UNITED STATES PATENT AND TRADEMARK OFFICE
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`Page 1
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`WOCKHARDT BIO AG, CASE IPR2016-01582
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` PETITIONER, PATENT 8,822,438
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`vs.
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`JANSSEN ONCOLOGY, INC.,
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` PATENT OWNER.
`
`___________________________
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` TUESDAY, MARCH 7, 2017
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` - - -
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` VIDEOTAPED DEPOSITION of PAUL A. GODLEY, M.D.,
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`PH.D., MPP, taken at the offices of Sterne Kessler
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`Goldstein Fox, 1100 New York Avenue NW, Suite 600,
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`Washington, D.C., beginning at 9:06 a.m., before
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`Nancy J. Martin, a Registered Merit Reporter, Notary
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`in and for the District of Columbia.
`
` Veritext Legal Solutions
`
` Mid-Atlantic Region
`
` 1250 Eye Street NW - Suite 350
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` Washington, D.C. 20005
`
`Veritext Legal Solutions
`215-241-1000 ~ 610-434-8588 ~ 302-571-0510 ~ 202-803-8830
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`JANSSEN EXHIBIT 2162
`Wockhardt v. Janssen IPR2016-01582
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`

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`Page 2
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`Page 4
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`1 EXHIBITS PREVIOUSLY MARKED
`2 NUMBER Description Page
`3 Exhibit Declaration of Paul Godley, M.D. 7
`1002
`
`4
`
`Exhibit Prostate Specific Antigen for 125
`5 1004 Assessing Response to Ketoconazole
` and Prednisone in Patients with
`6 Hormone Refractory Metastatic
` Prostate Cancer, 3 pages
`
`7
`
`Exhibit Hormonal Impact of the 98
`8 1005 17x-hydroxylase/C.20-lyase inhibitor
` Abiraterone acetate in patients
`9 with prostate cancer, 9 pages
`10 Exhibit Effect of Prednisone on 118
`1006 Prostate-Specific Antigen in
`11 Patients with Hormone-Refractory
` Prostate Cancer, 5 pages
`
`12
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`Exhibit Two Prevalent CUUP17 Mutations and 54
`13 1014 Genotype-Phenotype Correlations in
` 24 Brazilian Patients with
`14 17-Hydroxylase Deficiency, 12 pages
`15 Exhibit Two Prevalent C YP17 Mutations and 138
`1030 Genotype-Phenytype Correlations in
`16 24 Brazilian Patients with
` 17-Hydroxylase Deficiency, 12 pages
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`17
`18
`19
`20
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`Page 3
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`Page 5
`1 WASHINGTON, D.C., TUESDAY, MARCH 7, 2017; 9:06 A.M.
`2 - - -
`3 THE VIDEOGRAPHER: Good morning. My name is
`4 Solomon Francis, representing Veritext. Today's date
`5 is March 7, 2017. The time is approximately 9:06 a.m.
`6 This deposition is being held by the law offices of
`7 Sterne, Kessler, Goldstein & Fox, located at
`8 1100 New York Avenue, Northwest, Washington, D.C. and
`9 is taken by counsel for the patent owner. Caption of
`10 this case is Wockhardt Bio AG, Petitioner, v. Janssen
`11 Oncology, Inc., Patent Owner. This case is being held
`12 in the United States Patent and Trademark Office.
`13 Case No. IPR2016-01582. The name of the witness is
`14 Dr. Paul A. Godley.
`15 At this time will counsel present please
`16 identify themselves and the parties they represent.
`17 MR. KRAUSE: Todd Krause of Sidley Austin for
`18 patent owner, Janssen.
`19 MR. POWERS: Ralph Powers, III, Sterne,
`20 Kessler, Goldstein & Fox for Wockhardt.
`21 MR. GALLO: Christopher Gallo from Sterne,
`22 Kessler, Goldstein & Fox for Wockhardt.
`23 THE VIDEOGRAPHER: At this time our court
`24 reporter, Nancy Martin, representing Veritext, will
`25 swear the witness and we can proceed.
