[00:00:00] Speaker 01: The next case for argument is 23-1063, in-ray advanced cell diagnostics. [00:00:06] Speaker 01: Good morning. [00:00:08] Speaker 03: Good morning, Your Honors, and may it please the Court. [00:00:11] Speaker 03: There are several reasons in this case that the Board's factual findings are sufficiently flawed to warrant a determination by this Court that they are not supported by substantial evidence. [00:00:23] Speaker 01: And the emphasis here or the entirety of the argument, do we all agree that these three references in combination have it all? [00:00:31] Speaker 01: It's just a matter of motivation to combine the references. [00:00:34] Speaker 01: Is that what's at stake here? [00:00:36] Speaker 03: And reasonable expectation of success, Your Honor. [00:00:38] Speaker 03: I think we would agree that Kenny and Erdia and Ward each teach individual elements of the claims, but that the motivation to combine these references to ultimately arrive at the methods that we're claiming [00:00:52] Speaker 03: and the reasonable expectation of success. [00:00:55] Speaker 03: Both of those are missing. [00:00:57] Speaker 03: So yes, Kenny teaches an in-situ hybridization method using a series of nucleic acid based probes. [00:01:05] Speaker 03: So those are in intact morphologically intact cells. [00:01:09] Speaker 03: Or Dia teaches a method of detecting nucleic acids in lysed cells on a solid support. [00:01:16] Speaker 03: So it's a solution phase assay, which is a very different context. [00:01:20] Speaker 03: and Ward teaches multiplexed detection. [00:01:24] Speaker 00: Is the problem here with reasonable expectations success? [00:01:28] Speaker 00: Is it localized to ODEA and the fact that it's what in vitro? [00:01:34] Speaker 03: That is one element of it, your honor. [00:01:36] Speaker 03: Yes, so I can certainly address reasonable expectation of success first. [00:01:42] Speaker 03: So what we've argued is that, again, Kenny teaches detection of nucleic acids in morphologically intact cells, so it's known as an in-situ hybridization assay. [00:01:52] Speaker 03: Urdiya teaches a solution phase assay in which, as we've explained and as Dr. Urdiya explained in his declaration, the cells are lysed, so you're opening them up. [00:02:03] Speaker 03: and you're using a number of chemical components to disrupt the cells and destroy those components and then pull the target nucleic acid down onto a solid support and then detect it there after you've washed the other cell components away. [00:02:18] Speaker 00: Is it that process that you argue leads to an unreasonable expectation? [00:02:24] Speaker 03: That is one element of our argument, Your Honor. [00:02:27] Speaker 03: Yes, that's right. [00:02:28] Speaker 03: Is that you wouldn't reasonably expect success in modifying Kenny's assay in the way that you would need to when you combine it with the teachings from our idea. [00:02:37] Speaker 03: You wouldn't reasonably expect success in making that combination because of the different environments in which those assays are conducted. [00:02:45] Speaker 03: That is one of our reasonable expectation of success arguments. [00:02:49] Speaker 03: It also goes to motivation to combine, however. [00:02:54] Speaker 03: So in combining them in the first place, again, so Kenny's method uses a single nucleic acid-based probe, which it calls a target probe, that binds to the target nucleic acid first. [00:03:08] Speaker 03: And then after it binds, then it builds its amplification system in order to detect it. [00:03:14] Speaker 03: And verdia, and what's been cited by the examiner, is an element of verdia that's shown in figure 11, which we cited in our brief. [00:03:24] Speaker 03: in which it pulls down the target nucleic acid onto a solid support, and then it binds to what it calls label extender molecules, which is analogous to the target probe in Kenny. [00:03:35] Speaker 03: It's the thing that binds to the target nucleic acid. [00:03:39] Speaker 03: And then again, it binds its label probe. [00:03:42] Speaker 03: And our position is that first, one skilled in the art when viewing these references at the time of the invention, when it was looking at those disparate teachings in the very different context. [00:03:53] Speaker 03: Although they're both detecting nucleic acids, one skilled in the art with their knowledge at the time would not have been motivated to apply a probe use in a solution phase assay in that very different context. [00:04:09] Speaker 03: to the in vitro assay of Kenny. [00:04:11] Speaker 00: Why? [00:04:11] Speaker 00: Because that was a new unknown process? [00:04:15] Speaker 03: It's just a very different environment in