`
`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
`
`WITH SEALED PORTIONS
`
`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 15 , 2015
`14 BE F 0 R E :
`15
`16
`1 7
`18
`19
`20
`2 1
`2 2
`23 Certified as True and Correct as required by Titl e 28 , U. S . C. ,
`Section 753
`24
`2 5
`
`THE HONORABLE MARY L . COOPER
`UNI TED STATES DISTRICT JUDGE
`
`/S/ Regina A. Berenato- Tell, CCR, CRR, RMR, RPR
`/S/ Carol Farrell, CCR, CRR, RMR, C~'"'
`'"'o~~Reddy~"Laboratories. Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1043
`United States Dis r~cc ~ourc
`Trenton , New Jersey
`
`
`
`1
`
`2
`
`3
`
`UNITED STATES DI STRICT COURT
`FOR THE DISTRI CT OF NEW JERSEY
`
`1
`
`4 HELSINN HEALTHCARE , S . A. and
`ROCHE PALO ALTO , LLC ,
`
`5
`
`6
`
`Plai ntiffs ,
`
`- vs-
`
`CIVIL ACTION NUMBER :
`
`11- 3962
`
`TRIAL
`
`WITH SEALED PORTIONS
`
`7
`DR . REDDY ' S LABORATORIES , LTD .,
`8 DR . RE DDY' S LABORATORIES , INC .,
`TEVA PHARMACEUTI CALS USA, I NC .,
`9 and TEVA PHARMACEUTICAL
`INDUSTRIES , LTD .
`10
`
`Defendants .
`
`11
`Clarkson S . Fi s her United States Cour t house
`12
`402 East State Street
`Trenton, New Jer sey 08608
`13
`June 15 , 2015
`14 BE F 0 R E:
`
`THE HONORABLE MARY L. COOPER
`UNI TED STATES DISTRI CT J UDGE
`
`15
`
`16
`17
`18
`
`19
`20
`21
`22
`23 Certified as True and Correct as required by Titl e 28 , U. S . C.,
`Secti on 753
`24
`25
`
`/S/ Regi na A. Berenat o - Te l l , CCR, CRR, RMR, RPR
`/S/ Carol Farre ll, CCR, CRR, RMR, CCP, RPR, RSA
`
`United States Di stri ct Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`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 the Plaintiffs
`6
`7 BUDD LARNER
`BY :
`STUART D. SENDER, ESQUIRE
`MICHAEL H.
`IMBACUAN, ESQUIRE
`HUA HOWARD WANG , ESQUIRE
`9
`CONSTANCE S . HUTTNER, ESQUIRE
`KENNETH E . CROWELL , ESQUIRE
`10 Attorneys for 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 District Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`3
`
`I N D E X
`
`1
`
`2
`
`3
`
`4
`
`VOIR DIRECT CROSSREDIRECT RECROSS
`DIRE
`(Video deposition of Maurie Markman) , 7
`(Video deposition of Valentino Stella) , 28
`(Video deposition of Navin Vaya) , 81
`(Video deposition of Limor Zahavi) , 96
`
`AMIDON
`Dittmann 126
`
`143
`
`5 WITNESS
`6
`7
`8
`GORDON
`9 By Mr.
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`156
`.---------------Amidon - Di r ect ----------------,
`
`1
`
`2
`
`THE COURT : -- item, which would be --
`
`THE WITNESS : Prod uct s p eci fication , yeah .
`
`3
`THE COURT : And, so , although you use di fferent
`4 words , your s lides ,
`
`i n terms of process defi niti on , are not
`
`5
`
`6
`7
`
`8
`
`that different , are they? How are they different ?
`
`THE WITNESS : No .
`
`I mean ,
`
`I
`
`t h i nk the d i fferen c e is
`
`that the p rodu ct profile i n Dr. Ki rsch ' s de fi ni tion is
`
`something t hat mi ght -- l i ke , you g et a r e p ort a n d t he
`
`9
`formu lator is charged, okay, this is what we wan t to do ; you
`10 go make i t . My posit ion i s the formula t or i s invol ved in the
`
`11 p rodu c t profile .
`12
`13 your point .
`14 BY MR . DITTMANN :
`
`THE COURT : Okay .
`
`I
`
`t hought
`
`I understood that t o be
`
`15 Q .
`And j u st i f we can focus j ust on POX 709 f o r one moment .
`16 Just to make s u re the record is c l ear , it ' s your experience
`17 that t he formulator t eam member o f this deve l opment team wou ld
`
`18 b e
`
`i nvol ved wi t h all four step s seen on POX 709 , correct?
`
`19 A. Yes .
`20 Q .
`
`Now , we have tal ked about t he first two step s a b i t
`
`21
`
`22
`
`a l ready in connection wi t h your background .
