`571-272-7822
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`IPR2016-01332, Paper No. 82
`June 27, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`MYLAN PHARMACEUTICALS INC., ACTAVIS
`LABORATORIES FL., INC., AMNEAL HARMACEUTICALS
`LLC, AMNEAL PHARMACEUTICALS OF NEW YORK, LLC,
`DR. REDDY'S LABORATORIES, INC., DR. REDDY'S
`LABORATORIES, LTD., SUN PHARMACEUTICALS
`INDUSTRIES, LTD., SUN PHARMACEUTICALS
`INDUSTRIES, INC., TEVA PHARMACEUTICALS USA, INC.,
`WEST-WARD PHARMACEUTICAL CORP., and HIKMA
`PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
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`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-01332
`Patent 8,822,438 B2
`____________
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`Held: May 24, 2017
`____________
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`BEFORE: LORA M. GREEN, RAMA G. ELLURU, and
`KRISTINA M. KALAN, Administrative Patent Judges.
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`The above-entitled matter came on for hearing on Wednesday,
`May 24, 2017, commencing at 1:00 p.m., at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
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`BRANDON M. WHITE, ESQUIRE
`ROBERT D. SWANSON, ESQUIRE
`Perkins Coie, LLP
`700 13th Street, N.W., Suite 600
`Washington, D.C. 20005-3960
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`Case IPR2016-01332
`Patent 8,822,438 B2
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`APPEARANCES:
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`ON BEHALF OF THE PETITIONER:
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`ON BEHALF OF PATENT OWNER:
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`DAVID T. PRITIKIN, ESQUIRE
`BINDU DONOVAN, ESQUIRE
`ALYSSA B. MONSEN, ESQUIRE
`Sidley Austin, LLP
`787 Seventh Avenue
`New York, New York 10019
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`Case IPR2016-01332
`Patent 8,822,438 B2
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`P R O C E E D I N G S
`- - - - -
`JUDGE ELLURU: Good afternoon. We are here for
`the hearing in IPR2016-01332, Mylan Pharmaceuticals, Inc.,
`versus Janssen Oncology, Inc. I'm Judge Elluru. To my right is
`Judge Green. Appearing remotely is Judge Kalan.
`Could we start with appearances of counsel, please.
`May counsel for Mylan approach and introduce counsel.
`MR. WHITE: Good afternoon, Your Honor. Brandon
`White from Perkins Coie for petitioner, Mylan. Also with me are
`my colleagues, Rob Swanson, Shannon Bloodworth, Bryan Beel,
`Maria Stubbings and Matt Reiner from Mylan.
`JUDGE ELLURU: Thank you. Welcome. And for
`patent owner, Janssen.
`MS. ELDERKIN: Good afternoon. I'm Dianne
`Elderkin for Janssen Oncology. Presenting argument today for
`Janssen is David Pritikin from Sidley & Austin. And assisting
`him at counsel table from Sidley are Bindu Donovan and Alyssa
`Monsen.
`JUDGE ELLURU: Thank you and welcome. I would
`like to go over how we'll proceed today. Each side will have
`35 minutes of total time to present its arguments. Please keep in
`mind that we have one panel member who is appearing remotely.
`Typically she is the only one who can't see the screen in the
`hearing, but I have heard that none of us are going to be able to
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`see the screen today, so please be sure to refer to demonstratives
`by slide number.
`Petitioner has the burden to show that the challenged
`claims are unpatentable and will thus present its case first. Patent
`owner will then argue its opposition to petitioner's case. If
`petitioner has reserved any time, petitioner can use that time for
`rebuttal. I will give you a warning when you are reaching the end
`of your argument time.
`Do counsel have any questions, starting with petitioner?
`MR. WHITE: No.
`JUDGE ELLURU: And patent owner?
`MR. PRITIKIN: No, Your Honor.
`JUDGE ELLURU: Thank you. Mr. White, you may
`proceed when you are ready.
`MR. WHITE: Your Honor, since we are doing this the
`old-fashioned way, would you like hard copies of the slides?
`JUDGE ELLURU: That would be great, thank you.
`Would counsel like to reserve any time for rebuttal?
`MR. WHITE: Yes, ten minutes, please. So good
`afternoon, Your Honors. Once we get through the large volume
`of paper in this case, the petitioners would submit that the only
`question in this proceeding that we really need to decide is
`whether the person of ordinary skill in the art, a practicing
`oncologist treating patients with prostate cancer, would be
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`motivated to combine abiraterone acetate with prednisone. We
`believe the answer to that question is yes.
