Bristol-Myers Squibb Co. v. Aurobindo Pharma USA Inc.


August 5, 2020

GENERICally Speaking: A Hatch Waxman Litigation Bulletin

Case Name: Bristol-Myers Squibb Co. v. Aurobindo Pharma USA Inc., No. 17-374-LPS (Consolidated), 2020 WL 4500226 (D. Del. Aug. 5, 2020) (Stark, J.)

Drug Product and Patent(s)-in-Suit: Eliquis® (apixaban); U.S. Patents Nos. 6,967,208 (“the ’208 patent”) and 9,326,945 (“the ’945 patent”)

Nature of the Case and Issue(s) Presented: Eliquis was an FDA-approved anticoagulant indicated to treat and reduce the risk of certain cardiovascular disorders. Apixaban, covered in part by Bristol-Myers Squibb’s ’208 and ’945 patents, was the active ingredient in Eliquis. BMS sued Sigmapharm Laboratories, LLC, Sunshine Lake Pharma Co., Ltd. and HEC Phann USA Inc., and Unichem Laboratories Ltd., alleging infringement of the patents-in-suit in response to Defendants’ filing of ANDAs for a generic apixaban. Plaintiffs originally brought this action against more than 25 pharmaceutical companies. By the time of trial, they had resolved their disputes with all but Sigmapharm, Sunshine Lake, and Unichem. Specifically, BMS alleged that: (i) Sigmapharm and Unichem infringed claims 13 and 104 of the ’208 patent, which claimed apixaban; and (ii) all three Defendants infringed claims 21 and 22 of the ’945 patent, which claimed certain compositions containing apixaban. Defendants brought counterclaims that the patents-in-suit were invalid.

After a nine-day bench trial, the court held that: (i) Sigmapharm's proposed drug products infringed the asserted claims of the ’208 patent; (2) Sigmapharm, Sunshine Lake, and Unichem’s proposed drug products infringed the asserted claims of the ’945 patent; and (3) the asserted claims of the ’208 patent and ’945 patent were not invalid.

Why BMS Prevailed: Sigmapharm infringed the ’208 patent. Claim 1 of the ’208 patent recited that certain rings of the apixiban molecule were “substituted with” a certain number of R groups. Sigmapharm contended each of these ring limitations specified how many hydrogen atom “substituents” could be included in each ring. For example, to Sigmapharm, claim 1 required that ring M contain no more than two hydrogen “substituents.” To Sigmapharm, because it was undisputed that (for example) in apixaban ring M contained more hydrogen atoms than the claim allowed, apixaban did not meet the ring M limitation and, it followed, ring M was not covered by claim 1. BMS countered that these ring limitations specified how many R groups can be replaced in the rings of the claimed chemical structure. The court agreed with BMS and found that the plain and ordinary meaning to a POSA of “substituted with [N] R” was “replaced with [N] R,” where N is a number, because the plain and ordinary meaning of “substituted” was “replaced with”; the meaning was not “must include [N] hydrogen substituents.” This conclusion was further supported by the ’208 patent specification, which stated, “the term ‘substituted’ … means that any one or more of hydrogens on the designated atom is replaced.” Claim 13 of the ’208 patent, which depended from claim 1, also claimed the compound apixaban. Because Sigmapharm's ANDA product contained apixaban, Sigmapharm's ANDA product infringed claim 13. Finally, the court considered claim 104 of the ‘208 patent, which depended from claim 13 and added that the compound must be crystalline. For the reasons discussed below in connection with infringement of the ’945 patent, the court was persuaded that Sigmapharm’s ANDA product contained crystalline apixaban.

Defendants infringed claims 21 and 22 of the ’945 patent. The ’945 patent claimed apixiban formulations, wherein the crystalline apixaban particles had a D90 equal to or less than about 89 microns. In claims 21 and 22, the pharmaceutical compositions comprised 2.5 or 5 mg of apixaban. Defendants argued that their ANDA products did not contain crystalline apixaban, or meet the particle size limitations, by attacking the experimental evidence developed by BMS’s experts. Sigmapharm challenged BMS’s empirical findings as inconsistent with scientific theory. But the court was persuaded that BMS’s expert’s methodology was reliable and his conclusions—particularly, that Sigmapharm’s and Sunshine Lake’s ANDA products contained crystalline apixaban particles meeting all the limitations of the asserted claims of the ’945 patent—were sound. Ultimately, the court found that BMS proved by a preponderance of mostly experimental evidence that the ANDA products contained crystalline apixaban particles.

