Trials@uspto.gov
`571-272-7822
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`Paper No. 67
`Entered: June 17, 2015
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`NOVEN PHARMACEUTICALS, INC., and MYLAN
`PHARMACEUTICALS, INC.,
`Petitioner,
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`v.
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`NOVARTIS AG and LTS LOHMANN THERAPIE-SYSTEME
`AG,
`Patent Owner.
`____________
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
`____________
`
`Held: June 2, 2015
`____________
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`
`
`
`BEFORE: FRANCISCO C. PRATS, ERICA A. FRANKLIN,
`and CHRISTOPHER G. PAULRAJ, Administrative Patent
`Judges.
`
`
`The above-entitled matter came on for hearing on Tuesday, June
`2, 2015, commencing at 1:00 p.m., at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
`
`
`571-272-7822
`
`
`
`Paper No. 67
`Entered: June 17, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`NOVEN PHARMACEUTICALS, INC., and MYLAN
`PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`NOVARTIS AG and LTS LOHMANN THERAPIE-SYSTEME
`AG,
`Patent Owner.
`____________
`
`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
`____________
`
`Held: June 2, 2015
`____________
`
`
`
`
`BEFORE: FRANCISCO C. PRATS, ERICA A. FRANKLIN,
`and CHRISTOPHER G. PAULRAJ, Administrative Patent
`Judges.
`
`
`The above-entitled matter came on for hearing on Tuesday, June
`2, 2015, commencing at 1:00 p.m., at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
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`MICHAEL K. LEVY, ESQUIRE
`CHRIS J. COULSON, ESQUIRE
`Kenyon & Kenyon, LLP
`One Broadway
`New York, New York 10004-1007
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`BENJAMIN ANGER, ESQUIRE
`Knobbe Martens
`12790 El Camino Real
`San Diego, California 92130
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
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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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`CHARLOTTE JACOBSEN, ESQUIRE
`RAYMOND R. MANDRA, ESQUIRE
`NICHOLAS N. KALLAS, ESQUIRE
`Fitzpatrick, Cella, Harper & Scinto
`1290 Avenue of the Americas
`New York, New York 10104-3800
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
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` P R O C E E D I N G S
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`JUDGE PRATS: Good afternoon, everyone. We are
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`here for IPR2014-00549 and IPR2014-00550. This is the final
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`hearing for those cases. Welcome everyone and thank you for
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`coming.
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`These involve respectively, the 549 involves U.S. patent
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`number 6,316,023 and the 550 involves patent number 6,335,031.
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`The parties are -- Petitioner is Noven Pharmaceuticals and Patent
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`Owner is Novartis and LTS Lohmann Therapie-Systeme.
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`I would like to point out that the 549 and 550
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`proceedings have been joined with IPR2015-00265 and 00268
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`respectively. The Petitioner in those proceedings is Mylan
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`Pharmaceuticals. Mylan will not be presenting argument today.
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`At this time I would like counsel for the parties to
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`introduce yourselves and your colleagues, beginning with
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`Petitioner, Noven.
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`MR. LEVY: Good afternoon, Your Honors. Mike
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`Levy from Kenyon & Kenyon on behalf of Petitioner, Noven.
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`MR. COULSON: I'm Chris Coulson also for Noven,
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`Your Honors.
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`MS. JACOBSEN: Good afternoon, Your Honors.
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`Charlotte Jacobsen on behalf of Novartis and LTS. And with me
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
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`is Nicholas Kallas and Raymond Mandra from the firm
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`Fitzpatrick Cella.
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`MR. ANGER: Your Honors, I'm Ben Anger
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`representing Mylan Pharmaceuticals, Inc.
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`MR. LEVY: And Your Honor, on behalf of Petitioners,
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`Steve Lee is also counsel of record and joining us as well.
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`JUDGE PRATS: Thank you. Welcome to the Board.
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`Consistent with our hearing order, each party has 60 minutes to
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`present their arguments. Petitioner you may reserve rebuttal time.
