Naloxone - USA

On Jun. 22, 2020 in an unsealed opinion New Jersey court found Narcan® patents invalid as obvious over prior disclosure of claimed elements.

Adapt pharma / Opiant pharma (Plaintiffs) owns NDA for Narcan® (Naloxone, 4mg) Nasal Spray which was approved by USFDA on Nov. 18, 2015. Narcan is a branded nasal spray used to treat patients suffering from an opioid overdose. Teva (Defendant) filed ANDA with P-IV certification to market generic version of the drug. Plaintiffs sued Teva for infringement of patents, US 9,468,747 US 9,561,177, US 9,629,965 and US 9,775,838. Teva stipulated to infringement but asserted that patents-in-suit are invalid under obviousness. The Court held a two-week bench trial beginning on Aug. 26, 2019, and concluding on Sep. 6, 2019.

The asserted claims in the Patents-in-Suit relate generally to the pharmaceutical compounds, delivery methods, and devices used with Narcan. The compound consists of about 4.4mg of naloxone hydrochloride dihydrate, between about 0.005mg and about 0.015mg of benzalkonium chloride (“BZK”), between about 0.1mg and about 0.5mg of disodium edetate (“EDTA”), between about 0.2mg and about 1.2mg of sodium chloride, and an amount of acid sufficient to sustain a pH balance of 3.5–5.5 in about 100 microliters of solution. That solution is delivered into a single nostril of a patient by the Aptar Unit-Dose device.

Before the priority date of the patents certain things were known such dose of naloxone, excipients, device etc in different prior arts. The Court found the asserted claims of the Patents-in-Suit are obvious in light of the references such as Strang / Kulkarni / Djupesland combination. Strang discloses an intranasal form of naloxone formulated for the treatment of opioid overdoses. Strang noted that the volume of liquid delivered to the nostril should be less than 250 microliters and specifically preferred volumes of 50, 100, 150, and 200 microliters. The device described by Djupesland is filled with 125 microliters of solution and administers a dose consisting of 100 microliters of fluid, which is delivered in a single actuation. Strang states that “[i]t can be preferred to start with an amount equivalent to 4mg” of naloxone. Strang estimated that an intranasal dose of 3mg to 4mg would be bioequivalent to the FDA-approved 1mg injectable dose. As to the pH of the formulation, Strang prefers a pH that is less than or equal to 5.5, and Strang and Kulkarni specifically discuss using hydrochloric acid as an agent. As to the use of BZK as a preservative, Strang generally describes typical pharmaceutical excipients used in intranasal formulations. Kulkarni discusses specific preservatives that can be used to stabilize a nasal formulation in more detail and discloses a range of BZK with an upper limit of 0.119%. As to the use of EDTA, Kulkarni states a concentration of 0.5% of EDTA and describes using hydrochloric acid to adjust the pH of the formulation.

Alternatively, the Court found the asserted claims of the Patents-in-Suit are obvious in light of the Davies / Kerr 2009, Kerr Formulation / Bahal combination. Davies discusses formulations and devices that can be used to treat opioid overdoses and states that while intravenous administration is the standard method of administering naloxone, it poses significant difficulties in the community setting where naloxone is likely to be administered by individuals lacking medical training. It teaches that intranasal naloxone “can be given quickly and effectively without the need for the first-aider to find a blood vessel and give an intravenous injection.” As to the dose of naloxone, Davies describes a range of 0.2mg to 5.0mg as being appropriate. As to a tonicity agent, the Kerr Formulation used sodium chloride. Both Davies and Kerr discuss a sodium chloride concentration between 0.2 to 1.2mg per 100 microliters of solution. Bahal preferred formulations that included sodium chloride as a tonicity agent and hydrochloric acid to adjust the pH of the solution. The Kerr Formulation used BZK. Davies also states that formulation should have a slightly acidic pH and uses BZK as a preservative in one of his formulations. Bahal stated that the “addition of a chelating agent, such as [EDTA], to the commercial formulation prevents naloxone degradation, even in the presence of oxygen and after autoclaving.” Bahal preferred a range of 0.0001% to 1.0%.