which to do it. [00:04:18] Speaker 03: So both of them individually, yes or no. [00:04:21] Speaker 03: Kenny discloses one and Nordea discloses the other. [00:04:24] Speaker 03: But because the environment is so different, so in an in situ hybridization assay, [00:04:30] Speaker 03: Again, that's done in what's called morphologically intact cells. [00:04:33] Speaker 03: So all of the native cellular structures, all of the proteins... Why is the environment different? [00:04:38] Speaker 00: Is it because ODEA has a solution-based process in combination with an in-situ probing or in-vitro probing? [00:04:49] Speaker 03: ODEA is entirely in a solution phase. [00:04:52] Speaker 03: So you can call that an in-vitro process, some refer to it as. [00:04:56] Speaker 03: It's not in situ. [00:04:58] Speaker 00: If the solution process leaves you with a more stable collection or number of a cleaner universe of the sample that you're going to probe, why wouldn't that be something that a placida would look at? [00:05:16] Speaker 03: Well, our claims are in situ. [00:05:19] Speaker 03: So our claims are directed to a method of detecting two or more nucleic acid targets within an individual cell. [00:05:24] Speaker 03: So that's the environment that the claimed methods are conducted in. [00:05:28] Speaker 03: So what ERDIA is doing in that different setting, you're right, it is a cleaner environment. [00:05:33] Speaker 03: What it's done is the cells are broken open, subjected to conditions that destroy a number of the native biological materials. [00:05:41] Speaker 03: the target is pulled down onto the solid support. [00:05:44] Speaker 03: And again, this is all shown in Figure 11 of URDIA. [00:05:46] Speaker 03: And then there's washing steps, and those are disclosed in URDIA itself, which remove all of those off-target components. [00:05:55] Speaker 03: And so getting those probes that you would have to use from URDIA in combination with Kenny to arrive at the methods that are claimed in this patent application, [00:06:05] Speaker 03: you would have to take that probe configuration that's used in Ordea's solution phase assay and then apply it into an in-situ setting where, again, all of the morphologically intact cellular structures are there. [00:06:20] Speaker 03: You have off-target nucleic acids. [00:06:22] Speaker 03: You have off-target proteins. [00:06:23] Speaker 03: You have off-target cellular structures. [00:06:25] Speaker 03: So our claims are in situ. [00:06:28] Speaker 03: And then where Ordea is being used to modify Kenny is in solution. [00:06:35] Speaker 03: which is just a very different context. [00:06:37] Speaker 03: And we've made that argument throughout prosecution of the application, before the board. [00:06:42] Speaker 01: There are several arguments made here. [00:06:48] Speaker 01: But finally, the board rejected your reliance on the declaration. [00:06:55] Speaker 01: So if we start from there, and if we assume that the board [00:06:59] Speaker 01: we would affirm the board on a reasonable basis for rejecting the declarations. [00:07:07] Speaker 01: Where does that leave you? [00:07:09] Speaker 01: I mean, is a lot of the evidence or the argument you're relying on here based on those declarations? [00:07:15] Speaker 01: And if we agree with the board or at least defer to the board in its rejection of those analysis because they weren't supported or whatever, where does that leave us? [00:07:24] Speaker 03: I think, Your Honor, I think that the arguments that we've made, so the other arguments that were made by the board, the way that they combined the teachings of Rodea with those of Kenny, I think are clearly flawed. [00:07:36] Speaker 03: And we alluded to that extensively through our brief. [00:07:39] Speaker 03: Because what it did, so even before you get to the declarations, what the board did was it characterized the way you would need to modify Kenny by applying the teachings of Rodea is just to modify that step of how you detect [00:07:54] Speaker 03: the analyte target probe complex. [00:07:56] Speaker 03: And that's not the modification that needs to happen to arrive at our claims, which have two steps. [00:08:03] Speaker 03: We have the step of hybridizing in the cell and in the presence of non-targets nucleic acids, the capture probe system. [00:08:11] Speaker 03: And earlier in the claim, we referred to the capture probe system having two or more sets of capture probes, and each set comprises two or more different capture probes. [00:08:22] Speaker 03: That's the step that you would need to modify in Kenny in order to arrive at the methods that we're claiming, because Kenny only uses one target probe, and what we have in each