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` UNITED STATES PATENT AND TRADEMARK OFFICE
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
` = = = = = = = = = = = = = = = = = = = = = = = = = = =
`
`Page 1
`
` MYLAN PHARMACEUTICALS, INC.,
`
` et al.,
`
` Petitioners,
`
` -vs- Case No. IPR2016-01332
`
` Patent 8,822,438 B2
`
` JANSSEN ONCOLOGY, INC.,
`
` Patent Owner.
`
` = = = = = = = = = = = = = = = = = = = = = = = = = = =
`
` Videotaped Deposition of:
`
` JOHN BANTLE, M.D.
`
` Madison, Wisconsin
`
` April 24, 2017
`
` Reported by: Taunia Northouse, RDR, CRR, CRC
`
` Veritext Legal Solutions
`
` Mid-Atlantic Region
`
` 1250 Eye Street NW - Suite 350
`
` Washington, D.C. 20005
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`Veritext Legal Solutions
`215-241-1000 ~ 610-434-8588 ~ 302-571-0510 ~ 202-803-8830
`
`JANSSEN EXHIBIT 2188
`Mylan v. Janssen IPR2016-01332
`
`

`

`Page 2
`
`Page 4
`
`1 APPEARANCES CONTINUED
`2 TODD L. KRAUSE, Attorney
`SIDLEY AUSTIN, LLP
`3 787 Seventh Avenue, New York, New York 10019,
` appearing on behalf of the patent owner.
`4 tkrause@sidley.com 212-839-5696
`5
`
`Also present: Connie Hansen, videographer
`
`= = = = = = = = = = = = = = = = = = = = = = = =
`
`67
`
`89
`
` THE VIDEOGRAPHER: Good morning.
`10 We are now on the record. My name is
`11 Connie Hansen. I'm a videographer for
`12 Golkow Technologies. Today is April 24th,
`13 2017, and the time is 9 a.m. This video
`14 deposition is being held in Madison,
`15 Wisconsin, in the matter of
`16 Mylan Pharmaceuticals, et al., versus
`17 Janssen Oncology, Incorporated. The deponent
`18 is John Bantle.
`19 If counsel would please identify
`20 yourselves and then the court reporter,
`21 Taunia Northouse, will swear in the witness.
`22 MR. KRAUSE: Todd Krause of
`23 Sidley Austin for Janssen Oncology, Inc.,
`24 patent owner.
`25 MS. GREB: Emily Greb of
`
`Page 3
`
`Page 5
`1 Perkins Coie on behalf of Petitioner Mylan.
`2 MR. SWANSON: Robert Swanson on
`3 behalf of Mylan as well from Perkins Coie.
`4 MR. HAUER: Ryan Hauer from
`5 Winston & Strawn for the petitioners.
`
`6 7
`
` JOHN BANTLE, M.D.,
`8 called as a witness, being first duly sworn,
`9 testified on oath as follows:
`10
`11 EXAMINATION
`12 By Mr. Krause:
`13 Q Good morning, Dr. Bantle.
`14 A Good morning.
`15 Q Can you please state your name and home address
`16 for the record.
`17 A John Bantle, 1865 Hillcrest Avenue, St. Paul,
`18 Minnesota.
`19 Q Have you ever been deposed before?
`20 A No.
`21 Q There are a few points that I'd like to review
`22 before we get started. If I ask a question that's
`23 not clear or you don't hear me, please let me know
`24 so I can ask the question again. If you answer,
`25 I'll assume that you understood and heard my
`
`2 (Pages 2 - 5)
`
`1 I N D E X
`2 WITNESS Page(s)
`3 JOHN BANTLE, M.D.
