[00:00:00] Speaker 03: Our last case for argument today is 24-1664, Galp Derma Labs versus Lupin. [00:00:33] Speaker 03: Mr. Flatman, please proceed. [00:00:35] Speaker 01: Gerald Flatman on behalf of the appellant, Del Derma. [00:00:39] Speaker 01: Your Honor, the data submitted with Lupin Zanda about its commercial product should have controlled the infringement analysis here. [00:00:47] Speaker 01: Instead, the district court discounted and ignored that data based on an alleged credibility determination. [00:00:55] Speaker 01: But the data can't be ignored under this court's case law. [00:00:59] Speaker 01: The numbers don't lie. [00:01:01] Speaker 01: The intrinsic evidence directs us to the relevant data. [00:01:04] Speaker 01: We have functional claims here that are based on in vivo blood levels. [00:01:11] Speaker 01: And those limitations are met to a T. The preferred embodiment in the specification says use pH 4.5 and up to two to four hours as dividing lines for enteric-coated products in these tests. [00:01:26] Speaker 01: And those are the test results that we relied on. [00:01:28] Speaker 03: Well, you say you have a functional claim, but that's [00:01:31] Speaker 03: I don't think that's exactly right because this claim is to a composition consisting of, right? [00:01:40] Speaker 03: So while it's absolutely true that this composition consisting of [00:01:45] Speaker 03: has to result in certain blood levels, there is actually, there are quite tangible limitations in this claim about the composition of the pharmaceutical, correct? [00:01:57] Speaker 01: That's correct, Your Honor. [00:01:59] Speaker 01: And the district court has consistently construed those components as based on functional limitations. [00:02:06] Speaker 01: For instance, it defined immediate release in its claim construction opinion at A3101. [00:02:13] Speaker 01: as intended to release substantially all the active ingredient. [00:02:17] Speaker 03: Yes, I mean, I think we all know what delayed release and immediate release mean. [00:02:20] Speaker 03: That doesn't mean that this is a functional claim because it still requires 30 milligrams of doxycycline and it requires 10 milligrams of delayed release doxycycline, right? [00:02:34] Speaker 03: I mean, what am I missing? [00:02:35] Speaker 03: Those are the requirements of the claim. [00:02:38] Speaker 01: But what's missing is the actual client construction, which says that release, for terms immediate release and delayed release, is a functional limitation, I'm quoting from it, referring to a release that alters the subject's steady state blood levels of doxycycline. [00:02:54] Speaker 01: So we determine what immediate release is and delayed release are, about what it does to the blood levels in the body upon release. [00:03:01] Speaker 01: And that's part of the client construction here. [00:03:02] Speaker 01: So that's what I mean by function. [00:03:04] Speaker 03: So then are you saying in your ANDA, [00:03:06] Speaker 03: when you say you have 22 milligrams of immediate release and 18 milligrams of delayed release that you weren't using it in its standard understood sense the same way the district court construed it in this case you weren't using the words IR and DR in their functional capacity? [00:03:24] Speaker 01: Well it was there and there your honor. [00:03:26] Speaker 01: Whatever. [00:03:27] Speaker 03: You're saying it wasn't being used in its functional capacity? [00:03:30] Speaker 01: It was not. [00:03:31] Speaker 01: It was used in a structural capacity there. [00:03:33] Speaker 01: It simply referred to parts of the composition. [00:03:37] Speaker 03: So there are some times, according to you, when 22 milligrams of IR is talking about something structural, and other times when 22 milligrams of IR is talking about something functional? [00:03:49] Speaker 01: In the claims of the patent, IR and DR refer to functional release to create blood levels. [00:03:56] Speaker 01: In their ANDA, they call it a 22 IR 18 DR product. [00:04:01] Speaker 01: That's not what it is. [00:04:02] Speaker 01: It's not how it functions. [00:04:04] Speaker 01: We know that another eight milligrams is immediate release from what they call the delayed release portion. [00:04:10] Speaker 01: And we know that from the data, Your Honor. [00:04:12] Speaker 01: We know that from A6559. [00:04:15] Speaker 01: where we see one capsule that directly infringes and releases 75% immediately at pH 4.5, which is a relevant pH under the preferred embodiment. [00:04:25] Speaker 01: And we see a range right around 75%, and we see a mean of all 12 capsules of 71 and 75% at 1 and 2 hours. [00:04:35] Speaker 01: We also know that this product functions to create the blood levels that are required by the claim. [00:04:41] Speaker 01: Just like the reference drug, which is a 3010 product, is required by the claims. [00:04:46] Speaker 01: That didn't happen by coincidence. [00:04:49] Speaker 01: It happens because they designed a product that releases [00:04:52] Speaker 01: Immediate release and delayed release components functionally to create those blood levels Functions just as a 3010 product just like the reference drug and its bio equivalent to it now here that data was ignored and it was ignored because the judge the district court Decided that ph 4.5 wasn't irrelevant ph. [00:05:15] Speaker 01: That's one reason well he excluded the preferred embodiment in doing that and [00:05:21] Speaker 01: the preferred environment, which is set forth at A66 to 67 and A85 to 86, specifically says the right dividing line for an enteric-coated product is about pH 4.5. [00:05:36] Speaker 03: I think that your argument boils down to, unless I'm mistaken, the clear error in the infringement