[00:00:35] Speaker 04:
The next argued case is number 17, 2397, the University of Pennsylvania against Eli Lilly and Company, Mr. McCloud.

[00:00:52] Speaker 00:
Good morning.

[00:00:53] Speaker 00:
May it please the court?

[00:00:54] Speaker 00:
The Penn claims on appeal concern an extremely surprising invention that was made over 20 years ago.

[00:01:01] Speaker 00:
No one would have believed at that time that you could arrest tumor cells from dividing and then hit them with radiation and have a beneficial effect on radio sensitivity.

[00:01:14] Speaker 00:
Radiation was known then and was still known to work preferentially on dividing cells.

[00:01:21] Speaker 00:
But the pen inventors found when they inhibited tumor cell division using agents that act through herby receptors

[00:01:31] Speaker 00:
Not only did they get a beneficial effect, but the tumor cells responded in an extremely surprising way.

[00:01:39] Speaker 00:
Rather than dying a slow death by accumulated DNA damage to the chromosome, which you would typically see in radiation.

[00:01:48] Speaker 01:
The specification says that disruption of tyrosine kinase activity, such as by inhibiting dimer formation, results in

[00:02:00] Speaker 01:
cytostatic effect on tumor cells.

[00:02:03] Speaker 01:
In the great brief at 6 and 7, you argued that that passage, quote, cannot be reasonably read to mean that disruption of tyrosine kinase activities, such as by inhibiting dimerization, always results in a cytostatic effect in all tumor cells.

[00:02:21] Speaker 01:
Why isn't it a reasonable reading?

[00:02:24] Speaker 00:
So that passage, if you read the entire paragraph, that sentence is actually repeated twice in the patent.

[00:02:30] Speaker 00:
One was in the context of tumor cells that have heterodimers that have a mutant EGFR receptor.

[00:02:38] Speaker 00:
And the patent says, in those tumor cells, you could achieve the cytostatic effect by inhibiting dimerization.

[00:02:46] Speaker 00:
It also says it in the preceding paragraph that deals with heterodimers consisting of P185 and EGFR.

[00:02:55] Speaker 00:
So that sentence, while it provides

[00:02:58] Speaker 00:
written description support for the claim limitation does not set forth a universal rule.

[00:03:06] Speaker 00:
This distinction between a cytostatic effect and a cytotoxic effect is at the heart of this appeal.

[00:03:14] Speaker 00:
Because indeed, a combination of therapies that each have a cytotoxic effect on a tumor cell as a cancer therapy, not particularly surprising.

[00:03:26] Speaker 00:
But proceeding a therapy like radiation with another one that was expected to impede its efficacy, that is particularly surprising indeed.

[00:03:37] Speaker 00:
It is completely lost in the final written decision, nowhere to be found.

[00:03:47] Speaker 00:
This appeal comes to this court with at least three errors in the context of inherency, and I hope to have time to cover each one.

[00:03:56] Speaker 00:
The first was in the context of claim construction.

[00:04:00] Speaker 00:
The first was in the context of claim construction.

[00:04:03] Speaker 00:
Here, the board held that the cytostatic effect limitation was merely the inherent result of inhibiting dimerization.

[00:04:11] Speaker 00:
The immediate effect of that claim construction was to scoop into the scope of the claim what was disclaimed during prosecution.

[00:04:21] Speaker 00:
And that was the use of antibodies having a cytotoxic effect.

[00:04:25] Speaker 00:
The board could only reach this claim construction by one, ignoring the testimony of three experts, one of which was Lilly's.

[00:04:35] Speaker 00:
Dr. Reese specifically stated in his deposition that there were circumstances under which an antibody that inhibits dimerization does not have a cytostatic effect on the cell.

[00:04:47] Speaker 00:
That very sentence shows that the board's claim construction cannot be correct.

[00:04:54] Speaker 00:
Two, the board could only reach that claim construction by completely ignoring the prosecution history.

[00:05:01] Speaker 02:
Even if we agree with you on claim construction, didn't the board make the alternative finding that the combination of, I'm going to botch all of these names, Sally, DiNardo, and Balaban, inherently disclose a cytostatic effect, and then you get everything else through the combination?

[00:05:22] Speaker 00:
They did.

[00:05:22] Speaker 02:
And that determination... If that's correct and supported by substantial evidence, then would you agree that the claim construction doesn't matter?

[00:05:31] Speaker 00:
There are actually two questions, two issues of inherency in what they held.

[00:05:36] Speaker 00:
The first one was whether the cytostatic effect limitation was present in the references.

