`
`1
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE EASTERN DISTRICT OF TEXAS
`MARSHALL DIVISION
`
`ALLERGAN,
`
`INC.
`
`4
`
`vs.
`
`1
`
`2
`
`3
`
`5
`
`6
`
`7
`
`8
`
`* Civil Docket No.
`2:09-CV-97
`*
`* Marshall, Texas
`*
`*
`*
`
`August 4, 2011
`1:15 P.M.
`
`SANDOZ,
`
`INC.
`
`TRANSCRIPT OF BENCH TRIAL
`BEFORE THE HONORABLE JUDGE T. JOHN WARD
`UNITED STATES DISTRICT JUDGE
`
`9 APPEARANCES:
`
`10 FOR THE PLAINTIFF:
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`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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`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
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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.)
`
`23
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`24
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`25
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`Page 1 of 156
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`SENJU EXHIBIT 2137
`LUPIN v. SENJU
`IPR2015-01097
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 2 of 156 PageiD #: 6521
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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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`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)
`
`21
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`22
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`23
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`24
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`25
`
`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 156
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 3 of 156 PageiD #: 6522
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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 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
`
`****************************
`
`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.
`
`Proceed.
`
`MR. DENNING: Thank you, Your Honor.
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`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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`15
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`16
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`17
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`18 ROBERT J. NOECKER, M.D., PLAINTIFF'S WITNESS, PREVIOUSLY
`
`19
`
`20
`
`SWORN
`
`DIRECT EXAMINATION
`
`(CONTINUING)
`
`21 BY MR. DENNING:
`
`22
`
`23
`
`24
`
`Q.
`
`A.
`
`Q.
`
`Good afternoon, Dr. Noecker.
`
`Good afternoon.
`
`The next reference that the Defendants looked
`
`25 at with their experts yesterday that I want to show you
`
`Page 3 of 156
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 4 of 156 PageiD #: 6523
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`4
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`1
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`2
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`3
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`4
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`5
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`is DTX155.
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`155.
`
`I believe this is the Airaksinen article?
`
`Yes.
`
`And this is one in which they compared two
`
`6 different concentrations of the Timpilo drug to -- to
`
`7 Pilocarpine; is that correct?
`
`8
`
`9
`
`A.
`
`Q.
`
`Yes.
`
`And you already testified about Timpilo and
`
`10 Pilocarpine and the effects of -- the adverse effects of
`
`11 Pilocarpine on the eye, correct?
`
`12
`
`13
`
`A.
`
`Q.
`
`That's correct.
`
`Was -- did the addition of Timolol to
`
`14 Pilocarpine and Timpilo make it better?
`
`15
`
`16
`
`A.
`
`Q.
`
`It did not seem to be. Did not seem to.
`
`If we could look at the graph on Page 589,
`
`17 please, and we see on the left-hand side on the top,
`
`18 looks like the -- a Timpilo with .5% Timolol and 2%
`
`19 Pilocarpine; the middle one is .5% Timolol and 4%
`
`20 Pilocarpine; and then the bottom is Pilocarpine by
`
`21 itself.
`
`22
`
`23
`
`24
`
`25
`
`A.
`
`Q.
`
`A.
`
`Do you see that?
`
`I do.
`
`And what does this graph show you?
`
`Poor control of intraocular pressure.
`
`It's
`
`Page 4 of 156
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 5 of 156 PageiD #: 6524
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`5
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`1
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`important -- so this graph we have to be a little bit
`
`2 careful with, because unlike the other graphs we looked
`
`3 at earlier, which are frequently across times of day by
`
`4 hour, this drop on this graph is mean average.
`
`5
`
`So in this study, they put a drop in of the
`
`6 medication and then they checked -- they checked the eye
`
`7 pressure, put a drop in, and then checked the eye
`
`8 pressure two hours later. And then this data is mean
`
`9
`
`IOP of those two morning timepoints.
`
`10
`
`So this is a study where they only collected
`
`11 morning data, so it doesn't tell us anything about the
`
`12 effect on afternoon data.
`
`13
`
`And then they had a run-in period on the
`
`14 beta-blocker. And this is over a three-week -- this is
`
`15 days, 21 days to 42 days of average IOP.
`
`So, once
`
`16 again, it should be capturing the best timepoint, and
`
`17 then the morning
`
`the morning, you know, less
`
`18 effective timepoint.
`
`19
`
`So it doesn't tell us anything about afternoon
`
`20 pressure.
`
`But when you look at this, the eye pressures
`
`21 are all over the board.
`
`So this is even day-to-day.
`
`So
`
`22 this is not some fluctuation we were talking earlier
`
`23 about within the day.
