`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`ELI LILLY AND COMPANY
`Petitioner
`
`v.
`
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH
`Patent Owner.
`
`__________
`
`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
`RECORD OF ORAL HEARING
`Held on November 22, 2019
`__________
`
`
`Before JENNIFER MEYER CHAGNON, JAMES A. WORTH, and
`RICHARD J. SMITH, Administrative Patent Judges.
`
`
`
`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
`
`APPEARANCES:
`
`ON BEHALF OF THE PETITIONER:
`
`
`WILLIAM B. RAICH, Ph.D., ESQ.
`PIER D. DEROO, ESQ.
`of: Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
`901 New York Avenue, NW
`Washington, D.C. 20001-4413
`(202) 408-4000 (Raich)
`(202) 408-4418 (DeRoo)
`william.raich@finnegan.com
`pier.deroo@finnegan.com
`
`
`ON BEHALF OF THE PATENT OWNER:
`
`
`DEBORAH STERLING, Ph.D., ESQ.
`OLGA PARTINGTON, Ph.D., ESQ.
`Sterne, Kessler, Goldstein & Fox, PLLC
`1100 New York Avenue, NW
`Washington, D.C. 20005
`(202) 772-8501 (Sterling)
`(202) 772-8626 (Partington)
`dsterling@sternekessler.com
`opartington@sternekessler.com
`
`
`
`
`The above-entitled matter came on for hearing on Friday,
`
`November 22, 2019, commencing at 1:00 p.m. at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
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`2
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
`
`
`
`
`P-R-O-C-E-E-D-I-N-G-S
`
`1:01 p.m.
`JUDGE SMITH: Good morning, welcome. I'm Judge
`Richard Smith. To my right here is Judge Jennifer Chagnon. To my
`left is Judge James Worth. This hearing is the oral argument on six
`cases between Petitioner, Eli Lilly and Company, and Patent Owner,
`Teva Pharmaceuticals International GmbH.
`I will now read in the six cases for the record with the
`corresponding patent numbers. The first is IPR2018-01422, Patent
`No. 9,340,614. Second is IPR2018-01423, Patent No. 9,266,951. The
`third is IPR2018-01424, Patent No. 9,346,881. The fourth is
`IPR2018-01425, Patent No. 9,890,210. The next one is
`IPR2018-01426, Patent No. 9,890,211. The last one is
`IPR2018-01427. That's Patent No. 8,597,649.
`We note that Patent Owner filed several papers yesterday
`evening that included a request for a stay of these proceedings. We
`are proceeding today with oral argument, as scheduled. We'll start
`with introductions. Counsel for Petitioner, if you could introduce
`yourself.
`DR. RAICH: Good afternoon Your Honors, Bill Raich, of
`Finnegan, presenting for Petitioner Eli Lilly and Company. I have a
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
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`number of counsel with me today, including, at counsel table, Pier
`DeRoo and Yieyie Yang. There are also representatives from Eli
`Lilly and Company that have come here to be here today, including
`Mark Stewart, Sanjay Jiuraj, and Jerry Keleher.
`JUDGE SMITH: Thank you. Patent Owner.
`DR. STERLING: Good afternoon, Your Honors. My name is
`Deborah Sterling. I'm from Sterne, Kessler, Goldstein & Fox. I'm
`here on behalf of Patent Owner, Teva Pharmaceuticals International
`GmbH. I'm joined at counsel's table by Olga Partington, also from
`Sterne Kessler. I have with me, from Teva Pharmaceuticals, Lori
`Wolfe and Alastair Sayce.
`JUDGE SMITH: Thank you.
`DR. STERLING: Thank you.
`JUDGE SMITH: As you know, pursuant to our order of
`October 31, 2019, each party has 60 minutes to present its arguments.
