trials@uspto.gov
`571-272-7822
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`IPR2016-01582, Paper No. 74
`June 23, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`WOCKHARDT BIO AG,
`Petitioner,
`
`v.
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`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-01582
`Patent 8,822,438
`____________
`
`Held: May 24, 2017
`____________
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`BEFORE: LORA M. GREEN, RAMA G. ELLURU, and
`KRISTINA M. KALAN, Administrative Patent Judges.
`
`
`
`The above-entitled matter came on for hearing on Wednesday,
`May 24, 2017, commencing at 2:26 p.m., at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
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`571-272-7822
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`IPR2016-01582, Paper No. 74
`June 23, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`WOCKHARDT BIO AG,
`Petitioner,
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-01582
`Patent 8,822,438
`____________
`
`Held: May 24, 2017
`____________
`
`
`
`
`
`
`BEFORE: LORA M. GREEN, RAMA G. ELLURU, and
`KRISTINA M. KALAN, Administrative Patent Judges.
`
`
`
`The above-entitled matter came on for hearing on Wednesday,
`May 24, 2017, commencing at 2:26 p.m., at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
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`DENNIES VARUGHESE, ESQUIRE
`LESTIN KENTON, ESQUIRE
`Sterne, Kessler, Goldstein & Fox
`1100 New York Avenue, N.W.
`Washington, D.C. 20005
`
`Case IPR2016-01582
`Patent 8,822,438
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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 IPR2016-01582
`Patent 8,822,438
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`P R O C E E D I N G S
`- - - - -
`JUDGE ELLURU: Good afternoon. We are here for
`the final hearing in IPR2016-01582, Wockhardt Bio AG versus
`Janssen Oncology, Inc. I'm Judge Elluru. To my right is Judge
`Green. Appearing remotely is Judge Kalan. Let's please begin
`with appearances of counsel starting with petitioner. Please
`approach the microphone and state your name.
`MR. VARUGHESE: Good afternoon, Your Honors.
`May it please the Board, my name is Dennies Varughese from the
`law firm of Sterne, Kessler, Goldstein, and Fox on behalf of
`petitioner, Wockhardt. Joining me today are my colleagues,
`Deborah Sterling and Lestin Kenton.
`JUDGE ELLURU: Thank you, counsel. And for patent
`owner, Janssen.
`MS. ELDERKIN: Good afternoon. Dianne Elderkin
`for Janssen Oncology. Presenting argument today for Janssen is
`David Pritikin from Sidley Austin, and assisting him are his
`colleagues, Bindu Donovan, Alyssa Monsen and Jeff Kushan.
`JUDGE ELLURU: Thank you, counsel. I would like to
`go over how we'll proceed today. Each side will have 35 minutes
`of total time to present its argument. Please keep in mind that we
`do have one panel member who is appearing remotely.
`Typically, again, we can only see -- the remote judge can't see the
`screen. None of us can today, so please when you are referring to
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`your demonstratives, please refer to them clearly by slide number
`for our benefit as well as the benefit of the transcript.
`Petitioner has the burden to show that the challenged
`claims are unpatentable and thus will present its case first. Patent
`owner will then argue its opposition to patent owner's [sic] case.
`If petitioner has reserved any time, petitioner can use that time for
`rebuttal. I'll give you a warning when you are reaching the end of
`your argument time.
`Does counsel have any questions, starting with
`petitioner?
`MR. VARUGHESE: No, Your Honor.
`JUDGE ELLURU: And patent owner?
`MR. PRITIKIN: No, Your Honor.
`JUDGE ELLURU: Thank you. Counsel, you may
`begin when you are ready. And would you like to reserve any
`time for rebuttal?
`MR. VARUGHESE: Yes, Your Honor. I would like to
`reserve ten minutes for rebuttal. Your Honors, we have hard
`copies of the slides, if we may approach.
`JUDGE ELLURU: Yes, please.