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`As to procedure, I note that Patent Owner has made
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`objections to a number of Petitioner's demonstrative slides.
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`When we present a particular slide, we are not going to interrupt
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`the opposition and say, well, I object to that slide. We are just
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`going to continue through argument. Is that clear?
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`Let me go through and make sure I haven't missed
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`anything. Okay. Counsel for Petitioner, you may proceed.
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`Would you like to reserve any rebuttal time?
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`MR. LEVY: Yes, Your Honors, I would like to reserve
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`20 minutes for rebuttal.
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`Good afternoon, Your Honors, and may it please the
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`Court. Again, Mike Levy for Petitioner. The main question
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`posed to the Board is whether a person of ordinary skill in the art
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`or a POSA would have expected that rivastigmine was
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`susceptible to oxidation, whether the prior art suggested the
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`existence of the problem.
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`IPR2014-00549 and IPR2014-00550
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`There's no real dispute, or there shouldn't be, that the
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`solution to the problem, antioxidant use, is obvious. The
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`expectation of oxidative degradation provides the motivation to
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`take the otherwise unremarkable step of adding an antioxidant to
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`pharmaceutical compositions.
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`The Board is now aware of the Federal Circuit's recent
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`decision upholding a District Court's finding that other defendants
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`failed to prove obviousness by clear and convincing evidence
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`based on the record in that proceeding for the patents here. To be
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`sure, there is substantially more evidence here and different
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`evidence than that previous case, and it is particularly evidence
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`addressing the central issue of whether a POSA would have
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`suspected rivastigmine's susceptible to oxidation.
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`Petitioner provided expert testimony evidence from two
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`distinguished individuals. Dr. Christian Schöneich is the chair of
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`the department of pharmaceutical chemistry at the University of
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`Kansas. The focus of his professional work, his research since
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`the early 1990s has been free radical chemistry which includes
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`the very types of oxidation issues presenting in this case. He is
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`the only declarant in this case whose expertise is oxidation in
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`pharmaceutical chemistry.
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`And the other, Dr. Agis Kydonieus, is the president of
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`Samos Pharmaceuticals, a company serving the pharmaceutical
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`industry in the field of drug delivery. Dr. Kydonieus has spent
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`his entire professional career outside of academia in industry and
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
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`has spent the last 35 years of his career on the development of
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`transdermal delivery systems. He's the only expert in this case
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`whose career focus has been transdermals.
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`I'm on slide 2. As I said, the only real issue separating
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`the parties is the motivation to combine rivastigmine with an
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`antioxidant. That's the only real issue in this case because so
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`much is not in dispute. The Enz reference is a proper starting
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`point for the obviousness analysis. It's not disputed that all the
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`elements of the challenged claims of both patents are found in the
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`prior art. The particular features of any dependent claim are not
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`argued for separate patentability purposes.
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`It would have been routine work for the person of
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`ordinary skill in the art to select an effective amount of an
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`appropriate antioxidant. That is, there's no dispute that it is the
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`routine work of the POSA to identify an appropriate compatible
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`antioxidant and its effective amount for a composition.
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`And finally and perhaps most importantly, evidence of
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`secondary considerations in support of nonobviousness has not
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`been presented by Patent Owners.
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`Slide 3 shows the grounds for the '023 IPR. The
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`references are essentially the same that we are employing in the
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`'031 IPR on slide 4. What's important to note is that because of
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`the same references and the same claimed subject matter, the
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`Patent Owner has conceded in both IPRs, that the specific
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`differences among the grounds and the challenged claims is not
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
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`material. That's in their response at page 20 in the '031 patent
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`IPR.
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`I'm on slide 5. The similarity of the subject matter as
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`illustrated by comparing the claim 1, the two independent claims
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`of the two respective patents. In claim 1, of course both are
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`pharmaceutical composition. Claim 1 of the '031 patent on the
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`left requires a therapeutically effective amount of active. It's
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`more specifically required to be 1 to 40 weight percent in the '023
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`patent. And in the '031 patent they use the modifying language
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`about 0.01 to about 0.5 percent for the amount of antioxidant. In
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`the '023 it's more specifically claimed and limited to 0.01 to 0.5,
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`the subject matters thus lending itself to the consolidation
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`hearing.
