[00:00:00] Speaker 03:
The next case is Inray John L. Kouvaris, 2022, 1489, Mr. Sandel.

[00:00:11] Speaker 00:
Good morning.

[00:00:11] Speaker 00:
You may please the court.

[00:00:13] Speaker 00:
Lawrence Sandel on behalf of the appellant, Dr. John L. Kavaris.

[00:00:17] Speaker 00:
The director argues that granting Dr. Kavaris his patent would withdraw an obvious hypertension treatment from the public domain.

[00:00:25] Speaker 00:
But before Dr. Kavaris' research endeavors, his treatment simply never existed.

[00:00:30] Speaker 00:
The invention was not in the public domain because it was never in any domain.

[00:00:33] Speaker 03:
Well, both types of compounds were known to be antihypertensive.

[00:00:38] Speaker 03:
And the fire arch showed that it was common or permissible or desirable to combine antihypertensives at times.

[00:00:50] Speaker 03:
And so this is simply using two known types of compounds to create hypertension.

[00:00:59] Speaker 00:
And from the 10,000 foot view, I would agree with you.

[00:01:04] Speaker 00:
But when you get into the actual facts and the detail in this case,

[00:01:08] Speaker 00:
Nobody has ever discovered or even contemplated that these two compounds, when combined in a particular situation, could cause a vasodilatory effect.

[00:01:22] Speaker 03:
Now, I don't know if it was... So, Dr. Guevara has discovered a mechanism that the treatment of hypertension with these types of compounds is known or obvious.

[00:01:37] Speaker 00:
I would disagree that they were known or obvious.

[00:01:39] Speaker 00:
Each of the compounds was out there.

[00:01:41] Speaker 00:
The general concept of multi-drug treatment for hypertension also was out there.

[00:01:48] Speaker 00:
But the fact remains that there were 30 years where these both existed.

[00:01:52] Speaker 00:
And this is an extreme.

[00:01:52] Speaker 04:
And they both were known to treat hypertension.

[00:01:55] Speaker 00:
Both were known separately to treat hypertension in the art.

[00:01:59] Speaker 04:
And there was prior suggesting combining different types of hypertension

[00:02:03] Speaker 00:
medications for there what there is fire art talking about that if there's not not these particular ones but in general yes multi-drug treatment of hypertension so when you start with that 10,000 foot view I do understand why we're here but as you go down on the ground once you start looking at what's there is that dr. Kovars

[00:02:30] Speaker 00:
Dr. Kravars developed, he recognized a problem as to the two modalities potentially for treating hypertension.

[00:02:39] Speaker 00:
So we can start with that.

[00:02:40] Speaker 00:
One is combating constriction.

[00:02:43] Speaker 00:
And so this is what ARBs do, which is one of the two compounds.

[00:02:47] Speaker 00:
And the other compound was GABA.

[00:02:49] Speaker 00:
And the prior art taught that GABA does not aid in vasodilation.

[00:02:56] Speaker 00:
So we have constriction on one hand.

[00:02:59] Speaker 00:
And I'll use an analogy, even though it's a step away, but I think it can help clarify this.

[00:03:04] Speaker 00:
So we have a screen door.

[00:03:06] Speaker 00:
And you want that screen door to be closed, to be normotensive.

[00:03:09] Speaker 00:
When the screen door is open, it's a hypotensive patient.

[00:03:13] Speaker 00:
Constriction is a rock preventing this door from closing.

[00:03:17] Speaker 00:
You remove the rock, you remove the constriction.

[00:03:19] Speaker 03:
Your claims recite increasing prostacyclone release.

[00:03:24] Speaker 00:
Correct.

[00:03:24] Speaker 03:
This was inherent, right?

[00:03:29] Speaker 00:
We don't argue specifically against that this combination will do it.

[00:03:34] Speaker 00:
It's not our strongest argument.

[00:03:37] Speaker 00:
In the typical case, that will occur.

[00:03:39] Speaker 00:
But it is a comprising claim that we're focused on.

