Adapt Pharma Operations Ltd. v. Teva Pharm. United States, Inc.

• Decision Date: 10 February 2022
• Docket Number: 2020-2106
• Citation: 25 F.4th 1354
• Parties: ADAPT PHARMA OPERATIONS LIMITED, Adapt Pharma, Inc., Adapt Pharma Limited, Opiant Pharmaceuticals, Inc., Plaintiffs-Appellants v. TEVA PHARMACEUTICALS USA, INC., Teva Pharmaceuticals Industries, Ltd., Defendants-Appellees
• Court: U.S. Court of Appeals — Federal Circuit

25 F.4th 1354

ADAPT PHARMA OPERATIONS LIMITED, Adapt Pharma, Inc., Adapt Pharma Limited, Opiant Pharmaceuticals, Inc., Plaintiffs-Appellants

v.TEVA PHARMACEUTICALS USA, INC., Teva Pharmaceuticals Industries, Ltd., Defendants-Appellees

2020-2106

United States Court of Appeals, Federal Circuit.

Decided: February 10, 2022

Catherine Emily Stetson, Hogan Lovells US LLP, Washington, DC, argued for all plaintiffs-appellants. Plaintiffs-appellants Adapt Pharma Operations Limited, Adapt Pharma, Inc., Adapt Pharma Limited also represented by Jessamyn Sheli Berniker, David M. Krinsky, Jessica Palmer Ryen, Williams & Connolly LLP, Washington, DC.

Jessica Tyrus Mackay, Green, Griffith & Borg-Breen LLP, Chicago, IL, for plaintiff-appellant Opiant Pharmaceuticals, Inc.

John Christopher Rozendaal, Sterne Kessler Goldstein & Fox, PLLC, Washington, DC, argued for defendants-appellees. Also represented by Paul Ashley Ainsworth, Michael E. Joffre, Adam LaRock, William Milliken, Chandrika Vira ; Liza M. Walsh, Walsh Pizzi O'Reilly Falanga LLP, Newark, NJ.

Before Newman, Prost, and Stoll, Circuit Judges.

Dissenting opinion filed by Circuit Judge Newman.

Stoll, Circuit Judge.

Adapt Pharma Operations Limited, Adapt Pharma, Inc., Adapt Pharma Limited, and Opiant Pharmaceuticals, Inc. (collectively, "Adapt") appeal the United States District Court for the District of New Jersey's final judgment of invalidity. After a two-week bench trial, the district court determined that the asserted claims of U.S. Patent Nos. 9,468,747 ; 9,561,177 ; 9,629,965 ; and 9,775,838 (collectively, the "patents-in-suit") would have been obvious in view of the prior art. For the reasons below, we conclude that the district court did not err in its obviousness determination and therefore affirm.

BACKGROUND

I

The patents-in-suit claim methods of treating opioid overdose by intranasal administration

of a naloxone formulation, as well as devices for intranasal administration. Naloxone—the active ingredient in Adapt's NARCAN ® Nasal Spray—is an opioid receptor antagonist that blocks opioids from reaching the opioid receptors, thus helping reverse the effects of opioid overdose. '747 patent col. 2 ll. 13–15.¹

The use of naloxone

to treat opioid overdose was not a new concept at the time of the invention. Before the priority date of the patents-in-suit, numerous naloxone products had been used to treat opioid overdose. For example, the specification explains that naloxone "approved for use by injection" was an option for treating opioid overdose. Id. It was also known in the prior art to administer naloxone intranasally. For example, before the priority date, naloxone was administered intranasally by "combin[ing] an FDA-approved naloxone injection product with a marketed[ ] medical device called the Mucosal Atomization Device." Id. at col. 6 ll. 46–51. This device, which the parties and the district court refer to as the MAD Kit, allows a liquid formulation to be sprayed into the nostrils. The specification also describes a number of prior art studies that administered 2 mg of naloxone intranasally to overdose victims, id. at col. 3 l. 1–col. 4 l. 26, col. 5 ll. 29–54 (citations omitted), and another that administered 8 mg and 16 mg of naloxone intranasally, id. at col. 5 l. 55–col. 6 l. 3 (citing PCT Pub. No. WO 2012/156317).

Administering naloxone

by injection or using the MAD Kit was not without disadvantages. For example, the specification explains that only trained medical personnel can administer naloxone by injection (either intramuscularly, which is an injection in the muscle, or intravenously, which is an injection in the vein), id. at col. 6 ll. 14–35, preventing many first responders from administering naloxone to overdose

victims. And while the MAD Kit provided first responders with a mechanism to quickly administer naloxone intranasally, it too had disadvantages in that it required assembly prior to use and delivered too much fluid into the nose.