`MR. VARUGHESE: Thank you, Your Honor. Once
`again, Dennies Varughese on behalf of petitioner, Wockhardt.
`Your Honors, given the prior proceeding today and the Amerigen
`proceeding a few months ago, Your Honors have heard a lot.
`There's been a lot of papers submitted here. And in putting the
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`Wockhardt proceeding and trial on a fast track and compressed
`schedule, I presume that the Board recognized that there's some
`substantial overlap in the technology and the medical issues
`involved in these multiple proceedings. So to the extent possible,
`I'm going to try to avoid any redundancy in that regard and try to
`focus on the Wockhardt-specific issues and specific disputes
`between Wockhardt and Janssen. However, I am cognizant of the
`need to have a complete record, so I will touch upon all the major
`issues. And I'm happy to address any of the questions the Board
`may have as I do that.
`Turning to slide 2, this is an overview of our argument.
`Simply put, Wockhardt submits that claims 1 through 20 of the
`'438 patent would have been obvious over the combination of
`Gerber, O'Donnell, and Sartor. I'm going to address some of
`these points, but in their patent owner response Janssen has
`advanced a number of arguments that it believes tries to rebut or
`overcome this prima facie case, and for various reasons we
`submit that they have not done so. Then finally, I'll close by
`addressing some of the secondary considerations that Janssen has
`advanced.
`Turning to slide 4, in instituting the Amerigen trial, this
`Board issued claim constructions for some terms that appear in
`the claims of the '438 patent, namely "treat," "treating,"
`"treatment," and "therapeutically effective amount of
`prednisone." In Wockhardt's petition and in this trial, Janssen and
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`Wockhardt has applied that claim construction. However, as we
`understand it, there seems to be an ongoing dispute between
`Janssen on the one hand and the Amerigen and Mylan petitioners
`on the interpretation of the Board's construction, namely, it
`appears that Janssen argues that both abiraterone and prednisone
`need to be shown in the art to have some anticancer effect.
`Whereas, the petitioner seemed to suggest that just abiraterone
`needs to have the anticancer effect and prednisone can be shown
`to have treatment through its palliative effects and treatment of
`side effects.
`Turning to slide 5, Wockhardt submits that to the extent
`that that dispute exists, it's moot given the unique combination of
`references and ground that Wockhardt advanced in its petition.
`And as shown on slide 5, Wockhardt asserts that the claims of the
`'438 patent would have been obvious over Gerber, O'Donnell, and
`Sartor. Gerber, which published around 1990, established
`ketoconazole, a well-known C-Y-P or as I'm going to refer to it,
`CYP17 inhibitor, combined with prednisone for the treatment of
`prostate cancer. As we'll discuss shortly, Gerber established that
`this combination of ketoconazole and prednisone was both
`effective and tolerated in treating for this purpose.
`More than a decade later, in 2004, which is two years
`before the invention date here, which is August 2006, the
`O'Donnell paper published. O'Donnell showed abiraterone to be
`a new, better, improved CYP17 inhibitor than ketoconazole. And
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`within the four corners of the O'Donnell reference, the authors
`there specifically and expressly compared ketoconazole to
`abiraterone and asserted that abiraterone is more selective and
`potent and better, thereby providing an express motivation for a
`POSA to replace the ketoconazole in the Gerber combination
`with the better, newer abiraterone disclosed in O'Donnell.
`And in the Wockhardt petition, we cited this Board's
`recent case, Daiichi, albeit a different panel. But I submit that the
`Daiichi facts were squarely on point with the facts here. There,
`briefly put, the prior art showed a combination of clopidogrel, an
`antiplatelet that acted by inhibiting adenosine diphosphate,
`combined with aspirin. The claims at issue were to a
`combination of prasugrel, a newer ADP antagonist that was more
`selective, combined with aspirin. And the Board there found that
`the teaching that prasugrel was newer, better, more selective,
`more potent, was a sufficient basis to provide a POSA motivation
`to replace the older clopidogrel with prasugrel. And I think the
`same reasoning applies here.
