[00:00:29] Speaker 00: Next two cases are the Novartis versus Parr cases and the reverse. [00:00:38] Speaker 00: We're taking them together. [00:00:40] Speaker 00: 2015, 1061, 1141. [00:00:44] Speaker 00: And we're giving you 20 minutes each side. [00:00:49] Speaker 00: Mr. Brown, you have [00:00:51] Speaker 00: Broken up your argument into 17-3, I guess on the assumption that you've got a rather minor cross-appeal. [00:00:58] Speaker 00: We just assume you take your 20. [00:01:02] Speaker 00: And we understand the context. [00:01:06] Speaker 00: Understood, Your Honor. [00:01:08] Speaker 00: So Mr. Lowe, please proceed. [00:01:10] Speaker 02: May it please the Court. [00:01:15] Speaker 02: Nobartis proved by preponderance of the evidence that the acetaldehyde [00:01:20] Speaker 02: in the accused products is an agent that reduces oxidative degradation and therefore is an antioxidant. [00:01:28] Speaker 02: Novartis proved how acid aldehyde can work as an antioxidant. [00:01:33] Speaker 02: It said in scientific literature setting forth the undisputed fact. [00:01:38] Speaker 00: Wasn't acid aldehyde an impurity here? [00:01:41] Speaker 02: PAR characterizes it as an impurity in its product. [00:01:45] Speaker 00: Does the amount that was in it meet the percent percentages in the claims for an antioxidant? [00:01:53] Speaker 02: The PAR and its specification expressly sets forth an amount that falls within the claimed amount. [00:01:59] Speaker 00: For acetaldehyde? [00:02:00] Speaker 02: Yes, for acetaldehyde, Your Honor. [00:02:02] Speaker 03: Can I ask you a question? [00:02:03] Speaker 03: Is the determination of whether here acetaldehyde [00:02:09] Speaker 03: is an antioxidant dependent on whether it performs the role of oxidative degradation in a particular mixture or is it enough if it ever does that? [00:02:26] Speaker 02: It's the latter, Your Honor. [00:02:27] Speaker 02: An antioxidant here is an agent that reduces oxidative degradation without regards to the particular pharmaceutical formulation in which it does so. [00:02:36] Speaker 02: And that was an explicit finding in [00:02:38] Speaker 02: the district court's opinion in 2019. [00:02:42] Speaker 03: I guess I thought my question was more about claim construction. [00:02:49] Speaker 02: The claim construction doesn't require that it perform the act of reducing oxidative degradation. [00:02:55] Speaker 03: So even if it didn't do so when functioning in this patch, it would nevertheless meet the claim requirement? [00:03:06] Speaker 02: That's correct. [00:03:09] Speaker 02: So Novartis proved how acetaldehyde can work as an antioxidant. [00:03:13] Speaker 02: It said in scientific literature, setting forth the undisputed fact that acetaldehyde is a reducing agent which can readily undergo oxidation, thereby consuming oxidizing agents and preventing them from attacking other molecules. [00:03:27] Speaker 00: Well, the court found as a matter of fact that it is a reducing agent, but also as a matter of fact that it hadn't been previously considered to be an antioxidant. [00:03:36] Speaker 02: Well, that again, Your Honor, is irrelevant. [00:03:39] Speaker 02: Again, an antioxidant here is an agent that reduces oxidative degradation. [00:03:44] Speaker 02: And whether it was recognized to have done so previously or was proven in experimental testing here, as Dr. Davies did. [00:03:52] Speaker 00: Well, another finding, in fact, number 10, has not proven acetaldehyde is an antioxidant. [00:03:58] Speaker 02: And we submit that that was a clear error of the district court. [00:04:02] Speaker 03: So an abarticent fact. [00:04:03] Speaker 03: Because of a combination of [00:04:07] Speaker 03: testimony that it could do this, and second, experimental evidence that you think showed that it did do it. [00:04:15] Speaker 02: Well, not just testimony, Your Honor. [00:04:17] Speaker 02: The objective facts prove that. [00:04:19] Speaker 02: There's scientific literature establishing how acetaldehyde can work as an antioxidant, and there's also experimental proof showing that it does, in fact, reduce oxidative degradation to a statistically significant degree. [00:04:32] Speaker 00: And was the evidence for this Davies material? [00:04:36] Speaker 02: Yes, this is Dr. Davies' control. [00:04:38] Speaker 00: That was discredited, wasn't