[00:00:13] Speaker 05:
We're not leaving her.

[00:01:21] Speaker 02:
Good morning.

[00:01:22] Speaker 02:
Good morning, Your Honor.

[00:01:23] Speaker 02:
Thank you very much, and may it please the Court.

[00:01:27] Speaker 02:
This is a case about an agency that blatantly disregarded its own regulation, a regulation that was critical to maintaining the careful balance that Congress struck in the Hatch-Waxman Act between innovators and generics.

[00:01:44] Speaker 02:
When a generic applicant like HICMA wants to introduce a drug for a method of use that is already patented, the Hatch-Waxman Act allows them to do that.

[00:01:58] Speaker 02:
It allows them to use that patent.

[00:02:01] Speaker 02:
It allows them to copy that use.

[00:02:04] Speaker 02:
And it allows them to do that without authorization from the patent holder, without license, and before the patents expire, provided

[00:02:14] Speaker 02:
that the applicant provide a patent certification and that the patent holder be enabled to bring patent litigation before the drug is approved.

[00:02:27] Speaker 02:
FDA understood that mandate and it promulgated a regulation that deals precisely with that issue and with the facts of this case.

[00:02:36] Speaker 02:
The regulation requires specifically that if the applicant's drug includes an indication

[00:02:43] Speaker 02:
that is claimed by a use patent, the applicant shall submit an applicable certification.

[00:02:53] Speaker 02:
The regulation could not be clearer, and yet FDA did exactly the opposite here.

[00:03:00] Speaker 02:
FDA approved HICMA's drug for the prophylaxis of gout, knowing that it was already patented by Takeda

[00:03:10] Speaker 02:
and didn't require a patent certification and didn't allow Takeda to litigate those patent rights before it approved the drug.

[00:03:18] Speaker 07:
Are you saying that just because it was the same indication that requires a certification?

[00:03:24] Speaker 02:
No.

[00:03:24] Speaker 02:
What I'm saying, Your Honor, is that the indication which was patented

[00:03:30] Speaker 02:
required the certification.

[00:03:32] Speaker 07:
It's not the patient isn't patented.

[00:03:33] Speaker 07:
It's the particular method of use that's patented.

[00:03:36] Speaker 07:
I mean, they didn't patent Colchicine for an indication of prophylactic treatment of chronic gout, right?

[00:03:44] Speaker 07:
That's not the patent.

[00:03:46] Speaker 02:
Well, your honor, respectfully, the use code that's listed in the orange book says exactly that.

[00:03:52] Speaker 02:
which it describes the patent as the use of colchicine for the prophylaxis of gout.

[00:03:57] Speaker 02:
That's U1020.

[00:03:59] Speaker 02:
They hold four patents, all claiming that exact same use code.

[00:04:04] Speaker 02:
And what FDA was obligated to do was once it knew that those patents existed, FDA was obligated to require HICMA to provide a patent certification so that the parties could litigate the patent case before the drug got approved.

[00:04:20] Speaker 04:
If the statute is properly interpreted as the government argues that reliance refers to the applicant's reliance only, how do you square the regulation?

[00:04:36] Speaker 02:
Well, the regulation, Your Honor.

[00:04:38] Speaker 04:
You understand my question?

[00:04:40] Speaker 02:
I do, I do.

[00:04:40] Speaker 02:
The regulation uses different language and different words than the statute does.

[00:04:44] Speaker 02:
The regulation actually matches what Congress said in the legislative history, which is that where the drug the applicant is seeking approval for, and it uses that word the,

[00:04:58] Speaker 02:
The controlling use patents that cover those uses must be certified, too.

[00:05:04] Speaker 02:
And this is a clear indication, Judge Silverman, of where FDA speaks exactly to the statute and what it understands the statute to provide and what Congress said.

[00:05:15] Speaker 02:
And yet FDA saying, oh, no, no, we don't have to abide by our regulation.

[00:05:19] Speaker 02:
We're going to ignore that.

[00:05:21] Speaker 02:
And that, Your Honor, that's arbitrary and capricious right there on its face.

[00:05:26] Speaker 02:
This case on that issue alone can be resolved.

[00:05:29] Speaker 04:
Of course, they're entitled to deference with respect to the interpretation of the regulation.

[00:05:34] Speaker 04:
Special deference under Seminole Rock.

[00:05:36] Speaker 02:
Well, with regard to their interpretation of the regulation, but this regulation is not ambiguous.

[00:05:41] Speaker 02:
Nobody has ever claimed, including the government, that this regulation is ambiguous.

[00:05:46] Speaker 02:
This regulation has existed for 20 years after notice and comment, and there's never been a challenge to this regulation.

[00:05:53] Speaker 02:
This is just FDA ignoring it.

[00:05:58] Speaker 02:
In fact, Your Honor, if I can go one next step, the only explanation that the government gives, which is buried in two paragraphs at pages 38 and 39 of its brief,

[00:06:10] Speaker 02:
is that where it cites, the only citation that it provides is to a citizen's petition response that it gave in 2004 where it doesn't even talk about method of use patents.

[00:06:23] Speaker 02:
It's focusing on those other patents, Your Honor was pointing out, those patents that the applicant relies on.

[00:06:30] Speaker 02:
It doesn't even mention this regulation.

[00:06:32] Speaker 02:
It doesn't even mention the method of use patents.

[00:06:34] Speaker 04:
Give me a chance to look at page 38 and 39.

[00:06:38] Speaker 04:
See where you're referring to.

[00:06:40] Speaker 02:
This is in the... In the government's brief.

[00:06:46] Speaker 02:
Yeah, the FDA's red brief, I believe.

[00:06:48] Speaker 04:
Yes.

[00:06:55] Speaker 04:
Where are you referring to?

[00:06:57] Speaker 02:
Top of page 39, Your Honor.

[00:06:58] Speaker 04:
That's what I thought.

[00:06:59] Speaker 04:
It's not on 38.

[00:07:02] Speaker 04:
And here they're citing... It's the word applicable, right?

[00:07:06] Speaker 02:
Right.

[00:07:06] Speaker 02:
This is their argument on the word applicable.

[00:07:09] Speaker 02:
And then the next sentence down, Your Honor, the FDA says, but as FDA has explained... Reinforce the relationship.

[00:07:18] Speaker 02:
Right.

[00:07:18] Speaker 02:
And the citation there, Jay... It's the word applicable.

[00:07:20] Speaker 04:
It's the previous sentence.

[00:07:21] Speaker 04:
It's the word applicable that the government is relying on.

[00:07:25] Speaker 02:
Right.

[00:07:26] Speaker 02:
And what they've done with the word applicable is they've basically said, well, that word applicable

[00:07:32] Speaker 02:
makes this part of the regulation inoperable because of the prior certification requirement in the earlier subsection, I1I.

[00:07:42] Speaker 04:
Is this your strongest argument, the regulation?

[00:07:45] Speaker 02:
Yes, and not only the strongest, but it's the clearest and easiest for this court to resolve this issue.

[00:07:52] Speaker 02:
And that's what I thought I would present the court with, which is the most straightforward.

[00:07:57] Speaker 02:
And I'm happy to discuss the other arguments as well, but the regulation is very clear on its face.

[00:08:03] Speaker 02:
And like I said, there's no question that a certification should have been required.

[00:08:08] Speaker 02:
Nobody's even disputing

[00:08:09] Speaker 02:
the existence of the method of use patents and the use code that was in the orange book that FDA knew existed, knew was there, and decided it was not going to require a certification.

[00:08:24] Speaker 02:
If the court has other questions, I'm happy to answer them.

[00:08:26] Speaker 02:
Otherwise, I'll reserve my time for rebuttal.

[00:08:28] Speaker 02:
Thank you.

[00:08:46] Speaker 01:
Good morning, Your Honors.

[00:08:47] Speaker 01:
May it please the Court?

[00:08:48] Speaker 01:
My name is Kate Stetson.

[00:08:49] Speaker 01:
I represent Takeda.

[00:08:51] Speaker 01:
The questions in Takeda's appeal have to do with essentially three things.

[00:08:55] Speaker 01:
One of them has to do with this issue of reliance, and the other two have to do with whether FDA arbitrarily departed without explaining itself from its two past statements about information required on colchicine labeling.

[00:09:09] Speaker 01:
So just to start with reliance.

[00:09:10] Speaker 04:
Let me just ask you about your counsel

[00:09:14] Speaker 04:
The other petitioning counsel was relying on the regulation.

[00:09:18] Speaker 04:
You didn't rely on the regulation.

[00:09:21] Speaker 01:
We did not, no.

[00:09:22] Speaker 01:
We are making essentially both of our arguments arrive at the same point that the patents should have been certified to.

[00:09:29] Speaker 01:
Yes.

[00:09:30] Speaker 04:
Under either theory you win.

[00:09:32] Speaker 01:
Under either theory we win.

[00:09:34] Speaker 04:
But I'm sort of puzzled that you're not relying on the regulation.

[00:09:38] Speaker 01:
We chose to take, because of course this was our data, we chose to take an approach that was record-based, that is data-based, and that is a narrower ground, we think, on reaching the same conclusion.

[00:09:51] Speaker 01:
But both of them, as I've said, end up at the same place in the end.

[00:09:55] Speaker 01:
But with respect to reliance, the Hatch-Waxman Act requires applicants when they're filing a 505b2 application, which is the short-form application.

[00:10:05] Speaker 04:
Doesn't the more obvious reading of the statute, the one the government has, it says, the statute says, relied upon by the applicant.

[00:10:13] Speaker 04:
Doesn't say relied upon by FDA.

[00:10:16] Speaker 01:
There's two issues with that, Judge Silberman.

[00:10:18] Speaker 01:
I think the first is relied upon by the applicant can absolutely mean what we're saying it to mean in the circumstance where FDA steps in and does the applicant's job.

[00:10:29] Speaker 01:
Now, even FDA has recognized this.

[00:10:31] Speaker 01:
This is not something that FDA acknowledged in its brief, but its standard intake form for any of these applications, the 505b2 application form,

[00:10:40] Speaker 01:
asks the question, and this is a Joint Appendix 835, the purpose of the following two questions is to determine if there is an approved drug product that is equivalent or very similar to the proposed product that should be referenced as a listed drug.

[00:10:55] Speaker 01:
So it is attempting at JA 835, 836, 837 to flush out whether there is a drug that's not referenced by the applicant in its application, but upon which the applicant essentially is relying.

[00:11:07] Speaker 01:
And here's the key question, is it 836?

[00:11:10] Speaker 01:
Is there a pharmaceutical alternative already approved?

[00:11:14] Speaker 04:
What are you reading from?

[00:11:16] Speaker 01:
Joint Appendix 836.

[00:11:17] Speaker 04:
Yes, I know.

[00:11:18] Speaker 04:
What is it?

[00:11:19] Speaker 04:
What is the document?

[00:11:20] Speaker 01:
This is the standard intake form that FDA uses whenever it's assessing a 505B2 application.

[00:11:27] Speaker 01:
So the question is, is there an alternative?

[00:11:30] Speaker 01:
The box is checked, yes.

[00:11:31] Speaker 01:
The next question, is it approved for the same indication?

[00:11:34] Speaker 01:
The box is checked, yes.

[00:11:35] Speaker 01:
Next question, is it referenced as a listed drug?

[00:11:38] Speaker 01:
No.

[00:11:39] Speaker 01:
And then there's a little note at the top of page 837 of the Joint Appendix that says, what's the name of this drug?

[00:11:44] Speaker 01:
The name is Colchris.

[00:11:46] Speaker 01:
When FDA, in exactly that circumstance, the right thing for FDA to do would have been to return the application to HICMA or Westward in order for HICMA to certify to the drug upon which it was relying, but it didn't do that.

[00:12:03] Speaker 01:
Instead, it went further.

[00:12:04] Speaker 01:
And it started to pick up Colchris's data, and this is the point where the record becomes the key and overwhelming series of evidence in favor of our position.

[00:12:17] Speaker 01:
Just take, for example, essentially the whole block of appendix pages in about the 800 range.

[00:12:23] Speaker 01:
There you find, among other things, repeated communications among FDA officials about HICMA's proposed labeling, about HICMA's proposed medication guide.

[00:12:35] Speaker 04:
Is your strongest argument on the labeling, that the labeling shows there's reliance?

[00:12:43] Speaker 01:
I think our strongest argument is on the labeling for this reason.

[00:12:48] Speaker 01:
But the strongest argument on the record, of course, is the batch of sites ranging from about 895 to 930.

[00:12:56] Speaker 04:
But you have a conclusion that the FDA provides that they would have proved it without even any mention of Cochris.

[00:13:06] Speaker 04:
Aren't they entitled to deference with respect to that?

[00:13:11] Speaker 04:
Are we to conclude they were lying?

[00:13:14] Speaker 01:
I think you are to conclude that that statement is not supported by what FDA actually did.

[00:13:20] Speaker 01:
It is hard to understand how FDA could say that it could have approved this drug without reference to Colchris when it called 50 people into a meeting to talk about the Colchris data, and that's at Joint Appendix 895.

[00:13:36] Speaker 01:
But to your point about the labeling,

[00:13:38] Speaker 01:
One of the great mysteries of the labeling, and this is something that FDA talked about repeatedly, is why the labeling actually contains some of the statements that it did.

[00:13:49] Speaker 01:
HICMA's data, such as it was, showed that with respect to the four drugs that HICMA chose to assess to support its 505b2 application, there were no interactions with the drugs that it chose.

[00:14:02] Speaker 01:
There was nothing wrong with co-administering those four particular drugs.

[00:14:06] Speaker 01:
Mutuals data, of course, which tested all of the drugs that had been found previously to cause adverse events, found something different, which is why when you get to the FDA folks talking about this at page 882, one of the things that they are saying to each other is, I don't see how we can justify this on the basis of westward data.

[00:14:26] Speaker 01:
Any warnings about co-administration between colchicine and the what are called CYP3A4 or P-glycoprotein inhibitors, that won't be from Westward's data.

[00:14:37] Speaker 07:
And that's why... Was that available from research that was done prior to the Colchris application?

[00:14:44] Speaker 01:
No, it was not.

[00:14:45] Speaker 01:
The research that was done such as it was prior to the Colchris application showed that people died from being administered colchicine.

[00:14:53] Speaker 01:
What Colchris did, and this is again something that FDA was very forthright about in May of 2011 in its citizen petition response, what Mutual did when it submitted that data was to advance the field.

[00:15:05] Speaker 01:
That's why Mutual got patents on it, and that's why in 2009

[00:15:09] Speaker 01:
Right after Colchris was approved, FDA put out a safety alert that said, this is now the standard.

[00:15:15] Speaker 04:
Your basic point, if I understand it correctly, is the label approved for Mitigare, worn generally against combining with inhibitors, right?

