[00:00:05] Speaker 01:
Thank you, Your Honor.

[00:00:07] Speaker 01:
May it please the court, my name is Bill Lee, and together with Anna Lumeleski, I represent Millennium Pharmaceuticals.

[00:00:13] Speaker 01:
The bortezomid minotol ester, which is the subject of the patent for you and this appeal, was a new compound.

[00:00:21] Speaker 01:
Bortezomid itself was not suitable for administration to patients, and therefore was not suitable as a therapeutic for the treatment of the devastating disease multiple myeloma.

[00:00:33] Speaker 01:
It was the new compound that was covered by the claims of the 446 patent that made treatment, now known as Velcade, as described to you in the briefs, a medical reality.

[00:00:44] Speaker 03:
How do you get around all of the arguments that were made in the arbitration?

[00:00:49] Speaker 03:
I mean, those are what we litigators refer to as really bad facts, aren't they?

[00:00:54] Speaker 01:
Actually, Your Honor, I'm not sure getting around is what I'll do, but I think I can address those.

[00:01:00] Speaker 01:
And let me do it now.

[00:01:02] Speaker 01:
In the arbitration, there was an argument.

[00:01:05] Speaker 01:
No one was contesting that there was an invention, that this new compound was an invention with extraordinary properties that have made people's lives better, longer.

[00:01:15] Speaker 01:
The question was, who made the inventive contribution?

[00:01:19] Speaker 01:
We have never disputed that lyophilization was known.

[00:01:22] Speaker 01:
We have never disputed that mannitol was known.

[00:01:25] Speaker 01:
And there was back and forth between the two of them, between the respective

[00:01:29] Speaker 01:
groups as to who made the inventive contribution.

[00:01:33] Speaker 01:
At the end of the day, what they recognize is they did collectively because at the end, lyophilization with mannitol to create the bortezomid ester is what led to this new compound.

[00:01:46] Speaker 01:
And I think the way we get around it is this.

[00:01:50] Speaker 01:
In order to not recognize that the bortezomid mannitol ester was a new compound,

[00:01:55] Speaker 01:
The district court actually committed five legal errors.

[00:01:58] Speaker 01:
If I could summarize them very quickly, I think that actually goes to the heart, because what was said in the arbitration between people who were competing for inventorship positions doesn't go to these five issues.

[00:02:10] Speaker 01:
And the five issues, legal issues, are these.

[00:02:14] Speaker 01:
The district court did not apply this court's lead compound analysis.

[00:02:18] Speaker 01:
It doesn't even mention it.

[00:02:20] Speaker 01:
And in fact,

[00:02:21] Speaker 01:
At page A12, it identifies the closest prior art as bortezomid.

[00:02:27] Speaker 01:
But at page A20, it describes the closest prior art as the glycerol ester of bortezomid.

[00:02:33] Speaker 01:
Now, under this court's decisions, it could be both.

[00:02:37] Speaker 01:
It could be one or the other.

[00:02:38] Speaker 01:
But there has to be some indication that there was a motivation to modify, to obtain a new compound.

[00:02:46] Speaker 01:
And if I could draw the court's attention to arborates at page 13, you'll see the chemical structures of the two.

[00:02:52] Speaker 01:
These are distinctly different compounds.

[00:02:55] Speaker 01:
That's the first error.

[00:02:57] Speaker 01:
The second error is their expert, really their only witness, identified 17 really undifferentiated prior references.

[00:03:08] Speaker 01:
And when we asked him, is there a specific combination, a specific combination that would have made it obvious, he said, I can't give you one.

[00:03:17] Speaker 01:
I don't have one.

[00:03:18] Speaker 01:
In fact, he started with 51 before the trial, brought it down to 17 during his testimony.

[00:03:23] Speaker 01:
Completely undifferentiated.

[00:03:25] Speaker 01:
And that error relates to the first, which is, if you haven't gone through the analysis, and you then move to a series of prior references, not identifying what the combination is, it's a problem.

[00:03:38] Speaker 01:
And this case actually captures it, because there was-

[00:03:43] Speaker 03:
Some of the errors that you complain about are things where you think that the trial court's analysis fell short.

[00:03:50] Speaker 03:
So the question is, is this a situation where we should, if we agreed with you on those points, vacate and remand for the court to explain itself?

[00:03:59] Speaker 03:
Or are you saying that this is a situation in which the evidence wouldn't support the conclusions of the court?

[00:04:06] Speaker 01:
Your Honor, we would say that at a minimum, it would justify a vacate and remand.

[00:04:11] Speaker 01:
we would go one step further.

[00:04:13] Speaker 01:
And I think I can tell you why.

[00:04:14] Speaker 01:
Because there is, if I focus on the only articulation of any motivation to combine, it's a page A-19 of the opinion.

[00:04:24] Speaker 01:
And there are only four things that are referred to.

