[00:00:00] Speaker 05: Thank you. [00:00:00] Speaker 05: We'll call the next case, December 19, 2050, Dana-Farber Cancer Institute against Ono Pharmaceutical Company. [00:00:08] Speaker 05: Mr. Waxman. [00:00:10] Speaker 00: Thank you, Judge Newman, and may it please the court. [00:00:13] Speaker 00: The question for this court is not whether Drs. [00:00:17] Speaker 00: Freeman and Wood collaborated with Dr. Honjo or whether they made valuable scientific discoveries. [00:00:24] Speaker 00: The question here [00:00:26] Speaker 00: is whether they made significant contributions to the definite and permanent idea of Dr. Honjo's path-breaking methods for treating cancer. [00:00:36] Speaker 00: That is a question of law. [00:00:37] Speaker 00: And even accepting all of Judge Saris's findings of fact, the answer is respectfully no. [00:00:45] Speaker 00: Let me start first with the 474 patent and Dr. Freeman, where I think the court's legal errors seem particularly clear. [00:00:56] Speaker 00: I think there were three errors. [00:00:59] Speaker 04: First, Mr. Waxman, Judge Lurie, as you can tell. [00:01:04] Speaker 04: All of these patents related to treating tumors with a PDL antibody. [00:01:16] Speaker 04: And it's very clear that Dr. Honjo started out working on autoimmune diseases, and there was one [00:01:24] Speaker 04: Dr. Wood and Dr. Freeman got involved, and they certainly worked together. [00:01:30] Speaker 04: And they found that PDL ligand was expressed in tumors and inhibited an immune response. [00:01:41] Speaker 04: And so they clearly worked together on what was claimed. [00:01:46] Speaker 00: Isn't that correct? [00:01:49] Speaker 00: I don't think I fully agree with you. [00:01:51] Speaker 04: I think it's important, Judge Laurie, your question... You mean you partially do. [00:01:58] Speaker 00: Yes, I do. [00:01:59] Speaker 00: Let me clarify what I mean. [00:02:00] Speaker 00: Your question goes to the chronology of who did what when. [00:02:05] Speaker 00: And I think it's important to understand, and I'll refer the court to pages 14 to 16 of the Joint Appendix, that before [00:02:18] Speaker 00: The collaboration began. [00:02:20] Speaker 00: Dr. Hanjo and his team in 1999 had discovered the PD-1 receptor on T cells, had created antibodies against both mouse and human PD-1. [00:02:35] Speaker 00: Using knockout mice, they proved that this receptor was a negative regulator of immune response. [00:02:42] Speaker 00: And they had the idea that blocking PD-1 could have therapeutic effects for cancer. [00:02:49] Speaker 00: Now, everybody agrees that that didn't amount to conception. [00:02:53] Speaker 00: That was an idea. [00:02:55] Speaker 00: But that conception occurred only after Dr. EY and Dr. Hanjo completed their in vivo experiments in the fall of 2000 that allowed them to form the definite and permanent idea of the full scope of the invention. [00:03:12] Speaker 00: Everything that happened in between, and I'm including both Dr. Freeman and Dr. Wood, but I do hope that the court will focus on each individually. [00:03:22] Speaker 00: Everything that happened in between explains the biological, helps explain the biological mechanism for why Dr. Honjo was right. [00:03:33] Speaker 00: But you didn't need to know that biological mechanism, certainly for the 474 patent, which never mentions in the claims PD-L1 or it was the 474 patent is entirely agnostic as to the identity of the ligand or even whether the tumor cell expresses the ligand. [00:03:57] Speaker 00: Dr. Minato explained at pages 1990, [00:04:02] Speaker 00: 1994 and 2012 that the conceived invention was conceived to be effective as a therapy, an immunotherapy for cancer against tumors regardless of whether the tumors themselves [00:04:30] Speaker 00: The ligand itself, anything that activates the receptor, down regulates immune response. [00:04:40] Speaker 00: As all agree, there are many, many cells in the body, including immune cells, as Dr. Bonato explained, that express PDL1 or perhaps some other ligand. [00:04:53] Speaker 00: The presence of that, whether it's coming from the tumor or not, if blocked, [00:04:59] Speaker 00: will be an effective, could be an effective therapy against tumors, whether the tumors express PD-L1, PD-L2, or any other ligand. [00:05:12] Speaker 05: suggesting, and I didn't see this really pursued in your briefs, with the emphasis on 474, which is throughout, that some of these patents, they're all divisionals, should be treated differently as far as inventorship is concerned? [00:05:32] Speaker 00: Yes, Judge Newman, I think your case law is whether they were divisionals or not, although they are, the 474 is a divisional. [00:05:40] Speaker 00: I'm really there. [00:05:41] Speaker 00: I believe they're all divisionals following the 048 patent, but I think the court's case law is clear that joint inventorship is determined on a patent by patent basis. [00:05:55] Speaker 00: And indeed on a, you know, in some respects on a claim by claim basis in so far as we're talking about dependent claims. [00:06:03] Speaker 04: Yes. [00:06:03] Speaker 04: And so yes, you have a divisional here at divisional. [00:06:08] Speaker 04: cannot have, I don't believe a divisional can have different inventorship from a parent because the divisional claims material that was disclosed and originally claimed in the parent. [00:06:23] Speaker 00: So I don't think that's correct, and I don't think that could be correct, Judge Lurie, with all due respect. [00:06:33] Speaker 00: Inventorship is clearly determined, I mean you've said it over and over again, on a patent by patent basis. [00:06:39] Speaker 00: There is no question, divisionals or continuations or not, that all of the five HONJO patents employ the same specification, the same background of invention. [00:06:54] Speaker 00: What's different is the claim, but it is the claim that determines the invention and it has to be against the invention [00:07:02] Speaker 00: that joint inventorship is determined. [00:07:05] Speaker 00: It cannot be, and for reasons that we stated in our brief and that I can explicate here, even leaving aside Dr. Freeman and the 474 patent, we don't think that either Dr. Freeman or Dr. Wood qualify as having made a significant contribution to the definite and permanent idea of any of the inventions that are claimed in the different patents, but it cannot be. [00:07:32] Speaker 00: that because you make a determination, for example, that Dr. Wood should be considered a joint inventor on the 179 patent, that therefore, because that patent shares a specification with the 474, that he would ipso facto be a joint inventor on the 474. [00:07:53] Speaker 04: A divisional claims what was described in the parent. [00:08:00] Speaker 04: So I don't see how [00:08:02] Speaker 04: a divisional can have different inventorship from what is described in the parent. [00:08:07] Speaker 04: The divisional obtains its entitlement to a filing date on the basis of the parent. [00:08:15] Speaker 04: But move on. [00:08:16] Speaker 04: Go ahead. [00:08:17] Speaker 00: Well, I think, again, I do want to talk about all the patents, but before I leave the issue of Dr. Freeman and the 474 patent, the 474 patent claims [00:08:30] Speaker 00: blocking PD-1, not PD-L1 or any other ligand, blocking PD-1 to treat cancer. [00:08:39] Speaker 00: It directly follows from Dr. Hanjo's pre-collaboration discovery that blocking this receptor enhances the immune response. [00:08:55] Speaker 04: It's a treatment with an anti-PD-1. [00:08:58] Speaker 04: It's a treatment with an anti-PD-1. [00:09:00] Speaker 04: PD-1 monoclonal antibody. [00:09:03] Speaker 04: Does that not come from the ligand? [00:09:06] Speaker 00: It doesn't. [00:09:07] Speaker 00: The PD-1 monoclonal antibody does not depend on the ligand. [00:09:16] Speaker 00: The antibody was created by Dr. Honjo and Dr. Minato before the collaboration ever began. [00:09:24] Speaker 00: When the collaboration began, they sent that antibody [00:09:29] Speaker 00: and their discoveries that were soon to be published in the Immunity Journal, which discovered that blocking the antibody had the effect of avoiding suppression of the immune response to Dr. Wood. [00:09:48] Speaker 00: Dr. Wood took that anti-PD-1 antibody, and after Dr. Wood [00:09:56] Speaker 00: concluded that the 292 sequence was in fact a ligand and bound to PD-1. [00:10:03] Speaker 00: He used the PD-1 antibody and confirmed to Dr. Honjo what Dr. Honjo had discovered and disclosed in his immune article in immunity. [00:10:17] Speaker 00: The point is, if you look at the asserted contributions of Dr. Freeman, the district court found [00:10:25] Speaker 00: that Dr. Freeman located the 292 molecule in a public database, but it was Dr. Wood who discovered that 292 was a ligand for PD-1, and it was Dr. Wood who confirmed using Dr. Honjo's antibody that the ligand activated, in fact, activated the receptor and down-regulated the immune response. [00:10:54] Speaker 02: Mr. Raxman, this is Judge Stoll. [00:10:58] Speaker 00: Good morning. [00:11:00] Speaker 02: Good morning. [00:11:01] Speaker 02: I have one question for you, and this is specifically with regard to your argument about the 474 patents and that it doesn't talk about PD-L1. [00:11:13] Speaker 02: But this is my question. [00:11:16] Speaker 02: The district court judge found that all three, Dr. Wood, Dr. Freeman, and Dr. Hondo, [00:11:23] Speaker 02: we're all having a simultaneous focus on this pathway and cancer and using this pathway to treat cancer. [00:11:32] Speaker 02: This is like a page A 90 to 91. [00:11:35] Speaker 02: And so why doesn't that defeat your argument, even if the claims in the 474 patents are not talking about anti PD-L1 antibodies? [00:11:49] Speaker 00: Yes, thank you, Judge Stoll. [00:11:50] Speaker 00: I have three points I'd like to make in response. [00:11:53] Speaker 00: First of all, what Judge Saris was correctly identifying was the collaboration, and of course, collaboration is a necessary but not sufficient condition for joint inventorship. [00:12:06] Speaker 00: Number two, as Judge Saris found the [00:12:13] Speaker 00: Dr. Freeman and Dr. Wood did not establish by clear and convincing evidence that they were the ones who conceived of the idea of treating cancer by means of blocking the PD-1 receptor. [00:12:28] Speaker 00: She found on page 15 of her opinion that prior to this collaboration ever beginning, [00:12:39] Speaker 00: Once they conducted their knockout mouse experiments, Dr. Minato and Dr. Honjo specifically discussed the potential for that discovery to provide a possible immunotherapeutic response to cancer. [00:12:56] Speaker 00: And finally, the point here is that what we're talking about here, adjusting immune response, [00:13:08] Speaker 00: is utterly idiosyncratic. [00:13:11] Speaker 00: There are dozens of receptors on a T cell. [00:13:15] Speaker 00: There are hundreds of cells and structures in the body's immune system. [00:13:22] Speaker 00: No one can predict