[00:15:29] Speaker 04:
The information that Mitigare produced, however, showed no problems with the inhibitors they showed.

[00:15:38] Speaker 04:
So therefore, that warning, your argument is, could only have been based on Takeda's submissions.

[00:15:46] Speaker 01:
Correct, and I'm not even using sort of circumstantial evidence to get there.

[00:15:50] Speaker 01:
That's what FDA said over and over and over again.

[00:15:54] Speaker 01:
And to the question about whether, Judge Wilkins, there was anything before mutual that could have supported that warning.

[00:16:01] Speaker 01:
I mean, let's look at what, again, FDA says, and this is in its 2014 memo while they're assessing the sort of final mitigare approval.

[00:16:11] Speaker 01:
Before Colchris, there were no widely accepted specific recommendations for dose reduction with certain, these co-administered drugs, other than avoidance when possible and caution when necessary with vigilant monitoring of toxicity.

[00:16:24] Speaker 01:
That's the pre-mutual studies warning.

[00:16:26] Speaker 01:
Here's the warning on Mitigare's label.

[00:16:29] Speaker 01:
Co-administration with these drugs should be avoided.

[00:16:32] Speaker 01:
If co-administration is necessary, you should either reduce the daily dose or reduce the dose frequency, and I want to hold on to that point for a minute, and the patient should be monitored for toxicity.

[00:16:42] Speaker 01:
That is a return to the pre-calculus state of affairs, except for one thing, which is that mention of the reduction of dosage or dose frequency, and that is straight from mutuals data, but the problem was

[00:16:56] Speaker 01:
that because of the patents and because of HICMA's attempt, which it concedes to try to get around the patents, that information wasn't on the label, and that actually segues into the other two points of the argument.

[00:17:08] Speaker 07:
It seems that you didn't cite, at least I didn't see in your brief, a citation to 355D, but that's the provision that

[00:17:20] Speaker 07:
specifies when the secretary can refuse or can deny an application.

[00:17:28] Speaker 07:
But D1, the very first provision, says that the application has to have adequate tests to show that the drug is safe under the conditions that are recommended in the proposed labeling.

[00:17:42] Speaker 01:
Right.

[00:17:42] Speaker 07:
So I would think that that would, I'm going to ask the same question to the FDA, so prepare your response.

[00:17:50] Speaker 07:
Why doesn't that show that if you have to change the label for it to be deemed safe and effective and you use data from Colchris to as the grounds that you have by definition under the statute relied on on that data?

[00:18:11] Speaker 01:
I think the answer to your question is yes.

[00:18:14] Speaker 01:
By definition, you should be found to have relied on that data.

[00:18:16] Speaker 01:
And more to that point, you know, FDA, I think, was really struggling with what to do here.

[00:18:22] Speaker 01:
And you can see that, again, from that all-hands, 50-person meeting about the data, because one of the slides they put up in that range of pages I gave you earlier is a slide that said, what are we supposed to do at this point?

[00:18:35] Speaker 01:
The public is calling out for an alternative to Colchrist.

[00:18:40] Speaker 01:
what Mitigari is proposing for its label, or what HICMA is proposing for its label, isn't supported by the data.

[00:18:46] Speaker 01:
That's exactly what that slide says.

[00:18:48] Speaker 01:
And this should not have come as a surprise to HICMA at any point during the process, because right when HICMA, which was then Westward, was discussing with FDA what it needed to put forward, and this is at Joint Appendix 1008,

[00:19:02] Speaker 01:
There was a meeting in July of 2011 between FDA and Westward.

[00:19:07] Speaker 01:
And one of the questions that Westward posed to FDA is, what are we going to need to put on our label in order for us to satisfy your past statements?

[00:19:17] Speaker 01:
And what FDA came back at that time and said was specific recommended dose modifications.

[00:19:23] Speaker 01:
That's what they said in 2011.

[00:19:25] Speaker 01:
But what ended up in 2015 was a label that had no specific recommended dose modifications.

[00:19:32] Speaker 01:
No explanation, just to get to that separate arbitrary and capricious argument about why that change occurred.

[00:19:37] Speaker 01:
It's impossible for me to understand what that explanation could have been given that four years ago with respect to this very applicant, they told the applicant... That was for a tablet, not the capsule, right?

[00:19:49] Speaker 07:
That's a whole different application.

[00:19:51] Speaker 01:
No, it was actually as to both, because one of the, that's a question that's very pertinent to that meeting, because one of the questions that was raised at that meeting was, what if we change it to a capsule?

[00:20:03] Speaker 01:
Does anything change?

[00:20:04] Speaker 01:
And FDA's response was, there are still the same safety concerns.

[00:20:08] Speaker 01:
So there's no difference between a tablet and a capsule as far as FDA's position with respect to the recommended dose modifications.

[00:20:15] Speaker 06:
On your reliance point, I take your point that reliance doesn't mean the same thing as listed or cited, but how are we going to apply this in future cases?

[00:20:27] Speaker 06:
Namely, what do we look for in the record?

[00:20:31] Speaker 06:
And I take your point as to all the facts in this case, but what kind of standard are we applying in trying to dig into what FDA looked at or didn't look at?

[00:20:38] Speaker 06:
How are we supposed to do that?

[00:20:40] Speaker 01:
Well, I think this is, in that regard, a relatively straightforward case.

[00:20:45] Speaker 01:
This doesn't strike me as one that's kind of close to the decisional line, precisely because you have FDA not only taking great care to review the data to combine the data with Western and Mutual.

[00:20:58] Speaker 01:
That was another point of discussion at the all-hands meeting.

[00:21:02] Speaker 01:
And you have FDA repeatedly saying, you can't label this product without including this information.

[00:21:10] Speaker 06:
a real morass for the court to try to figure out, did the agency rely or did the agency not rely on certain data?

[00:21:20] Speaker 06:
And I take your point.

[00:21:21] Speaker 06:
Well, wherever the line's drawn in the future, we win.

[00:21:25] Speaker 06:
I get that, but I'm worried about the future.

[00:21:28] Speaker 01:
Right.

[00:21:28] Speaker 01:
I think in the immediate future what you would hope to see and what should have happened here presumably because of that intake form that I started with is a far more rigorous front-end assessment about what the applicant is asking for and whether that applicant is going to be able to close the gap between the data that it submitted

[00:21:50] Speaker 01:
which again, you know, just harkening back to this case, showed no interactions.

[00:21:54] Speaker 04:
And what FDA understood the state of play to be from all of Mutual's data, which... Suppose there was not a single mention of Colchris in the FDA's record or decision.

[00:22:09] Speaker 04:
What reaction then?

[00:22:13] Speaker 01:
Well, if there was not a single mention of Colchris in the FDA's record of decision, I would have a far harder time standing up and telling you.

[00:22:22] Speaker 01:
Would you have any time?

[00:22:23] Speaker 01:
Would you be able to?

[00:22:24] Speaker 01:
Would I have any time?

[00:22:25] Speaker 01:
I think that it would be an argument that I would have to draw from a lot of silent implications, and I wouldn't want to be in that position.

[00:22:37] Speaker 01:
Fortunately, I'm not, because FDA was very far from right.

[00:22:40] Speaker 06:
In that case, you'd argue it was arbitrary and capricious for the agency to approve it based on what they had before it, presumably.

[00:22:46] Speaker 01:
Presumably, because if it approved that drug.

[00:22:49] Speaker 06:
Because it didn't have enough before.

[00:22:50] Speaker 01:
Exactly.

[00:22:51] Speaker 01:
If it approved that drug, yes, based on the data that only HICMA presented.

[00:22:55] Speaker 04:
You'd still have an argument on the label.

[00:22:57] Speaker 04:
You'd still have an argument on the label.

[00:22:58] Speaker 04:
You would.

[00:22:59] Speaker 04:
Because the label makes no sense without your client's submission.

[00:23:04] Speaker 01:
Without reference to and reliance on that other data.

[00:23:07] Speaker 06:
That's right.

[00:23:07] Speaker 06:
And then what exactly do you want to transpire?

[00:23:11] Speaker 06:
So it goes back to the district court, it goes back to the agency.

[00:23:15] Speaker 06:
Tell me exactly what you want.

[00:23:18] Speaker 01:
I think in light of what FDA itself said at that Joint Appendix 1008, that exchange back in 2011, relating to not just the drug-drug interactions that we've been largely talking about with respect to the label, but also the acute doubt flare, that separate argument we've got.

[00:23:34] Speaker 01:
In both of those instances, it said, you need this information on the label.

[00:23:37] Speaker 01:
This is a safety concern.

[00:23:39] Speaker 01:
In the normal case, what I would tell you, particularly if you're looking at the failure to explain, is that often in those circumstances, you send it back for the agency just to explain itself and it's just a remand.

[00:23:50] Speaker 01:
I don't think that's appropriate here.

[00:23:52] Speaker 01:
I think whether we win on the certification point or we win on both certification and that failure to explain, the appropriate thing to do is to send it back to the district court

[00:24:02] Speaker 01:
for in to enter summary judgment in our favor, that's what we saw here, and then for that court to vacate, to direct the FDA to vacate its approval of mitigare.

[00:24:11] Speaker 06:
Which would mean, though, what going forward?

[00:24:13] Speaker 06:
That they have to, that you're going to get 30 months?

[00:24:16] Speaker 06:
Or how's this going to play out?

[00:24:17] Speaker 06:
That's what I'm trying to figure out.

[00:24:19] Speaker 01:
So as a practical matter, what it would mean, the vacator of the approval of Minigare would mean that Minigare would have to be pulled from the market.

[00:24:26] Speaker 01:
The 30-month stay goes to the certification point.

[00:24:30] Speaker 01:
So it's a separate issue from the failure to explain the acute gout flares and the combination interactions.

[00:24:36] Speaker 04:
Minnigar is in the market now.

[00:24:38] Speaker 01:
It is.

[00:24:39] Speaker 01:
But with respect to the 30-month stay, here's the situation.

[00:24:42] Speaker 01:
You saw in our briefing that right now there's a patent case going on in Delaware.

[00:24:46] Speaker 01:
That patent case, of course, was filed in a TRO posture because Takeda learned about this approval basically when the press release came out.

[00:24:56] Speaker 01:
It was litigated initially in a PI posture, went up to the Federal Circuit in that posture, and the denial of a PI or the denial of the PI was affirmed.

[00:25:05] Speaker 01:
What's happening now is a motion to dismiss.

[00:25:07] Speaker 01:
That's pending.

[00:25:09] Speaker 07:
The government says if that goes against Takeda, then our case is moot.

[00:25:17] Speaker 01:
That's not accurate, Judge Wilkins, for a couple different reasons.

[00:25:20] Speaker 01:
The first is it would depend on how it goes against Takeda.

[00:25:23] Speaker 01:
It may depend on whether it's appealed.

[00:25:25] Speaker 01:
I mean, all of this, of course, is exactly why the certification is supposed to occur, because Takeda shouldn't have been put in the position of having to litigate, carrying the burdens of an emergent kind of posture that it did.

[00:25:37] Speaker 01:
But be that as it may, the other reason that it's not moot is

[00:25:41] Speaker 01:
That patent case has nothing to do with our arguments here with respect to the failure to explain the labels, except for this important thing.

[00:25:50] Speaker 01:
The arguments in the patent case have to do with induced infringement.

[00:25:54] Speaker 01:
The reason that HICMA is contending that there was no induced infringement is that the labels were simply too vague to suggest that there would be infringement.

[00:26:05] Speaker 01:
That is exactly, of course, the point that we are making in this case, is that the labels were too vague and that FDA should have, because it specifically directed as to this single colchicine product,

[00:26:18] Speaker 04:
Referring to the alert they sent out.

[00:26:21] Speaker 01:
The alert and to the citizen petition response.

[00:26:24] Speaker 01:
It said, whenever you apply for this single ingredient product, you must include this in the label.

[00:26:29] Speaker 01:
And now, what FDA says... What is a single ingredient?

[00:26:33] Speaker 04:
Just a single active ingredient?

[00:26:35] Speaker 01:
Yes, it's as compared to something that's a combination drug, a single ingredient.

[00:26:39] Speaker 04:
Well, I figure I knew it couldn't combination, but it means a single active ingredient.

[00:26:41] Speaker 01:
Single active ingredient, right.

[00:26:43] Speaker 01:
But with respect to what FDA says now about that, if I could just have one moment to make this point, what FDA now says is, yes, we understand that back in the 2011 citizen petition response, we said that any application for a single ingredient

[00:26:59] Speaker 01:
colchicine product to treat prophylaxis, for prophylaxis of gout flares to prevent them, has to contain this language.

[00:27:08] Speaker 01:
But this is something different, because this product that HICMA sought approval for is for prophylaxis of gout flares.

[00:27:15] Speaker 01:
That, of course, was exactly the circumstance that FDA required that statement to be in.

[00:27:18] Speaker 01:
So that's the interaction between the patent case and this case.

[00:27:22] Speaker 04:
Counsel, I want to make sure I understand the difference between the two petitioners.

[00:27:29] Speaker 04:
My understanding is you do not associate yourself with a statutory argument which your other counsel makes.

[00:27:41] Speaker 04:
If I understand his position, it wouldn't matter whether or not FDA relied

[00:27:50] Speaker 04:
on Cochris material or not.

[00:27:53] Speaker 04:
He would win under his theory of the statute anyway.

[00:27:58] Speaker 04:
You don't associate yourself with that position.

[00:28:01] Speaker 04:
Your position depends on the argument that the FDA did rely and therefore circumvented the statute.

[00:28:08] Speaker 01:
Yes, that is the argument that we're pressing.

[00:28:11] Speaker 04:
You understand?

[00:28:12] Speaker 04:
I'm correct in expressing the differences between the two of you.

[00:28:16] Speaker 01:
You are correct, but if Mr. Sitzman's argument carries the day... Oh, you'd like it, too.

[00:28:19] Speaker 01:
Yeah, yeah, sure, I understand.

[00:28:21] Speaker 01:
We'll get behind it, yes.

[00:28:23] Speaker 01:
There are no further questions.

[00:28:24] Speaker 01:
Thank you.

[00:28:25] Speaker 05:
Thank you.

[00:28:43] Speaker 00:
Good morning.

[00:28:43] Speaker 00:
May it please the court.

[00:28:44] Speaker 00:
Sonia McNeil for the government.

[00:28:47] Speaker 00:
The FDA applied the statute and the regulations in a straightforward way.

[00:28:50] Speaker 04:
Can I ask you a question right at the outset?

[00:28:52] Speaker 00:
Yes.

[00:28:56] Speaker 04:
You conceded below that if the FDA explicitly relied on co-crisp material, you lose.

[00:29:10] Speaker 04:
Correct.

[00:29:11] Speaker 00:
Your Honor, I think that's not quite what we said below.

[00:29:13] Speaker 04:
Pretty close.

