[00:00:00] Speaker 04:
Our next case for argument is 21-1360, Teva Pharmaceuticals versus Corecept Therapeutics.

[00:00:11] Speaker 04:
Mr. Rosendahl, please proceed when you're ready.

[00:00:41] Speaker 02:
May it please the court.

[00:00:43] Speaker 02:
The drug at issue in this case, Coraline, is a tablet containing 300 milligrams of Mifopristo.

[00:00:51] Speaker 02:
And the FDA approved it to treat high blood sugar associated with Cushing's syndrome in daily doses of one, two, three, or four tablets corresponding to 300, 600, 900, or 1,200 milligrams.

[00:01:05] Speaker 02:
Coraline is metabolized by the CYP3A group of enzymes.

[00:01:09] Speaker 02:
and the PriorArt Coralum label states that medications that inhibit CYP3A could increase plasma Mifopristone concentrations and dose reduction of Coralum may be required.

[00:01:22] Speaker 02:
In order to figure out how big a reduction in dosage would be appropriate if Mifopristone is administered together with a strong CYP3A inhibitor, the FDA required Corecept to carry out a standard drug-drug interaction study, or DDI study,

[00:01:39] Speaker 02:
with mifepristone together with ketoconazole.

[00:01:43] Speaker 02:
And until the results of that DDI study became available, the FDA, as a precautionary measure, determined that not more than one mifepristone tablet, or 300 milligrams, should be administered together with a strong CYP3A inhibitor.

[00:01:59] Speaker 02:
Incidentally, Corsep's own expert admitted that

[00:02:03] Speaker 02:
600 milligrams of Mifopristone would be the next logical dose after 300 milligrams to test for co-administration with CYP3A inhibitors because it is the next highest dose in the FDA approved range.

[00:02:16] Speaker 02:
It would mean moving the maximum dose for co-administration from one daily tablet to two daily tablets.

[00:02:23] Speaker 02:
So, of course, that carried out the DDI study and found that it would indeed be safe to administer two daily tablets of Mifopristone.

[00:02:30] Speaker 04:
Are you familiar with the concept of obvious to try?

[00:02:34] Speaker 02:
I'm sorry, Your Honor, I did not hear your question.

[00:02:35] Speaker 04:
Are you familiar with the concept of obvious to try?

[00:02:38] Speaker 02:
Yes, Your Honor.

[00:02:39] Speaker 04:
So this would fall into that category, right?

[00:02:43] Speaker 04:
I mean, the FDA suggested that they should explore how much Mifepristone could be administered with a CYP3A inhibitor.

[00:02:55] Speaker 04:
It would be obvious to try, correct?

[00:02:57] Speaker 02:
Yes, Your Honor.

[00:02:57] Speaker 02:
It certainly would be obvious to try.

[00:02:59] Speaker 04:
Indeed, I would say that... Is the reasonable expectation of success requirement a separate requirement, or is it your view that because something is obvious to try, that there's always a reasonable expectation of success?

[00:03:15] Speaker 02:
Well, what the Supreme Court said in KSR in that very famous passage about obvious to try is that when there are

[00:03:24] Speaker 02:
When there's person to solve a problem, there are a finite number of identified predictable solutions.

[00:03:30] Speaker 02:
A person of ordinary skill in the art has good reason to pursue the known options within his or her grasp.

[00:03:35] Speaker 02:
And if this leads to the anticipated success... Ah, anticipated success.

[00:03:40] Speaker 04:
That goes back to what we've termed the reasonable expectation of success in many of our cases.

[00:03:45] Speaker 02:
Yes, but it's clear that in this circumstance, the success is success in finding

[00:03:51] Speaker 02:
suitable dosages for co-administration.

[00:03:53] Speaker 04:
No, really, because that's not what they claimed.

[00:03:54] Speaker 04:
If they had written a claim to, air quotes, suitable doses of administration, that would really be a problem.

[00:04:01] Speaker 04:
That would fall right within the umbrella of what you're arguing, but they didn't.

[00:04:05] Speaker 04:
They filed a claim for a specific dose amount.

[00:04:09] Speaker 04:
So you have to prove that there was a reasonable expectation of success as to that specific dose amount.