how they will all work in response even to a foreign pathogen like the COVID-19 virus, much less to a complex of cells like a tumor [00:13:37] Speaker 00: that are produced by one's own body. [00:13:39] Speaker 00: And that's why knowing the specific chemistry of a particular pathway does not amount to a significant contribution to conception. [00:13:57] Speaker 00: I think it's highly revelatory. [00:14:00] Speaker 00: If you look, for example, Judge Stoll, at the provisional patent application that Dr. [00:14:07] Speaker 00: Freeman and Dr. Wood filed in November of 1991, for which they ultimately received three patents on this pathway. [00:14:19] Speaker 00: They disclosed that the 292 sequence had been found in a tumor cell. [00:14:27] Speaker 02: Can I ask a question about that, actually? [00:14:30] Speaker 02: I'm glad you brought that up. [00:14:32] Speaker 02: So just so I understand, I mean, one of the arguments you make, and I'm moving off to a different argument a little bit, but one of the arguments you make is that some of the contributions of Dr. Freeman and Dr. Wood were actually in the prior ERT at the time of conception. [00:14:50] Speaker 02: You're not relying on that provisional PAD application to support that contention, are you? [00:14:55] Speaker 02: Because as I understand it, that would not have been published before conception. [00:15:00] Speaker 00: That's right. [00:15:02] Speaker 00: I was about to make a point on that provisional, a different point, which had to do with the unpredictability of how you use [00:15:13] Speaker 00: the knowledge about this pathway in order to... I understand, but I... Okay. [00:15:18] Speaker 00: I understand, that's in your... So our... Yeah, so our... I'm sorry, our prior art point, you know, turns on number one, the publication by Dr. Chen, who was the first person to identify the PD-L1 ligand, nine months before conception, and then the publication by [00:15:43] Speaker 00: Dr. Honjo, Dr. Wood, and Dr. Freeman of the article that was published, I believe, on October 1st, 2000. [00:15:51] Speaker 04: Dr. Honjo and his Nobel Lecture seem to give quite a bit of credit to Drs. [00:16:02] Speaker 04: Freeman and Wood. [00:16:04] Speaker 00: There's, you know, what Dr. Honjo's remarks in the Nobel lecture are public record and he acknowledged that they were valuable collaborators and there's no doubt, Judge Lurie, that they were. [00:16:16] Speaker 00: That's just not the test for joint. [00:16:19] Speaker 00: It is a condition of joint inventorship, but it's not sufficient. [00:16:25] Speaker 05: Let me interrupt to go back to this prior art question that Judge Stowell asked. [00:16:31] Speaker 05: I thought you were relying [00:16:33] Speaker 05: on the filing date of their separate initial filing as to what they had discovered, because a patent application is deemed a reference of its filing date, not as of its issue date. [00:16:51] Speaker 05: Yes, and so our point there, Judge... But you said no to Judge Stowell's question. [00:16:57] Speaker 00: Maybe I'm confusing myself. [00:17:01] Speaker 00: the disclosures in the provisional application, as I understand it, were not public as of the date of conception. [00:17:09] Speaker 05: They were public, but they technically are prior art. [00:17:15] Speaker 00: They are technically prior art, but those disclosures and more were published by Drs. [00:17:24] Speaker 00: Wood, Freeman, and Hanjo in an article that was available to everybody [00:17:30] Speaker 00: prior to the date of conception. [00:17:32] Speaker 05: Now, Judge Stoll... Well, that doesn't really say that they can't have been joint inventors, that collaborators decide... I'm just using the word collaborator in the sense that you're using it, if they decide to publish their findings as well as proceed through the patent system. [00:17:54] Speaker 00: So I do think, I mean, this is our proposition, and I think it's correct as a matter of first principles. [00:18:02] Speaker 00: The key to inventorship is the mental act of conception. [00:18:09] Speaker 00: Even if you provided earlier assistance to what ultimately became a conceived invention, if you choose to put those disclosures into the public domain, [00:18:24] Speaker 00: before conception, they become free for all to use because prior art is not an aspect of invention. [00:18:33] Speaker 05: Does your position depend on agreeing with that proposition? [00:18:39] Speaker 05: You really keep everything out of publication until a patent application is filed despite grace periods and all sorts of generally accepted law. [00:18:54] Speaker 00: So Judge Newman, first of all, this is one of three independent arguments that we're making as to why, with respect, we think the district court erred. [00:19:03] Speaker 00: But as to this point, I'm not making a point at all about the statutory one-year grace period or any other grace period for prior art disclosures before the filing of a patent application. [00:19:18] Speaker 00: This has to do with conception. [00:19:20] Speaker 00: which in this case occurred on October 27, 2000. [00:19:25] Speaker 00: The patent applications here weren't filed until 2003. [00:19:29] Speaker 00: And so the public disclosure in this case occurred well beyond outside the one year grace period. [00:19:40] Speaker 04: The fundamental point- We're talking about conception of a claim which has several aspects to it. [00:19:50] Speaker 04: The fact that one of those aspects may have been prior published does not defeat