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`2 (Pages 2 - 5)
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`1 A P P E A R A N C E S :
`2
`
` STERNE KESSLER GOLDSTEIN FOX
`3 BY: R. WILSON POWERS III, Ph.D., ESQ.
` CHRISTOPHER GALLO, ESQ.
`4 1100 New York Avenue NW
` Suite 600
`5 Washington, D.C. 20005
` (202) 371-2600
`6 tpowers@skgf.com
` Representing Wockhardt Bio AG
`
`789
`
` SIDLEY AUSTIN LLP
` BY: TODD L. KRAUSE, ESQ.
`10 787 Seventh Street
` New York, New York 10019
`11 (212) 839-5696
` tkrause@sidley.com
`12 Representing Janssen Oncology Inc.
`13
`14
`15 ALSO PRESENT:
`16 SOLOMON FRANCIS, LEGAL VIDEOGRAPHER
`17
`18
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`20
`21
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`1 I N D E X
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`2
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`3
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`TESTIMONY OF PAUL A. GODLEY, M.D., PH.D.
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`BY MR. KRAUSE 6
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`45
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` E X H I B I T S
`6 NUMBER DESCRIPTION MARKED
`7 Exhibit Declaration of Marc B. Garnick, 142
`2015 M.D., 93 pages
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`8
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`Exhibit Deposition Transcript of Marc B. 144
`9 2016 Garnick, M.D., 49 pages
`10 Exhibit Declaration of Dr. Scott R. Serels, 147
`2017 46 pages
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`11
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`Exhibit Deposition Transcript of Scott R. 148
`12 2018 Serels, M.D., 9 pages
`13 Exhibit Declaration of Dr. Scott R. Serels, 149
`2019 M.D., 13 pages
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`14
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`Exhibit Deposition Transcript of Scott 150
`15 2020 Serels, M.D., 90 pages
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`1 Q. Is the declaration marked as Wockhardt 1002
`2 an accurate statement of the opinions that you've
`3 reached in this case?
`4 A. Yes, it is.
`5 Q. Doctor, we'll be talking a lot about a person
`6 of ordinary skill in the art today. When I refer to a
`7 person of ordinary skill in the art, or POSA, P-O-S-A,
`8 I'm referring to the person as you've defined it in
`9 your expert report. Is that understood?
`10 A. I understand.
`11 Q. And when we talk about that person's
`12 knowledge, it refers to that person's knowledge as of
`13 August 25, 2006. Is that also understood?
`14 A. That is understood.
`15 Q. What is metastatic castration-resistant
`16 prostate cancer?
`17 (The witness further reviewed Exhibit 1002.)
`18 THE WITNESS: So it doesn't appear I define
`19 it directly, but "metastatic" implies that the cancer
`20 has spread beyond the region around the prostate to
`21 usually bone or lymph node. "Castrate resistance"
`22 implies a prostate cancer is no longer responding to
`23 our typical hormonal strategies of antiandrogen
`24 withdrawal. So by definition --
`25 REPORTER MARTIN: I'm sorry. Can you speak
`
`1 PAUL A. GODLEY, M.D., PH.D.,
`2 having been first sworn,
`3 was examined and testified as follows:
`
`4 5
`
` EXAMINATION
`6 BY MR. KRAUSE:
`7 Q. Good morning, Dr. Godley. Can you please
`8 state your name and home address for the record.
`
`
`11 Q. Have you ever been deposed before?
`12 A. I have.
`13 Q. There are a few points that I'd like to
`14 review before we get started. If I ask a question
`15 that isn't clear or you didn't hear me, please let me
`16 know so I can ask the question again. If you answer,
`17 I'll assume that you understood and heard my question.
`18 Okay?
`19 A. Yes.
`20 Q. We have a court reporter taking down your
`21 answers to my questions. So please try to give verbal
`22 answers to my questions. Okay?
`23 A. Yes.
`24 Q. And we'll try to take breaks about every hour
`25 or so, but please let me know if you need a break.
`
`Page 7
`1 I'll finish up my line of questions that I'm on, and
`2 then we can take a break. Okay?
`3 A. Yes.
