[00:00:00] Speaker 04:
Case number 23-5142, Epson Biopharmaceuticals, Inc., the balance, versus Xavier Becerra in his official capacity as Secretary of Health and Human Services at AL.

[00:00:12] Speaker 04:
Ms.

[00:00:13] Speaker 04:
Stetson for the balance, Ms.

[00:00:14] Speaker 04:
Mittal for the federal appellees, Mr. Burgess for the appellee, Invagen Pharmaceuticals, Inc.

[00:00:22] Speaker 03:
Morning, Ms.

[00:00:23] Speaker 03:
Stetson.

[00:00:24] Speaker 06:
Good morning, your honors, and may it please the court.

[00:00:26] Speaker 06:
My name is Kate Stetson.

[00:00:27] Speaker 06:
I represent the appellant Ipsum Biopharmaceuticals.

[00:00:31] Speaker 06:
Ipsum's product, simatuline depo, is a biological product.

[00:00:36] Speaker 06:
The active ingredient in simatuline depo and reatide acetate assembles into long, complex chains and structures.

[00:00:45] Speaker 06:
Those chains and structures are proteins, as FDA defines them, which means simatuline depo is a biological product.

[00:00:54] Speaker 06:
The district court concluded that FDA's definition of protein, however, unambiguously requires FDA to look not at the active ingredient as it exists in Ipsen's product, but at lanreotide acetate, just the eight peptide amino acid chain by itself before the product is even created.

[00:01:17] Speaker 06:
But FDA doesn't regulate amino acid chains.

[00:01:20] Speaker 06:
It regulates drug products and biological products.

[00:01:23] Speaker 06:
And both the statute and the regulation refer to biological products.

[00:01:27] Speaker 06:
The product is what's labeled.

[00:01:29] Speaker 06:
The product is what's marketed.

[00:01:30] Speaker 06:
And the product is what's used, as it was here, by a competitor as a reference product.

[00:01:36] Speaker 02:
And the active- I guess I'm not following why.

[00:01:40] Speaker 02:
where this is going with product or timing, and whether we look at, whatever time we look at, the active ingredient is, I'm not sure I'll pronounce it right, but lanreotide acetate, right?

[00:01:57] Speaker 06:
The active ingredient is lanreotide acetate.

[00:01:59] Speaker 06:
I think the question, Judge Katzis, is, I think everyone agrees and concedes that lanreotide acetate, when it is in Ibsen's product,

[00:02:10] Speaker 06:
assembles into these complex structures.

[00:02:13] Speaker 06:
So it's not a question, as we say in our brief, that often occurs when you're talking about the difference between an active ingredient and an active moiety, all the things that often come up.

[00:02:22] Speaker 06:
This is the question about what does the active ingredient, lanreotide acetate, look like in the finished drug product?

[00:02:30] Speaker 06:
Not what does lanreotide acetate look like off by its own, on the shelf,

[00:02:35] Speaker 06:
before it's manufactured.

[00:02:37] Speaker 06:
What you're looking at when you're asking the question about what is a biological product is, what is the thing that is in this product?

[00:02:46] Speaker 05:
And the question about what is in the product seems like a different question from what the active ingredient is.

[00:02:52] Speaker 05:
It seems that both Ibsen and the FDA agree that we have to look at the active ingredient in the product.

[00:02:59] Speaker 05:
And normally we think of active ingredient as the thing that has the pharmacological effect on the body.

[00:03:05] Speaker 05:
And isn't that the lanrea-tide acetate itself, not the nanotubes?

[00:03:10] Speaker 05:
I mean, I don't see Ibsen anywhere make the argument that it's the nanotubes that have the pharmacological effect.

[00:03:17] Speaker 06:
No, Judge Rao, I don't think we're arguing that the nanotubes themselves, you know, at least solely convey the pharmacological effect.

[00:03:24] Speaker 06:
I think they play an important role in how this drug is delivered.

[00:03:28] Speaker 06:
But I think FDA's focus on active ingredient and the definition of active ingredient and what it means to have pharmacological effect, of course, are getting one and two and three steps away from what the statute and the definition actually say.

[00:03:43] Speaker 06:
And when we're looking at the statute, when it talks about what is a biological product, a biological product is a protein.

[00:03:51] Speaker 06:
What is a protein?

[00:03:52] Speaker 06:
at the definition.

[00:03:53] Speaker 06:
A protein is a collection of amino acids with a specific defined sequence more than 40 in length and so on and so forth.

[00:04:01] Speaker 06:
The question about the active ingredient, I think, doesn't appear anywhere in the statute.

[00:04:06] Speaker 06:
So what FDA is doing is trying to draw your attention away from the word product and towards this entire other inquiry that isn't based in the text in front of you.

[00:04:16] Speaker 03:
I'm a little confused about why

[00:04:19] Speaker 03:
you and your brief don't say anything about the second sentence in the definition of active ingredient in the regulation that's at 21 CFR 314.3.

[00:04:38] Speaker 03:
So the first sentence

[00:04:41] Speaker 03:
reads active ingredient as any component that is intended to furnish pharmacological activity or direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of man or other animals.

[00:05:04] Speaker 03:
that's the first sentence and then the second sentence says the term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect.

[00:05:28] Speaker 03:
I mean that sounds like your argument

[00:05:31] Speaker 03:
But that language isn't in your brief other than citing to it in the statutory and regulatory addendum.

[00:05:42] Speaker 06:
Right.

[00:05:42] Speaker 06:
So Judge Wilkins, I do agree with your reading of that second sentence.

[00:05:48] Speaker 06:
I think it's more useful for our argument than for in the Gens or the governments.

[00:05:52] Speaker 06:
I think one reason why we weren't focusing on the definition of the active ingredient is because the definition of the active ingredient, as I was saying to Judge Rao,

[00:06:01] Speaker 06:
You know, all already begins to pull you away from the definition that matters here, but to the extent that you look at that definition and the definition expands in such a way as to include the active ingredient as it exists in that finished product that's intended to confer.

[00:06:18] Speaker 06:
not just the activity, but the function.

[00:06:20] Speaker 06:
I think that's an important part of the overall analysis.

[00:06:24] Speaker 06:
The other thing that I would add that's I think in a similar vein is if you look at the definition of biological product in the statute, which is 42 USC 262 I1,

[00:06:35] Speaker 06:
The term biological product includes a number of things, serums, venins, toxins, including proteins applicable to the prevention, treatment, or cure of a disease or condition of human beings.

[00:06:47] Speaker 06:
And I think to the extent, Judge Wilkins, that runs in parallel with the definition of active ingredient, then I think the two can be read somewhat consonantly in that way.

[00:06:57] Speaker 03:
But the intervener and FDA point out

[00:07:02] Speaker 03:
if we were to adopt your position about what is a biological product, then one formulation of this octopeptide would not be a biological product, it'd be a drug product, while the somatulin depo formulation would be a biological product because the drug is also administered instead of this

[00:07:28] Speaker 03:
extended release version, but as a, I guess, immediate release version where you don't have the nanotubes.

[00:07:38] Speaker 03:
And so let's say you did that problem.

[00:07:42] Speaker 06:
I think that is a feature of the way that FDA has decided to regulate.

[00:07:47] Speaker 06:
So if you read FDA's memorandum that supports its definition of protein, all of the different options they considered,

[00:07:54] Speaker 06:
If you read its proposed rule, when it's final rule, one of the things that FDA says repeatedly is we, we understand that by creating these bright line rules, we're going to be walling things in and walling things out and that there are things on either side of those walls that someone else could argue, you know, arguably our proteins.

[00:08:13] Speaker 06:
So just because there is a different formulation of an active ingredient in a product that doesn't satisfy that definition of protein, that's, I think, a feature of the definition.

[00:08:24] Speaker 06:
And to the extent that that becomes an actual problem rather than some theoretical problem, I think Congress and FDA have the ability to change the definition as it currently exists.

[00:08:35] Speaker 06:
What exists right now is a product that contains a protein.

[00:08:39] Speaker 06:
And the protein, of course, is a biological product.

[00:08:42] Speaker 03:
So your client Ibsen also markets and sells this in a formulation that's not the Sumatran Depot, the extended release with the same octopeptide, right?

[00:08:59] Speaker 06:
I believe that's correct.

[00:09:00] Speaker 06:
I don't know the extent to which, you know, how much is sold or so forth, and I don't even know.

[00:09:06] Speaker 03:
The big seller obviously is the

[00:09:09] Speaker 03:
Smudge on deep product.

[00:09:11] Speaker 03:
Correct.

[00:09:12] Speaker 03:
But the point remains that you would have one formulation be a biological product and one wouldn't.

[00:09:21] Speaker 06:
I think that's correct.

[00:09:24] Speaker 06:
But I think, as I mentioned, the answers do the same thing, right?

[00:09:30] Speaker 06:
They do not do the same thing.

[00:09:32] Speaker 06:
And to the extent that we start looking at the question of what they do, I think we're again not looking at the definition.

[00:09:38] Speaker 06:
One of the things that FDA said in its memorandum and in its proposed and final rule is we're actually not going to look at function.

[00:09:47] Speaker 06:
we are going to create, to the extent we can, a bright line rule so that we don't have to have extended debates about what falls in and outside that rule.

[00:09:55] Speaker 06:
So if we were looking at function, maybe then we could have a debate about whether the thing that extended release simatraline depot does is different than the other form of lamerian tight acetate.

[00:10:06] Speaker 06:
But by creating this definition as it did, intentionally to create these kind of concrete rules of application,

[00:10:13] Speaker 06:
FDA was necessarily making some judgments about how to go about assessing things.

[00:10:18] Speaker 05:
And one of the things that... People with a bright line, though, don't we still have to look at what the active ingredient is in the drug?

[00:10:25] Speaker 06:
Yes, you have to look at what the active ingredient is in the drug.

[00:10:29] Speaker 06:
That's exactly right.

[00:10:30] Speaker 06:
You don't look at the active ingredient as it exists in some kind of theoretical octopeptide form.

[00:10:35] Speaker 06:
You look at what it is doing in the product and what it's doing in this product.

