376
`
`NO. 14-1043 (RGA)
`CIVIL ACTION
`
`- VOLUME 2 -
`
` IN THE UNITED STATES DISTRICT COURT
` IN AND FOR THE DISTRICT OF DELAWARE
`CIVIL ACTION
`NOVARTIS PHARMACEUTICALS
`CORPORATION and NOVARTIS
`AG,
` Plaintiffs,
` vs.
`BRECKENRIDGE
`PHARMACEUTICALS INC.,
` Defendant.
`------------------------
`NOVARTIS PHARMACEUTICALS
`CORPORATION and NOVARTIS
`AG,
` Plaintiffs,
` vs.
`ROXANE LABORATORIES,
`INC.,
` Defendant.
`------------------------
`NOVARTIS PHARMACEUTICALS
`CORPORATION and NOVARTIS
`AG,
` Plaintiffs,
` vs.
`PAR PHARMACEUTICAL,
`INC.,
` Defendant.
`NO. 14-1289 (RGA)
`
`
` Wilmington, Delaware
` Tuesday, August 30, 2016
` 8:30 o'clock, a.m.
` - - -
`BEFORE: HONORABLE RICHARD G. ANDREWS, U.S.D.C.J.
`
`
`
`NO. 14-1196 (RGA)
`CIVIL ACTION
`
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`A.
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`665
`
`Roush - direct
`I did, ma'am.
`MS. JACOBSEN: Thank you, Doctor.
`No more questions.
`THE COURT: All right, Dr.
`Bissler. Thank you. You may step down. Be
`careful.
`
`THE WITNESS: Thank you.
`(Witness excused.)
`MS. SCHWARZ: Good afternoon, your
`Honor. Christina Schwarz on behalf of the
`plaintiffs.
`
`Novartis' next witness is William
`Roush, a medicinal chemist. We call him to the
`stand.
`
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`... WILLIAM RICHARD ROUSH,
` having been duly sworn as a witness, was
` examined and testified as follows ...
`MS. SCHWARZ: Your Honor, may I
`approach with a witness binder?
`THE COURT: Yes.
`(Ms. Schwarz handed a binder to
`the witness.)
` DIRECT EXAMINATION
`BY MS. SCHWARZ:
`666
`Roush - direct
`Q.
`Good afternoon, Dr. Roush.
`A.
`Good afternoon.
`Q.
`I believe you have a binder in
`front of you. Can you please turn to tab
`PTX-1034? I apologize. I don't think we've
`handed up the slides yet. Give us one moment.
`(Ms. Schwarz handed slides to the
`
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`MS. SCHWARZ: And plaintiffs offer
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`Dr. Roush as an expert in organic chemistry,
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`including medicinal chemistry and drug
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`development.
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`Roush - direct
`THE COURT: All right. You --
`MR. BOGGS: That's fine.
`THE COURT: You may proceed.
`BY MS. SCHWARZ:
`Q.
`Dr. Roush, could you please turn
`to tab JTX-one of your binder, which is the '772
`patent?
`A.
`Yes. I have it. Thank you.
`Q.
`Were you asked to consider the
`nonobviousness of claims 7 and 10 of this
`patent?
`A.
`Yes, I was.
`Q.
`Could you please summarize the
`conclusion you've reached on that issue?
`A.
`I've concluded after my analysis
`of all evidence, the prior art and the
`background, that claim seven, the subject matter
`of claim 7 and 10 would not have been obvious to
`a person of ordinary skill in the art as of the
`appropriate filing date.
`MS. SCHWARZ: Your Honor,
`plaintiffs move to introduce JTX-1 into
`evidence.
`
`MR. BOGGS: No objection, your
`Roush - direct
`668
`
`Honor.
`
`THE COURT: All right. And, by
`the way, are the only claims that are asserted
`claims 7 and 10?
`MS. SCHWARZ: Yes, your Honor.
`THE COURT: Thank you.
`(JTX-1 was admitted into evidence.)
`MR. BOGGS: Your Honor, maybe we
`pause here. This is something I wasn't aware
`of.
`
`Have you dropped the other claims
`in this case?
`MS. SCHWARZ: Yes. We're
`asserting claims 7 and 10.
