[00:00:41] Speaker 04:
Our next case is Novartis Pharmaceuticals v. Westward Pharmaceuticals, appeal number 181434.

[00:00:48] Speaker 04:
Mr. Zimmer, whenever you're ready.

[00:00:53] Speaker 01:
Thank you very much, Your Honor, and may it please the Court, David Zimmer on behalf of Appellant Westward.

[00:00:58] Speaker 01:
Your Honors, this is an unusual case in the sense that although the District Court ultimately ruled for Novartis, many of its key factual findings actually supported Westward.

[00:01:06] Speaker 01:
Most importantly, the District Court found, and this is on page 20 of the appendix,

[00:01:10] Speaker 01:
that given the promising Temsarolomus clinical data and the similarities between mTOR inhibitors Temsarolomus and Everolomus, that a skilled artisan would have been motivated to pursue Everolomus as a treatment option for advanced RCC.

[00:01:24] Speaker 01:
That finding alone compels the conclusion that a skilled artisan would have been motivated to combine the prior art to practice the claimed invention.

[00:01:32] Speaker 01:
The district court's factual findings also show why a skilled artisan would have reasonably expected that Everolomus would inhibit RCC tumor growth.

[00:01:40] Speaker 01:
In addition to acknowledging the promising Temsarolomus clinical data, the district court recognized that the ARC disclosed a strong scientific basis for expecting that an mTOR inhibitor like Temsarolomus or Everolomus would inhibit RCC tumor growth.

[00:01:54] Speaker 01:
Specifically, inhibiting the mTOR pathway blocks the production of proteins that promote the formation of the new blood vessels that are needed for RCC tumor growth.

[00:02:04] Speaker 01:
In the district court's conclusion that a skilled artisan would not have reasonably expected success,

[00:02:09] Speaker 01:
was based on both an erroneously heightened legal standard, as well as factual findings that even Novartis concedes were incorrect.

[00:02:16] Speaker 04:
So you think, for motivation, that that finding that you referred to, that Opposup would have been motivated to pursue everolumus, is one of several potential treatment options.

[00:02:27] Speaker 04:
That's on JA20.

[00:02:28] Speaker 04:
You think that's inconsistent with the finding that defendants failed to prove by clearing convincing evidence that Opposup would have been motivated to select everolumus.

[00:02:38] Speaker 01:
Yes, that's exactly right.

[00:02:39] Speaker 01:
And I think that really the only basis for that later statement that Your Honor quoted was the former statement, the statement that there were other treatment options available.

[00:02:47] Speaker 01:
And this Court has made clear in cases like Parvit, TWI, and Bayer v. Watson that

[00:02:53] Speaker 01:
that a proposed prior combination does not need to be the best option.

[00:02:56] Speaker 01:
It does not need to be the most preferred option.

[00:02:58] Speaker 01:
It simply needs to be a suitable option from which the prior art does not teach away.

[00:03:03] Speaker 04:
Do you think that the judge here was confused in referring to selection language and maybe thinking this was a lead compound case, or maybe thinking there's some law that would say there's thousands of options in a pharmaceutical case?

[00:03:18] Speaker 01:
one of orders from your there might be some additional motivation card select one out of a thousand or even a hundred is that what you think i think that may well be and yet you know i can't get a lot of those the kind of case in which a motivation to select would be well i think that there may be a lot of cases that case law as just also just there may be in a in a lead compound case in a case where there were

[00:03:43] Speaker 01:
You know, there were tens of thousands of options in the district court that might have concluded that there was no motivation to select this method at all.

[00:03:50] Speaker 01:
Then it could be relevant.

[00:03:51] Speaker 01:
But that's not what happened here.

[00:03:53] Speaker 04:
I mean, the district court... Why is this not a lead compound case?

[00:03:57] Speaker 01:
Well, because this is exactly like PAR-V-TWI, where you have a method.

[00:04:01] Speaker 01:
It's a method of treatment.

[00:04:02] Speaker 01:
And, you know, the question is basically whether a skilled artisan would have been motivated to pursue, you know, to select that method, to practice that method.

[00:04:11] Speaker 03:
What about obvious to try?

[00:04:14] Speaker 01:
Well, that sort of gets more to the reasonable expectation issue.

[00:04:17] Speaker 01:
But the issue is for motivation.

[00:04:19] Speaker 03:
Why is that so?

[00:04:20] Speaker 01:
Well, because we're not making an obvious to try argument.

[00:04:23] Speaker 01:
The issue is whether a skilled artisan would have been motivated to combine these prior art references to practice the claim dimension.

[00:04:29] Speaker 01:
And the district court effectively found that a skilled artisan would have been motivated to do that.

[00:04:33] Speaker 01:
That's what that finding on page 20 says.

[00:04:37] Speaker 03:
I'm just wondering why the obvious to try isn't also directed right at the motivation to combine.

[00:04:43] Speaker 03:
Oh, well, I mean, it may be a better way of saying the same thing.

