[00:00:00] Speaker 01: Amgen versus Sanofi. [00:00:38] Speaker 01: Give them a minute to settle down. [00:00:56] Speaker 03: Good morning, Your Honors, and may it please the Court. [00:00:58] Speaker 03: Paul Clement for the Appellants. [00:01:00] Speaker 03: Amgen has broadly claimed an entire genus of antibodies based on their functional ability [00:01:06] Speaker 03: to block the interaction of a well-understood antigen, PCSK9, and the LDL receptor. [00:01:13] Speaker 03: Nothing in Amgen's specification or claims materially advanced the state of the science. [00:01:19] Speaker 03: Both the existence of the PCSK9 and the existence of a target region on the PCSK9 or epitope that would allow an antibody to block the PCSK9 LDLR interaction [00:01:33] Speaker 03: were well understood at the time. [00:01:35] Speaker 02: Were the amino acids in that target region identified before this? [00:01:39] Speaker 03: They had not been identified at that point. [00:01:42] Speaker 03: But also, people who were doing the process of trying to identify human antibodies did not use the 15 amino acids that were identified on the epitope to usefully do anything in particular. [00:01:57] Speaker 03: So it didn't change. [00:01:58] Speaker 03: Once this was disclosed, it didn't change the way people went about [00:02:01] Speaker 03: identifying and trying to find additional antibodies. [00:02:05] Speaker 03: It didn't even change the way Amgen went about trying to identify additional antibodies. [00:02:10] Speaker 02: I'm sorry, I didn't quite understand that. [00:02:12] Speaker 02: Before this, people were not using this 15 amino acid region in finding antibodies? [00:02:22] Speaker 02: I think I may have misunderstood what you said. [00:02:25] Speaker 03: Before this, they weren't using that. [00:02:27] Speaker 03: And after this, they weren't using that. [00:02:29] Speaker 03: See, just knowing that there happen to be 15 amino acids that make up the epitope doesn't help you find additional antibodies in any way. [00:02:39] Speaker 03: So as a practical matter, this didn't disclose anything useful. [00:02:44] Speaker 03: And of course, the other problem, of course, with simply identifying the amino acid structure of the epitope is that's not the invention. [00:02:51] Speaker 03: That's not what they claim. [00:02:52] Speaker 03: What they claim is essentially [00:02:55] Speaker 03: the entire genus of PCSK9 inhibitors. [00:02:58] Speaker 03: And the fundamental problem here is that when you describe, even in some detail, the epitope, and then you provide two species, that doesn't satisfy written description, we say, as a matter of law. [00:03:14] Speaker 03: But the particularly acute problem in the way the trial proceeded is we weren't even able to put on the critical piece of evidence that this court used in AbbVie [00:03:25] Speaker 03: to determine that there wasn't sufficient representation among the species. [00:03:29] Speaker 03: So if you look at page 1293 of the Fed 3rd, in the Abbey decision, there's a big chart that shows essentially how Stellara was very different from [00:03:39] Speaker 03: the disclosed antitrust. [00:03:40] Speaker 01: I understand that. [00:03:41] Speaker 01: There's a little confusion for me in the briefs in what you and your friend are saying as to whether or not the determination by the district court to not include that evidence was a legal determination because of how she construed, in your view, misconstrued our case law, or whether or not it was just an evidentiary determination. [00:04:02] Speaker 01: It would confuse the jury. [00:04:03] Speaker 01: It was irrelevant. [00:04:04] Speaker 01: It was cumulative. [00:04:05] Speaker 01: So how do you see her determination? [00:04:08] Speaker 03: We see her determination as based fundamentally on a fundamental misconstruction about rules of post-priority evidence. [00:04:17] Speaker 03: I'm happy to talk about why we think that is misguided to a fairly well. [00:04:21] Speaker 03: But just to be clear, the suggestion that there was some sort of alternative rule 403 alternative there is simply wrong. [00:04:29] Speaker 03: And under Third Circuit case law that I think would govern this particular question, it's reversible error for a district court to exclude [00:04:37] Speaker 03: on the basis of Rule 403 without going through the balancing that's actually required by Rule 403. [00:04:43] Speaker 03: So that evidentiary ruling can't stand on this sort of phantom alternative ground. [00:04:48] Speaker 03: It stands on a fundamentally misguided idea that, based, I guess, on this court's Hogan decision, or the prior court's Hogan decision, that you just can't have this kind of evidence of the accused antibody. [00:05:04] Speaker 03: And it wasn't just the accused antibody we wanted to show the jury. [00:05:06] Speaker 03: We also wanted to show other antibodies that were within the genus. [00:05:11] Speaker 03: And we wanted to show the jury how structurally diverse these were. [00:05:14] Speaker 03: And of course, as I alluded to, that was the critical evidence that this court relied on on page 1293 of its decision in ABVI. [00:05:22] Speaker 03: And I think that if we'd been able to show that, it would have fundamentally changed the determination. [00:05:28] Speaker 03: Because if you think about what the jury was asked to do here, they're asked to decide whether or not the two specific antibodies that are claimed [00:05:37] Speaker 03: And there's a debate whether it's 2 or 24, but there are two that you actually have the x-ray crystallology for and you know exactly where they bind. [00:05:45] Speaker 03: Well, they're asked to decide whether those two species are representative, looking only at those two species. [00:05:51] Speaker 02: Can I ask you, what is your view of what these might be representative of? [00:05:57] Speaker 02: It seems to me to say representative, you need another property. [00:06:02] Speaker 02: Otherwise, all you have is, I don't know how many amino acids long these things are. [00:06:07] Speaker 02: and every possible numerical combination, which is an extremely large number, and nothing would be representative of anything else. [00:06:13] Speaker 02: So what is the concept that might even theoretically lead you to say, OK, I've got the following 1,000. [00:06:20] Speaker 02: They're representative of 20 to the 64th or something power. [00:06:28] Speaker 02: What's the concept? [00:06:29] Speaker 03: Well, I think the concept that's supplied by Ariad is that they need to be representative of the structural diversity of the genus. [00:06:38] Speaker 03: Now, I think, as your question suggests, that when you do as Amgen did here and you claim a nearly infinite genus, you're going to have an awful lot of trouble finding representative species. [00:06:50] Speaker 03: But it wasn't foreordained that they claimed a genus that broad. [00:06:54] Speaker 02: Representative of structural diversity, it seems to me, I'm still not beyond [00:06:58] Speaker 02: the sheer number of 20 amino acids at possibilities at every one of however many spaces. [00:07:06] Speaker 02: What is it representative of? [00:07:09] Speaker 03: Well, here it's not. [00:07:11] Speaker 03: Maybe I can try to answer the question by hypothesizing what they could have claimed. [00:07:15] Speaker 03: What they could have claimed is they could have taken their two species that they actually did claim in the specification, and they could say, and we claim [00:07:25] Speaker 03: essentially every antibody that has 95% of the same structure. [00:07:30] Speaker 03: Now, if they'd done that, then you could at least, I think, argue that what they disclosed actually was representative of the genus that they claimed, because it would have that overlapping structure. [00:07:43] Speaker 03: But when you claim every single thing that binds to an epitope, then I think you're setting yourself up for failure. [00:07:50] Speaker 03: I mean, please don't blame me. [00:07:52] Speaker 03: I didn't set forth the terms of the claim of the genus. [00:07:56] Speaker 03: Amgen came in and they wanted to claim everything