`4 Examination by Mr. Krause 5
`5 Examination by Ms. Greb 127
`
`67
`
` E X H I B I T S
`8 No. Description Identified
`9 Exh 2180 Copy of Exhibit C to Exhibit 1097 44
`10 Exh 2181 Copy of Exhibit C to Exhibit 1097 55
`11 Exh 2182 Copy of Exhibit C to Exhibit 1097 58
`12
`13 (Previously marked exhibits)
`14 Exh 1003 Paper by O'Donnell, "Hormonal 46
` impact of the 17 alpha-hydroxylase"
`
`15
`
`16
`
`17
`
`Exh 1004 Abstract by Glenn Gerber 109
`
`Exh 1005 Patent 5,605,213 118
`
`Exh 1025 Excerpt from Harrison's Internal 32
`18 Medicine
`19 Exh 1097 Dr. Bantle's Declaration 6
`20 (Attached to the original transcript
` and copies provided to all counsel)
`
`21
`22 REQUESTS Page
`23 (none)
`24 (Original transcript filed with Attorney Krause,
` copies provided to all counsel)
`
`25
`
`1 DEPOSITION of JOHN BANTLE, M.D., a witness
`2 of lawful age, taken on behalf of the the patent
`3 owner, wherein Mylan Pharmaceuticals, Inc., is
`4 Petitioner, and Janssen Oncology, Inc., is the patent
`5 owner, before the United States Patent and Trademark
`6 Office, pursuant to notice, before Taunia Northouse,
`7 a Registered Diplomate Reporter and Notary Public in
`8 and for the State of Wisconsin, at the offices of
`9 Perkins Coie, Attorneys at Law, One East Main Street,
`10 Suite 201, in the City of Madison, County of Dane,
`11 and State of Wisconsin, on the 24th day of April
`12 2017, commencing at 9 o'clock in the forenoon.
`13
`14 A P P E A R A N C E S
`15 EMILY J. GREB, Attorney
`PERKINS COIE
`16 One East Main Street, Suite 201, Madison, Wisconsin
` 53703, appearing on behalf of Petitioner
`17 Mylan Pharmaceuticals, Inc.
` egreb@perkinscoie.com 608-663-7494
`
`18
`
`ROBERT D. SWANSON, Attorney
`19 PERKINS COIE
` 700 13th Street NW, Suite 600, Washington, D.C.
`20 20005-3960, appearing on behalf of Petitioner
` Mylan Pharmaceuticals, Inc.
`21 rswanson@perkinscoie.com 202-654-1729
`22 RYAN B. HAUER, Attorney
`WINSTON & STRAWN, LLP
`23 35 West Wacker Drive, Chicago, Illinois 60601,
` appearing on behalf of the Petitioners.
`24 rhauer@winston.com 312-558-8116
`25
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`Page 6
`
`Page 8
`
`1 question; okay?
`2 A Yes.
`3 Q And we have a court reporter taking down your
`4 answers to my questions, so please try to give
`5 verbal answers to my questions; okay?
`6 A Yes.
`7 Q We'll try to take breaks about every hour or so.
`8 Please let me know if you need a break. I'll
`9 finish whatever question I'm on and we can take a
`10 break. Is that understood?
`11 A Yes.
`12 Q Is there any reason you cannot give complete and
`13 accurate testimony here today?
`14 A No.
`15 Q I've handed you a document that's been marked as
`16 Mylan Exhibit 1097. Is this your declaration?
`17 A It appears to be, yes.
`18 Q Is that your signature on the last page of the
`19 declaration?
`20 A Yes, it is.
`21 Q Was the declaration marked as Exhibit 1097 an
`22 accurate statement of the opinions that you've
`23 reached in this case?
`24 A Yes.
`25 Q Are there any errors in your declaration or --
`
`1 Q So when you're talking about adrenal
`2 insufficiency, you're referring to a deficiency or
`3 insufficiency of all of the adrenal steroids; is
`4 that correct?
`5 A Well, at least the ones that are necessary for
`6 health and maintenance of life.
`7 Q And which are those?
`8 A Those would principally be the glucocorticoids and
`9 the mineralocorticoids.
`10 Q And what are the necessary glucocorticoids?