`
`With respect to t h is t hird s t ep we s e e he r e ,
`
`23 considering t he dose , volume , clini cal parameter s , can you
`24 bri efl y descri be how thi s work is typically accomplished in a
`25 drug development team?
`
`Un i ted States Di stri ct Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`157
`.---------------Amidon - Direct ----------------,
`
`1 A. Yes.
`2 parameters , the dose , the efficacy of the drug
`
`I mean, I think that this comes from the clinical
`
`of the drug
`
`3
`4
`
`and, so , you have to provide a dose that woul d be e ffective ,
`
`and you have in this case for a parenteral product , use a
`
`5 volume that could be administered .
`6
`
`from the clinical considerations for the product .
`
`So , those parameters come
`
`7 Q . Once the dose --we ' l l start with that , once t he dose or
`
`8 doses to be p urs ued are selected, are the formulation team
`
`9 members able to consider the use of doses outside the range
`10 selected?
`11 A.
`No . No . You focus on what you need .
`12 Q. Moving next to vol ume , once the vol ume has been selected
`13 by the development team, do the formulation team members have
`14 any f lexibility with respect t o the volumes that they suggest
`
`15 for development as a product?
`
`16 A .
`
`A very small branch of volumes .
`
`I mean , it depends on
`
`1 7
`
`the product , but in a case of an i n j ectable product you would
`
`18 have a range of 1 or 2 mL maybe 5 mL, but you have a very
`
`19 small range of vol ume , so I would say there ' s a smal l amount
`20 of adjustability for the volume of your product , but no
`2 1 adjustment regarding dose .
`
`2 2
`
`THE COURT :
`
`In thi s particular project,
`
`i f you were
`
`23 changing it to a different dose you would be havi ng to start
`24 off a different project ,
`2 5
`
`r i ght?
`
`Is that what you ' re saying?
`
`THE WITNESS : Yeah , well , the particular API , the
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`158
`.---------------Amidon - Direct ----------------,
`
`1 particular drug that you ' re working on would have a projected
`
`2 dose , and, so , you would be working with your formulation and
`
`3 preformulation parameters in that dose range. And, yeah, the
`4
`
`as a scientist I would say I ' m interested in what
`
`science
`
`5 happens in other ranges , but a development scientist would
`6
`
`focus on the ranges that he needed to make into a product .
`
`7 Q . And, so, you would be focusing on the ranges that came
`
`8
`
`from the clinical considerations , correct?
`
`9 A. Yes , yes, yes , correct .
`10 Q .
`
`Now ,
`
`I want to turn to the fourth step in the process
`
`11 considering stability and manufacturability i ssues . Can you
`12 first describe why stability is important for a pharmaceutical
`13 product?
`
`14 A . Well , in my experience I mean , of course , you have to
`
`15 make a commercial product . You have to manufacture it , store
`
`16 it , transport it , get it to the site, administer it to the
`
`17 patient .
`
`I would say the pharmaceutical companies that I have
`
`18 worked with have always used a two-year shelf life as a
`
`19 minimum standard . You needed a two-year shelf life in order
`20
`
`to be able to commercialize a pharmaceutical product and that
`
`21 was the standard .
`
`I mean , of course , if it is longer that ' s
`
`22 great .
`
`I would say the time frame of the companies I worked
`
`23 with you want a shelf life between 2 and 5 years .
`24
`25 at room temperature, they have to be refrigerate d for mass
`
`Some of these things can ' t be maintained
`
`THE COURT :
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`159
`.---------------Amidon - Direct ----------------,
`
`1 distribution , right?
`
`2
`
`THE WITNESS : That ' s correct . And that makes it more
`
`3 difficult because you have to have cold storage and a cold
`4 chain, and, so , that ' s a less desirable
`
`I mean , if there ' s
`
`5
`no other way to stabilize a product, other than refrigeration
`6 or maybe freeze drying and shipping a product that would be
`7
`
`reconstituted at the site , which is what we do with
`
`8 antibiotics , for example , yeah , but cold storage would be
`
`9 would be one method of handling a stability issue , but not the
`10 preferred method .
`11 BY MR. DITTMANN :
`
`Now , do all pharmaceutical molecules have stability
`
`12 Q .
`13
`
`issues?
`
`14 A .
`
`No .
`
`15 Q .
`
`16 A.
`
`It varies from molecule to molecule?
`
`No.
`
`It varies from molecule to molecule. It is very
`
`17 much -- very drug chemical dependent .
`
`18 Q. Can we bring up DTX-0271 . And do you recognize this ,
`
`19 Doctor, as a Pharmaceutical Preformulation and Formulation
`20 Practical Guide?
