Paper No. 67
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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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`
`
`INCYTE CORPORATION,
`Petitioner,
`
`v.
`
`CONCERT PHARMACEUTICALS, INC.,
`Patent Owner.
`___________
`
`PGR2021-00006
`Patent 10,561,659 B2
`___________
`
`Record of Oral Hearing
`Held: February 10, 2022
`_____________
`
`Trials@uspto.gov
`571-272-7822
`
`
`
`
`
`
`
`
`
`Before CHRISTOPHER G. PAULRAJ, ROBERT A. POLLOCK, and
`DEVON ZASTROW NEWMAN, Administrative Patent Judges.
`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`
`INCYTE CORPORATION,
`Petitioner,
`
`v.
`
`CONCERT PHARMACEUTICALS, INC.,
`Patent Owner.
`___________
`
`PGR2021-00006
`Patent 10,561,659 B2
`___________
`
`Record of Oral Hearing
`Held: February 10, 2022
`_____________
`
`Trials@uspto.gov
`571-272-7822
`
`
`
`
`
`
`
`
`
`Before CHRISTOPHER G. PAULRAJ, ROBERT A. POLLOCK, and
`DEVON ZASTROW NEWMAN, Administrative Patent Judges.
`
`
`
`
`
`
`
`
`
`
`
`
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`
`PGR2021-00006
`Patent 10,561,659 B2
`
`
`
`APPEARANCES:
`
`ON BEHALF OF THE PETITIONER:
`
`
`MARK FELDSTEIN, ESQUIRE
`DREW CHRISTIE, ESQUIRE
`Finnegan, Henderson, Farabow, Garrett & Dunner,
`901 New York Avenue, N.W.Washington, D.C. 20001
`
`
`
`ON BEHALF OF PATENT OWNER:
`
`
`MARTA E. DELSIGNORE, ESQUIRE
`GERARD J. CEDRONE, ESQUIRE
`EMILY L. RAPALINO, ESQUIRE
`DARYL L. WIESEN, ESQUIRE
`Goodwin Proctor, LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018
`
`
`
`
`The above-entitled matter came on for hearing on Thursday, February
`10, 2022, commencing at 1:00 p.m., EDT, at the U.S. Patent and Trademark
`Office, by video/by telephone.
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`PGR2021-00006
`Patent 10,561,659 B2
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` R O C E E D I N G S
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`JUDGE NEWMAN: Hello everyone. Welcome. We are
`
`here in the matter of Incyte Corporation v. Concert
`Pharmaceuticals, Inc., in PRG 2021-00006 regarding patent No.
`10,561,659. Can you please for Petitioner's side identify who is
`here with us today? I'm sorry, I can't hear you speaking. You
`need to unmute yourself on the microphone.
`
`MR. FELDSTEIN: Sorry, Your Honor. This is Mark
`Feldstein from Finnegan, Henderson on behalf of Petitioner
`Incyte Corporation. I'll be joined today in the argument by my
`colleague, Drew Christie, also of Finnegan, Henderson.
`JUDGE NEWMAN: Thank you. And for Patent Owner?
`MS. DELSIGNORE: Good afternoon. Marta Delsignore of
`Goodwin Proctor. I am here today with Gerard Cedrone, Emily
`Rapalino and Daryl Wiesen who will be speaking on behalf of
`Patent Owner.
`JUDGE NEWMAN: All right. I have to admit I'm having
`some trouble hearing you. We need to find a way to get your
`volume much higher if possible.
`MS. DELSIGNORE: Can you hear me now, Your Honor?
`JUDGE NEWMAN: Still very light. Panel members, are
`you also having trouble hearing? Yes. We're going to need your
`volume much higher or if you could be closer to the microphone
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`PGR2021-00006
`Patent 10,561,659 B2
`somehow that would be helpful.
`MS. DELSIGNORE: Your Honor, can you hear me now?
`JUDGE NEWMAN: That is slightly better but it's still
`going to be a bit difficult.
`
`(Pause.)
`JUDGE NEWMAN: Okay. Why don't we take five minutes
`and see if we can't get our technology team to get better access
`on this.
`(Pause, due to technical difficulties.)
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`MS. DELSIGNORE: Is this better, Your Honor?
`JUDGE NEWMAN: I can hear that a little bit more clearly.
