`
` UNITED STATES PATENT AND TRADEMARK OFFICE
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
` ----------------------------x
` MYLAN LABORATORIES LIMITED,
`Petitioner,
`
`PATENT NO. 8,927,592
`
`-vs-
` AVENTIS PHARMA, S.A.,
`Patent Owner.
` ----------------------------x
`
`VIDEOTAPED DEPOSITION OF RAHUL SETH, DO
`Syracuse, New York
`December 9, 2016
`9:02 a.m.
`
`Reported by:
`PAMELA PALOMEQUE, NYRCR, RPR, CRR
`Job No. 47818
`
`AVENTIS EXHIBIT 2177
`Mylan v. Aventis IPR2016-00712
`
`
`
`2
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` RAHUL SETH, DO
` December 9, 2016
` 9:02 a.m.
`
` Videotaped Deposition of
` RAHUL SETH, D.O., held at the offices of
` SHERATON SYRACUSE UNIVERSITY HOTEL &
` CONFERENCE CENTER, Syracuse, New York, on
` December 9, 2016, before PAMELA PALOMEQUE,
` NYRCR, RPR, CRR, and Notary Public in and
` for the State of New York.
`
`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` APPEARANCES:
` For the Petitioner:
` WILSON SONSINI GOODRICH & ROSATI
` 701 Fifth Avenue
` Suite 5100
` Seattle, WA 98104-7036
` BY: JAD MILLS, ESQ.
` jmills@wsgr.com
`
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` WILSON SONSINI GOODRICH & ROSATI
` 650 Page Mill Road
` Palo Alto, CA 94304-1050
` BY: MATTHEW R. REED, ESQ.
` mreed@wsgr.com
`
`
` For the Patent Owner:
` FITZPATRICK, CELLA, HARPER & SCINTO
` 1290 Avenue of the Americas
` New York, New York 10104-3800
` BY: DANIEL J. MINION, ESQ.
` dminion@fchs.com
` WHITNEY MEIER, ESQ.
` wmeier@fchs.com
`
`
`
` Also Present:
` CORRINE GATES, Videographer
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` THE VIDEOGRAPHER: This begins the video
` deposition of Rahul Seth, DO for the United
` States Patent and Trademark Office before the
` Patent Trial and Appeal Board, Mylan
` Laboratories Limited, Petitioner, versus
` Aventis Pharma S.A., Patent Owner, case
` number IPR2016-00712 patent number 8,927,592.
` This deposition is being held at
` 801 University Avenue in Syracuse, New York
` on December 9th, 2016. Time is approximately
` 9:03 a.m.
` My name is Corrine Gates from the firm
` of David Feldman Worldwide and I'm the legal
` video specialist. The Court Reporter is
` Pam Palomeque in association with David
` Feldman Worldwide.
` Will counsel please introduce
` themselves.
` MR. MINION: Daniel Minion from
` Fitzpatrick, Cella, Parker, & Scinto on
` behalf of the Patent Owner Aventis. With me
` is Whitney Meier also from Fitzpatrick.
` MR. MILLS: Jad Mills with the law firm
` Wilson Sonsini Goodrich & Rosati here with
` Dr. Seth and also representing Petitioner,
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` Mylan Laboratories Limited, and with me is
` Matt Reed also with Wilson Sonsini.
` THE VIDEOGRAPHER: Will the Court
` Reporter please swear the witness in.
`
`5
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` R A H U L S E T H, M.D. having been called as a
` witness, being duly sworn by the notary public present,
` testified as follows:
` (Mylan-Exhibit 1002, Rahul Seth, DO
` Declaration, previously marked for
` identification, was introduced this date.)
` EXAMINATION BY MR. MINION:
` Q. All right. Let me start off, I'm going to
` hand you what's already marked Mylan-Exhibit 1002. You
` have the copy. It's your Declaration, if you want to
` use that one without the -- without the staple, that's
` fine with me.
` A. Okay.
` (Mylan-Exhibit 1001, US Patent Number
` 8,927,592, previously marked for
` identification, was introduced this date.)
` Q. And then I'm also going to hand you
` Mylan-Exhibit 1001, which is US patent number 8,927,592.
` Do you recognize that patent?