`Petitioner has the burden of proving unpatentability of the claims, so
`you will proceed first, followed by Patent Owner. Petitioner may
`reserve time for rebuttal, and Patent Owner may reserve time for
`surrebuttal. To the extent either party wants to argue any motions,
`they may do so during their allotted 60 minutes. Likewise, to the
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
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`extent either party wants to respond to any arguments about motions,
`they may do so during their allotted 60 minutes.
`During your presentations, please remember to clearly identify
`any demonstrative exhibits, such as by slide or screen number. This
`will ensure clarity and accuracy of the transcript. Please refrain from
`interrupting either party while they're presenting their case. If you
`have objections, you may raise those during your own allotted time
`for argument. This hearing is an open hearing. It's open to the public.
`Therefore, please refrain from disclosing any confidential
`information. On that score, we actually have, as I understand it,
`someone viewing the hearing from our San Jose regional office. Mr.
`Raich, would you like to reserve time for rebuttal?
`DR. RAICH: Yes, 15 minutes, please.
`JUDGE SMITH: You may proceed when you're ready.
`DR. RAICH: Your Honor, we have printed copies of our
`demonstratives. If you would like, may we approach and provide
`them?
`
`JUDGE SMITH: Thank you, yes.
`DR. RAICH: I'm here to tell you today that the challenged
`claims would have been obvious. The prior art discloses all elements
`of the claims. The prior art provides an express statement of
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
`
`motivation to explore humanized antibodies. The prior art provides a
`reasonable expectation of success. Indeed, Teva does not contest
`there's a reasonable expectation of success to make a humanized
`antibody. In an attempt to avoid strong showing of obviousness, Teva
`manufactures problems that are irrelevant to the claimed subject
`matter, antibodies, and unsupported by the prior art. We're going to
`walk through that today.
`Teva also attempts to raise secondary considerations to
`counter the strong prima facie case, but has a significant problem
`because their claims are too broad and there's no nexus. So let's get to
`it. Slide 4. The challenged claims are very broad. These are
`functional claims. They have no meaningful structural requirement.
`Slide 4 shows representative claims. These are claims one from the
`614 patent and the 649 patent. These claims claim human or
`humanized monoclonal anti-CGRP antagonist antibodies with known
`or routinely achievable features.
`For example, the 614 patent claims an antibody that
`preferentially binds to human CGRP, as compared to amylin. The
`649 patent contains an affinity limitation that's consistent with known
`antibodies measured using a technique standard in the art. Slide 5,
`turning to the prior art. Tan 1995, Exhibit 1022, discloses the use of
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
`
`an anti-CGRP antagonist monoclonal antibody called MAb C4.19.
`This antibody specifically bound to CGRP with high affinity. It was
`reported not to cross-react with amylin, as shown on the slide.
`JUDGE WORTH: Are you relying on the antibody or the
`antibody fragment?
`DR. RAICH: We're principally relying on the antibody, not
`the fragment. We have arguments in our petition relating to the
`fragment that we'll stand on, but our argument relates to the
`full-length antibody.
`JUDGE WORTH: Okay, so how do you respond to Patent
`Owner's argument that you're just not relying on the fragment?
`DR. RAICH: Again, our principal argument is that we are
`relying on the full-length antibody, not the fragment. The fragment is
`within the scope of many of the claims, but our arguments are
`centered on the full-length antibody.
`JUDGE SMITH: Counsel, is it your position that there would
`be a reason to humanize the fragment?
`DR. RAICH: A person would have been humanized
`to -- would have been motivated and would have expectations of
`success to humanize a fragment or a full-length antibody, any
`antibody that was intended, ultimately, to be used therapeutically.
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
`
`Tan, in addition to reporting that MAb C4.19 does not cross-react, it
`also shows in vivo activity, shown in the top. The study has clearly
`demonstrated the ability of the full-length antibody, as well as its Fab
`fragment, to block the hypotensive effects, the blood pressure
`lowering effects, of CGRP in vivo. Slide 6.
