Acorda Therapeutics, Inc. v. Roxane Labs., Inc.

• Citation: 903 F.3d 1310
• Decision Date: 10 September 2018
• Docket Number: 2017-2078,2017-2134
• Parties: ACORDA THERAPEUTICS, INC., Plaintiff-Appellant, Alkermes Pharma Ireland Limited, Plaintiff-Appellee, v. ROXANE LABORATORIES, INC., Mylan Pharmaceuticals Inc., Teva Pharmaceuticals USA, Inc., Defendants-Cross-Appellants
• Court: United States Courts of Appeals. United States Court of Appeals for the Federal Circuit

903 F.3d 1310

ACORDA THERAPEUTICS, INC., Plaintiff-Appellant,

Alkermes Pharma Ireland Limited, Plaintiff-Appellee,

v.ROXANE LABORATORIES, INC., Mylan Pharmaceuticals Inc., Teva Pharmaceuticals USA, Inc., Defendants-Cross-Appellants

2017-2078

2017-2134

United States Court of Appeals, Federal Circuit.

Decided: September 10, 2018

Bruce M. Wexler, Paul Hastings LLP, New York, NY, argued for plaintiff-appellant. Also represented by Stephen Blake Kinnaird, Igor Victor Timofeyev, Washington, DC; Garrard R. Beeney, Wenying Angela Chang, Stephen J. Elliott, Sullivan & Cromwell LLP, New York, NY; Anthony Michael, Jane G. Wasman, Acorda Therapeutics, Inc., Ardsley, NY.

Maryellen Noreika, Morris, Nichols, Arsht & Tunnell LLP, Wilmington, DE, for plaintiff-appellee. Also represented by Jeremy A. Tigan.

Charles B. Klein, Winston & Strawn LLP, Washington, DC, argued for defendants-cross-appellants. Defendants-cross-appellants Roxane Laboratories, Inc., Teva Pharmaceuticals USA, Inc. also represented by Andrew Curtis Nichols ; Bryce Cooper, George C. Lombardi, Reid Smith, Chicago, IL.

Robert Florence, Parker Poe Adams & Bernstein LLP, Atlanta, GA, for defendant-cross-appellant Mylan Pharmaceuticals Inc. Also represented by Micheal L. Binns, Karen L. Carroll.

Sarah Anne Kagan, Banner and Witcoff, Ltd., Washington, DC, for amicus curiae Biotechnology Innovation Organization. Also represented by Melissa A. Brand, Lisa Meredith Hemmendinger ; Hansjorg Sauer, Biotechnology Innovation Organization, Washington, DC.

Scott E. Kamholz, Covington & Burling LLP, Washington, DC, for amicus curiae Pharmaceutical Research and Manufacturers of America. Also represented by Brianne Bharkhda; David Evan Korn, Pharmaceutical Research and Manufacturers Association of America, Washington, DC.

Before Newman, Dyk, and Taranto, Circuit Judges.

Opinion dissenting filed by Circuit Judge NEWMAN

Opinion for the court filed by Circuit Judge TARANTO.

Before us are patents that claim the administration of a medication containing the active ingredient 4-aminopyridine (4-AP) to improve walking in individuals with multiple sclerosis

. Acorda Therapeutics, Inc., holds New Drug Application No. 022250, approved by the U.S. Food and Drug Administration (FDA). Pursuant to that approval, Acorda markets, under the name "Ampyra®," 10 milligram 4-AP sustained-release tablets for twice-daily oral administration. In the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations , or Orange Book, Acorda has listed, as claiming methods of using Ampyra, four patents that Acorda owns: U.S. Patent No. 8,007,826 ; No. 8,663,685 ; No. 8,354,437 ; and No. 8,440,703. Those patents ("the Acorda patents") are the main patents at issue on appeal.

One additional patent is before us. Acorda holds an exclusive license to an earlier, broader patent, U.S. Patent No. 5,540,938, referred to as "the Elan patent" because it was originally assigned to Elan Corporation, plc (whose successor in interest is Alkermes Pharma Ireland Ltd.). The Elan patent, listed in the Orange Book for Ampyra along with the Acorda patents, claims methods of treating patients having certain conditions, including multiple sclerosis

, by administering a drug containing a sustained-release formulation of any of certain agents, one of them 4-AP. The later Acorda patents claim species of the Elan patent's genus claims by adding further, more specific requirements to the Elan patent's claimed methods. While the Elan patent's claims broadly cover administering a sustained-release formulation of 4-AP to individuals with multiple sclerosis, the Acorda patents' claims further specify that such a drug must be administered (1) in a 10 mg dose twice a day (2) at that stable dose for the entire treatment period of at least two weeks (3) to achieve 4-AP serum levels of 15–35 ng/ml and (4) to improve walking.

Roxane Laboratories, Inc.; Mylan Pharmaceuticals, Inc.; and Teva Pharmaceuticals USA, Inc., have submitted Abbreviated New Drug Applications seeking FDA approval to market generic versions of Ampyra. In July 2014, Acorda and Alkermes sued those entities ("defendants") in the District of Delaware, alleging infringement of several claims in each of the Elan and Acorda patents. The defendants stipulated to infringement but challenged the validity of the asserted claims. The district court held that the asserted claims in the Acorda patents are invalid for obviousness. But the court upheld the asserted claims of the Elan patent against invalidity challenges and enjoined the defendants from activity infringing that patent until it expired on July 30, 2018.

