[00:00:01] Speaker 00: We have a busy morning in front of us. [00:00:05] Speaker 00: We have four cases that have been set for argument this morning. [00:00:11] Speaker 00: We have one case that's been submitted on the brief. [00:00:15] Speaker 00: In the first case, the Teva Pharmaceuticals versus Sandoz, which is related in part to Yale Research and Development versus Mylan, we asked the parties to come prepared to discuss [00:00:29] Speaker 00: the effect of the Supreme Court opinion in SAS on this particular case in general as to how the court should treat that opinion. [00:00:39] Speaker 00: And then, especially in this case, if there's a particular concern or issue with this case, then we'd like to hear that as well. [00:00:48] Speaker 00: So I'm going to ask the appellant to first address the issue and spend the time that you think is adequate in order to address the issue. [00:00:59] Speaker 00: We won't count that time against the merits of the case that we're here to hear. [00:01:07] Speaker 00: Correct. [00:01:08] Speaker 00: This would apply to the Yeda case and not the Teva case. [00:01:12] Speaker 00: So why don't we wait and we'll do that. [00:01:14] Speaker 00: We'll do that for the Yeda case. [00:01:19] Speaker 00: Okay, so the first case is Teva Pharmaceutical versus Sandals. [00:01:25] Speaker 00: Mr. Quinn? [00:01:39] Speaker 02: Thank you, Judge Raina. [00:01:40] Speaker 02: May it please the court, John O'Quinn on behalf of Teba. [00:01:44] Speaker 02: The district court's invalidity finding rises and falls with an obvious to try analysis that not even the defendants really tried to defend. [00:01:52] Speaker 02: That's the only analysis that the district court did, and it is an analysis that is riddled with inconsistencies, driven by hindsight, and fundamentally improper given all the unknowns surrounding glutarum or acetate. [00:02:05] Speaker 02: This court cannot avoid any of these issues, regardless of what it decides in the IPR appeal that my colleague Mr. Jay will be handling, because these are problems that apply to the 776 patent as well, which is not subject to an IPR. [00:02:18] Speaker 02: It's just that there are additional reasons why the district court erred with respect to the severity limitations at issue in that patent. [00:02:26] Speaker 02: Now, to take a step back, the district court's attempt. [00:02:28] Speaker 01: Sure. [00:02:29] Speaker 01: Were we to affirm in the other case then all of the [00:02:34] Speaker 01: issues except those pertinent to the 776 would go away, correct? [00:02:39] Speaker 02: No, Judge Bryson. [00:02:40] Speaker 02: I think that the other patents would go away. [00:02:43] Speaker 01: All right. [00:02:44] Speaker 01: When I said issues, I meant the other patents. [00:02:46] Speaker 02: Yes, the other three patents would go away. [00:02:48] Speaker 01: But those issues that pertain to the 776 would remain in the case. [00:02:52] Speaker 02: Well, the issues that are specific to the 776 addressing the severity limitations and the issues that I intend to address more broadly about why this was an improper [00:03:00] Speaker 02: obvious-to-try analysis because of the fundamental unknown surrounding glutarum or acetate, those arguments would all still apply as well. [00:03:08] Speaker 02: Obviously, in the IPR, there wasn't an obvious-to-try analysis. [00:03:12] Speaker 02: And the district court's attempt to shoehorn this case for all of the patents, including the 776, into the framework of finite, predictable solutions required for an obvious-to-try analysis simply does not work because it's, A, generally improper for the chemical and medical arts, it's eyesight, [00:03:28] Speaker 02: and Sanofi both recognize. [00:03:30] Speaker 02: And it's particularly inappropriate here because of the fundamental unknowns about glutarum or acetate. [00:03:35] Speaker 02: The optimal dose was unknown. [00:03:38] Speaker 02: The mechanism of action was unknown. [00:03:39] Speaker 02: The active species was unknown. [00:03:42] Speaker 02: The dose-response curve was unknown. [00:03:44] Speaker 02: And the pharmacokinetic-pharmacodynamic profile was unknown and likely unknowable. [00:03:49] Speaker 02: And that's what makes this case look like cyclobenzoprene and not like the Hoffman-Laroche decision that the defendants rely heavily upon. [00:03:58] Speaker 03: In my review of the prior art, it appeared as if there were just two dosage amounts that were being relied on, which was 40 milligrams and 20 milligrams. [00:04:09] Speaker 03: Were there others? [00:04:10] Speaker 02: There were, Judge Stoll. [00:04:11] Speaker 02: So it's true that the large-scale studies had been done on the 20 milligram and 40 milligram doses. [00:04:18] Speaker 02: But if you look, for example, Cohen reports, and this is Appendix 2389, that two and three milligrams were tested, five milligrams at different toasting, [00:04:27] Speaker 02: dosing frequencies had been tested. [00:04:29] Speaker 02: And indeed, 15 milligrams twice per day was described as, quote, well tolerated and demonstrated benefit on some endpoints. [00:04:37] Speaker 02: That's Appendix 2390. [00:04:39] Speaker 02: And Teva itself, the record reflects, was considering a number of options when it decided to test the 40 milligram three times per week, including 50 milligrams once or twice a week, [00:04:52] Speaker 02: And that's reflected in Appendix 4075. [00:04:54] Speaker 03: When you refer to large-scale studies, what are you referring to? [00:04:58] Speaker 02: Like Phase III trials. [00:05:00] Speaker 02: So the fact is, though, that the options that were available to a person of ordinary skill in the art at