[00:00:03] Speaker 03:
case this morning, it's number 231247, FANDA Pharmaceuticals 8 versus Kiva Pharmaceuticals 8, Mr. Groombridge.

[00:00:14] Speaker 02:
Thank you, Your Honor, and may it please the Court.

[00:00:16] Speaker 02:
I believe I had reserved two minutes for rebuttal.

[00:00:21] Speaker 02:
I would like to begin with the reissue 604 patent and talk about the errors that we believe compel reversal here.

[00:00:32] Speaker 02:
And to begin, I'd like to make clear that what we see here are pervasive errors of law, which in turn led to errors of fact.

[00:00:41] Speaker 02:
and the errors of law are the failure to consider the prior art as a whole and instead to use the claimed invention as a template from which to stitch together elements of the prior art in violation of the clear direction this Court has given going all the way back to the Penduit case.

[00:00:57] Speaker 02:
And I would begin with the

[00:01:01] Speaker 02:
The key part of the claim of the 604 patent, the question there is whether 20 milligrams of tazamaltion administered as claimed can entrain a patient.

[00:01:14] Speaker 02:
And I believe some aspects of this are common ground.

[00:01:18] Speaker 02:
What entrainment means is synchronizing the patient's natural circadian rhythm, which varies, one might think of it like a sine curve.

[00:01:28] Speaker 02:
synchronizing it to the rhythm of the sun, of the earth.

[00:01:33] Speaker 02:
And I believe it is common ground that at least one thing that is required in order for that synchronization is for the drug to be able to do what is called phase shifting.

[00:01:45] Speaker 03:
So just to try to move this along, if I understand your argument correctly, you're saying that the prior art references don't show a statistically significant

[00:01:57] Speaker 03:
effect on phase shifting, though they do show an effect on other aspects of sleep disorders, correct?

[00:02:07] Speaker 02:
Absolutely correct, Judge Daly.

[00:02:08] Speaker 03:
And on the cross-examination,

[00:02:11] Speaker 03:
the generics expert on which the district court relied heavily conceded that.

[00:02:20] Speaker 03:
But he also said that there were, even though it wasn't statistically significant, there were other aspects of those prior large studies that led him to conclude that it would have an effect on phase shifting.

[00:02:34] Speaker 03:
And there was no further cross-examination about that.

[00:02:38] Speaker 03:
So why isn't that sufficient for the district court to conclude that these prior art studies suggested something about the 20-milligram dose and phase shifting?

[00:02:50] Speaker 03:
Is my statement a fair summary of what happened?

[00:02:53] Speaker 02:
I think your statement is a fair summary of what happened, Your Honor.

[00:02:57] Speaker 02:
And I think if we dive into that and we look at it, the expert said at some point in his testimony, yes, there is a place in which, in the so-called Roger Atnam prior art, it shows a one-hour phase shift at the 20-milligram dose.

[00:03:15] Speaker 02:
But the Roger Atnam reference makes clear that that's not statistically significant.

[00:03:20] Speaker 03:
In other words...

[00:03:22] Speaker 02:
Right.

[00:03:23] Speaker 02:
And he agreed with that.

[00:03:24] Speaker 02:
And he also agreed that in the Harderland reference, which underpins a lot of the obviousness holding, that when Harderland was talking about the use of 20 milligrams to 50 milligrams, that was not for phase shifting.

[00:03:39] Speaker 02:
And that's in the record of 19303.

[00:03:43] Speaker 02:
So in our view, Your Honor, if we step back and look at the art and we say, what does it show?

[00:03:52] Speaker 02:
What would be a fair reading of this body of art if you were a skilled person in 2012?

[00:03:58] Speaker 02:
You would find one primary reference.

[00:04:01] Speaker 02:
and three secondary references, which in essence we package.

[00:04:04] Speaker 03:
But your witness said that nonetheless, despite a lack of statistical significance, there was data in there which led him to conclude that

[00:04:16] Speaker 03:
It was likely that there would be a phase effect from the 28-milligram study.

[00:04:23] Speaker 02:
I think he conceded, and this is at 19302, that in the primary reference, it was the only dose that showed statistically significant phase shifting was 100 milligrams.

[00:04:34] Speaker 03:
Yeah, he conceded that.

[00:04:36] Speaker 03:
But he also went on to say, nonetheless, I concluded that this prior art shows that it would have an effect.

[00:04:45] Speaker 02:
I think the only thing he pointed to was the 20-milligram result in the Roger Atnam reference, which, on the face of the reference, is not statistically significant.

