trials@uspto.gov
`571-272-7822
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`IPR2016-00286, Paper No. 85
`March 22, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`AMERIGEN PHARMACEUTICALS LIMITED and
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
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`v.
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`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-00286
`Patent 8,822,438 B2
`____________
`
`Held: February 16, 2017
`____________
`
`
`
`BEFORE: LORA M. GREEN, RAMA G. ELLURU, and
`KRISTINA M. KALAN, Administrative Patent Judges.
`
` The above-entitled matter came on for hearing on Thursday,
`February 16, 2017, commencing at 1:00 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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`IPR2016-00286, Paper No. 85
`March 22, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`AMERIGEN PHARMACEUTICALS LIMITED and
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-00286
`Patent 8,822,438 B2
`____________
`
`Held: February 16, 2017
`____________
`
`
`
`BEFORE: LORA M. GREEN, RAMA G. ELLURU, and
`KRISTINA M. KALAN, Administrative Patent Judges.
`
` The above-entitled matter came on for hearing on Thursday,
`February 16, 2017, commencing at 1:00 p.m., at the U.S.
`Patent and Trademark Office, 600 Dulany Street, Alexandria,
`Virginia.
`
`
`
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`
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`Case IPR2016-00286
`Patent 8,822,438 B2
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`WILLIAM D. HARE, ESQUIRE
`CHRISTOPHER CASIERI, ESQUIRE
`RENITA RATHINAM, ESQUIRE
`McNeely, Hare & War, LLP
`5335 Wisconsin Avenue, N.W.
`Suite 440
`Washington, D.C. 20015
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`DAVID T. PRITIKIN, ESQUIRE
`ALYSSA B. MONSEN, ESQUIRE
`BINDU DONOVAN, ESQUIRE
`Sidley Austin LLP
`One South Dearborn
`Chicago, Illinois 60603
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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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`Case IPR2016-00286
`Patent 8,822,438 B2
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`P R O C E E D I N G S
`- - - - -
`JUDGE GREEN: This is the final oral hearing in
`IPR2016-00286 involving patent number 8,822,438.
`IPR2016-01317 has been joined with this proceeding. I am Judge
`Green. Beside me is Rama Elluru. And Judge Kalan is joining us
`from Denver. As set forth in our hearing order, each side will
`have 45 minutes. Petitioner will go first to present its case in
`chief followed by patent owner. Petitioner may reserve time for
`rebuttal.
`I would like to ask the parties to introduce yourselves
`starting with petitioner.
`MR. HARE: Hello. My name is Bill Hare for
`Amerigen Pharmaceuticals and Argentum Pharmaceuticals here
`with my co-counsel, Chris Casieri, Renita Rathinam, and Teresa
`Rea and Shannon Lentz for Argentum Pharmaceuticals.
`JUDGE GREEN: Thank you very much. Patent
`
`owner?
`
`MS. ELDERKIN: Good afternoon, members of the
`Board. I'm Dianne Elderkin, lead counsel for the patent owner.
`And I would like to introduce David Pritikin, who will be doing
`the arguments, and his colleagues, Alyssa Monsen and Bindu
`Donovan.
`JUDGE GREEN: Thank you. I would like to remind
`the parties that this hearing is open to the public and a full
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`transcript of the hearing will be made part of the record. In
`addition, when discussing any particular demonstrative or slide,
`please refer to it by slide or page number to help us maintain a
`clear transcript. In addition, we have a colleague joining us from
`Denver who cannot see the demonstratives. So if you don't say
`what slide or demonstrative you are using, she cannot follow the
`argument very well.
`Petitioner, you have the burden of showing
`unpatentability of the challenged claims. You may begin. Would
`you like to reserve rebuttal time?
`MR. HARE: I would like to reserve ten minutes for
`rebuttal.
`JUDGE GREEN: Thank you. You may start when you
`are ready.
`MR. HARE: If we can jump to slide 2, so this IPR is
`about the '438 patent, which is directed towards a method of
`treating prostate cancer by administering therapeutically effective
`amount of abiraterone acetate and a therapeutically effective
`amount of prednisone. So the prior art shows all the elements of
`claim 1.