`O'Donnell, beyond that, also provides in various ways a
`motivation for a POSA to maintain coadministration of
`prednisone as taught in Gerber. So how does O'Donnell do that?
`Number one, there are multiple express statements where
`O'Donnell signals to a POSA you may need glucocorticoid
`supplementation; you may need to investigate this; there might be
`three different ways or three roles for glucocorticoid
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`supplementation. O'Donnell says it could be continuous, you
`may need it in times of crises or you may not need it at all. But
`the point is O'Donnell acknowledged it, highlighted it, and points
`a POSA to it.
`Next, O'Donnell, as Your Honors heard, and it's in our
`papers, study C of the O'Donnell paper specifically performed the
`Synacthen ACTH challenge test in 12 patients. O'Donnell would
`not have done that but for the fact that in 2004 O'Donnell's
`actions reflect what a POSA here would have thought. And who
`is a POSA here? This is going to be a recurring theme in
`petitioner's presentation. The POSA isn't a lay lawyer. The
`POSA isn't some professional athlete. It's a highly trained
`medical oncologist with years of treating prostate cancer who is
`aware of all the available treatments and the issues that are
`attendant there. And if there was any doubt beyond O'Donnell,
`Wockhardt has cited the Sartor reference, which published in the
`late '90s, which established that prednisone has independent,
`stand-alone antiprostate cancer activity apart from its
`supplementation effect or palliative effects.
`So moving to slide 12, when Wockhardt highlighted the
`Sartor reference in its petition, in its patent owner response,
`Janssen tried to diminish the effect of Sartor by saying, well,
`Sartor doesn't show a survival benefit, so it didn't establish
`treatment with prednisone alone. That is incorrect. And here on
`slide 2 , we've put forward the importance of the PSA assessment
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`in the treatment of prostate cancer. PSA stands for
`prostate-specific antigen. As both experts in this proceeding
`agree, Dr. Rettig for Janssen and Dr. Godley for Wockhardt, PSA
`assessment is a widely accepted marker for assessing treatment.
`In fact, these are Dr. Rettig's words; “Patients who showed a
`greater than 50 percent decrease in PSA were likely to have
`actually experienced a clinically significant response.” And then
`how you assess a positive PSA response, this is in the second box
`on slide 12, PSA response, according to the prostate cancer
`working group, is assessed: (a) when there is a decline of more
`than 50 percent and that decline is established four weeks later in
`a second test.
`Let's go to slide 22. This slide illustrates that Sartor did
`just that. Thirty-four percent of patients in Sartor achieved a PSA
`decline of at least 50 percent. In fact, 14 percent actually
`achieved a PSA decline of at least 75 percent with prednisone
`alone. And then the second box there shows that 20 out of 29
`patients, almost 70 percent, exhibited a progression-free time of
`at least eight weeks, which is double what the PSA working
`group requires. So looking at the PSA, a POSA would
`understand that Sartor shows that prednisone has antiprostate
`cancer treatment activity alone.
`So with that, I would like to move to slide 35.
`JUDGE GREEN: I just want to have one clarification.
`So I know you are citing Sartor to show that the prednisone itself
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`had anticancer activity. So are you in agreement, then, with the
`patent owner's construction that treatment as used in claim 1
`requires that the prednisone itself treat the cancer and it's not just
`using it for its treatment of side effects or other palliative effects?
`MR. VARUGHESE: So our position is that we side
`with the petitioners there, that prednisone can exert treatment
`activity through just palliative effects and it's addressing the side
`effects of abiraterone. So if we had to take a side, we would side
`with petitioners there. But the point is in the Wockhardt petition,
`that issue is moot because we have demonstrated through Sartor
`and actually other background references that prednisone was a
`standard of care in prostate cancer.