` A. I do believe this is the patent I've
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`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` reviewed before, yes.
` Q. So the first thing I want to get out of the
` way is we're going to be talking a lot about metastatic
` castration-resistant prostate cancer that has progressed
` during or after treatment with docetaxel. Can I
` abbreviate that? Can I say -- first of all, can I say
` mCRPC? Is that an abbreviation familiar with you, for
` the first part?
` A. Yeah, so the abbreviation mCR -- what did
` you say?
` Q. mCRPC?
` A. Right, metastatic -- sorry, that does stand
` for metastatic castrate-resistant prostate cancer, which
` I think is also appropriate to use that abbreviation for
` what we're discussing.
` Q. For docetaxel-resistant mCRPC, those --
` A. So the terminology you're using, metastatic
` castrate-resistant prostate cancer, that is what the
` abbreviation means. It does not mean that it is after
` specifically docetaxel. It can be after any other
` treatment. It is just hormone-refractory prostate
` cancer which is equivalent to metastatic
` castrate-resistant prostate cancer.
` Q. Okay. So if I use the term
` docetaxel-resistant mCRPC, is that the same thing to you
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` as mCRPC that has progressed during or after treatment
` with docetaxel?
` A. The statement of docetaxel -- sorry.
` Q. So I'm trying -- I just want to be able to
` abbreviate things and just make sure we're talking about
` the same thing, if I do that.
` A. Okay.
` Q. I just want to make sure we're on the same
` page.
` A. Right.
` Q. So if -- what I want to be asking questions
` about is mCRPC that has progressed during or after
` treatment with docetaxel.
` A. Okay.
` Q. Can I refer to that as -- would it be fair to
` refer to that as the docetaxel-resistant mCRPC?
` A. You would have to be very specific saying
` that patients were just treated with docetaxel and then
` progressed to metastatic castrate-resistant prostate
` cancer. You see, they're not equivalent because
` metastatic castrate-resistant prostate cancer patients
` are patients who are hormone-refractory; therefore, you
` would have to say specifically they have just failed
` docetaxel.
` So you can say docetaxel-resistant patients
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` that were just treated are metastatic castrate-resistant
` prostate cancers.
` Q. So if a patient has mCRPC that has progressed
` during or after treatment with docetaxel, that does not
` mean that the patient is docetaxel-resistant?
` MR. MILLS: Objection. Form.
` A. If a patient has progressed after use of
` docetaxel while on treatment for metastatic
` castrate-resistant prostate cancer, the patient can be
` categorized as saying they are metastatic
` castrate-resistant prostate cancer docetaxel failure or
` docetaxel-resistant.
` Q. Okay. What's the difference between
` docetaxel failure and docetaxel-resistant?
` A. Docetaxel failure and docetaxel resistance
` are words that can be synonymous in terms of
` representing a patient who's progressed after usage of
` docetaxel.
` Q. You used the term "hormone-refractory." Is
` the term castration-resistant prostate cancer and
` hormone-refractory prostate cancer, are those
` synonymous?
` A. At this time the terminology of
` hormone-resistant prostate cancer has been very
` similarly used with castrate-resistant prostate cancer
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` for metastatic prostate cancers. Metastatic prostate
` cancers are typically treated with hormonal agents first
` to decrease their prostate cancer progression. It is
` now been more of a recent terminology usage of castrate
` resistance instead of just saying hormonal refractory.
` Q. So if it's just to -- you said today to a
` person of ordinary skill in the art in 2009 --
` A. Yes.
` Q. -- if they -- if they heard the term or saw
` the term castration resistant prostate cancer, if they
` had a patient that had castration-resistant prostate
` case, that would mean they're hormone-refractory?
` A. To a general oncologist, yes.
` Q. How does a patient with prostate cancer
` become castrate-resistant? What's the mechanism?
` A. The -- as an oncologist, what we do know is
` that prostate cancer is driven by testosterone in men.
` We know that the testosterone can stimulate the prostate
` cells to produce prostate cancer which will progress.
`
` Typically many years ago beyond I think --
` before I became a medical student, treatments for
` prostate cancer, orchectomy was a surgical intervention.
` The analogy is to put men into menopause. Similarly to
` breast cancer women that have hormone positive diseases,
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` we put them into menopause to stop the production of
` estrogen in women. We would do the same thing in men to
` stop the production of testosterone.