[00:10:40] Speaker 06:
I think everyone would agree

[00:10:42] Speaker 06:
is assembling into these complex nanotube structures.

[00:10:46] Speaker 05:
But how do the nanotubes meet the definition of active ingredient in the regulation?

[00:10:52] Speaker 05:
I know you say that's moving away from the statute itself, but I think in your briefing you can see that it has to be the active ingredient.

[00:10:59] Speaker 05:
You said it just now, it has to be the active ingredient.

[00:11:02] Speaker 05:
So how do the nanotubes meet this definition?

[00:11:06] Speaker 06:
Well, I think the nanotubes meet the definition, what meets the definition of active ingredient is the lanreotide acetate.

[00:11:14] Speaker 06:
The active ingredient in the drug product, which is where your question started, also Judge Rao, is lanreotide acetate nanotubes.

[00:11:22] Speaker 06:
Keying off of Judge Wilkins' earlier point about that second sentence in the active ingredient definition, to the extent we need to smooth over what active ingredient means alongside what the definition of protein and the definition of biological product means, that's probably the hook to do it.

[00:11:38] Speaker 06:
But the important thing for asking this question, which is, is this a biological product, is that you're not asking, is lanreatide acetate a biological product?

[00:11:48] Speaker 06:
You're asking, is simacholine depot a biological product?

[00:11:51] Speaker 06:
And I think the question is, what is this product and what does it consist of?

[00:11:55] Speaker 06:
It consists of an active ingredient that has formed, self-assembled into nanotubes.

[00:12:00] Speaker 06:
Now, one of the things that FDA says, of course, is even if you take the active ingredient as it exists in the product, it still doesn't meet the definition of protein, because according to FDA, the way that these nanotubes assemble doesn't typically occur in nature.

[00:12:18] Speaker 02:
Let's stick with that.

[00:12:20] Speaker 02:
Sure.

[00:12:21] Speaker 02:
For a while, because that's where I am as well.

[00:12:23] Speaker 02:
Okay.

[00:12:25] Speaker 02:
Is it fair to say, my understanding, my limited understanding of the chemistry here is that the active ingredient is just being dissolved in acidic water, correct?

[00:12:39] Speaker 06:
It's being dissolved in water at room temperature.

[00:12:43] Speaker 06:
Yes.

[00:12:43] Speaker 02:
So I mean, there's no, the

[00:12:47] Speaker 02:
the relevant chemical or molecule is still amreotide acetate.

[00:12:54] Speaker 02:
And whatever's happening in water, I don't know, maybe the chemicals are aligning, it's aligning in a certain way because of the electric charge of water or whatever.

[00:13:06] Speaker 02:
I don't know what's going on there, but it's still the same molecule, just as we would say,

[00:13:13] Speaker 02:
water is H2O.

[00:13:17] Speaker 02:
H2O is H2O even when it assembles in these huge ice crystals.

[00:13:22] Speaker 06:
I think the difference, two points to Judge Katz's.

[00:13:25] Speaker 06:
The first is the definition of protein, I think, by even in itself contemplates that you're going to be looking at this question at some particular point in time.

[00:13:34] Speaker 06:
Because remember that second part of the definition, the one we're not talking about yet, talks about assembling in a manner that occurs in nature.

[00:13:42] Speaker 06:
So you're already making an assumption about when these proteins assemble together.

[00:13:46] Speaker 06:
And to your first part of your question, the definition of protein, the definition of biological product, the definition of active ingredient, none of those things asks the question, what is this molecule?

[00:13:58] Speaker 06:
And does this molecule standing alone do something, even going back to the definition of biological product that should ground the discussion?

[00:14:07] Speaker 06:
The definition of biological product is, among other things, a protein or analogous product, which we should talk about, applicable to the prevention, cure, or treatment of disease in human beings.

[00:14:17] Speaker 06:
The molecule of lanreotide acetate, you don't apply to a prevention treatment or cure.

[00:14:23] Speaker 06:
You apply simacillin depo.

[00:14:24] Speaker 06:
You apply insulin.

[00:14:26] Speaker 06:
Insulin itself consists of two peptides that don't themselves.

[00:14:29] Speaker 06:
qualify as a protein, but insulin is a protein.

[00:14:32] Speaker 06:
If you were to take insulin apart and look at those two separate molecules, they wouldn't qualify as a protein.

[00:14:38] Speaker 06:
But when you put them together, insulin becomes a protein.

[00:14:41] Speaker 06:
I think it's exactly the same analysis here.

[00:14:45] Speaker 02:
That has some force to it, but it just sounds like you're trying to unravel what I thought was a fairly clear acknowledgement in your briefs that

[00:14:59] Speaker 02:
What what we're talking about is the active ingredient.

[00:15:04] Speaker 06:
I embrace that idea.

[00:15:06] Speaker 06:
I think the question is what we're talking about is the active ingredient in the drug product.

[00:15:11] Speaker 06:
The active ingredient sort of off on its own, just the octopeptide.

[00:15:16] Speaker 06:
is not what the statute or the regulation tell you to look at.

[00:15:21] Speaker 06:
The regulation itself wouldn't have to say, you can count these separate structures towards the 40 amino acid count if you're just looking at those structures as they exist before anything happens to them, before the product is created, before semachelin depot is manufactured.

[00:15:38] Speaker 06:
And I know my time is up.

[00:15:40] Speaker 06:
If I can just maybe take a step back.

[00:15:42] Speaker 05:
So in terms of when we talk about a drug product, we're talking about the active ingredient plus the sort of substance or the form it takes and how it's administered.

[00:15:53] Speaker 05:
And you're suggesting, I mean, should we understand biological product in the same way, right?

[00:15:59] Speaker 05:
It's an active ingredient plus the form in which it's administered.

[00:16:03] Speaker 05:
And so it seems like the nanotubes are the form in which it's administered.

[00:16:08] Speaker 05:
It's what make up the product as it's used by a patient.

[00:16:12] Speaker 05:
But that doesn't mean that the nanotubes are the active ingredient.

[00:16:19] Speaker 05:
So it seems to me the protein is more analogous to the drug substance or the active ingredient.

[00:16:26] Speaker 05:
And you seem to be saying the biological product is just

[00:16:32] Speaker 05:
you know, the Sumatran Depot as it's administered.

[00:16:35] Speaker 05:
And so that seems like it would separate the definition of what a biological product is from what we think of as a drug product.

[00:16:43] Speaker 05:
And it seems the more natural reading is to think of those two things in a similar way.

[00:16:48] Speaker 06:
I do agree that we should think of those two things in a similar way.

[00:16:52] Speaker 06:
So one of the arguments that I hear FDA and Invegen making in their briefs is that it's wrong to look at the definition

[00:16:59] Speaker 06:
drug product because there's no similar definition of biological product.

[00:17:05] Speaker 06:
The definition of drug product under the regulations is the product in its finished dosage form.

[00:17:12] Speaker 06:
Keying off of your question, I think then it makes only logical sense for a biological product also to be the finished dosage form.

[00:17:21] Speaker 05:
That's why everything- The finished dosage form, but the active ingredient is not the finished dosage form.

[00:17:28] Speaker 05:
It's the thing that actually has the pharmacological effect.

[00:17:32] Speaker 06:
Exactly.

[00:17:34] Speaker 06:
The active ingredient in the finished dosage form.

[00:17:37] Speaker 06:
I think that's the difference.

[00:17:39] Speaker 06:
What FDA and Invagen are trying to do is to just strip out this idea of the active ingredient, separate it completely from the rest of the product, and just look at this molecule by itself.

[00:17:50] Speaker 06:
and ask the question, what does this molecule do and how long is it?

[00:17:54] Speaker 06:
But we already know that FDA already has defined something to be an addition of molecules in certain circumstances.

[00:18:01] Speaker 06:
We know that this definition that we're looking at asks the question about what is a biological product.

[00:18:06] Speaker 06:
We know that the active ingredient that matters is the active ingredient

[00:18:09] Speaker 06:
as it exists in the product, because to your earlier point, Judge Rao, that's what's doing the work.

[00:18:14] Speaker 06:
What's doing the work in the finished product is the active ingredient as it exists in that finished product.

[00:18:20] Speaker 05:
What is doing the work?

[00:18:21] Speaker 05:
The nanotubes aren't doing the work.

[00:18:23] Speaker 05:
The lanreotide acetate is doing the work.

[00:18:25] Speaker 05:
So I don't see you making an argument that the nanotubes themselves are doing the work.

[00:18:30] Speaker 05:
The nanotubes are just a way to slowly administer the lanreotide acetate.

[00:18:36] Speaker 06:
When I say doing the work, I think I'm using it as a rather a shorthand.

[00:18:41] Speaker 06:
It's not the pharmacological effect.

[00:18:44] Speaker 06:
It's not.

[00:18:44] Speaker 06:
And there's a reason I'm not saying pharmacological effect, because that gets us several steps removed from the definitions that we're actually concerned about.

[00:18:52] Speaker 06:
When I say doing the work, it means applicable to the prevention of illness disease or prevention or cure of illness disease under the definition of biological product.

[00:19:03] Speaker 06:
the thing that is doing the work is the product itself, including the active ingredient, as it exists in the product, not just some random octopeptide.

[00:19:11] Speaker 06:
That's not what's being regulated.

[00:19:13] Speaker 06:
It's not what's being used as the reference product.

[00:19:16] Speaker 06:
The reference product is simagolene depot.

[00:19:18] Speaker 02:
So you don't think FDA could reasonably distinguish between

[00:19:25] Speaker 02:
doing the work in the stricter sense that Judge Rao might have been getting at, pharmacological effect, affecting the structure and function of the body of man or whatever it is within the human body on the one hand, and doing the work in the sense of a dosage release mechanism.

[00:19:48] Speaker 06:
I think, again, maybe the way to marry up those two things is to look at that second definition sentence that Judge Wilkins pointed out, to the extent that we're going to talk about a biological product as containing... The second sentence presupposes a chemical change.

[00:20:07] Speaker 02:
It just goes back to the lambriotide acetate.

[00:20:11] Speaker 06:
The second sentence presupposes a chemical or structural change.

