Full opinion text
FINDINGS OF FACT AND CONCLUSIONS OF LAW RICHARD L. YOUNG, Chief Judge. Plaintiffs, Alcon Research, Ltd. (f/k/a Alcon Manufacturing, Ltd.), Alcon Laboratories, Inc. (collectively “Alcon”), and Kyowa Hakko Kirin Co. Ltd. (f/k/a Kyowa Hakko Kogyo Co. Ltd.) (“Kyowa”) (collectively “Plaintiffs”), filed suit against the Defendants, Apotex, Inc. and Apotex Corp. (collectively “Apotex” or “Defendants”), for infringement of United States Patent No. 5,641,805 (“the '805 patent”). The parties tried this case before the court from April 26, 2010, through May 7, 2010. Following the trial, the parties filed proposed findings of fact and conclusions of law. The parties presented their final arguments to the court on August 3, 2010. Being duly advised, the court finds that Plaintiffs have proven, by a preponderance of the evidence, that the Defendants’ generic equivalent of Plaintiffs’ patented allergy topical ocular medication, Patanol®, infringed claims 1-8 of the '805 patent. The court finds that Defendants have failed to prove by clear and convincing evidence that claims 1-8 of the '805 patent are invalid as obvious under 35 U.S.C. § 103, as anticipated under 35 U.S.C. § 102, and for lack of written description under 35 U.S.C. § 112. The court further finds that Defendants have failed to prove by clear and convincing evidence that the '805 patent is unenforceable due to inequitable conduct. The court now issues its findings of fact and conclusions of law pursuant to Federal Rule of Civil Procedure 52(a): FINDINGS OF FACT I. The Parties 1. Alcon Research, Ltd. (f/k/a Alcon Manufacturing, Ltd.) is a corporation organized and existing under the laws of the State of Delaware, having its corporate offices and principal place of business at 6201 South Freeway, Fort Worth, Texas 76134. (Docket # 173, Stipulation ¶ 1). 2. Alcon Laboratories, Inc. is a corporation organized and existing under the laws of the State of Delaware, having its corporate offices and principal place of business at 6201 South Freeway, Fort Worth, Texas 76134. (Docket # 173, Stipulation ¶ 2). 3. Kyowa Hakko Kirin Co., Ltd. (f/k/a Kyowa Hakko Kogyo Co., Ltd.) is a corporation organized and existing under the laws of Japan, having its principal place of business at 1-6-1 Ohtemachi, Chiyoda-ku, Tokyo 100-8185, Japan. (Docket # 173, Stipulation ¶ 3). 4. Apotex, Inc. is a corporation organized and existing under the laws of Canada, having its principal place of business at 150 Signet Dr., Weston, Ontario M9L 1T9. (Docket # 173, Stipulation ¶ 4). 5. Apotex Corp. is a corporation organized and existing under the laws of the State of Delaware, having its principal place of business at 2400 North Commerce Parkway, Suite 400, Weston, Florida 33326. (Docket # 173, Stipulation ¶ 5). 6. Alcon Laboratories, Inc. holds the approved New Drug Application (“ANDA”), #20-688, for Patanol® ophthalmic solution. The NDA was approved on December 18, 1996. (Docket # 173, Stipulation ¶ 6). 7. On June 6, 1995, Alcon Laboratories, Inc. and Kyowa Hakko Kogyo Co. filed United States Patent Application # 08/469,729 (the “'729 application”), naming John Yanni, Stella Robertson, Eiji Hayakawa, and Masashi Nakakura as inventors. (Docket # 173, Stipulation ¶ 7). 8. The '729 application issued on June 24, 1997, as the '805 patent, entitled “Topical Ophthalmic Formulations for Treating Allergic Eye Diseases.” Aeon Laboratories, Inc. and Kyowa Hakko Kogyo Co. Ltd., were the original assignees of the '805 patent. (Docket # 173, Stipulation ¶ 7). 9. Aeon Laboratories, Inc.’s interest in the '805 patent has been subsequently assigned to Aeon Research, Ltd. Aeon Laboratories, Inc. sells drug products covered by the '805 patent under the trademark Patanol® pursuant to an ANDA held by Aeon Laboratories, Inc. and approved by the Food and Drug Administration (“FDA”). (Docket # 173, Stipulation ¶ 8). 10. Kyowa Hakko Kogyo Co., Ltd.’s interest in the '805 patent has been subsequently assigned to Kyowa Hakko Kirin Co., Ltd. (Docket # 173, Stipulation ¶ 9). 11. Patanol® is approved for the treatment of the signs and symptoms of allergic conjunctivitis. TX 131 at NDA000008; NDA000029 (showing approved indications on Patanol®’s label). The active ingredient of Patanol® is olopatadine hydrochloride. The concentration of Patanol® is 1 mg/mL, or 0.1% w/v. (Docket # 173, Stipulation ¶ 10). 12. Apotex is the owner of ANDA # 78-350, which was submitted to the FDA under section 505(j) of the Federal Food, Drug and Cosmetic Act (“FDCA”), and seeks approval to engage in the commercial manufacture, use, and sale of a generic olopatadine hydrochloride product (“Apotex’s product”) prior to the expiration of the '805 patent. (Docket # 173, Stipulation ¶ 13). 13. By letter dated October 2, 2006 (the “Notice Letter”), Apotex notified Plaintiffs that Apotex had submitted ANDA # 78-350 to the FDA. (Answer ¶ 16). In the Notice Letter, Apotex notified Plaintiffs that, as part of its ANDA, it had filed a certification of the type described in section 505(j)(2)(A)(vii)(IV) of the FDCA (“Paragraph IV” certification). (Answer ¶ 18); TX 131 at ANDA000043 (Paragraph IV certification statement). 14. On November 15, 2006, Plaintiffs brought suit against Apotex, asserting infringement of the '805 patent, arising out of Apotex’s filing of ANDA # 78-350. (Docket # 1, Complaint). 15. Jurisdiction and venue are proper in this district pursuant to 28 U.S.C. §§ 1331, 1338(a), 1391, and 1400(b). (Docket # 21, Answer ¶ 8; Docket # 35, Entry on Defendants’ Motion to Transfer-at 3 (no dispute between parties that the Southern District of Indiana is a proper venue)). II. The Science of Allergy and the Invention of Patanol® A. The Human Eye, the Conjunctiva, and Mast Cells 16. Mast cells are specialized cells that exist in many places throughout the body, including the eye, and are the primary cells involved in allergic reactions. (Kaliner Tr. 466:8-469:2, 476:3-24, 484:15-485:3; Bielory Tr. 1033:1-8, 1051:8-16; 1053:8-16). 17. The mast cells in the eye are located in the conjunctiva, which is the mucous membrane that lines the inner surface of the eyelids and the sclera on the front of the eyeball. (Yanni Tr. 113:24-114:20; AA-026.02; AA-027; Kaliner Tr. 459:25-460:3). The conjunctiva does not cover the tissues responsible for sight, including the cornea, lens, and retina. (Yanni Tr. 114:21-115:3; Kaliner Tr. 460:12-18; AA-027). 18. Like all mucous membranes, the conjunctiva is designed to keep things that are meant to be in the body in, and to prevent foreign matter from entering the body. The secretion of mucous on the surface of the membrane removes and flushes foreign objects from the surface of the membrane and protects the surface. (Kaliner Tr. 461:10-463:16; AA-33; AA-71). 19. The mast cells do not reside on the very surface of the eye. Within the conjunctiva, the epithelial goblet cells are located closest to the surface. (Kaliner Tr. 462:20-463:16, 464:15-466:7; AA-071; AA-033). Below the epithelial layer is a basement membrane. (Kaliner Tr. 464:15-466:7; AA-033; AA-071). Below the basement membrane is an area referred to as either the substantia or lamina propria. (Kaliner Tr. 464:15-466:7; AA-033; AA-071). The mast cells in the eye are located below the basement membrane in the substantia propria. (Kaliner Tr. 465:2-13; AA-071). 