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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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`PAR PHARMACEUTICAL, INC., ARGENTUM PHARMACEUTICAL
`LLC, and WEST-WARD PHARMACEUTICALS INTERNATIONAL
`LIMITED,
`Petitioner,
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`v.
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`NOVARTIS AG,
`Patent Owner.
`____________
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`Case IPR2016-01479
`Patent 9,006,224 B2
`____________
`
`Record of Oral Hearing
`Held: November 1, 2017
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`Before LORA M. GREEN, CHRISTOPHER L. CRUMBLEY, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
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`Case IPR2016-01479
`Patent 9,006,224 B2
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`APPEARANCES:
`
`ON BEHALF OF THE PETITIONER:
`BRENDA DANEK, ESQUIRE
`DANIEL G. BROWN, ESQUIRE
`Latham & Watkins, LLP
`330 North Wabash Avenue
`Chicago, Illinois 60610
`
`ON BEHALF OF PATENT OWNER:
`CHARLOTTE JACOBSEN, ESQUIRE
`NICHOLAS N. KALLAN, ESQUIRE
`Fitzpatrick, Cella, Harper & Scinto
`1290 Avenue of the Americas
`New York, New York 10104-3800
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`The above-entitled matter came on for hearing on Wednesday,
`November 1, 2017, commencing at 9:00 a.m., at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
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`P R O C E E D I N G S
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`JUDGE CRUMBLEY: Good morning, everyone. So today we
`have oral hearing in IPR2016-1479 between Par Pharmaceutical,
`Argentum Pharmaceutical and West-Ward Pharmaceuticals as petitioners
`and Novartis as the patent owner. I think I recognize most everyone in
`the room, so I'm going to dispense with my opening remarks that I
`typically make, but I would like to get appearances from counsel first.
`MS. DANEK: Good morning, Your Honor. My name is
`Brenda Danek. I will be arguing on behalf of -- I'm counsel for
`petitioner, Par, and arguing on behalf of all petitioners.
`JUDGE CRUMBLEY: Who do you have with you here today?
`MS. DANEK: Today I have Daniel Brown, who is counsel for
`petitioner, Par. Also present are Keith Zullow on behalf of West-Ward,
`and Tyler Liu on behalf of Argentum.
`MS. JACOBSEN: Good morning. Charlotte Jacobsen on
`behalf of Novartis AG, and with me is Nicholas Kallas.
`JUDGE CRUMBLEY: Good morning. So I believe we gave
`both sides 45 minutes; is that correct?
`MS. DANEK: That's correct, Your Honor.
`JUDGE CRUMBLEY: So I will note for the record that both
`parties submitted demonstrative exhibits, and we did receive objections
`to petitioner's exhibits from the patent owner. There were no objections
`from petitioner?
`MS. DANEK: No, Your Honor.
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`JUDGE CRUMBLEY: So we've reviewed those objections.
`They appear primarily addressed to being new arguments and
`incorporation by reference. I'm just sort of generalizing here. We've
`considered those. I think for the purposes of the hearing today we are
`going to go forward with the slides as they are. I think when we review
`the record as a whole we can determine what's a new argument and
`dispose of those as necessary. So we are just going to proceed with the
`slides that were submitted.
`All right. Ms. Danek, you can proceed when you are ready.
`How much time do you want to reserve?
`MS. DANEK: I'd like to reserve 15 minutes, Your Honor. I
`have hard copies of the demonstratives.
`JUDGE CRUMBLEY: That would be great.
`MS. DANEK: May it please the Court, the prior art on which
`the Board instituted teaches the use of mTOR inhibitors to treat
`neuroendocrine tumors. The principal mTOR inhibitors known as of
`November 2005 were rapamycin and two rapamycin derivatives,
`everolimus and temsirolimus. The only difference between the prior art
`and the challenged claims is exchanging one well known rapamycin
`mTOR inhibitor for another. And that's what I would like to spend much
`of my time today talking about, the obviousness of that substitution and
`why a person of ordinary skill in the art would have had a reasonable
`expectation of success in making that modification.