[00:04:46] Speaker 03:
Why isn't it?

[00:04:47] Speaker 01:
Well, it may be in the sense that obviously, obvious to try isn't the standard, but that's not what we're arguing.

[00:04:53] Speaker 03:
The question here is just... I know that's not what you're arguing about.

[00:04:56] Speaker 03:
I'm trying to figure out what the right way of going about this case like this to decide whether or not you would combine the existing references.

[00:05:05] Speaker 03:
Well, I think the analysis is actually... Assuming you say, well, the whole notion that there was

[00:05:10] Speaker 03:
motivation to select a particular reference, and now we're going to throw that aside.

[00:05:16] Speaker 01:
Well, I don't think there really is.

[00:05:17] Speaker 01:
I think under cases like Parr and under cases like Bayer, that when there is a finding in this case where there's a limited set of options, the district court described there as being several potential treatment options available, that when you have a finding that the asserted prior combination is one of those several options, and there's no showing of teaching away, then under- What is it you're trying to combine here?

[00:05:38] Speaker 03:
You keep talking about a motivation to combine.

[00:05:40] Speaker 01:
So the asserted combinations are either Hidalgo 2000 or Hutchinson, which disclosed the use of Temsarolomus to inhibit the growth of advanced RCC with the Everolomus patents, the 972 and 773 patents, which disclosed the compound Everolomus as an mTOR inhibitor, like the compound Temsarolomus.

[00:06:00] Speaker 01:
And that's always been our motivation theory.

[00:06:03] Speaker 01:
And I think what the district court found on page 20 of the appendix is precisely

[00:06:07] Speaker 01:
the skilled artisan would have been motivated to make that combination would have been motivated to try ever on this is one of several one of several potential treatment options absolutely but under cases like party t w i and there he wasn't that is a motivation to combine it doesn't need to be the proposed combination doesn't need to be with us at half the test i mean what exactly you say yeah what you're doing was a reasonable expectation of success absolutely have a fact-finding here

[00:06:35] Speaker 03:
based on all the expert testimony in which the district court judge says, nope, I don't think you've satisfied that test.

[00:06:41] Speaker 01:
So that gets us to the reasonable expectation.

[00:06:45] Speaker 03:
Isn't that, I mean, you've spent half your time in oral argument talking about motivation to combine.

[00:06:52] Speaker 03:
That doesn't get you a nickel unless you can upset the other whole thing.

[00:06:56] Speaker 01:
Absolutely.

[00:06:56] Speaker 01:
And so let me turn to that.

[00:06:58] Speaker 03:
Oral argument ought to go to where your vulnerability is.

[00:07:03] Speaker 01:
Well, I was just responding to the questions, but I'd like to get to the reasonable expectation issue.

[00:07:09] Speaker 01:
Because we think that the district court's decision as to that issue was also based on really a fundamental legal error, but also on key factual errors.

[00:07:17] Speaker 02:
Explain the fundamental legal error you think the court made.

[00:07:20] Speaker 01:
So the legal error was really to focus, was this excessive focus on specific statements in the prior art that showed areas for further research.

[00:07:29] Speaker 01:
I think it's really the precise mistake that led this court to reverse the factual findings in Pfizer v Apotex, where the court relied too heavily on small identified uncertainties without focusing on the bigger picture of what the art actually taught here.

[00:07:43] Speaker 01:
And that legal error was really compounded by the fact that the purported... Why is that a legal error?

[00:07:50] Speaker 03:
Well, I mean, I think that... Why is it putting more emphasis on one fact than on another on legal error?

[00:07:55] Speaker 01:
Well, I think it misunderstood this court's reported

[00:07:59] Speaker 01:
repeated statements that the reasonable expectation of success does not need to be a certain one.

[00:08:05] Speaker 01:
So that's really, I mean, if it's a fact, you know, I think it's fine if it's, if the conclusion is that it's a factual error because the district court sort of erroneously weighed the evidence in that sense.

[00:08:16] Speaker 03:
Well, yeah, you don't want it to go there because of standard review.

[00:08:18] Speaker 03:
Well, right, and I think that... I'm not having trouble seeing where there's that, what Judge Plager suggested, that there's a legal error issue here for us to...

[00:08:27] Speaker 01:
look at right this topic i mean as as as we interpret the fighter the apotex case with this court basically said is that it is legal error to uh... you know to to basically require a certain expectation of success by discounted by placing excessive emphasis on sort of limited uncertainties in the art statements in the art that there are there are uncertainties uh... they need to be confirmed rather than focusing on what the art from the teachers but even if it is a factual are here

[00:08:56] Speaker 01:
We think that there's no question the district court committed clear error.

[00:08:59] Speaker 01:
And that's largely because there are two key factual findings that even Novartis does not defend.

[00:09:04] Speaker 01:
And these are the factual findings on page 13 of the appendix about the Maxwell reference and about the Zhang 1999 reference.