`
`24
`
`You know, this patient started, if this was a
`
`25 patient in my practice, once again, Patient Mrs. Jones'
`
`Page 5 of 156
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 6 of 156 PageiD #: 6525
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`6
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`1 pressure is in the 20s, we put you on this drug or two
`
`2 drugs. We don't know what your eye pressure is going to
`
`3 be the next time you come in.
`
`4
`
`Maybe one time it's 18, kind of below the
`
`5 overflow limit. The next time, it's above on the next
`
`6 visit. So this is not somebody we say, okay, see you in
`
`7 six months.
`
`I'm sure everything will be fine.
`
`8
`
`So this is poor eye pressure control, and
`
`9 we-- you know, we wouldn't use this, because it's
`
`10 showing the poor IOP control of this combination drug.
`
`11
`
`12
`
`Q.
`
`Thank you, Dr. Noecker.
`
`And just to -- before we move on, what does
`
`13 Airaksinen teach a person of ordinary skill in the art
`
`14 about combining Brimonidine and Timolol in a fixed
`
`15 combination drug?
`
`16
`
`A.
`
`Nothing. And it might give you pause about
`
`17 combination drugs in general.
`
`18
`
`19
`
`Q.
`
`Thank you, Dr. Noecker.
`
`Let's move on to Defense Exhibit 148, which
`
`20 was the Clineschmidt article.
`
`21
`
`22
`
`MR. DENNING: Thank you, Mr. Exline.
`
`Q.
`
`(By Mr. Denning) This is the article in which
`
`23
`
`they were comparing Cosopt on the one arm versus BID
`
`24 Timolol and TID Dorzolamide monotherapies; is that
`
`25 right?
`
`Page 6 of 156
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 7 of 156 PageiD #: 6526
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`7
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`A.
`
`Q.
`
`1
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`2
`
`3
`
`That's correct.
`
`And if we turn to Table 3 of this study --
`
`MR. DENNING: Which appears on -- on Page
`
`4 1955, Mr. Exline.
`
`5
`
`Q.
`
`(By Mr. Denning) -- what time periods are they
`
`6 measuring with this study?
`
`7
`
`A.
`
`They're looking at the pre-dose in the
`
`8 mornings of 8:00 a.m., putting the drop in, and then two
`
`9 hours, once again, at the time we'd expected to be the
`
`10 most efficacious.
`
`So morning time points, two hours
`
`11 apart.
`
`12
`
`Q.
`
`Okay.
`
`Does this show anything about that
`
`13 afternoon trough at all in this paper?
`
`14
`
`15
`
`A.
`
`Q.
`
`It doesn't give us any afternoon information.
`
`Okay. Well, let's look at what it shows
`
`16 for -- for the morning pressure.
`
`17
`
`MR. DENNING:
`
`If we could go and,
`
`18 Mr. Exline, highlight on the bottom for month 3 and the
`
`19 change, the second to the rightmost column, and then
`
`20 highlight for the combination and for Dorzolamide
`
`I'm
`
`21 sorry -- second to the right, Mr. Exline.
`
`22
`
`23
`
`There you go. Right there.
`
`Q.
`
`(By Mr. Denning) So what -- what do we see
`
`24 here as the comparison between Dorzolamide as a
`
`25 monotherapy and then the Cosopt combination?
`
`Page 7 of 156
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 8 of 156 PageiD #: 6527
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`8
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`1
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`A.
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`So the combination of Cosopt combination drug
`
`2 had a -- a mean change of minus 4.4, kind of the best --
`
`3 best timepoint, the 10:00 a.m. timepoint.
`
`4
`
`Q. Would you -- and compared to 2 points lower
`
`5 for Dorzolamide; is that right?
`
`6
`
`A.
`
`Correct.
`
`So about 2 milliliters of mercury
`
`7 better.
`
`So when determining how much benefit Timolol is
`
`8 giving us, adding on top of the Dorzolamide, it's about
`
`9 2 millimeters is what we see in this study.
`
`10
`
`Q.
`
`And what -- what impact does it have that this
`
`11 is at hour 2 versus if it were at hour 8?
`
`12
`
`A.
`
`Once again, this is the best timepoint,
`
`13 because it only goes -- gets worse from here.
`
`So this
`
`14 kind of tells us a best-case scenario, that two hours
`
`15 post-dosing is as good as it's going to get.
`
`So we
`
`16 by inference, we would suspect that it will be less of a
`
`17 beneficial effect in the afternoon.
`
`18
`
`19
`
`Q.
`
`A.
`
`Okay.
