trials@uspto.gov IPR2016-00510, Paper No. 43
`
`
`IPR2016-00512, Paper No. 36
`
`
`IPR2016-00514, Paper No. 37
`
`
`IPR2016-00516, Paper No. 36
`
`
`IPR2016-00517, Paper No. 36
`571-272-7822
`
`April 28, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`-----------------------------------------------------
`
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`-----------------------------------------------------
`
`MYLAN PHARMACEUTICALS, INC. and
`MYLAN LABORATORIES LIMITED,
`
`Petitioner,
`
`V.
`
`UCB PHARMA GMBH,
`Patent Owner.
`
`-----------------------------------------------------
`
`Case IPR2016-00510 (Patent 6,858,650 B1)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
`
`
`
`-----------------------------------------------------
`
`
` BEFORE KRISTINA M. KALAN, ROBERT A. POLLOCK, and
` MICHELLE N. ANKENBRAND, Administrative Patent Judges
`
` Reported By: Paul P. Smakula Patent hearing, held at the offices of:
`UNITED STATES PATENT & TRADEMARK OFFICE MADISON
`BUILDING 600 Dulany Street Alexandria, Virginia 22314
`
`
`
`
`
`IPR2016-00512, Paper No. 36
`
`
`IPR2016-00514, Paper No. 37
`
`
`IPR2016-00516, Paper No. 36
`
`
`IPR2016-00517, Paper No. 36
`571-272-7822
`
`April 28, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`-----------------------------------------------------
`
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`-----------------------------------------------------
`
`MYLAN PHARMACEUTICALS, INC. and
`MYLAN LABORATORIES LIMITED,
`
`Petitioner,
`
`V.
`
`UCB PHARMA GMBH,
`Patent Owner.
`
`-----------------------------------------------------
`
`Case IPR2016-00510 (Patent 6,858,650 B1)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
`
`
`
`-----------------------------------------------------
`
`
` BEFORE KRISTINA M. KALAN, ROBERT A. POLLOCK, and
` MICHELLE N. ANKENBRAND, Administrative Patent Judges
`
` Reported By: Paul P. Smakula Patent hearing, held at the offices of:
`UNITED STATES PATENT & TRADEMARK OFFICE MADISON
`BUILDING 600 Dulany Street Alexandria, Virginia 22314
`
`
`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
`
`
` P P E A R A N C E S
`
` A
`
`
`ON BEHALF OF THE PETITIONER:
`
`CLAY D. HOLLOWAY, ESQUIRE
`
`NITA GRAY, ESQUIRE
`
`KILPATRICK TOWNSEND & STOCKTON, LLP
`
`1100 Peachtree Street, Northeast
`
`Suite 2800
`
`Atlanta, Georgia 30309
`
`(404) 541-6667
`
`
`
`ON BEHALF OF THE PATENT OWNER:
`
`JEFFREY OELKE, ESQUIRE
`
`JAMES T. TRAINOR, ESQUIRE
`
`WHITE & CASE, LLP
`
`1155 Avenue of the Americas
`
`New York, New York 10020
`
`(212) 819-8580
`
`
`
`
`
`
`2
`
`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
`A P P E A R A N C E S C O N T I N U E D
`
`ON BEHALF OF ALEMBIC:
`
`MANISH MEHTA, ESQUIRE
`
`BENESCH, FRIEDLANDER, COPLAND & ARONOFF, LLP
`
`333 West Wacker Drive
`
`Suite 1900
`
`Chicago, Illinois 60606
`
`(312) 212-4953
`
`
`
`ON BEHALF OF AMERIGAN:
`
`WILLIAM D. HARE, ESQUIRE
`
`5335 Wisconsin Avenue, Northwest
`
`Suite 440
`
`Washington, DC 20015
`
`(202) 640-1801
`
`
`
`
`
`
`
`
`
`
`
`3
`
`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` P R O C E E D I N G S
`
` JUDGE ANKENBRAND: Good afternoon, everyone.
`
` We have this morning our consolidated final hearing
`
` in IPR2016-510, -512, -514, -516, and
`
` -517 between Petitioners Mylan Pharmaceuticals,
`
` Inc. and Mylan Laboratories and Patent Owner UCB
`
` Pharma GMBH. I also note for the record that
`
` Petitioners Alembic Pharmaceuticals Limited, Torrent
`
` Pharmaceuticals Limited, and Amerigen Pharmaceuticals
`
` have been joined as Petitioners to the 510 IPR.
`
` I'm Judge Ankenbrand. I'm joined by Judge
`
` Pollock and Judge Kalan, who's appearing remotely
`
` from our Denver office.
