throbber
trials@uspto.gov
`571-272-7822
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`IPR2015-01993, Paper No. 62
`January 10, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`COALITION FOR AFFORDABLE DRUGS V LLC; HAYMAN
`CREDES MASTER FUND, L.P.; HAYMAN ORANGE FUND
`SPC - PORTFOLIO A; HAYMAN CAPITAL MASTER FUND,
`L.P.; HAYMAN CAPITAL MANAGEMENT, L.P.; HAYMAN
`OFFSHORE INVESTMENTS, LLC; NXN PARTNERS, LLC;
`IP NAVIGATION GROUP, LLC; KYLE BASS and ERICH
`SPANGENBERG,
`Petitioner,
`
`v.
`
`BIOGEN MA INC.,
`Patent Owner.
`____________
`
`Case IPR2015-01993
`Patent 8,399,514 B2
`____________
`
`Held: November 30, 2016
`____________
`
`
`
`
`BEFORE: SALLY G. LANE, RICHARD E. SCHAFER, and
`DEBORAH KATZ, Administrative Patent Judges.
`
`
`The above-entitled matter came on for hearing on Wednesday,
`November 30, 2016, commencing at 9:31 a.m., at the U.S. Patent
`and Trademark Office, 600 Dulany Street, Alexandria, Virginia.
`
`
`
`

`

`JAMES T. CARMICHAEL, ESQUIRE
`CAROL A. SPIEGEL, ESQUIRE
`Carmichael IP, PLLC
`8000 Towers Crescent Drive
`Thirteenth Floor
`Tysons Corner, Virginia 22182
`
`MICHAEL J. FLIBBERT, ESQUIRE
`MAUREEN D. QUELER, ESQUIRE
`ERIN M. SOMMERS, Ph.D., ESQUIRE
`Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
`901 New York Avenue, N.W.
`Washington, D.C. 20001-4413
`
`Case IPR2015-01993
`Patent 8,399,514 B2
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`APPEARANCES:
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`ON BEHALF OF THE PETITIONER:
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`ON BEHALF OF PATENT OWNER:
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`Case IPR2015-01993
`Patent 8,399,514 B2
`
`
`P R O C E E D I N G S
`- - - - -
`JUDGE SCHAFER: Good morning. We have two oral
`arguments this morning. The first is for IPR2015-01993,
`Coalition For Affordable Drugs, et al., versus Biogen MA. The
`second argument is for interference 106,023, Biogen MA versus
`Forward Pharma. We'll take a short recess after the first
`argument so the parties can set up for the interference argument.
`The time for the argument in the IPR has been set for
`20 minutes on each side. Who will be arguing for Coalition?
`MR. CARMICHAEL: James Carmichael.
`JUDGE SCHAFER: How much time would you like to
`reserve for rebuttal?
`MR. CARMICHAEL: Five minutes, please.
`JUDGE SCHAFER: Who will be arguing for Biogen?
`MR. FLIBBERT: Mike Flibbert from Finnegan, Your
`
`Honor.
`
`JUDGE SCHAFER: How much time would you like to
`reserve?
`MR. FLIBBERT: One minute, please, Your Honor.
`JUDGE SCHAFER: Do the parties have
`demonstratives that they want to bring up to us?
`MR. CARMICHAEL: We do, sure.
`JUDGE SCHAFER: And if you could give one set to
`the court reporter. I'm going to have the court reporter attach the
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`demonstratives to the transcript. That's how we'll get them into
`the record. Okay, Mr. Carmichael, if you want to go ahead.
`MR. CARMICHAEL: Thank you. And may it please
`the Board, claims 1 through 20 of the '514 patent should be
`cancelled as obvious over the prior art. There are two main issues
`I would like to address. One is that the references have not been
`disqualified as prior art. And the other is that the claims are
`obvious over the references.
`Taking the first issue first, the Kappos 2006 qualifies as
`prior art under Section 102(b) and Joshi '999 qualifies as prior art
`under 102(a) both for the same reason that the provisional
`application does not provide 112 support for the claims in the
`later application.
`JUDGE SCHAFER: Why isn't the Kappos published
`application -- not the Kappos. The Joshi '999 published
`application, why isn't that being relied on as prior art? It would
`be 102(b) prior art, I think it issued. It was published in 2003 or
`'4.
`
`MR. CARMICHAEL: That's a good question. It was
`not part of the petition.
`JUDGE SCHAFER: Okay. Go ahead.
