[00:00:00] Speaker 03:
The next case for argument is 23-1763 in Ray Snyder.

[00:00:04] Speaker 03:
Please proceed.

[00:00:07] Speaker 02:
May it please the court.

[00:00:08] Speaker 02:
I'm Joseph Lucci, representing Snyder.

[00:00:11] Speaker 02:
The board's decision should be reversed because the board erred, at least in that the stated grounds for rejection lacked substantial evidence.

[00:00:19] Speaker 02:
The board's legal error

[00:00:21] Speaker 02:
specifically derives from its treatment of the NCT 172 publication and its closely related failure to address evidence indicating that those of ordinary skill did not have a reasonable expectation that the claimed combination therapy would work.

[00:00:38] Speaker 02:
Snyder's claimed therapies satisfied a critical need in the treatment of prostate cancer.

[00:00:43] Speaker 02:
And they relate to the surprising finding that administrating abiratero with niraparib works better than either drug alone.

[00:00:51] Speaker 02:
Following the examiner's lead, the board found it necessary to use five different publications to construct an obviousness rejection.

[00:01:00] Speaker 02:
And this included the NCT 172 disclosure of a different drug combination than what we have claimed here.

[00:01:08] Speaker 02:
The problem with the board's reliance on the NCT 172 publication is that this court has found that disclosures of this type do not provide a reasonable expectation of success

[00:01:21] Speaker 02:
that the agents they mention will actually have the indicated therapeutic effect.

[00:01:27] Speaker 02:
Which case is that?

[00:01:29] Speaker 01:
uh... o s i your honor o s i because of uh... unpredictability in the art or something that's one factor your honor it's the unpredictability coupled with the fact that it's merely statement of intention to try something uh... without any data being provided was there any record below in front of the agency as to the relative unpredictability of this particular art for this particular cancer therapeutic

[00:01:59] Speaker 02:
In general terms, I

[00:02:03] Speaker 02:
I don't believe there was anything of a review article type of nature.

[00:02:08] Speaker 02:
There was certainly the unpredictability of NCT 172 in that it didn't pan out the way that the... Oh, that's the Hussein publication, right?

[00:02:16] Speaker 02:
The Hussein publication reports the results for NCT 172.

[00:02:19] Speaker 02:
That's correct.

[00:02:20] Speaker 02:
Right.

[00:02:20] Speaker 01:
So that's a different question for me in terms of to what extent it was proper to exclude that as being a post-priority document.

[00:02:29] Speaker 01:
Just getting to the other question, it looked to me like before the agency you were more focused really on Hussain and then the unexpected results evidence that you relied on and then this reasonable expectation of success argument that seems to be

[00:02:49] Speaker 01:
really the main event of your appeal, was really much more of a very short reference of an argument made below to the board and examiner.

[00:03:01] Speaker 01:
It was made to the board and to the examiner, though, the reasonable expectation.

[00:03:04] Speaker 01:
Right, but in what I would call, in the most limited sense, as I understand it, there wasn't, you could have filed an expert declaration on this matter, or you could have cited or discussed any publications

[00:03:18] Speaker 01:
Or you could have cited and discussed OSI and Novartis because it seems to me that today on appeal, you're basically making an argument that as a matter of law, as a matter of federal circuit precedent,

[00:03:32] Speaker 01:
Cancer therapeutics, whether for any particular kind, is just a very unpredictable art.

[00:03:39] Speaker 02:
I think it's a broader argument, Your Honor, and I think it's well established that pharmaceutical therapies generally are unpredictable.

[00:03:45] Speaker 02:
It's not just cancer therapeutics.

[00:03:46] Speaker 02:
It's not just prostate cancer therapeutics.

[00:03:48] Speaker 02:
Pharmaceuticals, the authorities, I believe, that were cited in the briefing, support the proposition that therapeutics in general are recognized to be unpredictable.

[00:03:58] Speaker 02:
So there is that.

[00:04:00] Speaker 02:
I do think that there was greater emphasis on that issue in our briefing, but it was certainly an issue that was raised below.