[00:03:42] Speaker 00:
So there's always the possibility that another substance could prevent this from happening, which would undermine that inheritance claim.

[00:03:48] Speaker 03:
Is there a new argument that this is a comprising claim?

[00:03:51] Speaker 00:
We haven't addressed that specifically, so I can give another one.

[00:03:56] Speaker 04:
So you agree it's necessarily so that this is the mechanism setting aside your comprising argument?

[00:04:02] Speaker 00:
Yeah, this is the mechanism by which it works.

[00:04:06] Speaker 00:
And this is where I would pull in Honeywell and why Honeywell is incredibly important to show here that this was an unexpected

[00:04:18] Speaker 00:
an unexpected effect, it was an unknown effect, and it had an unexpected benefit.

[00:04:23] Speaker 04:
Do you think Honeywell says that when you combine two multiple references or modify a reference and then as modified, that's when you have the inherent property?

[00:04:33] Speaker 04:
That is, it's necessarily so that it works through this mechanism, that if it's an unexpected

[00:04:41] Speaker 04:
Inherent property I guess that that could in some cases show that there would have been motivation to combine That's my understanding.

[00:04:52] Speaker 04:
It's that is my understanding, but even if it's not your understanding you disagree with that But the answer I have is well here even if that's so I

[00:05:03] Speaker 04:
Why isn't there motivation to combine, as the board found, supported by substantial evidence, that there's motivation to combine for their reason to, because both of these drugs individually was known to treat hypertension, so why wouldn't combining them, you know, you'd combine them in order to improve hypertension?

[00:05:24] Speaker 04:
Even if you don't know the mechanism that is inherent.

[00:05:28] Speaker 00:
That's right.

[00:05:28] Speaker 00:
Yes, I see that initial gloss, of course.

[00:05:32] Speaker 00:
But I think it's a little bit different.

[00:05:33] Speaker 00:
And I think that the cardiac case talks about this a bit when you're in this medical space.

[00:05:41] Speaker 00:
There are questions about drug interaction and so on and so forth, that you don't just create a random cocktail of drugs that exist and slam them together.

[00:05:54] Speaker 00:
And I feel that this is sort of the point where I would

[00:05:58] Speaker 00:
turned towards the secondary considerations of non-obvious to rebut this motivation and to establish that the invention overall was non-obvious.

[00:06:11] Speaker 00:
And I raised the length of time considering first, even though it can't alone establish the finding of non-obvious, because I think that is particularly compelling.

[00:06:20] Speaker 00:
There's no dispute that for 30 years these two compounds existed.

[00:06:24] Speaker 00:
They were never put together.

[00:06:26] Speaker 00:
And this is also a field where there are billions of dollars in pharmaceutical sales every year.

[00:06:31] Speaker 00:
35,000 Americans die every year.

[00:06:34] Speaker 00:
And no one ever tried this.

[00:06:36] Speaker 03:
The board said you do not find any showing of unexpected results here.

[00:06:41] Speaker 00:
Yes.

[00:06:42] Speaker 00:
And actually, well, I don't actually think.

[00:06:45] Speaker 00:
They said they don't find unexpected results.

[00:06:47] Speaker 00:
But they also said that his discovery

[00:06:51] Speaker 00:
was unexpected.

[00:06:53] Speaker 00:
Ultimately, from my reading of that opinion, and I parsed it pretty carefully after the director's brief, was that they didn't believe there were unexpected results because no advantage was shown.

[00:07:03] Speaker 03:
The board also said, quoting one of our cases, CCPA case, the discovery of the cause of a problem does not always result in a patentable invention.

[00:07:13] Speaker ?:
Yes.

[00:07:13] Speaker 00:
And not always, but we believe this is a case where it should.

[00:07:17] Speaker 00:
Dr. Kavaris discovered something that was entirely new.

[00:07:20] Speaker 00:
It was entirely new modality treatment.

