Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 1 of 156 PageiD # : 6520
`
`1
`
`1
`
`2
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE EASTERN DISTRICT OF TEXAS
`MARSHALL DI VIS I ON
`
`3 ALLERGAN ,
`
`I NC.
`
`4 vs .
`
`SANDOZ ,
`
`INC .
`
`5
`
`6
`
`7
`
`8
`
`*
`*
`*
`*
`*
`*
`
`Civil Docket No .
`2 : 09-CV-97
`Marshall , Texas
`
`Augu st 4, 2011
`1 : 15 P.M .
`
`TRANSCRIPT OF BENCH TR I AL
`BEFORE THE HONORABLE JUDGE T . JOHN WARD
`UNI TED STATES DIS TRIC T JU DGE
`
`9 APPEARANCES :
`
`1 0 FOR THE P LAI NT I F F:
`
`11
`
`12
`
`1 3
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`MS . JUANI TA BROOKS
`MR . ROGER DENNING
`Fish & Richardson
`1 2390 El Camino Real
`San Diego , CA
`92130
`
`MR . JONATHAN SINGER
`MS . DEANNA REICHEL
`Fish & Richardson
`60 Sou th Sixth Street
`3200 RBC Plaza
`Minneapolis , MN
`
`55 4 02
`
`MR . W. CHAD SHEAR
`Fish & Richardson
`17 1 7 Main Street
`Suite 5000
`Dallas , TX
`
`75201
`
`20 APPEARANCES CONTINUED ON NEXT PAGE :
`
`21
`
`22 COURT REPORTERS :
`
`MS . SUSAN SIMMONS , CSR
`MS . SH ELL Y 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
`
`24
`
`25
`
`Page 1 of 156
`
`SENJU EXHIBIT 2137
`LUPIN v. SENJU
`IPR2015-01105
`
`
`
`1
`
`1
`
`2
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE EASTERN DISTRICT OF TEXAS
`MARSHALL DI VIS I ON
`
`3 ALLERGAN ,
`
`I NC.
`
`4 vs .
`
`SANDOZ ,
`
`INC .
`
`5
`
`6
`
`7
`
`8
`
`*
`*
`*
`*
`*
`*
`
`Civil Docket No .
`2 : 09-CV-97
`Marshall , Texas
`
`Augu st 4, 2011
`1 : 15 P.M .
`
`TRANSCRIPT OF BENCH TR I AL
`BEFORE THE HONORABLE JUDGE T . JOHN WARD
`UNI TED STATES DIS TRIC T JU DGE
`
`9 APPEARANCES :
`
`1 0 FOR THE P LAI NT I F F:
`
`11
`
`12
`
`1 3
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`MS . JUANI TA BROOKS
`MR . ROGER DENNING
`Fish & Richardson
`1 2390 El Camino Real
`San Diego , CA
`92130
`
`MR . JONATHAN SINGER
`MS . DEANNA REICHEL
`Fish & Richardson
`60 Sou th Sixth Street
`3200 RBC Plaza
`Minneapolis , MN
`
`55 4 02
`
`MR . W. CHAD SHEAR
`Fish & Richardson
`17 1 7 Main Street
`Suite 5000
`Dallas , TX
`
`75201
`
`20 APPEARANCES CONTINUED ON NEXT PAGE :
`
`21
`
`22 COURT REPORTERS :
`
`MS . SUSAN SIMMONS , CSR
`MS . SH ELL Y 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
`
`24
`
`25
`
`Page 1 of 156
`
`SENJU EXHIBIT 2137
`LUPIN v. SENJU
`IPR2015-01105
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 2 of 156 PageiD #: 6521
`
`2
`
`1
`
`2 APPEARANCES CONTINUED :
`
`3 FOR THE PLAINTIFF :
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10 FOR THE DEFENDANTS :
`( Sandoz , et al )
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`(Apotex)
`
`21
`
`22
`
`23
`
`2 4
`
`25
`
`MS . SUSAN COLETTI
`MS . A . MARTINA HUF NAL
`MR . SANTOS H CONTINHO
`Fish & Richardson
`222 Delaware Avenue
`17th Floo r
`Wilmington , DE
`
`19899
`
`MR . GREGORY LOVE
`Stevens Love F i r m
`111 West Tyler Street
`Longview, TX
`7 5601
`
`MR . WI LLIAM E. " BO " DAVIS, III
`The Dav i s Firm
`111 West Tyler Street
`Longview , TX
`7 5601
`
`MR. BARRY P. GO LOB
`MR . KERRY B. MCTIGUE
`MR . W. BLAKE COBLENT Z
`Duane Morris
`505 9th Street , NW
`Suite 1000
`Wash i ngto n, DC
`
`20004
`
`MR. RICHARD T. RUZICH
`Duane Morris
`1 90 South LaSalle Street
`Suite 3700
`Chicago ,
`IL
`
`60603
`
`MR . HARRY L . GILL AM ,
`Gil l am & Smith
`303 South Wash i ngton Avenue
`Marshall , TX
`75670
`
`J R .
