[00:00:00] Speaker 03: The next case for argument is 24-2002, Regeneron Pharmaceuticals versus Marlin. [00:00:42] Speaker 01: Good morning, Your Honor. [00:00:43] Speaker 01: May it please the court, Dianne Mazzocchi, for the Biocon and Mylan Defendants Appellants. [00:00:47] Speaker 01: May I proceed? [00:00:48] Speaker 06: Yes, please. [00:00:48] Speaker 01: Thank you. [00:00:49] Speaker 01: Thank you. [00:00:50] Speaker 01: The district court's infringement, validity, and remedy judgments require- Counsel, let me ask you a housekeeping question. [00:00:55] Speaker 06: Sure. [00:00:56] Speaker 06: Page 7 of your blue brief. [00:00:58] Speaker 00: Yes. [00:00:59] Speaker 06: There's a chart. [00:01:02] Speaker 06: I'd like you to turn to it. [00:01:03] Speaker 06: Yes. [00:01:05] Speaker 06: The chart shows that Lucennis has anti-VEGF Rens-Bismal. [00:01:12] Speaker 06: Am I right? [00:01:13] Speaker 00: Yes. [00:01:13] Speaker 06: It then shows that both Yesophilia and Aelia have anti-VEGF Abercept. [00:01:23] Speaker 06: Right. [00:01:24] Speaker 06: On the same page, you say, Yesafi adopts Genentex Cryoart Anti-VEGF Intervitreal Rens-Bisola formulation Lucennis, not Regeneron. [00:01:39] Speaker 01: Correct. [00:01:40] Speaker 01: Is that correct? [00:01:40] Speaker 01: Yes. [00:01:41] Speaker 01: So we're differentiating between the active ingredient, which is the anti-VEGF compound, and the formulation that you actually carry the drug in, which is the formulation. [00:01:52] Speaker 01: So all of the formulation ingredients are all of the ones that are under the anti-VEGF drug descriptor. [00:01:58] Speaker 01: So histidine is the same for lucentis and ours. [00:02:01] Speaker 01: Trihalose is the same for lucentis and ours. [00:02:04] Speaker 01: Polysorbate is the same for lucentis and ours. [00:02:07] Speaker 01: And then water. [00:02:08] Speaker 01: So those ingredients that are under anti-VEGF, those are the formulation ingredients. [00:02:15] Speaker 01: So the drug is the anti-VEGF compound. [00:02:18] Speaker 01: So lucentis has the anti-VEGF drug compound ranibizumab. [00:02:21] Speaker 01: And Yosophila and Ilea have the anti-vegic drug called the Fliversept. [00:02:26] Speaker 01: However, if you look at the formulation ingredients, and that's what the 865 patent is about. [00:02:31] Speaker 01: It's directed to pharmaceutical formulations. [00:02:34] Speaker 01: Our pharmaceutical formulation is actually different from the commercially marketed product. [00:02:38] Speaker 01: We use a histidine buffer. [00:02:40] Speaker 01: They use sodium phosphate buffer. [00:02:42] Speaker 01: We use trihalose as a sugar stabilizer. [00:02:44] Speaker 01: They use sucrose. [00:02:46] Speaker 01: Polysorbate, yes, in water, obviously. [00:02:48] Speaker 01: Those are all the same. [00:02:49] Speaker 01: But Regeneron also adds. [00:02:50] Speaker 01: a salt that's called sodium chloride. [00:02:53] Speaker 01: So they're not identical formulations. [00:02:57] Speaker 03: OK. [00:02:58] Speaker 03: There are a lot of issues in this case. [00:03:00] Speaker 03: And you've got a 300 page district court opinion. [00:03:04] Speaker 01: We do. [00:03:04] Speaker 03: So it's kind of hard to tackle. [00:03:08] Speaker 03: So let me just ask you some scattered questions. [00:03:10] Speaker 00: Sure. [00:03:10] Speaker 03: I know my questions about obviousness and then about anticipation. [00:03:14] Speaker 03: OK. [00:03:15] Speaker 03: What obviousness combination are you appealing? [00:03:19] Speaker 03: Is it Dix alone, or is it Frazier and Gutter, whatever the other one is? [00:03:23] Speaker 01: Yeah, both. [00:03:24] Speaker 01: So there were two issues. [00:03:26] Speaker 01: So first, we said that the claims were obvious in view of Dix alone, because Dix is the one that basically does have the ILEA formulation. [00:03:35] Speaker 01: And really, the only difference is the dose amount in terms of a range versus what Regeneron calls its species. [00:03:41] Speaker 01: Then we also had what we are referring to as [00:03:45] Speaker 01: the descriptions of a flippersip that were in the prior art, which was the Frasier reference, in combination with what we're calling the Lucentis prior art. [00:03:53] Speaker 01: And that's comprised of two main references, one of which is the Gaudreau reference, the other of which is called the Shams reference. [00:04:02] Speaker 01: But both of those references were essentially discussing this type of Lucentis formulation here, where it's an intravitreal formulation. [00:04:11] Speaker 01: It was actually used in the eye. [00:04:13] Speaker 01: and had the anti-VEGF drug in it. [00:04:17] Speaker 01: So one of them. [00:04:18] Speaker 05: How do you pronounce that anti-VEGF drug? [00:04:21] Speaker 01: So ranibizumab is. [00:04:22] Speaker 05: Can we just call it the R drug? [00:04:24] Speaker 01: We can absolutely call it the R drug. [00:04:26] Speaker 01: And then the other one, the A drug, is a flippersep. [00:04:28] Speaker 05: A flippersep. [00:04:29] Speaker 05: That's an important one. [00:04:30] Speaker 05: We should say a flippersep. [00:04:32] Speaker 03: Well, let me take you back to the anticipation. [00:04:37] Speaker 03: I mean, the two issues that are [00:04:40] Speaker 03: not disturbing to me, but that raised some questions are this criticality in the anticipation of 40 versus 10 to 50, and then the teaching away that the district court found. [00:04:53] Speaker 03: So what is your view of our case law and what it compels with respect to that? [00:04:58] Speaker 01: Sure. [00:04:58] Speaker 01: And I think you see that in cases such as Fairview. [00:05:01] Speaker 01: Yeah. [00:05:02] Speaker 03: It's hard, though, because I don't think we found a case. [00:05:04] Speaker 03: You've got cases with one range and the other. [00:05:06] Speaker 03: Prior Art has one range and the CAM has another. [00:05:09] Speaker 03: You've got some where the Prior Art has one. [00:05:12] Speaker 03: But I haven't found a case which is our case, which is the Prior Art has the range and the patent has just one. [00:05:21] Speaker 01: Right. [00:05:21] Speaker 01: Well, I think that one of the close ones that would come up would be the Purdue Pharma versus Epic. [00:05:27] Speaker 01: In that instance, you had a situation where it's similar to what Regeneron is arguing here in the sense that you had a broad description for the drug compound that was in the prior art that was for analgesics treating pain. [00:05:41] Speaker 01: And then this court said it was anticipatory. [00:05:44] Speaker 01: to have a formulation that was directed to opioids and opioids and analgesics. [00:05:49] Speaker 01: And the reason why is because opioids were known and established to those of ordinary skill in the art in the background knowledge as drugs that were used as analgesics to treat pain. [00:06:01] Speaker 01: And in that instance, you didn't even have the prior reference mentioning opioids specifically. [00:06:06] Speaker 01: But again, it was understood in the sense of, what does a person of ordinary skill in the art, when they see the reference, actually understand it to be [00:06:14] Speaker 01: not just teaching in terms of specific examples, but also, what is the nature of the enabling disclosure? [00:06:21] Speaker 01: And I think that's fundamentally where the district court fell down here, because the district court was very much focused on, well, you don't have an example that was actually put to intra-vitriol use in DICS. [00:06:33] Speaker 01: The problem with that, though, is that if, and Your Honor, to get to your point in terms of the chart on page seven, [00:06:39] Speaker 01: If we were to look at the ILIA formulation and we look at the formulations that are in the examples in DICS, you have those identical ingredients there in instances in the same amounts. [00:06:50] Speaker 01: So the only distinction in terms of what was there was a drug amount 10 to 50 versus they limited their claims here to 40. [00:06:59] Speaker 01: And when you have an enabling disclosure, and in fact, when the 865 patent itself [00:07:04] Speaker 01: says that not only that particular drug range in Dix, but an even broader range from 1 to 100 is also going to work to give you these people. [00:07:12] Speaker 05: I'm sorry to interrupt. [00:07:12] Speaker 05: I'm a little confused. [00:07:14] Speaker 05: I would have expected you to have said the word criticality by now. [00:07:17] Speaker 05: Sure. [00:07:17] Speaker 05: And you didn't say it. [00:07:18] Speaker 05: So now you went off on Purdue Pharma and then went to some other territory. [00:07:24] Speaker 05: And my understanding was the focus of your briefing was, [00:07:29] Speaker 05: It was the patent owner's burden to show that the 40 milligram per milliliter formulation was critical. [00:07:36] Speaker 01: Right, because that gets to the genus species issue. [00:07:39] Speaker 05: And then, obviously, the district court found otherwise. [00:07:43] Speaker 05: And now we have to sort out, what does our range case law really say and demand in terms of making an anticipation case? [00:07:54] Speaker 01: Right. [00:07:54] Speaker 01: And you're exactly right, Judge. [00:07:55] Speaker 01: And I think this is one of the reasons why the district court went astray as well. [00:08:00] Speaker 01: To me, when you're looking at criticality issues, you're looking at what is claimed [00:08:05] Speaker 05: compared to well the first question is before we try to assess what does criticality mean is do we even look to criticality in the first place and so the