Page 1
`Page 1
`
`
`
`ALCON RESEARCH, LTD. (f/k/a ALCON MANUFACTURING, LTD.), ALCON
`ALCON RESEARCH, LTD. (flkla ALCON MANUFACTURING, LTD.), ALCON
`LABORATORIES, INC., and KYOWA HAKKO KIRIN CO., LTD., Plaintiffs, vs.
`LABORATORIES, INC., and KYOWA HAKKO KIRIN CO., LTD., Plaintiffs, vs.
`APOTEX INC. and APOTEX CORP., Defendants.
`APOTEX INC. and APOTEX CORP., Defendants.
`
`1:06-cv-1642-RLY-TAB (Consolidated)
`1:06-cv-1642-RLY-TAB (Consolidated)
`
`UNITED STATES DISTRICT COURT FOR THE SOUTHERN DISTRICT OF
`UNITED STATES DISTRICT COURT FOR THE SOUTHERN DISTRICT OF
`INDIANA, INDIANAPOLIS DIVISION
`INDIANA, INDIANAPOLIS DIVISION
`
`790 F. Supp. 2d 868; 2011 U.S. Dist. LEXIS 55144
`790 F. Supp. 2d 868; 2011 U.S. Dist. LEXIS 55144
`
`May 23, 2011, Decided
`May 23, 2011, Decided
`May 23, 2011, Filed
`May 23, 2011, Filed
`
`SUBSEQUENT HISTORY: Motion granted by Alcon
`SUBSEQUENT HISTORY: Motion granted by Alcon
`Research, Ltd. v. Apotex Inc., 2012 U.S. App. LEXIS
`Research, Ltd. v. Apotex Inc., 2012 U.S. App. LEXIS
`1521 (Fed. Cir., Jan. 25, 2012)
`1521 (Fed. Cir., Jan. 25, 2012)
`
`PRIOR HISTORY: Alcon Mfg. v. Apotex, Inc., 2008
`PRIOR HISTORY: Alcon Mfg. v. Apotex, Inc., 2008
`U.S. Dist. LEXIS 96630 (S.D. Ind., Nov. 26, 2008)
`U.S. Dist. LEXIS 96630 (S.D. Ind., Nov. 26, 2008)
`
`[**1] For ALCON RESEARCH, LTD.,
`COUNSEL:
`[**1] For ALCON RESEARCH, LTD.,
`COUNSEL:
`ALCON LABORATORIES, INC., KYOWA HAKKO
`ALCON LABORATORIES, INC., KYOWA HAKKO
`KIRIN CO., LTD., Plaintiffs: Adam L. Perlman, Bruce
`KIRIN CO., LTD., Plaintiffs: Adam L. Perlman, Bruce
`Roger Genderson, Christopher J. Mandernach, Daniel P.
`Roger Genderson, Christopher J. Mandemach, Daniel P.
`Shanahan, Jessamyn S. Berniker, Shelley J. Webb,
`Shanahan,
`Jessamyn S. Bemiker, Shelley J. Webb,
`Thomas H. L. Selby, PRO HAC VICE, WILLIAMS &
`Thomas H. L. Selby, PRO HAC VICE, WILLIAMS &
`CONNOLLY LLP, Washington, DC; Deborah
`CONNOLLY LLP, Washington,
`DC; Deborah
`Pollack-Milgate,
`BARNES
`&
`THORNBURG,
`Pollack—Milgate,
`BARNES
`&
`THORNBURG,
`Indianapolis, IN; Donald E. Knebel, Paul B. Hunt, Todd
`Indianapolis, IN; Donald E. Knebel, Paul B. Hunt, Todd
`G. Vare, BARNES & THORNBURG LLP, Indianapolis,
`G. Vare, BARNES & THORNBURG LLP, Indianapolis,
`IN.
`IN.
`
`For APOTEX INC., APOTEX CORP., Defendants:
`For APOTEX INC., APOTEX CORP., Defendants:
`Abram B. Gregory, Gayle A. Reindl, TAFT
`Abram B. Gregory, Gayle A. Reindl,
`TAFT
`STETTINIUS & HOLLISTER LLP, Indianapolis, IN;
`STETTINIUS & HOLLISTER LLP, Indianapolis, IN;
`Brian J. Sodikoff, Craig M. Kuchii, Martin S. Masar, III,
`Brian J . Sodikoff, Craig M. Kuchii, Martin S. Masar, III,
`Robert B. Breisblatt, Thomas J. Maas, PRO HAC VICE,
`Robert B. Breisblatt, Thomas J. Maas, PRO HAC VICE,
`KATTEN MUCHIN ROSENMAN LLP., Chicago, IL.
`KATTEN MUCHIN ROSENMAN LLP., Chicago, IL.