`
`MR . STEP HEN P . BENSON
`MR. DENNIS C . LEE
`Katten Mu chin Rosenman
`525 West Monroe Street
`Suite 1 600
`Chicago ,
`IL
`
`60661
`
`Page 2 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 3 of 156 PageiD #: 6522
`
`3
`
`1 APPEARANCES CONTINUED:
`
`2 FOR THE DEFENDANTS:
`(Watson)
`
`MR. LARRY PHILLIPS
`Siebman Reynolds Burg &
`Phillips
`300 Nor th Travis Street
`Sherman, TX
`75090
`
`MR . GARY E. HOOD
`Polsinelli Shughart
`16 1 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
`
`COURT SECURITY OFFICER: All rise .
`
`THE COURT: Please be seated.
`
`Proceed.
`
`MR . DENNING: Thank you, Your Honor .
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18 ROBERT J. NOECKER, M.D . , PLAINTIFF'S WITNESS, PREVIOUSLY
`
`19
`
`20
`
`SWORN
`
`DIRECT EXAMINATION
`
`(CONTI NUING)
`
`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
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 4 of 156 PageiD #: 6523
`
`4
`
`1 is DTX155.
`
`2
`
`3
`
`4
`
`5
`
`A .
`
`Q .
`
`A .
`
`Q .
`
`155 .
`
`I bel i eve 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 l ook 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 contro l of intraocular pressure. It's
`
`Page 4 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08111 Page 5 of 156 PageiD #: 6524
`
`5
`
`1
`
`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 .
`
`1 0
`
`So this is a study where t hey only co l lected
`
`11 morning data, so it doesn't tell us anythi n g about t h e
`
`12 effect on afternoon data.
`
`13
`
`And then they had a run-in period on the
`
`14 beta - blocker . And this is over a th r ee-week -- th i s is
`
`15
`
`16
`
`days, 21 days to 42 days of average IO P .
`
`So, once
`
`again, it should be capturing the best tim e poin t ,
`
`and
`
`1 7
`
`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 ta l king ea r lier
`
`23 about within the day.
`
`24
`
`You know, this patient started, i f this was a
`
`25 patient in my practice, once again, Patient Mrs . Jones '
`
`Page 5 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 6 of 156 PageiD #: 6525
`
`6
`
`1 pressure is in the 20s, we put you o n this drug or two
`
`2 drugs . We don ' t know what yo u r eye pressure is going to
`
`3 be the next time y ou come i n .
`
`4
`
`5
`
`Maybe one time i t' s 18 , kind of below the
`
`overflow limit .
`
`The next ti me , it's above on t h e next
`
`6 v i sit .
`
`So this i s not somebody we say , okay , see you in
`
`7 six months .
`
`I ' m sure everything wi l l 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 co n trol of this combinat i on drug .
`
`11
`
`12
`
`Q .
`
`Thank y ou , Dr . Noecker .
`
`And ju s t
`
`to -- before we move on , what does
`
`13 Airaksinen teach a person of ordinary skil l
`
`in the art
`
`14 about combi n ing Brimon i dine a nd Timolo l
`
`in a fixed
`
`15 combination dr u g?
`
`16
`
`A .
`
`Nothing . And it might give you pause about
`
`17
`
`combination drugs in ge n era l.
`
`18
`
`19
`
`Q.
`
`Tha n k you , Dr . Noecker .
