trials@uspto.gov
`571-272-7822
`
`IPR2016-00084, Paper No. 17
`March 15, 2017
`
`
`
`RECORD OF ORAL HEARING
`UNITED STATES PATENT AND TRADEMARK OFFICE
`- - - - - -
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`- - - - - -
`PAR PHARMACEUTICAL, INC., BRECKENRIDGE
`PHARMACEUTICAL, INC., and ROXANE LABORATORIES, INC.
`Petitioners
`vs.
`NOVARTIS AG
`Patent Owner
`- - - - - -
`Case IPR2016-00084
`Patent 5,665,772
`- - - - - -
`Oral Hearing Held: February 2, 2017
`
`
`Before: CHRISTOPHER L. CRUMBLEY, LORA GREEN,
`ROBERT POLLOCK, Administrative Patent Judges
`
`The above-entitled matter came on for hearing on Thursday,
`February 2, 2017 at the U.S. Patent and Trademark Office, 600 Dulany
`Street, Alexandria, Virginia in Courtroom A, at 9:00 a.m.
`
`
`571-272-7822
`
`IPR2016-00084, Paper No. 17
`March 15, 2017
`
`
`
`RECORD OF ORAL HEARING
`UNITED STATES PATENT AND TRADEMARK OFFICE
`- - - - - -
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`- - - - - -
`PAR PHARMACEUTICAL, INC., BRECKENRIDGE
`PHARMACEUTICAL, INC., and ROXANE LABORATORIES, INC.
`Petitioners
`vs.
`NOVARTIS AG
`Patent Owner
`- - - - - -
`Case IPR2016-00084
`Patent 5,665,772
`- - - - - -
`Oral Hearing Held: February 2, 2017
`
`
`Before: CHRISTOPHER L. CRUMBLEY, LORA GREEN,
`ROBERT POLLOCK, Administrative Patent Judges
`
`The above-entitled matter came on for hearing on Thursday,
`February 2, 2017 at the U.S. Patent and Trademark Office, 600 Dulany
`Street, Alexandria, Virginia in Courtroom A, at 9:00 a.m.
`
`
`
`APPEARANCES:
`
`ON BEHALF OF THE PETITIONER PAR:
`
`
`DANIEL G. BROWN, ESQ.
`
`
`Latham & Watkins LLP
`
`
`53rd at Third
`
`
`888 Third Avenue
`
`
`New York, New York 10022-4834
`
`
`212-906-1200
`
`
`daniel.brown@lw.com
`
`
`
`
`
`
`
`
`
`
`BRENDA DANEK, ESQ.
`Latham & Watkins LLP
`330 North Wabash Avenue
`Suite 2800
`Chicago, Illinois 60611
`312-876-7700
`brenda.danek@lw.com
`
`
`
`
`
`
`
`
`
`
`
`2
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`
`APPEARANCES (Continued):
`
`
`JONATHAN M. STRANG, ESQ.
`
`
`Latham & Watkins LLP
`
`
`555 Eleventh Street, N.W.
`
`
`Suite 1000
`
`
`Washington, D.C. 20004-1304
`
`
`202-637-2200
`
`
`jonathan.strang@lw.com
`
`ON BEHALF OF PETITIONER BRECKENRIDGE PHARMACEUTICAL,
`INC.:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`B. JEFFERSON BOGGS, ESQ.
`MATTHEW L. FEDOWITZ, ESQ.
`Merchant & Gould
`1900 Duke Street
`Suite 600
`Alexandria, Virginia 22314
`703-684-2500
`jboggs@merchantgould.com
`mfedowitz@merchantgould.com
`
`
`
`3
`
`
`
`APPEARANCES (Continued):
`
`ON BEHALF OF PETITIONER ROXANE LABORATORIES:
`
`
`KEITH A. ZULLOW, ESQ.
`
`
`MARTA E. DELSIGNORE, Ph.D.,
`
`
`Goodwin Procter LLP
`
`
`The New York Times Building
`
`
`620 Eighth Avenue
`
`
`New York, New York 10018
`
`
`212-813-8846
`
`
`kzullow@goodwinlaw.com
`
`
`mdelsignore@godwinlaw.com
`
`
`
`
`
`
`
`
`
`
`ON BEHALF OF THE PATENT OWNER:
`
`CHRISTINA SCHWARZ, ESQ.