`
`We don't know exactly how much, but that's --
`
`20 it's going to be the best. That's all we can tell you.
`
`21
`
`Q.
`
`Okay. And at hour 0 up above for the same --
`
`22 for the same 2 in month 3 f we see a difference from 2.8
`
`23 to 1. 4; is that right?
`
`24
`
`25
`
`A.
`
`Q.
`
`That's right. It's about 1. 4 f 1-1/2, yes.
`
`Okay. Earlier when we looked at the
`
`Page 8 of 156
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`
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 9 of 156 PageiD #: 6528
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`9
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`1 demonstrative from opening that showed the afternoon
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`2
`
`3
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`4
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`trough, do you remember that?
`
`A.
`
`Q.
`
`Yes.
`
`And there was a -- the afternoon trough was
`
`5 about 3.25, I think, in that demonstrative.
`
`6
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`7
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`8
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`Do you remember that?
`
`A.
`
`I think it was 3.5.
`
`MR. DENNING: Mr. Exline, are you able to
`
`9 pull that up?
`
`10
`
`A.
`
`You're talking about the difference between
`
`11 TID Brimonidine and BID Brimonidine?
`
`12
`
`Q.
`
`(By Mr. Denning) That's -that's exactly
`
`13 right. That's what I was talking about.
`
`14
`
`A.
`
`I recall it being 3.5 millimeters of mercury.
`
`15 That's 3. 2 5
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`16
`
`Q.
`
`I think you may remember from Ms. Batoosingh's
`
`17 testimony when they looked at the actual underlying
`
`18 document.
`
`It was -- it was different.
`
`19
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`20
`
`A.
`
`Q.
`
`Perhaps.
`
`But in any event, does -- the 1.5 to
`
`21 2 millimeters of mercury benefit that we just saw from
`
`22 the Clineschmidt paper with regard to Cosopt, would that
`
`23 be enough to make up any afternoon trough in the
`
`24 difference between Brimonidine BID and TID?
`
`25
`
`A.
`
`Like I said, it doesn't give us really any
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`Page 9 of 156
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 10 of 156 PageiD #: 6529
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`10
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`1
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`information regarding Brimonidine, but if you were to
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`2 make the inference about what's the benefit of adding
`
`3
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`the Timolol in terms of eye pressure reduction, the most
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`4 these other papers indicate it might be in the best,
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`5 best-case scenario only at the morning is 1-1/2 to
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`6 2-ish, so not at the magnitude.
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`7
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`But, really, the inference I think you can
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`8 draw is that magnitude may fall short.
`
`It's not going
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`9 to be -- adding Timolol is just not going to be
`
`10 adequate.
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`11
`
`Q.
`
`Okay.
`
`So what would one of -- what, if
`
`12 anything, would one of skill in the art learn from
`
`13 Clineschmidt about the ability to reduce the number of
`
`14 doses of Brimonidine from three doses to two doses by
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`15 adding Timolol ln combination?
`
`16
`
`A.
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`That it would not be adequate to make up for
`
`17 the deficit we see in the afternoon -- that afternoon
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`18 dip in IOP control.
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`19
`
`20
`
`Q.
`
`Okay. You may set that exhibit aside.
`
`Dr. Tanna also looked at DTX200, and let's
`
`21
`
`look at that briefly, if we could, please.
`
`This is the
`
`22 Boyle reference?
`
`23
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`24
`
`A.
`
`Q.
`
`25 correct?
`
`Yes.
`
`Now, again, this is a study looking at Cosopt,
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`Page 10 of 156
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 11 of 156 PageiD #: 6530
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`11
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`1
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`2
`
`A.
`
`Q.
`
`Correct.
`
`And Cosopt, meaning the combination of
`
`3 Dorzolamide and Timolol, correct?
`
`4
`
`5
`
`A.
`
`Q.
`
`That's correct.
`
`Okay. What does that teach you as a person of
`
`6 skill in the art about combining Brimonidine and
`
`7 Timolol?
`
`8
`
`A.
`
`It doesn't teach you anything, because
`
`9 different
`
`Dorzolamide and Brimonidine are different
`
`10 drugs.
`
`11
`
`MR. DENNING: And, again, if we can
`
`12 Mr. Exline, if you could look at Table 2, which is on
`
`13 Page 1948.
`
`14
`
`Q.
`
`(By Mr. Denning) Again, the only time
`
`15 measurements made with -- in the Boyle paper were at
`
`16 hour 0 and hour 2; is that correct?
`
`17
`
`18
`
`A.
`
`Q.
`
`That's correct.
`
`So does that tell us any meaningful
`
`19 information about what the midday IOP control would be,
`
`20 even for this combination?
