`
`1
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE EASTERN DISTRICT OF TEXAS
`MARSHALL DIVISION
`
`ALLERGAN,
`
`INC.
`
`vs .
`
`SANDOZ,
`
`INC .
`
`* Civil Docket No .
`2 : 09-CV-97
`*
`* Marshall, Texas
`*
`*
`*
`
`August 3, 2011
`1:15 P.M.
`
`TRANSCRIPT OF BENCH TRIAL
`BEFORE THE HONORABLE JUDGE T. JOHN WARD
`UNITED STATES DISTRICT JUDGE
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`1
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`2
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`9 APPEARANCES :
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`10 FOR THE PLAINTIFF :
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`MS. JUANITA BROOKS
`MR . ROGER DENNING
`Fish & Richardson
`12390 El Camino Real
`San Diego , CA
`92130
`
`MR . JONATHAN SINGER
`MS . DEANNA REICHEL
`Fish & Richardson
`60 South Sixth Street
`3200 RBC Plaza
`Minneapolis, MN
`
`55402
`
`MR . W. CHAD SHEAR
`Fish & Richardson
`1717 Main Street
`Suite 5000
`Dallas, TX
`
`75201
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`20 APPEARANCES CONT INUED ON NEXT PAGE:
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`21
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`22 COURT REPORTERS :
`
`MS. SUSAN SIMMONS, CSR
`MS. SHELLY HOLMES, CSR
`Official Court Reporters
`100 East Houston, Suite 125
`Marshall, TX
`75670
`903/935 - 3868
`(Proceedings recorded by mechanical stenography,
`transcript produced on CAT system.)
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`Page 1 of 166
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`SENJU EXHIBIT 2136
`LUPIN v. SENJU
`IPR2015-01105
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`
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 2 of 165 PageiD #: 6188
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`2
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`1
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`2 APPEARANCES CONTINUED:
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`3 FOR THE PLAINTIFF:
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`4
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`5
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`6
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`7
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`8
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`9
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`10 FOR THE DEFENDANTS:
`(Sandoz, et al)
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`11
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`13
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`14
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`15
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`16
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`17
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`20
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`(Apotex)
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`21
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`22
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`24
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`25
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`MS. SUSAN COLETTI
`MS. A. MARTINA HUFNAL
`MR. SANTOSH CONTINHO
`Fish & Richardson
`222 Delaware Avenue
`17th Floor
`Wilmington, DE
`
`19899
`
`MR. GREGORY LOVE
`Stevens Love Firm
`111 West Tyler Street
`Longview, TX
`75601
`
`MR. WILLIAM E . "BO" DAVIS, III
`The Davis Firm
`111 West Tyler Street
`Longview, TX
`75601
`
`MR. BARRY P. GOLOB
`MR . KERRY B. MCTIGUE
`MR. W. BLAKE COBLENTZ
`Duane Morris
`505 9th Street, NW
`Suite 1000
`Washington, DC
`
`20004
`
`MR . RICHARD T. RUZICH
`Duane Morris
`190 South LaSalle Street
`Suite 3700
`Chicago, IL
`
`60603
`
`MR . HARRY L. GILLAM, JR .
`Gillam & Smith
`303 South Washington Avenue
`Marshall, TX
`75670
`
`MR. STEPHEN P. BENSON
`MR. DENNIS C. LEE
`Katten Muchin Rosenman
`525 West Monroe Street
`Suite 1600
`Chicago, IL
`
`60661
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`Page 2 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 3 of 165 PageiD #: 6189
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`3
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`1 APPEARANCES CONTINUED:
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`2 FOR THE DEFENDANTS:
`(Watson)
`
`MR . LARRY PHILLIPS
`Siebman Reyno l ds Burg &
`Phillips
`300 North Travis Street
`Sherman, TX
`75090
`
`MR . GARY E . HOOD
`Polsinelli Shughart
`1 61 North Clark Street
`Suite 4200
`Chicago ,
`IL
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`60601
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`MS. ROBYN H . AST
`Polsinelli Shughart
`100 South 4th Street
`Suite 1000
`St . Louis , MO
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`63102
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`****************************
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`P R 0 C E E D I N G S
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`COURT SECURITY OFFICER : All rise.
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`THE COURT : Please be seated.
`
`Ms. Brooks .
`
`MS . BROOKS: Thank you , Your Honor .
`
`ANGELO P . TANNA, M.D., DEFENDANTS ' WITNESS ,
`
`PREVIOUSLY SWORN
`
`DIRECT EXAMINATION
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`21 BY MS . BROOKS :
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`22
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`23
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`24
`
`Q.
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`A.
`
`Q .
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`Good afternoon, Dr . Tanna.
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`Good after, Ms. Brooks .
`
`Right before the lunch break ,
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`I was
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`25 frantically looking for a copy of Walters . We now have
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`Page 3 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 4 of 165 PagelD #: 6190
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`4
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`1 one before you 1 n yo u r binder . And it ' s DTX138 .
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`2 Oh ,
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`I ' m sorry . That ' s the abs t ract actually, which you
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`3 did look at . Now ,
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`le t' s look at DTX 1 37 . And that is
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`4 the Wa l ters paper.
