Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.

1. Case Identification

• Case #: IPR2019-00692
• Patent #: 9,561,177
• Filed: February 19, 2019
• Petitioner(s): NALOX-1 PHARMACEUTICALS, LLC
• Patent Owner(s): ADAPT PHARMA LTD, OPIANT PHARMACEUTICALS, INC.
• Challenged Claims: 1-30

2. Patent Overview

• Title: Nasal Drug Products and Methods of Their Use
• Brief Description: The ’177 patent describes pharmaceutical compositions for intranasal delivery of naloxone to treat opioid overdose. The claims are directed to methods of treatment, specific formulations containing naloxone and excipients like benzalkonium chloride (BAC), and the resulting spray/mist characteristics from a pre-primed device.

3. Grounds for Unpatentability

Ground 1: Obviousness of Claims 1-2 over Wang in view of HPE and Djupesland

• Prior Art Relied Upon: Wang (Chinese Patent No. 1,575,795), HPE (Handbook of Pharmaceutical Excipients, 6th ed., 2009), and Djupesland (a 2013 journal article on nasal drug delivery devices).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner asserted that Wang taught the core elements of independent claim 1: a method of treating opioid overdose with an intranasal naloxone formulation. Wang disclosed a dose range of 0.1-10 mg (encompassing the claimed 4 mg), the use of preservatives like BAC, and an isotonicity agent, all delivered in a nasal spray. Djupesland was cited to teach the use of single-dose, pre-primed nasal spray devices (like the Aptar device) suitable for emergency use, which inherently deliver a set volume (e.g., 100 µL) upon actuation. HPE was cited as a standard reference a Person of Ordinary Skill in the Art (POSA) would consult for common excipient concentrations, including for BAC.
  • Motivation to Combine: A POSA would combine Wang's formulation with Djupesland's device because Wang taught its composition was suitable for single-dose forms, and Djupesland taught that pre-primed, single-use devices are ideal for acute conditions like opioid overdose. A POSA would consult HPE as a matter of routine practice to optimize the concentration of known excipients like BAC for a nasal spray.
  • Expectation of Success: Petitioner argued success would be expected because it involved combining known naloxone formulations with standard, commercially available spray devices and well-understood excipients to achieve a predictable result.

Ground 2: Obviousness of Claims 3-8 over Wang in view of HPE, Djupesland, Bahal, and Kushwaha

• Prior Art Relied Upon: Wang, HPE, Djupesland, Bahal (Patent 5,866,154), and Kushwaha (a 2011 journal article on nasal drug delivery).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground built upon Ground 1 to address dependent claims requiring a stabilizing agent (disodium edetate) and a specific pH range. Petitioner argued Wang disclosed sodium edetate as a potential preservative. Bahal was cited for expressly teaching the use of disodium edetate to stabilize naloxone against oxidative degradation in solution formulations. Kushwaha was cited for teaching that EDTA (functionally equivalent to disodium edetate) acts as a permeation enhancer, which Wang explicitly taught should be included. For the pH limitation, Wang disclosed adjusting the solution to a pH of 3.8 ± 0.8, which overlaps with the claimed range of 3.5 to 5.5.
  • Motivation to Combine: A POSA, seeking to ensure the stability of the naloxone formulation from Wang, would have been motivated to add a known stabilizer. Bahal provided the express teaching to use disodium edetate for this purpose with naloxone. A POSA would also incorporate a permeation enhancer as suggested by Wang, and Kushwaha identified EDTA as a suitable candidate.
  • Expectation of Success: Success was expected because Bahal demonstrated the stabilizing effect of disodium edetate on naloxone. Using a known stabilizer and pH adjustment to optimize a known formulation was considered a routine and predictable development step.

Ground 5: Obviousness of Claims 12-15 & 21 over Wang in view of HPE, Djupesland, and the ’291 Patent

• Prior Art Relied Upon: Wang, HPE, Djupesland, and the ’291 patent (Patent 8,198,291).

• Core Argument for this Ground:

  • Prior Art Mapping: This ground targeted independent claim 12, which recited a "mist" with specific droplet size distribution characteristics. Petitioner argued that the composition elements were obvious for the reasons stated in Ground 1. The key additional reference, the ’291 patent, was introduced to teach the claimed droplet size parameters. The ’291 patent described an intranasal butorphanol formulation delivered from a Pfeiffer device (similar to the Aptar device in Djupesland) and disclosed specific volume-weighted droplet distributions (Dv10, Dv50, Dv90) and plume ovality ratios that met the limitations of claims 12 and 15.
  • Motivation to Combine: A POSA developing the intranasal naloxone of Wang for use in a device from Djupesland would have been motivated to consult a reference like the ’291 patent, which characterized the spray properties of a similar formulation from a nearly identical device. The goal was to ensure proper nasal deposition, which is a function of droplet size and plume shape.
  • Expectation of Success: Petitioner asserted a high expectation of success because the formulations in Wang and the ’291 patent were both aqueous solutions lacking viscosity-altering agents. Therefore, a POSA would reasonably expect them to produce nearly identical spray characteristics when delivered from the same type of device.

• Additional Grounds: Petitioner asserted numerous other obviousness challenges against all 30 claims, including combinations incorporating Wyse (Patent 9,192,570) for its teachings on naloxone bioavailability and pharmacokinetic profiles, and Zomig Review (an FDA review document) for its detailed disclosure of the components of an Aptar nasal spray device.

4. Key Claim Construction Positions

• Droplet Size Terms: Petitioner argued that terms like "no more than about [x]% of the droplets have a diameter less than 10 µm" should be construed as referring to volume-weighted distributions (e.g., Dv10). This was based on the ’177 patent’s consistent use of volume-weighted measurements (Dv10, Dv50, Dv90) when discussing droplet size.
• Pharmacokinetic Terms: For terms like "geometric mean naloxone Cmax," Petitioner identified an ambiguity. While the claim language used the singular "the patient," the term "geometric mean" implied a calculation across a population of subjects. Petitioner stated it would analyze the claims under both possible constructions. A similar ambiguity was noted for the term "bioavailable."

5. Key Technical Contentions (Beyond Claim Construction)

• Priority Date Challenge: A central contention was that the ’177 patent was not entitled to its claimed priority date of March 14, 2014, from the ’379 provisional application. Petitioner argued the ’379 provisional failed to provide adequate written description for the claimed concentration range of the preservative benzalkonium chloride (0.005% to 0.015%). Therefore, Petitioner asserted the patent’s effective priority date was no earlier than March 16, 2015, which rendered additional references like Wyse available as prior art.

6. Arguments Regarding Discretionary Denial

• Petitioner argued against discretionary denial under §325(d), which allows the Board to reject a petition if the same or substantially the same prior art or arguments were previously presented to the Office. Petitioner contended that while the primary reference, Wang, was listed in an Information Disclosure Statement during prosecution, it was only provided as a machine translation and was never substantively analyzed or relied upon by the Examiner in any rejection. Thus, the merits of Wang had not been properly considered by the USPTO.

7. Relief Requested

• Petitioner requested institution of an inter partes review and cancellation of claims 1-30 of Patent 9,561,177 as unpatentable under 35 U.S.C. §103.