[00:07:24] Speaker 00:
Going back to the expected or unexpected, there's nothing in the record whatsoever showing that anybody had found a way before Dr. Kavaris to increase process cycling or police.

[00:07:35] Speaker 00:
There is in the record evidence that two researchers, Dr. Bird and Dr. Magnus, had attempted to do this, and they had failed.

[00:07:43] Speaker 00:
And when it comes to, you know, unexpected and unknown, yeah, I would refer to the board's explicit finding that, quote, and this is appendix page 14, Dr. Kavars has established that the main beneficial result of his claimed invention is unexpected.

[00:08:02] Speaker 00:
And so were they taken?

[00:08:04] Speaker 02:
It was read in context since they say that it was not unexpected elsewhere.

[00:08:10] Speaker 02:
That's probably just a summary of what he said, that he said his testimony established this.

[00:08:16] Speaker 00:
Well, it starts with he has established.

[00:08:19] Speaker 00:
And if you read through that paragraph and parse that, they say this was an unexpected discovery and result, but we don't consider it

[00:08:29] Speaker 00:
sort of an actionable unexpected result, because there is no evidence that there is a benefit.

[00:08:34] Speaker 00:
And you agree there has to be a benefit?

[00:08:36] Speaker 00:
We agree that there has to be a benefit, but we also submit quite strongly that benefit was established below.

[00:08:46] Speaker 00:
First, in the examiner's own brief to the board, he said that these discoveries, quote, are considered

[00:08:55] Speaker 00:
another advantage, and that's on appendix page 1237.

[00:08:57] Speaker 00:
The examiner argued to the board that this was an advantage.

[00:09:02] Speaker 00:
And so under those circumstances, it's unreasonable for the board to fault us for not inundating it with evidence as to the advantage.

[00:09:11] Speaker 00:
But we did give them that evidence below, and it was ignored.

[00:09:16] Speaker 03:
Can you cite a case where we ever held a claim to a mechanism

[00:09:25] Speaker 03:
of action that didn't produce any different result from what prior treatments accomplished?

[00:09:35] Speaker 00:
I cannot, but I would submit that this is a different result.

[00:09:38] Speaker 00:
When you look at that 10,000 foot view again,

[00:09:42] Speaker 00:
hypertension, hypertension.

[00:09:44] Speaker 00:
But as you drill down and you look at the modality that Dr. Kouvaris was pursuing, he was pursuing release of a vasodilator compound, not merely trying to blunt the effects of constricting compounds like angiotensin II.

[00:09:59] Speaker 00:
So I think we're in a different category of what you're talking about, but no, I don't have a case that submits that.

[00:10:05] Speaker 04:
Do you have evidence that this mechanism in particular is more beneficial than, I'm just curious, because you seem to be arguing that the combination wouldn't have been obvious because of the mechanism.

[00:10:21] Speaker 00:
So I think when you look at is it more beneficial to promote vasodilation versus limit constriction, that's the question.

[00:10:32] Speaker 00:
What I would say is it's just the fact of having an additional modality in and of itself is a benefit.

[00:10:41] Speaker 02:
And by analogy, there may be antibiotics... Another way of reaching the same result, you mean?

[00:10:45] Speaker 00:
Well, not necessarily.

[00:10:47] Speaker 00:
It may be a better result for some people.

[00:10:50] Speaker 02:
But there isn't evidence that it was better, right?

[00:10:54] Speaker 00:
I guess what I'm saying, comparing them as apples to apples, no.

[00:11:00] Speaker 00:
Not specifically that it was better, but it doesn't have to actually be better.

[00:11:03] Speaker 00:
It just has to show an advantage and show a benefit here.

[00:11:09] Speaker 00:
A certain cancer drug may be more effective at killing cancer cells while at the same time maybe

[00:11:19] Speaker 00:
Patients may be less able to tolerate it.

[00:11:21] Speaker 00:
Is that better than the drug?

[00:11:23] Speaker 03:
Better or not, the claim was inherent.

[00:11:29] Speaker 03:
What is claimed is what was inherent, mainly that these compounds together increased prostacycline expression.