`MR. CARMICHAEL: So the claimed invention
`involves administering 480 milligrams of DMF on a daily basis to
`a patient in need of treatment for MS. The provisional
`application includes many different diseases. Not just MS. I
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`show you on the first slide here just a small example of the many
`diseases discussed, but you can see that they used the phrase "a
`variety of neurodegenerative diseases." They list here ALS,
`Alzheimer's and Parkinson's. Now, to be sure, MS is sprinkled
`throughout the application as well among dozens of other
`conditions, but by the time that we get to the section on dosage,
`it's not specific to any particular condition.
`Dr. Pleasure has testified that the paragraph relied on,
`the dosage section, which is Section 10 of the provisional
`application, in a particular paragraph 116, does not refer to MS or
`any other indication. He also testified that the dosing that's
`discussed blazes a trail only to 720 and to no other dosages.
`We can see that in the paragraph 116, that's the only
`mention of 480 milligrams. I have colored in red four amounts
`that represent the lower end of various ranges. The first one is
`0.1 grams, which is 100 milligrams up to 1,000 milligrams a day.
`The second range is 200 milligrams to 800 milligrams a day.
`And then in parentheses there are examples of ranges within the
`200 to 800 range, including 240 to 720, 485 to 720 and about
`720.
`
`What is especially interesting here is that the lower ends
`of these ranges, some of them were known to be ineffective to
`people of skill in the art at the time of the provisional. So a
`person of ordinary skill in the art would not see this and think that
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`these were being disclosed as effective amounts, these lower end
`points.
`
`I seem to have leaned on the computer. This is the
`patent owner's own expert, Dr. Wynn, testifying in Exhibit 1050
`that the 240-milligram dose, which we just looked at as one of the
`lower end points of the various ranges, was ineffective for
`treating MS. And he emphasizes I know it's listed there with all
`the other doses, but one of skill in the art would have known at
`the time of filing the application that 240 was not an effective
`dose.
`
`The institution decision in this case cites Atofina and
`applies it in this written description context. It was correct to
`apply Atofina to the written description context because this very
`panel, the same three judges, did the exact same thing in the
`Recro Technology versus Perdue Pharma interference case that
`we cited in our briefs. So for those reasons, the references cannot
`be disqualified as prior art.
`Moving on to the second question, the obviousness
`question, the claims are obvious over Kappos 2006 and the other
`references. I have up on the screen in slide 6 some excerpts from
`Kappos 2006, and they basically show that a daily dose of
`720 milligrams was shown to be effective, and the lower doses up
`to and including 360 milligrams on a daily basis was not shown
`to be effective.
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`
`The clinical trials reference shows, and I have
`highlighted these parts in red, that it was known that DMF caused
`side effects and explicitly suggests dose reduction when there are
`side effects to be addressed.
`Dr. Linberg testified that because side effects are
`always a concern in drug development, as they were for DMF,
`and because doses in multiples of 120 milligrams were readily
`available, it would have been obvious to try those particular doses
`between 360 that didn't work and 720 that did in order to reduce
`side effects. Because the pill sizes were 120 milligrams, there
`was only two choices of doses to try in between there, 480 and
`600.
`
`JUDGE SCHAFER: Is it your position that this is just
`optimization of the dosage?
`MR. CARMICHAEL: If that, yes. And Dr. Linberg
`said there would be a reasonable expectation of success trying the
`480 dose selection for a number of reasons stated -- quoted in the
`initial institution decision. But I want to highlight one particular
`aspect of Dr. Linberg's testimony that was quoted in the
`institution decision but never rebutted by the patent owner. The
`institution decision quotes Dr. Linberg relying on the ICH
`guideline discussion about the plateau effect, that it was known
`that an effective dose like 720 would commonly be found to be
`on a plateau of a dose-response curve. And so naturally one
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`would reasonably expect that a lower dose that has not been
`tested would also be therapeutically effective.
`This was quoted in the institution decision, Paper
`Number 20 at pages 17 to 19. I'm going to read into the record
`the two sentences, among others, that the Board cited or quoted
`from the ICH guideline in the institution decision. It says: It is all
`too common to discover at the end of a parallel dose-response
`study that all doses were too high, that is, on the plateau of the
`dose-response curve or that doses did not go high enough. A
`formally planned interim analysis or other multistage design
`might detect such a problem and allow study of the proper dose
`range.
`
`That's ICH guideline Exhibit 1004 at page 1 out of 27
`quoted in the institution decision, relied on in the -- by
`Dr. Linberg. And the plateau effect was relied on in the petition
`and never addressed in any way in the patent owner's opposition
`to the petition or subsequent papers during the trial.