[00:04:27] Speaker 01:
The first is their expert's testimony without identifying any prior art, just stating the conclusion that he thought it would have been obvious.

[00:04:35] Speaker 01:
And that's not enough.

[00:04:37] Speaker 01:
The second was some 30b6 testimony.

[00:04:39] Speaker 01:
But when you look at the testimony, the testimony is by someone who's testifying about personal experience, not prior art, with a different compound than bortezmid and a different ester.

[00:04:51] Speaker 01:
The third was testimony, as we've described to you by Dr. Anderson, where if you look at the testimony, it actually says the opposite of what the judicial court cited it for.

[00:05:03] Speaker 01:
The defendants have not made any effort to justify or to support that conclusion.

[00:05:08] Speaker 01:
And the last is this.

[00:05:10] Speaker 01:
The last is a reference to the Adams patent itself.

[00:05:13] Speaker 01:
And the quote from the court's opinion is, the Adams patent pointed directly to mannitol.

[00:05:20] Speaker 01:
The Adams patent doesn't mention mannitol at all.

[00:05:24] Speaker 01:
It does mention 10 dihydroxy compounds.

[00:05:28] Speaker 01:
None of them are mannitol.

[00:05:30] Speaker 01:
It says nothing about lyophilizing

[00:05:33] Speaker 01:
of mannitol.

[00:05:34] Speaker 01:
It says nothing about creating an ester of mannitol with bortezomid.

[00:05:39] Speaker 01:
There literally is nothing in when the district court says it pointed directly to mannitol.

[00:05:44] Speaker 01:
It's saying that it's pointing to something that's not even mentioned.

[00:05:49] Speaker 01:
If that's the evidence that the defendants produce on the motivation to combine, then we would suggest that it's a failure to prove by clear and convincing evidence.

[00:05:57] Speaker 01:
If you assume that the two possible lead compounds are bortezomid and the glycerol ester,

[00:06:03] Speaker 01:
and you assume that this is the only evidence of a motivation in capine, that would be enough to find the patent not invalid.

[00:06:11] Speaker 01:
And as you think through, the different errors are actually related because not going through the late compound analysis becomes a problem that's compounded by this undifferentiated group of 17 references.

[00:06:25] Speaker 01:
If you move to unexpected results, identifying a different closest prior art, the glycerol ester,

[00:06:32] Speaker 01:
what was identified eight pages before makes it very hard for us as the patentee to identify that which we should attack in order to justify the patent.

[00:06:44] Speaker 01:
So if you take, I've sort of jumped to the fourth, but if I take the third, so the first is the failure engaged in the lead compound analysis.

[00:06:53] Speaker 01:
The second is not specifically combining prior references.

[00:06:57] Speaker 01:
The third would be trying to use the Inherency Doctrine, which this Court has addressed in part, to sort of fill the gap.

[00:07:05] Speaker 01:
And much of the opinion is about the obviousness of a process.

[00:07:09] Speaker 01:
But when you're synthesizing chemicals, when you're making your chemical, many of these processes are new.

[00:07:15] Speaker 01:
When you're changing one radical, it's a process that's been well-known.

[00:07:19] Speaker 01:
It's the result.

[00:07:20] Speaker 01:
It's the key.

[00:07:22] Speaker 01:
And having focused on the process, and many times these processes will be known.

[00:07:27] Speaker 01:
The district court had to fill the gap with the inherency doctrine.

[00:07:32] Speaker 01:
But there are really three problems with that.

[00:07:35] Speaker 01:
The first is it's a doctrine that this court has said should be narrowly circumscribed when you're dealing with obviousness.

[00:07:41] Speaker 01:
The second is the court has said it must be tethered to the prior art.

[00:07:45] Speaker 01:
There must be some piece of prior art that makes it inherent.

[00:07:49] Speaker 01:
This goes back to the second error we've identified, which is having not identified what the specific priority is,

[00:07:56] Speaker 01:
It's very difficult to conclude what was inherent and what wasn't.

[00:08:00] Speaker 02:
Was there any prior showing reactivity of the hydroxyl groups or showing that mannitol would, during lyophilization, would react?

[00:08:11] Speaker 01:
I think it's two parts, Your Honor.

[00:08:14] Speaker 01:
The Adams patent describes the possibility of creating esters with dihydroxides.

[00:08:20] Speaker 01:
Everybody agreed that there are literally millions of dihydroxy compounds.

[00:08:24] Speaker 01:
There are 10.

[00:08:26] Speaker 01:
that are identified in the Adam's patent, none of them are Manitou.

[00:08:31] Speaker 01:
To move to the second half of your question, there was no discussion in the patent about lyophilizing with Manitou to create a bulking agent or to create an ester.

[00:08:42] Speaker 01:
And so there was nothing that would teach that.

[00:08:45] Speaker 01:
There was, to go to Judge O'Malley's first question, to be sure, there were publications on lyophilizing.

[00:08:53] Speaker 01:
There were publications on lyophilizing with Manitou.