`
` Counsel, can you please introduce yourself and
`
` let us know who will be presenting for today? We will
`
` start with Petitioner Mylan. Before you introduce
`
` yourself, we want to let counsel know that we
`
` received a response to our order that we issued on
`
` Monday requesting an explanation for Mr. Stockwell's
`
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`
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`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` absence from the hearing today, and we accept the
`
` representations in that filing.
`
` MR. HOLLOWAY: Clay Holloway on behalf of
`
` Petitioners Mylan.
`
` JUDGE ANKENBRAND: Good afternoon.
`
` MR. HOLLOWAY: And this is Ms. Gray, she'll be
`
` helping with the presentation.
`
` JUDGE ANKENBRAND: Okay. Will counsel for the
`
` joined Petitioners please introduce themselves for the
`
` record. We can start with counsel for Alembic.
`
` MR. MEHTA: Menish Mehta on behalf of Alembic.
`
` JUDGE ANKENBRAND: Good afternoon. And for
`
` Torrent? Anyone here from Torrent? [no response] And how about
`
` Amerigen?
`
` MR. HARE: Bill Hare for Amerigen. I'm here
`
` with Jonathan Embleton, Amerigen.
`
` JUDGE ANKENBRAND: All right. Good afternoon.
`
` And for the Patent Owner today, who do we have?
`
` MR. OELKE: Your Honor, I'm Jeff Oelke from
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`
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`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` White & Case for the Patent Owner UCB Pharma GMBH,
`
` and with me is my colleague Jim Trainor. I will be
`
` presenting the argument.
`
` JUDGE ANKENBRAND: Thank you everyone and
`
` welcome. It's good to have you here. We appreciate
`
` everyone making the effort to be here today. We set
`
` forth the procedure for today's hearing in our
`
` hearing order, but just to remind everyone of the way
`
` the hearing will work today, each side will have
`
` 45 minutes of total time to present arguments.
`
` Please keep in mind that Judge Kalan will not be able
`
` to view anything that is projected onto the screen.
`
` Accordingly, when you refer to an exhibit on the
`
` screen, please state for the record the exhibit and
`
` page number, or for demonstratives, state the slide
`
` number to which you are referring. It's also
`
` important to ensure the clarity and accuracy of our
`
` transcript.
`
` Moreover, please remember that because our
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`
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`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` microphones have limitations, Judge Kalan will be
`
` unable to hear your argument if you stray too far
`
` away from the podium, so just keep that in mind when
`
` you're making your arguments.
`
` And one more small point, the camera that
`
` broadcasts you into our hearing room in Denver is
`
` located right behind me. I know the screens are on
`
` the side of the room so it's tempting to look at the
`
` screens when you're answering a question from Judge
`
` Kalan, but if you are looking at the screen, she's
`
` going to see the side of your face, so if you just
`
` look at me or Judge Pollock while you're making your
`
` response, she'll be able to see and hear you more
`
` clearly.
`
` I'll give each counsel a warning when you are
`
` reaching the end of your argument time. Does counsel
`
` have any questions or concerns at this time? Counsel
`
` for Petitioner?
`
` MR. HOLLOWAY: No, Your Honor.
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`7
`
`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` JUDGE ANKENBRAND: For Patent Owner?
`
` MR. OELKE: No, Your Honor.
`
` JUDGE ANKENBRAND: All right. I also want to
`
` remind each party that under no circumstances are
`
` they to interrupt the other party while that party is
`
` making its presentation. If one of the parties
`
` believes that a demonstrative or argument presented
`
` is objectionable for any reason, you can only raise
`
` that objection during your argument time.
`
` So I just wanted to remind parties of that.
`
` And also just a reminder that this hearing is open to
`
` the public and a full transcript will be made part of
`
` the record. With that, I think we're ready to begin.
`
` Counsel for Patent Owner -- or Petitioner, I'm
`
` sorry. Do you wish to reserve any time for a
`
` rebuttal, Mr. Holloway?
`
` MR. HOLLOWAY: Yes, Your Honor, I'll aim for
`
` reserving about seven minutes.
`
` JUDGE ANKENBRAND: All right. Let me set the
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`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` time here. All right. I think we're ready whenever
`
` you're ready to begin.
`
` MR. HOLLOWAY: Thank you. Good afternoon.
`
` May it please the Board, each of the IPRs at issue
`
` today concerns the obviousness of a prodrug of 5-HMT,
`
` which includes fesoterodine and the fesoterodine
`
` fumarate salt. Both instituted grounds in each of
`
` the IPRs are the same amongst the IPRs. Each result
`
` in the same thing, and that's the identification of
`
` 5-HMT as a compound that the skilled artisan would've
`
` been interested in dosing to a patient and the
`
` resolution of how to accomplish that through the
`
` easily optimized and foreseeable consequence of
`
` prodrugging 5-HMT.