conception of the totality of what is ultimately claimed. [00:20:02] Speaker 00: I totally agree with you, Judge Lurie, and as a thought experiment, imagine that you have an invention to the combination of A, B, and C. You might disclose A to somebody else in confidence. [00:20:20] Speaker 00: And that person might be thinking about A while looking for B and C, but when that person figures out B and C and the time comes to put it all together, that is to conceive the combination of A, B, and C, you can't claim credit for A if it's in the public domain. [00:20:39] Speaker 04: The invention was putting... But if all of these people work together on A, B, and C, [00:20:46] Speaker 04: The fact that A was published earlier by one of the inventors doesn't defeat the conclusion that these people together worked on A, B, and C. Well, I guess what I would say, Judge Lurie, with respect is, let's just take a case of a sole inventor. [00:21:08] Speaker 00: If the sole inventor conceived, if the conception was the combination of A and B, [00:21:15] Speaker 00: and a, b, and c were all essential components. [00:21:19] Speaker 00: If the inventor, prior to conception, had put a in the public domain, he broke the chain by publishing a before the mental act occurred, at which point [00:21:33] Speaker 00: The contribution of A looks just like any other prior art. [00:21:37] Speaker 05: Let's assume that the statement of the law, as Judge Laurie has mentioned it, it certainly matches what I've always thought the law is. [00:21:48] Speaker 05: So it would be helpful, I think, to take a couple of more minutes, I know we're running over, to explain the other reasons. [00:21:59] Speaker 05: It seems to me that there is a [00:22:02] Speaker 05: strong argument that this could be used as a method for treating and curing cancer. [00:22:12] Speaker 05: I was struck by the fact that in the publication, the 1999 publication of [00:22:20] Speaker 05: doctors Wood and Friedman that they didn't say that, they suggested alternative future uses. [00:22:29] Speaker 05: And it does seem to me that the strong argument is the same one that it struck me, that the culture in awarding a Nobel Prize is that in your speech to the King of Sweden, you give credit to everybody who [00:22:45] Speaker 05: had anything to do with getting you to where you are and that Dr. Anjo did exactly that. [00:22:54] Speaker 05: But in terms of the technicalities of conception, and this is why I was trying to focus on the 474 patent, it does seem that the idea, the direction of curing cancer [00:23:09] Speaker 05: I did originate with Dr. Honjo. [00:23:13] Speaker 05: However, we've got some very strong claims and we've got very strong contributions. [00:23:19] Speaker 05: Where does the line get drawn? [00:23:22] Speaker 00: So I think that this court's case law has recognized a distinction between but for causation, including contributions, as this court said in Lilly, [00:23:39] Speaker 00: that help realize an invention, on the one hand, and on the other hand, the test for joint inventorship, which is significant contributions to the definite and permanent conception of an operative invention in all of its aspects. [00:23:59] Speaker 00: And your honor's reference to the November 1999 provisional, I think, is a good illustration [00:24:08] Speaker 00: of just how far the discovery of a particular molecular pathway is from the mental conception of something that had never even been thought to be true, that is, that the immune system of a complex organism could be used to treat cancer. [00:24:31] Speaker 00: In their November 1999 patent provisional application, [00:24:38] Speaker 00: They disclosed PD-L1, they disclosed its identity as a ligand, they disclosed their research on the pathway, they disclosed the concept that antibodies can block interaction, but in terms, and they posited that this discovery of this pathway could be an effective means of treating, and then they identified a whole number of classes of cancers. [00:25:04] Speaker 00: But one of the embodiments that they proposed of this invention was to elevate PD-1 levels in order to up-regulate the immune response, which is, as I think Your Honor's question was suggesting, the exact opposite and incorrect speculation [00:25:27] Speaker 00: of the, in fact, the efficacious method of doing this. [00:25:32] Speaker 00: And, you know, we have the fact that the patent app, that Honjo's patents were granted over all of these disclosures, which are also referenced in the background of the invention portion of the application. [00:25:49] Speaker 00: And we cited the court to the decision of the British Patent Court in [00:25:56] Speaker 00: Merck versus Bristol Myers Squibb, which involved a challenge by Merck, which had developed a competing checkpoint PD-1 inhibitor. [00:26:10] Speaker 00: And what the British Patent Court said on the very last page of its summary and conclusion, I don't believe I have public citation for it, [00:26:22] Speaker 00: And I'm quoting, and this is talking about the earlier Dana-Farber-Wood-Freeman application. [00:26:28] Speaker 00: The court said, quote, while its disclosure may be enough to support the general idea of using an agent which acts somehow on the PD-1 pathway in medicine, it does not make plausible the specific idea of an anti-PD-1 agent to treat cancer. [00:26:50] Speaker 00: A skilled person who conducted a test of PD-1 blockade against a tumor in a mouse would not have a fair expectation of success. [00:27:02] Speaker 