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`JUDGE PRATS: Counsel, should we consider claims 7
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`and 8 -- I think it's of the '031 patent that is the transdermal
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`formulation -- should we consider those differently?
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`MR. LEVY: No, they are certainly claims in the IPR
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`and should be addressed, as all of them should. The fact that a
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`transdermal is being introduced, that's really not a disputed
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`feature because those elements are also in the prior art. But those
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`claims do, of course, command the same attention. And on my
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`next slide, 6, you'll see that there's a method claim which is not
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`limited to a transdermal but simply also requires that rivastigmine
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`be combined with an antioxidant.
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`IPR2014-00549 and IPR2014-00550
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`The elements of the dependent claims cover in both
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`patents specific antioxidants, narrowed antioxidant ranges and the
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`elements of the transdermal system.
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`JUDGE PRATS: The reason I raise that is I think it's on
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`page 12 of your reply, you seem to argue that Enz isn't limited to
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`a -- it's teaching about a transdermal. So when you show the
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`more generic claim, I'm just trying to square that with what you
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`are saying here. I mean, Enz does teach a transdermal and pretty
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`much nothing else, right?
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`MR. LEVY: It does disclose the compositions can be
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`made for rivastigmine. The emphasis is on transdermals, but
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`there is broader disclosure outside of transdermals for the
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`delivery of that drug.
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`JUDGE PRATS: Thank you.
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`MR. LEVY: I'm on slide 7. The experts agree on what
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`constitutes a person of ordinary skill except in one point that I
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`wanted to emphasize. Petitioners’ experts testified that a POSA
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`would make reasoned predictions about the strength of particular
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`chemical bonds in a drug molecule and the susceptibility of the
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`molecule to degradation, including oxidative degradation. I think
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`that's a difference between the two parties.
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`Slide 8, turning to the central issue of whether a POSA
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`would have expected that rivastigmine was susceptible to
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`oxidative degradation. The reason that there is a reasonable
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`expectation of oxidative degradation is based on the chemical
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
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`structure of rivastigmine itself. And it's also based on the
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`similarity of rivastigmine's structure to other prior art compound,
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`nicotine, which was known to be susceptible to oxidation. I want
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`to walk through that with my time. But most importantly, the
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`POSA's appreciation of rivastigmine's structural issues that give
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`rise to the concern about oxidation inform the POSA's
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`understanding of the prior art in the case, Elmalem, Rosin,
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`Sasaki, Ebert and Enz.
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`I'm on slide 9. Now, the POSA, of course, would have
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`had reasonable expectation for rivastigmine's issue. And the prior
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`art is the basis for this. There is no speculation involved. It's not
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`theoretical. There is no hindsight here. The prior art instructs the
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`artisan to examine the structure of a molecule during
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`pre-formulation and make predictive assessments. We'll see that
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`art in a moment. The artisan is instructed to apply functional
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`group chemistry to anticipate potential modes of degradation. In
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`fact, Patent Owner's expert himself, Dr. Klibanov, did a very
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`elegant application of functional group chemistry in his own
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`declaration when he addressed the stability of carbamates. That's
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`Exhibit 1032 at paragraphs 27 to 29.
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`The third point is worth noting here. The mechanistic
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`pathways of a reaction are different from the threshold question
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`of susceptibility to oxidative degradation. We are talking about
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`that threshold question, susceptibility to oxidative degradation.
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`IPR2014-00549 and IPR2014-00550
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`Patent Owners have attempted to create an issue where none
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`should exist.
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`The parties agree that deciphering the reaction
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`mechanism of an organic compound's degradation is complex. It
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`involves intermediates, many of which may not exist long enough
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`to even be isolated or measured. But the question here differs
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`from deciphering an entire mechanistic pathway. The question
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`here is simply, is the molecule ab initio, from the start,
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`susceptible to oxidation? We've answered that the question for
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`rivastigmine is yes.