`
`Let ' s move on to Defense Exhibit 148, which
`
`20
`
`was the Clineschmi dt article .
`
`21
`
`22
`
`MR . DE NNING : Thank you, Mr . Exline .
`
`Q .
`
`( By Mr . Den n ing) This is the article in which
`
`23 the y were comparing Cosopt on the one arm versus BID
`
`24 Timolol and TID Dorzo l amide monotherapies ; is that
`
`25 right?
`
`Page 6 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 7 of 156 PageiD #: 6526
`
`7
`
`A .
`
`Q.
`
`1
`
`2
`
`3
`
`That ' s correct .
`
`And if we
`
`t urn to Table 3 of this study --
`
`MR. DEN NING: Which appears o n -- on Page
`
`4 1 955 , Mr . Exl i ne .
`
`5
`
`Q .
`
`(By Mr . Denning) -- what time periods are they
`
`6 measuring with this study?
`
`7
`
`A .
`
`They ' re loo k ing at the pre - dose in the
`
`8 mornings of 8 : 00a . m., putting the drop in , and then two
`
`9 hours , o n ce again , at the time we ' d expec t ed to be the
`
`10 mos t efficacio u s .
`
`So mor ni ng time points ,
`
`two hours
`
`11
`
`apar t.
`
`12
`
`13
`
`14
`
`15
`
`16
`
`1 7
`
`Q.
`
`Ok ay . Does this show any t h i ng about that
`
`a f ternoon trough at al l
`
`in this paper?
`
`A.
`
`Q.
`
`It doesn ' t give us a n y a f ternoon information.
`
`Okay. Wel l, l et ' s
`
`l ook at what it shows
`
`for -- for the morning pressure .
`
`MR . DENNING :
`
`If we could go and,
`
`18 Mr . Ex l ine , highlight on the bottom for month 3 and the
`
`19 c h ange ,
`
`the seco nd to the righ tmost co lu mn , and then
`
`20 high l ight for the combination a nd for Dorzolamid e
`
`I ' m
`
`2 1 sorry -- second to the rig h t , Mr . Ex l ine .
`
`22
`
`23
`
`There yo u go . Right there .
`
`Q .
`
`(By Mr . De n ni n g) So wha t -- wh a t do we see
`
`24 here as the comparison between Dorzolamide as a
`
`25 monotherapy and then th e Cosopt combinat ion?
`
`Page 7 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 8 of 156 PageiD #: 6527
`
`8
`
`1
`
`A.
`
`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 mercu ry
`
`7 bet t er .
`
`So when determining how much benefit Timolol is
`
`8 giving us, adding on top of the Dorzolamide, it's about
`
`9 2 mi llimeters 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 bes t-case scenario, t h at two ho u rs
`
`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 ho u r 0 up above for the same --
`
`22 for the same 2 in month 3, we see a difference from 2 . 8
`
`23 to 1. 4; is that right?
`
`24
`
`25
`
`A .
`
`Q.
`
`That ' s right .
`
`I t
`
`'s about 1 . 4' 1-1/2 , yes .
`
`Okay. Earlier when we looked at the
`
`Page 8 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 9 of 156 PageiD #: 6528
`
`9
`
`1 demonstrative from opening that showed t h e afternoon
`
`2
`
`3
`
`4
`
`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
`
`7
`
`8
`
`Do you remember that?
`
`A .
`
`I think it was 3 . 5 .
`
`MR . DENNING : Mr . Exline , are you able to
`
`9 pull that up?
`
`10
`
`11
`
`12
`
`A .
`
`You ' re talking about the difference between
`
`TID Brimonidine and BID Brimonidine?
`
`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 . 25
`
`1 6
`
`Q .
`
`I think you may remember from Ms . Batoosingh ' s
`
`17 testimo n y whe n
`
`t h ey looked at the actual underlying
`
`1 8 document .
`
`It was -- it was different .
`
`19
`
`20
`
`A .
`
`Q .
`
`Perha p s .
`
`But in any event, does-- the 1 . 5 to
`
`21 2 millimeters of mercury benefit that we
`
`j ust saw from
`
`22 the Cli n eschmidt p aper with regard to Cosopt , would that
`
`23 be enough to make up any afternoon trough in the
`
`24 differe n ce between Brimonidine BID and TID?