set are two. [00:08:34] Speaker 03: So the board's characterization of that modification as just being, oh, it's just simply a different way of detecting the analyte target probe complex. [00:08:45] Speaker 03: It boiled it down to that, and I think it was four or five times in total when it was [00:08:52] Speaker 03: discounting or dismissing our arguments. [00:08:55] Speaker 03: But Kenny teaches that you can detect it anyway. [00:08:58] Speaker 03: But that's not what you need to do to modify. [00:09:00] Speaker 03: And so this is where the declarations come in. [00:09:02] Speaker 03: Because of these repeated errors that were made in the way the board characterized the rejection, this is where, in our opinion, the declarations [00:09:12] Speaker 03: become of more significant importance again because they are from the two very inventors of these references. [00:09:18] Speaker 00: The standard review here is substantial evidence, right? [00:09:22] Speaker 00: Yes, it is. [00:09:23] Speaker 00: And the board found that this hybridization technology and even the nuclear technology is based on technology that had existed for decades. [00:09:40] Speaker 03: Basic nucleic acid hybridization technologies, yes, it had certainly been known for decades. [00:09:45] Speaker 03: I believe the first report of fluorescence in situ hybridization, known as FISH, was from 1969. [00:09:52] Speaker 03: But nucleic acid hybridization is a very broad field. [00:09:57] Speaker 03: when you just take one nucleic acid and hybridize it to another and then use that for a detection method. [00:10:03] Speaker 03: Yes, overall, nucleic acid detection was certainly known. [00:10:08] Speaker 03: But I think the evidence throughout the record here is sufficient to show that the different ways that these individual references do it, whether a broad field in general is known, but the individual methods cited in each of the references are very different [00:10:26] Speaker 03: Again, the only findings that the board made on reasonable expectation of success were just first, it found that the artisan would have had a reasonable expectation of success by the combination of known methods of detecting nucleic acids in cells. [00:10:48] Speaker 03: which that was one statement it made, which is flawed. [00:10:51] Speaker 00: Your argument shows to me to be more motivation to combine. [00:10:56] Speaker 00: It is both. [00:10:56] Speaker 00: And reasonable expectation of success. [00:10:59] Speaker 03: Yes. [00:11:00] Speaker 03: But I think it is both. [00:11:01] Speaker 03: So it's motivation to combine. [00:11:03] Speaker 03: But the particular argument we've made. [00:11:05] Speaker 00: You only argue reasonable expectation of success. [00:11:10] Speaker 03: I believe we did argue motivation to combine, Your Honor. [00:11:13] Speaker 00: No, no, you did. [00:11:15] Speaker 00: OK. [00:11:15] Speaker 00: I'm not saying you didn't. [00:11:17] Speaker 00: But with respect to the combination of Ordea and how that technology works, that seems to be, you phrase that as more of a reasonable expectation of success. [00:11:31] Speaker 03: I think it is, Your Honor. [00:11:32] Speaker 03: And what we've argued is that the board's findings on reasonable expectation of success were conclusory and limited to one or two statements that generally this technology is known. [00:11:42] Speaker 03: But that's not a sufficient factual finding in our view under KSR. [00:11:47] Speaker 03: I will reserve the rest of my time. [00:11:49] Speaker 01: Thank you. [00:11:49] Speaker 01: Thank you. [00:11:50] Speaker 01: Good morning. [00:11:59] Speaker 02: Good morning, your honors. [00:12:00] Speaker 02: And may it please the court. [00:12:01] Speaker 02: Substantial evidence supports the board's findings that a skilled artisan would have been motivated to improve Kenny's Institute hybridization method using Udea's TL capture probe system. [00:12:13] Speaker 02: That would be to increase the detection specificity and to decrease background. [00:12:18] Speaker 02: In other words, the rejection was based on using Udea's sets of TL capture probes, which cooperatively bind then to the single label probe, and that would increase and improve [00:12:29] Speaker 02: Kenny's detection method, and that finding is sufficient to affirm the board's decision of a motivation to combine. [00:12:36] Speaker 02: The board also correctly rejected ACD's arguments about the differences between Kenny's in situ hybridization method on the one hand and Judea's solution-based methods on the other. [00:12:46] Speaker 02: The board found that Kenny established that a person of skill in the [00:12:51] Speaker 02: would understand and reasonably