`
`21
`
`A.
`
`All you can do is surmise that it's not going
`
`22 to be as good in terms of eye pressure lowering.
`
`23
`
`Q.
`
`Okay. And does the Boyle paper about Cosopt
`
`24 and the 0- and 2-hour measurements, what does that teach
`
`25 a person of skill in the art, if anything, about the --
`
`Page 11 of 156
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 12 of 156 PageiD #: 6531
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`12
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`1 combining Brimonidine and Timolol and the effects that
`
`2 that might be, if they were in a combination drug
`
`3 together?
`
`4
`
`A.
`
`Nothing specific to the Brimonidine/Timolol
`
`5 combination, but, once again, specific to the addition
`
`6 as Brimonidine -- or Timolol as a tool, it will fall
`
`7 it may fall short or probably will fall short in the
`
`8 afternoon.
`
`9
`
`Q.
`
`Okay. And if you could look at Table 5 in
`
`10 this paper as well.
`
`11
`
`This -- this one deals with the ocular and
`
`12 local adverse experiences. Do you see that?
`
`13
`
`14
`
`A.
`
`Q.
`
`Yes.
`
`And can you tell me, are there any -- did the
`
`15 combination in this study experience any reduction in
`
`16 adverse experiences than the individual therapies?
`
`17
`
`A.
`
`It didn't -- it didn't reduce any.
`
`It may
`
`18 have stung a little bit more.
`
`19
`
`20
`
`Q.
`
`It may have stung a little bit more.
`
`Okay. Thank you. You can set -- you can set
`
`21 that to one aside.
`
`22
`
`And the last one of the articles that they
`
`23 showed yesterday that I'm going to show you is DTX201.
`
`24
`
`25
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`MR. DENNING:
`
`If you could pull that up?
`
`Q.
`
`(By Mr. Denning) This is the Hutzelmann
`
`Page 12 of 156
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 13 of 156 PageiD #: 6532
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`13
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`1 reference.
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`2
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`3
`
`A.
`
`Q.
`
`Yes.
`
`And this study, again, compared Cosopt on the
`
`4 one arm versus Dorzolamide BID/Timolol BID concomitant
`
`5
`
`6
`
`7
`
`therapy, correct?
`
`A.
`
`Q.
`
`Yes.
`
`And, again, if we look at -- if we look at
`
`8 Table 2, which appears on Page 1251
`
`9
`
`10
`
`A.
`
`Q.
`
`Yes.
`
`we can see that they, again, took the
`
`11 measurements only at hour 0 and hour 2; is that right?
`
`12
`
`13
`
`A.
`
`Q.
`
`That's correct. Yes.
`
`I'm sorry. So, again, it tells us nothing
`
`14 about the afternoon trough; is that correct?
`
`A.
`
`Q.
`
`15
`
`16
`
`17
`
`Right, same story.
`
`Okay. And if we look at the mean change.
`
`MR. DENNING:
`
`I'm sorry, Mr. Exline.
`
`18 Please go back to that table.
`
`19
`
`20
`
`Thank you.
`
`Q.
`
`(By Mr. Denning) If we look at the change
`
`21 column, second from the right, at month 3, we see the
`
`22 combination and the concomitant are both at the exact
`
`23 same pressure reduction; is that right?
`
`24
`
`A.
`
`Right.
`
`So in terms of efficacy, it's neutral
`
`25 for the morning.
`
`Page 13 of 156
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`
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`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 14 of 156 PageiD #: 6533
`
`14
`
`1
`
`Q.
`
`Okay.
`
`So based on what you read in
`
`2 Hutzelmann, Dr. Noecker, what does it teach, if
`
`3 anything, one of skill in the art about combining
`
`4 Brimonidine and Timolol in a single combination
`
`5
`
`6
`
`treatment for intraocular pressure?
`
`A.
`
`There's certainly nothing here specific for
`
`7 Brimonidine. And in terms of the addition of Timolol in
`
`8 a fixed combination, it doesn't seem like it's going to
`
`9 solve efficacy problems.
`
`10
`
`Q.
`
`Okay.
`
`So you can set that one aside as well,
`
`11 Dr. Noecker.
`
`12
`
`We've been through most of the art that the
`
`13 Defendants relied on yesterday at trial. Have you
`
`14 reviewed all of the art that Dr. Tanna and Dr. L~skar
`
`15 talked about yesterday?
`
`16
`
`17
`
`A.
`
`Q.
`
`Yes.
`
`And in your opinion, Dr. Noecker, as one of
`
`18 skill in the art, do these references
`
`would these
`
`19 references motivate a person of skill to develop a
`
`20 single composition drug of 0.2% Brimonidine and 0.5%
`
`21 Timolol?
