Last month, the Federal Circuit affirmed decisions from four separate trials in the District of Delaware involving seven different defendants regarding validity and infringement of patents directed to an opioid addiction treatment in Indivior Inc. v. Dr. Reddy's Laboratories, S.A.
The case arose in ANDA litigation over Indivior's suboxone film product Suboxone®, a rapidly dissolving film formulation of two active ingredients: buprenorphine, which decreases a patient's need for opioids, and naloxone, which deters abuse. The challenge for such formulations is drug content uniformity, i.e., having the ingredients homogeneously distributed in the films, which are produced from larger sheets that are cut into individual dosage units based on a particular size and shape to provide the appropriate dose of each drug. U.S. Patent Nos. 8,017,150, 8,603,514, and 8,900,497, licensed by Indivior from Aquestive Therapeutics, Inc., disclose methods for mixing the drugs with a polymer, casting the mixture to produce a wet film, and then "controllably drying the film to produce a solid sheet having less than ten percent variance in active ingredient throughout any given area." Relevant to the issues before the Court, prior art methods (involving drying the films by applying warm air to only the top surface) were inadequate to achieve content uniformity, with films produced in this manner having a "rippled" surface. The invention overcame these limitations by "applying heat to the bottom of the film, introducing controlled microwaves, controlling the air flow above and beneath the film, and employing furnace filters." A fourth patent, U.S. Patent No. 8,475,832, claims film formulations per se and is owned by Indivior.
The specification of the '514 patent disclosed that "drug content uniformity is required by regulatory authorities yet difficult to achieve in practice because of problems in manufacturing the films" and "[m]ultiple factors in the film-making process can affect uniformity." According to the claims of the '514 patent, "(1) the viscosity of the matrix must be "sufficient to aid in substantially maintaining non-self-aggregating uniformity" of the active ingredients (the "viscosity limitation"); and (2) the matrix must be "capable of being dried without loss of substantial uniformity of the active [ingredients]" (the "drying limitation"). The specification further discloses that "using conventional drying methods, which apply hot air to the top of the film, produces nonuniform films." To overcome these issues, "the specification discloses controlled drying processes that differ from conventional techniques" that include "controlled bottom drying or controlled microwave drying." The '150 patent is directed to uniform pharmaceutical films themselves and components thereof.
Indivior brought suit against Dr. Reddy's Laboratories (S.A and Inc. entities); Watson Laboratories Inc.; Actavis Laboratories UT, Inc.; Teva Pharmaceuticals USA Inc.; Par Pharmaceuticals, Inc.; Intelgenx Technologies Corp.; and Alvogen Pine Brook, LLC. The parties had engaged in ANDA litigation involving the '514, '497, and 150 patents brought in the District of Delaware. Claim 62 of the '514 patent and claim 1 of the '150 patent are informative:
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 so 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 taste- masking 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.
1. A mucosally-adhesive water-soluble film product comprising:
an analgesic opiate pharmaceutical active; and
at least one water-soluble polymer component consisting of polyethylene oxide in combination with a hydrophilic cellulosic polymer;
wherein:
the water-soluble polymer component comprises greater than 75% polyethylene oxide and up to 25% hydrophilic cellulosic polymer;
the polyethylene oxide comprises one or more low molecular weight polyethylene oxides and one or more higher molecular weight polyethylene oxides, the molecular weight of the low molecular weight polyethylene oxide being in the range 100,000 to 300,000 and the molecular weight of the higher molecular weight polyethylene oxide being in the range 600,000 to 900,000; and
the polyethylene oxide of low molecular weight comprises about 60% or more in the polymer component.
Indivior accused Dr. Reddy's Labs of infringing the '514 and '150 patents, and both Dr. Reddy's Labs and Watson of infringing the '497 patent; Watson of infringing the '514 and '832 patents; and Alvogen of infringing the '514 and '497 patents. (In a footnote, the opinion identifies the '514 patent claims asserted by Indivior against the various defendants: claims 62–65, 69, 71, and 73 against Dr. Reddy's Labs; claims 62, 64, 65, 69, and 73 against Watson; and claims 62, 63, 65, 69, 71, and 73 against Alvogen.)