[00:08:56] Speaker 01:
But this is a critical distinction, and I think goes to this problem of not identifying the specific priority.

[00:09:04] Speaker 01:
The patent itself identifies 10 dihydroxy compounds.

[00:09:09] Speaker 01:
In order to make their obviousness case, the defendants had Dr. Rept testify that from all these dihydroxy compounds, there are actually a half a dozen that one of ordinary skill merit would have considered if you were lyophilizing as a bulking agent.

[00:09:26] Speaker 01:
That's different than creating a new compound.

[00:09:29] Speaker 01:
There is no overlap between the two.

[00:09:33] Speaker 01:
The compounds that he identified as the obvious ones that one of ordinary skill in there would have considered are nowhere in the atom's pattern at all.

[00:09:42] Speaker 01:
So the heart of the question is, is there anything in the prior that would suggest that lyophilizing bortezomid with mannitol would have produced the new compound

[00:09:56] Speaker 01:
the ester with the solubility and the stability and the dissociation properties that have made it really a significant medical advance.

[00:10:06] Speaker 01:
And the answer to that would be no.

[00:10:09] Speaker 01:
And if you look at the history of what occurred in this case, we had people at the National Cancer Institute and the University of Kansas working for two years to try to come up with a formulation because everyone knew bortezomib had great therapeutic potential.

[00:10:25] Speaker 01:
But no one could figure out how to make it a medical reality.

[00:10:28] Speaker 01:
And if it were as simple as taking a reference off the shelf that talked about lyophilization, taking another reference off the shelf that talked about mannitol, which were describing a process to create basically a structure to hold the therapeutic and not a new compound, it would have been done before.

[00:10:49] Speaker 01:
And the reason it wasn't done, Your Honor, which I think answers both parts of your question, is this.

[00:10:55] Speaker 01:
If you have a compound that has the potential to treat a disease as significant as multiple myeloma, and you're trying to get it into patients, the last thing you want to do is to change the compound.

[00:11:11] Speaker 01:
Because if you do, you run the risk that the therapeutic properties no longer be there.

[00:11:16] Speaker 01:
And so the real genius of this invention, the real annotation is the solubility problems were solved.

[00:11:25] Speaker 01:
the stability problems were solved.

[00:11:27] Speaker 01:
It could go into patients, and bortezomib, after dissociation, could treat the cancer.

[00:11:33] Speaker 01:
Before this invention, there was no way to do it.

[00:11:38] Speaker 01:
And the only way we got to finding the claims to this new compound invalid were to focus on the process rather than the compound, to not focus on the specific pieces of prior art.

[00:11:53] Speaker 01:
but just to sort of toss them up and say, it's obvious.

[00:11:57] Speaker 01:
To use inherency in a place that this court has never used it before.

[00:12:02] Speaker 01:
And then when we got to unexpected results, there were two things.

[00:12:06] Speaker 01:
One was the idea that you compare to determine unexpected results to prior art that doesn't exist.

[00:12:13] Speaker 01:
It's never been created, never been tested, never been fabricated.

[00:12:19] Speaker 01:
This court has not only not required that, but it has said that it's not required.

[00:12:23] Speaker 01:
And then to suggest that in order to show unexpected results, you have to show precisely what would have been expected.

[00:12:30] Speaker 01:
By definition, particularly in the area of therapeutics, unexpected results are the results of innovation and invention that gives new, better, and meaningful results, which is precisely what happened here.

[00:12:43] Speaker 01:
I'll reserve the rest of my time for rebuttal if that's all right.

[00:12:45] Speaker 02:
Thank you, Mr. Lee.

[00:12:46] Speaker 01:
Thank you.

[00:12:49] Speaker 02:
Mr. Melora.

[00:12:58] Speaker 00:
Thank you, Your Honor.

[00:13:00] Speaker 00:
May it please the court.

[00:13:02] Speaker 00:
The judgment of the district court should be affirmed.

[00:13:05] Speaker 00:
The fact findings made after a full trial show that one skilled in the art would have been motivated to lyophilize bortazomib with mannitol, and the ester would form.

[00:13:18] Speaker 00:
The formation of the ester is inherent.

[00:13:21] Speaker 00:
The fact findings were clear that it would inevitably form.

[00:13:26] Speaker 00:
The evidence on these issues

[00:13:28] Speaker 00:
came from not just Dr. Repta and the prior arc, but also from the witnesses that Millennium either proffered or people that were Millennium were related to the named inventors.

[00:13:42] Speaker 03:
That's really the heart of the debate, isn't it?

[00:13:45] Speaker 03:
The leap from basically using a bulking agent for purposes of making a powder and actually synthesizing a new compound.

[00:13:58] Speaker 00:
Well, the use of mannitol in lyophilization procedures was, of course, known.

[00:14:04] Speaker 00:
And mannitol was highly popular.