`4 Q. Is there any reason you cannot give complete
`5 and accurate testimony here today?
`6 A. Not that I know of.
`7 MR. KRAUSE: I'm handing you a document
`8 that's been marked as -- I apologize. I don't have
`9 additional copies, but I'm sure you have a copy.
`10 A document that's been previously marked as
`11 Wockhardt Exhibit 1002.
`12 (Previously marked Exhibit 1002 was handed
`13 to the witness.)
`14 BY MR. KRAUSE:
`15 Q. Is this your declaration?
`16 A. It appears to be.
`17 Q. Would you like to review it to confirm?
`18 A. I would.
`19 (The witness reviewed Exhibit 1002.)
`20 BY MR. KRAUSE:
`21 Q. Is this your declaration?
`22 A. It is.
`23 Q. And is that your signature on the last page
`24 of the declaration?
`25 A. It is.
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`Page 9
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`1 up just a little bit, sir. "is no longer responding
`2 to typical" --
`3 THE WITNESS: Antiandrogen. Antiandrogens.
`4 And so by definition, resistant to castration, and
`5 castration is this withdrawal of androgens.
`6 BY MR. KRAUSE:
`7 Q. And is metastatic castration-resistant
`8 prostate cancer sometimes referred to as "MCRPC"?
`9 A. Yes, it is.
`10 Q. As of August 25, 2006, the prognosis for
`11 patients with MCP- -- let me start that again.
`12 As of August 25, 2006, the prognosis for
`13 patients with MCRPC was poor, and treatment focused on
`14 palliative care; is that correct?
`15 A. That is correct.
`16 Q. What treatment options would a person of
`17 ordinary skill in the art use in August 25, 2006 to
`18 treat MCRPC?
`19 A. So these would typically be patients who have
`20 failed Lupron. So they've failed first-line therapy,
`21 which makes the metastatic castrate resistant. And
`22 then they would receive, potentially, an antiandrogen,
`23 like Casodex or flutamide. They would then, failing
`24 that, potentially get ketoconazole and hydrocortisone.
`25 And, potentially, failing that, they may get
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`1 hydrocortisone alone or mitoxantrone chemotherapy
`2 agent.
`3 Q. So is it fair to say, then, that the
`4 first-line therapies were hormonal treatments? Is
`5 that right?
`6 A. So your question was treatment of metastatic
`7 castrate-resistant prostate cancer. So this would be
`8 after --
`9 Q. I see.
`10 A. -- hormonal treatment.
`11 Q. Okay. So hormonal treatment would precede
`12 this?
`13 A. Right. So in their failure of hormonal
`14 treatment would meet the criteria for castrate
`15 resistant. So even though your question started with
`16 castrate resistant, I did mention that they would have
`17 gotten something like Lupron or a bilateral
`18 orchiectomy first. After that, then their next
`19 treatment would be their first castrate -- metastatic
`20 castrate-resistant prostate cancer treatment, would
`21 likely be an antiandrogen, hydrocortisone and
`22 ketoconazole, potentially prednisone ketoconazole,
`23 potentially prednisone alone, a drug like mitoxantrone
`24 or another chemotherapy drug. Docetaxel was also
`25 available at that time.
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`Page 11
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`1 Q. I think in your report you talk about
`2 docetaxel?
`3 A. Yes.
`4 Q. So and docetaxel is a chemotherapy; is that
`5 right?
`6 A. Yes.
`7 Q. Where would the use of chemotherapy fit into
`8 kind of the landscape of therapies that a person of
`9 skill in the art would use for the treatment of
`10 prostate cancer in this 2006 time frame?
`11 A. There was, I think, incentives on the parts
`12 of physician to delay the use of chemotherapy because
`13 it's much less convenient for the patient who would
`14 have to come in every three weeks instead of every
`15 months, and the chemotherapy side effects tended to be
`16 more dramatic.
`17 And so there was a tendency to shift -- even
`18 though chemotherapy could be used earlier in these
`19 patients, it shifted later because you keep patients
`20 at home more and use oral therapies. And the
`21 antiandrogens were oral, the ketoconazole and
`22 prednisone were also oral. So there was a tendency to
`23 shift patients to use oral, oral hormonal treatments
`24 earlier.