[00:11:43] Speaker 00:
That being inherent, we turn

[00:11:48] Speaker 00:
If the Honeywell argument is disregarded, we turn to the secondary considerations.

[00:11:56] Speaker 03:
Which the board didn't find.

[00:11:58] Speaker 00:
Well, the board did not find.

[00:12:00] Speaker 03:
To which we owe deference.

[00:12:04] Speaker 00:
You owe deference to the extent that they can show substantial evidence.

[00:12:07] Speaker 00:
But I would like to point out a few things with respect to the recognition of

[00:12:17] Speaker 00:
With respect to the recognition of a problem, the board basically said the recognition lacks, quote, any non-obvious impact on treatment using anti-hypertensive agents.

[00:12:28] Speaker 00:
There is a non-obvious impact, and that impact is increasing the release of prostacyclin.

[00:12:35] Speaker 00:
There's no basis for that, and also that that's not the rule.

[00:12:39] Speaker 00:
And when you look to the failure of others, which was rejected,

[00:12:45] Speaker 00:
The board posits two arguments.

[00:12:48] Speaker 00:
First, they said, well, these two inventors didn't use the inventive product.

[00:12:53] Speaker 00:
Counsel, you're ending your bottle time, which you can use as a... I'll continue, and hopefully have a little left over.

[00:13:04] Speaker 00:
When it came to, they said these researchers, Dr. Byrd and Dr. Mannes, did not use the inventive product.

[00:13:11] Speaker 00:
But to show a failure of others, they don't have to use the claimed invention and fail.

[00:13:16] Speaker 00:
They have to just try to find a solution for the problem that was solved by the applicant.

[00:13:22] Speaker 00:
They did not do that, but they tried to find the same solution.

[00:13:25] Speaker 00:
They tried to find a way to increase frost acycline release.

[00:13:28] Speaker 00:
And the other attack that they had was that these inventors weren't aware of the critical prior art.

[00:13:34] Speaker 00:
But again, here the critical prior art is just these super well-known compounds.

[00:13:38] Speaker 00:
So that really doesn't add much there.

[00:13:40] Speaker 00:
And when it comes to TeachAway, I want to emphasize two references that the board entirely ignored.

[00:13:47] Speaker 00:
And I think these are very important references.

[00:13:49] Speaker 00:
It's the Inouye reference and the Elliott reference.

[00:13:51] Speaker 00:
And the reason that these are important is because both of these references taught that GABA does not produce a vast regulatory response.

[00:14:01] Speaker 00:
The board then goes to Kjeldsen, if I'm pronouncing that correctly, to say that it teaches combining an ARB with something.

[00:14:10] Speaker 00:
But given that Dr. Kavars was focused on the vascular regulatory response and the prior art taught away from GABA for that purpose, there's no reason why Kjeltsin would have combined ARB with GABA.

[00:14:23] Speaker 00:
And I'll reserve my last minute.

[00:14:25] Speaker 03:
We'll save a minute for you.

[00:14:27] Speaker 03:
Ms.

[00:14:28] Speaker 03:
Culler.

[00:14:29] Speaker 01:
Your Honors, and may it please the court.

[00:14:31] Speaker 01:
The board in this case weighed the strong evidence of obviousness, such as the prior art's disclosure of the same antihypertensive compounds

[00:14:39] Speaker 01:
to treat the same patient population and the Pirate's disclosure to combine the claimed ARB antihypertensive agent with other antihypertensive agents for better treatment.

[00:14:51] Speaker 01:
They weighed that together with Cabarrus's evidence of secondary considerations and based on that weighing, properly found that the claims would be obvious.

[00:15:00] Speaker 01:
Now, on appeal, Guveris disputes almost every single one of the board's factual findings except inherency.

[00:15:07] Speaker 01:
So moving away from inherency, unless your honors have any questions, I'll start with briefly the motivation to combine.

[00:15:13] Speaker 03:
Well, what about inherency?