`If we can go to slide 3, it's undisputed that the prior art
`teaches the treatment of prostate cancer with abiraterone acetate.
`That's shown in O'Donnell and Barrie. The prior art teaches
`abiraterone acetate is a selective CYP17 inhibitor -- CYP17 is an
`enzyme -- that's shown in O'Donnell and Barrie, and that
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`ketoconazole, another compound that inhibits the CYP17
`enzyme, was administered in combination with prednisolone in
`treating hormone refractory prostate cancer. And that's shown in
`Gerber.
`
`So I would like to move to slide 4 and talk a little bit
`about O'Donnell and Gerber. So O'Donnell teaches that
`abiraterone acetate treats prostate cancer, and O'Donnell teaches
`that abiraterone acetate is a selective CYP17 inhibitor and that it's
`more effective in suppressing testosterone levels than is
`ketoconazole. Then we have Gerber which teaches that
`ketoconazole was being administered to treat prostate cancer in
`combination with prednisone. And again, ketoconazole is a
`compound that inhibits the CYP17 enzyme.
`Now, Barrie and Gerber, that's the other grounds for
`institution, and this is on slide 5. So Barrie is also known as a
`'213 patent. This is in the Orange Book for Zytiga. This patent
`teaches that abiraterone acetate treats prostate cancer. Barrie, the
`'213 patent, also teaches that abiraterone acetate is a CYP17
`inhibitor that is more effective at suppressing testosterone levels
`than ketoconazole, another CYP17 inhibitor. And then you have
`again Gerber which we spoke about earlier, in which
`ketoconazole being a CYP17 inhibitor was administered in
`combination with prednisone to treat hormone refractory prostate
`cancer.
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`Patent 8,822,438 B2
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`If we can go to slide 50, so we have these two sets,
`these two grounds for institution, O'Donnell and Gerber, and
`Barrie and Gerber. There was a motivation to combine these two.
`It was, as patent owner's expert, Dr. Serels, testified and as in our
`petition, it was common practice in the art to administer a
`glucocorticoid as replacement therapy when administering
`ketoconazole. Again, ketoconazole is a CYP17 inhibitor and it
`was known that the combination of ketoconazole and prednisone
`was known to be safe and effective in treating patients with
`metastatic refractory prostate cancer based on at least the
`teachings of Gerber.
`If we can turn to slide 39, so a lot of this IPR has to do
`with some strong statements in Gerber and some strong
`statements in O'Donnell and the attempt of the patent owner to
`pull back from these statements and say they are irrelevant and
`they should be ignored. And the problem is these statements are
`clear and unequivocal. For example, in slide 39, it states -- in the
`Abstract, Gerber states there appears to be a small subgroup of
`patients with progressive prostate cancer despite androgen
`ablation who will benefit from ketoconazole and glucocorticoid
`treatment. Again, Gerber administered ketoconazole and
`prednisone to treat prostate cancer. Prednisone is a
`glucocorticoid. So you have that statement.
`Then, if you turn to slide 40, elsewhere in the article of
`Gerber he states that pretty much the same statement he made in
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`Patent 8,822,438 B2
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`the Abstract except he enhances it, you might say, with a
`significant benefit. These patients will derive significant benefit
`from the combination of ketoconazole and glucocorticoid
`replacement therapy. So from Gerber you have the reason to use
`prednisone for glucocorticoid replacement therapy when a
`compound inhibits the CYP17 enzyme.
`If you can turn to slide 41, so Gerber taught the
`effectiveness of ketoconazole in combination with prednisone for
`treating prostate cancer. As shown on slide 41, he reports that
`there was a certain number of patients that in another study with
`ketoconazole that had a regression in tumor mass and disease on
`bone scan. And then he talks about the patients who will benefit
`from ketoconazole treatment. This is showing that there was an
`effectiveness of ketoconazole and prednisone.
`He also tells us that ketoconazole -- I'm sorry, slide 42.
