[00:00:36] Speaker 00: Next case for argument is 151905, Merck-Sharp versus Xelia, pharmaceuticals. [00:00:44] Speaker 00: Mr. Zimmerman. [00:00:50] Speaker 04: May I proceed now? [00:00:52] Speaker 04: Yes, please. [00:00:52] Speaker 04: May it please the court. [00:00:53] Speaker 04: Good morning. [00:00:54] Speaker 04: Phil Zimmerman of Kenobi Martins on behalf of Xelia. [00:00:58] Speaker 04: The district court erred as a matter of law by construing the acetate buffer limitation [00:01:04] Speaker 04: to encompass subject matter that the applicants disparaged and relinquished throughout the specification and during prosecution, including the tartrate buffered formulations that are disclosed in the patent. [00:01:18] Speaker 04: And I'd like to begin with the prosecution history. [00:01:21] Speaker 00: But can we just begin? [00:01:22] Speaker 00: I mean, what is your view of what standards you need? [00:01:25] Speaker 00: Do you agree that the claim language is broad and does not limit acetate buffer in the way that you would like us to instill it? [00:01:32] Speaker 04: The claim language, when read in the context of the patent specification and the prosecution history, can't be given such a broad reading as to encompass acetate buffer that solely comes from the dissociation of the active ingredient caspofungin diacetate. [00:01:52] Speaker 00: But how would the parties have drafted the claim language to get them where you want to go? [00:01:57] Speaker 00: They would have had to include the word separately added by. [00:02:02] Speaker 04: or something akin to that. [00:02:04] Speaker 04: And they did not do that? [00:02:05] Speaker 04: They did not do that. [00:02:06] Speaker 04: And if you read the claim language acetate buffer in a vacuum, you could take a broad enough reading to cover that. [00:02:15] Speaker 04: But when you read it in the context of this specification and the way it's used, it's clear that they're talking about an added acetate buffer or a separate acetate buffer, not diacetate coming from [00:02:29] Speaker 04: the active pharmaceutical ingredient caspofungin diacetate and the specification only contains two types of formulations caspofungin diacetate with an added tartrate buffer and caspofungin diacetate with an added acetate buffer. [00:02:47] Speaker 04: The specification focuses on what the added buffer is. [00:02:52] Speaker 04: The briefs from Merck make it sound like the tartrate buffer [00:02:57] Speaker 04: is described in the specification or the prosecution history as a mixed buffer, as an acetate and tartrate buffer. [00:03:07] Speaker 04: There is not a single statement in the patent specification or in the prosecution history anywhere. [00:03:15] Speaker 04: What about the claim? [00:03:17] Speaker 04: The claim language says acetate buffer. [00:03:21] Speaker 04: And the question becomes, is that covered? [00:03:23] Speaker 02: It doesn't say an acetate buffer that's added separately. [00:03:26] Speaker 04: No, but if you look at the prosecution history, JA3886, you have the interview summary where the examiner says they showed unexpected results that acetate is a member of a genus and tartrate would destabilize. [00:03:48] Speaker 04: So what was the examiner comparing? [00:03:51] Speaker 04: The examiner tells us in the reasons for allowance. [00:03:55] Speaker 04: JA3889. [00:03:57] Speaker 04: The specification shows that tartrate buffer unexpectedly destabilizes the claimed peptides, while acetate has an unforeseen stabilizing effect. [00:04:10] Speaker 04: So he's comparing the tartrate examples in the specification to the acetate examples. [00:04:17] Speaker 04: The added buffer, added acetate versus added tartrate, [00:04:21] Speaker 04: And he says, you've shown unexpected results for one over the other. [00:04:26] Speaker 04: It can't be that you then get a claim that encompasses both when you show one has unexpected results compared to the other. [00:04:34] Speaker 04: And the specification confirms this. [00:04:36] Speaker 04: It says at JA 19, this is column 2, lines 23 through 30, the formulations of the invention provide enhanced chemical stability to the pharmaceutical compositions. [00:04:51] Speaker 04: It's not saying some stability. [00:04:54] Speaker 04: It's enhanced stability. [00:04:56] Speaker 04: Enhanced stability is lines 23 through 30 of column 2. [00:05:05] Speaker 04: The formulations of the invention provide enhanced chemical stability to the pharmaceutical compositions. [00:05:12] Speaker 04: So it's enhanced. [00:05:13] Speaker 04: Enhanced compared to what? [00:05:15] Speaker 04: If you read two sentences later, prior formulations employing a tartrate buffer [00:05:20] Speaker 04: contained pharmaceutically significant amounts of unwanted degradation products. [00:05:25] Speaker 04: So we have to have enhanced stability relative to the tartrate examples. [00:05:30] Speaker 04: And those tartrate examples, by Merck's own concession, contained both acetate and tartrate. [00:05:36] Speaker 03: And then the next sentence says the use of an acetate-buffered formulation results in the generation of fewer degradates and a more stable formulation. [00:05:44] Speaker 04: Exactly. [00:05:45] Speaker 04: It means the acetate-buffered formulation [00:05:48] Speaker 04: is not the tartrate buffered one. [00:05:50] Speaker 04: So you've got to use acetate buffers. [00:05:52] Speaker 04: You have to use an added acetate buffer or a separate one. [00:05:56] Speaker 00: But your friend tells us that just disparaging some alternative doesn't necessarily get you there and that you need a clear and unmistakable