[00:04:07] Speaker 02:
We raised in many different respects before the examiner and before the board just discussing

[00:04:14] Speaker 02:
what exactly ncp one seventy two is it's a clinical trial protocol rain very little about this thing we're going to try this we don't know whether it's going to work and statistics for pharmaceutical clinical trials are not very good usually things don't work so we were very explicit about hey this is a reference that is a clinical trial and there was greater weight put in that and was warranted and that was a legal error your honor

[00:04:43] Speaker 02:
As your honor mentioned, the problem with publications like this is they don't disclose any data or other information about the drug's efficacy in actually treating disease.

[00:04:53] Speaker 01:
There were other references, though, that talked about the efficacy for each of the two drugs.

[00:05:01] Speaker 01:
I don't even dare pronounce them.

[00:05:04] Speaker 02:
The N1 and the A1.

[00:05:05] Speaker 02:
I have a lot of practice.

[00:05:07] Speaker 02:
Yes, niraparib and dilaparib you're talking about, your honor, or aberraterib.

[00:05:11] Speaker 01:
The Abir-Taron and the Nir-Parib, they were references identifying efficacy for each of those.

[00:05:21] Speaker 02:
Individually, that's correct, Your Honor.

[00:05:23] Speaker 02:
The critical net here, though, is that things behave differently in combination than they do individually.

[00:05:30] Speaker 02:
And it's even a bigger issue.

[00:05:31] Speaker 02:
So as we mentioned in our briefing,

[00:05:34] Speaker 02:
The patent office has cherry-picked the reference, particularly the Jiang reference.

[00:05:38] Speaker 02:
And they focus on the fact that there's a statement there that are saying the rapid monotherapy, this is something that warrants some further results.

[00:05:45] Speaker 02:
It has promise here.

[00:05:47] Speaker 02:
Strong clinical rationale.

[00:05:49] Speaker 02:
I think that's the quote.

[00:05:51] Speaker 02:
It very well could be, Your Honor.

[00:05:53] Speaker 02:
I think what needs to be done is you have to have a broader perspective, and not just focus on statements in Jiang that they cite.

[00:05:59] Speaker 02:
to the exclusion of statements in Zhang that don't support their position, which they don't cite.

[00:06:04] Speaker 02:
I think you have to have a broader perspective here and look at all the references that were cited by the examiner.

[00:06:08] Speaker 02:
It's not things we put in the record.

[00:06:09] Speaker 02:
It's panelists putting these in the record.

[00:06:11] Speaker 02:
And what you have in the record is you have aviradirone being a known therapy.

[00:06:15] Speaker 02:
In fact, it was the standard of care for treatment of this type of prostate cancer.

[00:06:19] Speaker 02:
That's shown by the Logothetis reference.

[00:06:21] Speaker 02:
That was a 2012 publication.

[00:06:23] Speaker 02:
But before Zhang in 2014,

[00:06:26] Speaker 02:
You have niraparib being known to be a treatment for castrate-resistant prostate cancer.

[00:06:32] Speaker 02:
That's shown by the SANTU reference.

[00:06:34] Speaker 02:
Again, cited by the examiner.

[00:06:35] Speaker 02:
So you have these two drugs being out there.

[00:06:38] Speaker 02:
And for whatever reason, the first combination that was made that's of record in NCT 172, we're going to try villaparib with abiratero.

[00:06:49] Speaker 02:
Not niraparib, villaparib.

[00:06:51] Speaker 02:
So for whatever reason, the

[00:06:55] Speaker 02:
Those skilled in the art viewed valaparib as being the most promising candidate for combination with another drug, curab or adero.

[00:07:02] Speaker 01:
Well, maybe the people behind NC172, that's what they chose to be focused on.

[00:07:07] Speaker 01:
But then we have, as you pointed out, the Zhang reference, who says, well, guess what?

[00:07:12] Speaker 01:
I've been looking at these competing compounds, these competing PARP inhibitors.

[00:07:17] Speaker 01:
And it's really showing me that the neuraparib is better than the valaparib.

[00:07:24] Speaker 02:
I understand what you're saying, Your Honor.

[00:07:26] Speaker 02:
I don't think that's actually what Zhang says.

[00:07:28] Speaker 02:
What Zhang happens to be is a review article.

[00:07:31] Speaker 02:
And Zhang talks about a number of different PARP inhibitors.