00: And that's, that's again, just the demonstration of the leap between making or confirming a discovery that Dr. Ponjo and Dr. Minato and EY had made. [00:27:17] Speaker 00: that blocking the PD-1 receptor would up-regulate immune response to the conceived invention that all agree could only have been done after Dr. Eway's in vivo experimentation using real organisms that in fact down-regulate blocking PD-1 [00:27:47] Speaker 00: was both a safe and effective way of treating cancer. [00:27:52] Speaker 05: Okay, let's hear any more questions from Mr. Waxman at the moment. [00:27:56] Speaker 05: We'll say this is rebuttal time. [00:27:59] Speaker 05: Thank you, Your Honor. [00:28:00] Speaker 05: Okay, let's hear from the other side, Mr. Weir. [00:28:07] Speaker 01: Thank you. [00:28:08] Speaker 01: Are we unmuted? [00:28:10] Speaker 05: Yes. [00:28:11] Speaker 05: I hear you. [00:28:12] Speaker 01: I hear you. [00:28:13] Speaker 01: Thank you very much. [00:28:15] Speaker 01: Judge Newman, may it please the court. [00:28:18] Speaker 01: As this court heard in this appeal, appellants do not challenge as clearly erroneous one single finding of fact in Judge Saris' 111-page decision. [00:28:30] Speaker 01: The court could summarily affirm on that ground alone. [00:28:33] Speaker 05: Now, the real question is the conclusion that she drew and not the facts that she found. [00:28:40] Speaker 01: Isn't that right? [00:28:43] Speaker 01: Yes, but what's important here is what we're debating about is the significance of the contributions. [00:28:50] Speaker 01: And the argument that the appellants are making is that this is a question of law, that the court committed reversible error. [00:28:59] Speaker 01: It's a question of law, the significance of the contributions. [00:29:03] Speaker 01: Not the ultimate conclusion, but the factual, the subsidiary factual question, they say, is a question of law. [00:29:09] Speaker 01: And in case after case, [00:29:12] Speaker 01: This court has said that while the ultimate determination of inventorship is a question of law, it is premised on underlying questions of fact, such as the existence of collaboration, communication of the contributions, and the significance of the contributions to conception. [00:29:29] Speaker 01: This principle was articulated first in the Hess case in 1997. [00:29:34] Speaker 01: The issue in that case was whether... No, we understand that. [00:29:38] Speaker 05: But let's say that these scientists were not collaborators, but that Dr. Hondrew just read their scientific paper and thought that, and that this gave him some more ideas or the ultimate idea that he then threw their tests on the knockout mice and so on. [00:30:04] Speaker 05: confirmed. [00:30:06] Speaker 05: Would your answer be the same, that you pick up an idea from the published literature? [00:30:13] Speaker 05: Because scientists read the literature all the time. [00:30:17] Speaker 05: That's their stock in trade. [00:30:20] Speaker 01: Yeah, and absolutely not. [00:30:21] Speaker 01: Your Honor is absolutely correct. [00:30:23] Speaker 01: So there are several factors that enter into the ultimate legal conclusion, several factual questions, one of which is, were they collaborating? [00:30:31] Speaker 01: Were they working towards the same end? [00:30:33] Speaker 01: That's part of the proof. [00:30:34] Speaker 01: That's part of the burden of proof. [00:30:36] Speaker 01: And of course, in this case, Judge Saris found that there was lots and lots of evidence of collaboration. [00:30:43] Speaker 01: So that's not an issue in our case. [00:30:46] Speaker 05: No one said they weren't collaborating. [00:30:48] Speaker 05: The line that we're being asked to draw is the line between collaboration and conceptions. [00:31:00] Speaker 01: Is that right? [00:31:03] Speaker 01: No, I think collaboration is a separate issue, wasn't appealed. [00:31:09] Speaker 01: The issue is the significance of the contributions, whether they made significant contributions along the way to conception, not whether they were there at the final moment of the final experiment performed, but rather, did they make contributions that were significant along the way to conception? [00:31:28] Speaker 04: Now, Mr. Ware, Mr. Waxman has [00:31:33] Speaker 04: focused first on the 474 patent, which claims treatment of a tumor with an anti-PD-1 monoclonal antibody. [00:31:43] Speaker 04: Did Dr. Wood and Dr. Friedman contribute to that claim? [00:31:50] Speaker 01: Absolutely, Your Honor, and thank you for asking that. [00:31:54] Speaker 01: Let me say first that the appellants say that, well, these patents don't claim PD-L1. [00:32:01] Speaker 01: They don't claim the pathway. [00:32:02] Speaker 01: But nor did they claim as a separate patent, as a separate claim, they don't claim PD-1 or PD-1 antibodies, which has been known in the art for years. [00:32:14] Speaker 01: What they are claiming is a method of treating cancer by flocking PD-1. [00:32:20] Speaker 01: And when their expert opined, he was asked, excuse me, what was the dimension of the full invention? [00:32:29] Speaker 01: And he said, it was a method of treating cancer [00:32:32] Speaker 01: by blocking the PD-L1 pathway. [00:32:35] Speaker 01: And he said that with reference specifically to the 474 claims. [00:32:40] Speaker 01: Now, Judge Saris made specific findings of fact that bear on this. [00:32:44] Speaker 01: She found that Dr. Hanjo's conception of administering either PD-1 or PD-L1 antibodies both required