disclaimer. [00:06:06] Speaker 04: The specification in this case has repeated statements and you have the prosecution history where the examiner allowed the claim [00:06:15] Speaker 04: based on a comparison of the tartrate and the acetate example. [00:06:20] Speaker 04: If you look at, it spans column two and into column three, at lines 66 through 68 of column two, the patent's talking about the tartrate buffered formulation. [00:06:32] Speaker 04: Now, this is the one that Merck is telling us supposedly has a mixture of tartrate and acetate. [00:06:39] Speaker 04: It goes on in column three, lines one through four, to say, [00:06:43] Speaker 04: by switching to an acetate buffer. [00:06:47] Speaker 04: So you had these tartrate examples, and you switched to an acetate buffer. [00:06:52] Speaker 04: That has to mean that the tartrate formulations didn't have what this patent is calling an acetate buffer. [00:07:02] Speaker 02: And that's because the patent is not referring to... Just looking at that part of the specification, it says by switching to an acetate buffer, then it goes on, it creates a more stable [00:07:13] Speaker 02: product, you have less unwanted degrades. [00:07:17] Speaker 02: So this makes it attractive as a commercial product. [00:07:21] Speaker 02: That's not to say that. [00:07:23] Speaker 02: It says you can switch if you want, or you can add more if you want. [00:07:27] Speaker 02: But I'm still left with a claim that doesn't require that something additional be added. [00:07:34] Speaker 02: And the fact that something can be added, that you can add additional buffer, doesn't mean you have to. [00:07:41] Speaker 04: But if you look at the language, it says by switching to an acetate buffer. [00:07:47] Speaker 04: And the claim is to an acetate buffer. [00:07:50] Speaker 04: That means the Tartrate formulation didn't have an acetate buffer. [00:07:55] Speaker 04: You went from that formulation and switched to one that does have an acetate buffer as claimed here. [00:08:02] Speaker 04: And then you look at all of the examples. [00:08:05] Speaker 04: And the examples nowhere refer to the Tartrate examples as a mixed buffer. [00:08:11] Speaker 04: They're talking about what you put in. [00:08:14] Speaker 04: You put in the active ingredient and tartrate, or the active ingredient and acetate. [00:08:20] Speaker 04: And the specification tells us at column 8, line 65 through 67, it was surprisingly found that formulations 1, 5, 7, and 8, these are the ones that add acetate, were significantly more stable and showed significantly less of unwanted degradates [00:08:40] Speaker 04: than the other formulations. [00:08:42] Speaker 04: These are the ones with tartrate. [00:08:44] Speaker 04: This is the only data in the entire patent. [00:08:47] Speaker 04: These are what they're referring to as the unexpected results that were the basis for the examiner allowing this claim in the first place. [00:08:57] Speaker 04: So you can't look at the entirety of this specification and say that what they were talking about was caspofungin diacetate [00:09:06] Speaker 04: that dissociates in the presence of a tartrate buffer to create this acetate buffer. [00:09:11] Speaker 02: So understanding your argument, if I look at the prosecution history, where do I see a clear and unmistakable disclaimer? [00:09:18] Speaker 04: If you look at pages 3886 and 3889, it's the interview summary and the reasons for allowance. [00:09:29] Speaker 04: The examiner tells us you've shown unexpected results and [00:09:34] Speaker 04: Those unexpected results are in the specification. [00:09:39] Speaker 04: And so clearly, they showed unexpected results for one thing compared to another thing. [00:09:46] Speaker 04: And there's only two things in the specification. [00:09:48] Speaker 04: The caspofungin diacetate with an added acetate buffer and caspofungin diacetate with an added tartrate buffer. [00:09:58] Speaker 02: How is that a clear and unmistakable [00:10:01] Speaker 02: disclaimer of the acetate that's already in the compound. [00:10:08] Speaker 04: You have to show unexpected results compared to something. [00:10:12] Speaker 04: You can't look at this and say, there were unexpected results, but we didn't compare everything. [00:10:17] Speaker 04: You get everything in your specification. [00:10:21] Speaker 04: The examiner was clearly looking at this saying, you've shown unexpected results for one thing compared to another, and the only two things in the spec [00:10:30] Speaker 04: are tartrate and acetate. [00:10:33] Speaker 04: And that's consistent with what the patentee tells us at column 8, lines 65 through 67. [00:10:40] Speaker 04: The patentee says in the specification, it was surprising. [00:10:45] Speaker 04: It was unexpected. [00:10:46] Speaker 04: These are the unexpected results the examiner is looking at, that the one with added tartrate showed stability and the one with added acetate [00:10:56] Speaker 04: I'm sorry, the one with added acetate showed stability, and the one with added tartrate didn't. [00:11:02] Speaker 04: Well, if you look at what the specification says, and I'll go back to column two lines 23 through 30 again, they're not talking about some stability. [00:11:14] Speaker 04: The specification says the formulations of the invention, language that would suggest a disclaimer, provides enhanced chemical stability [00:11:23] Speaker 04: to the formulations, to the pharmaceutical compositions. [00:11:27] Speaker 04: They're not talking about some stability relative to the active ingredient itself. [00:11:32] Speaker 04: It says these have enhanced