finding. [00:05:46] Speaker 03: You think [00:05:48] Speaker 03: that their 22 IR 18 DR meets the claims 30 IR 10 DR limitation. [00:05:56] Speaker 03: And basically, I think all your arguments boil down to the district court should have accepted the single test in lupin's ANDA at 4.5 pH, right? [00:06:05] Speaker 03: Is that right? [00:06:06] Speaker 01: That's the primary argument. [00:06:07] Speaker 01: And it should have credited that with the in vivo data that's showed by what's not works. [00:06:11] Speaker 03: Well, what's the problem? [00:06:12] Speaker 03: Because the court now [00:06:15] Speaker 03: that there is a difference or you didn't show a correlation I should say that there could be a difference between the two-stage in vitro and in vivo test results. [00:06:29] Speaker 03: And so this one example at this one pH might be a problem. [00:06:34] Speaker 03: Can you address why I should disregard that? [00:06:38] Speaker 03: analysis by the district court. [00:06:40] Speaker 01: Yes, because that turns the burden of proof on its head in terms of what we're allowed to rely on under this court's case law, like Glaxo. [00:06:47] Speaker 01: The Glaxo line of cases says you can turn to the data that's part of the ANDA submission, which was certified to be true and correct. [00:06:55] Speaker 03: Only if the ANDA submission is to the same thing. [00:06:59] Speaker 03: I mean, if one is in vitro, one is in vivo, there has to be some [00:07:04] Speaker 03: You have the room of improving infringement. [00:07:06] Speaker 03: And if they say something in the ANDA, which is not exactly the same thing as your claim, you have to prove why it is the same thing as your claim. [00:07:13] Speaker 01: And we did, Your Honor. [00:07:15] Speaker 01: Their data proves that. [00:07:17] Speaker 03: But the district court says you didn't introduce anything to show that it would behave the same way in both the in vitro and in vivo settings. [00:07:24] Speaker 01: There's no requirement that we show an in vitro in vivo correlation in these claims. [00:07:29] Speaker 01: That's no way to claim. [00:07:31] Speaker 01: It doesn't say you have to show that correlation. [00:07:33] Speaker 01: It says show a 30-10 product that creates a certain amount. [00:07:37] Speaker 03: What about the district court's conclusion that this whole 4.5 pH is problematic because the drug is intended to be taken when fasting, and even if you add water, that is still putting you down in the 1 to 2 pH range, not at 4.5. [00:07:54] Speaker 03: So even if you showed, even if this experiment were accepted to demonstrate that in this one instance, at this one pH, which is not the way the drug is normally used, it might break down and you might have this IR-DR functional equivalent that you're talking about, but that that's not the normal use. [00:08:14] Speaker 03: I mean, that's what the District Court found. [00:08:16] Speaker 03: What do you make of that? [00:08:17] Speaker 01: I don't understand it at all, because it's a complete contradiction to the preferred embodiment of the specification, which was pointed out to the district court at Plain Construction and throughout the trial. [00:08:28] Speaker 01: And you can't write out the preferred embodiment and say, I'm not accepting test results at pH 4.5 based on some extrinsic evidence. [00:08:39] Speaker 03: I don't understand. [00:08:40] Speaker 03: What do you mean about the preferred? [00:08:42] Speaker 03: How is this the preferred embodiment? [00:08:45] Speaker 01: The specification at A? [00:08:47] Speaker 01: Sixty-six to sixty-seven. [00:08:51] Speaker 01: It says, and I'll take you to it, Your Honor. [00:08:55] Speaker 03: I'm in the pattern to sign the column and line number. [00:08:58] Speaker 01: Yeah, I will. [00:09:00] Speaker 01: If we go to column five, we see the first recitation of what the preferred embodiment is at line, my eyesight is terrible, fifty-fifty-eight. [00:09:17] Speaker 01: This is where we start talking about preferred environment. [00:09:20] Speaker 01: Then at line 62, it talks about the first unit being an immediate release dosage form. [00:09:28] Speaker 01: Then at column six, line 64, it talks about the second unit being a delayed release form. [00:09:38] Speaker 01: And if we flip the page, column seven, line 15, [00:09:47] Speaker 01: I'm sorry, High Sight Serum 15. [00:09:50] Speaker 01: It talks about the delay release form using enteric materials such as oidrajet. [00:09:57] Speaker 01: Oidrajet's mentioned at line 33, and that's where, that's exactly what the defendants use on their product to coat the so-called delay release portion. [00:10:08] Speaker 01: And here's the key. [00:10:10] Speaker 01: This is still part of the preferred environment. [00:10:12] Speaker 01: Column seven, line three, [00:10:16] Speaker 01: 7. [00:10:17] Speaker 01: With the enteric-coated pellets, there is no substantial release of doxycycline in an acidic stomach environment of approximately below pH 4.5. [00:10:26] Speaker 01: But it says below. [00:10:28] Speaker 01: That's the dividing line. [00:10:30] Speaker 01: That's exactly right. [00:10:31] Speaker 01: Because oigerjet, and this is part of the record, only starts dissolving at pH 5.5. [00:10:36] Speaker 01: That's the whole point here. [00:10:38] Speaker 01: So we're going to look at that dividing line. [00:10:40] Speaker 01: The doctor's cycling becomes available when the pH-sensitive layer dissolves at the greater pH of the small intestine. [00:10:47] Speaker 01: That's pH 5.5. [00:10:50] Speaker 01: After a certain delayed time or after the unit passes through the stomach, the preferred delay time is in the range [00:10:59] Speaker 01: of two to six hours. [00:11:02] Speaker 01: So Mr. Corey ignored that and