that was essentially that would block at the epitope. [00:08:03] Speaker 03: And I think they set themselves up for failure because I don't think they can identify a common structural feature of everything that binds at the site. [00:08:11] Speaker 02: What aspects of the difference in structure beyond its ability to bind does anybody care about? [00:08:20] Speaker 03: I have to stop you right there, because I don't think the ability to bind at the site is structure. [00:08:28] Speaker 03: I think it's function. [00:08:29] Speaker 03: I think it's the classic function that they've claimed here, which is what everyone was looking for. [00:08:34] Speaker 02: The function of blocking. [00:08:35] Speaker 02: I'll change the word aspect to property. [00:08:38] Speaker 02: What property of the structure, beyond the property of being able to bind to the epitope and then the second condition of the claim, namely the block, the PCSK9 from [00:08:50] Speaker 02: from interfering with the liver cells, does anybody care about? [00:08:55] Speaker 02: What did the evidence say? [00:08:56] Speaker 03: Traditionally, people have cared about the amino acid sequences. [00:09:00] Speaker 03: Why? [00:09:01] Speaker 03: Because that's traditionally how you've claimed essentially antibodies for years and years. [00:09:06] Speaker 03: And that maps on to how you claim small molecule drugs as well. [00:09:10] Speaker 03: You claim them by their chemical structure. [00:09:12] Speaker 02: Is there evidence in this case from presumably it would be your experts that say, [00:09:23] Speaker 02: Differences in the structure of PCSK9 binding antibodies could have different effects on human beings in the body when you give it to them as a medication. [00:09:36] Speaker 03: There actually is evidence to that effect. [00:09:39] Speaker 03: I don't know that it's actually ultimately material. [00:09:42] Speaker 03: In my view of the case, it may be material to you. [00:09:44] Speaker 03: There's a whole dispute below about the blocking properties of the various antigens. [00:09:49] Speaker 03: And, you know, we had, you know, essentially there was the issue that the two disclosed antibodies are, you know, allegedly edge blockers, which is to say, if you think about the 15 amino acids that make up the epitope, they sort of essentially bound on one edge or the other. [00:10:06] Speaker 03: And we, if we could have shown the jury this, which we couldn't, but, you know, our product, the accused product, praluin, actually happens to block in the center. [00:10:14] Speaker 03: And I believe that there was some testimony, certainly we would have been happy to proffer [00:10:18] Speaker 03: that there actually are some advantages to having a center blocker rather than an edge blocker. [00:10:23] Speaker 03: Now, honestly, I don't think that's relevant because I think what's relevant is the broader principle that you cannot claim everything that blocks on an epitope simply by describing the amino acids that make up the epitope and two species of antibodies [00:10:43] Speaker 03: that make up a nearly infinite genus. [00:10:45] Speaker 02: Let me just, I guess, ask what I keep thinking of as maybe the same question. [00:10:51] Speaker 02: Why should that be the rule that you have to specify the actual chemical structure, the amino acids, as opposed to if truly every single one of the trillions and trillions of polypeptides would in fact have a [00:11:11] Speaker 02: all the same properties of any interest anybody has been able to identify. [00:11:16] Speaker 03: Here's the answer, Judge Toronto, and I hope this is responsive. [00:11:19] Speaker 03: I mean, just because two substances, two antibodies, block at the site, that doesn't somehow make them biosimilars or fungible for all purposes. [00:11:29] Speaker 03: They are still very different chemical structures, and what we wanted to show, and weren't allowed to, is ours has a radically different structure, and it only shares 26 percent of [00:11:39] Speaker 03: the amino acid sequences in the CDRs. [00:11:41] Speaker 03: That's what we wanted to show. [00:11:43] Speaker 03: Now that can have all sorts of differences, and a great illustration of that is that Pfizer also had an antibody. [00:11:50] Speaker 03: This is discussed in the amicus brief. [00:11:52] Speaker 03: Pfizer also had an antibody that blocked at the site. [00:11:56] Speaker 03: The problem was that when Pfizer tried to take that antibody and tried to sort of manipulate it so it could be FDA approved, it failed the trials. [00:12:06] Speaker 03: And now imagine what would have happened [00:12:08] Speaker 03: if Pfizer had been the first one to identify the 15 amino acids on the epitope. [00:12:14] Speaker 03: You would now, instead of having two useful medicines on the market, you'd effectively probably have zero, because the party that had claimed the epitope would have been able to block everybody's antibody, even very different chemical antibodies, even though their antibody, their species, doesn't work as medicine. [00:12:34] Speaker 03: Now, we wouldn't want that in the small molecule space. [00:12:37] Speaker 03: It's a happy world that there are multiple statins on the market, but they all operate in the same basic way. [00:12:43] Speaker 01: Can I ask you about how we move on to a related question which deals with the jury instruction? [00:12:48] Speaker 00: Yes. [00:12:49] Speaker 01: I mean, it's a little troubling or a little hard when the district court essentially, in reaching her jury instruction, was plugging out sentences from opinions that some of us have written, including me, to then turn around and say she's wrong. [00:13:05] Speaker 01: Now your answer to that is, maybe correctly, that that was all dicta. [00:13:10] Speaker 01: And so that we can now disassociate ourselves from those remarks and say the instruction was wrong. [00:13:17] Speaker 01: But what more do we have? [00:13:18] Speaker 03: Well, I think you have more than that, Chief Judge Prost. [00:13:21] Speaker 03: I mean, first of all, I do think, and, you know, my friend on the other side describes this as nitpicking and is brief, but I don't think it is. [00:13:27] Speaker 03: And I think it maps on directly to what the court said in footnote four of Senate Corps, which is, [00:13:33] Speaker 03: Even if you're going to assume for a second that the newly discovered, newly characterized antigen instruction is good law. [00:13:41] Speaker 03: And I'd eventually like to tell you why it really is time to just end the madness and say it's not. [00:13:47] Speaker 03: But even if you assume that's good law, the key to making it work is that the generation of antibodies has to be routine. [00:13:56] Speaker 03: But as this court, I think, made crystal clear in Senate Court, [00:13:59] Speaker 03: And I think footnote four makes this point. [00:14:02] Speaker 03: What has to be routine is the generation of the claimed antibodies. [00:14:07] Speaker 03: And the word claimed, which I think is what is in this court's cases, was not in the instruction. [00:14:12] Speaker 03: And so if the question is, and it matters a lot because the generation of antibodies that don't actually block at the site, that don't have the characteristics, that is routine, I suppose. [00:14:23] Speaker 03: But to generate human antibodies that block at the desired site, [00:14:29] Speaker 03: That's not routine at all. [00:14:31] Speaker 03: And indeed, it's a process. [00:14:33] Speaker 03: It's an arduous process of trial and error that my clients were involved in, that Amgen was involved in. [00:14:40] Speaker 03: When Amgen came out with this invention, it didn't change what they did as a practical matter. [00:14:44] Speaker 03: They still had to engage in the same trial and error process. [00:14:48] Speaker 03: That was additional evidence that went to enablement, in our view, that we weren't able to put in front of the jury because of this misguided priority ruling. [00:14:55] Speaker 03: So the instruction doesn't follow this court's cases. [00:14:59] Speaker 03: And the distinction isn't a nitpick. [00:15:01] Speaker 