`25 The advantage of both mitoxantrone and
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`Page 12
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`1 docetaxel are that they're pretty effective in
`2 patients who have symptoms. So if you have a patient
`3 who is symptomatic, then the tendency would be to move
`4 chemotherapy up in your treatment paradigm because
`5 it's pretty well established the patient can have
`6 pretty dramatic palliation of their symptoms.
`7 Q. I see. And what is -- I apologize if you
`8 touched on this before, but what is "androgen
`9 deprivation therapy"?
`10 A. So androgen deprivation therapy is the analog
`11 of being castrate resistant. Prostate cancer as a
`12 disease feeds on androgens so that withdrawal of
`13 androgens can elicit a remarkable response. A guy
`14 named Hopps won the noble prize by figuring out in
`15 1960, figuring out that castrating men with metastatic
`16 prostate cancer led to a dramatic, prolonged sort of
`17 response in their cancer.
`18 So that -- we haven't gotten too far away
`19 from that, that it's clear that taking hormones either
`20 by bilateral orchiectomy or by -- with chemical like
`21 Lupron, removing hormones can have a dramatic effect
`22 in patients with metastatic prostate cancer.
`23 The problem that we face now is it doesn't
`24 last. And so a year later or two years later, you're
`25 faced with a patient who has, again, increasing
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`Page 13
`1 prostate cancer, your energy withdrawal therapy,
`2 either the castration or Lupron has stopped working,
`3 and now you need a sort of second line of therapy that
`4 would be effective in patients that are no longer
`5 responding to this antiandrogen withdrawal.
`6 Q. And that's where the physician would start
`7 using chemotherapy if they didn't decide to use it
`8 earlier; is that correct?
`9 MR. POWERS: Objection. Form.
`10 THE WITNESS: The -- there are a couple
`11 choices.
`12 BY MR. KRAUSE:
`13 Q. Okay.
`14 A. So the prevailing theory at the time was that
`15 there are additional androgens that are driving the
`16 prostate cancer after essentially eliminated androgens
`17 coming from the testicles, that there are additional
`18 androgens that are driving the prostate cancer, and
`19 the next step would be to eliminate those androgens
`20 and potentially get another response of the prostate
`21 cancer.
`22 And so there was a focus for decades on how
`23 to effectively eliminate adrenal androgens, and that's
`24 where drugs like -- well, Casodex has a different
`25 mechanism that's an antiandrogen, but drugs like
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`1 ketoconazole had come out to eliminate the synthesis
`2 of androgens coming from the adrenal gland.
`3 And that -- those are also effective, not as
`4 dramatic as the initial treatment, but they're also
`5 effective and they're also limited in terms of how
`6 long they'll be effective.
`7 So after maybe trying an antiandrogen, which
`8 blocks androgens at the receptor sites on prostate
`9 cancer cells, and after blocking adrenal androgens,
`10 then, typically you're ready for chemotherapy, which
`11 is a bigger deal in a number of ways, both for the
`12 patient and in terms of side effects.
`13 Q. Okay. I think you just referred to blocking
`14 adrenal androgens, and I think you mentioned
`15 ketoconazole, and you said, "drugs like ketoconazole."
`16 What other drugs were physicians using to try to block
`17 the adrenal androgens?
`18 MR. POWERS: Objection. Form.
`19 THE WITNESS: Aminoglutethimide is a drug
`20 that similarly blocks --
`21 REPORTER MARTIN: I'm sorry. What was --
`22 THE WITNESS: Aminogluthethimide.
`23 Works similarly in ablating adrenal steroid
`24 hormone synthesis and certainly abiraterone was known
`25 to be a drug that had a similar effect on adrenal
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`Page 16
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`1 treatment of metastatic castrate-resistant disease,
`2 and that can take on many forms that I discussed,
`3 antiandrogens, drugs that inhibit steroid hormone
`4 synthesis, various chemotherapy agents, and they're
`5 all mixed together in this category and can be used --
`6 and they've been moved back and forth in the treatment
`7 paradigm, depending on what exactly the issues are
`8 with that particular patient and their preferences.