[00:04:56] Speaker 02:
And Roger Atnam itself says that.

[00:04:59] Speaker 02:
In other words, what I would suggest, a witness, credible or not, can't override the express teachings of the prior art.

[00:05:07] Speaker 03:
Well, I don't think it's an express teaching.

[00:05:09] Speaker 03:
This is one example on 19304.

[00:05:13] Speaker 03:
He says, I think we do have some evidence to suggest that lower doses would work.

[00:05:20] Speaker 02:
He's talking about phase shifting.

[00:05:20] Speaker 02:
He says lower than 100.

[00:05:23] Speaker 02:
But he doesn't say that the only thing that he points to with respect to 20 is the bar chart in Rajaratnam, which on its face, and I believe everyone including he agreed, is not statistically significant.

[00:05:39] Speaker 02:
So there is, for example, a kind of passing statement in the Vanda 244 reference that 50 milligrams might work to phase shift.

[00:05:48] Speaker 02:
So you can find something in the record that says, well, maybe less than 100.

[00:05:54] Speaker 02:
But what you can't find is any, viewing the art as a whole, you cannot find anything that would say 20 milligrams will work to phase shift.

[00:06:09] Speaker 02:
And he also said, and I'm happy to engage further with that if the court wishes to or I can move on, but he also said that phase shifting is a necessary but not sufficient condition to accomplish entrainment.

[00:06:29] Speaker 02:
And the district court's opinion entirely skips over that and proceeds from the assumption that all one needs is phase shifting.

[00:06:37] Speaker 02:
Emmons indeed conceded that, and this is at 19298, that a drug could phase shift and yet be unable to entrain.

[00:06:50] Speaker 02:
And that, too, is something that the district court completely failed to engage with.

[00:06:56] Speaker 02:
And in our view, Your Honor, that's

[00:06:58] Speaker 02:
What's underlying this is a failure to consider the differences from what was in the prior art and looking merely at the similarities.

[00:07:05] Speaker 02:
And so this ability, there was a lot of testimony about a phenomenon that Dr. Emmons himself named called spillover in which, and what's going on here is the drug when one admits to it has to be able to pull the circadian rhythm into alignment.

[00:07:23] Speaker 02:
But if the drug persists in the patient's body for too long, it will then pull back and pull the rhythm out of alignment.

[00:07:32] Speaker 02:
And that it will undo the very thing that it was supposed that it was administered to do.

[00:07:38] Speaker 02:
And whether it does that depends upon the amount given, the time it's given, and the characteristics of the drug, how quickly it's cleared out of the body.

[00:07:48] Speaker 02:
And here what we've got, the district court said, well, tazamelton works just like melatonin.

[00:07:55] Speaker 02:
But the unequivocal evidence in the record here is that the half-life of melatonin is, let's say 30 minutes, might gust to 45 minutes, whereas the half-life of tazamelton is two hours.

[00:08:06] Speaker 02:
And so those things, what that's saying there to the skilled person is that

[00:08:10] Speaker 02:
there's no way to predict whether it would, in fact, do this.

[00:08:15] Speaker 02:
Even if it can phase shift at this dosage, no way to know whether it will still persist in the body and make it impossible to accomplish the entrainment that is part of the claim.

[00:08:27] Speaker 02:
The district court simply failed to engage with any of that and said... Judge Bryson.

[00:08:32] Speaker 01:
No, no, go ahead.

[00:08:32] Speaker 02:
And repeatedly through the district court opinion are statements that phase shifting, equating phase shifting with ability to entrain.

[00:08:43] Speaker 02:
In derogation of the admission on cross-examination by Dr. Emmons, that phase shifting is necessary but not sufficient, and something even that which phase shifts may not be capable of in training.

[00:08:54] Speaker 02:
District court simply didn't engage with that because it didn't address the differences

[00:08:59] Speaker 02:
between melatonin and tazamaltion, which bear critically on that issue.

[00:09:05] Speaker 01:
Could you turn to the food patent?

[00:09:07] Speaker 01:
Absolutely, Your Honor.

[00:09:09] Speaker 02:
Yes.

[00:09:10] Speaker 01:
And would you agree that testing for food effects is a very common procedure to employ in the process of getting

[00:09:23] Speaker 02:
I believe it is, Your Honor, although I'm not sure whether that's reflected in the record here, right?

[00:09:31] Speaker 02:
But I certainly think it's not uncommon.

[00:09:32] Speaker 03:
Yeah, it is reflected in the record because there's an exhibit, maybe it's 345 is the number, which talks about your 100-milligram food effect study, and it recognizes

[00:09:49] Speaker 02:
then that's certainly right.