`
` Can we go to the first slide. 5-HMT and
`
` fesoterodine are the closest structural analogs of
`
` any of the available OAB treatments at the time of
`
` the earliest effective filing dates of the patents at
`
` issue here.
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`9
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`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` 5-HMT and fesoterodine differ in one simple
`
` substitution. That's the replacement of the hydroxyl
`
` group at the number two carbon on the leftmost ring
`
` with an isobutyl short-chain ester. That's when
`
` we're talking specifically about fesoterodine. There
`
` are broader claims at issue here, including claim one
`
` of the '650 and other claims in the other family that
`
` are simply two prodrug genuses at the number two
`
` carbon involving esters.
`
` When compounds are this structurally similar,
`
` a prima facie case of obviousness exists if there's
`
` motivation to make the necessary modification to
`
` arrive at the claimed molecule. This is a two-step
`
` process as has been around since the In Re Dillon
`
` case, and through Lily and Daiichi and all of the
`
` others, it is not a six-step process that Patent
`
` Owner will argue for.
`
` At the end, it's whether there's a reasonable
`
` expectation of success that you would have gotten to
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`10
`
`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` the claimed molecule. It is not the test that at the
`
` outset of finding fesoterodine obvious, the person of
`
` ordinary skill in the art would've had to look at the
`
` OAB field and specifically pick fesoterodine. Nor is
`
` it the case that after 5-HMT was identified as the
`
` best compound for further investigation or a lead
`
` compound that the person of skill in the art would
`
` have had to say I know that the best or one of the
`
` best prodrugs of this will be fesoterodine fumarate.
`
` It's simply whether there was a motivation to make
`
` the necessary chemical changes to arrive at
`
` fesoterodine.
`
` Next slide, please, which is slide two for the
`
` Petitioners. Again, there's not going to be any
`
` dispute that 5-HMT is the closest structural analog
`
` to fesoterodine. We put forward evidence into the
`
` record and we'll talk about today that 5-HMT was a
`
` better starting point than tolterodine. And this was
`
` true for two reasons. One, the art included a strong
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`11
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`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` indication that you could dose 5-HMT as a prodrug
`
` because tolterodine in effect acted as a prodrug in
`
` most of the patients that received it. The second
`
` reason is that because administering tolterodine was
`
` essentially dosing two active ingredients,
`
` tolterodine as well as 5-HMT; a person of ordinary
`
` skill in the art would have said, I don't want to
`
` dose two actives when only one will do. So they
`
` would've focused on 5-HMT, which the art suggests had
`
` less drawbacks than tolterodine.
`
` The case law asks that we look for a molecule
`
` that has promising use properties that exist. And
`
` though the grounds differ between these two cases --
`
` the grounds differ between Ground One and Ground Two,
`
` again, the end result is the same. Postlind, on the
`
` one hand, in Ground One would have led a skilled
`
` artisan to 5-HMT because there was a
`
` metabolic-pathway issue with tolterodine. In Brynne,
`
` Brynne suggested there were drawbacks to the 5-HMT
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`12
`
`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` molecule building on what was known in Postlind and
`
` suggested that some of those are going to be the
`
` fault of tolterodine.
`
` Those two alone, plus the Detrol label, which
`
` suggests to the skilled artisan that the 3A4 part of
`
` the metabolic pathway caused a dose cap for
`
` tolterodine, all of these things suggested don't use
`
` the path that tolterodine goes through to get to the
`
` active 5-HMT, choose a different way. From there,
`
` the art then leads you directly to whether -- how you
`
` would go about prodrugging it, through the Bundgaard
`
` reference and then the various salt references, and
`
` we'll walk through that now.
`
` JUDGE POLLOCK: Mr. Holloway?
`
` MR. HOLLOWAY: Yes, sir.
`
` JUDGE POLLOCK: Is there evidence that 5-HMT
`
` is not metabolized through the 3A4 pathway?
`
` MR. HOLLOWAY: The evidence of 5-HMT's
`
` clearance after it has been used may involve the 3A4
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`13
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`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` pathway. But the issue is more of an upstream
`
` problem when we're talking about 3A4. It's the
`
` buildup of tolterodine that the label suggests is
`
` what you want to avoid. Because there's no -- it
`
` simply says if you dose the 3A4 pathway because of
`
` clearance and you're inhibiting that pathway, you're
`
` going to end up with too much tolterodine, so that
`
` they capped it.