[00:29:14] Speaker 00:
What we said below is that if the Colchris data were necessary to make the affirmative case to clear the hurdle that Judge Wilkins, you identified in 355D, then yes, it would be true that HICMA should have certified.

[00:29:30] Speaker 04:
So it doesn't matter.

[00:29:31] Speaker 04:
Whether it doesn't matter then, there's an objective test that overrides whether the applicant does rely or does not rely.

[00:29:42] Speaker 00:
So, Your Honor, here I think it's helpful to take a step back.

[00:29:46] Speaker 00:
So I'd like to make sure I understand the question if I could.

[00:29:49] Speaker 04:
I understand your position down below.

[00:29:53] Speaker 04:
And indeed, let me put a hypothetical to you.

[00:29:57] Speaker 04:
Suppose the FDA said, look, we relied heavily on the Cochris material.

[00:30:04] Speaker 04:
We look at it carefully, the label reflects it, and so forth.

[00:30:08] Speaker 04:
However, the applicant didn't rely, so therefore, the statute, as we interpret it, means that the applicant doesn't have to, will certify, will certify based on our own determinations.

[00:30:25] Speaker 00:
Your Honor, my answer to that question is that FDA has never had occasion to interpret whether the statute would preclude that, but that's not our practice, and that is not what happened here.

[00:30:35] Speaker 04:
Wait, wait, wait, wait, counsel.

[00:30:37] Speaker 04:
I want to make sure I understand, because down below, I understood, counsel, to concede that if the FDA did rely, I just said in my hypothetical, then petitioners win.

[00:30:54] Speaker 00:
If FDA had concluded that the Cochris study results were necessary for there to be substantial evidence of safety and efficacy as labeled for Mitigar, then it would be true that HICMA should have certified to Mitigar.

[00:31:09] Speaker 00:
But that's not our practice, and that's not what happened in this case.

[00:31:13] Speaker 04:
Okay, but that takes away the statutory question.

[00:31:17] Speaker 04:
In other words, there's not much strain on the question whether or not

[00:31:22] Speaker 04:
the statute should be read as limited to the applicant's reliance or whether the FDA relies, because on the hypothetical we've just described, if the FDA explicitly does rely, then it would be inappropriate to certify.

[00:31:38] Speaker 00:
Your Honor, I am not conceding that because, of course, that reading of the statute would read the applicant entirely out of Section 355B2.

[00:31:45] Speaker 04:
So then you're saying your position is, it's not the position down below, your position is, even under my hypothetical, where the FDA explicitly relies on the Cochris material,

[00:32:01] Speaker 04:
makes no bones about the fact that we're relying on it.

[00:32:04] Speaker 04:
But we can nevertheless certify because the applicant didn't rely.

[00:32:10] Speaker 04:
That's your position?

[00:32:11] Speaker 00:
Your Honor, without meaning to be obstinate, I want to take a step back and make sure I understand the implications of your question.

[00:32:18] Speaker 00:
And I think the way that's easiest to do that is to explain how the process actually works.

[00:32:23] Speaker 00:
And this is as 355D reflects.

[00:32:25] Speaker 04:
That's a pretty straightforward question.

[00:32:27] Speaker 04:
Yeah, I'm a very simple-minded judge.

[00:32:29] Speaker 04:
I gave you a straight question.

[00:32:31] Speaker 00:
Look, we don't accept in this case, and it's not our argument, that a reading of the statute that would make the words the applicant entirely superfluous is appropriate.

[00:32:42] Speaker 04:
But it would be absurd otherwise.

[00:32:44] Speaker 04:
Well, what's the answer to my hypothetical?

[00:32:47] Speaker 04:
That the FDA could explicitly rely on the Cochris material, say it over and over and over again.

[00:32:53] Speaker 04:
However, we certify anyway because the applicant didn't rely.

[00:32:58] Speaker 00:
So FDA doesn't certify, of course.

[00:32:59] Speaker 00:
I mean, what FDA would do in that circumstance.

[00:33:02] Speaker 04:
Approve, excuse me, not certify.

[00:33:04] Speaker 00:
What FDA would do.

[00:33:04] Speaker 04:
Certify is the other term.

[00:33:05] Speaker 04:
You don't have to certify.

[00:33:07] Speaker 04:
You approve.

[00:33:08] Speaker 00:
Your Honor, we think that case does not, that that hypothetical is not presented by this case.

[00:33:14] Speaker 00:
But, but, but.

[00:33:14] Speaker 04:
That is the worst answer.

[00:33:16] Speaker 04:
You know, that answer is not acceptable in this court ever.

[00:33:19] Speaker 04:
Many years ago, when late Justice Scalia was sitting as a judge here,

[00:33:25] Speaker 04:
And a lawyer answered that hypothetical by saying, that's not this case.

[00:33:29] Speaker 04:
He threw his briefs at them.

[00:33:31] Speaker 00:
Then, Your Honor, before I get hit with briefs, let me affirm that... Justice Glee is now dead.

[00:33:37] Speaker 04:
He can't do it.

[00:33:40] Speaker 00:
Our position is that the words the applicant in the statute mean something.

[00:33:46] Speaker 00:
And here, FDA, if it had been presented with an application that did not contain sufficient evidence to show safety and efficacy, it would have, as 355C and D set out,

[00:34:02] Speaker 00:
ordered the applicant or provided the applicant with the opportunity to supplement his application with sufficient data to show safety and efficacy.

[00:34:09] Speaker 06:
This is why the statute uses relied on rather than listed or cited, probably, because under Judge Silverman's hypothetical, it would be nuts, right?

[00:34:19] Speaker 06:
It would be nuts.

[00:34:20] Speaker 06:
And they probably realized it would be nuts to use the word listed or cited because that would

[00:34:28] Speaker 06:
create a situation that would allow, that would have allowed what Judge Silverman was hypothesizing, whereas relied upon is a broader term and encompasses not just explicitly listed or cited, but also encompasses a situation where even though you don't list it or cite it, you're necessarily relying on it, even if not cited, to get the approval because you need those, that data.

[00:34:54] Speaker 04:
My hypothetical, remember, you're explicitly relying on it.

[00:34:57] Speaker 04:
You're explicitly, you're not implicitly relying, you're explicitly relying.

[00:35:01] Speaker 00:
I remember your hypothetical, Judge Silverman, and I think that that would be a tougher case, and with apologies, a different case for the government, because there's good reason for Congress to have made the applicant the master of its application.

[00:35:14] Speaker 04:
If you concede that point, then the statutory argument goes out the window.

[00:35:18] Speaker 06:
Which is why you're probably not conceding it, but I just think relied upon

[00:35:24] Speaker 06:
Maybe this just shows why your statutory argument doesn't work, which is relied upon can't mean listed or cited, because otherwise it makes a hash of the whole scheme.

[00:35:37] Speaker 00:
So, Your Honor, here I think the facts are very helpful.

[00:35:39] Speaker 00:
And if you wouldn't mind, I think, an explanation of what actually happened in this case would illustrate perhaps more persuasively than I've been able to to date why the statutory question just truly is not presented here.

[00:35:50] Speaker 00:
It rests on a false premise.

[00:35:52] Speaker 00:
So, what FDA concluded in this case, and this is a scientific determination, was that HICMA's application within its four corners contained enough evidence to provide for a finding of safety and efficacy for Mitigar as labeled.

[00:36:07] Speaker 00:
It's perfectly right, as Counsel for Takeda points out, that FDA looked at whether or not there was a pharmaceutical alternative, remember

[00:36:17] Speaker 00:
I think that's a good point.

[00:36:21] Speaker 00:
I think that's a good point.

[00:36:35] Speaker 00:
FDA reached the scientific determination in this case that that was not necessary.

[00:36:41] Speaker 00:
And so I imagine your next question will be, well, why on earth, then, does the record say the word colchrus?

[00:36:47] Speaker 00:
There are a couple of things that are important.

[00:36:49] Speaker 04:
247 times.

[00:36:50] Speaker 00:
246, according to you.

[00:36:52] Speaker 00:
All right.

[00:36:54] Speaker 04:
I'm corrected.

[00:36:55] Speaker 04:
I'm corrected.

[00:36:55] Speaker 00:
Stop exaggerating, Judge Seward.

[00:36:59] Speaker 00:
That's a different case, Your Honor.

[00:37:00] Speaker 00:
That's a hypothetical that's not presented here.

[00:37:03] Speaker 00:
Now, remember, Takeda's argument is about the Colchris studies, their study results, their drug-drug interaction studies, and their agree trial studies.

[00:37:11] Speaker 00:
So let's all remember that when we consider the word 246, that saying the word Colchris is not an invocation of the Colchris study results.

[00:37:21] Speaker 00:
And so let's... What about the label?

[00:37:23] Speaker 04:
That struck me as a particularly strong argument with respect to reliance.

[00:37:28] Speaker 04:
So the labeling and... Both with respect to the dosage and with respect to the combined with inhibitors.

[00:37:39] Speaker 00:
Sure.

[00:37:40] Speaker 00:
So let me start with the combination because I think that that is an especially straightforward argument.

[00:37:47] Speaker 00:
Colchris is a tablet.

[00:37:49] Speaker 00:
It's a 0.6 milligram tablet.

[00:37:50] Speaker 00:
It can be split in half.

[00:37:52] Speaker 00:
And the Colchris dosage adjustments recommend that patients who are taking Colchris in combination with an enzyme inhibitor take half of a tablet instead of a whole one.

[00:38:03] Speaker 00:
And so when FDA was deciding what label would make a capsule, which cannot be split in half, safe and effective for approval,

[00:38:11] Speaker 00:
It directed, and this is at JA 1008 and elsewhere in that page range, as Takeda's counsel pointed out, it suggested that HICMA would be wise to conduct studies to determine what drug-drug interaction information should be included on the label because you cannot achieve the dose adjustment that the Colchris label contains with the Mitigar product.

[00:38:35] Speaker 00:
So HICMA did studies and concluded that there was not the risk of drug-drug interaction with enzyme inhibitors, certain enzyme inhibitors, that the previously published literature with which Takeda's data was consistent had suggested.

[00:38:52] Speaker 00:
And so FDA decided whether or not or how best to label Mitigar in light of this seemingly surprising information.

[00:39:02] Speaker 00:
Again, the published literature that predated either of these companies' products and the studies that Takeda performed suggested that drug-drug interaction was a concern.

[00:39:12] Speaker 00:
HICMA's data showed that at least with respect to certain enzyme inhibitors, it was not.

[00:39:17] Speaker 04:
If HICMA had come up first with just its

[00:39:21] Speaker 04:
showing that there was no problem with ABCD inhibitors, then the label presumably would have said no problem.

[00:39:30] Speaker 00:
So the label would read exactly as it does now.

[00:39:32] Speaker 00:
Because if HICMA had come up first, the label would say, as it does, with respect to the particular inhibitors that HICMA studied, drug-drug interaction is not a problem.

[00:39:42] Speaker 00:
There's no need for doctors to be concerned about dose-related toxicity.

[00:39:46] Speaker 00:
However, it had long been known, and FDA cited among other studies in 1997 study, that's on JA776, that drug-drug interactions

[00:39:56] Speaker 00:
could produce adverse results, and that responding by lowering a dose might be appropriate as a means to head off or address adverse reactions.

[00:40:06] Speaker 00:
And so FDA concluded, in light of what we know now, specifically that drug-drug interaction is more nuanced, more difficult to generalize than we had originally understood, we think that as a matter of safety and efficacy,

[00:40:20] Speaker 00:
Mitigar, a capsule that can't be split, should say, unless you are taking one of the enzyme inhibitors that HICMA specifically studied, be on alert for possible signs of interactions and consider adjusting the dose accordingly.

[00:40:35] Speaker 07:
Now your sister counsel, when I put that question or related question to her, said that the FDA was necessarily relying upon the Cochris data for

[00:40:49] Speaker 07:
that additional label language because the Colchrist data added something new because I specifically asked her could this language been based on prior research and she said no.

[00:41:02] Speaker 07:
So why was she wrong?

[00:41:04] Speaker 00:
So the Colchris data said something specific about a particular class of enzyme inhibitors called dual inhibitors, but it didn't reveal for the first time that drug-drug interaction was a problem.

[00:41:18] Speaker 00:
This is something that everybody had already known for many years, and that was reflected, among other places, in the published literature that HICMA supplied in support of its application.

[00:41:28] Speaker 00:
And so it's simply not correct to say that HICMA's label can't be reconciled except by looking at the Cochris data because, again, the Cochris data was consistent with what the medical community already knew.

[00:41:41] Speaker 00:
It was HICMA's data that was a surprise.

[00:41:43] Speaker 04:
What about a separate problem, a separate problem?

[00:41:45] Speaker 04:
The Cochris label specifically refers to the drug inhibitors that cannot be used or should not be used with the active ingredient, right?

[00:41:56] Speaker 00:
It says that some inhibitors pose a special risk of fatal interaction.

[00:42:01] Speaker 04:
But doesn't it list them?

[00:42:02] Speaker 00:
It lists some, that's right.

[00:42:04] Speaker 04:
It does, whereas the label for Mitigar, or do I pronounce that correctly?

[00:42:11] Speaker 04:
Mitigar.

[00:42:11] Speaker 04:
Mitigar does not list inhibitor drugs that are dangerous.

[00:42:16] Speaker 00:
That's not right, Your Honor.

[00:42:17] Speaker 00:
Of course, the Mitigar label, among other things, specifically highlights clarithromycin, which everybody agrees is an inhibitor.

[00:42:23] Speaker 00:
It does.

[00:42:24] Speaker 00:
Yes, it does.

[00:42:24] Speaker 04:
It doesn't list all the ones that Cochris lists.

[00:42:29] Speaker 00:
Well, I can't, as I stand here, represent whether it lists all the ones that Colchris lists.

[00:42:33] Speaker 00:
The Council for the Interveners may be able to highlight that.

[00:42:35] Speaker 00:
But remember, Takeda's predecessor, Mutual, studied inhibitors that had previously been found to have adverse reactions.

[00:42:44] Speaker 00:
And so it's not news to anybody.

[00:42:46] Speaker 00:
It wasn't news to anybody, even at the time that the Colchris studies were performed, that specific inhibitors created the potential for drug interactions.

[00:42:54] Speaker 00:
The question that FDA was answering was, since you can't achieve the culchris dose adjustments with a capsule that can't be split in half, what should FDA do?

[00:43:05] Speaker 00:
What should the label say so that patients and doctors can use this drug safely and effectively?

[00:43:10] Speaker 04:
I see your point.

[00:43:11] Speaker 04:
May I go back and ask you a question about, suppose we concluded

[00:43:17] Speaker 04:
that FDA had in fact relied on Colchris material.

[00:43:26] Speaker 04:
What is the proper resolution?

