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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`PFIZER, INC.,
`Petitioner,
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`v.
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`CHUGAI PHARMACEUTICAL CO. LTD.,
`Patent Owner.
`____________
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`Case IPR2017-01357 (Patent 7,332,289 B2)
`Case IPR2017-01358 (Patent 7,927,815 B2)
`____________
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`Record of Oral Hearing
`Held: August 2, 2018
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`Before GRACE KARAFFA OBERMANN, RAMA G. ELLURU, and
`JACQUELINE T. HARLOW, Administrative Patent Judges.
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`Case IPR2017-01357 (Patent 7,332,289 B2)
`Case IPR2017-01358 (Patent 7,927,815 B2)
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`APPEARANCES:
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`ON BEHALF OF THE PETITIONER:
`ROBERT E. COUNIHAN, ESQUIRE
`Fenwick & West, LLP
`1211 Avenue of the Americas, 32nd Floor
`New York, New York 10036
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`JOHN SCHEIBELER, ESQUIRE
`White & Case
`1221 Avenue of the Americas
`New York, New York 10020-1096
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`ON BEHALF OF PATENT OWNER:
`J. STEVEN BAUGHMAN, ESQUIRE
`MEGAN RAYMOND, ESQUIRE
`Paul, Weiss, Rifkind, Wharton & Garrison, LLP
`2001 K Street, N.W.
`Washington, D.C. 20006-1047
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`The above-entitled matter came on for hearing on Thursday, August 2,
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`2018, commencing at 1:00 p.m., at the U.S. Patent and Trademark Office,
`600 Dulany Street, Alexandria, Virginia.
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`Case IPR2017-01358 (Patent 7,927,815 B2)
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`P R O C E E D I N G S
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`JUDGE HARLOW: Good afternoon. Please be seated. Today
`we'll hear argument in IPR2017-01357 and 01358, Pfizer versus Chugai,
`concerning U.S. patent numbers 7,332,289 and 7,927,815. At this time we
`would like counsel to introduce yourselves and your colleagues, beginning
`with petitioner.
`MR. SCHEIBELER: Good afternoon, Your Honors. This is John
`Scheibeler of White & Case, LLP, for petitioner, Pfizer, Inc. With me is
`Robert Counihan of Fenwick & West, also for petitioner. Robert will be
`presenting the oral argument on behalf of petitioner today. To Robert's right
`is Matthew Mezger of Winston & Strawn, also for petitioner. And in the
`back with me is Jeff Oelke of Fenwick & West.
`JUDGE HARLOW: Thank you, Mr. Scheibeler. Patent owner?
`MR. BAUGHMAN: Your Honors, Steve Baughman and Megan
`Raymond from Paul Weiss for patent owner.
`JUDGE HARLOW: Thank you very much. Consistent with our
`prior order, each party will have 45 minutes to present its arguments today.
`Petitioner will proceed first to present its case as to the challenged claims
`and may reserve rebuttal time to address any subject matter that's
`specifically raised during patent owner's argument. Thereafter, patent owner
`will have the opportunity to respond to petitioner's case. Patent owner may
`also reserve rebuttal time, but in that instance only to address any arguments
`raised in petitioner's rebuttal regarding the asserted objective indicia of
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`nonobviousness. Rebuttal argument that deviates from those parameters will
`not be permitted.
`We would like to remind the parties that pursuant to Section
`316(e), petitioner bears the burden of proving any proposition of
`unpatentability by a preponderance of the evidence. And we also remind the
`parties that the hearing is open to the public and that a transcript of the
`hearing will become part of the record in both proceedings.
`For clarity of the record, because I'm participating via remote
`video link, if the parties could please identify any slide numbers or exhibits
`and page numbers verbally so that I can hear that and also for the benefit of
`the court reporter, that would be very much appreciated.
`And with that, I invite counsel for petitioner to inform us how
`much time you would like to reserve for rebuttal and begin your
`presentation.
`MR. COUNIHAN: Thank you, Judge Harlow. I would like to
`reserve ten minutes, please.
`JUDGE OBERMANN: I'm going to be running the clock. So I'm
`going to set you up with 35 minutes. And when you start speaking, I'll start
`the clock running.