district court said no in this context [00:08:22] Speaker 05: We don't, because there's a case called adafina that says you just look at size of the genus. [00:08:29] Speaker 05: And then if I conclude that the genus was too big, then I don't have to go any further. [00:08:34] Speaker 05: There's no anticipation. [00:08:36] Speaker 01: Right. [00:08:36] Speaker 01: But I think that if you look at subsequent cases, though, that have interpreted and applied adafina, such as the clear value polymers case, the critical issue in terms of why were we concerned that that genus in adafina was so big [00:08:48] Speaker 01: is because it was not actually describing and enabling what came later in the claimed species, so much so that it actually did operate in a different way. [00:08:59] Speaker 01: And I think that in the clear value case, they make that clear, that when they are discussing Adiphena, they said, yeah, but in Adiphena, that species that was selected fundamentally worked in a different way. [00:09:09] Speaker 05: So that to me is- And just getting to Judge Prost's initial question, cases like, I don't know, [00:09:17] Speaker 05: Ineos and clear value, et cetera, those seem to be a claimed range inside of a broader prior art range, right? [00:09:28] Speaker 05: Sure. [00:09:28] Speaker 05: And here we have not a claimed range, but a claimed point. [00:09:35] Speaker 05: And then the question is, well, when we look at Ineos or clear value or anything else I can get my hands on, I don't see that specific back pattern. [00:09:46] Speaker 05: a prior art range and then a claimed point inside of that range, do we think about that fact pattern the same or differently from the claimed range inside of a prior art range? [00:10:01] Speaker 01: Right, and that's why we went back to some of the earlier classic cases such as Petering and Ruschig, and I think there again, when you look at what those claims are talking about, when they're saying [00:10:11] Speaker 01: You know, it really gets back to when I think the phrase used was, was it really described for purposes of Section 102B? [00:10:19] Speaker 01: So I think here when you have a situation where we have with DICS and with the formulations here, [00:10:24] Speaker 01: You have the same ingredients, the same drug involved, and you've got a range of 10 to 50 to select the species. [00:10:31] Speaker 05: You're getting back to the facts. [00:10:33] Speaker 05: I'm thinking about the law. [00:10:35] Speaker 01: Right. [00:10:35] Speaker 01: But I think from the legal perspective, I think you just get back to what was described in Enable. [00:10:41] Speaker 01: So for example, do we have any blaze marks that sufficiently direct a person of ordinary skill in the art towards a particular issue? [00:10:49] Speaker 01: Maybe if you've got a genus that's got 10 billion compound possibilities in it, and now I'm going to select a single compound species. [00:10:57] Speaker 01: Maybe that's not going to be good enough. [00:10:59] Speaker 01: However, if you have a situation where you've already got an existing range, and the district court here actually made findings that a person of ordinary skill and the art would certainly be able to make the full scope of what's within this range, and it's the composition, and you haven't articulated any new use or any particular way in which this composition be used differently. [00:11:22] Speaker 06: But it's not that specific number the patient [00:11:25] Speaker 06: it has a possibility of blindness. [00:11:29] Speaker 01: No, see that's one of the issues with the district court where I think the district court actually got the test wrong because when you're going to talk about criticality it has to be criticality against [00:11:39] Speaker 01: what that prior art range was. [00:11:42] Speaker 01: So show me that 40, the species, somehow performs differently than 10 to 50. [00:11:49] Speaker 01: And he didn't make that finding. [00:11:51] Speaker 01: He said, oh, well, let me look at how I think it might compare based on how a ranibizumab drug compared and how a ranibizumab drug performed. [00:11:59] Speaker 03: Is it also your view that the burden was placed on the wrong side in terms of establishing criticality? [00:12:05] Speaker 01: Yeah, I think Regeneron had to first come forward with some type of demonstration that there was criticality. [00:12:12] Speaker 01: And moreover, to get to your point, tie it to some teaching in their specification so that the public is actually getting the benefit of a quid pro quo. [00:12:22] Speaker 05: Well, let's assume for the moment that we don't have to worry about express disclosure and specification. [00:12:27] Speaker 05: But I am trying to understand what, in your view, should Regeneron have done to establish [00:12:36] Speaker 05: criticality. [00:12:37] Speaker 01: I think Regeneron should have shown that there was something unique and special about 40 that worked better or differently as compared to everything else in the range of 10 to 50. [00:12:49] Speaker 05: When you say better, I'm just trying to get an understanding of what you think. [00:12:54] Speaker 01: Sure. [00:12:54] Speaker 01: One that meets this court's standards, for example, of a difference of degree and not in kind, or a new established utility, or something that actually [00:13:04] Speaker 01: a person of ordinary skill in the art wouldn't have been enabled to do with this composition that they already had in Dix. [00:13:10] Speaker 01: And that's where I think we get to the fundamental problem here, is that particularly once the district court said that these claims [00:13:17] Speaker 05: Getting to some of the other issues on 102, it seems like the district court identified other reasons for why there's a lack of anticipation with the Dix reference, aside from this 40, 10 to 50 business. [00:13:31] Speaker 01: Sure. [00:13:32] Speaker 01: Well, the only other one that he really focused on is he said, well, I don't see that you have an actual example of 40 milligrams per ml being put to intravitreal use in Dix. [00:13:43] Speaker 01: However, and he said that when Dix was talking about use of VEGF fusion protein, that that wasn't specific enough to get you to sequence ID number four that's glycosylated as in the claims. [00:13:56] Speaker 01: The problem, however, is that that is a very myopic view. [00:14:01] Speaker 01: It's not actually looking at the specification as a whole. [00:14:04] Speaker 01: Because in the specification as a whole, number one, all of Dix's examples use sequence ID number four. [00:14:10] Speaker 01: In the preferences that Dix expressed, [00:14:14] Speaker 01: for his preferences for the VEGF antagonist. [00:14:16] Speaker 01: He says, I prefer, preferably, sequence ID numbers two and four, more preferably, sequence ID number four. [00:14:23] Speaker 01: Well, that's a blaze mark to that. [00:14:31] Speaker 03: Do you want to check if that was a test? [00:14:37] Speaker 03: Or anything? [00:14:38] Speaker 03: Do you know what it was? [00:14:40] Speaker 03: Why don't you just go ask the [00:14:49] Speaker 05: What about the 98% stability limitation? [00:14:58] Speaker 05: I think there was a finding that all right, even if [00:15:13] Speaker 05: in DICS that necessarily leads to that particular formulation that would get you this particularized stability limitation in the plan? [00:15:22] Speaker 01: Sure. [00:15:22] Speaker 01: And I think there again, the district court was not focused on does DICS have an enabling disclosure. [00:15:28] Speaker 01: And here again, that's where I think the clear value polymers case is quite relevant. [00:15:34] Speaker 01: Because in that case, they had the 150 or less. [00:15:38] Speaker 01: They only had an example at 60 to 70. [00:15:40] Speaker 01: But nevertheless, 50 was sufficiently enabled. [00:15:42] Speaker 01: Here, Dix had a 25 milligrams. [00:15:46] Speaker 01: We good? [00:15:47] Speaker 01: Thank you. [00:15:48] Speaker 01: Dix had a specific example with a flippersept, all the same ingredients as Ilea, that was 98% stable or more at 25 milligrams per ml. [00:15:58] Speaker 01: He had another one at 50 milligrams per ml, also more than 98% stable. [00:16:05] Speaker 01: There again is where I get into. [00:16:06] Speaker 05: So did you have, I don't know, expert testimony or somebody say, yes, definitely. [00:16:12] Speaker 05: You can take it to the bank. [00:16:14] Speaker 05: If you did a 40 milligram version of Dix, you would get the 98% stability. [00:16:20] Speaker 01: Yes. [00:16:20] Speaker 01: And in fact, how do we know that you actually do get 98% stability? [00:16:23] Speaker 01: Because that's what the ILIA formulation is. [00:16:26] Speaker 01: It's got all of those ingredients. [00:16:28] Speaker 05: I agree with that. [00:16:29] Speaker 05: But we're working backwards with a Dix formulation, a Dix disclosure. [00:16:34] Speaker 05: and then trying to figure out whether Dix discloses this claimed embodiment. [00:16:40] Speaker 05: And at least on this 98% number, if there's something you can show me in the record where there's testimony, evidence, something. [00:16:49] Speaker 05: I mean, I thought I saw something where an expert said maybe most likely you would get 98%, but then to me, that doesn't quite tie things off for a true anticipation. [00:17:03] Speaker 01: Right, well, but I guess the issue is, Your Honor, again, these are formulation claims. [00:17:08] Speaker 01: And Regeneron, to justify enablement, and the district court made findings. [00:17:13] Speaker 01: I'll have to find the specific page where he said, well, once