Buprenorphine & Naloxone - USA

On Aug. 31, 2017, Judge Richard G. Andrews of District of Delaware ruled that patents related to SUBOXONE (Buprenorphine & Naloxone) film are valid & not infringed by Defendants.

Plaintiffs Reckitt Benckiser Pharmaceuticals and MonoSol Rx, LLC (collectively, "Plaintiffs") brought this suit against Dr. Reddy's Laboratories; Watson Laboratories, Inc.; Par Pharmaceutical, Inc. and IntelGenx Technologies Corporation (collectively, "Defendants") with respect to U.S. Patent Nos. 8,603,514 ('"the '514 patent"); 8,900,497 ("the '497 patent") and 8,017,150 (the "'150 patent").

The '514 patent relates to Uniform Films for Rapid Dissolve Dosage Form Incorporating I Taste-Masking Compositions. The '497 patent relates to Process for Making a Film Having a Substantially Uniform Distribution of Components. The '150 patent relates to Polyethylene Oxide-Based Films and Drug Delivery Systems Made Therefrom.

Infringement:

Dried / Drying:

DRL argued that it does not infringe the "dried" limitation of the asserted claims of the '514 patent or the "drying" limitation of the asserted claim of the '497 patent. Court construed the term "dried" in the '514 patent to mean "dried without solely employing conventional convection air drying from the top." DRL argues that their ANDA process is "conventional" because -

(1) drying method used by DRL was ordinary and commonplace in the web coating industry as of 2001,

(2) DRL's ANDA products are dried solely using top air, and

(3) no bottom air or heat is used during the drying of DRL's products.

Plaintiffs argued that DRL's ANDA process is unconventional because it employs bottom drying. Court however did not agree and said that the DRL’s CL02 and CL03 dryers use a conventional exhaust system, which suggests that any bottom drying is at most a conventional amount. DRL's use of "bottom drying" is essentially that the inside of the oven simply gets hot and as a result, the bottom of film is incidentally heated. This is a conventional bottom drying method. If court were to find infringement, it would effectively be construing the drying limitation to claim all drying techniques that solve the drug content uniformity problem. This is not what the patents claim, however.

Visco-Elastic:

DRL argued that its drying process does not meet the visco-elastic solid film limitation of the '497 patent. Claim 1 of the '497 patent requires "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-elastic film ....”

Court said that DRL's proposed product would lose about 20% of volatile solvent (water and alcohol) in about four minutes.  As a result, the majority of the wet matrix is still water. Rheological testing shows that the DRL's formulation is at best a visco-elastic liquid after four minutes of drying.

Drug Content Uniformity:

DRL argued that its ANDA products do not meet the drug content uniformity limitation of the '514 or the '497 patent. Court construed "without loss of substantial uniformity" to mean "such that individual dosage units do not vary by more than 10% from the intended amount of active for that dosage unit.”

Plaintiffs successfully established infringement of this limitation. DRL's ANDAs report drug content uniformity measurements for individual dosage units.

Viscosity:

DRL argues that its ANDA products do not meet the "viscosity" limitation of the '514 patent. Court construed the phrase, "said matrix has a viscosity sufficient to aid in substantially maintaining non-self-aggregating uniformity of the active in the matrix" to mean "viscosity sufficient to provide little to no aggregation of the active within the film." Viscosity plays a role to ensure that buprenorphine particles do not settle or aggregate. DRL's polymer matrix is specified to range between 5,000 centipoise to 20,000 centipoise. Further, the viscosity of all the tested lots fell within the "most preferred" range.

The ANDAs state that: "the selected compounding process ... results in acceptable drug uniformity in the final blend." Additionally, as discussed above, Plaintiffs establish infringement as to the drug content uniformity limitation. Plaintiffs have demonstrated that DRL infringes the viscosity limitation.

On similar lines Court also decided non-infringement in case of other defendants Watson & Par. Court concluded that for the foregoing reasons, Plaintiffs failed to meet their burden of showing that Defendants infringe claims of the '514 & 497 patents.

Invalidity:

Defendants argued that the asserted claims of the '514 and '497 patents are invalid as obvious. Defendants argued that a POSA would have been motivated to combine known techniques to achieve drug content uniformity. But court said that a POSA would not be motivated to combine the prior art to achieve drug content uniformity primarily because the POSA would have limited knowledge, and access to knowledge, of drying techniques. Based on the facts discussed above, a POSA would not have a reasonable expectation of success. Such a person would not have a strong grasp of prior web coating techniques to apply in the context of pharmaceutical films. A POSA would not have the experience of Dr. Gogolin with photographic film particulates, and bring it to bear into the context of pharmaceutical films. Court is not persuaded that such a POSA would be able to successfully resolve the issues with air bubbles and rippling. A POSA would have to engage in substantial experimentation in adjusting the mixing parameters, drying profile, and viscosity of the matrix to achieve drug content uniformity. A POSA would not have a reasonable expectation of success at achieving drug content uniformity.

Taking all of this evidence as a whole, Defendants have failed to demonstrate by clear and convincing evidence that the asserted claims of the '514 and '497 patents are invalid as obvious.

US’150 patent

With respect to the infringement of US’150 patent, the asserted claims required a water-soluble polymer component of PEO in combination with a HCP. The water-soluble polymer component comprises greater than 75% PEO and up to 25% HCP.

Plaintiffs argued that the sole infringement dispute is whether DRL, by substituting PVP for HCP in DRL's ANDA, infringes via the doctrine of equivalents. Defendants argued that Plaintiffs cannot apply the doctrine of equivalents to capture DRL's ANDA products because the patentees disclosed, but did not claim, PVP as an alternative to HCP. Plaintiffs argued that because there is no passage or example in the '150 patent specification that specifically discloses a combination of low and high molecular weight PEOs with PVP, the dedication-disclosure rule does not apply.

Court disagreed & said that it would be clear to a POSA reading the patent as a whole that PVP is disclosed as an alternative to the HCP element of the asserted claims. The strongest evidence that PVP can be used as an alternative to HCP is in the part of the specification where PEO, HCP, and PVP are listed as examples of useful water-soluble film-forming polymers. Further support is found in Example EA of the '150 patent, which describes films that include PEO and polyvinyl pyrrolidone (PVP) I polymeric blends." This example discloses that "the polymer component of the films contained about 80% PEO and 20% PVP, or a ratio of 4:1 PEO to PVP." Examples EI and EJ in Figure 38 also support the fact that PVP is an alternative to HCP. These examples are described as having similar properties to films made with polymer components comprised of PEO and HCP.

Because court found that the dedication-disclosure rule applies here, Plaintiffs failed to show that DRL infringes the '150 patent.