the time were literally infinite. [00:05:09] Speaker 02: There was no reason to limit. [00:05:11] Speaker 03: In Phase III studies, were there any other dosage amounts that had been studied? [00:05:15] Speaker 02: Judge, still I'm not aware of any other doses in Phase III studies. [00:05:19] Speaker 02: And I'm not aware of this court ever suggesting that having done phase three studies is necessary or appropriate for limiting the scope of the art for purposes of what would be considered an obvious to try analysis. [00:05:31] Speaker 02: And indeed, that's exactly the kind of reverse reasoning that this court rejected in Honeywell versus Mexican. [00:05:39] Speaker 02: fewer doses had been tested is not a reason to limit the universe to 20 and 40. [00:05:44] Speaker 02: It is a reason to expand the universe to consider the testing of other doses, the testing of other methods of administration. [00:05:52] Speaker 02: And that's exactly why it took some 13 years to develop this particular dosing regimen as compared to what had been approved by the FDA at 20 milligrams every day. [00:06:04] Speaker 02: And I think it also brings to bear an inconsistency in the district court's reasoning. [00:06:08] Speaker 02: The district court says, well, I'm going to look only at these two doses, 20 and 40 milligrams, because they've been extensively tested, while at the same time saying, well, a person of ordinary skill in the art wouldn't consider 20 milligrams exclusively, even though there was certainly evidence that it was the optimal dose. [00:06:28] Speaker 02: And at the same time, you have the inconsistency of the district court looking at known and tested dose amounts, but only untested dosing frequencies. [00:06:37] Speaker 02: That is entirely inconsistent. [00:06:39] Speaker 02: And again, the type of reverse reasoning. [00:06:42] Speaker 01: Let me go back to a statement you just made. [00:06:44] Speaker 01: You said that the 20 was the optimal dose. [00:06:46] Speaker 01: But there is certainly evidence in the record that 40 had the advantage of faster onset. [00:06:54] Speaker 01: It seems to me, in a progressive and serious disease, faster onset is a not negligible consideration. [00:07:01] Speaker 02: Judge Bryson, I appreciate you highlighting that, because that comes to yet another of the inconsistencies in the district court's reasoning. [00:07:07] Speaker 01: Well, before you get to the inconsistencies, this is an advantage of the 40 milligram dosage, is it not? [00:07:14] Speaker 02: Well, Judge Price, it might be an advantage to dosing 40 milligrams every day. [00:07:20] Speaker 02: But there's no evidence that it is an advantage to dosing 40 milligrams three times a week. [00:07:26] Speaker 02: When 40 milligrams is being dosed every day, that's 280 milligrams per week. [00:07:31] Speaker 02: The dosing regimen here [00:07:33] Speaker 02: is only 120 milligrams per week. [00:07:35] Speaker 02: That's less than the 140 milligrams per week that was in the 20 milligrams every day. [00:07:40] Speaker 02: So the district court is simultaneously saying, well, there's an advantage to early dosing, but there's also an advantage to pursuing a dosing amount that on a per week basis ends up being essentially similar to what had been previously approved by the FDA. [00:07:56] Speaker 02: Those two don't exist in the same world. [00:07:58] Speaker 02: They're inconsistent and there's nothing in the record. [00:08:00] Speaker 02: It gets back to the fundamental unknowns about [00:08:03] Speaker 01: Why isn't this just a question of balancing, though? [00:08:05] Speaker 01: I mean, you have certain advantages to the 40 milligram. [00:08:09] Speaker 01: You have certain advantages to the every other day. [00:08:13] Speaker 01: And why is that not simply a matter of deciding that you will balance off the advantages by going to something like 40 every other day or alternatively, 43 times a week, which is pretty close to 40 every other day? [00:08:30] Speaker 02: So Judge Bryson, I think that involves assuming and basically making the very kind of sort of inherently contradictory rationale that this court criticized in Cyclobenzaprine. [00:08:43] Speaker 02: Because it assumes you know more about how this drug works than the prior art actually reflects. [00:08:50] Speaker 02: And indeed, there is nothing to reflect. [00:08:53] Speaker 01: You have the clinical results that tell you something about how it works in that you understand something about [00:09:00] Speaker 01: onset of efficacy, you understand something about side effects. [00:09:05] Speaker 01: Why isn't it reasonable to say with respect to the competing clinical outcomes that you'll try to balance the advantages and disadvantages of various dosages and dosing regimens? [00:09:17] Speaker 02: So, Judge Bryson, you don't know. [00:09:19] Speaker 02: that there's early onset with dosing 40 milligrams three times a week. [00:09:24] Speaker 01: There is nothing about that that you know. [00:09:25] Speaker 01: No, but you do know that 40 milligrams, there's considerable evidence that 40 milligrams does give you earlier onset. [00:09:33] Speaker 01: You may not know why. [00:09:34] Speaker 02: No, that's my point, Judge Bryson, is that all you know is that dosing 40 milligrams every day gives you early onset. [00:09:41] Speaker 01: Right. [00:09:41] Speaker 01: So that's a data point that you start with. [00:09:44] Speaker 01: So you say, OK, 40 milligrams, that's an advantage. [00:09:46] Speaker 01: Now, do we want to... [00:09:49] Speaker 01: compromise that advantage, potentially, by getting another advantage that comes with less frequent than daily. [00:09:56] Speaker 