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`IPR2016-00318, Paper No. 81
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`June 8, 2017
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`571-272-7822
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`NEPTUNE GENERICS, LLC,
`Petitioner,
`v.
`ELI LILLY & COMPANY,
`Patent Owner.
`
`
`SANDOZ INC.,
`Petitioner,
`v.
`ELI LILLY & COMPANY,
`Patent Owner.
`______________
`
`Cases IPR2016-00237, IPR2016-00240, IPR2016-00318
`Patent 7,772,209 B2
`______________
`
`RECORD OF ORAL HEARING
`Oral Hearing Held: March 16, 2017
`
`
`Before JACQUELINE WRIGHT BONILLA and MICHAEL P.
`TIERNEY, Vice Chief Administrative Patent Judges, LORA M.
`GREEN, Administrative Patent Judge.
`
`The above-entitled matter came on for hearing on Thursday, March 16, 2017
`at the U.S. Patent and Trademark Office, 600 Dulany Street, Alexandria,
`Virginia in Courtroom A, at 9:30 a.m.
`
`
`
`trials@uspto.gov
` IPR2016-00240, Paper No. 78
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`IPR2016-00318, Paper No. 81
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`June 8, 2017
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`571-272-7822
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`NEPTUNE GENERICS, LLC,
`Petitioner,
`v.
`ELI LILLY & COMPANY,
`Patent Owner.
`
`
`SANDOZ INC.,
`Petitioner,
`v.
`ELI LILLY & COMPANY,
`Patent Owner.
`______________
`
`Cases IPR2016-00237, IPR2016-00240, IPR2016-00318
`Patent 7,772,209 B2
`______________
`
`RECORD OF ORAL HEARING
`Oral Hearing Held: March 16, 2017
`
`
`Before JACQUELINE WRIGHT BONILLA and MICHAEL P.
`TIERNEY, Vice Chief Administrative Patent Judges, LORA M.
`GREEN, Administrative Patent Judge.
`
`The above-entitled matter came on for hearing on Thursday, March 16, 2017
`at the U.S. Patent and Trademark Office, 600 Dulany Street, Alexandria,
`Virginia in Courtroom A, at 9:30 a.m.
`
`
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`Cases IPR2016-00237, IPR2016-00240, IPR2016-00318
`Patent 7,772,209 B2
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`APPEARANCES:
`
` ON BEHALF OF THE PETITIONER NEPTUNE GENERICS, LLC:
`
` PAUL J. SKIERMONT, ESQUIRE
` SARAH E. SPIRES, ESQUIRE
` PARVATHI KOTA, PH.D., ESQUIRE
` SKIERMONT DERBY, LLP
` 2200 Ross Avenue
` Suite 4800W
` Dallas, TX 75201
` (214) 978-6604
`
`ON BEHALF OF PETITIONER SANDOZ INC.:
`
` LAURA A. LYDIGSEN, ESQUIRE
` BRYAN T. RICHARDSON, PH.D., ESQUIRE
` RALPH J. GABRIC, ESQUIRE
` BRINKS, GILSON & LIONE
` 455 N. Cityfront Plaza Drive
` NBC Tower - Suite 3600
` Chicago, IL 60611-5599
` (312) 321-4200
`
`ON BEHALF OF THE PATENT OWNER:
`
` ADAM L. PERLMAN, ESQUIRE
` DAVID M. KRINSKY, ESQUIRE
` DOV P. GROSSMAN, ESQUIRE
` WILLIAMS & CONNOLLY, LLP
` 725 Twelfth Street, NW
` Washington, DC 20005
` (202) 434-5244
`
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`ALSO PRESENT:
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` JOSEPHINE LIU, PH.D.
` PAUL M. ZAGAR, ESQUIRE
` GERARD A. HADDAD, ESQUIRE
` CYNTHIA LAMBERT HARDMAN, ESQUIRE
` TOM PARKER, ESQUIRE
` PATRICK KILGORE, ESQUIRE
` GARY SPEIER, ESQUIRE
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` P R O C E E D I N G S
` JUDGE GREEN: Welcome, everyone.