`
`NICHOLAS N. KALLAS, ESQ.
`
`Fitzpatrick, Cella, Harper & Scinto
`
`1290 Avenue of the Americas
`
`New York, New York 10104-3800
`
`212-218-2579
`
`cschwarz@fchs.com
`
`
`
`
`
`
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`4
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`P R O C E E D I N G S
`
`(9:00 a.m.)
`JUDGE CRUMBLEY: All right. So good morning,
`everyone. Today we have the oral hearing in inter partes
`review IPR2016- 00084 between Par Pharmaceutical,
`Breckenridge Pharmaceutical, and Roxane Labs as Petitioners,
`and Novartis AG as Patent Owner.
`So I'm Judge Crumbley. To my right is Judge
`Green, and to my left is Judge Pollock. Let's get the parties'
`appearances, starting with Petitioner.
`MR. BROWN: Daniel Brown, Your Honor, from
`Latham & Watkins representing Petitioner, Par. And I will be
`speaking today on behalf of all of the Petitioners.
`JUDGE CRUMBLEY: Thank you. Do you want to
`get introductions from the other counsel while we're on that
`side of the room?
`MR. BOGGS: Yes, Your Honor, good morning. I
`am Jeff Boggs with Merchant & Gould. I am here representing
`Breckenridge. And I have with me Matt Fedowitz and also
`in- house counsel Rob Vroom.
`JUDGE CRUMBLEY: Good morning. Thank you.
`MR. ZULLOW: Good morning, Your Honor, Keith
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`Zullow from Goodwin Procter on behalf of Petitioner, Roxane.
`And with me is Marta Delsignore.
`JUDGE CRUMBLEY: Good morning. And who do
`we have from the Patent Owner?
`MS. SCHWARZ: Good morning, Your Honor,
`Christina Schwarz and Nicholas Kallas, both from Patent
`Owner.
`
`JUDGE CRUMBLEY: Very good. So we set forth
`the procedure on how today is going to run in our hearing
`order, but just to make sure we're all on the same page we're
`going to have 45 minutes total of argument time. Petitioner
`has the burden of proving unpatentability, so will go first.
`You can reserve rebuttal time at the beginning of your
`argument. Just let us know how much you want on the clock.
`The Patent Owner will have their chance to present
`their case-in-chief, followed then by rebuttal.
`I noted that both parties have submitted
`demonstrative exhibits and have also submitted objections to
`the other parties' demonstrative exhibits. We have reviewed
`those. We're going to overrule them at this time.
`The objections, as far as we have been able to
`determine, are to new arguments appearing either in the reply
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`briefs or in the observations or even in the demonstratives
`themselves. So in the panel's view, that's something that we
`can address when we review the record as a whole.
`Demonstratives, of course, are not evidence. So we aren't
`going to be taking those into account as part of the record.
`So, you know, we can disregard new argument if
`we determine it is improper. So, you know, I would counsel
`you that if you want to spend your time on new arguments
`here, that might be disregarded. That's at your own peril.
`But just to be on the safe side to make sure there is
`no prejudice going forward, what the panel is going to do is
`expunge the exhibits from the record after the hearing, just so
`we're all clear that they are not going to be any longer in the
`record, and any chance of them being new evidence.
`So is that understood by everybody? I am seeing
`
`nods.
`
`MS. SCHWARZ: Yes, Your Honor.
`JUDGE CRUMBLEY: All right. I also wanted to
`point out that we are aware that there are still pending
`prehearing requests on the joinder motions as to claim 7. We
`haven't forgotten about those. They involve an expanded panel
`request, at least one of them does, so they are still pending.
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`If we end up granting one or more of them, we will
`just have to reconvene with the parties and figure out the
`procedure going forward, but for now we didn't want to
`postpone this hearing on the remaining claims, since we have
`those instituted.
`All right. Unless there is anything else we need to
`address before we get under way, I will hand it to Mr. Brown.
`Do you want to reserve some time?
`MR. BROWN: Yes, thank you. I would like to
`reserve 25 minutes for rebuttal.