01: Why isn't that a reasonable way to look at the question? [00:09:59] Speaker 02: Well, I think two things, Judge Bryson. [00:10:01] Speaker 02: First, even if you think that it might be obvious to experiment in the way that you were describing, this court is clear in Cyclobenzeprine and in Leo Pharmaceuticals. [00:10:12] Speaker 02: And this is page 1070 of Cyclobenzeprine. [00:10:14] Speaker 00: But Cyclobenzeprine was a bioequivalence case. [00:10:16] Speaker 00: We don't have that here, correct? [00:10:19] Speaker 02: So just to finish the thought with Judge Bryson, it is not enough that there be a motivation to experiment. [00:10:28] Speaker 02: You've got to have a reasonable expectation of success, unless you're in the world of obvious to try. [00:10:32] Speaker 02: And nothing about the balancing that you just described explains why you would limit the options. [00:10:36] Speaker 02: To your point, Judge Raina, yes, it's true the issue in cyclobenzeprine was about bioequivalence. [00:10:42] Speaker 02: But the fundamental point that cyclobenzeprine was making, and I think what makes this case [00:10:47] Speaker 02: distinct from Hoffman-LaRoche is there must be a reliable basis for extrapolating from what is known. [00:10:54] Speaker 02: And that's what you don't have in this case. [00:10:56] Speaker 00: In this case, we knew that there was only one or two doses were shown to be safe and effective. [00:11:02] Speaker 00: And one of those two doses was a 40 milligram. [00:11:06] Speaker 00: And the timing is finite, too. [00:11:08] Speaker 00: There's only seven days in a week. [00:11:10] Speaker 02: So Judge Raina, built into that question are so many assumptions. [00:11:15] Speaker 02: Why are you assuming that there's only 20 and 40 milligram doses? [00:11:19] Speaker 02: And indeed, again, that's what was being asserted in terms of prior art here, but the fact is there are other dosing amounts that [00:11:28] Speaker 02: had been tested that were being considered, and it is purely through hindsight, and indeed a religious hindsight, to go back and limit. [00:11:35] Speaker 03: Why do you go beyond, for example, Pinchese? [00:11:38] Speaker 03: Starting with Pinchese as your primary reference, why do you need to go beyond that when it discloses either 20 milligram or 40 milligram and says that you could have a daily or every other day dosage amount or dosage schedule? [00:11:51] Speaker 02: So Judge Stoll, I think with respect to the Pincazi reference, that's how I've heard it, or Pinchesi, at the end of the day, question number one is, why do you start with that in the first place? [00:12:03] Speaker 02: And this court in WBIP versus Kohler, and in ISI, and in Daiichi versus Matrix has made clear, you've got to have a reason by clearing convincing evidence for why you're going to start with a primary reference. [00:12:14] Speaker 02: And it is purely hindsight. [00:12:16] Speaker 02: Indeed, the whole concept of closest prior art is a hindsight-driven concept under the grand factors for deciding whether or not there were unexpected results, not why does a person of ordinary skill in the art pick it in the first place. [00:12:29] Speaker 02: And here, of course, you have an untested [00:12:32] Speaker 02: dosing regimen, 40 milligrams every other day, from an abandoned patent application, and you have forte teaching you that there is no reason to use 40 as opposed to 20 because you don't get better results. [00:12:44] Speaker 02: And to one of the points you were asking, Judge Bryson, that is you don't get better results over the long haul, and one of the questions that you asked, when you start combining things [00:12:53] Speaker 02: The prior are taught that you have more adverse events using 40 milligrams. [00:12:57] Speaker 02: That's appendix 2418. [00:12:59] Speaker 02: And you have more adverse events and, indeed, higher dropout when you dose every other day. [00:13:04] Speaker 02: That's appendix 2439. [00:13:05] Speaker 01: Are you talking about the Flexter Table 5? [00:13:09] Speaker 01: Yes. [00:13:11] Speaker 01: Well, your time is short, and I don't want to draw you into a detailed discussion of that. [00:13:17] Speaker 01: But at minimum, [00:13:19] Speaker 01: That table, it seems to me, doesn't show a statistically significant difference. [00:13:25] Speaker 01: You would agree with that, would you not? [00:13:27] Speaker 02: I would agree that the flector itself isn't a test. [00:13:29] Speaker 02: And so the whole idea of having of the every other day, I agree that flector itself doesn't give you statistics. [00:13:36] Speaker 01: The comparison is between flector and minor, right? [00:13:40] Speaker 01: That's right. [00:13:40] Speaker 01: And minor is a much larger study. [00:13:49] Speaker 01: But Flector is a small study, and Flector and Miner's incidence rate for the alternate and everyday were very close. [00:13:59] Speaker 01: So statistically, even in table five, so statistically, there's no significant indication that alternate is worse in terms of side effects, correct? [00:14:10] Speaker 02: Well, Judge Bryson, I guess I'd answer it this way. [00:14:13] Speaker 02: uh... to the extent that you find think that flexor teaches anything in a statistically significant way i would dispute that it does in terms of the evidence you were dropped out then uh... it does teach fewer dropouts you would agree with that it teaches fewer dropouts at uh... twenty not for not adverse events i would not agree with that there were more dropouts due to adverse events as opposed to dropouts because they lost track of somebody or for some other reason more address uh... dropouts due to adverse