[00:00:00] Speaker 03: The case for argument this morning is 17907, University of California versus Broad Institute. [00:00:06] Speaker 03: Mr. Burrell, good morning. [00:00:08] Speaker 01: Good afternoon. [00:00:10] Speaker 01: Good afternoon. [00:00:11] Speaker 01: And may it please the court. [00:00:14] Speaker 01: When the University of California disclosed the necessary and sufficient components of CRISPR-Cas9 in 2012, researchers immediately understood its revolutionary potential as a simple, elegant, and powerful tool for editing genes. [00:00:29] Speaker 01: In just months, six different groups confirmed what UC predicted in 2012, which was that CRISPR-Cas9 could cleave DNA in eukaryotic cells. [00:00:40] Speaker 01: All six, including Broad, used only conventional techniques and common sense to achieve that predictable result. [00:00:48] Speaker 03: Well, I understand, and I understand you were under substantial evidence review, unless you can convince us that there's some legal error here. [00:00:55] Speaker 03: So on the question, you mentioned the word potential. [00:00:58] Speaker 03: But the board pointed us to statements, testimony, declarations that used words like very frustrating, weren't the same, it's not known whether, and various contemporaneous statements made at the time of your invention to point it to the fact that there was no reasonable expectation of success. [00:01:21] Speaker 03: How do we get around that? [00:01:22] Speaker 01: So I will answer your honest question directly. [00:01:24] Speaker 01: Permit me to make a framing point first, if I may. [00:01:28] Speaker 01: that the question of obviousness here, including the sub-question of reasonable expectation of success, of course, has to be decided on the basis of the entire record. [00:01:37] Speaker 01: And the question of substantial evidence, even if you're at the question of substantial evidence, is based on the record as a whole. [00:01:43] Speaker 01: Now, we think there were legal errors with respect to evidence other than the statements that would require vacatur, and we think even reversal on this record. [00:01:52] Speaker 01: But let's focus just on the statements now. [00:01:55] Speaker 01: But I do want to focus on those other issues, because I think they're critical. [00:01:59] Speaker 01: Now, with respect to the statements, I think a couple of things to bear in mind. [00:02:03] Speaker 01: First, we think that the way that the PTAP treated those statements is inconsistent with the law of the circuit with respect to the proper weight that ought to be given to inventor statements. [00:02:15] Speaker 01: And I would point the court in particular first to the Medicam case. [00:02:19] Speaker 01: And this is a case cited in our brief, and that's 437 F3rd. [00:02:22] Speaker 01: And this is at page 1157. [00:02:26] Speaker 01: And if the court will permit me, I want to quote the statement that the inventor made in that case, which the court found was insufficient to overcome the obviousness as shown by the prior art. [00:02:38] Speaker 01: The inventor in that case said, frankly, I as an organic chemist have no reason to say that there were grounds for expecting anything from the addition of a tertiary amine for the particular [00:02:50] Speaker 01: step at issue there. [00:02:51] Speaker 01: I'd also point the court to the Pfizer against... Time out. [00:02:55] Speaker 02: But the problem with the case you just cited is the fact finding made below went the other way. [00:03:00] Speaker 02: See, Mr. Grell, the problem you have here is you're trying to convince me there's substantial evidence for the outcome you want. [00:03:08] Speaker 02: I may agree with you, but that doesn't mean there isn't substantial evidence for the outcome the other side found. [00:03:14] Speaker 02: The case you cited, the fact was decided the other way. [00:03:18] Speaker 02: And our decision affirmed that that inventor statement did not require overruling the substantial evidence or overturning the substantial evidence. [00:03:27] Speaker 02: Do you see the problem I'm having? [00:03:28] Speaker 02: Here, you have to deal with whether there is substantial evidence for the position the PTO did reach. [00:03:34] Speaker 01: I see Your Honor's point. [00:03:36] Speaker 01: I don't think it's a problem. [00:03:37] Speaker 01: And let me try to explain why. [00:03:39] Speaker 01: First, that standard, the question of whether inventor statements, how you treat inventor statements in light of [00:03:48] Speaker 01: the prior art as a whole, that standard's gotta run, it's gotta apply the same way no matter which direction it's running in. [00:03:54] Speaker 01: And so I think it- I guess I don't understand that answer. [00:03:58] Speaker 02: It seems to me that an inventor's statement made contemporaneously is a piece of evidence. [00:04:03] Speaker 02: And it is a piece of evidence weighed with all the rest of the evidence. [00:04:06] Speaker 02: I don't think I understand what role you're giving it and whether it's something diminished as compared to other evidence or more significant as compared to other evidence. [00:04:14] Speaker 02: I don't think I understand your position [00:04:17] Speaker 02: that it has to play the same role no matter whether it's supporting the outcome or refuting the outcome. [00:04:23] Speaker 01: It's just a piece of evidence. [00:04:24] Speaker 01: We agree it's just a piece of evidence and that gets back to the point of why you can't consider, you can't resolve this case just based on the statements alone which is I would submit pretty close to what the PTAM did. [00:04:34] Speaker 01: If you look you'll see at the end of its discussion of the statements it says the evidence of the statements persuades us that there's no reasonable expectation of success here but then [00:04:43] Speaker 01: I actually think