it? [00:04:39] Speaker 00: It had a lot of flaws in it. [00:04:40] Speaker 00: It wasn't accepted. [00:04:42] Speaker 02: It was discounted by the district court based on the district court's misunderstanding of five objective facts. [00:04:48] Speaker 02: And again, these determinations and these misunderstandings do not turn on a evaluation of Dr. Davies' credibility, but upon a misunderstanding of the objective facts surrounding that testing. [00:05:03] Speaker 02: So let me talk about that testing in further detail. [00:05:06] Speaker 02: This was a controlled head-to-head stress test conducted by Novartis' expert Dr. Davies. [00:05:12] Speaker 02: That test showed that acetaldehyde reduced the oxidative degradation of ribostigmine by 30% under oxidizing conditions. [00:05:22] Speaker 02: Dr. Davies then took those results and he performed three independent statistical analyses on that. [00:05:28] Speaker 02: Each of those independent statistical analyses showed that the reduction of oxidative degradation in the test [00:05:36] Speaker 02: was statistically significant with a confidence of over 90%. [00:05:40] Speaker 00: The court made a finding that it did not yield statistically significant results. [00:05:47] Speaker 02: That was a clear error. [00:05:49] Speaker 02: Dr. Davies presented the district court with three independent statistical analyses. [00:05:54] Speaker 02: The first, a one-tailed t-test, showed a statistically significant reduction of oxidative degradation with a confidence of over 95%. [00:06:02] Speaker 02: The second, a two-tailed t-test, [00:06:06] Speaker 02: The one that the district court says was appropriate to consider here showed a statistically significant reduction with a confidence of greater than 90%. [00:06:14] Speaker 02: And the third, a linear regression analysis showed a statistically significant difference with a confidence of greater than 99%. [00:06:23] Speaker 02: So when you look at those three analyses, you are left with a definite and firm conviction that the district court made an error in selecting the 87% figure that it ultimately relied on. [00:06:36] Speaker 02: Now there's another aspect of the statistical analysis that the district court got wrong. [00:06:41] Speaker 02: That's the difference between equal variance and unequal variance. [00:06:45] Speaker 02: Dr. Davies explained at trial that equal variance was the appropriate statistical technique to use with regard to all of the three analyses he used here. [00:06:55] Speaker 02: And it went undisputed that those three independent statistical analyses he undertook were properly calculated using equal variance. [00:07:03] Speaker 02: And the 87% figure [00:07:05] Speaker 02: that he ultimately relied on was improperly calculated using unequal variance. [00:07:12] Speaker 02: So even if we take the district court at its word that the only appropriate statistical analysis to consider here was a two-tailed t-test, there were two two-tailed t-tests for the district court to have considered. [00:07:24] Speaker 02: One, the properly calculated one using equal variance, which showed a statistically significant difference with a confidence of greater than 90%. [00:07:34] Speaker 02: and the improperly calculated one, which showed 87% confidence. [00:07:39] Speaker 02: And the judge picked the wrong one. [00:07:45] Speaker 02: Now, that was one of the more egregious errors that the district court made in this instance. [00:07:50] Speaker 02: But let me just step back and talk about the basic science of oxidation. [00:07:56] Speaker 02: The district court made a fundamental mistake in misapprehending the chemical mechanism by which acid aldehyde, a known reducing agent, [00:08:04] Speaker 02: can work as an antioxidant. [00:08:07] Speaker 02: It erroneously found that reducing agents form a radical after being oxidized that is more stable than the radicals that cause oxidative degradation. [00:08:18] Speaker 02: And the district court then proceeded to rely on that error to assert that, quote, the likelihood that acid aldehyde is an antioxidant is decreased because it does not form a stable radical, unquote. [00:08:31] Speaker 02: That's incorrect. [00:08:33] Speaker 02: Now, there are some antioxidants which work that way. [00:08:35] Speaker 02: They're called free radical