[00:15:15] Speaker 03:
Do you think inherency is the best ground on which the board found obviousness?

[00:15:23] Speaker 03:
Well, the board found obviousness.

[00:15:26] Speaker 01:
Well, as this court has found, if a result naturally occurs or necessarily results from the combination of two prior art teachings,

[00:15:41] Speaker 01:
that can be inherent.

[00:15:42] Speaker 01:
And that was the case here.

[00:15:43] Speaker 01:
Increased prostacyclin release will naturally result or naturally incur when you follow the prior art's instructions to administer an ARB and a GABA together to treat hypertension.

[00:15:59] Speaker 03:
Is this a novel kind of claim, claiming a mechanism that's inherent

[00:16:07] Speaker 01:
I think there are other claims out there that people have tried to claim the mechanism of action.

[00:16:12] Speaker 01:
However, as Your Honor recognized, the mechanism of action is just what happens when you administer two drugs together and really trying to get a claim on a mechanism of action without any unexpected results where that combination

[00:16:25] Speaker 01:
would be obvious, really would open up patentability to a lot of obvious drug combinations.

[00:16:32] Speaker 04:
It's not- The board did say that the increasing their press to cycling release is unexpected.

[00:16:39] Speaker 04:
How does that play under Honeywell?

[00:16:43] Speaker 04:
Why shouldn't we take that into account in determining whether the combination would have been obvious from one of our nearest familiar?

[00:16:51] Speaker 01:
So under Honeywell, your honor's right.

[00:16:53] Speaker 01:
You do say, if a result is inherent, that doesn't mean we can completely disregard evidence of unexpected results.

[00:16:59] Speaker 01:
But here, the board did exactly what Honeywell said, and they looked.

[00:17:02] Speaker 01:
Are there any unexpected results?

[00:17:04] Speaker 01:
And they found affirmatively, at appendix 14, the very first sentence, there are no unexpected results.

[00:17:09] Speaker 01:
We do have that statement that the board, quoting Dr. Kavara, said it's unexpected.

[00:17:14] Speaker 01:
You can look at this two different ways.

[00:17:16] Speaker 01:
Neither of them change the fact that the board determined correctly that there's no unexpected results.

[00:17:21] Speaker 01:
The first is that yes, okay, maybe the board said it is unexpected, but it doesn't meet the status of an unexpected result because it's not beneficial.

[00:17:31] Speaker 01:
And they said there's no better hypertensive treatment, there's no reduced dosages, and this court's precedent establishes that an unexpected result needs to be beneficial.

[00:17:40] Speaker 01:
And there was no evidence of that.

[00:17:42] Speaker 01:
any evidence that was put in by Kouvaris on reply simply has been forfeited.

[00:17:47] Speaker 01:
And that's best demonstrated by the fact that up until the opening brief and until the director set forth all of the cases that said there needed to be an unexpected benefit, Kouvaris said,

[00:18:00] Speaker 01:
That's not a legal requirement.

[00:18:01] Speaker 01:
So in an opening brief at page 43, they said, you don't need a benefit.

[00:18:06] Speaker 01:
When we set forth all of our cases explaining why this court has said unexpected results require a benefit, they've now conceded that the fact that a benefit is required.

[00:18:16] Speaker 01:
But you can see, because they were coming from an incorrect legal position,

[00:18:19] Speaker 01:
They've forfeited any of the arguments that they're now making about why there is a benefit that simply wasn't before the board.

[00:18:26] Speaker 01:
And so even if the board's sentence there says, OK, it's unexpected, meaning nobody would have expected this, it does not say it's a benefit.

[00:18:33] Speaker 01:
And indeed, they say there's no better control of hypertension

[00:18:36] Speaker 01:
there's no reduced dosages.

[00:18:38] Speaker 01:
So the statement at the top remains true and supported by substantial evidence.

[00:18:42] Speaker 01:
The second way you can look at it is, as Judge Dyke recognized, they most likely could have just been quoting Dr. Kouvaris and made a poor choice of words.

