throbber
Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 1 of 165 PageiD #: 6187
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`1
`
`1
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`2
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE EASTERN DISTRICT OF TEXAS
`MARSHALL DIVISION
`
`3
`
`ALLERGAN,
`
`INC.
`
`vs.
`
`SANDOZ,
`
`INC.
`
`4
`
`5
`
`6
`
`7
`
`8
`
`* 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
`
`9 APPEARANCES:
`
`10 FOR THE PLAINTIFF:
`
`11
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`12
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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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`18
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`19
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`MS. JUANITA BROOKS
`MR. ROGER DENNING
`Fish & Richardson
`12390 El Camino Real
`San Diego, CA
`92130
`
`JONATHAN SINGER
`MR.
`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
`
`20 APPEARANCES CONTINUED ON NEXT PAGE:
`
`21
`
`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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`23
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`24
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`25
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`Page 1 of 166
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`SENJU EXHIBIT 2136
`INNOPHARMA v SENJU
`IPR2015-00903
`
`

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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)
`
`11
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`12
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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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`18
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`19
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`20
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`(Apotex)
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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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`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
`
`Page 2 of 166
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`

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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:
`
`2 FOR THE DEFENDANTS:
`(Watson)
`
`MR. LARRY PHILLIPS
`Siebman Reynolds Burg &
`Phillips
`300 North Travis Street
`Sherman, TX
`75090
`
`MR. GARY E. HOOD
`Polsinelli Shughart
`161 North Clark Street
`Suite 4200
`Chicago, IL
`
`60601
`
`MS. ROBYN H. AST
`Polsinelli Shughart
`100 South 4th Street
`Suite 1000
`St. Louis, MO
`
`63102
`
`3
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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
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`11
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`12
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`13
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`14
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`17
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`18
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`19
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`20
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`****************************
`
`P R 0 C E E D I N G S
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`COURT SECURITY OFFICER: All rise.
`
`THE COURT: Please be seated.
`
`Ms. Brooks.
`
`MS. BROOKS: Thank you, Your Honor.
`
`ANGELO P. TANNA, M.D., DEFENDANTS' WITNESS,
`
`PREVIOUSLY SWORN
`
`DIRECT EXAMINATION
`
`21 BY MS. BROOKS:
`
`22
`
`23
`
`24
`
`Q.
`
`A.
`
`Q.
`
`Good afternoon, Dr. Tanna.
`
`Good after, Ms. Brooks.
`
`Right before the lunch break, I was
`
`25 frantically looking for a copy of Walters. We now have
`
`Page 3 of 166
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`

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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 4 of 165 PageiD #: 6190
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`4
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`1 one before you ln your binder. And it's DTX138.
`
`2 Oh, I'm sorry. That's the abstract actually, which you
`
`3 did look at. Now, let's look at DTX137. And that is
`
`4 the Walters paper.
`
`5
`
`So you say, Dr. Tanna, you had not had a
`
`6 chance to look at this before rendering your opinion; is
`
`7 that right?
`
`8
`
`A.
`
`No, that's not true. Now that I see it, I do
`
`9 recognize it.
`
`I have looked at this reference.
`
`10
`
`Q.
`
`So you did consider it in rendering your
`
`11 opinion?
`
`12
`
`13
`
`A.
`
`Q.
`
`I did consider it, yes.
`
`All right. Then let's look, if we could,
`
`14 please, at Bates No. 346, the page ending in that Bates
`
`15 number.
`
`16
`
`17
`
`MS. BROOKS: And highlight, if we could,
`
`in the right-hand column where it begins similar
`
`18
`
`means
`
`mean decreases in IOP.
`
`19
`
`20
`
`A.
`
`Q.
`
`346?
`
`(By Ms. Brooks) Yeah, 346.
`
`It should be the
`
`21 bottom right-hand corner, the Bates No. 000346.
`
`22
`
`23
`
`24
`
`25
`
`A.
`
`Q.
`
`Do you have that?
`
`Yes,
`
`I do.
`
`Okay. And it's also up on the screen.
`
`So let's see what Walters also disclosed about
`
`Page 4 of 166
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`

