[00:00:01] Speaker 05: Okay, Mr. O'Quinn. [00:00:10] Speaker 02: Thank you, Judge Dyke, and may it please the Court, John O'Quinn, on behalf of the Appellants. [00:00:18] Speaker 02: The District Court's decision improperly raises the legal bar for obviousness and underreads the prior art, reading each reference narrowly in isolation without considering what a skilled artist would have understood from the art taken as a whole. [00:00:31] Speaker 02: To be clear, these claims are directed to using a known drug for a known purpose in amounts known to be safe and effective injected into one of three standard intramuscular injection sites, all of which was disclosed in the PriorArt 544 patent and also disclosed in the PriorArt W0384 application. [00:00:53] Speaker 02: Each one discloses all of those. [00:00:56] Speaker 02: The claims do not require any particular form of efficacy, not rapid efficacy, not comparative efficacy, for example, to the baseline risperidone product, not generalized majority population efficacy or efficacy in people with high BMI. [00:01:12] Speaker 02: Yet the district court read the claims as if they required each for purposes of what would motivate a skilled artisan and for what purposes of what would constitute a reasonable expectation of success. [00:01:24] Speaker 02: The inventors, however, at the time they filed the application, none of the things that the district court relied on were things that they were, number one, aware of, and number two, that they focused on with respect to the application that they submitted. [00:01:39] Speaker 02: Indeed, there's nothing critical about the specific claimed doses, all of which fall in the prior art ranges. [00:01:47] Speaker 02: The patent application specification and the original claims... Let me interrupt you because time is short. [00:01:54] Speaker 01: Let's assume that I agree with at least some of your criticism or suggestions about what was lacking in terms of the analysis here. [00:02:02] Speaker 01: I guess it leads me to wonder, what went awry? [00:02:06] Speaker 01: This is a very experienced, learned judge. [00:02:09] Speaker 01: So one of the answers to that could be that your evidence was just insufficient, that the record was insufficient, that you didn't have evidence and rebut. [00:02:20] Speaker 01: They made certain claims, their experts said stuff that maybe wasn't right, but there wasn't enough on the other side to rebut it. [00:02:31] Speaker 01: So help me out here. [00:02:33] Speaker 01: I mean, what, you know, I don't know what to make of this record. [00:02:37] Speaker 01: And that also affects sort of like what we do with this case in terms of reversals and remands and do-overs and things of that sort. [00:02:45] Speaker 02: Sure. [00:02:45] Speaker 02: And I'm happy to address each of those. [00:02:47] Speaker 02: I mean, let me just start by saying, I think what the district court did was commit methodological errors in how it assessed the significance of what the prior art teaches. [00:02:57] Speaker 02: Because there's no dispute about what the prior art actually says. [00:03:02] Speaker 02: And I don't think that there's really much of a dispute about what the prior art actually discloses. [00:03:06] Speaker 01: So are there errors of law, therefore, because she applied the wrong standard? [00:03:12] Speaker 02: I think that's exactly right, Judge Prost. [00:03:14] Speaker 02: I think at a minimum, that would require a remand. [00:03:17] Speaker 02: I think that at a maximum, the court can, based on the record, [00:03:21] Speaker 02: can simply flat out reverse because of the things that are not disputed here. [00:03:26] Speaker 01: So can we take, I mean there are three categories of stuff, or at least I've put them in three categories. [00:03:30] Speaker 01: So let's start with renal, or let's start with the question of where you inject the drug. [00:03:40] Speaker 01: Your argument is there are three options. [00:03:43] Speaker 02: I don't think there was any dispute that there were two or possibly three options for intramuscular injections. [00:03:49] Speaker 02: But she said your evidence was lacking because... That, I think, is a little bit of a mystery, Judge Prost, because when she, for example, looked at the two textbooks that made clear that deltoid and gluteal injections were interchangeable, yes, there were trade-offs, there were known trade-offs in terms of pain, in terms of [00:04:09] Speaker 02: the vascularization of the deltoid as opposed to the gluteal, but those are things that are all known. [00:04:14] Speaker 02: She then proceeds, the district court proceeds to distinguish the textbooks because they didn't expressly address caliperidone or that they didn't expressly address loading doses. [00:04:23] Speaker 02: You can see that at appendix 75. [00:04:25] Speaker 02: And I think that's doing exactly what this court said in Allergan versus Apotex that you can't do, an overly cramped view of what the art teaches. [00:04:33] Speaker 02: as opposed to looking at the art as a whole. [00:04:37] Speaker 02: And so the district court criticized our expert, for example, for saying, well, he was only relying on these textbooks to explain that deltoid and anglia were interchangeable, not for the concept of a loading or an initial dose. [00:04:52] Speaker 02: That