[00:20:15] Speaker 06:
And what we're talking about here is the structure of lamreotide acetate as it exists in the finished dosage product.

[00:20:23] Speaker 02:
The term includes components that may undergo chemical change in the manufacture of the drug product.

[00:20:32] Speaker 06:
When we talk about a chemical change, the chemical change that occurs is the, and let me actually take one step back because I think the more that we talk about

[00:20:44] Speaker 06:
chemical changes and molecules and so on.

[00:20:46] Speaker 02:
Molecules dissolving in water at room temperature.

[00:20:52] Speaker 02:
Maybe I'm misremembering my chemistry.

[00:20:54] Speaker 02:
I don't think that's a chemical change.

[00:20:56] Speaker 02:
It's the same molecule.

[00:20:58] Speaker 06:
Molecules associating lengths of amino acids associating with each other, forming complex structures, I think easily qualify as a chemical change.

[00:21:10] Speaker 06:
But again, even reading this definition of this word that doesn't appear in either the statute or regulation that we're talking about gets you further and further away from the text.

[00:21:21] Speaker 06:
What the text says is, ask the question, is this a biological product or an analogous product applicable to the prevention or cure of a disease or illness?

[00:21:31] Speaker 06:
If this is a protein, it is a biological product.

[00:21:34] Speaker 06:
You don't just ask the question, is this octopeptide floating around in the wild?

[00:21:40] Speaker 06:
biological product, you ask the question whether somatuline depot is a biological product.

[00:21:44] Speaker 05:
I think all of the work that... But you also agree that it's the active ingredient in the somatuline depot.

[00:21:50] Speaker 05:
I do.

[00:21:51] Speaker 05:
That is the protein.

[00:21:52] Speaker 05:
I do.

[00:21:52] Speaker 05:
But you haven't explained how the nanotube is the active ingredient.

[00:21:56] Speaker 05:
When we ask you that question, you say, well, active ingredient is too far from the statutory definition.

[00:22:02] Speaker 06:
Judge Rao, I think maybe the difference that you and I are having is just where the emphasis is being put.

[00:22:08] Speaker 06:
You're emphasizing active ingredient in the drug product.

[00:22:11] Speaker 06:
I'm emphasizing active ingredient in the drug product.

[00:22:14] Speaker 06:
The active ingredient, lanreotide acetate, forms nanotubes.

[00:22:18] Speaker 06:
The nanotubes are part of the lanreotide acetate structure.

[00:22:21] Speaker 06:
So I'm not looking at the nanotubes as some separate entity.

[00:22:25] Speaker 06:
They are nanotubes of lanreotide acetate.

[00:22:28] Speaker 06:
That's the active ingredient in the finished drug product.

[00:22:31] Speaker 06:
I think that's how to tie the two together.

[00:22:34] Speaker 06:
If I could take a couple minutes and just touch on the two other issues that I think are particularly important here, one of them is this question about associating in a manner that occurs in nature.

[00:22:45] Speaker 06:
This is a quintessential rewriting of an agency regulation.

[00:22:53] Speaker 06:
What the agency regulation says is when two or more chains associate with each other or are associated with each other in a manner that occurs in nature,

[00:23:02] Speaker 06:
You count them together for purposes of counting the size of that polymer.

[00:23:06] Speaker 06:
And what FDA said below, and what it says again in its briefs is, these amino acid chains, these nanotubes of limerotide acetate are not associated with each other in a manner that typically occurs in nature.

[00:23:17] Speaker 06:
We agree that this happens in nature.

[00:23:20] Speaker 06:
It just doesn't typically happen.

[00:23:22] Speaker 06:
But that is just flat out redlining of the regulation.

[00:23:25] Speaker 06:
So that's, I think, my short argument on the second point.

[00:23:29] Speaker 06:
The third point is even if you take FDA at its word that the thing that you look at is lanreotide acetate in the wild, even if you agree that these don't typically occur in nature, you're left with this question about whether this is an analogous product.

[00:23:45] Speaker 06:
And what FDA has argued before, and this is a Teva case, is that the critical element of a protein, the touchstone,

[00:23:55] Speaker 06:
And that's at the Teva case pin site 113 and 115.

[00:23:59] Speaker 06:
The critical element of a protein is a specific defined sequence of amino acids.

[00:24:05] Speaker 06:
And of course, we have a specific defined sequence of amino acids.

[00:24:09] Speaker 06:
But now, of course, what FDA is saying, there's actually one more critical touchstone.

[00:24:14] Speaker 06:
And that is it absolutely has to be more than 40 amino acids long.

[00:24:19] Speaker 06:
And it has to be typically occurring in nature.

[00:24:21] Speaker 06:
But with those touchstones, anything else can be a protein.

[00:24:24] Speaker 06:
Once you establish that the thing that is analogous to a protein has to actually be a protein, you're no longer reading anything into the words analogous product.

[00:24:33] Speaker 06:
So I think even if you disagree with us on our first two points, the FDA's reading of analogous product is simply

[00:24:41] Speaker 06:
not consonant with the way that that regulation must be read in order to have any substance to it.

[00:24:46] Speaker 02:
What about their example of the mixture?

[00:24:50] Speaker 02:
I think under the... The proteins and other non-amino acid molecules dissolve together.

[00:24:58] Speaker 02:
They both have pharmacological effect.

[00:25:03] Speaker 02:
It's a mixture containing proteins which provides a vehicle for

[00:25:08] Speaker 02:
treating the non-amino acid component as a protein as well as the protein component.

[00:25:14] Speaker 06:
I think under FDA's definition of protein, a mixture containing a protein is a protein.

[00:25:20] Speaker 06:
And I think that's the problem with FDA's sole example of the thing that it considers to be analogous to a protein is a thing containing a protein.

[00:25:28] Speaker 06:
That just doesn't work.

[00:25:30] Speaker 06:
If there are no further questions.

[00:25:32] Speaker 03:
All right, thank you.

[00:25:32] Speaker 03:
Thank you, Ron.

[00:25:34] Speaker 03:
Thank you.

[00:25:42] Speaker 03:
Good morning, Ms.

[00:25:44] Speaker 03:
Mittal.

[00:25:44] Speaker 07:
Good morning.

[00:25:45] Speaker 07:
May it please the court or Jemethil for the government?

[00:25:48] Speaker 07:
As you just heard, Ibsen agrees that the active ingredient is the proper frame of analysis for deciding whether its product is a protein.

[00:25:56] Speaker 07:
And Ibsen also agrees that the active ingredient in its product is made up of eight amino acids.

[00:26:01] Speaker 07:
That's enough to decide this case and conclude that Ibsen's product is not a protein.

[00:26:06] Speaker 07:
The active ingredient in Ibsen's product is made up of one eight amino acid chain.

[00:26:10] Speaker 07:
It's that 8-amino acid chain that has the specific therapeutic effect that Ipsin identifies on its product labeling.

[00:26:17] Speaker 07:
It's that 8-amino acid chain that binds to the somatostatin receptors in the body and mimics the function of natural somatostatin in the body.

[00:26:25] Speaker 07:
It is not the nanotubes that have that pharmacological effect.

[00:26:28] Speaker 07:
And those nanotubes are not the active ingredient, as Ipsin recognizes.

[00:26:31] Speaker 07:
The associations between the amino acid chains and the nanotubes are associations between copies of the active ingredient.

[00:26:38] Speaker 07:
And again, Ipsin has told you

[00:26:40] Speaker 07:
The active ingredient is the proper frame of analysis for deciding whether a product is a protein.

[00:26:45] Speaker 03:
Can I interrupt you for a second?

[00:26:47] Speaker 03:
The regulatory definition of active ingredient says that it's any component that is intended to furnish pharmacological activity or other direct effect.

[00:27:00] Speaker 03:
The regulation itself doesn't restrict active ingredient to furnishing pharmacological effect.

[00:27:09] Speaker 03:
It says other direct effect.

[00:27:12] Speaker 03:
So why can't direct effect be putting the ingredient in a formulation that gives it an extended release so that it can operate

[00:27:26] Speaker 03:
um, over time and person not have to get an injection, you know, every day.

[00:27:33] Speaker 07:
Your honor, there may be products that have active ingredients that are defined that way, but the product before the court today, so natural indigo, the active ingredient there is land, retired acetate and nips and told FDA that in its new drug application, it told FDA that in its product labeling, you look at J. A.

[00:27:50] Speaker 07:
305 J. A.

[00:27:52] Speaker 07:
309.

[00:27:53] Speaker 07:
on those, in that product labeling, Epson says the active ingredient is lanrethidacetate.

[00:27:58] Speaker 07:
It's a synthetic octopeptide.

[00:27:59] Speaker 03:
There's no mention.

[00:28:00] Speaker 03:
Is there authority that says that they're bound by that?

[00:28:05] Speaker 03:
I mean, my understanding of this is that that was in the context of getting a new drug of application approved.

[00:28:14] Speaker 03:
It goes in the orange book, right?

[00:28:17] Speaker 03:
That's right.

[00:28:17] Speaker 03:
And this is a whole different process.

[00:28:20] Speaker 03:
for biological product that goes in the purple book.

[00:28:25] Speaker 03:
It's a whole different kind of regulatory scheme.

[00:28:29] Speaker 03:
So what authority, what statute or regulation or case says that like once you say the context of trying to get approval under one provision,

[00:28:43] Speaker 03:
you were bound by kind of that description.

[00:28:47] Speaker 07:
It's not, it's not a question of an authority binding.

[00:28:51] Speaker 07:
Ibsen, it's a question of, as you said, Your Honor, defining what the active ingredient is and figuring out what role the nanotubes have to play in this analysis.

[00:29:00] Speaker 07:
And FDA explained that in its view, in its scientific judgment, the nanotubes are better considered to be the formulation property or the dosage form.

[00:29:08] Speaker 07:
So if you look at 314.3 in subsection B,

[00:29:13] Speaker 07:
There's also a definition of dosage form.

[00:29:15] Speaker 07:
And again, Ipsum identifies this as part of the dosage form, hence the emphasis on finished dosage form.