`THE COURT: I'm glad. This means
`that I actually have been paying attention
`because I thought somewhere these had been
`dropped and I just had missed it. But if you
`missed it, too, then I feel better.
`MS. SCHWARZ: I apologize if that
`wasn't clear.
`THE COURT: It's no problem.
`Let's go. We've only got two left.
`MS. SCHWARZ: We thought we'd
`74 of 151 sheets
`
`witness.)
`BY MS. SCHWARZ:
`Q.
`If you could please turn to tab
`PTX-1034 and identify that document.
`A.
`Yes. That's a copy of my
`curriculum vitae and list of publications.
`MS. SCHWARZ: Your Honor,
`plaintiffs move to introduce PTX-1034 into
`evidence.
`
`THE COURT: All right. Admitted
`without objection.
`(PTX-1034 was admitted into
`
`evidence.)
`
`Ex. 1116-0002
`
`

`
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`Roush - direct
`simplify things for you.
`THE COURT: Yes. Yes. Well, no
`objection here.
`BY MS. SCHWARZ:
`Q.
`Dr. Roush, did you render your
`opinions in this case from the perspective of a
`person of ordinary skill in the art or a POSA?
`A.
`Yes, I did.
`Q.
`What definition of a person of
`ordinary skill in the art did you use?
`A.
`Well, I've defined the person of
`ordinary skill as an individual who has a Ph.D.
`in either organic chemistry or medicinal
`chemistry along with several years of experience
`working in drug discovery. It's possible that
`the person of ordinary skill could have a lesser
`degree, either a Bachelor's degree or a Master's
`degree here in the United States. Again, in the
`area of medicinal or organic chemistry. But
`that individual would have, in my estimation,
`a greater number of years of practical
`experience to compensate for the lesser academic
`training.
`Q.
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`And would the person of ordinary
`Roush - direct
`670
`skill in the art consult with any others with
`different backgrounds or different areas of
`expertise?
`A.
`Yes. In my opinion, the person of
`ordinary skill would consult with individuals,
`as I've listed on the slide, on an individual
`with either an M.D. degree or a Ph.D. degree in
`immunology, with several years of experience
`working with immunosuppressive agents, and then
`a second category of individuals that the POSA I
`believe would consult with would be an
`individual with either an M.D. degree or Ph.D.
`degree and several years of experience working
`with antitumor agents.
`Q.
`And in arriving at your opinions
`in this case, did you consult with any other
`individuals with expertise differing from your
`own?
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`In a virtual sense, yes, I did. I
`20
`received and read and analyzed the expert
`21
`reports of Drs. Fung, Bissler and Burris, who
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`recited their testimony to the Court already. I
`23
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`75 of 151 sheets
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`Roush - direct
`Q.
`Are there any critical differences
`between your definition of a person of ordinary
`skill in the art and the one that Dr. Partridge
`offered during his testimony?
`A.
`Well, I think so. If I understood
`Dr. Partridge correctly and his testimony, and,
`frankly, it's a little bit confusing, I think.
`At one point he implied that his person of
`ordinary skill would be motivated to develop
`patents.
`
`On other occasions I think he said
`maybe not motivated. But in my estimation, a
`person of ordinary skill would not have a
`motivation to develop patents or to consult with
`individuals concerned with the patent strategies
`and so on.
`Q.
`And would your conclusions on the
`issue of nonobviousness change if you were to
`adopt Dr. Partridge's definition rather than the
`one that you've used?
`A.
`Well, I've considered that and
`certainly, there might be some changes here and
`there, but at a fundamental level, the question
`would be what a person of ordinary skill would
`Roush - direct
`672
`do when faced with this, the evidence in front
`of us.
`
`And ultimately my conclusion would
`be, as it is already, that the person of
`ordinary skill would not find the claims of
`the -- the matter of claims 7 and 10 to be
`obvious.
`Q.
`And in conducting your obviousness
`analysis, what date did you use?
`A.
`I used the priority date of
`October 9th of 1992.
`Q.
`Why did you use that date?
`A.
`Well, that's the date that I
`understand all parties in this case had agreed
`to.
`
`Q.
`Dr. Roush, could you please
`summarize your conclusions on the issue of
`nonobviousness?