it's important to remember who has the burden of proof in this situation. [00:04:48] Speaker 01: This is not a case in which it's coming up to you from the district court in which the patent was found valid and there's a clear and convincing standard and the burden's on us. [00:04:58] Speaker 02: The burden was on the road to show the absence of a reasonable expectation of success and if one looks at the statements... But the problem for you is that you have multiple statements by multiple of the UC inventors that are [00:05:13] Speaker 02: pretty strongly worded about many frustrations getting CRISPR to work in human cells. [00:05:18] Speaker 02: I hope you're sitting down, because CRISPR turns out to be absolutely spectacular. [00:05:23] Speaker 02: A Harvard geneticist just figured out how to make it work in human cells. [00:05:27] Speaker 02: So these are all statements that one of the inventors says, a bottleneck in getting this to work in human cells. [00:05:33] Speaker 02: Now, it turns out there wasn't a bottleneck. [00:05:35] Speaker 02: It turns out that traditional technologies [00:05:39] Speaker 02: allowed it to work with relative ease compared to other attempts to move from a prokaryotic environment into a eukaryotic environment. [00:05:49] Speaker 02: But the question isn't, did it turn out to be easy to do? [00:05:53] Speaker 02: The question is, what was the perception of the skilled artisan at the time it was done? [00:05:58] Speaker 02: And so you're trying to give me a lot of ex-post evidence, which I'm not saying is irrelevant. [00:06:04] Speaker 02: But the evidence of your very inventors at the time isn't consistent. [00:06:08] Speaker 02: with the belief that it was going to be done easily. [00:06:11] Speaker 02: And that's what the PTO had in front of it. [00:06:13] Speaker 01: So three points, if I may. [00:06:15] Speaker 01: First, if one looks at the way in which the PTAB analyzed that evidence, in each instance it took a specific quote and it said, this does not convince us that a reasonable expectation of success exists. [00:06:31] Speaker 01: You can go through that every single time. [00:06:33] Speaker 01: That's what they did. [00:06:34] Speaker 01: In other words, they put the burden on us and not on road to disprove. [00:06:37] Speaker 01: That's point one. [00:06:38] Speaker 01: point two, with respect to those statements, I think that really the only fair characterization, and I can go through them one at a time if your honor wants me to, is that they range from neutrality and uncertainty to positive. [00:06:51] Speaker 01: There isn't a single statement by anybody who says, we don't think this is going to work. [00:06:55] Speaker 01: And then take the bottleneck statement, for example. [00:06:58] Speaker 01: This is a related point about- Just because your time is running out, can I move us off of the statement issue because you're- I'd be delighted to do that because I do think [00:07:06] Speaker 03: Well let me point you in a direction and you might rather go off in another direction but there are a couple of kind of legal principles that the board applies and some of what they said may give someone pause. [00:07:19] Speaker 03: One of them for me at least is in the obvious to try context in their discussion on page 25 and how what they say about the obvious to try standard and then there's some other stuff about [00:07:32] Speaker 03: they're juxtaposing motivation and reasonable expectation of success, sort of suggesting if you're highly motivated, then you're not. [00:07:41] Speaker 03: There's no reasonable expectation of success, which is kind of something that I hadn't heard of before. [00:07:46] Speaker 03: So if you want to address those two, you might have others as well. [00:07:49] Speaker 01: Yes. [00:07:49] Speaker 01: I want to focus on two specific errors of law, which I think lead to a deeper error of law, which Your Honor's question identified. [00:07:57] Speaker 01: With respect to the two specific errors of law, one was that the PTAB [00:08:02] Speaker 01: ruled that the evidence of what the six other groups did, not just that they succeeded, and not just how fast they succeeded, but how they succeeded, what techniques they used, was irrelevant to the question of reasonable expectation of success. [00:08:19] Speaker 01: They said it with respect to the Kim provisional on pages 47 and 48, unambiguously. [00:08:24] Speaker 01: They said on page, I think it was 23, [00:08:28] Speaker 01: of their order, that they were going to consider that evidence. [00:08:31] Speaker 01: And instead of viewing such evidence, such work as evidence of an expectation of success, we consider the number of groups who attempted to use it as evidence of motivation. [00:08:40] Speaker 01: Then at page 32, you will see again, they say, they quote an inapposite case about the inventor's own state of mind to say that this evidence is irrelevant [00:08:52] Speaker 01: I would submit respectfully it is the most relevant evidence. [00:08:55] Speaker 01: And going back to something Judge Moore said earlier. [00:08:58] Speaker 03: Do they actually say it's irrelevant? [00:08:59] Speaker 01: Irrelevant. [00:09:00] Speaker 01: That's the quote from LifeTech. [00:09:02] Speaker 01: Irrelevant. [00:09:03] Speaker 01: On page 47, Kim Provisional has no relevance to this proceeding. [00:09:08] Speaker 03: With respect to Kim, I thought you were saying that they said that all these quick [00:09:13] Speaker 01: The Kim Provisional is one of the examples of evidence that we submitted. [00:09:16] Speaker 03: But I thought the Kim analysis had something to do with a different issue. [00:09:20] Speaker 03: They didn't say that all of those subsequent very quick. [00:09:25] Speaker 01: Well, they did. [00:09:26] Speaker 01: With all due respect, John, I'm sorry to interrupt. [00:09:28] Speaker 