Using Takeda's compounds as leads, E. I. du Pont de Nemours and Company sought to develop compounds having inreased angiotensin receptor binding, and therefore, better ARB activity. DuPont modified S-8307 to develop the compound losartan, which has ten-fold higher binding than Takeda's compounds. DuPont's losartan has the chemical structure:
DuPont disclosed losartan in U.S. Patent No. 5,138,069 along with more than 400 structurally related ARBs, including Example 118, which has the chemical structure:
Based on DuPont's success with losartan, a number of pharmaceutical companies, including Daiichi, initiated efforts to identify even better ARBs. Daiichi's work led to the synthesis of olmesartan, the active metabolite of olmesartan medoxomil, which differs from losartan in that it has a hydrophilic, hydroxy-isopropyl group at the 4-position of the imidazole ring instead of a lipophilic, chlorine atom (like Example 118 above), and a carboxy group masked by a medoxomil prodrug substituent at the 5-position of the ring instead of a hydroxymethyl group. Olmesartan medoxomil and olmesartan have the chemical structures:
The closest prior art structure to Daiichi's olmesartan is DuPont's Example 6, disclosed in U.S. Patent No. 5,137,902, which differs from olmesartan in that it lacks a single oxygen atom at the 4-position of the imidazole ring. DuPont's Example 6 has the chemical structure (wherein the circled hydrogen atom in Example 6 is an -OH in olemsartan):
Seeking approval to market generic olmesartan medoxomil, Mylan filed multiple ANDAs with the FDA. In response to Mylan's ANDA filings, Daiichi brought suit against Mylan for infringement of claim 13 of the '599 patent. The parties stipulated to infringement, leaving Mylan's counterclaim that claim 13 would have been obvious in light of: (1) the ARBs disclosed in DuPont's '902 patent, (2) Example 118 in DuPont's '069 patent, and (3) the well-known use of medoxomil as a prodrug. In particular, Mylan contended that one of skill in the art would have been motivated to select the ARBs disclosed in DuPont's '902 patent as lead compounds, and then modify the lipophilic alkyl groups at the 4-position of those compounds with olmesartan's hydrophilic hydroxyalkyl group in view of Example 118.
In affirming the District Court's finding of nonobviousness, the Federal Circuit agreed with Daiichi in determining that Mylan failed to show (1) that one of ordinary skill in the art would have been motivated to select the ARBs disclosed in DuPont's '902 patent as lead compounds or (2) that the skilled artisan would have been motivated to modify the '902 patent compounds to synthesize olmesartan medoxomil. The Court began its analysis by citingEisai Co. Ltd. v. Dr. Reddy's Labs., Ltd., 533 F.3d 1353 (Fed. Cir. 2008), andTakeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350 (Fed. Cir. 2007), for the proposition that:
Panel: Circuit Judges Lourie, Friedman, and Linn
Opinion by Circuit Judge Lourie