`11 A The most important is cortisol.
`12 Q And are there others?
`13 A There are other glucocorticoids, but they're
`14 basically precursors to cortisol, such that they
`15 occur in the process of developing the cortisol
`16 molecule, and they're not usually important in
`17 meeting body needs or maintaining normal adrenal
`18 function.
`19 Q Is it true that other glucocorticoids -- strike
`20 that. Is it true that other steroids other than
`21 cortisol have glucocorticoid activity?
`22 A Yes, that is true.
`23 Q And is it true that those steroids contribute to
`24 the glucocorticoid activity in the body?
`25 A I would have to qualify my yes and say that I
`
`Page 7
`
`1 A None of which I'm aware.
`2 Q Okay. Doctor, we'll be talking a lot about a
`3 person of ordinary skill in the art today. When I
`4 refer to person of ordinary skill in the art or
`5 POSA, P-O-S-A, I'm referring to a person as you've
`6 defined it in your expert report. Is that
`7 understood?
`8 A Yes.
`9 Q And when we talk about the person's knowledge, it
`10 refers to that person's knowledge as of
`11 August 25th, 2006. Is that also understood?
`12 A Yes.
`13 Q Your report uses the terms adrenal insufficiency,
`14 low adrenal reserve, and mineralocorticoid excess.
`15 What do you mean by adrenal insufficiency?
`16 A Adrenal insufficiency would be a situation where
`17 the adrenal glands have failed or are in the
`18 process of failing, where symptoms are produced;
`19 and if diagnosis is not made and treatment
`20 provided, death can ensue.
`21 Q Is it the same as glucocorticoid deficiency?
`22 A No. I would view that as somewhat different.
`23 With glucocorticoid deficiency one has not enough
`24 of a particular kind of adrenal hormone and may
`25 have adequate amounts of other things.
`
`Page 9
`1 don't think they usually do because they're not
`2 produced in significant amounts. They're simply
`3 precursors to cortisol.
`4 Q How is adrenal insufficiency diagnosed?
`5 A Well, the definitive test would be something
`6 called ACTH stimulation test referred to in this
`7 document as a Synacthen test.
`8 Q If a person of ordinary skill in the art wanted to
`9 determine whether a patient had adrenal
`10 insufficiency, what test or tests would that
`11 physician want to do?
`12 A Well, if one wanted to definitively make the
`13 diagnosis, one would do the Synacthen test.
`14 Q Are there any other tests that an individual would
`15 want to perform or have performed?
`16 A Yes. I think occasionally one might simply
`17 measure baseline cortisol value, typically first
`18 thing in the morning when cortisol values are
`19 highest. And if that cortisol value meets the
`20 threshold for full adrenal cortisol function, then
`21 one doesn't need to do the test.
`22 Q Are there any other tests that a physician would
`23 want to do in determining whether a patient has
`24 adrenal insufficiency?
`25 MS. GREB: Objection. Vague as to
`
`3 (Pages 6 - 9)
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`Page 12
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`1 time.
`2 Q You can go ahead and answer the question.
`3 A I'm to answer anyway. Definitely the Synacthen
`4 test is the most important. There are other tests
`5 that could be done that might provide insight, but
`6 to make the diagnosis definitively, one would do
`7 the Synacthen test.
`8 Q Is that true today?
`9 A Yes.
`10 Q As it was in August of 2006?
`11 A We call it something different, but yes, that is
`12 true today.
`13 Q Fair enough. To a person of ordinary skill in the
`14 art in 2006, would patients' symptoms play any
`15 role in the diagnosis of adrenal insufficiency?
`16 A Yes. Typically symptoms might be the first clue
`17 to testing for the condition. Although I think
`18 it's important to say the symptoms are not very
`19 specific, things like fatigue, which most of us
`20 have, at least from time to time. So it creates a
`21 problem in that the diagnosis is often overlooked
`22 because the symptoms are nonspecific.
