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`UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`__________________________________
`HELSINN HEALTHCARE, S.A. and
`ROCHE PALO ALTO, LLC,
`Plaintiffs,
`-vs-
`DR. REDDY'S LABORATORIES, LTD.,
`DR. REDDY'S LABORATORIES, INC.,
`TEVA PHARMACEUTICALS USA, INC.,
`and TEVA PHARMACEUTICAL
`INDUSTRIES, LTD.
`Defendants.
`__________________________________
`Clarkson S. Fisher United States Courthouse
`402 East State Street
`Trenton, New Jersey 08608
`June 15, 2015
`B E F O R E:
`
`CIVIL ACTION NUMBER:
`11-3962
`
`TRIAL
`WITH SEALED PORTIONS
`
`THE HONORABLE MARY L. COOPER
`UNITED STATES DISTRICT JUDGE
`
`Certified as True and Correct as required by Title 28, U.S.C.,
`Section 753
`/S/ Regina A. Berenato-Tell, CCR, CRR, RMR, RPR
`/S/ Carol Farrell, CCR, CRR, RMR, CCP, RPR, RSA
`
`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`United States District Court
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Trenton, New Jersey
`Reddy Exhibit 1022
`
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`

`
`1
`
`UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`__________________________________
`HELSINN HEALTHCARE, S.A. and
`ROCHE PALO ALTO, LLC,
`Plaintiffs,
`-vs-
`DR. REDDY'S LABORATORIES, LTD.,
`DR. REDDY'S LABORATORIES, INC.,
`TEVA PHARMACEUTICALS USA, INC.,
`and TEVA PHARMACEUTICAL
`INDUSTRIES, LTD.
`Defendants.
`__________________________________
`Clarkson S. Fisher United States Courthouse
`402 East State Street
`Trenton, New Jersey 08608
`June 15, 2015
`B E F O R E:
`
`CIVIL ACTION NUMBER:
`11-3962
`
`TRIAL
`WITH SEALED PORTIONS
`
`THE HONORABLE MARY L. COOPER
`UNITED STATES DISTRICT JUDGE
`
`Certified as True and Correct as required by Title 28, U.S.C.,
`Section 753
`/S/ Regina A. Berenato-Tell, CCR, CRR, RMR, RPR
`/S/ Carol Farrell, CCR, CRR, RMR, CCP, RPR, RSA
`
`United States District Court
`Trenton, New Jersey
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`Exh. 1022
`
`

`
`2
`
`A P P E A R A N C E S:
`PAUL HASTINGS
`JOSEPH O'MALLEY, ESQUIRE
`BY:
`ERIC W. DITTMANN, ESQUIRE
`ISAAC S. ASHKENAZI, ESQUIRE
`SAUL EWING
`CHARLES M. LIZZA, ESQUIRE
`BY:
`Attorneys for the Plaintiffs
`
`BUDD LARNER
`BY: STUART D. SENDER, ESQUIRE
`MICHAEL H. IMBACUAN, ESQUIRE
`HUA HOWARD WANG, ESQUIRE
`CONSTANCE S. HUTTNER, ESQUIRE
`KENNETH E. CROWELL, ESQUIRE
`Attorneys for the Defendant, Dr. Reddy's Laboratories
`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
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`United States District Court
`Trenton, New Jersey
`
`Exh. 1022
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`

`
`3
`
`I N D E X
`
`CROSSREDIRECT
`VOIR DIRECT
`WITNESS
`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
`GORDON AMIDON
`By Mr. Dittmann 126
`
`143
`
`RECROSS
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`United States District Court
`Trenton, New Jersey
`
`Exh. 1022
`
`