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`5
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`So yo u say , Dr . Tan n a , you had not had a
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`6 chance to look a t this before rendering your opinion ; is
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`7 that right?
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`8
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`A.
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`No , that ' s not true. Now that I see i t ,
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`I do
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`9 recognize it .
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`I have looked at this reference.
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`10
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`Q.
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`So you did consider i t
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`in rendering your
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`11 opinion?
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`12
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`13
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`A .
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`Q .
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`I did consider it , yes.
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`All right . The n
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`l et ' s
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`l ook , if we could,
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`14 please , at Bates No. 346 ,
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`t h e page ending in that Bates
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`15 number .
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`16
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`MS. BROOKS : An d h igh l ight , if we could ,
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`17 in the right-hand col um n wh ere it begins similar
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`1 8 means
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`mean decreases in IOP .
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`19
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`20
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`A .
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`Q.
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`346?
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`(By Ms. Brooks) Yeah , 346 .
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`It s h ould be the
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`21 bottom right -:- hand corner ,
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`t h e Bat es No . 0003 4 6 .
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`22
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`23
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`24
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`25
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`A .
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`Q .
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`Do you have that?
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`Yes ,
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`I do .
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`Okay . And it ' s also up on t he screen .
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`So let ' s see wh at Walters also disclosed abou t
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`Page 4 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 5 of 165 PageiD #: 6191
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`5
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`1 this study.
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`It says: Similar mean decreases in IOP
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`2 were noted for both dosing regimens at hours 2, 4, and 7
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`3
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`in the diurnal measurements.
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`4
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`In the three - times - daily group , an additional
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`5 mean decrease in IOP of 3.5 millimeters of mercury was
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`6 observed at hour 9, after the morning dosing, or two
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`7 hours following the afternoon dosing.
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`8
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`9
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`10
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`A.
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`Q .
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`Do you see that , Dr . Tanna?
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`Yes,
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`I do .
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`So isn't it true that one of skill in t he art
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`11 would look at Walters and see that there was a
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`12 statistically significant decrease in IOP at 9 . 0 hours
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`13 after morning dosing on the three-times-a-day
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`14 Brimonidine?
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`15
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`A .
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`Yes. And it is overall, in my opinion, that
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`16
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`three-times-a-day Brimonidine is more effectiv e than
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`17
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`twice-a-day Brimonidine . And ,
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`in fact, that is in my
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`18
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`expert opinion, and I used a different reference as the
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`19 main reference for that , specifically Konstas .
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`20
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`THE COURT :
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`Doctor, she hadn't asked you
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`21 any of that .
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`22
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`23
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`THE WIT NESS:
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`I'm sorry, Your Honor.
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`THE COURT:
`
`If they want you to repeat
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`24 that testimony or what's in your expert report, they ' ll
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`25 ask you . But unless everybody's not listening to me,
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`Page 5 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 6 of 165 PageiD #: 6192
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`6
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`1
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`the Court's going to start tightening up.
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`I'm not here
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`2 to listen to lectures.
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`I'm here for you to answer the
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`3 questions asked , and stop talking.
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`4
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`5
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`6
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`7
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`Are we clear?
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`THE WITNESS : Yes , Your Honor .
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`THE COURT : Thank you .
`
`Q .
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`(By Ms . Brooks) And let 's just see if we can
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`8 find the graph that correlates to this data in PTX134,
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`9 which you don't have before you, Dr . Tanna , because it's
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`10 too large, but has previously been discussed with
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`11 Ms. Batoosingh.
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`12
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`MS. BROOKS :
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`If we can go to PTX134 and
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`13 specifically at Bates No . 676465, Mr . Exline.
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`14
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`Q .
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`(By Ms. Brooks) And do you see this graph , Dr.
`
`15 Tanna?
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`16
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`17
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`A .
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`Q.
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`Yes,
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`I do.
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`Could you show the Court where that
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`18 3.5-millimeters of mercury difference occurs between the
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`19 twice-a-day dosing of Alphagan and the three-times-a-day
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`20 dosing of Alphagan?
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`21
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`22
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`23
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`24
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`25
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`A .
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`Q.
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`A .
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`Q .
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`It's not doing
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`Here, I' ll try to help you .
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`I have a pointer. May I use a laser pointer?
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`Sure. Or did I get it close right there?
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`A. Well, that's it, yes.
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`Page 6 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 7 of 165 Page!D #: 6193
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`7
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`1
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`Q.
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`Okay. And so, again, you agree that -- one of
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`2 skill in the ar t would know, based on this data, that
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`3 there was an actual statistically significant decrease
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`4
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`in the reduc t ion of i ntraocular pressure at
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`5 approximately hour 9 between the three - times - a-day
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`6 dosing of Alphagan and the twice - a - day dosing?
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`7
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`8
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`A.
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`Q.
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`Yes, in this study.
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`Now, let's move to your discussion of how the
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`9 amount of BAK that was claimed would have been obv i ous.
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`10 You said the BAK was the most common preservative; is
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`11 that correct?
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`12
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`A .
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`Most commonly used in ophthalmic formula t ions,
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`13 yes.
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`14
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`15
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`Q.
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`And,
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`i n fact, we saw --
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`MS. BROOKS: Mr. Exline , could you pull
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`16 up Defendants' Slide 1.0 that they used in opening
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`17 statemen t ? And if not, I can always put it on the ELMO.