[00:43:29] Speaker 00:
Well, I take Takeda's argument to be that FDA has merely given its say-so for why reliance on Colchris was not necessary to approve Mitigar.

[00:43:42] Speaker 00:
And so the appropriate course would be to remand for the agency for an explanation.

[00:43:47] Speaker 04:
Suppose we conclude, whether it was necessary or not, suppose we concluded the evidence suggests that, reasonably read, that FDA did in fact rely on Cochras.

[00:44:01] Speaker 04:
What is the proper resolution?

[00:44:03] Speaker 00:
Well, Your Honor, you would be reaching that conclusion in the face of statements by FDA in the record.

[00:44:08] Speaker 04:
I'm just thinking hypothetically.

[00:44:10] Speaker 04:
Suppose we should rely, conclude that.

[00:44:12] Speaker 04:
What is the proper resolution?

[00:44:14] Speaker 00:
So, again, I think a remand to the agency for an explanation of what it believes the proper course to be would be appropriate.

[00:44:21] Speaker 04:
In other words, you would agree that the issue in this case, from your point of view, is whether or not the evidence shows or the record shows that there was, in fact, reliance on the part of the FDA on coca-less material.

[00:44:36] Speaker 00:
As to the record, yes.

[00:44:38] Speaker 04:
That's the key issue in the case.

[00:44:40] Speaker 04:
Was there reliance or was there not?

[00:44:42] Speaker 00:
I think that that issue can dispose of the case without the need to engage in whether or not the applicant and the application part of the statute should be understood in the way that I've suggested.

[00:44:52] Speaker 07:
What is our standard of review on that question?

[00:44:57] Speaker 00:
on the question whether FDA relied on Colchris.

[00:45:00] Speaker 07:
I mean, the FDA says it doesn't.

[00:45:02] Speaker 07:
Colchris, you know, or Takeda says that they did.

[00:45:05] Speaker 07:
How, what is the precise standard of review for that question?

[00:45:10] Speaker 00:
So it's the standard of review that this court would apply to any other scientific determination because that is the nature of the determination that FDA is making.

[00:45:17] Speaker 00:
The determination that FDA made was that HICMA's application within its four corners through the combination of the prior finding of safety and effectiveness of Colprobenicid, which is a product that had been used to prevent gout for many, many decades.

[00:45:32] Speaker 00:
and the new studies that HICMA did to bridge the difference between its capsule and the Colprobenicid tablet were sufficient to provide evidence of safety and effectiveness as Mitigar was labeled.

[00:45:48] Speaker 04:
What about the regulation argument that Council for Elliott raises?

[00:45:53] Speaker 00:
Well, I mean, the first thing about the regulation argument is that it would impose a burden on applicants that the statute itself does not contemplate.

[00:46:00] Speaker 00:
And so I think that that is a good reason.

[00:46:02] Speaker 06:
But that text of the regulation, regardless of whether it's consistent with the statute, you haven't disavowed it.

[00:46:07] Speaker 06:
So we take the text of the regulation as it exists.

[00:46:09] Speaker 06:
So let's stick with the text of the regulation.

[00:46:11] Speaker 00:
So the text of the regulation, and here I'll go to page A9 of the government's addendum, FDA's position is that an applicable certification is a certification that is required by paragraph I-1, Romanet 1.

[00:46:26] Speaker 00:
All of this depends on the listing in the new applicant's application.

[00:46:33] Speaker 00:
It is only if

[00:46:34] Speaker 00:
the applicant relies on investigations that were done by somebody else that there is an obligation to provide patent certification.

[00:46:42] Speaker 04:
But that all depends on the interpretation of the word applicable, right?

[00:46:47] Speaker 00:
It depends on the interpretation of the word applicable, yes.

[00:46:50] Speaker 04:
And you're really giving a rather strained interpretation because it looks like applicable refers to the kinds of certifications, the four steps.

[00:47:00] Speaker 00:
I mean, if it did do that, Your Honor, it's sort of strange that it doesn't say, you know, appropriate under circumstances one through four.

[00:47:07] Speaker 04:
I admit the regulation looks pretty strange to me, but it's read more naturally the way counsel argues.

[00:47:17] Speaker 00:
Well, the possibility that the regulation could be clearer, as the Supreme Court recognized in the Caraco decision.

[00:47:21] Speaker 06:
Doesn't even look ambiguous.

[00:47:22] Speaker 06:
Looks pretty clear.

[00:47:24] Speaker 00:
Your Honor, I disagree.

[00:47:25] Speaker 00:
And here, it's helpful to recognize a couple of things.

[00:47:31] Speaker 00:
I mean, one, Eliot's reading would make Romanette III superfluous.

[00:47:35] Speaker 00:
Elliott thinks that such drug means a drug substance, remember?

[00:47:40] Speaker 00:
So that makes it the case that since HICMA relied on an investigation that concerned colchicine, it would have to certify to Colchris, and you would never get to the question of whether or not the label for Mitigar

[00:47:56] Speaker 00:
claims a use that is covered by a use patent.

[00:48:00] Speaker 00:
Now remember that drugs can be approved and patented for more than one use.

[00:48:06] Speaker 00:
Let's imagine that colprobenicid had patents attached to it.

[00:48:10] Speaker 00:
It doesn't, but I think the hypothetical is illustrative.

[00:48:13] Speaker 00:
Colprobenicid was approved for use to prevent gout flares and to treat acute gout flares.

[00:48:19] Speaker 00:
And it is possible, as the statute shows, as FDA has always recognized, for a new drug applicant to seek approval, as HICMA did here, for one, but not necessarily all, of protected methods of use.

[00:48:34] Speaker 00:
But under Elliott's reading of the statute, you would never get to the question whether an applicant had decided... We're just talking about the regulation for a moment.

[00:48:42] Speaker 00:
Yeah, I'm talking about the regulation, too.

[00:48:44] Speaker 00:
And I think under the regulation, you would never... If I understood Elliott's statutory argument,

[00:48:49] Speaker 04:
It wouldn't matter whether FDA relied or not.

[00:48:54] Speaker 04:
If there is a reference drug out there that uses the drug in a certain way, I can't pronounce it, colchicine?

[00:49:04] Speaker 04:
Colchicine.

[00:49:05] Speaker 04:
Colchicine in a certain way, bango, that's enough.

[00:49:08] Speaker 04:
I mean, I take it that that is their... That's Elliott's view.

[00:49:12] Speaker 00:
Yes, and it is precisely that view that makes their reading of the regulation and Roman at three do absolutely no work.

[00:49:19] Speaker 04:
Well, you could reject their reading of the statute as pretty extreme and still agree with them the regulation.

[00:49:29] Speaker 00:
I don't think so, Your Honor, because I think their reading of I-1-Romanet-1 makes I-1-Romanet-3 superfluous, whereas FDA has always recognized that this regulation, 314.50i, implements the statutory framework that's set out in 355b-2.

[00:49:48] Speaker 00:
We've never understood this to impose an entirely new burden, totally detached from whether or not an applicant has chosen to rely on investigations performed by somebody else.

[00:49:59] Speaker 00:
And that's for good reason.

[00:50:00] Speaker 04:
Remember... In other words, your basic point is the plain language of the regulation doesn't make any sense to you.

[00:50:08] Speaker 04:
Is that right?

[00:50:08] Speaker 00:
That's not right.

[00:50:09] Speaker 00:
My point is that if you read applicable in the way that we suggest, it makes clear that Romanet 1 identifies the universe of patents that are potentially relevant but doesn't tell you as to a use patent when you need to certify.

[00:50:25] Speaker 00:
You need to look at the label in order to come up with that.

[00:50:29] Speaker 00:
And this is perfectly congruent with the Hatch-Waxman scheme.

[00:50:32] Speaker 00:
Remember, the point of Hatch-Waxman is not to protect patent rights as such.

[00:50:37] Speaker 00:
That is the role of the patent laws.

[00:50:38] Speaker 00:
The point of Hatch-Waxman is on the one hand to encourage competition, and on the other, to encourage research.

[00:50:44] Speaker 00:
And so it's when a new applicant uses somebody else's research that the patent certification obligation attaches.

[00:50:51] Speaker 00:
Now, as this case illustrates, nothing prevents a patent holder

[00:50:58] Speaker 00:
from bringing a patent infringement suit if they believe that their intellectual property is infringed without regard to whether or not there has been reliance by the applicant.

[00:51:10] Speaker 00:
And an applicant- If they lose the period.

[00:51:13] Speaker 00:
They lose the period, but of course- Which is huge.

[00:51:17] Speaker 00:
Well, it's huge, but it's potentially also huge for the new applicant.

[00:51:19] Speaker 06:
Remember- I understand, but I mean, the idea that, oh, you can still file a suit.

[00:51:23] Speaker 06:
Yeah, but you lose the key that the statute provides you.

[00:51:27] Speaker 00:
But you potentially get trouble damages, of course, under 35 USC 284.

[00:51:31] Speaker 00:
I mean, this is not a statute that is set up or in which Congress contemplated there would be the sort of gamesmanship that FDA is being accused of engaging in.

[00:51:41] Speaker 07:
Here, the- What significance is it?

[00:51:45] Speaker 07:
I thought I saw on the record that the mutual data was public.

[00:51:51] Speaker 07:
It wasn't proprietary in the sense it wasn't confidential.

[00:51:56] Speaker 07:
Does that have anything, have any relevance to any of the questions that are before us?

[00:52:03] Speaker 07:
A, is that correct?

[00:52:05] Speaker 07:
And B, if it is correct, does it have any relevance to any of the issues before?

[00:52:09] Speaker 00:
So the answer to your first question is yes, that's correct.

[00:52:12] Speaker 00:
The answer to the second question, I think, is no.

[00:52:14] Speaker 00:
Because in terms of investigations,

[00:52:18] Speaker 00:
If HICMA had relied on Colchris's studies, it would be relying on the published results of those studies, not on sort of the underlying trade secret data.

[00:52:32] Speaker 00:
And so while it might be an easier case for us, Your Honor, if I accepted that distinction, I don't think that it's one that operates here.

[00:52:42] Speaker 00:
Your honor, you asked me a question earlier, and I fear we've gone away from it, about reliance and about how it can be that FDA said the word culchris so many times and yet did not rely on it.

[00:52:53] Speaker 00:
And again, as I think the explanation of the DDI, the drug-drug interaction studies, has gotten some way to explaining

[00:53:01] Speaker 00:
What FDA considered here was what the appropriate regulatory approach, not just for HICMA's product and HICMA's label, but for Takeda's product and the Colchris label, was in light of all of the information that it had before it about drug-drug interaction.

[00:53:19] Speaker 00:
But FDA nonetheless concluded

[00:53:21] Speaker 00:
as within its authority and expertise to do, that the four corners of HICMA's application contain sufficient evidence for approval and that the mutual study didn't rebut it.

[00:53:32] Speaker 00:
For instance, if this court were aware of a previously decided case in the same area and distinguished it, you wouldn't naturally say that the court had relied on that distinction in accepting a litigant's argument.

[00:53:46] Speaker 04:
What would we do if we concluded that the FDA was perhaps confused or perhaps wrong in concluding that the only obligation to certify was put on the applicant if the applicant explicitly relied on the reference, in this case, Cochris investigation?

[00:54:14] Speaker 04:
We conclude that the FDA apparently had a misreading of the statute and that that misreading of the statute may have affected

[00:54:23] Speaker 04:
their reasoning as to whether or not they relied or not.

[00:54:27] Speaker 04:
In other words, do you understand the point I'm getting at?

[00:54:30] Speaker 04:
Because we went through this dialogue.

[00:54:32] Speaker 04:
And I think you ultimately did agree that if the FDA explicitly relied on Colchris, then it would be arbitrary and capricious if they had not rejected the application that did not certify.

[00:54:51] Speaker 04:
You agreed to that.

[00:54:53] Speaker 00:
So I want to make sure that my answer preserves the distinction between the affirmative case for approval, the four corners of HICMA's application, and just concluding, as I think Judge Kavanaugh, your line of inquiry suggested earlier, that it is relevant, that it bears on, that it may raise a question about an application.

[00:55:14] Speaker 04:
But if you think, Your Honor, that FDA... If you're with me, suppose we conclude the FDA seems to have a misreading of the statute, concluding that

[00:55:23] Speaker 04:
As long as the applicant didn't rely on material, it's not relevant to a certification.

[00:55:30] Speaker 04:
Contrary to essentially our dialogue, would that affect our reasoning about whether or not the agency did rely?

[00:55:41] Speaker 00:
So, Your Honor, let me try to answer the question this way, and please tell me if I've misunderstood you.

[00:55:45] Speaker 00:
I think the appropriate recourse in that case would be to remand to the agency for a more fulsome explanation of what role exactly the Colchrist data played in its approval of Medigar.

[00:55:59] Speaker 04:
Or what role, in any case, a reliance by the FDA would amount to.

[00:56:07] Speaker 04:
What would be the result?

[00:56:10] Speaker 04:
You can see there'd be a sharp difference between a situation where it doesn't matter how much we, the FDA, look at, no matter how much we rely, as long as the applicant doesn't, there's no obligation to certify.

[00:56:23] Speaker 00:
And, Your Honor, I hope I've made clear that that's not our practice.

[00:56:26] Speaker 00:
It's never been how we understand the statute.

[00:56:27] Speaker 04:
Well, that's the statutory argument that's made in this Court.

[00:56:31] Speaker 00:
Well, we think you're preserving that.

[00:56:33] Speaker 00:
Yes, I'm preserving it.

[00:56:34] Speaker 00:
And I think you don't reach it because again, I mean, here FDA considered the Cochris study results.

[00:56:43] Speaker 00:
to decide whether or not, one, it was appropriate for Colchrist to continue to remain labeled as it was, and two, whether anything about those study results cast doubt on the studies that HICMA itself did.

[00:56:57] Speaker 00:
And again, it were the studies that HICMA itself did.

[00:56:58] Speaker 06:
Isn't the question, could the agency have approved without the Colchrist data?

[00:57:03] Speaker 00:
That is the question.

[00:57:04] Speaker 00:
The answer is yes, and that's a scientific determination.

[00:57:07] Speaker 06:
Well, we don't know that the agency did approve.

[00:57:09] Speaker 00:
Well, the agency's position is that it did approve, and I think that if you look at the Mitigar label, that that just goes to show that that's in fact what happened.

[00:57:17] Speaker 07:
What does 355D1 mean when it says that

[00:57:25] Speaker 07:
that in order to approve an application, you have to show that you've done enough studies to show that the drug is safe for use under the conditions prescribed on the label.

[00:57:45] Speaker 00:
So it means, I think colloquially speaking, that the stack of paper you provide to the agency in support of your application has to be tall enough and has to be detailed enough to support a finding of safety and efficacy.

[00:57:58] Speaker 00:
And remember, HICMA's application had two parts.