scavengers. [00:08:38] Speaker 02: But that's not how all antioxidants work. [00:08:41] Speaker 02: Noboros explained and PARS experts agreed that there is another class of antioxidants called reducing agent antioxidants or oxygen scavengers. [00:08:51] Speaker 02: These do not work by forming a stable radical. [00:08:54] Speaker 02: Instead, they work by undergoing oxidation in place of other molecules. [00:08:59] Speaker 02: Is that sacrificial oxidation? [00:09:01] Speaker 02: This is what is referred to as sacrificial oxidation. [00:09:06] Speaker 02: And that's how reducing agent antioxidants work. [00:09:08] Speaker 02: It's how acid aldehyde works. [00:09:10] Speaker 02: And that's how several well-known antioxidants work, including, for example, ascorbic acid or vitamin C. Now, the chemical mechanism that distinguishes free radical scavengers from reducing agent antioxidants is well-recognized in the art, including the art of record. [00:09:26] Speaker 02: Modern pharmaceutics recognizes it. [00:09:28] Speaker 02: The EMEA guidelines concerning the use of antioxidants in drugs recognizes it, and so too do PARS experts. [00:09:36] Speaker 02: But the district court did not. [00:09:39] Speaker 02: Instead, it confused the mechanism by which free radical scavengers work with the mechanism by which reducing agent antioxidants work. [00:09:47] Speaker 02: It erroneously found that because acetaldehyde, a reducing agent, does not form a stable radical like a free radical scavenger, [00:09:56] Speaker 02: it was unlikely to be an antioxidant. [00:09:59] Speaker 02: So that was the first of the district court's three clear errors. [00:10:05] Speaker 02: The second clear error that the district court made was in crediting our speculation that acid aldehyde promotes oxidation by forming unstable radicals. [00:10:17] Speaker 02: There was no reliable evidence in the record to support that speculation. [00:10:22] Speaker 02: Parcise one reference. [00:10:24] Speaker 03: Can I ask you if it were the case that acid aldehyde did form free radicals, which would then have essentially a counterbalancing effect from its sacrificial role, sacrificial oxidation role, what would become your argument? [00:10:50] Speaker 02: Well, again, whether or not acetaldehyde forms a stable or unstable radical is irrelevant to its antioxidant capability under the sacrificial oxidation mechanism. [00:11:01] Speaker 02: If a compound is capable of undergoing oxidation, it is satisfying the minimum requirement for an antioxidant, as even Dr. Gannem on Parside acknowledged [00:11:13] Speaker 03: Any compound that undergoes oxidation, so it's losing an electron, automatically becomes an antioxidant for the other molecules that it's mixed up with. [00:11:32] Speaker 02: No, but in this instance, certainly acetaldehyde fulfills that requirement. [00:11:36] Speaker 02: As you saw from the testing performed by Dr. Davies, [00:11:39] Speaker 02: done under conditions that model the effects in a pharmaceutical composition. [00:11:45] Speaker 02: Acetaldehyde, in fact, reduced and did not promote the oxidative degradation. [00:11:49] Speaker 03: Well, what I guess I'm trying to understand is this, whether there are potentially or theoretically potential countervailing mechanisms at work. [00:12:02] Speaker 03: Theoretically, the net effect is what would determine whether the oxidative degradation is being dampened. [00:12:11] Speaker 03: And to figure out whether in a particular case, the oxidative degradation of the molecule of interest is being dampened or not, that is the net effect, you would need to do a reliable experiment. [00:12:24] Speaker 03: And if that's the situation, then everything here turns on how reliable Dr. Davey's experiment was. [00:12:32] Speaker 03: And the district court found not so much. [00:12:34] Speaker 02: But again, the scientific literature here, at least a reliable scientific literature, shows that acetaldehyde reduces oxidative degradation. [00:12:42] Speaker 02: There is no reliable evidence to show that it promotes oxidation or forms unstable radicals that could do so in the case of ribostigny or any other drug. [00:12:50] Speaker 03: So the expert testimony you're saying just did not have a sound scientific foundation. [00:12:56] Speaker 02: That's correct, Your Honor. [00:12:58] Speaker 02: So