`JUDGE GREEN: Then do you argue that in your
`petition, that claim construction that was argued in the previous
`proceeding?
`MR. VARUGHESE: Yes, we explain that both in our
`petition and in our reply.
`So moving to slide 35, I would like to take this
`opportunity to address some of the points that patent owner has
`made to try to overcome this prima facie case. As I'm going to
`demonstrate, a lot of the arguments that they put forward, I think,
`suffer from either they are legally irrelevant, they are
`unpersuasive, or they are a red herring that doesn't really go to the
`heart of the issue here. The issue here is would it have been
`obvious to combine abiraterone in the prior art with prednisone in
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`the prior art. Not whether or not it would have been obvious to
`arrive at the abiraterone compound. I'm not going to stand here
`and disparage abiraterone. Abiraterone, you know, it's a good
`drug. But Janssen was rewarded for those efforts and that work
`through the '213 patent, the prior art patent.
`Let's go to slide 36. Janssen argues, for example, that
`Wockhardt's petition fails to establish that prednisone and
`ketoconazole were FDA approved for the treatment of prostate
`cancer or that the Gerber reference or the Sartor reference doesn't
`establish safety and efficacy from an FDA standpoint. But the
`claims of the '438 patent do not require this. FDA approval is not
`a precursor or prerequisite to obviousness. And nor did the '438
`patent claims require any particular survival benefit. Rather, they
`require treatment or a therapeutic effective amount. And as
`Dr. Rettig and Dr. Godley agree, the PSA responses shown in
`these references and in the prior art qualify to establish as
`treatment. And by extension, the PSA response would mean a
`lessened tumor burden which in turn could be extrapolated to a
`survival benefit. But there's absolutely no requirement that data
`showing survival benefit needs to be shown in these references to
`establish obviousness because that's not a requirement of the
`claims.
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`JUDGE GREEN: But you don't disagree that survival
`benefit could be used to maybe demonstrate secondary
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`considerations such as unexpected results even though it's not
`specifically recited in the claims, correct?
`MR. VARUGHESE: So we believe that survival
`benefit is one of the elements of the Board's construction of
`treatment. I think what Janssen is trying to do is collapse the
`entire definition of treatment down just to survival benefit and we
`disagree with that. Sure, survival benefit is one type of treatment
`and one type of benefit.
`JUDGE GREEN: But it could be used, if you get a
`better survival benefit than would have been expected by the
`prior art, you can use that to demonstrate a secondary
`consideration such as unexpected results, correct? So that does
`come into play at some point, right?
`MR. VARUGHESE: Certainly, if it's unexpected. I
`certainly agree with that if it can be demonstrated to be
`unexpected.
`If we can move to slide 37, Janssen then tries to
`disparage the Gerber reference as being a mere chart review.
`They say it's a chart review and not a controlled clinical trial
`designed to establish the safety or efficacy of a drug treatment.
`That also miss the mark. Obviousness does not require
`placebo-controlled randomized clinical trials. As the Federal
`Circuit has said, Gerber -- and this is referenced as prior art for all
`that it teaches, and we cited the Duramed case; a reference is
`prior art for all that it discloses and there is no requirement that a
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`teaching in the prior art be scientifically tested or even guarantee
`success.
`And we have testimony from Dr. Godley here that in
`this patient population, advanced stage prostate cancer chart
`reviews are particularly important and informative for a number
`of reasons. Number one, it shows that real-world patients were
`being treated in the clinical setting. They are actually patient
`charts from a hospital or treatment facility looking back to see
`what happened to these real patients. And also, these patients
`have such advanced disease, as Dr. Godley explained, it's very
`hard to have a placebo-control trial because it would be unethical
`to withhold treatment from these patients.