`
`25
`
`A .
`
`Like I said , it doesn ' t give us really any
`
`Page 9 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 10 of 156 PageiD #: 6529
`
`10
`
`1
`
`information regarding Brimonidine, but if you were to
`
`2 make the inference about what ' s the benefit of adding
`
`3 the Timolol in terms of eye pressure reduction, the most
`
`4 these other papers indicate it might be in the best,
`
`5 best-case scenario only at the morning is 1 - 1/2 to
`
`6 2-ish, so not at the magnitude.
`
`7
`
`But, really ,
`
`the inference I think you can
`
`8 draw is that magnitude may fall short. It's not going
`
`9 to be -- adding Timo lol is just not going to be
`
`10 adequate.
`
`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
`
`15 adding Timolol in combination?
`
`16
`
`A .
`
`That it would not be adequate to make up for
`
`17 the deficit we see in the afternoon -- that afternoon
`
`18 dip in IOP control.
`
`19
`
`20
`
`Q .
`
`Okay. You may set that ex hibit 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
`
`24
`
`A .
`
`Q.
`
`25 correct?
`
`Yes.
`
`Now, again, this is a study looking at Cosopt,
`
`Page 10 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 11 of 156 PageiD #: 6530
`
`11
`
`1
`
`2
`
`A.
`
`Q.
`
`Correct.
`
`And Cosopt, meaning the combination of
`
`3 Dorzolamide and Timo l ol, correct?
`
`4
`
`5
`
`A.
`
`Q.
`
`That's correct .
`
`Okay . What does that teach you as a person of
`
`6 skil l
`
`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.
`
`Al l 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
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 12 of 156 PageiD #: 6531
`
`12
`
`1 combining Brimonidine and Timolol and the effects that
`
`2 that might be ,
`
`i f they were in a combination drug
`
`3 together?
`
`4
`
`A .
`
`Not hin g specific to the Brimonidine/Timolol
`
`5 combination , but , once again , specific to the additio n
`
`6 as Brimonidine -- or Timolol as a tool , it will fal l
`
`7 it may fa ll short or p robably will fall short in the
`
`8 afternoon .
`
`9
`
`Q .
`
`Okay . And i f yo u co ul d look a t Table 5 in
`
`10
`
`t hi s paper as we l l .
`
`11
`
`This -- t h is one deals wit h the ocular and
`
`12 loca l adverse experiences . Do y ou see that?
`
`13
`
`14
`
`A .
`
`Q .
`
`Yes .
`
`And ca n you tell me , are there any -- did the
`
`15 combination in this study experience any reduction in
`
`16 adverse exper i e n ces t h an the individua l
`
`therapies?
`
`17
`
`A .
`
`It d i d n 't -- it didn ' t reduce any.
`
`It may
`
`18 have stu ng a little b it more .
`
`19
`
`20
`
`Q .
`
`It may ha v e stung a
`
`l i t t le b i t more.
`
`Okay . Thank you . You ca n set -- you ca n set
`
`21 that to one aside .
`
`22
`
`And the last one of the articles t hat they
`
`23 showed yesterday t h at I ' m going t o show you is DTX20 1.
`
`24
`
`25
`
`MR. DENNING :
`
`If yo u could pull t h at up?
`
`Q .
`
`(By Mr . Denni n g) This is the Hutzelmann
`
`Page 12 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 13 of 156 PageiD #: 6532
`
`13
`
`1 reference .
`
`2
`
`3
`
`A.
`
`Q .
`
`Yes .
`
`And this study, again, compared Cosopt on the
`
`4 one arm versus Do r zolamide BI D/Timolo l BID concomitant
`
`5 therapy, correct?
`
`6
`
`7
`
`A .
`
`Q.
`
`Yes .
`
`And, again, if we look at
`
`if we
`
`l ook 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 af t ernoon trough; is that correct?
`
`A.
`
`Q.
`
`15
`
`16
`
`17
`
`Righ t , same story.
`
`Okay. And if we look at the mean change.