`He also tells us that ketoconazole and prednisone
`coadministration was safe. On slide 42 he states ketoconazole
`was generally well tolerated. He talks about one patient having
`some nausea and vomiting and discontinuing the drug. He talks
`about prednisone, that two patients had minor bruising believed
`to be due secondary to the prednisone. So he's telling us that this
`combination treatment is safe.
`JUDGE GREEN: Now, I think one of the patent
`owner's arguments is about treatment. Is the prednisone, as
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`Patent 8,822,438 B2
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`taught by Gerber, treating the cancer or is it ameliorating the side
`effects of the enzyme inhibitor?
`MR. HARE: Well, it's being used as glucocorticoid
`replacement therapy because ketoconazole inhibits these enzymes
`in the adrenal steroid biosynthesis pathway. So it's doing that, he
`states that it's being used to -- Gerber states that it's being used to
`treat prostate cancer. So we know that it's being used as a
`replacement for the blockage of cortisol. As part of this whole
`adrenal steroid pathway, a CYP17 inhibitor, you reduce the
`production of cortisol, which is bad. You also reduce the
`production of testosterone, which is good. But by reducing the
`production of cortisol, you need to replace that. Prednisone is
`like a synthetic cortisol. So he's replacing it.
`Does prednisone treat prostate cancer? According to
`Gerber it does.
`JUDGE GREEN: And that's from your slide, I guess
`I'm looking at slide 41?
`MR. HARE: Slide 6. I mean, Gerber uses the word
`"treatment" repeatedly.
`JUDGE GREEN: Thank you.
`MR. HARE: So on slide 6 we have these statements
`that are from Gerber. The patent owner is asking us really to
`ignore these statements and dismiss the conclusions of Gerber.
`What they did was they brought back a coauthor of Gerber,
`Dr. Chodak, now to try to denigrate this article by attacking the
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`Patent 8,822,438 B2
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`fact that it wasn't a prospective well-controlled clinical trial
`designed to show safety and effectiveness. He attacks the
`conclusion. He says that today significant benefit means survival
`benefit.
`
`But these statements say what they mean and they mean
`what they say. And in 2006 we didn't know what Gerber was
`going to say in 2016. So one of skill in the art would have seen
`this article and seen these conclusions and concluded what
`Dr. Gerber and Chodak, the authors, concluded in 2006.
`Also keep in mind, this is a peer-reviewed journal.
`These articles were submitted. They are reviewed. Then they are
`published. In that review process, they could be revised. So this
`is a peer-reviewed medical journal. Physicians will look at this
`for what it states. They don't know what Dr. Gerber -- or
`Dr. Chodak -- is going to say 26 years later in a legal proceeding.
`JUDGE KALAN: Does it diminish the significance of
`Gerber at all that since that time ketoconazole hasn't really been
`used very much in the treatment of this type of prostate cancer?
`MR. HARE: I don't think it does. For example,
`Dr. Chodak, one of the coauthors, we've got this article here. He
`also -- there was a letter to the editor where someone questioned
`about the PSA results. Dr. Blacker. So a letter to the journal, the
`same journal, letter to the editor, questioned the PSA values.
`Dr. Chodak and Gerber responded and pointed out, you know,
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`they discussed the PSA bit, but they still said, this is about a year
`later, that there's still going to be a benefit to these patients.
`Then you also have, I think it was about in 2004
`Dr. Chodak with another author, Dr. Wilkinson, published
`another study on ketoconazole with glucocorticoid replacement
`therapy. So it continued on. So people were continuing to work
`with ketoconazole and treating prostate cancer with
`glucocorticoid replacement therapy.
`So O'Donnell, the combination of O'Donnell and
`Gerber, so O'Donnell -- and I'm looking at slide 8. Sorry.
`O'Donnell has a really clear statement in its abstract. O'Donnell
`says adrenocortical suppression may necessitate concomitant
`administration of replacement glucocorticoid. O'Donnell, another
`peer-reviewed article in a journal where they review these
`articles, makes this statement. Elsewhere, after presenting data,
`O'Donnell concludes in light of the clinical evidence, further
`studies with abiraterone acetate will be required to ascertain if
`concomitant therapy with glucocorticoid is required on either a
`continuous basis at times of physiological stress, if patients
`become symptomatic, or indeed at all. So O'Donnell makes these
`statements in the peer-reviewed journal.