`9 Q. And the combination of docetaxel and
`10 prednisone is a standard of care for patients that
`11 progressed on the androgen deprivation therapy; right?
`12 A. Yes.
`13 Q. But I think you indicated earlier, again it
`14 would depend on the patient profile as to when that
`15 combination might be used in the treatment of
`16 patients?
`17 A. Correct. And it's not uncommon -- it would
`18 not be uncommon for patients to say they don't want
`19 chemotherapy, and if you have some intermediate
`20 therapy that will keep their disease in check, that
`21 that's what they would prefer. So that's not
`22 uncommon.
`23 Q. And was the combination of docetaxel and
`24 prednisone combined -- approved for the use -- let me
`25 start that again.
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`Page 15
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`Page 17
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`1 androgens.
`2 BY MR. KRAUSE:
`3 Q. Any others that you can think of?
`4 MR. POWERS: Objection. Form.
`5 THE WITNESS: Those are the ones that come to
`6 mind.
`7 BY MR. KRAUSE:
`8 Q. Okay. And in August of 2006 a person of
`9 ordinary skill in the art would have known that the
`10 combination of docetaxel and prednisone was a standard
`11 of care for patients who progressed on androgen
`12 deprivation therapy; is that right?
`13 A. That is correct.
`14 Q. And just so I kind of understand the language
`15 here, the first-line therapy, those would be the
`16 antiandrogens, and then the second-line would be
`17 the -- blocking the adrenal androgens?
`18 MR. POWERS: Objection. Form.
`19 BY MR. KRAUSE:
`20 Q. Can you describe that.
`21 A. The first-line would be, essentially,
`22 treatment of hormone-sensitive disease, and that takes
`23 several forms, but all of it is withdrawal of
`24 androgens.
`25 The second step, much broader, is the
`
`1 Was the combination of docetaxel and
`2 prednisone approved for the use of prostate cancer
`3 around 2004?
`4 A. Yes.
`5 Q. And was it increasingly used by the time of
`6 2006?
`7 MR. POWERS: Objection. Form. Relevant.
`8 THE WITNESS: That is my understanding.
`9 BY MR. KRAUSE:
`10 Q. And is that because the combination of
`11 docetaxel and prednisone was the first and only known
`12 treatment for prostate cancer that provided a survival
`13 benefit?
`14 MR. POWERS: Objection. Form. Relevance.
`15 THE WITNESS: That is true. Up until that
`16 time, drugs had been approved for prostate cancer but
`17 only docetaxel and prednisone had demonstrated, to
`18 that point, a survival benefit.
`19 BY MR. KRAUSE:
`20 Q. So none of the drugs that had been used
`21 before the approval of docetaxel and prednisone had a
`22 survival benefit?
`23 A. Correct.
`24 Q. And that was also true as of August of 2006,
`25 docetaxel, prednisone were the only therapy that
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`1 provided a survival benefit; is that correct?
`2 MR. POWERS: Objection. Form.
`3 THE WITNESS: That is correct.
`4 BY MR. KRAUSE:
`5 Q. What is docetaxel?
`6 A. It's a chemotherapy drug. It stabilizes
`7 microtubules so that during the division process
`8 mitosis, where you need your microtubules to stretch
`9 and eventually break as you divide into two cells, the
`10 microtubules are stabilized. They don't stretch.
`11 They don't break. And so it uses that mechanism to
`12 essentially kill, or at least stop the growth, of
`13 prostate cancer cells.
`14 Q. What were the known side effects of docetaxel
`15 in 2006?
`16 A. Docetaxel caused -- could cause some decrease
`17 in blood counts. It could cause peripheral
`18 neuropathy. It could cause -- there were issues with
`19 excessive tearing from stenosis of the tear ducts. It
`20 causes nail changes. So patients would have
`21 discoloration of the fingernails and could have their
`22 fingernails come off. There were -- that's probably
`23 the major changes. Some alopecia associated with it.
`24 Fatigue.