` I would like to remind everyone, please make sure
`all cell phones are turned off. Even leaving them on, they
`can interfere with microphones and, thus, interfere with the
`transcript of this proceeding. So, please, turn off all cell
`phones.
` This is the final oral hearing in IPR2016-00237,
`IPR2016-002240 and IPR2016-00318. These proceedings all
`involve Patent Number 7,772,209.
` At this time we would like counsel to introduce
`yourselves and your colleagues, beginning with petitioners.
` Neptune, do you want to start?
` MR. SKIERMONT: Paul Skiermont on behalf of
`Neptune.
` MS. LYDIGSEN: Laura Lydigsen on behalf of Sandoz,
`Inc., and with me I have Bryan Richardson and Ralph Gabric,
`also for Sandoz, Inc.
` MR. PERLMAN: Good morning, your Honors. Adam
`Perlman on behalf of Patent Owner Eli Lilly & Company. With
`me, to my left, is my colleague David Krinsky, and directly
`behind me are lead counsel Dov Grossman.
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` JUDGE GREEN: Okay. Thank you, all.
` Welcome to the board. Consistent with our
`previous order, patent owner and petitioners have 90 minutes
`to present their arguments. Petitioners will proceed first
`to present their case-in-chief as to the challenged claims
`and may reserve rebuttal time to respond to arguments made by
`patent owner. Our understanding is that petitioners will
`split the 90 minutes.
` Who will be proceeding first?
` MS. LYDIGSEN: Sandoz, Inc., your Honor, and we
`will be using 15 minutes for our initial argument and
`reserving 30 minutes for rebuttal.
` JUDGE GREEN: Okay. You do understand that you
`can only respond to something patent owner says. Your
`case-in-chief has to be presented initially. So, to the
`extent that you're not responding to something that patent
`owner said or doing something with regard to your
`case-in-chief, we may cut you off.
` MS. LYDIGSEN: I understand, your Honor.
` JUDGE GREEN: So you may lose argument time.
` MS. LYDIGSEN: I understand, your Honor.
` JUDGE GREEN: Okay. Thereafter, patent owner will
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`respond to petitioners' case.
` We do note that we will take an approximately
`ten-minute recess between petitioners' case-in-chief and
`patent owner's presentation, given the length of the hearing
`today.
` Counsel for Sandoz, you may proceed. So, you're
`taking 15 minutes and reserving 30?
` MS. LYDIGSEN: That's correct. I also wanted to
`note that there are several enjoiners who are in the audience
`for our petition.
` JUDGE GREEN: If you would like to introduce them,
`that's fine.
` MS. LYDIGSEN: Yes. We have Cynthia Hardman from
`Goodwin Procter for Fresenius Kabi USA LLC; Tom Parker from
`Alston & Bird for Mylan Pharmaceuticals; Patrick Kilgore from
`Rakoczy, Molino, Mazzochi & Siwik LLP for Apotex Corp. and
`Apotex, Inc.; and Gary Speier from Carlson, Caspers,
`Vandenburgh & Lindquist for Teva.
` JUDGE GREEN: Okay. Thank you.
` MR. PERLMAN: May I raise one issue before Sandoz
`begins, your Honor?
` JUDGE GREEN: Yes, please.
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` MR. PERLMAN: My understanding is that after
`Sandoz gives its opening argument, Neptune intends to present
`an opening argument.
` JUDGE GREEN: That's my understanding, as well.
` MR. PERLMAN: Okay. Thank you.
` JUDGE GREEN: And that is correct?
` MS. LYDIGSEN: That's correct, your Honor.
` This case presents a straightforward issue of
`obviousness. The question is whether it would have been
`obvious to add vitamin B12 to a known folic acid pretreatment
`regimen for the known cancer drug pemetrexed prior to
`June 1999. The answer is yes, it would have been obvious at
`that time.
` The board's institution decision was correct as to
`the obviousness of adding vitamin B12. First, the inventor's
`own abstracts published more than a year prior to the
`earliest possible priority date for the '209 patent disclosed
`a link between pemetrexed toxicity and homocysteine levels.