Acorda appealed the invalidity ruling regarding the Acorda patents. The defendants cross-appealed the validity ruling regarding the Elan patent and the resulting injunction. We now affirm the judgment that the asserted Acorda patent claims are invalid. We dismiss the cross-appeal as moot.

I

A

In view of our decision that the issues concerning the Elan patent are moot, we focus on the background of the Acorda patents. Essential to understanding the obviousness issue is an understanding of the prior art.

4-AP, also called "dalfampridine" and "fampridine," was first identified in 1902. Acorda Therapeutics, Inc. v. Roxane Labs., Inc. , No. 1:14-cv-00882-LPS, 2017 WL 1199767, at *3, *5 (Mar. 31, 2017) ( Dist. Ct. Op. ). Belonging to a class of compounds that function as potassium-channel blockers, 4-AP "has been found to slow the potassium flow in nerve impulse transmission" and, by doing so, help "restor[e] conduction in blocked and demyelinated nerves," '826 patent, col. 2, lines 5–11, i.e. , nerves whose myelin insulation has been damaged. 4-AP was first used in human studies in the 1970s to investigate its effect on neurological diseases

resulting in muscle weakness. Dist. Ct. Op. at *5. For several decades, 4-AP has been the focus of research regarding the treatment of multiple sclerosis in particular. See, e.g. , id. at *5–7 (reciting studies); J.A. 6697 (paper published in 1987 describing study of the effect of 4-AP on subjects with multiple sclerosis ). Multiple sclerosis causes the demyelination, or loss of myelin, of nerves in the central nervous system and results in a wide variety of symptoms, including walking impairment, tingling or pain, brain scarring, cognitive changes, visual impairments, and fatigue. See '826 patent, col. 1, lines 36–42; Dist. Ct. Op. at *2. Eventually, 4-AP research led to the development, patenting, and FDA approval of Ampyra.

In the 1980s, researchers at the Rush Medical School conducted a study on 12 patients with multiple sclerosis

, and 5 without, to determine whether intravenous administration of 7 to 35 mg of 4-AP had any therapeutic effect on multiple sclerosis. J.A. 6697 (Dusan Stefoski et al., 4-Aminopyridine Improves Clinical Signs in Multiple Sclerosis , 21 Annals of Neurology 71 (1987) ). According to the published paper reporting that study (Stefoski), 10 of the 12 patients with multiple sclerosis"showed mild to marked improvement"; "[v]ision improved in 7 patients, oculomotor function in 5, and motor function (power, coordination, gait) in 5." J.A. 6697. Improvements were seen at doses as low as 2 mg: In one patient, gait improvement occurred within 25 minutes of administration of a total dose of 2 mg. J.A. 6699. Stefoski also reported:

[W]e observed no serious or bothersome side effects at total doses below 30 to 35 mg injected not less than 20 minutes apart for aliquots up to 3 mg. Moreover, the clinical improvements in many of our patients were of sufficient magnitude to represent a functionally noteworthy therapeutic benefit. Studies are currently in progress to determine the clinical usefulness of oral 4-AP as a symptomatic treatment.

J.A. 6701; accord J.A. 6697.

In 1990, an overlapping group of researchers published a paper (Davis) reporting another study on 4-AP's effect on symptoms of multiple sclerosis

. J.A. 6327 (Floyd A. Davis et al., Orally Administered 4-Aminopyridine Improves Clinical Signs in Multiple Sclerosis , 27 Annals of Neurology 186 (1990) ). In that study, 20 patients with multiple sclerosis were given either a single oral dose of 4-AP (15 patients) or a placebo (5 patients). J.A. 6327. Of those in the active treatment group, 4 patients were given a 10 mg dose of 4-AP, 2 were given 12.5 mg, 4 were given 15 mg, 4 were given 20 mg, and 1 was given 25 mg. Davis at 187 tbl.1. Davis states that "[m]ild to marked improvements occurred in all of the 15 [multiple sclerosis] patients given 4-AP." J.A. 6329; accord J.A. 6327. "Improvements developed gradually with doses as low as 10 mg 4-AP, usually beginning within 60 minutes after drug administration." J.A. 6329. Motor function improved in 9 of 13 patients in the active treatment group (motor function was not measured in 2). Davis at 187 tbl.1; J.A. 6329. The improvements were "most striking[ ] with respect to power and coordination" and "were apparent with both simple function tests and the performance of complex motor tasks such as gait and repetitive movements." J.A. 6329. Finally, Davis notes, no "serious or bothersome side effects," including seizures, were observed at single oral doses up to 25 mg. J.A. 6332.

A few years later, researchers at a university hospital in the Netherlands published a paper (Van Diemen) reporting a randomized, double-blind, placebo-controlled crossover study that "demonstrated efficacy of [4-AP] in improving disability of patients with multiple sclerosis

." J.A. 7037 (Harriët A. M. Van Diemen et al., 4-Aminopyridine in Patients with Multiple Sclerosis : Dosage and Serum Level Related to Efficacy and Safety , 16 Clinical Neuropharmacology 195 (1993) ). In the second phase of the study lasting 12 weeks, 69 patients were orally administered 10–20 mg 4-AP per day, split into two or three doses. J.A. 7038, 7042. The doses were escalated during the second week, and again during the sixth week, by 5–15 mg. J.A. 7038–39. The paper reports improvements in...