Orexo AB v. Actavis Elizabeth LLC

• Decision Date: 10 September 2018
• Docket Number: 2017-1333
• Citation: 903 F.3d 1265
• Parties: OREXO AB, Orexo US Inc., Plaintiffs-Appellants, v. ACTAVIS ELIZABETH LLC, Defendant-Appellee.
• Court: U.S. Court of Appeals — Federal Circuit

903 F.3d 1265

OREXO AB, Orexo US Inc., Plaintiffs-Appellants,

v.ACTAVIS ELIZABETH LLC, Defendant-Appellee.

2017-1333

United States Court of Appeals, Federal Circuit.

Decided: September 10, 2018

Errol Taylor, Milbank, Tweed, Hadley & McCloy, LLP, New York, NY, argued for plaintiffs-appellants. Also represented by Anna Brook, Jordan P. Markham, Fredrick Zullow.

George C. Lombardi, Winston & Strawn LLP, Chicago, IL, argued for defendant-appellee. Also represented by Tyler Johannes, Michael Keenan Nutter, Ivan Michael Poullaos ; Geoffrey P. Eaton, Washington, DC.

Before Newman, Hughes, and Stoll, Circuit Judges.

Newman, Circuit Judge.

Orexo AB and Orexo US Inc. (collectively "Orexo") appeal the decision of the United States District Court for the District of Delaware, holding claims 1, 3–6, and 8–10 of U.S. Patent No. 8,940,330 ("the ’330 Patent") invalid on the ground of obviousness.¹ The ’330 Patent, entitled "Abuse-Resistant Pharmaceutical Composition for the Treatment of Opioid Dependence," claims a product having the brand name Zubsolv®, approved by the FDA for treatment of opioid dependence.

Actavis Elizabeth LLC ("Actavis") filed an Abbreviated New Drug Application ("ANDA") for a generic counter-part of Zubsolv, accompanied by a Paragraph IV certification, leading to this Hatch-Waxman litigation in accordance with 21 U.S.C. § 355(j) and 35 U.S.C. § 271(e)(2)(A). Two Orexo patents were challenged by Actavis, but U.S. Patent No. 8,454,996 ("the ’996 Patent"), entitled "Pharmaceutical Composition for the Treatment of Acute Disorders," which was held valid in the district court, is not involved in this appeal.

We reverse the judgment of invalidity of the ’330 Patent, for we conclude that obviousness was not proved by clear and convincing evidence.

BACKGROUND

AThe ’330 Patent

The ’330 Patent specification explains that opioid-based pharmaceutical products intended for the relief of pain have become a source of addiction, dependency, and abuse. Treatment for opioid addiction includes a protocol called "substitution therapy," where partial opioid agonists² that have higher binding affinities at opioid receptors but produce lowered dependency than full agonists like heroin, can lead to cessation of addiction by relieving the opioid craving. The prior art shows use for this purpose of the partial agonist buprenorphine, administered in sublingual tablets and in oral films.

The ’330 Patent explains that while buprenorphine has less narcotic effect than a full opioid, addicts were known to dissolve the buprenorphine from the substitution therapy tablet, and inject the dissolved buprenorphine intravenously to achieve an enhanced opioid effect. To counteract this abuse, it was known to combine buprenorphine with the opioid antagonist³ naloxone in substitution therapy.

It was known that formulations containing buprenorphine to naloxone at a ratio of 4:1 provide the therapeutically optimal balance for sublingual treatment. Naloxone has poor transmucosal bioavailability so that if the mixture is taken in tablet form as directed, the buprenorphine will act as intended to treat opioid dependence with little interference from the naloxone. However, if the tablet is dissolved and injected, the naloxone will antagonize the effects of the buprenorphine, resulting in withdrawal symptoms and thus deterring abuse of the formulation. The 4:1 ratio provides for appropriate pharmacological amounts of naloxone to deter abuse when injected, but does not interfere with buprenorphine when taken in tablet form. ’330 Patent, col. 2, ll. 13–22; id. , col. 9, ll. 37–50. However, naloxone’s"functional blockade of buprenorphine’s action is also only partial and is short-lived in its nature," id. , col. 2, ll. 23–25, and there was a continuing need for improvement in substitution therapy formulations.

The ’330 Patent is for a sublingual tablet formulation that is less subject to abuse. The formulation enhances the agonist effectiveness of buprenorphine, permitting a reduced amount of buprenorphine in the tablet and thus reducing the amount available on dissolving and injecting the product. In this formulation, microparticles of buprenorphine are adhered to the surface of carrier particles of citric acid, and the formulation also contains naloxone in the 4:1 ratio. The ’330 Patent explains that the buprenorphine in the microparticles acts with little interference from the naloxone, but if the tablet is dissolved in water for injection into the bloodstream, the naloxone will also be dissolved and will antagonize buprenorphine’s effects.