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`18
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`19
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`There we · are.
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`Q .
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`(By Ms . Brooks) So this was shown to the Court
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`20 by the De f endants in opening statement showing a ll the
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`21 different drug products that contain BAK.
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`22
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`23
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`24
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`A .
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`Q .
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`Do you agree with that, Dr . Tanna?
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`I do .
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`But let's look at the amount of BAK in these
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`25
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`various
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`products.
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`Isn't it true that there are no less
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`Page 7 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 8 of 165 PageiD #: 6194
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`8
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`1
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`than six different amounts of BAK in these various
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`2 ophthalmic products?
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`3
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`4
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`5
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`A.
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`Q.
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`That looks right.
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`Thank you.
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`Let's move on now to your discussion of other
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`6 combination drugs. You to l d us about a drug cal l ed
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`7 Timpilo; is that right?
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`8
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`9
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`A.
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`Q.
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`I did, yes .
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`And you told us about a drug called Cosopt.
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`10 Of course, we know about that, right?
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`11
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`12
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`13
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`14
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`A.
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`Q .
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`A.
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`Q .
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`Yes.
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`And a l so a drug called Xalacom; is that right?
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`That's correct.
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`In fact, on Slide 36 that you used, you showed
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`15 both the Timpilo, the Cosopt, and the Xalacom .
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`16
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`Now, in look i ng more c l osely at the Timpilo
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`17 picture that you used, that's not actually a picture of
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`18 Timpilo, is it?
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`19
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`A .
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`I don't know that -- I can't tell from that
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`20 picture.
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`I don't know .
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`21
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`·o .
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`Isn't it, in fact ,
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`just a picture of the
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`22 bottle of Pilocarpine?
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`23
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`A .
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`I don ' t
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`think so, because it typically would
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`24 have a green cap .
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`So I can't tell from t his picture.
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`I
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`25 am no t sure what tha t 's a picture of.
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`Page 8 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 9 of 165 PageiD #: 6195
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`9
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`1
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`Q.
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`Okay . Now, Timpi l o has never been approved
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`2 for use in the United States, correct?
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`3
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`A .
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`I was under the impression that it was in use
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`4 in the United States .
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`That's my impression .
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`I could be
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`5 mistaken about it, but my understanding is that it was
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`6
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`in use in the United States .
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`7
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`Q.
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`Okay . What about Xalacom ; has Xalacom ever
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`8 been approved for use in the United States?
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`A .
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`Q .
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`9
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`1 0
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`11
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`No , it has not .
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`Now, while we're talki n g about Xalacom --
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`MS . BROOKS : Let's just leave that up
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`12
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`there,
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`if we could, Mr. Exline.
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`13
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`Q .
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`(By Ms . Brooks ) We ' re going to revisit some
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`1 4 organic chemistry .
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`15
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`Xalacom i s the active ingredient in
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`16 La tanopros t; is that right?
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`1 7
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`18
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`A .
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`Q .
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`That ' s correct.
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`And Latanoprost is what's known as a
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`19 prostagland i n analog ; is that correct?
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`20
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`21
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`A.
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`Q.
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`That is correct .
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`Are the prostaglandin analogs norma ll y your
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`22 first choice of medication for a new gla u coma patient?
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`23
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`24
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`A.
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`Q.
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`For me today , yes.
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`And ,
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`i n fact , the Latanoprost is sold here in
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`25 the United States as Xalatan ; is that right?
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`Page 9 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 10 of 165 PageiD #: 6196
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`10
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`1
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`2
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`A.
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`Q.
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`That's correct.
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`But the combination of Xalatan and Timolol,
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`3 also known as Xalacom, has never been approved for use
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`4
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`in the United States; is that correct?
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`5
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`6
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`A .
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`Q .
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`That is correct .
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`And you yourself have never prescribed the use
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`7 for Xalacom, correct?
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`8
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`A.
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`I have never prescribed Xalacom . That's
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`9 correct .
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`10
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`Q.
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`Now, in that same category of prostaglandin
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`11 analogs, would you put Travoprost?
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`12
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`13
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`A .
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`Q .
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`14 correct?
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`15
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`16
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`A .
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`Q .
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`It is in the same category.
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`And that 's also known as Travatan ; is that
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`That 's correct.
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`There is no combination drug of Travatan and
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`17 Timolol approved for us in the United States; is that
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`18 correct?
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`19
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`20
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`A .
`
`Q.
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`Tha t is correct.
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`And also within what you would call a
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`21 prostaglandin analog , or we would call a prostamide, is
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`22 a compound called Bimatoprost.
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`23
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`24
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`25
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`A .
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`Q .
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`Are you familiar with that?
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`Yes ,
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`I am .
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`And Bimatoprost is sold here in the United
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`Page 10 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 11 of 165 PageiD #: 6197
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`11
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`1 States by Allergan under the name Lumigan.
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`2
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`3
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`4
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`A .
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`Q .
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`Ar e you fami l iar with that?
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`Yes ,
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`I am .
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`There are no -- I
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`think you mentioned t h at
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`5 Ganfo r t, wh ich was a combination of Bimatoprost/Timolol
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`6 drug ; is that right?
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`7
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`8
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`A.