20. Mast cells contain granules, each of which contain pre-formed mediators. (Kaliner Tr. 467:10-468:15; AA-30; AA-32). Mediators are chemicals that, if released from the mast cells, have some effect on receptors located in the surrounding tissue. (Kaliner Tr. 467:10^168:15; AA-093). Each granule contains up to 25 different types of chemical mediators. (Kaliner Tr. 467:10-468:15; AA-093). 21. Adjacent to the conjunctiva is the conjunctival sac, which contains an extremely small amount of fluid that keeps the tissues moist. (Kaliner Tr. 460:19-461:6; AA-027). B. The Allergic Cascade 1. Mediator Release Through Degranulation 22. The allergic response is a mechanism that the human body uses to attempt to expel something it recognizes as a foreign invading substance. (Yanni Tr. 119:16— 120:4). 23. In the eye, the most common type of allergic disease is called allergic conjunctivitis. (Kaliner Tr. 507:2-13). 24. In general, an allergic reaction can occur in the sensitized human being upon exposure to an antigen. An antigen is a substance that has the ability to trigger an immunologic reaction, such as the production of antibodies. (Yanni Tr. 116:18— 118:14; Kaliner Tr. 470:2-22). 25. Common antigens include substances such as cat dander, pollen, and ragweed. (Yanni Tr. 117:10-118:6; Kaliner Tr. 470:2-22). 26. Exposure occurs when an antigen, like pollen, comes into contact with the outer epithelial layer of the conjunctiva. Small proteins break off from the pollen grain and move through the epithelium, through the basement membrane, and into the substantia or lamina propria where the mast cells are located. (Kaliner Tr. 465:2-13). 27. In the portion of the human population that is genetically predisposed to do so, exposure over a period of time to certain antigens through the mucous membranes causes the body to produce antibodies. The antibodies bind to the surface of the mast cells. (Yanni Tr. 117:10— 118:14; Kaliner Tr. 470:2-471:13; AA-19.01-03). 28. When antibodies bind to the surface of mast cells, they confer sensitivity to these cells. When those cells are subsequently exposed to the antigen, the antigen binds to the antibodies on the surface of the cells, causing them to secrete the chemical mediators within them. This process of releasing the pre-formed mediators is referred to as degranulation. (Yanni Tr. 118:5-119:6; Kaliner Tr. 471:8-472:10; AA-19.04-.07). 29. The pre-formed chemical mediators found in mast cells vary depending on the type of mast cell, and may include histamine, heparin, tryptase, chymase, and other chemicals. (Yanni Tr. 116:17-117:9; Kaliner Tr. 474:3-16; AA-93). 2. Mediator Production in the “Late Phase” of the Allergic Cascade 30. Mast cells also have the ability to synthesize and release other chemical mediators and cytokines that are synthesized and released after the release of preformed mediators, which occurs in what is called the late phase of the allergic reaction. (Kaliner Tr. 473:5-18). The late phase reaction is an inflammatory response in which white blood cells, called eosinophils, are attracted to the eye and make the eye quite irritable for an extended period of time. (Kaliner Tr. 473:5-18). 3. Signs and Symptoms of Allergy 31. Within the surrounding tissues of the eye, there are different types of receptors that correspond to the different mediators released from the mast cells. (Yanni Tr. 118:24-119:6; Kaliner Tr. 471:22-473:4; AA-19.01; AA-19.07-.09). 32. After mediators and cytokines are released from mast cells, they bind to the corresponding receptors and trigger physiological reactions in the body that are commonly identified as allergic symptoms— redness, itching, swelling, watering eyes, running nose, etc. (Yanni Tr. 119:7-15; Kaliner Tr. 471:22-473:4; AA-19.09; AA-20). C. Treating Allergic Eye Disease 33. Patients with allergic conditions are treated by interfering with the allergic cascade at one or more points in the process. (Kaliner Tr. 498:15-500:5). 34. In 1995, there were three primary classes of compounds used to treat allergic conjunctivitis: (1) antihistamines; (2) antihistamines combined with vasoconstrictors; and (3) cromolyn sodium, a compound that was reported to be a mast cell stabilizer based on animal testing. (Yanni Tr. 120:5-121:5). 1. Antihistamines (With or Without V asoconstrictors) a. Antihistamines Have Limited Effect 35. A standard antihistamine interferes with the allergic cascade toward the end of the process by preventing histamine that has been released from mast cells from binding to particular histamine receptor sites by blocking those receptors. (Kaliner Tr. 496:19-^98:8; AA-22.01-.03; AA-22.06; AA-22.08). 36. If an antihistamine is administered after histamine has already been released, the antihistamine can displace histamine from a histamine receptor and replace it, which stops the allergic symptoms caused by that mediator. (Yanni Tr. 122:19-123:25; Kaliner Tr. 496:19-498:8; AA-22.05a; AA-22.05b). 37. Antihistamines are only effective in relieving symptoms caused by histamine binding to those Hx receptors and do not have any effect on signs or symptoms caused by mediators other than histamine that are released from the mast cell. (Yanni Tr. 124:1-8; Kaliner Tr. 498:15-499:4). 38. Antihistamines also do not have any effect on the symptoms caused by the late phase of the allergic reaction. (Kaliner Tr. 498:15-499:20). b. Many Oral Antihistamines Cannot Be Made Into Topical Ophthalmic Preparations 89. Oral antihistamines have been on the market since around 1950 and were the first treatment used for allergic eye disease. (Kaliner Tr. 493:7-22). 40. Not all antihistamines can be used topically on the eye, (Bielory Tr. 1230:10-12), because of the challenges in turning an orally administered systemic antihistamine into a topically applied antihistamine. (Kaliner Tr. 494:21-495:12). In fact, none of the best-selling systemic antihistamines on the market — Claritin, Zyrtec, and Allegra — have been formulated as eye drops despite attempts to do so. (Kaliner Tr. 494:21^95:12; Abelson Tr. 1898:20-1901:3). 41. In 1995, the person of ordinary skill in the art (or “POOS”) understood that there were significant barriers to adapting a known systemic antihistamine for topical use in the eye. (Kaliner Tr. 493:15-495:12). Indeed, both sides’ experts agree that some antihistamines are simply not bioavailable when applied topically to the eye, others cannot be formulated in an eye drop that is tolerable in the eye or are not sufficiently soluble, and some antihistamines that are systemically effective exhibit unacceptable side effects when applied directly to the eye. (Kaliner Tr. 493:15-495:12; Bielory Tr. 1230:13-21; Abelson Tr.l901:7-1902:2). 42. In 1995, the POOS would not have been able to have a reasonable expectation regarding whether an antihistamine that was effective when given orally could have been formulated as an effective topical product. (Abelson Tr.l900:16-1901:3; Kaliner Tr. 495:13-496:14). 43. Furthermore, in 1995, the POOS would not have been able to predict whether an antihistamine that was effective when given orally would be bioavailable and pharmacologically effective if applied topically to the eye. (Kaliner Tr. 496:6-18). 2. Antihistamines with V asoconstrictors 44. Vasoconstrictors (also called decongestants) have also been used to treat allergic eye disease. (Kaliner Tr. 500:6-501:2). Decongestants act only on the end organ response to the allergic reaction by shrinking the blood vessels. (Kaliner Tr. 500:6-501:2). Decongestants have a limited effect and can lead to a rebound effect where the congestion becomes worse after use is discontinued. (Kaliner Tr. 500:6-501:2). 