In four bench trials the District Court found the '514, '497, and '150 patents were not invalid for obviousness and the '514 patent was not invalid for indefiniteness. Regarding infringement, the Court found Watson infringed the '514 patent under 35 U.S.C. § 271(e)(2), but that Dr. Reddy's Laboratories did not infringe the '514 patent nor the '150 patent, and Alvogen Pine Brook did not infringe the '514 patent. Finally, the District Court found claims 15-19 of the '832 patent to be invalid. (The Patent Trial and Appeal Board held claims 15–19 unpatentable as anticipated and obvious in a separate, parallel inter partes review proceeding.)
The Federal Circuit affirmed all the District Court's determinations but vacated invalidation of claims 15-19 of the '872 patent as moot in view of the PTAB's IPR decision. The opinion sets forth its basis for affirming the District Court's finding of non-infringement of the '514 patent by Dr. Reddy's Laboratories and Alvogen based on claim construction of the drying limitation. In both cases, the District Court construed the drying limitation of the '514 patent claims to mean "dried without solely employing conventional convection air drying from the top," and further that patentee's specification disclaimed (indeed, disparaged; see "Indivior Inc. v. Dr. Reddy's Laboratories, S.A. (Fed. Cir. 2018)") conventional convection air drying from the top surface of the film. Similarly, the Court found that Alvogen's film manufacturing process dries the films primarily from the top and does not satisfy the drying limitation recited in the '514 patent claims. Finding that Defendants used conventional convection air drying from the top surface of the film, the District Court found that Defendants did not infringe and the Federal Circuit affirmed.
Regarding the District Court's determination that Watson infringed the '514 patent, the Federal Circuit held that the District Court did not abuse its discretion when it properly refused to reopen its judgment under Federal Rule of Civil Procedure 59. Watson had amended its ANDA to eliminate bottom heating sources, but had not requested construction of the drying limitation in the claims of the '514 patent. On these facts, the Federal Circuit found "no manifest injustice" in the District Court's decision despite the different outcomes for two generic versions of Indivior's patented films. Separate trials had utilized separate strategies: Dr. Reddy's Labs and Watson challenged the drying limitation in one case, but Watson did not in the other, and this justified the disparate outcomes regarding infringement. The Federal Circuit opinion noted that "it is neither unusual nor unjust for a party to be bound by its litigation decisions, particularly here where Watson was fully aware of but did not request the claim construction it now seeks." In addition, accepting the broader construction of this term strengthened Watson's invalidity position but at the expense of its noninfringement case. On the merits, the District Court found that the viscosity of Watson's generic films fell "squarely within the most preferred range identified in the '514 patent." The Federal Circuit found no clear error in this determination and affirmed.
Regarding infringement of the '150 patent claims under Indivior's doctrine of equivalents contentions, the opinion notes that claim 1 of the '150 patent recites a pharmaceutical film with: (1) "at least one water-soluble polymer component consisting of polyethylene oxide [PEO] in combination with a hydrophilic cellulosic polymer [HCP]"; wherein (2) "the water-soluble polymer component comprises greater than 75% [PEO] and up to 25% [HCP]"; (3) the PEO comprises at least one L-PEO and at least one H-PEO; and (4) the L-PEO "comprises about 60% or more in the polymer component." It was undisputed that Dr. Reddy's Labs substituted polyvinyl pyrrolidone for hydrophilic cellulosic polymer, and the District Court held that Indivior could not capture these formulations under the doctrine of equivalents because embodiments of the claimed films comprising PVP were disclosed in the '150 patent specification but not claimed. Hence these embodiments were dedicated to the public according to the District Court, citing Johnson & Johnston Assocs. Inc. v. R.E. Serv. Co., 285 F.3d 1046, 1054 (Fed. Cir. 2002) (en banc). The Federal Circuit found no clear error in this determination and affirmed.
