[00:00:00] Speaker 00: Case number 16, S5229, Osuka Pharmaceutical Company Limited & L Appellants vs. Sylvia Matthews Burwell, Secretary & L. Mr. Saunders for the Appellants, Mr. Whitaker for Federal Appellees, and Mr. Jay for Intervenor Appellees. [00:00:45] Speaker 02: Good morning. [00:00:47] Speaker 07: May please the court. [00:00:49] Speaker 07: The FDA improperly treated alchemy's compound and the Atsuka compound it becomes in the body to achieve its therapeutic effect as legally equivalent for purposes of approving alchemy's drug, but as distinct for purposes of ignoring Atsuka's exoskeleton. [00:01:06] Speaker 04: Now legally equivalent is entirely your turn, right? [00:01:09] Speaker 04: Yes, legally equivalent is our term to describe what happened here because under... There are actually different provisions and statutes that are being brought into play that you're [00:01:18] Speaker 04: making a sort of all purpose term legally equivalent. [00:01:24] Speaker 07: Well they are two provisions of an integrated statute that in this respect have parallel structure because a 505b2 application [00:01:33] Speaker 07: must still meet all the requirements of 505B1. [00:01:36] Speaker 07: The only difference is you're relying on somebody else's studies. [00:01:40] Speaker 07: In 505B1, so the application to show the safety and efficacy of alchemy's drug, required studies, quote, made to show whether or not such drug is safe and effective. [00:01:55] Speaker 04: Yes, and whether to emphasize such drug. [00:01:57] Speaker 07: Right, and so the structure there is approval of alchemy's application [00:02:04] Speaker 07: the two compounds as legally equivalent, otherwise studies made to show that erpiprazole is safe and effective couldn't meet their requirement of showing that their compound was safe and effective. [00:02:17] Speaker 07: And so the problem with the FDA's interpretation is they gave a broad meaning and allowed such drug to encompass both at the same time for purposes of approval. [00:02:31] Speaker 07: But then when you come to take the bidder with the suite and have the parallel exclusivity provision. [00:02:43] Speaker 07: No, the fundamental structure of the statute here is that the follow-on applicant has a choice, and if they choose to rely on the studies of the pioneer applicant, then under the made to show whether or not such drug is safe and effective language, [00:03:04] Speaker 04: They are essentially saying that we are the same for these purposes. [00:03:17] Speaker 04: I mean, it seems to me when it uses the term such drug, conditions of approval of such drug, it perfectly reasonable, as a matter of language, reading that that is a drug which has certain core characteristic relating to previously applied, previously invoked, [00:03:42] Speaker 04: drugs and the FDA has to decide which characteristics are critical and it decided active moiety was critical. [00:03:56] Speaker 07: No, because I think there are two things. [00:04:00] Speaker 07: One is when you look at the conditions of approval of such drug, if you compare that structure to the structure of the patent certification, where someone is certifying to patents which claim a use for such drug for which the applicant is seeking approval. [00:04:20] Speaker 07: You have the same issue here, which is there you have a use for such drug, the pioneer drug, for which the applicant is seeking approval. [00:04:29] Speaker 07: So either one of two things is true, either such drug is a term that is not [00:04:36] Speaker 07: limited as narrowly as the FDA is saying it is for purposes of avoiding exclusivity or for purposes of a structure like that, a use for such drug, the operative language is use and the prepositional clause is orienting you but isn't limited. [00:04:53] Speaker 07: And here we have the same structure in the conditions of approval. [00:04:57] Speaker 07: It's conditions of approval of such drug. [00:05:00] Speaker 07: in terms of not necessarily equating those two, the of such drug being in the prepositional phrase, or if such drug is operative there, then it can't be interpreted more narrowly [00:05:15] Speaker 07: then the way that such drug would be interpreted for purposes of patent certification and for purposes of getting approval in the first place. [00:05:24] Speaker 01: When you say such drug, not for purposes of patent certification, I get the argument that we need to look for consistency across different provisions, but if we focus on the provision that's more directly at issue here, such drug, which drug are you talking about? [00:05:41] Speaker 07: the such drug in that refers back to the drug with exclusivity and based on these parallel provisions and structures of the statute, any equivalence of that drug that are close enough that studies of that would be considered made to show whether the follow-on applicant is approved? [00:06:05] Speaker 01: The last part of it I don't quite understand. [00:06:08] Speaker 01: it seems like you're presupposing that there's some relationship between the two drugs. [00:06:13] Speaker 01: In other words, it's not an entirely unmoored inquiry into conditions of approval. [00:06:19] Speaker 01: It's not the case that if one gets approval for a headache drug, then any other drug, no matter how distinct, that has to do with headaches is off limits that the exclusivity attaches to, even as to that, right? [00:06:32] Speaker 01: So there's some, [00:06:33] Speaker 01: relationship between the drug for which approval has already been obtained and as to which exclusivity attaches and the drug that we're talking about now that's asserted to be out of bounds because it's encompassed by the exclusivity provision. [00:06:50] Speaker 07: Right, the parallel with the patent provision points you to the broader definition, but we're saying the court doesn't need to go that far. [00:06:58] Speaker 07: There is a narrower but still clear and unambiguous interpretation here which arises from the such drug. [00:07:06] Speaker 07: It says even if you're going to give operative effect to that, then you have to be giving effect to that consistent across all these provisions. [00:07:13] Speaker 01: And what's the relationship