45. Combinations of antihistamines and vasoconstrictors have been used to try to block the itching caused by histamine and the redness caused by vasodilation. (Kaliner Tr. 501:3-9). These products do not work nearly as well as prescription products. (Kaliner Tr. 501:10-16). 3. Mast Cell Stabilizers 46. A more effective way to provide relief to the patient is to significantly reduce or prevent mast cell mediator release. This is referred to as stabilizing the mast cell or mast cell stabilization. Mast cell stabilization shuts down the start of the allergic cascade and significantly reduces or prevents all allergic symptoms. (Yanni Tr. 124:11-125:19; Kaliner Tr. 499:21-500:5). 47. A mast cell stabilizer will prevent or inhibit all of the mediators — of which there are many — from being released from the mast cells. (Kaliner Tr. 499:21-500:5; 474:3-16; AA-93). There are not individual mast cells, or even granules within a mast cell, that contain one type of mediator; instead each granule within each mast cell contains a host of different chemical mediators. (Kaliner Tr. 467:10^468:15). It is not possible to selectively inhibit the release of histamine from a mast cell but not inhibit the release of other mediators. (Yanni Tr. 125:11-19). 4. The Search for an Effective Mast Cell Stabilizer 48. As the role of the mast cell in the allergic cascade became widely known in the field, skilled practitioners realized the potential advantages of preventing mediator release through mast cell stabilization. (Kaliner Tr. 501:17-502:3). a. Early Experience with Cromolyn 49. In the 1970s, researchers believed that cromolyn was a mast cell stabilizer based on testing in animal mast cells. Cromolyn was thus classified as a mast cell stabilizer because it appeared to stabilize rat peritoneal mast cells, but it subsequently was shown not to effectively stabilize mast cells in any human tissue. (Kaliner Tr. 478:12 — 480:10). 50. Cromolyn was approved to treat a particular type of conjunctivitis called vernal keratoconjunctivitis, which is a special type of conjunctivitis in the eye that is not mast cell dependent and is therefore not treated through mast cell stabilization. (Yanni Tr. 121:14-23; Kaliner Tr. 507:2-13). 51. Clinical studies examining cromolyn used in the human eye found that cromolyn had marginal clinical efficacy for treating allergic conjunctivitis when compared to placebo. (TX 716 at 1027; Kaliner Tr. 508:15-25). 52. By 1995, scientists in the allergy field did not consider cromolyn to be a mast cell stabilizer in the human eye and the POOS would have known that it was not. (Kaliner Tr. 507:2-509:14; Yanni Tr. 121:11-13). The mechanism of action of cromolyn is still not known. (Yanni Tr. 121:6-10). b. Scientists Looked for Years for an Effective Mast Cell Stabilizer 53. For years, scientists in the area searched for a mast cell stabilizer that would be effective in various human mast cell populations, including the eye, and failed. (Kaliner Tr. 503:24-504:25; Abelson Tr. 1736:10-17). 54. The search for mast cell stabilizers that are effective in humans has involved many companies, compounds, and dollars. (Kaliner Tr. 503:24-504:25). The therapeutic benefits of an effective human mast cell stabilizer to treat allergic eye disease led researchers and drug companies to actively pursue that development. (Kaliner Tr. 503:24-504:25). 55. In 1995, there was a long felt need for a human conjunctival mast cell stabilizer that had not been met. (Kaliner Tr. 509:15-23; Abelson Tr. 1736:10-17). 56. Despite the efforts of many companies researching many compounds, nobody found an effective mast cell stabilizer for the human eye prior to the invention of the '805 patent. (Kaliner Tr. 503:8-23; Abelson Tr. 1736:10-17). 5. Compounds Referred to as “Anti-Allergic” 57. There is a difference between generally impeding an allergic response and inhibiting the release of mediators from a mast cell. (Kaliner Tr. 474:17-475:5). Just because a drug has an anti-allergic response does not mean that it is a mast cell stabilizer, and the POOS would not have had a reasonable expectation that merely because a compound was effective as an “anti-allergic” that it would be a mast cell stabilizer. (Kaliner Tr. 474:17-475:5; Abelson Tr. 1749:16-1751:17). Inhibition of an allergic reaction, standing alone, does not indicate by what mechanism of action a compound is inhibiting the allergic reaction. (Yanni Tr. 127:9-128:12; Kaliner Tr. 474:17-475:5). 58. The term “anti-allergic” is frequently used to describe a drug that interferes with some point in the allergic cascade, although, depending on the context, that term can have multiple meanings. (Kaliner Tr. 474:17-475:5). In.its most common usage, “anti-allergic” describes any drug that interferes with any point of the allergic cascade, including antihistamines, mast cell stabilizers, and drugs that interfere with or block the effects of any other mediator. (Kaliner Tr. 474:17-475:5). In a less common usage, the term “anti-allergic” can be used to indicate a drug that reduces the allergic reaction by stabilizing the mast cells by blocking histamine receptor sites. (Kaliner Tr. 474:17-475:5). The POOS would have understood that the meaning of the term anti-allergic depends on the context in which it is used. (Kaliner Tr. 474:17-475:5). D. Mast Cell Heterogeneity 1. Mast Cell Heterogeneity Was Well Known and Accepted by 1995 59. A major difficulty skilled artisans had in finding a compound that was an effective human conjunctival mast cell stabilizer was the recognition by the mid-1980s of “mast cell heterogeneity.” (Yanni Tr. 132:13-133:14; Kaliner Tr. 484:4-485:3). Mast cell heterogeneity means that mast cells in different species, and in different tissues within the same species, are different from one another and have different biological responses to, for instance, stimuli and attempts to stabilize them. (Yanni Tr. 132:19-22; Kaliner Tr. 475:6-480:10). 60. As far back as the 1970s, researchers in the area knew that mast cells were different and responded to stimuli and attempts to stabilize them differently. (Kaliner Tr. 475:9-476:2). 61. Mast cell heterogeneity was well known to the POOS by 1995, and numerous scientific publications confirming it had been published by that time. (Yanni Tr. 140:7-11; Kaliner Tr. 476:3-24, 480:16-483:11; TX 103A; TX 69A; TX 221A; TX 219; Bielory Tr. 1136:8-1137:1; Abelson Tr. 1732:18-25). Apotex is not challenging that mast cell heterogeneity was well-known by 1995. . Its expert agrees with Alcon’s experts, Dr. Mark Abelson (“Dr. Abelson”) and Dr. Michael Kaliner (“Dr. Kaliner”), that by 1995, the POOS understood that “[t]he concept of mast cell heterogeneity has emerged as a fundamental principle for the understanding of the possible roles of the mast cells in health and disease.” (Bielory Tr. 1137:10-22; Kaliner Tr. 481:25^82:8; Abelson Tr. 1732:20-1733:14; TX69A). 62. The specification of the '805 patent discusses and describes mast cell heterogeneity and also refers to various prior art references discussing this concept. (TX 3A; Yanni Tr. 142:9-146:12). 2. MCT and MCTC Mast Cells in the Human Body 63. In the early 1990s, it was widely accepted that there were at least two types of mast cells within the human body. (Yanni Tr. 134:19-23; Kaliner Tr. 480:11-482:19; TX 69A; TX 103A). Based on a protease contained in their granules, these mast cells were referred to as MCT, or tryptase containing mast cells, and MCTC, or tryptase and chymase containing mast cells. (Yanni Tr. 134:19-135:5; Kaliner Tr. 476:3-24; Bielory Tr. 1051:25-1052:21; TX 69A; TX 103A). 