`
`Kerry Brendan McTigue, PRO HAC VICE, DUANE
`Kerry Brendan McTigue, PRO HAC VICE, DUANE
`MORRIS LLP, Washington, DC; Kathleen I. Hart, BOSE
`MORRIS LLP, Washington, DC; Kathleen 1. Hart, BOSE
`MCKINNEY & EVANS, LLP, Indianapolis, IN; Larry
`MCKINNEY & EVANS, LLP, Indianapolis, IN; Larry
`Selander, PRO HAC VICE; Richard Thomas Ruzich,
`Selander, PRO HAC VICE; Richard Thomas Ruzich,
`DUANE MORRIS LLP, Chicago, IL; Robert M. Gould,
`DUANE MORRIS LLP, Chicago, IL; Robert M. Gould,
`PRO HAC VICE, DUANE MORRIS LLP, Chicago, IL;
`PRO HAC VICE, DUANE MORRIS LLP, Chicago, IL;
`Vincent L. Capuano, PRO HAC VICE, DUANE
`Vincent L. Capuano, PRO HAC VICE, DUANE
`MORRIS LLP, Boston, MA.
`MORRIS LLP, Boston, MA.
`
`For KYOWA HAKKO KIRIN CO., LTD., ALCON
`For KYOWA HAKKO KIRIN CO., LTD., ALCON
`RESEARCH, LTD., ALCON LABORATORIES, INC.,
`RESEARCH, LTD., ALCON LABORATORIES, INC.,
`[**2] Defendants: Christopher J. Mandernach,
`Counter
`Counter
`[**2] Defendants: Christopher J. Mandemach,
`Shelley J. Webb, Thomas H. L. Selby, PRO HAC VICE,
`Shelley J. Webb, Thomas H. L. Selby, PRO HAC VICE,
`WILLIAMS & CONNOLLY LLP, Washington, DC;
`WILLIAMS & CONNOLLY LLP, Washington, DC;
`Jessamyn S. Berniker, WILLIAMS & CONNOLLY LLP,
`Jessamyn S. Bemiker, WILLIAMS & CONNOLLY LLP,
`Washington, DC.
`Washington, DC.
`
`For APOTEX INC., APOTEX CORP., Counter
`For APOTEX INC., APOTEX CORP., Counter
`Claimants: Brian J. Sodikoff, Craig M. Kuchii, Martin S.
`Claimants: Brian J. Sodikoff, Craig M. Kuchii, Martin S.
`Masar, III, Robert B. Breisblatt, Thomas J. Maas, PRO
`Masar, III, Robert B. Breisblatt, Thomas J. Maas, PRO
`HAC VICE, KATTEN MUCHIN ROSENMAN LLP.,
`HAC VICE, KATTEN MUCHIN ROSENMAN LLP.,
`Chicago, IL.
`Chicago, IL.
`
`JUDGES: RICHARD L. YOUNG, CHIEF JUDGE.
`JUDGES: RICHARD L. YOUNG, CHIEF JUDGE.
`
`OPINION BY: RICHARD L. YOUNG
`OPINION BY: RICHARD L. YOUNG
`
`For SANDOZ, INC., Defendant: Donald R. McPhaiI,
`For SANDOZ, INC., Defendant: Donald R. McPhail,
`
`OPINION
`OPINION
`
`000001
`
`ARGENTUM PHARM. 1031
`
`ARGENTUM PHARM. 1031
`
`000001
`
`

`
`790 F. Supp. 2d 868, *; 2011 U.S. Dist. LEXIS 55144, **2
`790 F. Supp. 2d 868, *; 2011 U.S. Dist. LEXIS 55144, **2
`
`Page 2
`Page 2
`
`[*873] FINDINGS OF FACT AND CONCLUSIONS
`[*873] FINDINGS OF FACT AND CONCLUSIONS
`OF LAW
`OF LAW
`
`(f/k/a Alcon
`Plaintiffs, Alcon Research, Ltd.
`(f/k/a Alcon
`Plaintiffs, Alcon Research, Ltd.
`Manufacturing,
`Ltd.), Alcon
`Laboratories,
`Inc.
`Manufacturing,
`Ltd.),
`Alcon
`Laboratories,
`Inc.
`(collectively "Alcon"), and Kyowa Hakko Kirin Co. Ltd.
`(collectively "Alcon"), and Kyowa Hakko Kirin Co. Ltd.
`(f/k/a Kyowa Hakko Kogyo Co. Ltd.)
`("Kyowa")
`(f/k/a Kyowa Hakko Kogyo Co. Ltd.)
`("Kyowa")
`(collectively
`"Plaintiffs"),
`filed
`suit
`against
`the
`(collectively
`"Plaintiffs"),
`filed
`suit
`against
`the
`Defendants, Apotex, Inc. and Apotex Corp. (collectively
`Defendants, Apotex, Inc. and Apotex Corp. (collectively
`"Apotex" or "Defendants"), for infringement of United
`"Apotex" or "Defendants"), for infringement of United
`States Patent No. 5,641,805 ("the '805 patent"). The
`States Patent No. 5,641,805 ("the ’805 patent"). The
`parties tried this case before the court from April 26,
`parties tried this case before the court from April 26,
`2010,
`through May 7, 2010. Following the trial,
`the
`2010,
`through May 7, 2010. Following the trial,
`the
`parties filed proposed findings of fact and conclusions of
`parties filed proposed findings of fact and conclusions of
`law. The parties presented their final arguments to the
`law. The parties presented their final arguments to the
`court on August 3, 2010.