`Other panel members as well? Okay. I think we can proceed
`with that. Thank you. All right. So would you please, Ms.
`Delsignore, please identify again who is representing Patent
`Owner, yourself and who else.
`MS. DELSIGNORE: Representing Patent Owner today are
`Gerard Cedrone, Emily Rapalino and Daryl Wiesen. I apologize
`for the delay, Your Honor.
`JUDGE NEWMAN: That's quite all right. And court
`reporter, do you need spelling on any of those names?
`THE REPORTER: No.
`JUDGE NEWMAN: Great. Okay. We’ll proceed, and each
`side has 60 minutes but because there also has been an
`application for a LEAP practitioner speaking on each side we
`have an additional 15 minutes bringing the total to 75 minutes
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`Patent 10,561,659 B2
`per side. Petitioner will proceed first and Petitioner, would you
`like to reserve any time for rebuttal?
`MR. FELDSTEIN: Yes, Your Honor. I'd like to reserve 15
`minutes for rebuttal.
`JUDGE NEWMAN: All right. And for Patent Owner?
`MS. DELSIGNORE: We would like to reserve 15 minutes
`for rebuttal.
`JUDGE NEWMAN: And we'll give you a one minute
`warning unless you wanted some different period of time.
`MR. FELDSTEIN: That's fine for us, Your Honor.
`MS. DELSIGNORE: That's fine.
`JUDGE NEWMAN: Okay. Great. And we can jump right
`in but does anyone want to address the Motions for Exclusions of
`Testimony first? You don't have to but you're welcome to.
`MR. FELDSTEIN: Your Honor, on Petitioner's side we
`were going to address the motions. We had intended to do them
`second but we'll do them first if you prefer.
`JUDGE NEWMAN: You may choose the order, that's fine
`with us.
`MR. FELDSTEIN: We'll do it second then.
`JUDGE NEWMAN: All right. Are we ready to go? We
`can start the testimony clock. Okay. Let's go. Please begin.
`MR. FELDSTEIN: Thank you, Your Honor. Again, Mark
`Feldstein on behalf of Petitioner Incyte Corporation in this PGR.
`I'd like to direct the Court's attention, I understand we're not
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`Patent 10,561,659 B2
`going to be showing slides, but direct the Court's attention to
`slide 3 in our slide deck in our demonstratives just to lay the
`foundation for what the grounds are. The petition initially had
`three grounds, grounds 1 and 2 covering obviousness of claims 1
`through 21 under 103 based on two different sets of references
`and then a third ground, ground 3 anticipation of claim 8. Patent
`Owner disclaimed claim 8 prior to Institution mooting ground 3
`and reducing grounds 1 and 2 to all claims except for ground 3.
`Looking at slide 4 of our slide deck. The obviousness
`argument which is substantially the same in terms of the issues
`that have come up in the case, substantially the same between
`ground 1 and ground 2. On slide 4 there are three basic elements
`of the obviousness case and that (indiscernible) fundamentally
`simple. The Ruxolitinib was known to treat Alopecia Areata,
`that's a hair loss disorder. There are express teachings in the art
`to use Compound (1) in place of Ruxolitinib and the claimed
`dose ranges are within known ranges and are obvious to
`optimize.
`At a high level Concert's responses are that they're
`asserting a prior art exception of the 102(b) for parts of the
`Silverman reference but even if they could establish the 102(b)
`exception for parts of Silverman, it does not remove other
`relevant subject matter of Silverman that's more than sufficient
`to establish unpatentability. Concert also relies fairly
`extensively on trying to assert that the field is actually very
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`complex and that alternatives to -- there were alternatives that
`taught away from oral Ruxolitinib for Alopecia Areata. None of
`those, as we'll get into, hold water given that Ruxolitinib and
`other JAKs were already being used to treat Alopecia Areata and
`in fact were used by all clinicians in this case. So this is not a
`case where we have to hypothesize what wouldn't a person of
`ordinary skill in the art have done. We know they were already
`using oral JAK inhibitors including Ruxolitinib to treat Alopecia
`Areata and of course as we'll get into it Concert's allegation that
`alternatives teach away is mistaken legally and factually. More
`than one possibility can be obvious at the same time and the
`mere fact that you have alternatives doesn't teach away from
`another alternative, even if one of them is preferred over the
`other.