you have a stable example to follow and you have an ingredient list, then of course you can make all of these other formulations stable, because that's just routine experimentation. [00:17:29] Speaker 01: And furthermore, even in the 865 patent itself, [00:17:32] Speaker 01: It concedes that, and this is at column two, lines 53 to 57, they say that an even broader set of stable liquid formulations are going to have 40 to 50, which includes Dix's number, and are going to be able to be these stable liquid formulations of the invention. [00:17:54] Speaker 01: It actually does happen. [00:17:55] Speaker 01: And at Glenn, these prior art references are also under this court's case law presumed enabling. [00:18:00] Speaker 01: for the full scope of what they disclose. [00:18:03] Speaker 01: Regeneron is the party that should have had the burden to come forward to say, well, if somehow there's a way in which you practice this, [00:18:13] Speaker 01: does not actually lead to stability. [00:18:16] Speaker 01: But they couldn't do that here, because the very argument that they made to justify enablement is that once you've got an example to follow, and they used 40 and 50 milligram examples, here Dix has 25 and 50 milligram examples, then you are sure you have enough to get your stable formulation. [00:18:35] Speaker 05: So if it's- I just want to make it clear right now. [00:18:37] Speaker 05: I'm not worried about 112. [00:18:41] Speaker 05: considerations or anything like that. [00:18:42] Speaker 05: I'm only concerned about little old 102 and whether this one reference has everything that's in the claim. [00:18:50] Speaker 05: And that's all I need to know. [00:18:54] Speaker 05: Why should I feel comfortable in flipping the district court for making an unreasonable finding that Dix does not disclose the 98% limitation, even if it discloses the 40 milligram per millimeter limitation? [00:19:11] Speaker 01: Because Dix actually made the 50 milligram formulation 98% stable. [00:19:16] Speaker 01: He made a less concentrated version 98% stable. [00:19:20] Speaker 01: And this court has never held that you have to have an actual practiced example in the specification in order to anticipate. [00:19:29] Speaker 01: You need the enabling disclosure. [00:19:31] Speaker 01: That's the critical issue. [00:19:33] Speaker 01: And Dix gave the person of ordinary skill in the art the enabling disclosure for 40. [00:19:38] Speaker 01: And if I may, I would, if I can talk. [00:19:41] Speaker 01: I don't know if we need to. [00:19:42] Speaker 03: I want to take you back to criticality. [00:19:44] Speaker 03: Did you have something else? [00:19:45] Speaker 01: No, no. [00:19:45] Speaker 01: Go ahead. [00:19:46] Speaker 01: I just know I'm in my time, Your Honor. [00:19:48] Speaker 03: No, I know. [00:19:49] Speaker 03: We're going to be here a while. [00:19:54] Speaker ?: OK. [00:19:55] Speaker 03: Back to criticality, I think, and I'll discuss with your friend why I think the district court's findings may have put the wrong burden and asked the wrong question. [00:20:05] Speaker 03: But did Regeneron put up any evidence to show criticality? [00:20:09] Speaker 01: Within the range of what was already disclosed by Dix, no. [00:20:14] Speaker 01: All of the criticality evidence, and this is reflected in the district court's findings, [00:20:18] Speaker 01: was focused on, well, here's how a flippersept performs relative to ranibizumab, because of this inflammation risk. [00:20:28] Speaker 01: And because of that, that to me is exactly the problem here, is that these are composition claims. [00:20:34] Speaker 01: The district court construed the claims that's suitable for intravitreal administration. [00:20:39] Speaker 01: It only meant you need to have, Judge Waller, the list of ingredients on claim seven that had previously been used in intravitreal formulations, or in another example, [00:20:48] Speaker 01: We had that in Dix. [00:20:50] Speaker 01: So if we look at this for its cases, usually when you're assessing criticality, are we seeing some unusual property as compared to the genus? [00:21:02] Speaker 01: And that's what we don't have here. [00:21:04] Speaker 01: We don't have any evidence showing that 40 milligram per ml [00:21:08] Speaker 01: within the scope of the 865 claims is always going to outperform the DICS formulations. [00:21:15] Speaker 05: And they're not going to get there. [00:21:17] Speaker 05: At 8159, the district court makes a finding that this 40 mg per ml limitation hit some kind of sweet spot, maximizing half-life of the flibicep in the eye while at the same time minimizing toxicity and stability concerns. [00:21:37] Speaker 05: So the question in my mind is, is that enough to show this is something, this establishes that this particular value, 40, is critical to the operability of this drug product? [00:21:52] Speaker 01: Right. [00:21:53] Speaker 01: It's not, Your Honor, because first, if you actually go look at the citations that the district court offered to cite it, those citations don't actually say that. [00:22:01] Speaker 01: Second, because Regeneron here is trying to say there's something special about 40, well, you're going to get those same results if you're at 41. [00:22:09] Speaker 01: You're going to get those same results if you're at 39. [00:22:13] Speaker 01: How do we know that? [00:22:15] Speaker 01: Well, we know that because there is... What's the testimony to that effect? [00:22:21] Speaker 06: Well, because the testimony... That's Mr. Trout, yeah? [00:22:23] Speaker 01: Sure. [00:22:23] Speaker 01: The testimony here is that all the district court is saying is they chose the 40-milligram concentration to maximize the half-life of a flipperset in the eye. [00:22:34] Speaker 01: Well, flipperset, that's the molecule. [00:22:37] Speaker 01: And then that was already known in the prior art. [00:22:40] Speaker 01: The half-life had already been established. [00:22:42] Speaker 01: That's in the Holash publication. [00:22:44] Speaker 01: So the higher potency of a flog recept and its expected longer half-life in the eye, that was already background knowledge to one of ordinary skill in the art. [00:22:53] Speaker 01: So when it comes to then minimizing toxicity and stability concerns, this is where I get to, Judge Frost, your point, is that Regeneron never came forward to say there's anything [00:23:06] Speaker 01: They don't say it in their own specification. [00:23:08] Speaker 01: There's anything different about 40. [00:23:10] Speaker 01: I can certainly get you the testimony where the named inventors and Dr. Trout all agreed that in the 865 patent specification, they say nothing about that these formulations are going to have a better half-life, that there's some kind of superior technology or outcome that's going to result from this as against the broader range that was originally disclosed and claimed. [00:23:36] Speaker 01: and in the specification itself that it admits is going to be a stable intravitreal formulation suitable for injection. [00:23:43] Speaker 01: And furthermore, none of those particular elements actually made their way into the claims. [00:23:50] Speaker 01: So if we're going to look at the scope of what has actually been claimed here, these particular efficacy elements are not there. [00:23:58] Speaker 01: And Regeneron, in their briefing, was quite adamant that these claims should not be construed as requiring [00:24:05] Speaker 01: anyone or any composition to meet any efficacy standards. [00:24:09] Speaker 01: So I think if we were to go back to this court's recent decision in Janssen v. Teva, which we cited in our brief, 97F4, I'm not sure what the pin site is, this court was very clear that when it comes to doing these types of comparative analyses, if it involves an element that's not actually in the claims, you shouldn't be considering that as somehow establishing [00:24:36] Speaker 01: unexpected results or anything along those lines. [00:24:39] Speaker 03: OK. [00:24:40] Speaker 03: We will restore some of our double time. [00:24:41] Speaker 01: I did want to emphasize as well, if I could, I don't know, the non-infringement issues. [00:24:52] Speaker 03: No, we're not going to. [00:24:55] Speaker 03: We have the briefs for that. [00:24:57] Speaker 01: That's fine. [00:24:58] Speaker 01: Thank you, Your Honor. [00:25:12] Speaker 02: Good morning. [00:25:13] Speaker 02: Good morning. [00:25:14] Speaker 02: May it please the court? [00:25:15] Speaker 02: Andrew Trass for Regeneron. [00:25:18] Speaker 02: My friend on the other side focused her remarks on 102 and briefly on 103, so I'll do the same unless the court has other questions. [00:25:24] Speaker 03: Can we start on 102? [00:25:26] Speaker 02: Yes. [00:25:26] Speaker 03: And can we start on criticality? [00:25:28] Speaker 03: Yes. [00:25:31] Speaker 03: Tell me if I'm wrong. [00:25:33] Speaker 03: District court said you don't need to show criticality because of the size, relying on adiphenia. [00:25:39] Speaker 03: So let me first ask you about the size. [00:25:42] Speaker 03: True difference, even if we read Adaphena is our court has not subsequently read it. [00:25:49] Speaker 03: But in any event, the size is different and it's much larger in Adaphena than it is here. [00:25:55] Speaker 03: So I don't know how. [00:25:58] Speaker 03: slam dunk, full stop, the size there takes the size here. [00:26:03] Speaker 03: The other question I had about size, so you can respond together, is that your expert talked about, yeah, there are a million things in this because we're down to the tenths and the