`25 The major side effect for docetaxel was --
`
`1 Q. In August of 2006 a person of ordinary skill
`2 in the art would have known that docetaxel's mechanism
`3 of action is different than abiraterone acetate; is
`4 that right?
`5 A. Yes.
`6 Q. And a person of ordinary skill in the art in
`7 2006 would have known that before 2004 the standard of
`8 care would have been a combination treatment,
`9 mitoxantrone and prednisone; is that correct?
`10 MR. POWERS: Objection. Form. Foundation.
`11 THE WITNESS: I would say that before 2004
`12 there were a number of treatments for prostate cancer
`13 of modest efficacy, and even though mitoxantrone had
`14 been approved by the FDA for the treatment of prostate
`15 cancer, I would not say that was the standard just
`16 because it had, essentially, no effect on the disease
`17 itself.
`18 Mitoxantrone was approved by the FDA for its
`19 palliative effect. It was the first drug the FDA has
`20 ever approved that -- first chemotherapy drug that
`21 just had a palliative effect and didn't have a -- you
`22 know, a response rate or an effect on survival or
`23 decrease in PSA. It had none of that. So yes,
`24 mitoxantrone was the approved drug in that area, but
`25 because it was purely palliative, it was shunted more
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`1 the dose-limiting side effect was fatigue where
`2 patients would not be able to get out of bed for two
`3 or three days, potentially after receiving docetaxel.
`4 But that was incredibly variable with some patients
`5 not having much at all and some patients having
`6 overwhelming fatigue.
`7 Q. And was prednisone administered with
`8 docetaxel to address those side effects?
`9 A. Prednisone was administered with docetaxel to
`10 address those side effects. I'm not quite so sure if
`11 it addressed any of the side effects. The randomized
`12 trials that were done comparing the standard up to
`13 them, as far as chemotherapy, was mitoxantrone and
`14 prednisone.
`15 So the analogous treatment arm with docetaxel
`16 was docetaxel and prednisone, and then it was approved
`17 with prednisone. The role that prednisone played
`18 was -- in terms of side effects, I think is unclear.
`19 Certainly prednisone has its own modest effect on
`20 prostate cancer.
`21 Q. But prednisone wasn't demonstrated to enhance
`22 the survival benefit of docetaxel, was it?
`23 A. There is no such demonstration. Prednisone
`24 has a benefit, but there's no such -- there's no such
`25 study showing that it adds to docetaxel.
`
`1 towards, I think, the end of the regimens that you
`2 would try and go through with your patients.
`3 BY MR. KRAUSE:
`4 Q. And when you say, "it was purely palliative,"
`5 the same is true with respect to the combination of
`6 mitoxantrone and prednisone?
`7 A. Yes. I'm sorry. I said mitoxantrone --
`8 MR. POWERS: Objection. Form.
`9 Caution the witness to let me interpose an
`10 objection before he answers.
`11 Thank you. You may go ahead.
`12 THE WITNESS: Now I forgot what I was going
`13 to say.
`14 When I said, "mitoxantrone," I meant
`15 mitoxantrone and prednisone. That's what is approved,
`16 mitoxantrone and prednisone combination, and that's
`17 what I was talking about. When I said, "mitoxantrone
`18 is palliative," I meant the combination.
`19 BY MR. KRAUSE:
`20 Q. And what is mitoxantrone?
`21 A. Mitoxantrone is a cytotoxic chemotherapy
`22 agent. The mechanism also affects mitosis. I can't
`23 remember what exact mechanism that it uses, but it
`24 also affects dividing cells. It's pretty effective in
`25 several other tumor types, but in prostate cancer it
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`1 only helps with pain, and, you know, patients have a
`2 better feeling when they're getting mitoxantrone. So
`3 it helps with their outlook on life.
`4 But for the objective indicators that we
`5 had -- by then we had PSA -- it did not affect the
`6 PSA. So if you were interested, you know, in your
`7 putting together regimens for treating a patient, if
`8 you're -- if you have an ambulatory patient that were
`9 interested in being treated aggressively, then you
`10 would not use mitoxantrone.
`11 Q. I see. So the combination of mitoxantrone
`12 and prednisone do not have an anticancer effect?
