[00:00:03] Speaker 00: The United States Court of Appeals for the Federal Circuit is now open and in session. [00:00:07] Speaker 00: God save the United States and the Honorable Court. [00:00:15] Speaker 01: Good morning, everyone. [00:00:17] Speaker 01: The first argued case this morning is number 20-21-34, Cephalon Incorporated against Layback Farmer Limited. [00:00:25] Speaker 01: Mr. Feldman, please proceed. [00:00:27] Speaker 03: Thank you, Your Honor. [00:00:30] Speaker 03: May it please the Court. [00:00:31] Speaker 03: My name is Stephen Feldman. [00:00:33] Speaker 03: I represent the Apotex Appellants in this case. [00:00:36] Speaker 03: I will be addressing issues of obviousness. [00:00:39] Speaker 03: My co-counsel, Nicole Stafford, who represents Appellant Mylan, will address additional aspects of obviousness and also the issue of indefiniteness. [00:00:48] Speaker 03: The district court legally erred in filing to find the at-issue patents invalid for obviousness by applying a flawed teaching away analysis and an overly rigid motivation standard. [00:00:59] Speaker 03: The district court evidently thought that stating a preference for A over B in the prior art is a teaching away from B. However, the teaching away inquiry does not focus on whether a person of learning skill in the art would have merely favored one disclosed option over another disclosed option. [00:01:16] Speaker 03: There actually can be many alternative options, all of which are obvious. [00:01:21] Speaker 05: Mr. Feldman, this is Judge Toronto. [00:01:23] Speaker 05: Can I ask, [00:01:26] Speaker 05: I will assume for purposes of this question that there may be some question about the applicability of teaching away as a doctrine whose formulations have varied. [00:01:38] Speaker 05: Some of them have been strict. [00:01:39] Speaker 05: Some of them have not so much been strict. [00:01:43] Speaker 05: But why would we not read the district court's findings to be that when the prior art as to both formulation and administration [00:01:56] Speaker 05: is considered together rather than in isolation, a Relevance Guild artisan would not have been motivated to go down the paths of the two, the claimed paths. [00:02:12] Speaker 05: So that one did not need to rely on teaching away, though obviously the district court did use that terminology. [00:02:25] Speaker 03: Your Honor, if I could start with the formulation patent, I think because that finding without a teach-away is inconsistent with his finding about Oltoff, that Oltoff would have led a person of worthy skill in the art to combine the PEG and the PG. [00:02:40] Speaker 03: He then used Draeger to erase that finding, but without a teaching-away, he really can't erase that finding. [00:02:47] Speaker 03: Oltoff is in the prior art, and what the law requires is to teach both of them together for what they fairly teach and [00:02:55] Speaker 03: looking at the statute, which requires an analysis of the differences between the prior and the claimed invention, without erasing Oltoff, there really aren't differences. [00:03:06] Speaker 03: On the formulation side of things, you've got Price 1998, which again, basically... You mean the administration side of things. [00:03:12] Speaker 03: Sorry, yes. [00:03:12] Speaker 03: I misspoke. [00:03:13] Speaker 03: The administration side. [00:03:14] Speaker 03: You've got Price 1998, which again, taught basically the invention, which was fast, low-volume infusions, [00:03:23] Speaker 03: of Bendemustein, and those were found to be well tolerated. [00:03:30] Speaker 03: So again, without the teaching away of the ribomustein monograph, and again, we can get into why we believe that those findings are not supported by the actual data and evidence of that reference, but without that teaching away, then what you're left with is the difference between the prior art and the claimed invention is basically nil. [00:03:58] Speaker 03: So... Okay, thank you. [00:04:02] Speaker 03: So really, I would like to get into the data of Drager, which was the supposed teaching away reference, and the court's actual factual findings, which we don't believe support a legal conclusion ultimately of obviousness and even a factual conclusion of teaching away. [00:04:22] Speaker 03: Because if you actually look at what the court relied on in Drager to support [00:04:28] Speaker 03: teach away, what did it actually say, and what did the data of Drager actually show? [00:04:34] Speaker 03: So if we could go to figure three of Drager, which is APPX 22195, this is actual data of the thing that the court found Drager said was bad, which is a PG-only formulation approximating OLTOF. [00:04:52] Speaker 03: And what you see is that for six months, [00:04:55] Speaker 03: at refrigerated temperatures, which by the way is what Bendica is stored at and what our products are stored at, you actually have good stability. [00:05:03] Speaker 03: And if you actually go to the section of Drager where the court discusses the theory of why you would use an aprotic solvent over a protic solvent, right, and what Drager says is that you would do this so you could get stability at commercial levels, which he describes as 30 days, 90 days, 180 days, [00:05:24] Speaker 03: and about 365 days. [00:05:27] Speaker 03: And so what this shows is that with Oltoff's formulation, the PG only formulation, you're essentially within the zone of why Drager was doing this in the first place, which tells you that Oltoff cannot be a zero. [00:05:43] Speaker 03: You can't just eliminate Oltoff and the consideration rather what the court should have done is treat Oltoff and Drager together for what they fairly