[00:09:51] Speaker 02:
And that study is a study that was done in accordance with, I think, fairly typical FDA procedures.

[00:09:58] Speaker 01:
The guidance from the FDA on this, right?

[00:10:00] Speaker 02:
Yeah, right.

[00:10:01] Speaker 02:
But the effects of that are not public.

[00:10:03] Speaker 02:
So I think what we boil down to here is what I take

[00:10:08] Speaker 02:
district courts who have said is well it's a binary choice and so both either doing it with food or doing it without food are obvious and what we would say Dr. Emmons testified here and this is in the record at

[00:10:23] Speaker 02:
19292, that the only way you could know whether there would be a food effect that would bear on the efficacy of tasamaltion would be to do such a study.

[00:10:35] Speaker 03:
Sure.

[00:10:36] Speaker 03:
But doesn't the FDA suggest that you do such a study?

[00:10:40] Speaker 02:
Oh.

[00:10:40] Speaker 03:
And isn't that sufficient to point you in that direction?

[00:10:44] Speaker 02:
I think, Your Honor, my answer would be, regardless of whether the FDA suggested it's not sufficient, the question is whether in the prior art is there a teaching that this drug would have this effect.

[00:10:55] Speaker 02:
In other words, some drugs do, some drugs don't.

[00:10:57] Speaker 03:
There has to be a teaching, a specific teaching with respect to the drug in question.

[00:11:02] Speaker 02:
I think there has to be a specific teaching that the invention would have been obvious.

[00:11:07] Speaker 02:
And if you simply don't know, right, if the art is silent, and it could be that it matters, it could be that it doesn't matter, it could be that it matters with some kinds of food but not other kinds of food, which is, you know, can happen, then there's no way to predict that.

[00:11:23] Speaker 02:
And accordingly, simply because the choice is... It's quite obvious to try.

[00:11:28] Speaker 03:
It tells you this is something that's a matter of significance and you should look at it.

[00:11:33] Speaker 02:
I'm not sure that there are a finite number of possibilities.

[00:11:40] Speaker 02:
In other words, the question here is whether and to what degree does food affect the ingestion of this drug into the bloodstream.

[00:11:50] Speaker 02:
That doesn't seem, in our view, that's not something as to which there are a finite number of answers.

[00:11:55] Speaker 02:
It might, it might not, it might to some degree a greater or lesser degree.

[00:11:58] Speaker 02:
Whether that it does to such a degree that it's important enough for FDA to say, I require you as part of the labeling to

[00:12:09] Speaker 02:
to tell patients not to take it with food is not, in our view, a binary choice.

[00:12:15] Speaker 02:
You could only know that by having investigated it.

[00:12:18] Speaker 02:
And it could be that there is a modest effect, but it doesn't matter.

[00:12:22] Speaker 02:
And so it could be that it increases the efficacy to some degree, but that doesn't matter either.

[00:12:32] Speaker 02:
The fact that it is significant enough here in the context of this treatment, which comes back again in our view,

[00:12:39] Speaker 02:
to the need to have a, what we have termed in the briefing, a short, sharp pulse of the drug, which is related to entrainment.

[00:12:45] Speaker 02:
It needs to get in there, do its job, and then get out.

[00:12:49] Speaker 02:
That was not knowable in advance.

[00:12:51] Speaker 02:
And the discovery that in order to accomplish that and make the treatment effective, it must be done without food, is inventive.

[00:12:59] Speaker 02:
It's not known.

[00:13:00] Speaker 02:
There's nothing in the art that points to it.

[00:13:03] Speaker 02:
With that, cognizant that my time is running out, I would turn to the so-called 3A4 patent, unless any of the Your Honors have further questions.

[00:13:13] Speaker 02:
On 3A4, in our view, again, what we have here is a failure to consider the prior art as a whole.

[00:13:23] Speaker 02:
The district court acknowledged, and this is its finding of fact 88,

[00:13:27] Speaker 02:
that FDA requires in vitro testing of the metabolism of drugs.

[00:13:35] Speaker 02:
And the reason that the district court held that was that for the other drug-drug interaction pattern, the district court said, and that is what the starting point in an obviousness analysis.

[00:13:47] Speaker 02:
But for the 3A4 pattern, the district court ignored this unequivocal teaching in the prior art from the so-called Vashrajani reference.

[00:13:55] Speaker 02:
that this enzyme was not involved in the metabolism of tessemaltion.

[00:14:00] Speaker 02:
Now, Vander subsequently discovered that that teaching was wrong, just flat out wrong.