between those two drugs? [00:07:15] Speaker 01: Because what the agency says is the relationship is active moiety. [00:07:20] Speaker 01: And if it's not a circumstance of active moiety, then we're not worried about exclusivity at that point, because we're talking about something different. [00:07:28] Speaker 01: And as I understand your position, you of course don't agree that it's active moiety, at least you think that. [00:07:34] Speaker 01: In fact, you think that reading is prohibited by the statute. [00:07:37] Speaker 01: But you also don't agree that [00:07:39] Speaker 01: that no association between the drugs would still be OK. [00:07:43] Speaker 01: There's got to be some kind of chemical association. [00:07:45] Speaker 07: Right, and it's the association that makes them close enough that you can rely on the pioneer to get approval. [00:07:54] Speaker 01: So any time you rely on the initial drug, the first in time drug, whatever relationship there is, your argument is, look, if the relationship is good enough for you to rely on it, then it's also good enough to trigger exclusivity. [00:08:08] Speaker 07: With the caveat that if it's good enough for you to rely on it and for the FDA to accept it. [00:08:13] Speaker 07: In other words, what the FDA can't do is both simultaneously. [00:08:16] Speaker 07: If you come in and say, I'm relying on this completely unrelated drug, the FDA can look at that and say, I don't see how the studies of the first drug are made to show that your drug [00:08:30] Speaker 07: is OK. [00:08:31] Speaker 07: So we could reject it as the application, but once those two are close enough. [00:08:35] Speaker 01: So if it rejects it, then you're wrong. [00:08:36] Speaker 01: Exactly. [00:08:37] Speaker 07: But once those two are close enough, then they have been legal. [00:08:42] Speaker 07: This is our idea of legal equivalence under the structure of the statute. [00:08:45] Speaker 07: And then at that point, those two would be treated the same carrying forward. [00:08:50] Speaker 01: And then what do you do with the recognition that [00:08:55] Speaker 01: You can rely on, you don't have to rely on a drug at all. [00:08:58] Speaker 01: You can rely on scientific literature. [00:09:00] Speaker 01: You could also rely on, I thought this was an interesting example brought up on the other side, I think it might have been by the intervener, but you can rely on an inactive ingredient. [00:09:10] Speaker 01: So you have something, it makes all the sense in the world to rely on an inactive ingredient because you would say, look, there's been a bunch of stuff that shows that the inactive ingredient doesn't pose any safety issue. [00:09:20] Speaker 01: So we're fine as far as that goes. [00:09:21] Speaker 01: So don't worry about that. [00:09:23] Speaker 01: It doesn't have anything to do with the helpful qualities of the thing for which we're seeking to get approval. [00:09:29] Speaker 01: It's just that you don't have to worry about the inactive part. [00:09:31] Speaker 07: Right, so for the inactive ingredient, I think that it's going to be pretty rare that someone's gonna go down the 505b2 path and open themselves up to exclusivity for an inactive ingredient as opposed to treating that, there's a line that's drawn in terms of when you are relying on previous studies between reliance on something that's in the literature or an approved application [00:09:57] Speaker 07: that's tied to a particular clinical trial as opposed to just background principles in the literature. [00:10:04] Speaker 07: Not every citation of background principle in the literature. [00:10:07] Speaker 07: So I think people are gonna avoid exclusivities on inactive ingredients by citing the background principles. [00:10:15] Speaker 07: Now, to the extent that something is subject to exclusivity in the sense that someone did a clinical study [00:10:27] Speaker 07: That clinical study was essential to the approval of the drug and the key condition of approval of that. [00:10:34] Speaker 07: What you're adding that's new is the new inactive ingredient. [00:10:39] Speaker 07: Then at that point, if someone is relying on that as part of their drug, then I think you could say that they are equating the two, even though it is the inactive ingredient. [00:10:49] Speaker 07: I just think it's a far-fetched hypothetical in reality, because people will easily find ways around this not to do it as a 505b2. [00:11:00] Speaker 07: But if they think the only way I can do this, the only way I can take this shortcut, [00:11:06] Speaker 07: is by citing the pioneer and their clinical approval and that's the way we're going to do it, then they would be equating the two and would have to accept the exclusivity. [00:11:18] Speaker 07: Now that question, of course, is not before this court because here we have a very tight connection in the sense that we have a... Right, but we're just trying to understand the implications of your position and I guess the implications of your position is that [00:11:31] Speaker 01: Any time, even though Congress clearly wanted to create a regime under which reliance was promoted in order to streamline the approval process, your position is, when you say take the bitter with the sweet, that means that whenever you rely, you're subject to exclusivity, period. [00:11:49] Speaker 01: Even if you're relying on it only for purposes of dealing with an inactive ingredient, still, exclusivity kicks in, and you've got to figure out a way to do it without relying. [00:12:00] Speaker 07: Right, if you've met the stringent requirements to have gotten exclusivity, which means it has to be essential for approval. [00:12:07] Speaker 07: So if there was background literature that predated the pioneer's application that related to that inactive ingredient, then it's going to be very difficult for the pioneer to have any exclusivity that is actually covering that inactive ingredient. [00:12:23] Speaker 07: But yes, once they do this, and because I think the congressional purpose was to balance these two provisions in the sense that they wanted streamlining. [00:12:33] Speaker 07: They wanted people to be able to rely on what came before, but under certain