[00:05:43] Speaker 00:
And Dr. Reese's testimony alone shows that that isn't true, because he stated that C225

[00:05:50] Speaker 00:
sometimes doesn't cause a cytostatic effect.

[00:05:53] Speaker 00:
So, inherency of the cytostatic effect limitation was not proven.

[00:05:58] Speaker 00:
The second issue in the context of inherent obviousness was ignoring unexpected results.

[00:06:06] Speaker 00:
And this court recently dealt with this issue in the Millennium and Honeywell cases in which you held that unexpected results cannot be ignored in an obviousness analysis.

[00:06:18] Speaker 00:
The question must always be,

[00:06:20] Speaker 00:
whether there's a reasonable expectation of success in the claimed invention.

[00:06:26] Speaker 01:
During prosecution, Penn represented that the presently claimed invention uses antibodies that inhibit formation of ERB protein dimers.

[00:06:37] Speaker 01:
Continuing next sentence, the antibodies used in these methods are therefore also cytostatic.

[00:06:45] Speaker 01:
Doesn't that prosecution language support a conclusion that inhibition of ERB

[00:06:50] Speaker 01:
protein dimers and a cytostatic effect are coextensive?

[00:06:55] Speaker 00:
I think the Penn inventors did make that argument very early on, and it was not successful.

[00:07:02] Speaker 00:
And in fact, after that, they submitted a pretty extensive IDS with references that showed that that wasn't necessarily the case.

[00:07:11] Speaker 00:
And as a result, they amended the claim to add the cytostatic effect limitation.

[00:07:18] Speaker 00:
It was a critical limitation that was added to the claim that then resulted in allowance, and it was error for the board to read the claim as if it wasn't there.

[00:07:29] Speaker 00:
And I will add that the board reached their claim construction by following a claim construction argument that Lilly made for the first time at the oral hearing.

[00:07:41] Speaker 00:
This court in Del V. Acceleron held that the board was obligated to dismiss such a late stage argument.

[00:07:49] Speaker 01:
If we agree with Lily that the PTABs found the challenge claims would have been obvious even under Penn's construction of cytostatic effect, and if we affirm the obviousness finding, how are you prejudiced by the alleged APA violation?

[00:08:09] Speaker 00:
I would say that in this decision, the board ignored so much contrary evidence.

[00:08:18] Speaker 00:
Ignoring contrary evidence of record is by definition arbitrary and capricious, and the decision is entitled to no deference.

[00:08:27] Speaker 01:
There is such a thing as harmless error.

[00:08:29] Speaker 01:
You'd agree with that.

[00:08:30] Speaker 00:
Yes, but in this case, the error was not harmless.

[00:08:34] Speaker 00:
The court completely omitted a reasonable expectation of success analysis in the context of obviousness.

[00:08:41] Speaker 00:
And even though the final written decision said that they were

[00:08:46] Speaker 00:
following Penn's construction, they weren't.

[00:08:48] Speaker 00:
They completely omitted the fact that a cytostatic effect was distinguished during prosecution from a cytotoxic effect.

[00:08:58] Speaker 00:
They are not the same.

[00:08:59] Speaker 00:
They are not one and the same.

[00:09:03] Speaker 00:
Going back to the point that you raised about the two different kinds of inherency errors in this inherent obviousness context.

[00:09:12] Speaker 00:
Here, I think it's pertinent to note that Lilly has conflated these two points in their brief on pages 35 to 36 when they discuss the Honeywell case.

[00:09:23] Speaker 00:
They say, but Penn doesn't argue that the cytostatic effect limitation was unexpected.

[00:09:29] Speaker 00:
Therefore, Honeywell is not relevant.

[00:09:31] Speaker 00:
I think they completely missed the point that there is a sequence of events, and I think it was laid out very well in the Parr Farm case.

[00:09:39] Speaker 00:
where first you need to determine whether the claimed limitations are in the references, and then you consider whether there was a reasonable expectation of success in the claimed invention.

[00:09:56] Speaker 00:
I don't see any lights on, so I think I'm still within my time.

[00:09:59] Speaker 00:
I'd like to return to the three buckets of inherency error.

[00:10:08] Speaker 00:
The third was in the context of the heterodimer claims.

[00:10:12] Speaker 00:
Here, Lilly had argued that the P185 receptor was inherently present in the cells of Salah.

[00:10:20] Speaker 00:
When they didn't prove their case, the board substituted its own obviousness rationale based not on inherency, but based on whether it would have been expected or would have been understood

[00:10:34] Speaker 01:
Let me ask you this.