`court on August 3, 2010.
`
`Being duly advised, the court finds that Plaintiffs
`Being duly advised,
`the court finds that Plaintiffs
`have proven, by [**3] a preponderance of the evidence,
`have proven, by [**3] a preponderance of the evidence,
`that
`the Defendants' generic equivalent of Plaintiffs'
`that
`the Defendants‘ generic equivalent of Plaintiffs’
`patented allergy topical ocular medication, Patanol®;,
`patented allergy topical ocular medication, Patanol®;,
`infringed claims 1-8 of the '805 patent. The court finds
`infringed claims 1-8 of the ’805 patent. The court finds
`that Defendants have failed to prove by clear and
`that Defendants have failed to prove by clear and
`convincing evidence that claims 1-8 of the '805 patent are
`convincing evidence that claims 1-8 of the ’805 patent are
`invalid as obvious under 35 U.S.C. § 103, as anticipated
`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. § 102, and for lack of written description
`under 35 U.S.C. § 112. The court further finds that
`under 35 U.S.C. § 112. The court further finds that
`Defendants have failed to prove by clear and convincing
`Defendants have failed to prove by clear and convincing
`evidence that the '805 patent is unenforceable due to
`evidence that the ’805 patent is unenforceable due to
`inequitable conduct.
`inequitable conduct.
`
`The court now issues its findings of
`fact and
`The court now issues its findings of fact and
`conclusions of law pursuant to Federal Rule of Civil
`conclusions of law pursuant to Federal Rule of Civil
`Procedure 52(a):
`Procedure 52(a)1
`
`FINDINGS OF FACT1
`FINDINGS OF FACT1
`
`transcript will be
`Citations to the trial
`1
`transcript will be
`Citations to the trial
`1
`"[witness name] Tr." followed by "[transcript
`"[witness name] Tr." followed by "[transcript
`page: line];" citations to the deposition testimony
`page: line];" citations to the deposition testimony
`submitted by the parties will be "[witness name]
`submitted by the parties will be "[witness name]
`Dep." followed by "[dep. page: line]"; citations to
`Dep." followed by "[dep. page: line]"; citations to
`the trial exhibits will be "TX" followed by the
`the trial exhibits will be "TX" followed by the
`exhibit
`number;
`citations
`to
`Plaintiffs’
`exhibit
`number;
`citations
`to
`Plaintiffs'
`demonstrative exhibits will be "AA" followed by
`demonstrative exhibits will be "AA" followed by
`the exhibit number; citations to the parties'
`the exhibit number; citations
`to the parties‘
`[**4] 173,
`pre-trial stipulations, Docket Nos.
`pre—trial stipulations, Docket Nos.
`[**4] 173,
`179, and 204, which are part of the trial record,
`179, and 204, which are part of the trial record,
`will be "[Docket No.], Stipulation" followed by
`will be "[Docket No.], Stipulation" followed by
`
`the paragraph number; and citations to any other
`the paragraph number; and citations to any other
`document on the court's docket will be "[Docket
`document on the court's docket will be "[Docket
`No.]" followed by the title of the document.
`No.]" followed by the title of the document.
`
`I. The Parties
`I. The Parties
`
`1. Alcon Research, Ltd. (f/k/a Alcon Manufacturing,
`1. Alcon Research, Ltd. (f/k/a Alcon Manufacturing,
`Ltd.) is a corporation organized and existing under the
`Ltd.) is a corporation organized and existing under the
`laws of the State of Delaware, having its corporate offices
`laws of the State of Delaware, having its corporate offices
`and principal place of business at 6201 South Freeway,
`and principal place of business at 6201 South Freeway,
`Fort Worth, Texas 76134. (Docket # 173, Stipulation ¶
`Fort Worth, Texas 76134. (Docket # 173, Stipulation ‘H
`1).
`1).
`
`corporation
`a
`is
`Inc.
`2. Alcon Laboratories,
`corporation
`a
`is
`Inc.
`2. Alcon Laboratories,
`organized and existing under the laws of the State of
`organized and existing under the laws of the State of
`Delaware, having its corporate offices and principal place
`Delaware, having its corporate offices and principal place
`of business at 6201 South Freeway, Fort Worth, Texas
`of business at 6201 South Freeway, Fort Worth, Texas
`76134. (Docket # 173, Stipulation ¶ 2).
`76134. (Docket # 173, Stipulation ‘H 2).
`
`3. Kyowa Hakko Kirin Co., Ltd. (f/k/a Kyowa
`3. Kyowa Hakko Kirin Co., Ltd.
`(f/k/a Kyowa
`Hakko Kogyo Co., Ltd.) is a corporation organized and
`Hakko Kogyo Co., Ltd.) is a corporation organized and
`existing under the laws of Japan, having its principal
`existing under the laws of Japan, having its principal
`place of business at 1-6-1 Ohtemachi, Chiyoda-ku, Tokyo
`place of business at 1-6-1 Ohtemachi, Chiyoda—ku, Tokyo
`100-8185, Japan. (Docket # 173, Stipulation ¶ 3).