`A.
`Certainly. So the four categories
`of the obviousness analysis in terms of lead
`compound, it's my conclusion that rapamycin
`would not have been selected as a lead compound
`by the person of ordinary skill.
`In terms of motivations to modify,
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`Ex. 1116-0003
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`

`
`673
`Roush - direct
`I think there's no motivation for a person to
`have made a so-called "me too" compound as Dr.
`Partridge defined this.
`I see no motivation for a person
`of ordinary skill to select C40 on rapamycin as
`the sole site of modification.
`I also see there's no motivation
`to have selected the very specific groups, for
`example, the 2-hyrdoxyethyl ether that I believe
`Dr. Partridge has opined would be the obvious
`choices.
`
`In terms of reasonable expectation
`of success, it's my conclusion that that there
`really is no, there is no reasonable expectation
`that everolimus would retain rapamycin's
`immunosuppressive properties. And, moreover,
`there's no reasonable expectation that
`everolimus would -- could be expected in 1992 to
`have had all of the properties and biological
`features and properties that we now know it
`has.
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`Finally, in terms of objective
`indicia of nonobviousness, the Court here today
`has heard evidence of long-felt need, failure of
`Roush - direct
`674
`others, unexpected results, commercial success,
`industry praise and so on, and I factored all of
`that information in forming my opinion, and I
`think all of that evidence is supportive of my
`conclusion that the asserted claims in this case
`are non-obvious.
`Q.
`Thank you.
`Now, before discussing these
`conclusions in more detail, could you please
`walk the Court through the steps that one of
`ordinary skill would have taken in October of
`1992?
`
`After going through all of this
`analysis, then a person of skill can identify
`within that area an appropriate starting point,
`which we'll call the lead compound.
`And proceeding further, the person
`of ordinary skill then needs to identify what is
`it about this compound or compounds, what is it
`about these ones that I wish to work with for
`development of a drug, what is it about them
`Roush - direct
`676
`1
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`that's a problem? What is it that I can strive
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`to solve, improve by making chemical
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`modifications?
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`And there may be circumstances
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`where having identified a compound, a person of
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`drug by formulating or changing particle size or
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`But many times a person of skill
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`will approach the problem by pursuing chemical
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`modifications. That is changing the lead
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`compound into a new compound so as to attempt to
`A.
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`improve the biologic and pharmaceutic properties
`Certainly.
`Q.
`14
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`of the agent. That as we're working our way
`If he or she wanted to develop a
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`through this, once a person of skill has decided
`new drug?
`A.
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`that, they can say I do wish to make a chemical
`I will be happy to.
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`modification, then the question is where, why,
`So at a high level, at the
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`what do I want to do?
`starting point of the exercise, a decision to
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`And it has always been my opinion
`move forward to develop a new drug, you have to
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`on this, and it has been my experience as a
`identify the disease area, what -- the disease
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`researcher in this area that the types of
`area, the types of compounds that you want to
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`chemical modifications you then start to make
`work with, and to do this in terms of
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`really depends on the problem that you are
`identifying the target, you have to do the
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`research. That means examining the available
`striving to solve.
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`Page 673 to 676 of 769
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`Roush - direct
`literature that would be available to the POSA
`at that point in time in terms of the disease,
`understanding what agents, chemical, what drugs
`might have been in existence already for that
`disease or others that were in development in
`order to understand really the landscape of this
`area of science.
`And in doing this first part,
`which I'm calling the research, which is, you
`know, a conceptual research part, that's where
`the consultation with experts in the field that
`would be performed on an as needed basis.
`That's exactly what I've done here in relying on
`the expert reports of the other Novartis
`experts.
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`You need a problem to address and
`information within that body of art to help
`guide you in terms of what decisions and what
`steps you will take specifically moving forward.
`And, finally, it's to the
`laboratory. The compounds will need to be made
`and tested to evaluate whether they have
`properties that are of interest to keep this
`project moving forward.
`Q.
`Would each of the steps that
`you've just described apply if one of ordinary
`skill wanted to develop a drug to prevent
`transplant rejection in October of 1992?
`A.
`Yes, this would, yes.
`Q.
`Do you recall Dr. Partridge
`walking through these steps when he provided his
`opinions?
