IPR2015-00643, Paper No. 84
`IPR2015-00644, Paper No. 85
`IPR2015-00830, Paper No. 79
`June 6, 2016
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`trials@uspto.gov
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`571-272-7822
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`MYLAN PHARMACEUTICALS, INC. and
`AMNEAL PHARMACEUTICALS, LLC,
`Petitioners,
`
`v.
`
`YEDA RESEARCH AND DEVELOPMENT CO., LTD.,
`Patent Owner.
`____________
`
`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
`____________
`
`Held: May 11, 2016
`____________
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`
`
`
`BEFORE: SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`TINA E. HULSE, Administrative Patent Judges.
`
`
`
` The above-entitled matter came on for hearing on Thursday, May
`12, 2016, commencing at 1:02 p.m., at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
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`SHANNON M. BLOODWORTH, ESQ.
`BRANDON M. WHITE, ESQ.
`Perkins Coie
`700-13th Street, N.W., Suite 600
`Washington, D.C. 20005-3960
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`APPEARANCES:
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`ON BEHALF OF THE PETITIONER MYLAN:
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`DAVID L. ANSTAETT, ESQ.
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`Perkins Coie
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`One East Main Street, Suite 201
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`Madison, Wisconsin 53703-5118
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`JEFFREY W. GUISE, Ph.D., ESQ.
`LORELEI P. WESTIN, Ph.D., ESQ.
`Wilson Sonsini Goodrich & Rosati
`12235 El Camino Road, Suite 200
`San Diego, California 92130-3002
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`RICHARD TORCZON, ESQ.
`Wilson Sonsini Goodrich & Rosati
`1700 K Street, N.W., Fifth Floor
`Washington, D.C. 20006-3817
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`ELIZABETH J. HOLLAND, ESQ.
`WILLIAM JAMES, ESQ.
`Goodwin Procter
`The New York Times Building
`620 Eighth Avenue
`New York, New York 10018-1405
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`ON BEHALF OF THE PETITIONER AMNEAL:
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`ON BEHALF OF PATENT OWNER:
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`VINCENT L. CAPUANO, Ph.D., ESQ.
`CHRISTOPHER S. KROON, ESQ.
`Duane Morris
`100 High Street, Suite 2400
`Boston, Massachusetts 02110-1724
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`
`
`P R O C E E D I N G S
`- - - - -
`JUDGE YANG: Please be seated. We have a huge
`crowd here. You all came for the community day, right?
`So, welcome, everyone. We are here for consolidated
`hearing in IPR2015-00643, 644, and 830, between Mylan
`Pharmaceuticals and Patent Owner Yeda Research and
`Development. The subject of these cases are U.S. patent numbers
`8,232,250, 8,399,413, and 8,969,302. Another set of three cases,
`IPR2015-01976, 1980, and 1981, challenging the same patents,
`were filed by Amneal. We recently joined the Amneal petitions
`with the respective Mylan petitions, and the parties have agreed
`that Mylan will speak on behalf of both Petitioners.
`As you can see today, we have Judge Hulse joining us
`from the Silicon Valley office.
`Judge Hulse, can you hear us okay?
`JUDGE HULSE: Yes. I can hear you fine. Thanks.
`JUDGE YANG: All right, thank you.
`Now, Counsel, would you please introduce yourselves.
`Let's start with Petitioner.
`MR. ANSTAETT: Thank you, Your Honor. My name
`is David Anstaett, I'm with the firm Perkins Coie, and we
`represent the Petitioner Mylan Pharmaceuticals, and I will be
`arguing on behalf of all of the Petitioners today. With me at
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`counsel table is Shannon Bloodworth also of Perkins Coie.
`Mr. Russell will be helping me with demonstrative exhibits today.
`And then we also have Jeff Guise from the firm of Wilson
`Sonsini, who is lead counsel for Mylan.
`And then also here today are counsel for Amneal who I
`am going to let introduce themselves.
`JUDGE YANG: Thank you, welcome.
`MR. CAPUANO: Good afternoon, Your Honor.
`Vincent Capuano for Petitioner Amneal, and with me is my
`partner, Chris Kroon, both from Duane Morris.
`MR. KROON: Good afternoon.
`JUDGE YANG: Thank you. Welcome.