`Let's take a look at slide 2 of the petitioner's demonstratives.
`This is the claim 1 of the '224 patent. Novartis' '224 patent claims
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`methods of treating a type of pancreatic tumors called pancreatic
`neuroendocrine tumors or PNETs. The entire text of the claim is shown
`on slide 2 of petitioner's demonstratives. The claim includes one step,
`administering a therapeutically effective amount of everolimus as a
`monotherapy. The claim also limits the PNETs to those that are
`advanced, which the Board in its institution decision agreed with
`petitioners that advanced means metastatic or unresectable. And that's at
`the institution decision at 7. The claim also identifies that the tumors are
`after failure of cytotoxic chemotherapy. This is the subject matter that
`would have been obvious to a person of ordinary skill in the art as of the
`filing date.
`Now I would like to take a look at what Novartis includes in its
`specification. If we can go to slide 4 of petitioner's demonstratives,
`Novartis filed its patent application with no clinical data and no
`preclinical data. All the specification identifies is that certain known
`experiments could be done. The '224 patent specification from columns
`25, line 49 through column 26, line 64, includes a mere one and a half
`columns of these prophetic examples. The examples say that the utility
`of the mTOR inhibitors in treating endocrine tumors can be demonstrated
`in the various in vitro and in vivo assays.
`If we look at slide 6 of petitioner's demonstratives, the
`examples also include several prophetic clinical studies that could be
`performed at a future time, one of which essentially mirrors the language
`of the claim, a clinical study of pancreatic neuroendocrine tumors after
`failure of cytotoxic chemotherapy as a monotherapy. Based on this
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`disclosure, Novartis received claims to treating these tumors with
`everolimus. But why does this matter? Because the prior art already
`taught the person of ordinary skill in the art that these tumors could be
`treated with mTOR inhibitors.
`Novartis has spent a significant amount of time criticizing the
`data in the prior art, but the Federal Circuit has faced this exact question
`before. In Merck v. Teva, 395 F.3d, 1364 at 1374, which is cited in our
`reply at pages 12 and 19, the Federal Circuit held that when a patent,
`quote, adds nothing beyond the teachings of, quote, the prior art, it is
`clear error to find a difference between the disclosure of the prior art and
`the patent claims on that basis. In Merck, the patentee criticized the prior
`art for failing to demonstrate that the claimed dosage would be well
`tolerated, but the patent at issue, quote, set forth no human clinical or
`laboratory data showing the safety and tolerability of the treatment
`methods claimed in the patent.
`The same is true here. Novartis, having no clinical or
`preclinical data in its patent, cannot distinguish its claims from the prior
`art on this point. The Federal Circuit has held that it would be clear error
`to do so. And here the prior art teaches each and every limitation of the
`challenged claims.
`Looking at slide 7, the Board instituted review on the claims as
`obvious on four grounds. The grounds essentially fall into two
`categories, combinations that include Oberg and combinations that
`include Druan. All grounds include Boulay and O'Donnell. And grounds
`2 and 4 are directed to claim 2 only, but Novartis has not really raised the
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`limitation of claim 2 as a patentable distinction. So I'm going to focus on
`claim 1, and I'm going to start this morning discussing the Oberg
`combinations.
`If we go to slide 8, the Board found that the petition set forth
`sufficient evidence that a person of ordinary skill in the art viewing
`Oberg, Boulay and O'Donnell in combination would have had a
`reasonable expectation of success in treating advanced PNETs after
`failure of cytotoxic chemotherapy, and for good reason. Go to slide 10.
`Oberg discloses each of the elements of claim 1. In Figure 1 of Oberg,
`Exhibit 1027, Oberg describes treating NETs, which Novartis admits
`includes PNETs, in particular, their expert, Dr. Kulke, at 48 in his
`organizational chart and the organizational chart that is cited in page 10
`of their response.