[00:07:35] Speaker 02:
Zhang talks about a number of PARP inhibitors as monotherapies administered alone, Neuraparib being one of them, Olaparib being another.

[00:07:44] Speaker 02:
There's two trials for monotherapy of Olaparib, a related drug as well.

[00:07:51] Speaker 02:
There's two drugs that are mentioned as combination therapies in Zhang.

[00:07:55] Speaker 02:
Interestingly, neither of them have niraparib or elaborate.

[00:07:58] Speaker 02:
They have velaparib, the same drug that NCT172 is talking about.

[00:08:02] Speaker 02:
So the authors of NCT172 chose to combine velaparib with abiratero.

[00:08:08] Speaker 02:
But what Zhang also references is a test of velaparib with another drug, temozolomide.

[00:08:16] Speaker 02:
And they showed him there that the mouse study for that wasn't so great.

[00:08:20] Speaker 02:
Now, what is relevant here is if you look at this objectively, and without the benefit of hindsight, as the patent office has done, what the art suggests is that those skilled in the field had Velapirib in mind as the leading candidate among these drugs for combination.

[00:08:36] Speaker 02:
Because we have two studies demonstrated in Zhang.

[00:08:38] Speaker 02:
The only two instances we have in the record of people actually trying combinations were with Velapirib.

[00:08:44] Speaker 02:
So now the panel office is substituting its judgment with the benefit of hindsight, seeing our invention, and saying, oh, no, no.

[00:08:51] Speaker 02:
Yeah, we see there that people were trying valaparib.

[00:08:54] Speaker 02:
But we think it would have been honest.

[00:08:55] Speaker 01:
Does Zeng not say that naraparib has better efficacy than valaparib?

[00:09:03] Speaker 02:
No, it's not, Your Honor.

[00:09:04] Speaker 02:
It's saying it's a promising candidate.

[00:09:06] Speaker 02:
If you take a look at the comments about naraparib, they say here that it has good properties.

[00:09:13] Speaker 02:
I'm at appendix 416, Your Honor.

[00:09:20] Speaker 02:
In the paragraph, the beginning, the tumor suppressor.

[00:09:24] Speaker 02:
Which column?

[00:09:25] Speaker 02:
First column.

[00:09:27] Speaker 02:
First full paragraph.

[00:09:30] Speaker 02:
The tumor suppressor?

[00:09:32] Speaker 02:
That paragraph, the last sentence, it begins, although.

[00:09:36] Speaker 02:
They say, although one could argue that radical prostatectomy samples may not recapitulate,

[00:09:41] Speaker 02:
downstream events of PTEN loss in late stage prostate cancer.

[00:09:45] Speaker 02:
So is that qualification?

[00:09:47] Speaker 02:
Then they say here a recent phase one study, again phase one, safety principally, study with PARP inhibitor and a raparib did not observe association between loss of PTEN and anti-tumor activities in sporadic metastatic prostate cancer patients.

[00:10:04] Speaker 02:
In the next paragraph, there's a statement there.

[00:10:07] Speaker 02:
They talk about the 23 CRPC patients,

[00:10:11] Speaker 02:
They talk about nirafirib.

[00:10:13] Speaker 02:
And then they say here, they talk about the parameters of that study.

[00:10:16] Speaker 02:
And then they say, this is the first study to document clinical activity of a PARP inhibitor in sporadic CRPC.

[00:10:23] Speaker 02:
That's, again, monotherapy.

[00:10:26] Speaker 02:
And as we see here, it's in the record, things behave differently in monotherapy than combination therapy.

[00:10:33] Speaker 02:
We're different than people might expect.

[00:10:35] Speaker 02:
That's shown in the NCT172 clinical trial.

[00:10:38] Speaker 02:
where they combined vulaparib with abiraterone and found that the results were no better than abiraterone alone.

[00:10:46] Speaker 02:
So in that case, vulaparib, which was, again, objective evidence shows, that was deemed to be the leading candidate for combination therapies, didn't have anything to abiraterone.

[00:10:57] Speaker 02:
It was essentially inert.

[00:11:01] Speaker 02:
Contrast that with our inventors, which found that not only does niraparib and

[00:11:07] Speaker 02:
abiraterum provide a benefit.

[00:11:10] Speaker 02:
It provides a stark benefit.