`Patent Owner, please.
`MS. HOLLAND: Good afternoon, Your Honor.
`Elizabeth Holland of Goodwin Procter, LLP, for Patent Owner
`Yeda Research and Development. With me at counsel table is
`Bill James, also of Goodwin Procter.
`JUDGE YANG: Thank you. Welcome.
`MS. HOLLAND: Thank you.
`JUDGE YANG: Judge Hulse, when counsel for
`Amneal spoke, could you hear them, because they were not at the
`podium.
`JUDGE HULSE: I could hear, barely, yea.
`Mr. Capuano I believe is his name correct?
`MR. CAPUANO: Yes.
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
`
`
`JUDGE YANG: Okay, all right. So, obviously, we still
`have some technical limitations. So, when you speak, please be
`at the podium and speak directly into the microphone. Thank
`you.
`
`So, before we start, we have a couple of just
`housekeeping issues. As set forth in the trial order, each side has
`60 minutes to argue your case. Because Petitioner bears the
`ultimate burden to show unpatentability, you start first, and Patent
`Owner would follow.
`Petitioner, you have a chance to reserve time for
`rebuttal. Would you like to reserve some time?
`MR. ANSTAETT: Yes, Your Honor. I would like to
`reserve 30 minutes for rebuttal, please.
`JUDGE YANG: Thirty minutes, very well. During
`your rebuttal time, you can only respond to the issues Patent
`Owner raised during its response time.
`I have a few other things to take care of and --
`MR. ANSTAETT: Understood. Thank you, Your
`
`Honor.
`
`JUDGE YANG: Thank you.
`Both parties emailed us your demonstratives. Thank
`you for that. And each party, of course, objects to the other side's
`demonstratives. As we explained in the trial order, the
`demonstratives are not in the record and they are not evidence.
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`They are intended to help you to help us to understand your
`argument.
`So, to that front, we saw some objections along the lines
`of confusing and misleading. So, please, the presenting party,
`when you present your slides, make sure you don't confuse us or
`mislead us, because you don't know where we are going to end
`up.
`
`But more importantly, as we said in the trial order, the
`demonstratives are not a vehicle for you to introduce new
`evidence or new arguments. To that end, I would say if you do
`that, you are just wasting your own time because we will not
`consider those. Clear?
`Also, again, because Judge Hulse is joining us remotely,
`she cannot see what's projected there, but she has the record, and
`she has what you emailed us. She can follow us. So, when you
`do present, please identify each slide by its slide number, every
`paper, every exhibit, by not only the paper number and the exhibit
`number but also the page number.
`One last point. Please do not interrupt each other. That
`is, when one party is presenting an argument, if you have an
`objection, please hold it until your own time. And, Patent Owner,
`if you have an objection during the rebuttal time, you can state it
`before we adjourn.
`Are we all clear?
`MS. HOLLAND: Thank you.
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
`
`
`MR. ANSTAETT: Understood, Your Honor.
`JUDGE YANG: So, whenever you're ready -- oh, let
`me just set the time. You may begin.
`MR. ANSTAETT: Thank you, Your Honor. Your
`Honor, this case confronts the Board with essentially one
`question: whether administering 40 milligrams of glatiramer
`acetate three times per week to treat multiple sclerosis is
`patentable over administering 40 milligrams of glatiramer acetate
`every other day to treat multiple sclerosis. And the answer to that
`question is clearly, no, the claimed dosing regimen is obvious.
`The three patents at issue claim a dosing regimen for an
`old drug, glatiramer acetate, which has been long known in the art
`to treat a disease, multiple sclerosis, for which glatiramer acetate
`has long been known to be safe and effective. The traditional GA
`dosing regimen is 20 milligrams administered daily by
`subcutaneous injection. The patents here claim administration of
`twice that amount, 40 milligrams, administered about half as
`often, three times per week, and most of the claims require at
`least one day between each injection.
`Now, in July 2007, more than two years before the
`August 20th, 2009, priority date, a patent application was
`published that had been filed by Patent Owner's exclusive
`licensee and marketing partner, Teva Pharmaceuticals. Now, that
`application disclosed and claimed periodic dosing of 40
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`milligrams of GA, administered by subcutaneous injection for the
`treatment of MS, including dosing 40 milligrams every other day.