`MR. COUNIHAN: Good afternoon. My name is Robert
`Counihan speaking on behalf of Pfizer. This case is about inherent
`anticipation of two patents, which I'll refer to as the Chugai patents, by a
`patent publication called Shadle. I would first like to turn to slide 3 which
`sets out the law of inherent anticipation. The law is that merely discovering
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`and claiming a new benefit of an old process cannot render the process again
`patentable. As the Federal Circuit has instructed, that assessment is
`determined by assessing whether the natural result flowing from the
`operation of the prior art as taught would result in the performance of the
`questioned functions or the claimed function.
`JUDGE HARLOW: Counsel, petitioner emphasizes the case law
`concerning the natural result flowing from the operation as taught, but one of
`the questions that kept arising in my mind when I was thinking about this
`case is how do we know what the natural result from the operation of Shadle
`is as taught when Shadle doesn't expressly teach us what its molarity is or
`whether particles are forming in the other matters for which petitioner is
`relying on inherency.
`MR. COUNIHAN: So that's an excellent question. I want to jump
`ahead to slide 6. So the two key issues that relate to that question of whether
`the molarity and conductivity issue requirements are met, there's two
`disputes. One is patent owner has presented a fifth possible way to make the
`citrate buffer that is used to elute from the protein affinity column. And the
`second argument they make is that there's also a wash buffer present when
`the steps of Shadle are performed in that if you use the fifth method or if
`there's residual wash buffer present, that that means that the molarity and
`conductivity requirements are met.
`Importantly, if you determine that any of the four methods that we
`propose for making the citrate buffer, if you determine that those are the
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`natural and usual way to operate the Shadle process, there's no dispute that
`the claim limitations are met.
`JUDGE HARLOW: But counsel, doesn't the way you are applying
`the natural and usual way law take us from inherency back to possibilities
`and probabilities? So I understand that petitioner disputes whether patent
`owner's proposed method of making the buffer is even viable, but setting
`that aside, let's take a hypothetical scenario where petitioner has identified
`four possible ways to make the buffer. Patent owner has identified a fifth. If
`there are five viable ways to make the buffer, setting aside your inviability
`arguments, if there are five viable ways to make the buffer, how does the
`natural and usual result law get you out of the possibilities and probabilities
`problem that's part of our inherency law?
`MR. COUNIHAN: So in this situation, the fifth method, the
`alternative presented is not viable. Yes, it literally can make the citrate
`buffer with a pH of 3-1/2, but it's not a reasonable way that any person of
`ordinary skill would do it. It's not the natural and usual way that it would be
`done.
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`JUDGE HARLOW: Is viable different from reasonable?
`MR. COUNIHAN: Is viable different than reasonable? Sorry. I
`didn't mean to cut you off.
`JUDGE HARLOW: No, that's the heart of the question. Because
`you switched from viable to reasonable, and to me there seems to be a
`difference between an option that's not the best but it's still an option that
`could be used and an option that absolutely wouldn't work.
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`MR. COUNIHAN: So I'm going to move ahead to slide 17 which
`sets out the normal and usual operation law. So the law for inherent
`anticipation turns on normal and usual. Not what is viable. So while I might
`have used the word --
`JUDGE HARLOW: But isn't this normal and usual operation law
`having to do more with, for example, using a device in its normal and usual
`way as opposed to preparing the reagents to perform a process, which is
`more what we are talking about here?
`MR. COUNIHAN: Well, I think it's directly analogous, because
`while we are here talking about how to prepare the reagents that are used in
`the Shadle process, what I think is instructive is both what happened at the
`European Patent Office when the patent owner had an opportunity to present
`these arguments, and what they did was they too found -- I'm sorry. This is
`slide 24 now. And what I'm showing here is in the European Patent Office
`there was a similar claim that required a molarity of less than 100
`millimolar. In response to a rejection over Shadle, they amended the claim
`to 30 millimolar or less. And then they calculated the molarity of the Shadle
`process, and what they have calculated it as is 47.2 millimoles. And what
`that means, as they showed here, the molarity of the citrate buffer is 25. So
`they are not -- even when they had the opportunity to do this in another
`forum to a different patent office, they didn't make this argument that there
`was this fifth buffer because they know this fifth buffer method preparation -
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`JUDGE HARLOW: But counsel, isn't the calculation stating that
`the eluent can be calculated to be at least -- so first question, sorry to back up
`a bit. This is the elution buffer molarity, correct? Not the eluent molarity?