hundredths. [00:26:16] Speaker 03: But there was nothing I could find in the records, so you can show me, where that's the way those are the kinds of calculations they use with respect to these drugs. [00:26:26] Speaker 03: I mean, it seems to me [00:26:27] Speaker 03: As an edafina, we had degrees of 100, 200 integers and not expanding the scope into the hundreds or even the thousands. [00:26:38] Speaker 03: Then you can have millions no matter what the scope. [00:26:40] Speaker 03: So if you could respond to that first step before we get to criticality. [00:26:44] Speaker 02: Yes, your honor. [00:26:45] Speaker 02: Happy to. [00:26:46] Speaker 02: So on the size of the genus here, there's two important considerations. [00:26:51] Speaker 02: One is that there was testimony from both sides experts that this was not a small range. [00:26:56] Speaker 03: So we have a small. [00:26:58] Speaker 03: Where does that get us? [00:26:59] Speaker 02: Not a small range. [00:27:00] Speaker 02: Right. [00:27:00] Speaker 02: So that part of part of the analysis here is, as the Ostrom case explained, the perspective of the person of ordinary skill in the art [00:27:08] Speaker 02: And how they would view the size of the range is an important consideration in these overlapping ranges cases. [00:27:14] Speaker 02: And so that's where that testimony goes, is to that factor under the Osram case of this court. [00:27:20] Speaker 02: Both sides experts acknowledge this was a large range. [00:27:22] Speaker 02: Dr. Rabineau, Mylan's expert, pointed out that it encompassed digits to the tenths and hundreds place, which the district court found, that that encompassed hundreds or potentially thousands of discrete values. [00:27:33] Speaker 05: So both experts agreed to that? [00:27:36] Speaker 05: You look at the range, you don't just look at whole numbers, but you go all the way down to the tenths or even the hundredths? [00:27:42] Speaker 02: Dr. Rabinow, Myelin's expert, testified on cross-examination that that range encompassed not just whole values, but also digits to the tenths and the hundredths place. [00:27:54] Speaker 02: The district court acknowledges, made its finding at A157. [00:27:57] Speaker 02: Dr. Rabinow's testimony was at A9496 through 99 on that precise point, Your Honor. [00:28:03] Speaker 02: And then Dr. Trout, Regeneron's expert, [00:28:05] Speaker 02: also testified expressly that this was not a small range in the eyes of the post. [00:28:09] Speaker 02: That's at A10448. [00:28:12] Speaker 02: So that goes to the size of the range. [00:28:14] Speaker 02: But there's an even more fundamental issue here that distinguishes this case from some of the other overlapping ranges cases of this court. [00:28:24] Speaker 02: So in the [00:28:26] Speaker 02: In the Adaphena case, the Clear Value case, the Osram case, and others, the difference between the prior art and the claimed invention was the identity of the range. [00:28:39] Speaker 02: In Adaphena, it was a range of degrees Celsius disclosed and a range of degrees Celsius claimed. [00:28:46] Speaker 02: Clear value is the PPM range disclosed, the PPM range claimed, and so on. [00:28:51] Speaker 02: Here, there is a different scenario. [00:28:53] Speaker 02: There is agreement by the experts that the range in the prior art of 10 to 50 milligrams per milliliter [00:28:59] Speaker 02: was not specific to the claimed protein. [00:29:01] Speaker 02: It was not disclosed as a range of 10 to 50 milligrams per milliliter of a flip receptor. [00:29:07] Speaker 02: It was disclosed as a range of a genus of fusion proteins. [00:29:12] Speaker 02: A genus of what, two? [00:29:14] Speaker 02: No, more than two, Your Honor. [00:29:15] Speaker 02: So Milam's own expert agreed with this point. [00:29:18] Speaker 02: He testified it was a class of proteins. [00:29:20] Speaker 02: That's at A9497. [00:29:22] Speaker 02: And what the DICS reference says expressly at A12593, [00:29:27] Speaker 02: is that this 10 to 50 range corresponds to a genus of, quote, VEGF-specific fusion proteins. [00:29:34] Speaker 02: And there were two proteins called out specifically by their amino acid sequences in the DIC specification. [00:29:42] Speaker 02: But there are other proteins within this class of fusion proteins that apply to this range. [00:29:46] Speaker 02: How do we know that? [00:29:47] Speaker 02: Dr. Rabinow testified to it at eight nine four nine six through nine nine and Dr. Trout testified to the same at ten it's sorry eight ten what did they say did they say it was for fusion proteins fourteen four hundred four thousand and [00:30:04] Speaker 02: The upper bound on the number of fusion proteins encompassed by this class was not the subject of precise testimony, but the testimony was clear, and it was agreed by both sides, and the district court found at 8-157 that the 10-50 range in the prior art was not linked to a flibber set specifically. [00:30:26] Speaker 02: And because of that, what we have here is a genus on top of the genus. [00:30:31] Speaker 02: So we have a genus of fusion proteins and a genus of concentrations of fusion proteins. [00:30:36] Speaker 05: And so this is unlike... I'm just confused because the Dix reference only calls out to species, right? [00:30:44] Speaker 02: The disclosure, the DICS reference, apologies, the passage of the DICS reference that we're referring to here is at column two, lines 21 to 23. [00:30:55] Speaker 02: And this disclosure of the 10 to 50 range refers to this genus of fusion proteins. [00:31:00] Speaker 02: And it describes how they're made up. [00:31:02] Speaker 02: They have receptor regions. [00:31:03] Speaker 02: They have a constant region. [00:31:05] Speaker 02: So it's describing this genus as more than just the two discrete [00:31:09] Speaker 02: disclosed amino acid sequences, but rather this genus of proteins that contain these different structural features. [00:31:16] Speaker 02: So that's clear from the DICS reference. [00:31:18] Speaker 02: It was agreed upon by the experts from both sides. [00:31:23] Speaker 02: And it was found by the district court without, we would submit, clear error. [00:31:27] Speaker 02: So this is a different scenario from the other overlapping range cases, where you have the same parameter in the prior arc and in the current range. [00:31:36] Speaker 05: Just put that to the side for a moment. [00:31:40] Speaker 05: Then if we were to read INEOS in clear value, and especially the way they explain the meaning of adafina, then would you agree that putting this one factor to the side, that when we have something like this, 40 milligrams per milliliter, inside the range from the part of 10 to 50, [00:32:05] Speaker 05: then it's incumbent upon the patent owner to show and demonstrate some kind of criticality. [00:32:13] Speaker 02: So I acknowledge that those cases involve criticality in the context of overlapping ranges, of course. [00:32:20] Speaker 02: Criticality was not required here, as the district court correctly found, for several reasons. [00:32:25] Speaker 02: One, there were other. [00:32:27] Speaker 05: I'm just trying to understand our case law. [00:32:30] Speaker 05: That's what our case law calls for. [00:32:32] Speaker 02: So what the case law calls for, and I think what you're referring to, Judge Chen, is that upon a showing of prima facie anticipation, the burden shifts to the patentee to show criticality. [00:32:43] Speaker 05: So the threshold question is, did- If the range overlaps with the parallel art range, then- [00:32:48] Speaker 05: it's incumbent upon the pathway to show criticality for its claimed range. [00:32:53] Speaker 05: Is that correct understanding of our case law? [00:32:55] Speaker 02: That's not my reading of the case law precisely. [00:32:58] Speaker 05: OK, then what is it? [00:32:59] Speaker 02: If there's a prima facie case of anticipation. [00:33:03] Speaker 02: It's not simply a question of whether the ranges overlap, [00:33:05] Speaker 02: As Osram explained, for example, what is the size of the genus in the eyes of the posa? [00:33:10] Speaker 02: That's an important consideration, this court's precedent says. [00:33:13] Speaker 02: And so the question of whether that threshold has been crossed and whether a prima facie anticipation case has been made out needs to consider the size of the range, whether there's an overlapping genus, as we discussed a moment ago. [00:33:25] Speaker 02: All of those factor into whether a prima facie anticipation. [00:33:30] Speaker 05: Well, clear value talked about the size of the prior art range? [00:33:37] Speaker 02: Clear value talked about the relative size of the prior art genus. [00:33:41] Speaker 02: I'm sorry. [00:33:41] Speaker 02: I don't know the answer to that question off the top of my head, Your Honor. [00:33:45] Speaker 02: But the Osram case certainly discusses that as a factor in deciding whether the burden shifts to the patentee. [00:33:53] Speaker 02: And as I think Your Honor pointed out earlier. [00:33:56] Speaker 05: So as I understand your argument, you've [00:34:00] Speaker 05: Roadblocks are putting up before we have to worry about criticality. [00:34:05] Speaker 05: One is we're dealing with, as you would call it, a class of VEGF antagonists. [00:34:13] Speaker 05: And two, the size of the prior art range is just too big. [00:34:20] Speaker 02: That's right. [00:34:21] Speaker 02: I would say those are the main considerations. [00:34:26] Speaker 02: That's right. [00:34:27] Speaker 03: But didn't the district court also say, even if there were criticality, go ahead and analyze criticality? [00:34:33] Speaker 