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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.
`
`It says: Similar mean decreases in IOP
`
`2 were noted for both dosing regimens at hours 2, 4, and 7
`
`3
`
`in the diurnal measurements.
`
`4
`
`In the three-times-daily group, an additional
`
`5 mean decrease in IOP of 3.5 millimeters of mercury was
`
`6 observed at hour 9, after the morning dosing, or two
`
`7 hours following the afternoon dosing.
`
`8
`
`9
`
`10
`
`A.
`
`Q.
`
`Do you see that, Dr. Tanna?
`
`Yes,
`
`I do.
`
`So isn't it true that one of skill ln the art
`
`11 would look at Walters and see that there was a
`
`12 statistically significant decrease in IOP at 9.0 hours
`
`13 after morning dosing on the three-times-a-day
`
`14 Brimonidine?
`
`15
`
`A.
`
`Yes. And it is overall, in my opinion, that
`
`16 three-times-a-day Brimonidine is more effective than
`
`17 twice-a-day Brimonidine. And, in fact, that is in my
`
`18 expert opinion, and I used a different reference as the
`
`19 main reference for that, specifically Konstas.
`
`20
`
`THE COURT:
`
`Doctor, she hadn't asked you
`
`21 any of that.
`
`22
`
`23
`
`THE WITNESS:
`
`I'm sorry, Your Honor.
`
`THE COURT:
`
`If they want you to repeat
`
`24 that testimony or what's in your expert report, they'll
`
`25 ask you. But unless everybody's not listening to me,
`
`Page 5 of 166
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`

