`
`2
`
`3
`
`UNITED STATES DI STRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`1
`
`4 HELSINN HEALTHCARE , S . A. and
`ROCHE PALO ALTO , LLC ,
`
`CIVIL ACTION NUMBER :
`
`11- 3962
`
`TRIAL
`
`5
`
`6
`
`Plaintiffs ,
`
`- vs-
`
`7
`DR . REDDY ' S LABORATORIES , LTD .,
`8 DR . REDDY ' S LABORATORIES ,
`INC .,
`TEVA PHARMACEUTICALS USA,
`I NC .,
`9 and TEVA PHARMACEUTICAL
`INDUSTRIES , LTD .
`10
`
`Defendants .
`
`11
`Clarkson S . Fisher United States Courthouse
`12
`402 East State Street
`Trenton , New Jersey 08608
`13
`June 8 , 2015
`14 BE F 0 R E:
`15
`16
`17
`18
`19
`20
`21
`22
`23 Certified as True and Correct as required by Titl e 28 , U. S . C. ,
`Section 753
`24
`25
`
`THE HONORABLE MARY L . COOPER
`UNI TED STATES DISTRICT JUDGE
`
`/S/ Regi na A. Berenato- Tell, CCR, CRR, RMR, RPR
`/S/ Carol Farrell, CCR, CRR, RMR, CCP, RPR, RSA
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`ReddyExhibit1028
`~----------~--------------~
`
`United States Dis
`Trenton , New Jersey
`
`
`
`1
`
`2
`
`3
`
`UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`1
`
`4 HELSINN HEALTHCARE , S . A. and
`ROCHE PALO ALTO , LLC ,
`
`CIVIL ACTION NUMBER :
`
`11- 3962
`
`TRIAL
`
`5
`
`6
`
`Plaintiffs ,
`
`- vs-
`
`7
`DR . REDDY ' S LABORATORIES , LTD .,
`8 DR . REDDY ' S LABORATORIES ,
`INC . ,
`TEVA PHARMACEUTICALS USA,
`I NC . ,
`9 and TEVA PHARMACEUTICAL
`INDUSTRIES , LTD .
`10
`
`Defendants .
`
`THE HONORABLE MARY L . COOPER
`UNI TED STATES DISTRICT JUDGE
`
`11
`Clarkson S . Fisher United States Courthouse
`12
`402 East State Street
`Trenton , New Jersey 08608
`13
`June 8 , 20 1 5
`14 BE F 0 R E :
`15
`16
`17
`18
`19
`20
`21
`22
`23 Certified as True and Correct as required by Titl e 28 , U. S . C.,
`Section 753
`24
`2 5
`
`/S/ Regina A. Berenato- Tell, CCR, CRR, RMR, RPR
`/S/ Carol Farrell, CCR, CRR, RMR, CCP, RPR, RSA
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`A P P E A RAN C E S:
`
`2
`
`1
`
`2
`
`8
`
`PAUL HASTINGS
`3 BY :
`JOSEPH O' MALLEY, ESQUIRE
`ERIC W. DITTMANN, ESQUIRE
`4
`ISAAC S . ASHKENAZI , ESQUIRE
`SAUL EWING
`5 BY : CHARLES M. LIZZA, ESQUIRE
`Attorneys for t h e Plaintiffs
`6
`7 BUDD LARNER
`BY :
`STUART D. SENDER, ESQUIRE
`MICHAEL H.
`IMBACUAN, ESQUI RE
`HUA HOWARD WANG , ESQUIRE
`9
`CONSTANCE S . HUTTNER, ESQUIRE
`KENNETH E . CROWELL , ESQUIRE
`10 Attorneys f or the Defendant , Dr . Reddy ' s Laboratories
`11 WINSTON & STRAWN
`BY :
`JOVIAL WONG , ESQUIRE
`GEORGE LOMBARDI , ESQUIRE
`JULIA MANO JOHNSON, ESQUIRE
`BRENDAN F . BARKER, ESQUIRE
`LITE DePALMA, GREENBERG , LLC
`BY : MAYRA V. TARANTINO , ESQUIRE
`Attorneys for the Defendant, Teva
`
`12
`13
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`20
`21
`
`22
`
`23
`24
`25
`
`United States Di stri ct Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`3
`~--------------------------Colloquy --------------------------~
`
`I N D E X
`
`1
`
`2
`
`3
`
`4
`
`VOIR DIRECT
`DIRE
`
`CROSS REDIRECT RECROSS
`
`David G. Frame
`By Mr . Imbacuan
`By Mr. Ashkenazi
`
`5 WITNESS
`6
`
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`1 7
`18
`19
`20
`2 1
`2 2
`23
`24
`2 5
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`109
`r---------------------------Frame - Direct --------------------------~
`
`1 BY MR .
