[00:00:02] Speaker 00: The next case for argument is 16-27-22, Sanofi versus Warren. [00:00:43] Speaker 02: Good morning. [00:00:44] Speaker 02: I'd like to focus on three legal issues that the district court, three legal errors that the district court made in deciding this case against the defendants on the 167 patent and the 800 patent. [00:00:57] Speaker 05: What presidential authority is held that there's no infringement where an ANDA defendant's project is labeled for a use claimed in a patent? [00:01:07] Speaker 02: I'm sorry, Your Honor, what case? [00:01:09] Speaker 05: What presidential authority? [00:01:12] Speaker 05: has held there's no infringement. [00:01:15] Speaker 02: There is no case directly on point with respect to the infringement issue that's presented here. [00:01:20] Speaker 02: Okay. [00:01:21] Speaker 05: That answers my question. [00:01:24] Speaker 02: The issue, if I may, I'll address the inducement issue first. [00:01:30] Speaker 02: The legal issue that the court made a mistake on is the issue of intent and deferring intent based on [00:01:38] Speaker 02: a label that was ambiguous. [00:01:40] Speaker 02: So the general rule, there's no dispute that there were substantial non-infringing uses in this case for the product as labeled. [00:01:49] Speaker 02: And the only issue is whether or not the label itself induces infringement based on what it says. [00:01:59] Speaker 02: And the label itself doesn't contain an explicit instruction to administer the drug to the patients with a risk factor. [00:02:06] Speaker 04: What the district court... What do you mean by instruction? [00:02:10] Speaker 04: I mean, the pharmaceutical company doesn't instruct the doctors to do something. [00:02:15] Speaker 04: It gives information. [00:02:17] Speaker 04: It supplies a product, and then it provides information that the doctor will use to decide which patients to use the drug on. [00:02:27] Speaker 04: And here, the indications for use says it's for reduced hospitalization. [00:02:33] Speaker 04: And then it says, if you want to know for which patients we think [00:02:37] Speaker 04: that will occur, see section 14, most of which is a big Athena study that says, here are the patients for which this will be used. [00:02:48] Speaker 04: How is that not an intent that the product put out there will be used for that class of patients for which we spent a lot of money showing net benefit? [00:03:03] Speaker 02: So the indication section refers to the entire clinical study section, not just the Athena trial. [00:03:09] Speaker 04: That's why I said most, right? [00:03:10] Speaker 04: And there's a little section on urodes, is that how to say it? [00:03:14] Speaker 02: Urodes and adonis. [00:03:15] Speaker 04: Urodes and adonis, which are companion studies. [00:03:18] Speaker 04: And then there's one for Andromeda, which says there might be a problem here. [00:03:23] Speaker 04: So. [00:03:24] Speaker 02: Correct. [00:03:25] Speaker 02: By referring to the clinical study section, it's not referring to an instruction only to administer [00:03:31] Speaker 02: to the patients with the risk factors. [00:03:34] Speaker 04: Why should it have to be only? [00:03:36] Speaker 04: Why shouldn't there be inducement for all of the indications that the label says this is a good product for A and for B? [00:03:47] Speaker 04: You can induce both. [00:03:48] Speaker 02: Because under the case law, for example, the Vitamix case, an instruction that results in ambiguity or could result in infringing uses or could not result in infringing uses [00:04:01] Speaker 02: is not enough to demonstrate specific intent to induce infringement. [00:04:08] Speaker 04: In this case... So does Vitamix really stand for what I think your proposition is, or tell me if this is the wrong proposition? [00:04:16] Speaker 04: You put out a product and you say, you can use it for A, or you could use it for B. A is the infringing use, B is not. [00:04:24] Speaker 04: You're not liable for A because you also said you can use it in another way? [00:04:30] Speaker 02: It's probably a little more subtle than that, Your Honor, in that the instruction itself doesn't say you can use it for A or you can use it for B. The instruction itself is ambiguous as to who it can be used for, which is what the case is here. [00:04:45] Speaker 02: The instruction in the indication section is ambiguous as to the patient population. [00:04:51] Speaker 02: The closest it comes is the patient population [00:04:54] Speaker 02: describes in the indication is the patient population in uridus and adonis. [00:05:00] Speaker 02: So all it does is refer you to a clinical trials section that also contains information about uridus and adonis. [00:05:10] Speaker 02: The instruction itself is ambiguous as to what it's telling you to do with the drug. [00:05:16] Speaker 04: It's not telling you to do anything. [00:05:18] Speaker 04: All it's doing is providing doctors the information about what this massive set of scientific studies have indicated is beneficial. [00:05:29] Speaker 02: That's correct. [00:05:30] Speaker 04: And under those circumstances... But inducement doesn't require... Instruction is an ambiguous word. [00:05:37] Speaker 04: Often we use it to mean, I tell you what to do and I've just instructed you. [00:05:42] Speaker 04: That's not what goes on in this world or in general. [00:05:47] Speaker 04: You don't need that for inducement, for encouragement. [00:05:50] Speaker 02: Right. [00:05:51] Speaker 02: I agree with that. [00:05:52] Speaker 02: I think you do, though, in a circumstance where the actual [00:05:57] Speaker 02: instruction or what is being described in the label is ambiguous. [00:06:04] Speaker 02: Here, there isn't a... So, for example... Ambiguous to what extent? [00:06:10] Speaker 00: Ambiguous as to what population to administer the drug to? [00:06:14] Speaker 00: Correct. [00:06:15] Speaker 02: Correct. [00:06:16] Speaker 02: It's ambiguous as to what population. [00:06:17] Speaker 02: The only limit in the indication on the population is the population that's described in the Uritus and Adonis studies, which is a patient [00:06:26] Speaker 02: with either persistent or paroxysmal AF. [00:06:30] Speaker 02: That's the only limit in the instruction on who gets the drug. [00:06:36] Speaker 00: But the Athena study talked to patients over 70 and with certain risk factors. [00:06:43] Speaker 00: Correct. [00:06:44] Speaker 00: So that's section 14. [00:06:49] Speaker 00: points to potentially maybe more than one population to which this drug should be administered. [00:06:57] Speaker 00: But that population in the Athena study is at least one of those, right? [00:07:01] Speaker 00: That's correct. [00:07:02] Speaker 00: Okay. [00:07:03] Speaker 00: So if your inducement never or not able to be available, if you have something that points and encourages this can be used for A or B, [00:07:14] Speaker 00: And you're just in need? [00:07:15] Speaker 00: Can't that still be inducement? [00:07:17] Speaker 02: It could be, as long as there's enough evidence of intent for B. So it could be, the Vitamix case says it's not enough, just that is not enough. [00:07:28] Speaker 02: There has to be something [00:07:30] Speaker 00: Well, vitamins, the facts were a little differently. [00:07:33] Speaker 00: I mean, what we were dealing with in the blender was a little different. [00:07:38] Speaker 00: But vitamins did not preclude having two alternatives. [00:07:43] Speaker 00: If you encourage to do this or to do this, that doesn't preclude. [00:07:48] Speaker 00: I mean, there's substantial non-infringing uses, and that precludes contributory infringement, but not induced infringement, right? [00:07:55] Speaker 02: That's right. [00:07:56] Speaker 02: Again, but it depends on how much evidence there is of intent. [00:08:01] Speaker 00: The problem with what the district court did here is... Well, are you suggesting that because other than section 14, none of the other indications or instructions refer to a particular population, then we should ignore what's in section 14 or pay much less attention to it or what? [00:08:23] Speaker 02: I think what you can gather from section 14 [00:08:26] Speaker 02: is that there are multiple studies. [00:08:28] Speaker 02: It's a descriptor. [00:08:29] Speaker 02: It's a descriptor of studies that were performed. [00:08:32] Speaker 02: And under the Takeda case, a description by itself is not enough to show specific intent to induce infringement. [00:08:41] Speaker 02: So the reference to