Full opinion text
FINDINGS OF FACT AND CONCLUSIONS OF LAW FOLLOWING BENCH TRIAL SARAH EVANS BARKER, District Judge. This matter is before the Court for decision on the issues of validity, enforceability, and infringement of various patents held by Plaintiff, Eli Lilly and Company (“Lilly”). Lilly holds an approved New Drug Application (“NDA”) No. 20-815 directed toward the use of raloxifene hydrochloride 60 mg tablets for the prevention or treatment of osteoporosis in post-menopausal women. Lilly markets the product disclosed in NDA No. 20-815 under the tradename EVISTA®. In connection with this NDA, Lilly listed twelve patents in the Orange Book, including: U.S. Patent Nos. 5,393,763 (“the '763 patent”); RE39,049 (“the '049 patent”); 5,457,117 (“the '117 patent”); RE38,968 (“the '968 patent”); 5,478,847 (“the '847 patent”); RE39,050 (“the '050 patent”); 6,458,811 (“the '811 patent”); 6,797,719 (“the '719 patent”); 6,894,064 (“the '064 patent”); 6,906,086 (“the '086 patent”); 5,811,120 (“the '120 patent”); and 5,972,383 (“the '383 patent”) (collectively, “Lilly’s raloxifene patents”). Defendant, Teva Pharmaceuticals USA, Inc. (“Teva”), subsequently filed an Abbreviated New Drug Application (“ANDA”) No. 78-193 with the FDA for raloxifene hydrochloride 60 mg tablets for the prevention of osteoporosis in postmenopausal women. Teva sought FDA approval to market its generic raloxifene hydrochloride product before expiration of the patents Lilly listed in the Orange Book. Pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV), Teva’s ANDA included a “paragraph IV certification” to Lilly’s raloxifene patents, in which Teva certified that each of Lilly’s raloxifene patents is invalid, unenforceable, or would not be infringed by Teva’s manufacture, use, or sale of its generic raloxifene product. After receiving notice of the ANDA filing and paragraph IV certification, Lilly brought this suit against Teva for infringement of the '086 patent, the '968 patent, and the '049 patent (collectively, “the bone loss patents”); the '050 patent (“the low dose patent”); and the '811 patent, the '719 patent, and the '064 patent (collectively, “the particle size patents”). The bone loss and low dose patents cover the oral administration of raloxifene hydrochloride for prevention or treatment of postmenopausal osteoporosis. The particle size patents cover pharmaceutical compositions containing raloxifene particles having a certain size distribution. Teva concedes infringement of the bone loss patents and the low dose patent if they are found valid and enforceable, but challenges their validity and enforceability on the following grounds: obviousness, lack of enablement, and inequitable conduct. With regard to the particle size patents, Teva contends that its generic raloxifene product does not infringe, and that even if its product did infringe, the particle size patents are invalid on the basis of obviousness and lack of enablement. The hearing on Lilly’s motions for a temporary restraining order and preliminary injunction was consolidated with the trial, which was conducted to the Court over eleven (11) days, between March 9, 2009, and March 24, 2009. On the opening day of trial, Teva notified the Court that it had received notice of final approval from the FDA of its generic raloxifene product. On that same day, the Court entered a TRO prohibiting Teva from launching its generic raloxifene product in the United States for ten days, subject to extension based on the duration of Lilly’s proofs in support of its motion for preliminary injunctive relief. On the second day of trial, Teva informed the Court that it would voluntarily withhold launch of its generic raloxifene product until April 23, 2009, in order to allow the Court to have a sufficient opportunity to rule on the preliminary injunction issues. On April 22, 2009, 609 F.Supp.2d 782, the Court granted Lilly’s renewed motion for injunctive relief, preliminarily enjoining Teva from launching its generic raloxifene product in the United States, effective beginning on April 23, 2009, until the issuance of the Court’s final ruling on the merits. On the last day of trial, a post-trial briefing schedule was set for submission of the parties’ final findings and conclusions, post-trial briefs, and responses. The final submission was due on or before June 22, 2009 [Docket No. 595]. Having now considered the evidence adduced at trial and the parties’ post-trial submissions, we hold, for the reasons set forth in detail below, that: (1) the bone loss patents are valid and enforceable and Teva’s proposed commercial raloxifene product infringes claims 1-3 of the '086 patent; claims 1, 3, and 4 of the '968 patent; claims 1, 2, 5-9,11,12, 19, 20, 28, 31, 33, and 34 of the '049 patent; (2) the low dose patent is valid and enforceable and Teva’s proposed commercial raloxifene product infringes claims 1, 2, 5, 7, and 12-15 of the '050 patent; and (3) claims 1, 3, 6, 7, and 10 of the '811 patent and claims 1-3 of the '064 patent are invalid for lack of written description. Findings of Fact I. The Parties Plaintiff, Lilly, is an Indiana corporation that has its principal place of business in Indianapolis, Indiana. It is engaged in the business of research, development, manufacture, and sale of pharmaceutical products throughout the world. Defendant, Teva, is a Delaware corporation engaged in the business of making and selling both innovative and generic drugs which it distributes in Indiana and throughout the United States. II. The Patents in Suit The '086 patent (PTX 11) and the '968 patent (PTX 16), a reissue of U.S. Patent No. 5,457,117 (PTX 13), were issued to Larry Black. They were thereafter assigned to and are now owned by Lilly. PTX 348A; PTX 6A. The '049 patent (PTX 15), a reissue of U.S. Patent No. 5,393,763 (PTX 12), was issued to Larry Black and George Cullinan and was assigned to, and is now owned by, Lilly. PTX 5A. Collectively referred to as “the bone loss patents,” these patents share a common specification and have an effective U.S. application filing date of July 28, 1992. Lilly asserted claims 1-3 of the '086 patent, claims 1, 3, and 4 of the '968 patent, and claims 1-2, 5-9, 11-12, 19-20, 28, 31, and 33-34 of the '049 patent. The parties agreed by stipulation to present evidence at trial regarding the bone loss patents on representative claims 1, 2, and 3 of the '086 patent. Claim 1 of the '086 patent is representative and provides: 1. A method of inhibiting post-menopausal bone loss in a post-menopausal woman in need of treatment to prevent or treat post-menopausal osteoporosis comprising administering a single daily oral dose to said woman of an effective amount of ... [raloxifene] hydrochloride. PTX 11 at col. 20:2-8. The '050 “low dose” patent (PTX 17), a reissue of U.S. Patent No. 5,478,847 (PTX 14), was issued to Michael Draper and Larry Black. It was assigned to, and is now owned by, Lilly. PTX 347A; PTX 352A at ¶ 9; PTX 2214. It has an effective U.S. filing date of March 2, 1994. Lilly asserted claims 1-2, 5, 7, and 12-15 of the low dose patent. The parties agreed by stipulation to present evidence at trial on representative claims 14 and 15 of the '050 patent. Claim 14 of the low dose patent is representative and reads: 14. A method of preventing post-menopausal osteoporosis in a postmenopausal woman