`
`IMBACUAN :
`
`2 Q . Dr . Frame , Chelly is also a study concerning the use of
`
`3 palonosetron for PONV . So how do the findings relate to the
`4 use of palonosetron for CINV?
`
`5 A . Right. So you can ' t make an absolute direct correlation
`6 because PONV and CINV, as I explained earlier, are different
`7 entities . Okay?
`
`8
`
`Now , historically , we had studies with ondansetron ,
`
`9 dolasetron and granisetron in both PONV and CINV, PONV and
`10 CINV . And, in general , it usually was about 2-
`11 higher dose for CINV than it was for PONV. But you really
`
`to 10- fold
`
`12 have to do the trials in CINV to get the absolute dose because
`13 it ' s a fairly broad range .
`14
`
`But the more potent the drug was , the less conversion
`
`15
`
`that you actually needed because , again, the more potent that
`
`16 drug is , it can -- it binds to those receptors really, really,
`
`17 really strongly , right? Usually more potent has very high
`
`18 affinity so they bind to the receptors very strongly . And so
`
`19
`the lower the dose that ' s usually required with the more
`20 potent drug , it wasn't as big of a conversion .
`21
`
`THE COURT: Between --
`
`22
`
`23
`24
`25
`
`THE WITNESS : Between --
`
`THE COURT:
`
`-- CINV and PONV?
`
`THE WITNESS : Correct .
`
`THE COURT : Or vice versa?
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`110
`r---------------------------Frame - Direct --------------------------~
`
`1
`
`2
`
`3
`4
`
`THE WITNESS : Right .
`
`So , in general , again, what we
`
`saw in those trials was typically about a 2-
`
`to 1 0- fold change
`
`i n dose from PONV to CI NV . But you have to do the CINV trial s
`
`to see that exactly .
`
`5 BY MR.
`6 Q .
`
`IMBACUAN :
`
`So , Dr . Frame
`
`7
`
`8
`
`THE COURT : Starting with animal trial s.
`
`THE WITNESS : Exactly . You have to go back and look
`
`9 where that efficacious dose was so that you can really ,
`
`10 really, you know , plan your study appropriately to make sure
`
`11 you find where that curve is.
`12
`THE COURT : And you woul dn ' t give a -- you wouldn ' t
`13 glve a patient undergoing surgery the dosage that is
`14
`
`recommended for CINV?
`
`15
`
`THE WITNESS : No .
`
`16 BY MR.
`
`IMBACUAN :
`
`17 Q .
`
`18 A.
`
`Dr . Frame , let ' s just summarize the teachings in Chelly .
`
`Yes . So , again , this was a Phase II trial, so looking at
`
`19 an increase in doses of oral palonosetron to, again ,
`
`look at
`
`20 safety and efficacy, and then point out the safety was also
`
`21 good in this trial . They didn ' t find any unwarranted adverse
`
`22 events . And this trial showed that the mini mum dose of 1
`
`23 microgram per kil ogram o f palonosetron was where you started
`24
`25 Q .
`
`Is the methodology report ed in the Chelly abstract
`
`to reach that plateau .
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`121
`r---------------------------Frame - D i rect --------------------------~
`
`1
`
`THE COURT : Okay .
`
`2 BY MR .
`
`IMBACUAN :
`
`2- milligram dose ; is that correct?
`
`3 Q . Dr. Frame , the dose that Dr . Tang found effective was the
`4
`5 A.
`So, again , so Tang -- so Tang ' s conclusion in the paper
`6 was that the 2 milligram was the effective dose because,
`7 again , statistically that was the effective dose ; but , again ,
`
`8
`
`the arms are so small , you need to have that higher number of
`
`9 patients to be able to truly evaluate that statistically .