[00:14:07] Speaker 00:
Both Dr. Anderson, the Millennium Expert, and Dr. Repta testified to that.

[00:14:12] Speaker 00:
But mannitol was also known in the prior art to react with compounds like boronic acids to form esters.

[00:14:20] Speaker 00:
So it's not as though the chemistry was unknown or unexpected chemistry.

[00:14:25] Speaker 00:
In fact, Dr. Snow, who was Millennium's expert, testified at A, 1692, that the prior art would have told a person of ordinary skill in the art that the ester would form.

[00:14:38] Speaker 02:
And one would have expected that... But it doesn't say that this specific ester would be formed and that it would be such that as soon as you put it in water, it separates again.

[00:14:53] Speaker 02:
seems to be something for which I saw nothing in the prior art.

[00:14:58] Speaker 00:
The Adams patent itself taught that the esters would separate.

[00:15:02] Speaker 00:
Adams itself taught that the esters were prodrugs.

[00:15:06] Speaker 00:
Dr. Anderson admitted that having the claimed esters from the Adams patent in pharmaceutical compositions would show that they are indeed intended to be prodrugs.

[00:15:17] Speaker 02:
Well, we know it's a new product, and here there is an unexpected property.

[00:15:23] Speaker 02:
Is one to ignore the properties of the new product?

[00:15:27] Speaker 00:
The properties of the mannitol ester are that the bortezomib-free acid is stabilized.

[00:15:35] Speaker 00:
And the testimony was that that was exactly what one would have expected by lyophilizing the bortezomib with the mannitol.

[00:15:45] Speaker 00:
improved stability.

[00:15:46] Speaker 00:
Dr. Stella testified to that in addition to Dr. Repta.

[00:15:50] Speaker 03:
But I'm still having a problem with the difference between your exercise for purposes of using mannitol as a bulking agent for creating powder and actually getting to the ester.

[00:16:00] Speaker 03:
Didn't Dr. Repta himself admit that the ester was a new compound?

[00:16:06] Speaker 00:
The mannitol ester had not been made before

[00:16:11] Speaker 00:
these particular people did.

[00:16:13] Speaker 00:
The esters themselves were taught and claimed in the Adams patent.

[00:16:18] Speaker 03:
But Dr. Repta did... But not the mannitol ester in the Adams patent.

[00:16:22] Speaker 00:
The mannitol ester is... Your Honor, the mannitol ester is covered by the claims in the Adams patent.

[00:16:28] Speaker 00:
It is not specifically called out of the Adams patent.

[00:16:31] Speaker 00:
The Adams patent teaches esters of bortezomib.

[00:16:35] Speaker 00:
And Dr. Repta testified that one would have expected an ester to form

[00:16:40] Speaker 00:
And Dr. Repta also testified that one would have expected the mannitol ester to provide improved stability.

[00:16:49] Speaker 00:
And he cited prior art that specifically supported that expectation.

[00:16:53] Speaker 00:
That was the Brown and Korczak references that he relied on.

[00:16:58] Speaker 00:
And Dr. McCubbin?

[00:17:00] Speaker 03:
Why wasn't your expert able to?

[00:17:03] Speaker 03:
points to actual portions of these many prior art references that he felt could be combined.

[00:17:11] Speaker 03:
Didn't you see that as a huge gap in your presentation?

[00:17:16] Speaker 00:
Actually, the trial testimony has about 22 pages of testimony from Dr. Repta, where he goes through individual prior art references, sometimes one at a time, sometimes a few at a time.

[00:17:28] Speaker 00:
And what Dr. Repta did was

[00:17:31] Speaker 00:
put together that plausible rationale for putting those references together, just as Judge Sleet found in his opinion.

[00:17:39] Speaker 00:
So what we had, unlike the Coito case that was cited by Millennium in their brief, we had discussions of at least five different points where specific prior act was called out.

[00:17:52] Speaker 00:
So at A1149, mannitol was common for freeze drying.

[00:17:58] Speaker 00:
A1165, mannitol esters of boronic acids were known.

[00:18:03] Speaker 00:
And with each of these five points, A1166, 70, and 71, by trial exhibit number and sometimes by name, these references were called out and identified as one example.

[00:18:15] Speaker 03:
And I saw that.

[00:18:17] Speaker 03:
The problem is that it seemed more like

[00:18:20] Speaker 03:
These are out of here.

[00:18:21] Speaker 03:
And so you would have grabbed them all and somehow figured out a way to put them together.

[00:18:26] Speaker 03:
I don't see an actual discussion in your expert's testimony of what one of skill and the art would have perceived in terms of understanding how you would put these together and why it would be obvious to put them together.

[00:18:41] Speaker 00:
One skilled in the art, Dr. Reptta did testify that one skilled in the art would have been motivated to lyophilize bortezomib

[00:18:49] Speaker 00:
with mannitol, and specifically called out the prior art that supported that, some of which I just referenced.