concept, of course, comes from the 548 protocol, which was a phase three protocol, which is this court recognized. [00:05:00] Speaker 01: moving to the dosing, there is some differentiation in terms of the claimed amounts and the sequence and what was in the prior art. [00:05:11] Speaker 01: So somebody had to get you to the step of why you would have been motivated to make those changes, even though they may not be astronomical. [00:05:20] Speaker 02: Well, so two points, Judge Prost. [00:05:22] Speaker 02: First, I don't actually think that there's a difference in terms of the amount of the doses. [00:05:27] Speaker 02: Versus what was in the prior art that is to say in the claimed regimen the dose is 150 then a hundred then 25 to 150 Those are all each one of those doses is disclosed in both the 544 patent [00:05:42] Speaker 02: and the WO384 application. [00:05:46] Speaker 02: Each one of those is that because they disclose a range. [00:05:49] Speaker 02: They disclose a range. [00:05:50] Speaker 02: The WO384 actually does it very explicitly of the 25 to 150, saying that you can administer anything in between based on the dose needed by a particular patient. [00:06:02] Speaker 02: And so our legal argument that the district court didn't seem to appreciate [00:06:06] Speaker 03: is that under this court's case law about ranges, these are presumed obvious because all they did is take one... Is there a difference though between just the ranges and the specifics for just regular dosing and the specific numbers for the initial dosing, the loading doses? [00:06:26] Speaker 03: And so is there I mean, I don't know that there is any distinction from those range cases But let's just assume there are that you have to go beyond saying the prior art shows the range But you have to show the prior art shows that you would specifically pick out These amounts or close to them as the loading doses. [00:06:45] Speaker 02: So Judge Hughes, I think there are two issues one is [00:06:47] Speaker 02: Is the amount within a prior range such that the amount is obvious? [00:06:52] Speaker 02: And then the second question is, is it obvious that you could initiate therapy using loading doses? [00:06:58] Speaker 02: As to the first, I have multiple arguments, but one of them is the range one, because both the 544 and the W [00:07:05] Speaker 02: It would be obvious that you could pick any one of them for any one of the doses and a person of ordinary skill in the art would expect it to work because both the 544 and the WO384 teach [00:07:21] Speaker 02: that those injections are therapeutically effective. [00:07:24] Speaker 02: In fact, claim seven of the 544 is a method of treatment claim. [00:07:28] Speaker 02: Now with respect to the loading, and this is where I think the district court got somewhat wrapped around the axle, didn't understand that we weren't necessarily relying on a textbook [00:07:37] Speaker 02: in terms of deltoid versus versus gluteal for that, but instead we're relying on things like the 548 protocol. [00:07:45] Speaker 02: Because the 548 protocol, a phase three protocol, which is this court in Henry Montgomery 677 f3rd at 1382, said that, you know, protocols are far from abstract theories. [00:07:57] Speaker 02: They are things that persons of ordinary scale in the art can have expectations on. [00:08:01] Speaker 02: And the protocol tells you that you can expect that it will be safe and effective to dose on day one, and then dose again on day eight. [00:08:10] Speaker 02: And that teaches what the claim that loading doses, because that is the only difference between what the claims require [00:08:18] Speaker 02: and what is disclosed in both the 544 and the W038. [00:08:23] Speaker 01: What is your view led the district court astray? [00:08:26] Speaker 01: I mean, I presume you made all of these arguments, so your experts made these arguments before the district court. [00:08:31] Speaker 01: If I'm wrong about that, let me know. [00:08:33] Speaker 01: No, we certainly did. [00:08:39] Speaker 02: Well, I think in two ways, Judge Prost. [00:08:41] Speaker 02: I think one is the district court, as I said, I think fell into the mistake of approaching obviousness as though it was like anticipation and looking at each of the prior art [00:08:54] Speaker 02: of pieces in isolation and asking, okay, does it show not just the concept of loading, as with Arishevsky, but does it show loading with this particular drug? [00:09:05] Speaker 02: Or does it show that the deltoid would be obvious because it is known to be one of two, possibly three sites where you inject intramuscularly? [00:09:15] Speaker 02: And said, well, but the 584 protocol didn't involve [00:09:19] Speaker 02: deltoid, it only involved gluteal, even though the 544, for example, just says intramuscular, doesn't have any distinction. [00:09:26] Speaker 02: I think the other thing that she did was, I think frankly, was misled by the story that was told by the other side about why they thought this was a big accomplishment and their motivations. [00:09:39] Speaker 02: And there are two parts to that. [00:09:41] Speaker 02: One, if you look at the record, what they said their motivation was, this is an appendix 10,796, they were motivated to find a, quote, universal one-size-fits-all dosing regimen, end quote, or an appendix 