[00:58:01] Speaker 00:
It had FDA's prior finding of safety and efficacy with regard to colprobenazid, the combination product that we discussed, the product on which Takeda itself relied.

[00:58:11] Speaker 00:
and HICMA studies to show that the differences between Colprobenicid and Mitigar didn't undercut the conclusion that Mitigar was safe and effective for use to prevent gout.

[00:58:26] Speaker 00:
And so what D1 says, if you don't include all of those investigations in your submission to the secretary, the tests are not adequate to show that the drug is safe for use under the conditions in your label, that is grounds for refusing the application.

[00:58:41] Speaker 07:
I guess what I'm trying to understand is, because there are other provisions in the same statute that says if your label is false or misleading, then your application will be rejected, right?

[00:58:54] Speaker 07:
So the Secretary has two choices if they think that the label that has been proposed by an applicant

[00:59:02] Speaker 07:
doesn't say everything that it needs to say in order to conclude that the medication will be safe to the public.

[00:59:11] Speaker 07:
It could say your application is rejected or it could say change the label to include this language.

[00:59:21] Speaker 00:
Yes.

[00:59:22] Speaker 07:
Both of those outcomes are permitted or either one of those is you have to do one of those two things to comply with this statute, right?

[00:59:34] Speaker 00:
Yes, that's right.

[00:59:35] Speaker 07:
So if you tell an applicant, you have to change your label in order for us to approve this drug and you have to add these three words.

[00:59:48] Speaker 07:
And those three words were based on data from a competitor's product.

[00:59:58] Speaker 07:
Has the agency relied upon that data for approval of the label?

[01:00:05] Speaker 00:
So what's happened then is the agency has said, you, applicant, must amend your application to include the studies that would support those three words.

[01:00:16] Speaker 00:
And if those studies are product-specific, if those studies deal with some identified drug that is protected by a patent, you have to provide an appropriate certification.

[01:00:29] Speaker 00:
And so I guess, Judge Silberman, going back to the point where we started earlier, this may be in practice why the scenario that you posit hasn't come up, because FDA simply has no need to backfill a deficient application.

[01:00:44] Speaker 00:
Its response is instead to say to the applicant, who is the master of his application, look, we don't think we have enough information to approve your product.

[01:00:53] Speaker 06:
That's what they say should have happened here.

[01:00:56] Speaker 00:
That's what they say should have happened here.

[01:00:58] Speaker 00:
But again, it was FDA's scientific judgment that the application within its four corners contained enough evidence for Mitigar to be approved to prevent gout as labeled safely and effectively.

[01:01:08] Speaker 06:
And the oddity, then, is all the citations.

[01:01:12] Speaker 00:
Yes, the oddity is the citations.

[01:01:13] Speaker 06:
Because that does.

[01:01:15] Speaker 06:
And if we cite something 246 times, we've probably relied on it.

[01:01:18] Speaker 06:
Well, but here again, Your Honor, it's and I. That's too simplistic, but just as that's their point.

[01:01:24] Speaker 00:
That is their point.

[01:01:24] Speaker 00:
But I mean, it's it's it's important to realize with apologies how simplistic that point is, because the thing that necessarily cited it is is what your point is.

[01:01:35] Speaker 00:
No, it's not that we unnecessarily cited it.

[01:01:37] Speaker 06:
If it was not unnecessarily cited, why was it cited?

[01:01:43] Speaker 00:
I would love to talk about this.

[01:01:46] Speaker 00:
Many of the citations to Colchris, as we've discussed earlier, have nothing whatever to do with the Colchris studies.

[01:01:52] Speaker 00:
Now, let's tackle sort of the next tranche of citations, which are instances where FDA's Office of Description Drug Promotion used the word Colchris in its review of the proposed Mitigar label.

[01:02:04] Speaker 00:
Remember, Colchris and Mitigar rest on a common body of published information that preexisted either product.

[01:02:13] Speaker 06:
So, for instance... Wasn't the key that it was toxic?

[01:02:17] Speaker 00:
Again, that is something that was reflected in the published literature that predated either Colchris or Colprobenicid.

[01:02:24] Speaker 00:
And so quite appropriately, FDA said things like on JA-882, which is a citation that Takeda pulls out.

[01:02:33] Speaker 00:
This is the won't be from westwards data quote.

[01:02:36] Speaker 00:
If you look at the part of the label, and it's actually on 873, just because of how the track changes are displayed, what won't be from Westward's data, FDA is saying, is that toxicity has been reported.

[01:02:52] Speaker 00:
And it cross-references section 12.2 of the label where published case reports are discussed.

[01:02:59] Speaker 00:
And of course, FDA is perfectly right.

[01:03:01] Speaker 00:
that the toxicity information will not be from the studies of the four enzyme inhibitors that HICMA performed to bridge the gap between the old product and the new one.

[01:03:11] Speaker 00:
It will be from the literature that supported the finding of safety and efficacy for the old product in the first place.

[01:03:17] Speaker 00:
Similarly, at J8-59, 861 to 863 and 887,

[01:03:21] Speaker 00:
These are places where Takeda says we've relied because we identify the Colchris label as a comparator.

[01:03:27] Speaker 00:
The Office of Prescription Drug Control said, well, this is a comparator where it's applicable, and the comparison that it was making was unrelated to the Colchris

[01:03:36] Speaker 00:
studies.

[01:03:37] Speaker 00:
It was instead about, for instance, the side effects of colchicine include diarrhea and vomiting.

[01:03:42] Speaker 00:
This was not new information.

[01:03:44] Speaker 00:
And FDA quite permissibly and prudently thought that two labels that rest on a common body of literature should both reflect that literature consistently.

[01:03:55] Speaker 04:
Basically your argument is this, as I understand it.

[01:03:59] Speaker 04:
Even if the FDA honestly believed there was enough

[01:04:06] Speaker 04:
information either outside of Colchris or in the presentation that Mitigair presented.

[01:04:16] Speaker 04:
Even if they thought there was enough there to approve the application without any requirement of a certification, it would have been inappropriate not to look at the Colchris material anyway.

[01:04:30] Speaker 04:
which even if you weren't, even if you made a conclusion that you didn't need to rely on it, you'd still want to look at it.

[01:04:37] Speaker 04:
Is that your point?

[01:04:38] Speaker 00:
Your Honor, I think that's one of the points we're making, and particularly where there had been a citizen petition filed by Mutual arguing that Colchris is the sort of cornerstone, and must be the cornerstone, of any future application for a single ingredient colchicine product

[01:04:54] Speaker 00:
It's quite appropriate for FDA to consider whether what it's doing in one case is consistent with what it's done in another.

[01:05:01] Speaker 00:
But that is not reliance on the Colchris studies.

[01:05:05] Speaker 00:
It's not reliance on the studies that showed for drug-drug interaction purposes that you could split the tablet in half and resolve some concerns.

[01:05:13] Speaker 00:
It's not reliance on studies for the agree trial, which, of course, as is undisputed here, was not necessary for Colchris to be approved to prevent gout in the first place.

[01:05:21] Speaker 06:
But it is relying if you're using it as additional information to support your conclusion.

[01:05:28] Speaker 00:
But Your Honor, again, the statute reliance talks about the affirmative case for approval, and it only makes sense that it does.

[01:05:35] Speaker 06:
Because when an applicant... Suppose we cite five reasons for our conclusion, and we don't say what would happen if we only had three of those reasons, but we cite all five.

[01:05:48] Speaker 06:
Have we relied on all five?

[01:05:50] Speaker 00:
Well, the hypothetical here is a little bit different.

[01:05:52] Speaker 00:
In my hypothetical, I am citing five reasons for my conclusion.

[01:05:56] Speaker 00:
And you are saying, well, I could imagine reason six, but reason six wouldn't be inconsistent with anything that you've said.

[01:06:03] Speaker 00:
So you know what?

[01:06:04] Speaker 00:
You've made your case.

[01:06:05] Speaker 00:
Reasons one through five persuade us that you have made an argument in favor of safety and efficacy for your product.

[01:06:13] Speaker 00:
And so on the basis of your argument alone, we are approving it.

[01:06:17] Speaker 06:
That's, well, I think we're disagreeing on what six is, but anyway, that's probably neither here nor there.

[01:06:23] Speaker 00:
Well, so let me take a step back and explain why it makes sense to think of one through five and six in this way.

[01:06:29] Speaker 00:
Again, the fundamental trade-off that Hatch-Wax and Men made was between competition and research and innovation.

[01:06:36] Speaker 00:
If it were the case that an applicant who is taking the time and investing the money to perform these gap-bridging studies

[01:06:45] Speaker 00:
had no way to expect whether at the end of the day FDA would come up with something out of the blue that might require a certification to a different drug product that the applicant had no reason to believe they were relying on.

[01:06:58] Speaker 00:
Indeed, they didn't expect that they were relying on.

[01:07:01] Speaker 00:
That would not be consistent with the quid pro quo that is at the foundation of the statutory scheme.

[01:07:07] Speaker 00:
it would mean that rather than the applicant, the one who is making the choice to do its own research, to put forward its own drug to compete in the market, would have very little ability to predict how its application would be digested and to assess whether or not its investigations would win out in the end.

[01:07:32] Speaker 07:
And isn't it, isn't it further support for that argument that when Colchrist submitted its application for the prophylactic indication, they didn't do any new studies to support that paper NDA, right?

[01:07:49] Speaker 07:
They just relied on the published literature from the Cole, Probenicid, and whatever else was out there, right?

[01:08:00] Speaker 00:
Yes, and they did their own drug-drug interaction studies.

[01:08:03] Speaker 07:
Was that to support that application or was that used for the acute gout indication?

[01:08:11] Speaker 00:
So the agree trial was used for the acute gout indication, and it may be that the drug-drug interaction studies also supported the acute gout indication.

[01:08:22] Speaker 07:
I mean, that was my understanding of the record.

[01:08:25] Speaker 07:
So I guess my point is that it would support your argument that if they can get their drug approved based on coal perbinacid and whatever else was in the public domain,

[01:08:41] Speaker 07:
Why couldn't HICMA do the same thing?

[01:08:47] Speaker 00:
That is our argument, and Takeda's response to that argument is that FDA has a rule about choosing the most similar or the most appropriate product, and that after Colchris was approved, that it should have been true.

[01:09:01] Speaker 00:
that it was more similar to a single ingredient capsule than the old combination drug.

[01:09:09] Speaker 00:
And for the reasons we explain in our brief, that's not FDA's policy.

[01:09:13] Speaker 00:
That's not a policy that we've ever maintained with respect to pharmaceutical alternatives.

[01:09:18] Speaker 00:
And a pharmaceutical alternative is a different, among other things, a different dosage form.

[01:09:23] Speaker 00:
And so, Your Honor, you articulate our point exactly correct, and I only want to make sure that I explain why the only possible response to that point, which is the one that Takeda makes, doesn't apply to drugs of this kind.

[01:09:40] Speaker 00:
Again, drugs that are different in dosage forms, drugs that are not either identical or pharmaceutical equivalent.

[01:09:47] Speaker 00:
And to the extent, going back to the pages 832 to 838 in the record where FDA evaluates the 505b2 application,

[01:09:56] Speaker 00:
To the extent Takeda's argument is that FDA should have decided what other drug was most similar and reached its finding of safety and efficacy in accordance with that, FDA concluded it didn't need to.

[01:10:08] Speaker 00:
And that was as a matter of its scientific judgment, and that judgment is entitled to different.

[01:10:11] Speaker 06:
Why don't we hear from Mr. Klein?

[01:10:13] Speaker 06:
Thank you very much.

[01:10:31] Speaker 03:
Thank you, and may it please the court, Charles Klein for the interveners.

[01:10:35] Speaker 03:
I'd like to start, if I may, with the argument by Takeda's counsel that HICMA's label makes no sense without the culpris data.

[01:10:44] Speaker 03:
I believe they said that was their strongest argument.

[01:10:46] Speaker 03:
It is just not true.

[01:10:49] Speaker 03:
HICMA's label comes entirely, the label we're talking about, the portion of the label we're talking about is the portion discussing drug-drug interactions that says reduce the dose, avoid it, if necessary reduce the dose and monitor.

[01:11:02] Speaker 03:
That comes entirely from the literature.

[01:11:04] Speaker 03:
That's exactly what FDA repeatedly said in the record.

[01:11:10] Speaker 03:
And in particular, and this was noted briefly by the Department of Justice, but on JA776,

[01:11:20] Speaker 03:
FDA does talk about how the literature disclosed that you avoid when possible and use caution when necessary with vigilant monitoring for clinical signs of toxicity.

[01:11:35] Speaker 03:
That comes from the literature.

[01:11:37] Speaker 03:
More importantly, this discussion cites in footnote four an article called Tetesky, I don't know if I pronounced it correctly, from 1997.

[01:11:47] Speaker 03:
It's not in the record, but I'd be happy to provide it to the court.

[01:11:51] Speaker 03:
And that article repeats virtually, it's almost identical to what is in HICMA's label.

[01:11:57] Speaker 03:
It talks about how when you have two drugs that are known inhibitors of this P450,

[01:12:06] Speaker 03:
it's likely to cause toxicity and therefore it may necessitate dose reduction and careful monitoring.

[01:12:16] Speaker 03:
And then it specifically talks about colchicine and says the use of drugs, these types of drugs in combination with colchicine should be avoided, but in

[01:12:28] Speaker 03:
In case their administration is unavoidable, extra care should be exercised, and the patients should be followed closely for the development of excessive colchicine effects.

[01:12:38] Speaker 03:
That is exactly what is in HICMA's label.

[01:12:41] Speaker 03:
HICMA's label does not rely in any way, shape, or form on any culchris investigation.

[01:12:47] Speaker 04:
And I think... Well, what significance do you give to the alert that the FDA put out after Cochras did the studies and showed that certain inhibitors were combined with the culture chain were particularly dangerous?

[01:13:04] Speaker 03:
Well, that, too, was in the literature.

[01:13:06] Speaker 04:
The literature disclosed that... Well, and why did, if it was strictly in the literature, why did the FDA, based on the Cochras,

[01:13:17] Speaker 03:
uh... material put out the alert because the alert talked about the caucus investigations and that's the term from the statute want to be very clear about what those investigations were they were very specific there two of them the first one the the first caucus investigation

[01:13:33] Speaker 03:
concerned specific reduced colchicine doses when combined with these other drugs.

[01:13:40] Speaker 03:
The only thing that Takeda did that wasn't already done was come up with specific dosing.

[01:13:46] Speaker 03:
Right.

[01:13:47] Speaker 03:
Right.

[01:13:48] Speaker 03:
Reduced doses.

[01:13:49] Speaker 03:
Reduced specific reduced colchicine doses, which most of the time is half a tablet, which wouldn't even apply to Medigar.