64. The mast cells in the eye and skin are both primarily MCTC mast cells. (Yanni Tr. 135:6-13; Bielory Tr. 1051:25-1052:21; 1140:5-1141:8; TX69Aatl47; TX103Aat 35). The mast cells in the nose and the lung are primarily MCT. (Yanni Tr. 135:14-18; TX 69A at 147; TX 103A at 35). 65. Animal mast cells are not classified using the MCT or MCTC classifications. (Yanni Tr. 135:19-23; TX 69A; TX 103A). 66. In their 1989 article, Dr. Irani and Dr. Schwartz published data showing the relative populations of MCT and MCTC mast cells in various tissues in the human body. (Yanni Tr. 137:13-23; TX 69A). The following year, Dr. Irani and Dr. Butrus published data showing the relative populations of MCTC and MCT mast cells in the eye during both normal and diseased states. (Yanni Tr. 137:13-138:2; Kaliner Tr. 480:11-481:12; TX 103A at 37-39). The data shows that the mast cells in the human eye are predominantly MCTC mast cells regardless of whether there is an allergic condition. (Yanni Tr. 137:24-138:2; Kaliner Tr. 480:11-481:12; TX 103A at 37-39). 67. In the early 1990s, workers in the field of allergic eye disease did not know if mast cells in the human skin were different from mast cells in the human eye, or whether the response of mast cells in the skin would be indicative of the response of mast cells in the eye because both were known to be primarily MCTC mast cells. (Yanni Tr. 138:15-23; TX 69A; TX 103A). 68. By 1995, it was known that with regard to mast cell populations, the closest tissue to the human conjunctiva was the human skin. (Yanni Tr. 138:11-14; Kaliner Tr. 481:8-12; TX 69A at 147; TX 103A at 35). It was also known that with regard to mast cell populations, the closest tissue to the human conjunctiva was the human skin. (Yanni Tr. 138:11-14; Kaliner Tr. 481:8-12; TX 69A at 147; TX 103A at 35). 69. In 1996, Dr. John Yanni (“Dr. Yanni”) of Alcon published the first data comparing mast cells in the skin and the eye that shows that mast cells in the skin and the eye are very similar, but not identical, to one another. (Yanni Tr. 140:12-23). 3. Because of Mast Cell Heterogeneity, Testing on Animal Mast Cells Is Not Applicable to Human Mast Cells 70. Because mast cells are different and respond to attempts to stabilize them differently, a researcher cannot extrapolate results from animal mast cell studies to human mast cells or tests from one tissue in the human body to another tissue within the human body. (Yanni Tr. 132:23-133:14; Kaliner Tr. 477:10-478:11). Therefore, those searching for a human conjunctival mast cell stabilizer could not use animal data to obtain an expectation about what would happen in humans, nor could they use data from different human tissue testing. (Yanni Tr. 133:6-14; Kaliner Tr. 477:10-478:11, 484:4^85:3; Abelson Tr. 1733:1-14). 71. By 1995, this concept was understood by the POOS, who would not have expected that a compound which appeared to be a mast cell stabilizer in animal tests would be a mast cell stabilizer in humans. (Kaliner Tr. 484:4-485:3, 477:10-21). The compound would have to be tested in the target human tissue mast cells to determine if it could stabilize those specific mast cells. (Abelson Tr. 1733:8-14; Kaliner Tr. 484:4-14). In 1995, Dr. Yanni also did not expect that a compound that appeared to be a mast cell stabilizer in animal tests would also be a mast cell stabilizer in humans. (Yanni Tr. 153:3-153:7). Dr. Yanni believed that the compound of interest would have to be tested in the target human tissue mast cells to determine if it could stabilize those specific mast cells. (Yanni Tr. 153:3-153:7). 72. Because of mast cell heterogeneity, the POOS would not conclude that mast cell stabilization in other tissue mast cells within a human would mean that the compound would stabilize human conjunctival mast cells. (Kaliner Tr. 540:22-541:6). 4. Mast Cell Heterogeneity Does Not Mean that All Animal Testing Is Useless for All Purposes 73. There are animal tests that are predictive for certain types of activity not involving stabilizing mast cells. For instance, guinea pig models are useful for testing a compound’s antihistaminic activity, or evaluating the topical ocular availability of a compound. (Yanni Tr. 133:18— 134:2, 151:12-23). Animals are useful for screening, and researchers understand that they have to test in animals first. (Kaliner Tr. 485:4-20). But for testing mast cell stabilization, mast cell heterogeneity requires species and tissue specificity in order to have an expectation regarding a compound’s ability to stabilize mast cells in the human eye. (Yanni Tr. 133:18-134:2; Kaliner Tr. 484:4-485:3; Abelson Tr. 1733:1-14). E. The Biphasic Effect of Antihistamines 1. The Biphasic Effect Was Well Known by the 1990s 74. For several decades prior to 1995, researchers in the field knew that antihistamines have the ability to prevent mediator release from mast cells at low concentrations, but that they actually cause the release of mediators at slightly higher concentrations. (Yanni Tr. 154:12-18; Kaliner Tr. 511:6-514:6; TX 709; TX 735). 75. By 1995, this “biphasic effect” was well known in the art, had been repeatedly described in publications, and was known to be a common feature of antihistamines. (Yanni Tr. 154:1-14; Kaliner Tr. 514:7-11; Bielory Tr. 1235:20-1236:12; TX 709; TX 735; TX 738A; TX 741). There are published discussions of the biphasic effect from 1952 through the 1990s. (Yanni Tr. 154:15-18; Kaliner Tr. 511:6-514:6; Bielory Tr. 1235:20-1236:12; TX 709; TX 735; TX738A; TX741). 2. The Biphasic Effect Is Caused by Non-Specific Action on Cell Membranes 76. The biphasic effect of antihistamines affects all cells, not just mast cells, because it is caused by an interaction between the compound and the cell membrane. (Yanni Tr. 154:1-11; Kaliner Tr. 509:24-511:5, 755:3-6, TX 735; TX 227; AA-21.01-.08). 77. At low concentrations, antihistamines infiltrate the membranes of cells and cause them to become rigid, which prevents mediators from being secreted through the membrane. (Yanni Tr. 156:18-23; ■ Kaliner Tr. 514:12-516:21; TX 735; TX 227; TX 21.01-08). However, at slightly higher concentrations, the increased infiltration of the cell membrane causes increased intracellular surface pressure that damages the cell membrane, releasing all pre-formed mediators. (Yanni Tr. 157:2-14; Kaliner Tr. 514:12-516:21; Bielory Tr. 1247:25-1248:6; TX 735; TX 227; AA-21.01-.08). 78. The biphasic effect of antihistamines is reproducible in every laboratory model that has been used to study it. (Kaliner Tr. 516:22-517:1). 79. While there have been no clinical studies designed to test the phenomenon, there is evidence that the release of mediators caused by higher concentrations of antihistamines does occur in vivo in the human eye, including punctuate keratitis that occurred with the .05% concentration of ketotifen, a potent antihistamine. (Yanni Tr. 161:11-162:12; Kaliner Tr. 518:11— 519:3; Bielory Tr. 1242:21-25). Other clinical evidence consistent with the biphasic effect occurring in vivo includes the stinging caused by antihistamine eye drops and the large amounts of swelling and edema caused by local injection of antihistamines. (Kaliner Tr. 519:4-25). 