stability relative to some other composition. [00:11:37] Speaker 04: And then they tell us two lines later that that other composition is the tartrate buffered formulation. [00:11:44] Speaker 04: And the reason we end up in the situation we're in here is because during the prosecution of this patent, during the writing of this patent, [00:11:52] Speaker 04: Nobody paid any attention to the fact that when you take casco function diacetate and mix it with tartrate, you get this dissociation and salt exchange. [00:12:04] Speaker 04: That's not what this patent contemplated. [00:12:07] Speaker 04: You can read this patent backwards, forwards. [00:12:09] Speaker 04: You can read the entirety of the prosecution. [00:12:11] Speaker 04: There is not one word in there that suggests the tartrate example contains a mixed buffer. [00:12:20] Speaker 04: This patent was looked at like a recipe. [00:12:22] Speaker 04: And they said, this is the active ingredient we put in. [00:12:25] Speaker 04: This is the buffer. [00:12:26] Speaker 04: And they said, we want the added acetate buffer, not the other buffers, tartrate, lactate, phosphate. [00:12:34] Speaker 04: And so they merely went on their way. [00:12:36] Speaker 04: It wasn't until they had to encompass a product that used a different buffer, a succinate buffer, that this theory comes to light, that there is this salt exchange. [00:12:47] Speaker 04: And oh, yes, the tartrate buffered examples are covered. [00:12:50] Speaker 03: The rule is pretty strong against reading process limitations into a product claim. [00:12:57] Speaker 03: What case is strongest case for you, do you think, to warrant an exception here? [00:13:04] Speaker 03: Well, this is a case where, like one of our own Federal Circuit opinions. [00:13:11] Speaker 04: If I had to pick one, [00:13:21] Speaker 04: It would be the one that's cited in reply. [00:13:31] Speaker 04: Edward's Life Sciences, cited on page eight of our reply brief. [00:13:35] Speaker 04: But this is a case where, regardless of the standard, no matter how exacting you say it is, when you look at the entirety of the specification, the repeated statements that we switch to an acetate buffer, that the tartrate buffer doesn't give you enhanced stability, [00:13:52] Speaker 04: that the acetate examples showed enhanced stability. [00:13:56] Speaker 04: And then the basis of the allowance being a comparison based on the data in the spec, which only compares those two things, you can't read this as encompassing the tartrate examples of the patent. [00:14:10] Speaker 04: And so we would contend it's not reading in a process limitation, but it's giving the claim its due scope in view of the statements and the specification and the prosecution history. [00:14:20] Speaker 04: I see a minimum of my Republican time. [00:14:21] Speaker 04: Thank you. [00:14:30] Speaker 01: Mr. Nimrod. [00:14:30] Speaker 01: May it please the court? [00:14:32] Speaker 01: Ray Nimrod from Merck. [00:14:34] Speaker 01: Your Honor, Judge Ten, the Edwards case actually is not a process limitation case. [00:14:39] Speaker 01: So we asked a question about what case would he refer you to for the process limitation. [00:14:45] Speaker 01: We referred, Your Honors, to the Sanofi Aventis case, where [00:14:49] Speaker 01: The court stated that the specification never asserts that HPLC is required to obtain the optically pure explantan. [00:15:00] Speaker 01: And for that reason, there was no process limitation read in. [00:15:02] Speaker 01: In comparison to SHMA, which they cite in their brief and the reply brief says, the court reached this construction by reference to the prosecution history where Rhodia distinguished the prior art by emphasizing its claim that silica particulates [00:15:15] Speaker 01: could be obtained only by applying liquid pressure nozzle sprayers to the pulverized slurry. [00:15:22] Speaker 01: So the standard that the court applied was whether or not there was a statement saying the only way you could obtain what was required by the claim, the applicant said very explicitly, the only way you're going to get this is by doing a certain process. [00:15:34] Speaker 01: And that is not found here at all. [00:15:36] Speaker 01: Nowhere. [00:15:37] Speaker 00: Except for the claim language that refers to acetate buffer, can you point to anything in the intrinsic record? [00:15:44] Speaker 00: that suggests that this disassociation is what was covered by this claim? [00:15:50] Speaker 01: Yes, Your Honor. [00:15:51] Speaker 01: That would be the prosecution history, for example, if we go there. [00:15:53] Speaker 01: And I'd like to also go through the reasons for allowance. [00:15:57] Speaker 00: Anything in the spec before we get to the prosecution history? [00:15:59] Speaker 01: Well, the specifications read from the viewpoint of people skilled in the art, Your Honor. [00:16:02] Speaker 01: In the SALT exchange that we were talking about, all the experts agreed that occurred. [00:16:07] Speaker 01: So when a person skilled in the art is reading these examples, they understand that when you put a tar trade buffer in, [00:16:12] Speaker 01: to a system that has an acetate salt that the exchange takes place, and therefore all these examples have a mixed system unless they're pure acetate. [00:16:20] Speaker 00: So you read the specification and you say that anything that just has a tartrate buffer is also infringing. [00:16:27] Speaker 00: That that's also covered by the claim. [00:16:29] Speaker 01: Your Honor, it would be if there's an acetate salt being used, yes. [00:16:31] Speaker 01: And that was not disputed