` Second, at the time of June 1999, it was
`well-known that the way to lower homocysteine was by adding
`both folic acid and vitamin B12. The benefits of adding both
`folic acid and vitamin B12 were well-known by June 1999 and
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`were taught by numerous references, including the Calvert
`review article, which is Exhibit 1007 in the Sandoz matter,
`and a European patent publication that we call EP005, which
`is Exhibit 1033 in the Sandoz matter.
` The EP005 expressly teaches that treating with
`vitamin B12 and folic acid will result in lowering
`homocysteine levels more than folic acid or B12 alone.
` From the teachings of the Niyikiza abstracts,
`Calvert, and the EP005 reference, the person of ordinary
`skill would have been motivated to add vitamin B12 to the
`known folic acid pretreatment regimen prior to June 1999 and
`would have had a reasonable expectation of success in
`treating a patient's cancer with that regimen.
` I'd like to turn to slide 12. Actually, can you
`take me to the slide that's got the overview of the claims,
`Bryan? It's actually slide 8.
` So, just to give some context, there are generally
`three requirements for these claims. This is claims 12
`through 22. There are 22 claims in the patent. Claim 1 and
`12 are independent. Claim 12 is the narrower of those two.
`And, so, if these claims are obvious, claims 1 through 11
`will be obvious, as well.
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` The three requirements are pemetrexed disodium,
`which is in green there, and then there's also folic acid
`required, part of the pretreatment regimen, in red, and
`vitamin B12 in blue, and we've also kind of boxed in gray the
`dosing and scheduling limitations, which we'll also be
`talking about today.
` Go to slide 24. The folic acid pretreatment
`regimen was well-known in June 1999. Lilly's own
`publications, the Hammond and Worzalla studies, disclose the
`usefulness of using folic acid pretreatment with pemetrexed
`at that time.
` This is the Hammond -- these are the Hammond
`abstracts on slide 24. In these abstracts, the study authors
`describe the results of a phase one clinical trial in which
`scientists use folic acid to offset toxicities caused by
`pushing the dose of pemetrexed above the known maximum
`tolerated dose or MTD of prior studies. The authors
`concluded folic acid supplementation appeared to permit
`pemetrexed dose escalation by ameliorating toxicity.
` There's more disclosure of folic acid pretreatment
`conditioned to the Hammond abstracts though. The Worzalla
`mouse study, which is slide 40, in this full paper, the
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`authors concluded after pretreating mice with folic acid that
`folic acid supplementation was demonstrated to preserve the
`antitumor efficacy of pemetrexed while reducing toxicity.
`The combination of folic acid and --
` JUDGE GREEN: But none of these references mention
`B12; right? So the only thing that you're going on for B12
`is the 005, EP005?
` MS. LYDIGSEN: Well, it's not the only thing.
`That's certainly one reference that teaches using vitamin B12
`though. This is just going through the folic acid
`pretreatment portion.
` JUDGE GREEN: That's fine.
` MS. LYDIGSEN: But the authors did conclude in
`Worzalla that the combination of folic acid and pemetrexed
`would provide a mechanism for enhanced clinical antitumor
`selectivity. So the authors themselves in the abstract of
`the article concluded that folic acid pretreatment worked
`with pemetrexed and it both preserved the antitumor -- the
`antitumor efficacy and also reduced toxicity.
` Let's move on to vitamin B12. If you could go to
`slide 55. Here we have the Niyikiza abstracts. These are
`the author's -- the inventor's own abstracts that were
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`published in 1999, which is -- or 1998, excuse me, more than
`a year prior to the priority date of the patent. In these
`abstracts, Niyikiza establishes a link between pretreatment
`homocysteine levels and pemetrexed toxicity.
` He says in the highlighted portions the toxicity
`was seen in all patients with homocysteine levels above a
`threshold concentration of 10 micromolar.