3. Measuring Effect on Mast Cells Using the Human Conjunctival Mast Cell Assay 80. The human conjunctival mast cell (“HCMC”) assay is an in vitro model for assessing a test compound’s effect on the release of histamine from a mast cell at different concentrations. (Yanni Tr. 162:21-165:18). The HCMC model was designed by Dr. Yanni and Steve Miller (“Mr. Miller”), both of Alcon. (Yanni Tr. 162:21-165:18; Miller Tr. 1502:8-13). The test involves a series of controls to validate the accuracy of the test. (Yanni Tr. 165:19-167:15). 81. The results of the HCMC test are typically graphed on a logarithmic scale, meaning that the left side of the X-axis reflects very small differences in concentration, while the right side of the X-axis reflects larger differences in concentration. (Yanni Tr. 172:8-16; Kaliner Tr. 522:14-523:2, 527:19-528:3). Scientists graph data using a logarithmic scale, which allows a wide range of concentrations of a compound to be plotted on the same graph. Each increment on a log scale is a ten-fold increase in concentration. (Kaliner Tr. 527:19-528:3). 82. The Y-axis of the chart shows the percentage of inhibition of histamine release. (Yanni Tr. 165:9-15,170:7-21). 83. Zero on the Y-axis reflects that no histamine release has been inhibited. Below the zero line reflects that there has been stimulation or “potentiation” of histamine release. (Yanni Tr. 170:7-171:1; Miller Tr. 1512:23-1513:4). Compounds whose curves go up and then drop down are biphasic compounds. (Yanni Tr. 171:2-9). 4. The “Inhibitory” Effect of Biphasic Antihistamines at Low Concentrations Is Not Clinically Relevant Mast Cell Stabilization a. The POOS Did Not Consider Biphasic Compounds To Be Mast Cell Stabilizers 84. In 1995, the POOS did not consider the inhibition of histamine release seen on the left side of the biphasic curves of antihistamines to represent biologically or clinically relevant mast cell stabilization. (Kaliner Tr. 526:10-13, 535:10-535:14). Scientists who have observed the biphasic effect of antihistamines on histamine release have found that while antihistamines have been shown to have some stabilizing effect on mast cells, the effect is typically not at pharmacologically relevant doses. (Kaliner Tr. 532:15-21, 533:1-533:8; TX 724). 85. The biphasic curves generated by antihistamines do not reflect biological mast cell stabilization because they do not follow a typical dose response curve, which would have a plateau and not a sharp drop-off. (Kaliner Tr. 525:1-526:9; AA-23; AA-1.03). 86. The POOS in 1995 would have been aware of the biphasic effect of antihistamines, that it occurred as a result of a lipophilic compound penetrating the cell membrane, and that this phenomenon was not useful for stabilizing human conjunctival mast cells. (Kaliner Tr. 534:3-24). b. It Is Impossible to Give Patients a Dose of a Biphasic Compound that Would Cause Mast Cell Stabilization and Not Mast Cell Degranulation 87. Precise dosing of ophthalmic drugs cannot be predicted with certainty as a result of variability of many factors that affect the absorption rate, including the patient’s age, the patient’s blinking habits, the patient’s ability to administer the drop in the eye, the patient’s eye health, and the amount of fluid on the patient’s eye. (Banker Tr. 921:24-922:23, 923:22-924:5). For these reasons, most ophthalmic products are dosed much higher than is minimally effective. (Banker Tr. 942:18-943:5). Given this variability, it is much easier to formulate an ophthalmic product when you have a wide range of effective concentrations as opposed to a narrow range of concentrations. (Banker Tr. 927:10-17). 88. It would not be possible to use a biphasic antihistamine as a clinically relevant mast cell stabilizer because it is not possible to achieve the concentration at which biphasic antihistamines prevent the release of mediators in the actual human eye. (Kaliner Tr. 527:3-532:14). This is because the concentration at which these concentrations appear to show inhibition is too low to get across the barrier of the conjunctival membrane, and the range of an effective dose is so small, that it would be impossible to dose reliably in that narrow range given the variability in the application of eye drops and the variability among different patients. (Kaliner Tr. 527:3-532:14; AA-33; AA-74). 89. Even Apotex’s expert, Dr. Banker, agrees with that assessment. (Banker Tr. 943:11-15 (Q: Dr. Banker, if you were choosing a compound to act as a mast cell stabilizer in the human eye, from a formulation and dosing perspective, would it be preferable if the compound were not biphasic? A: I believe that would certainly be preferable.”)). 90. While Apotex’s other expert, Dr. Leonard Bielory (“Dr. Bielory”), opined that biphasic compounds could be mast cell stabilizers, he never addressed the fact that the concentration range at which biphasic compounds show an inhibitory effect is too narrow and too small to provide that dose to the mast cells in the human eye. He also testified that while he disagreed with the position taken by Dr. Yanni that olopatadine is a superior mast cell stabilizer compared to biphasic compounds that reach their peak inhibition at lower concentrations, Dr. Yanni’s position was “not an unreasonable” one. (Bielory Tr. 1248:20-1249:10). 91. Viewing the dose response curves of biphasic antihistamines on a non-logarithmic scale shows the linear relationship between the concentration used and the effect on mediator release. (Yanni Tr. 172:3-18). 92. Viewing the data in non-log format illustrates why biphasic antihistamines are not clinically relevant mast cell stabilizers. (Kaliner Tr. 527:18-528:13; AA-74). The range of effective concentrations is so narrow and so small, that the concentrations at which biphasic antihistamines appear to inhibit histamine release cannot be used to effectively stabilize human conjunctival mast cells. (Yanni Tr. 160:24-161:10; AA-74). F. The Invention of Patanol® 1. Alcon’s Screening of Compounds 93. When Dr. Yanni arrived at Alcon in 1990, he worked with Dr. Stella Robertson (“Dr. Robertson”) and developed a strategy to try to find a treatment for seasonal or perennial allergic conjunctivitis, as that type of conjunctivitis accounts for 95% of all allergic conjunctivitis cases. (Yanni Tr. 128:13-129:8). Their goal was to find a chemical molecule with an antihistamine component and also a mast cell stabilizing component. (Yanni Tr. 129:9-21). The advantage of such a dual-action compound is that it could provide immediate relief to a patient undergoing an allergic reaction by blocking histamine through its antihistaminic effect and prevent further allergic symptoms through its mast cell stabilizing effect. (Yanni Tr. 129:9-21; Kaliner Tr. 554:22-555:10). 94. In order to find such a compound with both an antihistaminic and mast cell stabilizing component, Alcon obtained compounds that had been described as antiallergic in order to test them in Alcon’s allergy models. (Yanni Tr. 151:12-152:16, 201:23-202:3). 95. Most of the compounds Alcon tested had previously-generated data from other pharmaceutical companies showing that they had a general anti-allergic effect. (Yanni Tr. 202:4-16). The standard assay used was an in vivo model of anaphylaxis known as the rat Passive Cutaneous Anaphylaxis (“PCA”) model. (Yanni Tr. 202:7-10). This model tests the “local allergic activity in the skin that [is] typically measured by swelling or a release of a dye from the vasculature of the animal.” (Yanni Tr. 203:141). 