Cross v. Teva Pharm.s USA.. Inc.

• Decision Date: 01 September 2010
• Docket Number: Nos. 2010-1005, 2010-1033.,s. 2010-1005, 2010-1033.
• Citation: 619 F.3d 1329
• Parties: ELI LILLY AND COMPANY, Plaintiff-Cross Appellant, v. TEVA PHARMACEUTICALS USA, INC., Defendant-Appellant.
• Court: U.S. Court of Appeals — Federal Circuit

619 F.3d 1329

ELI LILLY AND COMPANY, Plaintiff-Cross Appellant,

v.TEVA PHARMACEUTICALS USA, INC., Defendant-Appellant.

Nos. 2010-1005, 2010-1033.

United States Court of Appeals,Federal Circuit.

Sept. 1, 2010.

COPYRIGHT MATERIAL OMITTED.

Charles E. Lipsey, Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, of Reston, VA, argued for plaintiff-cross appellant. With him on the brief were L. Scott Burwell; David S. Forman, Howard W. Levine, Laura P. Masurovsky, Mark J. Feldstein, and J. Derek McCorquindale, of Washington, DC. Of counsel on the brief was Gilbert T. Voy, Eli Lilly and Company, of Indianapolis, IN.

Edward H. Rice, Loeb & Loeb LLP, of Chicago, IL, argued for defendant-appellant. With him on the brief were Marina N. Saito, Steven M. Lubezny and Julie P. Samuels.

Before RADER, Chief Judge, LINN and PROST, Circuit Judges.

RADER, Chief Judge.

Following an 11-day bench trial, defendant Teva Pharmaceuticals USA, Inc. (“Teva”) appeals the district court's permanent injunction preventing any manufacture or distribution of a generic version of the drug Evista® until the expiration of U.S. Patent Nos. 6,906,086 (the “'086 patent”); RE39,049 (the “'049 patent”); RE38,968 (the “'968 patent”) (collectively the “Bone Loss Patents”); and RE39,050 (the “'050 patent” or the “Low Dose Patent”). See Eli Lilly & Co. v. Teva Pharms. USA, Inc., 657 F.Supp.2d 967 (S.D.Ind.2009). Plaintiff Eli Lilly & Co. (“Lilly”) cross appeals the district court's ruling that certain claims of its U.S. Patent Nos. 6,458,811 (the “'811 patent”) and 6,894,064 (the “'064 patent”) are invalid for lack of written description. Detecting no reversible error, this court affirms.

I

A

Osteoporosis is a major debilitating disease that causes loss of bone mass (decreased density and enlargement of bone spaces) without a reduction in bone volume. Thus, osteoporosis makes bones porous and fragile.

Healthy human bones go through a number of changes over time, in part due to remodeling. Bone remodeling is the process by which a portion of the bone called the trabecular portion is removed and then replaced. The first stage of remodeling is bone absorption, whereby certain cells essentially dig out part of the bone and remove it. The second stage of the remodeling process is bone formation, or resorption, during which different cells replace the bone that was lost via absorption.

In healthy adults, the skeletal mass remains constant throughout the remodeling process because the amount of bone that is lost is replaced in similar amounts. With the onset of osteoporosis, the remodeling process does not completely replace the lost bone mass. Thus, more bone is removed than is replaced. Accordingly, remodeling leaves a thinner, weaker bone.

Osteoporosis is largely a consequence of a lack of sufficient estrogen in the system. Before menopause, estrogen naturally slows the process of remodeling in women, essentially acting as a “brake” on the process. Following menopause, when women's bodies lose significant levels of systemic estrogen, the remodeling process becomes more vigorous. Osteoporosis is a relatively common condition: approximately one in two women beyond the age of fifty suffers an osteoporotic fracture at some point during the remainder of their lives.

Because osteoporosis results mainly from a lack of estrogen in the system following menopause, the principal treatment, historically, for postmenopausal osteoporosis has been estrogen replacement therapy (“ERT”). ERT successfully prevents bone loss as well as fractures. ERT, however, presents other problems, including increased risk of both breast and uterine cancer. Therefore, researchers sought a therapeutic remedy to treat and prevent postmenopausal osteoporosis that would act like estrogen in preventing bone loss but would not cause damaging side effects in other tissues.

B

Evista® treats postmenopausal osteoporosis. The active ingredient in Evista® is raloxifene hydrochloride. Raloxifene is part of a class of compounds known as antiestrogens, which were originally developed for the treatment of estrogen-dependent breast cancer. A large number of breast cancers are estrogen dependent, which means that estrogen stimulates their growth. Antiestrogens work to inhibit the growth of a cancer by binding to estrogen receptors in breast cancer cells, thereby blocking the action of the estrogen.