`
` There's no such thing now in the art involving
`
` dosing fesoterodine and having that problem. So at
`
` the time the art didn't really suggest that clearing
`
` 5-HMT through 3A4 was a problem, but it did suggest
`
` that for tolterodine.
`
` JUDGE POLLOCK: Perhaps if you could walk us
`
` through that argument slowly.
`
` MR. HOLLOWAY: Okay. So if we could go to
`
` slide 5, please, Ms. Gray. This is the Detrol label,
`
` which is Exhibit 1009. On page two of the label, it
`
` talks about how there are poor metabolizers and
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`14
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`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` extensive metabolizers of tolterodine. Extensive
`
` metabolizers use the CYP2D6 pathway to arrive at
`
` 5-HMT. That's about 80 to 90 percent of the
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` population. The rest are poor metabolizers, in which
`
` the CYP2D6 does not convert tolterodine into 5-HMT.
`
` The alternative pathway of tolterodine if it
`
` doesn't go to 5-HMT is through the 3A4 pathway. That
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` leads to the N-dealkylated versions of tolterodine,
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` which the body then passes out. So what the label
`
` says about the 3A4 pathway is that if a patient
`
` receiving a 3A4 inhibitor -- therefore we've turned
`
` off the alternative pathway for tolterodine
`
` clearance, it puts a dose cap of one milligram twice
`
` daily, so it cuts the dose in half.
`
` As Dr. Patterson explained, a person of
`
` ordinary skill in the art would look at that and
`
` realize we don't want too much tolterodine building
`
` up in the body. The Brynne paper kind of sends that
`
` home where it points to tachycardia and visual
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`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` accommodation as being potential side effects
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` associated with the tolterodine molecule and not
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` 5-HMT. So our position is at the end of the day, the
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` person of skill in the art would have said, why give
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` tolterodine plus 5-HMT, why not just dose 5-HMT and
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` we can avoid these problems with tolterodine?
`
` So if we could go back to slide three, which
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` is the Postlind reference. So our Ground One in all
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` of the IPRs starts with Postlind. Postlind is a
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` detailed study of this exact issue. Tolterodine is
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` dosed and goes through the CYP2D6 metabolic pathway.
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` Important in Postlind is that it notes that clinical
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` studies have demonstrated that individuals with
`
` reduced 2D6 metabolism are a high-risk group in the
`
` population. Patent Owner argues, well, it's not that
`
` big of a deal and therefore there could be no
`
` motivation based on Postlind to view using 5-HMT.
`
` But the law doesn't say it has to be --
`
` everyone has to be affected by it or there has to be
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`
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`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` the strongest motivation, the art simply requires
`
` that there be a suitable motivation, not necessarily
`
` the best. There's a portion of the population,
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` upwards of ten percent, that is affected by this
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` issue.
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` The fact that there were so many papers,
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` including Postlind, what references it in Smith, and
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` other papers that Patent Owner cites to shows there's
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` enough concern about the CYP2D6 pathway, the person
`
` of skill in the art might consider avoiding it.
`
` JUDGE KALAN: If I may direct you to Patent
`
` Owner's presentation on page six, they present
`
` evidence that counters what you're saying here. How
`
` do you account for their citations to Brynne and
`
` Nilvebrant and then the Detrol label regarding the
`
` CYP2D6 pathway?
`
` MR. HOLLOWAY: So I'll take them in reverse
`
` beginning with the label. The label actually
`
` provides the skilled artisan with more important
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`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` information about what's going on with 5-HMT than
`
` Patent Owner's suggestion that it somehow teaches
`
` away from the metabolic problem. Patent Owner's
`
` position is incorrect because it is true that when
`
` you dose tolterodine to an extensive metabolizer, you
`
` get effect from 5-HMT.
`
` It's also true that when you dose it to a poor
`
` metabolizer, you get the same pharmacological effect
`
` from the tolterodine molecule. That gets back to
`
` what Dr. Patterson says would be a huge motivation to
`
` the skilled artisan to cut one of them out. Why give
`
` one -- why essentially dose two active ingredients
`
` when you can only dose one?
`
` So the label stands for more than just there
`
` was no metabolic problem. In fact, I think it
`
` teaches that the 5-HMT is a safe and effective
`
` molecule for treating the exact same disorder, it
`
` just doesn't have the drawbacks the tolterodine
`
` molecule has.
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`
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`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` The other reference to the Nilvebrant paper is
`
` essentially the same thing, that the tolerability and
`
` efficacy profiles in these patients, poor versus
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` extensive metabolizers is the same. We don't dispute
`
` that, that the effect of dosing tolterodine to the
`
` population is the same regardless of how you get the
`
` activity. What that tells a skilled artisan is why
`
` use tolterodine when I can just get away with using
`
` 5-HMT?
