[00:00:00] Speaker 04:
an admission this morning before we start with the act of Mr. Garcia when we come forward.

[00:00:06] Speaker 04:
And I invite Judge Rainer to make a motion if he chooses.

[00:00:13] Speaker 03:
Thank you, Judge Newman.

[00:00:16] Speaker 03:
Colleagues, I move for the admission of Edwin Garcia.

[00:00:20] Speaker 03:
Edwin is a member of the bar and is in good standing with the highest court of Texas.

[00:00:25] Speaker 03:
I have knowledge of his credentials and am satisfied that he possesses the necessary qualifications.

[00:00:32] Speaker 03:
Edwin, it's been a year since you've come and joined my chamber.

[00:00:36] Speaker 03:
And I'm sure that time has gone by pretty fast for you, because that's what happens when you work hard and when you're having fun.

[00:00:46] Speaker 03:
And I have a sense that you had both in your services as a clerk to me.

[00:00:51] Speaker 03:
You've performed exemplary.

[00:00:54] Speaker 03:
And your service both to my chambers and the court has been noted by the respect that you've developed among your peers.

[00:01:04] Speaker 03:
It's my colleagues before us stands an attorney that I'm sure will be an excellent practitioner in the future and will bring honor and dignity not only to this court, but to the legal profession as a whole.

[00:01:19] Speaker 04:
Thank you.

[00:01:20] Speaker 04:
I invite the panel to vote on the motion.

[00:01:22] Speaker 04:
What say you, Judge Clevinger?

[00:01:25] Speaker 05:
I'm delighted to vote in favor of the motion.

[00:01:28] Speaker 04:
I vote in favor of the motion.

[00:01:30] Speaker 04:
Thank you.

[00:01:31] Speaker 04:
Please approach the clerk to administer the oath.

[00:01:35] Speaker 00:
Please raise your right hand.

[00:01:39] Speaker 00:
Do you solemnly swear or affirm that you will support yourself as an attorney and counselor of this court, uprightly and according to law, and that you will support the Constitution of the United States of America?

[00:01:48] Speaker 00:
I do.

[00:01:48] Speaker 00:
Welcome to the bar of the United States Board of Appeals.

[00:01:50] Speaker 04:
Thank you.

[00:01:51] Speaker 04:
Welcome to the bar, Mr. Garcia.

[00:01:53] Speaker 04:
We will proceed with the program for this morning.

[00:01:58] Speaker 04:
The first argued case is number 18, 1225, Horizon Therapeutics against Ayan Ku.

[00:02:07] Speaker 04:
Mr. Morrison.

[00:02:10] Speaker 02:
Good morning, Judge Ewen, Judge Clevinger, Judge Raina.

[00:02:13] Speaker 02:
It's always a pleasure to be in front of this court.

[00:02:16] Speaker 02:
I want to start just by going back to the 559 patent in issue

[00:02:21] Speaker 02:
And just a quick review, which I know all of you are aware of, as to the claim.

[00:02:26] Speaker 02:
Because it's important to understand the specific aspects of the claims in the 559 patent.

[00:02:33] Speaker 02:
As I think all of you know, other than the claim four, claim three, the claims require, first, starting with a patient.

[00:02:42] Speaker 02:
But it's not any patient.

[00:02:43] Speaker 02:
It's the patient that's been determined to have UCD.

[00:02:48] Speaker 02:
That patient has already been administered

[00:02:51] Speaker 02:
Hpn 100 and has a fasting plasma ammonia level that's between the upper limit of normal and half the upper limit of normal That's what the claims are about now the claims require certain specific steps measuring first the fasting plasma ammonia level comparing that to the upper limit of normal and then administering an increased dose of Hpn 100 if that ammonia level is greater than half the upper limit of normal that's what's required by the claims those are all of the

[00:03:21] Speaker 02:
key aspects that you must find when you look at the prior art in order to find obviousness.

[00:03:27] Speaker 02:
Horizon's view is that the prior art's really devoid, absolutely devoid of any teaching or reason that would motivate a person of ordinary skill in the art to increase the dose of HPN-100 if the patient's fasting blood ammonia was already below the ULN.