` Now, there are two -- there are two abstracts
`here, and a lot of the prior art in this case involves these
`abstracts. There generally were two meetings of oncologists
`in this time period, one in America, and that would be -- the
`abstracts would be published in ASCO. That's usually the
`earlier of the two, spring time frame. Niyikiza II is
`actually from ASCO. It's the earlier abstract. And the
`Niyikiza I is the later abstract, which was published as a
`result of the European meeting, ESMO, in the annals --
` JUDGE WRIGHT BONILLA: Just to clarify, these two
`references don't talk about vitamin B12. They talk about
`increased homocysteine but not B12 itself.
` MS. LYDIGSEN: They do not use the words "vitamin
`B12," no, but --
` JUDGE WRIGHT BONILLA: The ordinary variation,
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`though, we should know about.
` MS. LYDIGSEN: No, they do not. But they use --
`they mention homocysteine as being the link to pemetrexed
`toxicity, and the person of ordinary skill would have the
`knowledge that vitamin B12 is an important part of lowering
`homocysteine levels.
` JUDGE GREEN: How about patent owner's argument
`that in the -- and I apologize if I butcher any of these
`names-- Niyikiza II, that the MMA levels stayed the same or
`not correlated with the toxicity and, therefore, you -- since
`MMA is -- correlates to B12 deficiency, one would not have
`added B12 to this mix?
` MS. LYDIGSEN: That's the language highlighted in
`pink on the slide, right. Let's -- I think Calvert is
`probably the most powerful rebuttal to that, and that's slide
`52. So, this is -- this is an article, a review article,
`that was published shortly after the Niyikiza abstracts in
`which the author, an oncologist, cites to the Niyikiza
`abstracts. And he says that any functional deficiency in
`either B12 or folate will result in a reduction in the flux
`through methionine synthase. And then he goes on to say that
`for pemetrexed specifically, the pretreatment levels of
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`homocysteine are a way to prevent toxicity. So he ties the
`B12 and the folic acid together. And if we go to the next
`slide --
` JUDGE GREEN: But he says, "B12 or folate," he
`doesn't say, "and," "or," or anything else. And I don't know
`that that rebuts patent owner's argument that it was MMA that
`was known to be the indicator for B12 deficiency and not the
`homocysteine.
` MS. LYDIGSEN: He says a reduction in either one
`is going to cause elevated homocysteine, which means that you
`have to have both, adequate levels of both, in order to lower
`homocysteine levels.
` I think if you go to the slide 53 where we're at,
`he shows this pictorially in figure 8, which is his cite for
`the first sentence there. And it shows that in order to have
`methionine synthase convert homocysteine to methionine, you
`need to have both B12, because it's a cofactor for methionine
`synthase, and also you have to have folic acid, because
`that's what the -- it pulls the carbon from.
` JUDGE GREEN: But if it was so well-known -- I
`mean I guess -- I know this is kind of an anticipation
`argument, but if this was so well-known that -- and I do know
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`that this particular cycle was known and everything else, the
`metabolism was understood, why did they suggest -- why did
`the articles, Hammond and the "W" one -- why did they only
`suggest folic acid and why not B12 if this was such a
`well-known -- you know, the way this was metabolized?
` MS. LYDIGSEN: The answer is the Niyikiza
`abstracts in 1998. They already kind of -- they already
`figured out that folic acid was helping patients,
`pretreatment with folic acid, but when the Niyikiza abstracts
`came out in 1998, it kind of explained why the folic acid was
`working. It was because of the homocysteine levels. And
`once you knew that the homocysteine levels were the key, you
`knew that you needed to look at B12, as well.
` JUDGE GREEN: And this is Calvert is what you're
`relying on to look at the B12?
` MS. LYDIGSEN: It's one of the pieces. There
`is -- in some of the -- going back to that sentence that we
`highlighted in red, the one that Lilly relies on to say that
`there's no correlation with -- between B12 and
`homocysteine -- or pemetrexed toxicity that was known, I
`think if you look at that sentence -- and if you can go to
`slide 56, Bryan -- there's another sentence a few lines above
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`that we highlighted in green where a different marker,
`cystathionine -- Niyikiza actually said, "Look, there was no
`correlation for cystathionine."
` And he notes that there was no correlation with
`the hematologic toxicity but there was with fatigue. So,
`cystathionine was acting differently than the homocysteine.
