The U.S. Court of Appeals for the Federal Circuit affirmed a district court’s findings of non-obviousness of four Eli Lilly & Co. patents, as well as a finding of invalidity of certain claims in two other Lilly patents for lack of written description. The Court also rejected Teva Pharmaceuticals USA Inc.’s bid to overturn a permanent injunction barring it from launching a copy of Lilly’s osteoporosis drug Evista® before March 2014. Eli Lilly & Co. v. Teva Pharmaceuticals USA Inc., Case Nos. 10-1005, -1033 (Fed. Cir., Sept. 1, 2010) (Rader, C.J.)
Lilly’s drug Evista is a treatment for postmenopausal osteoporosis. The active ingredient of Evista is raloxifene hydrochloride, which is classified as an antiestrogen. Antiestrogens, such as tamoxifen, block the effects of endogenous estrogen by competing with estrogen in receptor binding and are used to treat estrogen-dependent breast cancers. However, antiestrogens may have their own stimulatory estrogenic effect (referred to as intrinsic estrogenicity) on the uterus, particularly when endogenous levels of estrogen are low, such as in postmenopausal women. Increased intrinsic estrogenicity has been associated with an increased risk of endometrial cancer.
Raloxifene was first synthesized in the late 1970s. Pre-clinical and Phase I studies revealed it had low intrinsic estrogenicity, but appeared to have poor bioavailability, in part due to rapid conjugation to a different form. A published Phase II study reported that raloxifene did not show any antitumor activity, and recommended against further evaluations of the drug. However, Lilly determined that the rapid conjugation did not necessarily preclude efficacy and found that the conjugated form might be converted back to the parent compound under physiological conditions. Lilly undertook a Phase II study that showed raloxifene’s efficacy in inhibiting post-menopausal bone loss.
Lilly owns three families of patents directed to raloxifene: the "Bone Loss Patents," the "Low Dose Patent" and the "Particle Size Patents." The Bone Loss Patents are directed to a method of inhibiting post-menopausal bone loss by administering "an effective amount of" raloxifene. The Low Dose Patent is directed to the same method, but administration of 60 mg/day of raloxifene. The Particle Size Patents disclose that, within the claimed size rage, raloxifene particles provide "surprisingly consistent in vivo absorption/bioavailability characteristics" as well as manufacturing benefits.
Teva filed Abbreviated New Drug Application (ANDA) No. 78-193 with the U.S. Food and Drug Administration (FDA) for generic raloxifene. After an 11-day bench trial, the district court ruled that Teva failed to show the Bone Loss Patents and the Low Dose Patent were obvious and that the Particle Size Patents were invalid for failure to comply with the written description requirement of §112.
The Federal Circuit was unconvinced that Teva’s three primary prior art references rendered the Bone Loss and Low Dose Patents obvious, finding that in view of publications reporting concerns regarding raloxifene’s bioavailability, an ordinary artisan would not have had a reasonable expectation of successfully using raloxifene to treat any human condition.
Teva argued that because Lilly pursued raloxifene as a potential treatment, this indicates a person of ordinary skill would have had a reasonable expectation of success because "Lilly scientists … had to have a basis for reasonably believing raloxifene would work in humans" before pursuing costly clinical trials and research. Teva also argued the Bone Loss Patents and Low Dose Patent failed to meet the enablement requirement because of the prevailing view that raloxifene would not work in humans. The Court rejected this argument because the Bone Loss Patents included information regarding raloxifene’s bioavailability that were not found in the prior art, specifically, Lilly’s studies showing that conjugation of raloxifene might not affect its efficacy in treating bone loss and the details of Lilly’s then-ongoing human clinical trials of raloxifene. In addressing both of these arguments, the Federal Circuit admonished Teva for conflating Lilly scientists with those of ordinary skill in the art, because they "had both knowledge and credentials superior to the ordinary artisan."
During the litigation, Teva altered the particle size specification of its bulk raloxifene, avoiding the limitations of the Particle Size Patents. However, Lilly contended that upon processing the artificially large particles fracture into smaller particles that fall within the size range claimed in the Particle Size Patents. The district court determined that the question of infringement turned on an issue of claim construction, namely, "whether the particle size patents claim only size measurements made on bulk raloxifene before it is formulated or, by contrast, whether the patents also claim the particle size of raloxifene within a formulated tablet, as measured after extraction from the tablet." The district court concluded that the limitation "in particulate form" as used in the Particle Size Patents should be construed broadly to include raloxifene particles both before and after formulation and concluded that the breadth of the limitation rendered the Particle Size Patents invalid for failure to comply with the written description requirement. The Federal Circuit affirmed.