let me just talk about that reference in brief. [00:13:02] Speaker 02: The second error that the district court made was in crediting PAR's speculation that acid aldehyde could somehow promote oxidative degradation by forming unstable radicals. [00:13:10] Speaker 02: And then PAR cited McNeSB in connection with that speculation. [00:13:15] Speaker 02: But McNeSB only states that acid aldehyde forms peracetic acid at minus 30 degrees centigrade. [00:13:23] Speaker 02: Peracetic acid is not a radical. [00:13:26] Speaker 02: And McNeSB expressly states that peracetic acid degrades [00:13:30] Speaker 02: at temperatures above minus 30 degrees centigrade to acetic acid. [00:13:33] Speaker 02: And acetic acid is not a radical either. [00:13:36] Speaker 02: And to the extent that a magnesium shows radicals forming from an aldehyde, those radicals are the result of a purely hypothetical mechanism. [00:13:46] Speaker 02: So in sum, there is no reliable evidence of record to show that acid aldehyde could promote oxidative degradation. [00:13:52] Speaker 02: And it was clear error for the district court to have found otherwise. [00:13:58] Speaker 02: Turning to the third clear error that the district court made, and that was discounting Dr. Davies' stress test, which proves that acetaldehyde is an agent that reduces oxidative degradation to a statistically significant degree. [00:14:12] Speaker 02: And as I mentioned, this error did not turn upon an assessment of Dr. Davies' credibility, but upon the district court's misapprehension of five objective facts. [00:14:24] Speaker 02: First, the district court incorrectly found [00:14:27] Speaker 02: Dr. Davies did not cite any literature to support the use of this test to determine whether acetaldehyde could reduce oxidative degradation. [00:14:36] Speaker 02: That's wrong. [00:14:37] Speaker 02: Dr. Davies cited no fewer than five references establishing that tests like his done under conditions like his are widely used in the pharmaceutical industry to measure quantitatively the oxidative degradation of drugs and drug products. [00:14:54] Speaker 03: What about the criticism of Dr. Davies' test that he did not, in fact, run the stress test on a known antioxidant to see if it produced the results that it should if it was properly separating antioxidants from non-antioxidants? [00:15:11] Speaker 02: Well, that criticism is yet another clear error. [00:15:14] Speaker 02: The district court wrongly criticized Dr. Davies for not running his test with an antioxidant other than acetaldehyde. [00:15:21] Speaker 02: But there is no serious dispute [00:15:24] Speaker 02: that Dr. Davies' stress test measured what it intended to measure, which was the oxidative degradation. [00:15:30] Speaker 03: I'm not sure that's an answer to my question. [00:15:33] Speaker 03: I don't think that there's any dispute that the particulars of his stress tests were original. [00:15:40] Speaker 03: And what you said a couple of moments ago is that it's like other stress tests, but the particulars weren't. [00:15:47] Speaker 03: So the district court said, or at least the Vardas said, [00:15:50] Speaker 03: If you're going to figure out whether his particular stress test is a reliable discriminator between antioxidants and not, run it on some known antioxidants and see if you get the positive result. [00:16:05] Speaker 03: If you don't do that, I'm not going to trust your experiment. [00:16:08] Speaker 03: What's wrong with that reasoning? [00:16:10] Speaker 02: The problem with that reasoning is that running the test with another antioxidant would not have changed the fact... How do we know until it's run? [00:16:19] Speaker 02: Acetaldehyde, this is the most simple and transparent experiment one could imagine for answering the question whether acetaldehyde reduces oxidative degradation. [00:16:29] Speaker 02: You have two sets of test samples. [00:16:31] Speaker 02: They come from an identical stock solution. [00:16:33] Speaker 02: They have identical amounts of ribostigmine. [00:16:35] Speaker 02: They have identical amounts of the oxidizing agent TBHP. [00:16:40] Speaker 02: The only difference between the two samples is the presence or absence of acetaldehyde. [00:16:44] Speaker 02: You subject them to identical oxidizing conditions. [00:16:48] Speaker 02: At 6, 15, and 21 