`Concert's third main response is to rely on objective indicia
`and as we'll see there too none of the information they rely on is
`unexpected. None of the events they rely on has nexus with the
`claim and none is commensurate in scope and I'll note here, in
`case I forget to do it later, Concert doesn't appear to argue any of
`its objective indicia separately for any claim so we think for
`objective indicia focus on claim 1.
`We direct your attention now to slide 5 to the first point in
`the three elements of the obviousness case, the Ruxolitinib JAK
`inhibitor was known to treat Alopecia Areata. This is disclosed
`in the Christiano reference where it's taught and provided
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`rationale for why Ruxolitinib would be effective in treating
`Alopecia Areata and that it specifically claimed in the Christiano
`patent as a drug for the treatment of hair loss disorders.
`Xing goes one step farther, they're actually related groups
`Xing and Christiano, Xing goes one step farther and includes
`both a mechanistic basis of why JAK inhibitors treat Alopecia
`Areata, includes pre-clinical data in a mouse model of hair loss
`disorders and shows efficacy and in fact it shows clinical
`efficacy in pre-patients. One of them is shown in this figure
`that's been described in the art as providing striking efficacy in
`the treatment of Alopecia Areata and I noted and let me just
`reiterate that it was this pre-clinical efficacy that's important.
`We hear from Concert one of their arguments is that well, you
`can't trust your eyes basically in what you see in this figure and
`what the clinicians saw in terms of hair regrowth because there
`could have been spontaneous remission. Now there's no
`evidence and no suggestion that any of these patients actually
`underwent spontaneous remission so it's pure speculation on
`their part that it's something that could have happened but
`moreover, where Xing studied in a pre-clinical model they
`included a mouse that was -- mice that had no hair on their
`abdomen and they treated one half with a JAK inhibitor, one half
`was left untreated and they saw efficacy on the treated half and
`the untested area remained alopecic and that's in Xing, Exhibit
`1003 at page 10 and so you know from the mechanism, you know
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`from the pre-clinical data that there's proven efficacy than a
`treatment effect from the drug.
`It's not just Christiano and Xing. The results of Xing and
`the treatment of Alopecia Areata with a JAK inhibitor including
`Ruxolitinib are reinforced by larger studies for both Ruxolitinib
`and another JAK inhibitor called Tofacitinib. Both were
`presented in 2015 at the Alopecia conference and what the right
`hand side of our slide 5 the Mackay-Wiggan publication is an
`abstract Exhibit 1143. It had nine of twelve patients
`demonstrated a remarkable response to treatment with
`Ruxolitinib. The next citation on slide 5 is a reference to a
`treatment with Tofacitinib that actually included in the working
`group Concert's expert Dr. Ko and it was presented in 2015 and
`it would show that over three months this other JAK inhibitor
`produced significant hair growth in 75 percent of the patients.
`Concert argues that somehow notwithstanding all this
`evidence that somehow our focus on JAK inhibitors for Alopecia
`Areata is hindsight. That's not so. If we turn to slide 19 we
`have part of their argument on the left hand side of slide 19.
`Concert argues that the prior art as a whole did not single out
`JAK inhibitors as a particular subject of interest and in fact that
`is not true. We can again look at what was going on in 2015 at a
`national Alopecia Areata Foundation summit. They listed a
`number of future research priorities. Three of these were
`directly related to the treatment of Alopecia Areata with JAK
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`inhibitors. It got down to the level of advocating for insurance
`coverage of systemic or topical JAK inhibitors, so it clearly was
`a research priority. The reference Exhibit 2063 similarly
`recognizes that studies are focusing attention on the JAK
`pathway. The Schwartz reference, Exhibit 1015, recognizes that
`JAK inhibitors are "a new chapter in the treatment of new
`disorders" in which the paradigm has been fundamentally shifted
`yet again. Earlier in Schwartz, Exhibit 1015 at page 12,
`Schwartz recognizes that Ruxolitinib among others had been
`used successfully to treat Alopecia Areata and Alopecia
`Universalis-related disease.
`We also know it's not hindsight, if we can turn to slide 17,
`we know it's not hindsight to focus on JAK inhibitors for the
`treatment of Alopecia Areata because all the clinicians in this
`case are using JAK inhibitors for the treatment of Alopecia
`Areata by May, 2016. Dr. Ko, then Concert's expert, was using
`JAK inhibitors for Alopecia Areata. Dr. Shapiro and Dr.