`
`22
`
`23
`
`24
`
`A.
`
`Q.
`
`A.
`
`No.
`
`Why not?
`
`I have not seen compelling information that
`
`25 would lead me to -- looking at the -- all this prior
`
`Page 14 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 15 of 156 PageiD #: 6534
`
`15
`
`1 art, that there's a benefit to doing so. Basically,
`
`2
`
`looking at Timolol to solve efficacy problems that are
`
`3 associated with Brimonidine.
`
`4
`
`Q.
`
`And in your opinion, Dr. Noecker, do these
`
`5 references provide a motivation to one of skill in the
`
`6 art that making a fixed combination of 0.2% Brimonidine
`
`7 and 0.5% Timolol could allow you to reduce the number of
`
`8 dosage of Brimonidine from three doses a day to two
`
`9 doses a day without losing efficacy?
`
`10
`
`A.
`
`No,
`
`I don't see any evidence here that would
`
`11 lead me to believe that, that you could successfully
`
`12 reduce the dosing interval from three times a day to
`
`13 twice a day --
`
`14
`
`15
`
`16
`
`17
`
`Q.
`
`A.
`
`Q.
`
`Okay.
`
`-- of Brimonidine.
`
`Thank you, Dr. Noecker.
`
`We need to do one more -- one more run through
`
`18 the claims now in light of all of these references.
`
`19
`
`MR. DENNING:
`
`So, Mr. Exline, if you
`
`20 could please pull up AGX512. And I think we can be even
`
`21 more efficient than last time.
`
`22
`
`23
`
`Q.
`
`(By Mr. Denning) So here we have --
`
`MR. DENNING: Do we have the other 512,
`
`24 Mr. Exline?
`
`25
`
`There we go. Thank you.
`
`Page 15 of 156
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`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 16 of 156 PageiD #: 6535
`
`16
`
`1
`
`Q.
`
`(By Mr. Denning) Here we have all of the
`
`2 asserted -- all the claims at issue of the four patents
`
`3 that we're talking about. And, again, we have
`
`4 highlighted all of the limitations that relate to the
`
`5
`
`6
`
`. 2% Brimonidine and
`
`. 5% Timolol.
`
`And my question -- those limitations appear in
`
`7 Claim 1 of the '976, 1 and 7 of the '258, 4 of the '149,
`
`8 and 1 and 4 of the '463.
`
`9
`
`My question for you, Dr. Noecker, on the
`
`10 obviousness analysis, is there anything ln
`
`11 DeSantis/Timmermans, in light of all of the other
`
`12 references that you've seen in this Court, that would
`
`13 have taught one of skill in the art to choose the
`
`14 specific combination of 0.2% Brimonidine and 0.5%
`
`15 Timolol in a single combination?
`
`16
`
`A.
`
`I don't see any teaching in this prior art
`
`17 that would lead me to do so.
`
`18
`
`MR. DENNING: Okay.
`
`If we could pull up
`
`19 the AGX513, please, Mr. Exline.
`
`20
`
`Q.
`
`(By Mr. Denning) Now, we have put up only the
`
`21 claims that have the preservative BAK in it as well as
`
`22 the concentrations. And I want to direct your attention
`
`23 to Claim 2 of the '258, 8 of the '258, 2 of the '463,
`
`24 and 5 of the '463, each of which additionally claim the
`
`25 limitation of BAK preservative, Benzalkonium Chloride
`
`Page 16 of 156
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`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 17 of 156 PageiD #: 6536
`
`17
`
`1 preservative, at 0.001% to 0.01%.
`
`2
`
`And looking at those four claims, Dr. Noecker,
`
`3 is there anything in DeSantis/Timmermans, in light of
`
`4 all of the other references that you have seen in this
`
`5 courtroom, that would teach one of skill in the art to
`
`6 choose a specific combination of 0.2% Brimonidine and
`
`7 0.5% Timolol in a composition with 0.001% to 0.01%
`
`8 Benzalkonium Chloride?
`
`9
`
`10
`
`A.
`
`Q.
`
`No.
`
`And with respect to claims 3 and 9 of the '258
`
`11 and 3 and 6 of the '463, each of which include the
`
`12 limitation of BAK at a concentration of 0.005%, my
`
`13 question, Dr. Noecker, is, is there anything in
`
`14 DeSantis/Timmermans, in light of all of the references
`
`15 that you've seen in this courtroom, that would teach one
`
`16 of skill in the art to choose a specific combination of
`
`17 0.2% Brimonidine and 0.5% Timolol with a preservative
`
`18 concentration of 0.005% Benzalkonium Chloride?