`
`MR . DENNING:
`
`I 'm sor r y, 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
`
`
`
`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 Hutzel mann , Dr . Noecke r, what does it teach , if
`
`3 anything, one of skil l
`
`in the art about co mbining
`
`4 Brimonidi n e a nd Timolol in a sing l e 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 i n
`
`8 a fixed combination ,
`
`i t doesn 't seem like it ' s going to
`
`9 solve efficacy problems .
`
`10
`
`Q .
`
`Okay .
`
`So you can set t h at one aside as well ,
`
`11 Dr . Noecker .
`
`12
`
`We ' ve been through most of the art that the
`
`13 Defenda n ts relied on yesterday at trial . Have you
`
`14 reviewed al l of the art that Dr . Tanna and Dr. L~skar
`
`15 talked about yesterday?
`
`16
`
`17
`
`A .
`
`Q .
`
`Yes .
`
`And i n your opinion , Dr . Noecker , as one of
`
`18 skill in the art , do these re f ere n ces
`
`wou l d these
`
`19 references motivate a person of skill to develop a
`
`20 single composition dr u g o f 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 wou l d 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 ,
`
`t h at there ' s a benefit t o doing so . Basica ll y ,
`
`2
`
`looking a t Ti mo l o l
`
`to solve efficacy prob l ems that are
`
`3 associated with Brimonidine .
`
`4
`
`Q .
`
`And in your opinion , Dr . Noecker , do these
`
`5 references provide a motivation to one of sk i l l
`
`in the
`
`6 art that making a fixed combination of 0 . 2% Brimonidine
`
`7 and 0 . 5% Timolol could allow you to reduce t h e nu mber of
`
`8 dosage of Brimonidine f rom t h ree doses a day to two
`
`9 doses a day without l os i ng efficacy?
`
`10
`
`A .
`
`No ,
`
`I do n 't see an y e v idence here that would
`
`11 lead me to believe that , that yo u could success f u ll y
`
`1 2 reduce the dosing interval from thr ee times a day to
`
`13
`
`tw i ce a day --
`
`14
`
`1 5
`
`16
`
`17
`
`Q .
`
`A .
`
`Q .
`
`Ok ay .
`
`- - of Brimonidine .
`
`Thank you , Dr. Noecker .
`
`We need to do one more -- one more run through
`
`18 the claims now in ligh t o f al l o f
`
`t h ese references .
`
`19
`
`MR . DENNING :
`
`So , Mr . Exline ,
`
`i f you
`
`20 could p l ease pull u p AGX512 . An d
`
`I think we can be even
`
`21 more efficient than las t ti me .
`
`22
`
`23
`
`Q .
`
`(By Mr . Denning) So here we have --
`
`MR . DENNING : Do we have the other 5 1 2 ,
`
`2 4 Mr. Exline?
`
`25
`
`There we go . Thank you .
`
`Page 15 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 16 of 156 PageiD #: 6535
`
`1 6
`
`1
`
`Q .
`
`(By Mr . Denn i ng) Here we h ave al l of the
`
`2 asserted -- al l
`
`the c l aims at issue of the four patents
`
`3 that we ' re talking about . And , again , we have
`
`4 h igh l ighted al l of the limitations that rela t e
`
`t o the
`
`5
`
`6
`
`. 2% Brimonidine and
`
`. 5% Timolol .
`
`And my quest i on -- those limitat i ons a p pear in
`
`7 Claim 1 of the ' 976 , 1 and 7 of t h e
`
`' 258 , 4 o f
`
`t h e
`
`'1 49 ,
`
`8 and 1 and 4 of t he
`
`' 463 .
`
`9
`
`My quest i on fo r you , Dr . Noecke r, on the
`
`1 0 o b v i ousness a n a l ysis , is there anything in
`
`11 DeSantis/ T immermans ,
`
`in light of all of the ot h er
`
`12 refere n ces t h at you ' ve seen in this Court , that would
`
`13 h ave taught o n e of skill in the art to choose t h e
`
`14 specific combination of 0.2% Brimonidine and 0 . 5%
`
`15 Timo l ol in a single combination?
`
`16
`
`A .
`
`I do n 't see an y teaching in this prio r art
`
`17
`
`t h at wou l d lead me to do so .
`
`18
`
`MR . DE NNING : Okay .