03: It's absolutely critical. [00:15:03] Speaker 03: And I think it actually maps on to how I read this court's decision in Senate core, which is it said, well, that instruction doesn't apply here for among, I think, two reasons that are both fully applicable here. [00:15:15] Speaker 03: One is the generation of antibodies for human antibodies was not routine. [00:15:19] Speaker 03: That's footnote four. [00:15:21] Speaker 03: The other thing, of course, this court said there was that the relevant antigen wasn't newly discovered. [00:15:26] Speaker 03: Well, that's 100% true here. [00:15:28] Speaker 03: PCSK9 was not some invention of Amgen. [00:15:32] Speaker 02: Why, putting aside just the words of the prior presidents, why should there be a difference between newly discovered and newly characterized? [00:15:41] Speaker 03: Well, I misspoke. [00:15:42] Speaker 03: I mean, I don't think there is a difference, which is why I suppose I slipped from one to the other. [00:15:46] Speaker 02: The point is, they didn't newly characterize PCKS9. [00:15:50] Speaker 02: I thought you said the identification of the 15 listed amino acids was not known until this. [00:15:55] Speaker 03: The exact amino acid structure of it wasn't, but the idea that there was an epitope on PCSK9 was well understood. [00:16:03] Speaker 03: But of course, what the instruction in the case law talks about is not a newly characterized epitope, which is the 15 amino acids. [00:16:11] Speaker 03: It talks about a newly characterized antigen, which is PCSK9, the whole big thing. [00:16:17] Speaker 03: And that wasn't newly characterized at all. [00:16:19] Speaker 03: Everybody knew that was out there. [00:16:20] Speaker 03: Everybody was trying to do the same thing, which is to come up with a human antibody [00:16:25] Speaker 03: that blocked the interaction between PCSK9 and the LDL receptor. [00:16:31] Speaker 03: And both before and after this invention, that was a trial and error process that required essentially well-understood techniques, but techniques that were arduous and required trial and error. [00:16:43] Speaker 03: And the critical thing to understand here is just finding out that, OK, well, there's 15 amino acids that make up this particular epitope. [00:16:52] Speaker 03: That didn't make it any easier. [00:16:53] Speaker 03: It didn't change the way people were going about this. [00:16:56] Speaker 03: And again, it didn't even change the way Amgen was going about this, which is one of the many things we weren't able to put in front of the jury. [00:17:03] Speaker 03: I would like to just take a moment, though, to sort of say that I think this court in the Senate court decision, and I've reviewed the oral argument in that case, and I know it was a focus of the oral argument in that case, I think there's an excellent argument that at least if you're trying to transfer [00:17:19] Speaker 03: the newly characterized antigen and the so-called antibody exception to the human antibodies, it just doesn't work. [00:17:27] Speaker 03: It's based on a 1976 textbook, and the science just doesn't map on to the way the reality works today, at least if you're talking about human antibodies. [00:17:38] Speaker 03: As this court said in Seneca work, maybe it makes a little bit of logic to say that if you discover a keyhole, and that easily and routinely translates to one key, [00:17:48] Speaker 03: you can claim the keyhole and the key. [00:17:51] Speaker 03: But as this court put it in Senate Court, even if you have the keyhole, there's a ring out there with a million keys on it. [00:17:57] Speaker 03: And it really doesn't do you much good to simply describe the keyhole. [00:18:02] Speaker 03: And so I think for that reason, the science doesn't support it. [00:18:05] Speaker 03: I'd also like to make a humble point that the law doesn't support it. [00:18:08] Speaker 03: I mean, written description is a requirement that you describe the invention. [00:18:13] Speaker 03: The invention that's claimed here is an entire genus of antibodies. [00:18:17] Speaker 03: they don't claim that they invented the sweet spot or the epitope or the 15 amino acids nor could they in a post myriad world. [00:18:26] Speaker 03: So even, and again this is another aspect in which what's going on here is actually not what this court has talked about in its prior cases. [00:18:33] Speaker 03: This court talked about in its prior cases a hypothetical possibility where somebody could claim the newly discovered antigen and the antibodies that went with [00:18:43] Speaker 03: Now, in a post myriad world, I think it's common between the parties that you can't actually claim the epitope. [00:18:52] Speaker 03: No matter how many amino acids it makes up, it's in nature. [00:18:55] Speaker 03: You can't claim it. [00:18:57] Speaker 03: But if you're no longer claiming the antigen, then you've completely untethered what you're describing from what the statute requires you to describe. [00:19:07] Speaker 03: The statute requires you to describe your invention. [00:19:10] Speaker 03: The target of your invention, the problem you're trying to solve, [00:19:13] Speaker 03: is not your invention. [00:19:15] Speaker 03: And so no matter how much they describe in atomic level detail, as they like to say, the structure of the epitope, it doesn't matter. [00:19:25] Speaker 03: What they need to describe is their invention. [00:19:27] Speaker 03: What they claim is this entire genus of antibodies. [00:19:32] Speaker 03: And they haven't adequately described that. [00:19:34] Speaker 03: And just to go back to first principles, what AREA tells us is they have to show a common structure. [00:19:40] Speaker 03: There is no common structure. [00:19:42] Speaker 03: Or they can show it by these representative species, but as I alluded to earlier, it's representative species of the full structure that makes up the genus. [00:19:52] Speaker 03: And we don't think two can get that done. [00:19:55] Speaker 03: We think we should prevail as a matter of law based on the four corners of the specification. [00:19:59] Speaker 02: Can I just ask you before we sit down about the matter of law point? [00:20:02] Speaker 02: Sure. [00:20:03] Speaker 02: I haven't been able to find, do you have a case that says complete non-making of a 50A motion? [00:20:11] Speaker 02: Just not a matter of interpreting a couple of words, but just, you just never ever made a 50A motion by words or on paper. [00:20:21] Speaker 02: That that can be essentially excused on the ground that everybody knew this case was about sufficiency of the evidence. [00:20:28] Speaker 03: Yes, we have Third Circuit case law, and I think we cited it in our brief. [00:20:32] Speaker 03: I don't have it at the ready, but I will tell you that the case law that they cite in response to that, the Duralast case, doesn't help them at all. [00:20:39] Speaker 03: I mean, Duralast, I think, essentially drew exactly this distinction, which is to say, look, if things were being handled in a relatively informal way, and they were here in the sense that we had one-page briefs, and we were basically told, don't worry about it. [00:20:53] Speaker 03: I get your objection. [00:20:54] Speaker 03: It's preserved. [00:20:55] Speaker 03: When things are being done that way, the law in the Third Circuit, which is what's relevant here, says that you can, as long as you do something that sort of puts everybody at- That's right. [00:21:04] Speaker 02: I tried to frame my question as I'm not sure you did anything on this. [00:21:11] Speaker 03: But we didn't. [00:21:12] Speaker 03: We did. [00:21:13] Speaker 03: We essentially objected to the sufficiency of the evidence. [00:21:17] Speaker 03: We made clear that that was our objection. [00:21:19] Speaker 03: And we were essentially told by the district court judge, yeah, I got your objection. [00:21:24] Speaker 03: My point is there's nothing that sort of says it has to rise to this level of formality and then we'll take it the next step. [00:21:30] Speaker 03: You just have to do something essentially to apprise the court and then you can treat it as a constructive 