`So why do we believe the answer to that question is
`yes? Well, if we turn to slide 37, we can start with the
`proposition that this was a patent that was allowed to issue only
`on the basis of commercial success. The patent owner never
`overcame the prior art or the merits during prosecution. The
`examiner allowed the claims based on the Examiner's conclusion
`on the record before him that Zytiga was a commercial success.
`So we believe during prosection and shown in the proceeding the
`patent owner never overcame the prior art. All of the elements of
`claim 1 are in the prior art.
`JUDGE GREEN: Just to be clear, commercial success
`itself does not carry a day. We assume that the Examiner
`weighed that with the evidence of obviousness and just thought
`that when weighing all the evidence it supported the patentability
`of claims, correct?
`MR. WHITE: Certainly the Examiner, I'm sure,
`conducted the proper analysis and considered all of the evidence
`before him and allowed the claims to issue, as stated in his
`reasons for allowance based on commercial success, but we do
`think there are some issues with the evidence before him, and
`we'll get to that later.
`So the authors of the prior art here, particularly the
`O'Donnell reference and the Attard 2005 reference, Exhibits 1003
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`and 1023, laid out a clear path to the development of abiraterone
`acetate. All that was left to do for the person of ordinary skill in
`the art was make the clinical confirmation that it was necessary to
`administer prednisone with abiraterone acetate. Both abiraterone
`acetate and prednisone were known in the art. Janssen doesn't
`claim to have invented either of those here. So the question is
`why combine them? And the answer is because prednisone was
`the known solution to abiraterone's known side effects.
`JUDGE GREEN: So you are saying one would have
`administered the prednisone for the side effects and not for its
`cancer treatment properties per se?
`MR. WHITE: I think at the very least the person of
`skill in the art would have administered prednisone for the side
`effects. They might have wanted to administer prednisone for an
`anticancer effect, but certainly they would have been motivated to
`administer prednisone to treat the known and anticipated side
`effects for abiraterone.
`JUDGE GREEN: And does the claim require that the
`prednisone have cancer treating effects?
`MR. WHITE: I don't think so. If we could turn to
`slide 7, and during the institution -- slide 7 shows the express
`definition of the term "treatment" that's in claim 1. It's an
`open-ended and broad construction. And my understanding of
`the institution decision with this was the construction the Board
`adopted at least at that stage, and we believe that is the correct
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`and broadest reasonable construction. Patent owner had an
`opportunity to amend its claims here if they thought the claims
`needed to be narrower. They didn't take that opportunity.
`JUDGE ELLURU: So treatment has to have some sort
`of effect?
`MR. WHITE: Certainly treatment has to have some
`effect. Having a palliative effect, reducing the side effects
`associated this with abiraterone that allows abiraterone to be
`administered would certainly be treatment.
`JUDGE GREEN: We do have this statement at column
`10 of the patent saying -- it's at column 10, line 21, the amount of
`the steroid administered to a mammal having cancer is an amount
`that is sufficient to treat the cancer whether administered alone or
`in combination with the inhibitor, which to me suggests that at
`least there is some support that the steroid itself has some
`anticancer effect.
`MR. WHITE: I'm sorry, I was grabbing the patent.
`Which lines were you reading?
`JUDGE GREEN: Column 10, line 21.
`MR. WHITE: And I think that statement is consistent
`with the definition of the use of the word "treat," to treat the
`cancer. I certainly think administering a steroid to have --
`administering abiraterone acetate with the steroid, the steroid is
`treating the cancer. It's allowing abiraterone to be administered.
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`It's having a palliative effect. It's combatting the side effects of
`abiraterone. So I do think --
`JUDGE GREEN: But they do talk about it being
`administered alone.
`MR. WHITE: Prednisone?
`JUDGE GREEN: Yes. The amount of the steroid
`administered to a mammal having cancer is an amount that is
`sufficient to treat the cancer whether administered alone or in
`combination with the inhibitor.
`MR. WHITE: And I think that's certainly not within the
`scope of the invention, administering prednisone alone.
`JUDGE GREEN: No, but it does teach us a little bit
`about what they mean by treatment, correct?
`MR. WHITE: Yes. And I think there is a number of
`passages in the specification that also give some color as to what
`they meant by an anticancer agent versus a steroid. Nearly every
`iteration in the specification where they talk about an anticancer
`agent is saying an anticancer agent or a steroid.