[00:04:15] Speaker 02:
Well, no, Your Honor, because once we're in the realm of routine optimization, I think it's clear

[00:04:20] Speaker 02:
from cases such as Applied Materials and Galderma that one doesn't need to know in advance the specific value that will be the result of the optimization.

[00:04:31] Speaker 04:
Your view then is, again, you have collapsed, as I began, the motivation to try analysis with the reasonable expectation of success.

[00:04:40] Speaker 04:
You would like us to adopt a rule of law that once there's a motivation to try specific doses, it's

[00:04:47] Speaker 04:
it's irrelevant how a skilled artisan would think about their likelihood of success.

[00:04:54] Speaker 04:
Once there is a motivation to try, that is sufficient because only it is routine to therefore do those trials and anything that results is obvious.

[00:05:03] Speaker 02:
Well, I don't think I would go quite that far.

[00:05:06] Speaker 04:
Yeah, you can't because it's completely inconsistent with our case law.

[00:05:09] Speaker 04:
It's nonetheless what you're arguing.

[00:05:11] Speaker 02:
No, it's not quite what I'm arguing, Your Honor.

[00:05:12] Speaker 02:
There are two points that I would make.

[00:05:14] Speaker 02:
First of all,

[00:05:15] Speaker 02:
I don't think that this court has any case law saying that it is necessary to be able to predict and advance the result of an optimization in order for the optimization case law to be applicable.

[00:05:26] Speaker 04:
Do we or do we not claim that you have to have a reasonable expectation of success?

[00:05:31] Speaker 02:
Yes, a reasonable expectation of success in solving the problem that the patent purports to solve, which in this case is to have

[00:05:39] Speaker 02:
a dosage suitable for treatment of Cushing's syndrome when myphoprostone is administered together with a strong CYP3A inhibitor.

[00:05:47] Speaker 02:
And of course, we do do that.

[00:05:48] Speaker 04:
We don't know a person who orders... This patent didn't appear to me to be a hunting license.

[00:05:52] Speaker 04:
It didn't appear to me to cover a broad swath of dosages.

[00:05:57] Speaker 04:
It appeared to cover a specific dosage.

[00:05:59] Speaker 04:
So it seems to me the reasonable expectation of success

[00:06:03] Speaker 04:
would not be linked to the problem that you've laid out, but rather the claim, right?

[00:06:09] Speaker 04:
Don't we usually evaluate the obviousness of a claim as opposed to a problem in the prior art?

[00:06:14] Speaker 04:
Well, what the court has said, for example... Do we evaluate the obviousness of a claim?

[00:06:21] Speaker 02:
Yes, of course, Your Honor.

[00:06:22] Speaker 04:
Okay, so wouldn't we then focus on the claim limitations?

[00:06:26] Speaker 02:
Yes, Your Honor.

[00:06:27] Speaker 02:
And what the court has said, for example, in Enrique Cuban,

[00:06:32] Speaker 02:
is that there needs to be a reasonable expectation of success in deriving the claimed invention in light of the teachings of the prior art.

[00:06:42] Speaker 02:
So here we have a situation where the problem is known, it is known that one needs to reduce the dosage of mefopristone when it's administered together with a strong CIT3A inhibitor.

[00:06:54] Speaker 02:
We don't know by how much, but we know that there is a routine and standard test that will allow us to figure out how much.

[00:07:02] Speaker 02:
Our point is that under those circumstances, where all you're trying to figure out is the magnitude of the change, then we are in the realm of routine experimentation and not inventiveness.

[00:07:14] Speaker 00:
Does the prior art show how the two drugs would work together, interact?

[00:07:20] Speaker 02:
Yes, Your Honor.

[00:07:21] Speaker 02:
So that the prior art says expressly, and the label says expressly, that because mitropristone is metabolized by this group of enzymes,

[00:07:30] Speaker 02:
a group of an inhibitor of those enzymes would cause higher plasma blood levels of mephepristone.

[00:07:35] Speaker 02:
And therefore, one would need to lower the dosage of the drug.

[00:07:40] Speaker 02:
And I think it might help to understand how we got here.