teach. [00:05:52] Speaker 03: And when you do that, [00:05:54] Speaker 03: And when you take the teachings of Drager, which said, okay, well, maybe there is some deficiency in Oltoff in terms of forming P.G. [00:06:01] Speaker 03: Esters, but I can improve that by reducing the O.H. [00:06:04] Speaker 03: load. [00:06:05] Speaker 03: Well, taking that teaching and combining it with Oltoff says, okay, well, maybe there's another way to reduce the O.H. [00:06:10] Speaker 03: load, and that would be using PEG, which again, based on the court's initial finding that you could, would be, a postita would be motivated [00:06:19] Speaker 03: for Moltoff alone to do PG and PEG. [00:06:23] Speaker 03: Now you actually have a solution to the issue, which is to reduce the PGA sterification. [00:06:27] Speaker 05: Mr. Feldman, this is Judge Toronto. [00:06:29] Speaker 05: Can I ask another question, which I'm just a little puzzled about? [00:06:34] Speaker 05: The district court, and as far as I can tell, the parties here seem to assume either that the formulation claims require as solvents only the protic solvents, [00:06:47] Speaker 05: that is that they exclude aprotic solvents, or that at least the theory that you all presented as to what a relevant skilled artisan would be tempted and led to do would be to use only protic solvents, some combination of PEG or PG, but to omit [00:07:12] Speaker 05: any of the aprotic salvens such as the Drager one and what is your position about, and you haven't made any argument about this, it just seems to be an assumption. [00:07:23] Speaker 05: Can you clarify, do you think that claims actually prohibit aprotic salvens notwithstanding the comprising language or what? [00:07:34] Speaker 05: I'm not sure that this has any bearing on [00:07:36] Speaker 05: on the bottom line here, but I was left puzzled because there's an assumption that I don't quite see supported in the claim language. [00:07:45] Speaker 03: So, Your Honor, as you point out, it's a comprising claim, so I believe my initial time is up. [00:07:50] Speaker 03: Can I go ahead and answer it? [00:07:52] Speaker 01: Yes, please answer the question. [00:07:54] Speaker 03: Okay, so these are comprising claims. [00:07:57] Speaker 03: They do not exclude aprotic solvents as well. [00:08:02] Speaker 03: The formulation that [00:08:04] Speaker 03: we put on evidence of being obvious was Prodic only. [00:08:09] Speaker 03: And one of the main reasons for that is because the A-Product solvents that were known to exist, one of which was DMA, which is FDA approved, but the problem with DMA is that it was found to dissolve plastic. [00:08:25] Speaker 03: So there weren't good A-Product alternatives. [00:08:27] Speaker 03: And the other A-Products that are identified, for example, in Drager like DMSO and some of the others, [00:08:34] Speaker 03: have not been approved by the FDA for IV injectable solutions. [00:08:39] Speaker 03: So I agree with you that these claims do not exclude aprotic solvents, but we thought for the obviousness position that there are actual technical and real reasons that you wouldn't necessarily want to use aprotics, which again, [00:08:58] Speaker 03: teaches more towards using PEG to reduce your OH load and to reduce the esterification problem. [00:09:06] Speaker 01: Okay. [00:09:06] Speaker 01: Thank you. [00:09:07] Speaker 01: Anything else from Mr. Feldman at this stage? [00:09:09] Speaker 01: We'll save you rebuttal time. [00:09:12] Speaker 03: Thank you, Your Honor. [00:09:13] Speaker 01: Okay. [00:09:14] Speaker 01: Ms. [00:09:14] Speaker 01: Stafford, you have five minutes. [00:09:17] Speaker 00: May it please the court? [00:09:18] Speaker 00: Can the court hear me? [00:09:20] Speaker 00: Okay. [00:09:21] Speaker 00: Going to the last question. [00:09:23] Speaker 00: Myelin believes that the claims do not, the formulation claims do not exclude a-cardic solvents, which is another error to find that Draeger teaches away. [00:09:32] Speaker 05: Again, I'm not sure anything turns on it. [00:09:35] Speaker 05: I don't remember you saying anything at all about that in your brief. [00:09:38] Speaker 05: Did I miss something? [00:09:40] Speaker 00: I can't recall right now, to be honest. [00:09:42] Speaker 00: I believe we did say that it's not excluded, but the claims are comprising claims. [00:09:47] Speaker 00: I'd like to first turn to the indefiniteness. [00:09:51] Speaker 00: And in our review, the term stabilizing amount of antioxidant is indefinite. [00:09:56] Speaker 00: This is found in pages 35 to 46 of our opening brief. [00:10:00] Speaker 00: In short, there are multiple potential targets for determining the endomesting degradation and multiple ways of measuring it. [00:10:07] Speaker 00: Depending on when and how degradation is determined, an antioxidant may or may not be present in a stabilizing amount in the same formulation. [00:10:15] Speaker 00: Even plaintiff's expert conceded that degradation depends on storage time and temperature [00:10:20] Speaker 00: but the specification provides no objective standard for either. [00:10:24] Speaker 00: The proposter can choose their own way to determine degradation, and there is no objective boundary. [00:10:29] Speaker 05: Ms. [00:10:29] Speaker 05: Stafford, this is just for you. [00:10:31] Speaker 05: Can I just ask, as I read the district court's finding, which I think actually amounts to a claim construction, the meaning of the required stabilizing amount is a stabilizing amount of an antioxidant includes any amount [00:10:49] Speaker 05: that decreases the amount of degradation after any time period and at any temperature. [00:10:57] Speaker 05: That's exceedingly broad, or very broad, I don't know, exceedingly is maybe improper, but very, very broad so that if in a comparison between the presence of the antioxidant and the absence [00:11:13] Speaker 05: there is some time period and some temperature at which there's more degradation or less degradation with the antioxidant than without, then it's a stabilizing amount. [00:11:24] Speaker 05: And I didn't see you make any argument that applying that very, very broad standard that a skilled artisan would have difficulty understanding whether something was or was not a stabilizing amount. [00:11:42] Speaker 05: as opposed to I don't know what temperature to look at. [00:11:45] Speaker 05: And the answer from the claim construction is you got to look at them all. [00:11:50] Speaker 00: Well, the problem is that at some temperatures, for example, refrigerated or very low temperatures, you're not going to see any loss of stability or any degradation when there's no antioxidant present. [00:12:00] Speaker 00: And so then if you add antioxidant, you're not going to see an enhancement. [00:12:03] Speaker 00: And so therefore, that formulation, if measured at refrigerated conditions or a very short time period, is not going to be infringing. [00:12:11] Speaker 00: However, if I measure it at 100 or 200 degrees or 40 degrees and at an extended time period, say, you know, 40 days or a year, then I'm going to see an enhancement with the presence of some antioxidant. [00:12:24] Speaker 05: Right, but why isn't that ladder all by itself sufficient to come within the definition, even if you don't see it at other temperatures or at other times? [00:12:34] Speaker 05: I thought that's what the district court was saying. [00:12:37] Speaker 00: Well, I think that that's exceedingly broad and that that would not provide any real objective boundary. [00:12:43] Speaker 00: I could just keep something up and keep it for as long as possible. [00:12:46] Speaker 00: That's also inconsistent with the examples of the claims, examples of the methods of the formulation patents, which is examples 3 through 5, which equate having a stabilizing amount with having an amount sufficient to have a sufficient shelf life. [00:13:01] Speaker 00: Moreover, the patent has very many targets. [00:13:04] Speaker 00: So you can measure loss of initial bend of mustang. [00:13:07] Speaker 00: You can measure bend of mustang impurities. [00:13:09] Speaker 00: You can measure total impurities. [00:13:11] Speaker 00: And all of those give different results, potentially at different times and temperatures. [00:13:15] Speaker 00: But I'd now like to move on. [00:13:16] Speaker 00: Have I answered your question, Your Honor? [00:13:18] Speaker 00: Yes, thanks. [00:13:20] Speaker 00: Okay, I'd like to move on now to the method claims. [00:13:22] Speaker 00: For the method claims of the method patents, the only real issue is prima facie obviousness. [00:13:27] Speaker 00: As the court found, there were no secondary considerations. [00:13:31] Speaker 00: The claims are directed to administration at a slightly less volume and slightly less time than was known with Trianda. [00:13:38] Speaker 00: However, the lower volumes and faster infusion times were disclosed in prior art, and therefore, there was nothing new about that. [00:13:47] Speaker 00: Specifically, there were two price studies, one in 1985 that used a three-minute IV drip and one in 1998, which used a three to 10-minute administration of Benda Mustang. [00:13:59] Speaker 00: And the unrefuted testimony that the volume would be so low that it would overlap with the claimed ranges for volume. [00:14:07] Speaker 00: And that was not refuted by the other side. [00:14:10] Speaker 00: And therefore, the law of overlapping ranges should apply. [00:14:14] Speaker 00: And there was a presumption of obviousness, of trying to face the obviousness that the appellee would have had to rebut. [00:14:22] Speaker 00: However, that was not done. [00:14:24] Speaker 00: The district court instead looked at whether or not these were safety studies. [00:14:27] Speaker 00: and said that they weren't. [00:14:29] Speaker 00: That's error. [00:14:30] Speaker 00: Price 1998 is a safety study. [00:14:33] Speaker 00: Moreover, the case law doesn't require that you have safety studies or you can prove safety as would be done for FDA approvability. [00:14:42] Speaker 00: Moreover, EGLE and TEVA both used those as safety studies and viewed them as safe. [00:14:46] Speaker 00: The fact that Price also did a study several years later in 2003 for different purposes using different administration is not a teaching away. [00:14:54] Speaker 00: where the rival must be monographed is also not a teaching away. [00:14:58] Speaker 00: For reasons I can go into if you would like me to, but I believe I've already finished my initial time and therefore would like to reserve the rest of my time for rebuttal as to any questions. [00:15:09] Speaker 01: Okay. [00:15:09] Speaker 01: Any other questions for the staff right at this stage? [00:15:13] Speaker 01: No. [00:15:13] Speaker 01: Okay. [00:15:13] Speaker 01: We'll save you rebuttal time. [00:15:15] Speaker 01: Let's hear from Mr. Burrell. [00:15:17] Speaker 02: Thank you, Your Honor. [00:15:18] Speaker 02: May it please the court, David Burrell for Cephalon. [00:15:21] Speaker 02: I'd like to start with Judge Toronto's first question of whether a teachaway is even necessary here. [00:15:27] Speaker 02: And the answer to that question is no, it's not. [00:15:30] Speaker 02: This court's decision in Arctic Cat elucidates the principle very clearly. [00:15:35] Speaker 02: In that case, the