[00:29:24] Speaker 07:
And one of the elements of what a dosage form is, is a design feature that affects frequency of dosing.

[00:29:31] Speaker 07:
And that is what FDA characterizes and understands the nanotubes to be.

[00:29:36] Speaker 07:
They are a self-assembly of the lanreitide acetate molecules that affect the frequency of dosing.

[00:29:42] Speaker 07:
no different from sort of a tablet, capsule, or solution.

[00:29:45] Speaker 07:
They're a different form, but they're nonetheless a formulation property in Ibsen.

[00:29:49] Speaker 07:
And its reply rate doesn't contest that.

[00:29:51] Speaker 07:
So it seems to be settled to ground that the nanotubes are better understood to be the dosage form of the product, not the active ingredient.

[00:29:58] Speaker 07:
So we look.

[00:29:59] Speaker 03:
So explain to me what the second sentence of the active ingredient regulation, what that means.

[00:30:08] Speaker 07:
So the active ingredient, the second sentence, Your Honor,

[00:30:11] Speaker 07:
As Judge Katz says, first there's the question of whether the lanrytide acetate molecule when it self-assembles into a nanotube can properly be understood to be undergoing a chemical change.

[00:30:21] Speaker 07:
That's something FDA hasn't taken a position on nor has Ipsen argued that that's considered a chemical change.

[00:30:27] Speaker 07:
But an easier way to resolve the application of the second sentence of the definition of active ingredient here is the part that says it's in a modified form intended to furnish the specified activity or effect.

[00:30:40] Speaker 07:
nowhere has Ibsen said, nor has the FDA concluded, that the nanotube is a form intended to furnish the specified activity or effect.

[00:30:48] Speaker 07:
The specified activity throughout the new drug application, throughout the product labeling, throughout the briefing in district court, throughout the briefing in this court, is for the lanrotide acetate octopeptide to bind to the somatostatin receptors in the human cells.

[00:31:04] Speaker 07:
affects the human production of human growth hormone.

[00:31:07] Speaker 07:
That's the intended pharmacological effect of land re-tide acetate.

[00:31:12] Speaker 07:
And at JAA, I believe it's 480, FDA explains that it's not the nanotubes that have that biological effect.

[00:31:20] Speaker 07:
As your honor said earlier, the nanotubes affect the frequency of dosing.

[00:31:25] Speaker 07:
The pharmacological effect that Ibsen saw approval for was binding to those somatostatin receptors.

[00:31:31] Speaker 07:
even if we can look at the nanotubes as a modified form of land re-tide acetate under the second sentence, which again, FDA hasn't taken a position on, they wouldn't be intended to furnish the specified activity or effect because that effect is the binding.

[00:31:45] Speaker 07:
And the binding occurs at that eight amino acid level, at that octopeptide level.

[00:31:50] Speaker 07:
It's not a hypothetical form because that eight amino acid octopeptide is what separates from the nanotube and then binds to the receptors.

[00:31:57] Speaker 07:
It's not the nanotubes that do that.

[00:32:01] Speaker 03:
analogous product mean?

[00:32:04] Speaker 07:
So FDA has explained that for purposes of this case, all that this court has to think about is that it doesn't include those products that are specifically excluded from the definition of protein.

[00:32:16] Speaker 07:
And so a product with definition of protein set forth in FDA regulation is an amino alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size.

[00:32:28] Speaker 07:
This falls outside of that definition expressly.

[00:32:31] Speaker 07:
and therefore isn't analogous.

[00:32:32] Speaker 03:
I don't think I've ever understood anyone to ever contend that in order for something to be analogous, it has to have all of the properties of the thing that you're contending that it's analogous.

[00:32:51] Speaker 03:
This doesn't make sense.

[00:32:53] Speaker 07:
That's right, Your Honor.

[00:32:53] Speaker 07:
So the naturally derived mixtures are a good example of this.

[00:32:57] Speaker 07:
And contrary to sort of what Ibsen was describing,

[00:33:01] Speaker 07:
Naturally-derived mixture of the kind described in FDA's decision to Ipsin, which contains a protein component as well as a non-biological product component, that kind of a product is not a protein.

[00:33:14] Speaker 07:
It doesn't fit within the definition of a protein because it has this significant non-biological product component.

[00:33:20] Speaker 07:
And a protein is only present in that product in a smaller unknown quantity.

[00:33:24] Speaker 03:
But why does something not become a protein only because it's not 100% protein?

[00:33:31] Speaker 07:
Well, that might not be the only context in which something might not be a protein.

[00:33:34] Speaker 07:
And FDA decides whether something is analogous on a case-by-case basis.

[00:33:38] Speaker 03:
So to go back to that.

[00:33:39] Speaker 03:
But here's what I don't understand.

[00:33:42] Speaker 03:
If you have, let's say, alcohol that's dissolved in water and maybe for other liquid,

[00:34:02] Speaker 03:
And whether it's your beer, wine, or vodka, or whatever, you don't say that that mixture doesn't have alcohol in it because it's in a low concentrate or because it's mixed with one thing rather than another thing.

[00:34:20] Speaker 03:
It's still got alcohol in it.

[00:34:23] Speaker 03:
So I'm not sure how the mixture example really

[00:34:33] Speaker 03:
does anything to move the needle as far as giving analogous any meaning.

[00:34:39] Speaker 07:
So I think our intuition, FDA's intuition aligns exactly with yours, your honor.

[00:34:43] Speaker 07:
In the alcohol context, there is alcohol in that mixture that you described, if I understood your hypothetical correctly.

[00:34:49] Speaker 07:
And in the naturally derived mixture of the kind FDA described in its decision, there is a protein component.

[00:34:54] Speaker 07:
And that protein component meets the definition of a protein in the regulation defining a protein at 21 CFR 600.3.

[00:35:02] Speaker 07:
It is an alpha amino acid polymer with a specific defined sequence, but the overall mixture is not a protein and the active ingredient in that kind of mixture is the whole thing.

[00:35:11] Speaker 07:
It's the whole, it's the whole mixture.

[00:35:14] Speaker 07:
But FDA says, nevertheless, that's analogous.

[00:35:17] Speaker 07:
And I think going back to your honor's original question of how do we think about what are the bounds of an analogous product or when do we, when does that analysis apply?

[00:35:24] Speaker 07:
One way of thinking about the naturally derived mixtures is to say, well, those are mixtures.

[00:35:29] Speaker 07:
That's a kind of product that's not addressed by the definition of a regulation.

[00:35:33] Speaker 07:
That category is there for FDA to think about products that aren't addressed by the regulation.

[00:35:38] Speaker 07:
Regulation talks about alpha amino acid polymers with a specific defined sequence.

[00:35:43] Speaker 07:
It doesn't begin to help the FDA understand

[00:35:46] Speaker 07:
how to think about a naturally derived mixture.

[00:35:48] Speaker 07:
And so the mixture example gets analyzed under the analogous product provision of the statute instead.

[00:35:57] Speaker 07:
And so it's not a protein, but then deemed analogous to a protein.

[00:35:59] Speaker 07:
It's not specifically excluded from the definition of a protein the way an eight amino acid chain like Epson's product is.

[00:36:07] Speaker 07:
FDA drew a numerical bright line threshold, and this falls outside that threshold.

[00:36:12] Speaker 07:
I see my time has expired.

[00:36:13] Speaker 03:
In your mixture example,

[00:36:16] Speaker 03:
Is it a mixture because both protein and the other item that it's mixed with have pharmacological effects?

[00:36:28] Speaker 07:
So the way the FDA describes the kind of mixture that would be analogous to a protein is that it has a protein component, a non-biological product component, and then the protein component must be necessary for the functioning of the product and it has to specifically contribute

[00:36:46] Speaker 07:
to the product's intended therapeutic effects.

[00:36:48] Speaker 07:
So the protein there isn't meaningless, it's not useless, it's just not the only element of the product.

[00:36:55] Speaker 05:
Go ahead.

[00:36:57] Speaker 05:
I mean, just to follow up on Judge Wilkin's point, I mean, isn't that just saying that something that is part a protein is a protein?

[00:37:04] Speaker 05:
So I mean, that the analogous isn't doing any work.

[00:37:07] Speaker 05:
I mean, if it's just a protein and it's a mixture that includes a protein.

[00:37:12] Speaker 07:
It's not quite the same, Your Honor, because it doesn't meet the definition of a protein.

[00:37:16] Speaker 07:
So it is classified as a product that's analogous to a protein.

[00:37:19] Speaker 07:
It's nonetheless regulated as a biologic, but it is not quite the same because it has that significant other component.

[00:37:26] Speaker 07:
So the analogous product category captures that in FDA's view.

[00:37:31] Speaker 07:
And there exists, I mean, FDA has classified three products or transitioned three products to being regulated as a biologic.

[00:37:38] Speaker 07:
It's not an empty set.

[00:37:39] Speaker 07:
These actually drive mixtures, nor is

[00:37:41] Speaker 07:
the analogous product set and empty set for that for that very reason, but it doesn't quite fit in the definition of protein.

[00:37:47] Speaker 07:
The fact that it sounds analogous to a protein is exactly why it fits within the definition of an analogous product.

[00:37:52] Speaker 07:
That's sort of the very nature of that, that it feels so similar to a protein, but it's not specifically excluded by the definition of protein.

[00:38:00] Speaker 07:
And that's why that kind of a mixture, while it's not a perfect comparison,

[00:38:04] Speaker 07:
to Ipsen's product here is classified as analogous, whereas Ipsen's isn't.

[00:38:09] Speaker 07:
Ipsen's is an eight amino acid chain, and that's far from the 40 amino acid line that FDA drew in its regulation that's before the court and not challenged here.

[00:38:20] Speaker 02:
A sort of counterintuitive notion of analogous

[00:38:28] Speaker 02:
And I hear analogous to a protein, I think, a molecule, a chemical, an active ingredient that is almost a protein, but not quite.

[00:38:42] Speaker 02:
And the only example you've come up with is something where you have one

[00:38:51] Speaker 02:
one active ingredient that is a protein, another one that is nothing close to a protein, and the analogous provision is just giving you a hook for treating the wholly non-protein ingredient as a protein.