[01:13:56] Speaker 03:
And the other investigation we're talking about here is a specific dosing regimen, three pills in an hour, to treat an acute flare.

[01:14:05] Speaker 03:
That's it.

[01:14:06] Speaker 03:
That's the investigations we're talking about.

[01:14:09] Speaker 03:
They are very specific to dosing.

[01:14:12] Speaker 03:
None of that dosing

[01:14:13] Speaker 03:
is in HICMA's label.

[01:14:14] Speaker 03:
HICMA's label just says, reduce the dose without any specific instructions and monitor carefully, especially because you can't give, it wouldn't make sense to take the culchris label and put it in the mitigar label because you can't take half a capsule.

[01:14:30] Speaker 03:
And as a practical matter, the doctors aren't co-administering these drugs, that's what the Federal Circuit and Judge Robinson said, because it's dangerous to do so.

[01:14:41] Speaker 03:
And so that's why the label, the HICMA label says, avoid it if at all possible.

[01:14:46] Speaker 03:
And it's almost always possible to avoid, because there are alternatives to colchicine and these other drugs.

[01:14:52] Speaker 03:
And then they say, if it's really not possible to avoid, just be very, very careful.

[01:14:58] Speaker 03:
Monitor carefully.

[01:14:59] Speaker 03:
And you don't want specific dosing.

[01:15:01] Speaker 03:
In in the HICMA label because number one you can't take half a tablet and number two Toxicity turns on the particular drug that's being combined with colchicine and the particular patient So too and this is what FDA discussed.

[01:15:18] Speaker 03:
Wait a minute.

[01:15:19] Speaker 03:
I'm a little confused.

[01:15:20] Speaker 04:
Yours was a tablet No, ours was the capsule yours was a capsule.

[01:15:24] Speaker 04:
So why do you keep saying you can't take half a tablet?

[01:15:27] Speaker 03:
You can take half a tablet.

[01:15:29] Speaker 03:
You can take half, I'm sorry, if I said half a tablet, I misspoke.

[01:15:33] Speaker 03:
I meant you can't take half a capsule.

[01:15:34] Speaker 03:
I thought you were at it backwards.

[01:15:35] Speaker 03:
I apologize, right.

[01:15:36] Speaker 03:
So Takeda's label says take half a tablet.

[01:15:39] Speaker 03:
Right.

[01:15:40] Speaker 03:
You can't take half of the Midgar capsule.

[01:15:43] Speaker 03:
I know I am.

[01:15:43] Speaker 03:
I misspoke.

[01:15:45] Speaker 03:
All right.

[01:15:46] Speaker 03:
OK.

[01:15:47] Speaker 03:
And so it wouldn't make sense to put that type of sensitivity.

[01:15:50] Speaker 04:
You have to be old enough to know how you deal with capsules and tablets.

[01:15:55] Speaker 03:
Right.

[01:15:56] Speaker 03:
Yeah, half a capsule and everything falls out.

[01:15:59] Speaker 07:
Does the label for colprobenicid have any warning, similar type of a warning?

[01:16:06] Speaker 03:
I don't believe there's any type of warning like that in colprobenicid.

[01:16:10] Speaker 03:
The warning comes from the literature.

[01:16:13] Speaker 03:
It doesn't come from any culchris investigation.

[01:16:18] Speaker 03:
In terms of

[01:16:21] Speaker 03:
The reliance that, and we heard 246 times, Culchis was mentioned.

[01:16:27] Speaker 04:
Well, what FDA did- Will you concede as well as I think the FDA grudgingly conceded, if the FDA feels that it has to rely on its own material, that it must, as a matter of law, send back the application?

[01:16:45] Speaker 04:
I do agree.

[01:16:46] Speaker 04:
That's under D1.

[01:16:47] Speaker 04:
So the way the process would work.

[01:16:49] Speaker 04:
So all this talk about reliance refers to the applicant is it really an irrelevant argument?

[01:16:57] Speaker 03:
Well, it's relevant in this sense, Your Honor.

[01:17:01] Speaker 03:
The statute talks about reliance by the applicant on investigations.

[01:17:05] Speaker 03:
So you look at what the applicant relied upon.

[01:17:07] Speaker 03:
If the applicant's, if what the applicant relied upon is not sufficient for approval.

[01:17:12] Speaker 04:
But basically all I'm saying is that petitioners are correct.

[01:17:14] Speaker 04:
in so far as they argue that if the FDA relies on calculus material

[01:17:20] Speaker 04:
then it violated the APA in this case.

[01:17:25] Speaker 03:
Well, if FDA had relied upon the material, then it would be a question as to whether the application should have been rejected under D1.

[01:17:34] Speaker 03:
And that's a scientific determination.

[01:17:36] Speaker 03:
Wait a minute, wait a minute, wait a minute.

[01:17:37] Speaker 04:
If they had relied, if they, being the FDA, had relied, you agreed it would have been a violation of the APA.

[01:17:46] Speaker 03:
If they had to if they had to if the information was necessary for approval and the information it was submitted was insufficient FDA should have rejected required the paragraph for certification or required some other

[01:18:02] Speaker 04:
That's correct.

[01:18:02] Speaker 04:
So that really gets rid of 90 percent of some of the arguments that were presented in this case.

[01:18:07] Speaker 03:
Well, but the key issue here is when FDA found that HICMA's application was sufficient, that's a scientific determination entitled to the highest level of data.

[01:18:16] Speaker 06:
Absolutely.

[01:18:18] Speaker 06:
If there were no citations to Colchris, we probably wouldn't be here.

[01:18:22] Speaker 06:
That's the point.

[01:18:23] Speaker 06:
It really comes down to what does relied on mean.

[01:18:26] Speaker 06:
Well, relied on... As applied to a set of facts where it's cited all over the place.

[01:18:31] Speaker 03:
And I think a good analogy would be when this court issues an opinion and distinguishes a case, the court is not relying on the case, it distinguishes to support the conclusion in the opinion, even though the case is mentioned in the opinion.

[01:18:46] Speaker 07:
And that's what... Trying to act like what we do is science.

[01:18:51] Speaker 03:
Yeah.

[01:18:51] Speaker 03:
But that's what happened here.

[01:18:52] Speaker 03:
In fact, what FDA did is exactly what Takeda says FDA should do.

[01:18:57] Speaker 03:
It addressed its prior citizen petition ruling.

[01:19:01] Speaker 03:
FDA said- What about the regulation?

[01:19:03] Speaker 03:
Okay.

[01:19:04] Speaker 03:
I'm happy to talk about the regulation.

[01:19:05] Speaker 06:
The regulation- And also circle back after you do that to the word distinguish.

[01:19:11] Speaker 06:
I want to focus on that.

[01:19:12] Speaker 04:
But do the regulation- No, no, no.

[01:19:14] Speaker 04:
I'll let the presiding judge-

[01:19:16] Speaker 04:
How are you using the word distinguish?

[01:19:20] Speaker 06:
Why are you saying, what does that mean in your terminology?

[01:19:24] Speaker 06:
Because that was a key term you just used.

[01:19:25] Speaker 06:
If you are just distinguishing, what do you mean by distinguish?

[01:19:29] Speaker 03:
Well, there's a prior citizen petition ruling out there that said under the hypothetical before FDA at the time, if you had the caucus label and you redacted out the acute flare indication, would that be safe?

[01:19:42] Speaker 03:
And FDA said at that time, based on that label, well, that would raise safety concerns.

[01:19:48] Speaker 03:
Well, now it was presented with a different label and a different application.

[01:19:52] Speaker 03:
And so FDA did what it should do.

[01:19:55] Speaker 03:
It looked at its prior citizen petition ruling and say,

[01:19:58] Speaker 03:
The situation we now have is different and what is in the HICMA label is okay because it talks about how you shouldn't, the product's not approved for flares.

[01:20:12] Speaker 03:
We haven't conducted safety tests as to whether there'd be toxicity if you took it to take flares when you're taking it as a prophylactic.

[01:20:20] Speaker 03:
If you have a flare, consult your health care provider.

[01:20:23] Speaker 03:
And by the way, the maximum daily dose is 1.2 million.

[01:20:26] Speaker 06:
I don't know why, and we're going to get to the regulation, but why we should be doing this triple bank shot analysis here when parsing this, what they—it's cited a lot.

[01:20:38] Speaker 06:
It looks, in the common parlance, like something you would say is reliance.

[01:20:43] Speaker 06:
The agency could go back and tell us, no, actually, no.

[01:20:49] Speaker 06:
It's totally unnecessary to any of the Colchrist data.

[01:20:54] Speaker 06:
And you're saying that's a waste of time, but I'm saying that's a hard, that's hard for us to do at this point, I think.

[01:21:00] Speaker 03:
Well, actually, what I'm saying is FDA did say that in the record in JA 899, JA 773.

[01:21:07] Speaker 06:
But they also have all the other information.

[01:21:11] Speaker 06:
That's the problem.

[01:21:12] Speaker 06:
I mean, I guess that's the point is we don't know what relied on means as applied to this set of facts, given all the information in the record.

[01:21:20] Speaker 03:
Well, but ultimately, it's a scientific determination.

[01:21:25] Speaker 03:
FDA said in the record it approved HICMA's application based on what HICMA had provided.

[01:21:29] Speaker 03:
That's a scientific determination.

[01:21:31] Speaker 03:
So as long as there's a rational basis in the record, this court has to affirm.

[01:21:37] Speaker 03:
I mean, in fact, the court has said scientific determinations are entitled to the highest level of deference under the APA.

[01:21:43] Speaker 03:
All right, now I'll get to the regulation.

[01:21:44] Speaker 04:
Now for the regulations.

[01:21:45] Speaker 04:
The regulation on its face seems to support petitioners, doesn't it?

[01:21:49] Speaker 04:
No, I disagree.

[01:21:50] Speaker 04:
I know you like the use of the word apical.

[01:21:55] Speaker 03:
Let me take it from a different approach.

[01:21:58] Speaker 03:
I wouldn't be surprised.

[01:21:58] Speaker 03:
314.50 I1 Romanet 1 combined with Romanet 3 is implementing 505b2.

[01:22:13] Speaker 03:
And let me explain why.

[01:22:16] Speaker 03:
I'll just call Romanet 1, and hopefully we know we're on the same page.

[01:22:20] Speaker 03:
Romanet 1 is defining the types of patents that may require certification.

[01:22:26] Speaker 03:
And it talks about a patent that claims the drug, and there's no dispute that the reg and the statute are talking about a drug product here, like Colchris, or claims an approved use for such drug, referring back to the same drug product that's relied upon for approval.

[01:22:42] Speaker 03:
What the regulation doesn't say in Romanet 1 is what's in the statute in 505B2A, which when it talks about use patents, says use for such drug for which the applicant is seeking approval under this subsection.

[01:22:59] Speaker 03:
That language from 505B2A is not in Romanet 1.

[01:23:04] Speaker 03:
That language is

[01:23:07] Speaker 03:
In the beginning of the regulations?

[01:23:11] Speaker 03:
Well, it's in the Romaneth... No, it's the opposite.

[01:23:13] Speaker 03:
It's in Romaneth 3b.

[01:23:16] Speaker 03:
Okay, so this is how it works.

[01:23:18] Speaker 03:
It's a little convoluted.

[01:23:19] Speaker 03:
But Romaneth 1 says this is the universe of patents you may have to worry about.

[01:23:25] Speaker 03:
Patents covering the drug you relied upon or patents covering a use for the drug that you relied upon.

[01:23:34] Speaker 03:
And then you go to Romanet 3, which deals with method of use patents.

[01:23:38] Speaker 03:
And method of use patents can be complicated because, as Romanet 3A and B say, you now look to whether the applicant's seeking approval for the use.

[01:23:49] Speaker 03:
If the applicant's seeking approval for the use claimed by the method patent that's associated with the listed product, you have to certify to it.

[01:23:58] Speaker 03:
But if the applicant isn't seeking approval for that use, you just need a statement.

[01:24:03] Speaker 03:
And that's what Romanet 3 is doing.

[01:24:06] Speaker 03:
That's the role it's playing.

[01:24:07] Speaker 03:
It's not superfluous.

[01:24:08] Speaker 03:
It's implementing 505B2.

[01:24:12] Speaker 03:
A, when 505B2 says you have to certify to a patent which claims a use for such drug for which the applicant is seeking approval.

[01:24:22] Speaker 07:
Now your brother colleague from Elliott says that they are claiming or seeking to approval for the same use because you just look at the category in the orange book.

[01:24:36] Speaker 07:
Your response to that is

[01:24:38] Speaker 03:
Well, you start with, remember, Romanet 1 defines the universe of patents you have to worry about.

[01:24:44] Speaker 03:
And you only, if you're the applicant, you only need to worry about patents that are associated with the listed drug.

[01:24:50] Speaker 03:
And so, because HICMA relied solely on Colprobenicid, it did not have to certify to any patents, because there are no patents associated with that drug.

[01:25:03] Speaker 03:
You do not have to go through the entire orange book.

[01:25:07] Speaker 03:
So your argument is different than the government's argument on this.

[01:25:10] Speaker 04:
This is interesting.

[01:25:11] Speaker 03:
OK.

[01:25:12] Speaker 03:
I think we're essentially saying the same thing.

[01:25:14] Speaker 03:
It's consistent.

[01:25:15] Speaker 03:
No, no.

[01:25:15] Speaker 03:
No, it's a different argument.

[01:25:16] Speaker 03:
OK.

[01:25:17] Speaker 03:
It is.

[01:25:19] Speaker 03:
It is a different approach, I'll give you that.

[01:25:23] Speaker 03:
But I think it's also interesting that the industry on both sides all agrees with FDA on this.

[01:25:31] Speaker 03:
Takeda is not arguing that you have to go through the entire orange book.

[01:25:35] Speaker 03:
Pharma, which Violet Amicus isn't arguing that.

[01:25:39] Speaker 03:
The generic association isn't arguing.

[01:25:41] Speaker 03:
that this is the way it's always worked, this is the way the industry understands it works.

[01:25:46] Speaker 03:
What about Elliott?

[01:25:47] Speaker 03:
Don't you see they have a broader argument?

[01:25:49] Speaker 03:
They're not the industry, they are investors.

[01:25:54] Speaker 03:
So they don't have the same credibility in this court?

[01:25:58] Speaker 03:
No, I am by no means suggesting that.

[01:26:01] Speaker 03:
What I am suggesting is that those parties who are in the pharmaceutical industry all agree on how the statute works, and there's a quid pro quo.

[01:26:10] Speaker 03:
If you rely on another product for approval... That's why investors are around, because they can...

[01:26:18] Speaker 04:
at a comparative advantage.

[01:26:21] Speaker 03:
And I've nothing against investors at all.

[01:26:23] Speaker 03:
Oh, I'm glad to hear that.