`That publication, the so-called Pinchasi application, is
`practically anticipatory. As the Board found preliminarily in its
`institution decisions, the Pinchasi application discloses every
`element of the independent claims of the patents at issue, save the
`requirement for exactly three doses every seven-day period.
`Instead, the Pinchasi application's GA dosing regimen
`provides exactly three 40-milligram injections one week and then
`four such injections the next. That is extremely close prior art.
`The regimen claimed in the challenged patents differs only in that
`there's one less injection every two weeks.
`Now, beyond the Pinchasi application, there's a wealth
`of prior art human clinical data that we'll discuss today showing
`that skilled artisans were motivated long before the critical date to
`pursue less frequent GA dosing regimens and that they had more
`than a reasonable expectation that the claimed regimen would be
`effective and better tolerated than traditional GA dosing.
`JUDGE YANG: So, Counsel, what's the starting point?
`I guess, what's the closest prior art? Because Patent Owner
`argued in its response that your starting point is actually a
`20-milligram daily dosing, and there are two variables, right?
`You have the dose and you have the dosing frequency. So, going
`from 20 milligrams daily to 40 milligrams three times a week,
`you would have to change two, so --
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`MR. ANSTAETT: That's correct, Your Honor, but I
`believe very strongly that the closest prior art is the Pinchasi
`application, which discloses and claims 40 milligrams, the dose
`that is recited in all of the patent claims, administered every other
`day. And as I say, that administration schedule provides three
`doses, exactly three doses one week, and four doses the next. So,
`if you look at a four-week period, the only difference is that the
`Pinchasi -- or I should say the claimed regimen delivers two less
`doses in a four-week period than the Pinchasi application. So,
`that is the closest prior art.
`JUDGE YANG: I'm sure you're aware of Patent
`Owner's argument that in Pinchasi, the only data they presented
`were the 20 milligrams daily, and there is nothing besides, you
`know, just a general description of what you just said, and
`every-other-day dosing regimen.
`MR. ANSTAETT: I am quite well aware of that, Your
`Honor, and you are correct. The Pinchasi application discloses
`data on 40-milligram daily dosing. That's the data that's in the
`Pinchasi application. That's the data that is in the Cohen paper
`from Neurology in 2007. But that is not an issue in our view
`certainly because there is no data in the patents that are at issue.
`The three patents that are at issue -- and I'll just perhaps
`skip ahead a bit here. When I get to the slide I'll put it in the
`record. So this is slide 7 from our presentation. This is an
`important fact about the patents in suit. They disclose absolutely
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`no data concerning the claimed dosing regimen's efficacy, its
`tolerability, or anything else. There's only a single example in the
`patents in suit, and the parties all agree it's prophetic.
`The examiner of what eventually issued as the '302
`patent, which is the subject of IPR2015-830, described, in the
`prosecution history, Example 1 as "a statement of desired
`outcomes" and a "wish list." And that's important because, as you
`say, Patent Owner has leveled some criticism at the Pinchasi
`application because it doesn't actually disclose data on 40
`milligrams every other day. But that puts it exactly on the same
`footing as the patents in suit.
`And I think it's helpful here that we have some Federal
`Circuit case law that addresses this point directly, and that tells us
`that when neither the challenged patents nor the prior art disclose
`clinical data on efficacy or tolerability of the claimed dosing
`regimen, then the claimed invention adds nothing to the prior art
`on that score, and it's error to distinguish the prior art from the
`claimed patents on that basis.
`So, the fact that the Pinchasi application doesn't have
`data on a 40-milligram, every-other-day dosing regimen does not
`help Patent Owner here.
`JUDGE YANG: Thank you.
`JUDGE SNEDDEN: What about Patent Owner's
`argument that concerns why you would modify the dosing
`regimen in Pinchasi in that there is some evidence to suggest that
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`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`the 40-milligram dose was not -- would cause adverse effects,
`particularly at the injection site and also immediately after that.
`So, if we still have to modify the teachings of Pinchasi, why
`would we -- why would a person of ordinary skill in the art
`modify the 40-milligram dose when there's plenty of data and
`others suggesting that the 20-milligram dosing regimen might be
`the preferred route?