[00:03:45] Speaker 02:
And I have to say, I have found the finding of obviousness

[00:03:49] Speaker 02:
to be puzzling.

[00:03:51] Speaker 02:
Puzzling from this standpoint, what's the key reference that's relied on?

[00:03:55] Speaker 02:
It's the 859 publication.

[00:03:59] Speaker 02:
The 859 publication is a publication which I'm sure Judge Newman is going to recall.

[00:04:08] Speaker 02:
It morphed into, eventually, the 012 patent, which I had the honor of being in front of Judge Newman with respect to last year.

[00:04:16] Speaker 02:
And the 012 patent was found to be valid by the board.

[00:04:20] Speaker 02:
And that was affirmed by this court in, I believe, June of last year.

[00:04:25] Speaker 02:
Now, the 859 publication, and using that as a key basis for finding obviousness, I find it puzzling because of many factors.

[00:04:35] Speaker 02:
But among others, if you look at what the patent

[00:04:40] Speaker 02:
which came from that or the publication itself, the 859 publication says when you're dealing with using plasma ammonia level in order to determine how to treat a patient, how to do a dosing change if needed based on that.

[00:04:54] Speaker 05:
What happens if you have reason to believe that the plasma ammonia is going to spike in an individual who's already being treated with this particular pharmaceutical?

[00:05:06] Speaker 05:
And the circumstances are that you tested this individual and that they're at the low end range of normal.

[00:05:14] Speaker 05:
And there's an expectation that they're going to consume a lot of protein.

[00:05:20] Speaker 05:
And there is an expectation that's fact-based that the ammonia level is going to spike, right?

[00:05:28] Speaker 02:
The probability of a spike can certainly be present, depending upon the individual patient that's involved.

[00:05:34] Speaker 02:
But that has been...

[00:05:35] Speaker 05:
But so I was wondering, the reason why I was asking was I was wondering about if a situation where a patient may suffer from high blood pressure and is given a particular pharmaceutical to keep the blood pressure within range.

[00:05:48] Speaker 05:
And it's known that a couple of more milligrams will have this effect in terms of reducing.

[00:05:54] Speaker 05:
And you know that your patient is going to go into high altitude, for example, certain types of settings that will necessarily cause the blood pressure to spike even though it's being controlled.

[00:06:04] Speaker 05:
So as a matter of reason, why wouldn't one think to add a little more of the pharmaceutical if there are no side effects?

[00:06:12] Speaker 02:
Well, so let's start with a few things, Your Honor.

[00:06:15] Speaker 02:
Certainly, a physician is not going to give more doses, any product, to a patient.

[00:06:24] Speaker 02:
that isn't known to be needed, because doctors just don't do that.

[00:06:28] Speaker 05:
What you're trying to do, if your goal is to maintain my blood pressure in a normal range, and somebody says you take 20 mgs of this stuff, and it'll keep you from normal in a normal atmospheric range.

[00:06:42] Speaker 05:
But if you go in an altitude, we know your blood pressure is going to go up a certain number of points.

[00:06:47] Speaker 05:
And so the rational thing to do would be they can calculate how much more you take.

[00:06:54] Speaker 05:
to bring your blood pressure into normal.

[00:06:56] Speaker 05:
What I was saying is that your initial explication of what the patent is doing seemed to me that it didn't take into account the possibility of a person who's within a normal range when measured fasting in the morning or whatever.

[00:07:11] Speaker 05:
But there's an expectation, and they're at the low end of the range, there's an expectation that their plasma ammonia will spike.

[00:07:21] Speaker 05:
And I think the important way to look at this, Your Honor, is... And if you have the additional amount of the pharmaceutical, the spiking will be taken care of.

[00:07:32] Speaker 02:
So if you look at the history here, because it's an obviousness issue, the question is, well, when was an issue determined to arise because of spiking?

[00:07:45] Speaker 02:
During the use of a drug, it could have been any of the nitrogen scavenging.

[00:07:51] Speaker 02:
Eating, drinking, right?

[00:07:52] Speaker 02:
Over the years.