[00:11:12] Speaker 02:
That's shown by the mouse test data.

[00:11:14] Speaker 02:
The survival data is greater than the combination of either drug's activity.

[00:11:21] Speaker 02:
So it was a very surprising invention that our inventors had in the face of what was contrary direction that those in the field were taking in the research they were doing in the field.

[00:11:31] Speaker 02:
That's the objective evidence.

[00:11:32] Speaker 02:
And the panel office now

[00:11:34] Speaker 02:
looking at this again with the benefit of hindsight, piecing this together and saying, oh, no, we're not going to credit that.

[00:11:40] Speaker 02:
We're going to take a look at a cherry pick, the Zhang reference, and come up with a constructive rejection that produces the claim combination.

[00:11:54] Speaker 02:
As I said, the problem with NCT 172 is just a public version of a planned study or clinical protocol.

[00:12:01] Speaker 02:
It's a trial it's literally a trial and sometimes when you try things they work and sometimes they don't in this case It didn't and it's frequently the case as I mentioned in pharmaceutical tests that they did clinical trials don't pan out the odds are stacked against pharmaceutical companies particularly in the field of oncology cancer treatment and prostate cancer is part and parcel of that and

[00:12:23] Speaker 02:
And in spite of the clinical explicitly speculative nature of NCT 172 and the lack of any efficacy data, the board contended that those of ordinary skill would have drawn conclusions about the effectiveness of the drug combination that NCT 172 happens to mention.

[00:12:41] Speaker 02:
And the board did this even though there's no dispute that those of ordinary skill regarded such a conclusion as highly uncertain until such time as the results of the clinical trial became available.

[00:12:53] Speaker 02:
Indeed, combination therapies for the treatment of cancer were and are sufficiently speculative that clinical trials are needed.

[00:13:01] Speaker 02:
And here, to confirm the speculative nature of the clinical trials, we have the Zhang publication.

[00:13:07] Speaker 02:
Specifically, a full two years after the publication of NCT 172, Zhang remained, and this is a quote, they still, quote, remain to be seen, close quote, whether the combination of valaparib and abiraterone worked better than abiraterone alone.

[00:13:21] Speaker 01:
And again, I'm just curious, have you filed a continuation application or another RCE?

[00:13:26] Speaker 01:
Have we?

[00:13:27] Speaker 01:
Yeah.

[00:13:27] Speaker 01:
Yes, we have.

[00:13:28] Speaker 01:
Did you include anything like an expert declaration or?

[00:13:32] Speaker 02:
We haven't gotten to that spot in prosecution yet, Your Honor.

[00:13:36] Speaker 03:
You're into your rebuttal.

[00:13:37] Speaker 03:
Do you want to save it?

[00:13:41] Speaker 02:
Briefly, if I may, Your Honor, I just mentioned that with respect to another error that the board made

[00:13:46] Speaker 02:
was failing to give any weight to our evidence of unexpected results that we had in our patent application.

[00:13:53] Speaker 02:
It's pretty well established in the law that animal data, in terms of indicating the effectiveness of human pharmaceuticals, is entitled to some weight.

[00:14:02] Speaker 02:
In this instance, we had mouse data.

[00:14:05] Speaker 02:
But they're not just any mice.

[00:14:06] Speaker 02:
They're mice that harbored human tumors.

[00:14:09] Speaker 02:
So they were a very valid model for this.

[00:14:11] Speaker 02:
And the data, as we reference and we show in the record,

[00:14:16] Speaker 02:
The survival data in the patent application was a very stark improvement.

[00:14:20] Speaker 02:
And that's another legal error that the board made that warrants reversal.

[00:14:24] Speaker 02:
So I'll reserve my time for rebuttal.

[00:14:40] Speaker 00:
Please proceed.

[00:14:40] Speaker 00:
May it please the court?

[00:14:41] Speaker 00:
The claims here recite a combination of two known therapies for treating prostate cancer to do nothing more than treat prostate cancer.

[00:14:49] Speaker 00:
The claims are thus prima facie obvious.

[00:14:52] Speaker 00:
The board did not err in relying on the 172 proposed clinical trial.

[00:14:57] Speaker 00:
In this case, it shows what people were motivated to do at the time and provide some evidence of a reasonable expectation of success.