[00:09:12] Speaker 01:
As to Maxwell, the district court largely agreed with Westward that Maxwell's teachings largely favored our position in the sense that Maxwell taught that HIF-1 overexpression leads to angiogenesis and leads to tumor growth.

[00:09:26] Speaker 01:
and that using, but then the district court discounted Maxwell based on Maxwell's statement that it was unclear whether this HIP1 overexpression leads to oncogenesis, the formation of cancer.

[00:09:37] Speaker 01:
But as we explain in our brief, and Novartis doesn't really dispute, this is on page 44, whether or not mTOR inhibition will prevent oncogenesis, will prevent the formation of cancer is completely irrelevant because this court isn't about preventing the formation of tumors.

[00:09:51] Speaker 01:
It's about inhibiting the growth of tumors that already exist.

[00:09:55] Speaker 01:
And so that finding really has no basis in Maxwell.

[00:09:58] Speaker 01:
And the district court similarly concededly aired in interpreting the Zhong 1999 reference and concluding that it found that only one of two advanced RCC samples showed HIP1 overexpression.

[00:10:09] Speaker 01:
And again, Novartis doesn't defend this finding.

[00:10:12] Speaker 01:
Pages 45 and 46 of their brief, they concede that that's wrong.

[00:10:15] Speaker 01:
The Zhong 1999 actually looked at only one sample of advanced RCC and found that it showed the highest observed levels of HIP1 overexpression.

[00:10:24] Speaker 01:
And then went on, and this is at 2190 of the appendix, to specifically identify HIF-1 overexpression as a feature of advanced RCC.

[00:10:32] Speaker 01:
And these two findings were very important to the district court's ultimate decision.

[00:10:35] Speaker 01:
If you look at page 22 of the appendix, the district court specifically noted uncertainty concerning the role of HIF-1 in RCC tumor growth as one of the few facts in which it relied in finding no reasonable expectation of success.

[00:10:50] Speaker 01:
And that statement about the role of HIF-1

[00:10:54] Speaker 01:
clearly relates back to these two conceded factual errors the district court made in interpreting Maxwell and Zhang 1999.

[00:11:01] Speaker 01:
And so I think if you strip away these conceded factual errors, you strip away this erroneous reliance on facilitated statements about uncertainty, that the art really all points the same direction.

[00:11:13] Speaker 01:
You have this strong scientific basis for expecting that an mTOR inhibitor, like ever on this, will inhibit tumor growth.

[00:11:19] Speaker 01:
You have this phase one clinical data that the art repeatedly characterized

[00:11:24] Speaker 01:
as showing impressive anti-tumor activity, as showing profound inhibition of tumor growth.

[00:11:29] Speaker 01:
The 446 patent looks at this data and concludes that temsuralinus is useful in the treatment of advanced RCC.

[00:11:35] Speaker 02:
If Phase 1 doesn't address that issue, if I remember correctly from my work at HHS, Phase 1 only addresses the question of safety, not effectiveness.

[00:11:47] Speaker 01:
So that's what those studies are targeted at, but that's exactly why reference after reference in this case

[00:11:52] Speaker 01:
found this, these showings of effectiveness to be particularly surprising and particularly noteworthy.

[00:11:57] Speaker 01:
So the 446 patent, and again, this is a 2578 in column four, specifically describes these results as particularly surprising because they came in a phase one study.

[00:12:08] Speaker 01:
Sorry?

[00:12:08] Speaker 03:
There's a low dose.

[00:12:09] Speaker 01:
Exactly.

[00:12:10] Speaker 01:
And Hedalva 2000.

[00:12:11] Speaker 03:
Look what you, just a dab will do you.

[00:12:14] Speaker 03:
The whole notion is you're going to, look what you're seeing with a very low dose.

[00:12:18] Speaker 03:
Exactly.

[00:12:18] Speaker 03:
Let's crank it up and then let you see.

[00:12:20] Speaker 01:
Exactly, and so that's what the 446 patent says.

[00:12:23] Speaker 01:
Hidalgo 2000 reaches exactly the same conclusion and suggesting that these results are particularly noteworthy because they came in a phase one study in which effects are often limited.

[00:12:34] Speaker 01:
And so I think reference after reference actually found that the fact that these were phase one studies to be particularly revealing, particularly probative, and particularly surprising.

[00:12:44] Speaker 01:
And I think that especially given that that promising

[00:12:48] Speaker 01:
Phase one data was backed up by the strong scientific explanation of why a skilled artisan would expect inhibiting the mTOR pathway to work, to inhibit RCC tumor growth.

[00:12:58] Speaker 01:
Those two things together provide, at the very least, a reasonable expectation that inhibiting the mTOR pathway would inhibit tumor growth.

[00:13:10] Speaker 04:
You're into your rebuttal time.

[00:13:11] Speaker 04:
Would you like to present your time?

[00:13:13] Speaker 01:
Yes, absolutely.