[00:14:07] Speaker 02:
But here, you know, in our view, if one is sitting down to conduct an obviousness analysis in 2012,

[00:14:13] Speaker 02:
Manifestly, the starting point has to be with the single most direct teaching in the art.

[00:14:20] Speaker 02:
Is the enzyme, CYP3A4, involved in the metabolism of this drug?

[00:14:24] Speaker 02:
There's a clear and unequivocal teaching that the answer to that question was no.

[00:14:28] Speaker 01:
And... At least in an in-vitro test.

[00:14:30] Speaker 01:
It's absolutely an in-vitro test, but... Well, but that... But, Your Honor, the... The argument that's made by your opposing counsel is that isn't particularly telling given the inducement factor.

[00:14:43] Speaker 02:
Well, but at the same time, the district court, and indeed my learned adversary, say that for the 1A2 patent, it's completely telling.

[00:14:51] Speaker 02:
The in vitro testing answers the question.

[00:14:54] Speaker 02:
And what we would say here is FDA's procedure as laid out is one begins with the in vitro testing.

[00:15:01] Speaker 02:
If the in vitro testing shows there's no need to be concerned, very often one doesn't go any further.

[00:15:06] Speaker 02:
And here, by contrast, the obviousness analysis is let's ignore that.

[00:15:10] Speaker 02:
Let's start and go through some convoluted analysis to get to using an entirely different drug and say, OK, there's a problem.

[00:15:18] Speaker 02:
And then only then come back and say, you know what?

[00:15:21] Speaker 02:
The in vitro testing doesn't exclude the possibility that it might be wrong.

[00:15:25] Speaker 03:
But it's a convoluted path, as you characterize it, that the district court accepted and made findings about, right?

[00:15:34] Speaker 02:
It made findings about, and again, Your Honor, we would say that those findings are very hindsight driven, and that they ignore clear teachings in the art that of differences between the molecule at issue in that analysis, remelteon, and tazemelteon.

[00:15:50] Speaker 02:
And so, for example, if we look at the Harderland reference, which figures prominently in the business analysis, it says, and this is at 20525,

[00:16:01] Speaker 02:
it calls out differences in the metabolism between

[00:16:05] Speaker 02:
of Tazimeltion and Remeltion says that there's a metabolite that shows up from Remeltion that doesn't exist with Tazimeltion, teaching that they're not the same pathways.

[00:16:15] Speaker 02:
So again, if we go back in time and say I'm sitting down in 2012 looking at the array of relevant information that's in front of me, we would suggest that as an obviousness, as a conclusion of law, we can't get to the place that the district court arrived to.

[00:16:29] Speaker 02:
And I'll just, I recognize my time is finished, but the one final point I would make there is that

[00:16:33] Speaker 02:
Also in the record, this comes back to questions of half-life, right?

[00:16:39] Speaker 02:
That the record is scattered through the record that the half-life of tazamaltium is approximately two hours.

[00:16:46] Speaker 02:
And the effective half-life of remaltium is five hours.

[00:16:51] Speaker 02:
And what that bespeaks is a radical difference in how the two operate in the body.

[00:16:56] Speaker 02:
And so if one's going to posit, OK, I will begin with Remeltion because it's ostensibly because of its similarities, I should also look at the differences as it seems those differences are playing a major role here.

[00:17:11] Speaker 02:
And instead, the district court merely looked at the similarities and disregarded the differences.

[00:17:16] Speaker 02:
If we do that,

[00:17:16] Speaker 02:
Now, if we only consider one half of the ledger, that is going to put the thumb on the scale.

[00:17:21] Speaker 02:
I'm mixing my metaphors, but in such a severe fashion that the outcome is simply wrong.

[00:17:28] Speaker 03:
OK, I think we're about out of time here.

[00:17:30] Speaker 03:
I'll give you two minutes for rebuttal.

[00:17:32] Speaker 02:
Thank you, Your Honor.

[00:17:34] Speaker 03:
Mr. Rosendahl?

[00:17:41] Speaker 04:
May I please support?

[00:17:44] Speaker 04:
I prepared to address the validity issues in this appeal, and my colleague, Mr. Lucas, is prepared to address the infringement issue.

[00:17:51] Speaker 04:
I didn't hear that we got to the infringement issue, and so I'm not sure that there'll be much to say there.

[00:17:58] Speaker 04:
But the trial of this case was a classic battle of the experts, and Vanda lost it fair and square.