circumstances. [00:12:38] Speaker 07: And those circumstances mean [00:12:40] Speaker 07: respecting the exclusivity for the conditions of approval or change and in the scheme of things these are very short exclusivity periods for three years here or work out an agreement as often happens where you get a right to refer to the first and times applicant [00:12:59] Speaker 07: In other words, what you've done is you've created a rule that says, as the default, if you're going to do this, you'll have to respect their exclusivity, but created a ratting mechanism by which the parties can barge around. [00:13:09] Speaker 01: Is the period that short? [00:13:10] Speaker 01: Because as I understand it, it's three years. [00:13:11] Speaker 01: But what we're talking about here is [00:13:16] Speaker 01: I'm going to get the pronunciation wrong, is it arepiprazole? [00:13:18] Speaker 01: Arepiprazole, yeah. [00:13:19] Speaker 01: Okay, arepiprazole. [00:13:19] Speaker 01: So we're talking about arepiprazole, which that, for that in particular, was already at five years. [00:13:24] Speaker 01: And then we've tacked on a different three years because we're talking about a supplement. [00:13:28] Speaker 07: Well, no, you haven't tacked on it in three years. [00:13:30] Speaker 07: You've been given a separate and far narrower exclusivity period for three years. [00:13:35] Speaker 07: In other words, [00:13:37] Speaker 07: Alkermes was entirely free to make a tablet of Aripiprazole as the ten generic tablets that Dr. Kirlendew was entirely free to make its own tablet. [00:13:47] Speaker 07: It was entirely free to do a long-lasting injectable for some other indication of use. [00:13:52] Speaker 07: What happened here is it relied on Aripiprazole and it took the shortcut to the exact destination where Atsuka had exclusivity, which was for the long-lasting injectable [00:14:04] Speaker 07: And for the latest exclusivity period is for acutely relapsing patients. [00:14:10] Speaker 01: Right. [00:14:10] Speaker 01: Well, we don't know that yet, that part of it. [00:14:12] Speaker 01: I mean, that's your argument as to the scope of the exclusivity. [00:14:14] Speaker 01: I guess that hasn't been. [00:14:15] Speaker 01: The agency never got to that because the agency got off the train on active malady. [00:14:19] Speaker 07: That's correct. [00:14:19] Speaker 07: The agency decided this. [00:14:21] Speaker 04: Council, either the district court or opposing counsel made the argument that your view gives broader scope to the three-year exclusivity than to the five-year exclusivity, which they suggest is anomalous. [00:14:38] Speaker 04: And I didn't see an answer to that. [00:14:40] Speaker 07: Oh, no. [00:14:41] Speaker 07: Yeah, not at all. [00:14:42] Speaker 07: In the one respect. [00:14:44] Speaker 07: of active moiety, there's an argument because, number one, we get into tricky issues of whether the scope for five-year exclusivity is limited to the same active moiety, that there's a tension between the regulations and the statute. [00:15:00] Speaker 04: But even setting that aside... [00:15:03] Speaker 07: No, because there are other grounds by which the scope is narrower. [00:15:11] Speaker 07: Number one, you're talking about three years rather than five years. [00:15:14] Speaker 07: And number two, you're talking about five-year exclusivity attaches to the chemical for all of its uses. [00:15:24] Speaker 07: So it's very broad. [00:15:25] Speaker 07: It gives you almost more like patent protection. [00:15:28] Speaker 07: in the sense that if someone comes in and says, your drug for ADHD we now want to use for cancer, you still get to block them. [00:15:36] Speaker 07: Three-year exclusivity, because it's just the conditions of approval and the change, is far narrower and more targeted. [00:15:45] Speaker 07: And in particular, in this world, it gives you a lot less protection against off-label use, in the sense that if you have for approval, unlike if you've just kept the molecule out, [00:15:55] Speaker 07: If you've gotten your particular exclusivity for condition of approval, they're not going to be able to label the drug for that. [00:16:00] Speaker 07: They're not going to be able to promote for that. [00:16:02] Speaker 07: But if they can come in for some other indication, doctors will have flexibility. [00:16:06] Speaker 07: So the three-year exclusivity is still a far cry from the value of the five-year exclusivity, even without the identical actability requirement in it. [00:16:17] Speaker 07: And because the three years is focusing on that new and marginal innovation. [00:16:23] Speaker 07: What have you added? [00:16:25] Speaker 07: What is the change that you have made? [00:16:27] Speaker 07: And it's not focusing on what has remained the same. [00:16:30] Speaker 02: Thank you. [00:16:45] Speaker 05: May it please the court, Henry Whitaker for the FDA. [00:16:49] Speaker 05: The FDA reasonably concluded that the conditions of approval of a drug do not encompass the conditions of approval of a different drug with a different active moiety. [00:17:01] Speaker 05: And I take it that it is common ground in this case, as Judge Finlow-Watson pointed out, that to determine the conditions of approval of a drug requires some kind of comparison between the two drugs. [00:17:15] Speaker 05: And the FDA's way of making that comparison is indeed reasonable and in accordance with longstanding agency policy. [00:17:24] Speaker 05: And I would stress, in particular, this court's decision in activist, which addressed this question in a somewhat different context, but I think goes a long way towards saying that the FDA reasonably resolved the question for the court. [00:17:39] Speaker 05: I mean, in activist, the question was whether [00:17:42] Speaker 05: one drug that is a prodrug of another, of an already approved molecule, could be considered to be a new chemical entity entitled to five-year exclusivity. [00:17:51] Speaker 05: And the FDA said it was because it had a different active moiety than the already approved drug, even though, as it happened, the new chemical entity metabolized into the drug. [00:18:07] Speaker 01: So it seems like that case, of