[00:10:36] Speaker 01:
The PTAB identified the heterodimer claims as 5, 10, 14, 17, and 20.

[00:10:42] Speaker 01:
Do you agree that's all of them?

[00:10:44] Speaker 00:
I think there might have been one more.

[00:10:46] Speaker 00:
I don't have the list in front of me.

[00:10:52] Speaker 00:
But they were set forth at the beginning of our brief.

[00:10:59] Speaker 00:
Back to the heterodimer issue.

[00:11:01] Speaker 00:
They said they made an argument that it would have been understood that the heterodimers existed at the time, yet they cited Lilly's post-filing date references in support of that argument.

[00:11:13] Speaker 00:
This was legal error in the context of obviousness of the most egregious sort.

[00:11:18] Speaker 01:
You agree that absence, presence or absence of a reasonable expectation is a question of fact, right?

[00:11:26] Speaker 00:
Well, again, if the court is struggling with the deference to give to this case, I would say that ignoring contrary evidence is arbitrary and capricious and that overrides substantial evidence.

[00:11:37] Speaker 02:
That's just substantial evidence.

[00:11:38] Speaker 02:
I mean, if they ignore it too much, then their decision lacks substantial evidence.

[00:11:43] Speaker 02:
But ignoring just means they didn't believe it.

[00:11:50] Speaker 02:
It can't just be ignoring it.

[00:11:52] Speaker 02:
It has to be the weight of the evidence is so leaning one way that no reasonable person would come up with the board's conclusion.

[00:12:02] Speaker 02:
And it's not really the arbitrary and capricious standard.

[00:12:06] Speaker 02:
It's a substantial evidence standard for facts.

[00:12:08] Speaker 00:
I'd like to talk about the weight of that.

[00:12:11] Speaker 01:
And while you're answering that, how is that decision employing a new legal theory rather than making factual findings?

[00:12:20] Speaker 00:
Let's talk about the weight of the decision.

[00:12:23] Speaker 00:
Penn presented at least five references that taught away from the claimed invention and that led away from the claimed invention because they showed other instances where agents having a cytostatic effect were administered prior to radiation and had a detrimental effect on radio sensitivity.

[00:12:41] Speaker 02:
Sure.

[00:12:41] Speaker 02:
I mean, you have all kinds of evidence on your side, but the problem for you on the substantial evidence back in this review is that

[00:12:50] Speaker 02:
It doesn't need to be a ton for the board's decisions to be supported.

[00:12:54] Speaker 02:
And the board cites evidence on all of these points.

[00:12:58] Speaker 02:
Why doesn't that just defeat her claim?

[00:13:01] Speaker 00:
The board misapplies the law to those facts.

[00:13:05] Speaker 02:
How do you mean it misapplies the law?

[00:13:09] Speaker 02:
Because I thought we were talking about substantial evidence.

[00:13:11] Speaker 02:
You're not saying they misapplied

[00:13:15] Speaker 02:
the standards, how did they misapply the law?

[00:13:18] Speaker 02:
You're confusing me by going back and forth between weight of the evidence and a legal error.

[00:13:24] Speaker 00:
Sorry.

[00:13:24] Speaker 00:
I apologize.

[00:13:27] Speaker 00:
Back to the weight of the evidence.

[00:13:30] Speaker 00:
Even if this court disagrees that the references that Penn submitted did not rise to the level of teaching away, they were at the very least

[00:13:39] Speaker 02:
The question isn't whether we disagree with your references and whether they teach a way.

[00:13:44] Speaker 02:
It's whether the board's factual determinations on these key points lack substantial evidence.

[00:13:51] Speaker 02:
And when we're looking at that, we're not looking exclusively at what you think we should have decided because we're not the trier of fact.

[00:13:59] Speaker 02:
It's whether the evidence cited by the board

[00:14:02] Speaker 02:
is sufficient to reach that determination.

[00:14:05] Speaker 02:
We could entirely agree with you up here on the factual outcome and still have to affirm the board on the substantial evidence standard.

[00:14:13] Speaker 00:
I do not think that there's substantial evidence to support the board's decision.

[00:14:17] Speaker 02:
Why aren't you concentrating on the evidence cited by the board against you and why it's sufficient rather than repeating your arguments about why you should have prevailed in the first place?

[00:14:30] Speaker 00:
Because I think that the board ignored... Because that's what you have to do.