`MR. COUNIHAN: Yes, that's correct.
`JUDGE HARLOW: Okay. So for the elution buffer calculation
`that the patent owner presented to the EPO, don't they expressly describe it
`to be calculated to be at least 47.2 millimolar?
`MR. COUNIHAN: I apologize, Judge Harlow. This is actually
`the eluent because it includes the Tris base at the third -- so the elution
`buffer is the first line, the citrate. And then they have the second line which
`they say unknown. That's the to reflect where the Shadle process says
`there's an optional step if necessary to adjust the pH to 3.5. And then the
`third step is the adjustment to 5.5 with the Tris base in Shadle. That's the
`third line there. So this is actually the calculation for the eluent. Not the
`elution buffer. I apologize for that.
`JUDGE OBERMANN: So how do you get to the elution buffer?
`MR. COUNIHAN: So the elution buffer is simply the first line
`there. It's the citrate. So what they are telling me --
`JUDGE ELLURU: But does that account for all of the
`components in the buffer?
`MR. COUNIHAN: The way they are presenting it to the EPO, it
`presumably does because they are not arguing that you need to account for
`sodium hydroxide or hydrochloric acid or other components to make the
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`citrate buffer. They are just saying the molarity of the citrate that's added in
`Shadle is 25 millimolar.
`JUDGE ELLURU: I'm sorry, my colleague couldn't hear my
`question, so I'm going to repeat it. With respect to the 25 millimole
`molarity, I was wondering if that was with respect to just a citrate
`component.
`MR. COUNIHAN: So the first line -- so in the EPO proceeding,
`they had the opportunity to present this argument that the molarity of the
`citrate buffer was something other than 25, and they did not.
`JUDGE ELLURU: But don't you have the burden here, counselor?
`MR. COUNIHAN: Yes, of course. And I believe we've met that
`burden by showing that the -- so we've met the affirmative burden by
`showing that under the molarity calculation, whether it's under the
`calculation we put forward in the petition or under the calculation that the
`Board put forward in the institution decision, which I'll call the total
`molarity calculation, under either one of those, that -- under either one, the
`calculations that our expert did show that the 100 millimolar threshold is not
`met. What I'm pointing to this for, the European Patent Office proceedings,
`is to show that the patent owner agreed in a different forum, but they are
`changing their position now. And I find it -- it begs credibility that in the
`European Patent Office they said the eluent has a molarity of 47.2, but today
`they say the eluent has a molarity of 102, as shown on the bottom of this
`slide.
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`JUDGE HARLOW: Well, they are not saying that the eluent has a
`molarity of 47.2. They are saying that it has at least that molarity based off
`of this particular way of making the buffer.
`And then as an aside, the way that the patent owner calculated the
`molarity before the EPO would not comply with our construction of molarity
`as -- our preliminary construction as indicated in the institution decision; is
`that correct? Because it's just looking at the citrate component, for example,
`of the ProSep A buffer?
`MR. COUNIHAN: So the molarity they present here, part of the
`reason that -- when we presented our petition, we were aware of what they
`had said to the European Patent Office. So part of the reason that our
`petition focuses on the molarity of the citrate buffer itself is because that's
`what they had told the public as part of those proceedings that that's the right
`way to calculate it. So we were surprised when they argued something
`different. But understanding your construction on that term, it is different
`because they aren't talking about other molarities present -- I'm sorry, other
`constituents present.
`But if I could turn to --
`JUDGE OBERMANN: I'm having a little bit of trouble before we
`go further. You argued express disclosure for this in the petition, and you've
`changed your theory of the case now, it seems to me. I would like to know
`how you address a decision like the Dell case that was cited by your friend
`where we declined to analyze the inherency argument where the petition
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`argued express disclosure. How do we get you to where you need to be to
`change the theory of your case that way?
`MR. COUNIHAN: So I think what in the reply the patent owner is
`referring to as an express disclosure was in relation to the preamble.
`JUDGE OBERMANN: No. I have read your paper and you were
`relying on an express disclosure of that first requirement of the 100 molarity
`for the acidic solution. You are relying on an express disclosure of the 25
`molar citrate. And I see nothing else in your petition that supports that
`particular limitation, and I'm having difficulty understanding why we should
`even permit you to change course and argue inherency for that particular
`feature.