in need of treatment to prevent post-menopausal osteoporosis comprising administering to said woman a hydrochloride salt of ... [raloxifene] in an amount of 60 mg/day. PTX 17, col. 14:65-15:17. The '811 (PTX 18), '719 (PTX 19), and '064 (PTX 20) patents (collectively “the particle size patents”) were issued to Gordon Arbuthnot, Brian Dalder, Kerry Hartauer, Wayne Luke, and Robert Stratford and were assigned to, and are now owned by, Lilly. Hartauer 1237:1-1238:24; PTX 350A. These patents share a common specification and have an effective U.S. application filing date of March 26, 1996. Lilly asserted claims 1-3, 6-7, and 10-12 of the '811 patent. By stipulation, the parties presented evidence at trial on representative claims 1, 3, 6-7, and 10 of the '811 patent. Claims 1 and 6 of the '811 patent are illustrative and read: 1. A compound of formula I [raloxifene] and pharmaceutically acceptable salts and solvates thereof, characterized in that the compound is in particulate form, said particles having a mean particle size of less than about 25 microns, at least about 90% of said particles have a size of less than about 50 microns. 6. A pharmaceutical composition comprising or formulated using a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients. PTX 18, col. 39:24-41; col. 40:37-41. Lilly asserted claims 1-4 and 17-19 of the '719 patent and claims 1-3, 6, 8-9, and 11-12 of the '064 patent. By stipulation, the parties presented evidence at trial on representative claims 1-3' of the '064 patent. The claims of the '719 and '064 patents require a water-soluble diluent and surfactant. PTX 20, cols. 39-40. Claim 1 of the '064 patent is illustrative and provides: 1. A pharmaceutical composition comprising: a) 60 mg of [raloxifene hydrochloride] ... in particulate form, said particles having a mean particle size of less than about 25 microns, at least 90% of said particles have a size of less than about 50 microns; b) a surfactant; and c)a water-soluble diluent. PTX 20, col. 39:23-32. All of these patented inventions are embodied in Lilly’s EVISTA®, raloxifene hydrochloride for prevention and treatment of postmenopausal osteoporosis, introduced in the United States in 1998. PTX 1299. In September 2007, EYISTA® was also approved for reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk of invasive breast cancer. Id. III. The Markman Hearing On June 11, 2008, 2008 WL 2410420, following a Markman hearing, the Court issued its claim construction order construing definitions for disputed claim terms used in the particle size patents. Pursuant to that order, the disputed claims are construed as follows: Disputed Term_Court’s Construction_ surfactant A compound that reduces the surface tension of liquids, or reduces interfacial tension between two _liquids or a liquid and a solid._ water-soluble diluent A pharmaceutically inert substance, capable of being _dissolved in water, that increases the bulk of a tablet. size The equivalent spherical volume diameter of a parti_ele as determined bv laser light diffraction scattering. mean particle size Mean equivalent spherical volume diameter by laser _light diffraction scattering._ less than about 25 A measured value of less than 30.1 microns. microns_ less than about 50 A measured value of less than 67.4 microns. microns_ between 5 and about 20 microns A measured value between 5 microns and 24.1 _microns._ between about 5 and about 25 mi- A measured value between 4.0 microns and 30.1 crons_microns._ between about 5 and about 20 mi- A measured value between 4.0 microns and 24.1 crons_microns._ In addition, the parties stipulated that: “At least about 90%” means “at least 85.5%.” Docket No. 158. IV. The Bone Loss Patents The bone loss patents relate to the administration of a class of drugs known as benzothiophenes, such as raloxifene and raloxifene hydrochloride, for the prevention of bone loss. PTX 11, col. 1:15-17. According to the bone loss patents, osteoporosis is one ailment that may occur as a result of bone loss. Osteoporosis is described as “a major debilitating disease whose prominent feature is the loss of bone mass (decreased density and enlargement of bone spaces) without a reduction in bone volume, producing porosity and fragility.” PTX 11, col. 1:34-38. The bone loss patents characterize the benefits of the invention as follows: “the real benefit of the current discovery is that the benzothiophenes of formula I inhibit the loss of bone but do not elicit significant estrogenic responses in the primary sex target tissues.” PTX 11, col. 3:15-18. Definition of a Person Having Ordinary Skill in the Art for the Bone Loss Patents A person having ordinary skill in the art to whom the bone loss patents are directed would be a person who has at least a Bachelor’s degree in a scientific discipline who has experience performing, or has knowledge about, animal studies and their usefulness in osteoporosis research. Kinney 967:24-968:15. Because the specification of the '086 patent specifically defines and discusses the bioavailability problem associated with raloxifene and researchers in both the bone and cancer fields were publishing on the metabolism issues related to raloxifene and other compounds with free hydroxyl groups around the time of the invention, a person of ordinary skill in the art at the time would also necessarily have a general understanding of the person would be at least conversant in) pharmacokinetics and ADME (absorption, distribution, metabolism, and excretion) characteristics and have a basic background knowledge of how those characteristics relate to the success of a drug. Lindstrom 447:11-16. Postmenopausal Osteoporosis and Early Treatment of the Disease The scientific evidence adduced at trial established that human bone is comprised of two types of bone tissue — trabecular bone, which consists of a lattice work of interconnecting rods and plates, and cortical bone, which is a more solid structure. Russell 74:14-25. Approximately twenty percent (by weight or calcium content) of the adult skeleton is comprised of trabecular bone; cortical bone makes up the other eighty percent. Russell 79:23-80:1. These two types of bone present differing biologies: trabecular bone is more metabolically active and is also particularly responsive to the hormone, estrogen. Russell 80:6-9. Over time, human bones go through a number of changes, primarily due to growth and remodeling. Bone growth occurs lengthwise. During this process, cartilage is present at the region of the growth plate, becomes calcified, and is replaced by trabecular bone. By adulthood, almost all bones in humans have stopped growing because the growth plates have closed and new bone is no longer produced. Russell 82:3-11. Bone remodeling is the process by which the trabecular portion of the bone is removed and then replaced, which changes both the shape and substance of the bone. Russell 82:21-23. Approximately ten percent of the trabecular bone is replaced every year so that, over a ten-year period, the trabecular portion of the bone is entirely replaced. Russell 80:21-24. The first stage of remodeling is bone absorption, whereby cells called “osteoclasts” essentially dig out part of the bone and remove it. The second stage of the remodeling process is bone formation, during which cells called “osteoblasts” replace the bone that was lost via absorption by laying down a protein substance like “collagen.” Russell 83:11— 84:6. 