`JUDGE GREEN: So you think that inconsistency gives
`us leeway in how to interpret treatment in the claim?
`MR. WHITE: I'm sorry?
`JUDGE GREEN: You think that inconsistency or those
`maybe having different, you know, like you said anticancer agent
`or steroid in this statement here that the steroid itself can be used
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`alone, that that provides some tension that gives us leeway in how
`we administer treatment in the claim?
`MR. WHITE: Yes, I would agree with that. So we
`were discussing the motivation to combine abiraterone with
`prednisone, and I think the motivation in the art is clear, and
`there's at least three to me that stood out. You start with the
`clinical data in O'Donnell. Then you look at abiraterone's known
`effects on steroid synthesis and then you can look at the skilled
`artisan's prior experience with ketoconazole.
`So starting with O'Donnell, O'Donnell is the reference
`that conducted -- a phase 1 study that conducted three studies:
`Two single-dose studies, castrate and non-castrate males, and a
`multidose study. The multidose study conducted -- performed a
`Synacthen test on the patients. The Synacthen test is a test that is
`diagnostic for adrenal insufficiency. It's a test you wouldn't even
`do if a person of skill in the art would not think there was some
`potential impact on the adrenal system.
`In that study, study C, every patient in that study had an
`abnormal Synacthen test. That is a clear indication, even on the
`short duration of that study that abiraterone acetate administered
`alone was impacting cortisol production. A person of ordinary
`skill in the art would know that was a concern.
`So if we look at the O'Donnell paper, if we look at
`slide 19, slide 19 shows the abstract from O'Donnell. This is the
`headline result. This is what O'Donnell wanted a person of skill
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`in the art to take away from this publication. So what do they
`conclude in the last two sentences, “The enhanced testosterone
`suppression achieved in castrate men merits further clinical study
`as a second-line hormonal treatment for prostate cancer.” So they
`encourage abiraterone to continue in development. And they note
`adrenocortical suppression may necessitate concomitant
`administration of replacement glucocorticoid. So that's the
`headline result. That's the path as set out in O'Donnell. They
`need to evaluate the impact of this drug on cortisol suppression.
`JUDGE KALAN: So does it matter what happened
`after as far as testing, for example, that abiraterone acetate was
`tested as a monotherapy, or do you think O'Donnell stands alone
`or very clearly stands for what it says here in the abstract?
`MR. WHITE: I do think O'Donnell stands for what it
`says in the abstract. I think it's clear, particularly when you
`couple it with the Attard reference. And I would dispute that the
`later studies were, in fact, monotherapies. All of those studies
`allowed for a glucocorticoid or some other medication to be
`administered if side effects were to occur. So those studies,
`although they had a monotherapy protocol, they specifically had
`baked into those studies the administration if a glucocorticoid or
`some other treatment showed side effects, the anticipated side
`effects of abiraterone occurred. Of course that would not have
`been baked in if you didn't anticipate those side effects.
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`JUDGE GREEN: Do any of your experts talk about
`that? What's your evidence that that's baked in?
`MR. WHITE: We discussed that with -- and I think the
`best evidence for that is the cross-examination of Dr. Rettig. We
`discussed with him -- Dr. Rettig raised the issue that these were
`monotherapies. We discussed with him are these in fact
`monotherapies when they allow for this? Why would they have
`accounted for this in the protocol? Why is this in the article?
`And I'll get you those citations. That's probably the best
`testimony we have of that.
`JUDGE GREEN: Thank you.
`MR. WHITE: So if we go to slide 23, again, Your
`Honors are probably very familiar with this passage. This is the
`further instruction in O'Donnell that in light of the clinical
`evidence, the human clinical evidence in this phase 1 study,
`further studies with abiraterone acetate will be required to
`ascertain if a concomitant therapy with glucocorticoid is required
`on a continuous basis, at times of physiological stress, if patients
`become symptomatic or indeed at all. So this is the instruction to
`persons of skill in the art to make this determination.
`The teachings of O'Donnell aside, what else do we have
`in the art?
`JUDGE ELLURU: Isn't that just an invitation to
`experiment, though?