Intranasal Naloxone Was Known to Be Safe and Efficacious, and Was Widely Used Prior to March 16, 2015:

Court said that intranasal naloxone was known to be safe and efficacious, and was widely used before priority date of the invention. Naloxone was initially approved for the treatment of opioid overdoses in 1971 as an injection. It was known to be “an extremely safe drug” and it was known in the prior art that naloxone could be administered intranasally. Intranasal administration was popular in the community setting because it was needle-free and therefore did not pose the dangers associated with exposed needles that injectable naloxone did. To administer naloxone intranasally, individuals utilized a MAD Kit which consisted of a mucosal atomizer and a syringe of naloxone solution that had to be assembled prior to use. The MAD Kit was FDA-approved to deliver injectable formulations intranasally. When used to administer naloxone, the MAD Kit had numerous drawbacks which were well known to a POSA. Therefore, POSA would have looked to another device. The Aptar UnitDose Device used in Narcan® is an FDA-approved device that administers intranasal medications in 100 or 200 microliter volumes. The Aptar device was commercially available prior to March 16, 2015, and was not invented by the inventors of the Patents-in-Suit. The shortcomings of the MAD Kit were discussed at the 2012 FDA Meeting, with one physician noting that the administration of naloxone “could be improved with a one-step affordable FDA-approved intranasal delivery device.” A POSA, therefore, would have been motivated to select a Aptar device that was as easy to use.

The Prior Art Does Not Teach Away from a Higher Dose of Naloxone or Using BZK With Naloxone:

Court said that a POSA would have thought a 4 milligram intranasal dose was safe and would have preferred a higher initial dose of naloxone in the community setting. The prior art indicated that naloxone could be administered safely in a doses of 0.5mg to 20mg. Among the initial doses recommended by Strang was an initial dose of 4mg. When FDA conducted meeting in 2012 the purpose was “to promote or encourage the industry to develop an intranasal naloxone product that could be FDA-approved.” The FDA noted that they were not overly concerned about the safety implications of a higher dose of naloxone because it is known to be a relatively safe drug. Prior to March 2015, a POSA would have known that naloxone has a lower bioavailability when administered intranasally compared to when it is administered in an injectable dose because an intranasal dose must first be absorbed through the nasal mucosa prior to be absorbed into the bloodstream. Intranasal naloxone, therefore, requires a higher dose of naloxone to achieve the same bioavailability as an intravenous dose. Prior to March 2015, a POSA would have known that a layperson using a MAD Kit to administer a 2mg dose of intranasal naloxone had to re-dose nearly half of the time (noting that 48% of cases in the study required a second 2mg dose of naloxone). Also the 4mg intranasal doses of naloxone were administered via a MAD Kit to reverse the effects of higher potency opioids. Moreover, a POSA would have known that the benefits of a higher initial dose outweighed the concerns about withdrawal side effects.

The Inclusion of BZK, EDTA, Hydrochloric Acid, and Sodium Chloride was obvious:

Court said that a POSA who was developing an intranasal naloxone product would have been motivated to optimize prior MAD Kit formulation for nasal delivery. Strang noted that “[t]ypical pharmaceutical excipients used in intranasal formulations are known to the skilled person and can be used for the formulations according to the present invention. Adapt argued the prior art, particularly Wyse, taught away from using BZK as a preservative in intranasal naloxone formulations and, therefore, a POSA would have not have been motivated to select it for their formulation. Court, however, found this argument unconvincing. Court said that the concentration of BZK used by Wyse was significantly higher than the amount used in every other FDA-approved intranasal product. Wyse used a formulation containing a 0.125% concentration of BZK, which is 8.5 times higher than the concentration used in the Patents-in-Suit. A POSA would have understood from Wyse that high concentrations of BZK can cause naloxone to degrade but would not have been dissuaded from using BZK in naloxone formulations in a lower dose. Therefore, in light of the testimony given at trial and the exhibits entered into evidence, the Court found by clear and convincing evidence, that before the priority date of the Patents-in-Suit, a POSA would have optimized naloxone for intranasal administration and found it obvious to use sodium chloride, hydrochloric acid, BZK, and EDTA. Thus, a POSA would have been motivated to combine strang / kulkarni / djupesland and davies / kerr 2009, kerr formulation / bahal and would have had a reasonable expectation of success.

Finally, Court also found that Plaintiffs failed to show any secondary considerations of nonobviousness to support patentability sufficient to overcome teva’s prima facie showing of obviousness.