[00:07:53] Speaker 02:
And the fact is spiking certainly was recognized to occur.

[00:07:56] Speaker 02:
I mean, it's recognized all the way back to 1960 that that could occur.

[00:08:01] Speaker 02:
The use of nitrogen scavenging drugs has been out there for 40 years.

[00:08:06] Speaker 05:
And the purpose was to counteract the spiking.

[00:08:11] Speaker 05:
Bring the number down, so to speak.

[00:08:14] Speaker 02:
Well, it was always recognized that spiking could occur, but that was never used as a motivation to increase the dose of a nitrogen scavenging agent.

[00:08:25] Speaker 02:
And again, spiking is not new.

[00:08:26] Speaker 02:
This is why I find it to be somewhat astounding that based upon the teachings of the 859, there can be a conclusion of obviousness, because spiking is not new news.

[00:08:38] Speaker 02:
It's old news.

[00:08:39] Speaker 02:
It's 60 years old.

[00:08:41] Speaker 02:
And the fact that nitrogen scavenging agents could be used

[00:08:44] Speaker 02:
as a method for reducing the level here of, it could be of a problem, is not an issue that was considered to be of such a nature that you needed to continue to take the level down below.

[00:09:02] Speaker 05:
It's not anticipation here.

[00:09:04] Speaker 05:
It's obvious.

[00:09:05] Speaker 02:
Absolutely.

[00:09:06] Speaker 02:
And obviousness has to be looked at from the standpoint of a person of ordinary skill in the art.

[00:09:11] Speaker 02:
And those of ordinary skill in the art

[00:09:13] Speaker 02:
who looked at this over a 40-year period never said, we need to continue to dose to take it the level down below normal.

[00:09:22] Speaker 02:
That is never found.

[00:09:23] Speaker 05:
Well, it would be anticipated if that were the case.

[00:09:26] Speaker 05:
If one or more nurses going there in the past had recognized this problem and the way to solve it was with an additional dose.

[00:09:33] Speaker 02:
Well, not really.

[00:09:34] Speaker 02:
It depends upon how far we go here.

[00:09:36] Speaker 02:
I mean, there's nothing that says if a patient is at two or even three times.

[00:09:40] Speaker 02:
We've got the consensus paper, which is part of our argument here, which is a 2001 paper that is made up by some of the

[00:09:49] Speaker 02:
brightest people there.

[00:09:51] Speaker 02:
Saul Brusselot, for example, who invented, by the way, HPN 100 was there.

[00:09:56] Speaker 02:
And the consensus said, what?

[00:09:58] Speaker 02:
They said, we don't know whether we should give even a dose to a patient if they're only at the level of two to three times the upper limit of normal.

[00:10:07] Speaker 02:
So the fact that you could go above normal in the spike throughout the period has been recognized over this huge period of time of over 40 years.

[00:10:16] Speaker 02:
No one said you should even treat, once it's above, partially above the upper limb of normal, half of it, for example, or twice, even up to three times.

[00:10:27] Speaker 02:
The art doesn't say that.

[00:10:28] Speaker 04:
How do you distinguish, and this is where I have troubles, how do you distinguish that kind of observation from the kind of observation that we seem to be stuck with with the Supreme Court?

[00:10:41] Speaker 04:
You know the Mayo Prometheus case.

[00:10:44] Speaker 04:
and an observation of a physiological fact, a law of nature, which is then the basis of diagnosis, a straightforward diagnosis, and then a known treatment.

[00:11:00] Speaker 02:
Well, we have more than that in this case, Your Honor.

[00:11:02] Speaker 02:
What we have is a recognition that comes from the 559 patent.

[00:11:07] Speaker 02:
By the way, the 859 publication

[00:11:10] Speaker 02:
says don't use fasting ammonia levels, don't use ammonia level at all as a basis for treatment.

[00:11:17] Speaker 02:
So what do we find then, and I can give you the quotes on that if you would like, but so what do we find coming out of the 559 patent?

[00:11:24] Speaker 02:
It's not just looking for something out there, it's looking for a problem, finding the problem and finding the solution to that problem.