`Tan also discloses experiments with a rat saphenous nerve
`model. What Tan discloses is that the full-length antibody at 1 mg per
`rat, given 60 minutes before a nerve stimulation, did not block skin
`blood flow. A dose of 3 mg per rat, at 60 minutes, did not block skin
`blood flow. But when they looked at two hours with the 3 mg per rat
`dose, it produced a decrease in area under the curve, but not by more
`than 16 percent, so there was a trend toward some activity.
`JUDGE WORTH: Was that significant?
`DR. RAICH: There's no indication in the paper, one way or
`the other, whether or not it was significant. I think a fair reading of
`the paper is that the sample size of two animals was too small to do
`statistics, so we haven't taken a position that it's statistically
`significant. We've just taken a position that it showed a trend and it's
`reported in the paper.
`JUDGE WORTH: Tan seems to be primarily suggesting
`further experiments with a fragment. How do you respond to that?
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
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`DR. RAICH: I think that Tan offers extensive guidance on
`using a full-length antibody. I think people in the field would have
`understood that full-length antibodies had real value, in terms of their
`therapy, because they have a longer half-life. While Tan is proposing
`experiments with the fragment, it's also discussing, at some length,
`experiments with the full-length antibody. In part, Tan is providing
`guidance. This is shown on Slide 7. This is for using full-length
`antibody. Tan says that you can use active immunization, chronic
`administration, repeated administration, larger doses, and longer
`distribution times. Those are ways of improving immunoblockade
`with the full-length antibody.
`JUDGE WORTH: That's not something that Tan did. That's
`just a map for further experimentation.
`DR. RAICH: That is true. Tan does not disclose his
`experiments, although I will say that moving the incubation time from
`one hour to two hours did produce the 16 percent result that was
`observed in the two animals.
`JUDGE WORTH: Should we be applying a lead compound
`analysis?
`DR. RAICH: No, I don't think a lead compound analysis is
`really the appropriate framework. In general, in the antibody arts,
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
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`what the science tells us is that people of skill in the art would take the
`antigen, CGRP, and generate their own antibodies, murinized
`antibodies, and then humanize those antibodies. I don't think the
`proper legal framework is necessarily a lead compound analysis.
`JUDGE WORTH: Is this briefed at all?
`DR. RAICH: We've discussed our theory of obviousness at
`great length. I don't think that we framed it in terms of a lead
`compound analysis.
`JUDGE WORTH: When you say we should take the ligand
`and then raise the antibodies against it, isn't that already framing,
`almost with hindsight, what the goal was, as opposed to raising
`antibodies against a receptor or using a small molecule against a
`receptor, or even having to choose between a fragment versus the
`full-length antibody?
`DR. RAICH: I don't think so at all. I think that they were all
`viable alternatives that were being considered. Wimalawansa says
`that you should explore humanized antibodies. The Tan thesis
`discusses making antibodies against the full-length protein or a
`fragment. We'll look at that later. I think that these are just different
`alternatives.
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
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`The fact that there were alternatives doesn't mean that one
`would be discouraged versus the other. These were all avenues that
`were described favorably in the prior art. There were real advantages
`of using full-length antibodies, as we briefed, in terms of its half-life
`and stability. When you're thinking therapeutically, I think a person
`of skill in the art in 2005 would have been thinking full-length
`antibodies.
`JUDGE WORTH: The Patent Owner picks up on this in their
`brief and says that's why a person of ordinary skill would not have
`pursued the fragment, also because --
`DR. RAICH: I --
`JUDGE WORTH: -- the fragment -- sorry -- also because the
`fragment has a shorter half-life.
`DR. RAICH: I think -- what we said in our briefing is it
`intends on the purpose that you're using it. There may be purposes
`where you don't care so much about half-life, where if you don't need
`the antibody or the drug to persist for a long period of time, where a
`fragment may be appropriate. There are also methods in the art for
`stabilizing fragments, where you can sort of get a -- take a fragment
`and then modify it in a way that makes it more stable. But again, our
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
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`principal theory is centered on the full-length antibodies because there
`were good reasons for using them.