50A motion. [00:21:37] Speaker 03: So we think we satisfy that. [00:21:40] Speaker 03: The Duralast case addresses something completely different. [00:21:42] Speaker 03: It's a situation where they filed a formal 50A motion and they just didn't include obviousness as one of the claims and then the court said, well, we can't stick it in there for you. [00:21:51] Speaker 03: And I think in a way that that distinction actually makes some sense, because certainly in terms of the role of the reviewing court, the first one really flows sort of directly from the degree of formality that the district court wants to sort of run his or her court with. [00:22:07] Speaker 03: And if they're doing this in a way that makes clear that everybody sort of gets the idea that the fundamental issue here is we don't think there's sufficient evidence. [00:22:14] Speaker 03: We've made this clear from the beginning, and we continue to make that clear. [00:22:17] Speaker 03: If the district court judge doesn't want formal motions on that, [00:22:20] Speaker 03: I mean, so be it. [00:22:21] Speaker 03: And I certainly think once she found in the J-Moll motion that we'd preserved it and then went on and addressed the merits for 16 pages, that ought to be enough for this court. [00:22:32] Speaker 03: In contrast, the Duralast situation, which this court also said isn't regional circuit law but federal circuit law, there, if you've got a 50-A motion, we can't put something in there that's not. [00:22:44] Speaker 03: That really doesn't address the same degree of deference to the district court. [00:22:47] Speaker 03: So I actually think that distinction makes a world of sense. [00:22:51] Speaker 01: I think we'll restore some rebuttal time. [00:22:59] Speaker 00: Good morning, and may it please the court. [00:23:08] Speaker 00: I have not done this before, but I think this is the rare case in which a demonstrative would actually be helpful. [00:23:13] Speaker 00: Which is to say, here's the structure. [00:23:17] Speaker 00: By the way, these are demonstratives that were used in front of the jury by [00:23:20] Speaker 00: Amgen's expert witnesses, they were 3D printed based on the x-ray crystallography provided in the patent. [00:23:26] Speaker 00: This is one of the antibodies in the patent. [00:23:29] Speaker 00: This is PCSK9. [00:23:32] Speaker 00: And in terms of what was actually discovered, when Amgen started its research, all that was known was that PCSK9 affected cholesterol in some way. [00:23:39] Speaker 00: It was not known how. [00:23:41] Speaker 00: Amgen determined, and the record shows the following first, that the effect was that PCSK9 bound to what's called the LDL receptor. [00:23:48] Speaker 00: and that had the ultimate effect through biological pathways of destroying the LDL receptor, which then led to higher cholesterol. [00:23:54] Speaker 00: Amgen determined that the part of PCSK9 that bounded the LDL receptor is what we're now calling the sweet spot, the part that's in pink here, the 15 epitopes out of almost 700. [00:24:04] Speaker 00: It then determined that this was antigenic, the sweet spot, meaning that an antibody could bind there. [00:24:10] Speaker 00: Amgen then developed specific protocols for creating [00:24:13] Speaker 00: monoclonal antibodies that would have the requisite structure to bind and characteristics to bind to the sweet spot. [00:24:20] Speaker 00: So if you take these, for example, this again, this is one of the antibodies in the patent. [00:24:26] Speaker 00: This is the PCS canine sweet spot. [00:24:28] Speaker 00: As you can see, they have peaks and valleys and ridges and nooks and crannies. [00:24:33] Speaker 00: And to fit together, they have to have the shape complementarity. [00:24:37] Speaker 00: They're two pieces of a three-dimensional jigsaw puzzle. [00:24:40] Speaker 00: So that for these to fit together, [00:24:43] Speaker 00: There's a larger piece that goes here. [00:24:45] Speaker 00: It touches there and then rolls over. [00:24:48] Speaker 00: And at that point, they come together very tightly, tightly enough to allow the chemical bonds to form, which is what then causes them to have affinity, to bind together instead of just bouncing off of one another. [00:24:59] Speaker 00: And that's why there is so much disclosure in the claims here. [00:25:03] Speaker 00: First, the claims refer to a monoclonal antibody, which is well understood to have the characteristic Y-shaped structure of a monoclonal antibody with constant and variable regions. [00:25:13] Speaker 00: Almost all of any antibody is the same. [00:25:16] Speaker 00: The main difference is here in the tips the business ends. [00:25:21] Speaker 00: And that is where you get the structure from that because the claims reference the structure of the sweet spot. [00:25:27] Speaker 00: And you then know as these two fit together that disclosing the structure of this gives you all of the important common structural features of this. [00:25:34] Speaker 00: That's how they fit together. [00:25:36] Speaker 04: But how do we know that those pink structures [00:25:40] Speaker 04: And the two you have in the patent are the same exact structures as all the other antibodies. [00:25:47] Speaker 04: I mean, are they all exactly that three-dimensional shape? [00:25:50] Speaker 04: Are they going to form the same way? [00:25:52] Speaker 04: Or do they touch on part, but not all of that structure? [00:25:56] Speaker 00: There can be differences, but they have to have the common structural features. [00:26:00] Speaker 00: It depends on which test we're talking about. [00:26:01] Speaker 00: But if we're talking about, say, common structural features, they all have the common structural features to allow this. [00:26:07] Speaker 00: And I should emphasize, [00:26:09] Speaker 04: But isn't it important if there are, I don't know, is this the case where there's like 15 of these things? [00:26:17] Speaker 04: Let me just make it even more simple because I'm going to get the science wrong if I try to even talk about it. [00:26:23] Speaker 04: If your position is that it doesn't have to match up 100% every single one, which I assume it is, that they don't all work exactly the same way, isn't it your [00:26:36] Speaker 04: do we need to show that the structures are sufficiently similar that they don't have any other kinds of effects or the like? [00:26:43] Speaker 04: Or are you just saying anything that hooks up with that is sufficient to show written description? [00:26:48] Speaker 00: No, it's not just anything. [00:26:49] Speaker 00: It's anything, again, there are the multiple tests for written description. [00:26:52] Speaker 00: I could roll through them. [00:26:53] Speaker 00: But in terms of, say, the middle one, common structural features, it doesn't mean that they're identical. [00:26:58] Speaker 00: It means that they share the common, that the disclosed antibodies have the common structural features that others would. [00:27:06] Speaker 04: What if you have one that only touches on the middle portion of that? [00:27:10] Speaker 04: And then you have one that touches on one end. [00:27:14] Speaker 04: They're still hooking up. [00:27:15] Speaker 04: Maybe they still are hooking up enough to function the way your patent explains. [00:27:19] Speaker 04: But is that a common structure? [00:27:21] Speaker 00: Because they do have to have them. [00:27:22] Speaker 00: And so, for example, if you look at the antibodies in the patent, and by the way, I'll say again, it's a question of fact. [00:27:28] Speaker 00: And Amgen's experts, Petsco and Reese, testified contrary to absolutely everything. [00:27:33] Speaker 00: that you heard from counsel earlier this morning. [00:27:35] Speaker 00: And that's substantial evidence the jury was entitled to credit. [00:27:38] Speaker 00: But if we roll through the tests. [00:27:41] Speaker 02: But just in terms of your example, where your claim says, assuming there are 15 little pink nodules on the, let's call that blue, that all you need on the YNs is something touching one of those. [00:27:58] Speaker 02: And the effect of that is