`Going to slide 11, Oberg also describes treating with the mTOR
`inhibitor, rapamycin, the parent molecule of everolimus.
`Going to slide 12, Oberg describes rapamycin as an mTOR
`inhibitor and identifies using it as a single agent, therefore, as a
`monotherapy.
`Slide 13, Oberg describes treating advanced PNETs, again,
`those that are unresectable, that could not be removed via surgery. In
`slide 14, Oberg finally describes the use of the mTOR inhibitor
`rapamycin, that that compound should be used on those NETs after
`failure of cytotoxic chemotherapy.
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`JUDGE CRUMBLEY: Counsel, just to clarify, I thought I
`heard you say that Oberg here in Figure 1 disclosed all elements of
`claim 1. This is not an anticipation ground?
`MS. DANEK: No, Your Honor, this is not anticipation.
`JUDGE CRUMBLEY: You would agree with me that it
`doesn't disclose everolimus?
`MS. DANEK: I agree with you, yes, Your Honor. Each
`element is disclosed with the exception that Oberg talks about the parent
`molecule. Novartis' claims are directed to --
`JUDGE CRUMBLEY: I just wanted to make sure we are clear
`for the record.
`MS. DANEK: But the limitation of administering an mTOR
`inhibitor is disclosed in Oberg.
`JUDGE CRUMBLEY: That's a limitation of the claim?
`MS. DANEK: The subject matter of administering an mTOR
`inhibitor.
`JUDGE CRUMBLEY: I understand.
`MS. DANEK: Let's look at slide 15. Figure 1 of Oberg is not
`the only discussion of rapamycin for treating neuroendocrine tumors.
`Oberg specifically calls out the mTOR inhibitor rapamycin as an
`interesting new compound and identifies that clinical trials are planned.
`This discussion in Oberg is strikingly parallel to the clinical trial
`description that Novartis has included in its patent specification. The
`only difference between Oberg's teaching and claim 1 is the substitution
`of the well-known mTOR inhibitor, everolimus, for the well-known
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`mTOR inhibitor rapamycin. And that really is the question left to
`determine.
`JUDGE CRUMBLEY: Counsel, just before you move on,
`doesn't this passage here, I mean, the fact that it's a new compound, the
`fact that its clinical trials are planned, doesn't that cut against you on
`expectation of success?
`MS. DANEK: I don't believe it does, Your Honor. I think
`based on this discussion, what Oberg is saying is that an undisputed
`expert in the treatment of NETs, he is informing the community, a person
`of ordinary skill in the art that this compound is one of the therapies that
`should be investigated in clinical trials. Now, while there is some
`uncertainty that Novartis has raised, this provides a lot of information to
`a person of ordinary skill in the art that this would be an effective
`treatment. And as Dr. Kulke testified during his deposition, he said that
`Dr. Oberg's opinions would be taken into account in considering whether
`or not a treatment would be effective. That was cited in our reply. I will
`get the cite for you in just one second.
`JUDGE CRUMBLEY: That's all right. Maybe co-counsel will
`provide it for us later. So here is what I'm thinking of with this disclosure
`here in Oberg. So I mean, I think it's reasonable, it's a reasonable
`argument to make that, you know, rapamycin, it would be obvious to try
`rapamycin. I think it's reasonable also because it identifies the mTOR
`pathway, that other mTOR inhibitors would be reasonable to investigate
`as well. So I mean, also because of the structural similarity, I think it's
`reasonable to look at other structures that are similar. But even accepting
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`all of those things, what you are left with is either that the class as a
`whole, it would be obvious to investigate the class as a whole, and we
`need to get to the particular member of the class that you end up with,
`everolimus, or that, you know, why you would have a reasonable
`expectation of success with everolimus. And that's what you need
`Boulay for, I believe, because you are not getting that, at least I don't get
`that here, from Oberg.
`MS. DANEK: I think, in fact, the discussion in the Merck case
`actually speaks directly to this point.
`JUDGE CRUMBLEY: In what way?