[00:13:13] Speaker 01:
Thank you.

[00:13:23] Speaker 00:
May it please the court.

[00:13:25] Speaker 00:
Westward has not established that the district court made any reversible error in its analysis of reasonable expectation of success or motivation, let alone both, which it must do to succeed on this appeal.

[00:13:38] Speaker 04:
How do you explain these seemingly inconsistent statements in the district court's opinion on motivation to combine?

[00:13:48] Speaker 00:
There's no dispute that an obviousness analysis requires consideration of the art as a whole and cannot be based on hindsight.

[00:13:57] Speaker 00:
The person with ordinary skill can't start with the patent claims in hand and then work backwards with the art.

[00:14:04] Speaker 00:
They have to start by looking at the art as a whole because they don't have the solution.

[00:14:08] Speaker 00:
But there's no dispute that Dr. Cho, Westwood's expert here, used hindsight, started with the patent claims, and only looked at everolumus.

[00:14:17] Speaker 00:
He never looked at the art as a whole.

[00:14:19] Speaker 04:
Is this your answer to address the district court's two seemingly inconsistent fact findings?

[00:14:27] Speaker 00:
The district court here based its conclusion on the fact that Westward's expert performed the wrong legal analysis.

[00:14:34] Speaker 00:
He used hindsight, and he never considered the art as a whole.

[00:14:39] Speaker 00:
And for that reason, Westward and Dr. Cho failed to meet their burden on the motivation prong of the analysis.

[00:14:48] Speaker 00:
If you can assess motivation with hindsight.

[00:14:50] Speaker 04:
What do you think the district court meant when it said Opposa would have been motivated to pursue everolumus as one of several potential treatment options for advanced solid tumors, including advanced RCC?

[00:15:04] Speaker 00:
Well, that language is less than clear.

[00:15:05] Speaker 00:
The judge may have been using an obvious to try type standard in that statement.

[00:15:10] Speaker 00:
But there's no dispute here that Dr. Cho used hindsight in his motivation analysis

[00:15:17] Speaker 00:
and never looked at the art as a whole.

[00:15:19] Speaker 00:
That's an undisputed fact.

[00:15:21] Speaker 00:
And for that reason alone, the district court's decision on motivation has no reversible error.

[00:15:27] Speaker 04:
Why do you think the court then said, where it said a defendant has failed to prove by clearing convincing evidence that opposed it would have been motivated to select everolimus?

[00:15:36] Speaker 04:
Why was the word select used there?

[00:15:38] Speaker 04:
Was the court referring to some kind of lead compound analysis?

[00:15:43] Speaker 00:
It's possible that that's what the court was referring to.

[00:15:46] Speaker 00:
But coming back to my point, there's no dispute here that Dr. Cho did use hindsight in his motivation analysis, and that's not permitted.

[00:15:54] Speaker 00:
And for that reason alone, we think the district court's motivation conclusion should stand.

[00:15:59] Speaker 00:
So I'll turn now to reasonable expectation of success.

[00:16:04] Speaker 00:
There's no evidence here that the district court applied the wrong legal standard in its reasonable expectation of success conclusion.

[00:16:12] Speaker 00:
The judge repeatedly and consistently articulated the correct standard for obviousness and never suggested it required certainty.

[00:16:23] Speaker 00:
And regardless of specific language and individual fact findings, that doesn't mean the judge applied the wrong standard in his ultimate conclusion that there was no reasonable expectation of success under the clear and convincing evidence stance.

[00:16:38] Speaker 00:
that the district court's ultimate conclusion took into account the flaws and the knowledge gaps in each aspect of Westwood's case.

[00:16:47] Speaker 00:
And those rise far above the level of just some general uncertainty.

[00:16:51] Speaker 00:
They include Westwood's reliance on clinical study data that was subject to many undisputed limitations and that was designed to assess safety and not even powered to evaluate efficacy.

[00:17:03] Speaker 00:
It included Westwood's reliance on hypotheses that required further analysis, inconsistent results in the prior art, and oversimplification of the MTOR and HIF-1 pathways.

[00:17:17] Speaker 00:
The district court both correctly articulated and applied the correct legal standard for reasonable expectation of success.

[00:17:27] Speaker 00:
I'll turn now to Westwood's allegation that the district court aired in its factual conclusion

[00:17:32] Speaker 00:
of no reasonable expectation of success.

[00:17:34] Speaker 00:
And that conclusion was not clear error.

[00:17:37] Speaker 00:
It was supported by three categories of fact-linings relating to the limitations on the phase one study data, the differences between mTOR inhibitors, and the knowledge gaps in Westward's molecular biology argument.

[00:17:53] Speaker 00:
In nitpicking individual fact-linings, Westward ignores the totality of the evidence that supported the district court's conclusion.

[00:18:01] Speaker 00:
including the admissions of its own expert, Dr. Cho.