[00:07:44] Speaker 00:
What is your citation for that?

[00:07:47] Speaker 02:
For the proposition that one needs to lower the, yes, the label itself on appendix page 847.

[00:07:53] Speaker 01:
But the prior art disclosed how the two drugs would interact.

[00:07:56] Speaker 02:
The prior art discloses that because there's a tendency to raise the blood plasma levels, one would likely need to reduce the dosage when the two drugs are applied together.

[00:08:10] Speaker 02:
Now, one does not know exactly how big that effect is going to be.

[00:08:17] Speaker 01:
the actual effect of the coagulant?

[00:08:21] Speaker 02:
Well, it doesn't disclose the magnitude of the effect, right?

[00:08:25] Speaker 02:
It's clear that one has to do the tests to find out how big the effect is.

[00:08:29] Speaker 02:
And I think perhaps the best place to look for this, Your Honor, is at appendix page 694, which is the declaration that Dr. Greenblatt

[00:08:38] Speaker 04:
submitted together with the petition and a paragraph declaration is irrelevant the board found him not credible because his testimony contradicted his declaration and his testimony did why don't we turn to the testimony instead of the declaration since the board expressly found his contradictory testimony muted the declaration well i i think the board uh...

[00:08:59] Speaker 02:
The point that was being made in the declaration was slightly different and there wasn't an actual contradiction.

[00:09:05] Speaker 02:
There was certainly, if one reads the passage in the declaration as standing for the proposition, that one would have known in advance, because that was the question he was asked at his deposition, would you have known before conducting the DDI study specifically whether 600 milligrams was or was not safe?

[00:09:22] Speaker 02:
He said no, you would need to carry out the study to figure out whether that particular dosage was or was not safe.

[00:09:28] Speaker 02:
But the point that was made in the declaration was that there is a wide range, and I'll point you to paragraph 142 on Appendix 694, where he said, the results of the Mifepristone ketoconazole DDI study would not have been unexpected to APOSA.

[00:09:46] Speaker 02:
APOSA would have known that a wide array of outcomes, and this is the important point, ranging from a few percentage point increase to a 15 or 20-fold increase were possible.

[00:09:56] Speaker 02:
the 33% increase that CoreStep found was well within the range of outcomes that a skilled artisan would have expected.

[00:10:03] Speaker 02:
And so what this tells us is that when we start with a range of 300, 600, 900, or 1,200 milligrams per day, then the range of possible outcomes is that same set of four tablets, because if the effect is very small, if the effect of the code administration is very small, then four tablets per day would be just fine.

[00:10:25] Speaker 02:
Or, if it turns out that the effect is very large and the mythocrystone concentration spikes dramatically, then one would need to reduce the dose significantly.

[00:10:37] Speaker 02:
And so we have a range of up to four pills a day.

[00:10:41] Speaker 04:
When it's monotherapy.

[00:10:43] Speaker 02:
Well, yes, when it's monotherapy.

[00:10:45] Speaker 04:
And we know from this... And what we actually know is from journal articles, when CYP3A is introduced, it was the governing belief at the time, according to the board's express fact finding, and I believe it's page 47 of their opinion, pointing to the journal article at page 4164 of the appendix, that not more than 300 milligrams should be administered.

[00:11:09] Speaker 04:
Right, but what the board... So when there's co-administration, the journal articles, the medical evidence at the time, and the board's fact finding, which we review for substantial evidence, which is clearly supported by the journal article, is that you should not administer more than 300 milligrams.

[00:11:25] Speaker 02:
No, Your Honor, respectfully, I disagree with that reading of the board's opinion.

[00:11:28] Speaker 02:
What the board said was that people of skill in the art would give weight to the 300 milligram

[00:11:35] Speaker 02:
amount in the label and they would consider it safe.

[00:11:38] Speaker 02:
They would assume that the FDA would not allow 300 milligrams to be co-administered if it were not safe.

[00:11:44] Speaker 02:
But they also said that the 300 milligram limitation was not based on clinical data showing 300 milligrams, greater than 300 milligrams per day to be unsafe.

[00:11:53] Speaker 02:
And that is at appendix page 37.