`I would like to start by providing a brief overview
`of our argument. In a compound obviousness case, the analysis
`to be carried out is exemplified by the recent Federal Circuit
`case in Bristol-Myers Squibb versus Teva. And that was a
`decision regarding the entecavir compound known as
`Baraclude. And the law in this area is based on a presumption
`that compounds with similar structures will exhibit similar
`properties.
`And very typically what you see in a compound
`patent, the patentability of a new compound that might be
`similar to an old compound will be established by showing that
`there is an unexpected violation of this presumption that some
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`small change resulted in either a new kind of activity, the new
`compound treats something the old compound didn't, vastly
`superior property in one regard or another, something that is
`materially different caused by a relatively minor change. That
`is a pattern you see playing out in this area over and over.
`And in this case -- can we go to slide 2?
`But in this case we would submit that what we have
`is precisely what the law deems to be the expectation. The
`claimed 40- O-(2-hydroxyethyl) derivative of Rapamycin
`represents a straightforward minor structural change, and that
`change results in a compound with similar properties to the
`prior art Rapamycin compound. And this compound
`40- O-(2-hydroxyethyl) compound, also known as Everolimus,
`is claimed in claim 10.
`And so if claim 10 is obvious, this compound is
`obvious, then claims 1 through 3 fall and the other two
`remaining claims, 8 and 9, on the method of treatment, we
`haven't seen any material argument that those fall, if claim 10
`were to fall. So it is our belief that claim 10 is the
`battleground today.
`And what is missing here with respect to claim 10
`that we usually see in a compound case is evidence of some
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`expected beneficial difference in properties. Novartis has been
`working in this field since the very early 1990s. And yet all of
`that history and experience, there is no evidence, we would
`submit, to support an assertion that Everolimus, the
`40- O-(2-hydroxyethyl) derivative is surprisingly superior to
`Rapamycin in some particular property. We don't see that
`surprising different benefit.
`We would submit the evidence the Petitioners have
`submitted in this case makes a strong case that we have met
`our burden of showing unpatentability. I would like to go to
`slide 4.
`
`With my time this morning, I would like to briefly
`address the first two points that Rapamycin would have been a
`lead compound and that the prior art provided a motivation to
`improve the solubility.
`I am going to spend the majority of my time on
`point 3, how the person of ordinary skill in the art would have
`modified, I think, the fighting point is the Lemke and
`Yalkowsky combination. That's where I think most of the time
`is going to come in.
`And then I will also address secondary
`considerations in responding to Novartis' arguments.
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`Starting with the lead compound position, if we can
`go to slide 5, we think of all of the -- of all of the arguments,
`this one tilts pretty heavily in our favor. This is not some
`arcane compound found in a chart in a chemical abstract. This
`is a compound that has major publications by significant
`scientists directly related to the compound.
`The standard as set forth in the BMS case is that it
`is a natural choice for first development. That's a bar that
`Rapamycin very easily clears.
`It was specifically called out in a significant
`publication by Morris, who is a researcher at Stanford
`University. He noted that research was going on in parallel at
`Cambridge University. And then on top of that, you had a
`significant publication coming out showing the Rapamycin
`FKBP crystal structure. That was by Schreiber, et al. at
`Harvard in conjunction with Van Duyne and Clardy at Cornell.
`You have kind of have a who's who of significant
`scientists looking at this compound. And the reason they are
`looking at it is because it is -- it really is a breakthrough. And
`squarely the kind of compound that this Court, the Federal
`Circuit and the Patent Office and the courts consider a lead
`compound.
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`Novartis's responses, we don't think, hold a lot of
`water. First, they assert there are other lead compounds.
`There were other lead compounds. This was not the only
`research going on in the pharmaceutical industry or this field,
`but this was a lead compound and research was going on in this
`field.
`
`And we have specifically on top of the
`hypothetical, we know other researchers were using this as a
`lead compound, which we think puts this squarely within the
`Bristol-Myers case.
`The next issue I would like to address is the fact
`that solubility was a motivation in the art. And we pointed out
`in the petition that Morris identified Rapamycin as minimally
`soluble in water. We also pointed out that Stella had, in fact,
`made a prodrug modification for the specific purpose of --
`specific purpose of improving its solubility and noting also, I
`think they called it sparingly soluble.