course, gets you a long way with respect to pro-drug, or at least that's your position, it gets you a long way with respect to pro-drugs, and the permissibility of using active moiety, at least in that context. [00:18:24] Speaker 01: But I take it that Atuka's position is, that's all fine and dandy, but what we're talking about here is a reliance. [00:18:30] Speaker 01: And once you rely on a study with respect to a particular drug, well, you're relying on that drug to show that your drug's OK. [00:18:39] Speaker 01: If you rely on that, you're subject to the exclusivity for that drug on which you relied. [00:18:43] Speaker 01: If you don't want to deal with exclusivity, then don't rely on it. [00:18:45] Speaker 01: And what's the agency's response to that? [00:18:48] Speaker 05: Well, exclusivity, Your Honor, in contrast to the general nature of the B2 pathway, does not depend on reliance. [00:18:55] Speaker 05: And I think that's because when a drug is submitted under the B2 pathway, reliance, in the sense in which that's appropriate, is a different sense than whether two drugs are the same. [00:19:06] Speaker 05: And the reason for that is because, look, as I think Your Honor pointed out, I mean, you can rely [00:19:12] Speaker 05: on a drug in obtaining approval that may be a significantly different drug. [00:19:17] Speaker 05: And the intervener cites the example of the inactive ingredient example that we've discussed already. [00:19:22] Speaker 05: But there are others. [00:19:23] Speaker 05: I mean, you know, JA 73-74, it's an agency document that talks about a number of different examples where the relied upon drug may be significantly different. [00:19:34] Speaker 05: I mean, for example, the US Army got approval of a drug to treat [00:19:39] Speaker 05: a nerve gas poisoning, I guess, on the basis of animal trials for efficacy. [00:19:45] Speaker 05: So the nature of the B2 pathways is quite different, I think, from exclusivity. [00:19:52] Speaker 05: And look, Atsuka, I take it, is hanging their hat on this argument from statutory structure. [00:19:59] Speaker 05: But when you examine the statutory structure, I think it becomes clear that Congress is using the term [00:20:05] Speaker 05: drug in a variety of different senses. [00:20:08] Speaker 05: I mean, in the B2 pathway, at the front end of the statue, the drug that is being referred to is the applied for drug, and here that would be Aristotle. [00:20:17] Speaker 05: That is the drug that is being referred to. [00:20:20] Speaker 05: Fast forwarding to one subparagraph later in the patent certification provisions, Congress reverts to referring to a relied upon drug, which in this case would be Abilify tablets. [00:20:32] Speaker 05: In the patent notice provision, the drug being referred to [00:20:36] Speaker 05: is, once again, the applied-for drug here, aerosada. [00:20:41] Speaker 05: And then fast-forwarding to exclusivity, the drug that is being mentioned when talking about such drug is the drug product of the drug that received exclusivity. [00:20:51] Speaker 05: So this is a term that is highly context-sensitive. [00:20:54] Speaker 05: And the idea that you could say that this is the only, Tsuca's reading is the only reasonable way [00:21:00] Speaker 05: to read the statute, I think, is inconsistent with how Congress employed those terms in a variety of different senses. [00:21:07] Speaker 05: And actually, I think the comparison with the patent certification provision only underscores that reliance is not the touchstone of exclusivity, unlike [00:21:16] Speaker 05: patent certification because there really is in that provision an explicit focus on what drug was relied upon in contrast to exclusivity in which the only mention of reliance in that provision direction is a mention of reliance, but it is only in defining the kinds of applications that exclusivity applies to, namely B2 applications. [00:21:41] Speaker 05: reading the statute in context and in structure only underscores that we've acted reasonably. [00:21:51] Speaker 02: Trying to understand this always gives me something of an excedrin headache. [00:21:57] Speaker 02: I need you to go back, speak a little slower, and let me see if I can figure out what's happening here, okay? [00:22:06] Speaker 02: So as I understand this, [00:22:09] Speaker 02: What SUCA is talking about is the definition of conditions of approval. [00:22:17] Speaker 02: That is to say, if the drug that you're relying on, active ingredient or not, was essential to the approval, I'm assuming, archima, is that the way it's pronounced? [00:22:33] Speaker 05: Alchemy. [00:22:34] Speaker 02: Alchemy, okay. [00:22:36] Speaker 02: So if that was essential to the approval of their drug, then you're implicating the conditions of approval [00:22:46] Speaker 02: of Atsuka's drug, and thus their exclusivity comes into play. [00:22:51] Speaker 02: Is that correct? [00:22:52] Speaker 05: I don't think that's quite their argument, Your Honor. [00:22:55] Speaker 05: The investigations that were essential to the approval of the drug product that was granted exclusivity here, AbilifyMaintena, and the supplement to AbilifyMaintena, [00:23:09] Speaker 05: Those were the relevant investigations that established Atsuka's exclusivity at issue here. [00:23:20] Speaker 05: What Atsuka objects to were the investigations that alchemies relied on in securing approval of Aristata, this new chemical entity under the B2 pathway. [00:23:32] Speaker 05: And in securing approval of Aristata, alchemies relied on not Abilify-Maintena, [00:23:39] Speaker 05: which is the drug in this case that was granted exclusivity. [00:23:43] Speaker 05: Instead, alchemists relied on these old findings with regard to Abilify tablets, which was created. [00:23:51] Speaker 05: And Abilify tablets was a drug that was approved in 2002. [00:23:54] Speaker 05: Its exclusivity expired. [00:23:56] Speaker 05: It wasn't titled exclusivity. [00:23:59] Speaker 05: It expired in 2003. [00:24:01] Speaker 05: Seven. [00:24:03] Speaker 02: So I understand, but the pioneer drug, though, the active ingredient, is the same in both. [00:24:10] Speaker 02: Is that right? [00:24:10] Speaker 05: No, that's not right, Your