`MS. DANEK: The Court identified that even if there was some
`skepticism on the disclosure of the prior art as to whether or not in that
`case the dose would be well tolerated, that was not enough because the
`patent itself didn't resolve any of the skepticism. It did not advance it.
`So even if, as you identify, a person of ordinary skill in the art would be
`uncertain as to whether or not what Oberg is saying here would be
`guaranteed to work, the Merck case addressed that even in the face of
`skepticism, that cannot be a difference between the disclosure of the prior
`art and disclosure of the patent. And so this teaching in Oberg, we do
`think, addresses the reasonable expectation of success.
`JUDGE CRUMBLEY: Can you address the follow-on Oberg
`reference, the 2005 Oberg reference that does not mention rapamycin?
`And patent owner's argument about that is that that is directly addressed
`to PNETs and yet does not mention rapamycin. I understand your
`response to be, well, yes, but that article is more about clinical
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`applications as opposed to experimental therapies, which is what Oberg
`2004 is mentioning. Am I understanding your argument correctly?
`MS. DANEK: That is part of our argument, yes.
`JUDGE CRUMBLEY: So again, doesn't that cut against you
`on the expectation of success because you are admitting that rapamycin is
`not clinical, is experimental and that at least as of 2005 would not have
`been something that is applied in therapies in general?
`MS. DANEK: So I think if we could take a look at petitioner's
`slide 35 --
`JUDGE CRUMBLEY: I appreciate you jumping around with
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`me.
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`MS. DANEK: I'm happy to answer your questions. This sets
`up the analysis for the difference between Exhibit 1027 and Exhibit 1028.
`And as Your Honor identified, the Exhibit 1028 includes treatments for
`pancreatic neuroendocrine tumors and does not identify rapamycin. But
`one of the differences between the two is that as you identify the clinical
`data. Exhibit 1028 was published in a journal called Best Practice and
`Research Clinical Gastroenterology. It was directed to an audience of
`clinicians, practicing clinicians. Exhibit 1027 was published in
`Oncologia, and it was directed to cancer, people specifically interested in
`cancer. Not just general gastroenterologists.
`One of the things that Exhibit 1028 identified in its closing
`paragraph was that none of the treatments that it talked about with
`clinical data were actually enough that they needed more treatments
`based on cancer tumor biology. And that's precisely what Oberg had told
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`the cancer research community in Exhibit 1027, in identifying those
`treatments that that would fill the gap of the treatments that clinical data
`was available on.
`JUDGE CRUMBLEY: You state in your reply brief at page 7
`that the Oberg and Eriksson article in Exhibit 1028 describes only those
`treatments already in clinical use, and then you cite the reference itself. I
`don't know the page of the reference itself, and you go through that. I
`didn't find any statement in those that those things occur already in
`clinical use. Is it because of the journal that it was published in that we
`are to draw that conclusion or does it say somewhere that it's only talking
`about treatments that are already in clinical use?
`MS. DANEK: So we asked Dr. Kulke at his deposition to walk
`through the treatments and identify that each and every one of them had
`clinical data published in the Oberg reference regarding them. You don't
`have clinical data unless they have been given clinically.
`JUDGE CRUMBLEY: So it's a statement that he agreed with
`you that everything that was in there was in clinical use but not
`necessarily that was the reason they were. He never says we are only
`listing things here that are in clinical use?
`MS. DANEK: It does not make that explicit statement.
`JUDGE CRUMBLEY: Thank you.
`MS. DANEK: I would like to address -- I believe Your Honor
`brought up Boulay, so I would like to talk about Boulay. Actually,
`briefly, let me talk about the teaching of Boulay and the combination
`with O'Donnell. If we go to slide 16, at the time of the filing, everolimus
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`was well known in the art as an mTOR inhibitor being clinically
`developed as an anticancer agent. Boulay identifies at page 252 that it is
`an orally bioavailable derivative of rapamycin. Boulay identifies that
`everolimus has potent anti-proliferative effects against a variety of
`mammalian cell types. And Boulay also identifies again that everolimus
`is being clinically developed.