` The mechanism that we have used for this is
` orchectomy but then there is a, other chemicals that we
` have used in oncology to treat the hormones, bring down
` the testosterone level in men so, therefore, we are
` stopping the stimulation of the prostate cancer cells
` from growing.
` Typically, though, we do know that after a
` certain amount of time -- we don't know what time. We
` don't know how to predict that -- the prostate cancer
` cells can grow despite us using anti-hormones to stop
` the testosterone production.
` At that level, the manipulation of
` medications to stop hormone production, when that has
` been exhausted, that is when the terminology -- and say
` patient has a progression of prostate cancer onto the
` bones or into the lungs, the liver, the brain, that is
` when the terminology of hormone-resistant prostate
` cancer or castrate-resistant prostate cancer is applied
` to a patient. That is how a patient would become
` hormone-resistant to prostate cancer.
` Q. And you said you don't know how or when a
` patient is going to start becoming resistant to androgen
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` suppression therapy?
` MR. MILLS: Objection, form.
` A. In my previous answer to your previous
` question, as I've stated before, we have no way to
` determine patient X will progress after two years into a
` hormone-refractory prostate cancer.
` Q. Is it understood -- you know, is it
` understood by cancer physicians how it is -- like the
` mechanism by which a patient's cancer becomes resistant
` or refractory to hormone therapy?
` A. To answer your question, is the exact
` mechanism known? I feel in the oncology world we feel
` the cells become resistant to hormone manipulation.
` What is the exact mechanism of action that would make a
` prostate cancer cell say I don't care about your
` hormones; I'm going to grow now no matter what you do to
` me? I cannot say that every oncologist in the world
` would be able to say, yes, I know what that is.
` Q. Now, we were talking about metastatic
` castrate -- castration-resistant prostate cancer that
` has progressed during or after treatment with docetaxel.
` Is it correct to say that all patients with mCRPC will
` eventually develop resistant -- resistance to docetaxel
` therapy?
` A. To answer your question, most patients who
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` are metastatic castrate-resistant prostate cancer,
` metastatic, there may be a large percentage of patients
` or -- that can progress after docetaxel.
` Q. Okay. I think in your Declaration, in
` paragraph 65, on page 25, you're referring to this
` Rosenberg reference as a quote there, "nearly all HRCP
` patients eventually progress during or after
` taxane-based treatment." It says, "Rosenberg says that
` a patient whose cancer was treated with docetaxel was
` almost certain to have progressed during or after the
` treatment." So that's a correct statement?
` MR. MILLS: Objection.
` A. To answer your question, per Rosenberg's
` teaching that I have in my Declaration, yes.
` Q. Do you agree with Rosenberg's teaching?
` MR. MILLS: Objection. Form.
` Q. Let me ask you a different question. As of
` 2009, would a person of ordinary skill in the art
` understand that a patient whose cancer was treated with
` docetaxel was almost certain to have progressed during
` or after the treatment?
` A. I would have to answer -- at that time of
` 2009 you're asking?
` Q. Yes.
` A. Yes, I would have to say we, as oncologists,
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` we're always almost certain that docetaxel failure would
` happen. When that would happen, we do not know.
` Q. Was it understood -- we were talking about
` resistance to hormone therapy. Is it understood today
` the mechanism by which a patient becomes resistant to
` docetaxel therapy, a patient with mCRPC?
` A. Are you asking about in 2016 right now --
` Q. Yeah.
` A. -- or in --
` Q. Let me ask you now.
` A. To date, as oncologists, generally we do
` know that prostate cancers similar to other things will
` become resistant to docetaxel. The exact mechanism of
` action of the resistance, it has -- you know, it's
` theorized how they become resistant to docetaxel but
` nothing as to time has been presented as this is what
` happens to prostate cancer cells to become resistant to.
` We do have molecular ideas of why this happens.
` Q. Is it likely that there are different
` mechanisms by which a patient with mCRPC can become
` docetaxel-resistant?
` MR. MILLS: Objection. Form.
` A. To answer your question, I do not think
` there are multiple mechanisms of resistance to
` docetaxel.
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` Q. Can you name any that were known in 2009?