hours, you take measurements of ribostigmine and its two oxidative degradation products, MPRD4 and eCAV. [00:16:57] Speaker 02: If acid aldehyde does nothing, you see no difference. [00:17:00] Speaker 00: Mr. Lowe, you wanted to save some time. [00:17:02] Speaker 00: You can continue now or save it. [00:17:05] Speaker 02: I'll continue for one more minute, and then I'll stop. [00:17:10] Speaker 02: So at the end of this experiment, you either have acid aldehyde promoting oxidative degradation, as Par suggests may have occurred, [00:17:18] Speaker 02: you have acetaldehyde doing nothing, or you have, in this instance, a statistically significant reduction in oxidative degradation. [00:17:27] Speaker 02: And the only conclusion that can be drawn from these results, because the only variable in this test is that acetaldehyde was responsible for that reduction. [00:17:38] Speaker 02: Running the test with another antioxidant wouldn't have shown anything beyond what those results already show, that acetaldehyde reduces oxidative degradation. [00:17:48] Speaker 02: And they would not have changed those results. [00:17:50] Speaker 02: And part does not explain why. [00:17:52] Speaker 02: And I'll reserve the remainder of my time for rebuttal. [00:17:55] Speaker 00: We will hold it for you in the saloon, Mr. Brown. [00:18:11] Speaker 01: Good morning, Your Honors. [00:18:12] Speaker 01: May it please the court? [00:18:13] Speaker 01: we would submit this case presents the classic example of a district court judge weighing credibility, weighing evidence, considering competing in different testimony that was presented at trial, different documentary evidence that was submitted. [00:18:30] Speaker 03: If an expert doesn't actually have any sound science behind what the expert says, the expert's declaration in court just doesn't count. [00:18:39] Speaker 03: So it depends on [00:18:41] Speaker 03: the actual soundness of the explanation. [00:18:44] Speaker 03: So why is your expert sound? [00:18:47] Speaker 01: Because Dr. Gannum, who's a well-respected... I know the qualifications. [00:18:54] Speaker 01: Right? [00:18:54] Speaker 03: 0702 is about qualifications and what the man says. [00:18:59] Speaker 01: And Dr. Gannum testified based on the chemical reviews article in the Mcnesby reference. [00:19:05] Speaker 01: He gave very detailed testimony that went on for pages about what the mechanism of action is described there is [00:19:11] Speaker 01: how that makes acid albohide unlikely to be an antioxidant, because when it is oxidized, it creates additional radicals that can contribute to oxidative degradation. [00:19:22] Speaker 01: He specifically addressed Dr. Davey's criticism about the minus 30 degrees Celsius, which was a mechanistic study in which the researchers were trying to prove [00:19:36] Speaker 01: their mechanism they proposed by isolating a chemical compound. [00:19:40] Speaker 01: The fact that you can isolate a stable chemical compound is very different from that compound appearing as part of a chemical mechanism or reaction and being a reactive compound. [00:19:50] Speaker 01: The fact that it's not stable is the problem. [00:19:53] Speaker 01: It can cause further damage. [00:19:55] Speaker 01: And so Dr. Davies gave, or excuse me, Dr. Gannum gave very sound testimony based on the McNeasby reference. [00:20:03] Speaker 01: The district court found it credible, found it persuasive. [00:20:05] Speaker 01: and found that Dr. Davey's testimony about the minus 30 degrees C didn't really address Dr. Ganim's testimony. [00:20:17] Speaker 01: And so in that regard, with respect to the mechanism of action, I think Dr. Ganim's testimony is very well supported. [00:20:25] Speaker 01: His testimony and criticism of Dr. Davey's test is also very well supported. [00:20:29] Speaker 01: The test, as the district court found, had many [00:20:35] Speaker 01: fundamental errors and I think it's the combination of those errors and the combination of the fact finding that's particularly telling because what Novartis did here is they took an impurity in the product. [00:20:48] Speaker 01: It's not recognized to be an antioxidant. [00:20:50] Speaker 01: Okay, well fair enough. [00:20:51] Speaker 01: Can you show that it is one? [00:20:52] Speaker 03: The fact that this is an impurity is at least