[00:14:34] Speaker 02:
You have to show us that the evidence the board relied on is insufficient to support its findings under the substantial evidence standard, not that yours was good enough to reach the contrary result.

[00:14:47] Speaker 00:
Okay.

[00:14:51] Speaker 00:
I will point, since you're asking about the evidence,

[00:14:55] Speaker 00:
I think that the references, the combination of the references, already show us that Inherency did not exist.

[00:15:05] Speaker 00:
It's already in the record.

[00:15:07] Speaker 04:
Let's hear from the other side.

[00:15:09] Speaker 04:
I will save you rebuttal time.

[00:15:13] Speaker 04:
Okay.

[00:15:13] Speaker 04:
Any further comments?

[00:15:22] Speaker 03:
Mr. Cudson?

[00:15:24] Speaker 03:
Good morning, Your Honor.

[00:15:26] Speaker 03:
May it please the court.

[00:15:28] Speaker 03:
The combination of Saleh, DiNardo, and Balaban teach everything required by the claims of the 558 patent.

[00:15:35] Speaker 02:
What's your best argument and your response to your friend who says it doesn't, that Saleh shows cytotastic effects?

[00:15:46] Speaker 02:
And specifically, what evidence supports that?

[00:15:49] Speaker 02:
Because I think that's the key point here.

[00:15:53] Speaker 03:
Even if you were to take Penn's construction, the board found that there was a cytostatic effect, based primarily on the Gulliford reference, which is prior art, and shows an inhibition of growth of the A431 cells.

[00:16:09] Speaker 03:
The Sal A2 article shows that that inhibition is in the G0 or G1 phase, as required by Penn's construction.

[00:16:16] Speaker 03:
And Gulliford also shows that, I'm sorry,

[00:16:19] Speaker 02:
No, I get that.

[00:16:20] Speaker 02:
And that's where I thought it was.

[00:16:23] Speaker 02:
But what's your response to your friends?

[00:16:26] Speaker 02:
I think would be their argument that that's not enough to show inherency, because the record also shows that there's a cytotoxic effect of the same thing.

[00:16:39] Speaker 02:
And that if you have both of them going on at the same time, the cytostatic can't be inherent.

[00:16:50] Speaker 02:
when you have both of them possibly at the same time?

[00:16:53] Speaker 03:
Because the claims, despite what Penn argues in their reply brief, which I believe is a new argument in their reply, the patent does not talk about cytostatic antibodies or cytotoxic antibodies.

[00:17:06] Speaker 03:
It talks about effects.

[00:17:08] Speaker 03:
You inhibit the dimer formation or you disrupt the tyrosine kinase activity, and that result of that is a cytostatic effect.

[00:17:17] Speaker 02:
Both sides experts... So in your view, even if

[00:17:21] Speaker 02:
The effect of this was 75% cytotoxic and only 25% cytostatic.

[00:17:28] Speaker 02:
That would still be enough to show that there was a cytostatic effect from administering this.

[00:17:32] Speaker 03:
Yes.

[00:17:33] Speaker 03:
Both sides experts testify that you could have both a cytostatic effect and a cytotoxic effect.

[00:17:39] Speaker 03:
We've never disputed that cytostatic effects are different from cytotoxic effects, but the claim the scientists both agreed that it was possible to have both at the same time.

[00:17:49] Speaker 03:
Neither sides experts disputed that.

[00:17:51] Speaker 03:
Penn admitted that during the hearing.

[00:17:53] Speaker 03:
And the claims don't say cytostatic to the exclusion of cytotoxic effects.

[00:17:59] Speaker 03:
That's nowhere in the claim.

[00:18:00] Speaker 03:
And so Penn is trying to read in a negative limitation that simply doesn't have any support in the claim or in the specification.

[00:18:08] Speaker 03:
And I'd also like to point out as well that it isn't even part of their construction.

[00:18:14] Speaker 03:
My friend said that the court misapplied Penn's construction because it didn't deal with whether or not there was a cytotoxic effect.

[00:18:23] Speaker 03:
But I turned the court's attention to page 31 of their opening brief in which they specifically state what their definition of cytostatic was, and it was inhibiting growth

[00:18:37] Speaker 03:
by accumulating cells in the G0, G1 phase, such that when the agent is removed, growth resumes.

[00:18:44] Speaker 03:
Those were the three parts of their construction, and their construction did not require that a cytostatic effect means that you don't also have a cytotoxic effect.

[00:18:54] Speaker 01:
In the red brief at 34, you argue, I'll quote for you, legally, it's not necessary to show that C225's cytostatic effect was known at that

[00:19:06] Speaker 01:
at the time, close quote, because, quote, inherent properties need not have been recognized in the prior art.