[00:11:55] Speaker 04:
Page 47 of the board's opinion, the evidence supports that a posto would have had no expectation as to whether co-administering dosages of Mipha Perston above 300 milligrams a day threshold set forth in the Coraline label would be successful.

[00:12:11] Speaker 04:
In the absence of evidence supporting an expectation that doses above 300 would be safe, we find petitioners not carried its burden.

[00:12:20] Speaker 04:
So is that what the board held?

[00:12:22] Speaker 02:
Well, what the board said, so the board said, again, relying... Why don't we try to go into page 48 of the board's opinion.

[00:12:30] Speaker 04:
Here, the evidence of record supports that the general working conditions limited co-administration of Mifepristone with a strong CYPA3 inhibitor to just 300 milligrams a day.

[00:12:47] Speaker 04:
And then they cite the article, I believe it's the same article I was pointing to in the appendix for the quote, if used with the CYP3A inhibitor, the maximum dose should not exceed 300 milligrams a day.

[00:13:00] Speaker 04:
So it seems to me the board made an express fact finding that based on the current state of science at the time, Miffl-Crestone had to be limited to 300 milligrams a day if a CYP3A inhibitor was used.

[00:13:13] Speaker 02:
Well, again, Your Honor, I don't think that's a fair reading of that passage because the very same paragraph says, until additional drug-drug interaction data, I'm now four lines from the bottom of the page, the evidence says, until additional drug-drug interaction data become available, we suggest discontinuing and limiting to 300 milligrams a day.

[00:13:34] Speaker 02:
So people with skill in the art understood that there was no data on this.

[00:13:39] Speaker 02:
And the FDA required that the test be done to find the data.

[00:13:42] Speaker 02:
Corset did the test, found the data, and then tried to claim the result of the routine test.

[00:13:48] Speaker 04:
Because the understanding at the time, as found by the board, was that you cannot exceed 300 milligrams a day.

[00:13:56] Speaker 04:
Of course, it's going to be useful to see are there circumstances in which maybe you can, but the board's fact finding is that you could not exceed safely 300 milligrams a day based on the prevailing science at the time.

[00:14:12] Speaker 02:
No, Your Honor.

[00:14:13] Speaker 02:
Again, I would point you to appendix page 37.

[00:14:15] Speaker 02:
The board made no finding that above 300 milligrams would be unsafe.

[00:14:20] Speaker 02:
The board made no finding that people would have expected it to be unsafe.

[00:14:23] Speaker 04:
Page 48 and 49 of their opinion.

[00:14:27] Speaker 04:
Here, the evidence of record supports the general working conditions limiting co-administration to just 300 milligrams a day.

[00:14:36] Speaker 04:
And then they cite multiple different sources saying, if you're using a CYP3A inhibitor, dose should not exceed 300 milligrams a day.

[00:14:46] Speaker 04:
On the next page, daily dose should be

[00:14:49] Speaker 04:
300 milligrams a day.

[00:14:51] Speaker 02:
Your Honor, that's definitely what the label says.

[00:14:55] Speaker 02:
The label says that when you're co-administering, until we get the data, you're not supposed to go above 300 milligrams per day.

[00:15:02] Speaker 02:
I'm not disputing that.

[00:15:04] Speaker 04:
What I'm saying, though... They're not quoting from the label.

[00:15:07] Speaker 04:
What they're quoting from are the articles at the time, the science about what was known to be safe.

[00:15:14] Speaker 02:
The articles at the time, I believe, were referring to the label.

[00:15:17] Speaker 02:
But nevertheless,

[00:15:18] Speaker 02:
that it's clear that the board made a finding that the 300 milligram limitation was not based on clinical data and was not based on an expectation one way or another about safety above 300 milligrams per day.

[00:15:32] Speaker 02:
And that's very important because this line that Your Honor keeps pointing to about the general conditions of the claim being limited to 300 milligrams per day is precisely the legal error that we are pointing to for the board because in this case,

[00:15:47] Speaker 02:
the sort of the talismanic words, the general conditions of the claim, are the board's way of saying, we're not going to apply the range cases, we're not going to apply the routine optimization cases, because we don't think they apply because there was this 300 milligram limitation in the label.

