Page 1
`
`ALCON RESEARCH, LTD. (f/k/a ALCON MANUFACTURING, LTD.), ALCON
`LABORATORIES, INC., and KYOWA HAKKO KIRIN CO., LTD., Plaintiffs, vs.
`APOTEX INC. and APOTEX CORP., Defendants.
`
`1:06-cv-1642-RLY-TAB (Consolidated)
`
`UNITED STATES DISTRICT COURT FOR THE SOUTHERN DISTRICT OF
`INDIANA, INDIANAPOLIS DIVISION
`
`790 F. Supp. 2d 868; 2011 U.S. Dist. LEXIS 55144
`
`May 23, 2011, Decided
`May 23, 2011, Filed
`
`SUBSEQUENT HISTORY: Motion granted by Alcon
`Research, Ltd. v. Apotex Inc., 2012 U.S. App. LEXIS
`1521 (Fed. Cir., Jan. 25, 2012)
`
`PRIOR HISTORY: Alcon Mfg. v. Apotex, Inc., 2008
`U.S. Dist. LEXIS 96630 (S.D. Ind., Nov. 26, 2008)
`
`[**1] For ALCON RESEARCH, LTD.,
`COUNSEL:
`ALCON LABORATORIES, INC., KYOWA HAKKO
`KIRIN CO., LTD., Plaintiffs: Adam L. Perlman, Bruce
`Roger Genderson, Christopher J. Mandernach, Daniel P.
`Shanahan, Jessamyn S. Berniker, Shelley J. Webb,
`Thomas H. L. Selby, PRO HAC VICE, WILLIAMS &
`CONNOLLY LLP, Washington, DC; Deborah
`Pollack-Milgate,
`BARNES
`&
`THORNBURG,
`Indianapolis, IN; Donald E. Knebel, Paul B. Hunt, Todd
`G. Vare, BARNES & THORNBURG LLP, Indianapolis,
`IN.
`
`For APOTEX INC., APOTEX CORP., Defendants:
`Abram B. Gregory, Gayle A. Reindl, TAFT
`STETTINIUS & HOLLISTER LLP, Indianapolis, IN;
`Brian J. Sodikoff, Craig M. Kuchii, Martin S. Masar, III,
`Robert B. Breisblatt, Thomas J. Maas, PRO HAC VICE,
`KATTEN MUCHIN ROSENMAN LLP., Chicago, IL.
`
`Kerry Brendan McTigue, PRO HAC VICE, DUANE
`MORRIS LLP, Washington, DC; Kathleen I. Hart, BOSE
`MCKINNEY & EVANS, LLP, Indianapolis, IN; Larry
`Selander, PRO HAC VICE; Richard Thomas Ruzich,
`DUANE MORRIS LLP, Chicago, IL; Robert M. Gould,
`PRO HAC VICE, DUANE MORRIS LLP, Chicago, IL;
`Vincent L. Capuano, PRO HAC VICE, DUANE
`MORRIS LLP, Boston, MA.
`
`For KYOWA HAKKO KIRIN CO., LTD., ALCON
`RESEARCH, LTD., ALCON LABORATORIES, INC.,
`[**2] Defendants: Christopher J. Mandernach,
`Counter
`Shelley J. Webb, Thomas H. L. Selby, PRO HAC VICE,
`WILLIAMS & CONNOLLY LLP, Washington, DC;
`Jessamyn S. Berniker, WILLIAMS & CONNOLLY LLP,
`Washington, DC.
`
`For APOTEX INC., APOTEX CORP., Counter
`Claimants: Brian J. Sodikoff, Craig M. Kuchii, Martin S.
`Masar, III, Robert B. Breisblatt, Thomas J. Maas, PRO
`HAC VICE, KATTEN MUCHIN ROSENMAN LLP.,
`Chicago, IL.
`
`JUDGES: RICHARD L. YOUNG, CHIEF JUDGE.
`
`OPINION BY: RICHARD L. YOUNG
`
`For SANDOZ, INC., Defendant: Donald R. McPhail,
`
`OPINION
`
`APOTEX EX1031
`
`Page 1
`
`

`
`790 F. Supp. 2d 868, *; 2011 U.S. Dist. LEXIS 55144, **2
`
`Page 2
`
`[*873] FINDINGS OF FACT AND CONCLUSIONS
`OF LAW
`
`(f/k/a Alcon
`Plaintiffs, Alcon Research, Ltd.
`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 [**3] 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.
`
`fact and
`The court now issues its findings of
`conclusions of law pursuant to Federal Rule of Civil
`Procedure 52(a):
`
`FINDINGS OF FACT1
`
`transcript will be
`Citations to the trial
`1
`"[witness name] Tr." followed by "[transcript
`page: line];" citations to the deposition testimony
`submitted by the parties will be "[witness name]
`Dep." followed by "[dep. page: line]"; citations to
`the trial exhibits will be "TX" followed by the
`exhibit
`number;
`citations
`to
`Plaintiffs'
`demonstrative exhibits will be "AA" followed by
`the exhibit number; citations to the parties'
`[**4] 173,
`pre-trial stipulations, Docket Nos.
`179, and 204, which are part of the trial record,
`will be "[Docket No.], Stipulation" followed by
`
`the paragraph number; and citations to any other
`document on the court's docket will be "[Docket
`No.]" followed by the title of the document.
`
`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).
`
`corporation
`a
`is
`Inc.
`2. Alcon Laboratories,
`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).
`
`is a corporation organized and
`Inc.
`4. Apotex,
`existing under the laws of Canada, having its principal
`place of business at 150 Signet Dr., Weston, Ontario
`[**5] M9L 1T9. (Docket # 173, Stipulation ¶ 4).
`
`is a corporation organized and
`5. Apotex Corp.
`existing under the laws of the State of Delaware, having
`its principal place of business at 2400 North Commerce
`[*874] 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
`patent,
`entitled
`"Topical Ophthalmic
`'805
`Formulations for Treating Allergic Eye Diseases." Alcon
`Laboratories, Inc. and Kyowa Hakko Kogyo Co. Ltd.,
`
`Page 2
`
`