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`MR. COUNIHAN: Understood. I apologize. I misunderstood
`your question. So you are exactly correct. Here on slide 9 we have our
`petition and what we focused on in terms of the construction molarity. You
`are exactly right that our position in the petition was that the molarity is
`expressly disclosed where the Shadle reference says that the molarity is 25
`millimolar citrate.
`So our view with respect to the Dell case is that the construction
`that the Board gave is something that was not predictable when we were
`doing our petition. And the law is clear that we don't need to anticipate the
`arguments that patent owner is going to make, and that's part of the reason
`why we have the opportunity to make a reply.
`So with respect to the disclosure of the molarity of the acidic
`aqueous solution, the ability to account for the Board's construction is
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`something that we should have the ability to do. And that's exactly what we
`did, and we did that before our expert was even deposed. We provided those
`new calculations so that they were fully aware of what --
`JUDGE OBERMANN: You didn't ask us for permission to file
`supplemental information. And I have had plenty of cases where petitioners
`have tried to change theory of cases that way and bring in new evidence, and
`I have denied it. But you took that out of our hands. You didn't move to
`supplement the record here. And our rules contemplate supplemental
`information under very rigid circumstances. And I find it -- I would like to
`hear your position on that. Why should we permit this to go forward?
`MR. COUNIHAN: So our understanding of the rules is that we
`were allowed to provide updated calculations from our expert to reflect what
`the construction was. And we tried to do that as quickly as possible. So
`while we did not ask for permission from the Board, we did try to go -- we
`tried to address the issue as quickly as we could and in an expeditious
`fashion so that the patent owner could have an opportunity to respond.
`JUDGE OBERMANN: I think I'm less concerned by the fact that
`you updated the calculations and more concerned by the theory of the case.
`You went from an express disclosure and to an inherent disclosure, and to
`me I think that takes us out of the cases that you've cited in your reply for --
`I think there's a real tension here between how much we allow you to
`respond and then there's a tension with you have got to make that case in the
`petition. And when I look at your petition, you completely dropped the ball
`on that limitation.
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`MR. COUNIHAN: So our position remains that the proper
`molarity construction is the citrate buffer.
`JUDGE OBERMANN: So you are not abandoning that view?
`MR. COUNIHAN: Correct, we are not abandoning it. All we are
`saying is that even under the Board's construction of a total molarity, even in
`that situation, the buffer, the citrate buffer will meet the molarity
`requirement.
`JUDGE OBERMANN: How do you stand by the 25 molarity?
`What is your theory for that applying here, the molarity of the citrate 25 --
`JUDGE ELLURU: Under our construction. So assuming we do
`go forward with our initial construction, how does Shadle meet that
`limitation of the aqueous solution buffer?
`JUDGE OBERMANN: Expressly.
`MR. COUNIHAN: Just to make sure I have the question correctly,
`under the Board's construction is our position that the limitation is expressly
`disclosed?
`JUDGE ELLURU: Correct.
`MR. COUNIHAN: So to answer that I have to begin by saying we
`first disagree with the Board's construction, and we believe that our
`construction is correct. Under our construction it is expressly disclosed.
`Under the Board's disclosure -- I'm sorry, under the Board's construction, I
`think it's worth considering that for two of the four methods, the buffer
`concentration -- I'm sorry, the molarity would actually be 25 millimolars.
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`JUDGE OBERMANN: This is all an inherency argument. You
`don't have an express disclosure that would meet the preliminary
`construction in the DI.
`MR. COUNIHAN: Well, under the buffer preparation method that
`was disclosed in the Lily reference, the 1948 textbook that's the seminal
`textbook in how to prepare buffers, that reference teaches that you would use
`what Dr. Przybycien called this fourth method. And that fourth method
`yields a buffer preparation that has a molarity of 25 millimolar.
`JUDGE OBERMANN: And none of that is in your petition?
`MR. COUNIHAN: So in the petition, we do discuss the different
`buffer preparations.
`JUDGE OBERMANN: In the context of this limitation?
`MR. COUNIHAN: In the context of the conductivity limitation
`where we believed it was most relevant. But in the petition -- so our
`position remains. It's an express disclosure under our construction. But in
`view of the Board's construction, our position is that under the first way of
`calculating the buffer of molarity, it's still expressly met. But under the
`other ways it's still inherently met. And that view of inherency, that's to
`account for the Board's construction which we could not have predicted
`going in.