[00:18:56] Speaker 00:
And the inherent result of that is the formation of the ester.

[00:19:01] Speaker 03:
Dr. Repta also testified that as a matter of chemistry... Can you point to me the pages of the trial testimony that you think most clearly represent his testimony that one of skill in the art would have been motivated to combine specific prior art references with

[00:19:17] Speaker 03:
the understanding that there would be a likelihood of success.

[00:19:24] Speaker 00:
A, 1149 to 1171 is the discussion of the prior art references.

[00:19:34] Speaker 03:
Well, that's a lot of pages.

[00:19:36] Speaker 03:
Where does he get to the precise testimony that I'm concerned about?

[00:19:43] Speaker 00:
With regard to the expectations, A,

[00:19:47] Speaker 00:
1169 is testimony at around line 18 that you would want to form the ester because we know from the art that the esters stabilize the boronic acids against degradation.

[00:20:13] Speaker 00:
and that the mannitol ester would likely be more soluble than bortezomib itself.

[00:20:18] Speaker 00:
And that's building on prior testimony, where he's gone through the prior arc references, specifically identifying them.

[00:20:28] Speaker 00:
So at A1149, the use of mannitol in freeze drying is identified.

[00:20:35] Speaker 00:
And that was confirmed by Dr. Anderson and Dr. Lai.

[00:20:39] Speaker 00:
At A1165,

[00:20:41] Speaker 00:
The formation of mannitol esters in the prior art is identified.

[00:20:46] Speaker 00:
At A1166, Dr. Repta gives the identification of the specific prior art references at lines 1 and 2 that he's relying on for that.

[00:20:58] Speaker 00:
And Dr. Adams and Dr. Snow confirm that in their testimony.

[00:21:02] Speaker 00:
The dissociation, the prodrug aspect, that was at A1166.

[00:21:08] Speaker 00:
And he pointed to the Babcock book.

[00:21:11] Speaker 00:
And Dr. Anderson confirmed that the esters do hydrolyze in water.

[00:21:17] Speaker 00:
And the Atoms Table 2 confirms that as well.

[00:21:21] Speaker 00:
And then the stability of the boronic acids through ester formation was at A1170 and A1171.

[00:21:29] Speaker 00:
Those were the Brown and Korczak references.

[00:21:34] Speaker 00:
And that was confirmed by Dr. McCubbin at A1335.

[00:21:42] Speaker 00:
One skilled in the art would have been motivated to do exactly what is claimed here, to make a lyophilized ortesimib with mannitol.

[00:21:53] Speaker 00:
The formation of the ester is both an inherent result that is obtained.

[00:21:58] Speaker 00:
It is inevitable.

[00:22:00] Speaker 00:
And it is what one would have expected.

[00:22:03] Speaker 00:
Judge Sleet made those findings at A17 and 18.

[00:22:08] Speaker 00:
He discussed the inherency.

[00:22:10] Speaker 00:
And at A19.

[00:22:12] Speaker 00:
He discusses the expectations in terms of the ester formation, the improved stability of the ester, and the improved solubility, the dissociation.

[00:22:25] Speaker 00:
Now, counsel mentioned that the district court said at A-19 that Adams pointed directly to Manitoul.

[00:22:32] Speaker 00:
I don't know if I quoted counsel exactly, but that's what I have in my notes.

[00:22:37] Speaker 00:
That's not what the district court said.

[00:22:39] Speaker 00:
The district court did point

[00:22:42] Speaker 00:
directly to what Adams teaches, which is that the esters can be used in pharmaceutical compositions, and they would be prodrugs.

[00:22:51] Speaker 00:
And table two of the Adams patent confirms that because it compares esters to free acids.

[00:22:58] Speaker 00:
And the activity of three of the four esters is virtually identical, showing that the ester is freely dissociating

[00:23:06] Speaker 00:
to the free acid, which is the active here.

[00:23:08] Speaker 03:
Dr. Ruptam mean when he said at 1185 that solubility is not an issue in this case.

[00:23:19] Speaker 03:
That seemed strange to me.

[00:23:24] Speaker 00:
He says that the POSA would know that solubility would be increased.

[00:23:30] Speaker 03:
But then he went on to say he didn't think solubility was even an issue.

[00:23:35] Speaker 00:
He did say he didn't think solubility was an issue really in this case, but it would be increased.

[00:23:42] Speaker 00:
The apparent solubility would increase because you have a separate species.

[00:23:44] Speaker 03:
But isn't solubility at the heart of this question?

[00:23:48] Speaker 00:
Stability was at the heart of the question in the trial court.

[00:23:52] Speaker 00:
Stability was what the experts testified about.

[00:23:56] Speaker 00:
That's the motivation that would have

[00:23:58] Speaker 00:
led once skilled in the art to have lyophilized bortezomib with mannitol.

[00:24:04] Speaker 00:
It was that improved stability that provided the motivation.