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`Q .
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`Correct .
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`But Ganfort is not approved for use here in
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`9 the United States ; is t h at correct ?
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`10
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`11
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`A .
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`Q.
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`No , it ' s not.
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`And just to show how subtle d i fferences make a
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`1 2 very b i g difference , Bimatoprost and Latanoprost , would
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`13 you put the m in t he same category as far as mechanism of
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`14 action?
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`15
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`A .
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`Th ere may be small differences in terms of the
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`16 mechanism of actio n.
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`I
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`think it ' s a matter of
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`17 controversy .
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`18
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`Q.
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`We l l ,
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`in f act , Latanopros t is what ' s known as
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`19 1 7 - p h enyl-PGF2 - alpha , correct?
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`20
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`21
`
`A .
`
`Q .
`
`I know there ' s a PGF2 - alpha - agonist .
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`Okay . And at the C1 position on the alpha
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`22 chain is an ester ; is that righ t ?
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`23
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`24
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`A .
`
`Q.
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`That I don ' t know offhand .
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`So I may know a lit t le more organ i c chemistry .
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`25 What about Bimatoprost? Ar e you aware that if t h e Cl
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`Page 11 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 12 of 165 PageiD #: 6198
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`12
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`1 position o n the alpha chai n of Bi matoprost is an amide?
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`2
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`A.
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`I be l ieve that I can picture t h at and agree
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`3 with you on that , but I would have to look at the
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`4 structure to be s u re.
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`It's a complex - -
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`it ' s a big
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`5 molecule , and I don ' t know offhand for s u re .
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`6
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`Q .
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`Wo u ld you agree wit h me that a n ester is
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`7 differen t
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`t han an ami d e?
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`8
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`9
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`10
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`11
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`A.
`
`Q .
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`A.
`
`Q .
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`It certain l y is .
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`And can , in fact , behave differently in situ?
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`Yes , it can .
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`Now, let ' s go to -- back to the T i mpilo . You
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`12 should have in your binder, Dr . Tan n a ,
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`t h e labe l for
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`13 Timpilo ,
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`I hope. And I don ' t know if we numbered it
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`14 since it wasn't actua l ly previous l y in use , but i f you
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`15 go through your binder , you should see a
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`l abe l for
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`16 Timpilo .
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`17
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`18
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`19
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`20
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`21
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`A.
`
`Q .
`
`Can you tell me approx i mately where?
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`Oh , it ' s not in your binder . Sorr y.
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`MS . BROOKS : May I approach , Your Honor?
`
`TH E COURT: Yes.
`
`Q .
`
`(By Ms . Brooks) Now, Dr . Ta n na , you ' ve
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`22 referred t o T impilo as a combination drug ; is that
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`23 right?
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`24
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`25
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`A .
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`I t is a co mbination drug , yes .
`
`Q. Well , if we act u a l ly --
`
`Page 12 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 13 of 165 PageiD #: 6199
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`13
`
`1
`
`MS . BROOKS :
`
`If we can go to the ELMO,
`
`2 Mr. Exline.
`
`3
`
`Q.
`
`(By Ms . Brooks) And here's the label for
`
`4 Timpilo.
`
`5
`
`6
`
`7 cam up there?
`
`THE COURT: Not quite. Here we go .
`
`COURTROOM DEPUTY: Can you push the doc
`
`8
`
`MS . BROOKS:
`
`I sure can. Let's see here.
`
`9 Doc cam?
`
`10
`
`11
`
`COURTROOM DEPUTY : Uh-huh.
`
`MS. BROOKS : Perhaps --Mr . Exline, do
`
`12 you know -- do we have the Timpilo label in the system?
`
`13 We don't? Okay .
`
`It would help if I turn it on .
`
`I
`
`14 apologize. There we go .
`
`It's my fault.
`
`I 'm sorry.
`
`I
`
`15 didn't even turn it on .
`
`16
`
`Q.
`
`(By Ms. Brooks) Dr. Tanna, isn't it a fact
`
`17 that Timpilo is dispensed in what is described as a
`
`18 unique, two-chambered vial system?
`
`19
`
`20
`
`A.
`
`Q.
`
`Yes .
`
`And one of the chambers contains a
`
`21 concentrated solution of Timolol and Pilocarpine at a pH
`
`22 of approximately 3.5; is that right?
`
`23
`
`24
`
`A.
`
`Q.
`
`Correct . Correct.
`
`Now, in relation to the pH of the eye, 3 . 5 is
`
`25 extremely acidic, is it not?
`
`Page 13 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 14 of 165 PageiD #: 6200
`
`14
`
`1
`
`2
`
`3
`
`A .
`
`It is more acidic than the ocular surface and
`
`the pH of the eye in general , yes .
`
`Q .
`
`And the need for this low pH is to prevent the
`
`4 hydrolysis of Pilocarpine prior to dispensing ; is
`
`that
`
`5 correct?
`
`6
`
`7
`
`A .
`
`Q.
`
`Yes.
`
`So you would agree wi th me , Dr . Tanna ,
`
`that a
`
`8 pH can have a significant effect on an active
`
`9
`
`ingredient?
`
`10
`
`11
`
`A .
`
`Q .
`
`Yes, it can .
