Bristol-Myers Squibb Co. v. Teva Pharmaceuticals USA, Inc. (752 F.3d 967, 2014)

CHEN, Circuit Judge.

This patent infringement case concerns a drug for the treatment of hepatitis B. After a four-day bench trial, the United States District Court for the District of Delaware found claim 8 of U.S. Patent No. 5,206,244 (’244 patent) invalid as obvious. We affirm the district court’s invalidity judgment for the reasons that follow.

I.

Appellant Bristol-Myers Squibb Co. (BMS) owns the '244 patent. Claim 8 of the '244 patent is directed to a nucleoside analog composed of two regions: a carbo-cyclic ring and a guanine base. Nucleo-side analogs are manmade compounds designed to mimic the activity of natural nucleosides, the building blocks of DNA and RNA. These compounds are modified slightly from their natural counterparts to interfere with the replication of viral DNA — which means that they can serve as possible antiviral compounds. Claim 8 covers one such compound, entecavir. BMS markets entecavir as a treatment for hepatitis B under the trade name Bara-clude®.

Entecavir is a modified version of the natural nucleoside 2'-deoxyguanosine (de-oxyguanosine). Entecavir is structurally identical to deoxyguanosine except for one difference: it has a carbon-carbon double bond (also known as an exocyclic methylene group) at the 5' position of the carbo-cyclic ring where deoxyguanosine has an oxygen atom.

The chemical structures of entecavir and deoxyguanosine are illustrated below:

Appellant’s Br. 8; see also J.A. 11.

The structures referenced throughout this opinion include a “carbocyclic ring” of carbon atoms, which is illustrated above as the pentagonal structure at the left of each diagram, and a nucleoside base, which is illustrated above as the double ring structure to the right. In both figures above, the nucleoside base is guanine.

Entecavir is an effective treatment for hepatitis B. The drug is generally accepted as a safe drug, with a broad therapeutic window for treatment, providing for a wide gap between low doses of the drug that are effective against disease and the high doses that could cause .unwanted toxicity. It also has a high genetic barrier to resistance such that, if they have not previously received a nucleoside-based treatment, few patients treated with entecavir develop drug resistance to it.

The appellee, Teva Pharmaceuticals USA, Inc. (Teva), filed an abbreviated new drug application (ANDA) for a generic version of entecavir. In support of its ANDA, Teva filed “Paragraph IV” certifications, alleging that its generic products would not infringe the '244 patent, and/or that the patent was invalid or unenforceable. See 21 U.S.C. § 355