[00:18:06] Speaker 00:
Now the first category of those factual findings are those that relate to the phase one data for Temsarolomus, which is a different drug than the claimed drug Everolomus.

[00:18:16] Speaker 00:
The district court did not err in analyzing the preliminary phase one Temsarolomus data or statements about that data.

[00:18:24] Speaker 00:
The district court carefully considered those studies and the data in context

[00:18:29] Speaker 00:
and recognize their limitations.

[00:18:31] Speaker 03:
Judge recognized that those studies showed promise, right?

[00:18:35] Speaker 00:
That the judge used the word promise in one individual fact finding.

[00:18:40] Speaker 00:
But that doesn't mean there's a reasonable expectation that the drug would work.

[00:18:44] Speaker 00:
We need to look at the studies in context.

[00:18:46] Speaker 03:
What we need to look at is the emphasis that the judge put on each of the relevant data points in the factual analysis, right?

[00:18:55] Speaker 03:
When you add those up to see whether or not once you've added up

[00:19:00] Speaker 03:
the findings on the data points, whether or not one would have had a reasonable expectation of success.

[00:19:07] Speaker 00:
That's correct, Your Honor.

[00:19:08] Speaker 03:
And you've got prior phase one tests on a compound that is kissing cousin or brother, sister.

[00:19:15] Speaker 03:
How do you describe it?

[00:19:17] Speaker 03:
It's certainly related to Avramos, right?

[00:19:20] Speaker 00:
There is some structural similarity between the two compounds.

[00:19:23] Speaker 00:
And we do need to look at all of the data points.

[00:19:26] Speaker 00:
And the data points we need to consider

[00:19:28] Speaker 00:
including the statements about the promising data that council referred to, are those about the undisputed limitations of those phase one studies.

[00:19:36] Speaker 00:
The district court found that those studies were designed to test safety, not efficacy.

[00:19:41] Speaker 00:
And because they weren't even powered to determine efficacy, that's undisputed here, the district court didn't err in refusing to give the data, statements about that data, the elevated weight that Westwood suggests that we should give those statements or that data.

[00:19:57] Speaker 00:
The studies were also uncontrolled.

[00:20:00] Speaker 00:
They reported only a small number of RCC responses, and the trials were not specific to RCC patients, renal cell carcinoma patients in particular.

[00:20:11] Speaker 00:
So we don't know how many RCC patients were enrolled or what percentage of those patients had a response or no response at all.

[00:20:19] Speaker 00:
The data here was only preliminary.

[00:20:21] Speaker 00:
These trials were still ongoing, so we only have interim preliminary data

[00:20:27] Speaker 00:
not final data, and those results were subject to change in the final study publications, which were not yet published.

[00:20:36] Speaker 00:
Also, as of 2001, mTOR inhibitors were a relatively new line of research for RCC.

[00:20:42] Speaker 00:
No mTOR inhibitor had been approved for any type of cancer, and one of ordinary skill would have also been aware of the fact that there was a dismal success rate for cancer drugs generally and RCC drugs in particular.

[00:20:56] Speaker 00:
The district court here recognized these undisputed limitations and took them all into account in deciding to reduce the weight afforded to the preliminary phase one data.

[00:21:11] Speaker 00:
Now, even if that preliminary phase one data had shown that temps role in this was effective in the claim methods, that doesn't provide a reasonable expectation that ever role in this, the claim compound would also be effective.

[00:21:23] Speaker 00:
And that brings me to the second category.

[00:21:26] Speaker 03:
What are the distinguishing features of the two compounds that allow you to demonstrate what you just said?

[00:21:34] Speaker 00:
So as the district court correctly found, there were differences between the two compounds in terms of their biological and pharmacological properties that were relevant to inhibiting growth.

[00:21:46] Speaker 00:
These included differences between the compounds in terms of their half-lives, binding to FKBP12,

[00:21:53] Speaker 00:
as well as the relationship between dose and area under the curve.

[00:22:01] Speaker 04:
I'll turn now to... What impact would the half-life have, the difference in half-life?

[00:22:06] Speaker 00:
So Dr. Burris, Novartis's expert here, testified that all of those differences taken together would lead one of ordinary skill... What specifically?

[00:22:15] Speaker 00:
My question is specific.

[00:22:16] Speaker 00:
What difference would the half-life

[00:22:19] Speaker 00:
So Dr. Burris testified that differences in half-life will lead to differences in efficacy, whether or not a compound is active or inactive against a specific tumor.

[00:22:29] Speaker 00:
He testified that half-life is a complex function of drug distribution, biotransformation, and elimination, and all of these facts would create differences.

[00:22:38] Speaker 04:
Is half-life, do I understand correctly that half-life is the amount of time that the drug will be in the body before, I guess, it's metabolized?

[00:22:46] Speaker 00:
That's correct.

[00:22:46] Speaker 00:
It's essentially the amount of time the drug is in the body.

[00:22:49] Speaker 00:
before it's metabolized or eliminated or moved to a difference.