prior art taught the combination, the AES report taught the combination and even disclosed certain advantages of the combination with the claimed steering system. [00:15:46] Speaker 02: But as this court said, the prior art did not stop there and proceeded to provide reasons not to have the claim commented, including the increased incidence of potential accidents. [00:15:59] Speaker 02: This case held explicitly that those disadvantages did not slide to the level of a teachaway. [00:16:07] Speaker 02: Nevertheless, the court found, affirming the decision below, that that evidence negated a finding of motivation. [00:16:16] Speaker 05: I think you understand that putting aside different facts of different cases, there's something of a doctrinal issue here. [00:16:33] Speaker 05: What is left of teaching away doctrine if every kind of negative [00:16:41] Speaker 05: You know, every kind of case in which there is prior art, some positive, some negative, to use Medicam's language, you know, point in different directions, but why wouldn't teaching away doctrine, which does set something of a high standard, be, you know, rendered nuggatory [00:17:05] Speaker 05: by just reformulating it all as well. [00:17:08] Speaker 05: The balance of positive and negative leaves POSA without a relevant motivation. [00:17:13] Speaker 05: How do we draw the line between where one analysis is appropriate and the other is appropriate? [00:17:18] Speaker 02: I think, Your Honor, the answer is that both inquiries are appropriate. [00:17:22] Speaker 02: I would agree that teaching away requires a higher standard than simply a negative statement about a potential invention. [00:17:29] Speaker 02: This Court has phrased it as discouragement, as dissuasion, or leading the posa in some other path, towards some other path other than the invention. [00:17:39] Speaker 02: That I agree is a higher standard. [00:17:41] Speaker 02: I think it was met here repeatedly based on undisputed evidence. [00:17:46] Speaker 05: Never mind that. [00:17:46] Speaker 05: I'm really trying to figure out how to think about the line between the two different ways of looking at it. [00:17:57] Speaker 05: Does teaching away apply only or mostly if some prior art is very powerfully [00:18:08] Speaker 05: pointing toward it and then it has to be overcome or what? [00:18:13] Speaker 02: Yes, I think that if the prior art shows that a particular solution would be unsuitable or unlikely to be productive, as this court said in Medican or Bayer, that is met. [00:18:25] Speaker 02: And the prior art thereby teaches away from the invention. [00:18:29] Speaker 02: Where you don't have something that meets that higher standard, as you didn't in impacts, as you didn't in the Arctic Cat case, [00:18:36] Speaker 02: Then it becomes a balancing where the district court on the basis of all of the prior art looks at the advantages and disadvantages and asks the question of whether there's clear and convincing evidence of motivation to make or use the invention. [00:18:50] Speaker 02: I think there are two separate inquiries. [00:18:51] Speaker 02: I think there are certain presumptions that can be invoked in the law where it makes a difference whether one's operating under the teachaway rubric [00:18:59] Speaker 02: or simply the motivation rubric. [00:19:02] Speaker 02: And so it can make a difference there. [00:19:04] Speaker 02: But I think there are two different inquiries with two different standards. [00:19:07] Speaker 02: And I think there are cases in which the higher teacher waste standard is not met. [00:19:11] Speaker 02: But nevertheless, motivation is absent. [00:19:14] Speaker 02: I think, again, Arctic Cat provides such a scenario as does the impact case. [00:19:19] Speaker 05: Did the district court in this case, and here I'm just focused on the formulation patent, correct me if I'm wrong. [00:19:25] Speaker 05: I think the district court said if you looked at Olthoff [00:19:29] Speaker 05: in isolation, HOSA would be led to find it obvious to try the PEG-PG combination here. [00:19:41] Speaker 05: But Drager teaches a way. [00:19:44] Speaker 05: Is there some other place in the district court's opinion where the district court said something in substance to the effect in any event [00:19:55] Speaker 05: even if there weren't an obvious try or whatever, that a POSA would not ultimately be motivated to do this, independent of a teaching away conclusion? [00:20:10] Speaker 02: Yeah, I believe so. [00:20:11] Speaker 02: I would read the district court's opinion, for example, at A67, where it talks about the concerns about precipitation, to provide another reason why the POSA would not have gone down the path of using this solvent system with 90% PEG. [00:20:25] Speaker 02: Likewise, the district court found it at A50 that there was a significant concern about the formation of PEG esters based on unrefuted testimony from our expert Dr. Seidman that would provide another reason not to make or use the invention. [00:20:41] Speaker 02: Taken together, whether it's a teach-away or not, the prior art suggested that there were two major problems with bendimustine. [00:20:49] Speaker 02: It degrades at the nitrogen mustard and it degrades at the carboxylic acid. [00:20:53] Speaker 02: The district court found that the claim solvent system would make both worse. [00:21:01] Speaker 02: nitrogen-mustard degradation would get worse as a result of using PEG. [00:21:06] Speaker 02: And at age 63, it finds that the carboxylic acid degradation would get worse. [00:21:10] Speaker 02: So you're taking two problems. [00:21:12] Speaker 02: You're making most both of them worse. [00:21:14] Speaker 