[00:24:08] Speaker 00:
So in that sense, I guess Dr. Reptah's testimony about solubility was that there would be an increase, but the stability motivation was what Dr. Reptah had relied on.

[00:24:20] Speaker 02:
Stability, it was stable, was it not?

[00:24:22] Speaker 02:
The issue wasn't stability of the lyophilization, was it?

[00:24:28] Speaker 00:
The stability improvement of the free acid came about through the lyophilization with mannitol, your honor.

[00:24:36] Speaker 00:
And that improvement was expected.

[00:24:39] Speaker 00:
Dr. Stella himself said there was nothing inventive about that.

[00:24:43] Speaker 00:
The arbitration papers said there was nothing inventive about lyophilizing mannitol, excuse me, lyophilizing voitesimid.

[00:24:53] Speaker 00:
And the reason for that was that

[00:24:56] Speaker 00:
there was an expectation that that free acid would be improved in terms of its stability through lyophilization.

[00:25:03] Speaker 00:
Dr. Stella testified he would have been remiss not to try lyophilization.

[00:25:09] Speaker 00:
I won't say his name correctly, but Dr. V, who was the associate of Dr. Gupta, said he expected lyophilization to solve the problem.

[00:25:21] Speaker 00:
Dr. Rept appointed to prior art about improving stability with lyophilization.

[00:25:27] Speaker 00:
And Dr. Stella said there was nothing innovative, or it was not innovative.

[00:25:32] Speaker 00:
It was an obvious option to lyophilize.

[00:25:34] Speaker 03:
But all of this means that this depends on your inherency argument, right?

[00:25:39] Speaker 00:
Well, the inherency argument certainly leads to the conclusion of obviousness.

[00:25:43] Speaker 00:
But there also was an expectation from the chemistry that the ester would form and would have improved stability.

[00:25:50] Speaker 00:
And that was.

[00:25:51] Speaker 03:
Well, but Trafford seemed to think that the inherency piece of it was a necessary

[00:25:57] Speaker 00:
piece and the puzzle to get from point A to point B. I'm not sure I read it that way, but certainly the inherency gets you there.

[00:26:04] Speaker 00:
So in that sense, it's necessary.

[00:26:06] Speaker 03:
Well, have you ever seen any case law where we've applied inherency to render a new compound or a single structural limitation obvious?

[00:26:16] Speaker 00:
We have the case involving plasma concentrations, which the court

[00:26:24] Speaker 00:
said were inherent from the teaching of the formulation in the prior art, or the obviousness of the formulation from the prior art.

[00:26:31] Speaker 00:
And the plasma concentrations are only achieved if you have the right formulation.

[00:26:37] Speaker 00:
In other words, if you have a formulation that isn't the right formulation, you're not going to get the right plasma concentrations.

[00:26:43] Speaker 03:
Right, but that wasn't a case that was actually using inherency to find a structural limitation, right?

[00:26:53] Speaker 00:
It was a case which found inherency on the plasma concentration, which that plasma concentration is achieved by the structure of the formulation itself.

[00:27:04] Speaker 00:
And the PAR-TWI case doesn't speak just in terms of a property as being applicable for the inherency doctrine.

[00:27:14] Speaker 00:
It talks about limitations of claims.

[00:27:17] Speaker 00:
And if the limitation of a claim is the inherent, excuse me, the natural result

[00:27:23] Speaker 00:
of what would have been obvious from prior art, then that limitation can be met inherently under an obviousness analysis.

[00:27:30] Speaker 00:
And that's exactly what we have here.

[00:27:33] Speaker 00:
We have an obvious combination of bortezomib, mannitol, and lyophilization.

[00:27:41] Speaker 00:
And the natural result of that is the formation of the mannitol ester.

[00:27:47] Speaker 00:
Dr. Repta, Dr. Adams, Dr. Snow, Dr. McCubbin,

[00:27:52] Speaker 00:
They all testified as to the inevitability.

[00:27:55] Speaker 00:
Dr. McCubbin said it all goes very quickly.

[00:27:59] Speaker 00:
Dr. Snow says the prior art would tell you that it would form.

[00:28:02] Speaker 00:
Dr. Adams said he immediately thought the ester had formed, and he didn't view it as inventive.

[00:28:09] Speaker 00:
He's not an inventor.

[00:28:10] Speaker 00:
He was asking, are you OK with that?

[00:28:11] Speaker 00:
He says, I'm OK with that.

[00:28:13] Speaker 00:
That was at A1594 to 95.

[00:28:17] Speaker 00:
What happened here was people did what routine formulators do.

[00:28:22] Speaker 00:
Council keeps talking about a new chemical compound.

[00:28:25] Speaker 00:
The person of ordinary skill in the art here is a pharmaceutical formulator that was agreed by both parties with slightly different definitions and adopted by the court.