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`I'm on to slide 10. Here is an example of the prior art
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`instructing the POSA. The initial investigation begins through
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`knowledge of the drug's chemical structure which allows the
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`pre-formulation scientist to anticipate the possible degradation
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`reactions. There's no hindsight use of Dr. Schöneich's testimony
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`here. The prior art says, please, look at the structure and make
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`rational determinations about degradation modes.
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`JUDGE PRATS: Counsel, wouldn't anybody test any
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`drug to make sure it's not susceptible to oxidation?
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`MR. LEVY: Regulatory authorities may indeed require
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`that testing be done for all possible modes of degradation. That's
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`absolutely something we talked about in our petition, that there
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`are FDA guidelines in place. It's also common sense to see if
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`your drug is degrading to see if there's any toxic issues involved
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`as well. That is part of the pre-formulation process. Here,
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`though, we are saying not just testing, but looking at the structure
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`to make assessments before testing is even done.
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`JUDGE PRATS: How do you answer Patent Owner's
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`argument that if any testing is required, therefore, it's not
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`obvious?
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`MR. LEVY: Well, the person of ordinary skill in the art
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`has an expectation that oxidation can and will occur. It's
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`formulation-dependent. It doesn't happen under every
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`circumstance because different formulations may prohibit it or
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`mitigate it in some way. There could be antioxidants present that
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`were not known. There could be other reaction conditions not
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`favoring it. But once you have you have that expectation, that is
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`part of -- that's an intrinsic property of the compound. It travels
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`with the compound wherever it goes. In different formulations
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`you certainly would want to test to see if it happens and to the
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`extent, if any.
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`Slide 11. Here is another instruction from the prior art,
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`Exhibit 2014. The prior art taught the possible modes of
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`degradation that are likely to happen were identifiable by
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`applying functional group chemistry.
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`On slide 12, another example of the prior art from
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`Exhibit 1047. A study of functional groups is especially
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`profitable because the reactions of a functional group tend to be
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`about the same regardless of the nature of the rest of the
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`molecule.
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`I'm on slide 14. Here is the rivastigmine molecule. It's
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`shown with three-dimensional chemistry on the carbon on the
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`right-hand side. That's the carbon of interest in our case.
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`On slide 15, we've assigned colors to different
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`functional groups for the purposes of our discussion. Our focus is
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`on the red carbon-hydrogen bond.
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`In slide 16, I want to talk about what these various
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`functional groups are and then discuss the principles that are at
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`work here. On slide 16, the different functional groups are
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`identified. There's the red carbon-hydrogen that is our focus.
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`That red carbon is immediately adjacent to three groups at the
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`same time. One group shown in blue is an aromatic system. In
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`this case, a benzene ring. It's an aromatic ring. It's immediately
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`adjacent to an aromatic ring.
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`At the same time, the red carbon is immediately
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`adjacent a tertiary amine shown in green and at the same time, the
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`red carbon is immediately adjacent an additional carbon moiety
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`shown in purple. The fact that the red carbon is immediately
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`adjacent three other nonhydrogen entities at the same time
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`renders the red carbon a tertiary carbon. And that's an important
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`concept that I want to focus on in a little bit.
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`Dr. Schöneich, on behalf of Petitioners, testified that
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`these three groups are all immediately adjacent to the red carbon
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`and make the red carbon-hydrogen bond very weak.
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`JUDGE PAULRAJ: I want to ask you about your
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`reliance on Dr. Schöneich's testimony on this point, and I'll let
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`you continue your point after this question. It seems to me that
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`you are relying heavily on Dr. Schöneich's testimony to explain
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`the chemistry and the susceptibility of rivastigmine to
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`degradation based on these functional groups in the molecule.
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`But Section 311(b) of our statute says that inter partes review is
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`based on prior art and printed publications. How can we rely on
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`expert testimony on this point when the challenge is based on the
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`teachings in the prior art and teachings specifically in patent
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`publications?