the clinical studies is not an instruction as much as it is a descriptor. [00:08:48] Speaker 02: It's a descriptor of multiple studies, including the Uritus and Adonis study. [00:08:53] Speaker 02: as in addition to the Athena study, which again describes the population that matches the indication. [00:09:00] Speaker 05: You object to the district court's reliance on AstraZeneca and the Apotex and spend a couple of pages in the blue brief distinguishing it. [00:09:14] Speaker 05: And your position is that the case actually supports you and you cite some language to show your interpretation [00:09:23] Speaker 05: regarding substantial non-infringing uses. [00:09:30] Speaker 05: I went back and looked and what AstraZeneca actually says, regardless of the substantial non-infringing uses of a product, liability for active inducement may be found where evidence goes beyond a product's characteristics or the knowledge that it may be put to infringing uses. [00:09:49] Speaker 05: and shows statements or actions directed to promoting infringement. [00:09:54] Speaker 05: And such statements or actions may include instructions in proposed drug labels. [00:09:58] Speaker 05: How do you distinguish that language in AstraZeneca? [00:10:02] Speaker 02: I think in AstraZeneca, the instruction there was to titrate down. [00:10:08] Speaker 02: There was a positive, affirmative instruction to titrate down to the lower dose, which would lead to infringement. [00:10:16] Speaker 02: It's a little different than here where the instruction could either or. [00:10:22] Speaker 02: It could lead to infringement. [00:10:23] Speaker 02: It could not lead to infringement. [00:10:25] Speaker 02: So it's not enough to just have the instruction by itself. [00:10:30] Speaker 02: Especially the way the product was packaged. [00:10:33] Speaker 02: In the AstraZeneca case, you get a 0.25 milliliter vial. [00:10:39] Speaker 02: You use it. [00:10:40] Speaker 02: And if you're titrating down to the lower dose, you're going to only do it once a day. [00:10:45] Speaker 02: So that's where the extra instruction is evidence of intent that's not present in this case. [00:10:55] Speaker 00: Our clock is running. [00:10:57] Speaker 00: So can you turn us now to the obviousness argument? [00:11:00] Speaker 02: Yes, Your Honor. [00:11:00] Speaker 02: The legal error that district court made on obviousness was in applying the wrong standard for reasonable expectation of success. [00:11:09] Speaker 02: It's undisputed that the prior- If we disagree with you on- [00:11:12] Speaker 05: the obvious obviousness finding for the independent claims. [00:11:16] Speaker 05: Do we need to reach your arguments about that dependent claims? [00:11:20] Speaker 02: An obviousness? [00:11:22] Speaker 02: No. [00:11:23] Speaker 02: The court generally treated all the claims as a whole together. [00:11:28] Speaker 02: So there's no need to separate. [00:11:30] Speaker 00: And that's claim eight in particular. [00:11:31] Speaker 00: Claim eight in particular. [00:11:34] Speaker 02: It should be treated the same. [00:11:36] Speaker 02: And here's why. [00:11:36] Speaker 02: The court found that there was no difference as far as obviousness was concerned. [00:11:40] Speaker 02: and there was no, in a footnote, the court mentioned that it might have a less of a reasonable expectation of success, even then claim one, but the court didn't cite any factual finding in relation to that, but just mentioned it in a footnote. [00:11:58] Speaker 02: So I think that it's appropriate to treat all the claims the same. [00:12:02] Speaker 04: The issue with reasonable... Let me try to frame my question about that issue. [00:12:10] Speaker 04: So we don't waste time on something. [00:12:14] Speaker 04: Stipulate, for purposes of this question, that the District Court did not demand proof-positive certainty. [00:12:22] Speaker 04: Something else, something lower than that. [00:12:26] Speaker 04: Now what's the error the District Court committed? [00:12:29] Speaker 04: And if you can, articulate for me what you think reasonable expectation of success means, that something less than certainty, something more than a decently grounded hope, what does it mean? [00:12:47] Speaker 02: So in this case, there are a couple of things that you can look at. [00:12:51] Speaker 02: The first issue is the disclosures. [00:12:54] Speaker 02: So there are two disclosures, the Homeloser 2008 disclosure and the clinicaltrials.gov [00:12:59] Speaker 02: disclosure, both of which lay out every element of this, every element of the claimed invention except for the Fed, you know, feeding, administering it while feeding. [00:13:11] Speaker 02: In that case, under the case law, the Pharmastem case in particular, the issue is whether or not a person... [00:13:19] Speaker 04: Put aside PharmaSTEM because PharmaSTEM relies very heavily on the admission in the specification about what the mouse studies already showed. [00:13:32] Speaker 02: And I think the dispute there was whether or not the mouse studies actually disclosed that element. [00:13:36] Speaker 02: We don't even have that issue here. [00:13:38] Speaker 02: We don't have a dispute about what was disclosed in the art. [00:13:41] Speaker 02: It's indisputable everything was disclosed in the art. [00:13:45] Speaker 02: And in PharmaSTEM the rule, I mean the kind of [00:13:48] Speaker 02: law that was stated there was if the art guides you directly to the method, you can't claim you got an invention by just proving what the art told you it was going to do. [00:14:04] Speaker 02: So reasonable expectation is used as a measure to [00:14:08] Speaker 02: Guard against hindsight and to guard against grabbing elements from multiple different sources when there's no guidance as to how to use those elements to get to the result. [00:14:20] Speaker 02: In this case, that's not the circumstance here. [00:14:24] Speaker 02: Here, the method was taught in two prior art publications. [00:14:28] Speaker 02: The entire method was taught with the exception of one thing that is indisputably obvious. [00:14:34] Speaker 02: No one disputed it was obvious. [00:14:36] Speaker 02: This is almost an anticipation case, but for that giving it twice a day with meals element. [00:14:44] Speaker 04: So in that circumstance... And if it were an anticipation case, we probably wouldn't be talking about reasonable expectation of success. [00:14:53] Speaker 02: That's correct. [00:14:54] Speaker 02: We probably wouldn't be talking about it. [00:14:56] Speaker 02: And I think the issue here then becomes, with that statement, and again, along with [00:15:05] Speaker 02: the MPEP rule that it's presumed that if you have a protocol that's approved by the FDA that you're going to expect success with the statements in the art that said, all the contemporaneous statements in the art said we expect this to work, every single one. [00:15:23] Speaker 04: In that case... Well, every single one. [00:15:26] Speaker 04: Maybe I'm misremembering. [00:15:27] Speaker 04: I guess I was [00:15:30] Speaker 04: remembering two that were public. [00:15:33] Speaker 04: The private ones don't count because the private ones couldn't have informed what a person of skill in the art would have expected as opposed to what Dr. Holmloser, is that how we say it? [00:15:45] Speaker 04: Holmloser, yes. [00:15:47] Speaker 04: The issue is not what he expected, but what a person of skill in the art would expect. [00:15:52] Speaker 04: And I guess I'm remembering two things. [00:15:54] Speaker 04: One, the extraordinary statement in the 2008 article. [00:15:57] Speaker 04: Yes. [00:15:58] Speaker 04: And then the second thing that he told subjects of the clinical study. [00:16:04] Speaker 04: Right. [00:16:06] Speaker 04: Why would, and that clearly presented for Sanofi a serious question, how do we explain this at trial? [00:16:17] Speaker 04: And lo and behold, they come up with an explanation, right? [00:16:20] Speaker 04: Their expert says, [00:16:22] Speaker 04: a person of skill in the art would have understood that statement, at least in the 2008 article, I don't know about the other one, the subject, the statement to subjects, as a poorly formulated statement of the hypothesis being tested and no more. [00:16:38] Speaker 04: Why is, and Judge Andrews said, I'm persuaded by that. [00:16:42] Speaker 04: Why is that clearly erroneous? [00:16:44] Speaker 02: Because a hypothesis under the law [00:16:46] Speaker 02: would be enough in this case. [00:16:48] Speaker 02: A hypothesis would be enough under