events [00:14:41] Speaker 02: I was 20 every other day. [00:14:43] Speaker 02: I realize I'm in my rebuttal. [00:14:44] Speaker 02: Let me make a couple quick points with respect to the severity limitations of the 776 patent, because that patent requires reduced severity, not just reduced frequency. [00:14:55] Speaker 02: These are different concepts as the district court acknowledged. [00:14:59] Speaker 02: But at the same time, the district court then relies on testimony that it believes, quote, conflates frequency and severity. [00:15:06] Speaker 02: That's Appendix 44. [00:15:07] Speaker 02: Now, respectfully, that's not clear and convincing evidence [00:15:10] Speaker 02: of obviousness. [00:15:11] Speaker 02: Again, that's internally inconsistent reading. [00:15:13] Speaker 02: And in any event, the only point from the testimony of Dr. Fox was that in the abstract, if you reduce the frequency of a particularly severe event, you could reduce the overall severity of adverse events. [00:15:26] Speaker 02: But he never suggests that you will get that if you have an increase from 20 to 40 milligrams. [00:15:32] Speaker 02: And similarly, the district court's reliance on a press release, and to say a person of ordinary skill in the art would consider that to the degradation of [00:15:39] Speaker 02: The underlying data doesn't make sense. [00:15:42] Speaker 02: And in any event, all the press release shows is maintaining tolerability, not reducing severity. [00:15:48] Speaker 02: And you need the reduction. [00:15:50] Speaker 00: Let me stop you there, so you'll have a little bit of time for rebuttal, because we'll want to hear back from you. [00:15:54] Speaker 00: I'll restore you back to the four minutes of your time. [00:15:58] Speaker 00: So let's hear from the other side now. [00:15:59] Speaker 02: Thank you, Judge Raina. [00:16:07] Speaker 04: Thank you, Rhonda. [00:16:07] Speaker 00: Now you've divided your time between you and Councillor Maynard, is that correct? [00:16:13] Speaker 04: Yes, Your Honor. [00:16:13] Speaker 00: And you're going to speak for eight minutes? [00:16:15] Speaker 04: Yes, Your Honor, roughly half. [00:16:16] Speaker 00: Seven minutes? [00:16:17] Speaker 00: Okay. [00:16:18] Speaker 04: Thank you, Your Honor. [00:16:20] Speaker 04: May it please the Court, Shannon Ludworth, representing Mylan. [00:16:23] Speaker 04: And just to pick up on something that was just discussed, the Forte study, and it was presented to the District Court and found that the Forte study with 20 milligrams and 40 milligrams daily had the same adverse effect. [00:16:35] Speaker 04: They're very similar, and that's Appendix 20422. [00:16:39] Speaker 04: So in the prior art, you have 20 milligrams and 40 milligrams, both well tolerated and both with the same adverse events. [00:16:48] Speaker 04: You have reduced frequency that has been proven also to be efficacious in the Kahn 2008 study, as well as in the Fletker study. [00:16:57] Speaker 04: And Your Honor asked about the Fletker study. [00:16:59] Speaker 04: It did have a statistically significant reduction in dropouts. [00:17:04] Speaker 04: with the 20-milligram every other day versus the minor 20-milligram daily. [00:17:08] Speaker 04: And of course, that's a big point to the prior art, which here the concern is, are patients going to be adherent to their medication? [00:17:15] Speaker 04: And adherence is, do you take it? [00:17:18] Speaker 04: And if you don't take it, are you going to stay compliant on it? [00:17:20] Speaker 04: And so that was the problem with the prior art. [00:17:22] Speaker 04: It caused injection site reactions. [00:17:24] Speaker 04: And this was all presented to the district court. [00:17:27] Speaker 04: It was a seven-day bench trial with dozens of witnesses and a 50-page opinion that addresses these very issues. [00:17:34] Speaker 04: And those factual findings were made in defendant's favor. [00:17:36] Speaker 00: The injection site reactions, that's related more to frequency, correct? [00:17:41] Speaker 04: It is, Your Honor. [00:17:41] Speaker 00: OK. [00:17:43] Speaker 04: It is related, although Dr. Fox testified on his direct examination that if you reduce a severe reaction, such as lipoatrophy, if you reduce the frequency of that reaction, you reduce the severity, and you improve the tolerability. [00:17:57] Speaker 04: And so, again, the goal was improved tolerability. [00:18:00] Speaker 03: And that was the motivation to go from every other day [00:18:03] Speaker 03: regimen or a daily regimen to something that is three times a week? [00:18:08] Speaker 04: The motivation to do that is what Dr. Green testified in the district court credit is was that patients were more compliant and had better adherence when they took their drug Monday, Wednesday, Friday. [00:18:17] Speaker 04: They knew every day of the week what they were going to take, and they got their weekends off. [00:18:22] Speaker 04: And that makes sense, and the adherence increases. [00:18:25] Speaker 04: And that was the district court credited Dr. Green's testimony on that score, as well as citing an adherence project that occurred in a clinical study called Devonshire. [00:18:34] Speaker 04: And the rebiff three times a week had better adherence than the capaxone daily in that study. [00:18:39] Speaker 04: And the district court heard a lot of factual argument about this from both sides' experts. [00:18:43] Speaker 04: And the district court credited Dr. Green and Myelin's expert on those scores. [00:18:49] Speaker 04: Also, the court asked a question about starting with 20 versus 40, and I believe [00:18:58] Speaker 04: my colleague answered that there