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`MR. WHITE: No, I don't think so. Not when it's based
`on data. It's based on the results they saw in a phase 1 trial that
`impacted, that demonstrated there was an impact on adrenal
`steroid synthesis. Certainly you have to confirm this result, but
`when you couple that with the statement in the abstract expressly
`telling you that adrenocortical suppression may require a
`glucocorticoid to address that issue, I don't think that's a situation
`where you have some vague notion or you have some general
`idea that maybe we should look at this issue. This is clear
`guidance as to the exact question we need to answer. So I think
`that is a very specific instruction for a person of skill in the art,
`particularly when you couple that with the Attard 2005 reference.
`If we could turn to slide 29, so slide 29 shows Figure 1
`from the Attard reference. Attard 2005, Exhibit 1023. It's a
`somewhat complicated figure and we'll go through it briefly. You
`can see on the bottom kind of a horizontal pathway, the antigen
`pathway, testosterone is reduced. That is the goal of this
`treatment. That's desirable. If we kind of look at the middle
`horizontal pathway in the pink bubble, you see that cortisol is
`decreased. That's undesirable and that's a potential problem. If
`you look at the top line with the two green bubbles, you can see
`that the mineralocorticoids are increased. Again, a problem.
`Both of those are a problem. A person of ordinary skill in the art
`would have understood this pathway that the inhibition of the
`CYP17 enzyme creates these concerns not only because it is
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`expressly shown in this article, because of their experience, and
`this figure wasn't -- the authors didn't leave it up to interpretation.
`If you look in the legend just above the graphic, the last sentence
`reads, suppression of cortisol and its precursors causing a
`compensatory rise in ACTH and excess synthesis of aldosterone
`and its precursors is predicted. So that is mineralocorticoid
`excess. That's a serious problem that is predicted in the art and a
`person of skill in the art is not going to ignore that warning.
`We asked Dr. Rettig about that. If we turn to slide 27,
`so that's a passage from Dr. Rettig's cross-examination, and I
`asked him somewhat in the negative, you don't think that Figure 1
`from Attard 2005 provides a person of skill in the art the
`motivation to answer the question of what's going to happen to
`cortisol production in humans. His answer, “In order to answer
`that specific question, yes, one would be motivated based upon
`this, this prediction, to test the predicted changes in humans.”
`And I think that's right. A person of skill in the art
`would recognize the seriousness of the conditions and side effects
`associated with monotherapy administration of abiraterone
`acetate and are not going to ignore these possible conditions.
`So you couple these prior art teachings, you couple
`these references with the person of skill in the art's prior
`experience with ketoconazole, there's going to be a lot, I'm sure,
`on patent owner's side that ketoconazole is very different than
`abiraterone acetate. They have different inhibitions, different
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`enzymes and different characteristics. That may be true to a
`certain extent. But the end result is both drugs, ketoconazole and
`abiraterone, they upset the balance, the careful balance that the
`adrenal system has. We know that both drugs are going to reduce
`testosterone but they are also going to impact cortisol, they are
`going to impact the mineralocorticoids. We need to reset that
`balance. A person of skill in the art, Dr. Rettig agrees,
`Dr. Garnick agrees, when prescribed keto, they always gave a
`steroid. They didn't wait until clinical symptoms exhibited
`themselves. That would be too late. That would be potentially
`dangerous. It was always with a steroid. The person of skill in
`the art would learn from this. They would learn from the
`experience with ketoconazole and understand they needed to reset
`that adrenal steroid synthesis pathway and they knew or they
`would have known that prednisone would do that. When there's
`mineralocorticoid excess for adrenal insufficiency, a
`glucocorticoid would address both issues.
`So when you look at all of this art, it's clearly pointing
`in the direction and telling the person of skill in the art that they
`need to at the very least confirm whether abiraterone acetate
`needs to be administered with prednisone.
`So I kind of started off this discussion and said this was
`from our perspective we thought the only question needed to be
`answered was the motivation to combine. Why is that? From our
`perspective, both abiraterone acetate and prednisone were pretty
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`well known in the art. If we could turn to slide 2, in slide 2 we
`attempted to summarize what the person of skill in the art would
`have understood about abiraterone in 2006 with citations to the
`prior art where they would learn this. A person of skill in the art
`would have known that abiraterone is going to reduce
`testosterone, inhibit cortisol, increase mineralocorticoids. They
`knew that it was selected for CYP17. That was the very reason a
`person of skill in the art was driven from ketoconazole to
`abiraterone for its selectivity. They knew that at least in the
`O'Donnell paper there was an abnormal Synacthen test that was
`diagnostic for adrenal insufficiency and they had at least two
`references that suggested the need for a glucocorticoid
`replacement. So that's the base of knowledge a person of
`ordinary skill in the art is starting with in 2006.