`JUDGE OBERMANN: Okay. I don't want to hold you up on that.
`I think I understand your position.
`JUDGE ELLURU: So your argument is that it's still 25 millimolar
`under one of the four ways to make that buffer?
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`MR. COUNIHAN: Yes. It's actually under two of the ways is 25
`millimolar. It's method 3 and 4 as shown in Exhibit 1027. I can pull that up.
`JUDGE ELLURU: And under those other two methods?
`MR. COUNIHAN: Under the one method, it's 30.73, and under
`the fourth it's 44.
`JUDGE ELLURU: I see.
`JUDGE OBERMANN: And the fifth one, you are arguing it's not
`a normal way that someone would have done it and that for that reason,
`Shadle necessarily discloses?
`MR. COUNIHAN: That's exactly right. So if we turn to slide 19,
`this is testimony from our expert where he was asked why he viewed the
`alternative method, the Roth method, if you will, to be not the normal and
`usual. And what he said was in the Roth method what you are doing is you
`are starting with a very basic solution that has a pH of 9 and you are titrating
`it with significant amounts of hydrochloric acid to bring it through neutrality
`to a pH of 3.5 to acidity. And he compared that to someone driving from
`Baltimore to Washington, D.C. by way of Baltimore. So while you could
`literally do that drive because roads do connect those three cities, that's not
`the normal and usual way someone would go from Baltimore to
`Washington.
`And that's exactly what the alternative method is asking you to do.
`You are taking unreasonable steps by starting with something extremely far
`away from your target, which is a pH of 3.5, and then you are bringing it
`down, as opposed to the normal way you would do it where you would start
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`with something around 3.5 and then you would adjust as needed. And that's
`the four methods that our expert identified.
`JUDGE ELLURU: Do you agree that even using the fifth method,
`however, that you would be able to remove contaminant DNA, i.e., that the
`method would work normally to remove contaminant DNA?
`MR. COUNIHAN: So the teachings of the patent are that the
`molarity has to be below 100. The molarity of the fifth method is 102, and
`so it's not clear whether contaminant DNA would be removed or not.
`JUDGE HARLOW: But you could use the buffer of the fifth
`method to elute the antibody off of the column, correct?
`MR. COUNIHAN: So Dr. Przybycien talked about this as well.
`In the Roth reference where this method comes from -- and I'm going to
`jump ahead to slide 22 for a moment. In the Roth method, that buffer is
`from a situation where what they are trying to do is analyze amino acids
`present in blood samples. So in what we are talking about in the Chugai
`patents, you have an antibody that's bound to the chromatography column
`and then you use the elution buffer to release it. But what Roth is trying to
`do is put extremely strong agents through the blood sample because you are
`trying to break off all the amino acids. So what's likely to happen using the
`Roth buffer is you are going to denature your antibody. So I guess
`technically it would eluted but it would be destroyed in the process. So
`that's an additional reason why no one would use the Roth method in this
`situation of Shadle.
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`JUDGE HARLOW: And then your declarant's testimony on this
`point, does he identify support for the idea that the antibody would be
`denatured during the elution?
`JUDGE ELLURU: Actually, before you answer that, counsel, we
`have an objection by patent owner, I believe.
`MR. BAUGHMAN: I'm sorry to interrupt. Your Honors, I don't
`know your preference, whether you would like objections as to new
`arguments to be made at the time or we can save them for our time period,
`whichever Your Honors prefer. We don't think we've heard the argument
`about destroying the antibody before.
`JUDGE ELLURU: I'll leave that up to Judge Harlow.
`JUDGE HARLOW: Counsel for petitioner, was that argument
`addressed in your reply?
`MR. COUNIHAN: I believe in the reply declaration that Dr.
`Przybycien --
`JUDGE OBERMANN: Did you discuss it in your reply? It has to
`be discussed in the brief.
`MR. COUNIHAN: I would have to go back and check. I believe
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`it is.
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`JUDGE OBERMANN: Let's get the page number before you
`proceed. I stopped the clock.
`MR. COUNIHAN: I'm ready, Your Honor. So on page 13 of the
`reply, we wrote, And using Roth's citrate buffer, which included other
`excipients, would denature the very antibody Shadle sought to purify.
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`JUDGE OBERMANN: Mr. Baughman, does that extinguish your
`objection?
