013-00368, Paper 94 at 3.
7See, e.g., The Research Foundation of State University of New York v. Mylan Pharmaceuticals Inc., 809 F. Supp. 2d 296 (D. Del. 2011).
8The Research Foundation of State University of New York v. Mylan Pharmaceuticals, Inc., 531 Fed. Appx. 1008, 1010 (Fed. Cir. 2013).
9IPR2013-00368, Paper 2 at 7-8.
10See Patent Owner Preliminary Response, IPR2013-00368, Paper 6 at 7-9.
11Id. at 9.
12Id.
13Id. at 12.
14Institution Decision, IPR2013-00368, Paper 8 at 13-14.
15Id. at 5-6.
16Id. at 6-7.
17Patent Owner Response, IPR2013-00368, Paper 40 at 16-17.
18Id.
19Id. at 17-18.
20Id. at 18.
21Final Written Decision, IPR2013-00368, Paper 94 at 15.
22Id. at 8.
23Arguments for this IPR, in addition to arguments for IPR2013-00371 and IPR2013-00372 were heard during the same hearing. Winter 2016 Volume 4, Issue 1
24Id. at 6.
25See id. at 10-11.
26Id. at 12.
27Id.
28Id. at 13.
29Id.
30Id.
31Id. at 14.
32Id.
Originally printed in AIPLA Chemical Practice Chronicles on January 26, 2016. This article is for informational purposes, is not intended to constitute legal advice, and may be considered advertising under applicable state laws. This article is only the opinion of the authors and is not attributable to Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, or the firm's clients.
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