`
`Amidon - Direct
`
`156
`
`THE COURT: -- item, which would be --
`THE WITNESS: Product specification, yeah.
`THE COURT: And, so, although you use different
`words, your slides, in terms of process definition, are not
`that different, are they? How are they different?
`THE WITNESS: No. I mean, I think the difference is
`that the product profile in Dr. Kirsch's definition is
`something that might -- like, you get a report and the
`formulator is charged, okay, this is what we want to do; you
`go make it. My position is the formulator is involved in the
`product profile.
`THE COURT: Okay. I thought I understood that to be
`your point.
`BY MR. DITTMANN:
`Q. And just if we can focus just on PDX 709 for one moment.
`Just to make sure the record is clear, it's your experience
`that the formulator team member of this development team would
`be involved with all four steps seen on PDX 709, correct?
`A. Yes.
`Q. Now, we have talked about the first two steps a bit
`already in connection with your background.
`With respect to this third step we see here,
`considering the dose, volume, clinical parameters, can you
`briefly describe how this work is typically accomplished in a
`drug development team?
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`United States District Court
`Trenton, New Jersey
`
`Exh. 1022
`
`

`
`157
`
`Amidon - Direct
`A. Yes. I mean, I think that this comes from the clinical
`parameters, the dose, the efficacy of the drug -- of the drug
`and, so, you have to provide a dose that would be effective,
`and you have in this case for a parenteral product, use a
`volume that could be administered. So, those parameters come
`from the clinical considerations for the product.
`Q. Once the dose -- we'll start with that, once the dose or
`doses to be pursued are selected, are the formulation team
`members able to consider the use of doses outside the range
`selected?
`A. No. No. You focus on what you need.
`Q. Moving next to volume, once the volume has been selected
`by the development team, do the formulation team members have
`any flexibility with respect to the volumes that they suggest
`for development as a product?
`A. A very small branch of volumes. I mean, it depends on
`the product, but in a case of an injectable product you would
`have a range of 1 or 2 mL maybe 5 mL, but you have a very
`small range of volume, so I would say there's a small amount
`of adjustability for the volume of your product, but no
`adjustment regarding dose.
`THE COURT: In this particular project, if you were
`changing it to a different dose you would be having to start
`off a different project, right? Is that what you're saying?
`THE WITNESS: Yeah, well, the particular API, the
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`United States District Court
`Trenton, New Jersey
`
`Exh. 1022
`
`

`
`Amidon - Direct
`
`158
`
`particular drug that you're working on would have a projected
`dose, and, so, you would be working with your formulation and
`preformulation parameters in that dose range. And, yeah, the
`science -- as a scientist I would say I'm interested in what
`happens in other ranges, but a development scientist would
`focus on the ranges that he needed to make into a product.
`Q. And, so, you would be focusing on the ranges that came
`from the clinical considerations, correct?
`A. Yes, yes, yes, correct.
`Q. Now, I want to turn to the fourth step in the process
`considering stability and manufacturability issues. Can you
`first describe why stability is important for a pharmaceutical
`product?
`A. Well, in my experience I mean, of course, you have to
`make a commercial product. You have to manufacture it, store
`it, transport it, get it to the site, administer it to the
`patient. I would say the pharmaceutical companies that I have
`worked with have always used a two-year shelf life as a
`minimum standard. You needed a two-year shelf life in order
`to be able to commercialize a pharmaceutical product and that
`was the standard. I mean, of course, if it is longer that's
`great. I would say the time frame of the companies I worked
`with you want a shelf life between 2 and 5 years.
`THE COURT: Some of these things can't be maintained
`at room temperature, they have to be refrigerated for mass
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`United States District Court
`Trenton, New Jersey
`
`Exh. 1022
`
`