10,897. [00:09:55] Speaker 02: They said, quote, you don't want, as a big company, just to bring something to the market that works. [00:10:00] Speaker 02: It has to be as good for as high a percentage of patients as possible," end quote. [00:10:05] Speaker 02: And I think the district court embraced that with the idea that this had to be a generalized regimen in which was looking for expectation of success across a population, as opposed to what a skilled artisan would have looked like. [00:10:21] Speaker 02: And what would have motivated a skilled artisan is, knowing what I know about the ranges that are disclosed in the prior art, can I reasonably expect [00:10:28] Speaker 02: that this regimen and many others would work in a patient. [00:10:33] Speaker 01: Your other part of the argument in that regard is that you make two arguments about the claims. [00:10:38] Speaker 01: One, they don't specifically call out a generalized population. [00:10:42] Speaker 01: They deal with one patient. [00:10:43] Speaker 01: And two, they don't specifically require safe and efficacious use. [00:10:49] Speaker 02: Yes. [00:10:50] Speaker 01: On the second, whether they require it or not, if we're talking about the motivation to combine [00:10:58] Speaker 01: Isn't what we're talking about drugs, isn't safety a factor in that? [00:11:06] Speaker 01: And also, isn't it just in a regular non-drug case, you still have like, will it work? [00:11:14] Speaker 01: And will it work in the drug context means kind of like it's not going to kill people. [00:11:19] Speaker 01: It's going to help them. [00:11:20] Speaker 01: So I understand. [00:11:22] Speaker 01: I take your point. [00:11:23] Speaker 01: The claims don't explicitly require it. [00:11:26] Speaker 01: But why is thinking about that not relevant to the issues of motivation and reasonable expectation of success? [00:11:34] Speaker 02: Sure. [00:11:34] Speaker 02: So Judge Prost, just to be clear, I'm not saying that there's a categorical irrelevance to it. [00:11:39] Speaker 02: What I'm saying is that what the district court was looking at, both for purposes of efficacy, and I'll talk about safety in just a second, was the idea that it would be efficacious across the population. [00:11:49] Speaker 02: that this would essentially be the best, that this would be the one that would work the best. [00:11:54] Speaker 02: And you wouldn't expect. [00:11:55] Speaker 02: And in fact, when you look at what the district court says at appendix 78 and appendix 87 to 88, she specifically talks about the fact that you wouldn't expect success in a generalized way. [00:12:08] Speaker 02: And my modest point is simply that that's not what needs to be expected. [00:12:13] Speaker 02: What needs to be expected is that this regimen could reasonably be expected to work, [00:12:17] Speaker 05: Within a patient that is that with with some patient based on their specific conditions That you would expect that this regimen would potentially be useful now with respect to safety two points and There to the two issues here one is whether safety and efficacy is relevant to the satisfaction of individual claim limitations and That's not a requirement in this pattern or a decision United Therapeutics makes clear that you don't weed that in [00:12:47] Speaker 05: into their claims. [00:12:49] Speaker 05: Correct. [00:12:50] Speaker 05: Nonetheless, safety and efficacy can be relevant, as Judge Prost suggests, to the question of motivation. [00:12:57] Speaker 05: And she basically said, no motivation because no showing of safety and efficacy. [00:13:05] Speaker 05: What is your theory as to what the motivation to combine was if it wasn't safety and efficacy? [00:13:10] Speaker 02: Well, Judge Dyke, I think safety and efficacy was demonstrated by the 544 patent itself. [00:13:17] Speaker 02: Again, the 544 patent teaches, and then in terms of what motivates taking what the 544 patent teaches and using loading doses on the front end, very straightforward motivation, which is the challenge of adherence. [00:13:30] Speaker 02: There was a lot of testimony about schizophrenia patients not taking the oral medications that they would otherwise take at the front end. [00:13:38] Speaker 02: And so there was an obvious motivation. [00:13:40] Speaker 02: That was the whole point of the Prior Art 548 protocol was to examine the use of loading doses so that you could overcome the adherence problem. [00:13:50] Speaker 02: But with respect to safety and efficacy, [00:13:52] Speaker 02: Again, two points. [00:13:53] Speaker 02: The 544 expressly teaches that it results from, quote, investigations into development of an efficient, well-tolerated depot formulation which is therapeutically effective for one month, end quote. [00:14:06] Speaker 02: That's appendix 13238, column two, starting at line 38. [00:14:13] Speaker 02: 544 teaches you that these doses are both safe and effective. [00:14:18] Speaker 02: The only thing that the 544, and for that matter the W384 publication, doesn't address is is it safe and effective to do a second dose on day eight. [00:14:30] Speaker 02: Because it's already taught you about the one month intervals, it's about day eight. [00:14:36] Speaker 05: And surely if you could take... The problem with that is that [00:14:41] Speaker 05: actually says that the second