`There is a particular quote that I would like to
`point out. It comes from Stella at column 1, lines 25 to 30. It
`is not on this particular slide.
`But this was cited in Jorgensen, in Dr. Jorgensen's
`declaration at paragraph 75. The quote is, "There is a need in
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`the art for a Rapamycin- derivative or prodrug which is
`relatively soluble in water so as to form a safe injectable
`solution and which is as effective as Rapamycin in the
`treatment of tumors."
`So Stella in 1986 is calling out exactly the
`motivation that we are proposing here and identifying it as a
`motivation. Morris identifies the same issue.
`JUDGE CRUMBLEY: Well, as I understand it,
`Morris doesn't recognize an issue. It just says minimally
`soluble. So, I mean, it doesn't say that it is too low -- it is too
`low solubility. And what you just read from Stella just says
`relative solubility.
`So where in the record do we find that it was below
`some threshold where it needed to be improved?
`MR. BROWN: Well, I think what Dr. Jorgensen,
`Dr. Jorgensen characterized it as the low end of what would be
`acceptable, such that a person of ordinary skill in the art
`wouldn't see that solubility and say no, I can't proceed, they
`would see that solubility and say there are big advantages to
`making reasonable improvements.
`JUDGE CRUMBLEY: Okay.
`MR. BROWN: So we're not contending that it had
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`some solubility that would be a complete barrier, but it is kind
`of Dr. Jorgensen characterized, and I am paraphrasing, but it is
`almost optimally ripe for improvement. If it was horrible, a
`small improvement or even a reasonable improvement might
`still leave you with a horrible compound, but it was in the
`range where an improvement would be expected to yield good
`benefits.
`
`And also we would identify in the Fiebig reference,
`there they pointed out that at least one of the development
`efforts ran into issues because they were using formulation
`approaches to deal with this. And some of the formulations
`resulted -- the Cremophor that they used in the formulations
`resulted in toxicity issues, which again points in the direction
`of solving the solubility issue at the chemical compound with
`medicinal chemistry.
`JUDGE CRUMBLEY: One of Patent Owner's
`arguments, as I understand it, is that you haven't really said
`what an acceptable level of solubility would be. And,
`therefore, any level of -- any increase in solubility can't be
`enough because you need a reasonable expectation of success.
`And if you set that reasonable expectation too low, it makes
`obviousness too easy of a question.
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`I am paraphrasing, but that's how I understand their
`argument to go. Is there -- is there something in the record
`that it needed to be a certain degree of improvement or really
`would any amount of improvement in your view be enough to
`be a "success"?
`MR. BROWN: So I think that the two related
`questions is what is the motivation and then what would be a
`reasonable expectation of success?
`JUDGE CRUMBLEY: Right.
`MR. BROWN: And so for the motivation itself, I
`think from the testimony of Dr. Jorgensen, he set forth an
`expectation based on Yalkowsky that he calculated in the
`opening petition that you could expect a material improvement.
`He doesn't set a numerical quantitative value on it, but he says
`it will be material.
`And then I think from the reasonable expectation of
`success, it is also qualitative. Does it allow me to do things
`that I couldn't -- that I might not have otherwise be able to do?
`Does it open up flexibility for me in developing an injectable
`formulation because it is more soluble? Can I now do an oral
`formulation or better kind of oral formulation? The more
`water soluble it is, the more flexibility you have in the design
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`of things.
`
`So we haven't asserted that there is a quantitative
`or specific threshold. And I am not aware of cases saying you
`have to have a numerical or quantitative approach. You are
`looking for improvement, that's the art of medicinal chemistry.
`JUDGE CRUMBLEY: Thank you.
`JUDGE POLLOCK: Mr. Brown, there seems to be
`a lot of evidence of record of pendant groups being added to
`Rapamycin. Can you point me to any of those examples in the
`prior art where the pendant groups are of roughly the same size
`as the ethylene ether group and Everolimus?
`MR. BROWN: I think -- I think in the Hughes
`reference, you are dealing with at least qualitatively smaller
`groups of similar scale. And I am not sure -- if I can confer
`with my colleague -- I believe the Schiehser reference also
`deals with groups on smaller orders of magnitude.