`So, he actually says, "Look, you know that the -- you knew
`that that was not colinear. You could make a conclusion
`there was no correlation." He was kind of definitive about
`that.
` Whereas, with the other factors, he doesn't say
`that. He just says, "Look, I haven't seen it yet." And from
`that, what -- the next slide, Bryan, 57 -- both Drs. Chabner
`and Dr. Zeisel said, "Look" -- in this proceeding, at
`least -- I don't know if this happened in the Tava v. Lilly
`proceedings -- they said, "Look, you can't say from that
`sentence from the Niyikiza abstracts one way or the other
`whether or not there was -- B12 was -- you know, was
`correlated." You can't conclude it wasn't from that
`abstract. And knowing what you know about the biochemistry,
`which is what Dr. Schiff tells you, you would know that you
`need to add the B12, as well.
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` JUDGE WRIGHT BONILLA: So your position is the
`fact that it says no correlation was seen doesn't mean that
`there isn't a correlation.
` MS. LYDIGSEN: Well, evidence -- absence of
`evidence is not the same thing as evidence of an absence, and
`that's how a scientist reading this -- that's how they would
`understand it. He hadn't come to that conclusion yet. And
`knowing the biochemistry and the fact that B12 and folic
`acid -- B12 and homocysteine are tied together, you would
`understand as a person of ordinary skill in June 1999 that
`there could be a colinearity issue here that would preclude
`you from drawing that conclusion.
` And, in fact -- if you go to the next slide,
`Bryan -- that's exactly what Lilly told the FDA subsequently
`when they summarized the Niyikiza II studies. They said --
`or both the Niykiza studies. They noted that, "In the
`analysis above, the B12 deficiency marker, methylmalonic
`acid, was highly correlated with homocysteine and was
`therefore removed from the initial multivariate analysis
`conducted in 1998 to eliminate issues of colinearity."
` In this particular document, while it was -- it
`was used in district court, this particular page of the
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`document was not before the federal circuit and the Teva v.
`APP appeal was not an appendix. So I don't know that Teva
`made this argument, but it certainly wasn't at the appellate
`level.
` JUDGE GREEN: Now, going back to Niyikiza, patent
`owner also argues that the homocysteine levels about 10
`micromolar are not necessarily abnormally elevated and that
`the '005 patent teaches a cutoff of 16.3 micromolar. So,
`would one looking at homocysteine levels of 10 micromolar
`looked to the EP005?
` MS. LYDIGSEN: Yes. A person of ordinary skill --
`and I don't think we have a slide on this, but Dr. Schiff
`testified to it -- would understand that the cutoff for
`what's elevated to very -- on MMA levels varies by lab. So,
`for one lab, you might say 10 micromolars was the cutoff; for
`another, you might say it's 16. Regardless, the EP005
`teaches how to lower homocysteine levels, period, whether
`it's 16 or 10. It doesn't -- it would apply equally to --
`regardless of what the cutoff is.
` JUDGE GREEN: And do you know where that reliance
`on Dr. Schiff's testimony is in your papers? You don't have
`to answer right now; you can have your colleague look for it,
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`but if you could tell me where that is in your papers, I'd
`appreciate it.
` MS. LYDIGSEN: We can certainly look that up, and
`I can bring that to you in rebuttal.
` JUDGE GREEN: Okay. Thank you.
` MS. LYDIGSEN: I'd like to talk about the EP005,
`if I may. This is slide 66. So, the EP005 teaches a method
`for reducing homocysteine levels using both folic acid and
`vitamin B12. And it says that this -- this method using both
`of those -- both of those vitamins can be used across a wide
`array of different disciplines. It says, "whatever cause."
` Slide 67. It goes on further to indicate that
`some of the causes of homocysteine levels could be
`methotrexate, and suggests that this vitamin regimen would be
`useful for treating cancers.
` The EP005 also discloses specific dosages.