Sigmapharm further argued that even if its ANDA product met the crystalline-apixaban limitation, it did not meet the particle-size limitation of the asserted claims because BMS did not measure any crystalline apixaban particles. BMS countered that it did not need to measure or calculate precise D90 values because Sigmapharm’s manufacturing process made it impossible for any crystalline apixaban particles in Sigmapharm's product to have a D90 greater than 89 microns. “A patentee may prove infringement by any method of analysis that is probative of the fact of infringement, and circumstantial evidence may be sufficient.” Martek v. Biosciences Corp., 579 F.3d 1363, 1372 (Fed. Cir. 2009). BMS’s expert concluded that the ANDA product satisfied the particle-size limitation after analyzing Sigmapharm’s manufacturing process and applying well-known principles of crystallization. The expert demonstrated that in Sigmapharm's process: (i) apixaban is dried at a rapid rate, thereby dispersing apixaban throughout the polymer and preventing it from coalescing into large crystalline particles; (ii) apixaban is a relatively small percentage of the composition; and (iii) apixaban is kept in position in small pockets by the formulation's polymer and other excipients.

The only limitation Unichem disputed was the particle-size limitation. In response, BMS’s expert analyzed the particle size of Unichem’s ANDA product using SEM-EDS, a technique disclosed in the prior art for imaging pharmaceutical compositions and identifying their elements. The expert concluded that the crystalline apixaban in Unichem's ANDA products had a  D90 of much less than 89 microns and opined that his conclusions were consistent with Unichem's manufacturing process, which: (i) created a solution consisting of volatile solvents and highly dilute apixaban; and (ii) evaporated out the solvent, thereby “leaving behind small apixaban particles.”  The court was persuaded and found that Unichem's ANDA product infringed the ’945 patent claims.

Validity of the ’208 patent. Defendants argued that (i) claims 13 and 104 claimed subject matter not claimed by claim 1, from which they depended; (ii) the patent failed to enable the full scope of claim 13, which claimed “pharmaceutically acceptable” salts of apixaban; and (iii) the asserted claims lacked an adequate written description.

For the first defense, Defendants presented mostly the same arguments Sigmapharm did in contending it did not infringe claims 13 and 104 of the ’208 patent: that the claim language of “substituted with” required counting hydrogen as a substituent, and that the ring structures in apixaban contained more hydrogen atoms than were permitted in the claimed ring structures. The court found these arguments were no more persuasive in the context of invalidity (where Defendants bore a clear-and-convincing burden of proof) than they were in connection with non-infringement.

Next, Defendants argued that claim 13 was invalid because: (i) the ’208 patent did not disclose apixaban salts; (ii) pharmaceutically acceptable salts were not enabled; and (iii) apixaban could not be made into a salt suitable for use in contact with human or animal tissue. The court found these assertions categorically wrong, given that one of BMS’s experts was able to prepare sodium, potassium, and hydrochloride salts of apixaban in under five hours by following the guidance of the ’208 patent, and that another of BMS’s experts opined that in his “sound medical judgment,” a POSA would view an apixaban salt as “suitable for use ... commensurate with a reasonable benefit/risk ratio.”

Finally, Defendants argued that the ’208 patent included only a “general description of salt formation,” but the court, resting on its prior analysis, found that the ’208 patent specifically recited apixaban, outlined “pharmaceutically acceptable salts of the present invention,” and described how to make those salts.

Validity of the ’945 patent. Defendants argued that the ’945 patent was invalid because it was: (i) not enabled; (ii) not adequately described; and (iii) obvious. Defendants argued that the ’945 patent did not provide “examples or other guidance for determining the D90 of apixaban after formulation,” but Defendants did not show that the claims required measuring the D90 of any apixaban particle. Instead, the particle-size limitation stated a characteristic of the claimed crystalline apixaban, not a procedural (measurement) requirement. Furthermore, because the ’945 patent specification disclosed the use of laser-light scattering to determine whether a pre-formulation D90 were within the claimed threshold, and because the record evidence showed that apixaban particles would not grow during the formulation process, a POSA who used laser-light scattering could determine whether the crystalline apixaban in the formulated tablet were within the claimed threshold.

For written description, the Defendants argued that the ’945 patent “simply does not describe nor [sic] contemplate determining the D90 of the apixaban particles once formulated.” The court found Defendants’ contention unavailing as it was based on the inaccurate premise that the claims’ scope included determining the apixaban D90 value before or after tableting, and Defendants did not point to anything in ’945 patent that made such a determination at both times a requirement for practicing the particle-size limitation. Moreover, because the term “apixaban particles have a D90” was construed as having its plain and ordinary meaning, the court found the particle-size limitation to describe a feature of the claimed invention, not a measurement requirement.

Finally, the claims were not obvious because Defendants failed to prove that a POSA would have been motivated to reduce the particle size of crystalline apixaban. Nor did Defendants persuade the court that a POSA would have had a reasonable expectation of success that she could improve apixaban’s bioavailability by increasing its dissolution rate. Finally, Defendants failed to show that the asserted claims of the ‘945 patent would have been obvious to a POSA in view of Defendants’ prior-art combinations.

Oren D. Langer


Managing Partner, New York Office
Member of Executive Board

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