`
`A.
`
`No.
`
`19
`
`20
`
`MR. DENNING: And finally, if we could go
`
`21 to 514, Mr. Exline.
`
`22
`
`Q.
`
`(By Mr. Denning) We have Claim 4 of the '149
`
`23 patent displayed, and this is the one that talks about a
`
`24 method of reducing the number of daily topical
`
`25 ophthalmic doses of Brimonidine administered topically
`
`Page 17 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 18 of 156 PageiD #: 6537
`
`18
`
`1 to an eye of the person in need thereof for the
`
`2 treatment of glaucoma or ocular hypertension from three
`
`3 to two times a day without loss of efficacy.
`
`4
`
`And with respect to that limitation,
`
`5 Dr. Noecker, my question is, is there anything in
`
`6 DeSantis/Timmermans, in light of all of the other
`
`7 references that you've --you've seen in this courtroom,
`
`8 that would teach one of skill in the art a method of
`
`9 reducing the dose of Brimonidine from three doses to two
`
`10 doses without reducing efficacy in the treatment of
`
`11 glaucoma or ocular hypertension?
`
`12
`
`13
`
`14
`
`A.
`
`Q.
`
`A.
`
`No.
`
`And why not?
`
`Many of the -- much of the prior art does not
`
`15 really address the key timepoint, which is that
`
`16 afternoon trough, which is what's led to the labeling of
`
`17 Brimonidine.
`
`So we really don't have a lot of
`
`18 information or reason to believe that the addition of
`
`19 the Timolol to the Brimonidine would allow us to reduce
`
`20 the dosing interval without losing efficacy.
`
`21
`
`Q.
`
`So now,
`
`looking back at 512, 513, and 514, my
`
`22 ultimate question, Dr. Noecker, is, in light of the
`
`23 DeSantis/Timmermans reference and all of the other prior
`
`24 art that you've seen in this courtroom, is it -- what is
`
`25 your opinion regarding whether these claims of these
`
`Page 18 of 156
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`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 19 of 156 PageiD #: 6538
`
`19
`
`1 four patents would be obvious to one of ordinary skill
`
`2
`
`in the art in 2002?
`
`3
`
`4
`
`A.
`
`Q.
`
`They would not be obvious.
`
`Now, in addition to -
`
`to doing your
`
`5 anticipation and -- and obviousness analysis, have you
`
`6 also considered what are called objective considerations
`
`7 of non-obviousness?
`
`8
`
`9
`
`10
`
`A.
`
`Q.
`
`Yes.
`
`Okay.
`
`MR. DENNING:
`
`If you could -- if you
`
`11 could please pull up AGX111R.
`
`12
`
`Q.
`
`(By Mr. Denning) Okay. This is the -- this is
`
`13 the graph we've seen a couple times in your examination,
`
`14 and this is where you show the afternoon trough and the
`
`15 difference between Alphagan TID and Alphagan BID,
`
`16 correct?
`
`17
`
`18
`
`A.
`
`Q.
`
`Yes.
`
`Okay. With that in mind, if you could please
`
`19 grab PTX77 from your PTX binder.
`
`20
`
`21
`
`A.
`
`Q.
`
`Okay.
`
`And this is the Sherwood paper as it's been
`
`22 called, correct?
`
`23
`
`24
`
`25
`
`A.
`
`Q.
`
`A.
`
`That's correct.
`
`And what are the treatment arms in this study?
`
`This had Combigan, which was twice daily fixed
`
`Page 19 of 156
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`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 20 of 156 PageiD #: 6539
`
`20
`
`1 combination Brimonidine/Timolol. And then we had
`
`2 monotherapy with Timolol twice a day. And then we had
`
`3 Brimonidine monotherapy used three times a day.
`
`Those
`
`4 are three treatment groups.
`
`5
`
`Q.
`
`Okay.
`
`So we're comparing on the one hand
`
`6 Combigan in which patients are getting Brimonidine twice
`
`7 a day. And on the other hand, we're giving this
`
`8 concomitant
`
`concomitant therapy in which they're
`
`9 getting Brimonidine three times a day; is that correct?
`
`A.
`
`Q.
`
`10
`
`11
`
`12
`
`They're getting monotherapy three times a day.
`
`Thank you for correcting me.
`
`So there are three arms in this study. On the
`
`13 one hand, they're getting Combigan, which has
`
`14 Brimonidine, two times a day. On the second hand,
`
`15 they're getting Brimonidine three times a day. And then
`
`16 on the third hand, they're getting Timolol without any
`
`17 Brimonidine; is that correct?