[01:26:25] Speaker 03:
But they're not part of the quid pro quo.

[01:26:28] Speaker 03:
The quid pro quo is if you rely on another party's product for approval, you have to certify to that other party's patents.

[01:26:36] Speaker 03:
And there's a huge benefit.

[01:26:38] Speaker 03:
Because the quid pro quo here is that if the applicant's relying on data that's not theirs, well, then the patentee now can get a 30-month stay.

[01:26:47] Speaker 03:
It's a free injunction.

[01:26:48] Speaker 03:
It's an injunction that the Federal Circuit in this case said Takeda is not even entitled to.

[01:26:53] Speaker 03:
And so it's a huge benefit to invoke this quid pro quo, and it's tied to the listed drug.

[01:26:58] Speaker 03:
Well, the Federal Circuit is not deciding the same issue, are they?

[01:27:02] Speaker 03:
You mean the issue before this Court?

[01:27:04] Speaker 04:
No, the Federal Circuit decided the patent issue.

[01:27:06] Speaker 04:
Right.

[01:27:08] Speaker 04:
And if we thought the FDA had behaved arbitrarily and capriciously, the Federal Circuit's decision would not be relevant.

[01:27:18] Speaker 04:
I disagree because... Explain that.

[01:27:21] Speaker 03:
Well, because let's say hypothetically that this court were to rescind approval and then it goes back to the agency and then HICMA makes a paragraph four certification.

[01:27:33] Speaker 03:
Because of the Federal Circuit ruling, Takeda could not in good faith bring a lawsuit that HICMA's label induces infringement of the patents.

[01:27:43] Speaker 03:
The Federal Circuit already said, no, it doesn't.

[01:27:45] Speaker 03:
You're not entitled to an injunction.

[01:27:48] Speaker 06:
And in fact, just a couple weeks ago... Just to clarify, the 30-month period goes away, then?

[01:27:53] Speaker 03:
The 30-month period goes away upon a judgment of dismissal, and there hasn't yet been a judgment of dismissal.

[01:28:01] Speaker 06:
That was in a P.I.

[01:28:02] Speaker 06:
posture.

[01:28:03] Speaker 03:
That was in a P.I.

[01:28:03] Speaker 03:
but, yes, it was in a P.I.

[01:28:06] Speaker 06:
posture, but... And then it goes up in a P.I.

[01:28:08] Speaker 06:
posture of the Federal Circuit, and it's a 2-1 decision, right?

[01:28:11] Speaker 03:
That's correct, but the issue, the key issue is whether the label induces infringement of the patents, the contents of the label is undisputed.

[01:28:20] Speaker 03:
The label hasn't changed.

[01:28:22] Speaker 03:
And yes, it was in the PI posture, but this type of inquiry, whether a label induces infringement, is decided as a matter of law.

[01:28:29] Speaker 03:
So, technically, yes, it's in the P.I.

[01:28:31] Speaker 03:
context, but just a couple weeks ago, at the motion to dismiss hearing before Judge Robinson in Delaware, Takeda's counsel conceded that the approved Mitigar label, I'm sorry, this is what Takeda's counsel said, your honor and the Federal Circuit decided the label was not enough and that the label- Well, that's, keep going.

[01:28:51] Speaker 03:
Oh.

[01:28:52] Speaker 06:
I'm just going to say, a statement by counsel about the Federal Circuit in a P.I.

[01:28:56] Speaker 06:
posture, I'm not sure this is going to be binding, but go ahead.

[01:28:59] Speaker 03:
Well, no, I'll get to the point.

[01:29:02] Speaker 06:
It's a good gotcha, but I don't think it gets you very far, but go for it.

[01:29:05] Speaker 03:
Well, no, I do think it gets us to the point where what's the remedy here?

[01:29:10] Speaker 03:
It would be pointless to rescind.

[01:29:12] Speaker 06:
Not until there's a final Federal Circuit judgment, right?

[01:29:15] Speaker 06:
Well, no, because if it's, right now the issue, the only reason there's no... What if the Federal Circuit reaches the, we've done this, reach one conclusion about the law on a P.I.

[01:29:23] Speaker 06:
and reach the opposite conclusion when it comes in for the merits?

[01:29:27] Speaker 06:
That's, I mean, it's not every day, but it's happened.

[01:29:30] Speaker 03:
Well, but the issue now before the district court is really about whether there's some off-label market.

[01:29:35] Speaker 03:
That's the only reason there's no judgment.

[01:29:38] Speaker 03:
So Takeda amended its complaint and is now alleging that HICMA is taking certain conduct apart from its label that is inducing infringement.

[01:29:47] Speaker 03:
Right.

[01:29:48] Speaker 03:
And that's why there hasn't been a judgment.

[01:29:50] Speaker 06:
But that type of... The judgment would be the... Let me just make sure I understand and correct me if I'm wrong.

[01:29:55] Speaker 06:
The judgment would be the final judgment on appeal, correct?

[01:29:58] Speaker 03:
No, no district court judgment defeats the stay and so there's a motion to dismiss pending and Judge Robinson said she may rule by the end of this month So even if the if you get us and the question would be if you get a stay of that judgment from the Federal Circuit No, no, no, if the district even if you get a stay of the judgment from the Federal Circuit, that's oh If you get a stay of the judgment

[01:30:22] Speaker 03:
I don't know.

[01:30:22] Speaker 03:
I mean, the way the statute works is if the district court enters a judgment of non-infringement, which is... And there's no stay from them.

[01:30:30] Speaker 07:
Go ahead.

[01:30:30] Speaker 04:
Suppose the district court enters the judgment.

[01:30:32] Speaker 04:
Does that mean this case is moot?

[01:30:35] Speaker 03:
Is that what your argument is?

[01:30:36] Speaker 03:
Well, I would submit if the court, if the district court enters judgment, then the portion of the case, the main portion of the case asking for rescission of approval and a paragraph four certification would be moot because they couldn't get a 30-month stay.

[01:30:49] Speaker 03:
So there'd be no point.

[01:30:50] Speaker 07:
But the portion of the case saying that the label should say more than it does, that wouldn't be moot, right?

[01:30:56] Speaker 03:
That wouldn't be moot, although I would submit the remedy there, if the court were to find a violation, would be to remand back to FDA to explain and provide a justification for its, for HICMA's label in light of the citizen petition ruling.

[01:31:12] Speaker 03:
It wouldn't be, this court is not in a position to tell FDA what to put in HICMA's label.

[01:31:17] Speaker 03:
That's a scientific determination.

[01:31:19] Speaker 03:
That would be for FDA to decide.

[01:31:25] Speaker 06:
You mentioned a document.

[01:31:26] Speaker 06:
Could you provide that to the court?

[01:31:27] Speaker 03:
I'd be happy to.

[01:31:28] Speaker 03:
Thank you.

[01:31:29] Speaker 06:
Thank you.

[01:31:45] Speaker 02:
Give you a couple minutes for a bottle.

[01:31:47] Speaker 02:
Thank you, Your Honor.

[01:31:48] Speaker 02:
Let me start with the regulation, because as you heard, not even FDA and HICMA agree on it.

[01:31:56] Speaker 02:
Let me just start with FDA.

[01:31:59] Speaker 02:
Even today, when you heard the government get up, they did not suggest that its regulation was ambiguous.

[01:32:06] Speaker 02:
And we know, we know that the regulation

[01:32:11] Speaker 02:
3B has an independent duty.

[01:32:14] Speaker 02:
And the reason we know that it has an independent duty is because if you look in the regulations at I-6, which talks about the amended certifications, it talks about how amendments will be made to all certifications done under I-1I through I-1-3.

[01:32:40] Speaker 02:
The notion that HICMA says, well, it's all folded up, and if you don't comply with I1I, you're done, that does render I1-3 superfluous.

[01:32:52] Speaker 02:
That's what they're arguing.

[01:32:58] Speaker 02:
It gives, I-13 gives effect to that portion of the statute that reads, for which the applicant seeks approval.

[01:33:08] Speaker 02:
That does not appear in I-1I, and that's why it does appear in I-13.

[01:33:15] Speaker 02:
Real briefly, I wanted to respond to a couple other points that were made here.

[01:33:21] Speaker 02:
I would respectfully disagree with HICMA's counsel on the industry not agreeing.

[01:33:26] Speaker 02:
What has happened in this situation is we have three generics who are sitting on the sidelines who followed along and filed ANDAs, and they filed ANDAs for the Colchicine product.

[01:33:42] Speaker 02:
If all they had to do was change to a capsule and get on the market like HICMA did,

[01:33:48] Speaker 02:
Why on earth would three generics be sitting on the sidelines after litigating these cases?

[01:33:55] Speaker 02:
The industry does not agree with HICMA.

[01:33:58] Speaker 02:
HICMA is all alone on this issue because this issue of patent certification

[01:34:03] Speaker 02:
has been wrongly handled by the agency and that's why it's got to be sent back.

[01:34:09] Speaker 07:
But the briefs don't support your interpretation of the regulation that have been filed by the amicus.

[01:34:19] Speaker 07:
Either the generics or the brand name, if you want to divide it up like that.

[01:34:27] Speaker 02:
No, respectfully, Your Honor, they didn't address the issue.

[01:34:29] Speaker 02:
I think they were addressing the reliance issue and some of the labeling issues, I think.

[01:34:34] Speaker 02:
But I don't think they addressed the issue of the regulation one way or the other.

[01:34:38] Speaker 02:
Either side did.

[01:34:41] Speaker 02:
I was just bringing to bear this question of, you know, where is the industry on this question, which Hickman's Council raised, and I wanted to give you a full perspective.

[01:34:52] Speaker 04:
The one other point- I don't understand the point about the generics sitting on the sideline.

[01:34:56] Speaker 04:
What is the point you're making about that?

[01:34:58] Speaker 02:
Sure.

[01:35:00] Speaker 02:
The argument that HICMA advances here is that this is the way it's been done for years and years.

[01:35:06] Speaker 02:
There's never been a question until Elliott raised it, and this is the way the industry does it.

[01:35:12] Speaker 02:
They pick a drug, they rely on it, and they certify to those patents, and they ignore everything else.

[01:35:18] Speaker 02:
And the reason I say that the facts in this case and the situation doesn't support that is because there were three other generic companies that all wanted to do exactly what HICMA did.

[01:35:29] Speaker 02:
They wanted to release a generic version of colchicine.

[01:35:34] Speaker 02:
And if they all believed, as HICMA wants you to believe, that you just need to change to a capsule and reference a drug that has no patents on it,

[01:35:43] Speaker 02:
Why would three of the big competition generics not follow in their footsteps if HICMA was right that that's what the industry does?

[01:35:55] Speaker 02:
Well, surely if HICMA wins, they'll be there.

[01:35:58] Speaker 02:
No doubt.

[01:35:58] Speaker 02:
No doubt.

[01:35:59] Speaker 02:
And we fully expect that that would be the case.

[01:36:01] Speaker 06:
I still don't know what that shows.

[01:36:05] Speaker 06:
It shows that HICMA tried a different approach, I'll put it that way, neutrally.

[01:36:12] Speaker 02:
They're a pioneer.

[01:36:13] Speaker 02:
There's no doubt about it.

[01:36:15] Speaker 02:
A different legal approach.

[01:36:17] Speaker 02:
There's no doubt about it.

[01:36:18] Speaker 02:
But that's why I disagree that this is some sort of industry approach that has been going on for years and years and years.

[01:36:25] Speaker 02:
The last quick thing I wanted to mention, Judge Cavanaugh, I believe you mentioned it first, which was, well, what happens when this court reverses or sets aside the agency action, which is what happens?

[01:36:39] Speaker 02:
By the way, we're all talking about section D1.

[01:36:42] Speaker 02:
D6, that same statute, requires that it be set aside if the patent certification hasn't been made.

[01:36:50] Speaker 02:
So that's the other ground that exists as to why

[01:36:53] Speaker 02:
This needs to be set aside in terms of the agency action.

[01:36:58] Speaker 02:
The agency action gets put aside.

[01:37:00] Speaker 02:
The question then, Your Honor asked, was, well, then what happens?

[01:37:03] Speaker 02:
Do we get a 30-month stay?

[01:37:05] Speaker 02:
Do we get litigation?

[01:37:07] Speaker 02:
It will start from, what does HICMA do at that point in time?

[01:37:10] Speaker 02:
If HICMA knows that it has to serve— Does the agency get another crack?

[01:37:13] Speaker 02:
Well, they will get another crack depending upon what HICMA does.

[01:37:17] Speaker 02:
If HICMA decides to pursue this application further, then they're going to have to deal with the certification process.

[01:37:24] Speaker 02:
If they change to a tablet, which wouldn't be surprising, then they're going to have to deal with that certification process.

[01:37:29] Speaker 02:
But what will happen is, remember, the only reason they wanted it, they only wanted the capsule.

[01:37:34] Speaker 04:
No, wait a minute, Counsel.

[01:37:35] Speaker 04:
If we remand it to the agency, hypothetically,

[01:37:39] Speaker 04:
for a better explanation of a number of things, including the regulation.

[01:37:44] Speaker 04:
What is the status quo at that point?

[01:37:46] Speaker 02:
No, if you remanded for a better explanation, then you're right.

[01:37:50] Speaker 02:
The application, HICMA's application would have to stay, and the agency would have to give you a better explanation.

[01:37:55] Speaker 04:
If you reversed... So what would the market situation be?

[01:38:00] Speaker 02:
Well, the market, they would have to remove Mitigar from the market, because it would not be an approved drug at that point.

[01:38:07] Speaker 02:
and then HICMA would be selling an unapproved drug.

[01:38:11] Speaker 07:
So a remand is, for those purposes, the same as vacating?

[01:38:17] Speaker 02:
Right.

[01:38:18] Speaker 02:
It would be vacating, at least temporarily, the agency decision or setting aside that agency decision because there would be no final agency decision approving a drug.

[01:38:28] Speaker 04:
We'll have to ask counsel about that.

[01:38:31] Speaker 02:
I'm happy to answer any other questions the Court may have, either on the regulation or elsewhere.

[01:38:37] Speaker 02:
Okay.

[01:38:38] Speaker 02:
Thank you very much.

[01:38:45] Speaker 01:
If I could make three points, the first on reliance and science, the second on this, the capsule versus tablet business, and then the third on the label.

[01:38:53] Speaker 01:
The first is Judge Silberman, just to close off the original question you asked Government Council, the site you're looking for is Joint Appendix 338, and that's the place where Government Council below said, quote, if FDA had relied,

[01:39:06] Speaker 01:
we would have rejected this application because it would not be complete.

[01:39:10] Speaker 01:
So I think you finally brought government counsel around on that and what she ended up pivoting to was the idea that this was a scientific judgment.

[01:39:18] Speaker 01:
To begin with... What about that?