said, well, I'm not going to rely on these test results. [00:11:07] Speaker 01: They're at pH 4.5. [00:11:09] Speaker 01: That's too high. [00:11:09] Speaker 01: There's extrinsic evidence from the other expert that says that's too high for the stomach. [00:11:14] Speaker 01: Even though, by the way, there was documentary evidence submitted in the Klansky article and other portions of the ANDA, which show that 4.5 certainly does exist in the stomach. [00:11:26] Speaker 04: Okay, so if I'm understanding correctly and that's maybe a... [00:11:31] Speaker 04: The district court says, the district court credited the other testimony, Dr. Buckman's testimony, that the pill was already soaked in acid for two hours, which means that at the time of pH 4.5, it was not representative of how the pill would behave in the body. [00:11:47] Speaker 04: They found that it was not biologically relevant pH for fasted stuff. [00:11:53] Speaker 04: And they also disregarded this article you seem to be relying on for that proposition, Pallonzi, or whatever. [00:11:59] Speaker 01: Gillespie, yes. [00:12:00] Speaker 01: Yes, ma'am. [00:12:00] Speaker 04: Under the standard of review, how are we to reject those findings? [00:12:07] Speaker 01: Well, you can't accept that conclusion when the preferred body is being read out of the claim to get there. [00:12:15] Speaker 01: The claim doesn't say a thing about pH. [00:12:18] Speaker 01: The preferred environment says pH 4.5. [00:12:20] Speaker 01: And he's saying, well, there's some piece of extrinsic evidence out there and some extrinsic testimony by some expert that I credit over the other expert, so I'm not going to pay attention to this data. [00:12:31] Speaker 01: I mean, that's really a claim construction error in the application of the data to the claim. [00:12:40] Speaker 03: I don't know, it looks like the patent says below 4.5, it does, it actually suggests that if you start getting to 4.5, you will have breakdowns, so it's below 4.5, and then it didn't, he also talked, I mean I don't even know what all this stuff really means from a technical standpoint, but that there were also differences [00:12:57] Speaker 03: He said something about the RSD value, and he pointed to other differences that informed his decision that this was not the same. [00:13:05] Speaker 01: He pointed to variability in the data set, in the ANTA data set. [00:13:09] Speaker 01: But variability is not a bar to infringement. [00:13:12] Speaker 01: One instance of infringement is enough, and he admitted that capsule one infringed if he accepted pH 4.5 as an LKPH. [00:13:21] Speaker 04: But was this all done under the umbrella of his rejecting the two-stage requirement, which your case relied on? [00:13:29] Speaker 04: Rejected. [00:13:29] Speaker 04: And you gave like four different reasons, including the one I cited and the one the chief referenced, to establish that the two-stage test was not applicable. [00:13:41] Speaker 01: Not applicable and or unreliable in his view. [00:13:44] Speaker 04: And he had a number of reasons for that. [00:13:47] Speaker 01: He had a few reasons, but they're all incorrect and can't trump the intrinsic evidence here. [00:13:53] Speaker 02: Mr. Flatman, you referred to column seven, and you said the district court was wrong to ignore the preferred embodiment and to ignore the 4.5 pH. [00:14:02] Speaker 02: But the sentence after the sentence you pointed to says that oxycycline becomes available [00:14:10] Speaker 02: when the pH sensitive layer dissolves at the greater pH of the small intestine. [00:14:16] Speaker 02: Yes. [00:14:17] Speaker 02: That greater pH is 5.5, correct? [00:14:20] Speaker 02: That's correct, Your Honor. [00:14:21] Speaker 02: And isn't that exactly what the district court looked at? [00:14:30] Speaker 02: You know, 5.5 is more relevant than 4.5 is not the proper focal point for this test. [00:14:37] Speaker 01: But he got it totally wrong when he made that conclusion. [00:14:40] Speaker 01: It's not logical. [00:14:42] Speaker 01: At 5.5, the delayed release is going to release, okay? [00:14:45] Speaker 01: So that doesn't tell you anything about how much immediate release there is. [00:14:49] Speaker 01: You have to look at something below 5.5 to see how much immediate release there is. [00:14:53] Speaker 01: That's what the patent's telling us in that preferred environment. [00:14:56] Speaker 02: But that's why he's concluding that the [00:14:59] Speaker 02: the eight milligrams that you say are released in the stomach before it gets to the small intestine, but he concluded that that doesn't really happen. [00:15:12] Speaker 01: Well, he concluded that doesn't happen, but A6559 tells us it does. [00:15:18] Speaker 01: Because we know that before it gets to pH 5.5, those extra 8 milligrams have been released. [00:15:24] Speaker 01: We know that from the data set. [00:15:26] Speaker 01: And the best example being capsule 1. [00:15:28] Speaker 01: We know that from that data set because the mean release of the 12 capsules, whether they're variable or not, was 75%. [00:15:35] Speaker 02: Well, I'm not sure the mean is the right way to look at this. [00:15:39] Speaker 02: And that was only one capsule. [00:15:41] Speaker 01: Well, one capsule is enough under this court's law, under Broadcom. [00:15:45] Speaker 01: on your research foundation versus my own, a predecessor case to this case. [00:15:50] Speaker 01: It's enough. [00:15:51] Speaker 01: But there's more. [00:15:53] Speaker 01: This is a 230,000 capsule batch, the commercial batch. [00:15:58] Speaker 01: One out of 12 is hitting the bullseye. [00:16:02] Speaker 01: So it logically follows. [00:16:03] Speaker 01: It could be 20,000 more that are at or around that bullseye. [00:16:08] Speaker 