`MR. ANSTAETT: So, I think there are a number of
`answers to that question, Your Honor. First of all, the
`40-milligram dose -- as of the priority date, the 40-milligram dose
`was well established to be -- to have a good tolerability profile.
`That was -- that is in the art repeatedly. That is in the Cohen
`2007 paper; that is the results that were reported for the Forte
`Phase III clinical trial, which was the clinical trial that compared
`the 40 milligram daily to the 20 milligram daily; the conclusions
`of Dr. Comi, who was the principal investigator of that study,
`said they have equivalent tolerability.
`And so I think the notion that the 40-milligram dose is
`something that you would be steered away from is just simply
`incorrect. The tolerability profile is similar, and those papers also
`report that the 40-milligram dose does -- there does seem to be a
`trend that it has earlier efficacy on MRI activity. That's also in
`the FORTE trial results.
`Now, why the three-times-a-week dosing schedule?
`Because that's the other variable that you change from the
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`Pinchasi application. You go from every other day in the
`Pinchasi application to three times a week. Well, it was well
`known in the art that a three-times-a-week dosing schedule was
`particularly attractive to patients because you can take the
`medicine on the same days every week, Monday, Wednesday,
`Friday; you can take the weekend off from injections, so if you're
`taking a trip, you don't have to pack your needles.
`And there was another MS disease-modifying therapy
`that competed with glatiramer acetate and competed with
`Copaxone before the priority date that was dosed three times a
`week with one day between each injection. That's Rebif,
`interferon beta-1a. And so there was ample motivation to go to --
`from the 40 milligrams, every-other-day dosing regimen in
`Pinchasi to a 40 milligram, three-times-a-week regimen.
`People knew in the art that the three-time-a-week
`regimen for a subcutaneous -- a medication administered by
`subcutaneous injection was desirable. That's not something that
`was discovered with the filing of these patent applications or with
`the introduction of Copaxone. So, that's the motivation, I think
`clearly, to move to that dose. That's a matter of routine
`optimization.
`JUDGE HULSE: But isn't it a bit simplistic to say,
`well, just because my patients want to administer their dose three
`times a week -- I mean, there are other factors at play. You have
`to consider, you know, the mechanism of action, the -- whether
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`that drug will still remain in the system, you know, if you're
`taking three days off. What is your response to that?
`MR. ANSTAETT: So, my response to that, Your
`Honor, is that the prior art showed -- the prior art was replete with
`suggestions -- first of all, there was -- there was clearly
`motivation. The biggest single problem with Copaxone, the
`standard regimen of 20 milligrams seven days a week, the
`Achilles heel of that treatment was injection site reactions.
`Patients did not like to take daily injections in a life-long, chronic
`disease like MS, and there's simply no dispute on that score. So,
`that's the motivation to move to less frequent dosing, and we see
`that motivation from the very beginning.
`In 1996, before Copaxone's first sale in the United
`States, the FDA reviewer says, why are we dosing this drug every
`day? You should investigate -- an explicit suggestion to Teva --
`you should investigate less frequent, intermittent dosing of this
`drug. Skilled artisans in the field picked up on that.
`In 2002, Dr. Flechter conducted a clinical trial
`administering 20 milligrams every other day and found that it was
`equally efficacious to -- or at least there were suggestions that it
`was equally efficacious to dosing 20 milligrams every day.
`Then, in 2008, you have Dr. Khan, who also conducts a
`randomized, head-to-head, rater-blinded clinical trial between 20
`milligrams every other day and 20 milligrams daily, and finds
`equivalent efficacy and, of course, better tolerability for the
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`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`every-other-day dosing regimen. So, the whole arc of the prior
`art is moving in this direction, that it looks like this drug does not
`need to be dosed daily. Dosing daily causes big problems,
`because it's not just, you know, discomfort and pain, but it's
`noncompliance. You lose compliance and adherence to the drug
`because of the daily dosing regimen. And so the whole -- you
`know, the arc of the prior art is moving that way.
`Now, you raised the point that -- about how long the
`drug is in the system, and with a three-times-a-week dosing
`regimen, there is one 72-hour gap -- not between every dose,
`right, because between most doses, you just have the 48-hour gap
`that is disclosed in the prior art in Pinchasi and Khan and Caon
`and Flechter, but let's put that in context.