[00:11:32] Speaker 02:
We have affirmative steps that say once you determine that the patient is in this range,

[00:11:39] Speaker 02:
of between half and the upper limit of normal, there is a need at that point to do treatment.

[00:11:45] Speaker 02:
And that's what the patent says to do, increase a dose at that point.

[00:11:49] Speaker 02:
But it's not an issue that simply says don't do anything other than determine that there is a problem.

[00:11:56] Speaker 02:
It's got an affirmative step that says treat it.

[00:11:59] Speaker 02:
Treat it how?

[00:12:00] Speaker 02:
By making sure that if it's above half but below the upper limit of normal, you increase dose.

[00:12:06] Speaker 02:
That's not to be found anywhere.

[00:12:08] Speaker 02:
an issue of prior art, and it's also not an internal issue in your body.

[00:12:14] Speaker 02:
At this point in time, it's the physician taking an affirmative step to change that.

[00:12:21] Speaker 02:
So I think it is totally distinguishable from the decision that you referred to, Judge.

[00:12:29] Speaker 03:
Emphasize here what the problem where do you see that then that the board made its error?

[00:12:34] Speaker 02:
I mean I'll understand what you're saying, but you're arguing in Generalities give me a specific point where the board aired Well the the board made many errors, but the biggest error I would say that they made is they essentially found the obviousness decision based upon their expert

[00:12:59] Speaker 02:
And their expert specifically said that there was a motive.

[00:13:04] Speaker 02:
The reason that they found the way they did, their expert says there was a motivation to continue to increase the dose in order to get the level down below the upper limit of normal.

[00:13:19] Speaker 02:
And that's where the board turned to and said,

[00:13:23] Speaker 02:
in order to prevent spiking and so forth.

[00:13:26] Speaker 02:
A post-it would have done that because there are spikings that can occur during the day.

[00:13:31] Speaker 02:
But their finding is not based on any art.

[00:13:34] Speaker 02:
And it's also not based from the standpoint of their expert.

[00:13:37] Speaker 02:
Their expert had nothing to support that position either.

[00:13:41] Speaker 02:
Because again, if you look at what was out there available from a prior art standpoint, the only thing you have are articles that talk about

[00:13:50] Speaker 02:
But treatment from the standpoint of there's a need, maybe if you're up above three times, that you want to increase the dose.

[00:13:57] Speaker 02:
But no motivation to take an affirmative action if the patient's already within the normal range.

[00:14:03] Speaker 02:
That's void.

[00:14:04] Speaker 02:
That's not there.

[00:14:04] Speaker 02:
It doesn't exist.

[00:14:05] Speaker 05:
Well, the patient was in the normal range, but at the risk of getting beyond the normal range.

[00:14:11] Speaker 05:
That was the thought I thought.

[00:14:14] Speaker 05:
Because he was at the lower end, and there was an expectation of a spiking event.

[00:14:19] Speaker 02:
There is no expectation found in any prior art that would say that patient is not in good condition.

[00:14:27] Speaker 02:
That's the point, because they were accepting at that time much, much higher levels to be okay.

[00:14:34] Speaker 02:
You know, two and three times the upper limit of normal.

[00:14:37] Speaker 02:
So sure, spikes occurred, but there was no motivation once you were in that happy zone at or around or slightly below or above the ULN

[00:14:48] Speaker 02:
Physicians said, that's good.

[00:14:50] Speaker 02:
They never said there's a problem.

[00:14:52] Speaker 02:
That's what was found by Dr. Scharsmit in the research that he did, looking at this for the first ever 65 patients that had UCD and determined that there was a reason why you needed to lower that level.

[00:15:07] Speaker 02:
And if you look at the data that's in there, it shows that there is a vastly increased probability that the average during the day is going to be

[00:15:18] Speaker 05:
Normal and that the amount of spiking that occurs is going to be below one and a half times the upper limit of normal That was never seen before that's where the motivation wrong I thought there was understanding in in the art that there was a goal to keep a medicated patient in the normal range

[00:15:40] Speaker 02:
There was always a goal.

[00:15:43] Speaker 05:
So you established this goal.

[00:15:44] Speaker 05:
And you say, what we're trying to do is to keep the patient in the normal range, patients at the low end of the normal range.