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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.
`
`I'm not here
`
`2 to listen to lectures.
`
`I'm here for you to answer the
`
`3 questions asked, and stop talking.
`
`4
`
`5
`
`6
`
`7
`
`Are we clear?
`
`THE WITNESS: Yes, Your Honor.
`
`THE COURT: Thank you.
`
`Q.
`
`(By Ms. Brooks) And let's just see if we can
`
`8 find the graph that correlates to this data in PTX134,
`
`9 which you don't have before you, Dr. Tanna, because it's
`
`10 too large, but has previously been discussed with
`
`11 Ms. Batoosingh.
`
`12
`
`MS. BROOKS:
`
`If we can go to PTX134 and
`
`13 specifically at Bates No. 676465, Mr. Exline.
`
`14
`
`Q.
`
`(By Ms. Brooks) And do you see this graph, Dr.
`
`15 Tanna?
`
`16
`
`17
`
`A.
`
`Q.
`
`Yes,
`
`I do.
`
`Could you show the Court where that
`
`18 3.5-millimeters of mercury difference occurs between the
`
`19 twice-a-day dosing of Alphagan and the three-times-a-day
`
`20 dosing of Alphagan?
`
`21
`
`22
`
`23
`
`24
`
`25
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`It's not doing
`
`Here, I'll try to help you.
`
`I have a pointer. May I use a laser pointer?
`
`Sure. Or did I get it close right there?
`
`A. Well, that's it, yes.
`
`Page 6 of 166
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`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 7 of 165 PageiD #: 6193
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`7
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`1
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`2
`
`Q.
`
`Okay. And so, again, you agree that -
`
`one of
`
`skill in
`
`the art would know, based on this data, that
`
`3 there was an actual statistically significant decrease
`
`4 in the reduction of intraocular pressure at
`
`5 approximately hour 9 between the three-times-a-day
`
`6 dosing of Alphagan and the twice-a-day dosing?
`
`7
`
`8
`
`A.
`
`Q.
`
`Yes, in this study.
`
`Now, let's move to your discussion of how the
`
`9 amount of BAK that was claimed would have been obvious.
`
`10 You said the BAK was the most common preservative; lS
`
`11 that correct?
`
`12
`
`A.
`
`Most commonly used in ophthalmic formulations,
`
`13 yes.
`
`14
`
`15
`
`Q.
`
`And, in fact, we saw --
`
`MS. BROOKS: Mr. Exline, could you pull
`
`16 up Defendants' Slide 10 that they used in opening
`
`17 statement? And if not,
`
`I can always put it on the ELMO.
`
`18
`
`19
`
`There we are.
`
`Q.
`
`(By Ms. Brooks) So this was shown to the Court
`
`20 by the Defendants in opening statement showing all the
`
`21 different drug products that contain BAK.
`
`22
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`23
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`24
`
`A.
`
`Q.
`
`Do you agree with that, Dr. Tanna?
`
`I do.
`
`But let's look at the amount of BAK in these
`
`25 various products.
`
`Isn't it true that there are no less
`
`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
`
`2 ophthalmic products?
`
`3
`
`4
`
`5
`
`A.
`
`Q.
`
`That looks right.
`
`Thank you.
`
`Let's move on now to your discussion of other
`
`6 combination drugs. You told us about a drug called
`
`7 Timpilo; is that right?
`
`8
`
`9
`
`A.
`
`Q.
`
`I did, yes.
`
`And you told us about a drug called Cosopt.
`
`10 Of course, we know about that, right?
`
`11
`
`12
`
`13
`
`14
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Yes.
`
`And also a drug called Xalacom; is that right?
`
`That's correct.
`
`In fact, on Slide 36 that you used, you showed
`
`15 both the Timpilo, the Cosopt, and the Xalacom.
`
`16
`
`Now, in looking more closely at the Timpilo
`
`17 picture that you used, that's not actually a picture of
`
`18 Timpilo, is it?
`
`19
`
`A.
`
`I don't know that
`
`I can't tell from that
`
`20 picture.
`
`I don't know.
`
`21
`
`Isn't it, in fact, just a picture of the
`
`22 bottle of Pilocarpine?
`
`23
`
`A.
`
`I don't think so, because it typically would
`
`24 have a green cap.
`
`So I can't tell from this picture.
`
`I
`
`25 am not sure what that'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.
`
`Okay. Now, Timpilo has never been approved
`
`2 for use in the United States, correct?
`
`3
`
`A.
`
`I was under the impression that it was in use
`
`4 in the United States. That's my impression.
`
`I could be
`
`5 mistaken about it, but my understanding is that it was
`
`6
`
`in use in the United States.
`
`7
`
`Q.
`
`Okay. What about Xa1acom; has Xalacom ever