`O'Donnell further identifies that everolimus has known
`anticancer activity. O'Donnell is a report of a Phase I study reporting that
`everolimus in patients with advanced solid tumors was well tolerated and
`had mTOR inhibition activity. Everolimus was not an obscure
`compound. There was sufficient information about its anticancer activity
`to justify giving it to human patients. These disclosures identify
`everolimus as safe, well tolerated as an mTOR inhibitor that is
`appropriate to administer to patients, and a POSA would have been
`motivated to use everolimus in Oberg's method.
`But Boulay has more. If we go to slide 17, Boulay also reports
`that everolimus was effective as an anticancer agent in a preclinical
`in vivo experiment. Boulay, at 254, states that everolimus resulted in
`antitumor activity and significant inhibition of tumor growth as well as
`being well tolerated in the animal model. Boulay, at 258, concludes that
`based on these preclinical data, this rapamycin derivative demonstrates
`significant antitumor efficacy in this animal model of pancreatic cancer.
`Now, the tumor model using Boulay was the CA20948 cell
`line. There's been a lot of discussion between the parties as to the
`relevance of this cell line. If we can go to slide 18, Dr. Ratain testified at
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`paragraph 112 of Exhibit 1003 that at least one prior art reference,
`Exhibit 1010, identified the CA20948 cell line as a preclinical model for
`neuroendocrine tumors. Therefore, a person of ordinary skill in the art
`would have been aware of this connection between this cell line and
`neuroendocrine tumors.
`In the petition, petitioners incorrectly identified this cell line as
`PNET tumors in two places, pages 9 and 32 to 33. However, the petition
`at page 1 and 43 correctly identified the cell line as a model for these
`tumors. And further, Dr. Ratain testified that this cell line was used as a
`model for NET and as a PNET model in both paragraph 112 and
`paragraph 137.
`The Board, at page 9 of its institution decision, acknowledged
`this testimony from Dr. Ratain where it stated Dr. Ratain testified that the
`line was used as a model for PNETs in laboratory studies.
`JUDGE CRUMBLEY: Counsel, isn't it the case that you can
`have a line be a model for something, for some sorts of treatments but not
`for other sorts of treatments? Does that make sense?
`MS. DANEK: Yes, Your Honor. I believe what you are saying
`is what is the value of this model for pancreatic neuroendocrine tumors?
`JUDGE CRUMBLEY: Well, I mean, the cell line may have
`some similarities to PNETs that make it relevant as a model for certain
`sorts of treatment, but it may have differences in other ways that make it
`less applicable as a model for other sorts of treatment. Would you agree
`with me that that is the case?
`MS. DANEK: Yes, Your Honor.
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`JUDGE CRUMBLEY: So it seems to me that patent owner's
`argument here is that it may have been a relevant PNET model for
`De Jong's study, right, because of the similarities of pancreatic tumors as
`a whole. But when you get to the mTOR pathway, it's not a relevant
`model for the mTOR pathway, and so therefore, it would not have been
`considered a relevant model for everolimus. Can you respond to that?
`MS. DANEK: Yes, Your Honor. Preclinical assays provide
`useful information and in an artificial construct. None of these tumors in
`any preclinical assays or most preclinical assays actually reflect the
`natural course of human disease. But the use of them has been well
`founded in the science. They provide information but they are not
`necessarily predictive. But they do provide information about the fact
`that in a model of cancer, everolimus was found to have antitumor
`activities. And while there could be distinguishing features of why you
`could say, well, you can't predict that everolimus would be effective in
`NETs based solely on that, petitioners do not rely solely on the
`preclinical data in Boulay to form its arguments regarding reasonable
`expectation of success. As the Board recognized in its institution
`decision, it is the combination, and Boulay must be viewed through the
`lens of what Oberg has identified.