`23 Q And do the symptoms become accentuated as the
`24 disease progresses?
`25 A Yes. As the disease progresses, more symptoms
`
`Page 11
`1 appear and definitely would indicate something is
`2 wrong and would, I think, cause a doctor who has
`3 insight and competence to begin to wonder about
`4 adrenal insufficiency as the cause of the
`5 symptoms. But because the symptoms are so
`6 nonspecific, the diagnosis is often overlooked.
`7 Q How would a person of ordinary skill in the art in
`8 2006 diagnose a patient if they were concerned
`9 about CYP17 inhibition?
`10 MS. GREB: Objection. Vague.
`11 A Yes. Can you restate that?
`12 Q Sure. Well, let's back up a little bit. Have you
`13 heard the term CYP17?
`14 A Yes.
`15 Q And what is CYP17?
`16 A CYP17 is the short name for 17-alpha-hydroxylase,
`17 1720-lyase, L-Y-A-S-E, which is an enzyme that's
`18 important in cortisol production by the adrenal
`19 glands and also important in the production of
`20 adrenal and testicular androgens.
`21 Q And so CYP17 is an enzyme; is that correct?
`22 A Yes.
`23 Q And that enzyme has two activities; is that right?
`24 A Correct.
`25 Q And those two activities as you recited, one is
`
`1 the 17-alpha-hydroxylase activity?
`2 A Hydroxylase at the 17 position on the molecule.
`3 Q Okay. And the other is a 1720-lyase activity; is
`4 that correct?
`5 A Yes, cleaves off two carbon atoms from the
`6 molecule.
`7 Q If a person of ordinary skill in the art in 2006
`8 were concerned about the potential inhibition of
`9 the CYP17 enzyme and the potential development of
`10 adrenal insufficiency in light of that, what test
`11 would that person of ordinary skill want to
`12 perform to determine whether or not the patient
`13 had adrenal insufficiency or was developing
`14 adrenal insufficiency?
`15 A Synacthen test would be I think the definitive
`16 test.
`17 MS. GREB: Objection. Vague. And
`18 I'd just remind you to give me a second to
`19 object.
`20 THE WITNESS: I'm sorry.
`21 MS. GREB: That's okay.
`22 Q How would a person of ordinary skill in the art
`23 diagnose whether or not a patient had inhibited
`24 17-alpha-hydroxylase activity?
`25 MS. GREB: Objection. Vague.
`
`Page 13
`1 A Well, the Synacthen test would give information as
`2 to whether or not cortisol production remained
`3 adequate, and if there was inhibition of an
`4 enzyme, it should not be adequate. And then
`5 someone might look for other things that might be
`6 abnormal, like low DHEA or low androstenedione.
`7 Q When you say one might, would that be part of what
`8 a physician in your view, a person of ordinary
`9 skill in the art, would do in his or her
`10 diagnosis?
`11 A I think it's hard to say for sure what one might
`12 do. It's such an uncommon situation that most
`13 endocrinologists will never encounter it in their
`14 career, but I think that would be what I would do.
`15 Q But is it fair to say you don't know what a person
`16 of ordinary skill in the art would do?
`17 MS. GREB: Objection. Misstates
`18 prior testimony.
`19 A Should I still answer?
`20 Q Yeah. You can go ahead and answer.
`21 A Yes. I think -- I think so.
`22 Q And how would a person of ordinary skill in the
`23 art diagnose a patient if she or he were concerned
`24 that that patient had an inhibited 17-lyase
`25 activity -- 1720-lyase activity?
`
`4 (Pages 10 - 13)
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`Page 16
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`1 MS. GREB: Objection. Vague.
`2 A An isolated defect in the lyase?
`3 Q Yes, Doctor.
`4 A I think one would still want to do the Synacthen
`5 test to confirm cortisol production is normal.
`6 And then one would want to measure DHEA,
`7 androstenedione, A-N-D-R-O-S-T-E-N-E-D-I-O-N-E,
`8 and in a man testosterone.