that that blue thing will then not bind to the liver. [00:28:03] Speaker 02: So that, you know, you're not claiming only what fits nice and snug, right? [00:28:11] Speaker 02: Fitting like this, as long as it has the effect of blocking the liver binding, satisfies your claim. [00:28:19] Speaker 02: And you've claimed everything within that genus. [00:28:21] Speaker 00: Well, one of the important things that the experts testified about, too, though, is that these don't, you don't bind to just one residue. [00:28:28] Speaker 00: Your claim says you can. [00:28:30] Speaker 00: Well, the claims refer to, it depends on the claim. [00:28:32] Speaker 00: Some claims specify bonding to one residue. [00:28:35] Speaker 00: But the key point is that for these to get close enough for that to actually happen, for the chemical bonds to form, what we're talking about is complementing the surrounding region. [00:28:47] Speaker 00: You're not just going to bind to any one uptote. [00:28:49] Speaker 00: You have to find the surrounding region for sufficient chemical bonds to form for there to actually be binding. [00:28:55] Speaker 00: One of the record sites for that is appendix page 1256. [00:28:58] Speaker 00: Transfer page 608, line 22. [00:29:01] Speaker 04: But also, remember, in terms of- See, this is what I don't quite understand. [00:29:06] Speaker 04: Let's assume that the two you have bind at regions 1, 2, and 3. [00:29:11] Speaker 04: And that's the structure you can show based upon your patent and your specification, whatever the evidence you have. [00:29:18] Speaker 04: And they were precluded from showing that theirs all bind at 13, 14, and 15, which are completely non-overlapping regions. [00:29:28] Speaker 04: Why is that the same structure? [00:29:31] Speaker 04: And forgive me if I get the science wrong. [00:29:36] Speaker 00: I'm not going to fight the hypothetical. [00:29:38] Speaker 00: We don't agree with the premise there about completely. [00:29:40] Speaker 00: But in terms of the district court's ruling on this, which Judge Prost had asked about, the so-called fansome ruling on Rule 403 shows up in a couple places during the trial. [00:29:54] Speaker 00: But what the court explained [00:29:56] Speaker 00: And this is page 1157, to answer your question. [00:29:59] Speaker 00: Transfer page 20, it starts around... Line seven is the court explained that they didn't need specific examples to prove the absence of fact. [00:30:09] Speaker 00: Their experts testified that the sweet spot is this area that I just showed you. [00:30:16] Speaker 00: And they argued that exactly what you just said, which is that the specifically disclosed examples cover some parts of the sweet spot, not another. [00:30:24] Speaker 00: The district court pointed out, your expert's testified to that to prove the alleged absence of something, the alleged absence of something that binds to the middle, for example. [00:30:33] Speaker 00: You don't need to put in a specific example of a middle binder. [00:30:35] Speaker 00: And that's why she said this evidence would be cumulative, because they could make the same argument, they did make the same argument without specific examples. [00:30:43] Speaker 00: She then explained that it would also be confusing to the jury. [00:30:46] Speaker 00: Because the jury would then be in a situation, especially with the accused product in front of it, where it would naturally be inclined to compare. [00:30:53] Speaker 01: I understand, and those are transcript sites you gave us, but the memorandum order here, excluding the evidence, it's at 1030, the appendix, seems to me to be entirely based on her conclusion that the case law [00:31:10] Speaker 01: compelled her to exclude the evidence. [00:31:12] Speaker 01: It was all a legal argument, citing Hogan and Abbey and some other cases, I guess. [00:31:18] Speaker 01: Am I wrong about that? [00:31:19] Speaker 00: I agree with you that, if that's all there was, I would agree with you so far. [00:31:24] Speaker 00: This is the important thing. [00:31:25] Speaker 00: Before trial, she issued the two written opinions that cited the cases. [00:31:29] Speaker 00: During trial, when they kept trying to put this evidence in anyhow. [00:31:32] Speaker 01: And you were trying to put in some evidence too, right? [00:31:34] Speaker 01: I was confused in the transcript whether or not [00:31:37] Speaker 01: whether she was talking about your evidence sometime or their evidence, right? [00:31:41] Speaker 00: Our evidence was excluded before trial, along with their evidence. [00:31:46] Speaker 00: During trial, when they kept fighting this, and here would be one example, appendix page 1001, the very bottom of it, when the court was then revisiting this, she says, but again, this is an evidentiary question, not the general question that was read by the Federal Circuit in all the pieces they cited, including the Abbey case. [00:32:03] Speaker 00: I understand the principles. [00:32:05] Speaker 00: The question is how defendants tend to use it. [00:32:07] Speaker 00: She then goes on there, and then especially again on pages 11, 56 to 57, and a couple other places cited in her brief, to then treat this as a more nuanced, as an evidentiary question, as you saw the evidence coming in. [00:32:21] Speaker 00: And her opinion was that first this is cumulative, she said cumulative, because you don't need it to prove the absence of something. [00:32:27] Speaker 00: If you want to say that there are other amino acid sequences that aren't here, you don't need specific examples. [00:32:31] Speaker 00: If you want to say there are binding sites that aren't disclosed in here, you don't need specific examples. [00:32:36] Speaker 02: question is, as I think you acknowledge it is or at least can be, whether you have shown a sufficiently representative number of examples covered by your claimed class, representative of something or other. [00:32:58] Speaker 02: I'm not quite sure yet what. [00:33:03] Speaker 02: Why is it not important for [00:33:06] Speaker 02: the other side to be able to walk in some detail through an example to show, to be persuasive, look at just how different at the molecular level this is from that. [00:33:26] Speaker 02: Now, unless you're going to tell me the molecular level is really, really completely unimportant, and that's why I keep [00:33:36] Speaker 02: asking about what it means to be representative, because I'm not sure until I know the answer to that, how to evaluate the significance of the evidence that they were barred from putting up. [00:33:47] Speaker 00: Right. [00:33:47] Speaker 00: And we're talking about, I mean, generally speaking, representative of the diversity of the species within the genus, which I know is a fairly high-level statement. [00:33:55] Speaker 00: But that's why the application in any factual context is going to depend on the facts. [00:34:00] Speaker 00: And the testimony from Amgen's experts, this was disputed at trial, [00:34:05] Speaker 00: is that what's important is the three-dimensional structure. [00:34:07] Speaker 00: That's what affects binding. [00:34:09] Speaker 00: That's what affects blocking. [00:34:11] Speaker 00: Diversity in amino acid sequence beyond that is not important, and because you can have vastly different amino acid sequences that have exactly the same important common structural features. [00:34:21] Speaker 00: So for example, two of the antibodies, just to give you two pieces of evidence, two of the antibodies specifically disclosed in the patent are more than 50% different in terms of their amino acid sequences, but they co-bin, meaning they bind to the same area. [00:34:35] Speaker 00: Similarly, and that's at appendix pages 1276, 1162, Dr. Reese also gave an example of another situation based on Australian research, where antibodies with vastly different amino acid sequences had the same common structural features. [00:34:51] Speaker 00: The reason is this. [00:34:53] Speaker 00: If you write out the string of amino acids, what's important is then how they fold into a three-dimensional shape. [00:34:58] Speaker 00: And only some of