02: It's not clear to me how one possibly could have been motivated to make and use this invention, given those two factual findings, which again, were based largely on unrefuted testimony. [00:21:25] Speaker 02: And where it was refuted was based on credited testimony from our experts, Dr. Ancelin [00:21:31] Speaker 02: and Dr. Seidman. [00:21:32] Speaker 02: And Figure 3 of Drager, can you address what we heard about that 10 minutes ago? [00:21:37] Speaker 02: Absolutely, gladly. [00:21:39] Speaker 02: Drager itself says, looking to Figure 3, that the PG-only formulation, which is what it made to try to reproduce Olthoff unsuccessfully, was, in its words, not feasible. [00:21:52] Speaker 02: Our expert testified that that data fell far below the requirements of the POSA. [00:21:57] Speaker 02: That's at A19085, well below the POSA standards, and the district court cited and credited that testimony. [00:22:05] Speaker 02: And when asked on the basis of Drager, would the POSA use prodigal solvents alone, our expert testified, no, no, no. [00:22:17] Speaker 02: Drager teaches using aprotic solvents. [00:22:20] Speaker 02: And you can use protic solvents as long as you use aprotic solvents, too. [00:22:25] Speaker 02: That's the testimony that was cited by the district court. [00:22:27] Speaker 02: That's at A19093. [00:22:30] Speaker 02: And Drager says the same thing at Column 4, Lines 18 through 24. [00:22:34] Speaker 02: He says, you can use protic solvents, but as long as they're within the scope of the invention, as long as they're within 90% or less, then you won't get too much of these protic solvent bendimustine adducts. [00:22:47] Speaker 02: So while counsel today testified that the figure three data are very good, as Your Honor knows, those data must be read through the lens of the person of ordinary skill in the art. [00:22:59] Speaker 02: And the testimony at trial credited by the district court was clear that that data, as Drager himself says, [00:23:06] Speaker 02: And as our experts said, interpreting those data are unacceptable. [00:23:11] Speaker 02: It's infeasible. [00:23:12] Speaker 02: It's not good. [00:23:13] Speaker 02: And no, no, no, you can't do that. [00:23:16] Speaker 02: And that's exactly what Draeger is teaching. [00:23:18] Speaker 02: And that's what the district court found that it was teaching. [00:23:20] Speaker 02: And that is not clearly erroneous. [00:23:22] Speaker 02: That was plainly the correct finding by the district court. [00:23:27] Speaker 02: So with the court's permission, I'd like to turn to indefiniteness. [00:23:32] Speaker 05: Can you quickly address the administration claims and the obviousness [00:23:36] Speaker 05: issue on that before you... Absolutely. [00:23:39] Speaker 02: I was actually going to go there last because appellants went there last, but I'm happy, of course, to do it in that order. [00:23:45] Speaker 02: The district court's finding with respect to the administration claims likewise was based on undisputed evidence in some circumstances and credited expert testimony in others. [00:23:57] Speaker 02: While defendants focus solely on Price's administration, [00:24:01] Speaker 02: The court was not permitted to look at price and isolation, and was commanded by this court's jurisprudence to look at the prior art as a whole. [00:24:09] Speaker 02: It did so, and it found Shotsky, and it interpreted Shotsky, and this was fiercely disputed at trial, but it interpreted Shotsky to show that the longer the infusion time, the lower the toxicity, and the reverse was true, as Dr. Derendorf, our expert, said at 18682. [00:24:25] Speaker 02: Shotsky itself explicitly taught [00:24:29] Speaker 02: The infusion duration and dose fractionation appear to affect the toxicity profile. [00:24:34] Speaker 02: That is, the longer the infusion, the less toxicity. [00:24:38] Speaker 02: But it wasn't Shostky alone. [00:24:40] Speaker 02: The ribomustin monograph could not be more clear that the short infusion [00:24:44] Speaker 02: is associated with toxicity, with phlebitis and thrombophlebitis. [00:24:50] Speaker 05: I'm sorry, which monograph are you talking about now? [00:24:52] Speaker 02: This is the Ribomustin monograph. [00:24:54] Speaker 02: This is the monograph, and it says 23995 of the appendix, Your Honor, and this is the monograph that was approved by the German regulators, and what it says is that the thrombophlebitis occurs after ibibolus injection and can be reduced by administering bendamustin over 30 to 60 minutes. [00:25:14] Speaker 02: that cited a Ruffert article. [00:25:16] Speaker 02: Again, the interpretation of that article was disputed, but the court credited Dr. Derendorf's testimony, not their expert, Dr. Thurman. [00:25:23] Speaker 02: Dr. Derendorf says at 16689 that this Ruffert article is talking about Benda Mustine. [00:25:30] Speaker 02: causing the thrombophlebitis, not the other drugs, Benchristine, there's no other way to interpret it. [00:25:35] Speaker 02: So that's another clear reason not to administer in this low time. [00:25:40] Speaker 02: That's another clear teach-away that the district court credited. [00:25:43] Speaker 02: And the monograph here in the United States, the approved Prior Art Trianda label, likewise talks about a 30 to 60 administration and warns against departing downward. [00:25:54] Speaker 02: saying that if you have a higher C-max, that is, if you have higher blood levels, that's associated with nausea. [00:26:01] Speaker 02: So after Price, the Prior Art uniformly taught that using bendamustin in a short administration was dangerous. [00:26:10] Speaker 02: Dr. Derendorf reviewed the