dose, the 100-milligram dose, can be the same as the maintenance dose. [00:14:49] Speaker 02: That's exactly right. [00:14:50] Speaker 02: And so I was going to make two points about this. [00:14:51] Speaker 02: I mean, number one, the patent doesn't just claim 150, 125, which is the way that the district court seemed to treat it. [00:15:01] Speaker 02: It claims 150, 100, 100, 100, 100. [00:15:05] Speaker 02: So there's nothing special about that second dose. [00:15:07] Speaker 02: And in terms of day eight, a person of Organic Scale in the Art would know that it would be safe, and they'd know it from the 503, excuse me, they'd know it from the 548 protocol. [00:15:17] Speaker 02: That's a phase three protocol. [00:15:19] Speaker 02: Safety is generally considered to be established before you go into phase three trials. [00:15:24] Speaker 02: And as this court said in the Montgomery case that I cited just a moment ago, that you can have a reasonable expectation of success. [00:15:32] Speaker 02: with phase three trials. [00:15:33] Speaker 02: Now, in addition, a person of ordinary skill in the art, I see I'm well past my time. [00:15:38] Speaker 02: I'll finish this one point with the court's permission. [00:15:41] Speaker 02: And if the court has other questions, I'm happy to answer them. [00:15:44] Speaker 02: And that was just simply to say that between the 548 protocol, the phase two results which were in the prior art, the Jancic article at appendix 13,279, a person of ordinary skill in the art would have had every expectation, the dosing on day eight, [00:15:59] Speaker 02: whether you did 150 and 150 or 150 and 100 would be safe. [00:16:04] Speaker 02: And I think that answers all of the concerns that the district court didn't seem to address were in the record. [00:16:10] Speaker 02: I'm happy to answer additional questions, and I appreciate the court's indulgence. [00:16:15] Speaker 02: Thank you, Judge Steig. [00:16:26] Speaker 00: Thank you, Your Honor. [00:16:27] Speaker 00: May it please the court, Barbara Bowen, Representative Jansen. [00:16:31] Speaker 00: So what we've heard on appeal and the arguments that Teva is making are very much divorced from the actual trial record and what happened below. [00:16:41] Speaker 00: Teva is essentially asking this court to adopt its attorney arguments on how the prior art should be interpreted in lieu of the district court's factual findings. [00:16:52] Speaker 00: And if you look at the Zesta Court opinion, you'll see that what the court did was consider and reject each of Teva's theories that they advanced a trial. [00:17:02] Speaker 05: Citing to substantial- That may be, but the question is, was she right in doing it? [00:17:07] Speaker 00: Well, I can address each one of those points. [00:17:08] Speaker 00: I mean, I'm happy to take them in, I think, the order in which they came up. [00:17:14] Speaker 00: In terms of deltoid injection, deltoid injection is not just about it being one of three places where somebody can get an injection. [00:17:24] Speaker 00: In the context of this claim, when you look at what's being claimed as a whole, [00:17:28] Speaker 00: You are talking about giving a long-acting injectable or depot injection in the deltoid. [00:17:35] Speaker 00: And if you put this into the context of what Tevis' theories were, again, because what the court did was reject Tevis' theories. [00:17:42] Speaker 00: If you put it into the context of what Tevis' theories were at trial, it was that a skilled artisan would start with the 5-4-8 protocol, which requires all gluteal injections and all equal doses for the injections. [00:17:56] Speaker 00: The theory was that they would start with the 548 protocol, and a person of ordinary skill would be motivated to change that, to change one of those things to the deltoid injections. [00:18:06] Speaker 00: What was the case that Teva tried about that? [00:18:09] Speaker 00: They said they would be motivated to change the deltoid injections to achieve rapid efficacy. [00:18:16] Speaker 00: But as a matter of fact, the court determined that the references and the priority did not support that theory. [00:18:23] Speaker 00: Why? [00:18:24] Speaker 00: Because Tavis Exford said, we all know that there's more perfusion in the deltoid muscle than in the gluteal muscle. [00:18:31] Speaker 00: So I look at a reference, and it says, therefore, you may have faster absorption in the deltoid muscle. [00:18:37] Speaker 00: What he ignored, and what the district court noted, was that that only applies to immediate release formulations. [00:18:43] Speaker 00: It doesn't apply to long acting or depot formulations, like the formulations that issue here. [00:18:48] Speaker 00: But as he said at trial, he ignored that part because it was what he was relying on. [00:18:51] Speaker 01: Can I ask you about the district court's analysis of that point then? [00:18:54] Speaker 01: I mean, she had three reasons, and I got paused about all of them. [00:18:59] Speaker 01: But then the last reason, she concluded that even though half of all patients prefer shoulder injections, [00:19:06] Speaker 01: At best, that evidence would suggest using deltoid administration on an individualized basis, or be a mere lack of dissuasion from using shoulder injections. [00:19:20] Speaker 01: Is that right? [00:19:21] Speaker 