`JUDGE CRUMBLEY: I'll grant you that it's not your sole
`thing, but it is important and it is something we relied on in the institution
`decision. We relied on your expert's testimony that it was a PNET
`model, and he said that without qualification. But now it sounds like it's
`a lot more nuanced than it just being a PNET model and there may be a
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`better PNET in the model for De Jong. But I'm having a harder time
`making the conclusion that it's a PNET model in the context of mTOR
`inhibitors.
`MS. DANEK: Granted, Your Honor, petitioners never said that
`there's certainty based on the data from Boulay. And that, we believe, is
`the incorrect analysis to employ. But preclinical models do give
`necessary information in the progress of clinical development. In fact,
`Novartis' specification acknowledges this.
`If we can look at the patent, Exhibit 1001, column 25, lines 49
`through 52, at line 49 the patent acknowledges the usefulness of
`preclinical data. It says the utility of mTOR inhibitors in treating
`endocrine tumors may be demonstrated in in vitro and in animal test
`models. So this is a recognition of exactly what the art has known, is that
`preclinical models give useful information about the activity of the
`compounds that you are investigating. So Novartis' attempts now,
`particularly in view of the fact that their specification has no preclinical
`data, we think, merely is trying to require that there be some guarantee of
`success. And we think that's the inappropriate analysis, and again,
`inappropriate particularly in view of the absence of data in Novartis'
`specification.
`I see I'm running a little bit short on time here, so I would like
`to just address one of Novartis' primary response to the petition. And that
`is this idea that after failure of cytotoxic chemotherapy somehow
`provides some different expectation in how the treatments would
`respond.
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`Case IPR2016-01479
`Patent 9,006,224 B2
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`JUDGE POLLOCK: Counsel, quick question. Does the patent
`itself point to a model cell line for PNETs?
`MS. DANEK: Actually, that's a very interesting question. If
`we take another look at Exhibit 1001 starting at column 25, line 49, and
`actually starting at line 52, the patent identifies certain in vitro
`experiments that can be performed in certain cell lines. And if you look
`at these cell lines, we think this is actually quite interesting, the cell lines
`that are identified starting at line 55, these three cell lines are the exact
`same three cell lines that Novartis included in its prior art patent as
`indicative of activity in advanced solid tumors. That is at Exhibit 1050 in
`column 9. I don't have the line cite right now, but it is in column 9.
`So these three tumors Novartis identifies in its patent as, again,
`starting at line 49, demonstrating the utility of these mTOR inhibitors in
`endocrine tumors. At least the A549 cell line, as described in
`Exhibit 1050 at column 9, that's a lung cell tumor line. So Novartis is
`saying what a person of ordinary skill in the art would understand.
`Preclinical models, even if they don't mirror exactly a clinical state, give
`useful information about the utility of these compounds in the future as
`it's being clinically developed. Have I answered your question?
`JUDGE POLLOCK: So one of these is a lung cell-derived
`tumor? And the others?
`MS. DANEK: The KB31 cell line is described as an
`epidermoid cell line. It's described in the Exhibit 1050 as an epidermoid
`cell line. My understanding is that's cervical cancer, but the reference
`calls it an epidermoid. The HCT116 cell line, there's no explicit
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`Case IPR2016-01479
`Patent 9,006,224 B2
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`disclosure of what that cell line is in the prior art patent. My
`investigation has indicated it's not a PNET, but I have nothing in the
`record to identify that.
`JUDGE POLLOCK: Thank you.
`JUDGE CRUMBLEY: So is your point that the patent itself
`uses non-PNET models to show efficacy?
`MS. DANEK: Yes.
`JUDGE CRUMBLEY: And therefore, saying that you must
`have a PNET model showing efficacy is inconsistent with the
`specification?
`MS. DANEK: It's inconsistent with the specification. And we
`think the specification, in fact, is consistent with what a person of
`ordinary skill in the art would have been aware of in the utility of
`preclinical models.
`JUDGE CRUMBLEY: Thank you.
`MS. DANEK: Have I answered your question, Judge Pollock?