[00:19:14] Speaker 01:
Are you asking for a blanket role that in inherent obviousness cases and inherent reference needs to ante date the critical date of the claimed invention and keep in mind what the implications of that are?

[00:19:29] Speaker 03:
What we're saying here is that, and this was made clear in this court's recent decision in July of this year in endopharmaceuticals, that simply because a property was not known or appreciated by a person of skill in the art at the time of the invention does not mean that it can't be used as part of an inherency analysis, even in the context of obviousness.

[00:19:54] Speaker 01:
Would that undermine the purpose of an obviousness?

[00:19:58] Speaker 01:
analysis which looks to what it preceded and knew at the time the invention was made?

[00:20:05] Speaker 03:
Not in this case, because this is not a situation where we're talking about... That's why I said keep in mind the implication.

[00:20:13] Speaker 03:
Because we're not talking about a situation here where we're combining different compounds or combining different elements together.

[00:20:20] Speaker 03:
Uh, Penn relies, for example, on the Honeywell v. Mexicam case in which you were talking about, uh, forming a refrigerant by combining two different chemicals together.

[00:20:30] Speaker 03:
And although the properties of that combination were inherent, uh, you would, a person of skill in the art would have no reason to make that combination in the first place.

[00:20:41] Speaker 04:
The question that Judge Waller, the sentence Judge Waller read absolutely has to be wrong.

[00:20:48] Speaker 04:
But does that,

[00:20:49] Speaker 04:
It really depends on whether you're claiming the old composition, which you can't do no matter what you discover, or whether you're claiming a new use based on a newly discovered property.

[00:21:02] Speaker 04:
We all know that when you're dealing with chemicals and biologicals and so on, the properties are there.

[00:21:09] Speaker 04:
So you can all of a sudden say they're inherent in schools out.

[00:21:13] Speaker 04:
That's not how it works.

[00:21:14] Speaker 04:
So let's get back to the foundation of what it is

[00:21:19] Speaker 04:
that Penn contributed to this art and why the PTAB was correct or theories that they were correct in saying that, nonetheless, their claims are invalid.

[00:21:37] Speaker 03:
Sure.

[00:21:37] Speaker 03:
In this particular case, we're talking about the Saleh reference, which teaches administering C225, a known antibody,

[00:21:48] Speaker 03:
to A431 cells.

[00:21:51] Speaker 03:
Whenever you do that, and this much is undisputed, Penn has not disputed how the antibody works, you disrupt tyrosine kinase activity, you inhibit dimer formation, and under the board's claim construction, that's enough to have a cytostatic effect.

[00:22:05] Speaker 03:
So simply practicing exactly what's taught in solid

[00:22:09] Speaker 03:
We're not talking about combining different things or adding anything new.

[00:22:14] Speaker 03:
An automaton who was doing nothing more than repeating the experiments done in Soloway will inhibit dimer formation, will disrupt tyrosine kinase activity.

[00:22:25] Speaker 03:
It is that sense in which it is inherent because it is the natural, inevitable result

[00:22:32] Speaker 03:
of practicing exactly what Sally teaches.

[00:22:35] Speaker 03:
You don't need to use any combinations.

[00:22:36] Speaker 02:
But if we disagree with the board's claim construction that just inhibiting whatever that is is equivalent to cytostatic effects.

[00:22:46] Speaker 02:
What further do we need to do to support, because I do think the board made an alternative finding that SALI still inherently shows a cytostatic effect apart from its claim construction.

[00:22:58] Speaker 02:
What supports that view?

[00:23:00] Speaker 03:
There were actually two alternative grounds.

[00:23:03] Speaker 03:
One was that it applied Penn's construction, and I already talked about that a little bit, and that was relying on the Goldstein reference and SALI 2, which showed

[00:23:15] Speaker 03:
that you met all three portions, that you arrested cell growth by accumulating cells in the G cell.

[00:23:23] Speaker 02:
Cell A2 specifically shows that there's a cytostatic effect.

[00:23:27] Speaker 02:
Is that your position?

[00:23:29] Speaker 03:
Both Goldstein and cell A2.

[00:23:30] Speaker 03:
But it talks about, if you want to walk through Penn's construction, that was the evidence we cited for that.

[00:23:37] Speaker 03:
The third ground was that it's undisputed that M225, which is the murine antibody from which

[00:23:45] Speaker 03:
C225 was derived has a cytostatic effect.