01: But I think on page 32, that's exactly what they're saying. [00:09:31] Speaker 01: They're saying, you see points that this body of evidence, we don't think it defeats a reasonable expectation of success. [00:09:38] Speaker 01: It's irrelevant what an inventor thought before the inventor carried out the experiment. [00:09:44] Speaker 01: And I think, first of all, that's just wrong on the basis of- Well, time out. [00:09:50] Speaker 02: Unless I'm mistaken, what they are quoting is our life tech decision. [00:09:56] Speaker 02: It doesn't seem to me that the PTO stated something was relevant or irrelevant. [00:10:02] Speaker 02: They're directly quoting a Federal Circuit decision, right? [00:10:05] Speaker 02: Am I right? [00:10:06] Speaker 02: Am I mistaken? [00:10:06] Speaker 02: Is there another place other than the sentence on 32, which is the quote from LifeTech? [00:10:11] Speaker 01: So let me address that, and then I'll show you the two other places if I could. [00:10:15] Speaker 01: With respect to this, the prior sentence, which is not a quote, which is the PTAB saying, the ultimate results of an experiment do not indicate what one of ordinary skill in the art would have thought before the experiment was performed. [00:10:25] Speaker 01: That's wrong in two ways. [00:10:26] Speaker 01: First, that if you look at Echolachem, you look at Martin, you look at [00:10:31] Speaker 01: international glass, you look at trustees of Columbia, they all say that that is strong evidence that must be considered when present. [00:10:39] Speaker 01: So that's just an error on its own terms. [00:10:42] Speaker 01: But there's a more basic point here, which I think is absolutely critical, which is that we didn't introduce this evidence just to show success or the speed of success. [00:10:50] Speaker 01: We introduced this evidence to show that nothing more than conventional techniques and common sense were needed to succeed. [00:10:58] Speaker 01: And with respect, [00:11:00] Speaker 01: That's not post hoc evidence. [00:11:02] Speaker 01: That is the best possible contemporaneous evidence of what persons of ordinary skill in the art in 2012 thought. [00:11:10] Speaker 01: All of them took off the shelf conventional techniques, techniques that the PTAB itself on page 35 held were conventional techniques known to persons of ordinary skill in the art, applied them without any modification, any variation, any need to try to address any anticipated particular problem [00:11:29] Speaker 01: to achieve successful results. [00:11:31] Speaker 01: That is powerful evidence. [00:11:33] Speaker 01: It goes, as Nikola Kemp said, to the level of knowledge of a person of ordinary skill in the art, which is the baseline for evaluating a reasonable expectation of success. [00:11:42] Speaker 01: That's just a clear, absolute error. [00:11:45] Speaker 01: And I think the other legal error, I think, as clear as can be, is the PTABS ruling that it was going to require here [00:11:55] Speaker 01: specific instructions particular to the implementation of CRISPR-Cas9 in the eukaryotic environment. [00:12:02] Speaker 01: That's just a flat-out violation of the rules set forth in KSR. [00:12:06] Speaker 01: It's exactly what KSR said that you can't do. [00:12:09] Speaker 01: I think you can find those requirements of specific instructions on pages 28 and 29 and again on page 45. [00:12:18] Speaker 02: Well on page 28 it says [00:12:23] Speaker 02: These cases instruct us whether or not one of skill in the art would have had a reasonable expectation of success, and it depends on the specific nature of what was known from the prior art about closely related subject matter. [00:12:34] Speaker 02: Now, you don't have a problem with that sentence, do you? [00:12:36] Speaker 02: I don't have a problem with that. [00:12:37] Speaker 01: No, but it's where it leads. [00:12:38] Speaker 02: Specific instructions that are relevant to the claimed matter or success have directed findings of a reasonable expectation. [00:12:48] Speaker 02: Do you think that means the opposite? [00:12:50] Speaker 01: No, but what I do think it means, and it gets the Chief Judge's question from earlier about the way in which the PTAB went about its analysis here. [00:13:00] Speaker 01: PTAB goes through a whole list of this court's prior cases, some in one bucket finding reasonable expectations, excess others rejecting it. [00:13:10] Speaker 01: And then it purports to define a rule. [00:13:18] Speaker 01: What the PTAT did was go through that list and then purport to divine exactly this division that Judge Moore's question pointed to. [00:13:39] Speaker 01: But if you look at those cases, [00:13:42] Speaker 01: All but one of the cases in that list that find no reasonable expectation of success are pre-KSR cases that are applying the teaching suggestion or motivation test. [00:13:53] Speaker 01: And the only one that isn't is a case where there was specific prior R, the Pasteur case pointing, teaching away. [00:13:59] Speaker 01: And so I think really what you're seeing here is what the, what the PTAP did is, and I'm looking at these cases, relying on cases that now [00:14:08] Speaker 01: invoke an approach that the Supreme Court has rejected, and dividing a rule that says basically what we're going to do is look for specific instructions in certain situations, but that rule really has no basis. [00:14:26] Speaker 01: It has no basis in the law. [00:14:29] Speaker 01: It has no basis. [00:14:30] Speaker 01: It's inconsistent with KSR. [00:14:32] Speaker 01: And I think critically, too. [00:14:33] Speaker 03: Well, the only problem is whether or not they really did. [00:14:35] Speaker 03: I mean, just going back to Judge Moore's point, where they really said that in the absence of specific instructions, you didn't have to. [00:14:43] Speaker 01: Well, I would, again, I