the law. [00:16:50] Speaker 02: The MPEP state... The MPEP is not the law. [00:16:54] Speaker 02: Your Honor, I apologize. [00:16:54] Speaker 02: I would add, not only the MPEP says that we will presume that it's reasonably expected to succeed if you have an FDA approved protocol, because when you're giving the drug to patients, the FDA says [00:17:13] Speaker 04: I want to make sure that I'm not going to... Even taking that as a presumption, that doesn't mean that a finding to the contrary in a particular case is clear error. [00:17:25] Speaker 02: Correct, which is why I think the error... I'm sorry. [00:17:29] Speaker 02: The legal error is the application of the wrong standard. [00:17:32] Speaker 02: The factual error here is that it would have to... The factual error here is [00:17:42] Speaker 02: ignoring the contemporaneous evidence and relying on trial statements by an expert. [00:17:50] Speaker 05: Ignoring or weighing the other way? [00:17:54] Speaker 02: I think based on the way that the opinion reads, it reads like he ignored them by saying it's just a hypothesis. [00:18:04] Speaker 02: I'm not sure if just a hypothesis answers the question of whether it's a reasonable expectation. [00:18:11] Speaker 00: Well, here's what I understood that the district court concluded having heard all the evidence, which is, yes, this is quite a strong statement, but we've got the other experts saying this is nothing more than a hypothesis. [00:18:22] Speaker 00: This is how we write hypotheses. [00:18:24] Speaker 00: And the only thing in this article, it appears, led the author to these, whether you want to call them conclusions or hypotheses, [00:18:33] Speaker 00: are these two studies. [00:18:35] Speaker 00: And these two studies, and Judge Andrew spent a lot of time going through this post-hoc stuff and saying, this analysis doesn't give me anything. [00:18:44] Speaker 00: It doesn't give me anything. [00:18:45] Speaker 00: If anything, and he used a word like inconsistencies or whatever. [00:18:50] Speaker 00: So he looked at what appears to be the underlying basis for the hypothesis reached in this, and he dismissed both of those [00:18:58] Speaker 02: He actually didn't completely dismiss. [00:19:00] Speaker 02: He said a person of skill in the art would credit post hoc analysis, but would conclude ultimately that this statement was a hypothesis. [00:19:11] Speaker 00: No, no, no. [00:19:11] Speaker 00: Well, I disagree. [00:19:12] Speaker 00: I think he really spent a lot of time diminishing or demeaning the post hoc analysis. [00:19:18] Speaker 00: And even though it's a legal matter, he does say once, I think, well, it's got to give in some way. [00:19:23] Speaker 00: At the end of the day, I [00:19:26] Speaker 00: Couldn't see now you may think that's legal error, but I couldn't see that at the end of the day He really gave it any weight, but I'm not sure I think there's anything really wrong with that if he was relying on the conclusions of expert Well, maybe there's something wrong with that, but I don't see the clear error. [00:19:41] Speaker 02: So I think the error is because because None of the contemporaneous evidence at the time supports it [00:19:48] Speaker 02: There's no, none of the statements at the time support that conclusion. [00:19:53] Speaker 00: Well, how are we supposed to know? [00:19:55] Speaker 00: I mean, one of the big fights here is between the experts is whether this is just a general hypothesis. [00:20:02] Speaker 00: I mean, this is the way a science, when you're in high school science, you write a hypothesis and it brings you to one direction, but it's really nothing more than a hypothesis. [00:20:11] Speaker 00: And one expert says, no, no, no, no, no, this is the real deal. [00:20:15] Speaker 00: How are we supposed to evaluate that? [00:20:18] Speaker 02: You're supposed to evaluate it on a basis of reasonableness. [00:20:22] Speaker 02: And I think that's where the clear error problem comes in here because the analysis was not based on reasonableness. [00:20:31] Speaker 02: I mean, so putting aside the judges, the district court's analysis was not based on reasonableness because [00:20:40] Speaker 00: What, by determining... I'm sorry, I'm sorry to interrupt, but when you say reasonable, are you talking about reasonable expectation of success, the reasonableness in that definition? [00:20:49] Speaker 02: Correct, correct. [00:20:51] Speaker 02: Because when he discarded, when he evaluated the post-hack analysis and determined that it wouldn't, what he did was he determined that that wouldn't get you to a reasonable expectation of success. [00:21:09] Speaker 02: I don't think he [00:21:10] Speaker 02: He didn't determine that the post hoc analysis was wrong. [00:21:14] Speaker 02: It just didn't get you where you needed to go. [00:21:17] Speaker 02: That's how I read his opinion. [00:21:21] Speaker 02: It wasn't that I would think that this is completely wrong. [00:21:25] Speaker 02: I would credit it, but I would be skeptical of it. [00:21:29] Speaker 02: And in this case, there is no basis for being skeptical of the post hoc analysis based on what was disclosed in the art and what the Holmoser article actually said about what they expected. [00:21:40] Speaker 02: So I understand that some of the statements by Sanofi were not public, but they are evidence of what someone would expect at the time. [00:21:55] Speaker 04: So it's, we... But the someone may be something different. [00:21:58] Speaker 04: I mean, this whole project seems to have been, I don't know, half a life's work of Dr. Hohenzoller. [00:22:04] Speaker 04: What he would expect about this particular drug is, must be substantially better informed than what a person of skill in the art. [00:22:14] Speaker 04: And you have several people, I think, don't you, what's a good name, Tafreshi and a few others saying, even in light of Eurydice Adonis, [00:22:24] Speaker 04: This is kind of confusing and both the European and the US, the FDA and whatever the European one is called said, we're actually on the basis of Euridice and Adonis, we are not going to approve this. [00:22:41] Speaker 04: We aren't that uncertain, whatever that uncertain means about whether this is net beneficial. [00:22:51] Speaker 02: I think actually what happened was the FDA, what the FDA did was we took a look at Euridice and Adonis and then we took a look at Andromeda and said we want, we think you need to do one more study. [00:23:05] Speaker 02: That's what the FDA concluded. [00:23:06] Speaker 02: We think you need to do one more study, which is how we end up with it. [00:23:10] Speaker 05: No, yeah, they said we think you need to because it's so problematic. [00:23:15] Speaker 02: because they were concerned about the Andromeda study. [00:23:16] Speaker 02: Because they were concerned about the Andromeda study. [00:23:19] Speaker 00: Well, except there's a lot here. [00:23:21] Speaker 00: And I've just found parts of it on appendix 41 through 43 of the district court's decision. [00:23:26] Speaker 00: When he talks about the previous studies, he seems to buy Dr. Reifel's analysis of those studies, which is he calls it discordant results. [00:23:39] Speaker 00: And he goes on to, I almost read this as almost he was kind of arguing this almost the teaching away. [00:23:45] Speaker 00: his analysis, his evaluation of those studies, and he bought everything the other side's expert said about those studies, completely diminished. [00:23:54] Speaker 02: Well, he didn't discuss, the district court did not discuss [00:23:58] Speaker 02: what the conclusion was of the Andromeda study and what Dr. Riefel actually said about that study. [00:24:04] Speaker 00: No, I'm talking about the Uridus study. [00:24:07] Speaker 02: Uridus and Adonis, right. [00:24:08] Speaker 02: Yeah. [00:24:09] Speaker 02: I think what the FDA's conclusion about Uridus and Adonis was, was that it was not sufficient by itself given the Andromeda study to grant approval, and we need to do one more study. [00:24:22] Speaker 02: So that's how Athena ended up getting designed. [00:24:25] Speaker 00: So is that the question here, whether that is sufficient to establish a reasonable expectation of success? [00:24:33] Speaker 02: I think that's an explanation for what the district court did here, as far as how it analyzed the studies. [00:24:45] Speaker 02: But with respect to what the standard is for reasonable expectation of success, the issue is whether or not, if you're viewing this as a personal skill in the art in 2008 or 2009, would you