` A. In 2009 there was -- I don't want to
` misquote myself so give me a minute, please. Can I
` answer?
` Q. Mm-hmm.
` A. I think paragraph 63, page 22 on the bottom,
` this is where I'm saying -- I related the P-glycoprotein
` transport mechanism, that is a -- can lead to drug
` resistance, capture the drug molecules inside the cell
` and secretes them back out through the cell membrane.
` THE COURT REPORTER: You're going to
` have to read slow, thank you.
` A. So to answer your question the best I can,
` bottom of page 22, paragraph 63, Verweij speaks to this
` resistance in relation to a P-glycoprotein transport
` mechanism which captures the drug molecules inside the
` cell and secretes them back out through the cell
` membrane into the extracellular space leading to drug
` resistance.
` Q. So that was one proposed mechanism for
` docetaxel resistance?
` A. That was known. That is known.
` Q. Known in cell cultures?
` A. It is known to an oncologist in the state of
` the art that I practice as a medical oncologist that
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` this P-glycoprotein transport mechanism is possibly a
` reason why the resistance happens for prostate cancer
` patients to docetaxel.
` Q. Right. So it was the word possibly that I
` was looking for.
` A. Sorry, sorry.
` Q. So it wasn't clinically established in 2009
` that the mechanism of docetaxel resistance was related
` to P-gp?
` MR. MILLS: Objection. Form.
` A. In this world of medical oncology, there are
` many things but this is one transport mechanism that we
` know of that will cause resistance to docetaxel in
` prostate cancer patients.
` Q. You know that in patients or in cell
` cultures?
` A. We have studied this -- do we have this
` exhibit?
` Q. I don't have it with me.
` A. If I could be provided the document to make
` sure Verweij, what he was talking about, as I stated
` before.
` Q. Okay, but the quote you have here refers to a
` P388/DOX cell line?
` A. Correct. Yes, so that is -- you're saying
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` that what he's saying -- yes, it's a cell line but we
` have extrapolated that we feel as medical oncologists,
` this is the mechanism of action of why prostate cancer
` cells become resistant to docetaxel in men.
` Q. Okay. And as of 2009 there were other
` proposed mechanisms for docetaxel resistance?
` A. Sorry, could you repeat the question again?
` Q. Yeah. So you talked about overexpression of
` P-gp as a potential mechanism for docetaxel resistance
` that was known as of 2009 and I'm asking, did you look
` into other potential mechanisms for docetaxel resistance
` that would have been known in 2009?
` A. To answer that question the best I can, to
` the best of my ability I do not remember anything that
` was more -- that stood out as more of a mechanism of
` action to have docetaxel resistance.
` Q. What about alterations in tubulin? Is that
` known in 2009 to be a mechanism of docetaxel resistance?
` MR. MILLS: Objection. Form.
` A. The tubulin -- sorry, let me take that back.
` Sorry, you're asking --
` Q. Let me start with -- maybe start with a
` different question. Maybe this will be easier. Have
` you ever heard or read someone saying or writing that
` docetaxel resistant mCRPC is a heterogenous disease?
`
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` MR. MILLS: Objection, form.
` A. To the best of my recollection I do not --
` hetero --
` Q. Heterogenous?
` A. Heterogenous. I've heard heterogenous term.
` I do not remember any scientific paper that I am
` recalling at this time that had that.
` Q. Do you know what it means that a disease is
` heterogenous?
` MR. MILLS: Objection, form.
` A. Heterogenous, to the best of my ability, is
` about two different mechanisms of action, meaning
` they're two different things. Homogenous meaning the
` same, heterogenous meaning they're different.
` Q. Or more than two?
` A. More than two.
` Q. I'm going to ask you in a moment about your
` personal experience treating patients with prostate
` cancer but do you consider metastatic
` castration-resistant prostate cancer a difficult disease
` to treat?
` A. As a medical oncologist in 2016, after all
` these years, yes, it is a very difficult disease to
` treat.
` Q. Why?
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` A. Multiple variables. The age of these
` patients. The other core co-morbidities, as we say,
` their performance status, meaning other medical factors
` in patients that have metastatic prostate cancer. When
` we talk on paper about studies, medical practice, you
` are talking about prostate cancer patients and these
` factors, you know, they just don't have metastatic
` prostate cancer that are castrate-resistant. They have
` coronary artery disease. They have cardiac issues.