knowledge of PD-L1's molecular structure and inhibitory function. [00:32:58] Speaker 01: Point being that you can't treat cancer and you can't claim a method of treating cancer by administering a PD-1 antibody to prevent a tumor from using the pathway to inhibit the immune response without knowing if the antibody will block PD-1's interaction with PD-L1. [00:33:15] Speaker 01: It's not just a question of whether the antibody will bind to PD-1. [00:33:19] Speaker 01: It's will it block the interaction with PD-L1. [00:33:22] Speaker 01: And this is, you see this throughout the patent. [00:33:26] Speaker 01: What the patent describes as the invention is stopping the interaction between PD-1 and PD-L1. [00:33:32] Speaker 01: And you can't have a claim to that. [00:33:34] Speaker 01: You don't have 112 support for that if you don't know what PD-L1 is, if you don't know its identity and its molecular structure. [00:33:44] Speaker 01: I think it's notable also that in the patent itself, [00:33:48] Speaker 01: that the examples that were provided as the 112 support, examples one through five, all use PD-L1 antibodies. [00:33:59] Speaker 01: There is no example in the priority document, that is the 2002 filing, there is no example of using a PD-1 antibody. [00:34:09] Speaker 01: And what Dr. Hancho did and the inventors, they extrapolated from the fact that blocking the PD-L1 [00:34:17] Speaker 01: pathway with a PD-L1 antibody would also work by blocking it with a PD-1 antibody. [00:34:24] Speaker 01: There was nothing special about PD-1. [00:34:27] Speaker 01: And, in fact, the mouse experiments that they make so much of, the in vivo mouse experiments, simply tested the growth of an implanted tumor with and without PD-L1 in the tumor. [00:34:43] Speaker 05: verification of the entire concept, was it not? [00:34:47] Speaker 05: You say that they could have proceeded without the mouse experiment? [00:34:51] Speaker 01: Oh, I'm not... That isn't my point, Your Honor. [00:34:54] Speaker 01: My point is simply to say that those experiments didn't use a PD-1 antibody. [00:34:59] Speaker 01: Again, the conception was not based upon testing a PD-1 antibody. [00:35:04] Speaker 01: The conception was to determine in, in that case, finally to determine in a mouse model, in a [00:35:12] Speaker 01: in vivo model that blocking the pathway affected the growth of the tumor. [00:35:18] Speaker 01: And it didn't matter whether you blocked the pathway ultimately with a PD-1 antibody or a PD-L1 antibody. [00:35:26] Speaker 01: I also want to mention that Judge Serris made a finding of fact at A94 that the mouse tumor model experiments only triggered conception because Dr. Hanjo knew from Dr. Freeman's work that like the transfected tumors in the mouse experiments, [00:35:42] Speaker 01: Human tumors express PD-L1. [00:35:47] Speaker 01: She said this in a discussion of the 899, which is directed to PD-L1 antibodies. [00:35:52] Speaker 01: But the point is that that one doesn't, that one, that patent likewise does not expressly refer to expression of PD-L1 on tumor cells. [00:36:03] Speaker 01: But the conception in this case was based upon knowing that the, that tumors, that human tumors expressed PD-L1. [00:36:13] Speaker 01: which came from Dr. Freeman. [00:36:15] Speaker 01: Dr. Manato himself, who was a named inventor, admitted that unless human tumors naturally express PdL1, all of their mouse studies would mean nothing. [00:36:26] Speaker 01: That's a quote from his testimony. [00:36:29] Speaker 01: Since we're on the 474, I'd just like to take one minute to make a comment on the dependent claims which are directed to specific kinds of tumors. [00:36:42] Speaker 01: The appellants argue that even assuming that Dr. Honjo learned only from Dr. Freeman that the claimed tumors in the dependent claims highly expressed PD-L1, that Dr. Freeman's contribution to a sole limitation in a dependent claim cannot count for inventorship. [00:37:00] Speaker 01: They are wrong on this. [00:37:02] Speaker 01: This court expressly held in Eli Lilly versus Eridine. [00:37:06] Speaker 01: that if the putative inventor conceived the single limitation added independent claim six of that patent and communicated this conception to the patent owner, then he would be a co-owner. [00:37:18] Speaker 01: I'm sorry, a co-inventor. [00:37:20] Speaker 05: But you're not saying that doctors Wood and Freeman suggested to Dr. Hanjo, maybe this could be useful to cure cancer? [00:37:31] Speaker 01: Oh, yes. [00:37:32] Speaker 01: Judge Saris made extensive findings to that effect. [00:37:35] Speaker 01: That is to say, she said... No, she didn't. [00:37:38] Speaker 05: She cited their publication. [00:37:41] Speaker 01: No, no, no, no. [00:37:43] Speaker 01: Specific meetings. [00:37:44] Speaker 01: There were three collaboration meetings in 2000, and she said during those meetings, [00:37:49] Speaker 01: that they were working together and discussing the harnessing of the PD-L1 pathway to treat cancer. [00:37:56] Speaker 05: Yes, it's clear that these scientists didn't hold back in talking with each other what they were doing and trying to advance the science in this important direction, but she didn't say [00:38:15] Speaker 05: that until Dr. Honjo came along, there was no thought of this pathway to cure cancer. [00:38:26] Speaker 05: And in fact, I think there's emphasis in the briefs that in a separate earlier [00:38:34] Speaker 05: patent application that Dr. Freeman and Wood suggested alternative paths