[00:18:50] Speaker 01:
And if you look at Dr. Kouvaris' declaration and all the arguments that were made below, Kouvaris was tying

[00:18:58] Speaker 01:
Unexpected to silence.

[00:19:00] Speaker 01:
There's nothing in the prior art.

[00:19:02] Speaker 01:
No one has ever done it.

[00:19:02] Speaker 01:
Therefore, it has to be unexpected.

[00:19:05] Speaker 01:
And so the board could have simply been saying, it's silent, but that's because it's inherent.

[00:19:11] Speaker 01:
But really, there's no unexpected results, because as the examiner found, there really was no comparison to anything.

[00:19:18] Speaker 01:
There was not commensurate in the scope of the claims.

[00:19:22] Speaker 01:
But as the board found, as a threshold matter, before you can get there,

[00:19:26] Speaker 01:
There's no benefit and so you cannot establish Unexpected results without a benefit and so kind of coming back to the beginning of the question Which is this is completely consistent with Honeywell the board found it was inherent But then went on and looked at whether or not there were unexpected results finding none they found that secondary consideration did not weigh towards obviousness and

[00:19:47] Speaker 01:
with respect to the failure of others, the recognition of a problem, and the time secondary considerations that council has emphasized.

[00:19:58] Speaker 01:
I would say big picture.

[00:20:00] Speaker 01:
All of those kind of focus on the discovery, again, of a mechanism of action.

[00:20:06] Speaker 01:
None rebut why the board and the examiner found it would have been obvious to combine these two treatments, which is the treatment of

[00:20:16] Speaker 01:
hypertension.

[00:20:18] Speaker 01:
So none relate to the motivation of why you would combine these.

[00:20:23] Speaker 01:
And therefore, the board correctly found, as a big picture, none of these were probative of non-obviousness.

[00:20:30] Speaker 01:
A couple of specific points with respect to counsel's focus on the Bird and Mangis case, or the Bird and Mangis research.

[00:20:38] Speaker 01:
That was directed towards

[00:20:41] Speaker 01:
Increasing prostacyclin released by manipulating angiotensin 2 levels, it was not directed towards the administration of any drugs or any antihypertensive agents, and therefore it simply does not have nexus to the claims.

[00:20:57] Speaker 01:
A failure in the art that does not have nexus to the claims is not probative of non-obviousness.

[00:21:02] Speaker 01:
Someone could fail by saying, you know, I told my subjects to not sleep for two hours, or sleep only two hours a night, and therefore I didn't increase prostacyclin release.

[00:21:12] Speaker 01:
That doesn't have nexus to the claims.

[00:21:15] Speaker 01:
The same way here, the failure in trying to increase cross-decycline release by manipulating anti-intensin 2 levels is not an administration of an ARB, is not an administration of a GABA, is not focused on anti or hypertensive patients, therefore it does not have nexus to the claims.

[00:21:34] Speaker 03:
Are you saying that the motivations are combined to known anti-hypertensives?

[00:21:40] Speaker 03:
is simply the desire to improve treatment.

[00:21:45] Speaker 03:
And the result here was the same, except the discovery of the mechanism by which it occurred.

[00:21:52] Speaker 01:
That's correct, Your Honor.

[00:21:53] Speaker 01:
And that is consistent with this court's precedent in Kerkovin, which said the combination of two

[00:21:59] Speaker 01:
agents known for the same purpose to Provide a third agent also known for the same purpose as obvious But we also have the additional benefit here of the board's reliant on the Kelgen reference where it specifically directed you to

[00:22:14] Speaker 01:
to combine an ARB, one of the claimed agents, with another anti-hypertensive and told you the reason why.

[00:22:21] Speaker 01:
This will get you better hypertensive treatment.

[00:22:24] Speaker 01:
So in addition to the standard obviousness under Kirchhofen, we have the Kelgen reference.

[00:22:30] Speaker 01:
With respect to the recognition of a problem, again, this is a problem with whether or not we know what these drugs do.