` They may have lung issues, COPD.
` So that is why certain treatments you have
` to vary, depending on how you treat patients, and that's
` what makes it difficult because not every patient is the
` same. Every patient is different. And that's why you
` have to have regular follow-ups with patients and active
` surveillance of patients as I call it.
` Q. But is it your opinion that the biochemical
` mechanism by which a patient with mCRPC develops
` resistance to docetaxel is the same for every patient?
` A. Do I assume the mechanism of resistance is
` the same for every patient?
` Q. Yes.
` A. As a medical oncologist, and in 2016 as the
` time, we assume that patients are just becoming
` resistant to docetaxel for the mechanism of action and
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` we just need to move on and treat these patients. I
` don't -- we don't spend time thinking about why did this
` patient fail docetaxel.
` As a practicing medical oncologist, we know
` the patients failed docetaxel. If they've progressed,
` that's what you were saying. In your question --
` Q. Yeah, I understand what you're saying.
` A. Okay.
` Q. I guess I'm asking it more from a clinical
` researcher looking to develop a new treatment for
` patients with metastatic castration-resistant prostate
` cancer --
` MR. MILLS: Objection. Sorry, were you
` done, counsel?
` MR. MINION: No. Let me ask again.
` Q. So for -- let's step away from mCRPC for a
` moment. If I'm developing a drug for the treatment of a
` particular type of cancer and I understand that or I
` discover that the mechanism by which the cancer
` continues to grow is by overexpression of something such
` as, like you said, P-gp, if I develop a drug that
` counteracts that overexpression, does that mean that I'm
` going to be able to benefit those patients with that
` drug?
` MR. MILLS: Objection, incomplete
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` hypothetical, form.
` A. In the hypothetical world of what you're
` asking, you are hoping to benefit patients; however,
` that does not mean you will have success on every
` patient.
` Q. The -- in your -- in your Declaration in
` paragraph 3 --
` A. Paragraph 3 you said? Not page 3, sorry.
` Q. Yes.
` A. Okay.
` Q. Yeah, I guess I don't need to take you there.
` You make a comment that your practice has included
` treating over 60 patients with metastatic prostate
` cancer using active chemotherapy and such treatment
` typically includes administering taxane drugs.
` Which taxane drugs are you referring to
` there?
` A. To answer your question, the taxane drugs
` I'm referring to is docetaxel.
` Q. You've never treated a patient with
` cabazitaxel?
` A. I have treated a patient with cabazitaxel,
` too.
` Q. When you're referring to 60 patients with
` metastatic prostate cancer -- let me back up.
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` If you have a patient with metastatic
` prostate cancer, your preferred treatment is docetaxel?
` MR. MILLS: Objection, sorry, hold on.
` Form, incomplete hypothetical. Go ahead.
` A. As a practicing medical oncologist, for
` metastatic castrate-resistant prostate cancers,
` docetaxel is indicated first line treatment; whereas,
` cabazitaxel is FDA-indicated for second line treatment
` after docetaxel-resistant metastatic prostate cancer as
` we had discussed earlier before. That is the
` recommendations. Those are taxanes that are commonly
` used within treatment for metastatic prostate cancer
` patients.
` Q. Do you ever use cabazitaxel in first line
` metastatic prostate cancer?
` A. As a medical practicing oncologist in the
` United States, familiar with the art, I cannot use
` cabazitaxel as a first line treatment because it is FDA
` indicated for docetaxel-resistant metastatic prostate
` cancer.
` Q. But as a physician in the United States,
` you're allowed to use drugs off label in your
` discretion; right?
` MR. MILLS: Objection to the extent it
` calls for a legal conclusion.
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` A. As a medical practicing oncologist in the
` United States of America, I am -- I am not legally free
` to be using drugs that are not appropriately indicated
` for their usage.
` Q. Do you ever use any cancer drugs off label?
` MR. MILLS: Objection, form.
` A. As a practicing medical oncologist here, it
` is -- I cannot use drugs off label.
` Q. Why is that?
` A. Because we live in the United States of
` America.