[00:18:05] Speaker 04:
On each of the patents, the experts had competing narratives about what people of skill in the art at the pertinent time would have understood, and in each instance, the district court credited Teva's and APA Tech's experts and declined to credit the testimony of Vanda's experts.

[00:18:20] Speaker 04:
So what Vanda now tries to categorize as

[00:18:24] Speaker 04:
essentially hindsight.

[00:18:26] Speaker 04:
They say, well, there's no way that you could have arrived at these results without looking at our invention.

[00:18:33] Speaker 04:
They're simply just not liking the version of the facts that the district court ended up crediting that was presented by the experts on our side.

[00:18:41] Speaker 04:
And the resulting factual determinations are very well supported in the record.

[00:18:45] Speaker 04:
By the time of the January 2012 priority date,

[00:18:48] Speaker 04:
For the RE604 patent, there was a well-developed body of tazimeltion prior art discussing the treatment of totally blind non-24 patients by administering 20 milligrams of tazimeltion once daily before bedtime.

[00:19:04] Speaker 04:
The prior art discussed the structural and functional similarities between tazimeltion and melatonin, which had been shown to entrain circadian rhythms.

[00:19:14] Speaker 04:
and predicted that the Tazimeltion treatment protocol, now claimed in the Pattinson suit, would be useful in treating non-24.

[00:19:23] Speaker 04:
For example, the Hardiland reference stated not only that the drug may be useful in the treatment of sleep disturbances related to circadian rhythm sleep disorders or other types of entrainment difficulties, but also said that these properties are expected from a melatonergic drug, which is to say a drug that acts on the

[00:19:44] Speaker 04:
melatonin receptors in the brain.

[00:19:48] Speaker 04:
While we're on this patent, I'd like to go ahead and address the 20 milligram point that was discussed.

[00:19:54] Speaker 04:
So there was one major phase two study that was done that was the subject of an awful lot of testimony at trial.

[00:20:02] Speaker 04:
It was a study of essentially jet lag.

[00:20:05] Speaker 04:
So there were 39.

[00:20:07] Speaker 04:
It was a small study.

[00:20:08] Speaker 04:
There were 39 participants.

[00:20:09] Speaker 04:
They were divided into multiple groups of placebo, 10 milligrams, 20 milligrams.

[00:20:14] Speaker 04:
50 milligrams, 100 milligrams.

[00:20:16] Speaker 04:
And so each group had only a small number of participants.

[00:20:19] Speaker 04:
There were between six and eight people per group.

[00:20:22] Speaker 04:
And the phase shift that was attempted was a five-hour phase shift, which was supposed to mimic essentially the difference in time between London and New York or Washington.

[00:20:32] Speaker 04:
And what the results showed was that at the 100-milligram dose, there was a statistically significant phase shift of between two and three hours in the relevant population.

[00:20:47] Speaker 04:
There were smaller shifts at the other doses, but because there was

[00:20:54] Speaker 04:
a very small placebo group and a very wide variance.

[00:20:58] Speaker 04:
And the results of that group, the standard deviation was extremely large for the placebo group.

[00:21:03] Speaker 04:
And so although it looked like the placebo ended up with about a half an hour phase shift and the 20-milligram dose ended up with about an hour phase shift, when the numbers were crunched, there was not a statistically significant difference between those results.

[00:21:16] Speaker 04:
there was a statistically significant finding that there was a dose relationship between the phase shifting and the amount of the drug administered.

[00:21:26] Speaker 04:
And so I think the best way to understand what people in the art understood from that study at the time is to see what they said about it at the time.

[00:21:36] Speaker 04:
So the Roger Rotnam reference itself says,

[00:21:41] Speaker 04:
Although there was a dose-response relation, and it says the p-value was 0.008 by a Spearman rank correlation, only tazimeltion 100 milligrams shifted DLMO, which is to say dim light melatonin onset, significantly earlier than did placebo.

[00:22:00] Speaker 04:
And the court can find that in the famous bar graph that we've all been talking about.

[00:22:04] Speaker 04:
at Appendix 26064 to 65.

[00:22:08] Speaker 04:
So then when the other prior art references are talking about this result, what do they say?

[00:22:13] Speaker 04:
Well, Hardiland says that this dim light melatonin onset is a suitable measure of the circadian phase.

[00:22:21] Speaker 04:
It indicated a dose-dependent response, and it gives the p-value again, p.008.

[00:22:27] Speaker 04:
However, a significant phase shift was demonstrated only at 100-milligram dose.

[00:22:31] Speaker 04:
That can be found at appendix 2528.