[00:15:51] Speaker 05:
We're anticipating a spiking event, which will push them out of the normal range, give them a little more of the pharmaceutical to keep them in the range.

[00:15:59] Speaker 05:
So as far as keeping them as a matter, almost a reason, not of common sense, but a reason.

[00:16:05] Speaker 05:
You say, it makes sense that if someone is

[00:16:10] Speaker 05:
at a lower range medicated, gonna have a spiking event you know about.

[00:16:15] Speaker 05:
You know, if you add a little bit more of the pharmaceutical, you'll counteract the effect of the additional protein in order to bring the ammonia level, plasma ammonia level back down safely within the range.

[00:16:27] Speaker 02:
You know, Your Honor, I mean, that can be like your view or my view looking at it as not a POSA, but a POSA for 40 years.

[00:16:34] Speaker 02:
All of them had a chance to look at it.

[00:16:36] Speaker 05:
All I'm saying is I thought that evidence about the goal was a piece of the puzzle of

[00:16:41] Speaker 05:
why it was that one of ordinary skill in the art would find a reason to do this.

[00:16:47] Speaker 02:
The piece of the puzzle that was needed was really the testing that was done.

[00:16:55] Speaker 02:
for 65 patients that resulted in the data source that was then used by Dr. Scharshmit to determine that there was a problem at that point.

[00:17:04] Speaker 02:
Because they said, you have to look at obviousness from the standpoint of APOSA.

[00:17:09] Speaker 02:
And there was no article ever out there.

[00:17:12] Speaker 02:
No one ever went to a conference.

[00:17:13] Speaker 02:
No one ever said if there's a range that's above the upper limit

[00:17:18] Speaker 02:
or at or below the upper limit of normal, we should still increase the dose.

[00:17:23] Speaker 02:
Nobody did that.

[00:17:24] Speaker 02:
And you can look at it from the standpoint, too, you're treating a patient, and that patient has UCD.

[00:17:30] Speaker 02:
And it's very, very hard to maintain for a patient a level that is good for them.

[00:17:36] Speaker 02:
And in fact, that's one of the big issues.

[00:17:38] Speaker 02:
If you look at the history here and why Dr. Sharfman did the work that he did, the numbers are devastating.

[00:17:47] Speaker 02:
fine articles, for example, that show that the children, mainly children in that level, had numerous problems.

[00:17:57] Speaker 02:
They had cognitive problems and they had other life-threatening problems because the treatment wasn't good.

[00:18:05] Speaker 02:
But why wasn't it good?

[00:18:06] Speaker 02:
It was because there was no recognition that there was a need to make this into

[00:18:12] Speaker 02:
Find that between half and the upper limit of normal was really a problem because no posa is out there They had that feeling or wrote a book about it the data didn't exist Okay, but let's hear from the other side and we'll save some rebuttal time.

[00:18:28] Speaker 02:
Okay.

[00:18:28] Speaker 04:
Thank you judge This cap

[00:18:39] Speaker 04:
I said the other side.

[00:18:41] Speaker 04:
What happened to the petitioner in this case?

[00:18:44] Speaker 01:
Good morning, Your Honors.

[00:18:45] Speaker 01:
May it please the Court?

[00:18:46] Speaker 01:
The petitioner in this case dropped out after a settlement with Horizon Council.

[00:18:52] Speaker 04:
So why then, why are you here?

[00:18:56] Speaker 01:
We're here to defend the Board's decision, finding that the claims here are obvious over the prior art.

[00:19:02] Speaker 04:
But where is the controversy to bring you to an Article 3 Court?

[00:19:06] Speaker 01:
Well, under the AIA, the agency has the authority to intervene in these proceedings and the intervention.

[00:19:12] Speaker 04:
That's not the question.

[00:19:14] Speaker 04:
The question is where is the controversy between antagonists?

[00:19:20] Speaker 04:
The director is the adjudicator.

[00:19:23] Speaker 01:
Well, the agency has an interest in defending the decisions of its agency, and the statute specifically permits the agency to intervene in these cases under the AIA.