`10 Q .
`
`So , Dr . Frame , in light of the plateau effect that ' s
`
`shown in the data , what dosage would a clini cian study in a
`
`11
`12
`larger Phase II trial?
`13 A .
`14
`
`So, again , what I would really concentrate on here are
`
`the doses right on this curve .
`
`So , 0 . 3 micrograms per kilogram, 1 microgram per
`
`15
`16 kilogram, which is exactly what we saw in Chelly, and 3
`17 microgram per kilogram .
`
`18 Q.
`
`19 A .
`20 Q .
`
`Now , Tang was a PONV study; is that right?
`
`That ' s correct .
`
`And how does that relate to potenti ally effective doses
`
`for CINV?
`
`2 1
`2 2 A . Right .
`23
`So once again , when you look historically, it ' s
`24 CINV dose is usually 2 to 10 times the PONV dose .
`2 5 use the 1 microgram per kilogram, 0 . 07 , that woul d be 0 . 14 to
`
`the
`
`So , if you
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`122
`r---------------------------Frame - D i rect --------------------------~
`
`For a CINV dose?
`
`Two to 10 .
`
`1 0.7 milligrams .
`2 Q.
`3 A.
`For a CINV dose .
`4 Q. And that's based on using what --
`5 A.
`6 Q.
`7 PONV dose .
`8 A .
`
`So , the CINV dose would be 2 to 10 times higher than the
`
`So, again , you know , you have to -- you have to take this
`
`You ' r e still goi ng to get efficacy .
`
`It ' s just you need
`
`THE COURT : So , you would take your demonstrated,
`
`THE
`
`WI TNESS : Correct .
`
`THE
`
`COURT : And then you pass that up 2 to 10
`
`times
`
`larger
`
`THE
`
`WITNESS : Correct .
`
`THE
`
`COURT :
`
`-- if you ' re studying i ts effect
`
`in
`
`9 dose range into your CINV study so that you can find, again ,
`10 exactly where that curve is , right?
`11
`12
`to know exactly what that dose is going to be . And, so , yes ,
`13 you would use that range in your CINV dose to again find
`14 exactly where the curve sits in that range .
`15
`16 preliminarily demonstrated efficacy point for the PONV I . V .
`17 version .
`18
`19
`20
`21
`22
`23 CINV --
`24
`25
`
`THE
`
`THE
`
`WITNESS : Correct .
`- -
`
`COURT :
`
`type patients .
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`123
`r---------------------------Frame - D i rect --------------------------~
`
`1
`
`2
`
`3
`4 BY MR .
`
`THE WITNESS : Correct .
`
`THE COURT : Right?
`
`THE WI TNESS : Correct .
`
`IMBACUAN :
`
`So , Dr . Frame, how does t he Eglen data in animals compare
`
`to what was found in the Tang study?
`
`So , actually , what I showed you through all three of
`
`8
`
`these studies was that the range of these numbers are very ,
`
`5 Q.
`6
`7 A .
`
`. 4 milligrams .
`
`I ' m sorry .
`
`0 . 04 to . 4 milligrams . Chelly was
`
`. 07 milligrams . Tang is point -- i s right around
`
`. 07 milligrams .
`
`And the Eglen study, that was a study in the use of
`
`9 very similar . Eglen was , in the dog study was 0 . 4 to
`10
`11
`12
`13 Q .
`14 palonosetron to treat CINV?
`15 A .
`16 Q .
`
`Correct .
`
`And in light of the Tang data that was published , would
`
`17 you have ignored the animal data that was published in Eglen?
`
`18 A. No , absolutely not , because , again , you ' re dealing -- in
`
`19
`these clinical studies, you ' re deal ing with PONV . Eglen gave
`20 you the best idea of where that curve would be based on CINV,
`21 and as they should , they actually do correlate very well .
`22 Q . Okay .
`
`So , we ' ve talked about a lot of references and
`
`23 dosage ranges t hat were disclosed, and you have prepared a
`24
`
`summary --
`
`25 A .
`
`I did .
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`124
`r---------------------------Frame - D i rect --------------------------~
`
`1 Q.
`
`2 A .
`
`that we discussed today .