[00:22:34] Speaker 04:
And then the 244 publication, Vanda's own prior publication, again, discusses the same results and says that it shifted DLMO on the first night of treatment when compared to baseline

[00:22:51] Speaker 04:
in a dose-dependent manner, and it actually reports the data in table 11.1.1, which can be found at appendix 20621 and 20622.

[00:23:02] Speaker 04:
So people in the art at the time knew that 100 milligrams would give you a two to three hour shift

[00:23:09] Speaker 04:
and that the shift would be dose dependent, so a smaller dose would give you a smaller shift.

[00:23:15] Speaker 04:
And the testimony of trial was that because this is a condition non-24 in which people's circadian rhythms are out of sync by half an hour to an hour, you're going to want to have a phase shift of half an hour to an hour in order

[00:23:29] Speaker 04:
to treat.

[00:23:30] Speaker 04:
And therefore, as Dr. Emmons explained, something less than 100 milligrams would be needed, because 100 milligrams and a three-hour phase shift would be too much for what was being treated.

[00:23:41] Speaker 04:
And so we know that a smaller dose is what was needed.

[00:23:47] Speaker 04:
And it's remarkable that Vanda itself, in the 244 publication, after describing this data

[00:23:54] Speaker 04:
said that 20 to 50 milligrams is the most effective dose and actually wrote claims to 20 to 50 milligrams used to treat circadian rhythm sleep disorders half an hour before bedtime.

[00:24:07] Speaker 04:
And so I think rather than their current position where they say, oh, this taught away from 20 milligrams, you would never do anything less than 100, the fact that at the time they reported the data and then sought to get claims of 20 milligrams

[00:24:21] Speaker 04:
is the better indication of what people in the prior art understood.

[00:24:27] Speaker 01:
Could you talk about the food patent?

[00:24:29] Speaker 04:
Certainly.

[00:24:29] Speaker 04:
So the food patent

[00:24:33] Speaker 04:
I think what's noteworthy about the food patent is it literally just says take with food.

[00:24:38] Speaker 04:
It doesn't say take with food and get a better pharmacokinetic profile.

[00:24:45] Speaker 04:
Sorry, without food.

[00:24:45] Speaker 04:
Pardon me.

[00:24:46] Speaker 04:
Pardon me.

[00:24:46] Speaker 04:
It says take without food.

[00:24:47] Speaker 04:
It says take without food.

[00:24:49] Speaker 04:
It doesn't say take without food and get a more effective drug.

[00:24:53] Speaker 04:
It doesn't say take without food and get a safer drug.

[00:24:55] Speaker 04:
It doesn't say take without food and get a more convenient drug.

[00:24:58] Speaker 04:
All it says is take without food.

[00:25:00] Speaker 01:
But the specification indicates that this was expected, at least according to the applicant, to produce a superior result.

[00:25:10] Speaker 04:
Well, there's no evidence in the record that I'm aware of that it does in fact lead to a superior result.

[00:25:19] Speaker 01:
In terms of what the specification was indicating about the condition of not

[00:25:28] Speaker 01:
taking food, the specification seems pretty clearly to say we have a higher maximum and a quicker total.

[00:25:38] Speaker 01:
of the drug presence in the plasma, right?

[00:25:44] Speaker 04:
Yeah.

[00:25:45] Speaker 04:
So this notion of the short, sharp spike as being important for efficacy is something that surfaced in this case on the first day of trial.

[00:25:53] Speaker 04:
And the only person who espoused it was Dr. Pauli Moropoulos, who is the named inventor on the patent.

[00:25:59] Speaker 04:
So it's not something that came up in the expert reports.

[00:26:01] Speaker 04:
It's not something that you're going to find.

[00:26:03] Speaker 04:
in the prior art as being relevant to efficacy.

[00:26:05] Speaker 04:
And in fact, in the post-trial briefing, some articles were cited suggesting that maybe it would be better with food rather than without food.

[00:26:13] Speaker 03:
It's just not a... So what?

[00:26:17] Speaker 04:
Right, well, yes, thank you.

[00:26:18] Speaker 04:
So in any event, we have a situation where, as the court pointed out, the FDA instructs people or recommends that people do these food effect studies.

[00:26:29] Speaker 04:
Here, a study was done, and the resulting claim, we know that in the prior art, this drug was administered typically right before bedtime.

[00:26:38] Speaker 04:
Indisputably, you know, some people had some food, most people didn't have food.

[00:26:42] Speaker 04:
If we credit their expert, Dr. Seisler, four out of five people didn't have food and one out of five did.

[00:26:48] Speaker 04:
And the claim says, in substance, do it the way most people have been doing it in the prior art.