the amino acids have anything to do with how it folds into a three-dimensional shape or with the chemical complementarity at the end. [00:35:05] Speaker 00: Which is why you can have two that are more than half different but still have the same relevant characteristics. [00:35:09] Speaker 02: So why shouldn't they have been able to show that their particular version or any other specific examples that they were able to dig up, whether it was the accused one or anybody else's, Lily's or somebody else's, [00:35:25] Speaker 02: fold really, really quite differently and yet bind to at least one of these 15 amino acids on PCSK9 and have the effect of blocking PCSK9 from binding to the liver receptor. [00:35:42] Speaker 00: Sure. [00:35:43] Speaker 00: Because one, it is cumulative, because they could still make that argument without a specific highly prejudicial example of a post-priority antibody. [00:35:51] Speaker 01: But isn't the highly prejudicial? [00:35:55] Speaker 01: The district court made no conclusions about it being highly prejudicial. [00:35:59] Speaker 01: I think she said it was confusing, right? [00:36:01] Speaker 01: Right. [00:36:01] Speaker 01: She said it would be, quote, confusing. [00:36:03] Speaker 01: There's a big difference between confusing and highly prejudicial, right? [00:36:07] Speaker 01: Confusing was because she said, well, you stipulated to infringement, so it would confuse the jury to bring this evidence in. [00:36:18] Speaker 00: Well, the rationale for confusing, I believe the court's understanding of why it would be confusing, [00:36:25] Speaker 00: is that the question is if it's, and this again is at page 2018, I think it combined with cumulative, which is that if you're looking at what happened after the fact, after the fact, after the fact, it's normally not considered relevant. [00:36:41] Speaker 00: US Steel, for example, held that it doesn't matter whether subsequent antibodies are discovered that have these wildly different properties because Section 112 was determined at the time of the invention. [00:36:51] Speaker 01: Well, that's the legal issue that's presented. [00:36:54] Speaker 00: That's the relevance. [00:36:55] Speaker 00: But even then, if you want to put in more evidence, it's not only cumulative accusing, it's also remember it was even handed. [00:36:59] Speaker 00: Because before trial, they persuaded her to exclude Amgen's evidence that one of the antibodies specifically disclosed in the patent was, in fact, a middle binder. [00:37:07] Speaker 00: That was Amgen's evidence. [00:37:08] Speaker 00: One of them in the patent was a middle binder. [00:37:10] Speaker 00: The characterization that it was a middle binder just didn't come until afterward. [00:37:13] Speaker 00: Once they got her to exclude that, she thought during the trial, as a matter of trial management discretion, that she couldn't let them put in [00:37:20] Speaker 00: contrary evidence having already excluded ours. [00:37:24] Speaker 00: And especially under this rule 403 balancing, she doesn't have to use the numbers 403. [00:37:27] Speaker 00: Under this rule balancing it gets cumulative and prejudicial, cumulative versus confusing, and then also even handed to both sides. [00:37:35] Speaker 00: This is a review for even higher than abusive discretion. [00:37:37] Speaker 00: The question is whether it's an arbitrary or irrational decision on the facts of the case. [00:37:40] Speaker 01: Where is the site to where she talked about how she had already excluded yours so it would be prejudicial? [00:37:49] Speaker 00: That comes in also on page 1157 of the Joint Appendix as one of them. [00:37:56] Speaker 00: Transcript page 219, going down around like 21. [00:38:01] Speaker 00: If I let this in, then in all fairness, I've got to let Amgen rebut it. [00:38:06] Speaker 00: And then she explains over and then continues on to transcript page 222 where she says, you know, I'm being swept away into yet another quagmire, where, again, she had already issued an even-handed ruling, even-handed decision. [00:38:18] Speaker 00: This is during the trial. [00:38:19] Speaker 00: And once they moved to exclude Amgen's evidence at some point and succeeded on that, as a matter for considerable discretion under Third Circle law, she didn't see any reason to go back on that. [00:38:34] Speaker 00: Now, in terms of the disclosure, if there's emphasis everything that was disclosed here, it's not just the 15 epitopes on the sweet spot. [00:38:45] Speaker 00: The disclosure is of several different things that all have to be considered together. [00:38:49] Speaker 00: And also, of course, we agree on JMAAL. [00:38:52] Speaker 00: It's clearly waived because there's nothing resembling a real 50A motion. [00:38:56] Speaker 00: And that's the holding of Duralast. [00:38:58] Speaker 00: It's a matter of law, no 50A motion, no JMAAL. [00:39:02] Speaker 00: It's a very fundamental precept that protects, among other things, as Duralast explained in the Seventh Amendment. [00:39:06] Speaker 00: If you're going to challenge whether a fact question goes to a jury, you have to do that before it goes to the jury. [00:39:11] Speaker 00: But on the facts of JMAAL, and again, it's the testimony of Drs. [00:39:14] Speaker 00: Reese and Pesco, [00:39:15] Speaker 00: that's so important here, I would encourage you to take a close look at it. [00:39:20] Speaker 00: But the disclosure here is of several different things. [00:39:23] Speaker 00: First, you have the 24 representative antibodies. [00:39:29] Speaker 00: The testimony is that those bind across the sweet spot. [00:39:32] Speaker 00: They talk about edge binders. [00:39:33] Speaker 00: What that means is that each of them touches contrary edges, but they also almost come together in the middle. [00:39:39] Speaker 00: They cover the sweet spot virtually perfectly. [00:39:41] Speaker 02: Is that what makes them representative, that collectively they cover [00:39:46] Speaker 02: most of the territory on the binding region of the PCSK9. [00:39:51] Speaker 00: It's an important point, a part of it. [00:39:52] Speaker 00: You have a very small region of PCSK9 and you have these 24 amino acids that factually you can determine they are representative because they all have the comostructural features and they cover nearly the entire sweet spot. [00:40:04] Speaker 00: They also represent seven different gene families and the expert testimony is that there's considerable sequence diversity there, that this amount of diversity is extensive. [00:40:12] Speaker 00: I'd also point out it's far more extensive than in any other [00:40:15] Speaker 00: antibody case that this court has ever seen, at least in one that's written in opinion. [00:40:19] Speaker 00: So if this isn't sufficient, then the upshot of their position seems to be you can never have meaningful pattern protection for antibodies, which may be the most important takeaway here. [00:40:28] Speaker 00: Because if antibody claims were limited to specific amino acid sequences, they'd be all but worthless. [00:40:33] Speaker 00: Because the power of antibody technology is such that once you have what Amgen set forth here, 24 specific examples, description of how to go make many more, [00:40:45] Speaker 00: and a comprehensive roadmap, as Dr. Reese testified, for how to use those 24 to go make thousands of others, then what you have is a situation where it's always easy for someone to take the disclosures of a patent, the high level of skill in the art, and then just go make some that are materially the same except they have different amino acid sequences. [00:41:05] Speaker 00: At that point, this lifesaving body of research would dry up because no one could spend $2 billion to develop a product if others could work around it that easily. [00:41:13] Speaker 00: That's part of what the well-characterized antigen test reflects. [00:41:17] Speaker 00: A couple points on that. [00:41:19] Speaker 00: First, this court expressly, quote, adopted it as, quote, precedent, as the court indicated in Noel. [00:41:25] Speaker 00: And second, the scientific basis for it is absolutely