at all. [00:16:33] Speaker 00: And that's the way one skilled in the art would read all of these disparagement might be too common, but all of these views about how [00:16:41] Speaker 00: Tartrate buffers don't work, and we're switching in acetate buffers for tartrate buffers to accomplish this. [00:16:47] Speaker 01: It doesn't say that tartrate buffers won't work. [00:16:50] Speaker 01: In fact, what it says in column two is that when you added the tartrate buffer, the composition became relatively stable. [00:16:57] Speaker 01: And then when you go to column three, it says that, in fact, when you add more acetate, [00:17:01] Speaker 01: It becomes even better and suitable for commercial product. [00:17:04] Speaker 03: Well, wait a second. [00:17:06] Speaker 03: Add more acetate. [00:17:07] Speaker 03: I mean, it said switching from a tartrate buffer to an acetate buffer. [00:17:12] Speaker 03: And when it talked about the tartrate buffer, it talked about, yes, while relatively stable, resulted in the generation of degradates at a relatively high rate. [00:17:22] Speaker 03: And then, as your proposing counsel pointed out, towards the end of the written description, [00:17:29] Speaker 03: After going through all the examples, the ones with the Tartrate buffer and the ones using the acetate buffer, the windup of the spec is it was surprisingly found that formulations 1, 5, 7, and 8, the acetate buffer ones, were significantly more stable and showed significantly less of the unwanted degradates than the other formulations, i.e. [00:17:54] Speaker 03: the Tartrate formulations. [00:17:55] Speaker 03: To me, the comparison there is pretty clear [00:17:59] Speaker 03: that what these people are happy about and what these people have discovered is that the use of an acetate buffer, surprisingly, they don't know why and they don't know how, is producing a composition that is way more stable compared to other uses of other buffers, as well as something that gets away from all the unwanted degradation. [00:18:26] Speaker 01: explain this from the viewpoint of people skilled in the art. [00:18:28] Speaker 01: What this is teaching is that when you have no acetate buffer, it was highly unstable. [00:18:34] Speaker 01: Then we use an acetate salt, and you had a tartrate buffer. [00:18:37] Speaker 01: It improved for some reason. [00:18:38] Speaker 01: And this is the development. [00:18:39] Speaker 01: None of this is prior art in terms of using the tartrate buffer. [00:18:42] Speaker 01: What it's showing is how the inventors came about discovering that acetate buffer was the key, however it got there. [00:18:47] Speaker 01: So they found no buffer at all, highly unstable. [00:18:52] Speaker 01: They put in an acetate salt and a tartrate buffer, [00:18:55] Speaker 01: And all the experts agree that means there's going to be a mixed buffer system. [00:18:57] Speaker 01: There was no dispute on that at trial at all. [00:18:59] Speaker 01: Everybody agreed that would happen. [00:19:01] Speaker 01: And it got better for some reason. [00:19:02] Speaker 01: So in their development process, what they did, and it's just found in the prosecution history. [00:19:06] Speaker 00: OK, it got better. [00:19:07] Speaker 00: And then what did they claim? [00:19:08] Speaker 00: Was it good enough to be what you say they claimed? [00:19:10] Speaker 01: Well, the claim says there has to be an acetate buffer. [00:19:12] Speaker 01: There's no limitation on degrevens. [00:19:14] Speaker 00: Well, how come? [00:19:15] Speaker 00: Going back to column two, which is titled Detailed Description of the Invention, the formulations of the invention provide enhanced chemical stability. [00:19:25] Speaker 00: to the pharmaceutical compositions. [00:19:28] Speaker 00: And then it says, prior formulations employing a tartrate buffer contain pharmaceutically significant amounts of unwatered degradation. [00:19:37] Speaker 00: The use of an acetate buffer results in the generation of fewer degregates and a more stable formulation. [00:19:43] Speaker 00: Extended pharmaceutical shelf life offers significant economic advantages. [00:19:47] Speaker 00: They are talking about the invention. [00:19:49] Speaker 00: What in there can I read to say that the tartrate buffers are included in this invention? [00:19:54] Speaker 01: It's not the tartrate buffers. [00:19:56] Speaker 01: The question is whether acetate buffers are included. [00:19:59] Speaker 01: Right. [00:19:59] Speaker 03: But the way the spec talks, it talks about prior formulations using a tartrate buffer had problems. [00:20:09] Speaker 03: The inventions formulations using an acetate buffer has advantages. [00:20:13] Speaker 01: Well, the way it actually goes, Your Honor, is it says that the formulations were highly unstable. [00:20:17] Speaker 01: They added a tartrate buffer, and it was improved. [00:20:20] Speaker 01: And then they added more acetate by going to one which had an acetate salt. [00:20:24] Speaker 03: I wish you wouldn't call it more acetate. [00:20:26] Speaker 01: They added an acetate buffer in addition to having the acetate salt, Your Honor. [00:20:30] Speaker 01: And they also did other tests that are shown in the prosecution issue at A3812, where they say that when they use the Tartrate buffer, it improves stability relative to the neat drug. [00:20:40] Speaker 01: And then they ran a test. [00:20:41] Speaker 01: So this is how the whole discovery took place. [00:20:44] Speaker 01: The inventors put in the Tartrate buffer, [00:20:46] Speaker 01: with the acetate salt, and they saw an improvement. [00:20:48] Speaker 01: So what