01: Is the matter of law the way we think about the kind of motivation that's necessary, at least in an obvious, to try when there are three options on the table, two or three options on the table, and that way of analyzing it [00:19:37] Speaker 01: is a reason to not find motivation? [00:19:42] Speaker 00: Well, there's a few answers to that. [00:19:43] Speaker 00: One is the context of obvious to try. [00:19:45] Speaker 00: It would have to be one of a number of finite and predictable solutions or predictable outcomes that come from that. [00:19:51] Speaker 05: Well, why is that true here? [00:19:53] Speaker 00: Pardon me? [00:19:54] Speaker 05: Why isn't that true? [00:19:56] Speaker 00: Because nobody knew what was going to happen when you injected a long-acting injectable into the deltoid muscle. [00:20:01] Speaker 00: Nobody knew that that would achieve rapid efficacy. [00:20:04] Speaker 00: That was not something that was taught in the primary. [00:20:06] Speaker 01: Well, if we're talking about obvious to try, that's not that nobody knew it would work. [00:20:10] Speaker 01: It's obvious enough to try when there are a limited number of options. [00:20:14] Speaker 01: And you've got this kind of evidence about patient's preference. [00:20:19] Speaker 00: Well, patient's preference, the evidence was a little bit ambiguous. [00:20:23] Speaker 00: But the court is using it here in the same context as the court talked about the 544 patent and Arishevsky. [00:20:31] Speaker 00: In terms of, this is a regimen. [00:20:34] Speaker 00: It was not a Tavisteria trial that maybe [00:20:40] Speaker 00: They were trying to prove obviousness of something that wasn't a regimen. [00:20:44] Speaker 00: Everybody agrees this is a regimen. [00:20:46] Speaker 00: The court said it's for a person. [00:20:48] Speaker 00: It's true. [00:20:49] Speaker 00: But each and every a person gets the same regimen, which is 150 in the deltoid on day one, 100 in the deltoid about a week later, of a depot injection. [00:21:00] Speaker 00: So it's a regimen. [00:21:02] Speaker 00: And this is distinguished from the individualized approaches [00:21:05] Speaker 00: such as, for example, in the 544 patent, where dosing was 2 to 4 milligrams per kilogram of body weight. [00:21:14] Speaker 00: There is no evidence about ever being injected into a human. [00:21:16] Speaker 00: It was only injected into fecal dogs. [00:21:19] Speaker 00: And the prior art, all the prior art [00:21:22] Speaker 00: drugs for long-acting injectables, they were injected in the gluteal. [00:21:27] Speaker 00: And there was good reason, because as the district court noted, the Gavaldi reference teaches that when you give a depot injection, you give it in the gluteal. [00:21:34] Speaker 00: Why? [00:21:35] Speaker 00: They're big injections. [00:21:36] Speaker 00: It's very painful to put it in the deltoid. [00:21:39] Speaker 00: The prior art actually taught you, don't give this kind of injection in the deltoid. [00:21:44] Speaker 05: So if you're going to... So the invention is for the shoulder muscles? [00:21:49] Speaker 00: No. [00:21:49] Speaker 00: The invention is actually a unique [00:21:51] Speaker 00: combination of elements, that if you look at the 5-4-8 protocol, if you just want to say, rapid efficacy, let's give the highest dose possible, the 5-4-8 protocol would tell you to give 150 and 150 in the glial muscle. [00:22:07] Speaker 00: Didn't work. [00:22:08] Speaker 00: It didn't provide rapid efficacy. [00:22:11] Speaker 00: It failed to have any efficacy in US patients. [00:22:15] Speaker 00: It had only efficacy with respect to the 100-mig equivalent dose. [00:22:19] Speaker 00: The 150-mig equivalent dose had no efficacy anywhere. [00:22:23] Speaker 00: And for everyone who was tested, there was no rapid efficacy using the protocols in the 5-4-8 patent. [00:22:31] Speaker 00: Now, you change that. [00:22:33] Speaker 00: And what do you change? [00:22:34] Speaker 00: You change very specific things. [00:22:36] Speaker 00: You start to use unequal loading doses. [00:22:40] Speaker 00: Not 150, 150. [00:22:40] Speaker 00: I'm sorry. [00:22:41] Speaker 00: I didn't mean to cut you off, Your Honor. [00:22:44] Speaker 00: And you move away from the gluteal injection site, which was taught by the prior art as the location where you want to give these high-volume painful injections. [00:22:55] Speaker 00: So you're moving away from what the prior art taught, and you're saying, OK, let's give 150 and then 100 in the deltoid. [00:23:02] Speaker 05: And then maintenance dose of 100 after that. [00:23:06] Speaker 00: Well, the maintenance doses can vary after that. [00:23:07] Speaker 00: That's right. [00:23:09] Speaker 05: So the patent would cover a 150 [00:23:17] Speaker 00: It could, yes. [00:23:19] Speaker 01: And there's even a larger thing for the monthly stuff. [00:23:24] Speaker 01: There's even a larger range. [00:23:25] Speaker 00: There's a larger range, right, to 150. [00:23:29] Speaker 00: Right. [00:23:30] Speaker 00: But the point to this really is, as both experts agreed at trial, it's those first two loading doses that provide rapid efficacy. [00:23:38] Speaker 00: And that was something that had never been seen before with a long-acting injectable. [00:23:42] Speaker 05: When you say the first two loading doses, but