`JUDGE WORTH: Patent Owner looks at this set of
`experiments and says okay, well, the fact that you would have to do
`these additional steps, which are laid out in the roadmap for further
`experimentation, indicates that you wouldn't want to use a full-length
`antibody because, at that point, if you're using, let's say, larger
`concentrations, then you're risking systemic effects, so that's why the
`better choice was the fragment. That's why Tan is talking about the
`fragment.
`DR. RAICH: I think there's an immense amount of art that
`indicates that those purported concerns about the systemic effects just
`weren't real concerns. I think that the benefits of using the full-length
`antibody far outweigh the concerns that wouldn't exist. Certainly,
`there weren't concerns that existed that would have deterred people
`from pursuing longer half-life compounds.
`That's what people were actually investigating. For example,
`we discussed the aptamers. Aptamers were compounds that were
`specifically targeting the CGRP ligand. They had half-lives on the
`order of hours to days, so people were making modified aptamers that
`had longer half-lives. Those were used against CGRP in the prior art.
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
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`That just shows that this dichotomy or these concerns about safety, in
`our view, would not have deterred development of a full-length
`humanized antibody.
`JUDGE WORTH: Against CGRP or against the receptor?
`DR. RAICH: Against CGRP, itself, against the ligand, not the
`receptor, against CGRP. That's Exhibit 1240, the Messlinger
`reference. One thing that we just want to point out. Tan provides this
`guidance. This an excerpt of Teva's patent. This is Example 3. What
`it shows, that in fact, the investigators in Teva's patent followed the
`advice of Tan. They used a higher dose. They used a longer time, 72
`hours, instead of one to two hours. It's our position that just doing
`what the prior art instructs is not inventive.
`Turning to Wimalawansa, this is Slide 9. Wimalawansa is a
`review article from 1996. It discusses, among other things, the
`therapeutic potentials of CGRP antagonists. Wimalawansa expressly
`states that the role of CGRP antagonists in humanized monoclonal
`antibodies should be explored. It's an express statement in the prior
`art that humanized antibodies should be explored.
`Wimalawansa does also state clearly, more data from carefully
`designed studies are necessary before any definitive conclusions can
`be reached and before CGRP antagonist humanized anti-CGRP
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
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`monoclonal antibodies, or both, can be evaluated as therapeutic agents
`in humans. Two responses to that. One is if you're going to do those
`tests, you need to make a humanized monoclonal antibody to do tests.
`That is what is actually claimed in these patents. Second of all, and I
`think this is very important, is that there were nine years of studies
`that showed that administering these compounds would be safe. I'm
`going to walk through some of that evidence today.
`JUDGE WORTH: You're saying the motivation is not to
`treat; the motivation is to create a research tool.
`DR. RAICH: I think, ultimately, the motivation to make a
`humanized antibody is to treat patients. But the claim is directed to
`antibodies. You would need to have that antibody in order to -- it's a
`potential therapeutic. You would need to do studies with it. A
`therapeutic doesn't become an actual therapeutic until it's approved by
`FDA. That's a very, very high bar. The motivation here is to develop
`a potential therapeutic. I think that we briefed that in our papers.
`JUDGE WORTH: Let's make it a yes or no question. Is it
`sufficient motivation to make a research tool?
`DR. RAICH: It would be, yes. For these claims, I think that it
`would be. Although, again, the claims are directed to humanized
`antibodies and, ultimately, the goal would be therapeutic use. But we
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
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`don't need to prove that the antibodies would be safe or effective.
`These are just claims directed to antibodies.
`JUDGE WORTH: Wouldn't that go to motivation, whether
`something has cardiovascular side effects, stroke? Wouldn't that go to
`motivation?
`DR. RAICH: I think that potentially, yes, it would go to
`motivation. If there was indication in the prior art that taught away
`from pursuing these antibodies, then I think that would be relevant in
`the consideration. That is not the case here. I want to emphasize that.