[00:26:56] Speaker 04:
And so, sort of without getting, without even reaching the question of whether it's obvious to try or whether the FDA said it, to say,

[00:27:04] Speaker 04:
Do it the way we've always been doing it seems to me to be the epitome of obviousness But in any event it certainly is the case that to do things with food or without to test with or without food is an absolutely standard thing and and and I think the district court was correct to perceive that Suppose that you had a case in which there was a drug that could be either taken in a capsule form or in a tablet chewable tablet form and turns out that

[00:27:33] Speaker 01:
80% of the people took it in capsule form and 20% in a chewable tablet form.

[00:27:39] Speaker 01:
And sure enough, there were a lot of failures, someone discovered, among the chewable tablet form and almost no failures in the capsule form.

[00:27:49] Speaker 01:
So they sought a patent to limit the way the drug was administered to capsules.

[00:27:57] Speaker 01:
You think that's not patentable?

[00:28:01] Speaker 01:
Well, I think

[00:28:05] Speaker 01:
I mean, the discovery itself is presumably quite useful to stop people from using the chewable because they have a very low success rate.

[00:28:16] Speaker 04:
So I just want to be sure I understand the hypothetical.

[00:28:18] Speaker 04:
So you have a hypothetical where most people take capsules, some people take tablets, and it turns out that the tablets are... Right.

[00:28:28] Speaker 04:
So again, I think when we have a situation where someone discovers a problem that was not previously appreciated and

[00:28:40] Speaker 04:
I mean, I think that one of the key differences between Your Honor's hypothetical and what we have here is that, of course, it's absolutely routine that some drugs work better with food, some work better without food, some it doesn't make a big difference.

[00:28:54] Speaker 04:
And to try with them without food is sort of a standard thing to do in the course of drug development.

[00:28:59] Speaker 04:
I don't think there's a similar impetus when one has two competing dosage forms, like a tablet and a capsule,

[00:29:08] Speaker 04:
to expect the same sort of difference in outcome.

[00:29:13] Speaker 01:
But this is the question as to whether for purposes of obviousness to try.

[00:29:19] Speaker 01:
that there is an identifiable problem?

[00:29:22] Speaker 01:
Are you saying, in effect, that any time you have a food, no food question, that problem is present with respect to drugs and the capsule?

[00:29:34] Speaker 04:
Yeah, I think that's a fair way of putting it, Your Honor, yes.

[00:29:38] Speaker 04:
I think that's a fair way of stating it.

[00:29:40] Speaker 03:
Before you sit down, just one other question.

[00:29:43] Speaker 03:
The Tezmilkion patent on the compound itself expired in December, if I recall correctly.

[00:29:50] Speaker 03:
Yes, Your Honor.

[00:29:51] Speaker 03:
What is the launch situation?

[00:29:53] Speaker 04:
So currently, Teva has a product on the market.

[00:29:57] Speaker 04:
And I believe at the moment that that is the only generic that is on the market.

[00:30:01] Speaker 03:
That's because of the 180-day exclusivity?

[00:30:05] Speaker 04:
Well, so there was shared exclusivity in this product with Apotex, Teva, and at least one other company, although that third company has some sort of agreement with Vanda.

[00:30:17] Speaker 04:
We don't know exactly what the contents of the agreement are.

[00:30:20] Speaker 04:
So at least in principle for the 180 days, it would be possible for Apotex and possibly this third

[00:30:27] Speaker 04:
product to be on the market.

[00:30:28] Speaker 04:
But as far as I know, that has not yet happened.

[00:30:30] Speaker 01:
One more practical question, I guess not really legal.

[00:30:35] Speaker 01:
If any one of these four patents is sustained, setting aside the infringement issue for present, would that have the same effect, setting aside the expiration dates vary a little bit, would have the effect of keeping the generics off the market if any one of these four

[00:30:57] Speaker 04:
I don't think so, Your Honor, because there are unresolved questions of infringement for some of the patents, right?

[00:31:06] Speaker 04:
So in other words, if the district court for at least the drug-drug interaction patents declined to reach the question of infringement because he perceived it to be unnecessary.

[00:31:16] Speaker 01:
Presumably, for example, the food patent for which the Andes are presently

[00:31:22] Speaker 04:
So for the food patent, the parties have stipulated to infringement.

[00:31:27] Speaker 04:
So in that case, if that were to be found valid or not invalid, then that would.

[00:31:39] Speaker 01:
That would be enough in and of itself to keep the generic.

[00:31:42] Speaker 01:
That would suffice.