expect probes, and that includes the TL capture probes, could get to their targets even in the context of the cellular setting of an in-situ hybridization assay. [00:13:05] Speaker 00: What's your response to the other side's argument that the board mischaracterized the motivation necessary to modify Kenny? [00:13:16] Speaker 02: So I believe you're referring to their arguments about that when the board says any method can be used to detect the TL analyte complex in Kenny. [00:13:25] Speaker 02: And so the board clearly understood the examiner's rejection to be based on the sets of capture probes in UDIA that then bind to a single label probe. [00:13:36] Speaker 02: And I think that the examiner's rejection is quoted at JA-12 [00:13:43] Speaker 02: where it talks about using, an artisan will be motivated to use the cooperative binding of the capture probes to the target and the label probe. [00:13:53] Speaker 02: But I think it's also clear in the board's discussion at JA 12, where the board is rejecting the arguments between the differences between in situ hybridization and solution-based assays. [00:14:06] Speaker 02: And this is the second full paragraph, third sentence when it starts [00:14:12] Speaker 02: when it says for the reasons discussed above, or goes on, a person of ordinary skill in the art would understand and reasonably expect that once a TL probe is hybridized to its target, so that's the capture probe and the label extender probe of Eudaea, it may be [00:14:29] Speaker 02: So whether it's in situ or solution, any labeling probe or probe system could be used. [00:14:35] Speaker 02: And that's what the board means when they're modifying Kenny, that any label probe can be used to detect the TL probe. [00:14:46] Speaker 02: And the label probe is the detection step. [00:14:49] Speaker 02: And it's then detecting the TL [00:14:53] Speaker 02: DNA target complex. [00:14:55] Speaker 02: It necessarily then binds to a second TL capture probe because the whole point of using Udaya's label probe system is to cooperatively bind then to sets of TL capture probes. [00:15:08] Speaker 02: And again, the board said the motivation to do this is this would actually decrease your background and increase your detection sensitivity. [00:15:17] Speaker 01: So the board did not trouble us on page 16 of the board where the board says, in sum, the examiner's conclusion of obviousness is founded in decades-old basic nuclear acid hybridization that was not only well-known to those with skill in the art at the time the committee was expected to work. [00:15:35] Speaker 01: That's a little odd, right? [00:15:37] Speaker 01: I mean, that's a little conclusory. [00:15:39] Speaker 02: Well, I think the board is saying more than just that it's known, but that it's expected to work as intended so that it's predictable. [00:15:47] Speaker 02: And the board had earlier said, pointing to Kenny, that one of skill in the art knows how to design probes that don't bind non-specifically in the non-situationalization context. [00:15:57] Speaker 02: So the board is relying on Kenny's designing of the probes and teaching how to use probes, including a set of label probes, [00:16:06] Speaker 02: institute hybridization as that one of skill in the art can design probes and expects them to work as they are designed. [00:16:13] Speaker 02: So I think it's more than conclusory. [00:16:16] Speaker 02: It's based on the teachings of the prior art and what the prior art teaches about the known techniques of institute hybridization. [00:16:25] Speaker 02: And the examiner also had relied on the fact that Kenny discusses in the background section [00:16:31] Speaker 02: that it took the branch DNA probes, which are the TL capture probes, and they had been used in solution-based assays and then was able to use them in an in-situ hybridization context. [00:16:44] Speaker 02: So this basic technology has flowed back and forth between solution-based assays and in-situ hybridization assays, and they're not sort of two separate technologies that don't cross talk. [00:16:57] Speaker 02: So I think that what the board says about rejecting the argument about the differences between institute hybridization and solution-based assays, there's substantial evidence both for a motivation combined and a reasonable expectation of success. [00:17:13] Speaker 02: I could also answer questions about the reliance on Ward, which was [00:17:17] Speaker 02: relied on for the multiplexing detecting to target nucleic acids and substantial evidence for that. [00:17:23] Speaker 02: And then the board's rejection of the declarations because they didn't have an evidentiary basis and were contradicted by the evidence of the