Honor. [00:24:12] Speaker 05: That's not right. [00:24:13] Speaker 05: OK. [00:24:14] Speaker 05: So the drug that was approved is Aristotle. [00:24:18] Speaker 05: The active moiety, there's no dispute in this case. [00:24:23] Speaker 01: No, I thought Judge Brown was asking about the two drugs being the tablet and then maintenance. [00:24:30] Speaker 05: Those two drugs have the same active ingredient, and active moib, which is aripiprazole. [00:24:38] Speaker 05: And that has a significant chemical structural difference from the drug that was approved here, Aristotle. [00:24:50] Speaker 02: And as it turns out, Aristotle actually- Okay, so just so I understand, so if those are different, then how could they rely on [00:25:01] Speaker 02: the studies for the pioneer drug in seeking approval? [00:25:05] Speaker 05: Certainly, Your Honor. [00:25:07] Speaker 05: You can rely on studies concerning a different drug. [00:25:11] Speaker 05: It doesn't necessarily mean the two drugs are the same if they have similar characteristics. [00:25:16] Speaker 05: And the touchstone for knowing whether that reliance is appropriate is you have to show that it is scientifically appropriate to rely on the different drug. [00:25:27] Speaker 05: I just sure Boston talked about the example of if you have a different drug with a different active ingredient, but has the same inactive ingredient from. [00:25:41] Speaker 05: as a previous drug. [00:25:42] Speaker 05: And you can rely on the fact that the previous drug's inactive ingredient was demonstrated to be safe and effective. [00:25:48] Speaker 05: In other words, Luke, I'm sorry, go ahead. [00:25:49] Speaker 02: No, well, I'm just trying to follow this. [00:25:52] Speaker 02: So here, though, we have two drugs whose active ingredient is the same or not. [00:25:59] Speaker 05: Well, it depends on which two drugs you're talking about, Your Honor. [00:26:01] Speaker 02: Well, I understand the pro drug. [00:26:03] Speaker 02: So is there a difference between active ingredient and effective [00:26:11] Speaker 02: ingredient, because it seemed to me that what they were saying was this one metabolizes to the same ingredient as the pioneer drug. [00:26:21] Speaker 05: Yes, but that doesn't mean the two drugs are equivalent. [00:26:24] Speaker 05: One example outside of this context is Allegra and Seldane. [00:26:29] Speaker 05: Seldane is a prodrug of Allegra, in that Seldane metabolizes into whatever Allegra is. [00:26:37] Speaker 05: but selenium is off the market and Allegra is not because, as it happens, selenium causes heart problems, whereas Allegra does not, even though they are prodrugs. [00:26:49] Speaker 05: So it is often the case that prodrugs, even though one metabolizes into another, have significant differences, and there's some evidence in this case that bears that out. [00:26:58] Speaker 05: After all, [00:27:00] Speaker 05: Aristotle is effective for up to 50% longer than Abilify-Masonet. [00:27:06] Speaker 05: And that's quite significant when you consider that the entire, one of the main purposes of having a long-lasting injectable for the treatment of schizophrenia, which is what Masonet does and what Aristotle does, is precisely because schizophrenia patients are not necessarily the best at taking their medicine. [00:27:24] Speaker 01: Well, and our prior decision [00:27:26] Speaker 01: seem to accept the proposition that even though one drug may be a prodrug of the other one, they can still be considered different drugs for purposes of new drug approval. [00:27:37] Speaker 05: That's exactly right, Your Honor, and that's precisely because when one drug has a different act of moiety than another drug, that in general means that it has a significantly different pharmacological effect. [00:27:49] Speaker 05: And that was certainly, the score did uphold that judgment in activists. [00:27:54] Speaker 05: in the court. [00:27:55] Speaker 01: We think that goes a long way towards- And just to pick up on the questions that Judge Ramm was asking, can I ask you this? [00:28:00] Speaker 01: So from the agency's perspective, is this a fair or unfair characterization when the B-2 applicant relies on a study concerning something that's already been approved? [00:28:13] Speaker 01: Is the way the agency views that reliance something along the following lines? [00:28:18] Speaker 01: Even though that's a different drug by hypothesis, it's still relevant to the approval of this drug because there's enough of a relationship that the safety and efficacy that was approved with respect to that one is germane to this one. [00:28:32] Speaker 01: That's a different drug, but it's still relevant. [00:28:34] Speaker 05: I think that's exactly right, Your Honor. [00:28:35] Speaker 05: And it's important to stress as well that it's not as if this leaves [00:28:40] Speaker 05: The original innovator, without any protection, I mean the patent certification provisions do require certification if they're relevant patents. [00:28:53] Speaker 05: And Natsuka certainly could have sued alchemies for patent infringement. [00:28:58] Speaker 05: It was duly given a notice that [00:29:02] Speaker 05: that there were certain patents that might have been infringed by Abilify, and it didn't take that option. [00:29:09] Speaker 05: So there certainly is robust intellectual property protection here. [00:29:13] Speaker 02: Again, just so I understand, is it true, as counsel said, that the FDA is interpreting this phrase, such a drug, differently [00:29:31] Speaker 02: in different provisions of the statute? [00:29:36] Speaker 05: We're not interpreting them inconsistently. [00:29:38] Speaker 05: I think we're interpreting them differently because they do mean different things depending on the statute. [00:29:43] Speaker 05: I mean, again, for example, the term such drug in defining the B2 pathway is just talking about [00:29:51] Speaker 05: the applied for drug, which is Aristotle in this case, and obviously such, I mean, the term such refers back to some drug that's originally mentioned. [00:30:00] Speaker 05: Just because Aristotle relied on a different drug doesn't mean that the term such drug is referring to as, quote, simultaneous