[00:39:11] Speaker 02:
I mean, it hangs together.

[00:39:12] Speaker 02:
It's just an odd usage of analogous.

[00:39:16] Speaker 07:
So two points, Your Honor.

[00:39:17] Speaker 07:
On the naturally-derived mixture, the way

[00:39:19] Speaker 07:
FDA looks at those products, and there exists, as I said, certain products.

[00:39:24] Speaker 07:
The whole mixture is the active ingredient.

[00:39:25] Speaker 07:
You wouldn't quite say the protein component alone is an active ingredient.

[00:39:29] Speaker 07:
So it's the protein and, for instance, a lipid component.

[00:39:31] Speaker 07:
And in the case of the actual products before the FDA, there's also a peptide component that's fewer than 40.

[00:39:37] Speaker 02:
So because the protein itself in the hypo can't affect the bodily structure,

[00:39:45] Speaker 07:
Because the protein component alone wouldn't achieve the entire intended therapeutic effect.

[00:39:50] Speaker 07:
And so on your honor's first point about how we understand the definition of the term analogous, of course, FDA hasn't promulgated a definition.

[00:39:58] Speaker 07:
It's left that category somewhat undefined for purposes of regulating products that haven't yet come before the agency and for allowing for scientific advancement.

[00:40:11] Speaker 07:
But FDA doesn't understand that to mean products that are quite

[00:40:15] Speaker 07:
close to being a protein, but not quite.

[00:40:18] Speaker 07:
That would defeat the purpose of that right-line rule that FDA drew.

[00:40:21] Speaker 07:
And it would allow the term analogous product in the statute to wipe out or render meaningless the term protein, because everything that doesn't fit within the definition of protein could then be regulated as analogous.

[00:40:33] Speaker 07:
But FDA drew a clear line and a regulation that's not challenged here.

[00:40:37] Speaker 07:
That complex products that are greater than 40 amino acids in length

[00:40:43] Speaker 07:
and that meet the other properties of being a protein are going to be what count as proteins.

[00:40:47] Speaker 07:
And there was good reason for that.

[00:40:49] Speaker 07:
There isn't a single characteristic that unites all of the categories of biological products in the statute at 42 USC 262.

[00:41:00] Speaker 07:
But one of the common features of biologic products is that they're all fairly complex.

[00:41:05] Speaker 07:
And FDA, in deciding how to define a protein in the unchallenged regulation here,

[00:41:10] Speaker 07:
said, well, look, we've had peptides that are fewer than 40 amino acids in length.

[00:41:15] Speaker 07:
They're not quite complex.

[00:41:16] Speaker 07:
We have to draw a line for regulatory certainty.

[00:41:20] Speaker 07:
And we've regulated peptides as drugs so far.

[00:41:23] Speaker 07:
We've approved generic drug applications for peptides for their abbreviated NDAs for those.

[00:41:29] Speaker 07:
But proteins are complex and of a nature sort of.

[00:41:32] Speaker 02:
What you're doing

[00:41:35] Speaker 02:
makes a good bit of sense.

[00:41:38] Speaker 02:
I just wonder if it's consistent with statutory scheme which says one category of thing is protein and then the regulatory treatment extends to a broader category of thing which is anything analogous to a protein and your reasoning

[00:42:00] Speaker 02:
comes back to where Judge Wilkins started us, which is there's a very somewhat complex and very precise definition of protein.

[00:42:11] Speaker 02:
And the agency's reasoning is whatever falls outside those lines, not only is it not a protein, it can't be analogous to a protein, because otherwise you're undoing the deliberately precise line

[00:42:29] Speaker 02:
that FDA drew, and putting aside mixture just as a matter of abstract reasoning, that seems to write analogous out of the statute.

[00:42:40] Speaker 07:
So, Your Honor, we would disagree that it's writing analogous out of the statute, because there are, you can think of them as two separate categories.

[00:42:46] Speaker 07:
There are things, or maybe three, there are products that are proteins, and they meet the definition of proteins.

[00:42:52] Speaker 07:
They don't have other components.

[00:42:54] Speaker 07:
There are products that are specifically excluded by that carefully drawn regulation that

[00:42:59] Speaker 07:
the carefully drawn regulation specifically says cannot be proteins.

[00:43:03] Speaker 07:
And then there are products that aren't captured by that regulation where the regulation doesn't tell us what to do with that kind of a product.

[00:43:09] Speaker 07:
And so the mixtures fall in that third category.

[00:43:12] Speaker 07:
And now this product has, at least as to a protein, has been understood to include those kinds of mixtures.

[00:43:18] Speaker 02:
On the mixture, why is the definition silent as opposed to specifically excluded?

[00:43:29] Speaker 02:
Because you have these non-amino acid molecules that are essential to the pharmacological effect.

[00:43:39] Speaker 02:
You told me earlier that we have to think of the non-amino acid component as part of the active ingredient, and that would seem to make it not a protein.

[00:43:52] Speaker 07:
So the way FDA thinks about it is that it's not addressed because it contains an alpha amino acid polymer that otherwise meets the requirements, but also contains this other product.

[00:44:03] Speaker 07:
So sort of from a practical perspective, that's not quite the same as failing to meet the defining characteristic of a protein as set forth in the regulation.

[00:44:13] Speaker 07:
That seems to be more specifically excluded.

[00:44:16] Speaker 07:
You could, Your Honor, say that the mixtures are also excluded in some sense.

[00:44:20] Speaker 07:
There's some difference between it

[00:44:21] Speaker 07:
nature and extent to which it's excluded.

[00:44:25] Speaker 07:
OK, thank you.

[00:44:26] Speaker 05:
Has FDA approved anything as a mixture or anything as analogous to a protein?

[00:44:31] Speaker 07:
Yes.

[00:44:31] Speaker 07:
So there, as I mentioned, Your Honor, there are three products there are that FDA has evaluated and considered to fall within the definition of a naturally derived mixture with a protein component and a non-biological component.

[00:44:44] Speaker 07:
One of them is a product called Infosurf.

[00:44:48] Speaker 07:
The active ingredient there is chalfactant.

[00:44:50] Speaker 07:
It's a product for respiratory distress in newborns.

[00:44:53] Speaker 07:
And in that product, there's a protein called surfactant B. It's a surfactant protein.

[00:44:59] Speaker 07:
And that protein is an alpha amino acid polymer with a specific defined sequence that's 79 amino acids.

[00:45:06] Speaker 07:
That product also has a peptide, something that's fewer than 40.

[00:45:09] Speaker 07:
And then it has a non-biological component in that all of those components work together.

[00:45:14] Speaker 07:
They're all part of the active ingredient.

[00:45:16] Speaker 07:
Any of them alone couldn't have the specific therapeutic effect.

[00:45:20] Speaker 07:
but the protein component is necessary to the product's functioning and specifically contributes to that therapeutic effect.

[00:45:27] Speaker 03:
Can I just clarify something, one, what you were saying about dosage form.

[00:45:35] Speaker 03:
So in either the new drug application

[00:45:43] Speaker 03:
process, orange book process, or this biological product process, the purple book process.

[00:45:54] Speaker 03:
The FDA might approve one dosage form, but that doesn't necessarily mean that it approves all dosage forms of that active ingredient, right?

[00:46:10] Speaker 07:
That's right, Your Honor.

[00:46:11] Speaker 03:
So the FDA might

[00:46:13] Speaker 03:
approve extended release capsules, but not chewable tablets.

[00:46:21] Speaker 03:
If a company has approval to market extended release capsules containing the active ingredient, that company would be violating

[00:46:33] Speaker 03:
the Food, Drug, and Cosmetics Act, if they, without getting separate FDA approval, just started marketing chewable tablets with that, right?

[00:46:45] Speaker 03:
That's right.

[00:46:46] Speaker 03:
So in that sense, the FDA looks at the finished product as the drug product because

[00:46:58] Speaker 03:
you know, approval for one doesn't mean that it's going to be safe in another form, right?

[00:47:04] Speaker 07:
For approval purposes, it looks at formula.

[00:47:06] Speaker 07:
FDA looks at formulations and dosage forms.

[00:47:08] Speaker 07:
It looks at a host of factors.

[00:47:09] Speaker 07:
It looks at manufacturing.

[00:47:11] Speaker 07:
It looks at the purity or safety or effectiveness, depending on the kind of product.

[00:47:15] Speaker 03:
Exactly.

[00:47:16] Speaker 03:
And so when we're talking about biological products,

[00:47:22] Speaker 03:
doesn't it work the same?

[00:47:23] Speaker 03:
I mean, if the somatuline product that's ingested and the person has to get the daily ingestion by a doctor or at a hospital and that gets approved,

[00:47:43] Speaker 03:
That doesn't mean that Ipsen can then just come up with this extended release formulation and start marketing that without getting a separate approval, right?

[00:47:57] Speaker 07:
That's right, Your Honor.

[00:47:58] Speaker 07:
For approval, the formulation property matters.

[00:48:01] Speaker 07:
But for classification, that's not something that FDA, FDA has ever classified or drug or biologic based on formulation property or the concentration.

[00:48:10] Speaker 07:
This is at link JA 474.

[00:48:13] Speaker 07:
FDA doesn't look at dosage form there.

[00:48:17] Speaker 07:
And there's another product that's described in FDA decision letter to Ipsin named octrotide acetate.

[00:48:24] Speaker 07:
It's an octopeptide.

[00:48:26] Speaker 07:
It also mimics the function of somatostatin.

[00:48:29] Speaker 07:
That's approved for immediate and extended release.

[00:48:32] Speaker 07:
Both are approved as drugs.

[00:48:34] Speaker 07:
And for good reason, if you take a sort of more accessible example, it's not a protein, but if you think about ibuprofen, sort of everyday drug,

[00:48:42] Speaker 07:
It's regulated as ibuprofen.

[00:48:45] Speaker 07:
It's classified as a drug, whether it's an immediate release or extended release form.

[00:48:49] Speaker 07:
And so, too, when we're thinking about classifying a product like somatulin depo, for approval purposes, FDA looks at a host of factors.