96. The fact that a compound had activity in a rat PCA test, or another test demonstrating that the compound had anti-allergic properties, did not mean, however, that the compound would be a mast cell stabilizer. (Yanni Tr. 202:17-203:17). Inhibition in these models meant that there had been a general inhibition of the allergic reaction, and did not establish that mast cell stabilization had occurred or that the compound would be active in the HCMC assay. (Yanni Tr. 203:18-204:15, 204:23-205:2). 97. At the time Alcon was doing its testing, other pharmaceutical companies also were searching for mast cell stabilizers to treat allergies in the human body, including the eye. (Yanni Tr. 130:8-132:5). 98. The concept of mast cell heterogeneity meant that the POOS would not have a reasonable expectation that a compound would be a mast cell stabilizer in the human conjunctiva based on animal tests. (Kaliner Tr. 484:4-485:3, 477:24-478:14). However, in 1990, there was no human conjunctival mast cell test available, and Dr. Yanni and others at Alcon therefore decided to develop a HCMC assay. (Yanni Tr. 133:15-17,162:21-165:15). 99. The HCMC model is a scientifically valid model and was a huge step forward in allowing scientists to investigate the effect of various agents on human conjunctival mast cells. (Kaliner Tr. 524:2-7). 2. Alcon’s Determination that Olopatadine Could Be Used to Stabilize Human Conjunctival Mast Cells 100. Alcon obtained a test compound named olopatadine (the Z isomer) from Kyowa under a License and Supply Agreement dated July 27, 1993. (Yanni Tr. 205:3-19; 286:11-16; TX24). 101. When Dr. Yanni first received olopatadine, he was advised that it was a non-steroidal anti-inflammatory agent. (Yanni Tr. 205:3-19; see also Robertson Dep. 19:8-12 (testifying that Alcon originally tested olopatadine as an anti-inflammatory agent). Olopatadine was not active in the assays used to test non-steroidal anti-inflammatory drugs. (Yanni Tr. 205:20-206:1). 102. Alcon then learned that there must have been a misunderstanding as it was informed by Kyowa that olopatadine was an anti-allergy drug. (Yanni Tr. 206:2-8; Yanni Dep. 18:24-19:21). 103. Before testing olopatadine, Dr. Yanni understood that olopatadine was an antihistamine, and was concerned that olopatadine would be biphasic. (Yanni Tr. 206:17-22). Alcon therefore needed to test olopatadine to the limits of its solubility, because Alcon was not interested in developing biphasic compounds as mast cell stabilizers. (Yanni Tr. 207:25-209:11). 104. Upon testing olopatadine in the HCMC assay, see TX 971, Alcon learned that olopatadine inhibits the release of his-famine from human conjunctival mast cells at all concentrations tested up to its limit of solubility — in other words, that olopatadine stabilizes human conjunctival mast cells to an extent that would be clinically relevant. (Yanni Tr. 208:2-209:11). 105. Alcon’s testing demonstrated that olopatadine was topically bioavailable, that it was a moderately potent antihistamine with a long duration of action, and that it was a human conjunctival mast cell stabilizer. Alcon therefore decided to develop olopatadine, which ultimately resulted in the approval and introduction to the market of Patanol®. (Yanni Tr. 206:23-207:24). 106. Of all of the compounds that Alcon tested that had anti-allergy activity in animal testing, only olopatadine turned out to be a human conjunctival mast cell stabilizer. (Yanni Tr. 204:16-22). 107. In clinical studies, Patanol® has proven to be a clinically effective mast cell stabilizer that inhibits all signs and symptoms of the allergic response, including signs and symptoms that are not usually attenuated or blocked with antihistamines. (Yanni Tr. 213:6-11). III. Prosecution History A. The '227 Application 108. On October 8, 1993, Mr. Patrick Ryan (“Mr. Ryan”), on behalf of Alcon and Kyowa, filed United States Patent Application #08/134,227 (“the '227 application”) with the United States Patent and Trademark Office (“PTO”). It was entitled “Topical Ophthalmic Formulations for Treating Allergic Eye Diseases.” (TX 449 at ALP001-003004). The '227 application claimed the use of an olopatadine eye drop for use in the treatment of allergic eye disease. (TX 449 at ALP001-003014-15; Ryan Tr. 1559:17-25; Smith Tr. 1308:3-24, 1309:21-1310:4). The named inventors of the '227 application are the same as those of the '805 patent, namely, Dr. Yanni, Dr. Robertson, Eiji Hayakawa, and Masashi Nakakura. (TX 449 at ALP001-00301718). 109. The specification of the '227 application also included a description of the concept of mast cell heterogenity. (TX 449 at ALP001-003005-6; Ryan Tr. 1561:20-1563:21). As part of that discussion, the specification included Table 1 to show that well-known compounds reported in the literature as mast cell stabilizers in animals or other tissues — namely cromolyn and nedrocromil — were not effective mast cell stabilizers when tested on the specific mast cells in the human conjunctiva. (TX 449 at ALP001-003009-11; Ryan Tr. 1563:22-1564:13; Yanni Tr. 220:20-221:3). 110. On December 30, 1993, the patent examiner rejected each of the four pending claims as obvious in light of the United States Patent # 4,871,865 and United States Patent # 4,923,892 (the “Lever patents”). (TX 449 at APL001-003032). The examiner invited the applicants to submit data demonstrating unexpected properties over the prior art. (TX 449 at ALP001003033; Ryan Tr. 1568:2-10; Smith Tr. 1310:8-1311:13). B. Comparative Testing of Olopatadine (the Z and E isomer) and the Wellcome Compounds 111. In response to the examiner’s rejection, individuals at Alcon under Dr. Yanni’s direction conducted some experiments in order to determine whether there were unexpected results that could be shown. (Smith Tr. 1314:1014). 112. In February 1994, Alcon received samples of the Wellcome Compounds from Kyowa in limited quantities. (TX 425; Yanni Tr. 227:12-228:3). 113. Aleon thereafter performed three comparative tests of olopatadine (the Z and E isomers) and the Wellcome Compounds, and reported the results in a report to Kyowa known as the Kyowa Report. (TX 100; TX 244; TX 995; TX 1151; Ryan Tr. 1567:14-20). 114. Table 1 of the Kyowa Report contains the results of Alcon’s comparative antiallergic testing of olopatadine and the Wellcome Compounds in a passive anaphylaxis in rat conjunctiva (“PARC”) test. (TX 100 at ALP001-002286; Yanni Tr. 279:21-281:17-24). Figure 1 of the Kyowa Report contains the results of an in vitro test comparing the mast cell stabilizing effects of olopatadine and the Wellcome Compounds on human conjunctival mast cells (“Wellcome HCMC test”). (TX 100 at ALP001-002287; Bielory Tr. 1117:18-1121:1; Yanni Tr. 280:21-281:1). Figure 2 of the Kyowa Report contains the results of Alcon’s in vitro test comparing the mast cell stabilizing effects of the Z- and E-isomers of olopatadine on human conjunctival mast cells (“Z-E HCMC test”). (TX 100 at ALP001-002287; Yanni Tr. 281:8-11). 115. Dr. Yanni believed the results of the testing were very favorable to olopatadine as compared to the Wellcome Compounds. The PARC tests showed that both olopatadine and the E isomer were significantly more active than Wellcome I and Well-come II. (Yanni Tr. 279:21-280:20). Although the Wellcome HCMC tests were inconclusive as to Wellcome Compounds I and II, the upward slope on the left sides of their curves, coupled with the “rapid” downward slope in the second half of their curves, was consistent with those of biphasic compounds. (Yanni Tr. 246:9-249:9, 268:18-269:10; see also TX 244). 