Antiestrogens, however, often carry side effects similar to the side effects of estrogen itself. Researchers discovered that when certain antiestrogens were not competing with estrogen for receptors (i.e., when there was little estrogen already in the system, such as in postmenopausal women), the antiestrogens were found to have a stimulatory estrogenic effect in the uterus. This effect was ultimately associated with an increased risk of endometrial cancer.

Various antiestrogens mimic the effect of estrogen in varying degrees, and the degree to which a particular antiestrogen mimics estrogen is referred to as its intrinsic estrogenicity. One of the first clinically successful antiestrogens used in the treatment of breast cancer, tamoxifen, has significant intrinsic estrogenicity.

C

Researchers at Lilly first synthesized and tested the molecule now known as raloxifene in the late 1970s in an effort to find a purer antiestrogen that would have positive effects in breast tissue but less damaging effects in the uterus. Dr. C. David Jones and Mr. Larry Black, the ultimate inventor of the Bone Loss patents, first identified that molecule as “LY156758.”

Mr. Black published his findings in an abstract entitled “LY156758: A Unique Antiestrogen Displaying High Affinity for Estrogen Receptors, Negligible Estrogenic Activity and Near-Total Estrogen Antagonism In Vivo.” In that abstract, published in 1982, Mr. Black reported that raloxifene produced a very minimal increase in uterine weight in rats (one measure of a compound's intrinsic estrogenicity), while tamoxifen caused marked uterine growth.

Lilly completed pharmacokinetic tests of raloxifene, also referred to as “Phase I” tests, in September and October of 1982. A Phase I test is a safety test used generally in the drug development process before clinical trials in patients can begin. The results of Lilly's Phase I tests on raloxifene, as reported in Lilly's internal documents, revealed that the bioavailability of raloxifene was low. In other words, very little of the ingested raloxifene was detected in the human bloodstream.

The results of Lilly's Phase I tests were similar to the results of others published by Dr. Terry Lindstrom, another Lilly scientist, in 1983 and 1984. Dr. Lindstrom conducted various animal studies using raloxifene in which he found that the bioavailability of raloxifene was approximately 39% in rats, 17% in dogs, and 5% in monkeys. Dr. Lindstrom's study did not test whether, despite the bioavailability problem, raloxifene had any effect on the animals.

Although attempts at measuring the parent raloxifene in Lilly's Phase I tests had been unsuccessful, the human volunteers showed a considerable amount of raloxifene conjugated to glucuronide in their serum. A conjugate forms when a molecule in the body attaches to the administered (i.e., “parent”) compound.

Unlike tamoxifen, the chemical structure of raloxifene includes two free hydroxyl groups, which enable the liver to rapidly metabolize the raloxifene. In the vast majority of compounds, the process of glucuronidation serves to deactivate the drug. At least one compound, however, was known to be active in conjugated form (morphine-6), and certain enzymes were known to be able to reverse the effects of conjugation.

A number of researchers outside Lilly also published articles that discussed raloxifene's rapid metabolic conversion. For example, in a 1983 article A.E. Wakeling addressed the decreased potency of several compounds, including raloxifene, when administered orally versus when administered subcutaneously. Dr. Craig Jordan also stated in a 1983 publication that an analog to raloxifene with a similar chemical structure “should be classified as an ultra short-acting estrogen antagonist” when compared to tamoxifen. J.A. 9929. And in 1984, Dr. Jordan published a review article in which he discussed the hydroxylation of compounds such as raloxifene and stated that “[c]learly this will facilitate a rapid metabolism and excretion of those compounds.” J.A. 9929.

Following the Phase I tests, Lilly concluded that “it [was] not appropriate to go directly into breast cancer as first line therapy with a compound so extensively conjugated and possibly poorly bioavailable since other forms of therapy are available.” J.A. 9842. A clinical trial for raloxifene was then initiated in 1985 under the direction of Dr. Aman Buzdar for female breast cancer patients whose cancer had not responded to tamoxifen. Dr. Buzdar published the results of his study in a 1988 article titled “Phase II Evaluation of Ly156758 in Metastatic Breast Cancer.” In that article, Dr. Buzdar reported that, with the exception of one minor response, raloxifene produced no complete or partial responses. From these results, Dr. Buzdar concluded that raloxifene “did not show any antitumor activity ... and no further evaluation of this drug is recommended.” J.A. 6867. Although Dr. Buzdar's reports do not attribute raloxifene's lack of efficacy to a bioavailability problem, Lilly's Dr. Lindstrom testified at trial that he believed the breast cancer trials had failed for that reason. J.A. 3091 at 366:9-367:4.

D

Shortly after completing its Phase I tests on raloxifene, Lilly undertook an effort to determine whether raloxifene could still have efficacy notwithstanding its rapid conjugation. Mr. Black conducted studies on the raloxifene conjugate that led him to two conclusions. First, Mr. Black concluded that the lack of detectable parent compound did not necessarily preclude efficacy. Second, he concluded that, under...