`Next going to slide 38, Janssen similarly argues that the
`O'Donnell studies were not designed to assess the clinical
`effectiveness of abiraterone acetate. But that also is not a
`requirement for obviousness here. O'Donnell -- and there's no
`dispute here, as I show in the bottom bullet there, assessed the
`ability for abiraterone to suppress testosterone in this patient
`population. Suppressing testosterone is the very objective, is the
`very goal of these patients -- of these drugs, whether it be
`ketoconazole or whether it be abiraterone. And then O'Donnell
`established, and this also is not disputed that abiraterone is a more
`selective potent inhibitor than ketoconazole.
`Turning to slide 39, I think this is one of the arguments
`that Janssen really tries to hang its hat on. They say that, well,
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`ketoconazole and abiraterone were materially different and
`seemed to give off this impression that a POSA would have
`thought that glucocorticoid supplementation was needed with
`ketoconazole but not necessarily with abiraterone. That also is
`incorrect. Number one, I agree that ketoconazole is broader than
`abiraterone, but broader doesn't mean more potent. Abiraterone
`was demonstrated to be more potent and more selective for the
`relevant enzyme activity here for CYP17. I'm going to talk about
`that in a little more detail, which is 17-alkyl hydroxylase and the
`17, 20-lyase enzyme activity for CYP17. A POSA also here is
`starting with Gerber where the standard was CYP17 inhibitor
`with prednisone. It started in 1990. Dr. Rettig admitted that he
`followed that combination. Dr. Godley testified that he followed
`that combination. There's no dispute that in the prior art
`physicians were prescribing ketoconazole and prednisone in this
`manner off-label. Janssen hasn't provided any evidence to
`suggest that a POSA starting with Gerber would then take the
`remarkable and affirmative step of discontinuing prednisone from
`that combination simply because they replaced ketoconazole with
`abiraterone.
`I would like to turn to slide 41, if Your Honors, may.
`This is a figure that was cited in our petition and reproduced in
`Dr. Godley's opening declaration. I apologize it's a little busy and
`I'm going to try to simplify it. This is from the Harrison's
`Principles of Internal Medicine, which is a prevailing treatise in
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`this field of medicine at the time of invention. And this figure
`depicts pathways of adrenal hormone synthesis. And through the
`red boxes we tried to highlight the relevant steps here. So both
`abiraterone and ketoconazole, the relevant activity is a CYP17
`inhibition activity. We've highlighted that in the top three boxes.
`The end result is by inhibiting CYP17, both drugs inhibit
`testosterone production, which is good. That's the goal of
`treatment.
`But the box to the left on the bottom shows that it also
`inhibits cortisol production because CYP17 inhibition interferes
`with the pathway that develops cortisol. There are two pathways
`that develops cortisol relevant here. Two steps. One is the
`conversion of -- and I butcher this name -- pregnenolone to
`hydroxypregnenolone. That's the first box on the top and to the
`left. The second step is the conversion of progesterone to
`hydroxy progesterone.
`So now if we go to slide 40, what we have here is a
`depiction that begins with Dr. Rettig's figures that Mr. Pritikin
`presented earlier where he omits the fact that critical second
`pathway that's being inhibited by both abiraterone and
`ketoconazole to develop cortisol. And we've tried to highlight
`that with that purple box with the slash that says 17-alpha
`hydroxylase. There's no dispute that abiraterone inhibits that
`enzymatic activity, but that was omitted from Dr. Rettig's figures.
`And those figures were the basis on which Janssen relies on to
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`argue that there are these great big differences. So even giving
`Janssen the benefit of the doubt and let's say that cortisol might
`have been diminished to a lesser extent with abiraterone than
`ketoconazole, that's certainly not a reason that a POSA would
`take the remarkable step of discontinuing that prednisone.