`Damsky, our experts, were likewise using JAK inhibitors for the
`treatment of Alopecia Areata.
`In addition to Dr. Ko, Concert's expert, admitting that he
`used it he also, outside of litigation context, has published that
`Xing, our primary reference in ground 1, recognized that Xing
`taught that Ruxolitinib "induced inflammatory remission hair
`regrowth." This is in a paper written where Dr. Ko is the second
`author. It's Crispin paper Exhibit 1152 at page 2 and what the
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`authors write in Exhibit 1152 at page 2 on the right hand side is,
`"An important therapeutic insight was a discovery that
`blockade of common signaling pathways downstream of cytokine
`receptors, in particular JAK/STAT could reverse AA in mice,"
`citing reference 5 which is Xing. "Subsequently, treatment of 3
`patients with the JAK1/2 inhibitor Ruxolitinib," citing reference
`5 which is Xing, "induced inflammatory remission and hair
`regrowth."
`So there's no basis for Concert to assert that there's any
`hindsight in the focus of JAK inhibitors. JAK inhibitors were in
`fact in use. JAK inhibitors were a focus. JAK inhibitors were a
`priority for the treatment of AA.
`Concert's next argument is that preferences -- there were
`preferences for Tofacitinib, there were Ruxolitinib and
`preferences for oral -- excuse me, topical over oral -- that also
`was not the case and if we can go to our slide 2 even if it was the
`case the law is actually clear. In re Moutet is a well known case
`and it makes the point very well.
`"Just because better alternatives exist in the prior art does
`not mean that an inferior combination is inapt for obviousness
`purposes."
`In other words, even if there was a preference for
`Tofacitinib, even if there was a preference for topical JAK
`inhibitors, that does not make the use of Ruxolitinib orally any
`less obvious.
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`But in fact if we move on to slide 24, the alternative
`Tofacitinib did not teach away from Ruxolitinib. There is
`nothing shown in the evidence that Tofacitinib was better. If we
`look back at the Xing reference on the left hand side of slide 23,
`the graph -- you may have to zoom in on your screen if you're
`looking electronically -- but the two lines that go up on the graph
`are essentially overlapping curves, one for Ruxolitinib JAK1/2
`and one for Tofacitinib, the JAK3, their efficacy was as one can
`see equivalent and so there was nothing to show that Tofacitinib
`was better and --
`JUDGE NEWMAN: Counsel, just to interrupt you for one
`second. One of those if Tofacitinib and one of those is
`Ruxolitinib?
`MR. FELDSTEIN: Correct, Your Honor.
`JUDGE NEWMAN: Okay.
`MR. FELDSTEIN: The JAK1/2 is Ruxolitinib and the
`JAK3 -- so the orange curve is Ruxolitinib and the blue triangles
`is Tofacitinib.
`JUDGE NEWMAN: Thank you.
`MR. FELDSTEIN: You'll hear, and I think Concert tries to
`make too much of this unfortunately, that Dr. Shapiro was
`prescribing at the time Tofacitinib for Alopecia Areata and that's
`true. He testified to that. But the reason that he explained
`multiple times was because as a practical matter Ruxolitinib was
`more expensive and thus unavailable to the patients and what he
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`explained in Exhibit 2054 which was his deposition on cross-
`examination, lines 33 to 19, he was asked,
`"Q But you never used Ruxolitinib prior to May, 2016 to
`treat AA?"
`"A I wanted to, okay, but it was difficult for us to obtain
`for patients because of the high cost so we went with more for
`the Tofacitinib route."
`And there are other quotes and you may see in Concert's
`slides depending on if they use them, other times where they
`point to Dr. Shapiro's use of Tofacitinib prior to May, 2016 and
`if Your Honors read the context of the transcripts around those
`questions in each case he explains that it was a cost issue, a cost
`issue alone and as we cite in the Butamax Advanced Biofuels v.
`Gevo, Inc., IPR on slide 23 commercial viability does not control
`the obviousness situation. It was entirely obvious to use
`Ruxolitinib. It was already in use and the fact that doctors chose
`the less expensive Tofacitinib doesn't make Ruxolitinib any less
`obvious.