were many doses in the art. [00:19:01] Speaker 04: There weren't many doses in the art. [00:19:02] Speaker 04: The studies he referred to in the Cohen study, and if you wanted to look at that, but they are very small dose studies that were back in 1977 for whether or not you would even be able to have an efficacious treatment, and they were not in the art. [00:19:16] Speaker 04: Epixone was approved as a 20-milligram daily dose in 1996, and even through [00:19:24] Speaker 04: 2008 and the priority date of 2009, it was still unclear what the optimal dose was. [00:19:29] Speaker 04: So there are clinical trials studying 20-milligram dosing and 40-milligram dosing. [00:19:33] Speaker 04: And those are the predictable, identifiable choices that the district court selected, and which was confirmed by his discussion of the discovery content of the prior art. [00:19:43] Speaker 04: And of course, we know from the Pincazi application that Pincazi already combined the two concepts. [00:19:48] Speaker 04: And it was not hindsight. [00:19:50] Speaker 04: The district court went through the scope and content of the prior art, and he analyzed all of the art, starting at page 23 of his opinion. [00:19:57] Speaker 04: And I'm sorry, Your Honors, it's A23. [00:19:58] Speaker 04: The pages are one off. [00:20:01] Speaker 04: So it's A23 through A33. [00:20:04] Speaker 04: And at the end of that discussion, after going through all of the art, he said Pincazi would be the starting point. [00:20:10] Speaker 01: What about Mr. O'Quinn's argument that it's improper simply to start with Pincazi without a good reason to [00:20:20] Speaker 01: start with Pinkasi, WBIP. [00:20:23] Speaker 04: Two responses, Your Honor. [00:20:24] Speaker 04: First of all, this is a method of treatment claim, not a lead compound case. [00:20:26] Speaker 04: But second of all, the district court didn't just start with the compound. [00:20:29] Speaker 01: I'm not sure that WBIP was a lead compound case, was it? [00:20:33] Speaker 04: I thought it was. [00:20:34] Speaker 01: Well, it could be. [00:20:35] Speaker 01: I don't recall. [00:20:37] Speaker 01: But in any event, the opinion seems to have expressed the notion in a broader form than simply a lead compound. [00:20:44] Speaker 04: But go ahead and just tell me why that... To my second point was that the district court had already gone through the scope and content of the prior art and had identified Pinkazi as the starting point after doing so. [00:20:55] Speaker 04: So not starting with Pinkazi because it was the closest prior art. [00:20:58] Speaker 04: He went and identified, just like Graham tells you to do, the scope and content of the prior art. [00:21:03] Speaker 04: And he said it would be the starting point. [00:21:04] Speaker 04: And it would be the starting point because by this time, [00:21:07] Speaker 04: Clinical researchers had the Cohen study showing that the 40 milligram was advantageous, had a foster onset of action. [00:21:16] Speaker 04: And you have the Fletker study showing less frequent dosing is similarly efficacious. [00:21:23] Speaker 04: And so the Pincazi was the culmination of those two. [00:21:26] Speaker 04: And that's where the arc of the arc was heading, to less frequent dosing to address the problem with injection site reactions and tolerability. [00:21:35] Speaker 04: And it was in hindsight. [00:21:36] Speaker 04: I disagree with that. [00:21:37] Speaker 04: I think that Graham tells the court, and this is what the district court did, to analyze the scope and content of the prior art and compare that scope and content of the prior art with the claimed invention. [00:21:49] Speaker 04: And when you do that, there's no doubt that Pinkhase's 40-milligram every other day is the closest prior art. [00:21:55] Speaker 00: Your opponent argues that the problem here is that this analysis was done without, this obvious analysis was done without a PKPD study. [00:22:04] Speaker 00: and then assert Cyclobenzapine to back up that argument. [00:22:08] Speaker 00: What's your response to that? [00:22:11] Speaker 04: Your Honor, my response is that Cyclobenzapine is an apostate here. [00:22:14] Speaker 04: And the point is, as I think the questioning pointed out, the claims in Cyclobenzapine were for a therapeutically effective plasma concentration. [00:22:22] Speaker 04: That is for a PKPD relationship, as the court construed the claims. [00:22:26] Speaker 04: And here, we have clinical data. [00:22:30] Speaker 04: We have clinical data of a wide range of cells. [00:22:33] Speaker 04: So not only is it, we're not relying. [00:22:35] Speaker 00: You're not saying there's a PKPD study in this case. [00:22:39] Speaker 04: There's no PKPD relationship in this case, but that did not stop clinical researchers from experimenting with both the dosing and the dose frequency of GA. [00:22:48] Speaker 04: And nor would it, according to Dr. Green, the clinical researchers understand that this is a drug that works on the immune system. [00:22:55] Speaker 04: And your immune system has memory and persistence. [00:22:58] Speaker 04: And you would look at the clinical research, and you'd look at the total weekly dose, [00:23:02] Speaker 04: 20 milligrams every other day in Fletker, up through 40 milligrams daily in the Forte study. [00:23:08] Speaker 04: And you have a range of effective doses from 70 to 280. [00:23:11] Speaker 04: And you would want to pick the dose to address the compliance and tolerability issues that was as close to the effective dose as you can. [00:23:19] Speaker 04: And the district court found as a fact that 40 milligrams three times a week was very close to the FDA-approved