[00:16:08] Speaker 04:
But for Rosendahl, you've used all your time, all your rebuttal time, and you're beyond that.

[00:16:12] Speaker 04:
So let's hear from Mr. Stops.

[00:16:23] Speaker 03:
Good morning, Your Honors.

[00:16:24] Speaker 03:
That may please the Court.

[00:16:26] Speaker 03:
Teva is not challenging any of the Board's findings of fact, nor could it, because many of the Board's key findings are based on Teva's expert's own testimony, where they agreed with Korsev's positions.

[00:16:38] Speaker 03:
That means that the Board's findings concerning the scope and content of the prior art must be accepted for this appeal.

[00:16:45] Speaker 03:
These facts include whether a person of ordinary skill in the arts would have had a reasonable expectation of success in achieving the claimed inventions and what general working conditions are disclosed by the prior art.

[00:16:57] Speaker 03:
Council made a point that the 300-milligram limitation in the Corsep Coralum label was not based on clinical data, citing to appendix page 37.

[00:17:10] Speaker 03:
Council crops that quote and doesn't continue on to page 38.

[00:17:15] Speaker 03:
The board found that while we agree that the 300-milligram limitation was not based on clinical experience, it was not spun out of whole cloth.

[00:17:23] Speaker 03:
We find that the person who has shown the art still would have given that limitation weight.

[00:17:27] Speaker 03:
The board goes on to refer to several journal articles and the testimony of the experts in the PGR.

[00:17:34] Speaker 03:
The journal articles include the Flicerio article appendix page 1259 and the Morgan article appendix page 1272.

[00:17:42] Speaker 03:
Flicerio actually goes beyond just admonishing not to go above 300.

[00:17:47] Speaker 03:
but actually teaches that ketoconazole, the SIP3A inhibitor at issue, should be discontinued 14 days before administering Mifopristone.

[00:17:56] Speaker 03:
In other words, the teaching went even further that no dose of Mifopristone should be co-administered with a strong SIP3A inhibitor.

[00:18:04] Speaker 03:
The board also found that a person with skill in the art would not have had a reasonable expectation of success that administration of more than 300 milligrams per day of Mifopristone and a strong SIP3A inhibitor would be safe.

[00:18:16] Speaker 03:
That's at appendix page 47, and also appendix pages 43, 47, and 49.

[00:18:20] Speaker 03:
I'm sorry, that first one was appendix page 45.

[00:18:25] Speaker 03:
The board also made over 10 pages of finding a fact that dosimit pristone used in monotherapy do not apply to combination therapy with a strong SIP3A inhibitor.

[00:18:34] Speaker 03:
The board also found that the general working conditions limited co-administration of Pristone with a strong CYP3A inhibitor to just 300 milligrams per day and do not encompass the claims invention.

[00:18:47] Speaker 03:
These findings are dispositive of all the issues on appeal.

[00:18:50] Speaker 04:
Did your client invent 600 milligrams a day plus the CYP3A inhibitor?

[00:19:01] Speaker 03:
Our client was the entity that was the first approval of myphopristone, the only approval of myphopristone for the tumor of Cushing syndrome and the only entity that ever ran any type of analysis to determine whether this was safe.

[00:19:16] Speaker 03:
As set forth in the patent, this was an iterative process.

[00:19:20] Speaker 03:
The company was extremely concerned that there would be no dose of myphopristone that would be safe with a strong C3A inhibitor.

[00:19:27] Speaker 03:
So studies were run on a much smaller scale to see if there was any possibility that the two drugs could be administered at the same time.

[00:19:35] Speaker 04:
I guess the difficulty, though, from my perspective is you didn't undertake that study at your own initiative.

[00:19:41] Speaker 04:
You were directed to undertake that study by the FDA, correct?

[00:19:47] Speaker 03:
The FDA in the Lee reference does have a discussion.

[00:19:54] Speaker 03:
This was a back and forth with the FDA whether there should be a study run or whether there should be a complete ban on co-administration in the label.

[00:20:04] Speaker 03:
An agreement was reached that there would be a study run after the approval of the drug, a post-approval study.

