IP Law Daily Three generic drug manufacturers’ ANDA products infringe Eliquis® patents
Thursday, August 6, 2020

Three generic drug manufacturers’ ANDA products infringe Eliquis® patents

By Cheryl Beise, J.D.

Evidence at trial established that asserted claims of Eliquis® patents were valid and infringed by defendants’ proposed products containing apixaban formulations.

Three generic drug manufacturers infringed the asserted claims of two patents listed in the FDA’s Orange Book in connection with the cardiovascular drug Eliquis®, the federal district court in Wilmington, Delaware, has ruled after conducting an eight-day trial in Hatch-Waxman Act litigation initiated by Bristol-Myers Squibb and Pfizer Inc. The plaintiffs established that the defendants’ proposed bioequivalent ANDA products were infringing because they met the claimed limitations relating to the active ingredient apixaban in form and particle size. The defendants—Sigmapharm Laboratories, Unichem Laboratories, and Sunshine Lake—also failed to present clear and convincing evidence that any of the asserted claims were invalid for improper dependency, lack of enablement, inadequate written description, or obviousness (Bristol Myers Squibb Co. v. Aurobindo Pharma USA, Inc., August 5, 2020, Stark, L.).

Bristol-Myers Squibb Co. owns U.S. Patent Nos. 6,967,208 (the ’208 Patent), entitled, "Lactam-Containing Compounds and Derivatives Thereof As Factor Xa Inhibitors." Bristol-Myers Squibb and Pfizer Inc. (together, "BMS") jointly own U.S. Patent No. 9,326,945 (the ’945 Patent), entitled "Apixaban Formulations." Both patents are listed in the U.S. Food and Drug Administration’s Orange Book in connection with BMS’s Eliquis® drug product, used to treat cardio-vascular disease. Apixaban is the active ingredient in Eliquis.

BMS sued three drug manufactures that filed Abbreviated New Drug Applications (ANDAs) seeking FDA approval to market new drugs that are bioequivalent to BMS’s Eliquis drug. BMS alleged that (1) Sigmapharm Laboratories, LLC ("Sigmapharm"), and Unichem Laboratories Ltd. ("Unichem") infringed claims 13 and 104 of the ’208 Patent; and (2) Sigmapharm, Unichem, and HEC Pharm USA Inc. ("Sunshine Lake") infringed claims 21 and 22 of the ’945 Patent. The defendants brought counterclaims alleging that the asserted claims of both patents are invalid.

The court held a bench trial in October–November 2019. After considering the trial evidence and the parties’ proposed findings of fact and post-trial briefs, the court concluded that Sigmapharm’s proposed drug products infringe the asserted claims of the ’208 Patent; Sigmapharm, Sunshine Lake, and Unichem’s proposed drug products infringe the asserted claims of the ’945 Patent; and the asserted claims of the ’208 Patent and ’945 Patent are not invalid.

Infringement of ’208 Patent. BMS asserted claims 13 and 104 of the ’208 Patent against Sigmapharm and Unichem. Claim 13, which depends from nonasserted claim 8, recites apixaban or a pharmaceutically acceptable salt form of apixaban. Non-asserted independent claim 1, from which claim 8 depends, recites a structure that includes many chemical compounds, one of which is apixaban. Claim 104 recites "A compound according to claim 13, which is a crystalline compound." Unichem stipulated to infringement of the asserted claims of the ’208 Patent. Sigmapharm contested infringement, but admitted that its ANDA products contained apixaban.

Sigmapharm argued that BMS failed to prove that claim 1 covers apixaban. The court disagreed, finding that claims 1, 13, and 104 do claim apixaban. The court observed that if it were to accept Sigmapharm’s theory, none of the compounds specifically disclosed in the ’208 Patent would fall within the scope of claim 1. Sigmapharm’s only basis for disputing infringement was that apixaban, in Sigmapharm’s view, has more "substituents" attached to rings M, E, A, and Q than claim l allows. Claim I recites that rings M, E, A, and Q are "substituted with" a certain number of R groups. In Sigmapharm’s view, claim 1 captures no embodiments at all. This view of the "substituted with" claim limitations "would be in tension with well-established Federal Circuit precedent that discourages claim interpretation which results in preferred embodiments being excluded from the scope of the claims," the court said.

Claim 104 of the ’208 Patent depends from claim 13 and adds that the compound must be crystalline. BMS proved by a preponderance of the evidence, including the testimony of two experts, that Sigmapharm’s ANDA product contained crystalline apixaban particles.

Infringement of ’945 Patent. BMS asserted claims 21 and 22 of the ’945 Patent against all three defendants. Claims 21 and 22 depend from independent claim 12 and add that the compositions comprise 2.5 or 5 mg of apixaban, respectively. All three defendants contested infringement of the ’945 Patent.

Sigmapharm’s attacks on the methodology used and evidence presented by BMS’s experts were unavailing. The court found that BMS’s experts persuasively established that Sigmapharm’s ANDA product contained crystalline apixaban particles meeting all the limitations of the asserted claims of the ’945 Patent. Sigmapharm additionally argued that even if some of the apixaban in its ANDA product is crystallized, there was no "apixaban particle," but rather, at most, a "composite particle consisting of PVP-apixaban bonded together." However, Sigmapharm failed to show that such composite participles do not contain crystalline apixaban particles; rather, Sigmapharm showed only that they contain crystalline apixaban in addition toother substances, the court observed.