On April 12, 2012, amidst the growing opioid addiction crisis, the U.S. Food & Drug Administration (FDA) held a public meeting to "promote and encourage the industry to develop an intranasal naloxone

product that could be FDA-approved." J.A. 3859–60 (Trial Tr. 336:16–337:3). At this meeting, the FDA explained that any intranasal naloxone formulation should provide exposure at least comparable to already-approved injectable naloxone products. That is, the intranasal formulation should deliver the same amount of drug to the bloodstream as the injectable formulations. Shortly thereafter, on May 24, 2012, Lightlake Therapeutics, Inc.—Opiant's predecessor—met with the FDA to discuss a potential investigational new drug application. Although Lightlake expressed its view that there was "little if any commercial incentive" to develop an intranasal product, J.A. 3824 (Trial Tr. 301:3–17), it nevertheless sought input from the FDA on its plans to develop a 2 mg intranasal naloxone formulation, relying on an approved 2 mg intramuscular naloxone formulation as a reference formulation. In response, the FDA explained that numerous studies indicated that a 2 mg intranasal dose would have poor bioavailability compared to a 2 mg intramuscular dose and therefore recommended that Lightlake increase the dose of its proposed product to achieve bioavailability similar to the intramuscular product. Lightlake did just that, ultimately submitting New Drug Application (NDA) No. 208411 for a 4 mg intranasal naloxone product, approved under the name NARCAN ®.²

On March 16, 2015, Adapt filed U.S. Patent Application No. 14/659,472, from which each of the patents-in-suit claim priority. All of the patents-in-suit are listed in the FDA's publication "Approved Drug Products with Therapeutic Equivalence Evaluations," commonly known as the Orange Book, as covering NARCAN

®. At trial, the district court treated dependent claim 9 of the '747 patent as representative, which includes claims 1 and 2 in its dependency. Because the issues on appeal relate to the formulation limitations of the asserted claims, which are recited in claims 1 and 2, we reproduce only those claims below:

1. A method of treatment of opioid overdose or a symptom thereof, comprising nasally administering to a patient in need thereof a dose of naloxone

hydrochloride using a single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, having a single reservoir comprising a pharmaceutical composition which is an aqueous solution of about 100 µL comprising:

about 4 mg naloxone hydrochloride or a hydrate thereof;

between about 0.2 mg and about 1.2 mg of an isotonicity agent;

between about 0.005 mg and about 0.015 mg of a compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer;

between about 0.1 mg and about 0.5 mg of a stabilizing agent; and

an amount of an acid sufficient to achieve a pH of 3.5-5.5.

2. The method as recited in claim 1 wherein:

the isotonicity agent is NaCl;

the preservative is benzalkonium chloride

;

the stabilizing agent is disodium edetate ; and

the acid is hydrochloric acid.

'747 patent col. 53 ll. 8–29.

II

Teva Pharmaceuticals USA, Inc. and Teva Pharmaceuticals Industries, Ltd. (collectively, "Teva") asserted two different combinations of prior art at trial: (1) Davies³ in view of Kerr 2009⁴ /the Kerr Formulation and Bahal⁵ (the "Davies combination"); and (2) Strang⁶ in view of Kulkarni⁷ and Djupesland⁸ (the "Strang combination"). We discuss each combination and reference in turn.

A

The first combination involves Davies, Kerr 2009/the Kerr Formulation, and Bahal. Davies relates to spray applicators for administering naloxone

and formulations of naloxone for nasal administration. Davies, Abstract. Specifically, Davies "provide[s] systems of administering an opioid antagonist," such as naloxone, "which can be carried out by an unskilled person, rapidly and with a good chance of successfully reviving a patient suffering from opioid over-dosage." Id. at 1. Davies provides a detailed description and drawings of a spray applicator that can be used for intranasal administration. See id. at 4–5 & Figs. 1–2. Davies teaches that naloxone, the "preferred opioid antagonist," is preferably administered "as a sprayable liquid composition." Id. at 2. Davies also teaches that naloxone is "freely soluble in water ... when in the form of a salt, such as a hydrochloride," and so it therefore may be dissolved in dilute saline solutions such as a solution containing about 0.9% w/v sodium chloride. Id. Davies explains that the formulation should be slightly acidic (e.g., pH 6.5), to maintain the naloxone in its salt form. Id. at 2, 4. Additionally, Davies teaches that a suitable dose of naloxone for nasal administration ranges from 0.2 to 5 mg, with the volume for administration ranging from 20 to 100 µL. Id. at 3. One exemplary naloxone formulation in Davies includes benzalkonium chloride (BZK) as a preservative in an amount of 0.025% w/v. Id. Example 1.

Kerr 2009 recognized the benefits of administering naloxone

intranasally, noting that intranasal administration is one way to reduce the risk of accidental and unintended needlesticks often associated with injections. Kerr 2009 at 2067–68, 2072. Kerr conducted a study aimed at "determin[ing] the effectiveness and safety of concentrated (2 mg/m[L]) i.n. [intranasal] naloxone compared to i.m. [intramuscular] naloxone for treatment of suspected opiate overdose." Id. at 2068. Although the formulation Kerr used in their study (the "Kerr Formulation") was not disclosed in the reference itself, the evidence and testimony at trial established that the formulation Kerr used was purchased from a third party, ORION Laboratories Pty. Ltd., and is therefore prior art to the patents-in-suit. This is not disputed on appeal. This formulation comprised 0.2% naloxone

hydrochloride (HCl) (i.e., 2 mg/mL naloxone HCl),...