Buprenorphine & Naloxone - USA

On March 22, 2018, the District Court of Delaware issued an opinion in favor of Alvogen finding non-infringement of patents related to Suboxone® sublingual film.

Alvogen filed Abbreviated New Drug Application ("ANDA") No. 205954, seeking approval for a generic version of the 2 mg/0.5 mg, 4 mg/I mg, 8 mg/2 mg, and 12 mg/3 mg dosage strengths of Plaintiffs' Suboxone® sublingual film. Suboxone® sublingual film is indicated for maintenance treatment of opioid dependence. The Court held a bench trial September 26-27, 2017. At issue in this case is the process for drying the sublingual film. Plaintiffs asserted that Alvogen's ANDA submission constitutes infringement of claim 24 of U.S. Patent No. 8,900,497 ("the '497 patent"), and claims 62, 63, 65, 69, 71, and 73 of U.S. Patent No. 8,603,514 ("the '514 patent). Alvogen did not argue that the asserted claims are invalid.

Independent claim 1 of the '497 patent reads:

1. A process for making a film having a substantially uniform distribution of components, comprising the steps of:

(a) forming a flowable polymer matrix comprising an edible polymer, a solvent and a desired amount of at least one active, said matrix having a substantially uniform distribution of said at least one active;

(b) casting said flowable polymer matrix;

(c) rapidly evaporating at least a portion of said solvent upon initiation of drying to form a visco-elastic film within about the first 4.0 minutes to maintain said substantially uniform distribution of said at least one active by locking-in or substantially preventing migration of said at least one active within said visco-e/astic film;

(d) further drying said visco-elastic film to form a self-supporting edible film having a substantially uniform distribution of said at least one active component; and wherein said substantially uniform distribution of said at least one active component is measured by substantially equally sized individual unit doses which do not vary by more than 10% of said desired amount of said at least one active.

Independent claim 62 of the '514 patent reads:

62. A drug delivery composition comprising:

(i) a cast film comprising a flowable water-soluble or water swellable film-forming matrix comprising one or more substantially water soluble or water swellable polymers; and a desired amount of at least one active; wherein said matrix has a viscosity sufficient to aid in substantially maintaining non-self-aggregating uniformity of the active in the matrix;

(ii) a particulate active substantially uniformly stationed in the matrix; and

(iii) a taste-masking agent selected from the group consisting of flavors, sweeteners, flavor enhancers, and combinations thereof to provide tastemasking of the active; wherein the particulate active has a particle size of 200 microns or less and said flowable water-soluble or water swellable film-forming matrix is capable of being dried without loss of substantial uniformity in the stationing of said particulate active therein; and wherein the uniformity subsequent to casting and drying of the matrix is measured by substantially equally sized individual unit doses which do not vary by more than 10% of said desired amount of said at least one active.

At trial, the parties stipulated that Alvogen infringes all limitations of the asserted claims except (1) the "dried" limitation of the '514 patent and "drying" limitation of the '497 patent, and (2) the "visco-elastic film" limitation of the '497 patent.

"Dried"/"drying:

The Court construed the "dried" limitation of the '514 patent and "drying" limitation of the '497 patent to mean "dried without solely employing conventional convection air drying from the top." Plaintiffs argued that Alvogen's ANDA process does not employ "conventional convection air drying" as its drying process is "extremely unusual. Second, Plaintiffs argued that Alvogen's films are "substantially dried from the bottom," and therefore are not dried "solely ... from the top." Alvogen argued that it has converted the S-Coater into a conventional top-down impingement dryer by disabling the bottom-sourced air and removing the fuses. With the bottom-sourced air having been disabled, Alvogen's dryer supplies hot air solely from nozzles above the web.

Court said that construction for the "dried"/"drying" limitation makes clear that it refers to drying technique, as opposed to drying equipment. It found Dr. Carvalho's (Alvogen's expert) testimony that Alvogen uses a modified flotation dryer to carry out a "conventional" technique more convincing. Also if Alvogen's technique actually does avoid the rippling effect, which the parties dispute, that alone cannot render the technique unconventional. Lowering oven temperature and slowing drying speed were conventional controls for preventing the rippling effect and other defects in at least some films. Alvogen's parameter control techniques were sensible and well-known for use in films generally. As a result, the techniques were conventional for use in "pharmaceutical films."

As to Plaintiffs' argument that Alvogen's films are "substantially dried from the bottom" and therefore do not "solely employ conventional convection air drying from the top," Plaintiffs point to three sources of bottom heat: (1) drag bars, (2) contact between the web and lower plenum of the dryer, and (3) air flow underneath the web. Court however, agreed with Alvogen that any bottom drying during its ANDA process is at most an insubstantial amount. Any dryer that "solely" employs "conventional convection air drying from the top" will result in some drying from the bottom. Accordingly, Plaintiffs have not demonstrated "substantial" bottom drying such that Alvogen's dryer can be said to employ anything but "conventional convection air drying from the top." Therefore for these reasons, court found that Plaintiffs have not met their burden of proving by a preponderance of the evidence that Alvogen's ANDA products and process meet the "dried" /" drying" limitation, and therefore have not proven that Alvogen infringes any of the patents.

"Visco-Elastic Film":

The Court construed the phrase "to maintain said substantially uniform distribution of said at least one active by locking-in or substantially preventing migration of said at least one active" to mean "to maintain a distribution of [an active/a pharmaceutical active] by drying to form a viscoelastic solid film, thereby limiting its migration such that individual dosage units do not vary by more than 10% from the intended amount of the active for that dosage unit." Thus, the "visco-elastic film" limitation requires "form[ing] a viscoelastic solid film."

Alvogen affirmatively argued that "visual evidence confirms that Alvogen's mix remains a liquid after four minutes of drying." Plaintiffs argued that the material is not a liquid, but rather a viscoelastic solid that has been fluidized. Court found that the temperature difference indicates that Dr. Fassihi's measured viscosities differ at least somewhat from the ANDA product's actual viscosity after four minutes of drying. This further diminishes the weight of Dr. Prud'homme's slope calculations, which rely on Dr. Fassihi's viscosity measurements. Plaintiffs have therefore failed to meet their burden of proving infringement of this limitation by a preponderance of the evidence.