`A.
`I don't, no.
`Q.
`All right. Let's turn to your
`first conclusion, your first general topic, the
`selection of a lead compound.
`Did you hear Dr. Partridge testify
`that a person of ordinary skill would have
`selected rapamycin as a lead compound?
`Roush - direct
`678
`A.
`I do, yes.
`Q.
`And one of the references that Dr.
`Partridge discussed was Morris 1989, which is
`JTX-100. And if we could put that on the
`screen.
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`Roush - direct
`a program that we're researching with,
`experimenting with in our lab, an early stage
`program.
`
`And as of today, there might be a
`molecule that's in the lead, meaning that it's
`the best that we have today. But as we continue
`to make structural modifications and change the
`molecule, what was the lead today can fall off
`and drop behind another one in the same chemical
`series that leapfrogs over it.
`And so this whole notion that at a
`research level that's a very early stage pre-IND
`type of setting, the term is really used to
`mean, what am I working with today that is the
`best one that I know of from my specific
`laboratory right now, and I think that's the
`context of which Dr. Morris used the terminology
`here, and I think that's how a person of
`ordinary skill would read the statement in this
`publication.
`Q.
`Did Morris 1989 discuss any
`rapamycin derivatives or analogs?
`A.
`No, he did not.
`Q.
`And was Morris encouraging others
`Roush - direct
`680
`to research rapamycin derivatives or analogs?
`A.
`I think he was encouraging people
`because he made comments in this paper that, you
`know, he personally found the rapamycin to be
`interesting, exciting. He also said that in
`this paper, there's still so much unknown about
`it. I think he was encouraging both for himself
`and maybe others to study rapamycin to find out
`what its potential may be, but this is still
`far, far early in this process, far too early
`for rapamycin to have been elevated by this
`statement to the level of a lead compound for a
`person seeking to go forward to make a new
`immunosuppressive agent.
`Q.
`And for the record, PDX-4006
`references JTX-100 at page 610.
`Dr. Roush, were you in the
`courtroom when Dr. Fung provided testimony on
`the issue of selection of a lead compound?
`A.
`I was, yes.
`Q.
`And as a medicinal chemist, do
`you agree with Dr. Fung's conclusions on that
`issue?
`
`A.
`
`I completely agree with the
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`identifies rapamycin as a lead compound for
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`chemical modification?
`A.
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`I don't. So certainly, there's
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`the sentence here and the word lead compound is
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`in Morris and that is, I think, Dr. Partridge is
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`fixated on. But a lead compound as we're
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`working with here in this particular case
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`requires the analysis I just mentioned before,
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`assessing the prior art, assessing the available
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`options, and then making a decision once you've
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`compared strengths and weaknesses. And that's
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`not what I see that Dr. Morris did in this
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`particular publication.
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`Confusing or compounding this
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`problem is that practitioners in the lab on a
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`day-to-day basis, we use the term lead compound
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`all the time. It's just vernacular that we have
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`conclusions that he presented. It has always
`been my opinion that, and Dr. Fung provided the
`very detailed careful analysis here within the
`immunosuppressive area, but it has always been
`my opinion that a lead compound would be
`selected from among molecules that, for which
`there's information not only about how the
`molecule will behave in a human patient as
`opposed to an animal study.
`So human data, data from humans,
`and I think Dr. Fung beautifully -- he clearly
`enunciated that earlier today, trumped -- the
`human data trumps animal data.
`And so in this particular case
`where in 1992, October of '92, there was animal
`data showing certain, you know, immunologic
`properties of rapamycin, but there were other
`molecules that had human clinical data that was
`available, that could be assessed, toxicity data
`in humans.
`I agree with his assessment, that
`it would be among that group of molecules that a
`POSA would have made a selection of a lead or
`leads.
`
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`Roush - direct
`in the FK506 series to something in the
`rapamycin series, and I agree.
`It would be a very, very lengthy,
`difficult process. Be far more difficult than
`that if one picked any of the other
`immunosuppressive agents that Dr. Fung talked
`about.
`Q.
`Let's turn now to the next topic
`you addressed, the motivation to modify the lead
`compounds. And from this point forward, I'd
`like you to make the assumption that the POSA
`has selected rapamycin as their lead compound.