[00:48:56] Speaker 07:
But those aren't all the same factors that FDA looks at for classification.

[00:49:00] Speaker 03:
For classification, the question is... So help me understand, then, what does 262J mean?

[00:49:11] Speaker 03:
because the language in 262J says that the food, drug, and cosmetic acts, including certain requirements, applies to a biological product subject to regulation under this section.

[00:49:30] Speaker 03:
except that a product for which a license has been approved under subsection A shall not be required to have an approved application under section 505 of the food, drug, and cosmetic.

[00:49:47] Speaker 03:
So there, this statute about kind of how we're regulating biological products

[00:49:54] Speaker 03:
It harkens back to, well, you don't have to have approval under the Food, Drug and Cosmetic Act.

[00:50:05] Speaker 03:
I mean, that's actually the whole point of this statute, right, is that this is a separate way to get approval.

[00:50:11] Speaker 03:
But you're saying that

[00:50:16] Speaker 03:
The final formulation is relevant to approval, but it's not relevant to classification.

[00:50:22] Speaker 03:
And that's why we don't care about final formulation or dosage form when you're trying to define biological product.

[00:50:36] Speaker 03:
This statute here, subsection J, isn't it talking about approved applications?

[00:50:43] Speaker 03:
I mean, how am I to reconcile what you've been telling me?

[00:50:47] Speaker 07:
So that statute does say what your honor said.

[00:50:50] Speaker 07:
And it sort of points to the fact that even biologic products are subject to certain requirements under the Food, Drug, and Cosmetic Act.

[00:50:58] Speaker 07:
Biologic products aren't, depending on the kind of product at issue, some of the requirements of the FDCA will also apply.

[00:51:05] Speaker 07:
significant purpose and a primary purpose, one might even say the biologic statutes, is to create this different approval pathway for products that are classified as biologics.

[00:51:14] Speaker 07:
But I think the key inquiry here is not what is the entire regulatory regime that applies to this kind of a product, but is this the kind of product that's subject to the different approval pathways for biologics?

[00:51:28] Speaker 07:
And so that question turns us on 262i1,

[00:51:34] Speaker 07:
I admit, Your Honor, it's not particularly availing.

[00:51:36] Speaker 07:
It just lists the kinds of products that are biologics.

[00:51:39] Speaker 07:
But FDA then defined one of those categories and gave it content in the regulation.

[00:51:46] Speaker 07:
And that's the regulation that sort of focuses our analysis here.

[00:51:49] Speaker 07:
And that regulation doesn't say to look at the finished dosage form.

[00:51:52] Speaker 07:
Neither does the statute, Your Honor.

[00:51:54] Speaker 07:
The statute says defines a biological product.

[00:51:56] Speaker 07:
Nowhere does it say look at the finished dosage form.

[00:51:59] Speaker 07:
and their practical.

[00:52:01] Speaker 03:
My point is that this language in subsection J, 262 J, talks about, you know, we are exempting products that has a license that's been approved under as a biological product and then says shall not.

[00:52:26] Speaker 03:
be required to have an approved application under Section 505 of the Food Drug and Cosmetic Act.

[00:52:38] Speaker 03:
And I guess what I'm trying to get at is to the extent that this is a fight about whether

[00:52:47] Speaker 03:
in this case turns on whether we're looking at the active ingredient as far as the octopeptide versus the active ingredient in the viscous gel nanotubes.

[00:53:06] Speaker 03:
If in order to get the application approved under the Food, Drug, and Cosmetic Act, they really evaluated the gel, the extended release gel, because that's what you do when you get those applications approved.

[00:53:24] Speaker 03:
It's approved for a particular formulation.

[00:53:30] Speaker 03:
is that being incorporated here via this language in subsection J, section 262?

[00:53:41] Speaker 07:
So I think the direct answer to your question, Your Honors, no.

[00:53:45] Speaker 07:
Subsection J isn't speaking to classification.

[00:53:47] Speaker 07:
It's true that a product for which there's an approved application under the biologic statute doesn't require an approved application under the Food, Drug, and Cosmetic Act, but that

[00:54:00] Speaker 07:
That requirement doesn't then lead to the conclusion that all of the features outlined in the biologics application or in a new drug application are relevant for classification purposes.

[00:54:13] Speaker 07:
The question of whether something is a protein doesn't turn on whether what its dosage form is a protein, whether you look at it in a tablet form, gel form, capsule form.

[00:54:26] Speaker 07:
And it's important here to note, this would be a harder question if Ipsen had

[00:54:30] Speaker 07:
in its produce, or in its product labeling, or in its new drug application, frankly, had ever said the nanotube is the active ingredient.

[00:54:38] Speaker 07:
But it didn't.

[00:54:39] Speaker 07:
At every stage, Ibsen said, the active ingredient is just that octopeptide.

[00:54:44] Speaker 07:
So this isn't a case where you have to think about the nanotube as the relevant ingredient.

[00:54:49] Speaker 07:
The nanotube is, for purposes of this case, no different from other dosage forms, the tablet, the pill, the gel, the injection, a syringe.

[00:54:59] Speaker 07:
Even though that particular subsection of 262 cross-references the Food, Drug, and Cosmetic Act, that doesn't tell us how to think about the question for classification purposes.

[00:55:10] Speaker 07:
For classification purposes, we look at the active ingredient because that's the only logical thing to look at.

[00:55:15] Speaker 07:
To conclude otherwise would be to say Congress intended in writing 262i1 and defining the different categories of things that are biologics intended for FDA to look at the formulation, property, or dosage form

[00:55:29] Speaker 07:
which FDA has never done, all of the products that were transitioned, pursuant to the transition statute as proteins to biologics regulation, FDA looked only at the active ingredient.

[00:55:40] Speaker 07:
And that's why Ipsen conceded, from the very start of its brief, on pages 11, 20, and 30 of its brief, in its reply, it quotes FDA's brief and says, look, proper unit of analysis is the active ingredient.

[00:55:51] Speaker 07:
And so it wouldn't.

[00:55:54] Speaker 03:
finish the sentence in their brief.

[00:55:56] Speaker 03:
They said active ingredient in its final formulation.

[00:56:02] Speaker 03:
That's what they said in their brief.

[00:56:04] Speaker 03:
That's the gist of their cut off.

[00:56:06] Speaker 03:
You cut off the rest of sentence.

[00:56:09] Speaker 03:
And that's the whole thing that we've been debating about here for the last hour.

[00:56:15] Speaker 07:
In certain sections, they've said that that's true, that they should look at the active ingredient in the finished dosage form.

[00:56:20] Speaker 07:
And FDA says that active ingredient in the finished dosage form is still the land re-tide acetate.

[00:56:25] Speaker 07:
No one has ever said the active ingredient is an octopeptide somewhere outside the body and then nanotubes inside the body.

[00:56:33] Speaker 07:
Even inside the body, the active ingredient is still the octopeptide.

[00:56:36] Speaker 07:
And we know that because Ibsen explains

[00:56:38] Speaker 07:
in its drug approval application, and it's labeling that the unit that binds to the receptors that has the specific pharmacological effect of treating the indications for which this product is approved, that's carcinoid syndrome, sacromegaly, is that octopeptide.

[00:56:53] Speaker 07:
And so the nanotubes, from that you can infer, you don't have to infer, it's very clear from everybody's papers, are controlling the frequency of dosing.

[00:57:02] Speaker 07:
They're part of the dosage form, part of the analysis, and I think, Your Honor,

[00:57:05] Speaker 07:
trained in very early on 314.3, be as a helpful regulation for defining these different components of the product.

[00:57:12] Speaker 07:
And it's clear if you look at those different definitions and that regulation, how to look at these different parts of the product or these different stages, however you might characterize them.

[00:57:21] Speaker 03:
Just so I'm clear.

[00:57:23] Speaker 03:
When you use the term classification, you're using it to mean whether it's classified at the high level as a drug product versus as a biologic product.

[00:57:38] Speaker 03:
Is that how you're using it?

[00:57:39] Speaker 07:
That's right, Your Honor.

[00:57:39] Speaker 07:
Whether it's regulated for approval purposes as a biologic or drug, as Your Honor described earlier.

[00:57:46] Speaker 03:
Any other questions?

[00:57:47] Speaker 03:
All right.

[00:57:48] Speaker 03:
Thank you.

[00:57:48] Speaker 07:
Thank you.

[00:57:49] Speaker 07:
We urge this court to refer.

[00:57:58] Speaker 03:
All right, Mr Burgess.

[00:58:00] Speaker 01:
Thank you, Your Honor.

[00:58:01] Speaker 01:
Brian Burgess for Imogen Pharmaceuticals.

[00:58:03] Speaker 01:
I'd like to address, Your Honor, Judge Wilkins' questions regarding the regulation for what is an active ingredient that I'd like to touch briefly on analogous product or maybe say a word to conclude about remedy should the court find a need to reach it.

[00:58:16] Speaker 01:
So on the regulation for an active ingredient, you asked about or other direct effect, whether that could encompass

[00:58:25] Speaker 01:
dosage form, whether something is an extended release.

[00:58:29] Speaker 01:
And as government counsel indicated, the regulation specifically distinguishes the active ingredient, the drug substance from the drug product, from the dosage form.

[00:58:40] Speaker 01:
So it's well established FDA practice that the properties of a dosage form, determining whether it's an immediate release or an extended release, those are pharmacokinetic properties.

[00:58:49] Speaker 01:
but they're distinct from what's actually having the pharmacological effect.

[00:58:53] Speaker 01:
That's not what is determining what the active ingredient is.

[00:58:57] Speaker 01:
And I think it would work a pretty dramatic revolution in FDA practice if that kind of dosage form, that dosage property were considered to be part of the active ingredient.

[00:59:07] Speaker 01:
One thing that I think is worth noting, part of this statute, the trans... Yes.

[00:59:10] Speaker 05:
What would be a direct effect that's not a pharmacological effect?

[00:59:14] Speaker 05:
What would be an other direct effect?

[00:59:16] Speaker 01:
I think I don't know the full scope of what the agency is determined to be.

[00:59:21] Speaker 01:
I do know that it is excluded from our co-kinetic effects that just determine the release rate of the product and how it operates.