`
`So -- so this is a -- basically a summary of the three
`
`3
`trials that we talked about . And, so ,
`I put what the
`4 effective dose ranges were in these three tri als .
`
`5
`And , so , again , Eglen was the preclinical in ferrets
`6 and dogs . And , so , the range you saw in both of those animals
`7 were between 0 . 04 and 4 mil ligrams .
`
`8
`
`These two are -- I ' m sorry, Chelly and Tang are the
`
`9 post- op nausea and vomiting . Chelly was oral , and they found
`10 1 microgram per kil ogram, or 0 . 07 milligrams .
`11
`
`Tang was the preliminary I.V. Phase II t r ial , and you
`
`saw 0 . 02 to 0 . 2 milligrams . And, so , what I did -- the
`
`12
`13 question you had asked was approximately what would these
`14 doses be for CINV?
`
`And , so , as I said , they'd be approxi mately between 0
`
`15
`16 point -- I said 0 . 14 , approximately 0 . 14 to potentially up to
`17 4 milligrams . But as we saw very clearly i n these trials , it
`
`18 reall y looks li ke it woul d have been on the l ower end of
`
`19
`those .
`20 Q .
`
`So , Dr . Frame , just so the record i s clear, can we
`
`21
`
`just -- can you just tell us what the CINV dosage is that
`
`22 would have been suggested by Eglen?
`
`23 A .
`Yes . So , it was 0 . 04 potent i a l ly up to 4 mi lligrams .
`24 The curves were very clear that i t was closer to the 0 . 04 .
`25 Q .
`
`And from the Chelly abstract , what doses of -- what d oses
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`125
`r---------------------------Frame - D i rect --------------------------~
`
`o f palonosetron for CINV would have been suggested?
`
`1
`
`2
`
`THE COURT :
`
`In t he I . V. f orm?
`
`IMBACUAN :
`
`3 BY MR.
`4 Q .
`
`In t he I . V. fo rm .
`
`5 A .
`
`I n the I . V . form , yes .
`
`6
`7
`
`So,
`
`I ha d t o do a not her conver s i on i f the r e wasn ' t full
`
`a b sor p t ion . And , so ,
`
`t hese a r e est i mat es ,
`
`r i ght ? And, so , it
`
`8 was 0 . 28 to 0 . 7 milligr ams .
`
`So, here I have 0 . 17 t o 2 . 1 millig r a ms .
`
`9 Q .
`And based on the Tang data, what would have been t he
`10 dosage range fo r CINV in I . V. ?
`11 A.
`12
`13
`14
`
`THE COURT : Down t here at t he bottom, on e o f your
`
`footnotes is that to do an estimate of what the CINV dose
`
`should b e , you went 8 to 10 t imes the PONV dose , not 2 to 8 .
`
`15
`THE WITNESS : Yes , so I actually debated a bout this .
`16 And , so , in the way this went through , especial l y in the
`17 depos i t i ons , it was -- t here was a
`
`l ot mor e discu ssion abou t 8
`
`18
`
`19
`20
`
`21
`
`to 10 . However , we d id h ave data at this poi nt in time t h at
`
`i t was r eally mo r e 2 to 1 0 . So
`
`THE COURT : Two to 10 .
`
`THE WITNESS : Yes .
`
`I d i d 8 to 10 because i t was
`
`22 b ased off of true package
`
`i nser t data . But , again , we had
`
`23 data -- becau se just to g i ve you an exampl e , granisetron was
`24 not approved fo r PONV at t he
`25
`
`showed approximately 1 -- approximately 0 . 7 to 1 milligram of
`
`t ime , okay? But we had data t hat
`
`Un i ted States Di stri ct Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`126
`r---------------------------Frame - Direct --------------------------~
`
`1 granisetron was effective for both PONV and CINV . And, again,
`
`2
`
`it ' s a much more potent agent , and that ' s why these numbers
`
`3 are closer and closer together, but what I did is I
`
`4
`
`THE COURT : You mean palonosetron is more potent?
`
`5
`THE WITNESS: So, palonosetron is more potent than
`6 granisetron . Granisetron is more potent than ondansetron or
`7 dolasetron.
`
`8
`
`THE COURT : Okay .