the second loading dose could be the same as the maintenance dose. [00:23:46] Speaker 05: But it could be, in effect, another maintenance dose. [00:23:49] Speaker 00: Except that it's not given a month after the first dose. [00:23:51] Speaker 00: If you go back to the way long-acting injectables were given, they were given, even in the 544 patent, [00:23:57] Speaker 00: as my colleague pointed out, every month. [00:23:59] Speaker 01: But Judge Dyke's point is that the range is within the long-term range, right? [00:24:05] Speaker 01: So what's the answer to that? [00:24:08] Speaker 00: The 150 is within the range, but it's not a range. [00:24:11] Speaker 00: It's a specific dose. [00:24:12] Speaker 00: It's a specific sequence. [00:24:15] Speaker 01: What's the long-term dose? [00:24:17] Speaker 00: 25 to 150 every about month, monthly plus or minus seven days, right? [00:24:22] Speaker 00: And that is actually serving a different function in the claims, as both experts agreed. [00:24:28] Speaker 00: That actually provides long-term efficacy, which is what, for example, was described in the 5-4-4 patent. [00:24:34] Speaker 00: The 5-4-4 patent talked about a formulation of paliparadone palmitate that would be given every three weeks to a month. [00:24:41] Speaker 00: There's no mention in the prior 5-4-4 patent of using any paliparadone palmitate formulation as a loading dose. [00:24:50] Speaker 00: And in fact, again, if you look at the Gabaldi reference, Gabaldi teaches you don't use long depot injections to initiate therapy. [00:24:59] Speaker 00: So this was a deviation from what was going on in the prior art. [00:25:02] Speaker 00: And it was something, frankly, that, as I said, the five-way protocol, that was a phase three clinical trial. [00:25:09] Speaker 00: It failed. [00:25:10] Speaker 05: I thought there was plenty of evidence that in the prior art, people used loading doses. [00:25:14] Speaker 05: It wasn't something new. [00:25:17] Speaker 00: Loading doses were used in, for example, Arishevsky. [00:25:21] Speaker 00: Arishevsky talked about loading doses for haloperidol that were based on taking your oral dose that you've been stabilized on and multiplying it by 20 or 25 times and giving that as a long-acting injectable. [00:25:35] Speaker 00: That's not the approach in this patent. [00:25:37] Speaker 00: This is a regimen. [00:25:38] Speaker 00: This is a regimen where very specific doses are given. [00:25:41] Speaker 05: Yeah, but I thought there was evidence in the prior, in an injection context, of giving a loading dose. [00:25:47] Speaker 00: All right. [00:25:49] Speaker 00: Well, there's two things. [00:25:50] Speaker 00: One is Arashevsky talks about loading doses in terms of, but it's an individualized approach to dosing. [00:25:56] Speaker 00: It's not a regimen-based approach. [00:25:58] Speaker 00: The 548 protocol, I think, is what they rely on for the most part as talking about loading doses, at least if you consider the doses on day one and day eight to be loaded. [00:26:08] Speaker 00: But the critical part here [00:26:10] Speaker 00: is that the 548 protocol, which is a phase three trial, which everyone, I suppose, if you accept what they say, expected to succeed, failed. [00:26:22] Speaker 00: You gave 150 and 150 on day one and day eight, no efficacy. [00:26:27] Speaker 00: You give 100, no matter what you gave, it was 50 make equivalents in four doses, 100 make equivalents in four doses, 150 make equivalents in four doses, it didn't matter what you gave. [00:26:38] Speaker 00: Nobody got rapid efficacy that way. [00:26:40] Speaker 00: It wasn't until the inventors figured out that you had this combination. [00:26:44] Speaker 00: And not just of the highest doses, right? [00:26:47] Speaker 00: Because it does have to be safe. [00:26:50] Speaker 00: These are long-acting injectables with very serious side effects. [00:26:53] Speaker 00: You can't give somebody something that's going to give them a horrible side effect. [00:26:56] Speaker 04: What did the inventors discover about the dosage? [00:27:00] Speaker 00: Well, the inventors had actually originally developed the protocol that ended up as NCT 548. [00:27:07] Speaker 00: That's the 548 protocol. [00:27:09] Speaker 00: That was a phase three clinical study that they expected to work, which relied on giving 150 milligram equivalent doses on four different days, or 100 milligram equivalent doses on four different days, or 50. [00:27:21] Speaker 00: And they expected that that would succeed. [00:27:24] Speaker 01: But the 548 protocol doses on day one and day eight. [00:27:28] Speaker 00: Correct. [00:27:28] Speaker 01: So that's loading, right? [00:27:30] Speaker 00: That could be loading, but it failed. [00:27:32] Speaker 00: As a matter of fact, it failed. [00:27:34] Speaker 00: It did not load. [00:27:35] Speaker 00: It did not achieve rapid efficacy. [00:27:40] Speaker 00: That was the result of the clinical trial. [00:27:42] Speaker 05: I would have thought that your argument might be that there was a criticality here within the range, but my recollection is there wasn't any evidence about that. [00:27:52] Speaker 05: Am I mistaken? [00:27:54] Speaker 00: Because it's not really a range case. [00:27:58] Speaker 00: Right? [00:27:58] Speaker 00: It's not the first. [00:27:59] Speaker 00: But I'm right. [00:28:00] Speaker 05: There's no evidence of criticality. [00:28:01] Speaker 00: Well, there is evidence of criticality. [00:28:03] Speaker 00: If you look at the 508 protocol that says 150 and 150 doesn't work, 100 and 100 doesn't work. [00:28:09] Speaker 00: But now, if we give precisely 150 on day one and 100 on day eight, and we give those injections in the deltoid, now it works. [00:28:18] Speaker 00: So that is a criticality of 508 numbers. [00:28:20] Speaker 01: But you mentioned a few times there's no rapid efficacy. [00:28:24] Speaker 00: There is rapid efficacy with the claimed dose rate. [00:28:26] Speaker 01: Yeah, but not with the 5.8, but where is rapid efficacy required in the claims? [00:28:32] Speaker 00: Rapid efficacy was dealt is really, there's two points. [00:28:38] Speaker 00: One is that the experts all conceded that that was the purpose of the first and second loading doses, that it actually does achieve rapid efficacy. [00:28:46] Speaker 00: That's number one. [00:28:47] Speaker 00: But rapid efficacy was the motivation that Teva alleged for modifying the prior art. [00:28:54] Speaker 00: So the idea that you would change something to get rapid efficacy, the court rejected that as a matter of fact because Teva failed to prove its case. [00:29:08] Speaker 00: So [00:29:13] Speaker 00: It really is, I guess, the 548 patent is the closest prior art, or the 548 protocol is the closest prior art. [00:29:22] Speaker 00: This is a difference. [00:29:23] Speaker 00: The difference is the district court found in a matter of citing expert testimony at least 70 times in its opinion on how the prior art should be interpreted, the district court found that Teva had not met its burden of proving [00:29:39] Speaker 00: that it would have been obvious to modify or that there would have been an obvious motivation to modify the prior art. [00:29:47] Speaker 00: Let's go back to the 5-4-A protocol. [00:29:49] Speaker 00: That's the premise of the argument. [00:29:51] Speaker 05: So the modifications are putting it in the deltoid muscle and starting out with a 150 dose and reducing it there after our 200? [00:30:00] Speaker 00: Yes. [00:30:01] Speaker 00: That is different from the prior art. [00:30:03] Speaker 00: And the question is, and it achieved a different result in kind than what the prior art achieved, because it achieved rapid efficacy, whereas the 540 protocol did not. [00:30:15] Speaker 00: And the district court made its findings not just on the basis of the prior art and the expert's interpretation of what the prior art teaches, but also on credibility determinations. [00:30:28] Speaker 00: Todd, his expert, came in and essentially admitted that the way he got to this was by using hindsight. [00:30:35] Speaker 00: And the district court made numerous credibility findings where- I'm not sure that's an accurate statement. [00:30:40] Speaker 05: I mean, he looked at the patent. [00:30:41] Speaker 05: How could he not look at the patent? [00:30:43] Speaker 00: It was more than that. [00:30:44] Speaker 00: It's actually quoted in a footnote in the opinion. [00:30:46] Speaker 00: But he looked at the patent, and then he went back to see if he could find all the pieces in the prior art to match them up to the claims. [00:30:53] Speaker 00: He did more than that. [00:30:54] Speaker 05: Well, I mean, that's sort of what obvious [00:30:59] Speaker 05: obvious in the light of the prior R. And how could you do the analysis without looking at the claim? [00:31:05] Speaker 00: You're right. [00:31:06] Speaker 00: You can't do the analysis without looking at the claim. [00:31:08] Speaker 00: But then you have to go back and say, they still have to prove their obviousness case. [00:31:12] Speaker 00: And in order to prove their obviousness case, they have to prove that there's a motivation to modify the prior R. Where is that motivation? [00:31:19] Speaker 00: If you're going to assume that the 548 protocol was successful, why are you going to modify it? [00:31:25] Speaker 00: Right? [00:31:25] Speaker 00: There's nothing in the prior art to suggest that you should modify the 540 protocol at all. [00:31:30] Speaker 00: There's just nothing in the prior art to suggest it. [00:31:32] Speaker 00: So Teva's expert came up with his own, actually. [00:31:34] Speaker 01: I thought we would pass. [00:31:35] Speaker 01: I mean, KSR says you don't need a specific teaching suggestion or motivation. [00:31:42] Speaker 01: Just because something's working doesn't mean end of story. [00:31:46] Speaker 01: There's no motivation because something else is working, so no one would be motivated to try it. [00:31:52] Speaker 01: I don't understand the analytical framework you're using. [00:31:56] Speaker 00: The analytical framework is that when KSR is talking about it, it's talking about, and in the case that was recently cited, submitted, they're talking about doing something that's going to be predictable. [00:32:08] Speaker 00: You're going to have a predictable outcome. [00:32:11] Speaker 00: And it's not just that it's a change in location. [00:32:17] Speaker 00: If you look at Dr. Wermeling's testimony, and I think it's quoted. [00:32:26] Speaker 00: Let's see if I can find it. [00:32:27] Speaker 00: Dr. Wermeling's testimony at trial, he said that there were a number, a