`
`8 been approved for use in the United States?
`
`A.
`
`Q.
`
`9
`
`10
`
`11
`
`No, it has not.
`
`Now, while we're talking about Xalacom --
`
`MS. BROOKS: Let's just leave that up
`
`12 there, if we could, Mr. Exline.
`
`13
`
`Q.
`
`(By Ms. Brooks) We're going to revisit some
`
`14 organic chemistry.
`
`15
`
`Xalacom is the active ingredient ln
`
`16 Latanoprost; is that right?
`
`17
`
`18
`
`A.
`
`Q.
`
`That's correct.
`
`And Latanoprost is what's known as a
`
`19 prostaglandin analog; is that correct?
`
`20
`
`21
`
`A.
`
`Q.
`
`That is correct.
`
`Are the prostaglandin analogs normally your
`
`22 first choice of medication for a new glaucoma patient?
`
`23
`
`24
`
`A.
`
`Q.
`
`For me today, yes.
`
`And, in fact, the Latanoprost is sold here ln
`
`25 the United States as Xalatan; is that right?
`
`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.
`
`Q.
`
`That's correct.
`
`But the combination of Xalatan and Timolol,
`
`3 also known as Xalacom, has never been approved for use
`
`4 in the United States; is that correct?
`
`5
`
`6
`
`A.
`
`Q.
`
`That is correct.
`
`And you yourself have never prescribed the use
`
`7 for Xalacom, correct?
`
`8
`
`A.
`
`I have never prescribed Xalacom. That's
`
`9 correct.
`
`10
`
`Q.
`
`Now, in that same category of prostaglandin
`
`11 analogs, would you put Travoprost?
`
`12
`
`13
`
`A.
`
`Q.
`
`14 correct?
`
`15
`
`16
`
`A.
`
`Q.
`
`It is in the same category.
`
`And that's also known as Travatan; is that
`
`That's correct.
`
`There is no combination drug of Travatan and
`
`17 Timolol approved for us in the United States; is that
`
`18 correct?
`
`19
`
`20
`
`A.
`
`Q.
`
`That is correct.
`
`And also within what you would call a
`
`21 prostaglandin analog, or we would call a prostamide, is
`
`22 a compound called Bimatoprost.
`
`23
`
`24
`
`25
`
`A.
`
`Q.
`
`Are you familiar with that?
`
`Yes,
`
`I am.
`
`And Bimatoprost is sold here in the United
`
`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.
`
`2
`
`3
`
`4
`
`A.
`
`Q.
`
`Are you familiar with that?
`
`Yes,
`
`I am.
`
`There are no
`
`-
`
`I
`
`think you mentioned that
`
`5 Ganfort, which was a combination of Bimatoprost/Timolol
`
`6 drug; is that right?
`
`7
`
`8
`
`A.
`
`Q.
`
`Correct.
`
`But Ganfort is not approved for use here in
`
`9 the United States; is that correct?
`
`10
`
`11
`
`A.
`
`Q.
`
`No, it's not.
`
`And just to show how subtle differences make a
`
`12 very big difference, Bimatoprost and Latanoprost, would
`
`13 you put them in the same category as far as mechanism of
`
`14 action?
`
`15
`
`A.
`
`There may be small differences in terms of the
`
`16 mechanism of action.
`
`I
`
`think it's a matter of
`
`17 controversy.
`
`18
`
`Q. Well, in fact, Latanoprost is what's known as
`
`19 17-phenyl-PGF2-alpha, correct?
`
`20
`
`21
`
`A.
`
`Q.
`
`I know there's a PGF2 alpha-agonist.
`
`Okay. And at the C1 position on the alpha
`
`22 chain is an ester; is that right?
`
`23
`
`24
`
`A.
`
`Q.
`
`That I don't know offhand.
`
`So
`
`I may know a little more organic chemistry.
`
`25 What about Bimatoprost? Are you aware that if the C1
`
`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
`
`1 position on the alpha chain of Bimatoprost is an amide?
`
`2
`
`A.
`
`I believe that I can picture that and agree
`
`3 with you on that, but I would have to look at the
`
`4 structure to be sure.
`
`It's a complex -- it's a big
`
`5 molecule, and I don't know offhand for sure.
`
`6
`
`Q. Would you agree with me that an ester is
`
`7 different than an amide?
`
`8
`
`9
`
`10
`
`11
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`It certainly is.
`
`And can, in fact, behave differently in situ?
`
`Yes, it can.
`
`Now, let's go to --back to the Timpilo. You
`
`12 should have in your binder, Dr. Tanna, the label for
`
`13 Timpilo,
`
`I hope. And I don't know if we numbered it
`
`14 since it wasn't actually previously in use, but if you
`
`15 go through your binder, you should see a label for
`
`16 Timpilo.
`
`17
`
`18
`
`19
`
`20
`
`21
`
`A.
`
`Q.
`
`Can you tell me approximately where?
`
`Oh, it's not in your binder. Sorry.
`
`MS. BROOKS: May I approach, Your Honor?
`
`THE COURT: Yes.
`
`Q.
`
`(By Ms. Brooks) Now, Dr. Tanna, you've
`
`22 referred to Timpilo as a combination drug; is that
`
`23 right?
`
`24
`
`25
`
`A.
`
`It is a combination drug, yes.
`
`Q. Well, if we actually --
`
`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
`
`