`9 Q Is it true that just because a patient has a low
`10 cortisol level, that does not mean that they have
`11 adrenal insufficiency?
`12 MS. GREB: Objection. Incomplete
`13 hypothetical.
`14 A If they have a low cortisol after a Synacthen
`15 stimulation test, they have adrenal insufficiency.
`16 Q If one were just looking at the cortisol level --
`17 A Yes.
`18 Q -- would the cortisol -- would a low cortisol
`19 level alone mean that a patient has adrenal
`20 insufficiency?
`21 A If it is low after Synacthen administration, in my
`22 opinion, yes.
`23 Q And your declaration also refers to low adrenal
`24 reserve. What is low adrenal reserve?
`25 A Low adrenal reserve might be considered the
`
`1 a cortisol value in the Synacthen test that does
`2 not meet the threshold for normal.
`3 Q And what is the threshold for normal in your view?
`4 MS. GREB: Objection. Vague as to
`5 time.
`6 A It would be 500 nanomoles per liter or
`7 18 micrograms per deciliter, depending on which
`8 measure you would like to use.
`9 Q Would a person of ordinary skill in the art
`10 believe that is the threshold for normal?
`11 A Well, there's some debate about what normal is.
`12 And the literature would suggest there is some
`13 wiggle in that threshold. Some people say it
`14 needs to be 20 micrograms per deciliter based on
`15 data in the literature. Others say 18 is
`16 sufficient. But it's approximately the same.
`17 Q What are the symptoms of low adrenal reserve?
`18 A The symptoms of low adrenal reserve may be none.
`19 In other instances there might be fairly
`20 nonspecific symptoms like fatigue, poor appetite,
`21 lack of energy, and stamina.
`22 Q And why would a person of ordinary skill in the
`23 art believe low adrenal reserve could be an issue
`24 for patients?
`25 A A low adrenal reserve would be an important issue
`
`Page 15
`
`Page 17
`
`1 forerunner to adrenal insufficiency where adrenal
`2 function is partially compromised but not yet
`3 fully compromised such that a person might be able
`4 to meet basic cortisol production needs but could
`5 not augment cortisol production at times of great
`6 stress.
`7 I've been warned that using analogies is
`8 probably not a good idea in this proceeding, but I
`9 can't help myself in this case to say low adrenal
`10 reserve might be like a car whose engine is not
`11 working properly and can only go 30 miles an hour.
`12 You can get around town okay in that car, but take
`13 it out on the freeway and you're likely to have
`14 trouble.
`15 Q And how is low adrenal reserve diagnosed?
`16 A It would usually be diagnosed by the Synacthen
`17 test.
`18 Q Are there any other methods a person of ordinary
`19 skill in the art would use in determining
`20 definitively whether or not a patient had low
`21 adrenal reserve?
`22 A No, I don't think so.
`23 Q And when you refer to low adrenal reserve, how do
`24 you define low?
`25 A Low adrenal reserve would be defined as achieving
`
`1 because that individual will probably do fine in
`2 day-to-day life as long as nothing stressful
`3 happens. But should that person become ill, say
`4 develop pneumonia or some significant illness, or
`5 should that person require surgery, perhaps urgent
`6 surgery, they could quickly decompensate because
`7 of the low adrenal reserve and inability to
`8 augment cortisol production as would be necessary
`9 to meet the stress.
`10 Q What illnesses could lead to a decompensation with
`11 respect to low adrenal reserve?
`12 A All sorts of illnesses. The more serious the
`13 illness, the more likely the patient would be
`14 compromised. Pneumonia, as I previously
`15 mentioned, would be one that comes immediately to
`16 mind. Any sort of infectious process would
`17 potentially put the person at risk. Numerous
`18 other medical conditions that provide major stress
`19 for the body would potentially lead to
`20 decompensation.