[00:59:30] Speaker 05:
So whatever it is, it's not this.

[00:59:31] Speaker 01:
It's not this.

[00:59:32] Speaker 01:
It's not this.

[00:59:33] Speaker 01:
Yeah.

[00:59:33] Speaker 01:
I'm sure the FDA has

[00:59:37] Speaker 01:
has used that term in other places as kind of a catch-all, but it's clearly excluded these kind of release properties and what the rate of release of a drug product is.

[00:59:47] Speaker 01:
One thing the statute did, the transition statute, the BPTIA, was about creating a new abbreviated pathway for biosimilars as compared to because it had found that these more complicated protein other products, the ordinary generic show the same active ingredient

[01:00:06] Speaker 01:
pathway wasn't working, so they developed a new pathway.

[01:00:09] Speaker 01:
It would be a really odd result if, as a result of the statute and the agency's implementation of it, you would have some products that have the same active ingredient being subject to the similar pathway versus the ANDA pathway just based on concentration or other formulation properties.

[01:00:27] Speaker 01:
That would be a really odd

[01:00:28] Speaker 01:
I mean, these are the same, it's the same ingredient either way.

[01:00:32] Speaker 01:
And yet if you're having formulation properties make the difference, you have a totally different review standard that the agency applies.

[01:00:39] Speaker 01:
You have different reviewers engaged in this process.

[01:00:42] Speaker 03:
But in my past life, I used to litigate and the cases.

[01:00:48] Speaker 03:
And you would have people who would get patents for a different formulation.

[01:00:55] Speaker 03:
of an active drug, something that could be ingested in a capsule instead of ingested intravenously.

[01:01:07] Speaker 03:
In the FDA, you'd have to get a different new drug application for that different formulation, the capsule formulation, than the liquid, ingestible formulation.

[01:01:26] Speaker 03:
So, I mean, doesn't it happen all the time that the FDA, even if they're, I understand it's all the same classification as a drug product, but that they look at different formulations and it has to go through a whole separate application process depending on the formulation?

[01:01:48] Speaker 01:
You would need to get a new approval.

[01:01:50] Speaker 01:
You can sometimes buy a supplement.

[01:01:52] Speaker 01:
You can rely on the previous approval.

[01:01:54] Speaker 01:
And of course, the whole point of Ibsen's suit here is because they don't want us to be able to rely on the prior approval of this active ingredient as being safe and effective.

[01:02:03] Speaker 01:
They argue we need to go through a whole other regime and meet the different standards.

[01:02:08] Speaker 01:
That's what the suit is about, why they are trying.

[01:02:11] Speaker 03:
I want you to have to do all of that.

[01:02:12] Speaker 01:
that'll take you years right and they didn't them years of exclusive right and they didn't do it by the way they were of course approved under the drug approval regime and then now they're trying to transition by taking advantage of the transition statute to block a safe and effective product but yes your honor is right I mean certainly you have to get new approval for a different

[01:02:30] Speaker 01:
dosage form, but it's based on the same active ingredient.

[01:02:34] Speaker 01:
There's often an abbreviated process.

[01:02:35] Speaker 01:
You could use a 505b2 process or if it's your own application supplement, which has abbreviated review because you're relying on the agency's previous determination that the active ingredient is safe and effective for its intended use.

[01:02:50] Speaker 01:
And there are

[01:02:51] Speaker 01:
The Sandoz case that Judge Rao issued the decision on about a year ago focused on the fact that the active ingredient, for example, is what you determine whether you get new chemical entity exclusivity.

[01:03:01] Speaker 01:
So it's baked into the approval process that it's focused on the active ingredient.

[01:03:07] Speaker 01:
Yes, you get the overall drug product approved.

[01:03:10] Speaker 01:
Ibsen has not disputed that what we are ultimately looking to is the active ingredient in this product.

[01:03:17] Speaker 01:
The active ingredient in this product is something they described on their label repeatedly as being the octopeptide.

[01:03:23] Speaker 01:
Because 8 is less than 40, I really think that ought to decide this case.

[01:03:28] Speaker 01:
And I do want to push back on the suggestion that it's a new inquiry because we're dealing with the biological product pathway and the purple book versus drug approval.

[01:03:39] Speaker 01:
Ibsen is relying on regulations and cases from the drug approval context.

[01:03:43] Speaker 01:
They said it's the same.

[01:03:45] Speaker 01:
You look at the question of whether it is an active ingredient.

[01:03:47] Speaker 01:
And it would be quite odd, I think, if it was a different inquiry, because after all, we're trying to determine whether it goes in the drug process or whether it goes in the biological product process.

[01:03:56] Speaker 01:
And if the answer you get differs depending on where you start, that just couldn't work.

[01:04:01] Speaker 01:
So we are looking generally for what is the active ingredient.

[01:04:05] Speaker 01:
The agency has applied that consistently.

[01:04:07] Speaker 01:
The regulation clearly distinguishes between usage forms formulation properties versus what is actually having the pharmacological effect.

[01:04:16] Speaker 01:
Your honor also asked about the second sentence in the regulation involving

[01:04:20] Speaker 01:
a chemical change.

[01:04:22] Speaker 01:
What we think that that addresses is a situation that courts, FDA and the courts have dealt with cases involving pro drugs, where you have something that actually does metabolize into something different in the body.

[01:04:33] Speaker 01:
That's the active Elizabeth case from this court in 2010.

[01:04:36] Speaker 01:
And Ibsen relied on that below and has not relied upon it here, because Judge Friedrich, this is at joint appendix page 169, footnote 13,

[01:04:47] Speaker 01:
explained why that decision is not relevant here, because the lanurotide acetate is in the drug product all along.

[01:04:55] Speaker 01:
There's not a conversion where it changes into something different.

[01:04:58] Speaker 01:
And so that aspect of the regulation, we just don't think is relevant.

[01:05:04] Speaker 01:
On the analogous product, unless the court has any other questions about the protein issue, I agree with the government that ultimately all the court needs to decide here is, yes, analogous isn't going to mean the same thing.

[01:05:18] Speaker 01:
We think that's common ground, but it needs to share critical characteristics that I think is also ought to be common ground as to what it means

[01:05:24] Speaker 01:
to be analogous.

[01:05:25] Speaker 01:
And FDA has identified size as being a critical characteristic to determine whether something functioning is being like a protein.

[01:05:33] Speaker 01:
They've identified a bright line in the 40 amino acids.

[01:05:37] Speaker 01:
And as Judge Friedrich indicated, this one's not even close, because this is only an 8-peptide chain that is far below what could ever be considered a protein or like a protein.

[01:05:49] Speaker 01:
There's a reference.

[01:05:51] Speaker 01:
believe at 271 of the Joint Appendix where the agency indicates there's often gray area.

[01:05:57] Speaker 03:
But don't we have somewhat of a chinnery problem if we conclude that to the extent that the FDA when it ruled in this case that something can't be analogous to a protein if it has less than 40 amino acids.

[01:06:18] Speaker 03:
It just can't be.

[01:06:20] Speaker 03:
It just categorically can't be analogous.

[01:06:25] Speaker 03:
You seem to be saying, well, okay, I'm not defending that, but size is a relevant characteristic.

[01:06:33] Speaker 03:
And so eight isn't even close to 40, so we can say that that's a reasonable interpretation of the regulation.

[01:06:49] Speaker 03:
If it were 39, you know, Ibsen might have a case, but it's only eight.

[01:06:57] Speaker 03:
But all of that may be true, but that's not the way that

[01:07:02] Speaker 03:
the agency performed its analysis.

[01:07:05] Speaker 03:
So isn't that a generic?

[01:07:07] Speaker 01:
So to be clear, I think the agency applied the 40 line and that line was reasonable and that provides a sufficient basis to affirm.

[01:07:14] Speaker 01:
I was noting that as Judge Friedrich did that this case was not close, but ultimately whether you're determining it as a protein or analogous, if the agency is allowed to decide that size matters because that is relevant to determining complexity, there's going to be a line drawing problem.

[01:07:32] Speaker 01:
it is sensible that the agency would draw the same line for protein and analogous when it's dealing with the size feature.

[01:07:38] Speaker 01:
I agree, analogous needs to sweep more broadly than protein as a category.

[01:07:43] Speaker 01:
And we think the mixture example shows that it does.

[01:07:46] Speaker 01:
But when dealing with size in particular, it would be very odd if the agency were required to say 40 is a protein and 30 is analogous to a protein.

[01:07:53] Speaker 01:
I mean, it's really the same inquiry that size is a fundamental characteristic of whether something is a protein or analogous to it.

[01:07:59] Speaker 01:
And so it's sensible.

[01:08:00] Speaker 03:
And whether characteristics

[01:08:02] Speaker 03:
that makes something analogous other than the kind of three characteristics that defines whether something is a protein.

[01:08:11] Speaker 01:
So we agree with the government's characterization.

[01:08:13] Speaker 01:
The agency has provided clear rules of exclusion.

[01:08:17] Speaker 01:
It can't be out analogous to a protein that lacks these fundamental characteristics, one of which is size.

[01:08:24] Speaker 01:
It seems to have treated the analogous product category as a small residual category that is going to be able to sweep in things that are not clearly contemplated in or out of the rule.

[01:08:33] Speaker 01:
And we think the mixture example

[01:08:35] Speaker 01:
Certainly fits that in the argument that a mixture that contains a protein is actually just a protein.

[01:08:41] Speaker 01:
We don't think that can be right because as everyone here agrees if you're looking at the active ingredient.

[01:08:47] Speaker 01:
Okay, well the way the FDA interprets active ingredient in a mixture context that looks at the overall product.

[01:08:52] Speaker 01:
So it makes no more sense to say, well, it's really a protein when you have a mixture of a protein and a lipid, and to say, actually, it's really a lipid.

[01:09:01] Speaker 01:
So it doesn't fit cleanly into the category.

[01:09:03] Speaker 01:
The agency has said in the memorandum, and this is addressed in the TEVA decision, there's some discussion of the memorandum actually outlining the mixture example.