expect, when you're given the homeless argument, would you expect this is going to work? [00:25:05] Speaker 02: And yes, there were some questions. [00:25:08] Speaker 04: Quite right. [00:25:10] Speaker 04: I've been trying to think about whether there [00:25:13] Speaker 04: at least to my mind, more informative translation and reasonable expectation. [00:25:19] Speaker 04: Is it really whether the person of skill in the art would expect or whether the person would expect by some probability in the neighborhood of 50%, maybe a little bit more and have a scientifically reasonable basis for the expectation? [00:25:37] Speaker 04: Because lots of people, and I assume scientists are among them, [00:25:41] Speaker 04: have expectations that as soon as that they would immediately follow the explanation. [00:25:46] Speaker 04: But this is just kind of a scientific intuition based on past things. [00:25:51] Speaker 04: And now could I tell you what the scientifically reliable basis for that expectation is? [00:26:00] Speaker 02: I don't think there is a standard for scientific expectation. [00:26:03] Speaker 02: I think there is a reasonable scientific explanation or expectation here based on [00:26:10] Speaker 02: what happened in the Uredis and Adonis studies and what was reported in the New England Journal of Medicine about the post-hoc analysis and what was reported in Holmoser and the fact that the FDA approved this protocol to be used in patients. [00:26:24] Speaker 02: By the time Holmoser was actually published, it already had been, the study had been going on for a while. [00:26:30] Speaker 02: So under those circumstances, [00:26:33] Speaker 02: If your question is, does the standard require scientific evidence or some sort of scientific underlying? [00:26:39] Speaker 04: A scientifically reasonable basis for an expectation. [00:26:42] Speaker 02: I don't think that's the standard. [00:26:44] Speaker 02: I have not seen a case where that's the standard has been set. [00:26:47] Speaker 02: I don't think Pharmastem necessarily sets that standard either. [00:26:51] Speaker 02: But in this case, that standard would be met based on what was presented at the time in 2008 in the Holman-Loser article and what was known about [00:27:03] Speaker 02: Eurydice and Adonis studies and what the results were. [00:27:07] Speaker 04: Can I ask you, the statement in the Athena studies information to potential subjects, which also has this, it is expected language. [00:27:23] Speaker 04: That's the one other place that at least I'm remembering has it. [00:27:26] Speaker 04: Is that a common thing to put in [00:27:31] Speaker 04: statements to subjects in clinical studies? [00:27:33] Speaker 02: I have not seen a clinical study that said that before. [00:27:37] Speaker 02: I have not seen a clinical study protocol or patient information. [00:27:42] Speaker 02: I'm not saying it doesn't happen, but I've never seen it. [00:27:46] Speaker 02: I've done these cases a long time. [00:27:47] Speaker 02: I've never seen that before. [00:27:49] Speaker 02: And again, this is one of the circumstances where they're telling the FDA, we expect this to work. [00:27:53] Speaker 02: They're telling patients, we expect this to work. [00:27:55] Speaker 02: And now they're standing here saying, no one expected this to work. [00:27:58] Speaker 02: when they publicly announced that they expected it to work. [00:28:01] Speaker 02: So it's a little bit questionable. [00:28:06] Speaker 02: And I'm way over time. [00:28:08] Speaker 00: Yes. [00:28:09] Speaker 00: We've lost control. [00:28:10] Speaker 00: Thank you. [00:28:11] Speaker 00: We'll restore your rebuttal time, and we'll add another 10 minutes to the other side, but hopefully you will not need it. [00:28:19] Speaker 00: I may not need it, Your Honor. [00:28:21] Speaker 01: Good morning, and may it please the Court. [00:28:23] Speaker 01: Your Honor, I'd like to begin with the Court's decision on infringement. [00:28:28] Speaker 01: and in particular his findings on intent. [00:28:31] Speaker 01: The court did find that there was an intent to infringe here, and he did it on several factual basis. [00:28:37] Speaker 00: When you're going, I'm happy to hear what you have to say, but if you could just include in that analysis, I mean, we don't have that many cases, but it seems to me that whether we agree or disagree with you, this goes beyond where our cases have gone in terms of the inducement stuff. [00:28:53] Speaker 00: So could you just address the cases as well? [00:28:55] Speaker 01: I will address the cases as a go. [00:28:57] Speaker 01: But in terms of the factual findings, the court found that this product, according to the current label, is prescribed 80 percent of the time in an infringing manner. [00:29:08] Speaker 01: It found that these are undisputed facts. [00:29:11] Speaker 01: It found that when the defendant's product [00:29:13] Speaker 01: is sold with their labels, it will be infringed 80% of the time. [00:29:17] Speaker 00: Can I ask you about that? [00:29:18] Speaker 00: Because I have some question of that. [00:29:20] Speaker 00: I thought the number was 77, not 80% of the time. [00:29:23] Speaker 00: But the question I had about that number was, there's something on the record that says that the label initially was more specific and included the Athena study. [00:29:33] Speaker 00: And then that was taken off. [00:29:35] Speaker 00: So I guess my question was, did those prescriptions that comprise the 77% to 80% [00:29:41] Speaker 00: Could it be that those prescriptions were given at the time where the instructions and the indication clearly pointed you towards the Athena study? [00:29:49] Speaker 01: No, Your Honor, they have not changed. [00:29:50] Speaker 01: And Dr. Zussman, the defendant's witness, said that it did not change the prescribing patterns of the drug. [00:29:59] Speaker 01: And the last fact that the judge found with respect to intent was that the defendants were aware of the patent and that they continued to pursue approval of this particular label [00:30:11] Speaker 01: without any amendments to avoid infringement. [00:30:14] Speaker 01: Now, turning to the court's legal standards on inducement, I think there are... Yes, please, go ahead. [00:30:23] Speaker 03: Could they have pursued, sought a different label? [00:30:27] Speaker 01: I don't know, but we've seen it in other cases where that is exactly what the defendants did. [00:30:31] Speaker 01: And sometimes it took them out of inducement and sometimes not. [00:30:35] Speaker 04: And then they might make you, I mean, can their label be different from your label? [00:30:38] Speaker 01: No, I think what they would have to do is convince the FDA that they were entitled to a different label and it would not affect us, typically. [00:30:46] Speaker 01: I haven't heard of that particular instance. [00:30:49] Speaker 01: So with respect to the case law on inducement, I think there's a spectrum. [00:30:54] Speaker 01: There are those cases where [00:30:55] Speaker 01: There is no question that the product is going to be used in an infringing manner. [00:31:01] Speaker 01: In those cases, you are entitled to presume intent. [00:31:04] Speaker 01: I think the MGM case from the Supreme Court says that quite clearly. [00:31:09] Speaker 01: And you very rarely see those cases because that's not something that's often litigated. [00:31:13] Speaker 01: On the other end of the spectrum is where the label does not say anything about the infringing use. [00:31:20] Speaker 01: That's the Werner Lambert case. [00:31:21] Speaker 01: I contend that's the Vitamix case. [00:31:23] Speaker 01: And then there are cases in between. [00:31:25] Speaker 01: where the label says something about an infringing use and at the same time has a substantial non-infringing use. [00:31:31] Speaker 01: For example, the AstraZeneca case where the primary use of the product was non-infringing. [00:31:36] Speaker 01: It was twice a day daily dosing. [00:31:37] Speaker 01: That's what the defendants were trying to sell. [00:31:39] Speaker 00: Yeah, but there there's a clear label that pointed to more than one direction. [00:31:43] Speaker 00: That's why I think this case would go beyond AstraZeneca because there there was a clear [00:31:47] Speaker 00: label instruction, and here there's not. [00:31:50] Speaker 00: Here it's all about encouragement, I guess. [00:31:52] Speaker 00: Yes, that's right. [00:31:53] Speaker 00: Rather than instruction, because it's not in the light. [00:31:55] Speaker 00: So am I