[00:15:06] Speaker 00:
But its absence of clinical results are largely irrelevant in this case.

[00:15:09] Speaker 01:
Phase II clinical trials fail all the time, don't they?

[00:15:14] Speaker 00:
I have nothing in this record about the specific failure in prostate cancer for phase II trials.

[00:15:20] Speaker 00:
But it's true, cancer research in general is unpredictable.

[00:15:26] Speaker 01:
Right.

[00:15:26] Speaker 01:
Well, if that is true, then why didn't the agency take that into consideration in issuing its 103 rejection or evaluating it at the board?

[00:15:36] Speaker 00:
I mean, I don't think that the agency didn't take it into consideration.

[00:15:39] Speaker 00:
The thing is, there's two references here with the individual drugs.

[00:15:43] Speaker 00:
Ligothetis teaching treatment with abiraterone and prednisone to treat prostate cancer.

[00:15:48] Speaker 00:
And in Zang, the phase one clinical trial showing that niraparid had clinical activity

[00:15:54] Speaker 00:
in against prostate cancer.

[00:15:57] Speaker 00:
And I note the Zhang reference says that niraparid was the first PARP inhibitor to show clinical activity, which suggests it's a motivation for its use over any other PARP inhibitor, though that's not a requirement.

[00:16:12] Speaker 00:
But I think the board focusing on niraparid was

[00:16:16] Speaker 00:
because of its clinical activity in these studies.

[00:16:20] Speaker 00:
And the fact that the 172 then doesn't have clinical data on a different combination doesn't teach a way or undermine the reliance on those references.

[00:16:34] Speaker 00:
And the council's discussion of looking at filiparid in the clinical trial as opposed to niraparid

[00:16:44] Speaker 00:
It's just the timing issue.

[00:16:45] Speaker 00:
The 172 trial was proposed before the clinical results came out with noreparid.

[00:16:51] Speaker 00:
So whatever the motivations of the authors of the 172 trial, they didn't have the data in front of them about noreparid.

[00:17:00] Speaker 00:
And so it doesn't necessarily teach one way or the other about how one of skill of art would be motivated as the filing date of this application.

[00:17:12] Speaker 01:
Is it your view that any, let's say there were 20 known drugs for treating prostate cancer.

[00:17:22] Speaker 01:
Is it your view that it's prima facie obvious to do any combination of any of those 20, either taking drug one and drug 19 or drug four and drug seven or

[00:17:38] Speaker 01:
Drugs 1 through 20, all of them combined.

[00:17:42] Speaker 01:
Any combination is prima facie obvious?

[00:17:45] Speaker 00:
In your hypo, you're assuming that they've all shown clinical activity and progress.

[00:17:49] Speaker 01:
That's right.

[00:17:49] Speaker 01:
And I don't know statistics very well, but let's just assume that's like over a thousand different possible combinations.

[00:17:56] Speaker 01:
I think... They're all prima facie at 103?

[00:18:00] Speaker 00:
I think, yes, a prima facie case, there could be rebuttal evidence that would suggest that particular combinations wouldn't work or that one wouldn't be motivated to do that.

[00:18:10] Speaker 00:
On this record, we have the motivation provided by the 172 reference.

[00:18:14] Speaker 00:
to combine abiraterone specifically with a PARP inhibitor because of their different mechanisms of action.

[00:18:20] Speaker 00:
So one might expect that they would have a better efficacy.

[00:18:24] Speaker 00:
So in this case, there's further evidence of a particular motivation to combine these two drugs.

[00:18:31] Speaker 01:
So we're not... Do you know anything about the mechanism of action between the laparib and the niraparib?

[00:18:37] Speaker 00:
They're both PARP inhibitors.

[00:18:39] Speaker 01:
I know that, but is there anything beyond that that we know?

[00:18:43] Speaker 00:
Not in this record, and I don't know anything further about them, other than the clinical results and mouse results that are discussed in Zang, that veliparid has not shown clinical activity, whereas nirapariv has shown clinical activity.

[00:18:59] Speaker 00:
So that's the only distinction on this record between those two PARP inhibitors.