Sigmapharm also argued that BMS failed to prove that its ANDA product dose met the particle size limitation (a D90 equal to or less than 89 µm) because BMS did not measure any crystalline apixaban particles. However, BMS’s expert was not obligated to "perform actual tests or experiments on the accused product," the court noted. In this case, BMS did not need to measure or calculate precise D90 values because the evidence established that Sigmapharm’s manufacturing process made it impossible for any crystalline apixaban particles in Sigmapharm’s product to have a D90 greater than 89 µm.

The court additionally found that the ANDA products proposed by Sunshine Lake and Unichem met the crystalline apixaban and particle size limitations for largely the same reasons as Sigmapharm’s products. Unichem only disputed that its ANDA product met the particle size limitation. Sunshine Lake attempted to design around the asserted claims by making a so­called "amorphous dispersion," but evidence showing the presence of crystalline apixaban particles in Sunshine Lake’s ANDA products belied that effort.

Validity of ’208 Patent. The defendants argued that the asserted claims of the ’208 Patent are invalid because (1) claims 13 and 104 claim subject matter (apixaban) not claimed by claim 1, from which they depend, and (2) the patent fails to enable the full scope of claim 13, which claims "pharmaceutically acceptable" salts of apixaban; and (3) both asserted claims lack an adequate written description. The first assertion of improper dependency was rejected for the same reason as Sigmapharm’s unsuccessful noninfringement argument.

Claim 13 requires a "pharmaceutically acceptable salt form" of apixaban; that is, a salt form which is, "within the scope of sound medical judgment, suitable for use in contact with the tissues of human begins and animals." The defendants contended that claim 13 is invalid for lack of enablement because (1) the ’208 Patent does not disclose apixaban salts, (2) pharmaceutically acceptable salts are not enabled, and (3) apixaban cannot be made into a salt suitable for use in contact with human or animal tissue. The court determined that the ’208 Patent does disclose apixaban salts. The court noted that the ’208 Patent describes a conventional method for making salts and identifies specific reaction conditions and chemicals that can be used to prepare an apixaban salt. "Persuasive evidence establishes that a POSA with the 208 patent in hand could make apixaban salts without undue experimentation," the court said. Lastly, BMS’s expert, a clinical cardiologist and expert in clinical medicine including thromboembolic disorders, persuasively opined explained that an apixaban salt would offer tremendous benefits to patients suffering from atrial fibrillation without "any risk of excessive toxicity, irritation, or other complications."

The defendants also argued that the ’208 Patent includes only a "general description of salt formation" and a list of 80 compounds, "some of which have [salts] and some of which do not." While the inventors did not themselves ever make pharmaceutically acceptable apixaban salts, the court nevertheless found that a POSA would understand from the four comers of the ’208 Patent that the inventors possessed pharmaceutically acceptable apixaban salts.

Validity of ’208 Patent. The defendants contended that the ’945 Patent is invalid because the asserted claims (1) fail to meet the enablement requirement, (2) fail to meet the written description, and (3) are obvious in light of the prior art. However, the defendants did not establish any of the contentions by clear and convincing evidence.

The defendants argued that the ’945 Patent is not enabled because it does not provide "examples or other guidance for determining the D90 of apixaban after formulation," the prior art does not disclose any measurements of post­formulation D90, and BMS’s expert failed to conduct any such measurements. However, Defendants did not show that the claims require measuring the D90 of any apixaban particles, particularly after tableting, the court said. Furthermore, a POSA who uses laser light scattering can determine whether the crystalline apixaban in the formulated tablet is within the claimed threshold. BMS presented unrebutted evidence that laser light scattering is routinely used to measure particle size.

The defendants asserted that the ’945 Patent lacks written description support because it "simply does not describe nor contemplate determining the D90 of the apixaban particles once formulated." The defendants’ contention was unavailing, according to the court, because it was based on the inaccurate premise that the claims’ scope "includes determining the apixaban D90 value before or after tableting." The court’s claim construction understood the particle size limitation to describe a feature of the claimed invention, not a measurement requirement. In any event, a POSA would have known that the crystalline apixaban in the final composition would be within the claimed D90 threshold, the court said.

Lastly, the court rejected the defendants’ obviousness argument because they failed to prove that a POSA would have been motivated to reduce the particle size of crystalline apixaban. While the defendants insisted that a POSA would have been motivated by a desire to improve content uniformity, they pointed to no record evidence demonstrating that apixaban’s content uniformity was a concern in the prior art, the court said. The defendants’ suggestion that a POSA would have been motivated to improve apixaban’s bioavailability also was unpersuasive. "As BMS showed, the prior art explicitly taught that apixaban had good bioavailability," the court said. The court concluded that the defendants failed to show that the asserted claims of the ’945 Patent would have been obvious to a POSA in view of the defendants’ prior art combinations.

This case is No. 17-374LPS.

Attorneys: Joseph J. Farnan, Jr. (Farnan LLP) for Bristol Myers Squibb Co. and Pfizer Inc. Karen L. Pascale (Young Conaway Stargatt & Taylor, LLP) for Sunshine Lake Pharma Co Ltd., HEC Pharm USA Inc., and Unichem Laboratories Ltd.

Companies: Bristol Myers Squibb Co.; Pfizer Inc.; Sunshine Lake Pharma Co Ltd.; HEC Pharm USA Inc.; Unichem Laboratories Ltd.

MainStory: TopStory Patent GCNNews DelawareNews

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