Cubist Pharms., Inc. v. Hospira, Inc.

Case Name: Cubist Pharms., Inc. v. Hospira, Inc., 2015-1197, 2015-1204, 2015-1259, 2015 U.S. App. LEXIS 19662 (Fed. Cir. Nov. 12, 2015) (Circuit Judges Wallach, Bryson, and Hughes presiding; Opinion by Bryson, J.) (Appeal from D. Del., Sleet, J.)

Drug Product and Patent(s)-in-Suit: Cubicin® (daptomycin); U.S. Patents Nos. RE39,071 (“the ’071 patent”), 6,852,689 (“the ’689 patent”), 6,648,967 (“the ’967 patent”), 8,058,238 (“the ’238 patent”), 8,129,342 (“the ’342 patent”)

Nature of the Case and Issue(s) Presented: Daptomycin, used as an antibiotic, was originally developed by Eli Lilly & Co. (“Lilly”). Lilly’s patent on daptomycin expired in 2002. This case relates to five follow-on patents to Lilly’s original patent. Those patents relate to antibiotic compounds, methods of treating bacterial infections, daptomycin dosage regimens, and purification of daptomycin. In 2011, Hospira filed an ANDA seeking approval to manufacture and sell a generic daptomycin. Cubist filed suit alleging infringement of the five patents-in-suit. The district court found four of Cubist’s five patents invalid as obvious. The court also found that the remaining patent, the ’071 patent, was valid and infringed by Hospira. Both parties appealed the ruling, and the Federal Circuit affirmed the district court on all issues.

Why Cubist Prevailed: The dispute regarding the valid patent centered on a single amino acid in the structural diagram of daptomycin. At the time the ’071 patent was filed, the scientific community universally agreed that daptomycin contained the L-isomer of the amino acid asparagine. The structural diagram in the ’071 patent reflected this fact. Years after the ’071 patent issued, Lilly’s researchers discovered that daptomycin actually contains the D-isomer of asparagine as opposed to the L-isomer. Cubist requested a certificate of correction from the USPTO to change the structural diagram to reflect this new information. The USPTO agreed and issued the certificate of correction.

Hospira argued that the USPTO should not have issued the certificate of correction because it broadened the scope of the patent’s claims. The Federal Circuit disagreed, finding that the correction did not change the scope at all; it merely conformed the structural diagram to what was described accurately elsewhere in the specification of the patent. First, the specification taught the production of daptomycin through fermentation of Streptomyces roseosporus, a process that necessarily results in D-isomer daptomycin, not the L-isomer variant. Similarly, the patent referred to the claimed compound as LY146032, a code name given to it by Lilly when it was first developed. The evidence showed that LY146032 always referred to a compound containing D-isomer daptomycin, that fact was simply unknown at the time. Finally, at the time of patenting, the scientific community universally believed that daptomycin existed as the L-isomer variant. For all these reasons, the Federal Circuit concluded that it was clear the inventors of the ’071 patent were in possession of, and claimed, D-isomer daptomycin. Thus, certificate of correction did not broaden the claims.

Hospira also contended that the patent failed the written-description requirement because the patent specification did not describe D-isomer daptomycin. For the same reasons discussed above, the Federal Circuit rejected this argument. It found that the inventors only claimed what they had produced and described in a variety of ways—D-isomer daptomycin. That the inventors, and indeed, the scientific community, were mistaken about the structure of the compound they produced was not sufficient to invalidate the patent claims. Accordingly, the patent was valid and infringed.

Next,Cubist appealed the district court determination that four of its patents were invalid on obviousness grounds. Two patents related to daptomycin dosage regimens and two patents related to the purification of daptomycin. The Federal Circuit upheld the district court’s obviousness findings. The dosage patents taught administering daptomycin less frequently in order to minimize skeletal muscle toxicity. An article by James Woodworth, prior art to the dosage patents, reported that daptomycin would be an effective antibiotic at lower doses. While the article did not specifically address reduced toxicity, the district court found minimizing skeletal muscle toxicity was “a necessary accompaniment to the other disclosed claimed limitations and therefore was inherently disclosed by the Woodworth article.” In addition, at the time the patent was filed, those skilled in the art knew that daptomycin’s effectiveness is concentration-dependent. Therefore, those of ordinary skill also knew that less-frequent, more-concentrated, doses of daptomycin would have an enhanced antibiotic effect. The Federal Circuit agreed. Although the Woodworth article was based on data gathered in a laboratory setting, its predictions were reasonably applicable to real-world administration. In addition to daptomycin’s long half-life and concentration-dependent nature, it was well known that muscle toxicity caused by daptomycin was reversible. In other words, it was known that a greater interval between doses provided the tissue more time to heal, reducing the cumulative toxic effect. Daptomycin is also closely related to another group of antibiotic compounds, aminoglycosides. At the time the patent was filed, it was known that less frequent dosages of aminoglycosides reduced their toxic effects. Thus, it would be obvious to one of ordinary skill that daptomycin would behave similarly. Finally, the Federal Circuit determined that the secondary considerations were insufficient to render the dosage patents non-obvious. It found the commercial success of daptomycin was based on daptomycin itself, not its dosage schedule. Cubist pointed out that Lilly had failed to develop the dosage schedule in the patents, but the Federal Circuit found this fact irrelevant. At the time, Lilly had developed another drug that was also an effective antibiotic, and would have no motivation to cannibalize its sales with a substitutable drug.

Turning to the purity patents, those patents taught two primary purification steps: micelle filtration to filter out saponins from the daptomycin, and anion-exchange chromatography to further purify the daptomycin. The Federal Circuit determined that both techniques were obvious. A prior art article taught that micelle filtration could be used to purify most surfactants. Another article, also prior art, taught that daptomycin displayed the properties of a surfactant. Combining the two, micelle filtration would have been an obvious means to purify daptomycin. Similarly, anion-exchange chromatography was well understood to purify compounds similar in structure to daptomycin. Once the saponins were removed from the daptomycin, it would have been obvious to one of ordinary skill to use anion-exchange chromatography to purify the product. These steps could be used to obtain concentrations of daptomycin sufficiently pure to fall within the claims of the purity patents.