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. Russell 84:18-22. However, when osteoporosis occurs, the replacement of bone during the remodeling process is incomplete, meaning that, at the completion of each remodeling cycle, more bone is removed than is replaced, causing a thinner bone. Russell 85:25-86:6. Thus, the structure of the osteoporotic bone is not as strong as a normal, healthy bone, which makes it prone to fracture; that is the ultimate consequence of osteoporosis. Russell 86:9-12. Osteoporosis is largely a consequence of a lack of sufficient estrogen in the system. Russell 87:10-11. Before menopause, estrogen slows the process of resorption and remodeling, essentially acting as a “brake” on the process. Russell 88:5-8. Following menopause, when women’s bodies lose significant levels of systemic estrogen, the remodeling process becomes much more vigorous. Russell 88:7-9. 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. Russell 86:15-18. 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. Russell 93:15-22. However, there are significant problems associated with ERT, including increased risk of both breast and uterine cancer. Russell 93:22-94:2. Therefore, researchers perceived a need and an opportunity to develop a drug to treat and prevent postmenopausal osteoporosis, which would act like estrogen in preventing bone loss but would not cause such damaging side effects in other tissues. Early Development of Antiestrogens for Use in the Treatment of Breast Cancer The class of compounds known as antiestrogens, which includes raloxifene, were originally developed to be used in the treatment of estrogen-dependent breast cancer. A large number of breast cancers are estrogen dependent, which means that estrogen stimulates their growth. Estrogen-dependent breast cancer cells contain so-called estrogen receptors. Endogenous estrogen, that is, estrogen found naturally within the body, binds to those receptors, stimulating the cancer cells and promoting growth of the cancer. Antiestrogens work to inhibit the growth of the cancer by binding to the estrogen receptors, thereby blocking the action of the estrogen. Russell 95:4-96:7; 99:9-100:6. Some antiestrogens are very potent, allowing only a small amount to displace the natural estrogen. Others are weaker, requiring larger amounts to create the desired effect. Russell 97:13-15. By the 1970’s, two antiestrogen compounds, clomiphene and tamoxifen, were being investigated for their potential anticancer effects. Tamoxifen became one of the first clinically successful antiestrogens used in the treatment of breast cancer. Russell 100:10-11. However, side effects developed from various antiestrogens, including tamoxifen, that were similar to the side effects of estrogen, itself. Russell 102:10-12. Researchers discovered that, when certain antiestrogens were not competing with estrogen for the receptor (i.e., when there was little estrogen already in the system, such as in postmenopausal women), the antiestrogens, themselves, could interact with the estrogen receptors and display estrogenic properties of their own. Russell 102:10-103:2. For example, in the absence of estrogen, antiestrogens were found still to have a stimulatory estrogenic effect in the uterus, which 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. Russell 102:13-15. Tamoxifen, for example, has significant intrinsic estrogenicity; thus, despite being an antiestrogen, at sufficiently high doses it can produce an effect roughly equivalent to forty percent of the effect of estrogen itself. Russell 103:5-14; 103:23-104:2. Early Development of Raloxifene for Use in the Treatment of Breast Cancer Because of concerns associated with these estrogen-like side effects, researchers at Lilly, including Larry Black, set out to find a purer antiestrogen that would have positive effects in breast tissue, but lesser effects in the uterus. Larry Black, Lilly’s inventor, received a Bachelor of Science degree in biological sciences from Indiana Central College in 1966. He joined Lilly in 1966, where he remained employed until his retirement in December of 1993. Black 107:23-109:22. During the 1970’s and 1980’s, Mr. Black worked as a research scientist evaluating antiestrogen compounds, initially for use in the treatment of breast cancer. Black 110:13— 111:1. In the late 1970’s, Mr. Black and another Lilly scientist, Dr. C. David Jones, began their research on the antiestrogenic properties of a family of molecules known as “benzothiophenes.” One of the compounds within that family, known to the researchers only by its Lilly compound number “LY117018,” displayed potential for development. Black 115:2-6. In November 1979, in the course of exploring the properties of molecules structurally related to LY117018, Dr. Jones first synthesized, and Mr. Black subsequently tested, the molecule now known as raloxifene; at that time, it was referred to only by its Lilly compound number “LY139481,” which was an analog of LY117018. Black 131:20-132:18. The chemical structures of LY117018 and raloxifene are virtually identical. Unlike tamoxifen, both LY117018 and raloxifene contain free hydroxyl groups, the significance of which is discussed below. The chemical structure of raloxifene differs from LY117018 only in that the former has a six-membered nitrogen-containing ring, whereas the latter has a fivemembered nitrogen-containing ring. Mr. Black determined that this difference gave raloxifene (LY139481) an improved activity profile, meaning that it had a higher affinity for the estrogen receptor, a lower intrinsic estrogenicity, and a greater ability to antagonize estrogen. Black 115:19— 116:5; 117:11-17. In 1980, a project team was formed at Lilly to bring raloxifene through clinical trials for treatment of breast cancer. In the course of development, Lilly scientists discovered that the hydrochloride salt of raloxifene, identified as “LY156758,” was easily prepared and had somewhat better water solubility. Thus, the decision was made by Lilly scientists to work with raloxifene hydrochloride, which ultimately became the active ingredient in EVISTA®. In 1982, Mr. Black published his findings relating to raloxifene and its hydrochloride salt in an abstract of a presentation he delivered at the San Antonio Breast Cancer Symposium, entitled “LY156758: A Unique Antiestrogen Displaying High Affinity for Estrogen Receptors, Negligible Estrogenic Activity and Near-Total Estrogen Antagonism In Vivo.” PTX 1625. In that abstract, Mr. Black reported that raloxifene produced a very minimal increase in uterine weight (one measure of a compound’s intrinsic estrogenicity) in rats, while tamoxifen caused marked uterine growth. Additionally, he reported that raloxifene did not show any stimulatory effect on the luminal epithelial cells (another measure of a compound’s intrinsic estrogenicity). Id.; Black 134:22-136:1. Bioavailability Issues Associated With Raloxifene The pharmacokinetics of a compound, which term refers to the compound’s absorption into the systemic circulation, its distribution throughout the body followed by its metabolism or conversion into other forms, and excretion out of the body (“ADME characteristics”), present important considerations when