entirety of the Prior Art. [00:26:13] Speaker 02: If Your Honor looks to [00:26:14] Speaker 02: 18687-93, he reviews all of the prior art and concludes at the end that the POSA would have considered a 10-minute administration to be not safe. [00:26:26] Speaker 02: That is plainly within the heartland of this court's teachaway jurisprudence under the Allergan case and others. [00:26:33] Speaker 02: It was not safe and the POSA would not have done it. [00:26:36] Speaker 02: No, that's just the times. [00:26:40] Speaker 02: The volumes and concentrations provide independent basis for affirmance of the district court's judgments. [00:26:46] Speaker 02: Ms. [00:26:46] Speaker 02: Stafford suggested that there was somehow no dispute at trial that Price taught the claimed volumes. [00:26:53] Speaker 02: Respectfully, that's not true, and the district court found otherwise. [00:26:57] Speaker 02: He found at A84 through 85 that Price did not disclose the claimed volumes. [00:27:02] Speaker 02: He excluded, under Rule 26, testimony from the defendant's experts who sought to testify on this topic because it was not disclosed in the expert report, and he instead gave conclusory testimony that Price's volumes were, quote, likely closer, end quote, to 50 to 100. [00:27:19] Speaker 02: Now, the district court, having watched all of these witnesses testify, should not find that testimony persuasive or credible and rejected it. [00:27:28] Speaker 02: The district court was plainly permitted to do that and plainly permitted to find that there was no clear and convincing evidence that the prior ARC taught the claimed volumes. [00:27:38] Speaker 05: Do I understand correctly that the sentence, I guess, on A85 bars 100 to 250 milliliter suggestion did not cover the claimed volumes? [00:27:49] Speaker 05: All claims require 100 milliliters or less. [00:27:52] Speaker 05: that the reason and the only reason maybe that you say that that does not actually confess an overlap at exactly 100 milliliters is that the things being measured in the first clause and the thing being measured in the parenthetical are different. [00:28:11] Speaker 02: They are indeed. [00:28:12] Speaker 02: That's right. [00:28:12] Speaker 02: And at A-75, there's further evidence that the District Court understood it that way. [00:28:17] Speaker 02: It says, Barth suggested administering Benamustin in a solvent volume of 100. [00:28:23] Speaker 02: That's not a total volume of 100. [00:28:25] Speaker 02: That's a solvent volume of 100. [00:28:27] Speaker 02: If you then add the 36 milliliters of Benamustin, you're at 136, which informs the sentence that Your Honor just read on A-85 that there's no overlap. [00:28:38] Speaker 02: I would further observe that even if Barth had topped 100, and Barth of course did not peak 100 total volume, that would still be double the volume required by some of the claims, which is 50 milliliters or less. [00:28:54] Speaker 05: Would you mind, I know you wanted to talk about indefinite before, but maybe you could do so now. [00:29:00] Speaker 05: Do you agree with my [00:29:04] Speaker 05: I guess characterization of what the district court said about the very, very broad meaning of stabilizing amounts. [00:29:14] Speaker 02: I think it is a broad meaning of stabilizing amount. [00:29:16] Speaker 02: I think it flows directly from the definition that's explicit in the specification. [00:29:22] Speaker 02: This is an unusual indefiniteness challenge. [00:29:25] Speaker 02: It's not as if the parties disagreed about the scope of this claim or the meaning of this claim. [00:29:30] Speaker 02: It's an explicitly defined claim. [00:29:33] Speaker 02: and the lexicographical definition in the specification controls and everyone agrees. [00:29:39] Speaker 02: This is instead some sort of meta indefiniteness argument where the defendant suggests that there's some lack of clarity about how that definition would be applied. [00:29:48] Speaker 02: But per your honor's questions and per the district court's findings, there is no lack of clarity. [00:29:53] Speaker 02: Ms. [00:29:54] Speaker 02: Stafford said again what they said at trial and what they said in their briefs, that depending on what time and temperature one uses in the HPLC measurements, [00:30:02] Speaker 02: one may or may not have a stabilizing amount of antioxidant. [00:30:07] Speaker 02: That simply is untrue. [00:30:10] Speaker 02: Its speculation is unsupported by a shred of evidence in the record. [00:30:16] Speaker 05: Here's what I'm a little confused about. [00:30:20] Speaker 05: The way that I was thinking about this, and tell me if I'm wrong, is that that may well be true, but it's immaterial because the only thing that's required for something to come into the stabilizing amount [00:30:32] Speaker 05: definition is that there is some time or some temperature at which the difference, antioxidant or no antioxidant, would appear. [00:30:45] Speaker 05: So that there may actually be lots of individual times or individual temperatures at which there is no difference, but it doesn't matter under the definition. [00:30:54] Speaker 05: Am I wrong in understanding the definition that way? [00:31:00] Speaker 02: With Your Honor's permission, I... Yes, please respond. [00:31:04] Speaker 02: Yes. [00:31:05] Speaker 02: Well, Your Honor, the way I'd respond to that is that I think Nautilus does all the work in answering that question. [00:31:10] Speaker 02: I think the POSA would look to the specification and the usual techniques that are done with HPLC. [00:31:17] Speaker 02: So, one wouldn't use a thousand degrees. [00:31:19] Speaker 02: One wouldn't wait until time immemorial