at this stage of the case completely immaterial, correct? [00:20:58] Speaker 01: It is immaterial to the fact finding. [00:21:02] Speaker 03: We have to take as a given [00:21:04] Speaker 03: that there was acid aldehyde in there. [00:21:09] Speaker 03: And the district court didn't say in amounts too small. [00:21:12] Speaker 03: The district court said one and only one thing, this is not an antioxidant. [00:21:18] Speaker 01: Correct. [00:21:19] Speaker 01: The district court did not rule on the amount question at all and only ruled on the issue of is it an antioxidant or is it not an antioxidant. [00:21:28] Speaker 01: And so the combination of fact findings with regard to acid aldehyde [00:21:33] Speaker 01: The court first finds it's not known to be an antioxidant. [00:21:36] Speaker 03: And by the way, the first question I asked, Mr. Lowe, do you agree with the answer that whether something is an antioxidant, if it is under the definition, the claim construction, that it dampens the oxidative degradation, that as long as it does so ever, it doesn't matter whether it's doing so in the particular patch here? [00:21:59] Speaker 01: The court was very explicit that it doesn't have to be doing so in the particular patch. [00:22:05] Speaker 01: I think the court's claim construction was just a tad more general and now the court construed antioxidant as agent that reduces oxidative degradation. [00:22:13] Speaker 01: Oh, whatever. [00:22:14] Speaker 03: I mean, it doesn't even have to reduce the oxidative degradation of the rivastic me, right? [00:22:20] Speaker 01: That's correct. [00:22:21] Speaker 01: Of anything else. [00:22:22] Speaker 01: That's correct. [00:22:27] Speaker 01: So after making the finding that it's not known to be one, has never been described one in the pharmaceutical literature up to this point, so then the question, okay, Novartis, can you prove that it is one? [00:22:39] Speaker 01: The next step is, well, what test do you do? [00:22:41] Speaker 01: And do they do the test that's specifically laid out in the patent, which is the column four, lines 20 to 30? [00:22:46] Speaker 01: No. [00:22:47] Speaker 01: Do you do a test that's ever been reported in the literature to determine if a compound is or isn't antioxidant? [00:22:53] Speaker 01: No, we don't do those tests. [00:22:54] Speaker 01: We're gonna do a different test that's never been used [00:22:56] Speaker 01: a category of test that's never been used to determine if something is or isn't an antioxidant. [00:23:01] Speaker 01: Okay, fair enough. [00:23:02] Speaker 01: Or you're going to do the basic background to show that your test separates things that are antioxidants from things that are not antioxidants. [00:23:10] Speaker 01: Well, no, he doesn't do that either. [00:23:11] Speaker 01: He doesn't test things that are antioxidants to see what they do in the test. [00:23:15] Speaker 01: He doesn't test things that are not antioxidants. [00:23:17] Speaker 01: For all we know, anything you put in that test tube will show the results that he received from this test. [00:23:23] Speaker 01: The district court particularly found compelling that [00:23:26] Speaker 01: The fact that 20% of the reaction products were unknown, where you're relying on very tiny differences that where Dr. Davies is trying to find statistical significance, and you combine that with the fact that the test has never been used before for this purpose, Dr. Davies doesn't even know what's going on in his test tubes. [00:23:44] Speaker 01: He doesn't know what reactions are happening. [00:23:46] Speaker 01: And so all in all, the district court found because of those, the combination, and the court particularly caught up the combination of the unknown reaction products [00:23:55] Speaker 01: with the fact that the test hadn't been used for this purpose before as something that decreased his confidence in giving credibility to the test. [00:24:03] Speaker 03: And so... Can I take you back away from the experiment for a minute to what's going on conceptually? [00:24:15] Speaker 03: You don't dispute, I gather, the finding that acetaldehyde is a reducing agent. [00:24:19] Speaker 01: Not at all. [00:24:20] Speaker 03: Okay. [00:24:20] Speaker 03: So can you now explain what [00:24:23] Speaker 03: The mechanism is by which something that is