`
`And it says the other chamber contains -- can
`
`12 you pronounce that word for me , so I make sure I say it
`
`13 right?
`
`14
`
`15
`
`A .
`
`Q.
`
`It ' s diluent.
`
`Diluent so lut io n wi th a pH of 7 . 8 to 8 . 2 for
`
`16 Timpilo 2 ; and 8.5 to 9.5 for Ti mpilo 4 .
`
`17
`
`18
`
`19
`
`A .
`
`Q.
`
`Did I read that correct ly?
`
`Yes, you did.
`
`And the two solutions are separated by an
`
`20 internal plug?
`
`21
`
`22
`
`A .
`
`Q .
`
`Yes .
`
`So this isn ' t
`
`the convenience of having two
`
`23 active ingredients in one bottle , correct?
`
`24
`
`A .
`
`It is a little more complicated than that .
`
`25 You have to mix them together effectively by using the
`
`Page 14 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 15 of 165 PageiD #: 6201
`
`1 5
`
`1 system .
`
`2
`
`Q.
`
`And for whatever formu l ation reason ,
`
`the
`
`3 for mu l ators were not able t o simply put the Timolo l and
`
`4 the P il ocarpi n e in t o one bo t tle for shelf life?
`
`5
`
`6
`
`A .
`
`Q .
`
`Correct.
`
`And had to go to t h is two - chambered system
`
`7 with two different pHs and a plug in t h e mi ddle ; is t h at
`
`8 right?
`
`9
`
`10
`
`A .
`
`Q .
`
`Th at ' s rig h t
`
`.
`
`Now , another -- so that ' s the
`
`11 Pi l ocarpine/Timolol one .
`
`12
`
`You also men t ioned a combination produ ct
`
`13 ca ll e d Probeta , which is Levobunolol a n d Di pive f rin?
`
`A .
`
`Q .
`
`14
`
`15
`
`16
`
`1 7 go?
`
`18
`
`19
`
`20 back .
`
`I t's p rono u nced Dipive f rin ( p r onou n ces )
`
`Dipivefrin (pronounces) .
`
`Tha nk you .
`
`MS . BROOKS: Should I push some t hing to
`
`MR . LOVE :
`
`I t
`
`' s there .
`
`MS . BROO KS : There we go .
`
`I thi n k we ' re
`
`21
`
`Q .
`
`(By Ms . Brooks) And t hat ' s called Probeta ; is
`
`22 that right?
`
`23
`
`2 4
`
`A .
`
`Q .
`
`That's correct .
`
`Th at ' s available in Canada .
`
`So that ' s never bee n approved for use here in
`
`25 the United States, correct?
`
`Page 15 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 16 of 165 PageiD #: 6202
`
`16
`
`1
`
`2
`
`3
`
`4
`
`A .
`
`Q .
`
`A.
`
`Q .
`
`That 's correct.
`
`And you yourself have never prescribed it?
`
`Correct.
`
`Then we have the Xalacom, which we've already
`
`5
`
`talked about, the Ganfort which we've already talked
`
`6 about, and then something where it ' s Travoprost/Timolol
`
`7 combination; is that right?
`
`8
`
`9
`
`A .
`
`Q.
`
`DuoTrav, yes .
`
`DuoTrav . That also has never been approved
`
`10 for use in the United States, correct?
`
`11
`
`12
`
`13
`
`14
`
`A.
`
`Q .
`
`A .
`
`Q.
`
`Tha t's correct.
`
`And you yourself have never prescribed it?
`
`That's correct.
`
`Now,
`
`I take it you weren ' t part of -- well,
`
`15 have you ever been part of an FDA approval process for a
`
`16 combination drug?
`
`17
`
`A. Well, we were one of the clinical trial
`
`18 centers for DuoTrav for one of the Phase 3 studies in
`
`19 the U.S.
`
`20
`
`Q .
`
`So there were Phase 3 clinical trials
`
`21 conducted on DuoTrav here in the United States, correct?
`
`22
`
`23
`
`. A.
`
`That's .correct .
`
`Q.
`
`And
`
`I assume that you, as one of the centers,
`
`24 attempted to perform those studies accurately, correct?
`
`25
`
`A.
`
`Yes, we did.
`
`Page 16 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08111 Page 17 of 165 PageiD #: 6203
`
`17
`
`1
`
`Q.
`
`And attempted to gather the best data that you
`
`2 could?
`
`3
`
`4
`
`A.
`
`Q.
`
`Correct.
`
`And despite your efforts and all the other
`
`5 centers' efforts, to this day, the FDA has refused to
`
`6 approve DuoTrav for use in the United States?
`
`7
`
`A.
`
`That's correct. They're stuck in the
`
`8 approvable letter stage.
`
`9
`
`Q.
`
`And that's been going on for years, has it
`
`10 not?
`
`11
`
`12
`
`A.
`
`Q.
`
`Correct.
`
`Just a couple more areas to cover, Dr. Tann a .
`
`13 You showed us DTX167 on direct examination. That was
`
`14 the Larsson reference, and you said that this showed
`
`15
`
`t h at the patients -- well, actually, why don't you te ll
`
`16 us your recollection of what this study showed.