`
`790 F. Supp. 2d 868, *874; 2011 U.S. Dist. LEXIS 55144, **5
`
`Page 3
`
`were the original assignees of the '805 patent. (Docket #
`173, Stipulation ¶ 7).
`
`between parties that the Southern District of Indiana is a
`proper venue)).
`
`in the '805
`9. Alcon Laboratories, Inc.'s interest
`patent has been subsequently assigned to Alcon
`Research, Ltd. Alcon Laboratories,
`Inc.
`sells drug
`[**6] under the
`products covered by the '805 patent
`trademark Patanol®; pursuant
`to an ANDA held by
`Alcon 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).
`[**7] Apotex notified Plaintiffs
`In the Notice Letter,
`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
`to 28 U.S.C. §§ 1331, 1338(a), 1391, and
`pursuant
`1400(b). (Docket # 21, Answer ¶ 8; Docket # 35, Entry
`on Defendants' Motion to Transfer at 3 (no dispute
`
`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 [**8] of [*875] 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. [**9] 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.
`467:10-468:15; AA-093). Each granule contains up to 25
`different
`types of chemical mediators.
`(Kaliner Tr.
`467:10-468:15; AA-093).
`
`Page 3
`
`

`
`790 F. Supp. 2d 868, *875; 2011 U.S. Dist. LEXIS 55144, **9
`
`Page 4
`
`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).
`
`[**10] Common antigens include substances
`25.
`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. [**11] 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 [*876] 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
`
`[**12] Mast cells also have the ability to
`30.
`synthesize and release other chemical mediators and
`cytokines that are synthesized and released after the
`release of pre-formed 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 [**13] 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 Vasoconstrictors)
`
`Page 4
`
`

`
`790 F. Supp. 2d 868, *876; 2011 U.S. Dist. LEXIS 55144, **13
`
`Page 5
`
`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. 496:19-498:8;
`AA-22.01-.03; AA-22.06; AA-22.08).
`
`administered after
`is
`an antihistamine
`If
`36.
`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 H1
`receptors and do not have any effect on signs [**14] 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
`[*877] phase of the
`symptoms caused by the late
`allergic reaction. (Kaliner Tr. 498:15-499:20).
`
`b. Many Oral Antihistamines Cannot Be Made Into
`Topical Ophthalmic Preparations
`
`39. 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.
`494:21-495:12; 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' [**15] 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. 1901:7-1902:2).
`
`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.
`1900:16-1901:3;
`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 Vasoconstrictors
`
`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 [**16] 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).
`
`and
`antihistamines
`of
`Combinations
`45.
`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
`
`Page 5
`
`

`
`790 F. Supp. 2d 868, *877; 2011 U.S. Dist. LEXIS 55144, **16
`
`Page 6
`
`even granules within a mast cell, that contain one type of
`mediator;
`instead each granule within each mast cell
`[**17] a host of different chemical
`[*878]
`contains
`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).
`
`[**18] Clinical studies examining cromolyn
`51.
`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
`
`(Kaliner Tr.
`failed.
`1736:10-17).
`
`503:24-504:25; Abelson Tr.
`
`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 [**19] mast cell stabilizer that had not been
`met. (Kaliner Tr. 509:15-23; Abelson Tr. 1736:10-17).
`
`efforts of many companies
`the
`56. Despite
`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 [*879] 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
`[**20] 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
`
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`
`790 F. Supp. 2d 868, *879; 2011 U.S. Dist. LEXIS 55144, **20
`
`Page 7
`
`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 [**21] 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. 481:25-482:8;
`Abelson Tr. 1732:20-1733:14; TX 69A).
`
`62. The specification of the '805 patent discusses and
`describes mast cell heterogeneity and also refers to
`[**22] discussing this
`various prior art
`references
`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; TX 69A at 147; TX
`103A at 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).
`
`[*880] 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
`[**23] Butrus published data
`year, Dr. Irani and Dr.
`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, [**24] 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
`
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`

`
`790 F. Supp. 2d 868, *880; 2011 U.S. Dist. LEXIS 55144, **24
`
`Page 8
`
`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,
`484:4-485:3; 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.
`[**25] The compound would
`484:4-485:3, 477:10-21).
`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).
`
`[*881] 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.
`[**26] Animals
`(Yanni Tr. 133:18-134:2, 151:12-23).
`
`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.
`[**27] Kaliner Tr. 511:6-514:6;
`(Yanni Tr. 154:15-18;
`Bielory Tr. 1235:20-1236:12; TX 709; TX 735; TX
`738A; TX 741).
`
`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