reference to two different drugs. [00:30:11] Speaker 05: And again, so I think that what we're saying is that, I mean, the term drug is context [00:30:16] Speaker 05: sensitive. [00:30:16] Speaker 05: It doesn't necessarily mean the same thing everywhere it appears in the statute. [00:30:22] Speaker 01: I think the term drug means the same thing everywhere. [00:30:24] Speaker 01: It's just which drug you're talking about might be different, depending. [00:30:28] Speaker 01: Well, we're right. [00:30:28] Speaker 05: Although there is, sometimes drug refers to drug product. [00:30:33] Speaker 05: Sometimes drug refers to drug substance. [00:30:34] Speaker 05: I mean, there's various gradations even within just looking at the term drug. [00:30:39] Speaker 05: So it's a highly context sensitive term. [00:30:41] Speaker 05: And the idea that you could [00:30:43] Speaker 05: invalidate us as unreasonable based on that kind of structural inference seems to be not to hold water. [00:30:58] Speaker 02: They did have to give notice under the patent certification provision, right? [00:31:04] Speaker 02: So does that mean that FDA can approve a drug that would nevertheless be subject to an infringement action? [00:31:15] Speaker 02: Your approval has nothing to do with that. [00:31:17] Speaker 05: Yes, that's right, Your Honor. [00:31:19] Speaker 05: The statute takes patent law as it finds it, more or less. [00:31:25] Speaker 05: There is a stay of approval if they do bring a patent infringement suit in certain circumstances. [00:31:31] Speaker 05: But yes, whether it would infringe as a matter of patent law [00:31:34] Speaker 05: is a different matter. [00:31:36] Speaker 05: And I think that's one of the reasons why it is reasonable to interpret the patent certification provision a little bit differently, because that's really a prophylactic measure that's designed to capture any time a use for which an applicant is seeking approval might or might not meet with a potentially infringing patent. [00:31:56] Speaker 02: And so just one more question. [00:31:59] Speaker 02: FDA actually read these provisions in harmony. [00:32:04] Speaker 02: That is to say, the way Atsuka would like to read them. [00:32:09] Speaker 02: Would that protect from the patent infringement problem? [00:32:15] Speaker 02: Or would that make no difference? [00:32:18] Speaker 05: Well, I think if you accepted Atsuka's reading, we think our reading is quite harmonious. [00:32:24] Speaker 05: I understand that you do. [00:32:26] Speaker 05: Well, I mean, I think it would give [00:32:29] Speaker 05: give Atsuka a type of intellectual property protection under exclusivity that Congress never contemplated, or at least the agency reasonably concluded that Congress did not contemplate. [00:32:40] Speaker 05: Again, one of the anomalous things about Atsuka's position in this case is that they are claiming that effectively, Abilify Tablets exclusivity, which expired in 2007, can be sort of indefinitely extended by making subsequent more modest modifications [00:32:57] Speaker 05: to the drug. [00:32:57] Speaker 05: There's no question in this case, one of the oddities of this case, there's no question that alchemy didn't rely. [00:33:03] Speaker 05: on the new clinical investigations that ATSUKA conducted to secure approval of maintenance. [00:33:11] Speaker 05: It only relied on these very old studies, well, findings regarding a relatively old drug whose operation has been well known for some time. [00:33:22] Speaker 05: And I think that's exactly the kind of thing that Congress contemplated in creating the B2 pathway, was that so companies wouldn't have to [00:33:29] Speaker 05: reconduct clinical trials with regard to drugs whose effects are relatively well known. [00:33:36] Speaker 02: No, I think I understand your argument. [00:33:39] Speaker 02: They are arguing for a certain symmetry or reciprocity, and you're saying the agency doesn't read the statute that way. [00:33:48] Speaker 05: We do not read the statute to turn on reliance. [00:33:50] Speaker 05: No, Your Honor. [00:33:51] Speaker 05: And it's not as if this is always going to be sort of anti-exclusivity. [00:33:56] Speaker 05: I mean, we rely on the Veloxis case. [00:33:58] Speaker 05: I mean, there's sometimes where you can gain reliance to try to narrow the scope of exclusivity. [00:34:03] Speaker 05: So sometimes a drug [00:34:06] Speaker 05: applicant may try to rely on an old study to avoid exclusivity when in reality it's trying to copy a newer drug and we rejected that in Vlox. [00:34:16] Speaker 05: So reliance kind of works in both ways. [00:34:18] Speaker 05: I don't think that we've in any way read the statute to be, you know, [00:34:22] Speaker 05: not harmonious, I think that this is just a reasonable way of looking at the statute that reliance is something quite different and does not necessarily relate to the scope of exclusivity. [00:34:33] Speaker 05: And certainly there's nothing in the language of the exclusivity provision that would suggest that reliance is somehow the touchstone. [00:34:42] Speaker 02: Okay. [00:34:42] Speaker 02: Thank you. [00:34:52] Speaker 06: May it please the Court and William J. for the Alkermes parties. [00:34:56] Speaker 06: Each approval of a new drug adds to the storehouse of knowledge on which others may rely in developing their own innovations. [00:35:02] Speaker 06: Now, patent or exclusivity can give you the right to your own innovation, but it doesn't prevent others from building on the storehouse of existing knowledge to develop their own. [00:35:12] Speaker 06: This really is a good case to illustrate why it's important that innovators be allowed to rely on the storehouse of existing knowledge because the purpose of the B2 pathway, as Congress said in its committee report at age 16 and as the FDA has reiterated and as I think [00:35:29] Speaker 06: this court has recognized, is that B2 studies are not supposed to redo work that's unnecessary, to rediscover what's already been discovered unnecessarily. [00:35:42] Speaker 06: And this is a schizophrenia drug. [00:35:44] Speaker 06: To do a clinical trial of what alkenes relied on from the 2002 erypiprazole approval would