`Having selected rapamycin, what
`would the person of ordinary skill do next?
`A.
`Well, having selected rapamycin,
`the person of skill would have scoured, you
`know, examined the prior art to look for what
`problems to address and solve and then also
`strategies to attempt to solve.
`Q.
`And did Dr. Partridge identify any
`problems with rapamycin that he says the POSA
`was interested in solving?
`A.
`No. If I understood his testimony
`correctly, he said that the motivation would be
`Roush - direct
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`Roush - direct
`Q.
`1
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`to make a compound that is almost
`Now, Dr. Fung discussed various
`2
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`indistinguishable. He did not use that
`immunosuppressants that were known as of 1992.
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`terminology. He wanted to maintain all of the
` Do you recall that testimony?
`A.
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`properties and he called it a "me too."
`I do, yes.
`Q.
`5
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`"Me too" compounds are compounds
`Which of the immunosuppressive
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`which are almost indistinguishable from the,
`compounds that Dr. Fung discussed is most
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`whatever the parent was. I don't see that as a
`structurally similar to everolimus?
`A.
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`motivation in this field, for a POSA to come in
`The one that would be most
`9
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`and attempt to have such a goal, an objective.
`structurally similar to everolimus would be
`Q.
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`Is and based on the analysis that
`rapamycin.
`Q.
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`you conducted, were there any properties of
`And if a POSA, medicinal chemist
`12
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`rapamycin that a person of ordinary skill would
`had started with any of the compounds that Dr.
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`have been motivated to change or approve or any
`Fung identified as lead compounds, would he or
`14
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`problems to resolve?
`she get to everolimus by chemical modification?
`A.
`A.
`15
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`Well, certainly. By approaching
`I find it very, very hard to
`16
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`the 1992 time period up until the priority date,
`conceive that possible. There's a number of
`17
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`it had become apparent that rapamycin was
`different molecules that Dr. Fung presented
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`exhibiting rather strong toxicities in large
`which are structurally very, very dissimilar,
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`animals and we've seen from Dr. Fung's
`and it would take -- I recall Dr. Partridge's
`20
`20
`presentation either yesterday or this morning
`testimony.
`21
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`the toxicity data in baboons and other primates.
`Even with FK506, which is the
`22
`22
`Those would have been a red flag to a medicinal
`seconds closest, if you will, he said it would
`23
`23
`chemist who was interested in working with
`be well in excess of a hundred chemical steps
`24
`24
`probably to make that, that leap from something
`rapamycin moving forward, and I think those
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`685
`Roush - direct
`sorts of data would have been motivation to try
`to address and solve the toxicity issue.
`Q.
`Now, you mentioned that Dr.
`Partridge testified that a POSA would have
`wanted to make a "me too" compound of the same
`activity or essentially the same activity of
`rapamycin.
`What's your view on the motivation
`that Dr. Partridge proposed?
`A.
`Well, at a certain level, it
`sounds good. "Me too." I can just do something
`and get, you know, make a minor change and get
`exactly the same product, but in reality, that's
`not the way the world works. Structural
`modification is very unpredictable in terms of
`what the biological responses to those changes
`will be.
`
`687
`Roush - direct
`like you to make a second assumption, and that
`is to accept Dr. Partridge's motivation that the
`POSA wanted to make a "me too" compound.
`As of October 1992, what positions
`of rapamycin were those in the field modifying?
`A.
`Well, an assessment of the prior
`art shows that POSAs were, in fact, modifying
`every position that had a chemical functional
`group in rapamycin that could be modified.
`And I highlight here just, I
`guess, six different examples in the prior art
`of rapamycins which had been modified.
`So Dr. Partridge spoke and said,
`yes, the C40 position. But the prior art shows
`that there are molecules successfully modified
`at C32 and the arrow points to this part of the
`molecule.
`
`The evidence shows there are
`I don't know persons of ordinary
`molecules successfully modified at carbon 28
`skill, or even experts who are capable of
`with this hydroxyl group at carbon 28. There
`deciding that I will make this or this or that
`are modifications at 27. There's modifications
`change, and I will have exactly this set of
`at 26. There's some modifications that link all
`properties. That just isn't feasible.