dosing regimen. [00:23:28] Speaker 04: Actually, Your Honors, I'm going to turn the podium over to Ms. [00:23:31] Speaker 04: Maynard. [00:23:32] Speaker 04: Thank you very much. [00:23:33] Speaker 00: Thank you. [00:23:37] Speaker 00: Councilman Maynard. [00:23:39] Speaker 05: May it please the court? [00:23:40] Speaker 05: D.M. [00:23:41] Speaker 05: Maynard, I represent Sandoz and Memento. [00:23:45] Speaker 05: A live discussion here today about the evidence and the facts, but the district court had a trial and it made factual findings rejecting the assertions that Teva is making in this court. [00:23:55] Speaker 05: It rejected that 20 milligrams was the optimal dose. [00:24:00] Speaker 05: That is a finding the court made at A27 through 29. [00:24:07] Speaker 05: It rejected the claims that people would be dissuaded from using 40 milligrams because of supposedly more adverse events. [00:24:17] Speaker 05: That is the story the district court was told by Teva, and the court rejected it at A27. [00:24:22] Speaker 05: 28 to 29, and A, 35. [00:24:26] Speaker 05: The district court found that, although the Forte and Cohen reported slightly more injection reactions and dropouts, those studies still showed that the 40 milligrams was safe and well tolerated, and that persons of skill in the art would both be motivated and have reason to use it. [00:24:41] Speaker 05: The court made factual findings from which the only conclusion one can draw is that all of the asserting claims are obvious. [00:24:50] Speaker 05: The court found both. [00:24:51] Speaker 05: that persons of skill in the art would be motivated to use a 40-milligram dose, would be motivated to do that three times a week, and would have a reasonable expectation of success. [00:25:01] Speaker 05: The clearest statement of that is at the end of the court's opinion, after it's considering the objective considerations of non-obviousness, where the court concludes on A47. [00:25:16] Speaker 05: Both that the 40 milligrams three times a week would be [00:25:21] Speaker 05: motivated to be used and would be expected to succeed, and that it would be expected to be more tolerable. [00:25:28] Speaker 05: Judge Rainier, with your question about frequency and severity, the district court's findings on the 776 patent are fully supported by the record. [00:25:37] Speaker 05: The court relied on Dr. Fox's testimony. [00:25:40] Speaker 05: And this is at a 5523. [00:25:49] Speaker 05: A-44 to A-45. [00:25:50] Speaker 05: Oh, okay. [00:25:51] Speaker 01: I thought you were quoting the Appendix pages. [00:25:55] Speaker 05: Thank you of Dr. Fox. [00:25:57] Speaker 05: Okay. [00:25:57] Speaker 05: Yes, that too your honor. [00:25:58] Speaker 05: So he relied on Dr. Fox's testimony that there are certain adverse events that are so severe that if one reduces the frequency of those events one will by definition reduce the severity of adverse events. [00:26:14] Speaker 00: So here there's no [00:26:17] Speaker 00: No information or no knowledge of how the precise mechanism of the GA works, correct? [00:26:23] Speaker 05: That's true, Your Honor. [00:26:23] Speaker 05: And that evidence was also presented to the district court. [00:26:27] Speaker 05: Teva claimed in the district court, because of that, that these claims couldn't be found to be obvious. [00:26:32] Speaker 00: The district court heard... Doesn't that leave you still with like a shot in the dark? [00:26:36] Speaker 00: If you don't know how the GA actually, the mechanism, how it's working, then aren't you just left with guesswork? [00:26:45] Speaker 00: And that guesswork can be [00:26:47] Speaker 00: have unexpected results? [00:26:50] Speaker 05: Two points about that, Your Honor. [00:26:51] Speaker 05: One, again, the district heard competing expert testimony about this from persons of skill in the art, including Dr. Klinger, who was the inventor, who testified at A3998-9 [00:27:07] Speaker 05: And the district court relied on that testimony in concluding at A43 that PK data is irrelevant with respect to this drug, which works on the immune system. [00:27:18] Speaker 05: And our expert, Dr. Green, testified at A886 to 7. [00:27:24] Speaker 05: And the district court relied on Dr. Green, credited Dr. Green's testimony, that in the context of this drug, which works on the immune system, one would not look to PKP data. [00:27:34] Speaker 05: One would instead look to the clinical studies. [00:27:37] Speaker 05: And the clinical studies here showed and gave one a person of skill in the art, both the motivation to use and a reasonable expectation that it would work, 40 milligrams three times a week for the reasons that my colleague said, which is that it allows people to dose Monday, Wednesday, Fridays with the same total weekly dose as already approved, safe, and effective by the FDA. [00:27:59] Speaker 05: And those findings are in the district court's opinion. [00:28:02] Speaker 05: So with respect to the PKPD and rejecting the mechanism of action, [00:28:07] Speaker 05: Those findings are from on A43 at the bottom to A44, where the judge concluded, the fact that the PKPB profile was unknown is irrelevant here. [00:28:24] Speaker 05: GA is an MU modulating drug, but is not necessarily measurable in the bloodstream. [00:28:29] Speaker 05: And even if it is, measuring the levels in the blood does not indicate anything about the effect of the drug on the patient. [00:28:34] Speaker 05: Our expert, Dr. Fox, testified that instead, persons of skill in the art would look to the clinical studies. [00:28:41] Speaker 05: And in fact, that the clinical studies were strong evidence that no one was deterred. [00:28:47] Speaker 