`I do want to go through those studies because I think it's very
`important.
`JUDGE SMITH: Counsel, before you do that, this sentence
`uses the term or phrase or both. It seems to me that Petitioner is
`reading that as if it means if you're going to pursue either the blocking
`of the receptor or the binding to the ligand that you have to do tests on
`one of them or both of them. Because I suspect where you're going
`with these tests -- there's an issue about well, these are not really
`antibodies that are binding the ligand, as far as the tests go. Is
`Petitioner reading or both that way?
`DR. RAICH: Yes, that's absolutely correct. I think that
`antibodies -- things targeting the ligand and things targeting the
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
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`receptor were, in fact, viewed as alternatives. There's multiple prior
`art statements that said you could do one or you could do the other.
`Evidence about the safety of a drug that targets the receptor when it is
`administered systemically, that is relevant to the motivation of
`pursuing an antibody, as well, that targets the ligand. Just very
`briefly, these are some of the studies that are post-Wimalawansa.
`There was a study with Doods. This is a study using the small
`molecule, BIBN, that binds to the receptor. What they stated, in view
`of their studies, is we expect CGRP antagonists -- not limited to the
`receptor, but CGRP antagonists will be effective anti-migraine drugs.
`This adds to the motivation that was available in the prior art. Moving
`beyond references in the combination, Slide 11, this is a discussion of
`Salmon. This is a publication from 2002. Salmon made a knockout
`mouse. Salmon deleted the CGRP gene, so it was gone.
`The mice were reported as healthy, fertile, and not presenting obvious
`abnormalities. What did Salmon do, in view of having eliminated all
`CGRP function? She actually disclosed and claimed monoclonal
`antibodies directed against CGRP for therapeutic uses, here,
`amelioration of neurogenic inflammatory pain. I'll skip it, in the
`interests of time, but on Slides 12 and 13, we have similar disclosures,
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
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`Sveinsson from 2004, the 438 patent from 2002, also disclosing the
`use of CGRP antibodies for therapeutic use.
`JUDGE SMITH: Counsel, in terms of these studies, I'm
`wondering is there any evidence in the record of a person actually
`making a humanized anti-CGRP antibody prior to the filing of Teva's
`patents?
`DR. RAICH: No, there's not evidence of a humanized
`anti-CGRP antagonist antibody. There is merely the disclosure that
`they should be explored and the statement of the Tan thesis.
`JUDGE SMITH: Thank you.
`DR. RAICH: I'm going to skip to Slide 16. I want to discuss
`the Olesen reference. Olesen is Exhibit 1025. This was a very
`important study. This was from 2004. It was a publication in the
`New England Journal of Medicine. It established proof of concept
`that antagonizing CGRP effectively treats migraine in human patients.
`This was a multi-center, double-blind, randomized, placebo-controlled
`clinical trial, involving 126 patients. The CGRP antagonist was
`systemically administered. In other words, it wasn't just limited to
`one part of the body. It wasn't just directed, for example, to the brain.
`It was systemically administered. What the investigators observed
`and reported is that it hit all efficacy endpoints, primary and
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
`
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`secondary, so they concluded that proof of concept was established.
`The CGRP antagonist, BIBN4096BS, was effective in treating acute
`attacks of migraine. This directly goes to motivation. This was a very
`significant study in the field, and it opened up the investigation of
`antagonizing CGRP.
`JUDGE WORTH: Doesn't Olesen also say that it couldn't
`assess the cardiovascular effects using that study?
`DR. RAICH: Let me turn specifically to that. I think that is
`an excellent question. If we could have Slide 23. I want to talk a little
`bit about what Olesen says about safety. Olesen, first of all, reports
`that the compound caused only minor adverse events, had no
`constrictor effect. It had no effects in all of these different
`measurements that are on the slide. They said it is the first
`migraine-specific medication that is not a vasoconstrictor. Further, to
`your point, Slide 24, it confirmed the favorable and safety tolerability
`results.