`MR. BAUGHMAN: Your Honor, if the argument is limited to
`being denatured, yes.
`JUDGE OBERMANN: Thank you.
`MR. COUNIHAN: So unless there are other questions about the
`citrate buffer, I would actually like to turn to the wash buffer issue. So now
`at slide 25, so the patent owner's view is that because it is likely that there
`would be some amount of wash buffer present, it is impossible for the
`petitioner to prove that the wash buffer does not negatively affect the
`molarity -- I mean, does not destroy the molarity limitation. So first of all,
`they are misstating the law. The Federal Circuit has been clear that there is
`no impossibility standard. And the Federal Circuit has explained that
`inherency may be found even if another outcome could occur through
`extraordinary efforts.
`So what we have here is Dr. Przybycien has explained that when
`you look at Shadle and what they are doing, they do something called UV
`tracing. What UV tracing does is it identifies when protein has released. So
`when you add the elution buffer, when the antibody elutes or releases from
`the column, it will show up on the UV trace. And then you watch it as it
`moves down the column, and when it's reaching the bottom, that's when you
`start collecting. So the purpose of doing that is to minimize the amount of
`other things that you collect. And as Dr. Przybycien explained, you would
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`not want wash buffer solution in your collection if you can help it because
`it's basically just waste.
`But in response to patent owner's arguments that there would be
`some amount present and because we cannot prove that that some amount
`does not violate the molarity requirement, he did a calculation where he
`looked at the chromatography column of Shadle and he calculated the
`maximum amount -- this is the maximum amount. So to be clear, this is not
`his opinion as to how much wash buffer would have been collected. This is
`the maximum amount that could have conceivably have been collected. And
`he found that it was .582 liters.
`JUDGE ELLURU: And are you referring to slide 28?
`MR. COUNIHAN: I'm sorry, yes, this is slide 28.
`JUDGE HARLOW: And how do you reconcile that testimony
`with the evidence presented by patent owner from the EPO that there would
`have been a greater amount of wash buffer present in the eluent?
`MR. COUNIHAN: So that's great question. So what Dr. Cramer
`says -- and I think it's important to look at what he actually says in his
`declaration about the European Patent Office. He says, first of all, Shadle
`does not say anything about the amount of wash solution collected -- sorry.
`He explained, therefore, the exact amount of wash buffer cannot be known.
`And then when he looks at the European Patent Officer examiner's
`calculation, he says the examiner assumed that about 3.75 to 4.5 liters of
`wash buffer would be present. And then he moves on. He doesn't endorse
`that calculation. He doesn't repeat that calculation. He doesn't give any
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`basis for where that calculation comes from or why it makes sense. Instead
`what he does, he uses that as a comparator, and he says a conservative
`estimate compared to that is 1 liter. And then he says the 1 liter would cause
`the molarity requirement to be breached.
`So what the European Patent Office -- so what you have here is a
`situation where you only have speculation coming from the other side and
`you don't actually have them explaining why the European Patent Office is
`correct. All you have is using that as a reference point to make an
`assumption about how much could possibly have been there when they have
`no actual evidence to support that.
`JUDGE ELLURU: So your argument is the elution buffer, the
`molarity of the elution buffer is more or less the same molarity of the eluent
`buffer -- I'm sorry, of the molarity of the eluent?
`MR. COUNIHAN: No, because the eluent includes the Tris
`buffer. Probably the best example is on slide 24 looking at what the patent
`owner said to the European Patent Office. The elution buffer is just the
`citrate buffer. And then the eluent includes the Tris buffer, and then if
`necessary, as Shadle says, you can add hydrochloric acid to get the pH to
`3.5. So eluent has the citrate, the potential amount of hydrochloric acid and
`then the Tris base.
`So I would like to turn to the particle formation question which
`starts at slide 30. Slide 30 is just the claim. So the patent tells us -- and we
`are looking at slide 31 now. The patent tells us repeatedly that the only
`criteria that need to be met for particles to form are the molarity,
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`conductivity and pH requirements that are set forth in the claim. So what I
`have shown here is claim 1 of the '815 and then an excerpt from the patent.
`And what the patent is saying in blue, the present invention provides the
`following, and then there's a second example. And then in yellow,
`converting the sample containing a physiologically active protein into an
`acidic or alkaline aqueous solution of lo