PTAB

IPR2019-00691

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

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1. Case Identification

2. Patent Overview

  • Title: Nasal Drug Products and Methods of Their Use
  • Brief Description: The ’177 patent discloses pharmaceutical compositions for intranasal delivery of naloxone to treat opioid overdose. The claims are directed to methods of treatment, pharmaceutical solutions, and delivery devices containing specific formulations of naloxone hydrochloride, a preservative (benzalkonium chloride or BAC), an isotonicity agent, and other excipients, delivered in a pre-primed, single-dose nasal sprayer.

3. Grounds for Unpatentability

Ground 1: Obviousness over Wyse and HPE - Claims 1-5 and 10-11 are obvious over Wyse in view of HPE.

  • Prior Art Relied Upon: Wyse (Patent 9,192,570) and HPE (Handbook of Pharmaceutical Excipients, 6th Ed., 2009).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Wyse taught all key elements of independent claim 1 except for the specific preservative. Wyse disclosed concentrated intranasal naloxone formulations (5-50 mg/mL) delivered in a 100 µL spray from a single-use device (the Aptar device), rendering the claimed "about 4 mg" dose obvious as it falls within this range. Wyse also taught the use of an isotonicity agent (sodium chloride), a stabilizing agent (disodium edetate), and an acid to adjust pH, as recited in dependent claims. The key dispute during prosecution was the use of BAC as a preservative. Petitioner contended that while the Examiner found Wyse taught away from using BAC, HPE—a standard pharmaceutical compendium—disclosed that BAC is a common and effective preservative for nasal sprays, typically used in a concentration range (0.002-0.02% w/v) that squarely covers the claimed range of 0.005-0.015%.
    • Motivation to Combine: A person of ordinary skill in the art (POSA), specifically a formulator, seeking to develop the naloxone formulation taught by Wyse would have consulted a standard reference like HPE to select a suitable antimicrobial preservative. HPE's disclosure of BAC as a well-known, safe, and effective preservative for nasal sprays would provide a clear motivation to include it in Wyse's formulation.
    • Expectation of Success: A POSA would have a reasonable expectation of success in combining Wyse and HPE. BAC is listed in the FDA's inactive ingredient database, is known to be compatible with nasal administration, and HPE provides established concentration ranges, making its inclusion a routine and predictable formulation step.

Ground 2: Obviousness over Wyse, HPE, and the '291 patent - Claims 12-27 and 29 are obvious over Wyse in view of HPE and the '291 patent.

  • Prior Art Relied Upon: Wyse (Patent 9,192,570), HPE, and the ’291 patent (Patent 8,198,291).

  • Core Argument for this Ground:

    • Prior Art Mapping: This ground built upon the combination of Wyse and HPE to address limitations in independent claims 12 and 22 related to specific mist and spray characteristics, such as droplet size distribution and spray plume geometry. Petitioner asserted that the '291 patent, which disclosed an intranasal butorphanol formulation delivered from a similar Pfeiffer Unitdose device, taught the claimed droplet size limitations (e.g., "no more than about 10% of the droplets have a diameter less than 10 µm" and a median droplet size between 30-100 µm). The '291 patent also disclosed a round spray plume with an ovality ratio less than 2.0, as claimed.
    • Motivation to Combine: A POSA would combine these references because Wyse and the ’291 patent both described intranasal opioid compositions delivered from similar single-use devices. A POSA would have expected that two different formulations with similar, low-viscosity characteristics, when emitted from the same type of device, would have roughly the same droplet size and spray characteristics.
    • Expectation of Success: The expectation of success was high, as modifying the Wyse/HPE formulation to achieve the spray characteristics of the ’291 patent would have been a matter of routine optimization. Since neither the Wyse formulation nor the claimed formulation contained viscosity-altering agents, a POSA would reasonably expect the spray performance to be consistent with that disclosed in the ’291 patent for a similar device.

  • Additional Grounds: Petitioner asserted additional obviousness challenges, including grounds that added Djupesland (a 2013 journal article) to the Wyse/HPE combination to teach specific device features like a single 125 µL reservoir (Claims 6-9). Other grounds combined Wyse, HPE, the ’291 patent, and further references like Wang (Chinese Patent 1,575,795) or Zomig Review (a 2002 FDA review document) to address the remaining dependent claims 28 and 30.

4. Key Claim Construction Positions

  • Droplet Size Limitations: Petitioner argued that claim 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, Dv50, Dv90), as this is the only type of droplet size measurement consistently referenced in the ’177 patent's specification.
  • Pharmacokinetic (PK) Terms: For terms like "geometric mean naloxone Cmax" (Claims 10 and 22), Petitioner argued the claims were ambiguous. The use of "the patient" (singular) implied a single-subject measurement, while "geometric mean" implied a measurement across a population. Petitioner asserted the claims were obvious under either construction.
  • "bioavailable": For claim 16's recitation that "the naloxone is at least 40% bioavailable," Petitioner noted the term was not defined and could refer to absolute or relative bioavailability. Petitioner argued the claim was obvious under either interpretation.

5. Key Technical Contentions (Beyond Claim Construction)

  • Lack of Priority: Petitioner contended that the ’177 patent was not entitled to its claimed priority date of March 14, 2014, from the ’379 provisional application. The provisional application allegedly failed to provide written description support for the claimed BAC concentration range of 0.005% to 0.015%. Therefore, Petitioner argued the patent’s effective filing date was no earlier than March 16, 2015, which made certain publications, like Wyse, available as prior art under §102(a)(2).

6. Arguments Regarding Discretionary Denial

  • Petitioner argued that the Board should not exercise its discretion to deny institution under §325(d). The petition asserted that the grounds were not the "same or substantially the same" as those considered during prosecution because the core combination of Wyse in view of HPE was never evaluated. Petitioner contended the Examiner made a clear error in concluding that Wyse taught away from using BAC, an error that the new evidence from HPE and expert testimony corrected.

7. Relief Requested

  • Petitioner requested the institution of an inter partes review and the cancellation of claims 1-30 of the '177 patent as unpatentable under 35 U.S.C. §103.