`We're talking about two fewer doses of GA every four
`weeks as compared to the every-other-day dosing regimen in
`Pinchasi, and there was nothing in the art suggesting that
`dropping two doses over the course of four weeks would
`somehow undo the drug's efficacy. In fact, everything suggested
`that Copaxone was a forgiving drug, that missed doses were not a
`significant problem. And so those --
`JUDGE HULSE: I'm sorry. Where is that evidence?
`Because I know -- I believe in your briefs that you had relied on a
`website -- a recent website or whatnot for the forgiving aspect of
`the drug. Do you have any sort of precritical date or pre-priority
`date evidence of that?
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`MR. ANSTAETT: I will check because I believe that
`we have -- we also have evidence from Teva's website
`pre-priority date, but most pertinently, I think, we have the
`testimony of Dr. Green, who is an extremely skilled and
`experience clinician, runs the largest MS clinic west of the
`Mississippi at the University of California, San Francisco, and he
`testified and put it in his expert report that when my patients
`come in and tell me I missed a dose, you know, should I double
`up, should I take two doses the next day, he tells them, no, you
`don't have to do that. You missed a dose. That's fine. Just
`continue on.
`We also have -- you know, evidence that Copaxone is a
`forgiving drug is there's plenty of evidence that patients on
`Copaxone daily, 20-milligram daily injections, are not
`particularly compliant with their drug. There's the Devonshire
`study, which is -- which is in the record, Your Honor, and that is
`Exhibit 1037, that's the so-called Global Adherence Project paper,
`which looked at injectable MS disease-modifying therapies and
`said, which ones do patients comply with the best? And the ones
`they comply with the best are the ones that have a less frequent
`dosing regimen.
`As an example, Rebif, which, again, is dosed three
`times a week with one day between injections, fared better.
`Patients were more compliant on that -- on that drug than they
`were on Copaxone, glatiramer acetate. So -- but even though
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`there are adherence problems with Copaxone, it still exerts
`efficacy, and so I think there's a lot of evidence in the record that
`Copaxone is a forgiving drug.
`JUDGE HULSE: Can you point to where in your
`briefing you talked about Rebif?
`MR. ANSTAETT: Yes, I can, Your Honor, if you will
`just give me one moment.
`JUDGE HULSE: If you need to come back on rebuttal,
`that's fine.
`MR. ANSTAETT: No, that's okay. I think I can do it,
`Your Honor.
`So, if we look at Dr. Peroutka's opening expert report,
`and so that is Exhibit 1003, I believe he discusses Rebif at
`paragraphs 111 and 112, so, 111 and 112. And then also
`Dr. Green in his opening report, which is Exhibit 1004, he
`discusses that at paragraphs 50 and 55. And I would also note
`that the Board itself discussed Rebif in its institution decisions
`and noted that it was dosed three times a week with one day
`between injections, and so there was certainly a suggestion in our
`mind that there was market pressure to move to this regimen.
`JUDGE HULSE: Thank you.
`JUDGE YANG: I hate to interrupt you, but --
`MR. ANSTAETT: I'm happy to answer your questions.
`JUDGE YANG: -- I think it does help us or it helps me
`to understand certain things.
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`You mentioned changing from every other day to three
`times weekly, there is one window that goes for 72 hours. So, in
`the petition, there is this issue that's brought up that is the half-life
`of the drug, that's 80 hours. Patent Owner argued that first the PK
`was unknown. Second, even if it was, this is a monkey data, first
`of all -- well, second is your data -- the calculation was incorrect.
`And third, even if that data is correct, there is no cross-species
`kind of correlation. Can you address these issues?
`MR. ANSTAETT: I can, Your Honor. And, so, it
`raises a number of issues. The SBOA does have PK data that
`suggests that GA has a 80-hour half-life. That data was obtained
`from studies in monkeys, and, you know, there are criticisms
`certainly of the methodology that is used, but there are criticisms
`of every methodology where you --
`JUDGE YANG: Methodology in terms of the -- the
`data -- how it was collected or the methodology in calculating the
`80 hour -- to reach this number?
`MR. ANSTAETT: I think -- I think it's relatively
`straightforward how Dr. Peroutka came to his 80-hour half-life.