`
`A.
`
`Q.
`
`18
`
`19
`
`20
`
`That's correct.
`
`Okay. Thank you for correcting me.
`
`MR. DENNING:
`
`If we could look at
`
`21 Figure 3 of this -- of this study, which appears on
`
`22 Page 1235 of the journal.
`
`A.
`
`Yes.
`
`23
`
`24
`
`MR. DENNING: One more page. There you
`
`25 go, Mr. Exline.
`
`Page 20 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 21 of 156 PageiD #: 6540
`
`21
`
`1
`
`If you could blow up that figure in the
`
`2
`
`top right corner.
`
`3
`
`Q.
`
`(By Mr. Denning) Can you tell us what this --
`
`4 what this figure is showing, Dr. Noecker?
`
`5
`
`A.
`
`This is a result of the -- a graph of the
`
`6 result of this study in which they evaluated the -- the
`
`7 eye pressure, the eye pressure lowering of each of these
`
`8 three treatment regimens at four different timepoints
`
`9 during the day.
`
`10
`
`So in the morning before the dose, the eyedrop
`
`11 administration at 10:00 a.m., which is this peak best
`
`12 timepoint; 3:00 p.m., which is the problematic
`
`13 timepoint; and then 5:00 p.m., which is the final, end
`
`14 of the day for everybody,
`
`I guess, in the study.
`
`15
`
`So what we see is, once again, 10:00 a.m. the
`
`16 pressure is a little higher in the morning before
`
`17 everybody gets their medicine.
`
`10:00 a.m. is kind of
`
`18 the expected peek efficacy of these drugs.
`
`So the lines
`
`19 go down; the points go down, and we see kind of the
`
`20 best-case scenario at 10:00 a.m.
`
`21
`
`And then we start seeing the afternoon, we see
`
`22 the change in pressure. We see that the timepoint that
`
`23 we worry about, once again, is this 3:00 p.m. timepoint.
`
`24 So the circles are the Combigan, the triangles are the
`
`25 Timolol, and the squares are Brimonidine.
`
`Page 21 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 22 of 156 PageiD #: 6541
`
`22
`
`1
`
`And so being lower on the graph is better.
`
`We
`
`2 see Combigan occupies the lowest position in terms of
`
`3
`
`lOP-lowering; Timolol next; and then Brimonidine at
`
`4 the -- at the top.
`
`5
`
`And then it goes back down later on in the day
`
`6 after dosing.
`
`So we see -- we see good or the best
`
`7 efficacy with the combination formulation.
`
`8
`
`Q.
`
`And particularly, if we look at the 3:00p.m.
`
`9 and 5:00p.m. timeframes, that's the afternoon trough
`
`10 we've been talking about, correct?
`
`11
`
`12
`
`A.
`
`Q.
`
`That's correct.
`
`And in both of those instances, the -- the
`
`13 subjects who were on the Combigan treatment, Brimonidine
`
`14 only twice a day, had lower mean IOPs than those
`
`15 patients who were getting Brimonidine three times a day
`
`16 in the Brimonidine monotherapy arm, correct?
`
`17
`
`18
`
`A.
`
`Q.
`
`That's right. Somewhat surprising.
`
`And that's even after the folks who were on
`
`19 the Brimonidine three-times-a-day therapy had their
`
`20 second dose of Brimonidine at 3:00 p.m.?
`
`21
`
`22
`
`23
`
`24
`
`A.
`
`Q.
`
`A.
`
`Q.
`
`Uh-huh.
`
`And by 5:00p.m., that had kicked in.
`
`Right.
`
`Their pressures are still higher than those
`
`25 people who were on the Combigan treatment and haven't
`
`Page 22 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 23 of 156 PageiD #: 6542
`
`23
`
`1
`
`taken any eyedrop since 8:00 a.m. that morning; is that
`
`2 correct?
`
`3
`
`A.
`
`Right. Even with the additional dose, it's
`
`4 still numerically better to be on the combination.
`
`5
`
`Q.
`
`Is this something that you as one of skill in
`
`6 the art would have found surprising in 2002?
`
`7
`
`8
`
`9
`
`A.
`
`Q.
`
`A.
`
`Yes.
`
`And why is that?
`
`I think, based on our experience, we'd expect
`
`10 that it would be kind of a neutral effect, that we
`
`11 wouldn't see this beneficial effect from adding the
`
`12 Timolol onto the Brimonidine to be able to be -- have a
`
`13 positive effect.
`
`14
`
`We suspect that it might have some positive
`
`15 effect, but that magnitude is really what's rather
`
`16 striking.