02: That's correct, Judge Prost. [00:34:35] Speaker 02: We stand by the district court's finding that there was no need to show criticality. [00:34:38] Speaker 02: But even if there were a need to find criticality, the district court made ample findings on the record here regarding criticality. [00:34:45] Speaker 05: Isn't it peculiar, though, to try to do a comparison with the claimed embodiment [00:34:50] Speaker 05: against this R drug for teaching away unexpected results. [00:34:57] Speaker 05: Because as I understood, there's not a lot of case law and criticality, but it seems like the thrust of the thinking for criticality is comparing what you've claimed against other embodiments that come within the prior art range. [00:35:16] Speaker 02: So the district court didn't. [00:35:17] Speaker 05: So that's the type of apples to apples analysis you have to do, not an apples to oranges analysis comparing your drug to some other drug. [00:35:26] Speaker 02: So there was no dispute here that the Goudreau reference, which is the one that discloses the R drug, was the closest prior art here. [00:35:33] Speaker 02: In our view, it was appropriate for the district court to draw upon those comparisons. [00:35:37] Speaker 02: But there were also comparisons that were specific to a flibber sap. [00:35:41] Speaker 02: So I would direct your honor's attention to the court's findings at A159. [00:35:46] Speaker 02: These are the findings of criticality that I think Judge Chan you pointed to earlier in the district court's opinion. [00:35:52] Speaker 05: I didn't really see a comparison between here's why 40 is special. [00:35:59] Speaker 05: Because look what happens when you do 45 or 35. [00:36:04] Speaker 02: Right. [00:36:04] Speaker 02: Let me address that because I do think that there's a direct linkage between the claims of 40 milligrams per milliliter and the critical criticality findings on page 159. [00:36:15] Speaker 02: And so the district court on A159 cited several witnesses' testimony. [00:36:21] Speaker 03: Well, first she says, no record evidence shows that these desirable benefits of the claimed invention would obtain at other concentrations between 10 and 40, right? [00:36:31] Speaker 03: That's what she says in the middle of 159. [00:36:33] Speaker 02: That's correct, Your Honor. [00:36:36] Speaker 03: Accordingly, even if anticipation were required or showing of criticality, undisputed evidence at trial demonstrates that the 4D concentration is critical to the benefits." [00:36:48] Speaker 03: Is that the right standard? [00:36:50] Speaker 03: Firstly, I think she put the burden on them, not on you. [00:36:58] Speaker 03: Is that right? [00:36:59] Speaker 03: And the inquiry, doesn't seem to me, is whether the 40 milligram concentration is desirable, but whether it's critical to the operability of the claimed invention. [00:37:11] Speaker 03: In other words, the claimed invention is critical only if it can be shown that the claimed invention only works [00:37:17] Speaker 03: for 40 milligrams and not for others. [00:37:20] Speaker 03: So I don't understand how her analysis of the evidence jives with what I understand to be the criticality analysis. [00:37:26] Speaker 02: I understand, Your Honor. [00:37:27] Speaker 02: Let me explain that. [00:37:28] Speaker 02: So on that same page, and in fact, the sentence before the one that Your Honor just quoted, the District Court Judge Klee found that the testimony at trial demonstrated that the inventor specifically chose the 40 milligram per milliliter concentration to maximize the half-life of the flippersept in the eye [00:37:47] Speaker 02: while minimizing toxicity and stability concerns. [00:37:51] Speaker 02: And what the district court is citing there is the testimony of two of the inventors of the 865 patent, Dr. Furfine and Dr. Graham. [00:37:58] Speaker 02: And what that cited testimony says is, first of all, Dr. Furfine, this is at A9075, said that if you double the concentration of a flibrocept, you get an extra half-life. [00:38:11] Speaker 02: So the concentration of a flibrocept in the formulation is tied directly to... Everybody knew that, though, right? [00:38:18] Speaker 02: That's not right. [00:38:18] Speaker 05: Everybody knew that if you increase the concentration, you're going to improve the half-life. [00:38:24] Speaker 02: That's not, there's no finding to that effect, Judge Chen. [00:38:26] Speaker 02: And that assumes some kind of a constant, like a linear increase in pharmacokinetics, of which there was no finding that that would have been the case here. [00:38:36] Speaker 02: This was found by the district court to be a key insight of the inventors in developing this formulation. [00:38:41] Speaker 05: When you say key insight, what is the key insight particular? [00:38:44] Speaker 05: Not that you drive up concentration, you drive up half-life, because it's a correlation. [00:38:50] Speaker 02: The finding was that the concentration is directly tied to the half-life, such as if you double the concentration, you get an extra half-life, coupled with the additional testimony cited by Judge Klee on that same page of Dr. Graham. [00:39:05] Speaker 02: Dr. Graham testified that the propensity for aggregation, and this is sorry, this is at A 10040, that the propensity for aggregation of a fliter set increases as the square of the concentration. [00:39:19] Speaker 02: And so aggregation as well, which was acknowledged by experts at trial from both sides, was an extremely concerning phenomenon for this drug, which is injected into the eyeball. [00:39:29] Speaker 02: And so what the inventors found was that the propensity for aggregation increased as the square of the concentration, again, supporting Judge Klee's finding that they minimize toxicity and stability concerns by using this particular concentration. [00:39:42] Speaker 05: I guess the question that still remains is that the prior art range is 10 to 50. [00:39:49] Speaker 05: You've claimed 40. [00:39:51] Speaker 05: And I don't see anything in the record that indicates here's why 40 is something different and therefore critical to the operability of our claimed drug product compared to other things that are in that prior art range. [00:40:09] Speaker 05: And I thought that that is the nature of the criticality analysis. [00:40:14] Speaker 05: agree on that, that we have to look at the performance or the properties or the operability of the claimed embodiment against other things that are in the prior art range. [00:40:27] Speaker 02: I think that's a fair characterization of the criticality inquiry. [00:40:31] Speaker 02: The OSRAM, for example, asks whether the claimed value is central to the invention and whether the invention would operate differently at various points within the range. [00:40:41] Speaker 05: OK, so I think [00:40:44] Speaker 05: That's what I'm wondering if whether there's a gap in this record or in this case when it comes to the analysis on criticality. [00:40:53] Speaker 02: So I don't think there's a gap, Your Honor, for a couple of reasons. [00:40:56] Speaker 02: One is the testimony concerning the precise concentrations selected by the inventors, as found by the district court at A159, which balanced the half-life with concerns regarding safety and efficacy, as well as the district court's findings regarding [00:41:14] Speaker 02: unexpected results. [00:41:16] Speaker 02: And so these findings are at A198, and the district court found that the 40 milligrams per milliliter of a flip receptor claimed in all of the asserted claims had three critical and unexpected properties, safety, efficacy, and durability. [00:41:30] Speaker 02: And the court went on to explain how it was that this 40 milligram per milliliter concentration was surprisingly [00:41:38] Speaker 02: Comparable with respect to safety and efficacy compared to the closest prior art. [00:41:43] Speaker 02: Parties agreed with the Genentech Lucentis, sorry, Goudreau reference. [00:41:49] Speaker 02: and also had durability to be dosed half as frequently. [00:41:53] Speaker 02: As your honors can imagine, getting an injection into the eyeball is not a pleasant experience for patients, and so this was a revolutionary advance the district court found to have to dose patients only half as often. [00:42:03] Speaker 02: So that finding as well, I think, supports the district court's finding of criticality because it shows that the 40 milligram per milliliter concentration claimed in all of the asserted claims [00:42:13] Speaker 02: is critical to the invention and distinguished the invention from the closest prior art, which the parties agreed was the Boudreaux reference, which referenced the R-drug that Your Honor mentioned. [00:42:28] Speaker 02: The other thing I'd point out is that the testimony from Dr. Furfine, one of the inventors, that connected the concentration, 40 milligram per milliliter, with the half-life of a flippercept was unrebutted. [00:42:40] Speaker 02: The district court found that at A200, and there was no challenge by Mylan to that finding a trial and certainly unappealed. [00:42:48] Speaker 02: And so there's multiple ways in which the district court found criticality. [00:42:53] Speaker 02: The connection to a flippercept itself through the testimony of Dr. Furfine and Dr. Graham [00:42:58] Speaker 02: as well as to the comparison to the closest prior art in the good road. [00:43:03] Speaker 05: For getting away from the Dix 102, you're not relying on the preamble, I guess, for use in intravitreal administration compared to the cancer treatment that was disclosed. [00:43:19] Speaker 02: The preamble was never a basis to distinguish the prior art. [00:43:22] Speaker 05: Okay, I saw the district court in part rely on that. [00:43:25] Speaker 05: And then I saw that the referee does not. [00:43:28] Speaker 02: I don't think that's right. [00:43:30] Speaker 02: I mean, it's certainly true. [00:43:31] Speaker 05: You say that's not right. [00:43:32] Speaker 05: Which part's not right? [00:43:33] Speaker 02: Sorry, yes. [00:43:36] Speaker 02: I don't read the district court's decision as relying upon the preamble. [00:43:41] Speaker 02: words from his opinion that when I read it. [00:43:43] Speaker 03: Can I ask you one other thing? [00:43:46] Speaker 02: I'm not sure your honor which passage you're specifically referring to, but there was no dispute by the parties that there was no efficacy limitation built into the [00:43:56] Speaker 02: suitable for intravitreal administration term. [00:43:59] Speaker 02: It was never a term that either party had proposed to construe. [00:44:02] Speaker 02: And so there's unrebutted testimony by Dr. Trout that what that limitation means is contains components that can be used intravitrally and nothing more. [00:44:10] Speaker 05: What about 98%? [00:44:11] Speaker 05: How are we supposed to think about that? [00:44:15] Speaker 05: The other side you heard say, essentially, the 98% would be there in DICS, which you used the 40-milligram humiliator because [00:44:27] Speaker 05: All the examples at other concentration levels got me to 98%. [00:44:32] Speaker 05: And I don't know, 98% is what the FDA wants. [00:44:36] Speaker 05: So 98% is really not very meaningful here. [00:44:41] Speaker 02: So two responses to that, Your Honor. [00:44:43] Speaker 02: One is, I think you put your finger on it when you asked my friend on the other side about the testimony that best supported the notion that there would be [00:44:50] Speaker 02: 98% in 40 mil per mil from the Dix reference. [00:44:54] Speaker 02: And you pointed out that the most the expert said is it would be most likely. [00:44:57] Speaker 02: That's at A10526. [00:44:59] Speaker 02: That was your expert, right? [00:45:00] Speaker 02: That's our expert, correct. [00:45:02] Speaker 02: He acknowledged it. [00:45:02] Speaker 05: What did their experts say? [00:45:04] Speaker 02: Their expert offered no testimony on that fact. [00:45:07] Speaker 02: And what it seems to me, on appeal, is that they're arguing almost kind of an inherency type analysis. [00:45:12] Speaker 02: But certainly that was not a theory that was run below. [00:45:15] Speaker 02: And there's no evidence to support that necessarily there would have been [00:45:18] Speaker 02: 98% native confirmation in one of the DICS formulations. [00:45:23] Speaker 06: Frankly, what impressed me was how often Rabineau and Trout agreed with each other, which is unusual in reviewing experts. [00:45:30] Speaker 02: It is refreshing, perhaps. [00:45:32] Speaker 02: I agree with you, Your Honor. [00:45:34] Speaker 02: The other point I wanted to make in response to Judge Chen's question. [00:45:37] Speaker 05: The lawyers have, like, 40 disagreements. [00:45:40] Speaker 02: Well, I can't help that. [00:45:42] Speaker 02: There were a lot of issues raised in the opening brief. [00:45:45] Speaker 02: On the point about 98% being a known FDA requirement, I think this is an important point to flag. [00:45:51] Speaker 02: Mylan made this argument at page 24 of their reply brief. [00:45:55] Speaker 02: They said, quote, 98% native confirmation was a known FDA stability requirement, unquote, in support of that statement. [00:46:03] Speaker 02: They cite Dr. Graham. [00:46:04] Speaker 02: And I encourage your honors to look at that testimony. [00:46:07] Speaker 02: This is at A10102 through 03. [00:46:11] Speaker 02: Dr. Graham said precisely the opposite of what Mylon represented there. [00:46:16] Speaker 02: Dr. Graham said that 98% native confirmation was, quote, not an obligate requirement, unquote, for a product. [00:46:23] Speaker 06: What volume are you on? [00:46:25] Speaker 02: This is A10102, which is volume two. [00:46:36] Speaker 05: We've been talking about DICS 102. [00:46:41] Speaker 05: Just curious. [00:46:42] Speaker 05: DICS 103, your reliance on 103C1. [00:46:46] Speaker 05: It couldn't be conclusive yet, right, if we were to conclude that there was a problem with criticality because the district court never made an assessment on whether [00:47:04] Speaker 05: the 865 is entitled to an earlier provision application filing date. [00:47:09] Speaker 05: Is that right? [00:47:10] Speaker 02: So I think part of the reason that Dix was not a focus of Mylan's. [00:47:16] Speaker 05: I'm just trying to get to the bottom of something. [00:47:19] Speaker 05: I just need to know for housekeeping. [00:47:21] Speaker 02: Sure. [00:47:22] Speaker 02: So our view is that Dix is not a proper reference under 103 by virtue of the fact. [00:47:26] Speaker 02: Right. [00:47:26] Speaker 05: But the district court did not make an assessment on whether the patent's entitled to the [00:47:32] Speaker 05: provisional priority. [00:47:34] Speaker 02: The district court did not make that finding. [00:47:35] Speaker 02: That's right, Your Honor. [00:47:36] Speaker 02: Yeah. [00:47:36] Speaker 02: And so if the court decides that it can't reach that question as a result, then it wouldn't reach the 103C question. [00:47:44] Speaker 02: But our view is that Dick's. [00:47:46] Speaker 05: I mean, I could just keep asking questions. [00:47:48] Speaker 02: I don't know. [00:47:48] Speaker 03: Well, but do we get to teaching away? [00:47:49] Speaker 03: Because I'm sorry. [00:47:50] Speaker 03: I'm thinking about too many things at one point. [00:47:52] Speaker 03: So maybe this is redundant. [00:47:53] Speaker 03: But I want to get to the teaching away argument. [00:47:56] Speaker 03: Yes, Your Honor. [00:47:58] Speaker 03: It seems to me the district court relied heavily on Dr. Trout's analysis of this Goudreau reference. [00:48:04] Speaker 03: But I don't see anywhere in the record where he explains what a reference about, we're calling it R-right, formulation is indicative of how the A formulation would behave. [00:48:16] Speaker 03: And I only see discussions about how A is more potent than R. But did your expert provide anything additional as to why R and A would behave similarly? [00:48:28] Speaker 03: I mean, this is just an odd kind of teaching away when you're not directing it to what we're talking about, right? [00:48:36] Speaker 03: How do you get there? [00:48:37] Speaker 02: Sure. [00:48:38] Speaker 02: So it was undisputed at trial that this reference that's the subject of the Teachaway, the Goodrow reference, was the closest prior art. [00:48:44] Speaker 02: The district court found that. [00:48:46] Speaker 02: at A197. [00:48:47] Speaker 02: And the only thing that Mylan cites to support, they claim on appeal on page 36 of their reply brief that they disputed that contention. [00:48:56] Speaker 02: The only thing they cite is their proposed order, their proposed post trial order to the district court, which of course is not evidence. [00:49:03] Speaker 02: at A11698. [00:49:05] Speaker 02: And so there is no evidence of record that Goudreau is not the closest prior art, and it was not a position that Mylon ever advanced below. [00:49:13] Speaker 05: So there's- But I guess to put a finer point on it, your theory of teaching away, Mr. Court's theory of teaching away, is that aflibrocept and the R drug are essentially interchangeable, and the R drug stands as a proxy for what a skilled artisan would think about aflibrocept. [00:49:33] Speaker 05: and yet I don't see the basis for that premise that these two things are interchangeable or one is a fair substitute for the other. [00:49:47] Speaker 05: Where is the bridge for that kind of thinking that allows us to assume that whatever that might be bad about [00:49:57] Speaker 05: is also going to be equally bad, if not worse, for a fliversug. [00:50:01] Speaker 02: Sure. [00:50:02] Speaker 02: So the district court's teachaway findings were A174 to 77. [00:50:06] Speaker 02: And there were a number of findings there of relevance. [00:50:09] Speaker 02: But to your honor's point, both of these drugs, the R drug and the flivers FBA drug, had the identical mechanism of action, right? [00:50:16] Speaker 02: They bind VEGF in the retina. [00:50:19] Speaker 05: OK, this is you talking, and that's helpful. [00:50:22] Speaker 05: But I need something in the district court's [00:50:25] Speaker 05: findings and rationale and analysis that I can focus on and see, OK, oh, that's a fair fact finding that I can get behind versus, oh, there's a hole in the analysis that leaves me wanting. [00:50:45] Speaker 05: And I can't just rely on an attorney argument today trying to talk it away. [00:50:51] Speaker 02: Sure. [00:50:51] Speaker 02: I mean, so I think focusing on the point [00:50:54] Speaker 02: the pages that I just referenced, the A174 to 177, it seemed to be understood through the eyes of the posa that these two molecules had the same mechanism of action, and the performance of one would be indicative of the performance of the other. [00:51:13] Speaker 02: So for example, at A175, the district court found that because of flippersept was much more- Where were you in the page? [00:51:20] Speaker 02: Sure. [00:51:20] Speaker 02: This is A175. [00:51:21] Speaker 02: Yeah. [00:51:22] Speaker 02: I'm there, but- [00:51:32] Speaker 02: And I'm on the, it's the second beginning of the paragraph there. [00:51:37] Speaker 02: It says, moreover, it was