that, including the one that Dr. Hancho came up with and demonstrated, but that they hadn't taken the next step of focusing on and testing, shall we say, reducing to practice the particular path in the 474. [00:39:02] Speaker 05: Is that fair? [00:39:04] Speaker 01: It's not, Your Honor, and let me refer you, let me just give you a site. [00:39:09] Speaker 01: In Appendix 31 to 32, Judge Saris actually addressed what was in the professional application. [00:39:15] Speaker 01: And what you heard from Mr. Waxman was an argument that they made several times at trial and it was thoroughly debunked at trial by expert testimony and Judge Saris did not accept it. [00:39:28] Speaker 01: And what she said about that application, [00:39:31] Speaker 01: is that it claimed methods of modulating the immune response by blocking the PD-1 pathway, PD-L1 pathway. [00:39:39] Speaker 01: The patent explained that the PD-1-PD-L1 interaction inhibits an immune response. [00:39:48] Speaker 01: And it included a claim, and this is claim 22, in which PD-1 signaling is inhibited by an antibody in order to upregulate the immune response to a tumor. [00:40:01] Speaker 01: So these ideas were in that patent application. [00:40:05] Speaker 01: What was not in that patent application, contrary to Mr. Waxman's statement, is that it did not talk about expression of PD-L1 in tumor cells. [00:40:17] Speaker 01: And that work came later. [00:40:19] Speaker 01: And that's one of the reasons why you would issue the ultimate patents over that [00:40:29] Speaker 01: over that provisional application. [00:40:32] Speaker 01: It was important work, but nobody suggests that the work was done at that point and the work continued. [00:40:41] Speaker 05: Where were there experiments treating tumors actually seeing if it worked? [00:40:50] Speaker 01: The provisional application did not have experiments treating tumors. [00:40:56] Speaker 01: I hasten to add also that the in vivo mouse experiments in the fall of 2000 also did not treat a tumor and did not use antibodies. [00:41:10] Speaker 01: The in vivo mouse experiments were an important contribution. [00:41:19] Speaker 01: We don't disagree with that at all. [00:41:21] Speaker 05: And that's a joint inventor named Inventor. [00:41:26] Speaker 01: Is that right? [00:41:28] Speaker 05: The scientist who performed those experiments? [00:41:30] Speaker 01: Yes, Dr. Iwe. [00:41:32] Speaker 01: But that, too, that experiment was removed from the actual claims because it did not treat a tumor. [00:41:39] Speaker 01: It was actually, as their expert agreed, it was just showing that the pathway is inhibitory. [00:41:46] Speaker 01: That had been shown in vitro. [00:41:48] Speaker 01: I'm sorry. [00:41:48] Speaker 05: What did you say? [00:41:49] Speaker 05: The experiment was removed from the claim? [00:41:52] Speaker 05: What do you mean by that? [00:41:54] Speaker 01: What I mean is simply that the experiment was an experiment to show that the pathway was inhibitory. [00:42:04] Speaker 01: It showed that the pathway was inhibitory in an animal model. [00:42:09] Speaker 01: But it did not treat a tumor. [00:42:11] Speaker 01: It did not use an antibody. [00:42:13] Speaker 01: And of course, it was in mice. [00:42:15] Speaker 01: So we agree it was an important contribution. [00:42:18] Speaker 01: But it was one of many important contributions that ultimately led to the conception. [00:42:28] Speaker 01: I don't have time, I don't think, to really get into the prior art argument, but I just would like to say that the principle that this court has long applied concerns whether a putative inventor has done nothing more than explain the current state of the art. [00:42:48] Speaker 01: That is when the contribution is made, and thus in the cardiac case, [00:42:54] Speaker 01: The court said, we can't identify any case in which we barred co-inventorship as a matter of law just because the contribution later appeared in the public domain when the ideas were not contemporaneously available. [00:43:08] Speaker 01: And in fact, the principle that is being argued by the appellants would require this panel to overrule this court's presidential decision in Panouvi ILAB, which has been good law since 1998, where [00:43:25] Speaker 05: Please finish your thought. [00:43:27] Speaker 01: Thank you, Your Honor. [00:43:30] Speaker 01: Where in that case, Dr. Paneu had placed his contribution in the prior art more than a year before he even met Dr. Lincoln and began collaborating. [00:43:40] Speaker 01: And this court held that Paneu was still an inventor because he contributed his ideas to a total inventive concept as part of a collaborative enterprise. [00:43:51] Speaker 01: And so if publication of the contribution more than a year before the collaboration starts does not preclude inventorship, then certainly there can be no bright line rule precluding inventorship where the publication is nearly a year after the parties began collaboration. [00:44:07] Speaker 01: And indeed, the publication they're referring to now was only three weeks before conception. [00:44:13] Speaker 01: But the contributions had already been used by Dr. Hanjo and used to develop his further experiment. [00:44:21] Speaker 01: I think my time's up. [00:44:23] Speaker 01: I'm happy to go on. [00:44:25] Speaker 04: But the totality of the claims was not in the prior aus. [00:44:30] Speaker 04: Maybe one piece of it. [00:44:34] Speaker 01: I'm sorry. [00:44:35] Speaker 01: Is Your Honor referring to the Pnoo