` JUDGE GREEN: But I'm looking at your slide 67,
`and the drugs which induce elevated homocysteine include
`methotrexate, and that's at page four, and the statement
`about the situations in blood homocysteine levels may be
`elevated are the following, which is the cancer. But they're
`not talking about the treatment in cancer at page nine,
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`they're talking about the cancer itself causing homocysteine
`levels -- increases in homocysteine levels; correct? I mean
`that's how I read that.
` MS. LYDIGSEN: Yes, I think that's what they're
`saying, but it indicates that for people who have cancer,
`using these vitamins would be useful. And one of the ways --
`one of the things that Lilly argues in this case is that no
`one would ever think to add folic acid and vitamin B12
`because they would think it would -- feeding the cancer would
`be bad for patients with cancer. But, in fact, here we have
`the EP005 saying just the opposite, that patients with
`cancer, this is something that you should be giving them.
` JUDGE GREEN: Well, I don't know if it's -- I mean
`I think you're reading an awful lot into one statement from a
`long reference.
` MS. LYDIGSEN: There -- there are additional
`references that back it up, as well.
` JUDGE GREEN: No, I understand that. But as to
`EP005, I think -- and I think a lot of it ties, especially as
`to what was not argued and what the evidence wasn't before
`the district court and what wasn't before the federal
`circuit -- I think a lot of that rests on the EP005. So, I
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`think we have to be -- we have to look at how this -- what
`this actually teaches.
` JUDGE WRIGHT BONILLA: Can you talk about that a
`little bit, the distinction between what we're seeing here
`and what was before district court and the federal circuit.
`Is it correct that the EP005 is the primary difference
`between what they were considering before and what we're
`considering now?
` MS. LYDIGSEN: It is -- it is one difference. And
`in terms of the references in the grounds, I think it's the
`primary difference. There are a number of other secondary
`references that were not considered by the district court or
`the federal circuit. The EP005 -- it does --
` JUDGE WRIGHT BONILLA: Is there anything -- is
`there any subject matter in the secondary references you're
`talking about that's actually relevant to our analysis?
` MS. LYDIGSEN: Yes. Two that come to mind are the
`Nonprescription Physician's Desks Reference. That is a U.S.
`Physicians' Desk Reference that -- I see the amount of time.
`May I answer the question?
` JUDGE GREEN: Go ahead and answer the question.
` MS. LYDIGSEN: That --
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` JUDGE WRIGHT BONILLA: Can you tell us the exhibit
`number for that, again, please.
` MR. RICHARDSON: 1106.
` MS. LYDIGSEN: It's 1106 and it's on slide 84. It
`says, "Cancer may be treated with chemotherapeutic agents,"
`and then suggests vitamins, including ones that have both
`folate and vitamin B12.
` In addition, the Carrasco reference was not
`discussed by the district court and the federal circuit, and
`that is a patient who was actually given both antifolate and
`vitamin B12 and peme -- vitamin -- not pemetrexed, he was
`given methotrexate as an anti -- methotrexate -- but he was
`given both vitamin B12 and folic acid.
` Also, Tisman is a reference that was not before
`the district court or the federal circuit. That was a
`patient who was given the antifolate 5 fluorouracil, 5 FU --
`or not just a patient, it was a study. It was a whole study.
`The patient was given this 5 FU and also B12 and folic acid.
` JUDGE GREEN: But these are all references that
`are kind of relied on back -- not necessarily relied upon in
`your challenges.
` MS. LYDIGSEN: They are not in the grounds but
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`they are part of the background knowledge, the prior art.
` The last thing I'd like to point out is the Farber
`reference, which the district court did cite, but I think the
`district court misread it, and there's been additional
`testimony in this case that, actually, far from teaching away
`from adding folic acid and vitamin B12, Dr. Farber, even back
`in 1948, was giving both folic acid and vitamin B12 to
`counteract toxicities in patients.
` JUDGE GREEN: And then was the '974 reference used
`both in the obviousness ground, as well as the obvious double
`patenting or was it just considered as to -- obvious to
`patenting --
` MS. LYDIGSEN: At the district court?
` JUDGE GREEN: Yeah.