[00:19:06] Speaker 00:
And I would also note that there's no

[00:19:10] Speaker 00:
evidence on this record about some sort of problem with the combination therapy.

[00:19:14] Speaker 00:
It's not that the combination with the liparid resulted in no treatment.

[00:19:20] Speaker 00:
It's prostate cancer.

[00:19:20] Speaker 00:
It just didn't advance the response to aberraterone and prednisone.

[00:19:27] Speaker 01:
What if a declaration had been filed here by an expert in this field that says this is wildly unpredictable stuff when you're mixing two things, even two known things to work, just given the science of it all?

[00:19:43] Speaker 01:
you really can't be sure whether it's going to work or not.

[00:19:48] Speaker 01:
Clear examples of that are just the Hussein results of NCT 172.

[00:19:53] Speaker 01:
Not that I'm relying on Hussein to defeat NCT 172 per se, but it's just an illustration of how unknown of a world we're working in here.

[00:20:07] Speaker 00:
That would have been some evidence against a reasonable expectation of success that obviously isn't on that record.

[00:20:13] Speaker 00:
It would depend on how specific, I think, the arguments were made.

[00:20:18] Speaker 00:
Sure, there's lots of unpredictability in cancer research, but what is the unpredictability about combining an FDA-approved drug for prostate cancer with a drug that has shown success in phase one?

[00:20:31] Speaker 00:
Specific evidence that that was unpredictable, I think, might

[00:20:36] Speaker 00:
would be something the examiner and the board would consider then in weighing whether there was a reasonable expectation of success.

[00:20:43] Speaker 00:
But I'd also note that the expectation doesn't have to be complete certainty, just has to be reasonable in this field.

[00:20:50] Speaker 00:
But again, that kind of declaration and that evidence is not on this record.

[00:20:56] Speaker 01:
If a patent applicant files an application for a combination therapy where they haven't gotten approval yet for that combination therapy, but maybe they are looking to enter phase two clinical trials, would they have written description for that kind of claim to combination therapy at that stage?

[00:21:18] Speaker 00:
A description of a phase two trial and combination.

[00:21:22] Speaker 01:
Would they have possession of the invention?

[00:21:25] Speaker 01:
I mean, I think... Before they even got any data yet from a phase two clinical trial.

[00:21:34] Speaker 00:
I do think they would, because they are testing their... If the method to treatment is... Because they know if it works.

[00:21:41] Speaker 00:
They don't know if it works, but it shows possession that that's their invention.

[00:21:46] Speaker 00:
And if it doesn't work, then... I mean, that's post-filing information, and I don't know how that would affect their written description, but at the time of

[00:21:55] Speaker 00:
that I would say that it would provide written description and an enablement of support.

[00:21:59] Speaker 01:
So speculative utility is good enough for possession under 112?

[00:22:02] Speaker 00:
Well, the utility is that you could, to the point you've gotten to phase two trial, you've already got animal studies or in vitro studies or something that you've given to the FDA to support putting this drug into humans.

[00:22:17] Speaker 00:
And that would absolutely support a utility written description or enablement of the claims.

[00:22:25] Speaker 03:
Speaking of animal studies, what say you to your friend's argument with respect to not considering the mice?

[00:22:33] Speaker 01:
With human tumors.

[00:22:35] Speaker 00:
Right.

[00:22:36] Speaker 00:
The board found that these claims, the unexpected results in mice fell completely outside of the scope of the claims.

[00:22:44] Speaker 00:
to treating humans and that Snyder hadn't presented evidence that this unexpected result in mouse would in fact correlate with what was claimed, a treatment of prostate cancer in humans.

[00:22:57] Speaker 00:
I'd also note the board had an alternative ground that these unexpected results in mice were not in fact unexpected based on the results in Zhang.

[00:23:08] Speaker 00:
And Snyder didn't contest that finding by the board in their opening brief.

[00:23:12] Speaker 00:
So that argument is forfeited and sufficient for this court to affirm the board's decision.

[00:23:21] Speaker 00:
Unless there's any other questions, we'd ask this court to affirm the board's decision.

[00:23:26] Speaker 00:
Thank you.

[00:23:32] Speaker 02:
Just a few points, if you may.

[00:23:37] Speaker 02:
Council had mentioned that,

[00:23:40] Speaker 02:
The board did not error because NCT 172 provides some evidence that supports the rejection.

