Valeant Pharm. Int'l, Inc. v. Mylan Pharm. Inc.

• Decision Date: 08 April 2020
• Docket Number: 2018-2097
• Citation: 955 F.3d 25
• Parties: VALEANT PHARMACEUTICALS INTERNATIONAL, INC., Salix Pharmaceuticals, Inc., Progenics Pharmaceuticals, Inc., Wyeth LLC, fka Wyeth, Plaintiffs-Appellees v. MYLAN PHARMACEUTICALS INC., Mylan Inc., Mylan Laboratories Limited, Defendants-Appellants Actavis LLC, Defendant
• Court: U.S. Court of Appeals — Federal Circuit

955 F.3d 25

VALEANT PHARMACEUTICALS INTERNATIONAL, INC., Salix Pharmaceuticals, Inc., Progenics Pharmaceuticals, Inc., Wyeth LLC, fka Wyeth, Plaintiffs-Appellees

v. MYLAN PHARMACEUTICALS INC., Mylan Inc., Mylan Laboratories Limited, Defendants-AppellantsActavis LLC, Defendant

2018-2097

United States Court of Appeals, Federal Circuit.

Decided: April 8, 2020

Bryan Diner, Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Washington, DC, argued for all plaintiffs-appellees. Plaintiffs-appellees Valeant Pharmaceuticals International, Inc., Salix Pharmaceuticals, Inc., Progenics Pharmaceuticals, Inc. also represented by Justin James Hasford, Cora Renae Holt, Esther Lim ; Jessica C. Lebeis, Boston, MA; Charles E. Lipsey, Reston, VA.

Charles H. Chevalier, Gibbons P.C., Newark, NJ, for plaintiff-appellee Wyeth LLC. Also represented by Jonathon Brugh Lower.

Robert Florence, Parker Poe Adams & Bernstein LLP, Atlanta, GA, argued for defendants-appellants. Also represented by Micheal L. Binns, Karen L. Carroll.

Before Lourie, Reyna, and Hughes, Circuit Judges.

Lourie, Circuit Judge.

Mylan Pharmaceuticals Inc., Mylan Inc., and Mylan Laboratories Ltd. (collectively, "Mylan") appeal from the U.S. District Court for the District of New Jersey’s grant of summary judgment that claim 8 of U.S. Patent 8,552,025 ("the ’025 patent") is not invalid. Valeant Pharm. Int’l, Inc. v. Mylan Pharm., Inc., No. 2:15-cv-08180 (SRC), 2018 WL 2023537 (D.N.J. May 1, 2018) (" Decision "). For the reasons detailed below, we reverse and remand.

BACKGROUND

Valeant owns the ’025 patent, which claims stable methylnaltrexone pharmaceutical preparations. According to the ’025 patent specification, methylnaltrexone, a quitternary amine opioid antagonist derivative, can be useful for reducing the side effects of opioids but is unstable in aqueous solution. The inventors discovered, however, that when the pH of a methylnaltrexone solution is adjusted, optimally to between 3.0 and 3.5, the percentage of total degradants drops significantly. ’025 patent col. 2 l. 39.

The inventors’ preferred manufacturing process for their formulation, as described in Example 2, includes several ingredients acting in concert. Example 2 includes methylnaltrexone, sodium edetate

as a chelating agent, sodium citrate and citric acid as buffering agents, and sodium chloride as an isotonicity agent. Each ingredient in the formulation plays its own role. For example, the buffer stabilizes the formulation’s pH, which can drop during an autoclaving step, and adding isotonicity agents matches the formulation to the osmotic potential of human extracellular fluids. Chelating agents reduce methylnaltrexone degradation on their own, and the addition of disodium edetate in particular yields an additional, synergistic effect in concert with pH manipulation. The specification thus explains that "manipulating other parameters in concert with pH resulted in stable formulations of methylnaltrexone anywhere in a range from a pH of 2.0 to 6.0." ’025 patent col 8. ll. 62-66.

Relevant here are claim 1 and claim 8 of the ’025 patent. Claim 8 depends from claim 1, which recites:

A stable pharmaceutical preparation comprising a solution of methylnaltrexone or a salt thereof, wherein the preparation comprises a pH between about 3.0 and about 4.0.

’025 patent col. 19 ll. 25-27. Claim 8 recites "[t]he pharmaceutical preparation of claim 1, wherein the preparation is stable to storage for 24 months at about room temperature." Id. col. 19 ll. 44-46. Notably, claim 8 recites the same preparation as claim 1, but with a newly stated result: 24-month stability. Given that there are no limitations indicating any difference between the preparation of claim 1 and claim 8, it is unclear what, if anything, accounts for the added stability limitation. Apparently only the nature of methylnaltrexone and the pH matter. And there are no limitations in the claim to bring about the stated stability.

The ’025 patent is listed in the Orange Book for Relistor®, an injectable drug used to treat constipation as a side effect of taking opioid medication. Mylan filed an Abbreviated New Drug Application ("ANDA") seeking approval from the U.S. Food and Drug Administration to market a generic version of Relistor®, and Valeant responded by bringing suit against Mylan in the District of New Jersey, alleging that Mylan’s proposed product would infringe the ’025 patent. As relevant here, Mylan ultimately conceded that its ANDA product would infringe claim 8 of the ’025 patent but maintained that claim 8 was invalid as obvious over solutions of similar anti-opioids.