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`MR. LEVY: Because as we've shown, and it's on my
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`next few slides, all of the principles that Dr. Schöneich relies
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`upon are shown in the prior art organic chemistry textbooks. The
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`notion of carbon stabilization, bond association, all these
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`concepts that allow one to conclude that this molecule is
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`susceptible to oxidation are all in the prior art. We have
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`documented that in our papers with prior art textbooks and other
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`literature.
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`JUDGE PRATS: But the link between nicotine and
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`rivastigmine, that's not really shown in the art. It seems to me it's
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`Dr. Schöneich that's making that link, correct? Is there evidence,
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`direct evidence linking those two compounds except for that
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`testimony?
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`Patents 6,316,023 B1 and 6,335,031 B1
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`MR. LEVY: Nicotine is shown in the Ebert reference
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`in a transdermal to require an antioxidant because of its oxidation
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`issue.
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`Dr. Schöneich has indeed testified that nicotine, a prior
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`art compound, would be the type of compound one of skill in the
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`art would look at because of its similar structure. We have not
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`cited a reference, that is correct, that shows rivastigmine and
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`nicotine together side by side.
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`JUDGE PRATS: Thank you.
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`MR. LEVY: The principles on slide 17 are --
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`underlying the analysis is that oxidation involves breaking a
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`covalent chemical bond resulting in the formation of a radical.
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`Radicals are molecules with an unpaired electron that are formed
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`by breaking a chemical bond. Now, some chemical bonds are
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`weaker than others, depending on the structural context in the
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`molecule. We refer to it as the electronic neighborhood of that
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`particular atom. And thus, those bonds are more prone to
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`oxidation. Now, a drug molecule containing a chemical bond is
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`prone to oxidation and can lead to degradation of the drug.
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`On slide 18 I have one of the first principles I wanted to
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`illustrate. This is the notion of increasing the number of moieties
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`on the carbon to make it a tertiary radical, increasing its stability.
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`As you move left to right, the carbon, as it gains more
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`nonhydrogen entities becomes more stable. That allows the bond
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`to become weaker and the hydrogen that would be attached at that
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`IPR2014-00549 and IPR2014-00550
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`carbon would be easier to break. And this is shown in the prior
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`art. This is Exhibit 1007 from our papers.
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`The first four entries in that table are disclosing bond
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`association energies which is a measure of bond strength. The
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`higher the number, the stronger the bond. The first four entries
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`show the progression that was on slide 18. As you increase the
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`number of carbons attached to that central carbon, the
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`carbon-hydrogen bond becomes weaker. The bond association
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`energy goes down.
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`But a more important thing is illustrated in the seventh
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`entry that I have highlighted. When a phenyl group shown by the
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`pH, which is a benzyl group, the phenyl group attached to that
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`carbon has an even greater stabilizing effect, lowering the bond
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`association energy of that carbon even more. And that's
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`something we see in rivastigmine.
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`So here is the prior art teaching these basic principles
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`that the other prior art instructs you to consider when assessing a
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`molecule's stability.
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`JUDGE FRANKLIN: Exhibit 1007 is Kissel. And that
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`is relied upon for ground 4. So are you speaking in terms of
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`claim 8?
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`MR. LEVY: No. I'm trying to site to Carey &
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`Sundberg there. There may be a typographical error. I'm come
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`back to that, Your Honor.
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`IPR2014-00549 and IPR2014-00550
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`Slide 20 shows this influence of the benzene system, the
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`aromatic ring. The benzylic carbon, this central carbon here, is
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`immediately adjacent the aromatic system that has the weakening
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`effect on the carbon-hydrogen bonds. A benzylic carbon, by pure
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`definition, would be a carbon attached to a benzene ring. But
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`Dr. Schöneich has explained that benzylic can refer to an
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`aromatic system more broadly that is at least benzene-like, has
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`the same aromatic properties.