116. Trial Exhibit 419 contains the compound status reports for Wellcome Compounds I and II dated March 23, 1994. For both compounds, Dr. Yanni checked the box that said “no further interest” because he was not interested in further developing the Wellcome Compounds. (TX 419 at ALP-013-113813-14). Dr. Yanni testified that he had “no further interest” in the Wellcome Compounds because the test data Aleon had generated showed that olopatadine had superior activity in the PARC test and suggested that Wellcome I and II were biphasic. (TX 419; Yanni Tr. 269:11-272:8). 117. Dr. Yanni also checked the box that said “no further interest” for the E isomer of olopatadine because he was not interested in developing the E isomer. (TX 419 at ALP-013-113812). Dr. Yanni had data that the E isomer was equivalent to olopatadine, but not superior to olopatadine, so there was no advantage to the E isomer over the compound he already had. Moreover, because of Kyowa’s work with the compound, there was already a body of olopatadine test data in existence that Aleon could rely on addressing such issues as toxicology, genotoxicity, and carcinogenicity; whereas with the E isomer, all of the data would have to be generated, which would have delayed development of any E-isomer-based product. (TX 419 at ALP-013-113812; Yanni Tr. 275:6-276:19). 118. Even though Dr. Yanni was not interested in developing the E-isomer, he was still interested in getting a license to it, as he was concerned about a competitor developing it. (TX 419; Yanni Tr. 275:6-176:19). C. The Continuation-In-Part Application and the Abandonment of the '227 Application 119. Unlike the comparison between olopatadine and Wellcome I and II, there was no significant difference between olopatadine and its E isomer. (TX 442). As a result, Mr. Ryan believed that he had a problem because the E isomer was the closest prior art to the '227 application claims, but he could not show superiority over it. (Ryan Tr. 1587:9-22). He did not believe that he could disclose only the favorable data showing that olopatadine was superior to Wellcome I and II, but withhold the E isomer data that showed that the E isomer was as good as olopatadine. (Ryan Tr. 1587:9-22,1587:23-1588:15). 120. Given his understanding of the test results, Mr. Ryan decided to prepare a continuation in part (“CIP”) application that would claim the use of both olopatadine and the E isomer. With these new claims, the closest prior art would become the Wellcome I and II Compounds, and he could use the data that he understood existed to assert unexpected properties of olopatadine and the E isomer over those compounds, as he understood that olopatadine and the E isomer were superior to Wellcome I and II. (Ryan Tr. 1569:11-1571:8, 1572:2-22; Smith Tr. 1397:7-19). 121. In the spring of 1994, Mr. Ryan prepared a draft CIP application, which took the original '227 application and added the E isomer to the description and the claims. (Ryan Tr. 1570:6-1571:3, 1572:2-24; TX 2069). 122. In addition, Mr. Ryan added Table 2, which compares the Z and E isomers at a dose of 500 uM, to show that olopatadine and the E isomer behaved similarly in the Z-E HCMC test. (TX 2069; Ryan Tr. 1598:15-25). 123. Mr. Ryan also added the Kyowa Report’s description of the PARC test data and the data from Table 1 (the PARC test data) in preparing Table 3. (Compare TX 2069 at ALP001-002355-56, with TX 794 at ALP001-002285-86). 124. Mr. Ryan did not add the Wellcome HCTMC test data that is reflected in Figure 1 of the Kyowa Report. 125. Around this time frame, Kyowa, Aleon’s licensing partner, wrote a letter to Alcon, stating that Kyowa “would not like to disclose any biological data for the E-isomer to [sic] outside of Kyowa and Alcon” because of Japanese regulatory issues. The letter further states that “[i]n this regard, we would cordially ask that the data of E-isomer should not be included in our joint patent application for ophthalmic use.” (TX 774; Ryan Tr. 1574:25-1575:14). 126. Mr. Ryan believed that it would be improper to submit data to the PTO showing that olopatadine was superior to Well-come Compounds I and II, but withhold data showing that olopatadine was not superior to the closest prior art compound, the E isomer. Because he could not submit the E isomer data, and did not believe that it would have been proper to go forward without it, Mr. Ryan abandoned the '227 application in July 1994 and did not file the CIP. (Ryan Tr. 1575:15-1576:21; TX 449 at ALP001-003042-43; Smith Tr. 1322:3-7). D. The '729 Application 127. Kyowa subsequently allowed the disclosure of the E isomer data, and on June 6, 1995, the '729 application, which led to the '805 patent, was filed by Alcon Laboratories, Inc. (Ryan Tr. 1595:12-1596:17; TX 4 ALP001-42001). 128. To prepare the '729 application, Mr. Ryan took the CIP application that he had prepared in 1994 and reformatted it so that it was an original application. The substantive work on the application had been done in 1994, and Mr. Ryan did not go back and review his file for the abandoned '227 application in preparing the '729 application. (Ryan Tr. 1595:12-1596:17; TX2070; TX2071). 129. Like the CIP, the '729 application claimed methods of treating allergic eye disease using both (or either) olopatadine and the E isomer, including the data about the E isomer that Mr. Ryan had wanted to disclose to the PTO. (TX 4 at ALP001042004-5, ALP001-042008, ALP001042022-23; Ryan Tr. 1559:17-1560:3. 1597:7-19; Smith Tr. 1324:23-1325:13; TX 449; TX 2069). 130. The application was assigned to a different examiner than the previous '227 application. (TX 4 at ALP001-042001; Smith Tr. 1324:7-10). 131. The specification of the '729 application included the same Table 1 as had been included in the '227 application for the same purpose: demonstrating the principle of mast cell heterogeneity. (Ryan Tr. 1598:1-14; Yanni Tr. 311:18-312:23). 132. The specification also contained Tables 2 (comparison of the Z and E isomer) and 3 (PARC test comparing olopatadine to the Wellcome Compounds), which had been added to the draft CIP application. (TX4; TX 2069). 133. The results of the Wellcome HCMC test, which compared the mast cell stabilizing effects of olopatadine and the Well-come Compounds on human conjunctival mast cells, and is reflected in Figure 1 of the Kyowa Report, was not included in the '729 application. (See TX 4). 134. Contemporaneous with the filing of the '729 application, Alcon and Kyowa filed an Information Disclosure Statement disclosing to the PTO the Lever patents, the '863 patent, the Hamilton paper, and seven additional references, including all of the references that were identified during the prosecution of the '227 application. (TX 4 at ALP001-042028-29). E. The Rejection and Amendment 135. On July 17, 1996, the examiner issued an office action rejecting claims 1-12 of the '729 application. (TX 4 at ALP001042082-88). The examiner rejected claims 1-8 as anticipated under 35 U.S.C. § 102 by Kamei, and rejected claims 1-12 as obvious under 35 U.S.C. § 103 over Kamei as applied to claims 1-8, and also over Kamei in combination with the Lever '892 patent. (TX 4 at ALP001-042085; Ryan Tr. 1607:8-1608:4; Smith Tr. 1334:16-20). 