determining whether and how to develop a drug for human clinical use. This is because a significant number of drug candidates fail in clinical trials due to ADME problems. Lindstrom 328:3-11; 337:4-18. Thus, in order to optimize bioavailability in humans, Lilly researchers looked for compounds with low metabolism rates that would be well absorbed. Lindstrom 337:13-18. Due in large part to the two free hydroxyl groups in its chemical structure, however, raloxifene proved to be highly metabolized in the liver, that is, the parent compound was converted into a glucuronide conjugate that was rapidly excreted from the body. Lindstrom 341:15-342:7; 342:16-21; 343:13-344:6. In the vast majority of compounds, this process of glucuronidation serves to deactivate the drug. Hayton at 1186:2-5. It was known, in any event, prior to the issuance of the '086 patent, that at least one compound, morphine-6, was active in conjugated form (Hayton 1186:6-11) and that certain enzymes could in some cases reverse the effects of conjugation. Black 139:24-140:7. In preparation for developing raloxifene for the treatment of breast cancer, data relating to raloxifene’s bioavailability was discovered from pre-clinical animal tests performed by Dr. Terry Lindstrom, a member of Lilly’s raloxifene project team. In January 1983, in an abstract entitled “Disposition and Metabolism of a New Antiestro gen, LY156758, in Rats, Dogs, and Monkeys,” and also in 1984, in a comprehensive journal article entitled “Disposition and Metabolism of a New Benzothiophene Antiestrogen in Rats, Dogs, and Monkeys,” Dr. Lindstrom published the results of various animal studies he had conducted using raloxifene in which he found that the bioavailability of the parent raloxifene was approximately 39% in rats, 17% in dogs, and 5% in monkeys. Dr. Lindstrom further noted that in monkeys “the compound occurred primarily as the glucuronide conjugate of parent [raloxifene] with very little circulating free drug.” PTX 684 at EV 7002 956. However, Dr. Lindstrom’s study did not test whether, despite the bioavailability problem, raloxifene had any effect on the animals. Lindstrom 435:11-15. In the drug development process generally, before clinical trials in patients can begin, a compound must first be tested for safety through so-called “Phase I” tests. Thus, before raloxifene could be developed for human use, it had to undergo Phase I pharmacokinetic testing in humans. Lindstrom 472:8-472:18. In September and October 1982, in preparation for testing raloxifene for clinical purposes, Lilly completed a Phase I test of raloxifene using doses of up to 200 mg in male human volunteers. The results of these tests, as reported in Lilly’s internal documents, revealed that, although a considerable amount of the conjugate glucuronide was present in the serum of the human volunteers, attempts to measure the parent raloxifene had been unsuccessful. PTX 594 at EV 141 341; PTX 816 at EV 7250 215. Lilly conducted a second test in male human volunteers in which a 200 mg dose of raloxifene was administered once daily for fourteen days, but levels of parent raloxifene still could not be measured. PTX 597 at EV 141 577. In 1985, raloxifene was given for the first time to humans for clinical purposes in a study conducted by Dr. Aman Buzdar. That study involved giving raloxifene to female breast cancer patients whose cancer had not responded to tamoxifen. In a 1988 article entitled “Phase II Evaluation of Lyl56758 in Metastatic Breast Cancer,” Dr. Buzdar published the results of his study, reporting that, with the exception of one minor response, there were no complete or partial responses to raloxifene. From these results, Dr. Buzdar concluded that raloxifene “did not show any antitumor activity in this study and no further revaluation of this drug is recommended.” PTX 437. Dr. Buzdar did note toxicity results suggesting possible drug effects, including the existence of hot flashes, fatigue, leg cramps, and mild nausea. Id However, there was no placebo control group in Dr. Buzdar’s study, so there was no way to ascertain the existence or frequency of these side effects in untreated women. Kinney 1088:6-24. Although Dr. Buzdar’s reports do not attribute raloxifene’s lack of efficacy to a bioavailability problem, some Lilly researchers, such as Dr. Lindstrom, believed that to be the cause. Lindstrom 366:9-367:4. In August 1987, Alan Schreiber and George Farnbach from the University of Pennsylvania visited Lilly to discuss developing raloxifene for the treatment of autoimmune diseases. A group of Lilly scientists who had been associated with the raloxifene clinical trial was convened to discuss Dr. Sehreiber’s proposal. In an internal memorandum, the group explained its reasons for rejecting the proposal, including their belief that, in light of the rapid glucuronide conjugation, it was “highly unlikely that sufficient [raloxifene] would be available in the serum to have any clinical effect.” PTX 796 at EV 7245 55. On October 5,1987, Lilly’s rejection of Dr. Schreiber’s proposal was communicated by letter to Dr. Farnbach, which stated: “Not insignificant in our consideration of [raloxifene] are the disappointing bioavailability results observed during our Phase I clinical trial.” PTX 1203 at EV 7419 7. Throughout this time period, a number of researchers outside Lilly also published on raloxifene’s rapid metabolic conversion. For example, in 1983, in an article entitled “Antioestrogenic and Antitumour Activities of a Series of Non-Steroidal Antioestrogens,” A.E. Wakeling and B. Valcaccia address the decreased potency of several compounds, including raloxifene, when administered orally versus when administered subcutaneously. Wakeling stated that: Metabolic differences may account for these discrepancies, since, in contrast to tamoxifen and trioxifene, both LY 117018 and LY 139481 [raloxifene] have free hydroxyl groups [citations omitted]. These compounds are likely to be susceptible to rapid conjugation and excretion, particularly when administered orally. PTX 673 at EV 50 1039. Dr. Craig Jordan also published on this issue. In 1983, in an article entitled “Differential Antiestrogen Action in the Immature Rat Uterus: A Comparison of Hydroxylated Antiestrogens with High Affinity for the Estrogen Receptor,” Dr. Jordan and B. Gosden stated that: With regard to pharmacokinetics, LY117018 [the benzothiophene dihydroxyl analog of raloxifene] is a dihydroxylated antiestrogen and, as such, would be expected to be more rapidly conjugated and excreted than monohydroxytamoxifen.... This in fact seems to be the case as LY117018 is excreted from the immature rat five times more rapidly than monohydroxytamoxifen [citations omitted]. If monohydroxytamoxifen is considered to be a short-acting antistrogen compared with tamoxifen [citation omitted] then LY117018 should be classified as an ultra short-acting estrogen antagonist. PTX 913 at 1257. In 1984, Dr. Jordan published a review article entitled “Biochemical Pharmacology of Antiestrogen Action” 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.” PTX 843 at EV 8521 12448. The results discussed above from Lilly’s Phase I testing, in which a significant amount of the conjugate glucuronide was present in the serum of the human volunteers, but no parent raloxifene was measured, were cited in