undisputed that a flibrocept was much more potent than rennibizumab. [00:51:43] Speaker 02: Because of its higher potency, less of flibrocept is needed to inhibit the same amount of VEGF as compared to rennibizumab. [00:51:50] Speaker 02: And then a little further down, it says, Dr. Trott explained that the POSA would have been motivated to use a concentration of a flugercept lower than the 10 milligrams per milliliter ranibizumab in view of a flugercept's higher potency. [00:52:03] Speaker 05: And so, Dr. That's not quite teaching away. [00:52:06] Speaker 05: That is more like about how perhaps a skilled artisan just wouldn't be motivated to crank up the concentration up to 40 milligrams for, but that's not saying [00:52:21] Speaker 05: It's a really bad idea to use a flippers up to 40 milligrams per minute. [00:52:26] Speaker 03: And just to tag onto that, I can't recall any other cases on teaching away where one was relying on something different. [00:52:35] Speaker 03: because maybe there's some similarity to then say, this teaches a way, even though it's different, for this. [00:52:42] Speaker 03: Do you know of any cases that have done that? [00:52:44] Speaker 02: Well, I'm not sure I know exactly this particular scenario. [00:52:49] Speaker 02: But these are not two different disclosures in the sense that these are the two leading VEGF antagonists at the time. [00:52:58] Speaker 02: They were kind of both in development at the time. [00:53:00] Speaker 02: And the evidence is that the POSA was looking at the development of ranibizumab, the R drug, in order to inform how to go about developing [00:53:10] Speaker 02: a flibbersept, the A drug. [00:53:12] Speaker 02: And so these are drugs that had the same mechanism of action. [00:53:15] Speaker 02: And the undisputed testimony of trial, through Dr. Trout, over pages of the district court's findings, is that the performance of ranibizibab informed the POSA how one would expect a flibbersept to perform, because they had the identical mechanism of action. [00:53:29] Speaker 02: And so there was a finding that this- Where is that finding? [00:53:32] Speaker 05: same mechanism of action, and then the experts say because they have the same mechanism of action, we would certainly think of a flipper set in the same way that we would think of the R drug. [00:53:47] Speaker 02: I might need a moment to locate that, but I would say that the [00:53:53] Speaker 02: All of the testimony that I've been referring to is based upon the understanding, which is undisputed, that the performance of the R drug informed the post's expectations regarding a flip receptor. [00:54:07] Speaker 02: That was the understanding on which Dr. Trout was testifying. [00:54:11] Speaker 03: I'm looking at that page with the district court. [00:54:15] Speaker 03: Is there anything the district court, did the district court make a finding like that? [00:54:20] Speaker 03: I mean, she says the comparison she has that you called out, which is that a flipper set is more potent than the R drug. [00:54:28] Speaker 03: But you know, OK. [00:54:34] Speaker 02: I'm phoning a friend here. [00:54:44] Speaker 02: Another finding here is that A187, which compares ranibizumab and fusion proteins like a flow receptor. [00:54:59] Speaker 03: What heading is this under? [00:55:02] Speaker 02: This is in the context of the invalidity analysis. [00:55:10] Speaker 02: for obviousness. [00:55:15] Speaker 02: OK. [00:55:15] Speaker 02: And the discussion here on A187 talks about the POSA wouldn't expect that a different protein would have the same native confirmation. [00:55:24] Speaker 02: The higher required concentration of a fliverset compared to Rinibizumab undermine any reasonable expectation of success. [00:55:31] Speaker 02: So again, comparing these two drugs at the same mechanism of action, both VEGF antagonists, [00:55:37] Speaker 02: and comparing their, and contrasting the expectations. [00:55:42] Speaker 05: This seems to, if I'm not mistaken, kind of work against what your position is. [00:55:48] Speaker 05: Your position for purposes of teaching away is to tell us that these two drugs are very, very, very close cousins. [00:55:57] Speaker 05: This passage seems to say just because you would get some amount of stability in one doesn't necessarily mean you'll get that same stability in the other. [00:56:07] Speaker 02: So there was no contrary testimony on this point, that the two drugs have the same mechanism of action and would have performed similarly. [00:56:18] Speaker 02: The post-it would have understood that because of the severe inflammation exhibited by Lucentis at 40 milligrams per milliliter, you would expect that a fliversept would need a far lower concentration in order to achieve a beneficial therapeutic effect with a lower amount of... I suppose you have backup arguments, though, on this, right? [00:56:44] Speaker 02: We do. [00:56:44] Speaker 02: We do. [00:56:45] Speaker 05: Yes. [00:56:46] Speaker 05: of the teaching the way analysis, yet there's half a dozen other issues that have been identified. [00:56:54] Speaker 02: That's exactly right. [00:56:55] Speaker 02: The afliversep sequence is not disclosed in the Frazier and Lucentis combination. [00:57:01] Speaker 02: The glycosylated afliversep is not disclosed in that combination. [00:57:07] Speaker 04: Neither reference has afliversep? [00:57:09] Speaker 02: No, I'm talking about the Frazier and Lucentis combination. [00:57:11] Speaker 02: Right. [00:57:12] Speaker 02: Yeah. [00:57:12] Speaker 04: Neither reference has afliversep? [00:57:14] Speaker 02: In Frazier and Lucentis, I'm sorry, Frazier discloses what's called a VEGF trap R1, R2, which does not disclose a flippersept and does not disclose the amino acid sequence of a flippersept. [00:57:26] Speaker 02: That's right. [00:57:27] Speaker 02: And Lucentis, of course, was about the Renovizumab drug. [00:57:29] Speaker 02: There's no disclosure of glycosylated afliprocept. [00:57:33] Speaker 02: There's no motivation to glycosylate afliprocept. [00:57:35] Speaker 02: Is this court found last week in the related appeal involving Samsung? [00:57:38] Speaker 05: How come we didn't get a 28J letter? [00:57:40] Speaker 03: Oh, yes. [00:57:42] Speaker 03: Well, that goes to the next case, though. [00:57:44] Speaker 03: No, it counts here, too. [00:57:45] Speaker 03: No, but it counts more on the last case. [00:57:47] Speaker 02: Yeah, I will take responsibility for that. [00:57:49] Speaker 02: We weren't sure. [00:57:51] Speaker 03: Well, on the other side as well, we should have gotten something from someone. [00:57:54] Speaker 02: We weren't sure if the [00:57:56] Speaker 02: we should presume that the court was aware of a decision in the same consolidated appeal. [00:58:01] Speaker 02: Perhaps we should have just submitted the 28-J letter out of the abundance of questions. [00:58:04] Speaker 03: Well, that's a fair assumption, but that doesn't answer the next question of the reason we have 28-J letters, which is to explain the relevance of that opinion to what the case is, the case we haven't got to yet. [00:58:16] Speaker 03: And we'll talk more about that. [00:58:18] Speaker 02: OK, yeah. [00:58:19] Speaker 02: But to your honor's point, there are a number of differences with respect to the reasonable expectation of success. [00:58:25] Speaker 02: the motivation, as well as the oblivious subsequence that differentiate the prior arc from the claimed invention here. [00:58:34] Speaker 02: The last point I'll raise is that you started, Judge Peros, by asking my friend on the other side what obviousness combinations are running here. [00:58:43] Speaker 02: And I heard that they're maintaining the Frazier and Lucentis and the Dix references. [00:58:50] Speaker 02: In their briefing, they combined those teachings. [00:58:56] Speaker 02: I believe it's at page 69 of their briefing. [00:58:58] Speaker 02: Did you say in your rhetoric that they didn't raise that to the trial judge? [00:59:02] Speaker 02: No, that's not right, Judge Wallach. [00:59:05] Speaker 02: We objected to the trial judge, in front of the trial judge, to the combination because it wasn't disclosed. [00:59:11] Speaker 02: The district court precluded Mylan from relying on that combination. [00:59:14] Speaker 02: This is at A167 to 168. [00:59:18] Speaker 02: And yet, their opening brief argues these references together as if it's a proper combination. [00:59:23] Speaker 02: And so I just wanted to make sure the court was aware of that point. [00:59:25] Speaker 03: Thank you. [00:59:29] Speaker 02: Thank you very much, Your Honors. [00:59:32] Speaker 03: OK, trying to keep things even, if necessary, on my calculations, which may be wrong. [00:59:38] Speaker 03: But I think you went eight over, and he went 18 over. [00:59:42] Speaker 03: So that gives you plus 10. [00:59:44] Speaker 03: But we hope you don't need it. [00:59:54] Speaker 01: I will try not to. [00:59:56] Speaker 01: use it all if I don't have to, Your Honor. [00:59:59] Speaker 01: A couple of things I'd like to point out. [01:00:03] Speaker 01: First, if the tens and hundreds apply from the perspective of a person of ordinary skill in the art to 10 to 50, then it also applies to 40. [01:00:13] Speaker 01: So then you've got a range versus a range, as opposed to a point within a range. [01:00:18] Speaker 03: In addition, I do want to point out that my colleague- But you agree with your friend that your expert conceded that? [01:00:26] Speaker 01: Well, what he said is numerically, 10 to 50 can include tenths and hundredths. [01:00:33] Speaker 01: That's not necessarily