`
`If we could pu l l up
`
`19 the AGX513 , please, Mr . Ex l ine .
`
`20
`
`Q .
`
`( By Mr . Denning) Now , we h ave put up only the
`
`21 claims that have th e preservative BAK
`
`i n 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 additio n ally claim the
`
`25
`
`l imitation of BAK preservative, Benza l koni u m Chloride
`
`Page 16 of 156
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 17 of 156 PageiD #: 6536
`
`17
`
`1 preservative , at 0 . 00 1 % 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 t each one of skill in the art to
`
`6 c h oose a specific combi n at i on of 0 . 2% Brimonidine and
`
`7 0.5% Timolol in a compos iti on wi t h 0.001% t o 0 . 0 1 %
`
`8 Benzalkoni u m 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 a t a concentration of 0 . 005% , my
`
`13 questio n, 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 i n the art to choose a specific combination of
`
`17 0 . 2% Brimo n idine and 0 . 5% Timolol with a preservative
`
`18 concentration of 0 . 005% Be n zal k onium Chloride?
`
`19
`
`20
`
`21
`
`22
`
`A .
`
`No .
`
`MR . DENNING :
`
`And finally , if we cou l d go
`
`to 514 , Mr . Exline .
`
`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 nu mber of daily topical
`
`25 ophtha l mic 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 th e
`
`2 treatment of g l aucoma or ocular hypertension from three
`
`3 to two times a day without loss of efficacy .
`
`4
`
`And with respect to that limi t ation,
`
`5 Dr . Noecker , my questio n is , is there anyt h i n g in
`
`6 DeSantis/Timmermans ,
`
`i n light of all of t h e other
`
`7 references that you've -- you ' ve seen i n this courtroom ,
`
`8 that would teach one of ski ll in the art a method of
`
`9 reducing the dose of Brimonidine from three doses to two
`
`1 0 doses wit h out reducing efficacy in the t rea t men t of
`
`11 glauco ma or ocular hypertension?
`
`1 2
`
`1 3
`
`1 4
`
`A .
`
`Q .
`
`A.
`
`No .
`
`And why not?
`
`Many of the -- much of the prior art does not
`
`1 5 really address the key timepoint, wh ich is t h at
`
`1 6 afternoo n trough, which is wha t 's led to the labe l ing of
`
`1 7 Br imonidine .
`
`So we really don 't have a
`
`l ot of
`
`18 information or reason to believe that the addi t ion o f
`
`19 the Timolol to t he Br i monidi n e would a l low us to reduce
`
`20 the dosing interval wit h o u t
`
`losing efficacy .
`
`21
`
`Q .
`
`So now,
`
`l ooking back at 512 , 513 , and 51 4, my
`
`22 u ltimate question, Dr . Noecker, is ,
`
`in l ight of the
`
`23 DeSantis/Timmermans reference and a l l of the other prior
`
`2 4 art that you ' ve seen in this courtroom , is it -- what is
`
`25 your opinion regarding whether these c l aims of these
`
`Page 18 of 156
`
`
`
`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 skil l
`
`2 in the art i n 2002?
`
`3
`
`4
`
`A .
`
`Q .
`
`They would not be obvious .
`
`Now ,
`
`in additio n to -- to doing your
`
`5 anticipation and -- and obvious n ess analysis , have you
`
`6 also considered what are called objective considerations
`
`7 of non - obviousness?
`
`8
`
`9
`
`10
`
`A.
`
`Q.
`
`Yes .
`
`Okay .
`
`MR. DEN NING :
`
`If you could - - if yo u
`
`11 could p l ease pul l u p AGX 1 1 1 R .
`
`12
`
`Q.
`
`(By Mr. Denning) Okay .
`
`This is the -- this is
`
`13 the graph we ' ve seen a couple times in your exa mination ,
`
`1 4 and this is wh ere you show the afternoon trough a n d the
`
`15 d i fference between Al p h agan T ID and Alphagan BID ,
`
`16 correct?
`
`17
`
`18
`
`A .
`
`Q .
`
`Yes .
`
`Okay. With that in mind, if you could please
`
`19 grab P TX77 from your PTX binder .
`
`20
`
`21
`
`A .
`
`Q .
`
`Okay.