[00:22:52] Speaker 04:
That can have an impact on how it impacts the body and the growth of tumor?

[00:22:56] Speaker 04:
Is that what the experts said?

[00:22:57] Speaker 00:
Yes, that's correct.

[00:22:58] Speaker 00:
Half-life in combination with FKBP12 binding also has an impact.

[00:23:02] Speaker 00:
And there's a significant difference in the half-lives here.

[00:23:05] Speaker 00:
Temsarolomus has a half-life of 15 hours.

[00:23:08] Speaker 00:
Everolomus has a half-life of 60 hours.

[00:23:10] Speaker 00:
So these are not similar half-lives.

[00:23:12] Speaker 03:
Well, the problem is I don't frankly know whether or not the half-life

[00:23:15] Speaker 03:
difference makes any real difference for purposes of this pharmaceutical or not.

[00:23:19] Speaker 03:
That's a question.

[00:23:20] Speaker 03:
We simply don't know.

[00:23:21] Speaker 03:
If there's a question there, then the question undermines the notion that you would have a reasonable expectation.

[00:23:26] Speaker 00:
That's correct.

[00:23:27] Speaker 00:
We simply don't know.

[00:23:28] Speaker 00:
When this patent was filed, everolimus, the claimed compound, had never been tested as an anti-tumor agent in any tumor at all.

[00:23:38] Speaker 00:
And I'll turn now to the molecular biology argument, which is the third category of facts that support the district court's conclusion.

[00:23:47] Speaker 00:
Now Westward has overstated what was known about molecular biology of RCC in 2001.

[00:23:53] Speaker 00:
There was no established causal connection between HIF-1 overexpression and RCC growth, as they've suggested.

[00:24:02] Speaker 00:
The district court found correctly that there were knowledge gaps in this understanding and only a working hypothesis of RCC's molecular biology.

[00:24:13] Speaker 00:
This evidence did not rise to the level of clear and convincing evidence of a link between inhibiting mTOR and inhibiting RCC growth.

[00:24:24] Speaker 00:
And Council for Westward referenced factual findings with respect to Maxwell and Zong 1999.

[00:24:31] Speaker 00:
And it suggested that Novartis has conceded that there were errors in the district court's conclusion.

[00:24:36] Speaker 00:
We certainly don't concede that.

[00:24:38] Speaker 03:
Novartis doesn't concede, right?

[00:24:41] Speaker 00:
With respect to the Maxwell statement that Westward has emphasized, that statement was merely a hypothesis.

[00:24:49] Speaker 00:
Hypothesis, that's the language that the district court used in its decision.

[00:24:53] Speaker 00:
A hypothesis that HIF-1 activation may be linked to angiogenesis in certain tumors.

[00:25:02] Speaker 00:
And Westward also referenced a statement in Maxwell about oncogenesis, but its explanation for why that statement is not relevant

[00:25:10] Speaker 00:
That's a new argument on appeal that was not presented to the district court.

[00:25:15] Speaker 00:
It also has no expert support.

[00:25:18] Speaker 00:
Dr. Cho, their expert, never testified that oncogenesis was not relevant to the claimed invention.

[00:25:26] Speaker 00:
He said only that oncogenesis was different from angiogenesis.

[00:25:30] Speaker 00:
That doesn't address the issue here.

[00:25:33] Speaker 00:
And as for Zong, 1999, even though the district court did mistakenly suggest that both

[00:25:39] Speaker 00:
RCC samples there were advanced RCC samples when only one of the two samples was an advanced sample.

[00:25:47] Speaker 00:
That error is harmless.

[00:25:49] Speaker 00:
It doesn't impact the court's statement that the ART reported mixed results for HIF-1 expression in RCC.

[00:25:57] Speaker 00:
The district court also relied on SAMENZA for that point.

[00:26:01] Speaker 00:
SAMENZA also reported mixed results for RCC in cell line and biopsy samples.

[00:26:08] Speaker 00:
and Westward hasn't disputed the district court's reliance on Simenza in this appeal.

[00:26:15] Speaker 00:
And even if we were to accept Westward's interpretation of Zong 1999, its own expert testified that Zong would have only suggested that additional investigation of HIF-1 may make it an attractive and a novel target for therapeutics.

[00:26:33] Speaker 00:
So again, its own expert is expressing

[00:26:36] Speaker 00:
the opinion that additional research is required to link HIF-1 to RCC growth.

[00:26:43] Speaker 00:
On top of this, research on mTOR inhibitors was only at the early stages.

[00:26:48] Speaker 00:
No mTOR inhibitor had been shown to be therapeutically effective in any cancer, and as I mentioned, there was no preclinical or clinical data for everolimus as an anti-tumor agent.

[00:27:02] Speaker 00:
Also, Westwood's expert, Dr. Chiu, admitted that tumors could proliferate despite mTOR inhibition.