01: That's more than enough for infringement. [00:16:11] Speaker 01: and certainly under this court's case law. [00:16:13] Speaker 01: Now the meeting does matter. [00:16:14] Speaker 03: You're over all of your time. [00:16:16] Speaker 03: I'm sorry, Jocelyn, if you have other questions. [00:16:17] Speaker 03: No, no, I don't. [00:16:19] Speaker 03: You're over all your time. [00:16:20] Speaker 03: I'll restore some time for rebuttal, though. [00:16:23] Speaker 03: But let's hear from the public counsel. [00:16:25] Speaker 03: Thank you. [00:16:34] Speaker 00: Morning, may it please the court, William Roccozi for Lupin. [00:16:37] Speaker 00: I'll start with that 4.5 issue. [00:16:40] Speaker 00: So we heard a lot of how the court supposedly ignored the 4.5, or the two-stage 4.5 data. [00:16:47] Speaker 00: They say ignored, he disregarded. [00:16:49] Speaker 00: We had an entire trial just about that two-stage pH 4.5 data. [00:16:54] Speaker 00: The court rejected it for a number of factual determinations. [00:16:58] Speaker 00: Number one, the credibility. [00:17:00] Speaker 00: He found their expert not credible. [00:17:01] Speaker 00: He credited our expert, Dr. Buckton. [00:17:03] Speaker 03: But that doesn't answer any questions at all, because the data is in the ANDA, so... Yes. [00:17:11] Speaker 03: He credited our expert. [00:17:12] Speaker 03: Who told you about your expert? [00:17:14] Speaker 03: The evidence is in the ANDA. [00:17:15] Speaker 03: So tell me what your expert said in particular that he credited that allowed him to disregard the evidence in the ANDA. [00:17:24] Speaker 00: I wouldn't say he disregarded it, Your Honor, but I was just going to that point, too. [00:17:29] Speaker 00: The court found as a factual matter, crediting Dr. Buckton and the literature that Galderma relied on, Kalancy and Dressman, that the fasted stomach pH, which is what is relevant here, is one to two or slightly higher. [00:17:41] Speaker 00: It is not pH 4.5. [00:17:43] Speaker 00: That's a problem for their whole infringement theory and appeal, because everything relies on pH 4.5 being the pH of the fasted stomach for them. [00:17:52] Speaker 00: The second fact finding he made, that you can't prove immediate release using the second stage of a two-stage test at 150 minutes, 180 minutes, and 240 minutes, because you can't infer how that would behave in vivo, both because it's the wrong time points, you don't prove IR using the second stage time points, and because it's the wrong pH. [00:18:16] Speaker 00: Three, he found as a factual matter that the skilled person wouldn't rely on that test because of the evident flaws and anomalies given in the data that, again, they completely ignored. [00:18:26] Speaker 00: Those flaws and anomalies included things like an incredibly high relative standard deviation for Lupin, 18 to 22 percent. [00:18:34] Speaker 00: The testimony was if it's above 10, that's unacceptable and you need to further investigate. [00:18:39] Speaker 03: Can I ask, I mean, you're wanting us to cabin in, and certainly the district court did, the notion that [00:18:45] Speaker 03: this analysis should occur only in pH ranges of 1 to 2 and certainly less than 4.5. [00:18:53] Speaker 03: Why did your ANDA include this 4.5 pH data then? [00:18:57] Speaker 03: Why is it there? [00:18:58] Speaker 03: Because it did demonstrate some [00:19:01] Speaker 03: Some delayed release jumping out early. [00:19:03] Speaker 00: Well actually, two responses to that, Your Honor. [00:19:06] Speaker 00: First off, the FDA requires what they call multimedia testing in pH 1.1 and then various pH's after that. [00:19:14] Speaker 00: It's in one of their guidances. [00:19:16] Speaker 00: Number two, the data actually did not show release of DR pellets in pH 4.5. [00:19:22] Speaker 00: And the district court went through this in detail. [00:19:24] Speaker 00: That test is actually not at pH 4.5. [00:19:27] Speaker 00: It is not at 30. [00:19:29] Speaker 03: Because it's soaked first. [00:19:30] Speaker 03: Is that why? [00:19:31] Speaker 00: So the clock doesn't start over. [00:19:32] Speaker 00: First, you stress it in acid for two hours. [00:19:36] Speaker 00: It hydrates. [00:19:36] Speaker 00: He credited Dr. Buckton's testimony at that point. [00:19:39] Speaker 00: The clock doesn't start over after two hours at the second stage. [00:19:43] Speaker 00: That's number one. [00:19:44] Speaker 00: This is the hotspot theory thing. [00:19:46] Speaker 00: Not yet. [00:19:47] Speaker 00: I'm getting passed by here. [00:19:49] Speaker 00: And then number two, Your Honor, it's not at pH 4.5. [00:19:52] Speaker 00: First, it's pH 1.12 hours. [00:19:54] Speaker 00: The paddles are stopped. [00:19:55] Speaker 00: Then it's pH 11. [00:19:57] Speaker 00: Then once it gets up to 4.5, the paddles start again. [00:20:01] Speaker 00: So it's not actually being tested at pH 4.5. [00:20:05] Speaker 00: But the product was tested at pH 4.5. [00:20:08] Speaker 00: Lupin tested the rebuttal batch in pH 4.5, and there was no release at all from the DR pellets. [00:20:15] Speaker 00: And that raises a very interesting scientific question. [00:20:18] Speaker 00: If your entire case is based on what happens to these little DR pellets in pH 4.5, would the skilled person and a reasonable scientist rely on a test that actually is not testing in pH 4.5? [00:20:29] Speaker 00: The second stage of a test, which is not for measuring IR. [00:20:34] Speaker 03: That's the test you did in the ANDA, and it was, right? [00:20:37] Speaker 00: No, we took their theory when they raised this feature. [00:20:41] Speaker 03: I'm not talking about the rebuttal testing. [00:20:43] Speaker 03: I'm talking about in the ANDA. [00:20:45] Speaker 