The U.S. Court of Appeal for the Federal Circuit affirmed a district court’s holding that Mylan failed to establish a prima facie case of obviousness for Daiichi’s olmesartan medoxomil, which is the active ingredient in Benicar®, an angiotensin receptor blocker (ARB) used to treat high blood pressure. Daiichi Sankyo Company, Ltd. v. Matrix Laboratories, Ltd., Case No. 09-1511 (Fed. Cir., Sept. 9, 2010) (Lourie, J.).

In chemical cases, the standard for determining whether a claimed compound is obvious is analyzed under what has become known as the "lead compound" doctrine. The Federal Circuit has stated in cases such as Eisai and Takeda that obviousness based on structural similarity can be proved by identification of some motivation that would have led a medicinal chemist of ordinary skill in the art to select and then modify a known compound (e.g., a lead compound) in a particular way to achieve the claimed compound.

Mylan filed multiple Abbreviated New Drug Applications with Paragraph IV certifications challenging Daiichi’s patent directed to olmesartan medoxomil and seeking U.S. Food and Drug Administration (FDA) approval to market generic olmesartan medoxomil. Daiichi filed suit against Mylan alleging infringement. Olmesartan medoxomil consists of an imidazole ring comprising, among other substituents, a hydrophilic group at the 4-position. Other second-generation ARBs have a lipophilic group at the 4-position of the imidazole ring

The parties subsequently stipulated to infringement, leaving only Mylan’s counterclaim that the claimed subject matter would have been obvious in light of the following: second-generation ARBs (i.e., lead compounds) in prior art U.S. Patent No. 5,137,902; example 118 in U.S. Patent 5,138,069 that allegedly provided motivation for one of ordinary skill in the art to replace a lipophilic group of the ’902 compounds with the hydrophilic hydroxyalkyl group of the claimed compound; and the well-known use of medoxomil as a prodrug. The district court held that Mylan failed to establish a prima facie case of obviousness. The district court also found evidence of unexpected results based on olmesartan medoxomil’s favorable biological properties (e.g., enhanced potency) and commercial success based upon significant market penetration of Benicar® despite it being the seventh ARB on the market.

On appeal, the Federal Circuit cited to its earlier decisions and agreed with Daiichi that Mylan failed to demonstrate either that one of ordinary skill in the art would have been motivated to select the ARBs disclosed in the prior art ’902 patent as lead compounds or that the skilled artisan would have modified the ’902 compounds to produce olmesartan medoxomil. Mylan argued that the ’902 compounds structurally are the closest prior art and "should have been dispositive of the lead compound issue." The Court stated that selection of a lead compound requires consideration of structural similarity, but also knowledge in the art of the functional properties and limitations of the prior art compounds. Of note, the Court stated that "potent and promising [compound] activity trumps mere structural relationships."

Mylan also argued that example 118 in the ’902 patent provides motivation for the skilled artisan because it contains a compound with a lipophilic group. In response, the Court stated that the few compounds with a hydrophilic group are "drowned out" by the sea of compounds with lipophilic groups at the same position. The Court further stated that the district court correctly found that the prior art taught away from replacing the lipophilic group of the ’902 compounds with a hydrophilic group to arrive at the olmesartan medoxomil. To support its position, the Court cited the structure-activity relationship data in the ’069 patent and lipophilic, not hydrophilic, groups in other second-generation ARBs. Consistent with KSR, the Court considered how the skilled artisan would have viewed the prior art as a whole rather than in a vacuum.

Since the Federal Circuit affirmed the district court’s findings that Mylan failed to establish either that the skilled artisan would have selected the ’902 patent ARBs as lead compounds or that one of ordinary skill in the art would have modified the ’902 patent ARBs at the 4-position of the imidazole ring to obtain olmesartan medoxomil, it did not address the district court’s alternative grounds for holding that Mylan failed to establish a prima facie case of obviousness or its findings on secondary considerations.