[00:27:08] Speaker 00:
So just because you inhibit mTOR, that doesn't provide a reasonable expectation that you will inhibit tumor growth.

[00:27:19] Speaker 00:
Unless your honors have any additional questions.

[00:27:22] Speaker 04:
Anything else?

[00:27:23] Speaker 00:
Thank you.

[00:27:28] Speaker 02:
And where do you begin?

[00:27:30] Speaker 01:
Well, let me just try to take these three in turn.

[00:27:32] Speaker 01:
I realize I don't have a ton of time.

[00:27:34] Speaker 01:
But as to the data, I think the most important thing here is to look at the way the art itself characterized this data.

[00:27:39] Speaker 01:
And this is over and over again.

[00:27:41] Speaker 01:
I mean, Hidalgo 2000, this is at 2028, describes the data as showing impressive anti-tumor activity.

[00:27:47] Speaker 01:
The 446 patent concludes that the data shows that Temsarolomus is useful in the treatment of renal carcinoma.

[00:27:53] Speaker 01:
All of the district court's findings as regard to the limitations of the data fly directly in the face of what the skill of the artisans, the art references themselves, how they characterize the data.

[00:28:04] Speaker 01:
And especially, I'd just like to focus on the number of this issue on which counsel focused quite a bit on, the number of RCC patients.

[00:28:11] Speaker 01:
Dr. Cho testified, and this is at 1112 to 1113, that a skilled artisan would have expected, based on the prevalence of advanced RCC in the population, that the number of RCC patients in the sample would be small.

[00:28:22] Speaker 01:
And that is unrebutted testimony, and it's consistent with what the art itself said.

[00:28:26] Speaker 01:
So at 2031, Hidalgo 2000 describes these results as showing consistent, uses the word consistent tumor suppression.

[00:28:34] Speaker 01:
And again, I think that undermines any suggestion that there was actually some huge number of RCC patients who were not showing success.

[00:28:42] Speaker 01:
In terms of the difference between the mTOR inhibitors, if you look at the art that discusses mTOR inhibitors as a whole, so if you look at, for instance, the Huang reference, or Hidalgo 2000, or Zhong 2000,

[00:28:52] Speaker 01:
These references treat these compounds as a class.

[00:28:55] Speaker 01:
There's no suggestion in any of these references that one mTOR inhibitor might work and one might not.

[00:29:00] Speaker 01:
And that makes sense because they're doing the same thing.

[00:29:02] Speaker 01:
Now, does that mean they're going to have exactly the same efficacy?

[00:29:05] Speaker 01:
No.

[00:29:05] Speaker 01:
And Dr. Cho acknowledged this.

[00:29:08] Speaker 01:
This is at 987, but testified that a skilled artisan would have expected the inhibitors to behave similarly.

[00:29:14] Speaker 01:
And Dr. Burris actually never disputed that.

[00:29:16] Speaker 01:
If you look at 1399 to 1402 of the appendix,

[00:29:19] Speaker 01:
he testified that a skilled artisan would not have expected the two mTOR inhibitors to be the same.

[00:29:24] Speaker 01:
But whether they're the same isn't the question.

[00:29:25] Speaker 01:
The question is whether a skilled artisan would have understood them to behave sufficiently similarly that an artisan would look at this Temsarolomus data and expect it to show similar results in the context of Everolomus.

[00:29:37] Speaker 01:
And again, I think the way the art characterized these references, the way the experts testified, it all points the same way.

[00:29:43] Speaker 01:
And the binding affinity and elimination half-life issues

[00:29:49] Speaker 01:
are really just, they don't contradict that at all in the sense that there's no evidence that any of those differences have any clinical effect.

[00:29:56] Speaker 01:
So if you look at the Shuler reference, this is at 2088 of the record, Shuler specifically says- There's no evidence that they don't have that effect.

[00:30:04] Speaker 01:
Well, yes.

[00:30:05] Speaker 01:
So that's what I'm getting to.

[00:30:06] Speaker 01:
Shuler specifically says that despite the differences in binding affinity between Everolumus and rapamycin, that the two drugs are equipotent.

[00:30:14] Speaker 01:
And Shuler actually uses this word at 2088.

[00:30:17] Speaker 01:
So the evidence suggests that while these differences may exist, that they don't have these clinical effects.

[00:30:23] Speaker 01:
And all of the references and all of the testimony suggests that a skilled artisan would have understood these references, would have understood these compounds as behaving similar.

[00:30:31] Speaker 02:
Ultimately, the trial judge's problem is to determine whether all that body of evidence is causative.

[00:30:38] Speaker 02:
Isn't that right?