`If we go on to slide 24, in terms of topical the situation is
`similar but as Dr. Damsky explained, and I think there's no
`dispute on this in the evidence or the testimony from their
`experts either, in practice most often the use the JAK inhibitors
`for AA was oral, most of it was oral and they're going to rely
`heavily -- Concert's going to rely heavily on generic preferences
`for topical over oral and what they leave out every time they
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`point to this is Dr. Shapiro's explanation here on slide 24 that
`you would favor topical over oral if they have the same efficacy.
`So the problem with Concert's argument is there is no evidence
`that they had the same efficacy. They were using oral because
`oral had been shown efficacious in humans. It hadn't been --
`topical hadn't been shown to be equally efficacious with oral and
`so it's just wrong that topical was preferred in this case because
`there was in fact no equal efficacy of the topical.
`I can go on to the second point of our argument, go back to
`slide 6, the obviousness of substituting known equivalents. This
`is a legal principle I don't think is disputed by Concert. In re
`Fout, Coalition for Affordable Drugs IX LLC v. Bristol-Myers
`Squibb Co. IPR and In re Ruff basically explain that where that
`it's prima facie obvious to substitute one known equivalent for
`another and that is exactly our facts here.
`If we go on to slide 7 which is on the left hand the
`Silverman patent. The Silverman patent expressly teaches the
`substitution and the equivalents and the interchangeability of
`Compound (1) for Ruxolitinib. It tells you in column 20, lines
`57 to 62 of Exhibit 1002, it tells you,
`"According to another embodiment the invention provides a
`method of treating a disease that is beneficially treated by
`Ruxolitinib and the subject in need thereof comprising the steps
`of administering to the subject an effective amount of a
`compound or a composition of this invention."
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`So Silverman tells you explicitly that to substitute its
`compounds which would include Compound (1), its compositions
`which would include compositions of Compound (1) in where
`Ruxolitinib is being used. Concert's counter to this, as I
`understand it, is that there's no motivation to select Compound
`(1) specifically from Silverman relying on -- I think they rely on
`at least the lead compound analysis, for example UCB, Inc. v.
`Accord Healthcare, Inc. , and if we can go to slide 26 in our deck
`the lead compound analysis just doesn't apply in the context of
`the method claim with the one they're claiming. The Novartis
`case, Novartis Pharms. Corp. v. W-Ward Pharms. Int'l. Ltd.,
`from the Federal Circuit 2019 rejected the idea that there had to
`be a reason for the compound to have stood out in the lead
`context analysis and what it held was that all you need is
`motivation of one of several potential alternatives and so it
`matters not that there are 63 or something like that species in
`Silverman of Silverman formula A. They're all taught to be used
`in place of Ruxolitinib and you don't need a lead compound
`analysis pointing to Compound (1) specifically to make the use
`of Compound (1) obvious where Silverman tells you use my
`compounds in place of Ruxolitinib.
`But in fact there's additional motivation that does point
`directly to Compound (1) in particular and we go to our slide --
`JUDGE NEWMAN: Counsel, if I could interrupt one
`moment to ask a question. There is some evidence on the record
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`PGR2021-00006
`Patent 10,561,659 B2
`that some of these compounds could be toxic and so is there any
`reason to believe that any one of the disclosed compounds in
`Silverman would not be toxic?
`MR. FELDSTEIN: There's no --
`JUDGE NEWMAN: (Indiscernible).
`MR. FELDSTEIN: -- there's no reason and I don't believe
`there's any evidence that the deuterated versions of Ruxolitinib
`could be toxic. I think the toxicity is a hypothetical issue where
`deuteration can affect other processes like side reactions and
`such, metabolic side reactions, and what we know is that -- and
`if I can direct us to slide 31 -- Silverman tells you where the
`metabolic hotspots are on formula A. It tells you that they're the
`2 and 3 positions and what the art taught and what actually -- if I
`can actually go back to slide 30 for a second, what the art taught
`and it was basically the premise of the prior IPR between the
`parties -- a finding was that you would know to deuterate
`Ruxolitinib's metabolic hotspots to achieve improved safety,
`tolerability, efficacy and that's confirmed here by Dr. Montellano
`in this case as well as Dr. Guengerich and Dr. Patterson and so to
`answer your question if I can more directly, there is evidence
`that in other systems where the metabolism is different that you
`could maybe create a toxic metabolite. Here we know what the
`metabolites are. We know the metabolites have in the 2 and 3
`positions and there's no evidence that the metabolites of
`Ruxolitinib are toxic.