`In the interest of time, I would like to move on to
`slide 42. There is another problem. Mr. Pritikin in the prior
`proceeding, and this reflects their arguments in this proceeding,
`said that, well, because abiraterone doesn't block the production
`of corticosterone, the corticosterone would then somehow
`compensate for the lack of cortisol. That leads to another
`problem. Now you have a second problem with abiraterone that
`you don't have with ketoconazole that is solved again with
`glucocorticoid supplementation like prednisone. And that
`problem is mineralocorticoid excess. Corticosterone, as
`Dr. Auchus admitted, is a week glucocorticoid. So the amount of
`corticosterone you would need to offset the loss of cortisol would
`lead to mineralocorticoid excess. And as we show in slide 43,
`abiraterone's activity in this regard, the diminished cortisol, the
`excess corticosterone actually mimics patients who have a
`deficiency in 17-alpha hydroxylase and 17, 20-lyase. And
`Dr. Auchus, as I've shown on slide 43, admitted that the
`cornerstone, quote, his word, the cornerstone of therapy for those
`patients with that congenital disease that mimics abiraterone is
`glucocorticoid suppression. And this was all in the prior art.
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`I would like to turn now to slide 44. Quickly, just, you
`know, respectfully, I think Janssen has taken some extreme
`positions in this case, and slide 44 demonstrates one of them. It
`just defies logic. They say a skilled person would have found no
`justification from O'Donnell for providing a patient on
`abiraterone acetate with glucocorticoids. Well, below there I
`have express statements from O'Donnell. I don't know how one
`can draw that conclusion. At the very least O'Donnell highlights
`for a POSA and then leaves it to the POSA and says, look, you
`are a highly trained medical physician treating oncology.
`Exercise your medical judgment to determine whether or not
`prednisone is needed.
`That does not negate obviousness here. The practice of
`supplementing prednisone or supplementing CYP17 inhibitors
`with glucocorticoids is something that's been practiced for
`decades. Janssen is trying to hold petitioner, Wockhardt, to an
`absolute certainty standard when all the law requires is a
`reasonable expectation of success. And we have that with
`O'Donnell, but turning to slide 45, also with the POSA doesn't
`evaluate prior art references in a vacuum. The POSA is a
`presumed to be aware of all the art and is a person of ordinary
`creativity and ordinary experience and knowledge. Here we've
`defined -- there is no dispute as to a POSA -- it's a highly
`advanced individual with advanced training and advanced
`education.
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`Turning to slide 47, another argument that Janssen has
`made here is they pointed to drugs like docetaxel and
`mitoxantrone and other drugs that were available and they said,
`well, these were more popular. They never used the words
`teaching away, but their arguments amount to that there's a
`teaching away here. But there isn't. Let's turn to slide 48. The
`Federal Circuit case law is clear, the mere disclosure or existence
`of more than one alternative does not amount to a teaching away.
`And that alternative can even be better than the claimed invention
`at issue. It is still not a teaching away.
`Turning to slide 49, Janssen also makes a similar
`argument about prednisone side effects. I think several times
`Mr. Pritikin said a POSA would have had another option,
`eplerenone, to treat mineralocorticoid excess. Eplerenone is an
`aldosterone inhibitor. Again, the same Federal Circuit law
`applies. The availability of eplerenone doesn't render the
`combination with prednisone any less obvious. And again, going
`back to the Daiichi case that we cited, the same concerns of side
`effects and long-term side effects were highlighted in Daiichi.
`There the Board found, look, this is at most a caution. Not a
`prohibition. In fact, it's an express acknowledgment that this
`combination is something that a POSA would follow, but then it's
`basically telling the POSA exercise your medical judgment to
`make a determination as to whether this combination is
`appropriate for your particular patient. That's all the law requires.
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`To turn quickly to slide 51, one point. In Janssen's
`papers against Wockhardt, a number of times they try to rely on
`testimony of Dr. Serels and Dr. Garnick. Dr. Garnick is Mylan's
`expert. Not an expert for Wockhardt in this proceeding. Not an
`expert for Janssen in this proceeding. Similarly, Dr. Serels was
`an expert for Amerigen. Not an expert for Wockhardt or Janssen.