`
`17
`
`A. Well, this looked at normal subjects, not
`
`18 normal volunteers, and t hey were dosed with Timolol
`
`19 concomitantly with Brimonidine, each on a sort of BID
`
`20 schedule, but only a total of three doses were given.
`
`21 And then the investigators evaluated the rate of
`
`22 production of aqueous humor in the eyes as well as the
`
`23 intraocular pressure. And what they observed was that
`
`24 the intraocular pressure was lowest in the group of
`
`25 people getting both Timolol and Brimonidine, and the
`
`Page 17 of 166
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`
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 18 of 165 PageiD #: 6204
`
`18
`
`1 aqueous product i on f l ow rate was also lowest in that
`
`2 group . And t h e pressures were higher in the other two
`
`3 groups , people getting just Timolo l or just Brimonidine.
`
`4
`
`Q.
`
`So this would lead one to believe that t h ere
`
`5 may be some benefit to concomitant therapy wit h Ti mo l o l
`
`6 a n d Brimonidine , correct?
`
`7
`
`A .
`
`I t sort of validates and explains that when
`
`8 you us e the two together , you get a lower pressure and
`
`9 you get an additive reduction in the prod u ction of
`
`10 aqueous humor .
`
`11
`
`Q .
`
`But this doesn ' t te l l anyone of ski l l in the
`
`1 2 ar t whether one wo u ld be able to successfully combine
`
`13 these two drugs in the same bottle , correct?
`
`14
`
`15
`
`A .
`
`Q .
`
`That is correct .
`
`And the individuals who were tested in this
`
`16 reference were actually healthy volunteers and not
`
`17 actually individuals suffering fro m glaucoma ; is that
`
`18 right?
`
`19
`
`2 0
`
`A .
`
`Q.
`
`2 1 given?
`
`22
`
`23
`
`A .
`
`Q .
`
`That is correct .
`
`And th ere were only a to t al of t hree doses
`
`That is correct .
`
`And Larsson itself, this reference , is
`
`24 actua ll y disclosed on the face of all of t he patent s
`
`i n
`
`25
`
`t his case ; is that right?
`
`Page 18 of 166
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`
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 19 of 165 PageiD #: 6205
`
`19
`
`1
`
`2
`
`A.
`
`Q.
`
`That is correct.
`
`Now, let's move on . You showed and discussed
`
`3 with the Court the 19T study and the 0 - - 507T study.
`
`4
`
`5
`
`6
`
`A .
`
`Q .
`
`Do you remember that?
`
`I do .
`
`Now , neither the 19T study nor the 507T study
`
`7 are prior art to the patents-at-issue; is that correct?
`
`8
`
`9
`
`A .
`
`Q .
`
`That is correct.
`
`Now, let's go, if we could, to your written
`
`10 description opinion.
`
`11
`
`You stated in your opinion that Claims 1, 2 ,
`
`12 and 3 of the '1 49 patent were invalid based on lack of
`
`13 written description; is that right?
`
`14
`
`15
`
`A.
`
`Q.
`
`That's correct .
`
`You did not render that opinion in relation to
`
`16 Claim 4, correct?
`
`17
`
`18
`
`A.
`
`Q.
`
`Tha t is correct .
`
`Now, Claims 1, 2, and 3 deal with a method of
`
`19 treating g l aucoma or ocular hypertension by topical
`
`20 administration of about
`
`2 £,
`0 Brimonidine by weight to an
`
`•
`
`21 eye of a person in need thereof , said improvement
`
`22 comprising topically administering to said eye in a
`
`23 single composition about .2% Brimonidine by weight and
`
`24 about .5% Timolol by weight twice a day as the sole
`
`25 active agents, wherein said method is as effective as
`
`Page 19 of 166
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`
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 20 of 165 PageiD #: 6206
`
`20
`
`1 admi nistration of . 5% Timo l ol twice a day and
`
`.2%
`
`2 Brimonidine three times a day to said eye , wherein the
`
`3
`
`two compounds are administered i n separate compositions .
`
`4
`
`5
`
`6
`
`A .
`
`Q .
`
`Did I get the c l aim correct, I hope?
`
`Yes .
`
`All right . Now , let's look at where the
`
`7 effectiveness of administration is discussed in the
`
`8 patent i t self.
`
`9
`
`If you would go , please , sir , to Column 4 and
`
`10 begi n with Example 2 . Do you see t h at?
`
`11
`
`A .
`
`I do .
`
`I can go to it in my own exhibit ,
`
`12 because I can ' t see -- okay . There we go .
`
`13
`
`14
`
`Q .
`
`There we go .
`
`So this is saying here , this is a study that
`
`15 it ' s describing, correct?
`
`16
`
`17
`
`1 8
`
`19
`
`A .
`
`Q .
`
`A .
`
`Q .
`
`In Example 2 , yes.
`
`Yes .
`
`Uh - h u h.
`
`And did you have an oppor t unity , Dr . Tanna ,
`
`t o
`
`20 compare the description of this study to the 13 T study
`
`21 that was submitted by Al1ergan to the FDA?
`
`22
`
`23
`
`24
`
`25
`
`A .
`
`Q.
`
`A.
`
`Q.
`
`I did .
`
`Now, were yo u here when Dr . Whitcup tes t ified?
`
`I was.