[00:20:10] Speaker 04:
So okay, help me understand just the timing.

[00:20:14] Speaker 04:
So your client came up with the method of treating Cushion Syndrome through a combination of 300 milligrams

[00:20:24] Speaker 04:
of Mifepristone plus CYP3A or any amount of Mifepristone.

[00:20:30] Speaker 04:
I'm trying to understand why did the FDA prompt your client to undertake safety studies about this combination?

[00:20:38] Speaker 04:
What was the state of your client's invention at the time where the FDA said to do this?

[00:20:48] Speaker 03:
The drug was in the approval process, Your Honor.

[00:20:52] Speaker 04:
It was... Approval process for what?

[00:20:54] Speaker 03:
Pre-approval for any dose.

[00:20:56] Speaker 04:
Any dose.

[00:20:57] Speaker 04:
Any dose in combination?

[00:20:59] Speaker 03:
No.

[00:20:59] Speaker 04:
With a CYP3A or just any dose of mitocrystone?

[00:21:03] Speaker 03:
No, Your Honor.

[00:21:04] Speaker 03:
The latter.

[00:21:05] Speaker 03:
A monotherapy.

[00:21:06] Speaker 04:
A monotherapy.

[00:21:07] Speaker 03:
Okay.

[00:21:07] Speaker 04:
So your drug was in the FDA approval process as a monotherapy.

[00:21:11] Speaker 04:
Yes, Your Honor.

[00:21:14] Speaker 04:
And then how did it come up that CYP3A

[00:21:18] Speaker 04:
T3A inhibitors could

[00:21:21] Speaker 04:
caused significant problems in combination with myphopristone?

[00:21:25] Speaker 03:
Sure.

[00:21:26] Speaker 03:
Based on the mechanism of action, there was a possibility of both a pharmacokinetic interaction.

[00:21:31] Speaker 03:
In other words, the two drugs together would, the 3-NA inhibitor would inhibit the metabolism of the pristone, causing the blood levels to rise, potentially causing extreme safety issues such as adrenal insufficiency or hypokalemia.

[00:21:46] Speaker 03:
The other possibility was a pharmacodynamic interaction

[00:21:49] Speaker 03:
Some of the SIP3 inhibitors, notably ketoconazole, work by a different mechanism of action on the same condition.

[00:21:58] Speaker 03:
The ketoconazole prevents the synthesis of cortisol, and mipopristone blocks the activity of cortisol at the receptor.

[00:22:05] Speaker 03:
So there was a concern that even if the blood levels themselves weren't going to be affected,

[00:22:10] Speaker 03:
that the two drugs together could have a synergistic effect in the body and cause these potentially fatal interactions.

[00:22:17] Speaker 04:
And was that concern brought to your company's attention by the FDA or was it something that you brought to the attention of the FDA?

[00:22:24] Speaker 03:
The latter.

[00:22:25] Speaker 03:
This was something that the company was concerned about running the studies at the outset and actually didn't want to have a complete ban on the co-administration of the two initially.

[00:22:36] Speaker 03:
Based on the back and forth, there was a... This is what comes out in Lee, that there was a question of whether any dose would be possible.

[00:22:47] Speaker 04:
And this is the discussion that... Okay, so is this a fair characterization of the facts, and are these in the record?

[00:22:53] Speaker 04:
Meaning that you all brought to the FDA's attention a concern about co-administration, and then the FDA responded by ordering you to

[00:23:05] Speaker 04:
undertake testing to ensure the safety and efficacy.

[00:23:10] Speaker 04:
I know that latter part is in this record, is the former part in this record, as far as you know.

[00:23:15] Speaker 03:
In the board's decision on APPX 36, it states that Lee... That doesn't answer the specific question.

[00:23:22] Speaker 03:
Lee also states that the use of strong CYP3A4 inhibitors is proposed to be contraindicated by the sponsor.

[00:23:28] Speaker 03:
Okay.

[00:23:28] Speaker 03:
And that sponsor recommended administration of moderate CYP3A inhibitors also be avoided.

[00:23:33] Speaker 03:
So, yes, Your Honor.