[01:09:13] Speaker 01:
If you have a mixture that is primarily composed of protein components, that's a protein.

[01:09:17] Speaker 01:
The agency acknowledges that.

[01:09:19] Speaker 01:
But what the analogous product mixture is designed to encompass

[01:09:22] Speaker 01:
You have a situation where the protein is contributing to the therapeutic effect.

[01:09:27] Speaker 01:
It's necessary for it, but it might only be a small part of it.

[01:09:29] Speaker 01:
There are other necessary components.

[01:09:31] Speaker 01:
It could be that there's a much greater concentration of lipids in this mixture than protein.

[01:09:35] Speaker 01:
So it wouldn't make sense to say, because it contains this one component out of others, it's a protein.

[01:09:41] Speaker 01:
The agency has included this analogous to one.

[01:09:43] Speaker 05:
Mr. Rogers, if we concluded that this mixture category was a null set, would that be a problem for the agency's interpretation?

[01:09:51] Speaker 05:
included as a null set and there was like there was nothing in fact that was analogous to a protein that wasn't a protein stance.

[01:09:57] Speaker 01:
The district court suggested the null set would be a problem.

[01:10:02] Speaker 01:
As my colleague from the government indicated, it's clearly not a null set.

[01:10:05] Speaker 01:
The agency has identified products that fit within this category and has transitioned them as a result.

[01:10:10] Speaker 01:
In terms of whether it would be, as a statutory interpretation matter, it would be a problem.

[01:10:14] Speaker 01:
I think everyone agrees that analogous product modifies, as a grammatical matter, all the enumerated categories on the list.

[01:10:21] Speaker 01:
including proteins, so it needs to be analytically possible that there would be an analogous product, but whether it's an empirical matter, there would be something that fits into that category or how many there would be.

[01:10:31] Speaker 01:
We don't think the statute speaks to that, and that's how I understood Judge Friedrich's point on that category, that if you don't identify a substantial number or even any examples, that doesn't mean that this is a superfluous term.

[01:10:44] Speaker 02:
Is this a fair summary?

[01:10:46] Speaker 02:
of your position, which is when you look at the definition, any essential element of the definition will be a critical characteristic for purposes of this analogous assessment.

[01:11:05] Speaker 02:
And therefore, what's swept in by analogous is just

[01:11:11] Speaker 02:
Um, things as to which definition is silent or ambiguous.

[01:11:16] Speaker 01:
I think that's essentially right.

[01:11:18] Speaker 01:
I mean, the definition doesn't doesn't have that many criteria.

[01:11:20] Speaker 01:
It's not a list of a dozen things that it needs to satisfy.

[01:11:23] Speaker 01:
It needs to be an alpha amino acid.

[01:11:25] Speaker 01:
It needs to be a chain of at least 40.

[01:11:27] Speaker 01:
amino acids, and it needs to be a definite, you know, specific defined sequence.

[01:11:32] Speaker 01:
It needs to be those three things.

[01:11:34] Speaker 01:
We think that Ibsen's argument that the Teva case supports them is clearly incorrect.

[01:11:38] Speaker 01:
It was just one of the two or one of the three criteria that were at issue there.

[01:11:42] Speaker 01:
But yes, I think that's essentially right.

[01:11:44] Speaker 02:
Which solves your surplusage problem.

[01:11:48] Speaker 02:
It's just a very odd way of saying construe the term protein to include cases of ambiguity.

[01:11:58] Speaker 01:
Well, the analogous product category does modify each of these terms.

[01:12:02] Speaker 01:
It's been in the statute since 1902.

[01:12:03] Speaker 01:
And Ibsen, I think this is at page 400 of the Joint Appendix, it's acknowledged that there's not going to be a clear way to apply analogous across each enumerated category.

[01:12:15] Speaker 01:
It's going to be something that depends case by case.

[01:12:18] Speaker 01:
It's a scientific judgment.

[01:12:19] Speaker 02:
And maybe there's a square peg round hole problem when Congress just sticks protein into the list long after analogous was already there.

[01:12:30] Speaker 01:
Well, we think that it creates a situation where the agency has to reasonably interpret how to apply it.

[01:12:34] Speaker 01:
It understands analogous is going to share certain fundamental characteristics but not be coterminous with.

[01:12:41] Speaker 01:
How it hashes that out is something that it can do on a case by case basis and that it has done reasonably here.

[01:12:47] Speaker 01:
If the court has no other questions on the merits, I did just want to note that we had an objection on remedy to Ibsen's argument that even if, for example, a court were to conclude that the agency hadn't adequately explained what an analogous product is, that

[01:13:02] Speaker 01:
By no way would justify an order removing our client's product from the market.

[01:13:07] Speaker 01:
Status quo is that Ibsen's product is regulated as a drug.

[01:13:11] Speaker 01:
If there is a court order finding FDA's reasoning inadequate, then that decision would be vacated and the agency would have to determine

[01:13:20] Speaker 01:
based on the court's reasoning, what the right analysis is.

[01:13:23] Speaker 01:
But it wouldn't automatically convert Ipsin's product to being a biologic.

[01:13:26] Speaker 01:
It wouldn't preclude the FDA's determination that invigin's product is safe and effective and should be able to stand the market.

[01:13:33] Speaker 01:
And it would be quite disruptive to order the removal of an oncology product that people have been using for a number of years.

[01:13:41] Speaker 01:
It's an extended-release product.

[01:13:43] Speaker 01:
from the market.

[01:13:44] Speaker 01:
So we don't think that issue is actually presented here, both because the court should affirm and because the district court didn't reach remedy and we didn't take abstinence reply brief to dispute the notion that if there is a question about remedy, that should be addressed on remand.

[01:13:55] Speaker 01:
But we did want to make sure the court was aware of that issue.

[01:13:59] Speaker 01:
Thank you.

[01:13:59] Speaker 03:
Thank you.

[01:14:02] Speaker 03:
All right.

[01:14:02] Speaker 03:
Miss Stetson, you were out of time, but we'll give you three minutes.

[01:14:07] Speaker 06:
Thank you, your honors.

[01:14:07] Speaker 06:
Just a couple of quick points.

[01:14:10] Speaker 06:
The first is the product that was submitted to FDA, that was reviewed, that was approved, and that Invagen used as its reference product is a product with lanreotide acetate in complex nanotube structures.

[01:14:24] Speaker 06:
Now that, of course, we're talking about a transition from a drug product to a biological product, all of a sudden the lanreotide acetate in those complex nanotube structures doesn't matter.

[01:14:33] Speaker 06:
What matters is the eight

[01:14:35] Speaker 06:
chain, octopeptide, that is not consistent with the way that FDA, as Judge Wilkins, you asked counsel for the government, that is not consistent with the way that FDA reviews, approves drug products or biological products, and it's not consistent with the way in which those products are used as reference products.

[01:14:54] Speaker 06:
The second is, FDA counsel, in response to your question, Judge Katz, said, FDA does not understand analogous to be close to a protein, but not quite.

[01:15:04] Speaker 06:
that I think is the exact problem.

[01:15:07] Speaker 06:
What FDA's counsel then went on to say is, if something that contains a protein that, where the protein is necessary for functioning of the product and specifically contributes to the functioning of the product, that can be a protein that's in a mixture.

[01:15:22] Speaker 06:
But as we say at page 18 of our reply brief, what FDA has said before, and this is the Amarin case that we cite there, a mixture is treated as a single active ingredient.

[01:15:35] Speaker 06:
So a mixture containing a protein is a protein.

[01:15:39] Speaker 06:
The third thing I want to say has to do with the Teva case because I take a little bit of issue with the idea that we're not accurately reciting what was said there.

[01:15:47] Speaker 06:
What FDA said in Teva,

[01:15:50] Speaker 06:
and you can find this at pin site 113, is that the critical component of a protein is the specific defined sequence.

[01:16:01] Speaker 06:
FDA's description was seconded by the district court at page 115 as the touchstone of a protein being specific defined sequence.

[01:16:10] Speaker 06:
And here's what the district court said.

[01:16:12] Speaker 06:
Under FDA's construction, I'm quoting,

[01:16:15] Speaker 06:
It's simply restricted to products that although they may not satisfy the criteria to be a protein in other respects, have the characteristic specific defined sequence of amino acids.

[01:16:27] Speaker 06:
The specific defined sequence, of course, clearly exists here.

[01:16:30] Speaker 06:
Now that it does, FDA's critical touchstone component becomes something different.

[01:16:35] Speaker 06:
This structure in the final product of lanreotide acetate is a protein

[01:16:42] Speaker 06:
Lanreotide acetate and samashalin depot should be treated as a biological product.

[01:16:48] Speaker 06:
And the remedy should be, of course, that it should be transferred over to the biological product category.

[01:16:53] Speaker 02:
Do you think the statutory structure which distinguishes proteins from things analogous to proteins forecloses FDA from using a bright line regulatory definition

[01:17:12] Speaker 02:
as opposed to a fact and circumstances and maybe it's 40, but not quite.

[01:17:19] Speaker 02:
So we'll give you 38 and everything just devolves into case by case assessments.

[01:17:25] Speaker 06:
I think for purposes of defining protein, FDA could and did permissibly decide that it was going to try to create some bright line rules.

[01:17:35] Speaker 06:
I do think to your point, Judge Katz's earlier,

[01:17:38] Speaker 06:
The idea that something has to be analogous to a protein and it can't be a null set does muddy the waters a little bit.

[01:17:46] Speaker 06:
Then the question is, what's the baseline that's required?

[01:17:50] Speaker 06:
FDA has already said...

[01:17:51] Speaker 06:
what the baseline is.

[01:17:52] Speaker 06:
It has to be, at least the critical thing, is a specific defined sequence of amino acids.

[01:17:58] Speaker 06:
And here what we would suggest is when you're looking at this product, the product that was reviewed, submitted, approved, and referenced, and you have a specific defined sequence of amino acids that is a complex structure of many, many peptides put together, that thing is a protein.

[01:18:15] Speaker 06:
That's analogous to the protein at the very least.

[01:18:19] Speaker 03:
Thank you for the questions.

[01:18:20] Speaker 03:
Thank you.