`
`9
`THE WITNESS : So, each one of those agents have less
`10 and less doses , right? So just to give you an example , so --
`
`11 and where this became confusing is ondansetron was approved
`12 for CINV at 32 milligrams , but we had studies done at that
`13
`14
`
`time that showed 8 milligrams was really where you hit that
`
`inflection point , okay?
`
`15
`
`So it was approved at 32 . Really we were using 8 ,
`
`16 okay? It was approved for PONV at 4 milligrams. So, that ' s
`
`17 why I say it was approximately 2-
`
`to 10 - fold because the
`
`18 dolasetron was clearly 10-fold, okay?
`
`19
`So I used the package insert doses so that there
`20 wouldn ' t really be question about that, and that ' s why it ' s 8
`21
`
`to 10 rather than 2 to 10 . So, the lower number here would be
`
`22
`
`lower, right , if I did 2 to 10 .
`
`23
`24 BY MR .
`25 Q .
`
`THE COURT: Sure .
`
`IMBACUAN :
`
`So, Dr . Frame, based on t he dosages that were taught in
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`127
`r---------------------------Frame - D i rect --------------------------~
`
`1
`
`the prior art , what dosage range would a clinician study in a
`
`2 dose- ranging Phase II trial to determine the effective dose of
`
`3 palonosetron for CINV?
`4 A .
`
`Yes . So , so , again , you don ' t want a lot of those doses ,
`
`5
`right? And, so ,
`I would really concentrate on the lower end
`6 of this . And, so ,
`7 about 2 milligrams .
`
`I would have probably approximately 0 . 1 to
`
`8 Q .
`
`And that , that would be an I . V. dose?
`
`9 A.
`10 Q .
`11 A .
`
`That would be an I . V. dose , yes .
`
`And how would a clinician go about doing that study?
`
`So, exactly the same that we saw that these tri als were
`12 done , that you would put this into a Phase II dose- ranging
`13 study, preferably a large enough study that you could truly do
`14 analysis on it .
`
`15
`
`You would narrow it down to hopefully the one or two
`
`16 doses that are on that curve , and then lead that into a larger
`
`17 Phase III trial with a comparator .
`
`18 Q. And
`
`19
`20
`
`THE COURT : Your bottom end would be . 1.
`
`THE WITNESS :
`
`So ,
`
`I would -- yeah , my bottom end
`
`21 would be approximately . 1 , because , again ,
`
`I want to have low
`
`22 enough to see the curve .
`
`I mean , it could be a litt l e bit l ower because , as I
`
`23
`24 said ,
`25 would be probably a little bit lower than that .
`
`I actually overestimated thi s . So , yes , it actually
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1028
`
`
`
`128
`r---------------------------Frame - D i rect --------------------------~
`
`1
`
`2
`
`3
`4
`
`Yes . You ' re right .
`
`It would probably be a little
`
`lower than that because I do want to see that curve so --
`
`you ' re right .
`
`I overestimated this number a littl e bit , so
`
`i t --
`
`5
`THE COURT : Well , but the curve that you want to see
`6 begins before some real good efficacy kicks in .
`
`7
`
`8
`
`9
`10
`11
`
`THE WI TNESS : That ' s correct .
`
`THE COURT : So --
`
`THE WITNESS :
`
`So that ' s why I would want a little bit
`
`lower number . Yes .
`
`I apologize , yeah .
`
`THE COURT : But that lower number wouldn ' t
`
`12 necessarily be your minimal effective dose . You would expect
`13 it not to be .
`14
`
`I would expect it not to be , yes .
`
`THE WITNESS :
`
`15
`
`And this is honestly what ' s hard about doing clinical
`
`16 trials because you know some people are going to get sick,
`
`17
`
`18
`
`r i ght?
`
`I mean , it ' s a hard thing to do , but , un f ortunately,
`
`that ' s how you have to define , you know, your minimum
`
`19 effective dose .
`20
`
`THE COURT :
`
`2 1 hoping to help .
`
`I ' m sure they signed up for the trial
`
`2 2
`23 BY MR .
`
`THE WITNESS : That ' s correct .
`
`IMBACUAN :
`
`24 Q .
`
`The dose- ranging , Phase II dose- ranging study that you
`
`2 5 would do using the dosage ranges suggested by the prior art ,
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1028