`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08111 Page 14 of 165 PageiD #: 6200
`
`14
`
`1
`
`A.
`
`It is more acidic than the ocular surface and
`
`2
`
`the pH of the eye in general, yes.
`
`3
`
`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 with 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 solution with a pH of 7.8 to 8.2 for
`
`16 Timpilo 2; and 8.5 to 9.5 for Timpilo 4.
`
`17
`
`18
`
`19
`
`A.
`
`Q.
`
`Did I read that correctly?
`
`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
`
`

`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 15 of 165 PageiD #: 6201
`
`15
`
`1 system.
`
`2
`
`Q.
`
`And for whatever formulation reason, the
`
`3 formulators were not able to simply put the Timolol and
`
`4 the Pilocarpine into one bottle for shelf life?
`
`5
`
`6
`
`A.
`
`Q.
`
`Correct.
`
`And had to go to this two-chambered system
`
`7 with two different pHs and a plug in the middle; is that
`
`8 right?
`
`9
`
`10
`
`A.
`
`Q.
`
`That's right.
`
`Now, another -- so that's the
`
`11 Pilocarpine/Timolol one.
`
`12
`
`You also mentioned a combination product
`
`13 called Probeta, which is Levobunolol and Dipivefrin?
`
`A.
`
`Q.
`
`14
`
`15
`
`16
`
`17 go?
`
`18
`
`19
`
`20 back.
`
`It's pronounced Dipivefrin (pronounces)
`
`Dipivefrin (pronounces). Thank you.
`
`MS. BROOKS: Should I push something to
`
`MR. LOVE:
`
`It's there.
`
`MS. BROOKS: There we go.
`
`I think we're
`
`21
`
`Q.
`
`(By Ms. Brooks) And that's called Probeta; is
`
`22 that right?
`
`23
`
`24
`
`A.
`
`Q.
`
`That's correct. That's available in Canada.
`
`So that's never been approved for use here in
`
`25 the United States, correct?
`
`Page 15 of 166
`
`

`
`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.
`
`That'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.
`
`Q.
`
`That's correct.
`
`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
`
`

`
`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. Tanna.
`
`13 You showed us DTX167 on direct examination. That was
`
`14 the Larsson reference, and you said that this showed
`
`15 that the patients -- well, actually, why don't you tell
`
`16 us your recollection of what this study showed.
`
`17
`
`A. Well, this looked at normal subjects, not
`
`18 normal volunteers, and they 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
`
`

`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 18 of 165 PageiD #: 6204
`
`18
`
`1 aqueous production flow rate was also lowest 1n that
`
`2 group. And the pressures were higher in the other two
`
`3 groups, people getting just Timolol or just Brimonidine.
`
`4
`
`Q.
`
`So this would lead one to believe that there
`
`5 may be some benefit to concomitant therapy with Timolol
`
`6 and Brimonidine, correct?
`
`7
`
`A.
`
`It sort of validates and explains that when
`
`8 you use the two together, you get a lower pressure and
`
`9 you get an additive reduction in the production of
`
`10 aqueous humor.
`
`11
`
`Q.
`
`But this doesn't tell anyone of skill in the
`
`12 art whether one would 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 from glaucoma; is that
`
`18 right?
`
`19
`
`20
`
`A.
`
`Q.
`
`21 given?
`
`22
`
`23
`
`A.
`
`Q.
`
`That is correct.
`
`And there were only a total of three doses
`
`That is correct.
`
`And Larsson itself, this reference, is
`
`24 actually disclosed on the face of all of the patents in
`
`25 this case; is that right?
`
`Page 18 of 166
`
`

`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 19 of 165 PageiD #: 6205
`
`19
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`A.
`
`Q.
`
`That is correct.
`
`Now, let's move on. You showed and discussed
`
`with
`
`the
`
`Court the 19T study and the 0
`
`-
`
`507T study.
`
`Do you remember that?
`
`I do.
`
`Now, neither the 19T study nor the 507T study
`
`A.
`
`Q.
`
`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 '149 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.
`
`That is correct.
`
`Now, Claims 1, 2, and 3 deal with a method of
`
`19 treating glaucoma or ocular hypertension by topical
`
`20 administration of about
`
`.2% 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
`
`