[00:23:49] Speaker 03:
That's, again, never been disputed by Penn.

[00:23:53] Speaker 03:
And the board found that, relying on the Goldstein reference, that C225 has the same biological effect as M225.

[00:24:03] Speaker 03:
So the fact that M225 had a cytostatic effect, the effect of C225 is the same as the effect of M225, also shows that C225 has a cytostatic effect.

[00:24:15] Speaker 03:
So those were the two alternative grounds that the court relied on, independent of its claim construction.

[00:24:21] Speaker 01:
In the blue brief, Penn argues that the PTAB aired relying on three references, Waterhouse, Gabaret, and Guilford.

[00:24:32] Speaker 01:
When I look in the red brief at 59, you argue Guilford is Prior Art, but you don't mention the other two.

[00:24:40] Speaker 01:
Are you conceding?

[00:24:42] Speaker 03:
Guilford is the only one of those three that is Prior Art.

[00:24:45] Speaker 03:
The other two were published later, but the fact that the board cited additional references that confirm what was already known in the prior art doesn't take away from the substantial evidence supporting the board's finding.

[00:25:03] Speaker 03:
I'd like to turn then to the question of the P185 heterodimer claims that were addressed briefly.

[00:25:09] Speaker 02:
I mean, isn't there a fundamental problem here that the board used a different theory than was in the petition?

[00:25:17] Speaker 02:
And that's not a substantial evidence problem.

[00:25:19] Speaker 02:
That's a kind of fundamental APA due process issue.

[00:25:23] Speaker 03:
I disagree that it's a different theory.

[00:25:25] Speaker 03:
The theory was obviousness based on a combination of Saleh, DiNardo, and Bolivar.

[00:25:29] Speaker 02:
And that's exactly why... Sure, but you argued that Saleh

[00:25:33] Speaker 02:
inherently showed heterodimers too and the board didn't accept that or they pivoted from that.

[00:25:39] Speaker 03:
The board did not actually use the word inherent, that's true.

[00:25:43] Speaker 03:
But what the board did look is it looked at all of the evidence put forward by both sides.

[00:25:47] Speaker 03:
It looked at both Lilly's evidence and Penn's evidence and it credited Lilly's evidence as teaching that A431 cells do in fact express P185 and it specifically rejected Penn's evidence as

[00:26:02] Speaker 03:
not addressing the issue.

[00:26:04] Speaker 03:
So there is a very strong factual finding there.

[00:26:07] Speaker 03:
But again, that's not a different legal theory.

[00:26:09] Speaker 03:
That's a factual finding.

[00:26:10] Speaker 02:
When you say express P185, is that equivalent to saying it showed heterodimers?

[00:26:15] Speaker 02:
I get tangled up in the list stuff.

[00:26:18] Speaker 03:
So Gulliford shows both that it expresses P185 and that P185 forms heterodimers with EGFR.

[00:26:28] Speaker 03:
And that's shown in Goldstein.

[00:26:32] Speaker 02:
Your position is that Guilford expressly shows heterodimers?

[00:26:37] Speaker 03:
Yes, it does.

[00:26:41] Speaker 03:
It's Figure 5 of Guilford.

[00:26:45] Speaker 03:
It's page 2842 of the appendix.

[00:27:00] Speaker 03:
And this is explained in the Reiss reference, the Reiss Declaration as well, that in Figure 5 on page 2842, Figure 5B, the top left corner there of that assay.

[00:27:20] Speaker 03:
Figure 5B, the figure on the right hand side, the top left corner.

[00:27:26] Speaker 03:
shows the fact that it's in both the row and the column shows that it's a combination that it's both EGFR and P185.

[00:27:37] Speaker 03:
And this was explained in the Greece Declaration as well.

[00:27:39] Speaker 02:
Here's the problem with this.

[00:27:42] Speaker 02:
Does it use the word heterodimer here anywhere?

[00:27:45] Speaker 02:
You're asking me to look at this figure and

[00:27:49] Speaker 02:
I mean, believe you.

[00:27:51] Speaker 02:
And then you're pointing me to the Reiss Declaration.

[00:27:53] Speaker 02:
Does the Reiss Declaration specifically explain why this shows heterodimer?

[00:27:59] Speaker 03:
Yes, and I would point the court to the legend beneath the figure as well, which talks about hetero-olgo... and now I have trouble pronouncing it... hetero-olgo-merization.

[00:28:12] Speaker 03:
And that's... I mean, but the board relied on... I'm not a chemist.