require taking patients suffering from schizophrenia, [00:35:57] Speaker 06: taking them off their medications and doing a clinical trial where some of them get placebo. [00:36:02] Speaker 06: In other words, would not get treatment in order to measure the efficacy of the aripiprazole molecule, which is already known. [00:36:10] Speaker 06: That's exactly why Congress adopted the B2 pathway. [00:36:12] Speaker 06: And so for an innovation like Aristotle, which builds on but is not the same as aripiprazole, [00:36:20] Speaker 06: it does not make sense to instruct alchemy to go and redo that study and follow the B1 pathway for innovator drugs when the B2 pathway was created for a situation just like this. [00:36:33] Speaker 02: So just so I understand, it seemed like to the layperson that B1 would be attractive because you get longer and perhaps broader exclusivity, but is that [00:36:48] Speaker 02: I mean, from what you're describing, perhaps that's not a good deal. [00:36:54] Speaker 02: But I guess my question is, since the argument is that you have created something new, would you have been able to do that? [00:37:04] Speaker 06: B1 doesn't get longer exclusivity than B2. [00:37:08] Speaker 06: The longest exclusivity is from romenet 2. [00:37:10] Speaker 06: It's the new chemical entity exclusivity. [00:37:13] Speaker 06: When you develop a new chemical entity that has not been previously approved in any other drug, that's the most significant innovation. [00:37:18] Speaker 06: And so that's why you get five years of exclusivity. [00:37:20] Speaker 02: And so I'm asking, have you done that? [00:37:23] Speaker 02: In other words, you're arguing that it's a new drug. [00:37:25] Speaker 06: Yes, Aristotle is a new drug. [00:37:27] Speaker 06: It contains an active moiety that's never been previously approved. [00:37:30] Speaker 06: And that's why we are a new chemical entity entitled to that five-year exclusivity. [00:37:33] Speaker 02: You are entitled to the five-year exclusivity, but did you get that? [00:37:37] Speaker 02: Yes. [00:37:37] Speaker 02: Did you go under that provision? [00:37:40] Speaker 06: We have the five-year exclusivity, meaning that if someone else came in and said, I would like to make aripiprazole lauroxyl, they can't do that during the five-year period for which Aristotle, aripiprazole lauroxyl is the active ingredient [00:37:55] Speaker 06: The active moiety has a longer name, which I will try and pronounce. [00:38:00] Speaker 06: N-hydroxymethylarapiprazole is the active moiety. [00:38:03] Speaker 06: If they wanted to make a drug with that in it, they would be blocked by our five-year exclusivity. [00:38:07] Speaker 06: It doesn't matter whether you go under the B1 pathway or the B2 pathway. [00:38:10] Speaker 06: If your active moiety is new, you are entitled to that five-year exclusivity. [00:38:14] Speaker 01: So the way you were speeding out of your argument, it made it sound like [00:38:18] Speaker 01: not about your five-year exclusivity, but about the scope of the three-year exclusivity for Mantana, which is what's given rise to this dispute. [00:38:26] Speaker 01: It made it sound like you were saying that if the agency had read the statute in the way that Atsuka suggests the statute should be read, in other words, that exclusivity extends beyond the same act of maliety, but is a related drug and is somehow related to the fact that you've relied on the study [00:38:46] Speaker 01: I don't know how the agency would do it, but let's just suppose the agency comes up with a test. [00:38:50] Speaker 01: It makes it sound like you're saying that that would be forbidden by the statute. [00:38:53] Speaker 06: So I think that there are two-step answers. [00:38:56] Speaker 06: Number one, I think there has to be some limiting principle beyond reliance. [00:38:59] Speaker 06: And I think your colloquy with my friend in his opening argument has brought this out, that it can't just be if reliance, then blocked. [00:39:08] Speaker 06: And it can't just be the same conditions, then blocked. [00:39:11] Speaker 06: There has to be, as I think Mr. Saunders said, it has to be, in some sense, close enough, right? [00:39:17] Speaker 06: And the statute requires the conditions of approval to be of such drug. [00:39:23] Speaker 06: So the question is, what's the same drug? [00:39:25] Speaker 06: What is close enough, to adopt my friend's phrase? [00:39:29] Speaker 06: The agency, I think, has reasonably decided that active moiety, which is broader than some conceptions of what an active ingredient might be, because it captures other things like salts, [00:39:38] Speaker 06: and esters, which the agency has concluded are not chemically significant. [00:39:43] Speaker 06: So the answer to your question is, we're not arguing that the agency's active moiety reading is itself compelled by the statute. [00:39:52] Speaker 06: We are because it could have gone narrower, for example. [00:39:55] Speaker 06: But we are saying that they have drawn it right on it. [00:39:57] Speaker 03: But it could have gone broader? [00:39:58] Speaker 06: Could they have gone bright? [00:39:59] Speaker 06: It would still have to be, in some sense, the same drug. [00:40:02] Speaker 06: And I think that the agency is on very solid ground, concluding, based on its experience of physiology, medicine, and chemistry, that when there is a non-ester covalent bond that separates one drug from the other, [00:40:16] Speaker 06: You just can't say that those are the same thing, because in the body, they tend to act differently. [00:40:23] Speaker 06: And that is exactly the point this court made in its activist decision, quoting at length the FDA's determination that even minor COVID-19 structural changes could have major effects. [00:40:32] Speaker 01: But it deferred to the agency's interpretation. [00:40:33] Speaker 01: I guess all I'm asking is, if the agency had a different interpretation where it says, for example, all products are the same drug, [00:40:40] Speaker 01: then activists wouldn't tell you much because it deferred to an interpretation that went the opposite way, but it sounded like you were saying the agency couldn't even do that consistent with