[01:39:20] Speaker 04:
What about that?

[01:39:23] Speaker 04:
Let's assume hypothetically you have a drug like Colchris and the government really genuinely believes

[01:39:34] Speaker 04:
that it isn't necessary to discuss Cochris.

[01:39:40] Speaker 04:
It's not necessary to rely on it, but we want to discuss it because it is a comparable drug, and we look at it just to see various factors.

[01:39:51] Speaker 04:
But we make a scientific judgment it is not necessary to rely on it.

[01:39:56] Speaker 04:
How can we gainsay that?

[01:39:59] Speaker 01:
I think in the circumstance where you're talking about a general discussion that the FDA engages in about a particular drug substance or an active moiety and how it interacts with other drugs and all of those generalities, you probably couldn't gainsay it.

[01:40:14] Speaker 01:
But the problem is here, what government council omitted to talk about was really the motherload of sites that show that that wasn't just a conversation in the air.

[01:40:25] Speaker 01:
It was a comparison and combination of data.

[01:40:28] Speaker 01:
And those are the sites relating to that all-hands, 50-person FDA meeting.

[01:40:33] Speaker 01:
So, 908, 915 of the Joint Appendix, 928, 929, which is where FDA specifically says the label is not supported by HICMA's data, 930, 933.

[01:40:46] Speaker 01:
All of those talk about the data, not just about Colchris, not just about the fact that there's another Colchicine drug out on the market.

[01:40:53] Speaker 01:
So to the extent that there was a scientific determination that really lies at the bottom of this, as you heard 11 times, it was in part on our science.

[01:41:02] Speaker 06:
But Judge Kavanaugh... They used the word distinguish.

[01:41:04] Speaker 06:
You want to respond to that?

[01:41:06] Speaker 01:
I do.

[01:41:07] Speaker 01:
I think it is impossible to square the idea that this was a mere distinguishment of different data from what the label actually holds for the reason that FDA previously said.

[01:41:18] Speaker 01:
I mean, that's one of the remarkable things about this case is that everything we have to offer you is based on an affirmative statement that FDA made in the record

[01:41:26] Speaker 01:
relating to what the label had to say.

[01:41:29] Speaker 01:
And one of the things that the FDA said was not just that HICMA's data showed something different from Mutual's old data.

[01:41:37] Speaker 01:
It was that you can't reconcile what needs to go on the label with HICMA's data.

[01:41:41] Speaker 01:
So that's not a distinguishing.

[01:41:43] Speaker 01:
That's actually adopting in part the holding of another decision.

[01:41:47] Speaker 04:
In other words, HICMA's data by itself would be inadequate.

[01:41:51] Speaker 04:
Council said, however,

[01:41:53] Speaker 04:
Even if that was true, there was other information out there.

[01:42:00] Speaker 04:
unrelated to Colchris, that would have led to the same modification of the label.

[01:42:07] Speaker 01:
That's right.

[01:42:08] Speaker 01:
I believe what government counsel said was that this was not news.

[01:42:13] Speaker 01:
And I think the FDA, at least as of 2011, would beg to differ, because what the FDA again said in the citizen petition response was, without this review by FDA of the Colchris data,

[01:42:24] Speaker 01:
Outdated assumptions of what is safe and effective for treatment with oral colchicine would have remained unchecked, and patients would have continued to suffer from adverse reactions, such as severe GI complications and even death.

[01:42:36] Speaker 01:
Joint Appendix 479.

[01:42:37] Speaker 01:
Joint Appendix 487.

[01:42:39] Speaker 04:
That was a citizen petition filed by?

[01:42:43] Speaker 01:
No.

[01:42:44] Speaker 01:
No, that was FDA responding.

[01:42:46] Speaker 04:
No, I know.

[01:42:48] Speaker 04:
That was in response to a citizen.

[01:42:50] Speaker 04:
It was.

[01:42:51] Speaker 04:
By whom?

[01:42:52] Speaker 01:
It was in response to a citizen petition by Mutual.

[01:42:55] Speaker 04:
That's what I thought, Mutual.

[01:42:56] Speaker 01:
So this is FDA's statement about Mutual's data, followed by this.

[01:43:00] Speaker 04:
What was prompting, remind me, Mutual's citizen petition?

[01:43:04] Speaker 01:
The mutual citizen petition was filed because when HICMA originally filed its application, what it filed was a 505b2 application, which is this short-form new drug application for a tablet.

[01:43:18] Speaker 06:
For the duplicate.

[01:43:19] Speaker 01:
For the duplicate, for the exact duplicate.

[01:43:21] Speaker 06:
The FDA said you can't do the duplicate through that, and they said, okay, we'll go to the capsule.

[01:43:25] Speaker 01:
Okay, how about a capsule?

[01:43:26] Speaker 01:
Right, and I'd like to get to that in one moment, but just to tie this point off, thank you.

[01:43:31] Speaker 01:
At Joint Appendix 487, what FDA says is the requirements for approval of a single ingredient colchicine product have changed based on the safety concerns identified during review of the Colchris application, Joint Appendix 487.

[01:43:47] Speaker 01:
So the idea that this was not news,

[01:43:50] Speaker 01:
that Colchris's data was not new, that there was nothing to add, that some 1997 article that none of us has seen actually revealed all this is belied by what FDA says.

[01:43:59] Speaker 04:
So is your argument the key evidence of reliance is in the citizen petition rather than in the basic opinion that we have before us?

[01:44:07] Speaker 01:
No, I think it goes to two different strands of what you heard from the government's response.

[01:44:11] Speaker 01:
My argument on reliance is very similar to the question Judge Kavanaugh posed to Council for HICMA, I believe, which is this isn't really a scientific determination.

[01:44:20] Speaker 01:
It's just trying to decide what reliance means.

[01:44:23] Speaker 01:
And what reliance clearly means is when you look at the data and you assess it and you combine it with the data that you got from the other guy and you decide to make a label based on all that data, you've relied.

[01:44:33] Speaker 01:
That's not a scientific determination, nor is it a scientific determination to decide that you're not going to include information that you required be included five years ago.

[01:44:42] Speaker 07:
But if, you know, we've been using hypotheticals based on how courts write opinions, if we write an opinion and we say we're relying on, you know, Marbury v. Madison, but then we have see also five other cases, have we relied on the cases in the see also?

[01:45:06] Speaker 01:
I think you would, I think in those circumstances you would have the best case that you relied on Marbury because that's what you said you were doing.

[01:45:15] Speaker 01:
And a C also is just kind of aggregating additional information around the edges.

[01:45:19] Speaker 01:
Colchris was Marbury versus Madison here, if we're going to draw that analogy.

[01:45:23] Speaker 01:
Colchris was the gorilla in the middle of the room.

[01:45:26] Speaker 01:
That's why they brought 50 people in to talk about it.

[01:45:28] Speaker 06:
Who does that make Chief Justice Marshall then?

[01:45:31] Speaker 06:
The active moiety, Your Honor.

[01:45:35] Speaker 06:
not only could we have approved without the Colchrist data, but we said that we could have approved and would have approved.

[01:45:42] Speaker 06:
So you want to respond to that as well?

[01:45:43] Speaker 06:
I want to make sure you respond to everything they said.

[01:45:45] Speaker 01:
So with respect to could have approved with the Colchrist data, I think without the Colchrist data, here's the problem with that.

[01:45:52] Speaker 01:
What government council is now suggesting is, well, if you let us go back and give us another chance to explain how we could have approved this without the Colchrist data, that ship has sailed.

[01:46:04] Speaker 05:
Why?

[01:46:04] Speaker 05:
Why is that sealed?

[01:46:05] Speaker 01:
Because what this record is based on is the Colchrist data.

[01:46:09] Speaker 01:
So you couldn't just go back and ask for a new explanation.

[01:46:11] Speaker 06:
What you'd have to do is remand, direct vacator, and get— Vacator, but they could go through the same process again, presumably quickly, and conclude without any reference or reliance, no matter how broadly you define it.

[01:46:25] Speaker 06:
on the Colchris data and reach the same bottom line, theoretically.

[01:46:28] Speaker 06:
And then you would argue, actually, that the information in there doesn't support the bottom line.

[01:46:34] Speaker 01:
In comporting with what you said when I first stood up, Your Honor, yes.

[01:46:37] Speaker 01:
That would be the problem with that subsequent conclusion.

[01:46:40] Speaker 01:
The data is necessary.

[01:46:42] Speaker 01:
This wasn't just sort of a chance mistake by FDA.

[01:46:45] Speaker 01:
It was necessary for FDA to reach this conclusion.

[01:46:48] Speaker 04:
You would draw a line between the application

[01:46:53] Speaker 04:
and the label and say, well, the label doesn't make any sense.

[01:46:59] Speaker 04:
If you just look at the application, you have to look at Cochras data to explain the label.

[01:47:05] Speaker 01:
That's correct.

[01:47:06] Speaker 01:
In that hypothetical, that is correct.

[01:47:08] Speaker 01:
I think that is what we would have to do.

[01:47:10] Speaker 04:
So if I can... So if we were inclined to remain, what is your explanation of what the record would look like down below?

[01:47:21] Speaker 01:
So as I put it when I first stood up, I think the proper course would be for this court to reverse and direct summary judgment be entered.

[01:47:31] Speaker 01:
Judge Jackson would then direct— I suppose we didn't quite buy all that.

[01:47:35] Speaker 04:
What intermediate position is there?

[01:47:39] Speaker 01:
Your Honor, with respect to our latter two arguments, the failure to explain the acute gout flare indication, the failure to explain the decision not to include reduced dose adjustments, those are more on the label.

[01:47:54] Speaker 01:
Those are more quintessentially susceptible to a remand rather than a flat-out vacator.

[01:48:01] Speaker 06:
It might be confusing.

[01:48:02] Speaker 06:
Remand to the agency?

[01:48:03] Speaker 01:
Yes.

[01:48:04] Speaker 06:
The district court has to get it back to the agency under your review.

[01:48:06] Speaker 01:
Yes.

[01:48:07] Speaker 01:
The district court, in all of these scenarios, I think, is the pass-through.

[01:48:10] Speaker 01:
We're almost moving it back to the agency.

[01:48:11] Speaker 01:
Yes.

[01:48:12] Speaker 01:
The pass-through to the agency.

[01:48:13] Speaker 01:
But in the usual case, when you've got a failure to explain, you would remand for the agency to explain, with this exception.

[01:48:20] Speaker 01:
Here you have the agency, again, at Joint Dependents 1008, 1009, 110, saying there are safety issues associated with how this drug is labeled.

[01:48:29] Speaker 01:
So I would suggest that when it gets back to the agency, to the extent, and we can brief this if you wish, to the extent that the remand itself does not work an automatic vacator of the approval, as Mr. Sitzman suggested, to the extent there is something left of the approval, FDA needs to vacate it on that ground.

[01:48:47] Speaker 01:
The statute and the regulations may do the work for it.

[01:48:51] Speaker 01:
FDA could make that determination, but we think in either case, FDA would have to vacate.

[01:48:55] Speaker 01:
Let me say one more word, though, if I can, on the capsule and the tablet issue.

[01:49:01] Speaker 01:
What you heard both

[01:49:03] Speaker 01:
government counsel and counsel for HICMA say is that the label couldn't contain the same kind of information.

[01:49:09] Speaker 01:
It's on the Colchris label because this is a capsule.

[01:49:12] Speaker 01:
They said it a number of times.

[01:49:13] Speaker 01:
That issue, by the way, comes up exactly once in the Joint Appendix at Joint Appendix 954 back in 2011.

[01:49:21] Speaker 01:
So the fact that they're relying on it, I will let that slide.

[01:49:23] Speaker 01:
But in any event, what that one statement says is dose modifications wouldn't be appropriate where we're talking about a capsule because a capsule can't be split.

[01:49:33] Speaker 01:
So what the label says is, and this is Joint Appendix 628, if you have to administer this with those other drugs, reduce your dosage or reduce the dose frequency.

[01:49:45] Speaker 01:
That's how they got around the capsule tablet problem.

[01:49:47] Speaker 01:
And it is in any event no explanation for the failure of FDA to require the information it said was required on the label.

[01:49:56] Speaker 01:
So for all of those reasons, FDA plainly relied, plainly abdicated its previous conclusions about the information that was required.

[01:50:04] Speaker 01:
It should be reversed and the approval vacated.

[01:50:06] Speaker 07:
But I don't really understand the point you just made because

[01:50:13] Speaker 07:
they said reduce your dose.

[01:50:16] Speaker 01:
They said reduce the dose or the dose frequency.

[01:50:19] Speaker 07:
Yes, but so even if you even if they didn't say or dose frequency, your argument would be that they're relying on the Colchrist data to say reduce your dose.

[01:50:30] Speaker 01:
Oh, I certainly would say that, yes, but I'm saying if they are thinking that the capsule is some kind of a basis for distinguishing what should have gone on the label, yes, the fact that it says reduce your dose at all pertains to the Colchris mutual data.

[01:50:45] Speaker 04:
Are you making a separate argument now that the label is unsafe?

[01:50:50] Speaker 01:
No, I'm not.

[01:50:52] Speaker 01:
We have never made that argument in this court that the label is unsafe, except for this.

[01:50:58] Speaker 01:
The FDA has said this is the information that needs to be on the label.

[01:51:02] Speaker 01:
Without this information, the label is unsafe.

[01:51:04] Speaker 01:
That's not our argument.

[01:51:05] Speaker 01:
That's FDA's argument.

[01:51:08] Speaker 04:
No, I'm a little confused about your difference between the tablet and the capsule.

[01:51:14] Speaker 04:
I thought you were suggesting that the label regarding the capsule, Mitigar,

[01:51:21] Speaker 04:
is inadequate.

[01:51:23] Speaker 01:
Oh, no.

[01:51:23] Speaker 01:
What I'm saying is what you heard government counsel and Counsel for HICMA say is the information... It sounds different because you can't break it in half.

[01:51:32] Speaker 01:
Right.

[01:51:33] Speaker 01:
So what they say is because you can't break it in half, the other thing you can do is reduce how often you take it.

[01:51:38] Speaker 01:
Right.

[01:51:38] Speaker 01:
That's the difference.

[01:51:39] Speaker 04:
So, and... Oh, so in either event, you're relying on your argument culprits.

[01:51:44] Speaker 01:
Exactly.

[01:51:45] Speaker 01:
That's exactly right.

[01:51:46] Speaker 01:
Yes.

[01:51:47] Speaker 01:
Okay.

[01:51:47] Speaker 01:
I see.

[01:51:47] Speaker 01:
There are no further questions?

[01:51:50] Speaker 06:
Thank you.

[01:51:50] Speaker 06:
Thank you.

[01:51:52] Speaker 06:
Thank everyone for well done arguments.

[01:51:55] Speaker 06:
The case is submitted.