right about that? [00:31:57] Speaker 01: I think, Your Honor, what the court found, if I could just talk about our label for a moment, and how the court analyzed it. [00:32:04] Speaker 01: The court said, basically, that if a physician was presented with a patient, let's say a 75-year-old patient that had diabetes and a diuretic, and wanted to keep that patient out of the hospital, [00:32:17] Speaker 01: The physician would know a few things. [00:32:18] Speaker 01: First of all, based on the prior art, no other anti-arrhythmic drug ever treated that condition to keep the patient out of the hospital. [00:32:26] Speaker 01: It was never shown to do that. [00:32:27] Speaker 01: In fact, all of them were shown not to have that effect. [00:32:30] Speaker 01: Second. [00:32:31] Speaker 01: Also, it killed people. [00:32:32] Speaker 01: Yes, that's right. [00:32:33] Speaker 01: It killed people. [00:32:34] Speaker 01: And then, so he would consider the dronetirone label, and he would see right in the indication that it is meant for the prevention of cardiovascular hospitalization. [00:32:44] Speaker 01: Reduces the risk of cardiovascular hospitalization. [00:32:47] Speaker 01: right in the indications. [00:32:49] Speaker 01: And it says then in the indications, see clinical studies 14. [00:32:55] Speaker 01: The doctor would then go to the clinical studies. [00:32:58] Speaker 01: And the first thing he would see most prominently is the Athena study. [00:33:02] Speaker 01: The Athena study, as the judge found, is the only study that reasonably relates to the prevention of cardiovascular hospitalization. [00:33:10] Speaker 01: He would see that a patient needing. [00:33:12] Speaker 04: Yes. [00:33:13] Speaker 04: That was designed to relate to it. [00:33:17] Speaker 04: Your Honor, actually... Isn't the whole point of the post-hoc analysis is that when you look back at Eurydice Adonis, it does turn out to relate to reduced hospitalization? [00:33:27] Speaker 01: The design of the study had nothing to do with it. [00:33:30] Speaker 01: It wasn't an endpoint. [00:33:31] Speaker 01: And that's why everybody would know that this was a post-hoc analysis, whether or not it said it in Hohenloser or not, because it had nothing to do with the endpoints. [00:33:39] Speaker 01: And so what the post-hoc analysis was used for in Dr. Hohenloser's paper was to design Athena to figure out how many patients do we have to [00:33:47] Speaker 01: It's a guess. [00:33:48] Speaker 01: You never know how many patients you have to enroll unless you make some estimate as to what the effect size is going to be. [00:33:54] Speaker 01: And remember, again, the primary thing that they were looking for in the Athena study was no difference on mortality, neutrality on mortality. [00:34:07] Speaker 01: It was a total surprise that it reduced cardiovascular hospitalizations. [00:34:10] Speaker 01: That finding was commented on in the art as a breakthrough and as remarkable. [00:34:15] Speaker 01: A total surprise that that happened. [00:34:17] Speaker 01: And that's what they were able to seek FDA approval on that particular indication. [00:34:21] Speaker 01: But the post-hoc analysis was used solely to construct the patient population size of the Athena study. [00:34:32] Speaker 01: That's why it was done. [00:34:37] Speaker 01: Sorry. [00:34:38] Speaker 01: Right. [00:34:40] Speaker 01: I'm sorry. [00:34:40] Speaker 01: But back to the physician with the label. [00:34:42] Speaker 01: So the physician would read the Athena [00:34:44] Speaker 01: study information. [00:34:46] Speaker 00: Can I ask you about that? [00:34:47] Speaker 00: Please, go ahead. [00:34:49] Speaker 00: But one thing that just confused me, in the Athena study, in 14.1, the second paragraph talks about giving it that the patient population is those over 70. [00:34:58] Speaker 00: And then three paragraphs later it talks about patients ranging from 23 to 97. [00:35:04] Speaker 00: Yes. [00:35:05] Speaker 00: So how are we getting to 23 when I thought the patient population was 70 and over? [00:35:11] Speaker 01: The patient population in Athena, I believe, was 70 and then raised to 75. [00:35:15] Speaker 00: That's right. [00:35:16] Speaker 01: Are you talking about Eurydice and Adonis? [00:35:18] Speaker 00: No, I'm talking about the... It's page 7624. [00:35:21] Speaker 00: I'm sorry. [00:35:26] Speaker 01: I now know the answer. [00:35:27] Speaker 01: It's over 70 or has a risk factor. [00:35:31] Speaker 00: Or has a risk factor? [00:35:33] Speaker 00: Yes. [00:35:34] Speaker 00: Well, that's not what... [00:35:37] Speaker 00: It's not what paragraph two says in the Athena study. [00:35:40] Speaker 00: They stay at or over 70 with at least one risk factor. [00:35:44] Speaker 01: The Athena study was modified at some point in the original protocol halfway through because they were not seeing enough, frankly, enough deaths. [00:35:55] Speaker 01: in the enrollees in order to have a successful. [00:35:57] Speaker 04: And the pre-modification version included 24-year-olds with risk factors. [00:36:02] Speaker 04: Yes, I believe that's right. [00:36:03] Speaker 04: But not the post-modification. [00:36:04] Speaker 04: Yes, I believe that's right. [00:36:05] Speaker 04: Post-modification, it was only young people. [00:36:08] Speaker 01: It was older patients, I believe. [00:36:09] Speaker 01: You had to be older. [00:36:10] Speaker 01: Yes. [00:36:11] Speaker 00: OK, sorry to just jump to it. [00:36:14] Speaker 00: OK, so you were saying that. [00:36:16] Speaker 01: So the physician has the label. [00:36:17] Speaker 01: The physician consults the Athena study. [00:36:20] Speaker 01: And he sees that a patient just like the one he is presented with is helped. [00:36:25] Speaker 01: That exact type of patient is the one in which droneterone was shown to reduce the risk of cardiovascular hospitalization. [00:36:31] Speaker 01: And what the judge found was that based on that evidence, that the physician would be encouraged to give that drug to a patient according to the label. [00:36:41] Speaker 01: And as this court has found, it is not an instruction that's necessary. [00:36:45] Speaker 01: It's encourage, recommend, or promote. [00:36:47] Speaker 01: And promotion or recommendation is similar to what the Supreme Court has said about inducement in the [00:36:54] Speaker 01: MGM case. [00:36:54] Speaker 01: That's the language that they used. [00:36:56] Speaker 01: We want to turn to obvious. [00:36:58] Speaker 01: Yes. [00:37:00] Speaker 01: Your Honor, the court considered the home-loser statement and the... Two statements. [00:37:06] Speaker 04: I mean, how is it that in the information given to subjects, [00:37:13] Speaker 04: that that could reasonably be viewed, and this is not a scientific readership, this is not the New England Journal of Medicine, that that could be understood as anything but jump into the study. [00:37:27] Speaker 01: You should think it's going to work. [00:37:30] Speaker 01: Okay, so there's a couple things to say about that document. [00:37:33] Speaker 01: First of all, there was no evidence that it was ever promulgated to anybody. [00:37:36] Speaker 04: Well, the subjects. [00:37:37] Speaker 01: No, no. [00:37:38] Speaker 01: In fact, that document that was referred to and entered into the record might have been a draft. [00:37:43] Speaker 01: It was contained within Sanofi's files and at most was given to physicians at their hospitals that were going to run the study. [00:37:52] Speaker 01: Now what physicians did at their hospitals, and there's clear evidence of this in the record because this is what Dr. Zussman did. [00:37:57] Speaker 01: They have a negotiation with their institutional review board which governs the administration of that in their hospital. [00:38:04] Speaker 01: And in his instance, he rewrote that section. [00:38:07] Speaker 01: He rewrote it to take all of the expectation language out of it. [00:38:11] Speaker 01: And that you can find on, at the record, at Appendix 236, page 338, starting at about line 5 through 340, line 13. [00:38:23] Speaker 01: So at his institution, he rewrote it. [00:38:24] Speaker 01: So the evidence of what was actually given to patients is not the document that was, was talked about at the, at the court. [00:38:31] Speaker 04: Did Judge Andrews make any specific finding on this specific point? [00:38:35] Speaker 01: I don't think he said. [00:38:36] Speaker 01: I think he said it wasn't prior art. [00:38:38] Speaker 01: I think he concluded that in a non-prior art