the statute, and it wasn't clear to me why the agency couldn't do that. [00:40:51] Speaker 01: It didn't, obviously, but... [00:40:52] Speaker 06: No, no, my answer is as long as it is rendering a reasonable interpretation of what it is, what it means to be the same drug, I don't think that it could just equate, you know, take the active ingredient, colloquy that your honor had with my friend, for example, to say that, you know, the example that we give in footnote 10 of our brief is called Bloxifers. [00:41:15] Speaker 06: which is a drug that essentially wakes up your muscles after surgery and anesthesia. [00:41:22] Speaker 06: And it relied on two active ingredients from two prior approvals, neither of which was that kind of drug at all. [00:41:28] Speaker 06: One of them was a muscle relaxant. [00:41:30] Speaker 06: The other was an anti-nausea medicine. [00:41:31] Speaker 06: So to say that the anti-nausea medicine and the new medicine that wakes up your muscles were the same drug, I don't think you could do that. [00:41:39] Speaker 06: I hope that answers your question, but the active moiety test is a bright line that the agencies have drawn, not just because it makes scientific sense, but because it's important to have a bright line for the purposes of this statutory exclusivity. [00:41:53] Speaker 06: You don't have to have such a bright line for the patent certification provision. [00:41:56] Speaker 06: You can just have reliance be the touchstone, because all that happens when you have to certify the patents [00:42:01] Speaker 06: is you go and you look at the patents listed in the orange book, and you see whether there are patents claiming that substance, and you certify. [00:42:08] Speaker 06: But if, for example, the patent claims only the molecule aripiprazole, and my client's product doesn't use the molecule aripiprazole, it doesn't infringe. [00:42:17] Speaker 06: And so in those circumstances, the brand doesn't sue. [00:42:21] Speaker 06: But if the brand does sue, [00:42:23] Speaker 06: within 45 days, it gets an automatic 30-month stay on the FDA's approval. [00:42:27] Speaker 06: And this goes back, Judge Brown, to your question. [00:42:29] Speaker 06: The patent certification provision is baked into the approval process in that way, that it stops the approval for 30 months while the parties litigate whether the patent does, in fact, block the new drug. [00:42:44] Speaker 06: And a patent can be written more broadly than an active moiety. [00:42:47] Speaker 06: A patent could be written to cover, for example, a whole class of [00:42:50] Speaker 06: active ingredients. [00:42:52] Speaker 06: It could be written to cover a formulation that includes inactive ingredients as well. [00:42:56] Speaker 06: And it can be written to cover a method of use. [00:42:59] Speaker 06: So the pioneers are free to write their patents how they wish, as long as they can get them from the patent office, subject to the requirements of novelty and non-obviousness. [00:43:09] Speaker 06: And then the parties can hash that out through the paragraph four certification process. [00:43:14] Speaker 06: But exclusivity needs a bright line. [00:43:17] Speaker 06: The agency has reasonably concluded that if it's the same drug, then it's blocked. [00:43:22] Speaker 06: That includes things like salts and esters. [00:43:24] Speaker 06: But if it's not the same drug in that sense, and Aristotle is not because of its different chemical structure, then it's not blocked. [00:43:31] Speaker 06: And to remove it from the market would be depriving patients of, as Mr. Whitaker mentioned at the end of this presentation, of the only drug on the market that has the [00:43:41] Speaker 06: six-week dose, and the different chemical structure, as the FDA acknowledges in footnote 80 of its decision, page 440 of the Joint Appendix, the different chemical structure may well be exactly what is the reason for that longer acting time period. [00:43:56] Speaker 06: If the court has no further questions. [00:43:59] Speaker 06: Thank you, Your Honor. [00:43:59] Speaker 02: Thank you. [00:44:03] Speaker 02: All right, you may have two minutes of rebuttal time. [00:44:07] Speaker 07: We've heard a lot of discussion of the bright line and the active mobility requirement, but I think if we look at the text of the statute here, you understand how the FDA itself has not honored that bright line for purposes of approval. [00:44:24] Speaker 07: In a 355B2, the hallmark of a 355B2 application is an application submitted under paragraph one, under B1, [00:44:34] Speaker 07: for a drug for which the investigations described in clause A of such paragraph and relied upon by the applicant for approval of the application were not conducted by or for the applicant. [00:44:45] Speaker 07: So the relative investigations in B1 are the ones you're relying on for the B2 pathway. [00:44:53] Speaker 07: But a B2 drug must still meet the requirements of B1. [00:44:57] Speaker 07: and the critical language there, and these investigations we're talking about under B1, they only get you to approval if there are full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective. [00:45:17] Speaker 07: So the problem with saying we have the Brightline rule, we have the Act of Motor Requirement, that's the clarity here, is that for purposes of approval, [00:45:26] Speaker 07: studies made to show whether or not aripiprazole was safe and effective for use were used to meet the requirement of the studies made to show whether or not alkermes compound was effective for use. [00:45:40] Speaker 07: And so the fundamental problem here is in blurring those lines for purposes of approval, [00:45:47] Speaker 07: but then suddenly springing back and saying there's this bright line for purposes of exclusivity. [00:45:54] Speaker 07: And we're not asking for something that extends the tablets. [00:45:56] Speaker 07: We're asking for their view wouldn't honor exclusivity even if there was still exclusivity on the tablets. [00:46:02] Speaker 07: It's because they're trying to take the shortcut to our later innovation where we have exclusivity. [00:46:10] Speaker 02: Thank you. [00:46:11] Speaker 02: The case will be submitted.