[00:28:17] Speaker 02:
I can't translate from this to the fact that it actually shows heterodimers.

[00:28:25] Speaker 03:
This is what the board relied on, however.

[00:28:28] Speaker 03:
This was the board's finding.

[00:28:30] Speaker 02:
Yeah, but if this doesn't actually show heterodimers, then the board's reliance on it lacks substantial evidence, because I think this is the only piece of prior art that shows it.

[00:28:41] Speaker 02:
The other two the board used were not prior art.

[00:28:44] Speaker 03:
That's correct, but again, there's never been any dispute that this in fact does show it.

[00:28:52] Speaker 03:
Penn has never argued, has never denied that A431 cells at least sometimes express P185.

[00:29:02] Speaker 02:
They had a question.

[00:29:05] Speaker 02:
I get confused with all this stuff, but the problem, I think their argument is not the problem that it shows heterodimer, but it doesn't show that the C225 does whatever their claim is to heterodimers.

[00:29:22] Speaker 03:
Right.

[00:29:22] Speaker 03:
Again, this was a point that was conceded below.

[00:29:25] Speaker 03:
They acknowledged in their patent donor response and at trial that C225 disrupts

[00:29:35] Speaker 03:
dimer formation.

[00:29:39] Speaker 03:
And I believe this is page nine of their patent owner response in the footnote.

[00:29:43] Speaker 03:
They specifically acknowledge that.

[00:29:46] Speaker 03:
So again, that's not an issue that was raised below.

[00:29:49] Speaker 03:
That was something that Penn admitted before the Patent and Trial and Appeal Board.

[00:29:58] Speaker 03:
But again, I just want to make the point that this was not a new legal theory.

[00:30:04] Speaker 03:
This was a factual argument that Penn braced for the first time in their patent donor response as to the extent to which A431 cells expressed P185.

[00:30:15] Speaker 03:
I don't know.

[00:30:16] Speaker 02:
It sounds like a new legal theory to me.

[00:30:18] Speaker 02:
I thought you were arguing that heteroadimer was inherent in Salé, and they didn't agree with that.

[00:30:25] Speaker 02:
They had to go to Guilford to get there.

[00:30:28] Speaker 02:
That sounds like a new combination to me that they didn't have a chance to respond to.

[00:30:33] Speaker 03:
This court has said in Genzyme and Ariosa that the board may properly look to other references as to what a person of skill in the art would have understood in reading Saleh at the time.

[00:30:48] Speaker 03:
And that's exactly what the board did here.

[00:30:52] Speaker 03:
We specifically talked about Guilford, Waterhouse, and Gaborid in the petition.

[00:30:57] Speaker 03:
The board relied on the exact same references, the exact same teachings within those references.

[00:31:03] Speaker 03:
So this is not a situation where there was some new art or some new legal theory that was put forward for the first time.

[00:31:12] Speaker 03:
It's exactly the same legal theory, obviousness based on the combination of Saleh, DiNardo, and Balaban.

[00:31:18] Speaker 03:
And all the board did was it relied on an admission by Penn that

[00:31:26] Speaker 03:
A431 cells at least sometimes express P185.

[00:31:30] Speaker 03:
And under this court's decision in Rovalmo v. Buller-Edelstein, the court is allowed, sorry, the board is allowed to do that.

[00:31:39] Speaker 03:
The board is allowed to rely on admissions from the patent donor in making its determination.

[00:31:47] Speaker 03:
Penn cites the Dell case and some others, but in Rovalmo,

[00:31:55] Speaker 03:
This court specifically said that those cases don't limit the board's ability to make its own legal conclusions based on a fact that has been admitted by the patent donor.

[00:32:07] Speaker 03:
And that's exactly what's happened in this situation.

[00:32:11] Speaker 04:
OK.

[00:32:11] Speaker 04:
Any more questions?

[00:32:12] Speaker 04:
Any more questions?

[00:32:14] Speaker 04:
All right.

[00:32:15] Speaker 04:
Thank you, Mr. Kutzy.

[00:32:17] Speaker 04:
Thank you, Your Honors.

[00:32:22] Speaker 00:
We have some time.

[00:32:25] Speaker 00:
I'd like to respond to several points that my friend here made.

[00:32:30] Speaker 00:
He cited Endo B. Custafarm.

[00:32:32] Speaker 00:
What this case held was that a party cannot take advantage of inherency to reach an undisclosed, unknown limitation that is not necessarily present in a prior art.