`
`Amidon - Direct
`
`159
`
`distribution, right?
`THE WITNESS: That's correct. And that makes it more
`difficult because you have to have cold storage and a cold
`chain, and, so, that's a less desirable -- I mean, if there's
`no other way to stabilize a product, other than refrigeration
`or maybe freeze drying and shipping a product that would be
`reconstituted at the site, which is what we do with
`antibiotics, for example, yeah, but cold storage would be
`would be one method of handling a stability issue, but not the
`preferred method.
`BY MR. DITTMANN:
`Q. Now, do all pharmaceutical molecules have stability
`issues?
`A. No.
`Q. It varies from molecule to molecule?
`A. No. It varies from molecule to molecule. It is very
`much -- very drug chemical dependent.
`Q. Can we bring up DTX-0271. And do you recognize this,
`Doctor, as a Pharmaceutical Preformulation and Formulation
`Practical Guide?
`A. Yes. We have a number of texts from the eighties and
`nineties until today on Pharmaceutical Preformulation and
`Formulation Guidelines that a normal POSA would -- would be
`well versed in, yes.
`Q. And can we please turn to the second page. And what do
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`United States District Court
`Trenton, New Jersey
`
`Exh. 1022
`
`

`
`Amidon - Direct
`
`160
`
`we see here, Doctor?
`A. Well, this is a particular article, a particular chapter
`in that book on parenteral dosage forms by a scientist from
`AstraZenica.
`Q. And is this the Broadhead 2001 reference that Dr. Kirsch
`discussed during his testimony in this case?
`A. Yes.
`Q. Would you please turn to Page 5.
`I want to focus at the bottom under the "Choice of
`Excipients" heading. And I'll read into the record the first
`sentence. "As with all pharmaceutical products, the most
`important rule to bear in mind when formulating parenterals is
`the 'keep it simple' principle."
`Do you see that, Doctor?
`A. Yes.
`Q. Can you explain what this principle means?
`A. Well, this is kind of the golden rule the formulation --
`for all pharmaceuticals, especially true for parenteral
`products is you only include in the formulation what you need
`and what you can justify based on some need. So, you do not
`add anything you don't need to the product. So, this is kind
`of a golden rule for formulators.
`Q. Can you explain how this "keep it simple" rule for I.V.
`formulations would apply in the situation you mentioned
`earlier where there did not appear to be a stability issue?
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`United States District Court
`Trenton, New Jersey
`
`Exh. 1022
`
`

`
`161
`
`Amidon - Direct
`A. Well, as I think we will discuss during my testimony, but
`if there's no stability issue, you don't need anything.
`Q. Now, how would a POSA go about trying to determine
`whether a given molecule has a stability issue?
`A. Well, I mean, in one case you do high stress studies to
`try and identify potential degradation products, and you do
`expiration dating protocols. Again, there's general guidance.
`I think there's one in my book on how to do expiration dating
`studies, experimental design and interpretation.
`There would be, you know, general guidance as to how to
`provide with expiration dating determination.
`Q. Can we please bring up PDX 710.
`THE COURT: Now you have put this thing into some
`kind of solution, if it is to be a parenteral, right?
`THE WITNESS: Yes. For a parenteral product, yes, it
`is put in the liquid form.
`So, here, of course, the preformulation research
`there's the systematic search. I mean, this is what's
`described in the textbooks in the chapter of the types of
`variables that you look at, particularly pH, temperature,
`concentration of the drug, what we're calling API, which
`that's a specific designation of something that can be, you
`know, FDA-approved, but the drug concentration, particular
`variables, and you systematically would explore those
`variables. And you generate the data, characterizing a
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`Trenton, New Jersey
`
`Exh. 1022
`
`

`
`Amidon - Direct
`
`162
`
`specific product and characteristics of that product and the
`properties of the drug molecule, and you develop what's called
`a preformulation and formulation report that would become part
`of your data package for the drug product.
`BY MR. DITTMANN:
`Q. Can we please bring up PTX-325. Do you recognize this,
`Doctor, as a textbook titled "Pharmaceutical Dosage Forms:
`Parenteral Medications Volume 1"?
`A. Yes.
`Q. If we can please turn to Page 3. Do you see towards the
`middle there's a date, 1992; is that correct?
`A. Yes.
`Q. If you can please turn to the next page, Page 4. And do
`we see, Doctor, this is a chapter of this book authored by a
`Sol Motola and Shreeram Agharkar?
`A. Yes.
`Q. We can turn to the second sentence under the
`introduction, and I'll, again, read this into the record.
`"Experiments are designed to generate data characterizing
`specific pharmaceutically important, physicochemical
`properties of the drug substances and its combination with
`selected solvents, excipients, and packaging components.
`These studies are carried out under stressed conditions of
`temperature, light, humidity, and oxygen in order to
`accelerate and detect potential reactions."
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`Exh. 1022
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`