`Now, the patent owner argues about minimum effective
`dose and maximum tolerated dose but never actually addresses
`this plateau effect that was an important part of the petition and
`the institution decision. Therefore, there was an unrebutted
`reasonable expectation of success at 480 milligrams of DMF to
`treat MS.
`The patent owner's main argument seems to be that
`there were secondary considerations, especially that there were
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`surprisingly improved results at 480. But the opposition actually
`only says that there were almost as good results. They used the
`word "almost" in the petition -- in the opposition, excuse me, at
`page 47. So they say that 480 turned out to be almost as good as
`720 and that was somehow surprising.
`Well, it wasn't surprising because of several reasons.
`One is the ICH guidelines that I just discussed addressing the
`plateau that was common for dose-response curves. And that
`plateau was exemplified in another MS drug that was well known
`to have experienced this plateau effect that Dr. Pleasure testified
`about. In particular, it was the drug Copaxone. In Copaxone
`there had been approved an initial dose, and it was discovered
`that they could administer the same dose at a less ---less
`frequently and still have the same therapeutic effect but have less
`side effects. So those of skill in the art were well aware of this
`plateau effect as applying to MS drugs in particular.
`There's one more reason that the 480 dose was not
`surprising, and that is Dr. Pleasure's testimony about the
`importance that one of skill in the art would have attached to the
`point dose that was being used in the Kappos study. You
`remember that I said that it was shown 360 was not effective but
`720 was. Well, the 720 was the only dose that was administered
`with point doses of 240 milligrams. The other ones had lower
`point doses. Dr. Pleasure testified that one of skill in the art
`would have attached importance to that finding that 240 was an
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`effective point dose and would therefore not have been surprised
`that administering that point dose two times a day instead of three
`times a day was therapeutically effective.
`How are we on time?
`JUDGE SCHAFER: You have got about two minutes.
`MR. CARMICHAEL: So these secondary
`considerations -- sorry, objective indicia of nonobviousness
`alleged are not enough to overcome the strong obviousness case
`that I've laid out. And under Allergan, even if results are
`surprising, they might not be enough to overcome the strong
`finding of obviousness. And the claims don't recite any particular
`level of effectiveness. They don't claim the same effective level
`as 720.
`
`They also argue, the patent owner also argues that there
`was a long-felt need met. But a long-felt need has limited value
`when there are prior approved treatments like in this case where
`there were prior approved oral treatments for MS already
`approved before patent owner's product was approved. That's
`under the Bristol-Myers Squibb case, 752 F.3d 967.
`It's also not at all clear that any merits of the
`480-milligram dose selection drove any success or accolades
`because as opposed to the patent owner's original patent on this
`same invention, giving DMF to treat MS, which is the Joshi '999
`patent.
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`
`Patent owner also argues that there was industry praise.
`But if you look at the documents they cite, the industry praise
`appears to be based on Biogen press releases before the actual
`product was put out. And those press releases claim that there
`would be no side effects and in particular there would be no PML
`side effects. Now, that turns out to have been a little too
`optimistic because the FDA recently added PML to the label as a
`warning for this particular product. That's Exhibit 1066. Not
`1055 like we said in our papers. It's Exhibit 1066 is the Tecfidera
`label.
`
`I would like to save my remaining time for rebuttal,
`
`please.
`
`JUDGE SCHAFER: What evidence would you point to
`in the record to show that there was an expectation of a particular
`dose response? Because a dose response usually is somewhere if
`they are too low, there's not enough of the medication to have any
`effect, and then as dosages increase, you might get to a point
`where you start seeing some effectiveness, and then you get to a
`point where effectively the body gets saturated or something and
`you've got as much as is going to make a difference. So you have
`a plateau. But what evidence would indicate that one skilled in
`the art would expect that you have that type of dose relationship
`between the amount of the drug versus the effectiveness?
`MR. CARMICHAEL: One of the patent owner's expert
`witnesses, I'll have to get you the name in a minute because there
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`were 11 of them, testified that they were seeing some effect at
`360, which would suggest that they were already starting up the
`dose-response curve. And then the next and only data point from
`Kappos 2006 was that 720 was great. And so that in itself would
`probably be a reasonable -- provide a reasonable expectation of
`success at the lower doses, and especially in combination with the
`ICH guideline that it was common to discover that there was a
`plateau and that the effective doses you found were too high.
`JUDGE SCHAFER: Thank you.
`MR. CARMICHAEL: Thank you.