`I think a theme that we see, you see a lot of bigger
`groups that have been pointed out. Stella, for example, has
`bigger groups. And there are some other ones that are bigger
`groups.
`
`A lot of those would be considered -- Stella called
`those prodrugs. And a lot of the other ones would be
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`considered prodrugs because the bigger group isn't going to
`matter for the binding purposes. It is going to be cleaved by
`the liver or cleaved in the process of being introduced.
`And so in the Hughes and the Schiehser reference,
`you have the direct evidence of them, those compounds being
`directly tested for efficacy, so that we think that's evidence
`that the distinction between the prodrug and the derivative is
`material when it comes to the issue of is it going to interfere
`with my binding site or not. You don't have to worry about
`that with a prodrug because the attachment is gone and you are
`left with Rapamycin itself being what binds.
`JUDGE CRUMBLEY: Do you have a cite for that
`reference you just cited, just an exhibit number?
`MS. DANEK: I think it is 1011 -- it is 1010. I'm
`sorry, 1011 is Schiehser.
`JUDGE CRUMBLEY: 1011?
`MS. DANEK: Yeah.
`JUDGE CRUMBLEY: All right. Thank you.
`JUDGE POLLOCK: Just to follow up on that, in
`the record is there any examples of use of the ethylene ether
`group being added to any molecule, being used as a pendant
`group?
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`MR. BROWN: We -- within Dr. Jorgensen's
`declaration, he cites some examples where it was inserted into
`-- inserted into a molecules. In other words, it was put in the
`middle.
`
`And I believe that was in an antihistamine
`compound. And he also cites the example of this is one of the
`repeating units in PEG, in pegylation, is a known technique for
`increasing water solubility.
`JUDGE POLLOCK: Would you kindly point me to
`where that is?
`MR. BROWN: Yes.
`JUDGE POLLOCK: And if your colleague wants to
`look for it, you can certainly go ahead.
`MR. BROWN: Certainly.
`JUDGE CRUMBLEY: One of the dangers of a
`record that is as large as this.
`JUDGE GREEN: But with pegylation we have
`multiple copies. With pegylation you are hanging up a huge
`group, correct?
`MR. BROWN: Yes. It can be a huge group,
`certainly. I think there are examples where it is, you know,
`smaller numbers, but still more than one.
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`JUDGE GREEN: But, I mean, it is still much
`larger than just the ones that you are adding -- that is being
`added by the patent at issue here?
`MR. BROWN: Correct, pegylation does regard
`more groups, yes, Your Honor.
`JUDGE CRUMBLEY: I don't want to throw you
`off your outline. As you can tell from some of the questions, I
`would -- I think it would behoove you to talk about the
`substituents and the Lemke and Yalkowsky references, if you
`want to turn to that.
`MR. BROWN: Yes. I will jump right to that. So
`if we can go to slide 35, so we relied specifically, and it is
`throughout Dr. Jorgensen's declaration and throughout our
`petition on the combination of Lemke and Yalkowsky. And we
`specifically relied on the combination for a reason.
`There are two effects going on. There is the
`entropy effect and there is the solvent effect, which is the
`interaction between the solvent and the molecule. And the
`interaction between the solvent and the molecule is addressed
`empirically by Lemke.
`And it shows you for water solubility carbons are
`bad, that create a negative effect, and what the countervailing
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`effect of various groups can be, can be expected. And they do
`it very empirically in terms of number of carbons offset by
`these various substituents.
`And adding polar groups is good. Adding carbons
`is bad. And in addition to that effect, Yalkowsky addresses the
`entropic effect. And so when you are -- a person of ordinary
`skill in the art, as Dr. Jorgensen testified, is going to be
`looking at the combined effect.
`And so if you take Yalkowsky, for example, one of
`the things Dr. Jorgensen pointed out in his deposition, you
`can't just take an alkyl group and hang it off of something and
`expect to get an improvement in solubility. You are adding
`degrees of flexibility. That is great for entropy. It is great for
`the entropy of dissolution, but you get the countervailing effect
`of hydrophobicity.