`
`Did yo u hear Dr . Whitcup say that what the FDA
`
`Page 20 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 21 of 165 PageiD #: 6207
`
`2 1
`
`1 requires for initial clinical trials of a combination
`
`2 product is that the combination product be compared to
`
`3 each of the monotherapies?
`
`4
`
`5
`
`A.
`
`Q .
`
`Yes ,
`
`I heard him say that.
`
`And you have no reason to disagree wit h that ;
`
`6
`
`i s that right?
`
`7
`
`8
`
`A .
`
`Q .
`
`I don ' t disagree .
`
`So what t h e FDA wanted to see was t h e efficacy
`
`9 of Combigan as compared to Brimonidi n e
`
`t h ree-times - a-day
`
`10 monotherapy , correct?
`
`11
`
`12
`
`A .
`
`Q .
`
`Yes.
`
`And the FDA wanted to see the efficacy of
`
`13 Combigan as compared to twice-a-day Timolol monotherapy ,
`
`14 correct?
`
`15
`
`A .
`
`That was part of what the FDA wanted to see ,
`
`16 yes .
`
`1 7
`
`Q .
`
`And if we go on Example 2, which begins at
`
`18 Co l umn 4 f Line 4 9,
`
`i t goes a l l
`
`the way thro u gh to the
`
`19 bot t om of Column 4 , all the way through to the Co l umn 5 ,
`
`20 and all the through to Co l umn 6 f 7, 8 , and essentia ll y
`
`21 ends at Col u mn 9 where it ends with Examp l e 2 · f
`
`is that
`
`22 right , Dr . Tanna?
`
`23
`
`24
`
`A .
`
`Q .
`
`That ' s correct .
`
`And what the conc l usion as reported of the 1 3T
`
`25 study in the patent says: Conclusions-- and I 'll stic k
`
`Page 21 of 166
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`
`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 22 of 165 Page!D #: 6208
`
`22
`
`1 with the right specification so we have the numbers
`
`2 right.
`
`3
`
`Conclusion starts at the bottom of Column 8
`
`4 and runs over into Column 9. Here we go .
`
`5
`
`Conclus i ons: The combination treatment ,
`
`6 Brimonidine Tartrate .2% with Timolol . 5% administered
`
`7 twice a day for t h ree months was superior to Timolol
`
`8
`
`twice a day and Brimonidine t hree times a day in
`
`9
`
`lowering the elevated IOP with patients with glaucoma or
`
`10 ocular hypertension; is that right?
`
`11
`
`12
`
`A.
`
`Q .
`
`That's what it says.
`
`And it says the combination administered twice
`
`13 a day demonstrated a favorable safety profile that was
`
`14 comparab l e to Ti molo l
`
`tw ice a day and better tha n
`
`15 Brimonidine three times a day with regard to the
`
`16 incidence of adverse events and discontinuations due to
`
`17 adverse events ; is that right?
`
`18
`
`19
`
`A .
`
`Q .
`
`Yes.
`
`So all of this is in the specification of the
`
`20
`
`' 149 patent , correct?
`
`21
`
`22
`
`A .
`
`That's correct .
`
`. Q.
`
`Both the methodology of how the test was run ,
`
`23 correct?
`
`24
`
`25
`
`A.
`
`Q.
`
`That ' s correct .
`
`The fact that there were three groups in the
`
`Page 22 of 166
`
`
`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 23 of 165 PageiD #: 6209
`
`23
`
`1 test, correct?
`
`2
`
`3
`
`A.
`
`Q.
`
`4 correct?
`
`5
`
`6
`
`A.
`
`Q.
`
`Correct.
`
`The dosing regimen for each of the groups,
`
`Correct.
`
`And, in fact, Dr . Whitcup told us t ha t
`
`in
`
`7 order for the Timolol-only group not to know that they
`
`8 weren ' t getting Brimonidine, they were given a
`
`t hird
`
`9 drop as a placebo?
`
`10
`
`A.
`
`And the same is true for the fixed combination
`
`11 group .
`
`12
`
`Q.
`
`Exactly.
`
`So in order to keep this a
`
`13 double-masked study, there was even a placebo drop
`
`14 administered to the combination group, and a placebo
`
`15 drop administered to the Timolol monotherapy group; is
`
`16 that right?
`
`17
`
`18
`
`A.
`
`Q.
`
`19 correct?
`
`20
`
`21
`
`A.
`
`Q.
`
`Right . That's very standard.
`
`And this is all detailed in the patent ,
`
`Correct.
`
`Then if we look specifical l y at Table -- t h e
`
`22 table that is at the bot tom of Column 3, Mr. Beck told
`
`23 us that this is the actual formulation that was the
`
`24 final formulation for Combigan.
`
`25
`
`Are you aware of that, Dr. Tanna?
`
`Page 23 of 166
`
`
`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 24 of 165 PageiD #: 6210
`
`24
`
`1
`
`A .
`
`That he testified to t hat effect ,
`
`I was n ot
`
`2 aware of that , but I accep t
`
`t hat to be tr u e .
`
`3
`
`Q .
`
`Okay .
`
`So in t h e patent , one of skill in the
`
`4 art would know how to ma k e Combigan , correct?
`
`5
`
`6
`
`A .
`
`Q.
`
`Correct .