section. [00:38:40] Speaker 01: He cites it somewhere. [00:38:41] Speaker 00: My recollection is there's a citation to it. [00:38:48] Speaker 00: It's, I think, at page appendix 39. [00:38:51] Speaker 00: I mean, he seems to accept that he says Dr. Sussman also points out that the written [00:38:58] Speaker 00: subject information provided to the Athena trial patients started the expectation. [00:39:06] Speaker 00: So he seems to assume that this was, or find, that this was given to patients. [00:39:13] Speaker 00: I'm sure you're going to tell me I'm wrong. [00:39:16] Speaker 01: Well, Your Honor, that was not, I don't know that this is a factual finding. [00:39:20] Speaker 01: I think he's pointing out that that's what Dr. Zussman said. [00:39:22] Speaker 01: I'm not sure that rises to the level of a finding that he made to the court. [00:39:25] Speaker 01: I think what he's saying is it didn't matter in his [00:39:28] Speaker 01: in his analysis, just like the Holm-Loser statement that's in the prior art publication and like the post-hoc analyses, that they didn't, they didn't overcome the overwhelming evidence of uncertainty that he found both based on the prior administration. [00:39:43] Speaker 05: That can be read two ways. [00:39:45] Speaker 05: That is, the initial one did, but not what was given. [00:39:49] Speaker 00: Well, I guess we can look at the testimony that he said it, but I mean, I assume on cross-exam, I mean, [00:39:54] Speaker 00: That's right. [00:39:56] Speaker 01: That was on cross-examination that you'll find that, Your Honor. [00:40:00] Speaker 01: So the back to the consideration of that evidence, when he looked at the Hohnloser statement in the article, he said, the judge said, you have to look at that in the context of two or three different sets of evidence, of prior art evidence. [00:40:17] Speaker 01: The first one was the prior art failure with other antiarrhythmic drugs. [00:40:23] Speaker 01: So a lot of antiarrhythmic drugs were tested. [00:40:26] Speaker 01: They were tested. [00:40:27] Speaker 01: They had better antiarrhythmic properties than dronetarone has. [00:40:32] Speaker 01: And they were found in each and every case to either worsen or to not, not better cardiovascular hospitalizations. [00:40:41] Speaker 01: They didn't show a reduction in cardiovascular hospitalizations, and sometimes they worsened them. [00:40:46] Speaker 01: And what, what the defendants say is, well, all of those are irrelevant because they're different drugs. [00:40:53] Speaker 01: That's not the case. [00:40:54] Speaker 01: Imagine if the opposite were true. [00:40:55] Speaker 01: Imagine if every other antiarrhythmic drug were tested, and in every single instance, it reduced the risk of hospitalization. [00:41:02] Speaker 01: I think that would be the primary argument in terms of obviousness of this patent. [00:41:06] Speaker 01: The fact that every single other antiarrhythmic drug, which had better, that had better antiarrhythmic properties than dronetarone, failed to reduce cardiovascular hospitalization, I think is very important, and would set the mindset of a post-cardiologist that knew about that evidence. [00:41:21] Speaker 01: in viewing things like the Holmoser paper. [00:41:24] Speaker 04: The other... Can I bring you back to the subject? [00:41:26] Speaker 04: Yes. [00:41:27] Speaker 04: So I'm looking at page 210 of the appendix, page 236 of the transcript. [00:41:32] Speaker 01: No, I'm sorry, it's appendix 236. [00:41:35] Speaker 01: Are you looking at my site or something different? [00:41:37] Speaker 04: Appendix 210. [00:41:39] Speaker 04: Oh, I'm looking at the judge's site, Judge Andrew's site. [00:41:47] Speaker 04: 210 at the bottom, page 230. [00:41:49] Speaker 04: He cites pages 236 to 237, and this is Dr. Sussman testifying. [00:41:54] Speaker 04: It seems to me he says pretty plainly, at least twice, was this given to patients? [00:42:03] Speaker 04: Yes. [00:42:05] Speaker 04: That's it. [00:42:06] Speaker 04: 236, line 13. [00:42:06] Speaker 04: 237, line 18. [00:42:10] Speaker 04: And that's the information that was being provided to patients? [00:42:14] Speaker 04: Right. [00:42:14] Speaker 04: Right. [00:42:15] Speaker 01: And is there cross-examination here? [00:42:16] Speaker 01: Yes, this is cross-examination. [00:42:18] Speaker 01: So he's being shown the Massachusetts General Hospital version of that form on those pages. [00:42:24] Speaker 04: Is DTX 24? [00:42:27] Speaker 01: Is that the... Oh, DTX 24. [00:42:29] Speaker 01: I'm sorry. [00:42:30] Speaker 01: Again, Your Honor, could you go back to the page number? [00:42:32] Speaker 01: I'll follow you. [00:42:33] Speaker 01: I apologize. [00:42:35] Speaker 04: So he's being shown DTX 24. [00:42:38] Speaker 01: This is on transcript page 236? [00:42:39] Speaker 01: 210. [00:42:40] Speaker 01: No, transcript page 210. [00:42:41] Speaker 01: 210. [00:42:41] Speaker 01: Okay. [00:42:44] Speaker 01: I'm with you. [00:42:44] Speaker 04: What is DTX 24? [00:42:57] Speaker 01: It is the written subject information. [00:43:00] Speaker 04: Right. [00:43:00] Speaker 04: OK. [00:43:01] Speaker 04: So that's at page 7977 of the appendix. [00:43:03] Speaker 04: So that's the one with the it is expected phrase. [00:43:07] Speaker 01: That's right. [00:43:07] Speaker 04: He says that those two pages, [00:43:10] Speaker 04: 236 and 237 of the transcript. [00:43:12] Speaker 01: Yes, I'm with you. [00:43:14] Speaker 04: Which is what Judge Andrews cites at page Appendix 39, that this was in fact being given to patients. [00:43:22] Speaker 04: So patients are being told, expect success. [00:43:27] Speaker 01: No? [00:43:27] Speaker 01: Your Honor, I disagree with the question. [00:43:29] Speaker 01: Does this reflect information that was to be provided to your patients? [00:43:32] Speaker 01: Yes. [00:43:33] Speaker 01: This would be the information they expected us to share with the patients. [00:43:37] Speaker 05: Later on. [00:43:40] Speaker 05: Oh, next. [00:43:42] Speaker 05: 237. [00:43:44] Speaker 05: Right, this is the proposed language. [00:43:47] Speaker 01: Right. [00:43:48] Speaker 01: And he rewrote it at his institution. [00:43:50] Speaker 04: And so did he say, you had said when we started on this subject, that somewhere he testifies that, in fact, he doesn't know whether he rewrote it and that he doesn't [00:44:04] Speaker 01: Yes, I'll take you right there if I could. [00:44:10] Speaker 01: Page 338, at line 16, he's shown a question. [00:44:17] Speaker 01: This is what the patient's got, yes. [00:44:20] Speaker 01: So now we're talking about what the patient's actually received. [00:44:23] Speaker 01: Only evidence in the trial is to what the patient's received. [00:44:27] Speaker 01: And this is the Massachusetts General Forum, he said yes. [00:44:30] Speaker 01: Every individual reviewed it, yes. [00:44:32] Speaker 04: And since your [00:44:33] Speaker 04: Since the table of contents of the joint appendix unhappily does not list exhibit numbers, is that exhibit number, this is joint exhibit 218 in our appendix? [00:44:45] Speaker 01: I don't know if it is, but the relevant language is in the transcript. [00:44:48] Speaker 01: Are you about to tell me where? [00:44:50] Speaker 01: Yeah, it's right on the bridging from 339 to 340. [00:44:59] Speaker 01: Based on currently available information. [00:45:05] Speaker 01: that's right and that's and that's what they they took whatever information was given to them from Sanofi rather this this or something else and Dr. Raphael testified to the same and was there any [00:45:21] Speaker 04: testimony besides the Zustin testimony that we've been talking about, other witnesses about how DTX24, the proposed patient information, was or was not given to patients? [00:45:34] Speaker 04: Or is this the record on this? [00:45:36] Speaker 01: I believe Dr. Rayfield also testified that his institution changed it. [00:45:43] Speaker 04: And I believe one of the witnesses that... I sort of would expect it to come from the other side. [00:45:49] Speaker 01: No, not that I'm aware of. [00:45:50] Speaker 01: The only testimony I'm aware of were a witness at Santa Fe was shown this document. [00:45:53] Speaker 01: They said, I'm not sure if it's a draft. [00:46:00] Speaker 00: Since you raised Dr. Reifel, one of the concerns I have in the case is his testimony. [00:46:05] Speaker 00: I mean, the district court clearly credited a lot of what he said. [00:46:08] Speaker 00: And one of the major issues here is just how we read the 2008 document or what a