`three of these simultaneously. There's still
`So point number one then is that
`further modifications at carbon 9, over here on
`chemical modification is unpredictable.
`Roush - direct
`688
`Roush - direct
`686
`1
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`the left side of the molecule.
`A second point I've highlighted
`2
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`So a person of skill looking at
`here, as I've already mentioned, testified, in
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`the prior art sees that individuals actually
`my opinion, a POSA is not an inventive person.
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`working with rapamycin were looking at the
`So that was the second part, I think the second
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`molecule broadly and not limiting themselves to
`part of Dr. Partridge's motivation to develop a,
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`one specific part of the molecule.
`you know, a patentable compound.
`Q.
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`And were any of the positions that
`In terms of moving forward with
`8
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`you just discussed considered to be positions
`the compound that is biologically as close as
`9
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`that are on the macrolide ring of rapamycin?
`possible to rapamycin, there has been testimony
`A.
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`Yes. In fact, all of these
`from Dr. Fung this morning that the transplant
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`positions that I've indicated, the carbon 32,
`physicians weren't terribly interested in
`12
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`carbon 28, carbon 27, carbon 26, and C9 are all
`looking at "me too" type compounds. You would
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`on the macrolide ring.
`look at something different.
`Q.
`14
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`And were derivatives at each of
`And I understand -- I've read Dr.
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`the positions that you just mentioned tested for
`Grabowski's report, and I understand what is in
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`biological activity?
`his report. I don't know what he -- the
`A.
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`Yes. Yes.
`testimony, but I understand there are arguments
`Q.
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`And were they reported to be
`from an economic standpoint that Dr. -- that
`19
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`immunosuppressive?
`this "me too" argument does not mesh well with.
`A.
`Q.
`20
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`Yes. These ones, there are
`Let's turn now to the next issue
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`examples at each of these positions reported to
`that you considered, where to modify the lead
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`be, to have the immunosuppressive activity.
`compound. And I've already asked you to assume
`Q.
`23
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`Now, Dr. Partridge testified that
`that a POSA would have selected rapamycin as
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`their lead, and from this point forward, I would
`a POSA would select the C40 hydroxyl group
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`691
`Roush - direct
`by Van Duyne, which describes the structure of
`the immunophilin FKBP-12. That's the protein
`that binds with rapamycin.
`Q.
`And is there any specific
`information in this paper that supports your
`opinion?
`A.
`There is. There's a comment in
`one of the paragraphs, I forget exactly where it
`is, but there's a paragraph that discusses the
`hydrogen bonds that rapamycin makes with FKBP,
`and -- thank you. You've found it here.
`It's right after, sort of
`two-thirds of the way down, the paragraph
`immediately following footnote 12. Yes. Thank
`you.
`
`So here, the second hydrogen bond
`is from the glutamine 53, that's part of the
`protein, main chain carbonyl to the C40 hydroxyl
`group.
`
`So this paragraph is talking about
`the hydrogen bonds involved in binding of
`rapamycin to FKBP.
`So from a -- a person of skill to
`read this, and this evidence says that, yes, the
`Roush - direct
`692
`C40 hydroxyl is like a little piece of glue.
`It's helping the molecule bind to the protein.
`So by definition, any part of
`rapamycin that's involved in interacting, which
`this is an interaction, any part that's
`interacting with a protein has to by definition
`be part of the binding domain. So the C40
`hydroxyl, a POSA would conclude is actually part
`of the binding domain.
`MS. SCHWARZ: And plaintiffs move
`to introduce JTX-51, the Van Duyne paper, into
`evidence.
`
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`because it was the easiest position to modify.
`Do you have a response to that?
`A.
`Well, I do. Chemistry -- we have
`a very complex molecule with different
`functional groups in it. And the chemists, Dr.
`Partridge used the term we have this toolbox of
`different reagents and different reactions, and
`depending on the mechanism and time of reaction,
`it is going to be possible to do chemistry
`select selectively I think all of these
`positions that I've identified.
`So under certain conditions, yes,
`it may be 'parentheses' relatively easy to do a
`chemistry at C40, but using a different set of
`chemistries, you could do chemistry selectively
`at C28 hydroxyl because of differences in the
`chemical environment, the reactivity of those
`groups that a person, a chemist, a person of
`ordinary skill would appreciate.