`Also in 2006 prednisone had been used for decades. It
`was commonly administered by oncologists. They were
`comfortable with it. They understood its impact. They
`understood its side effects. They could balance the risk and the
`benefits of the administration of prednisone and knew what to
`expect from it.
`So based on the slides, I expect we'll hear a lot on the
`patent owner's side about what our experts have said, and maybe
`we are at a point of disagreement, but I don't really think this case
`needs to be won on the battle of the experts. I think the prior art
`is very clear in terms of where it points a person of skill in the art.
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`JUDGE GREEN: But does all of that, I mean, it may
`give you a reason to try it, but what about a reasonable
`expectation of success?
`MR. WHITE: I definitely think a person of skill in the
`art would have a reasonable expectation of success. You know
`the side effects associated, the potential side effects for
`abiraterone acetate monotherapy. It's either going to be an
`adrenal issue with cortisol production or a mineralocorticoid
`excess. O'Donnell predicts one. It's on short-term therapy. You
`are not necessarily going to see the mineralocorticoid excess on
`just 11 days, as Dr. Bantle testified. It takes longer to occur.
`Attard 2005 predicted mineralocorticoid excess. A person of
`ordinary skill in the art would have understood administering a
`glucocorticoid like prednisone would have addressed both of
`those issues from their experience with ketoconazole and simply
`how the pathways are being affected. You need more of a
`glucocorticoid to shut down the ACTH overdrive that's pushing
`the mineralocorticoid. You need that replacement dose of the
`glucocorticoid to reset the balance. So I think the person of
`ordinary skill in the art would absolutely expect this combination
`would work.
`JUDGE KALAN: Though again, the administration of
`prednisone in your argument would be mostly for palliative
`reasons, but patent owner is taking the position that the
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`administration of prednisone has to have an anticancer effect. Do
`you have any arguments in response to that?
`MR. WHITE: Certainly. I think whether or not
`prednisone is there for a palliative effect, to alleviate side effects
`or an anticancer effect, a person of ordinary skill in the art is
`motivated to make this combination. So once they make this
`combination, if it has an anticancer effect, they have that. I don't
`think they need the specific motivation to achieve the anticancer
`effect to arrive at this invention. I think regardless, there is ample
`reason for the person of skill in the art to come to this
`combination.
`JUDGE GREEN: But that leads us to the secondary
`considerations because I think one of the things that patent owner
`is arguing is that one wouldn't have expected the prednisone to
`have an anticancer effect based on the references that have been
`cited.
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`MR. WHITE: Thank you, Your Honor. That is perfect
`timing because I just got the note that we are to move on to
`unexpected results. So it's a good time to do that. I don't think
`they have shown that there are any unexpected results. I don't
`think they have shown that prednisone has an anticancer effect.
`On the issue of unexpected results, let's start with the
`question Your Honors asked, whether prednisone has some
`anticancer effect. If you turn to slide 50, so patent owner
`advances this theory that steroids somehow reverses resistance,
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`clinical resistance of abiraterone acetate monotherapy. I don't
`think they have shown that based on the Attard 2008 studies. The
`Attard 2008, the two charts that they cite are included in the
`appendix. They didn't get much of a mention in the article itself.
`It's two patients in a much larger study. And interestingly, they
`are on dexamethasone. Those patients were not given
`prednisone. So what that tells you, assuming that tells you
`anything, it tells you something about the combination of
`abiraterone with dexamethasone. It tells you nothing about the
`combination we have here, abiraterone plus prednisone.
`JUDGE GREEN: Do you have any evidence of record
`that you would expect the dexamethasone and the prednisone to
`have different effects?
`MR. WHITE: We do. We asked Dr. Rettig specifically
`about that question, and he agreed that these steroids had
`potentially different activities, that dexamethasone and
`prednisone had different activities. We can get those cites for
`you as well.
`JUDGE GREEN: That would be great.
`MR. WHITE: So on the more general unexpected
`results issue, so if we could turn to slide 46, please, so one of the
`points Dr. Rettig tried to make was that there's unexpected results
`for this combination because the time to PSA progression in the
`abiraterone monotherapy trial and the abiraterone with prednisone
`trial were nearly double in the abiraterone plus prednisone trial.