Turning to Defendants' various invalidity contentions, the Federal Circuit affirmed the District Court's finding that the claims of the '514 patent were not indefinite. The basis for Watson's indefiniteness contention focused on the claim term "cast film comprising a flowable water-soluble or water swellable film-forming matrix" because the film is not "flowable" in its final dosage form. Watson's position was that the recited property needed to be possessed by accused infringing article, but the District Court disagreed and analogized to the Gemtron Corp. v. Saint-Gobain Corp., 572 F.3d 1371, 1375–76 (Fed. Cir. 2009) case, where the claimed property was only present during assembly. The Federal Circuit characterized as nonsensical the argument (which Watson and Teva advanced at trial) that the finished film product needed to be flowable to fall within the scope of the claim. The Federal Circuit agreed with the District Court that "a product claim may recite elements 'in the state in which they exist during manufacture, before the final product exists'" and thus the claims were not indefinite.
The Court also affirmed the District Court's decision that the claims of the '514 patent were not obvious. Dr. Reddy's Labs asserted three prior art references at trial: U.S. Patent Nos. 4,849,246 ("Schmidt"), 6,552,024 ("Chen"), and 5,881,476 ("Strobush"). The '246 patent discloses methods for making pharmaceutical films but Indivior proffered persuasive expert testimony that the uniformity of the film not assessed. The '024 patent taught top-air drying pharmaceutical films. And the '476 patent taught methods for drying non-pharmaceutical films without introducing "mottle." The District Court found insufficient motivation to combine these references on two grounds. First, there was no evidence that the '246 and '024 patents disclosed uniform drug content as a property of the disclosed films (a property required of the claimed invention), and second, the status of pharmaceutical films was "nascent." In addition, the Court noted that there was even less motivation to combine the '476 patent because this reference did not disclose not a pharmaceutical film. Finally, Indivior asserted evidence of secondary considerations that supported its nonobviousness position.
The Federal Circuit found no clear error on these facts. It found Dr. Reddy's Labs' arguments disputing the level of skill in the art used by the District Court to be "nitpicking," and that the District Court properly relied on expert testimony regarding the relationship between "mottle" in the prior art and uniformity as recited in the '514 patent claims. The assertion by Dr. Reddy's Labs of the skilled artisan's expectation of success was undercut, in the Court's view, by the "multiple factors throughout the manufacturing process that contribute to the uniformity of pharmaceutical films, that adjusting the various factors would have been unintuitive, and that the field was still emergent at the time of invention." The Federal Circuit found no clear error in District Court's finding regarding the totality of the evidence for these facts and affirmed the nonobviousness of the '514 patent claims.
Finally the Federal Circuit affirmed the District Court's determination that Watson had not established by clear and convincing evidence that the claims of the '150 patent were obvious. This determination rested on whether the '150 patent was entitled to the priority date of the earlier-filed U.S. Provisional Patent Application No. 60/473,902, i.e., whether that application satisfied the disclosure requirements of 35 U.S.C. § 112 for the '150 patent claims. The District Court held that the priority claim was proper (and thus the '150 patent claims were not obvious), relying expressly on the following disclosure in the '902 application:
For instance, certain film properties, such as fast dissolution rates and high tear resistance, may be attained by combining small amounts of high molecular weight PEOs with larger amounts of lower molecular weight PE[O]s. Desirably, such compositions contain about 60% or greater levels of the lower molecular weight PEO in the PEO-blend polymer component.
To balance the properties of adhesion prevention, fast dissolution rate, and good tear resistance, desirable film compositions may include about 50% to 75% low molecular weight PEO, optionally combined with a small amount of a high molecular weight PEO, with the remainder of the polymer component containing a hydrophilic cellulosic polymer (HPC or HPMC).
The Federal Circuit found no clear error in this determination by the District Court because "the application discloses that a polymer component with 60% L-PEO has desirable properties and that the remainder of the component may include H-PEO and HCP," consistent with '150 patent claims.
Indivior Inc. v. Dr. Reddy's Laboratories, S.A. (Fed. Cir. 2019)
Panel: Circuit Judges Newman, Mayer, and Lourie
Opinion by Circuit Judge Lourie; dissenting opinion by Circuit Judge Mayer