think the place to look there is their holding at page 45, which says, the preponderance of the evidence cited by Broad persuades us [00:15:00] Speaker 01: that there would not have been specific instructions relevant to CRISPR-Cas9 to give one of ordinary skill in the art a reasonable expectation success would work in your carryouts successfully. [00:15:10] Speaker 01: And I think essentially what happened here is that the PTAB took that body of case law and said, well, KSR is going to apply in certain circumstances. [00:15:20] Speaker 01: But in other circumstances, we go to a totality of the circumstances kind of analysis. [00:15:25] Speaker 01: But I really think that that's completely inconsistent with what this circuit said [00:15:30] Speaker 01: in Kubin, where, and I really think that the analysis here is set forth in Kubin, that in a situation in which there is motivation, where it's obvious to try, basically we look to see whether, as KSR said, there are a finite number of solutions, there's motivation, there are a finite number of solutions, and the person of ordinary skill in the art uses one of those finite number of solutions to achieve the anticipated results. [00:15:58] Speaker 01: The other side of the spectrum is a situation which, you know, Kubin quoting the O'Farrill case, so it was a, says a situation where the inventor would have had to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result where the prior art either gave no indication of which parameters are critical or no direction as to which of the many possible choices is likely to be successful or later on to explore a new technology or general approach that seemed to be promising. [00:16:29] Speaker 01: This case is nothing like that situation. [00:16:32] Speaker 01: There are a handful of conventional techniques, the ones that PTAB validated as within the knowledge of a person of ordinary skill in the audit, page 35 of the order. [00:16:42] Speaker 01: The nucleic targeting, the codon optimization, the direct injection. [00:16:47] Speaker 01: Those are the exact techniques that the Broad used and no others. [00:16:51] Speaker 01: And they're the exact techniques that every other one of the groups used [00:16:55] Speaker 01: And that's powerful contemporaneous evidence of exactly what a person of ordinary skill in the art thought would be needed to solve the problem of trying to introduce CRISPR-Cas9 into eukaryotic cells. [00:17:10] Speaker 01: And I think it's quite striking. [00:17:11] Speaker 01: I would urge the court to take a look at this chart, which appears in volume 7 of the appendix. [00:17:18] Speaker 01: And it's in particular pages 5177 through 5179. [00:17:24] Speaker 01: If you look at it, you'll see that you just kind of go down the list and see they all do exactly the same thing. [00:17:32] Speaker 01: They all use exactly the techniques that the PTAB found were conventional techniques. [00:17:37] Speaker 01: They, if you look at page 1579, for example, they all use codon optimization, except for one who didn't, who provenly didn't even need it. [00:17:47] Speaker 01: They all use the NLS [00:17:49] Speaker 01: They all used vectors. [00:17:51] Speaker 01: These are the tools that the PTAB itself said are within the knowledge or person of ordinary skill in the art. [00:17:59] Speaker 01: They all used them. [00:18:00] Speaker 01: None of them thought that there was a problem of the kind that the PTAB hypothesized. [00:18:06] Speaker 01: The PTAB hypothesized based on Dr. Simon's expert testimony that, well, because [00:18:15] Speaker 01: Some other systems had required variations in order to account for unique conditions that a person of ordinary skill in the art wouldn't have had a reasonable expectation of success that you could introduce CRISPR-Cas9 into eukaryotic cells because you would have been worried about these unique conditions. [00:18:32] Speaker 01: But what I, what I, the reason I think it was such a grave error on the part of the PTAP not to look at this evidence as relevant to the question of expectation of success is that it refutes that inference. [00:18:43] Speaker 01: It shows you that, confronted with this exact question, people of ordinary skill in the art did not vary the parameters, did not try to design around this hypothetical problem. [00:18:52] Speaker 01: There's any hindsight here. [00:18:54] Speaker 01: The hindsight is in that PTAB analysis, taking an expert who, several years after the fact, said, well, a few years ago, they would have been worried about these things. [00:19:02] Speaker 01: Well, look at what the people actually did at that time. [00:19:05] Speaker 01: They weren't worried about those things. [00:19:06] Speaker 01: And so, your time, you're way over your time. [00:19:10] Speaker 03: We'll reserve some time for everybody. [00:19:11] Speaker 01: Thank you very much. [00:19:12] Speaker 03: Thank you. [00:19:24] Speaker 00: Good afternoon. [00:19:25] Speaker 00: This is the court. [00:19:28] Speaker 00: Your Honor, UC's argument focuses on the wrong time period for assessing obviousness and re-electrification of success. [00:19:36] Speaker 00: It looks to whether in hindsight, after experiments were done, whether it took what they were calling innovative techniques to get to the invention. [00:19:44] Speaker 00: But that is not the proper inquiry. [00:19:46] Speaker 00: It's what Opposa thought at the relevant time before the experiments were conducted. [00:19:51] Speaker 00: We heard counselors say that everybody designed their tests with the expectation it would work. [00:19:56] Speaker 00: There's not a shred of evidence on that anywhere in this record. [00:20:00] Speaker 00: They rely on six groups. [00:20:01] Speaker 00: One of them are the UC inventors. [00:20:03] Speaker 03: do you see inventors as your honor made the question is what the test was