`JUDGE SCHAFER: Okay. Whenever you are ready,
`Mr. Flibbert.
`MR. FLIBBERT: Good morning, Your Honor. Mike
`Flibbert from Finnegan. My colleagues, Erin Sommers and
`Maureen Queler, are here with me. I would like to address the
`Section 103(c) issue first, if I may, and then I'll respond to some
`of the other reasons why the petitioner has not established any of
`the three grounds here. Your Honor, the Joshi patent is
`disqualified as prior art under Section 103(c), and this is a
`case-dispositive issue. Petitioner has not challenged any of our
`evidence of common ownership. So the only issue is the
`Section 112 question. So let me address that.
`The provisional application fully supports the claims
`here. That's slide 2, please. Right from the very first sentence,
`the application states that the invention relates to the use of
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`therapeutic compounds for the treatment of multiple sclerosis. So
`it's clear from the beginning that the application is directed to
`MS.
`
`Now, the first page refers to MS nine times and doesn't
`refer to any other disease specifically. And the overall
`application refers to MS 33 times. So one would immediately see
`from reading the application that MS is the principal neurological
`disorder of concern. Now, Dr. Wynn, who is an MS clinician,
`testified that the provisional repeatedly directs persons skilled in
`the art to MS as the neurological disease targeted for treatment.
`That's in Dr. Wynn's declaration at paragraph 29, which is
`Exhibit 2046. And then in paragraphs 29 through 33, the
`provisional discusses DMF's neuroprotective and
`antiinflammatory properties and suggests that DMF could be used
`to treat MS.
`Now, Dr. Pleasure, in reviewing this information in the
`application, acknowledges that the application suggests that DMF
`would be therapeutically effective for treating neurological
`disorders such as MS.
`Slide 4, please. And then in paragraph 116, the
`application discloses that for DMF or MMF specifically an
`effective dose includes a dose of about 480 milligrams per day.
`So the application contains express written description support
`for the claimed dose of about 480 milligrams per day of DMF or
`MMF for treating MS. Now, Dr. Wynn interpreted paragraph 16
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`Case IPR2015-01993
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`from the point of view of one of ordinary skill, and he made two
`key points. Slide five, please. First he explained that those who
`treat MS would readily understand that DMF would be
`administered as a particular effective daily dose and not as a
`range of doses. So it would be apparent that 480 milligrams per
`day is a particular effective daily dose.
`Now, the second point he made, if I could have slide 6,
`please, is that the application guides one to the claimed dose
`because the dose ranges are progressively narrowed in
`paragraph 116 so that a dose of about 480 milligrams per day is
`the lowest end point of the narrowest or most preferred range.
`Now, of course we know that the most preferred range
`of about 480 to 720 is entirely appropriate and hits the mark
`precisely because the phase 3 studies show that 480 and 720 are
`effective.
`Now, Dr. Wynn also explained why the claims are
`enabled. For example, the application instructs one to treat MS
`with a dose of about 480 milligrams per day and no more
`information would be required to practice the claimed method.
`Now, there are further details in his declaration and also
`in the chart which is appended to it which provides a
`claim-by-claim analysis of the Section 112 support.
`Now, in response, petitioner relies on an analysis by
`Dr. Pleasure. Dr. Pleasure argues, for example, that MS is not
`mentioned in paragraph 116. But he overlooks the detailed
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`Case IPR2015-01993
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`discussion of MS on the first page of the application. He
`mentions the title of the application but then he skips over to
`page 2, and you'll see that from his paragraphs 50 and 51 of his
`declaration. But of course the person of ordinary skill wouldn't
`simply skip over that entire detailed discussion of MS at the
`beginning. So we would suggest the Board should not give much
`weight to Dr. Pleasure's incomplete analysis of the disclosure.
`Now, in any event, there was no need to discuss MS in
`paragraph 116 when the application repeatedly refers to MS 33
`times throughout the application.
`JUDGE KATZ: Does the application refer to other
`diseases as well in the same negative?
`MR. FLIBBERT: There are other aspects of the
`application, for example, the idea of screening for other
`compounds that might useful to treat other diseases. But by and
`large, the focus is on MS throughout the application, and that's
`what Dr. Wynn testified to. So the fact that there is a mention
`that you could have other illnesses that you could try to screen for
`does not detract from the focus on MS, which is throughout the
`application.