` MS. LYDIGSEN: I don't know the exact answer to
`that question, whether or not it was considered in both. I
`thought it was considered as part of the obviousness analysis
`but I'm not sure it was given much -- it certainly doesn't
`show up much in the district court's opinion. So --
` JUDGE GREEN: Okay. Thank you. I will give you
`29 minutes on rebuttal.
` MS. LYDIGSEN: Thank you.
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` JUDGE GREEN: Good morning. Would you like to
`save time for rebuttal?
` MR. SKIERMONT: Good morning, your Honor. Yes,
`I'd like the same, reserve 30 minutes for rebuttal.
` JUDGE GREEN: Again, I warn you that to the extent
`that you're going over your case-in-chief and not responding
`to what patent owner says, we will cut off that argument --
` MR. SKIERMONT: I understand, your Honor.
` JUDGE GREEN: -- because this is the time to
`present your case-in-chief.
` MR. SKIERMONT: Thank you.
` As the board knows, Neptune petitioned for two
`grounds of obviousness that were both instituted. In the 237
`proceeding, the ground was Niyikiza with the '974 patent and
`EP005; and in the 240 proceeding, the combination was
`Rusthoven with EP005.
` The primary references in each ground disclose the
`claim elements of administering pemetrexed to a patient in
`need, administering pretreatment with folic acid and B12, and
`also discloses and overlaps with the ranges of the dose --
`doses and schedules of the asserted claim.
` Slide 4. The institution decision itself cites
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`important prior art admissions from the '209 patent,
`including at column 1, lines 62 to 64, that a limitation to
`the development of these drugs is that the cytotoxic activity
`and subsequent effectiveness of the antifolates may be
`associated with substantial toxicity for some patients.
` The board's institution decision also cited the
`patent at column 2, lines 16 to 26, for the proposition that
`homocysteine levels have been shown to be a predictor of
`cytotoxic events related to the use of certain antifolate
`enzyme inhibitors.
` And what this proceeding comes down to is not
`whether the references disclose the elements; the issue is
`the motivation to combine, which here should be
`straightforward under KSR's -- under KSR's holding that when
`there is a need to solve a problem and there are a finite
`number of identified predictable solutions, a POSA has good
`reason to pursue the known options within his or her
`technical grasp, and if this leads to the anticipated
`success, that is not -- that is not inventive. And that's
`precisely what we have here, I would submit.
` Slide 13. The Niyikiza reference, which was
`presented at a conference in November 1998 and then published
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`in December of 1998, taught POSAs that homocysteine levels
`are strong predictors of pemetrexed toxicity.
` Slide 19 -- actually, slide 22. And, in
`particular, EP005 discloses preparations for lowering
`homocysteine levels, administering a folate or folic acid and
`B12, including for the prophylaxis for cancer patients and
`folate antagonist treatments.
` Lilly contends that there is no --
` JUDGE GREEN: Where does it treat -- where does it
`teach prophylaxis of cancer patients? I mean it does suggest
`that cancer -- certain cancers -- that you may have elevated
`homocysteine, but I don't know that it necessarily teaches
`prophylactic treatment of cancer patients.
` MR. SKIERMONT: Slide 19. Next one.
` JUDGE GREEN: I mean it may suggest it, but I
`don't think it comes out and teaches it.
` MR. SKIERMONT: So, on slide 21, the EP005
`discloses that the present invention relates to
`pharmaceutical preparations for lowering levels of
`homocysteine or for the prophylaxis or treatment of elevated
`levels of homocysteine -- of homocysteine in patients and for
`counteracting the harmful effects associated with
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`homocysteine. So, that is a disclosure in EP005 that the
`vitamin combination that is disclosed in EP005 may be used to
`prevent homocysteine levels that cause harm.
` And we know from Niyikiza that there are
`homocysteine levels that strongly predict pemetrexed
`toxicity. And the person of ordinary skill in the art
`seeking a way to reduce those homocysteine levels to avoid
`the strong predictor of toxicity would naturally look to
`EP005, which is an invention directed to lowering
`homocysteine.
` Lilly contends that there is no motivation to
`combine these primary references. And -- and their first
`argument is that pemetrexed toxicity is m
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