[00:23:35] Speaker 04:
And so the FDA said, well, I won't approve the co-administration until you do safety and efficacy study.

[00:23:47] Speaker 03:
Go ahead, clarify what I'm getting wrong here.

[00:23:52] Speaker 03:
So the FDA and the company, I guess your answer is that the company chose what studies to run.

[00:24:00] Speaker 04:
So it seems to me that we have multiple doctrines in the obviousness area, one of which is called obvious to try.

[00:24:08] Speaker 04:
And it feels to me like this falls into that category based on the

[00:24:14] Speaker 04:
track and forth between your company and the FDA that it sort of became obvious to try and explore which doses would be safe.

[00:24:27] Speaker 03:
No, Your Honor.

[00:24:29] Speaker 03:
At the time of the invention, there was a very strong teaching in the art that the two things should not be co-administered.

[00:24:36] Speaker 03:
Not at all?

[00:24:38] Speaker 04:
Or not at more than 300 milligrams?

[00:24:42] Speaker 03:
The preference was not at all.

[00:24:43] Speaker 03:
And it was, if medically necessary, they were permitted to go up to 300 milligrams.

[00:24:48] Speaker 03:
So the preference was not at all.

[00:24:50] Speaker 03:
I set forth in the journal articles and in the testimony of the experts in the case.

[00:24:54] Speaker 03:
With respect to the obvious to try,

[00:24:56] Speaker 03:
The concept that set forth in KSR focused on the predictable solutions.

[00:25:01] Speaker 03:
Here, the board found repeatedly that the solution here, going above 300 milligrams, was not predictable.

[00:25:10] Speaker 03:
And that was focused both on the specific 600-milligram dose as well as any dose above 300 milligrams generally.

[00:25:18] Speaker 03:
And that finding on the reason why patient success is not challenged and therefore dispositive on the obviousness-to-try issue.

[00:25:25] Speaker 04:
And the reasonable expectation of success prong is, as you understand it, a separate requirement from whether it's obvious to try something.

[00:25:33] Speaker 04:
It could be obvious to try it, but there still has to be a reasonable expectation of success in order to satisfy obviousness.

[00:25:41] Speaker 03:
The reasonable expectation of success is to be predicated before you get to trying anything.

[00:25:48] Speaker 03:
Does that answer your question, Your Honor?

[00:25:49] Speaker 04:
Not really, because if that were the case, then what if the FDA had actually

[00:25:54] Speaker 04:
given you a document that said, we'd like you to give us the results of a study administering Mifepristone in each of the relevant dose amounts, 300, 600, 900, and 1200, to a co-extensive CYP3A inhibitor user.

[00:26:15] Speaker 04:
What if they had sort of pushed with a roadmap with great clarity of exactly what they wanted you to do?

[00:26:24] Speaker 04:
It seems like that would make it awfully obvious to do that, right?

[00:26:32] Speaker 03:
We could spin different facts that may come to a different conclusion, but here the focus for the KSR obvious to try is on a identified predictable solution.

[00:26:43] Speaker 03:
So the solutions need to be predictable.

[00:26:46] Speaker 03:
In other words, there needs to be an expectation that those solutions would yield the claimed invention.

[00:26:53] Speaker 03:
So without predictable solutions, you can't have obviousness to try.

[00:26:59] Speaker 04:
But didn't the FDA tell you to go explore the level at which these two things could be used in combination?

[00:27:08] Speaker 03:
The FDA was concerned that there could be no dose of a strong SIP3A inhibitor that could be used in conjunction with

[00:27:17] Speaker 03:
And in that situation, that's why there was a discussion of moderate SIP3A inhibitors.

[00:27:23] Speaker 03:
If the dose was zero, the next things to look at was moderate SIP3A inhibitors.

[00:27:29] Speaker 03:
And that's the appendix at 35 to 36 in the discussion of the Lee reference.

[00:27:36] Speaker 04:
And did the FDA approve 300 milligrams plus the CYP3A inhibitor?

[00:27:42] Speaker 04:
I kind of thought it did, but I may not remember.

[00:27:44] Speaker 03:
It's not part of the indication, Your Honor.