`So what the patent owner is trying to do is dismiss this
`by bringing an endocrinologist, Dr. Auchus, not a person of skill
`in the art, an endocrinologist, to come back and interpret some of
`the data, some of the test data in O'Donnell. Again, O'Donnell, a
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`peer-reviewed journal. He comes to interpret this Synacthen test
`and say you would ignore those results from which O'Donnell
`makes his conclusions based on the way the data was presented.
`Real briefly, it's a test that measures adrenal gland
`function. You inject a synthetic hormone that stimulates the
`adrenal gland; you see how well it works. Adrenal gland function
`will be somewhat compromised with abiraterone acetate because
`it's a CYP17 inhibitor, so you will make less cortisol. So he
`measures the baseline of cortisol, injects this ACTH hormone,
`measures it half an hour later to see what level we are at, and you
`get what's called a delta cortisol, the change in cortisol. You are
`testing the ability of the adrenal gland to pump out cortisol.
`Dr. Auchus doesn't like that O'Donnell, the author of the
`article, reported this as a delta cortisol, the change from baseline,
`from pre-stimulation to stimulation. He doesn't like that it's a
`percentage change and a number change. He thinks it should be
`the absolute value, that you should have a value of 560
`millimoles per liter or something like that.
`The problem is O'Donnell had all the data. O'Donnell
`had the absolute values because he calculated the delta cortisol.
`He decided what values to present when he made this article. If
`there were problems with the data as it was presented in 2004 and
`it's a peer-reviewed journal, somebody would have said, no, no,
`you need to present it a different way.
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`Let's move to slide 9, please. O'Donnell states that in
`clinical use of both aminoglutethimide and ketoconazole, it's
`common practice to administer supplemental hydrocortisone, a
`glucocorticoid. And this may prove necessary with a
`17α-hydroxylase and C17,20-lyase inhibitor, CYP17 inhibitor such
`as abiraterone acetate. He makes these statements. One of skill
`in the art would have seen these.
`We can go to slide 10. So in response to patent owner
`bringing an endocrinologist, Dr. Auchus, to raise questions about
`the Synacthen test, petitioner had to bring an endocrinologist,
`Dr. Dorin, again, not a POSA, but an endocrinologist to look at
`these cortisol test results that are reported in O'Donnell.
`Dr. Dorin states that these cortisol results in O'Donnell were
`compelling, significant and interpretable for a POSA. The fact
`that it's a delta cortisol and a percentage change is sufficient.
`Dr. Auchus said it would have been nice to have some
`variation, some measure of variation of these results. So you
`have three patients that got 500 milligrams of abiraterone acetate
`for 11 days. You had three patients who got 800 milligrams of
`abiraterone acetate for an extended period. And Dr. Auchus
`would like some variation measures for the changes in cortisol
`due to a Synacthen test. Dr. Dorin said it would have been nice
`to have that, like, for example, standard deviation, but those
`wouldn't have influenced an interpretation of the O'Donnell data.
`It's sufficient with what he reported.
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`If we can go to slide 13, some of the questions that have
`been raised in this have to do with a mechanism of action. Are
`they the same or are they different? Well, they had the same
`mechanism of action of treating prostate cancer. They reduce the
`production of testosterone. You want that, otherwise the
`testosterone fuels the prostate cancer cells. But when you go
`through this pathway, you also reduce the production of cortisol.
`When you inhibit the CYP17 enzyme, you inhibit the production
`of cortisol. You also increase ACTH production. ACTH is a
`hormone that stimulates the adrenal gland which attempts to
`make more cortisol. So they have that all in common. They both
`inhibit the CYP17 enzyme. Both O'Donnell and Barrie tell us
`that. Granted, ketoconazole inhibits additional enzymes in the
`adrenal steroid biosynthesis pathway, but they both inhibit the
`CYP17 enzyme.