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`On slide 21 we see why this aromatic system has such a
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`stabilizing effect. When an electron becomes delocalized, it can
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`be shifted around the ring because of the aromatic system and the
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`electron passed around like a hot potato. That has a stabilizing
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`effect and explains the contribution of the aromatic system.
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`Slide 22 refers to an additional property, an additive
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`property that these immediately adjacent groups have. This table
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`from the prior art on slide 22 shows the relative reactivities of
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`some aromatic systems to oxygen. Again, this is from Carey &
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`Sundberg and we have cited it as Exhibit 1007.
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`Your Honor, in the different IPRs, 1007 took on a
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`different identity. In the '023 IPR, 1007 was Kissel. But in the
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`'031, which we have been using our controlling citation, 1007 is
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`Carey & Sundberg.
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`My point here in this table is that when the phenyl
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`group or the aromatic system is attached to three carbons at the
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
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`same time, it has the most reactivity towards oxygen. That's the
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`entry in the upper left-hand corner receiving the number 1.
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`The weakest system is when a benzene system or an
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`aromatic system is attached to a methyl group. That was the last
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`entry on the previous table I showed from slide 19. So slide 22
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`shows an ever increasing additive effect of these immediately
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`adjacent moieties favoring the stability of the central red carbon
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`which makes the carbon hydrogen bond that much weaker.
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`Slide 23, again, shows the rivastigmine molecule.
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`We've now learned about the influence of the aromatic ring and
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`the tertiary nature of the red carbon. Dr. Schöneich has also
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`testified that the tertiary amine that is immediately adjacent the
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`red carbon has additional, yet additional influence on stabilizing
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`that red carbon so it can become a radical and the
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`carbon-hydrogen bond easily broken.
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`On slide 24, again, the prior art ties this up nicely. The
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`prior art teaches that benzylic, allylic and tertiary positions are
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`especially susceptible to oxidation. Benzylic and tertiary
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`positions are both present on the rivastigmine molecule. This is
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`in the prior art, again, the Carey & Sundberg text.
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`Now, very important here is that the Patent Owners
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`have not disputed that rivastigmine's red carbon-hydrogen bond is
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`very weak based on the principles that we have discussed here.
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`The technical conclusion is unchallenged and I would like to
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`know that the material that I have presented on slides 10
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
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`through 24 was not of record or of evidence in that Watson
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`Federal Circuit case.
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`On slide 25, this is the nicotine molecule. And we have
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`said that the person of ordinary skill in the art would not just draw
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`conclusions alone from looking at the molecule. They would find
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`that that conclusion could be reinforced by similar molecules in
`
`the prior art. Nicotine was known to be susceptible to oxidation.
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`Slide 26, here on this slide nicotine has been assigned --
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`the moieties, the functional groups in nicotine have been assigned
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`the same color coding that we use for rivastigmine for purposes
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`11
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`of comparison. The important thing to note here is that the red
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`central carbon is attached to an aromatic system. It's called a
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`pyridine ring. It's not a benzene ring. It's got a nitrogen atom in
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`14
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`it. That's a pyridine ring. Dr. Schöneich has testified that the
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`pyridine ring provides the same stabilizing influence as a benzene
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`16
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`ring would. Therefore, these two compounds can be closely
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`compared. The red carbon is also attached immediately adjacent
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`18
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`to a tertiary amine in green and another carbon moiety in purple.
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`19
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`That same carbon, that red carbon in nicotine is a tertiary
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`20
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`immediately adjacent a tertiary amine and an aromatic system.
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`21
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`In slide 27 we show the side-by-side comparison more
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`22
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`clearly. This slide confirms that one of skill in the art, knowing
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`23
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`that nicotine is susceptible to oxidation, having already drawn the
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`conclusion about rivastigmine, this reinforces that conclusion.
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
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`JUDGE PAULRAJ: Wasn't -- if nicotine was known to
`
`be subject to oxidative degradation, we also have testimony in
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`evidence saying that prior art nicotine transdermal patches did not
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`include an antioxidant. Is that -- how do you resolve that issue?