`JUDGE POLLOCK: Yes, thank you.
`MS. DANEK: So I would like to talk briefly, very briefly
`about one of Novartis' arguments regarding the use of cytotoxic
`chemotherapy and how that affects what a person of ordinary skill in the
`art may expect as far as response to treatment.
`If we go to slide 20 -- I'm sorry, slide 40, the prior art -- if we
`look at -- actually, let's go to slide 16 -- 14. I apologize. Right. The
`prior art through Oberg explicitly identifies that the right time to use
`mTOR inhibitors is exactly after the failure of cytotoxic chemotherapy.
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`Case IPR2016-01479
`Patent 9,006,224 B2
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`Oberg describes this and makes no mention that there would be some
`question that this is not the right time. This is exactly what Oberg is
`teaching there.
`And if the Board needs to look further, Duran at Exhibit 1011
`also identifies patients with prior chemotherapy were given mTOR
`inhibitors. So the prior art doesn't support that a person of ordinary skill
`in the art would not give mTOR inhibitors to these patients previously
`treated with chemotherapy.
`Finally, Dr. Kulke's testimony in a prior proceeding indicated
`that this is precisely what a person of ordinary skill in the art does
`when -- at Exhibit 1095, page 798, line 11 through 21, when a patient
`becomes refractory to treatment, you have to look to another type of
`treatment. And that's exactly what Oberg is saying and that's exactly
`what a person of ordinary skill in the art would do. They would give a
`different type of treatment.
`So unless there's any questions, I'll save the rest of my time for
`rebuttal.
`JUDGE CRUMBLEY: I don't believe so. Thank you. You
`have 15 minutes and 9 seconds.
`MS. JACOBSEN: Good morning. The claims at issue concern
`the use of an amount of everolimus that is therapeutically effective as a
`monotherapy to treat patients with a very specific subset of
`neuroendocrine tumors. Those are advanced pancreatic neuroendocrine
`tumors or PNETs after failure of cytotoxic chemotherapy. As of
`November 2005, there were no effective treatments for these tumors.
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`Case IPR2016-01479
`Patent 9,006,224 B2
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`Now, petitioners advanced four grounds of unpatentability. I'll
`focus my presentation on the absence of a reasonable expectation that
`everolimus would be therapeutically effective to treat the claimed
`PNETs. Therapeutic efficacy is a requirement of the claims here because
`they recite methods of treatment comprising a therapeutically effective
`amount of everolimus. Now, Dr. Kulke explained that a POSA would
`have understood that claim element to mean an amount of everolimus
`that is safe and effective as a monotherapy to produce the desired
`therapeutic effect, namely the treatment of advanced PNETs after failure
`of cytotoxic chemotherapy. And neither petitioners nor their expert,
`Dr. Ratain, have disputed that claim construction.
`In Eli Lilly v. Actavis, the Federal Circuit upheld the validity of
`a method of treatment claim reciting an effective amount of a drug where
`the prior art did not reasonably suggest that the drug would be
`therapeutically effective to treat the disease at issue in that case. So here
`petitioners must prove a reasonable expectation that everolimus would be
`therapeutically effective to treat the claimed PNETs. And as I will
`explain, petitioners have not met that burden.
`But before I do that, I would like to address petitioner's reliance
`on the '224 patent specification. Challenges to a patent specification
`belong under Section 112. And Section 112 is not at issue in these
`proceedings. Under Section 103 and Supreme Court precedent, including
`Graham v. John Deere, obviousness requires a comparison between the
`differences between the prior art and the claimed invention. That's
`claims 1 to 3 of the '224 patent. Not the patent specification.
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`JUDGE CRUMBLEY: But you would agree with me that the
`specification of the patent is indicative of just the background of skill in
`the art. When we read the claims and read the prior art, shouldn't we be
`informed by how the specification describes and uses the terminology?
`MS. JACOBSEN: How the patent specification uses the
`terminology is relevant to claim construction. And
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