hypothesis is and what it means in the scientific community and in this context in particular. [00:46:20] Speaker 00: And so one of the difficulties I had, and I guess it's Appendix 369, [00:46:28] Speaker 00: Dr. Reifel, and this kind of goes to what he was talking about when he was talking about hypothesis, when he was evaluating what a reasonable expectation of success is, what that all meant to him. [00:46:41] Speaker 00: And he says something like, it may be worth testing prospectively the hypothesis derived from it. [00:46:48] Speaker 00: I would make no other statements about it. [00:46:50] Speaker 00: I would not use it to alter my clinical care. [00:46:53] Speaker 00: Question, I understand that. [00:46:54] Speaker 00: Let me just make sure I understand what standard you're applying. [00:46:58] Speaker 00: You're saying a person skilled in the art cannot expect success until they have placebo-controlled phase three clinical trials, establishing that the drug works in that way. [00:47:07] Speaker 00: Isn't that right? [00:47:09] Speaker 00: Yes. [00:47:09] Speaker 00: That's your position? [00:47:11] Speaker 00: Yes. [00:47:12] Speaker 00: That's what a reasonable expectation means to you? [00:47:15] Speaker 00: Yes. [00:47:16] Speaker 01: That's not the law, right? [00:47:17] Speaker 01: No, I agree with you, Your Honor, that the law may require less in other instances. [00:47:23] Speaker 01: For example, in this case, had Sanofi run [00:47:26] Speaker 00: Well, in this instance, he's talking about this case, though. [00:47:30] Speaker 00: And isn't it a little troubling, or wouldn't it lead you to question his evaluation? [00:47:34] Speaker 00: And this is the context of whether or not this was a hypothesis that was meaningful. [00:47:40] Speaker 00: And if he thinks the only meaningful measure for reasonable expectation of success is three clinical trials, that leads you to question his view. [00:47:48] Speaker 05: But doesn't hypothesis mean something different? [00:47:52] Speaker 01: Well, a hypothesis means something that needs to be tested. [00:47:54] Speaker 05: The way I understand it means it's something that needs to be disproved, if it can be. [00:48:00] Speaker 01: Well, that's right. [00:48:00] Speaker 01: Ordinarily, hypotheses are written in a positive way, and the point of the trial is to try to see if it's been disproven. [00:48:08] Speaker 01: So you never necessarily prove something. [00:48:10] Speaker 01: You can disprove things. [00:48:12] Speaker 01: So that's why a hypothesis is always written as an affirmative, declarative sentence, like it was in the Dr. Holmes trial. [00:48:17] Speaker 04: Why is this statement, in this context, [00:48:21] Speaker 04: in which he says, what reasonable expectation of success means to me in this context is a successful phase three clinical trial, which is probably too high of standard. [00:48:36] Speaker 01: Well, in this, okay, so in this instance, he was faced with all of the uncertainty that we've discussed. [00:48:43] Speaker 01: He was faced with his own personal view that when you look at the, well, his scientific view, [00:48:50] Speaker 01: that when you look at those prior studies, you saw patients being killed. [00:48:54] Speaker 01: When you looked at the Andromeda study, which overlapped substantially with the population that eventually was within Athena, about 50 people were being killed. [00:49:02] Speaker 04: But once you start focusing on his personal view, then I mean what he thought, what he thought, I don't mean his quirky personal view, I mean his view [00:49:15] Speaker 04: Was he involved in writing the written, the proposed written statement to the subjects of the study? [00:49:22] Speaker 04: Everybody else may have said, well, we can't say that. [00:49:24] Speaker 04: We got to change it. [00:49:25] Speaker 04: This is what Sanofi proposed. [00:49:28] Speaker 01: He was always testifying from the point of view of what a posa would think. [00:49:32] Speaker 01: So if I'm using he thinks, I meant by he thinks what a posa would think. [00:49:36] Speaker 01: I don't know that he was involved in, he certainly wasn't involved in writing any of the Sanofi. [00:49:40] Speaker 01: Documents not dr. Raffel. [00:49:42] Speaker 01: He had no involvement with it at all. [00:49:43] Speaker 01: He I see. [00:49:44] Speaker 01: Yeah, I got the wrong piece. [00:49:46] Speaker 00: Yeah, it's not I didn't know what Okay, you've been talking about dr. Raffel. [00:49:51] Speaker 01: I have been yes. [00:49:52] Speaker 01: Yes, okay Okay, so back to dr. Raffel's statement what I think he was saying is in light of all the uncertainty That at best what dr. Holoser was saying was a hypothesis and in his view to test that particular hypothesis You needed a phase three clinical study [00:50:10] Speaker 01: because of the risk of mortality that you saw in Andromeda and the modest effects on antiarrhythmia that you saw in Athena. [00:50:22] Speaker 01: Given those very modest effects and given the mortality you saw in the other drug and the fact that no other AAD had ever been shown to do this, that's the type of study that he thought you would need. [00:50:34] Speaker 01: Could there be another study? [00:50:36] Speaker 01: Is the law that you need FDA approval or a phase three clinical study? [00:50:40] Speaker 01: No, it is not the law. [00:50:43] Speaker 01: One could conceive of a large phase two study that would answer this particular question. [00:50:49] Speaker 01: That didn't happen in the prior art here. [00:50:51] Speaker 01: And in fact, many companies run a phase two study before they do a phase three to reduce the risk of a phase three study. [00:50:58] Speaker 01: That did not happen here. [00:51:00] Speaker 01: So the only evidence that this drug ever actually reduced cardiovascular hospitalization came from the phase three study. [00:51:09] Speaker 01: And he thought to answer that question in light of all of the prior art, that's what you needed. [00:51:16] Speaker 04: Did Dr. Reifel testify or did anybody else testify about whether language like the it is expected [00:51:25] Speaker 04: is can be found in other scientific publications as clearly meaning nothing more than we hypothesize, and we obviously have a hope that we wouldn't be doing it, but we're not stating an actual expectation of that result. [00:51:44] Speaker 01: Yes, if I could take you in the appendix to page 231. [00:51:48] Speaker 01: And this is the protocol [00:51:53] Speaker 01: that we're talking about here. [00:51:54] Speaker 01: This is the protocol for the Andromeda study. [00:51:57] Speaker 01: So remember, this is the one that failed in the prior art. [00:51:59] Speaker 01: It had to be stopped early because of greater mortality. [00:52:02] Speaker 01: So on appendix 231 on page 320, the question says, who is this? [00:52:09] Speaker 01: This would be Dr. Zussman, I believe. [00:52:13] Speaker 04: I'm sorry. [00:52:14] Speaker 01: Zussman. [00:52:14] Speaker 01: So this is their primary witness. [00:52:16] Speaker 01: Page 320. [00:52:17] Speaker 01: Yeah, 231 of the appendix. [00:52:19] Speaker 01: 231 of the appendix, page 320 of the transcript. [00:52:22] Speaker 01: starting around late 18. [00:52:25] Speaker 01: And they state that given those properties, this is the authors of the Andromeda protocol, we anticipated that droneterone would reduce the rate of hospitalization. [00:52:37] Speaker 04: And that was disappointed. [00:52:38] Speaker 01: Yes. [00:52:39] Speaker 01: Actually, Your Honor, that's not the protocol. [00:52:41] Speaker 01: That's the final study result. [00:52:44] Speaker 01: But that is the hypothesis of the study. [00:52:46] Speaker 01: We anticipated that it would do this. [00:52:49] Speaker 00: Wait, what about the Andromeda? [00:52:50] Speaker 01: It's the final report of the Andromeda study. [00:52:52] Speaker 01: It's not the protocol. [00:52:54] Speaker 01: But that's the way the hypothesis was stated for Andromeda. [00:52:58] Speaker 01: So that's a similar type language. [00:52:59] Speaker 04: We anticipate that. [00:53:00] Speaker 04: I realize this is a transcript. [00:53:02] Speaker 01: Yes, I understand. [00:53:03] Speaker 04: No, are they? [00:53:04] Speaker 04: Is that language that was in the Andromeda document? [00:53:08] Speaker 01: Your Honor, I don't have it in front of me. [00:53:09] Speaker 01: I believe that's the way that I would read that. [00:53:11] Speaker 04: In Exhibit 219? [00:53:11] Speaker 01: Yes. [00:53:12] Speaker 04: Again, I don't know if that's an