`
`MR. LEVY: In the prior art, I believe there are nicotine
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`patches with antioxidant, that's the Ebert reference, and there are
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`marketed products containing nicotine patches that adopt a
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`different system for mitigating oxidation. Nicotine also has the
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`problem of photodegradation. So special packaging is often
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`10
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`employed to eliminate light and at the same time oxygen. So
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`11
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`sometimes in commercial products they choose a different
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`method and don't need an antioxidant as long as they are still
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`addressing oxidative degradation in some way.
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`On slide 28, I want to sum up the points that we have
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`addressed. The prior art instructed the artisan to make
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`16
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`assessments about a molecule's chemical and physical properties
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`17
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`during pre-formulation. The prior art taught that structural
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`features of affect bond strength and in turn, susceptibility to
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`oxidation. This reasonable expectation is confirmed by a
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`structurally similar compound, in this case nicotine, in the prior
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`art. And Dr. Schöneich concluded that the person of ordinary
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`22
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`skill would have predicted rivastigmine's susceptibility to
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`23
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`oxidative degradation based on the molecule's chemical structure.
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`24
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`I would like to now turn to the prior art that is the basis
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`for the IPRs. This Enz reference on slide 30, there's no dispute
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
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`that the Enz reference discloses everything in claim 1 of the two
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`respective patents except the antioxidant. It discloses the
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`structure of rivastigmine from which a person of ordinary skill
`
`would have known of rivastigmine's susceptibility to oxidation.
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`It discloses a therapeutically effective amount of rivastigmine and
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`it discloses an unfinished formulation containing rivastigmine in
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`a polymer for transdermal delivery.
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`The next important piece of prior art is the Handbook of
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`Pharmaceutical Excipients. I'm on slide 32. The Handbook
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`discloses the variety and conventionality of antioxidants as a
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`pharmaceutical excipient. It also confirms that the person of
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`ordinary skill in the art would not have been discouraged from
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`using an antioxidant. There are so many identified in the
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`Handbook, they are a common excipient. There is not a credible
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`story to be told that someone of skill in the art would be
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`discouraged from using such a conventional excipient.
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`And the Handbook confirms that antioxidants are
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`actually being used and safe. Many of the -- all of the
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`antioxidants claimed in the '031 and '023 patents are set forth in
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`the Handbook and they are identified as safe or GRAS listed,
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`generally regarded as safe.
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`The next important reference is Rosin. I'm on slide 34.
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`Now, Rosin discloses a series of compounds that have been
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`engineered to have greater in vivo activity than the prior art
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`IPR2014-00549 and IPR2014-00550
`Patents 6,316,023 B1 and 6,335,031 B1
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`compound, namely a compound called physostigmine that you've
`
`read a lot about.
`
`Rosin discloses what is called an RA series. They
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`assign numbers to these new novel compounds. One of them was
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`RA7 that's shown in red. That is racemic rivastigmine. The
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`rivastigmine molecule is part of RA7. It's the racemate. And
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`there is experimental data for a number of the compounds
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`disclosed. And in fact, preferences are called out in the patent for
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`the most successful biologically active compounds that were
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`measured. RA7 is among them. In fact, that patent only claims
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`three species disclosed in the whole patent, and RA7 is one of
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`them.
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`It's also noted in Rosin that preferred antioxidants for
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`use with the compounds of the present invention include sodium
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`metabisulfite and ascorbic acid. Not just any antioxidants. They
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`specifically call out preferred antioxidants to be used with the
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`compounds of the invention.
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`JUDGE PAULRAJ: Why should we read Rosin
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`19
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`differently than how the Federal Circuit and the District Court
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`20
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`read? You quoted one sentence here for antioxidants but the
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`immediately prior sentence that the Federal Circuit focused on
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`said that antioxidants can be incorporated as required. And of
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`course, the reading in the Fed Circuit was that we don't know if
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`it's required. So we don't know if we want to use antiox
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