`In terms of a group like carbon
`32, this is in a totally different Venn diagram.
`The chemistry that you would do at C40 or types
`of chemistry you could perform the a C40 is in a
`totally different Venn diagram than chemistries
`Roush - direct
`690
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`you might wish to use to operate a C32.
`2
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`So depending again on what problem
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`the person of skill was interested in addressing
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`and solving, the person could approach any
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`number of these positions and do studies of
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`derivatives at each of those positions.
`Q.
`7
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`Now, Dr. Partridge also said that
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`a POSA would modify the C40 position because it
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`falls between what he refers to as the binding
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`and effector domains of rapamycin.
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`Now, first, would a POSA agree
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`that the C40 position is located between the
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`binding and effector domains of rapamycin?
`A.
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`It's my opinion that the person of
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`ordinary skill would not agree with that
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`conclusion.
`Q.
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`Are you aware of any references
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`that would support your been?
`A.
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`Yes. I specifically think of the
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`Van Duyne reference.
`Q.
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`Can we look at the Van Duyne
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`reference, please. JTX-501. Is this the paper
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`you were referring to, Dr. Roush?
`A.
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`Yes. Yes. This is the 1991 paper
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`MR. BOGGS: No objection.
`THE COURT: Admitted without
`
`objection.
`(JTX-51 was admitted into evidence.)
`BY MS. SCHWARZ:
`Q.
`And, for the record, Dr. Roush was
`referring to a passage on page 474 of JTX-51. I
`apologize. Page 7434 of JTX-51.
`Dr. Roush, were those in the field
`modifying positions within the binding domain of
`rapamycin as of October 1992?
`A.
`They were, yes.
`
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`Q.
`What positions were they modifying
`in particular?
`A.
`Well, the binding domain that Dr.
`Partridge has identified with this segment on
`the left with this blue bracket and the C9
`position that I already mentioned a moment ago
`is a site of modification. That's described,
`modifications are described here in the 876
`patent and I'm specifically referring to Example
`2 in that patent. So this is one example of a
`modification in the binding domain.
`Dr. Partridge presented lots of
`evidence that derivatives have been made at the
`C40 position. All of those derivatives would be
`within the binding domain, but there's one
`additional one. That's the C28 hydroxyl group,
`which, based on the Van Duyne paper that we just
`looked at, it is quite clear from the first part
`of that paragraph that the C28 hydroxyl is also
`involved in a hydrogen bond to FKBP, so it would
`now be the viewed. And by October of 1992, a
`POSA would recognize that the C28 hydroxyl along
`with the C40 and along with C9 are all involved
`in, or part of the binding domain.
`694
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`And just for the record here, let
`me just mention that some of the patents and
`examples where there are C28 modifications, the
`399 patent, Examples 1 and 3. The '447 patent,
`Example 3. The '307 patent, Examples 2, 8, and
`11. And the '670 patent, Example No. 2.
`Q.
`And for the record, PDX-4011
`references JTX-221, which is the '876 patent.
`JTX-174, which is the 399 patent. JTX-208 which
`is the '447 patent. JTX-98, the '307 patent.
`JTX-214, the '670 patent. JTX-51, Van Duyne
`1991, and the summary exhibit, PTX-1081.
`And plaintiffs move to introduce
`into evidence PTX-1081.
`MR. BOGGS: No objection.
`THE COURT: Admitted without
`
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`objection.
`18
`(PTX-1081 was admitted into evidence.)
`19
`BY MS. SCHWARZ:
`Q.
`20
`Now, we heard Dr. Partridge
`21
`testify that a POSA would not modify the C28
`22
`position. Based on the examples that you just
`23
`presented, would a POSA share Dr. Partridge's
`24
`view?
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`A.
`No. A POSA who reviewed this body
`of work, this landscape of prior art, would see
`this multiple number of examples of
`modifications having been performed at C28
`giving rise to products that did retain
`immunosuppressive activity, and would conclude
`that that, that C28 remains a fertile site for
`making additional modifications.
`Q.
`Now, in connection with his
`opinions regarding the C28 position, do you
`rec