that the board applied to all of these statements I mean we feel to see how no guarantees you know they said some they relied on the fact there were no guarantees as your friend pointed out they seem to rely on specific the need for specific or suggest the need for specific instructions so the question if we step back a minute certainly we know there may be competing [00:20:33] Speaker 03: statements and maybe your friend loses because of the substantial evidence review, but tell me the question of why the things that have been pointed out don't suggest that the board may have applied the problematic standard. [00:20:48] Speaker 00: Okay, let me start with the no guarantee and then I'll go to the specific instructions. [00:20:51] Speaker 00: On the no guarantee, the PTAB recited the reasonable expectation of success standard 30 times in its opinion. [00:20:57] Speaker 00: Never once did it say that it was requiring a guarantee. [00:21:00] Speaker 00: In fact, it's only mention of certainty [00:21:03] Speaker 00: was to point out that it is not required at appendix pages 12 and 13. [00:21:07] Speaker 00: The PTAB relied on the statement that Dr. Carroll said contemporaneously that there was no guarantee that the system could access the chromatin. [00:21:17] Speaker 00: But in that article, they also relied on the statements that there were problems that RNA issues, the RNA might get chopped up. [00:21:24] Speaker 00: They relied on statements that there might be toxic to the system. [00:21:27] Speaker 00: At appendix page 18, the PTAB relied on Dr. Carroll's statement when he was cautioning the readers at the end of his article [00:21:34] Speaker 00: that the results for other systems were, quote, discouragingly low, close quote. [00:21:39] Speaker 00: That's on appendage page 18. [00:21:41] Speaker 00: It's not just the no guarantee. [00:21:43] Speaker 00: Dr. Carroll wrote an article contemporaneously with the Genic-20-Tel publication and said, the results of other systems have been discouragingly low. [00:21:53] Speaker 00: This thing might get eaten up with the RNA defenses. [00:21:55] Speaker 00: It might be toxic to the cell. [00:21:57] Speaker 00: There's a whole lot of concerns here. [00:21:59] Speaker 00: He never once said, I think this is going to work at all. [00:22:01] Speaker 00: And the PTAP made the affirmative finding [00:22:04] Speaker 00: According to what the council said, that on Appendix 19, the only conclusion we draw from Dr. Kirill's statement is at the time he did not have a reasonable expectation of success the system would work. [00:22:15] Speaker 00: Not a neutral thing. [00:22:16] Speaker 00: There was no burden put on them. [00:22:18] Speaker 03: Yeah, but those statements are preceded. [00:22:21] Speaker 03: Move up a few lines there. [00:22:23] Speaker 03: We feel to see how no guarantee indicates an expectation of success. [00:22:30] Speaker 03: That's kind of [00:22:31] Speaker 03: The burden is on you all, not on them. [00:22:34] Speaker 03: And then they go on to say, correctly, although there need not be absolute predictability, at best, Dr. Carroll's statement, I guess they're talking about the statement that there are no guarantees, highlights some specific reasons why CRISPR system might fail. [00:22:51] Speaker 03: Thus, the only conclusion we draw from his statement is that at the time, he did not have a reasonable expectation. [00:22:58] Speaker 03: That seems really kind of skewed, right? [00:23:01] Speaker 03: I mean, maybe there was some on one side and some on the other, but that seems quite strong. [00:23:06] Speaker 00: Well, Your Honor, on the prior page, they point out the fact that if we go to Appendix 18, they say Dr. Carroll also, excuse me, at the top of the page, they quote at line 2 the idea of the RNA hydrolysis. [00:23:20] Speaker 00: That's where the RNA can get chopped up by the system. [00:23:23] Speaker 00: He also raised technical questions about whether CRISPR could be used successfully in the same commentary. [00:23:28] Speaker 00: He pointed out [00:23:29] Speaker 00: potentially to enhance the activity of cleavage in eukaryotic cells while cautioning about the risk of undesirable side effects. [00:23:36] Speaker 00: There's no guarantee only to do with the chromatin. [00:23:38] Speaker 00: The side effects would be just chopping up the cell itself and killing it. [00:23:42] Speaker 00: And then they go on. [00:23:42] Speaker 00: If you look at this, Your Honor, at Appendix 18, there's this quote here, and it says that, second line, the efficiency of modification by introduction of simple oligonucleotides, it goes on, remains discouragingly low in most cases. [00:23:58] Speaker 00: So they're not just going with the no guarantee about chromatin. [00:24:01] Speaker 00: They say that his statements in this article, they're referring to all of these things. [00:24:06] Speaker 00: He lists out three major concerns. [00:24:08] Speaker 00: Chromatin is the one they said no guarantee about. [00:24:10] Speaker 00: Toxicity to the cell, RNA getting chopped up for the system, and that the results in other types of systems like this have been discouragingly low. [00:24:21] Speaker 00: That is telling the reader, [00:24:23] Speaker 00: We have not had much success with any of these kinds of systems so far. [00:24:26] Speaker 03: But doesn't he conclude, and maybe it's apples and oranges, but when the citation they have at the middle of page 18 concludes with whether the CRISPR system will provide the next generation of targetable cleavage reagents remains to be seen. [00:24:39] Speaker 03: But it is clearly well worth a try. [00:24:42] Speaker 03: That's right. [00:24:43] Speaker 03: Stay tuned. [00:24:44] Speaker 00: That's right. [00:24:45] Speaker 00: And he's just told the readers that the other ones that have been worth a try, there's been many