did they do? [00:20:49] Speaker 01: As shown at A3812, they went from this relatively stable formulation with 50 millimoles of tartrate buffer and went to 100 millimoles, thinking, well, we'll have more tartrate. [00:20:59] Speaker 01: It'll be better. [00:21:00] Speaker 01: It actually got worse. [00:21:02] Speaker 01: And from that, they concluded that the acetate buffer was the key. [00:21:05] Speaker 01: In other words, you had this mixed system. [00:21:06] Speaker 01: They assumed it was the tartrate that was doing the work, but it wasn't. [00:21:10] Speaker 01: So then they added acetate buffer after that. [00:21:12] Speaker 01: And they found that, yes, it is the acetate buffer that is, in fact, giving us the stability. [00:21:16] Speaker 03: The spec itself, which represents what the inventors knew at the time of this invention and the time they filed their plans, says in the windup that it was surprisingly found that when you use an acetate buffer, it's significantly more stable than when you use tartrate buffer. [00:21:35] Speaker 03: So the idea is, especially when it refers to [00:21:41] Speaker 03: the compositions using tartrate buffers as prior formulations, it's really leaning towards telling us that the invention is. [00:21:51] Speaker 03: Surprise, using acetate buffer is really exceptional. [00:21:58] Speaker 01: What it's doing is telling the person what is in fact giving them improved stability. [00:22:02] Speaker 01: Prior formulations here, there's no dispute, that's not prior art. [00:22:05] Speaker 01: This is just the inventors [00:22:07] Speaker 01: development story. [00:22:08] Speaker 01: When they went along, they used the tartrate buffer and discovered there was some improvement. [00:22:12] Speaker 01: And then they went on with their research to find out that that system that had acetate buffer in it, the reason it was getting better was because of the acetate buffer. [00:22:19] Speaker 01: And if we read the reasons for allowance, I think it's very important here to understand what the examiner was saying. [00:22:24] Speaker 00: But you're saying they claim that the tartrate buffer is included within the scope of this claim. [00:22:29] Speaker 01: We have a comprising claim, Your Honor. [00:22:31] Speaker 01: So acetate, we're not saying an acetate buffer is in fact a tartrate buffer. [00:22:35] Speaker 01: And in fact, they don't use tartrate in their product. [00:22:37] Speaker 01: There's a disavowal, which they didn't even raise below. [00:22:39] Speaker 01: It may apply to a tartrate buffer, but that's not even disavowed, because the claim is directed to having three components, one of which is an acetate buffer. [00:22:48] Speaker 01: The only question for infringement is whether or not you have an acetate buffer. [00:22:52] Speaker 01: You can have another ingredient, because it's a comprising claim. [00:22:54] Speaker 01: It's a composition claim that requires three elements, and it is a comprising claim. [00:22:59] Speaker 01: So if you take a tartrate buffer, [00:23:03] Speaker 01: and mix it with a diacetate salt, and there is this salt exchange, and all the experts agreed you'll have some acetate buffer and some tartrate buffer. [00:23:12] Speaker 01: We are not saying that tartrate buffer is what is called for by the claim. [00:23:15] Speaker 01: We're saying the acetate buffer meets element C, and whether or not you have additional buffer doesn't matter, because it's a comprising claim. [00:23:22] Speaker 01: And that's what was going on with those tartrate examples. [00:23:25] Speaker 01: They mixed them, they got better stability, and they had two buffers in there. [00:23:28] Speaker 01: So they ran tests, and the tests showed that the tartrate was not the thing that was doing it. [00:23:32] Speaker 01: It was making it worse. [00:23:33] Speaker 01: So the claim is a broad claim to three elements, one of which is an acetate buffer. [00:23:38] Speaker 01: And we are not alleging, we have never alleged, that the tartrate buffer is an acetate buffer. [00:23:43] Speaker 01: We had to prove, and we did prove, that in fact there was an acetate buffer present in their product. [00:23:49] Speaker 01: If they had another buffer present as well, that wouldn't matter, because it's a comprising claim. [00:23:55] Speaker 00: I cut you off before your time runs out. [00:23:57] Speaker 00: Are you going to tell us about the prosecution history? [00:23:59] Speaker 01: I was just going to read the reasons for allowance, Your Honor. [00:24:03] Speaker 01: In the prosecution history, the applicants submitted a paper explaining their research. [00:24:08] Speaker 01: And at A3812, they explained that when they added this tartrate to this diacetate salt, they got improved stability relative to the neat drug. [00:24:17] Speaker 01: And they go on and describe this experiment where they added more of the tartrate buffer. [00:24:21] Speaker 01: And they concluded, in addition, increase in tartrate concentration to 100 millimoles enhanced the instability. [00:24:28] Speaker 01: And they go on and then add [00:24:30] Speaker 01: a separate acetate buffer, and get things even better. [00:24:33] Speaker 01: So from that, they concluded the acetate buffer is the key. [00:24:37] Speaker 01: You can have other things, but the claim says, as long as you have an acetate buffer, you are infringing. [00:24:41] Speaker 01: And in the reasons for allowance, here's what the examiner said. [00:24:45] Speaker 01: He didn't say, I understand that the tartrate examples are disclaimed, that they're not covered. [00:24:49] Speaker 01: He said, Remington's teaches