[00:31:43] Speaker 01:
That would suffice.

[00:31:44] Speaker 01:
Yes.

[00:31:56] Speaker 00:
Morning.

[00:31:56] Speaker 00:
May it please the court?

[00:31:58] Speaker 00:
I just have a few brief remarks.

[00:32:00] Speaker 00:
On your last question, Judge Bryson, on the food patent, there was also an unresolved issue of written description, a 112 issue, because the food patent dealt with healthy volunteers.

[00:32:13] Speaker 00:
And so the court elected to go with obviousness and set aside the 112 argument that the defendants made at the district court.

[00:32:21] Speaker 01:
But I believe that- The study in the food patent was healthy volunteers?

[00:32:24] Speaker 00:
It was, Your Honor.

[00:32:25] Speaker 00:
Yeah, so that would require remand back to decide the 112 issue based on a finding of validity based on non-obviousness.

[00:32:32] Speaker 00:
With respect to infringement, I just wanted to address one issue that came up in the reply brief from Vanda.

[00:32:38] Speaker 00:
In his reply brief at pages 19 to 20, Vanda argued for the first time that there was legal error and factual error based on a failure of the district court to consider these clinical practice guidelines for treating 924.

[00:32:51] Speaker 00:
And that's in the record of 244.54 through 9.1.

[00:32:55] Speaker 00:
In short, these arguments were never presented to the district court.

[00:32:58] Speaker 00:
So that document, the guidelines, were only offered into evidence through Vanda's invalidity rebuttal expert, and that's at 19314 to 15.

[00:33:07] Speaker 00:
And his testimony concerned their disclosure of prior clinical studies that involved melatonin.

[00:33:13] Speaker 00:
Vanda only cited those guidelines in their post-trial briefing with regard to secondary indicia of non-obviousness.

[00:33:20] Speaker 00:
And as this court held in Ray Google Technologies, these arguments were not made below, and they therefore should be viewed as forfeited.

[00:33:29] Speaker 00:
And with respect to the inducement claim in its entirety, I would submit that the district court's findings are supported by substantial evidence.

[00:33:39] Speaker 00:
And a lot of those findings were based on witness credibility.

[00:33:43] Speaker 00:
And for that reason, I believe this court should affirm.

[00:33:51] Speaker 02:
Thank you, Your Honor.

[00:33:52] Speaker 02:
Just to pick up where we left off, one of the things that we were frankly surprised by in the red brief is a concession that when you look at the clinical studies, there were two clinical studies, one that first sought to entrain, called SET, and one that then discontinued that treatment called RESET.

[00:34:11] Speaker 02:
And after many years of litigation, there was a concession that at least some of the patients who came out of the first study were entrained.

[00:34:18] Speaker 02:
And to us, that pretty much wraps up the inducement question, because those two studies are both referenced in the labels.

[00:34:26] Speaker 02:
And so that question of does the label encourage, recommend, or promote usage in a way that would entrain things now, given that the generic labels include the SET study, it would seem that there frankly couldn't be much debate about it now.

[00:34:42] Speaker 02:
The other point I would like to make is that Mr. Rosendahl said that, as of the priority date, there was a well-developed body of prior art with respect to the use of tazamaltion to treat non-24.

[00:34:56] Speaker 02:
We do not think that is correct.

[00:34:59] Speaker 02:
The only disclosures of tazamaltion to treat this disease condition, non-24, are the Langford reference, which says no more than that a clinical trial is underway.

[00:35:11] Speaker 02:
And VanderZone

[00:35:12] Speaker 02:
report or disclosure on clinical trials.gov that again says a trial is underway.

[00:35:19] Speaker 02:
All of the rest of the prior art dealt with other circadian rhythm sleep disorders, not non-24.

[00:35:27] Speaker 02:
And one of the key problems that we see in the district court opinion is a constant blurring

[00:35:32] Speaker 02:
They're just sort of a sweep of the hand to say anything that relates to a circadian rhythm sleep disorder equals non-24, and that's just not correct.

[00:35:41] Speaker 02:
There are many circadian rhythm sleep disorders.

[00:35:44] Speaker 02:
A lot of these drugs were used to treat insomnia, for example, or attempted to be used to treat insomnia.

[00:35:48] Speaker 02:
It has nothing to do with entrainment.

[00:35:50] Speaker 02:
And so there is no showing in the art that tazamaltione would have been effective for this disease condition, because that only happened when the clinical trial results were unveiled, and that's not prior art.

[00:36:05] Speaker 02:
And with that, Your Honors, my time is up, and I thank the Court.