a 1987 article entitled “Hormonal Modulation of Macrophage Clearance of IgG-Sensitized Cells,” by M.C. Sanders, A.I. Levinson, and A.D. Schreiber. In that article, the authors report that, while raloxifene was well-tolerated in the studies, the compound “appears to have a short serum half-life, which may be a result of rapid biotransformation.” PTX 844 at EV 8521 4134. Black’s Studies on the Glucuronide Conjugate of Raloxifene In an effort to address the widely discussed concerns regarding the bioavailability of raloxifene, Mr. Black began to conduct studies to attempt to determine whether, despite its rapid conjugation, the compound could still have efficacy. In 1983, Mr. Black conducted a study on ovariectomized rats in which he lowered the oral dose of raloxifene administered until no parent was detected, yet a large amount of the glucuronide was present, which duplicated the conditions observed in the human subjects in Lilly’s Phase I testing. Despite there being no detectable parent in the serum, Mr. Black was able to measure an end-point response, to wit, an antiestrogenic effect in the uterus of the rat. Black 140:20-141:18; PTX 715. Mr. Black believed that these results showed that the mere fact that the parent was not detectable in the serum did not necessarily indicate that it could produce no effect. Black 141:18-20; see also PTX 715 at EV 7080 1133. Later in 1983, Mr. Black obtained a sample of the raloxifene conjugate from the human subjects in the Phase I tests, which had been isolated from the urine collected from the subjects, which he administered intravenously into rats in an effort to reproduce the condition observed in the human subjects in which only the conjugate was present in the bloodstream. Black 142:25-143:19. Black’s study included a control group and a second group that had been administered the parent raloxifene. The control group showed no effect, but the group administered the conjugate extract showed antiuterotropic activity similar to that caused by the parent compound. Black 143:10-144:8; PTX 817 at EV 7250 222. Thus, Mr. Black concluded that these results supported the conclusion that the lack of detectable parent compound does not necessarily preclude efficacy. Black 144:8-13. The results of this study were not published, but the study is discussed in the '086 patent. Black 145:1-4. Mr. Black obtained a second sample of the human conjugate that had been extracted from the urine of the human subjects involved in the Phase I testing. Using that sample, Mr. Black conducted a study in which he evaluated the effect of the conjugate, the raloxifene parent, an estrogen control group, and a control extract on uterine tissue in vitro, that is to say, in a test tube assay, to determine their respective abilities to bind directly to the estrogen receptor. Black 147:23-148:12. Mr. Black tested the groups at two temperatures — four degrees and twenty-five degrees — and incubated them for one hour, four hours, and twenty-four hours. Black 148:14-20. At four degrees, the estrogen and the parent raloxifene bound normally to the receptor, but neither the blank control nor the conjugate interacted with the estrogen receptor. At twenty-five degrees, the blank control still did not show activity. However, as the conjugate was incubated, it displayed increasing levels of response, and, by twenty-four hours of incubation, its competition for the estrogen receptor was similar to that in the estrogen control and parent raloxifene. Black 149-16-23; PTX 72 at EV 7243 1. From this series of experiments, Mr. Black concluded that, under physiological conditions, the conjugate observed in the human bloodstream could possibly be converted back to the parent compound. Black 151:7-13. The results of these experiments were not published but also were referenced in the '086 patent. Black 151:14-18. The Prior Art to the Bone Loss Patents A. The Beall Article As various antiestrogens were being investigated and developed for clinical use in the treatment of breast cancer, researchers in the field began to hypothesize, based on data sharing, given that estrogen inhibits bone loss and antiestrogens, in some cases, act like estrogen, antiestrogens might also be effective in the treatment of osteoporosis. For example, in 1984, Paula Beall, et al., published an article entitled “Clomiphene Protects Against Osteoporosis in the Mature Ovariectomized Rat” (“the Beall Article”). PTX 1962. The Beall Article disclosed that clomiphene, a mixed estrogen agonist-antagonist, prevents reductions in calcium content, cortical thickness, and trabecular bone in the femurs of ovariectomized rats, and concluded that these results “suggest a possible new line of investigation of the use of antiestrogenic drugs as therapeutic agents for hormone-dependent osteoporosis in animals and humans.” Id. at 123. B.The Jordan Reference Because clomiphene is a partial estrogen, it was unclear whether those estrogen-like properties were responsible for Dr. Beall’s observed response on bone or whether other antiestrogens could also produce such an effect. PTX 218 at 31. In light of the concern that long-term tamoxifen treatment in breast cancer patients could lead to premature bone loss, following the publication of Dr. Beall’s study, Dr. V. Craig Jordan conducted a similar study on intact and ovariectomized 9-month-old retired breeder rats to determine the effects of tamoxifen and raloxifene (then called “keoxifene”) on bone density. In October 1987, the results of that study were published in an article authored by V. Craig Jordan, Erik Phelps, and J. Urban Lindgren entitled “Effects of anti-estrogens on bone in castrated and intact female rats” (“the Jordan Reference”). PTX 218. The Jordan Reference reported that both tamoxifen and raloxifene inhibited bone loss in overiectomized rats and that raloxifene had a minimal estrogenic response in the uterus. Dr. Jordan concluded that these results “may have important implications for the clinical [human] applications of antiestrogens.” Id. at 34. He further stated that “[i]t is possible ... that in the future, tamoxifen could be considered to be used as a substitute for estrogen [for the prevention of osteoporosis in postmenopausal women].” Id. Dr. Jordan called for clinical work to be conducted with tamoxifen to determine whether the results obtained in the rat studies would be applicable to humans: These contrasting pharmacological actions of antiestrogens suggest that patients receiving long-term adjuvant tamoxifen therapy for breast cancer should be evaluated to determine whether tamoxifen can retard the development of osteoporosis. Id. at 31. The Jordan Reference did not discuss further development of raloxifene for the purpose of treating or preventing postmenopausal osteoporosis. At the time, only tamoxifen had been approved for clinical use in humans. Kinney 963:17-23. C. The Feldmann Article In 1989, in an article entitled “Antiestrogen and Antiandrogen Administration Reduce Bone Mass in the Rat” (“the Feldmann Article”), S. Feldmann et al. reported, contrary to the Jordan Reference, that raloxifene did not inhibit bone loss in ovariectomized rats and that tamoxifen produced an effect only at the highest dose administered. PTX 181 at 251. Dr. Feldmann noted that the lack of an effect observed with raloxifene “might be a dosage