that acetate is a member of, excuse me, this is at A3889, is a member of a genus of buffers, [00:25:00] Speaker 01: that are suitable for dissolving compounds for subsequent lyophilization. [00:25:04] Speaker 01: However, applicant has demonstrated that the species of the genus are not equivalent. [00:25:09] Speaker 01: The specification shows that tartrate buffer, the tartrate buffer, not the examples, not everything in that example, the tartrate buffer unexpectedly destabilizes the claims of the peptide, while acetate has the unforeseen stabilizing effect on the formulation. [00:25:24] Speaker 01: What the examiner understood based on the experiments that have been shown to him was that [00:25:29] Speaker 01: The tartrate buffer itself was destabilizing. [00:25:32] Speaker 01: The acetate buffer was the key. [00:25:34] Speaker 01: If you had acetate buffer, you were going to get the positive effect. [00:25:36] Speaker 01: And that is what the claim, in fact, covers. [00:25:39] Speaker 03: What about 8383-84? [00:25:42] Speaker 03: This is a response to, or maybe this is your notice of appeal to the board, where you disputed the obviousness type double patented rejection by pointing out that [00:25:59] Speaker 03: The whole course of the prosecution history was the examiner saying it would be obvious to use an acetate buffer to buffer these kinds of compositions. [00:26:08] Speaker 03: And then your side kept pushing back and then saying, you know, how do you choose the right buffer? [00:26:16] Speaker 03: And there's more going on in using the acetate buffer here than controlling the pH of the solution. [00:26:23] Speaker 03: And then at the bottom of 3883, [00:26:27] Speaker 03: If one skill in the art would not expect acetate acid to be an effective buffer for the formulation of the invention period, the use of an acetate buffer is clearly doing more than merely buffering the formulation. [00:26:39] Speaker 03: It would not be obvious to one ordinary skill in the art. [00:26:42] Speaker 03: So again, this seems to underscore that your push that the use of an acetate buffer [00:26:50] Speaker 03: in creating these compositions is what the invention is and why it's not obvious to do it because, number one, it has a pH that's far away from the pH of the caspofungin diacetate, but also it has all these surprising results. [00:27:08] Speaker 01: Well, Your Honor, when you take caspofungin diacetate and mix it with a tartrate buffer or, in their case, a succinate buffer, let's focus on that, you are using an acetate buffer and you have acetic acid. [00:27:19] Speaker 01: The science shows that [00:27:20] Speaker 01: I think we should understand there's the three steps of making this product. [00:27:23] Speaker 01: First, you make a bulk solution. [00:27:26] Speaker 01: That's prior to localization. [00:27:27] Speaker 01: And the patent talks about different ways of getting an acetate buffer in there. [00:27:31] Speaker 01: There's some that are formed in situ, for example. [00:27:33] Speaker 01: You can add sodium acetate, which is not an acetate buffer. [00:27:37] Speaker 01: But when you put it in a bulk solution, when you put in the API and other ingredients, it forms an acetate buffer. [00:27:43] Speaker 01: So it's not like you have to get the acetate buffer to use it. [00:27:47] Speaker 01: that you have to add in something that says on the label, acetate buffer. [00:27:50] Speaker 01: You can put in, for example, sodium acetate. [00:27:52] Speaker 01: That's not an acetate buffer. [00:27:53] Speaker 01: It forms in situ. [00:27:55] Speaker 01: So you're forming a bulk solution, and you want to get an acetate buffer in there to get the benefits of the acetate buffer when you lyophilize. [00:28:02] Speaker 01: You want to use an acetate buffer. [00:28:04] Speaker 01: So the bulk solution is you put in the caspifunginae acetate, for example, a succinate, and the acetate buffer forms in situ. [00:28:11] Speaker 01: No dispute. [00:28:12] Speaker 01: There's acetic acid in there. [00:28:13] Speaker 01: And there's acetate anion. [00:28:14] Speaker 01: There's an acetate buffer present in that bulk solution. [00:28:18] Speaker 01: Then, and this is critical, you lyophilize. [00:28:20] Speaker 01: The key thing about lyophilizing is you have to have an acetate buffer present. [00:28:24] Speaker 01: And when you do that salt exchange, you do have an acetate buffer present. [00:28:28] Speaker 01: You are using an acetate buffer. [00:28:30] Speaker 01: And you're getting the benefit of the invention. [00:28:31] Speaker 01: That's all that is required. [00:28:32] Speaker 01: So the bulk solution says, get me an acetate buffer in there somehow. [00:28:36] Speaker 01: Whether it's with sodium acetate, acetic acid, as long as I have that acetate buffer, I use that. [00:28:41] Speaker 01: And then I lyophilize, I get this [00:28:43] Speaker 01: For some reason, no one knows why you get this great stability upon storage. [00:28:48] Speaker 01: And storage is always done in a lyophilized state. [00:28:51] Speaker 01: So you are using an acetate buffer when you have this salt exchange take place. [00:28:56] Speaker 01: And all the experts agreed on that, that that bulk solution has an acetate buffer in it. [00:29:01] Speaker 01: And it's going to give you the benefits if you're using it at that point. [00:29:04] Speaker 01: The other side said in the reply brief that it says to formulate in the presence of an acetate buffer. [00:29:09] Speaker 01: And we said, well, lyophilization, that's part of the formulation. [00:29:12] Speaker 01: You're using the acetate buffer. [00:29:14] Speaker 