prior art, the teachings of the prior art. [00:17:34] Speaker 02: If this court has no more questions, we'd ask the court to affirm the board's decision. [00:17:38] Speaker 02: Thank you, Your Honor. [00:17:48] Speaker 03: Your Honor, there's just a few additional points I'd like to clarify here. [00:17:54] Speaker 03: My colleague referred to the fact that Kenny and the board's reliance on Kenny and the fact that it disclosed an in situ method that appeared to work in its context. [00:18:05] Speaker 03: And yes, that is the case. [00:18:07] Speaker 03: And the board also did make a statement that one skilled in the art would understand how to design probes that don't bind non-specifically in situ. [00:18:15] Speaker 03: But those are individual probes. [00:18:17] Speaker 03: So when you have an assay such as this that necessarily requires the cooperative hybridization of a number of different probes, they all have to work together [00:18:28] Speaker 03: to binds to the target nucleic acid and then be detected, each individual probe will encounter non-specific binding in that context. [00:18:37] Speaker 03: And so when you're combining a number of them together, that's where the problem occurs. [00:18:41] Speaker 03: And Dr. Urdea did refer to this very specifically in his declaration where he said that the controlling non-specific binding in an in situ assay is significantly more complex. [00:18:52] Speaker 03: And that makes sense because of all those off target nucleic acids. [00:18:55] Speaker 03: So I would disagree [00:18:57] Speaker 03: that it's sufficient to say that because one skilled in the art could design an individual probe that would minimize off-target binding, that would necessarily lead to a conclusion that in these systems that have multiple nucleic acid-based probes that all must hybridize in the exact right way in order for a signal to be detected. [00:19:18] Speaker 03: That means that there's substantial evidence supporting all of those arguments there. [00:19:24] Speaker 03: Also, the other issue that we raised that I want to come back to, again, is despite the board's ultimate conclusion that if you just looked at a picture of what you end up with as a result of our method claim, that all of those pieces are in the prior art, that that would necessarily render obvious the method steps that we have. [00:19:46] Speaker 03: I would disagree with that. [00:19:47] Speaker 03: Again, our claimed methods require those two steps. [00:19:51] Speaker 03: First, you hybridize the capture probe system, and then you capture to that the label probe system. [00:19:59] Speaker 03: And the director's position is that that second TL probe is a part of that label system, but it's not. [00:20:07] Speaker 03: In the claimed methods, you have to have a set of capture probes that have two different capture probes. [00:20:13] Speaker 03: And that's added in that step of hybridizing, not in the step of detecting. [00:20:18] Speaker 03: So if you attempt to rescue the board's analysis where, again, they repeatedly characterize that step in Kenny of detecting, that's where the problem comes in, is that you don't ultimately end up with the methods that we're claiming. [00:20:34] Speaker 03: The other thing I do want to comment on is the declarations. [00:20:38] Speaker 03: Again, there's been an argument that [00:20:41] Speaker 03: that they're insufficiently supported by evidence. [00:20:46] Speaker 03: Again, I would look to the Ulrich case and that case did discuss the proposition that [00:20:51] Speaker 03: These statements were made by individuals that were uniquely within their competence to opine on these issues. [00:20:58] Speaker 03: And when we have the number of errors that were made by the board and how they characterized the claims and how you would have to combine these references, and then you have declarations, the two authors of two of the cited references, and again, especially with Dr. Udia, he was the CSO of Bayer Corporation and worked extensively in nucleic acid diagnostics. [00:21:20] Speaker 03: We have their statements that these would not have been obvious, and they do have reasons for those. [00:21:26] Speaker 03: They didn't conclude they wouldn't have been obvious. [00:21:28] Speaker 03: They concluded, Dr. Urdea stated that you wouldn't reasonably expect success, and Dr. Kenney commented on motivation to combine unreasonable expectation of success. [00:21:37] Speaker 03: When we have those up against the errors the board made, those declarations should be given some consideration. [00:21:45] Speaker 03: Happy to answer further questions. [00:21:47] Speaker 01: Thank you. [00:21:48] Speaker 01: We thank both sides and the cases.