[00:19:33] Speaker 04:
The agency may have an interest, but where is the Article III controversy?

[00:19:43] Speaker 01:
Again, the agency's authority to intervene in this case is dictated by statute.

[00:19:49] Speaker 01:
Congress authorized cases to intervene.

[00:19:52] Speaker 05:
Do you think that answers the question?

[00:19:54] Speaker 05:
My recollection is that we've addressed this issue previously in a case.

[00:19:58] Speaker 05:
Do you have any familiarity with it?

[00:20:00] Speaker 05:
I can't remember the name of the case.

[00:20:02] Speaker 05:
I was on the panel.

[00:20:06] Speaker 04:
We've addressed it in various cases.

[00:20:07] Speaker 01:
I think it was the Knowles case, perhaps.

[00:20:09] Speaker 01:
Perhaps it was the Knowles case that addressed this issue.

[00:20:12] Speaker 05:
No, it was in the last year and a half.

[00:20:13] Speaker 05:
Last year and a half.

[00:20:15] Speaker 05:
We can look at it.

[00:20:17] Speaker 04:
Well, I proceed on the merits.

[00:20:19] Speaker 04:
Thank you, Your Honor.

[00:20:20] Speaker 04:
This is a fundamental issue.

[00:20:24] Speaker 04:
We appreciate the statute authorizes the director to intervene, but I don't see that it authorizes the director to substitute itself when there's no longer a controversy.

[00:20:38] Speaker 04:
That doesn't seem to have been contemplated in the statute that granted the right to intervene without making a motion to do so.

[00:20:47] Speaker 01:
Your Honor, we did move to intervene in this case, which was granted by the court.

[00:20:52] Speaker 01:
But I will turn to the merits now.

[00:20:55] Speaker 05:
You moved to intervene, the motion was granted.

[00:20:58] Speaker 01:
Correct.

[00:20:59] Speaker 01:
As to the merits of the decision.

[00:21:01] Speaker 04:
The motion to intervene was made at an early stage.

[00:21:04] Speaker 04:
We have been automatically granting those motions.

[00:21:09] Speaker 04:
But the issue has been focused more clearly in recent cases.

[00:21:16] Speaker 04:
But proceed with the minutes.

[00:21:17] Speaker 05:
If it were true that you didn't have standing to be here, then the decision would stand and the patent would be invalidated without any opportunity for the other party to.

[00:21:28] Speaker 05:
They would be able to appeal here, correct?

[00:21:30] Speaker 05:
That's correct, Your Honor.

[00:21:31] Speaker 05:
And you simply wouldn't be able to defend?

[00:21:33] Speaker 03:
Correct, Your Honor.

[00:21:36] Speaker 03:
I shared Judge Newman's concerns as to whether we even have jurisdiction in this case.

[00:21:41] Speaker 03:
And I would propose that the parties provide briefing on this particular issue so that we may resolve the question at a later time.

[00:21:52] Speaker 04:
Is that supplemental briefing that may be helpful?

[00:21:56] Speaker 04:
The issue has arisen in a number of cases.

[00:21:59] Speaker 04:
And so the briefing is being, but proceed with the merits.

[00:22:02] Speaker 01:
Your Honor, we're happy to provide an additional briefing on that issue.

[00:22:05] Speaker 01:
And as to the merits of this case, Judge Clevenger pointed to the issue that's at issue here.

[00:22:11] Speaker 01:
Here there was an expectation that plasma ammonia levels will spike after eating.

[00:22:16] Speaker 01:
Blau teaches this clearly.

[00:22:18] Speaker 01:
In fact, Blau teaches that plasma ammonia levels after eating can spike between 30 to 60 micromoles per liter.

[00:22:25] Speaker 01:
which shows that one of ordinary still in the art looking at blouse teachings along with the teachings of the 859 publication would know that at the fasted state, a plasma ammonia level that indicates the concentration of ammonia being at a normal level or even below normal would indicate that once that individual ate something, their ammonia level would spike significantly.

[00:22:52] Speaker 05:
And thus, in your view, the person would see there's a problem to be solved.

[00:22:57] Speaker 05:
Correct, Your Honor.