[00:23:49] Speaker 02:
That's an interesting change when you look at the way this is all developed.

[00:23:52] Speaker 02:
NCT 172 was the first listed reference that the examiner relied upon.

[00:23:57] Speaker 02:
If you take a look at the summary that the board provided in its decision, and that appears at appendix

[00:24:10] Speaker 02:
18, NCT 172 again, the first listed reference.

[00:24:15] Speaker 02:
And you've seen the progression.

[00:24:16] Speaker 02:
When we finally got to briefing before this court, there's been a further change in stepping away from NCT 172.

[00:24:23] Speaker 02:
And we think that that change is very telling.

[00:24:26] Speaker 02:
It's pretty clear that what the board did was substituting its judgment for what was the objective evidence of record.

[00:24:34] Speaker 02:
On that point, I had mentioned earlier that there were two combinations with respect to volaparib, that that was viewed as being the leading candidate for combination.

[00:24:43] Speaker 02:
They mentioned how the NCT172 just happened to be a timing issue, that it was the same year as the publications I mentioned for niraparib and abiraterum.

[00:24:53] Speaker 02:
But we also had, as I mentioned, as summarized in Jiang, there was a study with temozolomide.

[00:25:00] Speaker 02:
That combination also was with volaparib.

[00:25:03] Speaker 02:
That was a 2009 study.

[00:25:05] Speaker 02:
It's discussed in Appendix 418.

[00:25:08] Speaker 02:
It's footnote number 48.

[00:25:09] Speaker 02:
It's a 2009 publication.

[00:25:12] Speaker 02:
So again, it's not just a timing issue that people thought that Velapirib was a leading candidate for combination.

[00:25:17] Speaker 02:
It's all the way back in 2009.

[00:25:20] Speaker 02:
So it's two combinations of Velapirib, none with anything else, until our inventors came along and found the very surprising results with respect to Nourapirib.

[00:25:31] Speaker 02:
It's in the record, the very stark results that were obtained in our mouse data.

[00:25:37] Speaker 02:
That appears in the appendix at 58.

[00:25:52] Speaker 02:
The survival data was stark.

[00:25:56] Speaker 02:
Neuraparib alone provided

[00:26:00] Speaker 02:
No real improvement in survival.

[00:26:03] Speaker 02:
Aberradorum provided 13% improvement.

[00:26:13] Speaker 02:
The combination provided 31% improvement.

[00:26:15] Speaker 02:
So very stark there.

[00:26:20] Speaker 02:
There was a statement made in opposing counsel's argument.

[00:26:24] Speaker 02:
It's throughout the other papers in the briefing that these were all PARP inhibitors.

[00:26:30] Speaker 02:
That's too broad a brush to draw with these compounds.

[00:26:34] Speaker 02:
Saying that they're all PARP inhibitors doesn't do it justice.

[00:26:37] Speaker 02:
They're united by the fact that they inhibit the enzyme PARP.

[00:26:40] Speaker 02:
But it's not much different than saying that, well, we're all lawyers.

[00:26:44] Speaker 02:
Well, lawyers do different things.

[00:26:45] Speaker 02:
You wouldn't want me to prepare your will.

[00:26:47] Speaker 02:
Trust me when I say that.

[00:26:49] Speaker 02:
You wouldn't want a PARP inhibitor.

[00:26:50] Speaker 02:
They don't all do the same thing.

[00:26:53] Speaker 02:
They act different mechanisms.

[00:26:54] Speaker 02:
Some work better than others.

[00:26:55] Speaker 02:
And we see that in the record here.

[00:26:57] Speaker 02:
In combination with abiratero,

[00:26:59] Speaker 02:
There was a stark difference between the way the lapar had behaved and the way nirapar had behaved.

[00:27:05] Speaker 03:
I thought you're beyond your time.

[00:27:08] Speaker 02:
Very good.

[00:27:08] Speaker 02:
Thank you.

[00:27:09] Speaker 03:
Thank you for entertaining my comments.

[00:27:12] Speaker 03:
We thank both sides.

[00:27:13] Speaker 03:
The case is submitted.

[00:27:14] Speaker 03:
That concludes our proceedings.