All parties agree that the product in the ’330 Patent provides improved treatment of opioid dependence, as compared with the prior art. The ’330 Patent specification includes data from clinical trials comparing the related sublingual product Suboxone ®. Patent Example 2 shows a 66% improvement in bioavailability of buprenorphine, and Patent Examples 7 and 8 show bioequivalent results for a sublingual tablet containing 29% less buprenorphine than in Suboxone tablets.

Actavis does not dispute the improvement, or its value in treatment of addiction. Rather, Actavis argues that this formulation is obvious based on a combination of references, and that improved function and use are irrelevant if the product is obvious. This theory is flawed, for an unobvious improvement in properties or use is highly relevant to patentability of a new product.

Claims 1 and 6 were deemed representative:

1. A tablet composition suitable for sublingual administration comprising:

microparticles of a pharmacologically-effective amount of buprenorphine, or a pharmaceutically-acceptable salt thereof, presented upon the surface of carrier particles,

wherein microparticles of buprenorphine or a pharmaceutically acceptable salt thereof are in contact with particles comprising citric acid,

wherein the buprenorphine or pharmaceutically acceptable salt thereof and the citric acid are not in the same particle;

a pharmacologically-effective amount of naloxone, or a pharmaceutically-acceptable salt thereof;

and a disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crosslinked polyvinylpyrrolidone and mixtures thereof.

6. The composition as claimed in claim 1, wherein the particles of citric acid are presented and act as carrier particles.

The district court found that all the ingredients in the claims were generally known, and held that although the specific formulation was not shown or suggested in any reference, the new combination would have been obvious to a person of ordinary skill. However, the prior art does not show or suggest the claimed combination, and does not show or suggest that this combination would achieve enhanced therapeutic effect while being less subject to abuse.

BThe Prior Art

1. Suboxone ® and Subutex ®

The buprenorphine and naloxone combination in the 4:1 ratio has been used for substitution therapy at least since 2002. The prior art Suboxone sublingual tablets are a homogeneous combination made by mixing the ingredients of buprenorphine, naloxone, citric acid, sodium citrate, and sublingual excipients. Dist. Ct. Op. at 769 n.17 (citing Physicians’ Desk Reference, 58th ed. 2004). Subutex ® is the same formulation as Suboxone, but without the naloxone. WO2008/152347 ("Cairns"), cited by the examiner during prosecution, describes the tablet formulation as a wet granulation process where buprenorphine, citric acid, and sodium citrate are dissolved together and then mixed with excipients. See Orexo Br. at 14 & n.2 ("Cairns provides the manufacturing process for Subutex ® tablets, a product with essentially the same formulation as Suboxone ® tablets, but without naloxone.").

Orexo attributes the improvements achieved by the Zubsolv product to the microparticles of buprenorphine adhered to the surface of citric acid carrier particles. Orexo states that the 66% higher bioavailability is not suggested or reasonably predictable from the prior art. We have been directed to no reference to show or suggest otherwise. Orexo stresses the Examiner’s statement in allowing the ’330 Patent, that the improvement is due to the ingredients and the structure:

[T]he mere presence of citric acid in the sublingual tablets formulated according to the prior art (e.g. Cairns) is insufficient to achieve the superior pharmacokinetic profile exhibited by the instant invention. Applicant has persuasively demonstrated that the instant tablet exhibits unexpectedly superior sublingual buprenorphine bioavailability due to the ingredients as well as the structural characteristics recited in the instant claims.

Notice of Allowability at 5 (emphasis original), Application No. 14/127,470 (issued as the ’330 Patent ) (Nov. 4, 2014); see also Orexo Br. at 29 (quoting Notice of Allowability at 5).

2. Suboxone ® Film

U.S. Patent No. 8,475,832 ("the ’832 Patent") describes an orally dissolvable film that cannot be easily removed once placed inside the mouth. The film contains the buprenorphine /naloxone combination in the 4:1 ratio, and is described as bioequivalent to Suboxone sublingual tablets. The ’832 Patent teaches that optimum bioavailability of buprenorphine and naloxone from the film is achieved at pH 3–3.5, with citric acid included in the film to lower the pH. The district court relied on this presence of citric acid to render obvious the citric acid carrier particles in the Zubsolv formulation.

However, the ’832 Patent does not reduce the amount of buprenorphine needed to provide an effective substitution therapy dose. And the use of film in substitution therapy presents recognized problems, as stated in the ’330 Patent, for the film does not dissolve quickly and a maximum of only two films may be administered simultaneously, producing inadequate dosage as well as problems of compliance and administration. ’330 Patent, col. 2, ll. 43–50.

3. The Orexo Application

Orexo’s U.S. Patent Application No. 2010/0129443 ("the ’443 Application"), titled ...