[00:22:58] Speaker 01:
Also, the only error that Horizons Council has identified today is the board's reliance on Dr. Vo's testimony.

[00:23:06] Speaker 01:
And the board found that Dr. Vo is a person of ordinary skill in the art.

[00:23:10] Speaker 01:
That's because Dr. Vo has significant experience treating patients for over 20 years who had UCDs.

[00:23:17] Speaker 01:
So because of that experience and because Dr. Vo's testimony is also supported by the priority record.

[00:23:25] Speaker 05:
And I said he was not an expert, but his testimony would be credited because he was a practitioner.

[00:23:31] Speaker 01:
Correct.

[00:23:32] Speaker 01:
It's because he was a practitioner and has had experience treating patients.

[00:23:35] Speaker 01:
In addition to that, Dr. Vo's testimony is supported by the priority record, including the Blau reference and the 859 publication.

[00:23:44] Speaker 01:
And thus, the force decision here should be affirmed.

[00:23:53] Speaker 01:
And again, the 859 publication also taught the goal of maintaining blood plasma ammonia levels at 40 micromoles per liter or lower.

[00:24:03] Speaker 01:
And so the goal here was taught as was the fact that blood ammonia plasma levels can spike after eating.

[00:24:10] Speaker 01:
If there are no further questions, we ask that the court confirm the board's decision below.

[00:24:20] Speaker ?:
Thank you.

[00:24:20] Speaker 04:
Mr. Green, three minutes of rebuttal.

[00:24:24] Speaker 02:
Thank you, Judge.

[00:24:28] Speaker 02:
Dr. Inns was our expert.

[00:24:31] Speaker 02:
He is a person of extraordinary skill in the art.

[00:24:37] Speaker 02:
That is what he does as he treats UCD patients.

[00:24:40] Speaker 02:
He has been doing this for years.

[00:24:44] Speaker 02:
I don't want to get into Inns versus Dr. Vaux, but I can say that the conclusion that counsel came to is wrong.

[00:24:54] Speaker 02:
turning to BLOW, 859, if you look at BLOW, it doesn't say a thing about increasing the dose for a patient who is below the upper limit of normal, but above half.

[00:25:14] Speaker 02:
There's no discussion on that.

[00:25:18] Speaker 02:
And the whole problem is the idea that

[00:25:22] Speaker 02:
there's motivation to do it is, again, missing because the prior art never went that direction.

[00:25:28] Speaker 02:
It was happy with it.

[00:25:29] Speaker 05:
Was there a problem to be solved?

[00:25:32] Speaker 05:
If you have a patient who is at the lower end of normal and is about to incur a spiking event, it was known that the plasma ammonia level would rise outside of the normal event.

[00:25:49] Speaker 05:
So here's a problem.

[00:25:51] Speaker 02:
The fact that there can be spiking, yes, it was known for 40 years, 60 years, actually.

[00:25:57] Speaker 05:
And what would be a reasonable, rational way to solve the problem?

[00:26:02] Speaker 02:
Well, if you look at what happened was to realize... You get a little bit more of the drug.

[00:26:08] Speaker 02:
The fact that there's spiking though, like you say, your blood pressure can go up during the day.

[00:26:13] Speaker 02:
And that doesn't mean you have to take blood pressure medication.

[00:26:16] Speaker 02:
This, because you have an interim spike for a moment, doesn't necessarily mean that there's a problem.

[00:26:21] Speaker 05:
I know there's a difference between an interim spike and then a known event that's going to occur.

[00:26:26] Speaker 05:
It isn't a matter of normal fluctuation.

[00:26:29] Speaker 05:
You say, if I go into altitude, my blood pressure is going to go up 20 points.

[00:26:34] Speaker 05:
And every doctor could tell you that, and you would know it.

[00:26:38] Speaker 05:
And the doctor would say, well, take another 20 milligrams of the pharmaceutical.

[00:26:44] Speaker 05:
And let's assume that's- If there were demonstrated side effects, I mean, real high risks of taking the additional dose, it'd be scary.

[00:26:54] Speaker 05:
My understanding in this record was that there were no known with the PN 100, there weren't any problems.