`13 A. Correct.
`14 Q. And what were the known side effects of
`15 mitoxantrone?
`16 A. Mitoxantrone had a much more prominent effect
`17 on suppressing your bone marrow production of red
`18 cells, platelets, and white cells. So that creates a
`19 bit more of a management problem in keeping track of
`20 these blood counts and supplementing them when
`21 necessary. Mitoxantrone, at higher cumulative dose
`22 levels does -- can have an effect on the heart, and
`23 that's been documented. It's not as bad as some other
`24 drugs, but it does have that.
`25 Those are probably the primary mitoxantrone
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`Page 24
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`1 BY MR. KRAUSE:
`2 Q. So would that -- what sorts of treatments are
`3 you aware of that were being explored at that time for
`4 the treatment of MCRPC?
`5 A. Well, certainly better antiandrogens were
`6 being explored, and abiraterone was actively being
`7 investigated, and lots of -- several Taxotere analogs
`8 were also under investigation. So, you know, drugs
`9 similar to what we already had. Better drugs, but
`10 similar to the ones we already had were being looked
`11 at.
`12 Q. And when you refer to "Taxotere," are those
`13 chemotherapy agents?
`14 A. Docetaxel -- oh, yeah. The more microtubules
`15 stabilizers have worked in the same way that docetaxel
`16 does.
`17 Q. And were combinations of different drugs also
`18 being looked at in that time period for the treatment
`19 of MCRPC?
`20 MR. POWERS: Objection. Form.
`21 THE WITNESS: There wasn't as much enthusiasm
`22 about combinations. My impression is that the
`23 enthusiasm for combinations comes after you have a
`24 really effective intervention, and at that point, I
`25 guess, docetaxel was clearly effective, but there
`
`Page 23
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`Page 25
`
`1 side effects to be aware of.
`2 Q. And was prednisone coadministered with
`3 mitoxantrone to treat side effects?
`4 A. Prednisone was coadministered with
`5 mitoxantrone, and again, the rationale for
`6 coadministering it I think is unclear. It certainly,
`7 since mitoxantrone was primarily palliative and
`8 prednisone is primarily palliative, there may have
`9 been some additive effect of using the two together in
`10 that situation. So it does make some sense.
`11 But I don't think prednisone directly
`12 addresses the lower blood counts or the possibility of
`13 myocardial damage in terms of making these things not
`14 happen. I don't think prednisone does that.
`15 Q. And the person of ordinary skill in the art
`16 in 2006, August of 2006 would have known that
`17 mitoxantrone's mechanism of action was different than
`18 that of abiraterone acetate; is that correct?
`19 A. That is correct.
`20 Q. And as of August 25, 2006, a number of
`21 treatments for MCRPC were being explored; is that
`22 correct?
`23 MR. POWERS: Objection. Form.
`24 THE WITNESS: As far as I know, a number of
`25 treatments were being explored.
`
`1 weren't other clearly effective drugs to combine it
`2 with that were available at that time.
`3 BY MR. KRAUSE:
`4 Q. So is it fair to say that in August of 2006 a
`5 person of ordinary skill in the art would not have
`6 been aware of any drug combinations for the treatments
`7 MCRPC where one drug had been demonstrated to extend
`8 survival benefit in combination with another drug?
`9 MR. POWERS: Objection. Form.
`10 THE WITNESS: Well, certainly, prednisone was
`11 being used with other drugs, but I don't think I'd --
`12 since the rationale for using prednisone in a lot of
`13 these regimens is, in some cases, to ameliorate side
`14 effects, other cases to have a mild effect in
`15 combination -- antitumor effect in combination with
`16 the main drug. So I would guess, you know, if you
`17 considered prednisone an alternative therapy, that
`18 there were some combinations with prednisone that a
`19 person of ordinary skill would have known about.
`20 But in terms of combining, say, two drugs
`21 known to improve survival, like docetaxel, there
`22 weren't two drugs to combine like that. So in term of
`23 how we normally think about combinations, we're taking
`24 two effective agents and putting them together really
`25 didn't have that opportunity at that time.