argument. [00:53:14] Speaker 01: I don't think it is. [00:53:15] Speaker 01: OK. [00:53:16] Speaker 01: OK, but you were asking me, is there anything else in the prior that's similar to that? [00:53:19] Speaker 01: Yes, that's another way of stating a hypothesis. [00:53:22] Speaker 01: It's always a declarative sentence. [00:53:26] Speaker 01: Your Honor, one other note, if I just may. [00:53:29] Speaker 01: I see I'm out of time, actually. [00:53:31] Speaker 05: Are you glad you got that answer? [00:53:32] Speaker 01: I'm sorry. [00:53:33] Speaker 01: Thank you very much, Your Honor. [00:53:34] Speaker 01: You can make another point because, you know, we may go ahead. [00:53:37] Speaker 01: The other point was, if you look at the Honlozer, there are contemporaneous statements by Dr. Honlozer at the same time as this 2008 article where he says the potential [00:53:46] Speaker 01: to reduce credit. [00:53:47] Speaker 01: He says that. [00:53:49] Speaker 01: Emphasize potential. [00:53:51] Speaker 01: That's a quote from him. [00:53:52] Speaker 04: Right, but then somebody else reading it, another skilled artisan, I forget the other guy's name, says, note that Cohen-Loser uses the word potential. [00:54:04] Speaker 01: Yeah, I believe that's right. [00:54:05] Speaker 01: I thought it was his quote to a journalist, both of them. [00:54:09] Speaker 01: Potential, and I must emphasize potential. [00:54:12] Speaker 01: And that's another thing that the person who orders guilty are. [00:54:15] Speaker 01: Thank you very much. [00:54:16] Speaker 01: Thank you. [00:54:21] Speaker 02: Very briefly with respect to the issue of reasonable expectation of success and what was examined here by the district court and how the district court went about analyzing the issue. [00:54:34] Speaker 02: The district court didn't look at [00:54:38] Speaker 02: reasonable expectation at the time in 2008. [00:54:42] Speaker 02: It's apparent from the analysis that what the court did was take it backwards, take it from not expecting success and then backward, I'm sorry, the word I'm looking for is escaping me, but looking at it from a backwards angle. [00:55:03] Speaker 02: Instead of saying what is a reasonable expectation of success, [00:55:07] Speaker 02: he looked at whether or not the art at the time taught that you would expect it concretely to work. [00:55:14] Speaker 02: And that's why the court discounted the statement in Hohenzoller as a hypothesis. [00:55:21] Speaker 00: Do you have any more information about whether or not this written instruction was given or not given? [00:55:26] Speaker 00: You heard the dialogue about what's in the appendix. [00:55:29] Speaker 02: I don't have any more information about whether it was given. [00:55:33] Speaker 02: My understanding is that's what [00:55:36] Speaker 02: Sanofi presented to the FDA as what they wanted to present to the participants in the clinical trial, and that we don't know whether or not all of them changed that. [00:55:49] Speaker 02: But that was the proposed written study information. [00:55:54] Speaker 02: And along with that was a statement to the FDA, we expect this to work. [00:55:59] Speaker 02: So it's not just patients that they wanted to tell that they would expect it to work. [00:56:04] Speaker 02: but it was also the FDA in order to get approval for a protocol that they published as prior art. [00:56:12] Speaker 02: So on the reasonable expectation analysis, instead of looking at what would a person skill, would a person reasonably expect it based on kind of what the law was, what the law is, which is when you publish something with almost all of the elements, [00:56:31] Speaker 02: you have more of an expectation than when you're trying to pull elements from multiple different sources. [00:56:38] Speaker 02: And when the court analyzed the reasonable expectation, instead of looking at it from a reasonable perspective, he started knocking down all of the evidence that was in the art at the time in 2008 that suggested a reasonable expectation. [00:56:57] Speaker 04: he analyzed it from the back and forward in a hindsight sort of manner rather than... Just to address that, if the question is whether a person of skill in the art, relevant person, would have had a reasonable expectation of success, [00:57:16] Speaker 04: doesn't that person, in fact, look at the body of evidence existing at that time? [00:57:22] Speaker 04: And that includes suddenly the new 2008 publication of basically the protocol in the New England Journal of Medicine with Dr. Honlozer's characterization. [00:57:32] Speaker 04: But it also includes the other stuff, some of which points in the other direction. [00:57:38] Speaker 04: And as long as the totality of it, so you do have to have some kind of retrospective look [00:57:44] Speaker 04: And Judge Andrews says somebody looking at all of that would conclude what, I forget, one of the publications said that this was sort of confusing and uncertain. [00:57:59] Speaker 04: Certainly the word was confusing was in there. [00:58:02] Speaker 04: Confusing and severely challenged so far, namely the clinical data. [00:58:07] Speaker 02: So I don't think the clinical data was actually confusing. [00:58:11] Speaker 02: The clinical data [00:58:12] Speaker 02: And this is where I think the district court erred in the stringency of the expectation requirement. [00:58:20] Speaker 02: When you look at the body of evidence at the time, the body of evidence did not teach away from, it didn't teach away from using droneterone in the protocol that was published. [00:58:33] Speaker 02: It didn't say don't do this, right? [00:58:36] Speaker 02: It didn't teach away from the very protocol that was published and Holmoser said you would expect to work. [00:58:42] Speaker 02: It might have caused someone to not have a concrete expectation of success, but that is not the standard. [00:58:51] Speaker 04: That is not the legal standard for reasonable expectation of success. [00:58:59] Speaker 04: to me, an unfamiliar one in this area. [00:59:02] Speaker 04: I mean, concrete doesn't seem to tell you something about probabilities, but something about the specificity of the basis. [00:59:10] Speaker 04: And that doesn't seem to me that when Judge Andrews used the word concrete, I don't read that as meaning [00:59:18] Speaker 04: extremely high probability only a something other than basically a specific evidence foundation for the expectation. [00:59:34] Speaker 02: What's that? [00:59:34] Speaker 02: I read it as requiring more than a reasonable expectation of success. [00:59:38] Speaker 02: He said the 2008 Pohnloser article represents a hypothesis that requires future testing [00:59:46] Speaker 02: requires future testing rather than a concrete expectation of success. [00:59:50] Speaker 02: So as I interpret that phrase, that is requiring something more than just reasonable. [00:59:57] Speaker 02: You have to do testing in order to prove it, which to me suggests an actual success. [01:00:06] Speaker 02: You have to demonstrate an actual success. [01:00:08] Speaker 02: And there are other parts of the opinion where he does that as well. [01:00:12] Speaker 00: He uses the term concrete multiple times in discussing... When he uses it at least the primary way, he juxtaposes it against a hypothesis. [01:00:21] Speaker 00: So I think that supports kind of Judge Toronto's view that we're not talking about concrete versus reasonable. [01:00:29] Speaker 00: We're talking about a concrete expectation of success as opposed to a hypothesis. [01:00:34] Speaker 00: He juxtaposed those two terms. [01:00:36] Speaker 02: He did sometimes and sometimes he did not. [01:00:39] Speaker 02: But I will point you to the court did also discredit Dr. Zussman's testimony by misstating what Dr. Zussman said. [01:00:47] Speaker 02: He says that Zussman testified that a person of skill in the art would look at the Holman-Noser 2008 article and conclude that it was obvious that the trials would successfully hit their primary endpoint. [01:00:59] Speaker 02: That is not the standard. [01:01:00] Speaker 02: That's not the standard Dr. Zussman applied and that's not the standard in this court. [01:01:05] Speaker 02: for reasonable expectation of success, showing that the trials will successfully hit their primary end point. [01:01:13] Speaker 02: And with that, I will finish. [01:01:15] Speaker 00: Thank you. [01:01:16] Speaker 00: We thank both sides. [01:01:17] Speaker 00: Very helpful presentation. [01:01:18] Speaker 00: Thank you. [01:01:19] Speaker 00: This case is submitted.