`JUDGE KALAN: And this is one of patent owner's
`primary criticisms of the motivation to combine. Why would one
`of ordinary skill in the art, given the sledgehammer effect of
`ketoconazole, look to abiraterone acetate, apart from the fact that
`they both can be characterized in some limited way as CYP17
`inhibitors?
`MR. HARE: That's a good question. The answer, I
`believe, is that O'Donnell and Barrie both tell us to. What does
`O'Donnell compare abiraterone acetate to? Ketoconazole. You
`look in Barrie, he gives IC50 values for what drugs? Abiraterone
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`acetate and ketoconazole. So O'Donnell and Barrie tell us to look
`at ketoconazole. They made the comparisons. So we believe that
`provides a motivation to combine. I mean, O'Donnell compares
`them to ketoconazole and says you need glucocorticoid. Does
`that answer your question sufficiently or would you like to ask
`more?
`
`JUDGE KALAN: There's still an issue about the
`selectivity. For example, in the mechanism of action on your
`slide 15, AA doesn't inhibit the pathway that leads to, say,
`corticosteroid which apparently has a weak cortisol-like effect.
`Wouldn't one of ordinary skill in the art look at those two
`differently as a result of at least that factor?
`MR. HARE: Well, again, I think you come back to
`what Barrie and O'Donnell do as they compare ketoconazole and
`abiraterone acetate. In O'Donnell they don't have this chart and in
`Barrie they don't have this chart. In Barrie they have some IC50
`values that show some different selectivity -- difference of IC50
`values, but both Barrie and O'Donnell make the comparison
`between abiraterone acetate and ketoconazole.
`JUDGE GREEN: Do we have any evidence of when
`these mechanisms of actions were known to the ordinary artisan?
`Would the ordinary artisan at the time of the invention been
`aware of these differences between these two inhibitors?
`MR. HARE: I think that in O'Donnell he describes
`ketoconazole in its inhibitory mechanisms and then he moves on
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`from there and says that abiraterone acetate was -- led to the more
`selective, basically, CYP17 inhibitor. So I think these were all
`known. And I believe also that there was textbooks, I believe it's
`Harrison's in the prior art that is cited that provides all this
`information about inhibition of the enzymes.
`JUDGE GREEN: Thank you.
`JUDGE KALAN: Is that what O'Donnell is referring to
`when he says some impact on adrenal reserve was predictable
`from the steroid synthesis pathway or is he only talking about one
`or the other?
`MR. HARE: I think he is talking about abiraterone
`acetate and the fact that it inhibits the CYP17 enzyme, that you
`would expect that. I mean, Barrie, which, again, is a patent to
`abiraterone acetate provides IC50 data for abiraterone acetate. So
`you would know which enzyme it's inhibiting and you would be
`able to figure out what the results when you blocked this
`pathway, what happens when you block that pathway. From that
`you know what's going to happen. You know that cortisol
`production will be reduced, testosterone production will be
`reduced.
`Can we jump to slide 34? So there are some questions
`about prednisone. Why would you go to prednisone? There are
`the concerns of the long-term side effects of prednisone that have
`been raised in this case. Keep in mind in 2006, at the time of this
`patent, patients with metastatic castration-resistant prostate cancer
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`Case IPR2016-00286
`Patent 8,822,438 B2
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`had about an 18-month survival. So I hate to talk like this, but
`they would be lucky to live long enough to have long-term side
`effects of prednisone affect them.
`So our endocrinologist explained that the known risk of
`concomitant administration of replacement glucocorticoid would
`be far more acceptable to a POSA in comparison to the unknown
`but predictable risk of abiraterone acetate without concomitant
`administration of a replacement of glucocorticoid. That's on slide
`34. Sorry, I jumped ahead. But there's the risk of giving the
`prednisone and not giving the prednisone, the side effects of
`reduced cortisol levels. These patients were frail, elderly and
`sick.