`Now, Dr. Pleasure argues that the provisional singles
`out a dose of 720. But even if that were true, that would not be
`relevant. Biogen was not required to disclose only a single
`most-preferred dose. The inventors reasonably disclosed a
`most-preferred range from about 480 to 720. He also asserts that
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`Case IPR2015-01993
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`480 was only disclosed once. But again, that's not relevant.
`There's no requirement to have multiple disclosures of an
`expressly disclosed embodiment. And it also doesn't matter
`whether 240 was effective or ineffective. The claim here is to
`480. Not 240.
`And petitioner's slide 5 quoted pages 86 to 87 of
`Dr. Wynn's testimony. But if you read on further on pages 89 to
`90, he testified that one would still have been called to the
`narrowest listed range and that the application teaches one to use
`480 milligrams per day. So if you read it in context, that's what
`he said.
`
`Also they have a discussion of the oxidative stress that's
`mentioned in paragraph 6 of the application. But that's fully
`consistent with the focus on MS. And in fact, MS is repeatedly
`mentioned both before and after that section. For example, in
`paragraph 9, it states that there's a need to develop compounds for
`treating MS. So we just have to look at it in context.
`Now, importantly, Dr. Pleasure doesn't address any of
`Dr. Wynn's testimony.
`JUDGE KATZ: Is there any testing about MS, either
`examples or otherwise, to show that DMF actually does anything
`with MS in this provisional?
`MR. FLIBBERT: There are examples, Your Honor.
`They are essentially arguing for a have-made standard for written
`description. They argue that there are no examples showing
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`clinical trial data in humans. But we submit that's not required.
`The inventors contemplated that 480 would be effective to treat
`MS. It is. That's what's disclosed. So there is written description
`of that invention. They weren't required to have clinical data, for
`example, showing that it actually works. They said it would and
`it does. That's enough.
`There was a brief mention to Atofina. I just wanted to
`point out we've briefed it, but the Atofina case doesn't apply here.
`That is an anticipation decision. No federal court has ever
`applied Atofina to the written description context in the last ten
`years. It was issued in 2006.
`JUDGE SCHAFER: Has the issue come up? Do you
`know a case where it came up?
`MR. FLIBBERT: I don't know that it has come up but
`it hasn't been argued or hasn't come up in a case that I'm aware of.
`Now, the Federal Circuit has actually narrowly interpreted
`Atofina in the cases where Atofina has come up in an anticipation
`context. But essentially the decision avoids what would
`otherwise be a harsh rule that a prior art range always anticipates
`a claimed range no matter how slight the overlap. So the Federal
`Circuit was trying to ameliorate that harsh situation. I think that's
`all the case really stands for.
`Now, here the issue is written description. It's a highly
`fact-dependent question. It's not amenable to general rules, as the
`Federal Circuit said in Union Oil. So the controlling law is
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`Wertheim and Union Oil and those line of written description
`cases. And also as sort of a common sense matter, the inventors
`contemplated a most preferred range of about 480 to 720 and they
`disclosed that in their application. One could ask how else were
`they supposed to disclose that. Were they supposed to write out a
`list of individual doses? So I think from a common sense
`standpoint it also doesn't make sense that it would apply.
`JUDGE SCHAFER: Tell me what you think, if you
`reversed the situation, if your provisional was actually prior art to
`your claim, would you say Atofina applied to say it wasn't
`anticipated?
`MR. FLIBBERT: Your Honor, I don't know the answer
`to that. I can't say. That's a difficult hypothetical. It hasn't been
`argued here.
`So for these reasons, we believe we have established
`that Biogen is entitled to the 2007 filing date. And for that
`reason, Joshi is disqualified as prior art under Section 103
`because all three grounds depend on Joshi.
`Now, there was some argument in the briefing that the
`Board could simply disregard Joshi and move on to have a
`decision without Joshi. And we would disagree with that. Joshi
`has been in the case from the very beginning. The petition
`presented only grounds that relied on Joshi. And they relied on
`Joshi for six different features in the claims, that DMF is effective
`against MS, that DMF causes GI irritation, that DMF converts to
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`Case IPR2015-01993
`Patent 8,399,514 B2
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`MMF, that DMF can be formulated with excipients, that DMF
`can be orally administered and that DMF can be formulated as
`tablets or other forms. Dr. Linberg's declaration relied on Joshi.
`The institution decision relied on Joshi and limited trial to
`grounds, et al., depend on Joshi. Then after institution they
`continued to rely on Joshi in their reply to our patent owner
`opposition and in Dr. Pleasure's declaration. So this entire
`proceeding has involved their assertions concerning Joshi. They
`chose to rely on it, but it's not prior art. And because it's
`disqualified, none of the three grounds are viable.