[00:28:35] Speaker 00:
What we have in the end are pharmaceutical formulators doing what pharmaceutical formulators do, taking the obvious steps and getting to the natural result, which is the mannitol ester.

[00:28:46] Speaker 03:
That would mean every chemical compound

[00:28:48] Speaker 03:
is obvious or unfathomable, because obviously when you put chemicals together and they react, that reaction is something that you may or may not expect, but ultimately occurs.

[00:29:02] Speaker 00:
Well, Your Honor, I would say that the reactions themselves form products.

[00:29:07] Speaker 00:
However, you have to be motivated to do the specific chemical reactions with the specific ingredients at the specific conditions that would get you that result.

[00:29:16] Speaker 00:
And that's why most chemical compounds

[00:29:19] Speaker 00:
that are new and not otherwise suggested by the prior art, they then become patentable.

[00:29:23] Speaker 00:
There's nothing that disqualifies obviousness from the fact that where you're motivated to do something and you get the natural result of doing it, then the invention is obvious, absent some secondary consideration.

[00:29:39] Speaker 03:
So in the ordinary case...

[00:29:43] Speaker 03:
that you're not motivated to actually put it together to get the end result.

[00:29:48] Speaker 03:
You're actually arguing that you're motivated to do something else.

[00:29:51] Speaker 00:
Here it's both.

[00:29:52] Speaker 00:
You're motivated to stabilize through the lyophilization with mannitol, but you're also motivated to form the ester.

[00:30:00] Speaker 00:
And Judge Sleet found that at A-19 and the improved stability of the ester.

[00:30:05] Speaker 02:
Except that you don't know the ester's going to form.

[00:30:09] Speaker 02:
or what properties it's going to have.

[00:30:11] Speaker 02:
But you're saying that that's inherent, or at least the district court said it was inherent.

[00:30:16] Speaker 00:
The inventors may not have known that it formed, but one skilled in the art would have expected it to form based on the chemistry and what was taught in the art.

[00:30:24] Speaker 02:
With the perfect hindsight of a successful experiment.

[00:30:28] Speaker 00:
Well, the evidence of record was that the prior art actually suggested ester formation.

[00:30:34] Speaker 00:
This was

[00:30:34] Speaker 00:
a chemical reaction between the boronic acids and mannitol that was known and taught in the art.

[00:30:40] Speaker 00:
And Dr. Repta identified six particular mannitol esters that had been created in the prior art and published in the prior art.

[00:30:49] Speaker 00:
So there was a suggestion not only to do what the inventors did, but there was a suggestion that you would get the result that they got in addition to it being an inherent result.

[00:31:00] Speaker 02:
OK.

[00:31:01] Speaker 02:
Any more questions?

[00:31:02] Speaker 02:
Any questions?

[00:31:03] Speaker 02:
OK.

[00:31:04] Speaker 02:
Thank you, Mr. Millarro.

[00:31:06] Speaker 02:
And would you add the time we ran over to Mr. Lee's time?

[00:31:14] Speaker 01:
Let me make these five points quickly.

[00:31:18] Speaker 01:
To go to your question, there is nothing in the prior art that describes lyophilizing with mannitol to create an ester.

[00:31:28] Speaker 01:
There's nothing in the prior art that describes using

[00:31:31] Speaker 01:
biophilizing with mannitol to create cortisomal ester.

[00:31:35] Speaker 01:
That's why the combination becomes particularly important.

[00:31:40] Speaker 01:
That's point one.

[00:31:41] Speaker 01:
Point two, at A 1195 to 96, Judge Malley, go to your question.

[00:31:47] Speaker 01:
I asked Dr. Upton-Cross, do you have a specific combination?

[00:31:51] Speaker 01:
And he said, no.

[00:31:53] Speaker 01:
This is after he had given the testimony given here.

[00:31:56] Speaker 01:
And here's the reason it becomes important

[00:31:58] Speaker 01:
The defendants have given you a series of citations to mentions of different pieces of prior art.

[00:32:05] Speaker 01:
For a couple, Dr. Repta had suggested that those prior art references indicated that stability could have been achieved with the mannitol ester of Bortezumet.

[00:32:16] Speaker 01:
When we cross-examined him, there were two, Brown and Adams.

[00:32:20] Speaker 01:
When we cross-examined him, he said, I can't find it in Brown.

[00:32:25] Speaker 01:
And actually, it's not in Adams.

[00:32:27] Speaker 01:
That's why the articulation of a specific combination is so important, so people can know what the target is to shoot it.

[00:32:35] Speaker 01:
The third point is this.

[00:32:37] Speaker 01:
There's nothing in atoms.

[00:32:38] Speaker 01:
Atoms is the only piece of prior art that describes Fortesmit in any way.

[00:32:43] Speaker 01:
There is nothing in atoms that talks about what you should do to get greater solubility and greater stability.

[00:32:51] Speaker 01:
There's not a word about it.

[00:32:53] Speaker 01:
And that's why this ester became so

[00:32:56] Speaker 01:
important.