05: No one of skill in the art was deterred from the fact that they didn't know exactly how this drug works from testing and using it in patients less than every day and in 40-milligram doses. [00:29:00] Speaker 01: What about the obvious to try? [00:29:03] Speaker 01: point that the district court embraced. [00:29:07] Speaker 01: I think he even made it a heading, one portion of his opinion. [00:29:11] Speaker 05: He did, Your Honor. [00:29:12] Speaker 05: And it's one subheading in his whole entire obviousness discussion. [00:29:15] Speaker 05: And I think there's a couple of points you made about that. [00:29:17] Speaker 05: One, as the Supreme Court has made clear, there's only one obviousness analysis. [00:29:21] Speaker 05: The question is, under Section 103, would a person of skill in the art consider what is claimed to be different enough? [00:29:27] Speaker 05: Would it be so similar to what they already know that it's obvious, the subject matter is obvious as a whole? [00:29:32] Speaker 05: And you can get to that inquiry a couple of different ways. [00:29:34] Speaker 05: And this court often looks to facts of motivation to use and a reasonable expectation of success. [00:29:41] Speaker 05: And if you look at it through that frame, the district court made ample findings here. [00:29:44] Speaker 05: And I'm happy to walk you through them all to find it on that grounds. [00:29:48] Speaker 05: The district court also, though, did look at the obvious to try analysis and found. [00:29:52] Speaker 05: And I think the question to emphasize is it's identified [00:29:58] Speaker 05: predictable solutions, finite identified predictable solutions. [00:30:01] Speaker 05: And the identified predictable solutions were 20 milligrams and 40 milligrams, which had both been extensively studied. [00:30:06] Speaker 05: The district court did make a reference to the fact that Teva was looking at two doses, but those two doses were the only ones that weren't anticipated by the prior art. [00:30:17] Speaker 05: The district court then went on to explain and make factual findings why a person of skill in the art would be motivated to choose three times weekly. [00:30:25] Speaker 05: And that's based on our expert's testimony again. [00:30:28] Speaker 05: And that's because, and this is on page A38, the top paragraph, the last second to last sentence, the total weekly dose the patients would receive under the new regimen was very close to the total weekly dose known for the approved 20 milligram everyday regimen. [00:30:47] Speaker 05: 120 milligrams a week versus 140 milligrams a week. [00:30:51] Speaker 05: So that's our expert's testimony that he's crediting Dr. Green again, A4-883 to A4, and that a person of skill in the art would be motivated. [00:31:00] Speaker 05: And this court has held in cases like Allergan v. Sandoz that one can look to the FDA for possible motivation. [00:31:08] Speaker 05: And Dr. Green testified that a person of skill in the art would look at the total weekly doses, that this was a forgiving drug, [00:31:16] Speaker 05: that as Mr. Aquinn acknowledged, that successful dosage ranged from 70 milligrams to 280 milligrams, and that a person with skill in the art would be motivated to choose this particular regimen three times a week for convenience, again, and those findings again relying on our expert, as well as the Devonshire study about a drug rebiff, which had good patient adherence, A40, and also on the Kahn 2008 study. [00:31:45] Speaker 05: which studied 20 milligrams daily versus 20 milligrams every other day. [00:31:49] Speaker 05: And after two years, every single patient switched. [00:31:53] Speaker 03: OK. [00:31:53] Speaker 03: I have one more question for you, which is, do you have any additional thoughts on the argument being made about PINCASI being that the district court didn't have a basis for choosing it as the closest reference or lead reference? [00:32:07] Speaker 05: Well, I think PINCASI is virtually anticipatory here, Your Honor. [00:32:11] Speaker 05: And the district court recognized that persons of skill in the art would see that it was only two doses, that over the course of two weeks, you only have one dose difference. [00:32:21] Speaker 05: But I don't think the court looked at it in the lead compound way. [00:32:25] Speaker 05: The court instead marched through the art. [00:32:28] Speaker 05: Pincazi was the culmination, in a way, of the art to that point. [00:32:32] Speaker 05: There was art showing 40 milligrams had a faster onset of action. [00:32:35] Speaker 05: And there was art showing that you didn't need to give the drug every day. [00:32:38] Speaker 05: And Pincazi, teva. [00:32:41] Speaker 05: the vice president of research and development at Teva claimed in the Bikazi application that 40 milligrams every other day. [00:32:50] Speaker 05: And the district court found, based on that, and this is in its subheading called Three Times Weekly, Your Honor, and this is where I think the Supreme Court found that persons from the art work would have motivation and reasonable expectation of success at 40 milligrams three times a day. [00:33:05] Speaker 05: Because this was only one dose off, Your Honor, that that would provide adequate motivation. [00:33:09] Speaker 05: And then that, Poncazi, was itself then later confirmed by the Forte study and studies that came after it. [00:33:18] Speaker 00: OK, thank you. [00:33:19] Speaker 05: Thank you. [00:33:21] Speaker 00: So we'll restore you back to four minutes. [00:33:29] Speaker 02: Thank you, Judge Raina. [00:33:29] Speaker 02: So starting on Pincazi, again, you have to look at it as the first act in a trilogy, and you have to look at it in light of what was subsequently learned in Forte. [00:33:38] Speaker 02: But regardless, the defendants say, oh, well, Pincazi is just a difference of one dose every two weeks. [00:33:43] Speaker 02: But what that allides is that is a difference of now having every week a 72-hour gap in dosing. [00:33:50] Speaker 02: There was no prior art, no experiments, no data on a 72-hour gap in dosing. [00:33:57] Speaker 01: Well, there was the half-life for the monkeys. [00:33:59] Speaker 02: Well, Judge Bryson... 