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`PGR2021-00006
`Patent 10,561,659 B2
`JUDGE NEWMAN: All right.
`MR. FELDSTEIN: There's no reason why Ruxolitinib at
`these hotspots would shift to some other toxic metabolite. So in
`essence I see it as a hypothetical concern, sort of an abstract
`metaphysical possibility that sometimes you have a problem of
`toxicity but it's just not applicable to the facts that we have
`Ruxolitinib that has a very well established metabolism and a
`teaching where its hotspots are.
`JUDGE NEWMAN: All right. Let me ask this question
`then. Of the compounds disclosed in Silverman how many of
`them are deuterated at that 2 and 3 position?
`MR. FELDSTEIN: I think Compound 111 using the
`Silverman nomenclature is the only that's deuterated at all eight
`of those positions because there are four 2-positions and there
`are four 3-positions (indiscernible) and so there's only one
`compound that has those eight. There's another one, Compound
`127 that has all nine, looking at our slide 31, there's a Y1-
`position that's not circled. Compound 127 has that ninth turning
`to deuterium and there are multiple versions where the Y2s are
`deuterated or the Y3s are deuterated but not both. Compound
`111 is the only one where it's eight and just eight.
`JUDGE NEWMAN: So if I'm understanding your
`argument, you're saying that one of skill in the art would
`naturally be looking at those deuterated 2 and 3-positions and
`selecting which compounds to proceed with?
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`PGR2021-00006
`Patent 10,561,659 B2
`MR. FELDSTEIN: Correct. It you deuterate at the 2 and
`3-positions as suggested by the statement in Silverman there's
`one unique compound that you get out of that and that is in
`Silverman nomenclature Compound 111, in the '659
`nomenclature it's Compound (1). It brings you to a single
`compound.
`JUDGE NEWMAN: Okay. Thank you.
`MR. FELDSTEIN: So again, to back up half a step. It's
`not necessary that the art pointed to Compound (1) but the art
`did point to Compound (1) based on the deuteration of its
`metabolic hotspots.
`If I go now to the third element of our obviousness position
`on, if we turn to slide 35 regarding the dosage amounts and
`there's lots of clear law such as E.I. DuPont de Nemours & Co. v.
`Synvina C.V., such as Galderma Lab'ys, L.P. v. Tolmar, Inc.,
`that makes it clear that when the claimed invention falls within a
`prior art range there's a presumption of obviousness and a burden
`of production falls on the patentee to come forward with contrary
`evidence. That here those apply here because if we go on to
`slide 36 Silverman provides repeated sub-ranges within the range
`of 5 to 50 milligrams, all of which would be obvious to optimize
`within. Silverman points to the Ruxolitinib prescribing
`information,
`"For example, guidance for selecting an effective dose can
`be determined by reference to the prescribing information for
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`PGR2021-00006
`Patent 10,561,659 B2
`Ruxolitinib. "
`So Silverman points you to the prescribing information.
`The Ruxolitinib prescribing information provides a dose range of
`5 to 50 milligrams per day and so there is an effective dose range
`for Ruxolitinib. There's an effective dose range for Compound
`(1) and it's a range that includes 5 to 50 within which it would
`have been obvious to optimize.
`What Concert argues, as I understand it, is that they ignore
`all the green ranges that we have marked on slide 36 or at least
`try to point away from those in favor of the very first range 1 to
`500 milligrams with the argument relying on DuPont that broad
`ranges are not necessarily obvious to optimize. There's actually
`no reason to think that in the evidence we have that a 1 to 500
`milligram range is not obvious to optimize. What DuPont
`pointed to, for example, on an example of the range that would
`be too big would be a prior case where there were 68,000
`permutations of a protein and that was too big for obvious
`optimization but Galderma, for example, went in a range I
`believe of from a hundredfold range of .005 to 5 -- excuse me,
`from .01 to 1 percent and so Galderma relied on a hundredfold
`range from 1 milligram to 500 is a five hundredfold range but
`there's nothing particular to say that you couldn't even optimize
`the 1 to 500 milligram range and don't think that Concert points
`to anything to say otherwise.