`100-8185, Japan. (Docket # 173, Stipulation ‘H 3).
`
`is a corporation organized and
`Inc.
`4. Apotex,
`is a corporation organized and
`Inc.
`4. Apotex,
`existing under the laws of Canada, having its principal
`existing under the laws of Canada, having its principal
`place of business at 150 Signet Dr., Weston, Ontario
`place of business at 150 Signet Dr., Weston, Ontario
`[**5] M9L 1T9. (Docket # 173, Stipulation ¶ 4).
`[**5] M9L 1T9. (Docket # 173, Stipulation ‘H 4).
`
`is a corporation organized and
`5. Apotex Corp.
`is a corporation organized and
`5. Apotex Corp.
`existing under the laws of the State of Delaware, having
`existing under the laws of the State of Delaware, having
`its principal place of business at 2400 North Commerce
`its principal place of business at 2400 North Commerce
`[*874] Parkway, Suite 400, Weston, Florida 33326.
`[*874] Parkway, Suite 400, Weston, Florida 33326.
`(Docket # 173, Stipulation ¶ 5).
`(Docket # 173, Stipulation ‘H 5).
`
`6. Alcon Laboratories, Inc. holds the approved New
`6. Alcon Laboratories, Inc. holds the approved New
`Drug Application ("ANDA"), # 20-688, for Patanol®;
`Drug Application ("ANDA"), # 20-688, for Patanol®;
`ophthalmic solution. The NDA was approved on
`ophthahnic
`solution. The NDA was
`approved on
`December 18, 1996. (Docket # 173, Stipulation ¶ 6).
`December 18, 1996. (Docket # 173, Stipulation ‘H 6).
`
`7. On June 6, 1995, Alcon Laboratories, Inc. and
`7. On June 6, 1995, Alcon Laboratories, Inc. and
`Kyowa Hakko Kogyo Co. filed United States Patent
`Kyowa Hakko Kogyo Co. filed United States Patent
`Application # 08/469,729 (the "'729 application"),
`Application # 08/469,729 (the
`‘"729
`application"),
`naming John Yanni, Stella Robertson, Eiji Hayakawa,
`naming John Yarmi, Stella Robertson, Eiji Hayakawa,
`and Masashi Nakakura as inventors. (Docket # 173,
`and Masashi Nakakura as inventors.
`(Docket # 173,
`Stipulation ¶ 7).
`Stipulation ‘H 7).
`
`8. The '729 application issued on June 24, 1997, as
`8. The '729 application issued on June 24, 1997, as
`the
`patent,
`entitled
`"Topical Ophthalmic
`'805
`’805
`patent,
`entitled
`"Topical Ophthahnic
`the
`Formulations for Treating Allergic Eye Diseases." Alcon
`Formulations for Treating Allergic Eye Diseases." Alcon
`Laboratories, Inc. and Kyowa Hakko Kogyo Co. Ltd.,
`Laboratories, Inc. and Kyowa Hakko Kogyo Co. Ltd.,
`
`000002
`
`000002
`
`

`
`790 F. Supp. 2d 868, *874; 2011 U.S. Dist. LEXIS 55144, **5
`790 F. Supp. 2d 868, *874; 2011 U.S. Dist. LEXIS 55144, **5
`
`Page 3
`Page 3
`
`were the original assignees of the '805 patent. (Docket #
`were the original assignees of the ’805 patent. (Docket #
`173, Stipulation ¶ 7).
`173, Stipulation ‘H 7).
`
`between parties that the Southern District of Indiana is a
`between parties that the Southern District of Indiana is a
`proper venue)).
`proper venue)).
`
`in the '805
`9. Alcon Laboratories, Inc.'s interest
`in the ’805
`9. Alcon Laboratories, Inc.'s interest
`patent has been subsequently assigned to Alcon
`patent has
`been
`subsequently assigned to Alcon
`Research, Ltd. Alcon Laboratories,
`Inc.
`sells drug
`Research, Ltd. Alcon Laboratories,
`Inc.
`sells drug
`[**6] under the
`products covered by the '805 patent
`products covered by the ’805 patent
`[**6] under the
`trademark Patanol®; pursuant
`to an ANDA held by
`trademark Patanol®; pursuant
`to an ANDA held by
`Alcon Laboratories, Inc. and approved by the Food and
`Alcon Laboratories, Inc. and approved by the Food and
`Drug Administration ("FDA"). (Docket # 173, Stipulation
`Drug Administration ("FDA"). (Docket # 173, Stipulation
`¶ 8).
`‘I8)-
`
`10. Kyowa Hakko Kogyo Co., Ltd.'s interest in the
`10. Kyowa Hakko Kogyo Co., Ltd.'s interest in the
`'805 patent has been subsequently assigned to Kyowa
`’805 patent has been subsequently assigned to Kyowa
`Hakko Kirin Co., Ltd. (Docket # 173, Stipulation ¶ 9).
`Hakko Kirin Co., Ltd. (Docket # 173, Stipulation ‘H 9).