`21 Q To your knowledge, does metastatic resistant --
`22 (Reporter interrupts)
`23 Q To your knowledge, does metastatic resistant --
`24 I'm sorry, let me start that again. To your
`25 knowledge, does metastatic castrate resistant
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`Page 18
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`Page 20
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`1 prostate cancer lead to a decompensation?
`2 MS. GREB: Objection. Outside the
`3 scope of the report.
`4 A I think the answer is perhaps. If the person has
`5 simply been medically or surgically castrated,
`6 that won't lead to decompensation, at least after
`7 the surgical procedure has been accomplished. But
`8 if it's metastatic, it depends on the status of
`9 the metastases. If there's an isolated metastasis
`10 somewhere in the bone or the lung then perhaps
`11 not. But if they're more diffuse metastases or if
`12 the metastases have struck an important part of
`13 the body, then yes, decompensation could occur and
`14 could occur rapidly.
`15 Q And would a person of ordinary skill in the art in
`16 2006 believe that a patient with metastatic
`17 castration resistant prostate cancer necessarily
`18 have a low adrenal reserve?
`19 MS. GREB: Objection. Outside the
`20 scope of the report.
`21 Q Or could lead to a decompensation? I'm sorry.
`22 A Could you restate the question? I'm not sure I
`23 understand it.
`24 Q Sure. It wasn't a very good one. Would a person
`25 of ordinary skill in the art in 2006 believe that
`
`1 patient's complaints, their exam, their blood
`2 pressure, whether they were headed down that path
`3 or, alternatively, whether they were still
`4 supported by adequate adrenal function. It would
`5 be a judgment call.
`6 Q So is it fair to say the patient may or may not
`7 develop an adrenal crisis -- strike that. So
`8 would it be fair to say in a patient that I just
`9 described, that patient may or may not develop
`10 adrenal crisis?
`11 MS. GREB: Objection. Vague and
`12 incomplete hypothetical.
`13 A Yes.
`14 Q What is the difference between adrenal
`15 insufficiency and low adrenal reserve?
`16 A Adrenal insufficiency would be the completed
`17 disorder where the adrenal glands are
`18 malfunctioning and not meeting body needs.
`19 Low adrenal reserve would be a situation
`20 where in a baseline state body needs are being
`21 met, but there would be potential for
`22 decompensation in a more stressful situation.
`23 Q Can a patient have adrenal insufficiency without
`24 low adrenal reserve?
`25 MS. GREB: Objection. Incomplete
`
`Page 19
`
`Page 21
`
`1 a patient with metastatic castrate resistant
`2 prostate cancer be prone to having an adrenal
`3 crisis?
`4 MS. GREB: Same objection. Also
`5 vague.
`6 A Well, if I understand your question -- I'm not
`7 sure I do yet -- the person would not have a
`8 reason to have adrenal insufficiency because they
`9 have not been given abiraterone or any other
`10 situation that would lead to adrenal problems. So
`11 I think it would be unlikely to worry about that,
`12 but it would be something to keep in the back of
`13 one's mind.
`14 Q Good point. So let me try rephrasing the question
`15 a third time. Would a person of ordinary skill in
`16 the art in 2006 believe that a patient with
`17 metastatic castration resistant prostate cancer
`18 who had been treated with abiraterone acetate
`19 would be prone to an adrenal crisis?
`20 MS. GREB: Objection. Same
`21 objection. Vague and incomplete
`22 hypothetical.
`23 A But my answer would be yes. That would be at the
`24 forefront of one's mind, and one would have to
`25 make a judgment based on the situation, the
`
`1 hypothetical. Vague.
`2 A Would you restate it. I got distracted.
`3 Q Sure. Can a patient have adrenal insufficiency
`4 without low adrenal reserve?
`5 MS. GREB: Same objections.
`6 A By definition, someone with adrenal insufficiency
`7 has low to nonexistent adrenal reserve. So if you
`8 have adrenal insufficiency, I think the other
`9 condition has already occurred.