systems that have been worth a try. [00:24:50] Speaker 00: And the results of those, as he points out, [00:24:52] Speaker 03: There's no teaching away here, right? [00:24:55] Speaker 03: There's no teaching away argument. [00:24:56] Speaker 00: No, there's no teaching away argument. [00:24:58] Speaker 00: No. [00:24:58] Speaker 00: But he's telling the readers in that same paragraph, keep in mind the results of prior experiments in these types of systems have been discouragingly low. [00:25:08] Speaker 00: And the board considered his statements in the view of the entire record here, including the statements of the inventors, to see where people thinking this had an expectation of success. [00:25:17] Speaker 00: They reviewed the Carol article in its entirety and said, we think Carol had no expectation of success. [00:25:24] Speaker 00: Certainly nothing positive said, yes, there was a motivation, but that is it. [00:25:28] Speaker 03: What about the boards not giving much emphasis, not placing much emphasis on all the simultaneous inventions going on, the simultaneous work, the stuff that all, by coincidence or whatever, five, seven people, whatever, came up with this within a very short period of time? [00:25:46] Speaker 00: If I could take just like 30 seconds first to address your second question about the specific instructions and then jump to it? [00:25:54] Speaker 00: Sure. [00:25:54] Speaker 00: Sure. [00:25:54] Speaker 01: I'm sorry. [00:25:54] Speaker 00: Just want to turn, Your Honors, to Appendix Page 28. [00:25:58] Speaker 00: I'm sorry, 28? [00:26:00] Speaker 00: Yes, 28, Your Honor. [00:26:05] Speaker 00: And this is after the board has analyzed 11 of this Court's decisions. [00:26:10] Speaker 00: And Institute Pasture is one where this Court said that the KSR decision does not [00:26:15] Speaker 00: take away the requirement for a reasonable expectation of success. [00:26:19] Speaker 00: And they acknowledge at line 20, the availability of only generalized instructions and evidence of failures have indicated the opposite. [00:26:30] Speaker 00: So they say, we look to general instructions as well. [00:26:33] Speaker 00: And above that said, specific instructions can be relevant. [00:26:36] Speaker 00: And they then spend 10 pages going over what the record has been using general instructions. [00:26:41] Speaker 00: And they make a finding at appendix page 45 and 46. [00:26:45] Speaker 00: based on the RNA-based systems, that the failures have demonstrated there's no expectation of success. [00:26:51] Speaker 00: So they're applying that standard. [00:26:53] Speaker 00: How have prior systems worked with generalized instructions? [00:26:57] Speaker 00: Every single RNA-based system of record has failed. [00:27:01] Speaker 00: That's their finding. [00:27:02] Speaker 00: And that's because they acknowledge, under this court's precedent, you can use general instructions. [00:27:07] Speaker 00: But in this situation, as a fact finding, they found they'd all failed. [00:27:11] Speaker 00: So they did not ignore. [00:27:13] Speaker 00: general instructions. [00:27:14] Speaker 00: They looked at them. [00:27:15] Speaker 00: Every general instruction at the other side put forward. [00:27:18] Speaker 00: Turning to the evidence of simultaneous invention, the PTAB did not dismiss that as being legally irrelevant. [00:27:26] Speaker 00: If we turn to appendix page 19, first of all, they acknowledge that this evidence is put in the record. [00:27:38] Speaker 00: And we're at line seven at appendix page 23. [00:27:45] Speaker 00: And they say that UC alleges that because some research groups were immediately able to use it, there was a reasonable expectation of success. [00:27:53] Speaker 00: And they go on and they say, regardless of how many groups achieve success in eukaryotic cells, we are not persuaded that such success indicates there was an expectation of success before the results from these experiments were known. [00:28:06] Speaker 00: They don't say they're irrelevant. [00:28:09] Speaker 00: They actually are analyzed to see in this situation, because this court has said, in the Lindemann case, [00:28:15] Speaker 00: that simultaneous invention, quote, may or may not be an indication of obviousness. [00:28:21] Speaker 03: But if the person undertaking the invention believes that, thinks it will yield that that is evidence? [00:28:26] Speaker 03: Excuse me, I'm out of time. [00:28:27] Speaker 03: If the person undertaking that act believes it's going to yield success, then it would be relevant. [00:28:34] Speaker 00: Yes, it could be relevant. [00:28:34] Speaker 00: That's right, Your Honor. [00:28:35] Speaker 00: So there is no. [00:28:36] Speaker 03: OK, then how do you juxtapose that with the statement the board has on page 24, which says, we are not persuaded that a scientist believes [00:28:45] Speaker 03: in the success of his or her own experiments is necessarily a reasonable expectation of success that indicates obviousness. [00:28:53] Speaker 03: Were this true, the requirement for reasonable expectation of success in the context of such a matter that would have been obvious to try would be rendered meaningless. [00:29:01] Speaker 03: So isn't the board saying there that they are not going to consider whether a scientist believes there's reasonable expectation of his or [00:29:10] Speaker 03: essentially because every scientist does, or they wouldn't undertake it. [00:29:13] Speaker 03: I don't really understand this. [00:29:14] Speaker 03: I'm not that clear on what they were saying in that. [00:29:16] Speaker 03: But isn't that your read? [00:29:18] Speaker 03: What's the point of that? [00:29:19] Speaker 00: What they're getting to, Your Honor, is at the top of the page, UC made an argument that... No, no, no. [00:29:23] Speaker 03: But look at this, if you wouldn't mind. [00:29:25] Speaker 