problem,” but concluded that “an antiestrogen which does not show an estrogenic effect on sex organs, will not with respect to bones.” Id. at 250-51. As discussed above, by the time the Feldmann Article was published, it was known in the field that raloxifene was a relatively pure antiestrogen that had a negligible estrogenic effect in the uterus. D. The Turken and Love Articles The 1987 article by Sheila Turken et al. entitled “Effects of Tamoxifen on Spinal Bone Density in Women With Breast Cancer” (“the Turken Article”) disclosed the results of a study examining the effect of tamoxifen on the bone mineral density of the spine over one year of its administration to post-menopausal women with a history of breast cancer. PTX 1969. The Turken Article disclosed that tamoxifen preserved the spinal bone mineral density in the postmenopausal breast cancer patients, whereas healthy bone mineral control subjects experienced a significant loss of spinal bone mineral over the same period of time. Id. at 1088. In March 1992, in an article entitled “Effects of Tamoxifen on Bone Mineral Density in Postmenopausal Women With Breast Cancer” (“the Love Article”), Richard Love et al. published results of a study on the effects of tamoxifen on spinal bone density in postmenopausal women with breast cancer. PTX 1917. Similar to the results disclosed in the Turken Article, Dr. Love disclosed that tamoxifen is associated with preservation of the bone mineral density of the lumbar spine in postmenopausal women. Id. at EV 8521 13098. E. The Moon Article In 1991, Lilly Moon et al. published an article entitled “Dose-Dependent Effects of Tamoxifen on Long Bones in Growing Rats: Influence of Ovarian Status” (“the Moon Article”). PTX 349. The Moon Article disclosed the results of a study testing the effects of tamoxifen on bone in intact and ovariectomized rats in which tamoxifen treatment prevented the decrease of trabecular bone volume in the ovariectomized rats, but resulted only in a small decrease in intact rats with the highest dose. Id. at 1568. Dr. Moon concludes that these results “are consistent with tamoxifen behaving as a partial estrogen agonist on rat bone.” Id. The study published in the Moon Article did not test raloxifene, but with regard to tamoxifen, the authors conclude that their “findings are consistent with the results of Jordan et al. [citation to the Jordan Reference], who reported that tamoxifen reduced the decrease in femur ash weight/volume in adult OVX [ovariectomized] rats, but did not alter this measurement in intact rats.” Id. at 1573. Distinguishing the conflicting results of tamoxifen’s effect on bone in ovariectomized rats reported in the Feldmann Article, Dr. Moon criticized the measurement technique used in the study, the lack of a baseline control group, and the failure to include an estrogen-treated group in the study. Id. at 1573-74. F. The '068 (“Jones”) Patent In 1981, Lilly filed an application that claimed the discovery of a class of compounds, including raloxifene. On November 29, 1983, the patent application issued to Charles Jones as U.S. Patent No. 4,418,-068 (“the Jones patent”). The Jones patent teaches that the claimed compounds have less inherent estrogenicity and cause fewer estrogenic side effects than earlier compounds, such as tamoxifen. PTX 2029 at col. 37:28-46. It also discloses that raloxifene can be administered in a pharmaceutical composition such as a tablet “formulated to contain a daily dose” (PTX 2029 at col. 39:7-11) and that it can be administered in dosages ranging from 0.05 mg/kg/day up to about 50 mg/kg/day. PTX 2029 at col. 38:55-58. The Invention and the '086 Patent In 1984, Mr. Black’s raloxifene research shifted from the study of raloxifene’s possible use in the treatment of breast cancer to a new therapeutic target, the menopausal syndrome, a component of which is postmenopausal osteoporosis. Black 154:23-155:7; 157:2-20. In February 1987, a proposal for Lilly’s bone biology program targeted the investigation of the benzothiophene series of compounds in an effort to find an alternative to estrogen for the treatment of postmenopausal osteoporosis that would have advantages, such as reducing estrogenicity in the breast and uterus tissues, but that would also have an effect on bone and other menopausal problems. Black 160:2-18; see PTX 1806. In March 1988, Mr. Black began his experiments to study the effects of raloxifene on bone in various ovariectomized rat models. Initially, he experienced difficulty in finding a validated animal model that would consistently demonstrate bone loss from which it could then be shown to be prevented by estrogen. Black at 173:17-22. In a series of experiments beginning in July 1988, Mr. Black used an older, retired breeder rat model, but found inconsistent results in his intact controls. In some of the experiments, he was unable to demonstrate bone loss upon ovariectomy with the retired rat model, but in other experiments, the retired breeder rats did show bone loss upon ovariectomy, which led him to conclude that the retired breeder rat was an unreliable model for bone loss. Black 174:12-18. Mr. Black next undertook similar experiments using an approximately 3-month-old virgin rat model, which he determined showed bone loss with ovariectomy and prevention of the bone loss with estrogen. Black 187:24-188:13. In March 1989, he studied the effects of raloxifene on the younger ovariectomized rat model, the results of which study revealed that the mean trabecular bone density observed for raloxifene was statistically significantly greater than the control. This finding led him to conclude that raloxifene prevented bone loss in that model. Black 191:1-23. In November 1991, Lilly’s PTAC approved a human clinical trial of raloxifene in postmenopausal women for the treatment of postmenopausal osteoporosis. Black 192:12-22. However, significant concerns regarding bioavailability issues were raised at the PTAC meeting relating to raloxifene. Many of the members were concerned about going forward with a compound that was associated with known ADME issues. According to Dr. Thomas Bumol, a member of PTAC at the time, the committee gave its approval for the clinical test despite these concerns, at least in part because Lilly already had an open IND on raloxifene, which would allow the clinical tests to be conducted within six months, rather than the usual twelve to twenty-four months. Bumol 491:5^92:7. Before the results of the PTAC-approved clinical study had been collected, Lilly filed its patent application for the bone loss patents. Thus, there is no clinical human data included in the '086 patent. However, the PTAC-approved clinical study is described as Example 5 of the '086 patent, using doses of 200 mg per day and 600 mg per day. PTX 11 at col. 18:15-col. 19:20. Example 1 of the '086 patent explains Mr. Black’s study on ovariectomized rats and provides the mean results of assays using raloxifene in four different doses on thirty rats per dose. PTX 11 at col. 14:55-col. 16:10. The patent specification addresses the bioavailability issue and provides a rationale, derived from the results of the studies Mr. Black conducted in which he administered the glucuronide conjugate found in the bloodstream of the human subjects to rats, explaining the reason that the conjugation