`Now, we don't think the Board needs to reach any other
`issues, but to the extent it does, I would like to address the
`obviousness questions. We presented testimony from four
`distinguished technical experts who considered the prior art and
`the evidence of unexpected results. And they testified first of all,
`that there was no reason to select a dose of 480. The response at
`360 was statistically no different from placebo. And Dr. Rudick,
`who has 35 years of experience with MS research, testified that
`one of ordinary skill reviewing the phase 2 results would have
`selected a dose of 720 for further investigation because that was
`the only dose shown to be effective.
`And our experts also explained why there would have
`been no reasonable expectation of success that a dose of 480
`would be effective, principally because 480 was only a small
`incremental increase away from the ineffective dose. And at
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`Case IPR2015-01993
`Patent 8,399,514 B2
`
`most, they explained, one would have expected the results with
`480 to be more likely ineffective results at 360. So there was no
`expectation of success. And Dr. Linberg did not give any reason
`for expectation of success. I'm not sure what counsel is referring
`to in the record on that. He really gave no reason.
`Our experts also concluded that one would not have
`expected and could not have predicted the phase 3 results based
`on the phase 2 results. The phase 3 results surprisingly show that
`480 was just as effective as 720 or at least similarly effective on
`all measures of disease activity with a high level of statistical
`significance.
`JUDGE LANE: What about the argument about the
`plateau effect as being a basis for a reasonable expectation of
`success?
`MR. FLIBBERT: You know, I don't recall that in the
`testimony. He could cite perhaps where Dr. Linberg actually said
`that. But we did address this idea which may have been argued.
`In Dr. Brundage's declaration, for example, in paragraph 38, in
`that entire section, paragraphs 33 to 39. We also addressed it in
`pages 40 to 41 and 44 of our patent owner response. But the
`point is there was only one effective dose. One of ordinary skill
`could not have known where the plateau was. They would have
`had no idea.
`JUDGE SCHAFER: Wouldn't they experiment? Once
`you found the one dose that was successful and gets reported in
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`Case IPR2015-01993
`Patent 8,399,514 B2
`
`the literature, why wouldn't you go say let's see what other dose is
`out there. Once somebody finds out one works, why aren't you
`going to investigate what else works? Because the general rule, I
`would think, from my doctor is the less you give that's effective,
`the better.
`MR. FLIBBERT: Now, in terms of a doctor and
`individual dose titration, Dr. Rudick testified that that's not
`possible for MS. That was mentioned and relied upon in the
`institution decision because Dr. Linberg said that. But he’s
`incorrect. For MS, because it's a disease that has a long and
`variable course and the patients go through relapses and
`remissions and it's unpredictable for a given patient and also
`varies between patients, it is not possible, as he testified, to dose
`titrate, to adjust the dose for an individual patient. So you have to
`do clinical studies. That's the only way you can talk about dose.
`So that was one point. They have no contrary testimony on that.
`So Dr. Rudick's testimony is unrebutted on that point of
`individual dose titration.
`Now, the point about the ICH guideline, Dr. Linberg, in
`paragraph 32 and elsewhere, does quote this thing that's stated in
`the ICH about it's common to discover at the end of the study that
`all the doses were either too high or didn't go high enough. But
`you notice the only thing they addressed was the first part, that all
`doses were too high. So they failed to address the second part,
`which is that it's possible that the doses didn't go high enough.
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`Case IPR2015-01993
`Patent 8,399,514 B2
`
`And that's why Dr. Brundage's testimony is quite important. Dr.
`Brundage, in paragraph 38, explained that administering a dose
`higher than 720 might have provided greater efficacy with no
`increase in adverse events. So that would have actually
`motivated one of ordinary skill to test higher doses.
`JUDGE SCHAFER: Why wouldn't you go both ways?
`You have one value and it works. So why wouldn't you try to do
`tests with both ways even if you have to do it in the context of a
`phase 3 trial?
`MR. FLIBBERT: Even if you tried lower doses, one of
`ordinary skill would not have had a reasonable expectation that
`480 would be effective. They would have no expectation,
`because as our experts testified, that would be close to an
`ineffective dose. That's why it was so surprising that 480 was
`effective. As Dr. Vista testified, it was stunning and unexpected
`to see that that dose, which was only a small incremental increase
`above an ineffective dose, was not only effective, but it was just
`as effective as 720. So that was unexpected results. And it also
`shows a lack of any reasonable expectation of success.
`But we think this reflects their hindsight ap

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