`
`11. Patanol® is approved for the treatment of the
`11. Patanol® is approved for the treatment of the
`signs and symptoms of allergic conjunctivitis. TX 131 at
`signs and symptoms of allergic conjunctivitis. TX 131 at
`NDA000008;
`NDA000029
`(showing
`approved
`NDA000008;
`NDA000029
`(showing
`approved
`indications on Patanol®'s label). The active ingredient of
`indications on Patanol®'s label). The active ingredient of
`Patanol® is olopatadine hydrochloride. The concentration
`Patanol® is olopatadine hydrochloride. The concentration
`of Patanol®is 1 mg/mL, or 0.1% w/v. (Docket # 173,
`of Patanol®is 1 mg/mL, or 0.1% w/v. (Docket # 173,
`Stipulation ¶ 10).
`Stipulation ‘H 10).
`
`12. Apotex is the owner of ANDA # 78-350, which
`12. Apotex is the owner of ANDA # 78-350, which
`was submitted to the FDA under section 505(j) of the
`was submitted to the FDA under section 505(j) of the
`Federal Food, Drug and Cosmetic Act ("FDCA"), and
`Federal Food, Drug and Cosmetic Act ("FDCA"), and
`seeks approval to engage in the commercial manufacture,
`seeks approval to engage in the commercial manufacture,
`use, and sale of a generic olopatadine hydrochloride
`use, and sale of a generic olopatadine hydrochloride
`product ("Apotex's product") prior to the expiration of the
`product ("Apotex's product") prior to the expiration of the
`'805 patent. (Docket # 173, Stipulation ¶ 13).
`’805 patent. (Docket # 173, Stipulation ‘H 13).
`
`13. By letter dated October 2, 2006 (the "Notice
`13. By letter dated October 2, 2006 (the "Notice
`Letter"), Apotex notified Plaintiffs that Apotex had
`Letter"), Apotex notified Plaintiffs that Apotex had
`submitted ANDA # 78-350 to the FDA. (Answer ¶ 16).
`submitted ANDA # 78-350 to the FDA. (Answer ‘H 16).
`[**7] Apotex notified Plaintiffs
`In the Notice Letter,
`In the Notice Letter,
`[**7] Apotex notified Plaintiffs
`that, as part of its ANDA, it had filed a certification of the
`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
`type described in section 505(j)(2)(A)(vii)(IV) of the
`FDCA ("Paragraph IV" certification). (Answer ¶ 18); TX
`FDCA ("Paragraph IV" certification). (Answer ‘H 18); TX
`131 at ANDA000043 (Paragraph IV certification
`131
`at ANDA000043
`(Paragraph IV certification
`statement).
`statement).
`
`14. On November 15, 2006, Plaintiffs brought suit
`14. On November 15, 2006, Plaintiffs brought suit
`against Apotex, asserting infringement of the '805 patent,
`against Apotex, asserting infringement of the ’805 patent,
`arising out of Apotex's filing of ANDA # 78-350.
`arising out of Apotex's filing of ANDA # 78-350.
`(Docket # 1, Complaint).
`(Docket # 1, Complaint).
`
`15. Jurisdiction and venue are proper in this district
`15. Jurisdiction and venue are proper in this district
`to 28 U.S.C. §§ 1331, 1338(a), 1391, and
`pursuant
`pursuant
`to 28 U.S.C. §§ 1331,
`l338(a), 1391, and
`1400(b). (Docket # 21, Answer ¶ 8; Docket # 35, Entry
`1400(1)). (Docket # 21, Answer ‘H 8; Docket # 35, Entry
`on Defendants' Motion to Transfer at 3 (no dispute
`on Defendants‘ Motion to Transfer at 3 (no dispute
`
`II. The Science of Allergy and the Invention of
`H. The Science of Allergy and the Invention of
`Patanol®
`Patanol®
`
`A. The Human Eye, the Conjunctiva, and Mast Cells
`A. The Human Eye, the Conjunctiva, and Mast Cells
`
`16. Mast cells are specialized cells that exist in many
`16. Mast cells are specialized cells that exist in many
`places throughout the body, including the eye, and are the
`places throughout the body, including the eye, and are the
`primary cells involved in allergic reactions. (Kaliner Tr.
`primary cells involved in allergic reactions. (Kaliner Tr.
`466:8-469:2,
`476:3-24,
`484:15-485:3; Bielory Tr.
`466:8-469:2,
`476:3-24,
`484:15-485:3; Bielory Tr.
`1033:1-8, 1051:8-16; 1053:8-16).
`103311-8, 1051:8-16; 1053:8-16).
`
`17. The mast cells in the eye are located in the
`17. The mast cells in the eye are located in the
`conjunctiva, which is the mucous membrane that lines the
`conjunctiva, which is the mucous membrane that lines the
`inner surface [**8] of [*875] the eyelids and the sclera
`inner surface [**8] of [*875]
`the eyelids and the sclera
`on the front of the eyeball. (Yanni Tr. 113:24-114:20;
`on the front of the eyeball. (Yanni Tr. 113:24-114:20;
`AA-026.02; AA-027; Kaliner Tr. 459:25-460:3). The
`AA-026.02; AA-027; Kaliner Tr. 459:25-460:3). The
`conjunctiva does not cover the tissues responsible for
`conjunctiva does not cover the tissues responsible for
`sight, including the cornea, lens, and retina. (Yanni Tr.