right because, as this court explained in Noel, it reflects the well-known structural characteristics of antibodies, the nature of antibody-antigen binding, and then the high level of skill in the art. [00:41:42] Speaker 00: In terms of structure, you know if it's a monoclonal antibody, it's going to have this basic structure. [00:41:46] Speaker 00: In terms of binding, you then know that the important variable part, the business end of the antibody, if once you have newly and well-characterized the antigen, which was done here, you then know it's the mirror image of this, the two pieces of a three-dimensional jigsaw puzzle. [00:42:03] Speaker 00: And then, armed with especially the closures of the patent and then also the very high level of skill in the art as of this point in time, [00:42:10] Speaker 00: People can then just go and make others. [00:42:13] Speaker 00: And it was also said that Amgen, after the fact, was still doing the same sort of essentially blind screening that was before. [00:42:19] Speaker 00: Not true at all. [00:42:21] Speaker 00: Here's what the patent actually discloses in terms of the comprehensive roadmap. [00:42:24] Speaker 00: There are a couple things that Dr. Reese testified to on this. [00:42:28] Speaker 00: First is that the patent discloses you can take one of the 24 representative antibodies and use it as a reference antibody to screen others. [00:42:36] Speaker 00: So instead of screening others blindly, you take others and see if they [00:42:40] Speaker 00: been with this one if they can both bind at the same time. [00:42:43] Speaker 00: If not, then they have overlapping binding sites, and that's shown in example 10 of the patent. [00:42:49] Speaker 00: Then if you want to confirm that it really does bind to the sweet spot, example 3 of the patent shows you how to then do a blocking test to confirm whether the new antibody would in fact cause the requisite blocking. [00:42:59] Speaker 00: And if you want to know exactly which residues it binds to within the sweet spot, you then do alanine scanning under example 19 of the patent. [00:43:05] Speaker 00: The other approach is to take one of these and make minor changes to it, which is especially where the ready evasion would come in if patents were as limited as they want them to be. [00:43:15] Speaker 00: There are two ways to describe them according to Dr. Reese and in the patent itself for that. [00:43:20] Speaker 00: The first is conservative substitutions. [00:43:23] Speaker 00: There are formulas and algorithms in the patent where you can substitute. [00:43:26] Speaker 00: Say I'll take out an amino acid and put in another one according to the formula. [00:43:30] Speaker 00: You know that will still work. [00:43:31] Speaker 00: That would get you out of the claim scope that they say is all you can have. [00:43:34] Speaker 00: There's also then CDR shuffling, which essentially means you take two reference antibodies and mix and match their parts according to formulas to get other antibodies that would work. [00:43:43] Speaker 00: And Dr. Reese testified that doing that, you can create thousands of other antibodies. [00:43:49] Speaker 00: Antibody protection, if that would get around a valid antibody patent, especially in the extensive disclosure here, it would be worthless. [00:43:56] Speaker 00: The area of research would have to dry up because you can't spend billions of dollars if you're not going to get meaningful patent protection. [00:44:01] Speaker 04: I'm going to stop you there. [00:44:02] Speaker 04: Can I just ask one more question? [00:44:04] Speaker 00: Sure. [00:44:04] Speaker 04: This is very, very, very simplistic, but given everything you just described about what the patent describes about how to do this and the like and how it all operates and things like that, am I understanding you? [00:44:18] Speaker 04: And if I'm not, then let's just move on because I don't want to get into a whole big mess, that your view is on this evidentiary issue, the fact that they can bring in different types of structures where they can point to they only have overlapping [00:44:33] Speaker 04: things in 20% versus 90% of the stuff is irrelevant because they all still operate in the same way. [00:44:43] Speaker 04: Sorry, I'm not sure exactly what the 20% or 90% is, but... Of the, I guess, amino acids. [00:44:49] Speaker 04: I think it was some kind of example he used. [00:44:53] Speaker 04: Yeah, sorry. [00:44:55] Speaker 04: It's the... All of the... The point [00:44:57] Speaker 04: But what they were trying to get in, the kind of evidence. [00:45:00] Speaker 04: Let me get rid of the 20 over 90%. [00:45:02] Speaker 04: They have evidence that they wanted to get in that they show this structure is so substantially different from yours that you haven't shown proper written description for the entire genus. [00:45:13] Speaker 04: Is your point that that structure is irrelevant to the written description claim of how this all works? [00:45:19] Speaker 00: The amino acid sequence is irrelevant because what matters is the actual structure of the business end of the antibody, which is not dictated [00:45:27] Speaker 00: You can have bacillus for amino acid sequences with the same structure, is one point. [00:45:31] Speaker 00: The other point, though, is that they were able to argue, as the district court said, it's cumulative. [00:45:35] Speaker 00: You can argue these points. [00:45:36] Speaker 00: You don't need specific examples to do that, which is at least within her considerable discretion. [00:45:42] Speaker 00: And then the other thing they wanted to put in, apart from the post-priority examples, sorry, I'll wrap it up, is this evidence of Amgen's third generation program, where they said that showed that Amgen later on was seeking a middle binder. [00:45:53] Speaker 00: But remember, she had already excluded Amgen's evidence that the patent included a middle binder. [00:45:58] Speaker 00: Thank you. [00:46:00] Speaker 03: I'll give you five additional minutes if you need it. [00:46:04] Speaker 03: Thank you, Your Honors. [00:46:05] Speaker 03: Just a few points in rebuttal. [00:46:06] Speaker 03: First of all, Judge Toronto, I think I gave my friends on the other side too much credit because Novartis had already disclosed 12 of the 15 amino acids on the binding site. [00:46:14] Speaker 03: Do you mind leaving those out for a second? [00:46:16] Speaker 03: I'd just like to make use of them. [00:46:18] Speaker 03: So they'd already disclosed 12 of the 15. [00:46:20] Speaker 03: So what this really added as to the structure of this was three more amino acid sites. [00:46:25] Speaker 03: But the reason I wanted to keep these out is this isn't the invention. [00:46:29] Speaker 03: It's fine that they describe three amino acid sites here that nobody knew about, but this isn't what they're claiming. [00:46:34] Speaker 03: This isn't what they're claiming either, at least not exclusively. [00:46:37] Speaker 03: To the extent this is rapatha, they claim that in a separate patent by amino acid sequence, which is the way most people do it in this space. [00:46:45] Speaker 03: They can have it. [00:46:46] Speaker 03: We have no beef with this. [00:46:47] Speaker 03: The problem is that this courtroom should be filled with a nearly infinite number of these yellow things with pink on them. [00:46:54] Speaker 03: Because that's how many are in the genus they claimed. [00:46:58] Speaker 03: And they completely precluded us from showing that the structure, which again, is not function. [00:47:04] Speaker 03: The fact that something has the pink site might mean that it has the function of binding. [00:47:08] Speaker 03: But the structure could be very different. [00:47:09] Speaker 03: I mean, they all have the basic Y shape, and everybody knows that. [00:47:12] Speaker 02: But they could be- Were you precluded from having your expert testify that there were an infinite number of such structures? [00:47:20] Speaker 02: Or were you merely precluded in saying, [00:47:24] Speaker 02: Here is an example that happens to be ours. [00:47:27] Speaker 02: Look at this. [00:47:29] Speaker 