[00:32:44] Speaker 00:
Their own expert testified that there are circumstances under which C225 does not cause a cytostatic effect.

[00:32:53] Speaker 00:
That is the answer.

[00:32:54] Speaker 00:
There is no inherency of that limitation in the prior audit.

[00:32:59] Speaker 00:
I'd like to respond to the point that they made about SALE.

[00:33:02] Speaker 00:
SALE, my friend said, administering C225 when you do this, it's enough to have a cytostatic effect.

[00:33:09] Speaker 00:
This was disproven in SALE2, same group of authors, same system in which they disclosed that C225 was cytotoxic.

[00:33:19] Speaker 00:
And not only that,

[00:33:21] Speaker 00:
We already know from that reference what happened when they administered C225 in front of radiation.

[00:33:28] Speaker 00:
It was not radiosensitizing, which is not a surprise because it was not cytostatic.

[00:33:34] Speaker 00:
I'd like to respond to another point that they made about Genzyme.

[00:33:38] Speaker 00:
Here I think there's a distinction between new evidence and new arguments.

[00:33:43] Speaker 00:
Switching from an inherency argument where you're arguing that something

[00:33:48] Speaker 00:
necessarily exists to an obviousness argument, that is a new rationale.

[00:33:53] Speaker 02:
Are you talking about the heterodimer issue now?

[00:33:56] Speaker 00:
Yes.

[00:33:56] Speaker 00:
Yes, I am.

[00:33:58] Speaker 00:
There is a distinction between arguing that they were inherent and whether it would have been obvious to treat cells that express such heterodimers because those types of tumors were extremely aggressive.

[00:34:09] Speaker 02:
I get that.

[00:34:09] Speaker 02:
Can you address that one on the merits too?

[00:34:11] Speaker 02:
Why Guilford

[00:34:14] Speaker 02:
even if they'd properly raise the obviousness argument based upon Saleh and Guilford, that they don't show whatever the hydrodimer issue?

[00:34:27] Speaker 00:
Guilford showed that in that system there was a low level of P185 expression.

[00:34:34] Speaker 00:
We submitted, talking about the weight of the evidence, we submitted, I think it was at least six references showing systems

[00:34:43] Speaker 00:
where A431 cells do not express P185.

[00:34:47] Speaker 00:
And Gullyford technically was not prior art because Penn established a date of conception that predated that reference.

[00:34:55] Speaker 02:
What I really wanted you to address was the very specific part of that reference he showed me and talked about and said it meant something.

[00:35:03] Speaker 02:
Do you agree with what it means and that the problem is that it doesn't, even though it might express

[00:35:10] Speaker 02:
Heterodimers, it still doesn't teach using whatever the other thing is to... Oh, absolutely.

[00:35:17] Speaker 00:
You raised the point about the Lee reference.

[00:35:20] Speaker 00:
It wasn't until the Lee reference that we even knew that C225 inhibited dimerization.

[00:35:27] Speaker 02:
So even if... So even if Gilford shows heterodimers, it doesn't itself teach... It doesn't itself teach that

[00:35:38] Speaker 00:
One could take C225 and inhibit those heterodimers without the teaching of LEAP.

[00:35:44] Speaker 00:
You're still relying on an inherency argument.

[00:35:47] Speaker 00:
And in that context, the fact that A431 cells sometimes express heterodimers is not enough.

[00:35:57] Speaker 00:
I want to use my last minute and a half to close here.

[00:36:01] Speaker 00:
In sum, there is not a single reference of record or combination of references

[00:36:07] Speaker 00:
that establishes a reasonable expectation of success in treating a tumor with an Herb B antibody or any agent for that matter that has a cytostatic effect on the tumor cell prior to radiation.

[00:36:20] Speaker 00:
Rather, the art suggested that the opposite, that this order of administration would have been expected to have an adverse effect.

[00:36:29] Speaker 00:
Yet the inventors found that the nature of the response of the cells to radiation

[00:36:36] Speaker 00:
was radically and beneficially changed.

[00:36:40] Speaker 00:
This is the very essence of non-obviousness, and it was legally improper for the board to dismiss these results as merely inherent after combining references that teach neither the claimed limitations nor the unexpected effect.

[00:36:58] Speaker 00:
For this reason, we respectfully ask that this court reverse the decision of the board.

[00:37:05] Speaker 00:
and I still have 20 seconds if there's any remaining questions.

[00:37:10] Speaker 04:
More questions?

[00:37:12] Speaker 04:
Thank you very much.

[00:37:13] Speaker 04:
This is taken under submission and thank you both.