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`He did this by looking at several point estimates in those studies.
`So if you look at the top line in red and we look at the top half of
`that, that's the 7.5 number, he compares that to the abiraterone
`plus prednisone trial as showing 16.3. What was noticeably
`absent from Dr. Rettig's analysis was the confidence intervals. If
`you look as plotted on slide 46 --
`JUDGE ELLURU: Counsel, I want to let you know
`you have two minutes remaining.
`MR. WHITE: Thank you. You can see that the
`confidence intervals overlap. Dr. Rettig made no effort to show
`that there was a statistically meaningful difference between those
`point estimates and the confidence intervals that would suggest
`otherwise.
`That becomes more of a problem, if you look at the
`second line, the second line in red on the top of slide 46, you see
`a different number, 11. That's what we found on the
`clinicaltrials.gov for the exact same study. I don't have a reason.
`I can't tell you why the article and what was reported at the FDA
`are different, but they were. But when you look at what was
`reported to the FDA, even if you think -- even if patent owner
`argues the amount of overlap is somehow so small that it's
`insignificant, when you compare the 11.0 number as reported to
`the FDA, you see it's a lot closer to 16.3 and the confidence
`intervals have a lot of overlap.
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`JUDGE GREEN: Are these confidence intervals from
`the references or did your expert --
`MR. WHITE: They are directly from the references.
`So if that issue alone maybe doesn't move Your Honors, but
`there's a series of added problems here. If you look at slide 48, so
`this is showing that the patient populations in these two studies,
`and you can see that the 001 study, the study that had the shorter
`time to PSA progression that was at the top, the median baseline
`PSA level was 110 nanograms per milliliter. And the 16-month
`time to PSA progression, it was 23 nanograms per milliliter. The
`patients in the abiraterone monotherapy study were sicker at the
`outset, had higher PSA at the outset. Dr. Garnick offered
`testimony in his reply declaration, 1104 at paragraph 98, that
`these patients were substantially sicker and it is not at all
`surprising that they advanced more quickly.
`With that, Your Honors, I see I'm out of time. So I'll
`save the rest of my time for rebuttal.
`JUDGE ELLURU: Mr. Pritikin, you can start when
`you please.
`MR. PRITIKIN: Good afternoon, Your Honor. In the
`original petition that was filed, the petitioners argued that it was
`primarily the side effects that were the supposed motivation to
`combine. But they also offered up an argument that the possible
`anticancer effects of prednisone would provide some additional
`motivation to combine. That was totally undercut by admissions
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`from their expert. And that is in slides 2, 3, 19, 20. We've
`collected the quotations from the testimony of their expert that it
`would have been -- that a person of skill at the time would not
`have expected the prednisone to have either anticancer effects
`alone or in combination with abiraterone acetate. And as a
`consequence, that was pretty much abandoned in the reply. And
`the argument then proceeded along the lines of the side effects of
`abiraterone alone would provide the supposed motivation to
`combine.
`The fundamental problem with the argument that is
`being presented on the motivation to combine is that it is
`hindsight driven. It is based on testimony of experts long after
`the fact looking back on it, conjuring up the problems that might
`have, could have occurred. It's not based on what was actually
`recorded in the literature at the time. We know that O'Donnell is
`the only publication that reported on actual clinical trials in
`patients of abiraterone. And we know that in O'Donnell there
`was no clinical manifestation that was found that required a
`glucocorticoid supplement.
`Now, I want to come back to that, to the motivation to
`combine, and I'm going to deal with that, but I want to turn first
`to the unexpected results. And I want to cover that topic initially
`and the question of the benefits that are derived from the
`combination of abiraterone with prednisone. I'm going to direct
`your attention first to slide 2. And this contains the admissions of
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`their expert that one would not have expected the administration
`of the combination to provide any additional clinically significant
`anticancer benefit. In slide 3 would a person of skill have been of
`the view that it would have any measurable cancer-treating effect
`when combined with abiraterone acetate? No. And the other
`slides and testimony are to the same effect on 20 and 21. So
`there's really no dispute in these proceedings that there are
`unexpected results here. And that, of course, has a varying
`amount of reasonable expectation of success as well.
`So what is the response now that is being offered by the
`petitioners? We heard a little of it today. This was entirely new
`in the reply that was filed, new declarations from statisticians,
`Dr. McKeague and others, beginning to question for the first time
`whether or not there is, in fact, a