03: You did this test, and your data showed release. [00:20:50] Speaker 03: So you're saying this test is not what? [00:20:53] Speaker 03: Like, it's your end up. [00:20:55] Speaker 00: Well, as the district court found out, there were evident flaws and anomalies in the data. [00:20:59] Speaker 00: Number one, standard deviation. [00:21:01] Speaker 00: And number two, remember, it's a comparative test. [00:21:03] Speaker 00: It's running the Lupin product versus the Oratia commercial embodiment. [00:21:08] Speaker 00: And in that same test, the Oratia percent dissolved was going down. [00:21:12] Speaker 00: Are you talking about the ANDA data? [00:21:14] Speaker 00: The ANDA test was testing two products. [00:21:17] Speaker 04: I just want to focus on one narrow thing, which I think coincides with what the chief was getting at, which is there's a lot of evidence here, and a lot of it goes on your side. [00:21:27] Speaker 04: But the district court, in one of his conclusions, concluded, as I understood it, that the data submitted in the ANDA was unreliable. [00:21:36] Speaker 04: And if we have pause about saying that and concluding that, is there an alternative basis? [00:21:45] Speaker 04: I mean, I think his finding about this two-stage being unreliable was broader than that. [00:21:50] Speaker 04: It was that it doesn't replicate what goes on in the human body. [00:21:55] Speaker 04: But is there a way to avoid or to explain, or do we necessarily have to include that the data submitted in the end was unreliable? [00:22:06] Speaker 00: Well, first off, Your Honor, there were flaws in the data, which we then investigated. [00:22:13] Speaker 00: Flaws in the data you submitted to the FDA? [00:22:17] Speaker 00: Flaws in the test, and proved there was no release. [00:22:21] Speaker 03: Did you submit then, did you submit corrections to the FDA? [00:22:23] Speaker 00: We absolutely did not, Your Honor. [00:22:26] Speaker 03: So you're telling me you submitted flawed data to the FDA in pursuit of approval of your application, [00:22:33] Speaker 03: You're now testifying in court basically that you know and your client knows that that data is flawed but you didn't submit any sort of correction to the FDA to clarify? [00:22:42] Speaker 00: The testimony was that the data was given to the FDA as is. [00:22:46] Speaker 00: The FDA reviewed it and the FDA approved the product as 2218. [00:22:50] Speaker 03: Yes, but they rely on your testing and you're now telling them that you know your testing was unreliable. [00:22:56] Speaker 03: So you know, you submit, your client now knows it submitted unreliable data to the FDA, and you're telling me there is no obligation on your client to follow up and correct the record with the FDA? [00:23:06] Speaker 00: No, I never use the word unreliable, Your Honor. [00:23:09] Speaker 00: We did not submit unreliable data. [00:23:11] Speaker 00: We submitted the actual data and outputs from that test. [00:23:15] Speaker 00: What I'm saying is the district court found, and as Dr. Buchanan, Mr. Avachat, and Ms. [00:23:19] Speaker 00: Gray testified, the data is the data, but there are artifacts from the test protocol itself [00:23:26] Speaker 00: that raised questions for further investigation, which we did, and proved there is no release whatsoever from those DR appellates at 4.5. [00:23:35] Speaker 00: And to get back, Judge Pros, to your question was, there are several fact findings outside of that which are problematic for the appellates here. [00:23:45] Speaker 00: The first one, even putting the credibility determination aside, the first one is that pH 4.5 is not the relevant pH. [00:23:52] Speaker 00: That's a major problem for them. [00:23:54] Speaker 00: The second one is he wouldn't try to prove immediate release using 150 minutes, 180 minutes, 240 minutes. [00:24:01] Speaker 00: That's a problem for them. [00:24:03] Speaker 00: And then even if we put aside the test protocol itself, we still have the testing that was run in PH4.5 and showed no release from the DR pellets whatsoever. [00:24:18] Speaker 00: So there's layer after layer of fact findings here that would have to be reversed in order for them to prevail. [00:24:28] Speaker 00: As far as the FDA issue goes, there was nothing to correct. [00:24:33] Speaker 00: The data is the data. [00:24:35] Speaker 00: The FDA reviewed it. [00:24:36] Speaker 00: They didn't have a problem with it. [00:24:37] Speaker 04: I assume there was a lot more data than this one page of test results. [00:24:42] Speaker 00: Oh, there were dozens of similar multimedia tests in various PHs and various stages, single and double stage tests. [00:24:52] Speaker 00: It just wasn't this one. [00:24:53] Speaker 00: This is the one they narrowed in on. [00:24:55] Speaker 00: when they raise their two-stage pH 4.5 theory. [00:25:02] Speaker 04: They mean the other side, not the FDA. [00:25:04] Speaker 00: Correct. [00:25:05] Speaker 00: The FDA never questioned any of this data. [00:25:08] Speaker 00: The FDA approved the product as correctly labeled as 22 milligrams immediate release, 18 milligrams delayed release. [00:25:16] Speaker 02: How is it that a drug that has a different in vivo IRDR dissolution ratio, how is it that a drug can be bio equivalent? [00:25:32] Speaker 00: Bioequivalence is different from in vitro dissolution. [00:25:37] Speaker 00: So in vitro dissolution, the industry standard tests of pH 1.1 followed by the 6 is testing how does that release the first part release in the stomach in vitro and then how does the second part release [00:25:53] Speaker 00: and the higher pH's of the intestine. [00:25:55] Speaker 02: But I'm talking about in vivo. [00:25:56] Speaker 02: In vivo it's testing. [00:25:59] Speaker 02: You're