`10 Q And let's -- let me ask the question the other
`11 way. Can a patient with low adrenal reserve not
`12 develop adrenal insufficiency?
`13 MS. GREB: Same objections.
`14 A Yes. I think hypothetically it's possible for
`15 someone to exist for many years indefinitely with
`16 low adrenal reserve and without decompensating to
`17 complete adrenal insufficiency.
`18 Q And your declaration also talks about
`19 mineralocorticoid excess. What is
`20 mineralocorticoid excess?
`21 A It is a condition where the adrenal glands
`22 overproduce mineralocorticoids, principally
`23 aldosterone which is the most potent of the
`24 corticoids. It's a fairly common condition often
`25 produced -- it's a condition where -- often
`
`6 (Pages 18 - 21)
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`Page 22
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`1 produced by adrenal tumors where there is
`2 overproduction of mineralocorticoids, of which
`3 aldosterone is the most important. This leads to
`4 avid retention of sodium such that it's not
`5 adequately secreted in the urine, and that sodium
`6 retention causes fluid retention, high blood
`7 pressure, and also low potassium develops. And
`8 over time those things can be very problematic.
`9 Q And how is mineralocorticoid excess generally
`10 diagnosed?
`11 A The usual way of making that diagnosis would be to
`12 measure plasma aldosterone and plasma renin
`13 activity and then divide plasma aldosterone by
`14 plasma renin to determine the aldosterone-renin
`15 ratio.
`16 (Reporter interrupts)
`17 A And if that ratio is high, that would suggest
`18 hyperaldosteronism. One would then proceed to a
`19 confirmatory test, like measuring 24 urine
`20 aldosterone, and if that test is positive, the
`21 diagnosis would be made.
`22 Q Are there any other considerations that a person
`23 of ordinary skill in the art would take into
`24 account in making a diagnosis for
`25 mineralocorticoid excess?
`
`Page 24
`1 A Well, in adrenal insufficiency you typically have
`2 inadequate amounts of cortisol and you usually
`3 also would have inadequate amounts of
`4 mineralocorticoids. That would lead to things
`5 like low blood pressure, low blood sugar, loss of
`6 appetite, nausea, vomiting, weight loss.
`7 With mineralocorticoid excess you would have
`8 adequate amounts of cortisol but excessive amounts
`9 of aldosterone, the principal one being
`10 mineralocorticoid, and that would lead to a
`11 situation where you might feel fine. Appetite,
`12 energy, stamina might all be normal, but your
`13 blood pressure would be high, and you would be
`14 likely to develop low potassium. So you might not
`15 be aware anything is wrong until your doctor
`16 determined, oh, your blood pressure is too high
`17 and your potassium is too low.
`18 Q And is it true that mineralocorticoid excess is
`19 rarely due to a defect in cortisol biosynthesis?
`20 MS. GREB: Objection. Vague.
`21 A Would you restate that, please.
`22 Q Sure. Is it true that mineralocorticoid excess is
`23 rarely due to a defect in cortisol biosynthesis?
`24 MS. GREB: Objection. Vague.
`25 A Yes, I think that's correct. In the usual kind of
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`Page 23
`1 A Well, one might give passing thought to genetic
`2 disorders that can produce mineralocorticoid
`3 excess, which would be orders of magnitude less
`4 common than the usual hyperaldosteronism,
`5 mineralocorticoid excess, and then different tests
`6 might be considered.
`7 Q And what would those tests be?
`8 A It would depend on the specific genetic defect, an
`9 enzyme abnormality that one is searching for. And
`10 I think one might measure things like
`11 11-deoxycorticosterone or corticosterone to see if
`12 they were present in abnormal amounts or higher
`13 than normal levels. But let me also add if I may
`14 that encountering that situation, I think a person
`15 of average skill in the art would probably have to
`16 refer to the literature to look up the specific
`17 tests that would be definitive. And if you want
`18 me to say with certainty what tests I would order,
`19 I would have to do that too.