[00:30:40] Speaker 01:
well whether a skilled artisan would have viewed it as creating a reasonable question is which direction is it pointing is it pointing in any direction at all and if so sufficiently so correct absolutely and we think that a question of fact or is that a question of law well ultimately it's a question of fact i mean i think that the the way any individual reference points is is going to be a factual question but again we think that most of these findings if you actually compare what the district court concluded to the art itself and even to the expert testimony

[00:31:09] Speaker 01:
that it just doesn't get to where they were not clear convincing right that's right absolutely a lot of takes a lot of it doesn't we think that this is a case where that evidence exists it's actually unusual to have this kind of clinical data and scientific art that all points in the same direction and notably there's no secondary considerations evidence here there's no teaching away there's nothing pointing the other way but the trial judge was not convinced they all same uh... well

[00:31:37] Speaker 01:
actually i think he was i think what the trial judge said was that some of it there was some ground for uncertainty but nothing the trial judge identified nothing suggesting that any of this pointed away from these compounds work i think what the trial judge found uh... again we would say your your burden to show their point uh... will succeed going going

[00:31:57] Speaker 01:
Well, respectfully, no, Your Honor.

[00:32:00] Speaker 01:
Our obligation is to show that there was a reasonable, a skilled artisan would have had a reasonable expectation.

[00:32:04] Speaker 01:
Not necessarily that it would.

[00:32:06] Speaker 01:
This Court has made that abundantly clear, that a reasonable expectation is not certain.

[00:32:10] Speaker 03:
Oh, that reasonable expectation makes the test a fudgy one.

[00:32:14] Speaker 01:
Right?

[00:32:14] Speaker 01:
I suppose that's one way of putting it.

[00:32:16] Speaker 03:
In whose mind is it reasonable?

[00:32:18] Speaker 01:
In the mind of a skilled artisan as of the priority date.

[00:32:21] Speaker 01:
So, I mean, and I think that

[00:32:22] Speaker 01:
You know, under cases like O'Farrill and Pfizer, the record here really compels a conclusion that the expectation of success was at least reasonable.

[00:32:31] Speaker 01:
I see my time has expired.

[00:32:32] Speaker 01:
I'm happy to answer any more questions.

[00:32:33] Speaker 02:
So there really are two vague ideas we're working with.

[00:32:39] Speaker 02:
One of them is, what is reasonable?

[00:32:41] Speaker 02:
And what did the judge think a skilled artisan would think was reasonable?

[00:32:46] Speaker 02:
Isn't that fair?

[00:32:49] Speaker 01:
Yes, I mean, I think they're kind of, I guess you can separate them out in that way.

[00:32:53] Speaker 02:
I think the question is, you know, whether the trial judge here permissibly concluded that a skilled artisan... If we treat that as a question of fact, we have to conclude, for your benefit, that there was clear aura in the trial judge's estimate of where everything pointed, isn't it?

[00:33:13] Speaker 01:
That's right, although again I would note that despite Novartis saying that they didn't concede these factual hours, they effectively still conceded them.

[00:33:20] Speaker 01:
And I'd point to pages 44 and 46 of their briefs.

[00:33:23] Speaker 01:
So I think there's no question that at the very least the district courts conducting that inquiry rested on several sort of conceded mistakes about what the art actually taught.

[00:33:34] Speaker 01:
So I think that certainly has to be factored in to the bigger picture as to whether... And what is our job to determine whether the

[00:33:43] Speaker 02:
evidence all points that way, or whether even putting aside the errors that he made, whether there's enough ambiguity in it that you didn't prove your case being clear.

[00:33:56] Speaker 01:
Yeah, I think this court has described the clear error standard as something along the lines of a distinct sense that a mistake has been made or something like that.

[00:34:05] Speaker 01:
And so I think that's the question.

[00:34:06] Speaker 01:
The question is, once you take away what are effectively conceded factual errors, once you take away

[00:34:12] Speaker 01:
what we argue is the excessive reliance on certain issues in the art let the district court listens to the experts and becomes more persuaded by one another so that's right your honor but i think it's notable here along those lines of the district actually didn't make any adverse any credibility findings about the experts the expert the district would actually relied on it let's all come in absolutely any any in fact you've got someone who says half-life doesn't matter

[00:34:38] Speaker 03:
half-life wouldn't possibly make any difference at all in this type of a setting, and the other side's got somebody who said, well, it might.

[00:34:45] Speaker 01:
Well, again, I point out there that what the other side said was that what a skilled artisan would understand from these half-life data is that a skilled artisan would not have expected these compounds to behave in the same way.

[00:34:57] Speaker 01:
And again, I point the court to 1399 to 1402.

[00:35:00] Speaker 01:
You can actually look at what he said.

[00:35:01] Speaker 01:
He never actually disagreed that a skilled artisan would understand these compounds as behaving similarly.

[00:35:07] Speaker 01:
And that's really the question.

[00:35:07] Speaker 01:
It doesn't matter whether a skilled artisan would view the compounds as identical or having the same efficacy.

[00:35:12] Speaker 01:
The question is whether the data would translate.

[00:35:16] Speaker 01:
Thank you very much.

[00:35:17] Speaker 01:
Thank you.

[00:35:17] Speaker 04:
Case is submitted.