would not necessarily be detrimental to the efficacy of raloxifene in humans. PTX 11 at col. 3:28-60. In May 1992, enrollment began for Lilly’s Phase II, GGGB “proof of concept” study to test raloxifene’s efficacy in humans described in Example 5 of the '086 patent. See PTX 339 at EV 133 2499. It was conducted by Dr. Michael Draper. The study ran from September 1992 to December 1992 and the results came back at the beginning of January 1993. Draper 683:14-684:1. Both the 200 mg and the 600 mg doses of raloxifene showed statistically significant changes in one or more of the bone markers tested, unequivocally demonstrating activity in humans. Draper 688:3-689:22. The patent examiner twice rejected the original parent application to the '086 patent, based on the Jordan Reference. Following these rejections, Lilly scientist, Dr. Henry Bryant, submitted a declaration dated January 11,1994, in which he asserted that, at the time of the invention, he would have had doubts about the conclusions set forth in the Jordan Reference because: (1) Dr. Jordan’s statistical analysis was flawed; (2) the rats used in Dr. Jordan’s research were an inappropriate model; (3) Dr. Jordan’s measurement techniques were improper, and (4) Dr. Jordan was an expert in cancer, not in bone, and his article was not published in a bone journal. PTX 217. On June 16, 1994, following a third rejection by the patent examiner, the Lilly patent attorney in charge of the prosecution of the bone loss patents at the time, James Sales, submitted a response to the PTO’s final rejection, reiterating the criticisms raised in Dr. Bryant’s declaration. PTX 2-TA at 430-31. The parent application to the '086 patent was subsequently allowed by the examiner. Lilly’s Criticisms of the Jordan Study Lilly based its appeals of the PTO rulings on its view that the Jordan study was flawed in terms of making raloxifene obvious for the treatment of osteoporosis. Part of Lilly’s criticism was based on the statistical methodology used by Dr. Jordan. In the Jordan Reference, Lilly pointed out, the Student’s t-test was used in the statistical analysis to compare five treatment groups. Lilly argued that the Student’s t-test is an appropriate statistical method to evaluate differences between two groups and that a properly conducted Student’s t-test would demonstrate that two groups are statistically different at a ninety-five percent confidence level. Miller 542:4-8; 543:11-15. However, as more and more groups are compared against the control, the likelihood increases that the Student’s t-test will show a difference simply by chance, which is called a Type I error. Russell 650:10-23. Therefore, Student’s t-test can appropriately be used to compare multiple groups when a publication concludes that a compound has no effect at all, because, when used on multiple groups, Student’s t-test is more likely to show a difference when there is not actually a difference than to inaccurately show no effect. Russell 649:2-18. Nevertheless, in exploratory drug research, it can be preferable to have a Type I error (false positive) over a Type II error (false negative) because the cost of a false positive is merely that further testing will show that the drug actually does not work, while the cost of a false negative is that a potentially valuable drug is eliminated from further study. Buncher Rep. ¶¶ 37-41. As discussed above, depending on their reproductive history, retired breeders rats, such as those used in Dr. Jordan’s study, can have varying levels of trabecular bone based on how recently they went through the lactation process. Also, as previously noted, when the animals go through reproductive cycles, they lose a significant amount of trabecular bone due to lactation. Following lactation, there is a recovery phase during which the rats recover their lost bone mass. Thus, if a retired breeder rat has too recently been lactating, its trabecular bone may be so depleted that it is unable to show bone loss upon ovariectomy, which can affect the results of a bone loss prevention study. Miller 513:25-514:15. Although variability in the retired breeder rat model can occur, it does not necessarily lead to unreliable outcomes, if a baseline control study is performed and the experiment continues a sufficient period of time to allow the transient effects due to lactation to pass. Kinney 1024:21-1025:14. To be a proper model for osteoporosis, an animal model must, as is the case with the osteoporotic woman, lose bone upon ovariectomy but also have estrogen sensitivity, so that estrogen can be shown to inhibit that bone loss. Miller 512:16-513:4. A drug can then be compared against the estrogen control to determine its effect. Miller 513:12-22. Although estrogen slowed the decrease in bone density produced by ovariectomy in Dr. Jordan’s study, the decrease “was not statistically significant.” PTX 218 at 34. However, the Jordan Reference explicitly provided that it is known that estrogen can reverse osteoporosis in rats and that a low dose of estradiol benzoate was purposefully selected to control the weight gain observed upon overiectomy. Id. Y. The Low Dose Patent The low dose patent is generally directed to the art of dosing regimen design. Hayton 1112:17-21. The concept that the '050 patent adds to the bone loss patents, which claim that raloxifene will prevent or treat postmenopausal osteoporosis, is a particular dosage level at which to administer raloxifene. Specifically, the '050 patent discloses the GGGC study conducted by Lilly, which tested doses of 10, 50, and 200 mg/day and claims a 60 mg/day dose of raloxifene as a method of preventing or treating osteoporosis in postmenopausal women. PTX 17. Definition of a Person Having Ordinary Skill in the Art for the Low Dose Patent A person having ordinary skill in the art of the '050 patent would not have to have a specific educational background, but would need experience in the application of dosing regimen design principles to the design or interpretation of clinical trials. Hayton 1113:23-1114:8. Because the '050 patent is directed to using raloxifene at a specific dose to treat or prevent postmenopausal osteoporosis, a person having ordinary skill in the art would also have to have some knowledge about research regarding postmenopausal osteoporosis and the ADME characteristics of raloxifene to have an understanding of whether the drug could be beneficial in treating or preventing the disease. Miller 574:1-7; Lindstrom 445:5-447:16. The GGGB Study and the Hong Kong Papers As discussed above, in September 1992, prior to the filing of the March 2, 1994, application that led to the low dose patent, Dr. Draper designed and conducted the GGGB “proof of concept” study testing doses of 200 and 600 mg/day of raloxifene in order to demonstrate Mr. Black’s basic invention in humans. Draper 683:6-20; see PTX 339. Dr. Draper chose the doses to be used in the GGGB study. Draper 683:9-11. According to Dr. Draper, he selected the 200 mg dose because it had previously been deemed a safe dose for humans in Lilly’s earlier cancer studies, such as the Buzdar cancer study conducted in 1988. Draper 682:21-24; 711:17-712:3. He chose the 600 mg dose because it was a multiple of the 200 mg dose and was the highest dose that Lilly’s toxicologists had informed him would be safe to administer in