03: Just look at the second... Are you top of page 24? [00:29:30] Speaker 00: Yes, Your Honor. [00:29:31] Speaker 00: I'm at top of 24, Your Honor. [00:29:33] Speaker 00: The argument UC made below was that because [00:29:36] Speaker 00: The research groups undertook the experiments. [00:29:38] Speaker 00: They necessarily had an expectation of success. [00:29:41] Speaker 00: That was their argument. [00:29:43] Speaker 00: They didn't come up with any evidence from any of the groups and said, we believe pre-experimentation, the before, that there was an expectation of success. [00:29:51] Speaker 00: Their argument was, we don't have any evidence on that. [00:29:54] Speaker 00: So we want you to conclude, PTAB, that- Wait, where were they saying that? [00:29:57] Speaker 03: What are you referring to here? [00:29:59] Speaker 03: I guess, were you putting me to something? [00:30:01] Speaker 00: OK, so UC argues that the research groups that were reportedly at the top of the page, sorry, Your Honor. [00:30:05] Speaker 00: successful after the publication could not have undertaken the use of the type two systems unless there was sufficient motivation and expectation of success. [00:30:21] Speaker 02: They're not saying it's not relevant. [00:30:22] Speaker 02: They're not saying they're not considering it. [00:30:23] Speaker 02: They're just saying it doesn't necessarily. [00:30:25] Speaker 02: The fact that somebody tried something doesn't necessarily mean they had an expectation it would be successful. [00:30:30] Speaker 00: That's right, Your Honor. [00:30:30] Speaker 00: And that was their only argument. [00:30:32] Speaker 02: That may be my only sentence, this argument. [00:30:35] Speaker 00: I appreciate that, Your Honor. [00:30:37] Speaker 00: That was the point there. [00:30:39] Speaker 00: At the top of the page, the PTAB is going over UC's only argument in their brief as to why this showed an expectation. [00:30:45] Speaker 00: They said you wouldn't do experiments unless they necessarily, you necessarily thought they were going to be successful. [00:30:50] Speaker 00: And so they go on and say, no, that's not the case here. [00:30:53] Speaker 00: And by the way, once again, one of the groups, they said, that supposedly had this pre-experiment expectation of success was the Doudna group. [00:31:01] Speaker 00: And we know Doudna said, I thought this wasn't going to work. [00:31:04] Speaker 00: She said there was a big problem. [00:31:05] Speaker 03: Okay. [00:31:06] Speaker 03: But so the board's treatment of these simultaneous actions starts at page 23 and runs through page 25, right? [00:31:15] Speaker 00: That's right. [00:31:16] Speaker 03: So one of their reasons is they reject UC's argument because it doesn't necessarily provide a reasonable expectation. [00:31:24] Speaker 03: And the only other point we seem to be making is taking the KSR quote with regard to obvious to try. [00:31:32] Speaker 03: And even though the quote says it is likely the product, not of innovation, whatever, they restated to say may show it would have been obvious. [00:31:42] Speaker 03: And then [00:31:44] Speaker 03: I don't understand the second sentence starting at line 10 of page 25, really. [00:31:50] Speaker 03: I mean, there again, they're making the sort of necessarily. [00:31:53] Speaker 03: Well, we can't adopt what KSR, we adopt what KSR says, but we can't say that it would always or necessarily be the case. [00:32:02] Speaker 03: So I mean, I guess their analysis seems to be taking the extreme and saying that wouldn't necessarily be so. [00:32:09] Speaker 03: But that doesn't, in my mind, provide a very [00:32:12] Speaker 03: fulsome analysis of really what the issue is with regard to these simultaneous inventions. [00:32:17] Speaker 00: I think, Your Honor, what you're seeing in the PTAB decision is, it's not, the PTAB's not saying that we, you show it's necessarily so, it's that UC was arguing that if you undertake the experiments, this is a continuation of the UC argument, they were, the PTAB's given- So the UC was arguing necessarily, just because they took the experiment, [00:32:36] Speaker 03: That was Zirk's argument, Your Honor, that because you- So they didn't have to say anything else about the kinds of arguments that have been raised on appeal here about the importance of the significance of simultaneous inventions, or what? [00:32:46] Speaker 00: Your Honor, they didn't mention the word simultaneous inventions. [00:32:48] Speaker 03: So you're saying it's sort of a waiver thing, that they didn't make the kind of arguments they're making here on appeal about the importance of these? [00:32:57] Speaker 00: They did waive to the extent they say that simultaneous inventions should be used for secondary considerations. [00:33:01] Speaker 00: What they raised it for below was that the fact that these [00:33:05] Speaker 00: groups undertook the experiments meant they had an expectation of success. [00:33:11] Speaker 00: And that is not the case. [00:33:12] Speaker 00: So the board addressed the argument that was being made. [00:33:14] Speaker 00: The argument made was, and that's what they're explaining in Appendix Page 24, is that UC is telling us that because they undertook this experiment, it necessarily meant they expected success, because someone wouldn't go in a lab and do an experiment unless they thought they were going to be successful. [00:33:29] Speaker 02: And they were rejected. [00:33:30] Speaker 02: So the board says, it's not necessarily true. [00:33:32] Speaker 02: It's not always true. [00:33:34] Speaker 02: And the last sentence says, thus we look at the specific context of the art at the time. [00:33:38] Speaker 02: Then they spent the next 15 pages going painstakingly and detailed through the art at the time and the record evidence. [00:33:45] Speaker 00: That's