[00:32:58] Speaker 01:
The fourth point is this.

[00:33:03] Speaker 01:
Fourth and just one more after this.

[00:33:06] Speaker 01:
The fourth point is that the district court did say, and a predicate of the opinion was, the Adams patent pointed directly to Manitou.

[00:33:15] Speaker 01:
That's an A-16.

[00:33:17] Speaker 01:
I wasn't trying to characterize the opinion.

[00:33:19] Speaker 01:
That's precisely what he said.

[00:33:21] Speaker 01:
And the last thing is this.

[00:33:23] Speaker 01:
Judge Amali, we don't think that there's any inherency decisions of this court in the office's context that supply a missing structural feature of a compound.

[00:33:34] Speaker 01:
Nor do we think there are any that provide a basis for finding a compound inherent itself.

[00:33:40] Speaker 01:
And the reason is this.

[00:33:41] Speaker 01:
All of the experts agree that the question of whether you got the bortezomid ester of Manitou that had the properties that Velcade has was dependent upon

[00:33:52] Speaker 01:
the different conditions, the different experimental conditions, the different solvents.

[00:33:58] Speaker 01:
And you'll see from the record that there are actually a host of experiments with lyophilization by the folks at Kansas working with the folks at the National Cancer Institute that were unsuccessful.

[00:34:11] Speaker 01:
At the end, Velcade is a new compound.

[00:34:16] Speaker 01:
And in fact, the ester itself was

[00:34:21] Speaker 01:
The ester itself was one that combined two compounds from before and actually had the risk that it would affect the therapeutic properties of bortezomib because it was attached close to the operative site.

[00:34:35] Speaker 01:
The fact that these inventors, applying techniques to Xomeli, that for sure, when they had their arbitration, they were saying were known techniques.

[00:34:43] Speaker 01:
And we don't contest that for a second.

[00:34:47] Speaker 01:
But using known processes and known techniques,

[00:34:50] Speaker 01:
They came up with a new compound, with a new structure, never disclosed in the prior art, that has allowed people to live better and live longer.

[00:35:02] Speaker 03:
Your biggest problem here is that the district court could have made

[00:35:07] Speaker 03:
specific findings of fact.

[00:35:09] Speaker 03:
And the district court may not have articulated everything perfectly, but the district court specifically found that there was a rational motivation articulated by Dr. Repta with respect to this compound.

[00:35:25] Speaker 03:
And how do we get over that?

[00:35:27] Speaker 01:
Your Honor, I think there are two ways.

[00:35:29] Speaker 01:
One is that, this goes to your question about reversal or remand, it's important that

[00:35:36] Speaker 01:
Whatever the reasons are, they'd be articulated within the analytical framework that this court has defined.

[00:35:41] Speaker 01:
Because if it's not, then we don't know if the legal requirements you set forth have been satisfied.

[00:35:48] Speaker 01:
We don't really, to use my example of Brown and Adams, we don't really know how to attack them because we don't know what they're using them for.

[00:35:57] Speaker 01:
So I think the question of going through the lead compound analysis, identifying a specific combination,

[00:36:05] Speaker 01:
dealing with the inherency doctrine as it exists today, not having different prior art when you get to unexpected results.

[00:36:13] Speaker 01:
These are all part of the analytical framework and legal issues.

[00:36:16] Speaker 01:
And the factual issues, Your Honor, not to repeat what I said earlier, but if you go to A19, which is the only place, bottom of A18 and A19, where they address the question of the evidence for motivation combined

[00:36:32] Speaker 01:
There is Dr. Reptah's conclusion not tethered to any prior art at all, which this Court has said is not sufficient.

[00:36:41] Speaker 01:
There is a 3b6 testimony of someone not testifying about prior art, testifying about a different compound and a different ester.

[00:36:50] Speaker 01:
There is, thirdly, the testimony of Dr. Interson, which I think we all agree now doesn't say what it's cited for.

[00:36:57] Speaker 01:
And lastly, there's the question of whether the Adams patent points directly to Manitol.

[00:37:02] Speaker 03:
So if we agreed with you that those were inadequate bases for a motivation to combine, we wouldn't have to question some of the other findings of fact that you attacked.

[00:37:12] Speaker 01:
That's true.

[00:37:12] Speaker 01:
The teaching way.

[00:37:14] Speaker 01:
If that's the predicated, even if we assume that the analytical framework had been properly done, that would be insufficient to sustain a clear and convincing evidence burden to invalidate that.

[00:37:24] Speaker 02:
Thank you.

[00:37:25] Speaker 02:
Any more questions?

[00:37:25] Speaker 02:
Any questions for Mr. Reed?

[00:37:27] Speaker 02:
Thank you.

[00:37:28] Speaker 02:
Thank you.

[00:37:28] Speaker 02:
Thank you both.

[00:37:29] Speaker 02:
The case is taken under submission.