136. In response to the office action, Mr. Ryan submitted an amendment to the PTO on October 7, 1996. (TX 4 at ALP001042089-94). Mr. Ryan amended claim 1 to recite that the claimed method is for treating allergic eye diseases “in humans” and to require that the method comprise “stabilizing conjunctival mast cells.” (TX 4 at ALP001-042089; Ryan Tr. 1609:1-8; Kilworth Tr.l988:17-1989:6). He then presented argument to the PTO. (TX 4 at ALP001-042092-94; Ryan Tr. 1609:9-12). 137. In response to the examiner’s obviousness objection based on Kamei and the Lever '892 patent, Mr. Ryan made four alternative arguments in numbered paragraphs (i) through (iv). (TX 4 at ALP001042092-94). His argument in paragraph (iv) is discussed infra. In numbered paragraph (ii), Mr. Ryan discussed mast cell heterogeneity, arguing that “as the data in Applicant’s Specification illustrates, not all compounds which are known to be mast cell stabilizers in rats are effective human conjunctival mast cell stabilizers.” (TX 4 at ALP001-042093; see also Kaliner Tr. 674:10-23). 138. In paragraph (iv), Mr. Ryan argued that even if one ignored his prior arguments, there is “no way to predict, given the disclosures of Kamei et al. and Lever, that the compounds recited in Applicants’ Claims would possess significantly superi- or conjunctival mast cell stabilization activity compared to the structurally similar compounds exemplified by Lever.” (TX 4 at ALP001-042094). He then referred to Table 3 of the specification (the PARC test data) and explained that it “illustrates the statistically significant superior mast cell stabilization activity that the Z- and E-isomers of the 2-aeetic acid derivative [olopatadine and the E isomer] have compared to the 2-earboxylic acid and 2-acrylic acid derivatives exemplified by Lever [Well-come I and II].” (TX 4 at ALP001-042094). 139. As noted above, on June 24, 1997, the '805 patent issued. (Docket # 173, Stipulation ¶ 7). IV. '805 Patent 140. Claim 1 of the '805 patent reads: A method for treating allergic diseases in humans comprising stabilizing conjunctival mast cells by topically administering to the eye a composition comprising a therapeutically effective amount of 1 l-(3-dimethylaminopropylidene)-6, 11-dihydrodibenz[b,e]oxepin-2-acetic acid or a pharmaceutically acceptable salt thereof. (TX 3A, col. 7,11. 28-34). 141. Olopatadine is a particular three-dimensional form of ll-(3-dimethylaminopropylidene)-6, ll-dihydrodibenz[b,e]oxepin-2-acetic acid, and is referred to as the “cis” or “Z” isomer of the compound. An alternative isomer having the same atoms bonded in the same sequence but differing in them orientation in three-dimensional space is called the “trans” or “E” isomer. (Docket # 173, Stipulation ¶ 11). 142. Olopatadine is also sometimes referred to as KW-4679 or AL4943A. (Docket # 173, Stipulation ¶ 12). 143. In the '805 patent, the use of the term 1 l-(3-dimethylaminopropylidene)-6, ll-dihydrodibenz[b,e]oxepin-2-acetic acid refers to olopatadine, its E isomer, or mixtures of both. (TX 3A, col. 7, 11. 28-34). 144. Claims 2 through 8 of the '805 patent are dependent claims stemming from claim 1, each adding various limitations. (TX 3A, col. 7,1. 35-col. 8,1. 22). 145. Dependent claims 2, 3, and 4 limit the method of claim 1 to methods using solutions in which the amount of olopatadine in the composition is limited to about 0.0001 to 5% w/v, about 0.001 to about 0.2% w/v, and about 0.1% w/v, respectively. (TX 3A at col. 7,1. 35-col. 8,1. 3). 146. Dependent claim 5 is limited to methods using compositions employing the “Z isomer” “substantially free” of the “E isomer.” (TX 3A, col. 8, 11. 4-11). The '805 patent defines “substantially free” as meaning that there is “less than about two percent” of the other isomer present in conjunction with the desired isomer. (TX 3A, col. 3,11.15-17). 147. Dependent claims 6, 7, and 8 are further limited to methods using compositions in which the Z isomer is limited to about 0.0001 to about 5% w/v, about 0.001 to about 0.2% w/v, and 0.1% w/v, respectively. (TX 3A, col. 8,11.16-22). V. Infringement 148. Plaintiffs allege that Apotex’s filing of ANDA # 78-350 is an act of infringement of claims 1-8 of the '805 patent under 35 U.S.C. § 271(e)(2)(A). Plaintiffs further allege that Apotex is liable for inducing infringement under 35 U.S.C. § 271(b) and for contributory infringement under 35 U.S.C; § 271(c). A. Apotex’s ANDA Product Infringes Claim 1 of the '805 Patent 149. Claim 1 of the '805 patent, as construed by the court, requires that Apotex’s ANDA product stabilizes mast cells to a clinically relevant extent in the human eye. (See Docket # 282). The only issue in dispute is whether Apotex’s ANDA product meets this limitation. 150. Dr. Michael Kaliner (“Dr. Kaliner”), Aeon’s expert witness in allergies and a practicing physician, testified that, in his opinion, Patanol® is a clinically effective mast cell stabilizer in the human eye. (Kaliner Tr. 543:4-10). Patanol® blocks mast cell degranulation not only because it blocks itching, a common symptom associated with histamine, but also because it blocks symptoms that antihistamines alone cannot resolve, including swelling, irritation, tearing, and redness. (Kaliner Tr. 543:8-10; see also Yanni Tr. 210:15-19, 213:6-15 (Patanol® is clinically effective as a mast cell stabilizer in humans because of “the clinical utility noted with the compound ..., being able to inhibit all signs and symptoms of allergic response, including signs and symptoms that are not typically effective or particularly attenuated or blocked with antihistamines.”). 151. Dr. Kaliner also testified that, based upon his review of the relevant peer-reviewed scientific literature, Apotex’s ANDA product would likewise stabilize conjunctival mast cells to a clinically relevant extent in the human eye. (Kaliner Tr. 563:11-19 (“[A] huge body of information published in the peer-reviewed literature ... demonstrates that [Patanol®] inhibits mast cell degranulation, and does so in a clinically effective way in humans in the eye.”). 152. Apotex’s ANDA product is “the same product as Patanol®.” (Kaliner Tr. 561:15-18). Apotex’s ANDA product contains “the same active and inactive ingredients in the same concentration” as in Patanol®. (Kaliner Tr. 561:2-18; TX 131 at ANDA000011). In its ANDA, Apotex represented to the FDA that “[t]he drug product described herein is equivalent to PATANOL® (Olopatadine Hydrochloride Ophthalmic Solution), 0.1%, marketed by Alcon Laboratories, Inc.” (TX 131 at ANDA000038; see also TX 131 at ANDA000008 (the “conditions of use, active ingredient, inactive ingredients, dosage form, route of administration and strength of [Apotex’s ANDA product]” are the same as Patanol®)). 153. Because Apotex’s product “[c]ontains the same active and inactive ingredients in the same concentration as” Patanol®, Apotex requested a waiver of evidence showing in vivo bioequivalence. (TX 131 at ANDA000011). 154. Apotex’s ANDA product will be used for the same use as Patanol® and administered the same way as Patanol®. (Kaliner Tr. 574:1-8, 578:1-8, 579:14-20). Apotex’s ANDA product states that its product “will be administered ... for the same indications as the ‘listed’ drug PATANOL®.” (TX 131 at ANDA000009). The “Indications and Usage” sections of the labels for both Patanol® and Apotex’s ANDA product are identical, listing only “the treatment of the signs and symptoms of allergic conjunctivitis.” (TX 131 at ANDA 000029). Apotex’s product “will be administered at the same dosage level, for the same duration and for the same ind