the same thing, I don't think, as a person of ordinary skill in the art would concede all of those to be the same. [01:00:41] Speaker 01: But nevertheless, if a person of ordinary skill in the art is going to see a number 10 to 50 and see tenths and hundredths, and then they're going to see a number 40, then that also means you see tenths and hundredths, and that's a range. [01:00:55] Speaker 01: When it comes to what Dix says about this class of VEGF antagonists, and that, I think, is actually where the Samsung decision that just were recently issued would, in fact, be relevant here. [01:01:09] Speaker 01: So one of the things that my colleague argued is that, well, Dix doesn't actually tell you about the full sequence that we've got claimed in claim one. [01:01:20] Speaker 01: Well, here's what Dix does do. [01:01:22] Speaker 01: Dix, in its examples, [01:01:24] Speaker 01: always uses sequence ID number four. [01:01:26] Speaker 01: Dix, in the specification, has a clear preference for sequence ID number four. [01:01:32] Speaker 01: And if we go to Dix, this is an A12595, under the heading VEGF antagonists. [01:01:39] Speaker 01: So he's talking about the fusion proteins. [01:01:42] Speaker 01: Column five, lines 30 to 42. [01:01:47] Speaker 01: He specifically says, here's what the VEGF antagonists are. [01:01:52] Speaker 01: It includes fusion proteins. [01:01:54] Speaker 01: In a preferred embodiment, the VEGF antagonist is the fusion protein of two or four, more preferably sequence ID number four. [01:02:04] Speaker 01: And then further on, then the next couple lines, this is the same thing that the Samsung decision decided was going to be written description support for Regeneron for its claims in the 865 pattern relating to the sequencing glycosylation patterns. [01:02:23] Speaker 01: Dix has the same identical language under the same heading, because Dix and the 865 patent are reading almost verbatim on this. [01:02:32] Speaker 01: It then says, in a specific embodiment, the fusion protein comprises amino acids 257 to 457 of sequence ID number 4 and is glycosylated at ASN residues 62, 94, 149, 122, and 308. [01:02:45] Speaker 01: That is the single sequence that is claimed in claim one of the 865 patent here. [01:02:52] Speaker 01: So Dix, this is where the district court went wrong, because the district court only focused on just that one description of column two that's saying, here's what the embodiment is for 10 to 50 milligrams. [01:03:04] Speaker 01: But then he ignored where the specification then expands on what it means to be a VEGF fusion protein of the invention. [01:03:12] Speaker 01: So I think in this court's claims, when we're talking about is something arranged as in the claim, when we clearly have an interrelated teaching, here's the fusion proteins. [01:03:22] Speaker 01: Here's the ones that I prefer. [01:03:24] Speaker 01: Here's what I most prefer. [01:03:25] Speaker 01: So the district court went wrong by not looking at that particular thing to say, oh, a flibbercept is something that Dix is specifically contemplating. [01:03:38] Speaker 01: Similarly, if we then go to Dix's examples, the 226 patent, example one, so that Dix, this is at A12596, example one, [01:03:49] Speaker 01: What does Dix have there? [01:03:52] Speaker 01: And now let's go to the 865 patent, example one. [01:03:56] Speaker 01: What are the ingredients? [01:03:59] Speaker 01: They're titled the same. [01:04:00] Speaker 01: Stability of a 50 milligram per ml. [01:04:03] Speaker 01: Now, the 865 patent says it's VEGF-TREP liquid formulation. [01:04:07] Speaker 01: Dix just says liquid formulation of VEGF-TREP. [01:04:10] Speaker 01: What's contained in it? [01:04:11] Speaker 01: 10 millimoles of phosphate in Dix, 10 millimoles of phosphate in the 865 patent. [01:04:18] Speaker 01: 50 millimoles of NACL, also 50 millimoles of NACL in the 865 patent. [01:04:25] Speaker 01: Then we've got 0.1% polysorb 820. [01:04:29] Speaker 05: Just so I can clarify, which specific issue is what you're talking about driving at? [01:04:35] Speaker 01: Right. [01:04:35] Speaker 01: This gets to the idea of my colleague from Regeneron was saying that somehow there's other elements that were missing from the DICS formulations that didn't get you to the complete claim. [01:04:46] Speaker 01: and particularly the stability elements. [01:04:48] Speaker 01: Well, as you go down, as you march through these, you then get to table one in Dix, table one in the 865 patent. [01:04:56] Speaker 01: You've got the same visual appearance, turbidity, pH, and stability data, all above 98%. [01:05:02] Speaker 01: So you've got the near identical ingredients. [01:05:07] Speaker 01: And both Dix's 50 milligram example one, [01:05:11] Speaker 01: That meets each and every element of claim one and claim four and all the other asserted claims here. [01:05:17] Speaker 01: It just doesn't have the number 40 in it. [01:05:21] Speaker 01: You go to the 865 patent, yes, they've got a 50 milligram example, same stability numbers as in Dix. [01:05:27] Speaker 01: They've got a 40 milligram number, same stability results in Dix. [01:05:30] Speaker 01: Then you look at the Dix 25 milligrams for ML. [01:05:33] Speaker 01: So he dropped the concentration, and that's at column 12. [01:05:37] Speaker 01: And guess what? [01:05:38] Speaker 01: He uses those same formulation ingredients [01:05:40] Speaker 01: gets the same stability outcome. [01:05:43] Speaker 05: So do you have expert testimony on this? [01:05:45] Speaker 01: Yes. [01:05:46] Speaker 01: And where is that? [01:05:49] Speaker 01: That it is throughout. [01:05:51] Speaker 00: Let me pull out some of those. [01:05:59] Speaker 00: I apologize. [01:06:10] Speaker 01: I will get you those. [01:06:11] Speaker 01: I know we had the citations in there where we basically did go back and forth between matching each of these up. [01:06:21] Speaker 01: OK, can I? [01:06:25] Speaker 01: Do you have anything? [01:06:27] Speaker 01: Yeah. [01:06:27] Speaker 01: A couple other points, Your Honor, that I did want to make. [01:06:29] Speaker 03: Dave, just one quick point. [01:06:31] Speaker 03: It was so long ago that I don't remember. [01:06:33] Speaker 03: But I know your friend said something about a gray brief and a citation to one of the experts, and that your description of what he said was the exact opposite, I think your friend said, of what he actually said. [01:06:44] Speaker 03: Did you have a response to that? [01:06:46] Speaker 01: Right. [01:06:47] Speaker 01: I did not get a chance to check it. [01:06:49] Speaker 01: If we did, then obviously we would. [01:06:52] Speaker 01: We would withdraw that or see if that was an errant sight and there's an additional citation that needs to be made. [01:06:57] Speaker 01: But on a certain level, I don't think it's actually relevant because Dix already achieved 98% stability. [01:07:05] Speaker 01: He teaches it. [01:07:06] Speaker 01: He talks about it. [01:07:07] Speaker 01: He specifically teaches one of ordinary skill in the art how to get there. [01:07:11] Speaker 01: So you don't even need to look at FDA's motivations to get you there. [01:07:15] Speaker 01: He already got you there. [01:07:17] Speaker 01: So there again, that's where I get to what is the enabling disclosure. [01:07:22] Speaker 01: In addition, Your Honor, I did want to point out, we did dispute below that this ranibizumab drug was, in fact, the closest prior art. [01:07:29] Speaker 01: Now, I know my colleague from Regeneron said, well, you just talked about that in your briefing. [01:07:32] Speaker 01: That's because our whole point was it's not legally relevant. [01:07:37] Speaker 03: Well, did you ever say it's not legally relevant? [01:07:39] Speaker 01: Yes. [01:07:39] Speaker 03: Did you tell that to the district court? [01:07:41] Speaker 01: Yes, that was in our proposed findings of fact, conclusions, and law that the court had submitted. [01:07:47] Speaker 01: that the closest prior art was going to be the Dix formulation. [01:07:51] Speaker 01: It was not going to be ranibizumab. [01:07:55] Speaker 01: And I think the Janssen v. Teva case that was decided that we cited in our brief also bears this out, is that you're not supposed to be looking at what's happening with another drug to say this is how it's going to behave. [01:08:11] Speaker 01: for hours. [01:08:11] Speaker 01: And then additionally, I also wanted to point out that when it comes to this issue of criticality, we do know from Dix that the desirable benefit of stability was actually achieved, not only for the lower concentration, but for even higher concentrations, 50 milligrams, 75, 100 milligrams per ml. [01:08:32] Speaker 01: So under Abbott versus Baxter, 471 at third at 1368, [01:08:37] Speaker 01: The fact that they may have found, even if we assume from the district court's findings, we may have found some additional property that we think is beneficial, that doesn't change the fact. [01:08:48] Speaker 01: And I think Abbott even said, even if you put it in your claims, that still doesn't change the fact that when these are composition claims and the compositions are achieving the same outcomes, the same utilities, there just isn't any difference there. [01:09:03] Speaker 01: And there's no anticipation. [01:09:05] Speaker 01: And I think that Ineos likewise rejected the idea that you can start having these little chains of inferences to also get to criticality to somehow support the claims. [01:09:17] Speaker 03: Thank you very much. [01:09:19] Speaker 03: We thank both sides. [01:09:20] Speaker 03: The case is submitted.