arguing that your client's drug is different and doesn't infringe. [00:26:06] Speaker 02: Correct. [00:26:06] Speaker 02: Because it has a different IRDR dissolution ratio. [00:26:11] Speaker 02: Different ratio and different dissolution, yes. [00:26:15] Speaker 02: But yet it is somehow bio-crumble. [00:26:19] Speaker 02: Just as a matter [00:26:19] Speaker 02: science, I'm having trouble understanding that. [00:26:23] Speaker 00: Because bioequivalence is a different measure with a wide goalpost of 80 to 125 percent blood level comparison with the reference drug or the brand drug. [00:26:36] Speaker 02: The graphs were pretty similar, were they not? [00:26:40] Speaker 00: Well, they were within the 18 to 125 percent, which means they're bi-equivalent, Your Honor, which is not enough to prove infringement. [00:26:46] Speaker 00: But there was also evidence at trial that Dr. Buston testified to that the blood levels were not identical, actually. [00:26:53] Speaker 00: If you look at the individual plots at 20 minutes, 40 minutes early on, they actually are not identical. [00:27:01] Speaker 00: And they're actually not identical. [00:27:04] Speaker 00: There are some substantial differences at certain time points, and their expert was not able to reconcile why that was, or he was also unable to testify what would a 2218 product look like. [00:27:20] Speaker 00: Remember, his position was it's not 2218, it's 3010. [00:27:23] Speaker 00: He couldn't answer, well, what would the blood levels of a 2218 product look like? [00:27:28] Speaker 00: He also admitted that you cannot infer composition ratios from blood level data. [00:27:35] Speaker 00: And so that was a bit of a sideshow on the blood level data. [00:27:40] Speaker 03: I have a dumb question. [00:27:44] Speaker 03: What about the claim imports into it the fasting component? [00:27:48] Speaker 03: It just says, you know, oral pharmaceuticals achieve this blood level and it doesn't talk about pH in the claim and nor does it talk about, you know, the criteria under which somebody would therapeutically receive this particular drug. [00:28:04] Speaker 00: And I was actually, excuse me, I was actually just going to get to that point in this preferred embodiment issue. [00:28:10] Speaker 00: The claim itself does not say fasted stomach or have a particular pH, but all parties agree [00:28:15] Speaker 00: that when you are measuring IR and DR, you need to use a fasted stomach. [00:28:20] Speaker 00: Because if you don't, in a fed stomach with a super high pH, everything would be 110% immediate release. [00:28:27] Speaker 00: These products have to be taken on an empty or fasted stomach, or they will not work with their IR and DR. And that is actually set forth in the patent and the preferred embodiment. [00:28:39] Speaker 00: I disagree. [00:28:41] Speaker 00: The preferred embodiment is set forth in those columns. [00:28:44] Speaker 00: The preferred embodiment is in examples 1, 2, 3. [00:28:46] Speaker 00: and then test it in figures 1, 2, 3. [00:28:49] Speaker 00: It is a 30-10 composition, 30 IR, 10 DR. That's exactly how it's made compositionally, Judge, to your earlier point. [00:28:57] Speaker 00: You structurally take 30 milligrams of IR pellets, 10 DROs. [00:29:01] Speaker 03: You agree with your opponent's arguments about this being functional claim language. [00:29:06] Speaker 03: I mean, suppose that when you ran all the rebuttal tests, you did find that due to a weakened encapsulation layer, [00:29:15] Speaker 03: you had the delayed release releasing earlier, right? [00:29:18] Speaker 03: I mean, if that were the case, would you agree that there's infringement here, even though you have 22 and 18 as opposed to 30 and 10? [00:29:29] Speaker 00: I would say you are correct, Your Honor. [00:29:31] Speaker 00: There is compositional and functional elements of these claims. [00:29:34] Speaker 00: There are both. [00:29:35] Speaker 00: I agree with that. [00:29:37] Speaker 00: If it was done at a reasonable appropriate pH and reasonable time points, and if you could show that the Lupin product was actually immediately releasing 30 milligrams and delaying release of 10 milligrams, then that would be a 30-10 composition. [00:29:55] Speaker 03: I have one more really dumb question. [00:29:57] Speaker 03: These are just dumb science questions. [00:29:59] Speaker 00: But it doesn't. [00:30:00] Speaker 00: I just want to say it does not do that. [00:30:02] Speaker 00: I'm sorry. [00:30:03] Speaker 03: But when you're talking about immediate release or delayed release, are those different underlying chemical compositions or are they different only in the layer that is put onto the delayed release to keep it from digesting and therefore releasing as quickly? [00:30:18] Speaker 03: So meaning, is it the exact same underlying active ingredient? [00:30:24] Speaker 03: It's just a matter of [00:30:25] Speaker 03: You protect a little bit of it so it doesn't get digested as quickly. [00:30:29] Speaker 00: Yes. [00:30:29] Speaker 00: If you look at examples one, two, three, you make the exact same immediate release pellets or beads, whichever you want to call them, which don't have any coating on them. [00:30:37] Speaker 00: So they'll release immediately in the stomach and the stomach pH of one to two. [00:30:42] Speaker 00: And then you take those same beads [00:30:45] Speaker 00: You put a portion to the side, and you put an enteric coat on them. [00:30:49] Speaker 00: Right. [00:30:49] Speaker 03: Because that's the whole argument about the coating, and you used a weaker coating, right? [00:30:54] Speaker 00: That's their argument, yes. [00:30:55] Speaker 03: OK. [00:30:56] Speaker 03: So your 2218 is predicated on the ones that have no coating and the ones