to measure it. [00:31:22] Speaker 02: I think that if one is using the usual times and temperatures that the POSA would have used guided by the specification and one sees that with and without an antioxidant there's a difference with respect to the amount of bendimustine remaining. [00:31:37] Speaker 05: So that there's a difference at every temperature and at every time? [00:31:42] Speaker 05: I think you, maybe I'm not communicating. [00:31:45] Speaker 05: I understood that within the realm of practicality [00:31:50] Speaker 05: All there has to be is one time or one temperature at which there is a difference. [00:31:56] Speaker 05: Is that incorrect or correct under this claim construction? [00:32:00] Speaker 02: I think under this claim construction, if one measures at a given time and temperature and finds a stabilization, you are within the scope of the claim. [00:32:08] Speaker 02: I think that's right. [00:32:08] Speaker 05: Even if you find no difference at other times and temperatures? [00:32:13] Speaker 02: If one finds no difference, I think that's correct, Your Honor. [00:32:16] Speaker 05: Okay, so that leaves one thing, which was not much the focus, I think, of either the district court's opinion a little bit more in the briefs. [00:32:24] Speaker 05: There was a suggestion that measuring degradation is itself uncertain. [00:32:32] Speaker 05: Can you address that? [00:32:34] Speaker 05: Never mind time and temperature, just what measuring degradation? [00:32:39] Speaker 02: So I think there was some dispute at trial about what one would have measured. [00:32:43] Speaker 02: Would one have measured the impurities, the amount of impurities, or the amount of bendamustine remaining? [00:32:48] Speaker 02: And the district court found, and this is based on the specification, that the inquiry is how much bendamustine is remaining. [00:32:54] Speaker 02: That's what the definition says. [00:32:56] Speaker 02: That's what our experts said. [00:32:57] Speaker 02: And that testimony was credited by the district court. [00:33:00] Speaker 05: So I don't think there's any lack of clarity there. [00:33:03] Speaker 05: What's the site in the district court for that, if you have it? [00:33:07] Speaker 05: I can find it if you don't. [00:33:11] Speaker 02: A95. [00:33:12] Speaker 02: Okay. [00:33:12] Speaker 05: Thank you. [00:33:13] Speaker 02: And he's citing A19116 through 17. [00:33:16] Speaker 02: That's Dr. Seidman's testimony as well as A19121. [00:33:19] Speaker 02: Unless the court has further questions. [00:33:28] Speaker 01: We'll see. [00:33:28] Speaker 01: Any more questions for Mr. Burrow? [00:33:31] Speaker 01: No. [00:33:32] Speaker 01: Okay. [00:33:32] Speaker 01: Thank you, counsel. [00:33:34] Speaker 01: All right. [00:33:35] Speaker 01: Thank you. [00:33:35] Speaker 01: Mr. Feldman, you have two minutes. [00:33:41] Speaker 01: Are you unmuted? [00:33:45] Speaker 03: Sorry, I was muted. [00:33:47] Speaker 03: Let's go back to Draeger. [00:33:49] Speaker 03: Can you hear me? [00:33:51] Speaker 03: So at APPX 22200, Mr. Burl was talking about the court's finding about nitrogen muster degradation with respect to the polyols. [00:34:02] Speaker 03: And Table 2 of Draeger demonstrates that that just does not happen. [00:34:06] Speaker 03: So you had speculation from [00:34:08] Speaker 03: Dr. Seidman and Dr. Ancelin talking about how, well, maybe they could form theoretically, but there's no Benda-Mustein-specific evidence of nitrogen mustard degradation with respect to polyols. [00:34:19] Speaker 03: And in fact, that's why Drager's able to use up to 90% of a PG-PEG-ester combination in his formulation, okay, up to 90%. [00:34:28] Speaker 03: So if nitrogen mustard degradation was a problem, he would have noted it and he would have explained it. [00:34:33] Speaker 03: Instead, what you see in Table 2 is a comparison [00:34:36] Speaker 03: between DMA by itself, which is aprotic, and then a combination of DMA with PG, 34% PG. [00:34:43] Speaker 03: And if you look at HP1, which is the hydrolysis degradant, which is what happens at the nitrogen mustard, you see that the number is the same. [00:34:52] Speaker 03: So the number for DMA by itself with no polyol at all degrades and creates an HP1 impurity. [00:35:00] Speaker 03: And then you add some polyol, OK, and nothing different happens at the nitrogen mustard. [00:35:06] Speaker 03: So that is a clearly erroneous finding. [00:35:09] Speaker 03: It's contrary to the actual Benamstein-specific evidence. [00:35:12] Speaker 03: The other point I wanted to make is if you go back to figure three, okay, the point is that that's PG-only. [00:35:19] Speaker 03: None of the claims are PG-only. [00:35:20] Speaker 03: Sure, PG-only could be improved, okay? [00:35:23] Speaker 03: And Drager actually teaches you how to improve it, which is by reducing the OH load, which is what happens when you add PEG. [00:35:30] Speaker 03: You actually reduce the OH load. [00:35:33] Speaker 03: And the other critical finding [00:35:35] Speaker 03: that's not made and yet the evidence shows and Dr. Ancel and their experts said it, is that the PG-ester formation when you compare a 9010 PEG-TG formulation to a 6634 DMA-PG formulation, which is what Drager's preferred one is, is exactly the same. [00:35:52] Speaker 03: So the fact that you may have some esterification happening because of the protic solvent isn't a stop, isn't don't use it, isn't... May I continue your honor and just finish my thought? [00:36:02] Speaker 01: Yes, please finish your thought. [00:36:04] Speaker 03: Thank you. [00:36:04] Speaker 03: Okay. [00:36:06] Speaker 03: It's not a stop. [00:36:07] Speaker 