`
`And one of skill in the art wou l d k n ow how to
`
`7 co nduct a study to determine whether or not Combigan was
`
`8 as effective as Brimonidine three-times-a-day
`
`9 monot h erapy and as effective as Ti molol twice - a - day
`
`10 monotherapy , correct?
`
`11
`
`A .
`
`That one wou l dn ' t know how to conduct such a
`
`12 study?
`
`13
`
`14
`
`Q .
`
`A .
`
`Yes .
`
`I t
`
`' s a l l laid out in the patent itself .
`
`I'm not sure it real l y tells you how to
`
`15 conduct a study in the future .
`
`I don't -- I don ' t see
`
`16 tha t
`
`in the pate n t
`
`.
`
`17
`
`Q.
`
`Is t h e met h odo l ogy of the study laid out in
`
`18 the patent ?
`
`19
`
`A .
`
`Th e methodology of the study that was do n e in
`
`20 the exa mp l e is laid o u t
`
`in the patent , but you ' re
`
`21 describing a different s t udy , aren ' t you?
`
`22
`
`23
`
`2 4
`
`Maybe I misunderstood .
`
`Q .
`
`Oh ,
`
`I ' m sorry , Dr . Tanna.
`
`The st u dy as described in the patent is a
`
`25 study where Combi gan or the combination product was
`
`Page 24 of 166
`
`
`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 25 of 165 PageiD # : 6211
`
`25
`
`1 compared to Brimo ni dine t h ree-times-a-day mo n otherapy
`
`2 and was compared to T i molol t wice-a-day monotherapy ,
`
`3 correct?
`
`4
`
`5
`
`A .
`
`Q.
`
`6 correct?
`
`7
`
`8
`
`A.
`
`Q.
`
`That ' s correc t.
`
`And that st u dy is l aid out in the patent,
`
`Yes, it is . Yes .
`
`And the results of that stud y are laid o u t
`
`in
`
`9 the patent , correct?
`
`10
`
`11
`
`A .
`
`Q.
`
`Yes .
`
`And the f ormu l ation for the combi n ation
`
`12 product is out -- a l so spe ll ed out in the patent ,
`
`13 correct?
`
`14
`
`15
`
`16
`
`A.
`
`Q.
`
`Tha t' s correct .
`
`Than k you.
`
`Now ,
`
`I have jus t one more area of q u estioning ,
`
`17 and it sort of goes to yo u r overa l l obviousness opinion.
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`18
`
`My understanding , if I heard you correctly ,
`
`19 Dr . Tanna, is t h at -- we l l ,
`
`I do n' t want to overstate
`
`20
`
`i t
`
`. You seem to show us references t hat would encourage
`
`21 one to want to combine Brimonidi n e wi t h Timolol in the
`
`22 same bottle .
`
`23
`
`24
`
`A.
`
`Q .
`
`Correct .
`
`And yo u d i dn ' t
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`s h ow u s any references that
`
`25 might discourage one fro m doi n g that ; is that right?
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`Page 25 of 166
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`
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 26 of 165 PageiD #: 6212
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`26
`
`1
`
`2
`
`A .
`
`Q.
`
`That ' s correct.
`
`Now, let ' s
`
`look at the Brimonidine label
`
`3 itself.
`
`It's DTX129 that you showed the Court.
`
`4
`
`MS . BROOKS: And if we go to the second
`
`5 page of that reference and blow up, Mr. Exline .
`
`It ' s
`
`6 very hard to see, but if we can blow up the top part
`
`7 here.
`
`8
`
`Oops,
`
`I don't know what happened.
`
`If you
`
`9 can -- the second column, if we can blow up about
`
`a
`
`1 0 little lower than that, please, about
`
`blow up the top
`
`11 part but all the way to where there's a break.
`
`12
`
`13
`
`There we go.
`
`Q.
`
`(By Ms. Brooks) If we look right down here,
`
`14 Dr. Tanna, right before it says at the very bottom
`
`15 tricyclic antidepressants.
`
`16
`
`17
`
`Do you see that?
`
`A.
`
`I do it .
`
`It specifically says to use it with
`
`18 caution and take with beta - blockers.
`
`19
`
`20
`
`21
`
`Q.
`
`A.
`
`Q .
`
`Timolol is a beta-blocker?
`
`That's correct.
`
`And the actual label for Brimonidine tells one
`
`22 of skill in the art to combine Brimonidine with caution
`
`23 with a beta-blocker, correct?
`
`24
`
`25
`
`A.
`
`Q .
`
`That's correct.
`
`And certainly one of skill in the art would
`
`Page 26 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 27 of 165 PageiD #: 6213
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`27
`
`1 have read t h e
`
`l abel?
`
`2
`
`3
`
`4
`
`5
`
`6
`
`A .
`
`Q .
`
`That ' s correct .
`
`Thank you .
`
`MS. BROOKS : No furt h er questions .
`
`THE COURT : Redirect?
`
`REDIRECT EXAMINATION
`
`7 BY MR . BENSON :
`
`Q .
`
`A .
`
`8
`
`9
`
`10
`
`Good afternoon , Dr. Tanna.
`
`Good afternoon .
`
`MR . BENSON :
`
`If I cou l d have t h e Timpilo
`
`11 reference th a t Counsel was showin