`20 Q And mineralocorticoid excess is not the same as
`21 adrenal insufficiency; is that right?
`22 A Yes. They're different disorders, sort of
`23 opposite disorders producing opposite sorts of
`24 problems.
`25 Q What do you mean by opposite disorders?
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`Page 25
`1 mineralocorticoid excess, cortisol production is
`2 normal.
`3 Q Of these different groups we talked about of
`4 adrenal insufficiency, low adrenal reserve, and
`5 mineralocorticoid excess, which would a person of
`6 ordinary skill in the art in 2006 be the most
`7 concerned about upon treatment with abiraterone
`8 acetate?
`9 MS. GREB: Objection. Vague.
`10 Incomplete hypothetical. Outside the scope
`11 of the report.
`12 A In my opinion, it would be adrenal insufficiency.
`13 That is potentially the most serious and
`14 potentially catastrophic. If that diagnosis is
`15 not made and treatment not provided, the person is
`16 at risk to die, and it can be fairly quickly.
`17 The other two situations are also serious but
`18 are more insidious and slowly progressing, slow
`19 enough time to determine if they are present and
`20 address treatment for them if they are.
`21 Q Your report refers to three steroid pathways:
`22 antigen, glucocorticoid, and mineralocorticoid. I
`23 think, as we discussed earlier, those different
`24 pathways are not exclusive in that, for example,
`25 corticosterone can have cortisol or glucocorticoid
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`Page 26
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`1 activity; is that right?
`2 MS. GREB: Objection. Vague. And
`3 I'd just mention your report's in front of
`4 you if you need to take a look at it.
`5 A Yes. But let me qualify to say that normally
`6 production of corticosterone is trivial, so it
`7 doesn't contribute in any meaningful way.
`8 Q But corticosterone can play a role in preventing
`9 the development of adrenal insufficiency; isn't
`10 that correct?
`11 MS. GREB: Objection. Vague.
`12 A I think potentially corticosterone could prevent
`13 adrenal insufficiency if present in very large
`14 amounts. And I would add I don't know of good
`15 literature that would address how effective it
`16 would be or what amounts would be necessary.
`17 Q Well, let me ask you -- let me direct your
`18 attention to paragraph 58 in your report, footnote
`19 -- I believe it's 3. Footnote 6, I'm sorry, on
`20 page 35. Do you see the first sentence?
`21 A I'm sorry, first sentence of footnote 3.
`22 Q Of footnote 6, I'm sorry. I misspoke. On page
`23 58.
`24 A Paragraph 58?
`25 Q Let me try again. Page 35.
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`Page 28
`1 developing adrenal insufficiency, and that would
`2 be understood by a person of ordinary skill in the
`3 art in 2006; correct?
`4 MS. GREB: Objection. Misstates
`5 the report. The report is in the record and
`6 says what it says.
`7 A Yes, but it would take a very large amount of
`8 corticosterone, and I think no one could tell you
`9 how much would be necessary and if the adrenal
`10 glands could produce that much.
`11 Q Okay. And are you aware that corticosterone has
`12 about the same glucocorticoid activity in humans
`13 as cortisol?
`14 MS. GREB: Objection. Outside the
`15 scope of the report. Incomplete hypothetical
`16 and vague.
`17 A No. It's my opinion and understanding it has less
`18 glucocorticoid activity than cortisol.
`19 Q Now I'd like to talk about steroid biosynthesis.
`20 The biosynthesis of all steroids begins with
`21 cleavage of the side chain of cholesterol to
`22 pregnenolone; correct?
`23 MS. GREB: Objection. Vague.
`24 Incomplete hypothetical.
`25 A Yes.
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`Page 27
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`Page 29
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`1 A Uh-huh.
`2 Q Footnote 6. I'm sorry for causing that confusion.
`3 At the very bottom of the page.
`4 A I don't se