`
`If you go to slide 33, Dr. Dorin, an endocrinologist,
`works with the Veteran's Administration Hospital, sees these
`patients. He says that a POSA would take into consideration the
`clinical issues specific to these treatment population.
`Recognizing the risk of concurrent stress and adrenal crisis would
`be far greater in a high-risk elderly population. And he concludes
`that a POSA would reach the same conclusions of O'Donnell and
`recognize that adrenal suppression may necessitate concomitant
`administration of replacement glucocorticoid in patients receiving
`long-term abiraterone acetate treatment for metastatic
`castration-resistant prostate cancer. These patients are on
`abiraterone acetate for life.
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`If we can go to slide 90, so questions were raised does
`prednisone fuel prostate cancer cells? Well, the FDA has
`approved docetaxel for treating prostate cancer in combination
`with prednisone. We have articles out there that talk about
`ketoconazole with prednisone. So I think that answers the
`question that it's probably better to have the prednisone in treating
`the prostate cancer with these drugs, and that's why the FDA
`approved it.
`We can go to slide 50. Actually, skip that. How about
`to slide -- I would actually like to jump on to the commercial
`success/secondary considerations unless you want to talk more
`about some of these other issues, the prima facie case.
`JUDGE GREEN: We are fine.
`MR. HARE: If we can go to slide 58 now, the patent
`owner hasn't overcome the prima facie case of obviousness with a
`showing of commercial success or unexpected results. The
`product embodying the patented invention is -- for the patent
`owner to show commercial success, they need to show that the
`product embodying the patented invention is both commercially
`successful and that there's a nexus between the claimed patentable
`features of the invention and the commercial success of the
`product. And they haven't shown either prong here.
`We can go to slide 68. So we are at slide 68. The
`effects of Zytiga coadministration with prednisone derived from
`known elements in the prior art, if commercial success is due to
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`Case IPR2016-00286
`Patent 8,822,438 B2
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`only the known elements in the prior art, no nexus exists. So here
`success of Zytiga does not derive from the unique characteristics
`of the '438 patent claims, the coadministration of abiraterone
`acetate and prednisone. Both abiraterone acetate and prednisone
`were known in the art to be individually effective in treating
`prostate cancer, according to the examiner, who was examining
`the '438 patent. So what you have here in the '438 patent is
`abiraterone acetate acting as an anticancer agent known from
`O'Donnell and Barrie and you have prednisone acting as a
`glucocorticoid replacement, as is known from Gerber, known
`from Gerber for treating prostate cancer. So we have these
`known compounds acting in the roles for which they are known.
`Nothing is new here in this combination.
`Let me go to slide 67. So the patent owner is trying to
`argue in this case that there's some improved efficacy, some
`special synergistic effect between the two. But any enhanced
`efficacy of co-prescribing prednisone with abiraterone acetate is
`incidental to the reduction of side effects. And it's not the result
`of an unexpected synergistic anticancer or antitumor effect.
`We can go to slide 69. The patent owner has provided
`no convincing evidence that physicians overwhelmingly prescribe
`Zytiga due to the effects of the drugs in combination.
`Dr. Vellturo, an economist retained by the patent owner, states --
`makes the assertion that physicians overwhelmingly prescribe
`Zytiga due to an enhanced therapeutic effect deriving from the
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`Case IPR2016-00286
`Patent 8,822,438 B2
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`combination. But the label makes no mention of any
`therapeutic -- of some enhanced therapeutic effects. They just --
`JUDGE GREEN: But the label does discuss
`administered with prednisone, right?
`MR. HARE: Definitely describes administering it with
`prednisone.
`JUDGE GREEN: And then do we have any evidence
`that it's prescribed off label so that it's not prescribed with the
`prednisone?
`MR. HARE: You know, I think the only data that we
`have presented for this was an IBM Explorys data that
`Dr. Vellturo had. And it had very little information. What it
`showed was, I believe, monthly data of prescriptions of
`abiraterone acetate. And I believe the way he described it is that
`these are patients who received a prescription for abiraterone
`acetate and prednisone within three years of each other. And it
`showed that 89 percent of these patients had the two within three
`years of each other.