a reducing agent might not dampen oxidative degradation. [00:24:32] Speaker 03: And I'm using the word dampen because I'm using the word reduce in an example about oxidation. [00:24:38] Speaker 03: It's only confusing. [00:24:39] Speaker 01: Understood. [00:24:40] Speaker 01: So when, as I understand it from the trial testimony, when a reducing agent, all that means chemically is it's capable of being oxidized. [00:24:50] Speaker 01: So that's step one. [00:24:51] Speaker 01: And then a lot of things could possibly happen. [00:24:54] Speaker 03: And one of the things... It's capable of being oxidized doesn't mean that it's actually giving electrons to something else, to the agent, the thing that the agent is acting on? [00:25:05] Speaker 01: Correct. [00:25:06] Speaker 01: And it's capable of being oxidized. [00:25:11] Speaker 01: And at that point, then, the question is, does it stop the cyclical oxidation reaction that's going on in the product? [00:25:21] Speaker 01: If it makes something, and Novartis only ever addressed that first step, yes, it can be oxidized. [00:25:27] Speaker 01: But what happens then? [00:25:29] Speaker 01: And what happens within the test tube or the formulation at that point? [00:25:35] Speaker 01: If it continues to contribute to the cyclical oxidation product and doesn't shut it down, then it's not going to be likely to be an antioxidant. [00:25:44] Speaker 01: If it does shut it down, then it's a potential antioxidant, or it could be found to be so. [00:25:50] Speaker 01: Here, the point of the McNeSB reference is the ultimate outcome of acetaldehyde being oxidized is acetic acid. [00:26:01] Speaker 01: The point of the McNeSB reference was, how does it get there? [00:26:04] Speaker 01: How do we get from A to B? [00:26:05] Speaker 01: What's the mechanism that happens? [00:26:07] Speaker 01: That mechanism, as McNeSB laid out, was it goes through four different other radicals to get there, among other things. [00:26:14] Speaker 01: And it's not the kind of chemical reaction that you would expect would shut down the cyclical oxidation reaction. [00:26:20] Speaker 01: And this is reinforced by the fact that the pharmaceutical literature has never considered it to be one. [00:26:28] Speaker 01: And so we would submit for all those reasons that the district court was absolutely correct in crediting Dr. Gannon's testimony. [00:26:38] Speaker 01: The defendants had Dr. Klebenoff, who testified at the Watson trial, who was a credentialed chemist [00:26:44] Speaker 01: He didn't address Dr. Gannon's testimony that a non-chemist provide very limited testimony in response to Dr. Gannon. [00:26:53] Speaker 01: The court was perfectly justified in crediting that testimony. [00:26:59] Speaker 01: The court was further justified in considering all of the factors that it considered in not crediting Dr. Davies' test. [00:27:11] Speaker 01: And then finally, with regard to the statistical significance issue, [00:27:14] Speaker 01: The court was justified in the court's primary holding, which was that neither party submitted a statistician to explain this to the court and that therefore Novartis with the burden of proof failed. [00:27:31] Speaker 01: And then the court's alternative finding that our expert Dr. Micheniak-Cohn's testimony that the one-tailed test was rarely appropriate was also properly credited. [00:27:41] Speaker 01: She supported that with treatises [00:27:44] Speaker 01: And then beyond that, all the other statistical analyses that were in play were after the fact analyses that are improper to do in a scientific context. [00:27:55] Speaker 01: And so in sum total, Dr. Davies' test was unreliable. [00:28:00] Speaker 01: The district court provided no usable evidence. [00:28:03] Speaker 01: And Dr. Gannum's testimony that acid aldehyde may, in fact, promote oxidative degradation was credible. [00:28:12] Speaker 01: And the court did a classic balancing act, and we would submit the court addressed a very similar issue in the bio-bail. [00:28:19] Speaker 01: The Andricks case that we cited in our brief, this is scientific evidence that is subject to a fact-finding and there's no clear error here. [00:28:29] Speaker 01: And with that, unless the court has any other questions. [00:28:33] Speaker 00: Thank you, Mr. Byrne. [00:28:35] Speaker 00: Mr. Lowe has