`
`And this is the Sherwood paper as it ' s been
`
`22 ca ll ed, 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
`
`
`
`Case 2:09-cv-00097-JRG Document 243 Filed 08/08/11 Page 20 of 156 PageiD #: 6539
`
`20
`
`1 combina t ion Brimon i din e / Ti mol o l . And t hen we h ad
`
`2 monotherapy with Timolo l
`
`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,
`
`t hey'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 th e n
`
`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 -- t he
`
`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 5:00p.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 lowe r on the graph i s better.
`
`We
`
`2 see Combigan occupies the l owest position in ter ms of
`
`3
`
`lOP-loweri n g; Timolol next ; and then Brimon i dine at
`
`4 the - - at the t op .
`
`5
`
`And then it goes back down later on in the day
`
`6 after dosi n g.
`
`So we see -- we see good or the best
`
`7 efficacy wit h the combination formulation .
`
`8
`
`Q.
`
`And particular l y ,
`
`i f we look at the 3 : 00 p . m.
`
`9 and 5:00p . m . time f rames , that ' s the afternoo n trough
`
`10 we ' ve been t a l k i ng about , correct?
`
`11
`
`12
`
`A .
`
`Q .
`
`That ' s correct .
`
`And in both of those instances ,
`
`the - -
`
`the
`
`13 subjects who were on the Combigan treatmen t, Brimonidine
`
`14 on l y twice a day , had lower mean lOPs than those
`
`15 patients who were getting Brimonidine three times a day
`
`16 in t he Br imo nidi ne monotherapy arm , correct?
`
`17
`
`18
`
`A .
`
`Q .
`
`That's right .
`
`Somewhat surprising .
`
`And tha t' s even after the folks who were on
`
`19 the Brimonidine three-times - a - day therapy had their
`
`20 second dose of Brimonidi n e at 3:00 p . m. ?
`
`21
`
`22
`
`23
`
`24
`
`A .
`
`Uh - huh .
`
`. Q .
`
`And by 5 : 00p . m., that had kicked in .
`
`A .
`
`Q .
`
`Right .
`
`Their pressures are st i ll higher than those
`
`25 peop l e who were on the Combigan t reatment 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 i is that
`
`2 correct?
`
`3
`
`A.
`
`Right . Even with the additional dose , it ' s
`
`4 still numerical l y better to be on the combination.
`
`5
`
`6
`
`7
`
`8
`
`9
`
`Q .
`
`I s this something that you as one of sk i ll in
`
`the art would have found s u rprising in 2002?
`
`A .
`
`Q .
`
`A .
`
`Yes .
`
`And why is that?
`
`I
`
`think , based on o u r experience , we ' d expect
`
`10 that it wou l d be kind of a neutral effect , that we
`
`1 1 wou l dn ' t see this beneficial effect from adding the
`
`12 Timolol onto the Brimonidine to be able to be -- have a
`
`13 positive effect .
`
`1 4
`
`We suspect that it might have some positive
`
`1 5 effect , but t h at magnitude is really what ' s rather
`
`16 striking .
`
`It rea l ly 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 yo u, Dr . Noecker .
`
`Let ' s also-- let ' s change s u bjects slight l y
`
`21 a n d ta l k about side effects . We ' ve heard abo u t ocular
`
`22 al l ergy a couple of times , and I don ' t mean to belabor
`
`23 the poin t , but did you bring some pictures to -- to s h ow
`
`2 4 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 . E xl i ne, 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 pictur e , but they kind of get
`
`15 this rubbery , flaky appearance on t he 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 fol li cu l osis .
`
`It looks
`
`23 like little fish eggs in th e r e .
`
`So i t
`
`' s these little
`
`24 blister-like bubbles, hundreds of them on the inside of
`
`25 the eyelid , which kind of tel l s us t hat 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 Brimo ni dine .
`
`So these people are miserable .
`
`2
`
`MR . DENNING : And if we could go t o
`
`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 t h is is a patient of mi n e who ' s
`
`8 receiving
`
`we have another picture of Alphagan allergy
`
`9
`
`in one eye ,
`
`in h er right e y e -- this is the lef t one in
`
`10 this picture, she ' s ge t t in g no thi ng .
`
`So kind of
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