[00:27:04] Speaker 05:
with side effects of additional dosage.

[00:27:08] Speaker 02:
There was none that was discussed in the 859.

[00:27:11] Speaker 05:
I certainly wouldn't be having this discussion with you at all if there had been known side effects with additional dosages because you're not doing a patient any favor by giving it more high blood pressure medication if it's going to drive them down to zero.

[00:27:27] Speaker 02:
Yeah, well, there can be side effect problems.

[00:27:29] Speaker 02:
In fact, we do have that in our... I mean, that's the... Yeah, we do go through the fact that there can be... Well, there was a finding that you didn't challenge that on appeal.

[00:27:36] Speaker 05:
There was a finding that the HPN 100 didn't have side effects.

[00:27:43] Speaker 02:
Well, the A5... Sorry.

[00:27:46] Speaker 02:
Well, we did challenge the view that, in fact, that there was no problem with increasing the dose.

[00:27:54] Speaker 05:
But you haven't challenged that on appeal as a fact finding.

[00:27:57] Speaker 02:
We have that in the reply brief.

[00:28:00] Speaker 05:
On HPN 100?

[00:28:03] Speaker 05:
It's a general statement that if you increase... HPN 100, the evidence was that there was no side effects, no adverse side effects.

[00:28:09] Speaker 02:
Well, the only evidence that related to HPN 100 is that evidence that's in the 859, which had nothing to do with increasing doses whatsoever.

[00:28:18] Speaker 02:
And that's one of the most defined things, is that there is a position taken that somehow the 859 patent was dealing with dose increases.

[00:28:26] Speaker 02:
It wasn't.

[00:28:27] Speaker 02:
The 859 patent, when it was looking at the data that resulted from the small clinical study that was done at that time, was a comparison between bufenol and HPN 100.

[00:28:38] Speaker 02:
And all they did in that case is they took the same amount of active that would come and would be administered then to the individual patient and found in some instances when the HPN 100 was given, there was a change, but it wasn't necessarily due.

[00:28:55] Speaker 02:
no indication as to the reason why there was a change.

[00:28:58] Speaker 02:
If you look at the table 12 in the 859 patent, you'll see some of the changes are actually kind of massive, but there was nothing that said that there was any control that was put on those patients when those levels were taken.

[00:29:13] Speaker 02:
Those levels that were taken were not

[00:29:15] Speaker 02:
Designed to be nor were they said to be fasting blood ammonia levels and all it shows is when you changed the dosing for some of the patients there was a when you changed from Perfinal to HP and 100 there in fact was some change in the result for some of the patients But you don't know what that was for but my point is it doesn't say to increase the dose anywhere in the 859 publication and

[00:29:42] Speaker 02:
And if you look at the 859 publication when it comes to dealing, and this is what I find puzzling, using plasma ammonia levels, it says, 859 says plasma ammonia levels are less reliable and provide no direct information about whether the drug is actually working.

[00:29:58] Speaker 02:
It says that the 859 publication, it teaches only that urinary P-A-G-N, which we had a discussion about a year ago, Judge Newman,

[00:30:08] Speaker 02:
with respect to the O1-2 patent is convenient and reliable as a direct measure of the nitrogen scavenging effect.

[00:30:14] Speaker 02:
So as of the 859 timeframe, what did your principal reference say?

[00:30:21] Speaker 02:
It said don't look at the values that you have for a FASC and plasma ammonia level, look at urinary P-A-G-N.

[00:30:30] Speaker 02:
And because of that, I can

[00:30:32] Speaker 02:
I just can't envision how there was any motivation for APOSA to do that, and there's no indication that APOSA would have relied on the level.

[00:30:43] Speaker 04:
OK.

[00:30:44] Speaker 04:
Any questions?

[00:30:46] Speaker 04:
OK.

[00:30:47] Speaker 02:
Thank you.

[00:30:47] Speaker 04:
If we think that we need further briefing on anything, we will talk it over, and we'll let you know at the moment.

[00:30:55] Speaker 04:
The case is taken under submission.

[00:30:57] Speaker 04:
Thank you both.