some rebuttal time, 3.20. [00:28:41] Speaker 02: Yes, Your Honor. [00:28:42] Speaker 02: Let me just address the various points that Mr. Brown made. [00:28:46] Speaker 02: Mr. Brown said that McNeasby showed that radicals formed from acetaldehyde. [00:28:52] Speaker 02: The court can see for itself at page A1404 that that is a hypothetical mechanism. [00:28:58] Speaker 02: There is no proof that the four radicals that he referred to, in fact, form at minus 30 degrees at room temperature or at 60 degrees or at any other temperature or cause oxidative degradation of any drug. [00:29:10] Speaker 02: Mr. Brown criticized the tests that Dr. Davies ran as not having been done before simply because the tests specifically under the conditions that Dr. Davies ran and has not been done before does not mean that the underlying scientific reality of that test is not valid. [00:29:28] Speaker 02: If a test can quantitatively measure the extent of oxidative degradation of a drug, it can also measure a reduction in the oxidative degradation of that drug. [00:29:40] Speaker 02: Mr. Brown said that acetaldehyde was never recognized to be an antioxidant. [00:29:44] Speaker 02: That's incorrect. [00:29:45] Speaker 02: The 4-4-0 Chinese patent that we attempted to introduce into evidence expressly calls acetaldehyde an antioxidant. [00:29:53] Speaker 02: And when the district court questioned Dr. Klebenov and specifically asked him, is acetaldehyde an antioxidant, he said yes, and he explained why. [00:30:05] Speaker 02: Mr. Brown said that Dr. Davies didn't perform the test that's described in the patent. [00:30:10] Speaker 02: Doing the test that's described in the patent would require the creation of a transdermal patch, including all the excipients that would go into that patch. [00:30:18] Speaker 02: That would have confounded the results. [00:30:19] Speaker 02: It would not have been as simple, clear, straightforward, and transparent as the test that Dr. Davies actually did, which again shows a statistically significant reduction based on the presence of acetaldehyde in the samples. [00:30:32] Speaker 02: Mr. Brown said that there was no idea of what was happening in the test and that anything that could have been included in the test [00:30:38] Speaker 02: may have produced a reduction in oxidative degradation. [00:30:41] Speaker 02: That's not the case. [00:30:42] Speaker 02: This test was very carefully controlled. [00:30:44] Speaker 02: And you can see what happens when something other than acid aldehyde isn't in there. [00:30:50] Speaker 02: There is oxidative degradation. [00:30:51] Speaker 02: That's exactly what the control samples were intended to show. [00:30:55] Speaker 02: Mr. Brown said that Dr. Davies did not account for 20% of the mass of his test samples. [00:31:01] Speaker 02: And that is incorrect. [00:31:04] Speaker 02: Dr. Davies ran mass balance calculations [00:31:06] Speaker 02: showing that over 99% of the mass of his test samples were ribostignee and its two oxidative degradation byproducts, impure D4 and ECAV. [00:31:17] Speaker 02: Those calculations confirm that the only reaction occurring in the test was the oxidative degradation of ribostignee. [00:31:24] Speaker 02: But even if we credit Mr. Brown's speculation that some side reaction could have been occurring, Mr. Brown did not address, and Parr has never addressed, the fact that if such a side reaction had occurred, [00:31:36] Speaker 02: it would have affected all of the samples equally and would not have disturbed the observed reduction in oxidative degradation in the test caused by acetaldehyde. [00:31:47] Speaker 02: Last, Mr. Brown raised the bio bale case. [00:31:50] Speaker 02: In that case, the patentee actually took a picture of the product, the accused product, using a scanning electron microscope and found that it did not contain the claimed homogenous admixture. [00:32:03] Speaker 02: In other words, [00:32:04] Speaker 02: The testing done by the plaintiff did not support its arguments. [00:32:07] Speaker 02: That is not the case here. [00:32:09] Speaker 02: We have statistically significant proof that acetaldehyde is an agent that reduces oxidative degradation. [00:32:16] Speaker 02: We therefore have proved by our proponents of evidence that acetaldehyde is an antioxidant. [00:32:23] Speaker 00: Thank you.