`sight, including the cornea, lens, and retina. (Yanni Tr.
`114:21-115:3; Kaliner Tr. 460:12-18; AA-027).
`114:21-115:3; Kaliner Tr. 460:12-18; AA-027).
`
`18. Like all mucous membranes, the conjunctiva is
`18. Like all mucous membranes, the conjunctiva is
`designed to keep things that are meant to be in the body
`designed to keep things that are meant to be in the body
`in, and to prevent foreign matter from entering the body.
`in, and to prevent foreign matter from entering the body.
`The secretion of mucous on the surface of the membrane
`The secretion of mucous on the surface of the membrane
`removes and flushes foreign objects from the surface of
`removes and flushes foreign objects from the surface of
`the membrane and protects the surface. (Kaliner Tr.
`the membrane and protects the surface.
`(Kaliner Tr.
`461:10-463:16; AA-33; AA-71).
`461:10-463116;AA-33;AA-71).
`
`19. The mast cells do not reside on the very surface
`19. The mast cells do not reside on the very surface
`of the eye. Within the conjunctiva, the epithelial goblet
`of the eye. Within the conjunctiva, the epithelial goblet
`cells are located closest
`to the surface. (Kaliner Tr.
`cells are located closest
`to the surface.
`(Kaliner Tr.
`462:20-463:16, 464:15-466:7; AA-071; AA-033). Below
`462:20-463:16, 464115-466:7; AA-071; AA-033). Below
`the epithelial layer is a basement membrane. (Kaliner Tr.
`the epithelial layer is a basement membrane. (Kaliner Tr.
`464:15-466:7; AA-033; AA-071). Below the basement
`464115-466:7; AA-033; AA-071). Below the basement
`membrane is an area referred to as either the substantia or
`membrane is an area referred to as either the substantia or
`lamina propria.
`(Kaliner Tr. 464:15-466:7; AA-033;
`lamina propria.
`(Kaliner Tr. 464115-466:7; AA-033;
`AA-071). The mast cells in the eye are located below the
`AA-071). The mast cells in the eye are located below the
`basement membrane in the substantia propria. (Kaliner
`basement membrane in the substantia propria. (Kaliner
`Tr. [**9] 465:2-13; AA-071).
`Tr. [**9] 465:2-13; AA-071).
`
`20. Mast cells contain granules, each of which
`20. Mast cells contain granules, each of which
`contain
`pre-formed
`mediators.
`(Kaliner
`Tr.
`contain
`pre-formed
`mediators.
`(Kaliner
`Tr.
`467:10-468:15; AA-30; AA-32). Mediators are chemicals
`467:10-468:15; AA-30; AA-32). Mediators are chemicals
`that, if released from the mast cells, have some effect on
`that, if released from the mast cells, have some effect on
`receptors located in the surrounding tissue. (Kaliner Tr.
`receptors located in the surrounding tissue. (Kaliner Tr.
`467:10-468:15; AA-093). Each granule contains up to 25
`467:10-468:15; AA-093). Each granule contains up to 25
`different
`types of chemical mediators.
`(Kaliner Tr.
`different
`types of chemical mediators.
`(Kaliner Tr.
`467:10-468:15; AA-093).
`467:10-468:15; AA-093).
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`790 F. Supp. 2d 868, *875; 2011 U.S. Dist. LEXIS 55144, **9
`790 F. Supp. 2d 868, *875; 2011 U.S. Dist. LEXIS 55144, **9
`
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`
`21. Adjacent to the conjunctiva is the conjunctival
`21. Adjacent to the conjunctiva is the conjunctival
`sac, which contains an extremely small amount of fluid
`sac, which contains an extremely small amount of fluid
`that keeps the tissues moist. (Kaliner Tr. 460:19-461:6;
`that keeps the tissues moist. (Kaliner Tr. 460:19—461:6;
`AA-027).
`AA—027).
`
`B. The Allergic Cascade
`B. The Allergic Cascade
`
`1. Mediator Release Through Degranulation
`1. Mediator Release Through Degranulation
`
`22. The allergic response is a mechanism that the
`22. The allergic response is a mechanism that the
`human body uses to attempt
`to expel something it
`human body uses to attempt
`to expel something it
`recognizes as a foreign invading substance. (Yanni Tr.
`recognizes as a foreign invading substance. (Yarmi Tr.
`119:16-120:4).
`119:16—120:4).
`
`23. In the eye, the most common type of allergic
`23. In the eye, the most common type of allergic
`disease is called allergic conjunctivitis.
`(Kaliner Tr.
`disease is called allergic conjunctivitis.
`(Kaliner Tr.
`507:2-13).
`507:2—13).
`
`24. In general, an allergic reaction can occur in the
`24. In general, an allergic reaction can occur in the
`sensitized human being upon exposure to an antigen. An
`sensitized human being upon exposure to an antigen. An
`antigen is a substance that has the ability to trigger an
`antigen is a substance that has the ability to trigger an
`immunologic
`reaction,
`such as
`the production of
`immunologic
`reaction,
`such as
`the production of
`antibodies.