03: Our expert, we didn't have to have our experts say that there were a nearly infinite number of antibodies in the genus because that came from their expert, Dr. Petsco. [00:47:39] Speaker 03: So that was before the jury. [00:47:41] Speaker 03: But this gets to this issue of sort of cumulativeness or effect. [00:47:45] Speaker 03: I mean, this is being argued to a jury. [00:47:48] Speaker 03: A jury's being told that there's this sweet spot and [00:47:52] Speaker 03: We have one species that we've disclosed that parks here and one that parks on the other side. [00:47:58] Speaker 03: And to a jury that's not told that there's something else, that looks pretty representative. [00:48:03] Speaker 03: The fact that they're edge binder seems like a good thing, because they're on both edges. [00:48:08] Speaker 03: What could be more representative? [00:48:10] Speaker 03: Of course, if we were allowed to come in and show that no, actually there are multiple other antibodies that have been independently developed that have very different structural characteristics. [00:48:22] Speaker 03: They may not have this exact Y shape, they may fold a little different, but in all events, they bind in a very different place. [00:48:29] Speaker 03: And then if we were allowed to tell you what everybody in this field thinks of as part of the structure, which is the amino acid sequence, then, I mean, I love my friend's phrase, the business ends of these things, because that's exactly what our testimony focused on. [00:48:43] Speaker 03: And it showed that on the business end of Prelolent, there was only 26% overlap in the amino acid [00:48:51] Speaker 03: That's what we wanted to show the jury. [00:48:54] Speaker 03: Now, in terms of what would be most effective for the jury, would it have been 26%? [00:48:58] Speaker 03: Would it have been the fact that it parked right in the middle? [00:49:01] Speaker 02: I'm not a trial lawyer. [00:49:02] Speaker 03: I can't tell you that. [00:49:03] Speaker 02: Can I just ask this question? [00:49:04] Speaker 02: I guess I'm confused. [00:49:09] Speaker 02: The district court seemed to draw a line between post-priority date evidence and pre-priority date evidence. [00:49:16] Speaker 03: Right. [00:49:16] Speaker 02: Did there exist, or were you [00:49:19] Speaker 02: And were your experts allowed to testify that there existed structures that would meet the claim limitation and that they would bind, but they would look very, very different and maybe even bind on different, the middle as opposed to the wings. [00:49:39] Speaker 02: Were you not able to put in evidence that many, many different structures looking very different [00:49:47] Speaker 02: um, would satisfy the claim. [00:49:50] Speaker 03: I mean, our experts may have been able to say something about that constrained by the same post-priority ruling, which is fundamentally wrong. [00:49:58] Speaker 03: And if I can address that for a second, I mean, you know, we all know sort of, you know, a false consistency is the hobgoblin, et cetera. [00:50:05] Speaker 03: I mean, you know, Ariad specifically says that there's a problem with an inventor putting in post-priority evidence to make the written description something that it wasn't at the time. [00:50:15] Speaker 03: But nothing in ABVI or common sense suggests that if you have something that's in the claimed genus that structurally looks completely different from the only two disclosed species, that you can't get that before the fact finder. [00:50:33] Speaker 03: And in ABVI, there was an unresolved issue about anticipation. [00:50:38] Speaker 03: If there really were this cliff you fall off of, if it's post-priority, there's no way the court in ABVI would have considered that and made it the focal point [00:50:45] Speaker 03: of its decision at page 1293. [00:50:47] Speaker 03: And the way I think about it is this, which is if you had something that was in the claimed genus that was pre-priority, that would give you both an anticipation argument and a darn good argument that the disclosed species were not representative of the structure of the whole genus. [00:51:06] Speaker 03: If you have one of those that comes into being afterwards, it no longer shows anticipation, but it's every bit as relevant. [00:51:13] Speaker 03: as showing that at the time of the priority date, the written description showed something that they just didn't possess, because they need to show structure. [00:51:24] Speaker 03: Structure is not function. [00:51:26] Speaker 03: Binding at the site is the function that they've claimed. [00:51:30] Speaker 03: It's not structural. [00:51:31] Speaker 03: What's structural in this context is amino acid sequence, and we're not trying to limit them just to the amino acid sequence. [00:51:40] Speaker 03: though that is how they principally claimed Rapatha, and that is how we principally claimed Prelulent. [00:51:45] Speaker 03: As I pointed out in my opening argument, you can claim a genus if it's a genus of thousands, and that genus, if it's based on what you've disclosed in 95% homology, will avoid all of this substitution my friend talked about in evasion. [00:52:02] Speaker 03: That's the way you can claim a genus where you actually have a species that's representative. [00:52:08] Speaker 03: But you can't claim a nearly infinite genus based on a description of the epitope and two disclosed species. [00:52:17] Speaker 03: If I could just make two other points in rebuttal, my friend on the other side said that you don't have to invoke the number 403. [00:52:26] Speaker 03: Well, the third circuit in the Glass decision says that you do. [00:52:30] Speaker 03: And you have to do the balancing before you could exclude the evidence. [00:52:34] Speaker 03: As the chief judge indicated, I don't see how you could say that [00:52:37] Speaker 03: allowing us to disclose a radically different structure would be unduly prejudicial. [00:52:43] Speaker 03: And in the context of a trial where they have these two yellow things that represent their two disclosed species and we can't put on ours, I mean that's Hamlet without the prints. [00:52:55] Speaker 03: That is not cumulative. [00:52:57] Speaker 03: That would have made a huge difference both in a court of law but especially in front of a jury. [00:53:01] Speaker 03: The last point I want to make [00:53:03] Speaker 03: is, I actually really would like to just invite you to read Duralast. [00:53:07] Speaker 03: Because Duralast is a case that both involves a formal 50A motion that just omits one legal argument. [00:53:12] Speaker 03: And this court also said that because what was omitted was obviousness, it was going to apply its own law and not the circuit law, which Duralast itself recognized was more lenient. [00:53:22] Speaker 03: So Duralast is our case. [00:53:24] Speaker 03: So the point I wanted to end on is simply this. [00:53:27] Speaker 03: This whole idea that there is an antibody exemption, I think, is fundamentally misconceived. [00:53:33] Speaker 03: There isn't any antibody exemption in the relevant statute. [00:53:37] Speaker 03: And the rule here should be the same for large molecules as it is for small molecules. [00:53:42] Speaker 03: Nobody thinks that one company gets to make every statin just because they discovered the binding site. [00:53:49] Speaker 03: Nobody thinks that there should only be one AIDS protease inhibitor on the market just because one company described the binding site. [00:53:57] Speaker 03: Nobody thinks there should only be one COX-2 inhibitor on the market. [00:54:01] Speaker 03: The rule shouldn't be any different in the antibody [00:54:03] Speaker 03: Somebody, whether it's Amgen or Pfizer, whose product ended up not working as medicine, should not be able to corner the market on PCSK9 inhibitors, just because they described an additional three amino acids on the binding site and came up with two species that aren't representative of the entire species. [00:54:22] Speaker 01: Thank you. [00:54:22] Speaker 01: We thank both sides and the case is submitted. [00:54:25] Speaker 01: That concludes our proceedings.