01: for lyophilization. [00:29:14] Speaker 01: They said, well, that's not part of the formulation. [00:29:17] Speaker 01: But in fact, the part of the specification they rely on in that says, and it's the part your honor's been talking about, the pharmaceutically acceptable salts are significantly more stable on storage. [00:29:28] Speaker 01: This is in column two, lines 54 to 56. [00:29:31] Speaker 01: They're more stable on storage when formulated in the presence of an acetate buffer. [00:29:37] Speaker 01: That, in fact, is the lyophilized formulation. [00:29:39] Speaker 01: It's not a solution. [00:29:40] Speaker 01: Storage, in this patent, every single time it's stored, it's stored as a lyophilized cake. [00:29:45] Speaker 01: You can't store this as a solution. [00:29:47] Speaker 01: So you make that bulk solution. [00:29:49] Speaker 01: And the critical thing is to have an acetate buffer present. [00:29:52] Speaker 01: Have some acetic acid and acetate anion. [00:29:54] Speaker 01: And if you have that, and then you do your lyophilization, you're going to get the benefits of the invention. [00:29:58] Speaker 01: So in every instance we've been talking about, no matter how the acetate buffer is formed, it ends up in the bulk solution. [00:30:05] Speaker 01: And it ends up being used in the bulk solution. [00:30:07] Speaker 01: And then it gets lyophilized and gives you the benefits. [00:30:10] Speaker 01: It doesn't matter to the bulk solution how the acetate buffer got there. [00:30:14] Speaker 01: And I'd like to give one example that we mentioned in our brief, and they're expert agreed with, which was if I take caspifungin tartrate and I add an acetate buffer, I put it in bulk solution. [00:30:26] Speaker 01: Before allophilization, there will be an acetate buffer present in there, acetic acid and acetate anions. [00:30:32] Speaker 01: They'll be present. [00:30:33] Speaker 01: Then you'll allophilize. [00:30:34] Speaker 01: You get the benefit of the invention. [00:30:36] Speaker 01: If I do the exact same thing, but instead I put a caspifungin diacetate salt in, [00:30:40] Speaker 01: and put in a tartrate buffer, you put in a bulk solution, and they do this exchange. [00:30:44] Speaker 01: You get the identical bulk solution in both instances, A and B. In one instance, you added the buffer. [00:30:51] Speaker 01: In one, you did not add the buffer. [00:30:52] Speaker 01: It came in and formed in the bulk solution. [00:30:54] Speaker 01: In both instances, you liophilize. [00:30:57] Speaker 01: You'll be using an acetate buffer. [00:30:58] Speaker 01: You get the benefit of the invention. [00:31:00] Speaker 01: Everybody agrees that takes place. [00:31:02] Speaker 01: In fact, their expert, Dr. Myrtle, agreed when I cross-examined him, saying, yes, I agree that that, in fact, would take place. [00:31:08] Speaker 01: And that's at A34, 79 to 82. [00:31:10] Speaker 01: That if I start with the salt of the tartrate versus the salt of the acetate, I get the exchange. [00:31:17] Speaker 01: They're identical. [00:31:17] Speaker 01: It's the same bulk solution. [00:31:19] Speaker 01: Yet according to Zellie's interpretation, one would infringe and one would not infringe. [00:31:24] Speaker 01: The Lafayette's cake would be exactly the same. [00:31:26] Speaker 01: The reconstit solution would all be the same. [00:31:29] Speaker 01: You're using an acetate buffer. [00:31:32] Speaker 01: no matter how you form it, as long as it gets in the bulk solution. [00:31:35] Speaker 01: And this is being read by persons skilled in the art. [00:31:37] Speaker 01: They're saying, well, there's no talk about a mixed buffer. [00:31:40] Speaker 01: A person skilled in the art reading this knows that where this salt exchange is not some novel thing. [00:31:45] Speaker 01: As soon as that acetate salt goes in and a tartrate buffer goes in, they know that, in fact, there's an exchange. [00:31:50] Speaker 01: You're going to have a mixed buffer system. [00:31:52] Speaker 01: And then the inventor said, boy, I guess it's probably the tartrate. [00:31:55] Speaker 01: They found that it wasn't the tartrate. [00:31:56] Speaker 01: It was the acetate. [00:31:58] Speaker 01: And that's what the claim goes to. [00:31:59] Speaker 01: The claim says you just have to have an ashtate buffer. [00:32:02] Speaker 01: It doesn't matter how you get there. [00:32:04] Speaker 01: There's no disclaimer saying that you have to do it via a certain process. [00:32:08] Speaker 01: It just says, get it in the bulk solution. [00:32:09] Speaker 01: If you have an ashtate buffer and it has an effective to provide the pH, then you are, in fact, infringing and covered by the claims. [00:32:17] Speaker 00: Thank you. [00:32:20] Speaker 00: I'll give you four minutes to try to keep it even. [00:32:29] Speaker 04: I will be brief. [00:32:30] Speaker 04: I just want to make four quick points. [00:32:32] Speaker 04: In response to Judge Chen's earlier question about case, I was looking at a disclaimer case. [00:32:38] Speaker 04: That's why I cited Edwards. [00:32:39] Speaker 04: On pages three and four of our reply brief, we address the process issue. [00:32:44] Speaker 04: And the non-precedential Sanofi case that they cite makes clear that there are situations where you can and situations where you can't read a process limitation in, if you want to call it that, based on the spec, the prosecution history, the entirety of the intrinsic record. [00:32:59] Speaker 04: The story that you just heard about this was the invention story, and everybody knew it was a mixed buffer, and everybody would have assumed it