`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 20 of 165 PageiD #: 6206
`
`20
`
`1 administration of .5% Timolol twice a day and
`
`.2%
`
`2 Brimonidine three times a day to said eye, wherein the
`
`3
`
`two compounds are administered in separate compositions.
`
`4
`
`5
`
`6
`
`A.
`
`Q.
`
`Did I get the claim correct, I hope?
`
`Yes.
`
`All right. Now, let's look at where the
`
`7 effectiveness of administration is discussed in the
`
`8 patent itself.
`
`9
`
`If you would go, please, sir, to Column 4 and
`
`10 begin with Example 2. Do you see that?
`
`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
`
`18
`
`19
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`In Example 2, yes.
`
`Yes.
`
`Uh-huh.
`
`And did you have an opportunity, Dr. Tanna, to
`
`20 compare the description of this study to the 13T study
`
`21 that was submitted by Allergan to the FDA?
`
`22
`
`23
`
`24
`
`25
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`I did.
`
`Now, were you here when Dr. Whitcup testified?
`
`I was.
`
`Did you hear Dr. Whitcup say that what the FDA
`
`Page 20 of 166
`
`

`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 21 of 165 PageiD #: 6207
`
`21
`
`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 with that;
`
`6 is that right?
`
`7
`
`8
`
`A.
`
`Q.
`
`I don't disagree.
`
`So what the FDA wanted to see was the efficacy
`
`9 of Combigan as compared to Brimonidine three-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.
`
`17
`
`Q.
`
`And if we go on Example 2, which begins at
`
`18 Column 4, Line 49, it goes all the way through to the
`
`19 bottom of Column 4, all the way through to the Column 5,
`
`20 and all the through to Column 6, 7, 8, and essentially
`
`21 ends at Column 9 where it ends with Example 2; is that
`
`22 right, Dr. Tanna?
`
`23
`
`24
`
`A.
`
`Q.
`
`That's correct.
`
`And what the conclusion as reported of the 13T
`
`25 study in the patent says: Conclusions-- and I'll stick
`
`Page 21 of 166
`
`

`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 22 of 165 PageiD #: 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
`
`Conclusions: The combination treatment,
`
`6 Brimonidine Tartrate .2% with Timolol .5% administered
`
`7
`
`twice a day for three months was superior to Timolol
`
`8 twice a day and Brimonidine three times a day in
`
`9
`
`lowering the elevated lOP 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 comparable to Timolol twice a day and better than
`
`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.
`
`Q.
`
`23 correct?
`
`24
`
`25
`
`A.
`
`Q.
`
`That's correct.
`
`Both the methodology of how the test was run,
`
`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 that in
`
`7 order for the Timolol-only group not to know that they
`
`8 weren't getting Brimonidine, they were given a third
`
`9 drop as a placebo?
`
`10
`
`A.
`
`And the same lS 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; lS
`
`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 specifically at Table -- the
`
`22 table that is at the bottom 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 08/08111 Page 24 of 165 PageiD #: 6210
`
`24
`
`1
`
`A.
`
`That he testified to that effect, I was not
`
`2 aware of that, but I accept that to be true.
`
`3
`
`Q.
`
`Okay.
`
`So in the patent, one of skill in the
`
`4 art would know how to make Combigan, correct?
`
`5
`
`6
`
`A.
`
`Q.
`
`Correct.
`
`And one of skill in the art would know how to
`
`7 conduct a study to determine whether or not Combigan was
`
`8 as effective as Brimonidine three-times-a-day
`
`9 monotherapy and as effective as Timolol twice-a day
`
`10 monotherapy, correct?
`
`11
`
`A.
`
`That one wouldn't know how to conduct such a
`
`12 study?
`
`13
`
`14
`
`Q.
`
`A.
`
`Yes.
`
`It's all laid out in the patent itself.
`
`I'm not sure it really tells you how to
`
`15 conduct a study in the future.
`
`I don't -- I don't see
`
`16 that in the patent.
`
`17
`
`Q.
`
`Is the methodology of the study laid out in
`
`18 the patent?
`
`19
`
`A.
`
`The methodology of the study that was done in
`
`20 the example is laid out in the patent, but you're
`
`21 describing a different study, aren't you?
`
`22
`
`23
`
`24
`
`Maybe I misunderstood.
`
`Q.
`
`Oh, I'm sorry, Dr. Tanna.
`
`The study as described in the patent is a
`
`25 study where Combigan 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 Brimonidine three-times-a-day monotherapy
`
`2 and was compared to Timolol twice-a-day monotherapy,
`
`3 correct?
`
`4
`
`5
`
`A.
`
`Q.
`
`6 correct?
`
`7
`
`8
`
`A.
`
`Q.
`
`That's correct.
`
`And that study is laid out in the patent,
`
`Yes, it is. Yes.
`
`And the results of that study are laid out in
`
`9 the patent, correct?
`
`10
`
`11
`
`A.
`
`Q.
`
`Yes.
`
`And the formulation for the combination
`
`12 product is out -- also spelled out in the patent,
`
`13 correct?
`
`14
`
`15
`
`16
`
`A.
`
`Q.
`
`That's correct.
`
`Thank you.
`
`Now,
`
`I have just one more area of questioning,
`
`17 and it sort of goes to your overall obviousness opinion.
`
`18
`
`My understanding, if I heard you correctly,
`
`19 Dr. Tanna, is that -- well, I don't want to overstate
`
`20 it. You seem to show us references that would encourage
`
`21 one to want to combine Brimonidine with Timolol in the
`
`22 same bottle.
`
`23
`
`24
`
`A.
`
`Q.
`
`Correct.
`
`And you didn't show us any references that
`
`25 might discourage one from doing that; is that right?
`
`Page 25 of 166
`
`