`
` And Brynne's statement that it doesn't appear
`
` to be of great importance in the antimuscarinic
`
` effect is again confirmation of the same thing we see
`
` in the Detrol label. You dose two actives, they both
`
` do the same thing, one's got a metabolic pathway
`
` concern, the other does not. We'll cut the one out
`
` with the metabolic pathway concern.
`
` Can we go to the next slide, please, which is
`
` slide four. That's the Brynne reference. Brynne
`
` comes later in time than Postlind; it takes the same
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`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` information about how you start with 5-HMT -- or
`
` start with tolterodine and go through CYP2D6
`
` metabolism and end up with two groups of the
`
` population, extensive and poor metabolizers.
`
` Brynne tells you that the tachycardia issue is
`
` likely the result of the higher fluctuation in drug
`
` concentration as a result of the larger extraction
`
` rate, and that's from Exhibit 1011, page 10.
`
` That's not saying that 5-HMT is the cause of
`
` tachycardia, it's saying that the rapid metabolism
`
` via the CYP2D6 pathway is the likely culprit. Same
`
` is true for visual-accommodation issues. The author
`
` suggests that because of tolterodine being ten times
`
` more lipophilic than 5-HMT, it crosses membranes more
`
` rapidly and is likely the cause of the
`
` visual-accommodation issues.
`
` So in Ground Two, which starts with Brynne,
`
` the person of skill in the art is left with a
`
` combination of Brynne in the label, suggesting there
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`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` are problems with the tolterodine molecule, but we
`
` have a safe and effective ingredient in 5-HMT, why
`
` don't we consider doing something with 5-HMT?
`
` Can we go to slide six, please. We've already
`
` talked about the label. Patent Owner's response to
`
` that is, well, slow down, there's a bunch of other
`
` molecules that were being used in the OAB treatment
`
` area, why didn't we focus on those? And that's
`
` because the prior art told us that the
`
` antimuscarinics, which included tolterodine and would
`
` ultimately include fesoterodine, that's where the
`
` focus is because they're the best.
`
` Almost all of the drug products that the
`
` authors of the Anderson paper -- again, that's
`
` Petitioner's slide six, 1006, and there's a table on
`
` page two that I will be speaking about. It talks
`
` about how -- which drugs that were available had been
`
` studied, were in the process of being studied, were
`
` actively being used for the treatment of
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`
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`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` overactive-bladder-type issues, and the authors point
`
` out that if you go through this table, most of the
`
` ones that were good for this treatment fall into this
`
` antimuscarinic effect. Other compounds like calcium
`
` antagonists and other things like that didn't get the
`
` same grades. They didn't get as highly rated as
`
` these authors which point to these antimuscarinic
`
` compounds.
`
` And so where we are now in the prior art is
`
` whether 5-HMT is a good molecule to look at. And I
`
` want to think -- I think it's important to stop for a
`
` second and realize what the lead-compound analysis --
`
` which from Petitioner's viewpoint is being applied by
`
` Patent Owners incorrectly in such a way that is too
`
` strict to violate -- and therefore violates KSR.
`
` The lead compound purpose is to make sure we
`
` don't pluck a molecule from an unrelated field and
`
` stick it into, say, the pharmaceutical arts where we
`
` don't know anything about the underlying molecule and
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`
`
`IPR2016-00510 (Patent 6,858,650)
`IPR2016-00512 (Patent 7,384,980 B2)
`IPR2016-00514 (Patent 7,855,230 B2)
`IPR2016-00516 (Patent 8,338,748 B2)
`IPR2016-00517 (Patent 7,985,772 B2)
` say, okay, they look similar, and if we make this one
`
` small modification, we end up with the claimed
`
` invention. That's not what we have here. We have a
`
` known, safe, and effective ingredient for the same
`
` treatment of overactive bladder that's at issue in
`
` this case; we see that molecule, and it's only
`
` different in one small substitution.
`
` The lead-compound part of this case is so
`
` strong that it really drives the skilled artisan to
`
` not ask how to redevelop an OAB drug or start from
`
` scratch, but instead it tells the skilled artisan how
`
` do I get 5-HMT into the body in such a way to create
`
` a new and commercially-viable drug product?
`
` I want to point out that unrebutted testimony
`
` in this IPR are things that Dr. Patterson said. For
`
` example, the person skilled in the art doesn't go
`
` back and start over from scratch, they take what's
`
` known and build forward. And that's in Exhibit 1003,
`
` paragraph 78. It also requires knowledge of more
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`
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