case? [00:44:37] Speaker 04: No, no, this case. [00:44:39] Speaker 04: The totality of what's claimed was not in the prior aus. [00:44:43] Speaker 01: Oh, no, not at all. [00:44:44] Speaker 01: Not at all. [00:44:47] Speaker 04: Mr. Waxman is saying if a portion of it is, then that cannot be used to show co-inventorship of the totality of the claims by including the author of the disclosed portions. [00:45:09] Speaker 01: No, that's wrong. [00:45:10] Speaker 01: And in this case, just to emphasize this, all of the tumor expression data that Dr. Freeman contributed [00:45:17] Speaker 01: at the collaboration meeting in September 2008, just weeks before the alleged conception date, that work was not even published until 2003. [00:45:27] Speaker 01: And the significance of the PD-L1 expression in tumors runs throughout the patent. [00:45:32] Speaker 01: It is the key to why the inventors in the patent say that you can treat cancer by blocking the PD-1 PD-L1 pathway because of the fact that [00:45:47] Speaker 01: human tumors express PD-L1, and that's why all of their experiments artificially transfected tumors to express PD-L1 in order to show that their invention would work with tumors that express PD-L1. [00:46:02] Speaker 01: Thank you. [00:46:03] Speaker 05: Okay. [00:46:04] Speaker 05: Thank you. [00:46:04] Speaker 05: Any more questions for Mr. Ware? [00:46:07] Speaker 01: No. [00:46:08] Speaker 05: No. [00:46:09] Speaker 05: Okay. [00:46:09] Speaker 05: Thank you, Mr. Waxman. [00:46:11] Speaker 05: You have three minutes. [00:46:12] Speaker 00: Thank you, Your Honor. [00:46:14] Speaker 00: Judge Lurie, with respect to your question about divisionals and whether somebody who's a named inventor on one patent must be a named inventor on the other, I just want to point the court to 7 CFR section 1.53, which says that a continuation or divisional application that names as inventors the same or fewer than all of the inventors named in the prior application [00:46:42] Speaker 00: may be filed under this paragraph, the inventorship in the divisional application must include at least one inventor in the prior application, prior filed application. [00:46:54] Speaker 00: I'll make, I'll just respond briefly to Mr. Ware's points about the 474 patent and his assertion that conception of the 474 patent depended on PD-L1. [00:47:09] Speaker 00: and then a point about Panu and his prior art point. [00:47:16] Speaker 00: It is wrong, as a conclusion of law, that conception of the 474 patent depended on PD-L1, and in any event, even if it were right, [00:47:28] Speaker 00: that would not help Dr. Freeman. [00:47:30] Speaker 00: It was Dr. Wood, not Dr. Freeman, who discovered that 292 was in fact a ligand for PD-1, and it was Dr. Wood, not Dr. Freeman, who determined that the ligand's interaction with the receptor would down-regulate immune response, confirming something that Dr. Honjo had already discovered and published. [00:47:58] Speaker 00: The point about antibodies and the fact that Mr. Ware was pointing out the fact that the in vivo experiments didn't even use antibodies just underscores the point that you don't need antibodies for conception. [00:48:13] Speaker 00: They use the knockout mouse. [00:48:15] Speaker 00: the use of antibodies to block receptors was well known in the art and Judge Saris correctly concluded that the development of particular antibodies and all of the antibodies in the specification were developed by Honcho and Minato is just reduction to practice. [00:48:36] Speaker 00: The Wood and Freeman in their November 99 provisional [00:48:43] Speaker 00: made reference to the fact that asserted that antibodies blocking this pathway would affect the immune response. [00:48:51] Speaker 00: They didn't have any antibodies at the time other than the PD-1 antibody that Dr. Honjo had provided them. [00:49:00] Speaker 00: On this question about prior art, we have explained why we think PANU doesn't stand in the way of what we think is a first principles point [00:49:13] Speaker 00: uh... judge lori i know you author catapulted and it probably doesn't do me any good to explain what it means i'd i'd be my time is expired let me proceed with this issue um... we do think that this issue was actually directly confronted in the much to case which we site uh... i recognize that it's an unpublished decision and maybe this is an appropriate case to really clarify this court's [00:49:40] Speaker 00: case law, the point here that Mr. Ware was making, which is, well, even if that's true with respect to the disclosures that were published in the October 1 article, it's not true with respect to the results of the staining experiments that Dr. Dorfman did, which showed [00:50:05] Speaker 00: that PD-L1 was expressed on a number of different tumors and many, many different healthy cells. [00:50:12] Speaker 00: Judge, at page 103 of her opinion, Judge Saris correctly concluded that the identification of specific tumors or healthy cells expressing PD-L1 was not a significant contribution to the 474 patent. [00:50:30] Speaker 05: Any more questions for Mr. [00:50:33] Speaker 05: Mr. Waxman. [00:50:36] Speaker 04: Thank you for a well-argued case. [00:50:38] Speaker 05: Thank you, Your Honor. [00:50:40] Speaker 05: Thank you all. [00:50:41] Speaker 05: The case is taken under submission. [00:50:45] Speaker 00: Thank you. [00:50:46] Speaker 05: That concludes this panel's argued cases for this session. [00:50:51] Speaker 00: The Honorable Court is adjourned until Monday morning at 10 a.m.