humans. Draper 680:4-14; 682:21-22; 712:4-10. Dr. Draper testified that, in light of the known bioavailability concerns associated with raloxifene, he wanted to use the highest dose possible of the drug in the proof of concept study in order to ensure that a lack of response did not merely indicate that a sufficiently high dose had not been administered. Draper 680:15-681:2. In addition to the 200 mg and 600 mg dosage groups, the GGGB study included a placebo group and an estrogen comparator group in order to observe how the effect seen with raloxifene, if any, compared to that of estrogen. Draper 682:14-20. In January 1993, the results of the GGGB study revealed that both the 200 mg and the 600 mg doses of raloxifene showed statistically significant changes in one or more of the bone markers tested, for the first time unequivocally demonstrating that raloxifene showed activity in humans. Draper at 688:3-689:22. The 600 mg dose showed a statistically significant change in both serum osteocalcin and serum alkalin phosphate, two biochemical markers of antiresorptive activity in bone. Similar to the 600 mg dose, the 200 mg showed a statistically significant change in serum alkalin phosphate. However, although there was a slight change in the serum osteocalcin with the 200 mg dose, it was not statistically significant. Draper 687:12-689:10; 698:2-10; see PTX 336. According to Dr. Draper, these results established that the 600 mg/day dose would be an effective antiresorptive dose and that the 200 mg/day dose showed “some suggestion” of effectiveness. Draper 689:12-22. In March 1993, Dr. Draper presented the results of the GGGB study at the Fourth International Symposium on Osteoporosis in Hong Kong. Shortly after the presentation, various articles were published discussing the results, including an article entitled “Effects of Raloxifene (LY134981 HC1) on Biochemical Markers of Bone and Lipid Metabolism in Healthy Postmenopausal Women,” co-authored by Dr. Draper, D.E. Flowers, W.J. Huster, and J.A. Neild (“the Draper Article”) (PTX 436), an abstract coauthored by Dr. Flowers and Dr. Huster (“the Draper Abstract”) (PTX 324), and reports in the newsletter Scrip World, Pharmaceutical News (“the Scrip Article”) (PTX 435) and the medical journal The Lancet (“the Lancet Article”) (PTX 434), collectively referred to as “the Hong Kong Papers.” It is undisputed that Dr. Draper was the Lilly scientist primarily responsible for designing and conducting the GGGB study that is disclosed in the publications and, at trial, Dr. Draper testified that, while the co-authors of the Draper Article and the Draper Abstract assisted with the clinical trial and in drafting the documents, they did not contribute to the selection of the doses. Draper 686:5-687:7. The Invention and the '050 Patent After the results of the GGGB study showed activity in humans, but still prior to the application date of the '050 patent, Dr. Draper designed and conducted the GGGC study, which was a dose response trial designed to further characterize the dose response curve of raloxifene. Draper 727:14-728:22. The GGGC study was the first of a number of dose-ranging studies conducted by Lilly in order to determine the minimal effective dose of raloxifene. As mentioned above, Dr. Draper chose 10, 50, and 200 mg/day doses for the GGGC study. According to Dr. Draper, although raloxifene’s complex pharmacokinetic profile (or ADME characteristics) necessitated the proof of concept (GGGB) study to determine whether raloxifene would even be active in humans, it did not drive his dose selection process for the GGGC study because “assays of effectiveness [of any drug] have nothing to do with the pharmacokinetics of the drug.” Draper 729:8-25. Dr. Draper testified that he chose the 10 mg dose as a placebo or “no-effect” dose and the 200 mg dose because it had shown promising results in the GGGB study. The 50 mg dose was chosen because it was “somewhere in between” 10 mg and 200 mg. Draper 699:4-16. As expected, the results showed no response with the 10 mg dose of raloxifene. The 200 mg dose effected statistically significant changes in both serum alkaline phosphatase and serum osteocalcin, the two bone markers tested in the GGGC study. Draper 700:14-701:5. The 50 mg dose also showed a change in both of those bone markers; however, neither change was statistically significant. Draper 701:6-17. Notwithstanding the absence of statistical significance, Dr. Draper nevertheless believed that there was a possibility that the drug was in fact working at that dose, but that it just needed to develop over a longer period of time in order to be fully effective. Draper 701:18-702:6; 702:20-24; see PTX 17 at col. 13:3-6 (“Because of development over time seen with many bone markers, a raloxifene dose of 50 mg/day will likely be fully active when evaluated during a study of longer duration.”). This conclusion was supported by the changes Dr. Draper observed with the 50 mg dose in serum lipids, which are more responsive to change at an earlier time period than the bone markers. Draper 702:7-24; see PTX 17 at col. 13:30-40. Following the GGGC study, Dr. Draper planned two Phase 3 clinical studies in which different doses of raloxifene would be tested. Based on the effect observed with the 50 mg dose, Dr. Draper chose doses of 30, 60, and 150 mg/day of raloxifene for those studies, reporting on October 28, 1993, to Lilly’s Global Plans Approval Committee that “[t]he marketed dose is expected to be 60 milligrams.” PTX 1687 at EV 7124 434; see also Draper 705:19-706:24. Before the results of the Phase 3 studies were collected, the May 2, 1994, application for the '050 patent was filed, based solely on the results of the GGGC study. The low dose patent disclosed the 60 mg/day dose of raloxifene as a dose that would work to treat or prevent osteoporosis in postmenopausal women. Draper 698:11-699:24; Ettinger 782:2-4; PTX 287. Following a number of longer, more extensive clinical tests conducted after the filing of the low dose patent application, the 60 mg/day dose came to be recognized as the optimal dose of raloxifene for such treatment and prevention. Ettinger 788:6-10. Advantages of the 60 mg/day Dose The '050 patent does not identify any advantage to the claimed 60 mg/day dose over any other dose, nor does it identify any “unexpected result” for the 60 mg/day dose. Ettinger 789:11-18; Hayton 1164:17-1165:1. However, approximately four years after the application for the '050 patent was filed, based upon data gathered from a long term clinical trial (“MORE” study), Lilly found that the side effect profile of the 60 mg/day dose evidences two statistically significant advantages over the 120 mg/day. The MORE study demonstrated that the 120 mg/day dose is disadvantageous compared to the 60 mg/day dose in terms of overall mortality and incidence of “vasomotor” side effects, e.g., hot flashes. Draper 708:4-23; 709:7-21; PTX 438 at Tbls. 2-3; PTX 661 at EV 307 615 (Tbl. 4). After the application for the low dose patent was filed, Lilly also found through experience using raloxifene to treat or prevent postmenopausal osteoporosis at a dose of 60 mg/day that such treatment reduces the risk of invasive breast cancer in women so treated. See Ettinger 762:11-18; PTX 1299. Lilly’s Failure to Disclose the Jordan Reference During Prosec