that have coating. [00:31:05] Speaker 00: Correct. [00:31:06] Speaker 00: The 22 IR do not have the enteric coat, and the 18 milligrams DR do have the enteric coat. [00:31:13] Speaker 03: And so even though you say that, it could be possible that it, depending on how you construct the enteric coat, it doesn't actually keep those pellets from releasing for as long. [00:31:25] Speaker 03: I know that you're saying it's not what's happening here, but obviously in some circumstances it could, because under your ANDA, under different type circumstances, I understand it did cause an immediate release, at least that one example. [00:31:37] Speaker 00: Well, there was no evidence, Your Honor, that the coat is weak. [00:31:40] Speaker 00: That was a theory they had that using a certain solvent [00:31:43] Speaker 00: was somehow intentionally designed to be weak. [00:31:46] Speaker 00: The actual testimony at trial and the court's fact findings were that the coating was just fine. [00:31:51] Speaker 00: It was a perfectly good functional coating. [00:31:53] Speaker 00: It passed all tests. [00:31:55] Speaker 00: And again, when it was tested in pH 4.5, the DR pellets and that coating did not leak. [00:32:01] Speaker 00: and did not release at all. [00:32:04] Speaker 00: The last point, quick two points, I see I'm running out of time. [00:32:07] Speaker 03: Can I have another science question? [00:32:09] Speaker 03: Sorry. [00:32:09] Speaker 03: Don't lie to the science guy at this point for me. [00:32:12] Speaker 03: Anyway, you said, I'm still troubled by the same thing that Judge Lynn is, and I realize this doesn't resolve your case in its entirety by any stretch. [00:32:20] Speaker 03: But just this notion that these two products could be bio-equivalent despite the fact that they're saying 30, 10, and you're saying 22, 18, and you said, oh, it's good enough if it's between 80 and 125 percent. [00:32:34] Speaker 03: Well, if I just take 30 milligrams and figure out what 80 percent of that is, [00:32:39] Speaker 03: It's not 22, right? [00:32:41] Speaker 03: It doesn't sound like it's within 80%. [00:32:43] Speaker 00: The blood levels don't correlate to composition. [00:32:45] Speaker 00: And they're expert admitted. [00:32:46] Speaker 00: You can't infer compositional ratios from blood levels. [00:32:50] Speaker 00: But I will tell you, Judge, to go even more directly to your point. [00:32:53] Speaker 00: It's unremarkable that a non-3010 could be bioequivalent. [00:32:57] Speaker 00: There's evidence in this record from Dr. Buckton and another gall derma patent called the 516 in this record. [00:33:03] Speaker 00: It was a 32-8 and a 34-6 composition. [00:33:10] Speaker 00: So it's not 3010. [00:33:10] Speaker 00: Those were also bioequivalent. [00:33:13] Speaker 00: So you don't need to have the magic 3010, I guess, to answer your question, to be bioequivalent. [00:33:18] Speaker 00: Last quick point, the preferred embodiment actually is 3010, it's described, and then the patent gives you the industry standard test for proving not just the 3010, but the release. [00:33:31] Speaker 00: It gives you that in Figure 3. [00:33:33] Speaker 00: You put it in the pH 1.1, the industry standard for the fasted stomach. [00:33:37] Speaker 00: You see how much it releases. [00:33:39] Speaker 00: It then changes over to pH 6 or 7. [00:33:42] Speaker 00: They stress it for two hours at pH 1.1 to make sure that none of those little delayed release guys release. [00:33:49] Speaker 00: Then they change it at two hours to a pH 6 or 7, which is the higher pH in the intestine. [00:33:57] Speaker 03: They've now eaten or is it because it moved to the intestine? [00:33:59] Speaker 00: It's moved to the intestine. [00:34:01] Speaker 00: Okay, got it. [00:34:01] Speaker 00: It quickly moves from the stomach where the IR dissolves, then the DR pellets and that dissolved IR, well less than an hour. [00:34:09] Speaker 00: Dr. Buck testified 20 minutes, moves into the duodenum or the intestine where the much higher pH, six or seven, then dissolves the DR pellets. [00:34:17] Speaker 00: That's how it's supposed to work. [00:34:19] Speaker 00: The tests and the patents in figure one, two, and three actually measure that. [00:34:22] Speaker 00: That's the industry standard test for measuring IR. [00:34:26] Speaker 00: Last point on the 4.5. [00:34:29] Speaker 00: In the specification, no expert ever testified at trial that that portion of the specification somehow delineates IRDR, or that 4.5 is the measurement. [00:34:39] Speaker 00: That never came up. [00:34:40] Speaker 00: That argument didn't arise until closing arguments. [00:34:43] Speaker 00: It solely came from counsel. [00:34:45] Speaker 00: And that passage doesn't say what they say it says. [00:34:48] Speaker 00: It says below 4.5, which is unremarkable because as a factual matter, we know that the faceted stomach is well below 4.5. [00:34:58] Speaker 03: Okay, thank you for your time. [00:35:02] Speaker 03: You have three and a half minutes, please, because that's how much is on the other side. [00:35:05] Speaker 01: Thank you, Your Honor. [00:35:07] Speaker 01: Your Honor, the Consul says that the 4.5, two to four hours is not the preferred embodiment. [00:35:13] Speaker 01: That's the only thing that's called out in the specification as a preferred embodiment. [00:35:18] Speaker 01: It's not figures one, two, or three, as Consul was saying. [00:35:21] Speaker 01: It's important to understand the importance of this 4.5 data for this product. [00:35:26] Speaker 01: At pH 1.1, there's no delayed release. [00:35:30] Speaker 01: The product is locked down. [00:35:32] Speaker 01: This 1.1 pH does nothing to the oid-rejected coating. [00:35:37] Speaker 01: It could sit there for