[00:22:40] Speaker 01:
It does not dispute, it does not overcome the obviousness of combining these drugs for hypertension treatment.

[00:22:48] Speaker 01:
And that's what the board said when they said there's no obvious impact or non-obvious impact of this recognition of a problem.

[00:22:55] Speaker 01:
It was already obvious from another problem that was out there, which is the treatment of hypertension.

[00:23:00] Speaker 01:
And finally, to comment on the teaching away argument, the board properly found that the prior art did not teach away.

[00:23:10] Speaker 01:
With respect to the two references, the board did not specifically discuss, which is the Elliott and then Inouye reference.

[00:23:17] Speaker 01:
Those, like all the other evidence here of secondary considerations, was focused on the mechanism of action.

[00:23:23] Speaker 01:
It questioned whether or not GABA was a vasodilator.

[00:23:27] Speaker 01:
It did not question that GABA was a hypertensive treatment.

[00:23:30] Speaker 01:
Elliott and Inouye are one of the references relied on by the examiner.

[00:23:34] Speaker 01:
It says GABA is used for hypertension treatment.

[00:23:37] Speaker 01:
So the statement that it doesn't know how it works does not teach away from its use as a hypertensive agent.

[00:23:44] Speaker 01:
So unless your honors have any other questions, I'm happy to concede the rest of my time.

[00:23:48] Speaker 03:
Thank you, counsel.

[00:23:50] Speaker 03:
Mr. Sandel has a minute left.

[00:23:53] Speaker 00:
Just want to hit quickly again on the Honeywell concept.

[00:23:58] Speaker 00:
There is no evidence in the record at all that this wasn't an expected result.

[00:24:03] Speaker 00:
It's never been done before.

[00:24:05] Speaker 00:
Dr. Vars explained it at great detail in his declaration why it was new and that people were searching for a way to find out how to release prostacycline, and nobody actually got there.

[00:24:18] Speaker 00:
All we're left with on that unexpected result is whether or not there was a benefit

[00:24:22] Speaker 02:
and in the reply brief... When we're talking about unexpected results the mechanism of action may have been unexpected and that seems to be what the testimony of Dr. Calaro says but the effect on the patient is not unexpected of the combination of these two drugs.

[00:24:45] Speaker 00:
Your Honor, I would posit that the release and

[00:24:51] Speaker 00:
Obviously, this comes from the nexus as well.

[00:24:52] Speaker 00:
But the actual release of a vasodilator, that different treatment modality was unexpected.

[00:25:00] Speaker 02:
And it was unexpected that this combination would release a vasodilator?

[00:25:04] Speaker 00:
Yes.

[00:25:05] Speaker 00:
It was absolutely unexpected.

[00:25:06] Speaker 00:
There was nothing there.

[00:25:08] Speaker 00:
Angiotensin 2, and this is where the dichotomy between a vasodilator and compounds that

[00:25:18] Speaker 00:
rebut constriction, or address constriction, that's where the distinction is.

[00:25:24] Speaker 00:
ARBs are known to stop constriction.

[00:25:26] Speaker 00:
GABA, according to the prior art, is doubted to have anything to do with vasodilation.

[00:25:34] Speaker 00:
But prostacyclin is a potent vasodilator, and it has a totally different effect.

[00:25:39] Speaker 00:
And this is also, this distinction is also made clear even in the director's brief, I believe, page four.

[00:25:45] Speaker 00:
It talks about

[00:25:47] Speaker 00:
The anti-constriction effect of ARBs.

[00:25:51] Speaker 00:
And on page 5, it talks about the vasodilatory effect of process cyclin.

[00:25:57] Speaker 00:
And this distinction is critical.

[00:25:58] Speaker 00:
When you lump them together as antihypertensive agents, and don't pay attention to this distinction in the modalities of treatment, the obvious in this case stands tall.

[00:26:10] Speaker 00:
But once you dig into the details and see how there is a distinction, the result is this vasodilatory effect.