`(Yanni Tr. 116:18-118:14; Kaliner Tr.
`antibodies.
`(Yanni Tr.
`116:18-118:14; Kaliner Tr.
`470:2-22).
`470:2—22).
`
`[**10] Common antigens include substances
`25.
`[**10] Common antigens include substances
`25.
`such as cat dander, pollen, and ragweed. (Yanni Tr.
`such as cat dander, pollen, and ragweed.
`(Yanni Tr.
`117:10-118:6; Kaliner Tr. 470:2-22).
`117:10—118:6; Kaliner Tr. 470:2—22).
`
`26. Exposure occurs when an antigen, like pollen,
`26. Exposure occurs when an antigen, like pollen,
`comes into contact with the outer epithelial layer of the
`comes into contact with the outer epithelial layer of the
`conjunctiva. Small proteins break off from the pollen
`conjunctiva. Small proteins break off from the pollen
`grain and move through the epithelium,
`through the
`grain and move through the epithelium,
`through the
`basement membrane, and into the substantia or lamina
`basement membrane, and into the substantia or lamina
`propria where the mast cells are located. (Kaliner Tr.
`propria where the mast cells are located. (Kaliner Tr.
`465:2-13).
`465:2—13).
`
`27. In the portion of the human population that is
`27. In the portion of the human population that is
`genetically predisposed to do so, exposure over a period
`genetically predisposed to do so, exposure over a period
`of
`time
`to certain antigens
`through the mucous
`of
`time
`to certain antigens
`through the mucous
`membranes causes the body to produce antibodies. The
`membranes causes the body to produce antibodies. The
`antibodies bind to the surface of the mast cells. (Yanni
`antibodies bind to the surface of the mast cells. (Yanni
`Tr.
`117:10-118:14;
`Kaliner
`Tr.
`470:2-471:13;
`Tr.
`117:10-118:14;
`Kaliner
`Tr.
`470:2-471113;
`AA-19.01-.03).
`AA—19.01—.03).
`
`28. [**11] When antibodies bind to the surface of
`28.
`[**11] When antibodies bind to the surface of
`mast cells, they confer sensitivity to these cells. When
`mast cells, they confer sensitivity to these cells. When
`those cells are subsequently exposed to the antigen, the
`those cells are subsequently exposed to the antigen, the
`antigen binds to the antibodies on the surface [*876] of
`antigen binds to the antibodies on the surface [*876] of
`the cells, causing them to secrete the chemical mediators
`the cells, causing them to secrete the chemical mediators
`within them. This process of releasing the pre-formed
`within them. This process of releasing the pre—formed
`mediators is referred to as degranulation. (Yanni Tr.
`mediators is referred to as degranulation. (Yarmi Tr.
`
`118:5-119:6; Kaliner Tr. 471:8-472:10; AA-19.04-.07).
`118:5-119:6; Kaliner Tr. 471:8-472: 10; AA-19.04-.07).
`
`29. The pre-formed chemical mediators found in
`29. The pre—for1ned chemical mediators found in
`mast cells vary depending on the type of mast cell, and
`mast cells vary depending on the type of mast cell, and
`may include histamine, heparin, tryptase, chymase, and
`may include histamine, heparin, tryptase, chymase, and
`other chemicals. (Yanni Tr. 116:17-117:9; Kaliner Tr.
`other chemicals. (Yanni Tr. 116:17—117:9; Kaliner Tr.
`474:3-16; AA-93).
`47413-16; AA—93).
`
`2. Mediator Production in the "Late Phase" of the
`2. Mediator Production in the "Late Phase" of the
`Allergic Cascade
`Allergic Cascade
`
`[**12] Mast cells also have the ability to
`30.
`[**12] Mast cells also have the ability to
`30.
`synthesize and release other chemical mediators and
`synthesize and release other chemical mediators and
`cytokines that are synthesized and released after the
`cytokines that are synthesized and released after the
`release of pre-formed mediators, which occurs in what is
`release of pre—formed mediators, which occurs in what is
`called the late phase of the allergic reaction. (Kaliner Tr.
`called the late phase of the allergic reaction. (Kaliner Tr.
`473:5-18). The late phase reaction is an inflammatory
`473:5—18). The late phase reaction is an inflammatory
`response in which white blood cells, called eosinophils,
`response in which white blood cells, called eosinophils,
`are attracted to the eye and make the eye quite irritable
`are attracted to the eye and make the eye quite irritable
`for an extended period of time. (Kaliner Tr. 473:5-18).
`for an extended period of time. (Kaliner Tr. 47315-18).
`
`3. Signs and Symptoms of Allergy
`3. Signs and Symptoms of Allergy
`
`31. Within the surrounding tissues of the eye, there
`31. Within the surrounding tissues of the eye, there
`are different types of receptors that correspond to the
`are different types of receptors that correspond to the
`different mediators released from the mast cells. (Yanni
`different mediators released from the mast cells. (Yanni
`Tr. 118:24-119:6; Kaliner Tr. 471:22-473:4; AA-19.01;
`Tr. 118:24-119:6; Kaliner Tr. 471:22-473:4; AA-19.01;
`AA-19.07-.09).