`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 26 of 165 PageiD #: 6212
`
`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
`
`10 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
`
`

`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 27 of 165 PageiD #: 6213
`
`27
`
`1 have read the label?
`
`2
`
`3
`
`4
`
`5
`
`6
`
`A.
`
`Q.
`
`That's correct.
`
`Thank you.
`
`MS. BROOKS: No further 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 could have the Timpilo
`
`11 reference that Counsel was showing you on the screen, if
`
`12 that's possible.
`
`13
`
`Was there a DTX number with that or
`
`14 anything?
`
`15
`
`MS. BROOKS: No, I'm afraid not, but we
`
`16 gave you a copy.
`
`17
`
`18
`
`MR. BENSON: Well, that's okay.
`
`Q.
`
`(By Mr. Benson) Do you have a copy of that in
`
`19 front of you?
`
`20
`
`21
`
`22
`
`23
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`You're referring to the Timpilo product label?
`
`That's right.
`
`I have it.
`
`Now, you agreed with Counsel that the
`
`24 Pilocarpine and Timolol Maleate of Timpilo could not be
`
`25 formulated in the same bottle, correct?
`
`Page 27 of 166
`
`

`
`Case 2:09-cv-00097-JRG Document 241 Filed 08/08/11 Page 28 of 165 PageiD #: 6214
`
`28
`
`1
`
`2
`
`A. Well,
`
`I would say that they weren't formulated
`
`in the same bottle.
`
`I don't know for sure that they
`
`3 cannot be formulated in the same bottle, but they were
`
`4 not.
`
`5
`
`Q. Well, let's look at the front of this --of
`
`6 this label, and Counsel showed you the first
`
`the
`
`7 first paragraph right under presentation.
`
`8
`
`9
`
`10
`
`A.
`
`Q.
`
`11 about?
`
`Do you see that?
`
`I do.
`
`And that was the paragraph you testified
`
`12
`
`13
`
`A.
`
`That's correct.
`
`THE COURT:
`
`I've got a copy of it here,
`
`14 so I can follow you.
`
`15
`
`16
`
`MR. BENSON: That's okay.
`
`Q.
`
`(By

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