`
`It really eliminated that -- that difference
`
`17 we saw in those other studies, which was the TID dose,
`
`18 three-times a-day dosing, and twice-a-day dosing.
`
`19
`
`20
`
`Q.
`
`Okay. Thank you, Dr. Noecker.
`
`Let's also-- let's change subjects slightly
`
`21 and talk about side effects. We've heard about ocular
`
`22 allergy a couple of times, and I don't mean to belabor
`
`23 the point, but did you bring some pictures to -- to show
`
`24 the Court what ocular allergies really are?
`
`25
`
`A.
`
`Yes.
`
`Page 23 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 24 of 156 PageiD #: 6543
`
`24
`
`1
`
`MR. DENNING: And, Mr. Exline, if we
`
`2 could please bring up the first of those.
`
`I think it's
`
`3 called 510.
`
`4
`
`Q.
`
`(By Mr. Denning) What are we seeing in AGX510,
`
`5 Dr. Noecker?
`
`6
`
`A.
`
`A bad-looking eye.
`
`So what we see here is the
`
`7 eye is red.
`
`So the conjunctivae of vessel, the kind of
`
`8 clear covering that has the blood vessels, they're very
`
`9 engorged.
`
`So this would also show up in study reports
`
`10 as hyperemia.
`
`We've looked at tables reporting that
`
`11 side effect.
`
`So eye redness or vessel engorgement.
`
`12
`
`We see that the skin of the eyelid around the
`
`13 eye is kind of thickened and red and scaly. The color
`
`14 is not the best on this picture, but they kind of get
`
`15 this rubbery, flaky appearance on the skin that's
`
`16 really, really itchy.
`
`You can kind of see from across
`
`17 the room.
`
`18
`
`And then what we're trying to show here is the
`
`19 eyelid is pulled down, and we're trying to show the
`
`20 inner surface of the eyelid.
`
`It doesn't come out so
`
`21 great here, but you get these bumps called follicles.
`
`22 We were talking earlier about folliculosis.
`
`It looks
`
`23 like little fish eggs in there.
`
`So it's these little
`
`24 blister-like bubbles, hundreds of them on the inside of
`
`25 the eyelid, which kind of tells us that this is allergy
`
`Page 24 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 25 of 156 PageiD #: 6544
`
`25
`
`1 due to Brimonidine.
`
`So these people are miserable.
`
`2
`
`MR. DENNING: And if we could go to
`
`3 AGX511, please, Mr. Exline, the second of the two
`
`4 pictures you brought.
`
`5
`
`Q.
`
`(By Mr. Denning) What do we see here,
`
`6 Dr. Noecker?
`
`7
`
`A.
`
`So this is a patient of mine who's
`
`8 receiving
`
`we have another picture of Alphagan allergy
`
`9 in one eye, in her right eye -- this is the left one in
`
`10 this picture, she's getting nothing.
`
`So kind of
`
`11 normal-looking eye.
`
`12
`
`In her other eye, you see, once again, the
`
`13 vascular engorgement, the hyperemia, the kind of pinking
`
`14 around the eyelids, the eyelid changes. That's
`
`15 basically what you see on this.
`
`And a complaint of
`
`16 extremely itchy eye.
`
`17
`
`And this particular patient, who actually was
`
`18 one of my favorites, and she was somebody
`
`-
`
`she came
`
`19 from Indiana, Pennsylvania.
`
`So she came from 80 miles
`
`20 away to see me, because she was on this drug and just
`
`21 miserable. She said, look,
`
`I walk around town and
`
`22 everyone tells me
`
`I
`
`look like a vampire.
`
`23
`
`And I helped her.
`
`I stopped the drug.
`
`I
`
`24 changed her therapy around because she was allergic.
`
`I
`
`25 said you have an allergy, and we stopped it, and she was
`
`Page 25 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 26 of 156 PageiD #: 6545
`
`26
`
`1 one of my happiest -- I know her well.
`
`I can tell you
`
`2 everything about her.
`
`She was my most loyal patient.
`
`3 Referred a hundred other people from this little town to
`
`4 come in and see me just because we recognized her
`
`5 allergy.
`
`We stopped it and made her a very happy
`
`6 person.
`
`7
`
`Q.
`
`In your experience, Dr. Noecker, are allergies
`
`8 common with Brimonidine as a monotherapy?
`
`9
`
`A.
`
`Over time, yes. We don't see them right away,
`
`10 but the longer patients are on the drug, they -- they
`
`11 tend to occur. The original Alphagan, why clinicians
`
`12 grew not to love it is because the rate would approach
`
`13 25 percent, and over a longer p