80 hours, I think, right? [00:34:03] Speaker 01: Am I wrong about that? [00:34:05] Speaker 02: I'm not sure about that specifically, Judge Bryson, but what I do know is that in terms of the prior art that they point to, there's no prior art in which there was a 72-hour gap in dosing that was shown both to be efficacious and to have the effects that are claimed here. [00:34:20] Speaker 02: And this is important because this is why the district court is forced to resort to an obvious-to-try analysis. [00:34:26] Speaker 02: Because for all they have to say about data, [00:34:28] Speaker 02: There is no data showing that this is going to be efficacious once you introduce a 72-hour gap. [00:34:34] Speaker 02: Meanwhile, there was plenty of testimony to the district court that explained why it was that having a constant activation was an important theory here. [00:34:44] Speaker 02: And our expert, Mr. Simpson, described this at appendix 5189. [00:34:47] Speaker 02: Dr. Klinger talked about this at 3998 to 4,000. [00:34:55] Speaker 02: The Flector Priorit reference itself says, our results may indicate that the dose on alternate days already has a maximal effect, or it's possible the biologic effect is not dose-related, but it's related to the exposure of the immune system by its presence of the continuity of administering the drug. [00:35:12] Speaker 02: The point is, nobody knew. [00:35:13] Speaker 02: And you've now got a 72-hour gap that's being introduced. [00:35:18] Speaker 02: Nothing in the Priorit teaches that. [00:35:21] Speaker 02: And the district court never finds, you will look at this opinion in vain to find a reasonable expectation of success when you've introduced the 72 hour gap. [00:35:31] Speaker 02: What the district court does is an obvious to try analysis. [00:35:35] Speaker 02: That's the only analysis it does. [00:35:37] Speaker 02: And the defendants don't even defend it. [00:35:39] Speaker 02: They didn't say a single word about it, either one of them, until they got a question from the court. [00:35:44] Speaker 02: And that's because they recognize it's a fundamentally flawed obvious to try analysis. [00:35:49] Speaker 02: And it's inconsistent with what this court has done in cyclobenzeprine. [00:35:53] Speaker 02: It's inconsistent with what this court recognized in Hoffman-LaRoche that made it obvious to try. [00:36:00] Speaker 00: There, the court said that there was a... But obvious to try is not a separate obviousness inquiry. [00:36:05] Speaker 00: Well, Judge Raina... I mean, there's only... And this is something that your opponent said. [00:36:08] Speaker 00: There's only one obviousness inquiry. [00:36:10] Speaker 00: So included in that would be obvious to try. [00:36:13] Speaker 02: So I agree, Judge Raina, that after KSR, the court looks at obviousness writ large, [00:36:18] Speaker 02: This court, of course, has made clear in Cycle of Benzoprene, in Leo Pharmaceuticals, in Hoffman-Laroche that there are some circumstances where an obvious to try analysis is proper, and sometimes where that type of mode of analysis is legally improper. [00:36:31] Speaker 02: And that's my argument today, that there is a legally improper mode of analysis here. [00:36:36] Speaker 02: And because what you don't have is something from which you can, quote, reliably predict [00:36:42] Speaker 02: the efficacy. [00:36:43] Speaker 02: In Hoffman-LaRoche, you could reliably predict the efficacy depends on the total dose administered over a given period of time and not the amount administered at any single point in time. [00:36:54] Speaker 02: Contrast that to the evidence at Appendix 2440, at Appendix 3999, and at Appendix 5189. [00:37:04] Speaker 02: It's exactly the opposite of what you had in Hoffman-LaRoche. [00:37:09] Speaker 02: The fundamental unknowns here [00:37:11] Speaker 02: made it such that you can't just simply say that there is a reliable basis for extrapolating. [00:37:16] Speaker 02: Again, it doesn't matter whether there's PKPD data. [00:37:18] Speaker 02: The fact that there wasn't, the fact that it wouldn't perhaps be indicative, makes it worse. [00:37:22] Speaker 02: What you would need is something like dose ranging clinical studies. [00:37:26] Speaker 02: And here, of course, you have the invention in which you are simultaneously adjusting two different parameters. [00:37:32] Speaker 02: You're changing the dosing amount, you're changing the dosing frequency, and there is nothing, not one single thing in the prior art to suggest [00:37:40] Speaker 02: that if you change both of those, that you can have a reasonable expectation of success. [00:37:45] Speaker 02: The data certainly that they point to doesn't support and doesn't give a basis for the gaps and for the changes that are made. [00:37:54] Speaker 02: And that is why the district court ultimately falls back on obvious to try. [00:37:57] Speaker 02: And that is legally improper given the unknowns here in the art. [00:38:01] Speaker 00: OK. [00:38:01] Speaker 00: Thank you, Mr. Clinton. [00:38:03] Speaker 02: Thank you, Judge Raymond. [00:38:03] Speaker 00: We thank the party for the arguments in this case.