`AA—19.07—.09).
`
`32. After mediators and cytokines are released from
`32. After mediators and cytokines are released from
`mast cells, they bind to the corresponding receptors and
`mast cells, they bind to the corresponding receptors and
`trigger physiological
`reactions in the body that are
`trigger physiological
`reactions in the body that are
`commonly identified as allergic symptoms -- redness,
`commonly identified as allergic symptoms —— redness,
`itching, swelling, watering eyes,
`running nose, etc.
`itching,
`swelling, watering eyes,
`running nose, etc.
`(Yanni Tr.
`119:7-15; Kaliner Tr.
`471:22-473:4;
`(Yanni Tr.
`119:7-15; Kaliner Tr.
`471:22-473:4;
`AA-19.09; AA-20).
`AA—19.09; AA—20).
`
`C. Treating Allergic Eye Disease
`C. Treating Allergic Eye Disease
`
`33. Patients with allergic conditions are treated by
`33. Patients with allergic conditions are treated by
`interfering with the allergic cascade [**13] at one or
`interfering with the allergic cascade [**13] at one or
`more points in the process. (Kaliner Tr. 498:15-500:5).
`more points in the process. (Kaliner Tr. 498:15—500:5).
`
`34. In 1995, there were three primary classes of
`34. In 1995,
`there were three primary classes of
`compounds used to treat allergic conjunctivitis:
`(1)
`compounds used to treat allergic conjunctivitis:
`(1)
`antihistamines;
`(2)
`antihistamines
`combined with
`antihistamines;
`(2)
`antihistamines
`combined with
`vasoconstrictors; and (3) cromolyn sodium, a compound
`vasoconstrictors; and (3) cromolyn sodium, a compound
`that was reported to be a mast cell stabilizer based on
`that was reported to be a mast cell stabilizer based on
`animal testing. (Yanni Tr. 120:5-121:5).
`animal testing. (Yanni Tr. 12015-12115).
`
`1. Antihistamines (With or Without Vasoconstrictors)
`1. Antihistamines (With or Without Vasoconstrictors)
`
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`790 F. Supp. 2d 868, *876; 2011 U.S. Dist. LEXIS 55144, **13
`790 F. Supp. 2d 868, *876; 2011 U.S. Dist. LEXIS 55144, **13
`
`Page 5
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`
`a. Antihistamines Have Limited Effect
`a. Antihistamines Have Limited Effect
`
`35. A standard antihistamine interferes with the
`35. A standard antihistamine interferes with the
`allergic cascade toward the end of
`the process by
`allergic cascade toward the end of the process by
`preventing histamine that has been released from mast
`preventing histamine that has been released from mast
`cells from binding to particular histamine receptor sites
`cells from binding to particular histamine receptor sites
`by blocking those receptors. (Kaliner Tr. 496:19-498:8;
`by blocking those receptors. (Kaliner Tr. 496119-498:8;
`AA-22.01-.03; AA-22.06; AA-22.08).
`AA—22.01—.03; AA—22.06; AA—22.08).
`
`administered after
`is
`an antihistamine
`If
`36.
`administered after
`is
`an antihistamine
`If
`36.
`histamine has already been released, the antihistamine
`histamine has already been released,
`the antihistamine
`can displace histamine from a histamine receptor and
`can displace histamine from a histamine receptor and
`replace it, which stops the allergic symptoms caused by
`replace it, which stops the allergic symptoms caused by
`that mediator. (Yanni Tr. 122:19-123:25; Kaliner Tr.
`that mediator.
`(Yanni Tr. 122:19-123:25; Kaliner Tr.
`496:19-498:8; AA-22.05a; AA-22.05b).
`496119-498:8; AA—22.05a; AA—22.05b).
`
`37. Antihistamines are only effective in relieving
`37. Antihistamines are only effective in relieving
`symptoms caused by histamine binding to those H1
`symptoms caused by histamine binding to those H1
`receptors and do not have any effect on signs [**14] or
`receptors and do not have any effect on signs [**14] or
`symptoms caused by mediators other than histamine that
`symptoms caused by mediators other than histamine that
`are released from the mast cell. (Yanni Tr. 124:1-8;
`are released from the mast cell.
`(Yanni Tr. 124:1-8;
`Kaliner Tr. 498:15-499:4).
`Kaliner Tr. 498: 15-499:4).
`
`38. Antihistamines also do not have any effect on the
`38. Antihistamines also do not have any effect on the
`[*877] phase of the
`symptoms caused by the late
`symptoms caused by the late
`[*877] phase of the
`allergic reaction. (Kaliner Tr. 498:15-499:20).
`allergic reaction. (Kaliner Tr. 498115-499120).
`
`b. Many Oral Antihistamines Cannot Be Made Into
`b. Many Oral Antihistamines Cannot Be Made Into
`Topical Ophthalmic Preparations
`Topical Ophthalmic Preparations
`
`39. Oral antihistamines have been on the market
`39. Oral antihistamines have been on the market
`since around 1950 and were t