By Donald Zuhn --
Yesterday, the Federal Circuit affirmed a decision by the District Court for the Southern District of New York finding that Defendants-Appellants Barr Laboratories, Inc. and Pliva-Hrvatska d.o.o. ("Barr") infringed U.S. Patent No. 5,214,052. The '052 patent, which is assigned to Plaintiff-Appellee Mitsubishi Chemical Corp., relates to argatroban solutions containing ethanol, water, and a saccharide. Argatroban is an anticoagulant used in the treatment of heparin-induced thrombocytopenia.
The '052 patent discloses that the solubility of argatroban increases dramatically when it is dissolved in ethanol, water, and a saccharide. At the time the application that issued as the '052 patent was filed, argatroban was known to have low aqueous solubility at neutral pH levels, which presented problems for its use in pharmaceutical compositions. The '052 patent has four claims:
1. A method for dissolving an arginineamide, comprising:
dissolving [argatroban] and/or its salt in a solvent containing ethanol, water and a saccharide.
2. The method according to claim 1, wherein the saccharide is at least one member selected from the group consisting of sorbitol, glucose, glycerin and sucrose.
3. A pharmaceutical composition for injection, comprising:
[argatroban] and/or its salt together with ethanol, water and a saccharide.
4. The composition according to claim 3, wherein the saccharide is at least one member selected from the group consisting of sorbitol, glucose, glycerin and sucrose.
Seeking approval to market a generic version of Misubishi's Argatroban Injection product, which consists of a high concentration of argatroban dissolved in a solution of ethanol, water, and sorbitol at a pH between 3.2 and 7.5, Barr filed an Abbreviated New Drug Application (ANDA) with the FDA. In response to Barr's ANDA filing, Mitsubishi brought suit against Barr for infringement of the '052 patent. The parties stipulated that Barr's ANDA product would infringe all four claims of the '052 patent. Barr answered by asserting that the claims were invalid as anticipated by an article published by Mitsubishi employee Toshihiro Yamamoto, and rendered obvious by several combinations of nine other references.
At trial, Mitsubishi and Barr battled over the proper translation of a single sentence in the Yamamoto reference that described the preparation of an argatroban solution administered to rats for experimental purposes. The District Court considered four translations of the sentence, concluding that the translation submitted by Mitsubishi's expert was the only reliable translation. Mitsuibishi's expert translated the relevant sentence as follows: "In 7.5% D-sorbitol-4% ethanol, an argipidine solution dissolved under hydrochloric acid acidity (pH 1.5 to 1.7) was intraperitoneally administered at a dosage of 1 ml/kg, 15 minutes before common carotid artery occlusion." Using this translation, the District Court determined that Yamamoto does not anticipate claims 1 and 2 because a person of ordinary skill in the art would have understood Yamamoto to teach dissolution of argatroban in hydrochloric acid alone, i.e., without ethanol or a saccharide (another Mitsubishi expert, and native Japanese speaker, testified that the disputed sentence from the Yamamoto reference should be understood to mean "in hydrochloric acid the [argatroban] was dissolved and after that it's been put into D-sorbitol and ethanol"). The District Court concluded, therefore, that the phrase "[i]n 7.5% D-sorbitol-4% ethanol" referred to how the argatroban solution was administered and not how it was dissolved. As for claims 3 and 4, the District Court concluded that Yamamoto's argatroban solution was not "[a] pharmaceutical composition for injection" because a pharmaceutical composition must have a pH above 3 (the District Court based this conclusion on the testimony of a third Mitsubishi expert).
With respect to Barr's obviousness argument, the District Court dismissed four of Barr's nine references as not addressing argatroban solubility or methods of formulating the drug. The District Court found that while the other five references described solvent systems including ethanol, water, and a saccharide, none of these references directed the skilled artisan to use ethanol, water, and a saccharide to dissolve argatroban. The District Court therefore determined that the claims of the '052 patent would not have been obvious.
On appeal, Barr first challenged the District Court's selection of the Mitsubishi expert's translation of Yamamoto, arguing that two other translations were not prepared for purposes of this litigation. The Federal Circuit noted that "[t]he district court's selection of the appropriate translation in this case was based in large part on a credibility determination, and such determinations are 'virtually never' overturned for clear error." The opinion also discounted Barr's argument that the translation adopted by the District Court should be disregarded because it was prepared for purposes of this litigation, stating that this was "not a sufficient reason to conclude that the district court's choice of the [Mitsubishi expert's] translation was clearly erroneous."
With respect to claims 3 and 4, Barr argued that the phrase "pharmaceutical composition for injection" in the preamble of claim 3 means "a medicinal drug composition that can be administered by injection," and that this claim therefore covers any composition that includes a "medicinal drug" (i.e., argatroban), along with ethanol, water, and a saccharide, regardless of whether it can be injected into a patient with therapeutic effect. In dismissing Barr's argument, the Court noted that "[t]he problem with Barr's construction is that the word 'pharmaceutical' in claim 3 modifies the entire 'composition' referred to in the claim, not simply the argatroban component of the composition." The Court pointed out that "Barr's claim construction would allow a 'plainly toxic composition, such as a cleaning fluid or a pesticide,' to meet the limitations of claim 3, even though such a composition would not be medicinal under any definition of that word." The Court "therefore reject[ed] Barr's attempt to broaden the phrase 'pharmaceutical composition for injection' to cover any composition that includes a medicinal product, regardless of its suitability for injection into humans." Because the District Court concluded that the pH of the Yamamoto argatroban solution was below 3, and that such a solution would not be acceptable for use as a medicine, the Federal Circuit determined that Barr had failed to show by clear and convincing evidence that Yamamoto disclosed a pharmaceutical composition for injection.
As for Barr's obviousness argument, the Federal Circuit determined that the District Court did not clearly err in determining that the prior art taught away from the use of ethanol to dissolve argatroban. The Federal Circuit also found no reason to disturb the District Court's determination that a number of Barr's references were not specific to argatroban, despite describing solvent systems including ethanol, water, and a saccharide.
Mitsubishi Chemical Corp. v. Barr Laboratories, Inc. (Fed. Cir. 2011)
Panel: Circuit Judges Bryson, Dyk, and Prost
Opinion by Circuit Judge Bryson