`Those experts were not made available in this proceeding either.
`We respectfully submit that the Board should give no weight to
`any so-called admissions that Janssen wants to rely on from these
`experts.
`Turning now to slide 52, I have about three minutes left,
`I want to quickly touch upon some of the secondary
`considerations. In short, I believe and I submit that Janssen has
`not established secondary considerations here and hope that I'll
`have a chance to talk about some more in detail in rebuttal.
`Number one, slide 53, I have four points to make about
`unexpected results. Number one, to the extent that Janssen tries
`to draw any conclusion between studies that involve a
`combination with dexamethasone, we respectfully submit that
`there's no nexus there and the Board should give that no weight.
`Janssen was in the driver's seat in its claim drafting
`strategy. It could have drafted claims that says abiraterone plus
`the class of glucocorticoid. They didn't do that. In order to get
`those claims issued or allowed, they narrowed those claims to
`prednisone. They can't now go back and say, well, it's the whole
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`class, it's dexamethasone, it's hydrocortisone, it's anything else
`that mimics prednisone. They can't have that. Dexamethasone is
`not what's claimed and there's no nexus to the claims.
`Secondly, this is Janssen's chart, if they try to draw any
`conclusions from the findings of the third row or the second row
`to the first row which shows abiraterone alone, that also, even if
`the Board were to consider it, they all come from the Attard 2009
`studies. The confidence intervals there overlap. There's no
`statistically significant difference.
`Finally, the last row, Ryan 2011, they try to show that
`the findings of Ryan 2011 which combine abiraterone to
`prednisone was better than abiraterone acetate monotherapy
`alone. Those studies are like comparing apples and oranges.
`Those studies were not designed to evaluate a comparative effect
`of abiraterone monotherapy versus the combination. And they
`are two years apart, and there's testimony here that shows that the
`Ryan patients were much more healthy than the sick patients in
`Attard. So it would have not been unexpected for the patients in
`the Ryan 2011 study to have a longer time to PSA progression.
`And I think the most important point is that we
`established through Sartor and other background art that
`prednisone has actual antiprostate cancer treatment activity. So
`by combining the two, a POSA would have expected some added
`effect. This is not unexpected. A POSA would have expected
`that when you combine two drugs that have independent
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`antiprostate cancer effect, of course there's going to be some
`additive effect. And we highlighted in our briefs, it's Federal
`Circuit law, differences in degree do not sustain a finding of
`unexpected results. They have to be differences in time. At most
`even if we were to give Janssen all of the benefit of the doubt,
`they haven't established this is unexpected because this is just a
`mere difference in degree and it would have been expected.
`As to failure of others, skepticism and long-felt need,
`we expanded on this in our papers. They haven't demonstrated a
`nexus. All the failure, skepticism all went to the abiraterone
`compound, what happened in the late '90s and early 2000. As of
`2004, O'Donnell published, people knew the value in abiraterone,
`and Janssen hasn't come forward with any failure of combining
`abiraterone with prednisone or any skepticism of combining
`abiraterone with prednisone. They don't have nexus to the
`claims.
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`And finally, I think same nexus problem applies to
`commercial success, and depending on what Mr. Pritikin says, I
`would like to offer some rebuttal on commercial success.
`JUDGE ELLURU: Thank you, counsel.
`Mr. Pritikin, you may begin when ready.
`MR. PRITIKIN: Good afternoon, Your Honors.
`Wockhardt's petition largely embraces the same flawed scientific
`assumptions of the two earlier petitions, but it differs from them
`in two respects. First it rearranges the order of the primary
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`references, Gerber and O'Donnell, and argues that a skilled
`person would have swapped abiraterone for ketoconazole in
`Gerber but continued to give prednisone. And then it adds a new
`reference, Sartor, to try to show that prednisone would have been
`expected to have an anticancer effect in the claimed combination.
`Now, the challenge doe
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