The parties stipulated to the construction of claim 8’s stability limitation, and the district court did not hold a claim construction hearing. Specifically, the court entered the parties’ stipulation that the phrase "the preparation is stable to storage for 24 months at about room temperature" means "the methylnaltrexone degradation products in the preparation do not exceed 2.0% of the total methylnaltrexone present in the preparation and the preparation is suitable for pharmaceutical use when stored for 24 months at room temperature." Stipulation and Order, Valeant Pharm., Int’l v. Mylan Pharm. Inc., 2:15-cv-08180-SRC-CLW (May 30, 2017), ECF No. 148; J.A. 651.

Before the district court, Valeant moved for summary judgment that claim 8 would not have been obvious, and the district court granted Valeant’s motion. The court rejected Mylan’s expert testimony and cited references as insufficient, largely because the references did not teach methylnaltrexone formulations but instead formulations of similar but different compounds, naloxone

and naltrexone. Decision, 2018 WL 2023537, at *8. The court also rejected Mylan’s theory that the claimed pH range would have been obvious to try. Ultimately, the court held that there was nothing in the record suggesting that a pH of 3-4, "without added stabilizers," was associated with 24-month stability for injectable pharmaceutical solutions. Id. at *10.

Mylan appealed, and we have jurisdiction under 28 U.S.C. § 1295(a)(1).

DISCUSSION

We review a grant of summary judgment under the law of the regional circuit, which in this case is the Third Circuit. See Charles Mach. Works, Inc. v. Vermeer Mfg. Co., 723 F.3d 1376, 1378 (Fed. Cir. 2013) (citing Grober v. Mako Prods., Inc., 686 F.3d 1335, 1344 (Fed. Cir. 2012) ). We exercise plenary review over the district court’s grant of summary judgment, Capps v. Mondelez Glob., LLC, 847 F.3d 144, 151 (3d Cir. 2017) (citing Seamans v. Temple Univ., 744 F.3d 853, 859 (3d Cir. 2014) ), reviewing it de novo, Heraeus Med. GmbH v. Esschem, Inc., 927 F.3d 727, 733 (3d Cir. 2019) (citing Faush v. Tuesday Morning, Inc., 808 F.3d 208, 215 (3d Cir. 2015) ).

Summary judgment is appropriate when the moving party demonstrates that "there is no genuine dispute as to any material fact and the movant is entitled to judgment as a matter of law." Fed. R. Civ. P. 56(a) ; Celotex Corp. v. Catrett, 477 U.S. 317, 322-23, 106 S.Ct. 2548, 91 L.Ed.2d 265 (1986). We construe the evidence in the light most favorable to the nonmovant and draw all reasonable inferences in that party’s favor. Capps, 847 F.3d at 151 (citing Prowel v. Wise Bus. Forms, Inc., 579 F.3d 285, 286 (3d Cir. 2009) ). "Only disputes over facts that might affect the outcome of the suit under the governing law will properly preclude the entry of summary judgment." Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 248, 106 S.Ct. 2505, 91 L.Ed.2d 202 (1986).

The sole issue in this appeal is obviousness. Obviousness is a question of law, supported by underlying fact questions. In re Baxter Int’l, Inc., 678 F.3d 1357, 1361 (Fed. Cir. 2012). In our obviousness analysis, we consider the scope and content of the prior art, differences between the prior art and the claims at issue, the level of ordinary skill in the pertinent art, and any secondary considerations. Graham v. John Deere Co., 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966) ; see also Apple Inc. v. Samsung Elecs. Co., 839 F.3d 1034, 1048 (Fed. Cir. 2016) (en banc) ("Objective indicia of nonobviousness must be considered in every case where present.").

Before the district court, Mylan argued that claim 8 would have been obvious in view of three references teaching formulations of either naloxone

or naltrexone and in view of two treatises on pharmaceutical formulation. We begin by reviewing those references.

The primary reference at issue here is U.S. Patent 5,866,154 ("Bahal"), entitled "Stabilized Naloxone

Formulations" and issued to inventors Surendra Mohan Bahal and Lei-Shu Wu. Bahal teaches stable compositions of naloxone for injection with a pH of 3.0 to 3.5. Similar to the methylnaltrexone formulation described in the ’025 patent, the Bahal solutions comprise an opioid antagonist derivative—in this case, naloxone—an acidic or buffer component, a tonicity-adjusting agent, and a stabilizing agent.

Mylan also relied on Oshlack, U.S. Patent Application Publication 2003/0229111, which describes stable naltrexone

hydrochloride compositions. Oshlack teaches dissolving a "stabilizer" in solution before adding naltrexone hydrochloride. Stabilizers can be organic acids, and, in certain preferred embodiments, the stabilizer is butylated hydroxytoluene or ascorbic acid. Oshlack ¶ 0051. Thereafter, the pH of the solution may be adjusted to about 3 to about 5, but preferably to about 4. Id. ¶ 0054.

The respective structures of methylnaltrexone, naloxone

, and naltrexone are as follows:

Fawcett, a journal article about formulations of naltrexone

for oral administration, describes decomposition studies on naltrexone in solution at 4, 25 and 70 degrees Celsius over 90 days. J. Paul Fawcett et al., Formulation and Stability of Naltrexone Oral Liquid for Rapid Withdrawal from Methadone, 31 ANNALS OF PHARMACOTHERAPY , 1291-95 (1997). At 25 degrees, decomposition was not significant, but at 70 degrees, the color of the...