was the Tartrate, and a site to JA 3812 of the prosecution history, none of that's in the intrinsic record. [00:33:17] Speaker 04: There isn't a statement anywhere in the prosecution history. [00:33:21] Speaker 04: He was asked directly. [00:33:22] Speaker 04: Merck doesn't have any statement to show a mixed buffer or to say that the Tartrate example [00:33:29] Speaker 04: was understood to be a mixed buffer in the written documents. [00:33:33] Speaker 04: There is none. [00:33:34] Speaker 04: What the patent talks about and the prosecution history talks about is the active ingredient caspofungin diacetate and what you add to it as a buffer. [00:33:44] Speaker 04: Now, whether you make that buffer in situ by mixing two things, like sodium hydroxide and acetic acid, as the specification talks about, you're still adding that to the active ingredient. [00:33:58] Speaker 04: in every example in the specification. [00:34:00] Speaker 02: But that's not adding an acetate buffer at that point. [00:34:02] Speaker 02: It's adding other compounds that create an acetate. [00:34:06] Speaker 04: It's making two things, adding two chemicals to make an acetate buffer and then adding that. [00:34:13] Speaker 02: Can you include two different chemicals that will result in an acetate buffer? [00:34:18] Speaker 04: You can as long as it doesn't come from dissociation of the active ingredient caspofungin diacetate [00:34:25] Speaker 04: Because if it comes from there, you recapture the tartrate-buffered examples that were relinquished. [00:34:32] Speaker 04: And I would submit that on the entirety of the intrinsic record, you cannot read the specification of this patent and the prosecution history and the examiner's statement that we're giving up all buffers other than acetate. [00:34:46] Speaker 02: Is it your argument that the acetate buffer cannot be formed in situ? [00:34:52] Speaker 04: No. [00:34:53] Speaker 04: It's our argument the acetate buffer [00:34:55] Speaker 04: cannot be formed from the dissociation of the active ingredient caspofungin diacetate mixed with a nonacetate buffer like tartrate or succinate. [00:35:07] Speaker 04: Because if that is the case, you cover the very tartrate examples that the intrinsic record makes clear were disclaimed. [00:35:17] Speaker 04: That the examiner said here, there's a genus of buffers. [00:35:21] Speaker 04: And he was very clear on 3889 of the joint appendix. [00:35:25] Speaker 04: I'm not giving you the entire genus. [00:35:27] Speaker 04: You get acetate. [00:35:29] Speaker 04: You don't get tartrate. [00:35:30] Speaker 04: You don't get phosphate. [00:35:31] Speaker 04: You don't get citrate. [00:35:32] Speaker 04: But the key thing is the specification shows that tartrate buffer unexpectedly destabilizes the claimed peptide, while acetate has an unforeseen stabilizing effect. [00:35:46] Speaker 04: The only two things in the specification are formulations that have the active ingredient caspofunction diacetate [00:35:55] Speaker 04: mixed with tartrate or caspofungin diacetate mixed with additional acetate. [00:36:02] Speaker 02: And the examiner says you get one, not the other. [00:36:05] Speaker 02: Is your argument that the only way you can have acetate buffer in the final compound is that if you add it separately, you get a bottle that says acetate buffer on it, and you add it to the formula? [00:36:19] Speaker 04: No. [00:36:20] Speaker 04: So there's other ways of doing that. [00:36:21] Speaker 04: Yes, the specification tells you you can mix [00:36:24] Speaker 04: sodium hydroxide and acetic acid or sodium acetate and I forget what the other one is, it's a column three second paragraph down. [00:36:34] Speaker 03: I guess another way of asking it is there can be multiple different ways where an acetate buffer appears in the final composition but you're saying that this claim requires [00:36:49] Speaker 03: at least one particular way of it getting there. [00:36:51] Speaker 03: Can that be by using an acetate buffer as an ingredient? [00:36:56] Speaker 04: Yes. [00:36:56] Speaker 04: The prosecution history and the specification make clear you could mix two things to make an acetate buffer and then drop your active ingredient in it. [00:37:06] Speaker 04: You could take your active ingredient and add acetate buffer to it. [00:37:09] Speaker 04: What you can't do is take the active ingredient, caspofunction diacetate, mix it with tartrate or mix it with succinate, and then say, [00:37:19] Speaker 04: Oh, that dissociates and forms an acetate buffer, because that would encompass the very compositions, the tartrate compositions, that they said aren't covered. [00:37:29] Speaker 04: And I would like to ask one issue, one additional point. [00:37:34] Speaker 04: And it's the issue of reverse versus remand. [00:37:40] Speaker 04: There was a statement in their brief that you would need to send this back to the district court to assess [00:37:47] Speaker 04: whether there's infringement should the court change the claim construction. [00:37:50] Speaker 04: There is absolutely no dispute about our product. [00:37:53] Speaker 04: Zelia takes caspofungin diacetate. [00:37:56] Speaker 04: They mix it with a succinate, succinic acid. [00:38:00] Speaker 04: That's what goes into it. [00:38:01] Speaker 04: There's no separate acetate. [00:38:03] Speaker 04: There's no chemicals that mix to form acetate. [00:38:07] Speaker 04: Everybody agrees what the product is. [00:38:09] Speaker 04: So there's no need for a remand. [00:38:11] Speaker 04: And that's important because this patent expires in March of 2017. [00:38:15] Speaker 00: Thank you.