`JUDGE GREEN: But the burden is yours, right,
`because under PPC, if they come in the product appears to be --
`meet the claims of the patent, the label says administer this
`compound with the prednisone, under PPC there is a presumption
`the commercial success is due to the patented invention. So what
`I'm asking is, do you have any evidence that it's not due to the
`patented invention, that it's due to something else?
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`I know you have your arguments about the blocking
`patents, but do we have any evidence that it's prescribed off label,
`that it's really due to just the AA alone or anything else like that?
`Do we have any evidence of that on the record? Because the
`ultimate burden of persuasion is yours.
`MR. HARE: Well, one thing we have that's on the
`record is that this is approved as an oral dosage form. At the time
`of this invention, there was docetaxel approved with prednisone
`for IV injection. So you have, there's a patient convenience, to be
`able to take an oral tablet once a day rather than have to go to an
`infusion center to receive an infusion of a chemotherapy drug. So
`we have that as what could be driving the sales of this Zytiga.
`And we don't -- what we also don't have any evidence
`that there is an unexpected efficacy improvement.
`JUDGE GREEN: I understand. We were talking about
`the commercial success. If you want to switch gears, that's fine,
`but I'm just talking about the commercial success.
`MR. HARE: So we have the blocking patent. Let me
`go to, we have the fact that it's FDA approved. The prescribing
`information states to prescribe the two together. We have
`Dr. Serels and Dr. Ratain both saying that a physician would
`prescribe it according to the prescribing information.
`JUDGE GREEN: But that supports the patent owner,
`right, that they are going to prescribe it due to -- in accordance
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`Case IPR2016-00286
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`with the prescribing information? If it didn't work, it wouldn't be
`prescribed.
`MR. HARE: Well, both Dr. Serels and Dr. Ratain state
`that they prescribe per the label. Not for the combination. So
`they are not viewing this as -- that there's some enhanced efficacy
`of the two, but it's just following the label, which is what you
`would have gotten from combining O'Donnell and Gerber or
`Barrie and Gerber.
`Let's see, if we can go to slide number 82, so there have
`been no unexpected results shown in this case. During the
`prosecution, there was no evidence of a relevant -- there was no
`relevant evidence of unexpected results. The patent owner, the
`applicant argued that the combination of the two had unexpected
`results. But the patent examiner said that wasn't persuasive
`because they were being used for their known purposes. And
`since then there's been no new evidence.
`If you go to slide 91, there is no relevant comparative
`data. So this, I think, is important. We have abiraterone acetate
`and prednisone compared to prednisone. But we know from
`O'Donnell and Barrie that the closest prior art was abiraterone
`acetate. The proper comparison, the comparison to the closest
`prior art would have been abiraterone acetate and prednisone
`compared to abiraterone acetate. So without that comparative
`data, we have no idea. It's impossible to know whether the
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`Case IPR2016-00286
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`addition of prednisone to abiraterone acetate provided any
`unexpected anticancer effect.
`JUDGE KALAN: What is the problem with
`Dr. Rettig's Table 1 which has, I think, as the fourth and final line
`item acomparison of the abiraterone acetate plus prednisone to
`other data sets?
`MR. HARE: So let's see, I'm not sure which slide that
`is, but what he is showing is he's showing a bunch of some
`studies. Those studies were of abiraterone acetate with
`dexamethasone, and from there they are drawing the conclusion
`that there is an unexpected result of abiraterone acetate with
`prednisone. But the claims are to prednisone. Not to
`dexamethasone.
`JUDGE GREEN: But the first line of the table seems to
`be to the AA monotherapy. So they have the AA monotherapy,
`the AA plus the dexamethasone and then the third line as well,
`and then the fourth line is AA plus prednisone. And that is at
`page 47 of their slides.
`MR. HARE: You don't have a single study that's
`comparing -- you have different studies.
`JUDGE GREEN: So your issue is that these are
`different studies that they kind of pulled together into one table?
`MR. HARE: You don't ever have a direct comparison
`between the closest prior art, abiraterone
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