days, and there was testimony to that effect at A4882. [00:35:42] Speaker 01: And nothing would happen. [00:35:43] Speaker 01: So this is a red herring in terms of the effect of this pH 1.1 in the two-phase test. [00:35:48] Speaker 01: At pH 4.5, there should still be nothing [00:35:52] Speaker 01: coming out of the orogid coated pellets. [00:35:54] Speaker 01: And yet here, the data tells us that there is. [00:35:57] Speaker 01: That's not a miracle. [00:36:00] Speaker 01: The data doesn't lie, the numbers don't lie. [00:36:02] Speaker 01: We see an additional eight milligrams. [00:36:05] Speaker 01: as exemplified in Capsule 1 at 6559, coming out at pH 4.5. [00:36:10] Speaker 03: There should be nothing coming out at pH 4.5, I think, if I understand your opponent's argument. [00:36:15] Speaker 03: It would be, yes, under what are the normal circumstances, but that particular test which they submitted involved soaking for two hours and something first and doing this other stuff. [00:36:27] Speaker 03: It wasn't under the normal test circumstances. [00:36:31] Speaker 01: These are the normal circumstances. [00:36:32] Speaker 01: These are the FDA required protocols. [00:36:35] Speaker 01: And they were used by the defendant in submitting this anti-data. [00:36:38] Speaker 01: They certified the data was true and correct. [00:36:40] Speaker 01: They never told the FDA there was anything wrong with the data or that it was flawed. [00:36:45] Speaker 01: They are not even today saying that it's unreliable and it doesn't lie. [00:36:51] Speaker 01: This hotspot issue was proven at trial to be ethereal. [00:36:59] Speaker 01: And that's throughout the retina. [00:37:00] Speaker 03: About the fact that in their description of Figure 1, it explains that this is within the scope of the present invention. [00:37:07] Speaker 03: So why wouldn't we look at the Figure 1 dissolution profile for the doxycycline as the relevant thing to look at when it expressly says this is within the scope of the present invention? [00:37:20] Speaker 01: It's within the scope, Your Honor. [00:37:22] Speaker 01: And for the correct product, it would be the right test. [00:37:25] Speaker 01: but not for a product that is loosely and terrically coated, intentionally, with a low 18% coating as opposed to a usual 30% coating, such that some of the pallets are releasing early. [00:37:37] Speaker 01: This is by design, it's not a miracle. [00:37:40] Speaker 01: There was no burden on us to do these tests. [00:37:43] Speaker 03: Why couldn't you replicate it? [00:37:45] Speaker 03: Like, why couldn't you replicate it, if it's true? [00:37:48] Speaker 03: Because you had these rebuttal batches and things. [00:37:51] Speaker 03: Why couldn't you replicate it? [00:37:52] Speaker 01: Why shouldn't we have? [00:37:53] Speaker 01: Glaxo tells us we can rely on their anti-submissions. [00:37:56] Speaker 01: The data was right there. [00:37:57] Speaker 01: They never told FDA there was anything wrong with that data. [00:38:00] Speaker 01: And the specification told me that pH 4.5 was a good dividing line. [00:38:04] Speaker 03: It says below 4.5. [00:38:08] Speaker 01: That doesn't matter. [00:38:10] Speaker 01: It tells you right after that sentence, Your Honor, it says approximately below 4.5. [00:38:16] Speaker 01: Here we have a 4.5 test. [00:38:18] Speaker 01: And it tells you that the oidrogen is going to start dissolving at the higher pH of 5.5. [00:38:22] Speaker 01: So 4.5 is a good dividing line. [00:38:25] Speaker 01: SPECT tells us that. [00:38:26] Speaker 01: And they conducted that test. [00:38:28] Speaker 01: And they didn't say there was anything wrong with it. [00:38:30] Speaker 01: The patent says up to two to four hours, so their criticism and the trial judge's criticism of the time points is not well taken. [00:38:41] Speaker 01: They did this post hoc testing. [00:38:44] Speaker 01: That's exactly what this court's president says you shouldn't rely on. [00:38:48] Speaker 01: Because it's not what was submitted to the FDA and certified to be the commercial batch and what's going to be sold commercially under Glaxo. [00:38:56] Speaker 01: All we know is that it's something else. [00:38:58] Speaker 01: It was 6,000 pellets instead of 230,000. [00:39:00] Speaker 01: It produced different results, which tells me it was a different product. [00:39:05] Speaker 01: Now, the district court understood at an early point that the in vitro dissolution data that you heard about was a proxy for blood levels. [00:39:13] Speaker 01: And it relied, and it was shown that those blood levels at 6520 to 22, those curves, as Judge Lynn noted, line up pretty darn closely. [00:39:25] Speaker 01: And that's not by accident. [00:39:28] Speaker 01: The blood levels are mentioned only once in the specification. [00:39:33] Speaker 01: in connection with in vitro dissolution. [00:39:37] Speaker 01: And they're mentioned as being a proxy for the right ratio of IR to DR. So we can infer from bioequivalence here, as we shouldn't do in most anti-cases, but here bioequivalence is in the claim where it says to hit these steady state blood levels. [00:39:53] Speaker 01: And the specification tells us that the in vitro is a proxy for the in vivo numbers that we get later. [00:40:00] Speaker 01: So they somehow end up with the same blood levels as the 3010 product. [00:40:05] Speaker 01: The data at 6559 tells me why. [00:40:08] Speaker 01: Because the release is the same. [00:40:09] Speaker 01: When you take this drug on steady state, you're getting on average 75% release, and you're getting the same blood levels. [00:40:17] Speaker 01: That's not a miracle. [00:40:18] Speaker 03: I thank both counsels. [00:40:19] Speaker 03: This case is taken under submission.