large number of combinations of injection sites and dose amounts that would change [00:32:41] Speaker 00: the level of drug in the bloodstream. [00:32:46] Speaker 00: So in other words, it's going to change the efficacy of the drug. [00:32:48] Speaker 00: He said there's a large number of possible combinations. [00:32:55] Speaker 00: So he admits that this is not the situation where it is a finite number of predictable solutions. [00:33:03] Speaker 00: And it's not really, again, we're taking this claim apart into pieces as an obvious challenge should not. [00:33:09] Speaker 00: This should be the invention as a whole, which is very different from the prior art. [00:33:16] Speaker 00: It provided results that were not achieved by the prior art. [00:33:23] Speaker 05: OK, I think we're about out of time. [00:33:35] Speaker 02: Judge Dyke, you asked why they're not arguing criticality, because they can't. [00:33:38] Speaker 02: And I point you to appendix 170 and 172. [00:33:41] Speaker 02: This is the patent itself. [00:33:43] Speaker 02: There is nothing special about the 150-100 loading dose protocol. [00:33:49] Speaker 02: The patent itself disclosed it is one of at least three optimized loading doses. [00:33:55] Speaker 02: One is 150-150. [00:33:56] Speaker 02: One is 150-25. [00:33:58] Speaker 02: Those are just the ones that they happen to test. [00:34:00] Speaker 02: after they had figured out that they had a problem with the needle length, which is what led to their so-called failures, which weren't failures. [00:34:06] Speaker 02: And that whole narrative, I think, is part of what misled the district court. [00:34:09] Speaker 02: But on this issue of criticality, especially look at appendix 172, column 28, lines 3 through 7. [00:34:16] Speaker 02: And what you see is that all of these different loading dose combinations, 150 to 100, [00:34:22] Speaker 02: 150 to 150, 150 to 25, they were all better than placebo. [00:34:26] Speaker 02: The patent actually reports that the best two were 150-150 and 150-25. [00:34:31] Speaker 02: There is nothing critical. [00:34:33] Speaker 02: Those were the only two that the patent reports as having rapid efficacy by day eight in the actual subsequent trials, not 150-100. [00:34:41] Speaker 01: So what do we do with this? [00:34:42] Speaker 01: I mean, you're not suggesting that there's a basis on this record to necessarily reverse. [00:34:49] Speaker 02: Well, Judge Prost, I think you can reverse under this court's ranges cases, because every one of these falls within a range. [00:35:00] Speaker 02: Every one of these things, one of these doses. [00:35:04] Speaker 01: So is it a hodgepodge that some of the issues can be resolved here and others have to go back? [00:35:10] Speaker 02: Well, I think that the ultimate question of obviousness, as the court's well aware, is a question of law. [00:35:15] Speaker 02: And I think that the court can resolve that question based on this record. [00:35:19] Speaker 03: But at a minimum, I think- I mean, I understand what you're saying. [00:35:23] Speaker 03: But how do we, if we find that the district court applied the wrong obvious analysis, which led her to improperly reject the motivation to combine, how do we as an appellate court come up with our own motivation to combine? [00:35:38] Speaker 03: Isn't that factual? [00:35:39] Speaker 02: So Judge Hughes, I agree with you. [00:35:41] Speaker 02: If you think that the only error here was a methodological one that comes to how the district court considered the prior arc, that you need to correct that error, and then the appropriate course would be for the fact finder to then consider that under the proper method. [00:35:57] Speaker 02: I do think, and this is what we argued, and what I'm arguing today is consistent, which you'll find [00:36:01] Speaker 02: and our post-trial brief pages 9 to 18 about, for example, the ranges, I think that is an issue that the court could resolve for itself. [00:36:10] Speaker 02: I know I've passed my time, but two points that I really want to respond to, because I think that they were somewhat misleading. [00:36:17] Speaker 02: First, this idea that the 150-150 injections [00:36:20] Speaker 02: in the 548 protocol didn't work. [00:36:23] Speaker 02: That's not consistent with what the evidence showed at trial. [00:36:26] Speaker 02: What the evidence showed was that their experimenters mixed up placebo and mixed up the 150 doses. [00:36:33] Speaker 02: And you can see this at appendix 22,792, 10,893. [00:36:36] Speaker 02: And that's why they didn't have data on 150. [00:36:41] Speaker 02: What's your other point? [00:36:42] Speaker 02: And my other point, Judge Dyke, is that the 548 protocol was not a failure. [00:36:45] Speaker 02: You can see that every one of those doses, with one exception, did better than placebo. [00:36:50] Speaker 02: And you can see that at appendix 22792 and 10893. [00:36:55] Speaker 02: And so we respectfully request that the court vacate the court's obviousness decision, neither reverse or remand. [00:37:02] Speaker 02: I'm happy to answer any additional questions. [00:37:04] Speaker 02: that the court might have about the record or the legal issues here. [00:37:08] Speaker 05: OK, I think we're out of time. [00:37:09] Speaker 05: Thank you. [00:37:09] Speaker 05: Thank you, Judge Steig.