`Concert also argues that none of these ranges are specific
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`PGR2021-00006
`Patent 10,561,659 B2
`to Compound (1) for Alopecia Areata, in fact Silverman ranges
`are very specific to Compound (1). Those are the doses for the
`compounds of their invention which include Compound (1) and
`moreover, what Silverman teaches is it's teaching methods of
`treating diseases that are beneficially treated by JAK1/2
`inhibition and so these are the doses for treating diseases by
`inhibiting the JAK1/2 pathway which is the mechanism for
`treating Alopecia Areata. So we would beg to differ with
`Concert that these are not doses for Alopecia Areata, they may
`be doses for other JAK mediating conditions as well but based on
`Silverman, Silverman is teaching doses for Compound (1), for
`immune diseases and for diseases where Ruxolitinib is beneficial
`and that would include Alopecia Areata.
`Even if we didn't have these ranges, if we go on to slide 37
`there's additional bases for --
`JUDGE NEWMAN: Counsel, let me ask one quick question
`here. For prescribing information for Ruxolitinib what other
`applications did Ruxolitinib have that were different from
`Alopecia Areata?
`MR. FELDSTEIN: So to be clear the Ruxolitinib package
`insert was not approved for Alopecia Areata so the use of
`Ruxolitinib for Alopecia Areata was according to Xing and these
`other references. Ruxolitinib was approved in its package insert
`covered treatment of two different JAK mediated cancers,
`myelofibrosis being one of them.
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`PGR2021-00006
`Patent 10,561,659 B2
`JUDGE NEWMAN: And Xing, was there information about
`dosing or Christiano?
`MR. FELDSTEIN: Correct. And that's actually on our
`slide 37 we include that and in the chart at the bottom we can see
`that there is on the bottom right there's a 40 milligram dose of
`Xing. They just use one daily dose, 40 milligram dose of
`Ruxolitinib and what we're illustrating here on this slide and the
`testimony supports this, when people used Ruxolitinib off-label
`for other than its cancer indications, when they used it off- label
`for immune diseases they worked within the approved dose
`range, Ruxolitinib approved dose range, of 5 to 50 milligrams
`and so I think all or essentially of the evidence in the record
`showing the off-label use of Ruxolitinib it falls within this 5 to
`50 milligram range and so Silverman pointed you to the
`Ruxolitinib label. It's consistent with the way persons skilled in
`the part used Ruxolitinib and other similar drugs off label to
`work within the prescribed range and it makes sense that they did
`that because this is something explained by Dr. Shapiro in his
`declaration which is Exhibit 1009, paragraph 50. What Dr.
`Shapiro explained is that, he said,
`
`"Given that Ruxolitinib provided systemically effective
`JAK inhibition of these doses, the 5 to 50 milligram doses, a
`POSA would have expected that doses in this range also would
`treat hair loss disorder via JAK inhibition as described in
`Christiano, Xing and others."
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`PGR2021-00006
`Patent 10,561,659 B2
`In other words, you're administering Ruxolitinib in its
`approved range and you're getting systemically effective JAK
`inhibition. You would expect to have systemically effective JAK
`inhibition for other diseases within that dose range too because
`you've established that for its approved condition you're getting
`systemic efficacy and JAK inhibition. Dr. Patterson, Exhibit
`1007, one of our other experts at paragraph 119 makes a similar
`point that these dose ranges of the 5 to 50 milligram per day dose
`ranges on the Ruxolitinib label are the known effective doses for
`systemic JAK1/2 inhibition by Ruxolitinib and so it's consistent
`that Silverman points to the Ruxolitinib prescribing information
`because that's where a person of ordinary skill would have
`looked anyhow and we know they would have looked there, or at
`least their prescribing habits are consistent within that range and
`so you've got a range of 5 to 50 in the approved dose range that
`guides treatment.
`Just briefly, if we can go to slide 39 there's a strong
`response of Ruxolitinib in 30 and 40 milligrams per day plus it's
`linear form of kinetics provided motivation for lowering the dose
`to be able to still get efficacy as a further reason to lower the
`dose and then just briefly also on slide 40 there's a whole ton of
`art to this effect but the point of deuterium modification or a
`point of deuterium modification is optimization and o
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