`He used the TCA-precipitable radioiodinated GA from Table 7.2
`in the SBOA, and the average half-life was about 80 hours.
`Now, there are criticisms of the methodology that when
`you use a radio label like that, it can become detached from the
`intact GA molecule, but the point of this is the PK data is useful
`if, potentially, glatiramer acetate works through the systemic
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`circulation, and there is certainly evidence that that's one
`possibility because, as Patent Owner has gone to lengths -- great
`lengths to argue, nobody knows exactly what the mechanism of
`action is.
`So, if it does work through the systemic circulation,
`then the 80-hour half-life provides you a useful data point, but
`what we think is really the more critical data than PK data that
`was collected back in 1996 is the human clinical data that we get
`in the Flechter trial in 2002, and then we get again in the Khan
`trial in 2008, and all of those human clinical trials suggest that
`less frequent dosing does not sacrifice efficacy.
`And so I think, as Dr. Green explained, and I think
`somewhat persuasively, whether the criticism is based on the PK
`data or whether the criticism is based on one particular
`mechanism of action for a drug in which nobody knows what the
`exact mechanism of action is, the skilled artisan is going to look
`to the clinical data, again, which suggests that less frequent
`dosing maintains efficacy and is better tolerated for patients.
`So -- and there's nothing -- there's nothing in the prior
`art that points away from even this one 72-hour gap. And, again,
`I stress that -- remember, most doses on the claimed dosing
`regimen have only a 48-hour gap. Almost 70 percent of the doses
`on that regimen, there is only a 48-hour gap. The 72-hour gap
`happens infrequently.
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`And so on the mechanism of action theory, if I can just
`say a word about that, too, presumably, if this one particular
`mechanism of action that they have plucked out and say it teaches
`away from less frequent dosing, presumably, somebody would
`have said so in the art, because the clear arc of the art is all going
`towards less frequent dosing. So, if there was art that said, wait,
`you can't do that, the mechanism of action says that you can't
`have less frequent dosing, presumably, they would have pointed
`out something that said that, that said, yes, we know that this is
`what patients want, this is what clinicians are interested in, this is
`what people are running clinical trials on, but you can't do that
`because of the mechanism of action.
`There are no studies that say that. There are no studies
`that look at mechanism of action as between daily dosing or less
`frequent dosing, and that's admitted by Dr. Ziemssen, their expert.
`And so I think those are arguments that are picking around the
`edges, trying to take something that's relatively simple and
`straightforward, something that's a matter of routine optimization,
`and making it complicated, but the clinical data that we have
`strongly suggests that you don't need to dose this medicine on a
`daily basis.
`JUDGE SNEDDEN: I understand your argument with
`respect to clinical data, but if we look at -- if we go back to
`half-life again, and I understand not only do we -- is it unclear
`what the mechanism of action is, but we also don't really know
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`Cases IPR2015-00643, 644, 830
`Patents 8,232,250 B2; 8,399,413 B2; 8,969,302 B2
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`what the active ingredient is. If we don't know what the active
`ingredient is, how are we able to determine what the half-life is?
`MR. ANSTAETT: I think -- I think that's actually a
`point in our favor, I would say, Your Honor. Half-life data
`matters if the drug gets into systemic circulation and acts that
`way, and we know -- so, one of their criticisms of the PK data is,
`well, you don't know if you're measuring intact GA, you don't
`know if you're measuring some kind of degradation product
`that's, you know, hydrolyzed at the site of the injection, but as
`you point out, we don't know what the active species is, we don't
`know if it's intact GA, we don't know if it's a degradation product.
`And so it could -- you know, in -- again, this is another
`admission from one of Plaintiff's experts or one of Patent
`Owner's -- I'm sorry -- experts, Dr. Fox, that you can't rule out the
`notion that this is drug is acting systemically, that it gets into the
`plasma, it's filtered through the spleen, it encounters
`antigen-presenting cells there and activates T-cells. So, the point
`with the PK data, which suggests an 80-hour half-life, is it's a
`data point. It's a data point that tells a skilled artisan, if this is
`working systemically -- and we don't know exactly how it
`works -- the 80-hour half-life would suggest that a dosing interval
`of 72 hours is okay.
`But if it's working on an immune basis and if it's acting
`locally, you know, at the site of injection through the lymph
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