03: It's not a zero. [00:36:08] Speaker 03: What it is, is you can tolerate some PGA certification. [00:36:11] Speaker 03: You just have to control it, and the way you control it is by reducing the OH groups, and PEG does exactly that. [00:36:18] Speaker 01: Okay. [00:36:18] Speaker 01: Any more questions for Mr. Feldman? [00:36:21] Speaker 03: Nope. [00:36:22] Speaker 01: All right. [00:36:23] Speaker 01: Thank you. [00:36:23] Speaker 01: Ms. [00:36:24] Speaker 01: Stafford, you saved three minutes. [00:36:27] Speaker 00: Thank you, Your Honor. [00:36:28] Speaker 00: I'd like to start off with responding [00:36:30] Speaker 00: on the administration claims. [00:36:32] Speaker 00: First, the district court never made a finding that the prior art taught that administering between 3 and 10 minutes was not safe. [00:36:40] Speaker 00: That's just not true. [00:36:41] Speaker 00: The district court did not reference and credit Dr. Durand-Dore's testimony on that. [00:36:44] Speaker 00: If you look at what the district court said, this is an appendix 80 through 83, it said that it didn't consider price because you wouldn't have relied upon it to determine a safe and effective infusion time, volume, or concentration because there wasn't enough data. [00:36:58] Speaker 00: There wasn't enough safety data. [00:37:00] Speaker 00: He faults Price 85 as only testing seven patients. [00:37:03] Speaker 00: When he gets to Price 1998, who tested 50 patients, which is a sufficient number, and a safety study that was included in the Sal Medics Trianda brochure and also relied upon by EGLE to FDA to show that it was safe, he just said, well, they didn't disclose how the side effects were monitored, how many times side effect information was collected from patients, et cetera. [00:37:24] Speaker 00: None of that is required. [00:37:25] Speaker 00: That is applying an FDA standard to show motivation and obviousness. [00:37:29] Speaker 00: That is against the law. [00:37:31] Speaker 00: Moreover, with respect to repeated cycles, that's another reason he discounts price. [00:37:37] Speaker 00: That is not required by any of the claims. [00:37:39] Speaker 00: At most, they require administration over two consecutive days, and that is actually provided by price 1998, which discloses giving bendamustine in three to 10 minute infusions over four days. [00:37:52] Speaker 05: And so they're- Ms. [00:37:53] Speaker 05: Stafford, does it really matter whether the claims [00:37:59] Speaker 05: require multiple, even two sessions if the person of skill in the art looking at the prior art and thinking, what might I change, would be certain that what I'm trying to use this for is a multi-session regimen. [00:38:24] Speaker 05: even if a particular claim is to an individual session, if a POSA would not go down the path because the only thing a POSA would be finding worthwhile is an amount that would work for a multi-session regimen. [00:38:44] Speaker 00: I think it does matter because you're looking at the obviousness of the claims and the claims don't require and could have required repeated sessions. [00:38:51] Speaker 00: The unrefuted testimony is that when you have toxicity with repeated cycles, that's due to total dose. [00:38:58] Speaker 00: It's not due to infusion time and volume. [00:39:00] Speaker 00: It's because any chemotherapeutic agent, as you continue to give it month after month, will have effects on bone marrow and have effects on blood cell counts. [00:39:08] Speaker 00: And that's why Dr. Thurman testified that this will decrease the dose. [00:39:13] Speaker 00: But moving on to ribomustin, the ribomustin monograph does not say, for example, don't give shorter infusions. [00:39:20] Speaker 00: In fact, it says that it was well tolerated. [00:39:24] Speaker 00: But if you look at the actual studies that are talked about, that's the Ruffert 1998 study. [00:39:28] Speaker 00: Sorry, 1989 study. [00:39:30] Speaker 00: Can I continue or? [00:39:31] Speaker 01: Yes, please finish your thought. [00:39:33] Speaker 00: Thank you. [00:39:35] Speaker 00: The study that it's documenting doesn't give dendymustin as a bolus. [00:39:39] Speaker 00: And this is at APPX 23953. [00:39:42] Speaker 00: In fact, Ben DeMustin is given over one hour. [00:39:44] Speaker 00: The unrefuted testimony from both sides' experts is that Ben Christin, which is co-administered in the study that's discussed in the Rod DeMustin monograph, is actually what was given as a bonus. [00:39:59] Speaker 00: And so the discussion about there being a thrombophlebitis and local irritation due to a bolus is due to the vesicin, vincristine, not due to bendimustine. [00:40:10] Speaker 00: And there's nothing that says this is a teaching away. [00:40:14] Speaker 00: And that's what the district court relied upon for saying why you wouldn't go down that road is that it taught a way. [00:40:19] Speaker 00: And this is exactly at appendix 83. [00:40:22] Speaker 00: It's not because [00:40:24] Speaker 00: It's not because there was an argument that it was unsafe or there was a teaching that it was unsafe and therefore you shouldn't go down that road. [00:40:31] Speaker 00: And under Galderma, the idea that maybe you have a tradeoff and you change your dosage and that may cause a tradeoff with respect to side effects is not a teaching away. [00:40:42] Speaker 00: Thank you very much for your time. [00:40:44] Speaker 00: Do you have any more questions for Ms. [00:40:46] Speaker 00: Stafford? [00:40:47] Speaker 01: No. [00:40:48] Speaker 01: All right, thank you. [00:40:49] Speaker 01: All right, thanks to all council. [00:40:51] Speaker 01: The case is taken under submission.