`And so everybody knows skilled in the art if you
`hang an alkyl group, despite the flexibility, you don't get
`improved solubility. So you have to look at the combined
`effects.
`
`And what we feel like Novartis did throughout their
`responding papers is they focused intently on Lemke, and then
`they turn and focus intently on Yalkowsky, but they don't do
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`what Dr. Jorgensen said a skilled artisan would do and look at
`both of them together.
`And so the way I like to think about it is if you are
`a company, if I can increase revenue and not increase
`expenses, I'm going to increase profit. And Yalkowsky tells
`you you are going to get this very powerful effect by -- from
`the entropic effect of adding flexible bonds.
`And then the next question is: Well, do I lose
`anything? Am I going to lose effect because of
`hydrophobicity? What Dr. Jorgensen said is he didn't --
`Dr. Jorgensen didn't do the sort of molecular accounting that
`Novartis does. He just says you would add polar groups to
`offset the -- to offset any effect of the carbons, and then look
`at what Yalkowsky tells you. Now I am going to realize this
`entropic benefit because I don't have the countervailing effect.
`Novartis correctly points out in their petition when
`you do the molecular accounting through Lemke, you come out
`with zero. But that's great. Now that tells me in contrast to an
`alkyl group where the alkyl group is going to add
`hydrophobicity, and I don't know whether the entropy is going
`to prevail or whether the hydrophobicity is going to prevail, I
`am not losing anything, and I should realize the net benefit I
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`am getting from the Yalkowsky proposition for adding flexible
`bonds.
`
`JUDGE CRUMBLEY: Well, counsel, I take your
`point that, you know, general teachings of both references lead
`you a certain directions, but, I mean, Dr. Jorgensen in his first
`declaration, and I am reading from paragraph 149, says that
`based on the teaching of Lemke and in view of the teaching of
`Van Duyne group, a person of ordinary skill in the art would
`have first selected alcohol hydroxyl, amine, and lastly
`carboxylic acid groups with which to modify Rapamycin.
`Patent Owner points out you are not modifying
`Rapamycin with the hydroxyl group. You are adding an ether
`group and two carbons.
`MR. BROWN: Well, that's the end result. In each
`of those, when you add an amine, you lose a hydroxyl and you
`get an amine. So the net effect in all of those, you have to
`change the hydroxyl to an ether, and then add the amine,
`change the hydroxyl to an ether and add the alcohol.
`So that is -- and he is discussing the synthetic
`addition, not the net result. And he doesn't do the sort of
`molecular counting.
`JUDGE CRUMBLEY: But isn't Lemke all about
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`the net result? Isn't that the point of Lemke is telling us what
`the net result of adding different functional groups is and what
`the solubilization potential of those functional groups are?
`MR. BROWN: That is what Lemke discusses.
`Dr. Jorgensen just addressed it in a sort of qualitative term.
`He is looking to realize the Yalkowsky effect.
`And so he says you want to add -- you want to add
`these groups, and that's going to be a positive effect. He didn't
`do the addition or subtraction, but Lemke certainly allows you
`to do that. And you add two carbons, you add three flexible
`bonds, two carbons, and you end up with a net addition of the
`ether. That's -- there is not any dispute as to what those
`differences are. Those are the differences.
`So a person of ordinary skill would know those and
`look at what effect do I get from the flexible bonds, and what
`effect do I get from the changes in adding new polar groups.
`Then the other response that Novartis has that I
`wanted to address is what I have been calling Dr. Klibanov's
`relevant fragment argument. And we think this is just not a
`good argument at all. I would like to address why.
`If we can go to Novartis slide 17 first. I think this
`slide highlights the mistake being made here. In the title it
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`says Yalkowsky's Figure 2 Only Applies to Long- Chain
`Derivatives. But now it goes down in the quote and it says, "It
`does become important, however, for long-chain molecules."
`Thermodynamics being what it is, a molecule
`doesn't know if it is a derivative or not. And so the idea that
`by adding flexible bonds to the end of a flexible molecule, the
`molecule is somehow going to know that some of these bonds
`came because of a derivatization reaction, that is just -- that
`just doesn't hold water.