`21 A . Yes. We have a number of texts from the eighties and
`22 nineties until today on Pharmaceutical Preformulation and
`
`23 Formulation Guidelines that a normal POSA would -- would be
`24 well versed in , yes .
`25 Q .
`
`And can we please turn to the second page. And what do
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`160
`.---------------Amidon - Direct ----------------,
`
`1 we see here , Doctor?
`
`2 A . Well , this is a particular article , a particular chapter
`
`3
`in that book on parenteral dosage forms by a scientist from
`4 AstraZenica .
`
`5 Q. And is this the Broadhead 2001 reference that Dr . Kirsch
`6 discussed during his testimony in this case?
`7 A .
`8 Q .
`
`Would you please turn to Page 5 .
`
`Yes .
`
`9
`I want to focus at the bottom under the " Choice of
`10 Excipients " heading . And I ' ll read into the record the first
`
`"As with all pharmaceut i cal products ,
`
`the most
`
`important rule to bear in mind when formulating parenterals is
`
`the ' keep it simple ' principle . "
`
`Do you see that , Doctor ?
`
`Yes .
`
`11 sentence .
`12
`13
`14
`15 A .
`16 Q .
`
`Can you explain what this principle means?
`
`17 A .
`
`Well , this is kind of the golden rule the formulation
`
`18 for all pharmaceuticals , especially true for parenteral
`
`19 products is you only include in the formulation what you need
`20 and what you can justify based on some need .
`
`So , you do not
`
`21 add anything you don ' t need to the product . So, this is kind
`
`Can you explain how this " keep it simple" rule for I. V.
`
`22 of a golden rule for formulators .
`23 Q .
`24
`25 earlier where there did not appear to be a stabil ity issue?
`
`formulations would apply in the situation you mentioned
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`161
`.--- - - - - - - - - - - - -Amidon - Direct ----------------,
`
`1 A. Well , as I think we will discuss during my testimony, but
`
`2
`
`if there ' s no stability issue , you don ' t need anything .
`
`3 Q .
`Now, how would a POSA go about trying to determine
`4 whether a given molecule has a stability issue?
`
`I mean , in one case you do h igh stress studies to
`
`5 A. Well ,
`6
`7 expiration dating protocols . Again , there ' s general guidance .
`
`try and identify potential degradation products , and you do
`
`8
`
`I think there ' s one in my book on how to do expiration dating
`
`studies , experimental design and interpretation .
`
`9
`10
`11 provide with e xpiration dating determination .
`
`There would be , you know , general guidance as to how to
`
`Can we please bring up POX 710 .
`
`12 Q .
`13
`14 kind of solution , if it is to be a parenteral,
`
`THE COURT : Now you have put this thing into some
`
`r ight?
`
`15
`
`THE WITNESS : Yes . For a parenteral product , yes , it
`
`16 is put in the 1 iquid form .
`
`17
`
`18
`
`So , here , of course , the preformulation research
`
`there ' s the systematic search .
`
`I mean , this is what ' s
`
`19 described in t he textbooks in the chapter of the types of
`20 variables that you look at , particularly pH , temperature ,
`
`21 concentration of the drug , what we ' re calling API , which
`
`22
`
`that ' s a specific designation of something that can be , you
`
`23 know , FDA-approved, but t he drug concentrat ion, particular
`24 variables , and you systematically would explore those
`25 variables . And you generate the data , characteri zing a
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`162
`.---------------Amidon - Direct ----------------,
`
`1
`
`specific product and characteristics of that product and the
`
`2 properties of the drug molecule, and you develop what ' s called
`
`3
`a preformulation and formulation report that woul d become part
`4 of your data package for the drug product .
`
`5 BY MR. DITTMANN :
`6 Q .
`7 Doctor , as a textbook titled " Pharmaceutical Dosage Forms :
`
`Can we please bring up PTX- 325 . Do you recognize this ,
`
`8 Parenteral Medications Volume 1 " ?
`
`9 A . Yes.
`10 Q .
`
`If we can please turn to Page 3 . Do you see towards the
`
`11 middle there's a date, 1992; is that correct?
`12 A . Yes .
`13 Q .
`If you can please turn to the next page, Page 4. And do
`14 we see , Doctor , this is a chapter of this book authored by a
`
`15 Sol Motola and Shreeram Agharkar?
`
`16 A. Yes.
`17 Q . We can turn to the second sentence under the
`
`18
`
`introduction, and I ' ll, again , read this into the record.
`
`"Experiments are designed to generate data characterizing
`
`19
`20 specific pharmaceutically important , physicochemical
`
`21 properties of the drug substances and its combination with
`
`22 selected solvents , excipients , and packaging components .
`
`23 These studies are carried out under stressed conditions of
`24
`25 accelerate and detect potential reactions ."