`
`7 (Pages 22 - 25)
`
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`Page 26
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`Page 28
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`1 BY MR. KRAUSE:
`2 Q. So then in August of 2006 a person of
`3 ordinary skill in the art would not have been aware of
`4 any drug combinations for the treatment of MCRPC where
`5 one drug had been demonstrated to extend the survival
`6 benefit in combination with another drug?
`7 A. That had been shown to -- that had also been
`8 shown to extend their survival benefit.
`9 Q. Yes.
`10 A. Right. I think that is an accurate
`11 statement.
`12 Q. And let's take the scenario where one drug
`13 had demonstrated a survival benefit but the other drug
`14 had not been demonstrated to provide a survival
`15 benefit. A person of ordinary skill in the art
`16 wouldn't have been aware of any combination of such
`17 drugs that would have provided an extended survival
`18 benefit; is that correct?
`19 MR. POWERS: Objection. Form.
`20 THE WITNESS: So one drug that does extend
`21 survival benefit combined with another drug that did
`22 not.
`23 BY MR. KRAUSE:
`24 Q. Yes.
`25 A. Well, I mean docetaxel is an example of that.
`
`1 BY MR. KRAUSE:
`2 Q. I'd like to shift gears a little bit and talk
`3 about steroids. The biosynthesis of all steroids
`4 begins with cleavage of the side chain of cholesterol
`5 to break down; is that correct?
`6 A. That is correct.
`7 Q. So if the conversion of cholesterol to
`8 pregnenolone is blocked, so is the biosynthesis of
`9 steroids; is that correct?
`10 A. If that were to occur completely, you have
`11 100 percent blockage of the cleavage of the steroid
`12 side arm, then side chain, then that would be true.
`13 It is not, as far as I know, the case with any
`14 intervention that you get 100 percent blockage of the
`15 side-chain cleavage.
`16 Q. And, in fact, no drug provides 100 percent
`17 inhibition. Is that fair to say?
`18 A. That's pretty -- that would be a good
`19 statement.
`20 Q. But if the cleavage of the side chain of
`21 cholesterol was blocked 100 percent, that would
`22 inhibit the biosynthesis of all steroids; correct?
`23 A. That is correct.
`24 Q. Your report refers to "CYP17." What is
`25 CYP17?
`
`Page 27
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`1 Q. But I believe you testified earlier that it's
`2 not clear that the survival benefit for docetaxel is
`3 extended by its combination?
`4 A. Oh. I see what you're saying.
`5 MR. POWERS: Objection. Form.
`6 THE WITNESS: So you're saying that you're
`7 getting a -- you're documenting a synergistic or some
`8 additive effect from the two --
`9 BY MR. KRAUSE:
`10 Q. Yes, Doctor.
`11 A. -- in terms of survival.
`12 Q. Yes, Doctor.
`13 A. That's pretty clearly not happening. So
`14 that's -- that would be nice, but that's pretty
`15 clearly not happening. I mean lots of combinations,
`16 they may be helpful, but it's not clear that there's
`17 any synergistic effect from these combinations.
`18 Q. So a person of ordinary skill in the art in
`19 2006 wouldn't have been aware of any combinations for
`20 the treatment of MCRPC where one drug that did extend
`21 survival benefit, another drug that did not, the sum
`22 of which would have even greater survival benefit than
`23 the first drug; is that correct?
`24 MR. POWERS: Objection. Form.
`25 THE WITNESS: I think that's accurate.
`
`Page 29
`1 A. It is a family of enzymes that work in the
`2 steroid synthesis, steroid hormone synthesis pathway.
`3 Q. And what does CYP17 do?
`4 A. It has a myriad of functions. It works on
`5 pregnenolone as a 17 alpha hydroxylase. It works
`6 on -- your copy didn't print very well here, but
`7 hydroxypregnenolone as a 17-20 lyase. So it works at
`8 various points to catalyze the development of both
`9 testosterone and cortisone.
`10 Q. Let's talk about the 17 hydroxylase activity
`11 of CYP17 first. I believe you indicated that -- well,
`12 what