` Q. Okay. Is there a specific rule you're aware
` that says you're -- as an oncologist you're not allowed
` to use drugs off label?
` MR. MILLS: Objection, form.
` A. As a practicing medical oncologist, it would
` not be good professionalism to be using drugs off label.
` Q. Do you think it would be "good
` professionalism" for a practicing medical oncologist to
` have treated a patient with cabazitaxel before it was
` approved by the FDA?
` MR. MILLS: Objection, form, incomplete
` hypothetical.
` A. As a medical practicing oncologist, if
` you're asking me would I look down on somebody who had
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` used cabazitaxel before it was FDA-approved?
` Q. You used the term "good professionalism."
` I'm just using your term. You said, yeah, as a
` practicing medical oncologist, it would not be good
` professionalism to be using drugs off label.
` What do you mean by "good professionalism"?
` MR. MILLS: Objection, form.
` A. As a practicing oncologist, good
` professionalism is that you're using these oncological
` drugs for the benefit of a patient in the manner that it
` is either FDA-approved and for the benefit of the
` patients.
` Q. So now going back to my question, do you
` think it would have been good professionalism for a
` practicing medical oncologist to have treated a patient
` with metastatic castration-resistant prostate cancer,
` who has progressed during or after docetaxel treatment,
` with cabazitaxel before it was approved in the United
` States by the FDA?
` MR. MILLS: Objection, form, incomplete
` hypothetical.
` A. As a medical practicing oncologist, to best
` answer your question, if the patient was on a clinical
` trial and they had used cabazitaxel in a clinical trial
` that a patient was enrolled in, that would be okay.
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` Q. What about in a clinical setting? I'm not
` talking about in an investigational setting. I'm
` talking clinical practice, prior to 2009. You have a
` patient come to you and Aventis has given you
` cabazitaxel. Do you think it would have been good
` professionalism on your part to give that patient
` cabazitaxel?
` MR. MILLS: Objection, form, incomplete
` hypothetical.
` A. To best answer your question, if we were in
` a hypothetical world and I did not have to worry about
` the Federal Drug Administration, FDA approval of
` medications, and say I was on an island and I had a
` patient with me who had been taking docetaxel for his
` metastatic castrate-resistant prostate cancer and I had
` data about cabazitaxel from before, and it was not
` FDA-approved yet and I had nothing else to give the
` patient, would I have given the patient cabazitaxel?
` Yes. I would have given cabazitaxel in that setting
` that I had set before of a hypothetical setting where I
` didn't have to worry about anything.
` Q. Okay. Well, let's talk about my world now,
` where in my understanding you're free as a practicing
` medical oncologist to use cancer drugs off label. Let's
` assume I'm correct.
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` MR. MILLS: Objection.
` Q. Okay?
` MR. MILLS: Form.
` Q. Sorry, can we assume we're correct?
` MR. MILLS: Okay, I'm going to -- maybe
` we should start off, I didn't mean to cut you
` off.
` MR. MINION: Let's do one thing here, I
` don't really care about your objections. You
` understand when we're in an IPR, you can only
` object to the form? There's no leeway like
` in District Court. I don't really care but I
` want to point that out you.
` MR. MILLS: I thought you were done with
` your question. If you'd like to start over.
` I wasn't going to interrupt your question.
` BY MR. MINION:
` Q. Let's talk about -- let's assume today as a
` practicing medical oncologist you are at liberty using
` your clinical judgment to prescribe cancer drugs off
` label. Can we assume that?
` MR. MILLS: Objection, form. Incomplete
` hypothetical.
` A. Your assumption of me as a medical
` oncologist practicing in the United States, am I
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` completely legally free to use anything I want for any
` patient?
` Q. That wasn't my question. That wasn't my
` question.
` A. What was your question then, sir?
` Q. I'm asking you as -- I'm asking you to assume
` that using your best clinical judgment, that you are
` legally permitted in the United States to prescribe a
` cancer drug off label.
` MR. MILLS: Same objections.
` Q. I'm just asking you to assume that.
` A. To answer your question.
` Q. Yes. Under that construct, if you are, as an
` oncologist, at liberty to prescribe cancer drugs off
` label, are you -- would you consider using cabazitaxel
` as first line in mCRPC instead