`If we can go to our slide 34. Here a freshman
`college chemistry student can see when you are going down the
`chain from where you have added the molecules on to
`Rapamycin, there is not a non- flexible bond until you get to
`one of the double bonds land to the ring, the three double
`bonds on the far side of the ring. Most of this molecule is
`tremendously flexible. Dr. Klibanov agrees with this.
`JUDGE CRUMBLEY: But doesn't Yalkowsky say
`it applies to rigid molecules with flexible side chains?
`MR. BROWN: Well, there is two parts to
`Yalkowsky. The thermodynamic discussion that goes with
`figure 2, doesn't discuss -- the thermodynamics apply whether
`it is rigid or not rigid.
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`JUDGE CRUMBLEY: But the portion that
`Dr. Jorgensen cited in his testimony, and which we relied on in
`the Institution decision, was that 2.5 EU increase in entropy of
`solution -- or fusion.
`MR. BROWN: Yes, so in that part, Yalkowsky is
`using a model. He is using an ideal model. And so he is
`saying if you start with a rigid part, as you add molecules and
`get farther away from the rigid part, you need to get a certain
`distance away.
`And then beyond that, each one will add 2.5.
`Dr. Jorgensen relies on the 2.5 as the delta. I can compare,
`since I am not near a rigid part, I can count on each flexible
`bond adding the 2.5.
`There is a lot of dispute as you get into the
`deposition testimony and a lot of the quotation that appears in
`Novartis' papers from the deposition are directed to efforts to
`use the entirety of that equation and calculate a hypothetical
`model or ideal solubility for the compound.
`Jorgensen says you would not do that calculation.
`You wouldn't try to apply the whole equation and come up with
`an idealized solubility, but you would know the concept, he
`said, you would -- a skilled artisan would know the concept
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`from this. This is the delta I can expect.
`I can get an idea of how much more I can expect,
`but I am not going to use this part of Yalkowsky to try to
`calculate a theoretical solubility. I am going to make the
`compound and then test the solubility. That's how medicinal
`chemists would operate.
`JUDGE CRUMBLEY: I mean, what do we do with
`Dr. Jorgensen's repeated statements in his deposition that a
`medicinal chemist wouldn't look to ideal solubility, wouldn't
`look to -- wouldn't consider, I think he says, it is not relevant
`to medicinal chemists?
`MR. BROWN: So I think if I could, there is a
`section of his -- I think the entire context of the principal
`quotation that Novartis relies on might be helpful. They
`quoted -- and it is on their slide 9 -- they quoted his
`deposition, his August deposition transcript at page 45, lines
`11 to 24 for the proposition that "this is not an article --
`Industrial Engineering Chemistry Fundamentals -- that a
`medicinal chemist, you know, would have looked at."
`The entirety of the quotation -- this is actually
`immediately following what is cited there. This is on page 45,
`lines 25 to 46.
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`"Question: So if the POSA here was seeking to
`improve Rapamycin's water solubility, they would not look to
`the Yalkowsky 1979 reference?
`"Answer: They -- the concept here, which is being
`illustrated, is something that they would know. And if they,
`like me, had to go find an illustration of it, they would likely
`stumble upon this reference. So this reference underpins their
`understanding of flexible, the flexible side chain's concept. So
`if they -- a person of ordinary skill -- would understand what is
`represented in this document, and if they were motivated to
`try, as I was to try to find an example of it, you know, a
`medicinal chemist says I know flexible side chains with polar
`groups increase solubility, and I know I want to dig deeper in
`that, you know, what do I do? Then they would find
`Yalkowsky, just like I did."
`And so what he said very clearly multiple times in
`his deposition is this is -- this is representative of foundational
`information that's in a medicinal chemist's tool box. And so
`we would submit that it is reported here in a reference. This
`reference references drug solubility in the opening sentence.
`And it is clearly something that is within what the Patent
`Office and the Courts would recognize as analogous art that
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`would be referred to. Dr. Jorgensen is talking about the
`practicalities of what an actual medicinal chemist would do.
`And so we think the context, and we think the
`context of that is such that a -- throughout his deposition
`testimony, I would submit that reading the full context, there is
`a lot of snippets and quotes and things taken. Dr. Jorgensen
`was very forthcoming i
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