`
`Amidon - Direct
`
`163
`
`Do you see that?
`A. Yes.
`Q. Can you please explain what the Motola book chapter is
`referring to here?
`A. Okay. In the process of developing a product you have to
`ensure ultimately its potency and purity. I mean, that's
`required in order to have marketing authorization to
`distribute a product, so you have to be able to ensure its
`potency and purity, and you have to be able to show that you
`can detect various degradation products in your product.
`And, I mean, if you see a high level of degradation
`product you have to test that for toxicity, too. So you have
`to show that your degradation products are below a certain
`level. So you have to develop the analytical techniques for
`those degradation products, and, so, you need enough of the
`material to be able to develop your analytical detection
`techniques.
`So, you generally use stress conditions, and you'll
`detect more degradation products than you'll see under typical
`pharmaceutical storage conditions, but you have to be able to
`detect them -- identify them and detect them.
`THE COURT: And this is in the preformulation stage?
`THE WITNESS: That you would do these experiments,
`
`yes, yes.
`BY MR. DITTMANN:
`
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`Exh. 1022
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`

`
`164
`
`Amidon - Direct
`Q. And is what we're seeing here in the Motola book chapter
`the sort of preformulation experiments that you were
`describing earlier?
`A. Yes.
`Q. Can we please turn back to PDX 702. I want to shift now,
`Doctor, into your opinions that you have provided in this
`case.
`
`THE COURT: I think maybe this would be a moment for
`us to take a little recess. Off the record.
`(Discussion held off the record)
`(Brief Recess.)
`
`BY MR. DITTMANN:
`Q. Welcome back, Doctor.
`Could we please have up on the screen again PDX-702.
`And so I'd like to now turn, Doctor, to your opinions in this
`case and we'll start with the first one we see here: "A POSA
`would have had no motivation to add a chelating agent like
`EDTA."
`
`Do you have a slide summarizing your opinions on this
`first topic?
`A. Yes, I do.
`Q. Please bring up PDX-711.
`And can you please explain what we see on this slide?
`A. Okay. So here's the basis for my conclusions. There is
`no -- my conclusion is there's no motivation to add a
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`
`Exh. 1022
`
`

`
`Amidon - Direct
`
`165
`
`stabilizing agent, including EDTA. For instance, there was no
`indication of stability issues from the prior art. The only
`potentially commercially viable palonosetron formulation was
`disclosed in Example 13 of the '333 patent, which is silent on
`stability.
`And so, absent any stability issue, a POSA would not
`have been motivated to add a stabilizing agent, and much less
`a chelating agent like EDTA. So that's the summary of my
`opinion.
`Q. How did you confirm that the prior art did not disclose
`any stability problem with respect to palonosetron?
`A. Well, I reviewed the -- the information and background
`provided by the defendants in this case, I think I got that
`right, the defendants in this case, the information that they
`used, and also my own literature search and knowledge in the
`chemical stability area, and I could not -- I did not find
`any -- any information regarding the stability or
`stability-related issues for palonosetron.
`So, there's nothing in the literature prior to the 2002
`to 2003 time frame regarding the instability of palonosetron
`that -- there's no prior art in my conclusion.
`Q. And, as part of generating that conclusion, did you
`perform your own search, Doctor, of the prior art?
`A. Yes, yes, yes. I performed --
`Q. Were there -- I'm sorry -- go ahead.
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`Trenton, New Jersey
`
`Exh. 1022

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