`Now, they did say, to get the quote correct, that BIBN does
`not seem to have vasoconstrictor properties, but our database was too
`small for us to assess cardiovascular safety. They asked our expert,
`Dr. Charles, about this. They said isn't the point that the reader would
`say I don't know if this is safe or not based on the data sample that I
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
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`have here? He said no, I think the reader would be reassured by the
`fact that there were no demonstrable changes in heart rate, blood
`pressure, and there were no vascular adverse events reported. We
`can't determine to a fault that there is no possible risk, whatsoever, but
`the point is that all of the evidence, the evidence in Olesen, the
`evidence in two other human clinical trials, the evidence in numerous
`animal experiments, all showed that there was no concern. If I could
`move to Slide 21, this is a timeline that Dr. Charles prepared that
`we've adopted for the slide. In terms of discussing the safety
`concerns, the references on the left-hand side are primarily the
`references that Teva is relying on.
`They fall into what I would consider three buckets. There are
`observational studies, where people just looked at the levels of CGRP
`and speculated as to potential roles for CGRP. There are studies
`involving exogenous administration of CGRP, where CGRP was
`infused into the animals, typically, sometimes the people, and they
`look at the effect of adding CGRP.
`But that doesn't tell you what happens when you antagonize
`the pathway, when you inhibit CGRP. There were indiscriminate
`modifications that would affect not just CGRP, but a bunch of
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
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`different neuropeptides. You can't really figure out what it is that
`CGRP is doing.
`After about 1998 -- these are the references that they did not
`consider shown in pink -- there were multiple different studies in
`animals and in humans. Time after time after time, from antagonizing
`the pathway, no effect was seen, ill effect, not a vasoconstrictor,
`without cardiovascular side effects. This is the aptamer that I
`mentioned. This is targeting CGRP, itself, not the ligand, that the
`blood pressure was unchanged. This included, as I mentioned, human
`clinical trials, Exhibit 1025, 1042, and 2019. It also included animal
`studies. In these animal studies, specifically Exhibits 1283, 1284 and
`1285, they stressed the animals. They generated ischemic conditions.
`They actually generated myocardial infarction in these animals and
`asked, what is the effect of inhibiting the CGRP pathway? In every
`instance, the answer was mild effects or no effects. Slides 71 to 81,
`I'm obviously not going to walk through them, go through a lot of
`these references and show the evidence that I've been telling you
`about and walk through the testimony.
`I encourage you to look at that if you have any questions about
`it. It is fundamentally our position that these drugs would have been
`viewed as sufficiently safe so as not to deter further research. If
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
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`anything, the opposite; they would have encouraged additional
`research.
`JUDGE SMITH: Counsel, how difficult is it to actually
`humanize an antibody like an anti-CGRP antibody? How difficult or
`time-consuming --
`DR. RAICH: It is undisputed that it would have been routine
`as of this time.
`JUDGE SMITH: Are we talking about half an afternoon of a
`scientist's time or what are we talking?
`DR. RAICH: I'm not sure I can speak to that specifically. It's
`more than that, but there's also no doubt that it was ultimately
`considered to be a routine technique. There was cost involved. There
`was time involved. There would be work involved. But it was
`routine.
`JUDGE WORTH: The brief's saying that, actually, more than
`one compound -- we're not talking about, necessarily, whether the
`compounds are covered by the claims, but more than one compound
`has picomolar affinity. Is it possible that is a different research tack
`than what Tan was talking about, in terms of increasing the
`concentration?
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`Case IPR 2018-01422 (Patent No. 9,340,614)
`Case IPR 2018-01423 (Patent No. 9,266,951)
`Case IPR 2018-01424 (Patent No. 9,346,881)
`Case IPR 2018-01425 (Patent No. 9,890,210)
`Case IPR 2018-01426 (Patent No. 9,890,211)
`Case IPR 2018-01427 (Patent No. 8,597,649)
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