[00:27:47] Speaker 03:
It's in the warnings and precautions and in the pharmacokinetic interactions section, there's a statement in it that essentially says, if medically necessary, co-administer but limit the dose of the strong CYP3A inhibitor to no more than 300 milligrams.

[00:28:21] Speaker 03:
If you have no other questions, Your Honor, I'll delay the rest of my time.

[00:28:27] Speaker 04:
Okay.

[00:28:27] Speaker 04:
Mr. Rosenthal, I'll restore two minutes of rebuttal time.

[00:28:33] Speaker 02:
Thank you, Your Honor.

[00:28:40] Speaker 02:
Two points.

[00:28:42] Speaker 02:
First of all, the logic underlying this Court's

[00:28:49] Speaker 02:
range optimization precedence is that the existence of a range creates an implicit motivation for people of skill and the arts to find optimal values within the range.

[00:29:00] Speaker 02:
But in this case, the motivation was explicit, not implicit.

[00:29:06] Speaker 02:
lead document, which was part of the FDA approval package, and the FDA requirement was that there should be a DDI study for the purpose of determining the appropriate dose, the extent to which dose reduction would be required.

[00:29:21] Speaker 02:
And so for people of skill in the art to go down the path prescribed in the prior art to carry out the optimization is not inventive.

[00:29:32] Speaker 02:
It is simply the product of routine optimization.

[00:29:37] Speaker 02:
I think the most charitable reading of the board's decision on the range optimization cases was they refused to apply those cases because they determined that 600 milligrams or greater than 300 milligrams had not been shown to be co-administered in the prior ART with a strong CIF3A inhibitor.

[00:30:00] Speaker 02:
I think implicit in the passage that Judge Moore pointed us to earlier,

[00:30:04] Speaker 02:
is this notion that if there had been a prior art reference that said 300 to 900 milligrams with a strong CIT3A inhibitor and the patent claimed 600 in the middle of the range, then that would have been fine.

[00:30:18] Speaker 02:
But what we know from the Valiant case is that focusing exclusively on a range that is exactly what is in the claim

[00:30:27] Speaker 02:
is not appropriate.

[00:30:28] Speaker 02:
And if there are other ranges in the prior art that point to the appropriate range, and here we have a monotherapy range that goes up to 1200 milligrams, and we know that somewhere between 300 and 1200 is going to be the safe dose for co-administration, then when you carry out the experiment to find out the right answer,

[00:30:48] Speaker 02:
That's not inventive.

[00:30:49] Speaker 02:
That's completely routine.

[00:30:50] Speaker 04:
How is it that we know somewhere between 300 and 1,200 is going to be the safe amount?

[00:30:55] Speaker 04:
It seemed to me that all of the evidence of record was not to do it at all, and if you have to do it, don't go above 300.

[00:31:01] Speaker 04:
But you just wanted to get to obviousness by saying that everybody knew the correct amount was somewhere between 300 and 1,200.

[00:31:09] Speaker 02:
Well, it is that same passage, Your Honor, that I pointed you to

[00:31:14] Speaker 02:
in the Greenblatt Declaration, which is undisputed.

[00:31:17] Speaker 02:
I don't think there's any contradictory evidence in the record that the range of possible outcomes of the DDI study could be a negligible effect all the way up to a very extreme effect.

[00:31:27] Speaker 02:
And the reason why we were making that argument and why Dr. Greenblatt put in that evidence, and this is, again, Appendix 694, paragraph 142, is because the way they got the patent in the first place was by claiming unexpected results.

[00:31:40] Speaker 02:
They said that there was an extreme spike in

[00:31:43] Speaker 02:
concentrations when the two drugs would be co-administered, and therefore the expected range of outcomes for a DDI study would not include anything above 300 milligrams.

[00:31:54] Speaker 02:
And that is what Dr. Greenblatt was rebutting, and that is what the board found not to be true.

[00:31:59] Speaker 02:
They found that it was not unexpected, that there wasn't this huge spike in concentrations would not have been expected, and there wasn't an expectation that it would be unsafe,

[00:32:11] Speaker 04:
There was an expectation that it could be anywhere in the range, but you wouldn't know until you did the study where in the range it would fall.