`
`temperature , light , humidity , and oxygen in order to
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`163
`.----------------Amidon - Direct ----------------,
`
`1
`
`Do you see that?
`
`2 A .
`
`Yes .
`
`Can you please explain what the Motola book chapter is
`
`referring to here?
`
`3 Q .
`4
`5 A. Okay .
`In the process of developing a product you have to
`6 ensure ultimately its potency and purity .
`7
`
`required in order to have marketing authorization to
`
`8 distribute a product , so you have to be able to ensure its
`
`I mean , that ' s
`
`9 potency and purity , and you have to be able to show that you
`10 can detect various degradation products in your product .
`11
`
`And ,
`I mean , if you see a high level of degradation
`12 product you have to test that for toxicity , too . So you have
`13
`14
`
`to show that your degradation products are below a certain
`
`level .
`
`So you have to develop the analytical techniques for
`
`15
`
`those degradation products , and, so , you need enough of the
`
`16 material to be able to develop your analytical detection
`
`17
`
`18
`
`techniques .
`
`So , you generally use stress conditions , and you ' ll
`
`19 detect more degradation products than you ' ll see under typical
`20 pharmaceutical storage conditions , but you have to be able to
`21 detect them -- identify them and detect them .
`
`22
`
`23
`
`THE COURT : And this is in the preformulation stage?
`
`THE WI TNESS : That you would do these experiments ,
`
`24 yes , yes .
`25 BY MR. DITTMANN :
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`164
`.---------------Amidon - Direct ----------------,
`
`1 Q. And is what we ' re seeing here in the Motola book chapter
`
`2
`
`the sort of preformulation experiments that you were
`
`3 describing earlier?
`4 A .
`
`Yes .
`
`5 Q.
`Can we please turn back to PDX 702 .
`I want to shift now ,
`6 Doctor, into your opinions that you have provided in this
`7 case .
`
`8
`
`THE COURT :
`
`I
`
`t hink maybe this would be a moment for
`
`9 us to take a little recess . Off the record .
`10
`11
`
`(Discussion held off the record)
`
`(Brief Recess . )
`
`12 BY MR . DITTMANN :
`13 Q. Welcome back , Doctor .
`14
`
`Could we please h ave up on the screen again PDX- 702 .
`
`15 And so I ' d like to now turn , Doctor , to your opinions in thi s
`
`16 case and we ' ll start with the first one we see here:
`
`"A POSA
`
`1 7 would have had no motivati on to add a chelat i ng agent like
`
`18 EDTA. "
`
`Yes,
`
`I do .
`
`Please bring up PDX- 711 .
`
`And can you p l ease expl ain what we see on this
`
`s lide?
`
`19
`Do you have a s lide summarizing your opinions on t his
`20 first topic?
`2 1 A.
`2 2 Q.
`23
`2 4 A.
`2 5
`no --
`
`Okay .
`
`So here ' s the basis for my conclusions .
`
`There is
`
`my conclusion is there ' s no motivation to add a
`
`United States Distri ct Court
`Trenton , New Jersev
`
`Exh. 1043
`
`
`
`165
`.---------------Amidon - Direct ----------------,
`
`1 stabilizing agent, including EDTA . For instance , there was no
`
`2
`
`indication of stability issues from the prior art . The only
`
`3 potentially commercially viable palonosetron formulation was
`4 disclosed in Example 13 of the ' 333 patent , which is silent on
`
`5 stability.
`6
`7 have been motivated to add a stabilizing agent, and much less
`
`And so , absent any stability issue , a POSA would not
`
`8
`
`a chelating agent like EDTA .
`
`So that ' s the summary of my
`
`9 opinion .
`10 Q .
`
`How did you confirm that the prior art did not disclose
`
`11 any stability problem with respect to palonosetron?
`12 A . Well ,
`13 provided by the defendants in this case ,
`14 right ,
`
`I reviewed the -- the information and background
`
`I think I got that
`
`the defendants in this case , the information that they
`
`15 used , and also my own literature search and knowl edge in the
`
`16 chemical stability area, and I could not -- I did not find
`
`17 any -- any information regarding the stability or
`
`18 stability-related issues for palonosetron .
`
`19
`20
`
`So, there ' s nothing in the l iterature prior to the 2002
`
`to 2003 time frame regarding the instability of palonosetron
`
`21
`
`that
`
`there ' s no prior art in my conclusion .
`
`22 Q . And, as part of generating that conclusion , did you
`
`23 perform your own search , Doctor, of the prior art?
`
`24 A .
`25 Q .
`
`Yes , yes , yes .
`
`I performed
`
`Were there -- I ' m sorry -- go ahead .
`
`United States District Court
`Trenton , New Jersev
`
`Exh. 1043