correct, Your Honor. [00:33:45] Speaker 00: And they go through and they look at what the attempts were with RNA-based systems. [00:33:50] Speaker 00: And there's three RNA-based systems, just three, that had any kind of ability to go into eukaryotic cells. [00:33:56] Speaker 02: Right? [00:33:56] Speaker 00: Rubber zimes and the group two introns. [00:33:59] Speaker 00: And the group two introns, Your Honor. [00:34:01] Speaker 02: The other three of them required innovative techniques to make them work in the more complex animal and plant cells. [00:34:07] Speaker 02: They didn't just convert over easily. [00:34:09] Speaker 00: That's right. [00:34:09] Speaker 00: And very important to that, Your Honor, general instructions didn't work. [00:34:13] Speaker 00: And each one of those three required a completely different approach. [00:34:17] Speaker 00: So you couldn't take what was learned from one and apply it to the next or to the CRISPR. [00:34:22] Speaker 00: And that's why we have all of these statements from Carroll [00:34:26] Speaker 00: And Dr. Simmons, our expert, saying that there'd be no expectation of success, because everybody was aware of these prior failures. [00:34:36] Speaker 00: When you tried to apply conventional techniques, and they're aware of the fact that if you were going to come up with something, it could take years to get something like the group two introns, 16 years of effort. [00:34:46] Speaker 00: They were aware of all these conventional techniques, and the system ended up being unusable. [00:34:52] Speaker 00: That's in appendix page 38, 16 years of effort. [00:34:54] Speaker 00: That's what Opposa was aware of at the relevant time here. [00:34:59] Speaker 03: Can I just ask you a completely different question, which is about the cutoff date. [00:35:03] Speaker 03: If the board had used the prior cutoff date of October 2013, would you lose? [00:35:13] Speaker 00: used to cut update October 2013 I think the board no we wouldn't lose your honor the board would have to would not I'm sorry no we would not lose because the board would then resolve the issue of whether we're entitled to a 12 12 12 date and the answer would be yes to that and I would also point out in other words the board did not need feel the need to get to whether or not we were entitled to the date of October 12 well certainly by October 2013 one skilled in the art would have had in light of UC's [00:35:41] Speaker 03: claim a reasonable expectation of success, right? [00:35:43] Speaker 00: Yes, Your Honor. [00:35:44] Speaker 00: That's correct. [00:35:45] Speaker 00: My point is, though, if you went with that date, then the board would necessarily have made the determination as to whether or not we could go back to the 12-12-12 date. [00:35:53] Speaker 00: But they didn't need to, because both parties agreed to use that date in these motions. [00:35:58] Speaker 00: In fact, the other side embraced the fact, as part of its simultaneous invention argument, that Broad had made the invention by October 5, 2012. [00:36:08] Speaker 00: It's actually in the appellate briefs here. [00:36:10] Speaker 00: There's a table they put together saying that Broad rapidly came to the invention, and they cite our date as October 5, 2012. [00:36:20] Speaker 00: Your Honor, just in closing, I'd like to point out that this is a situation where substantial evidence supports the decision here, and the other side is simply asking you, Your Honors, to second-guess the PTAP's decision, which should not be done, and we request affirmance. [00:36:34] Speaker 00: Thank you. [00:36:40] Speaker 01: Thank you, Your Honor. [00:36:43] Speaker 01: A couple of corrections to start. [00:36:45] Speaker 01: My friend said that the only argument that UC made before the PTAB was that anybody who conducts an experiment necessarily has an expectation of success. [00:36:57] Speaker 01: I think that it is true that that's one of the arguments that UC made. [00:37:00] Speaker 01: It's an aggressive argument. [00:37:01] Speaker 01: We're not making it here. [00:37:03] Speaker 01: But it is completely wrong to say that it is the only argument that UC made. [00:37:07] Speaker 01: And I would ask the court to read pages 235 to 255 of the appendix, which goes through our arguments. [00:37:14] Speaker 01: And the key one is a carryover paragraph from 245 to 246 in which we make exactly the argument there that we are making here, which is a different argument and which I think is critical. [00:37:26] Speaker 01: And it goes to the core of what's at stake here and the core of the error that the PTAB made. [00:37:32] Speaker 01: What we were saying to the PTAB was the most powerful contemporaneous evidence of what a person of ordinary skill in the art would have thought and therefore what is, what the ex, of the expectation of success is what the scientists in these six groups actually did in that exact moment in 2012. [00:37:51] Speaker 01: And none of them felt any need to innovate around these supposed unique conditions that several years later, [00:37:59] Speaker 01: Brode's expert hypothesized people would have thought about. [00:38:02] Speaker 01: The evidence in the moment shows that nobody thought that was a problem. [00:38:07] Speaker 01: And the PTAP did refuse to consider that evidence as going to the issue of reasonable expectation of success. [00:38:13] Speaker 01: We were talking about page 23. [00:38:15] Speaker 01: It definitely, the PTAP definitely says on page 23, instead of viewing this evidence as relevant to reasonable expectation of success, we view it as relevant to motivation. [00:38:25] Speaker 01: They specifically say that right in the middle of the page. [00:38:28] Speaker 01: Another point I want to correct about these other three systems we've been talking about. [00:38:33] Speaker 01: There's two points to make about that. [00:38:35] Speaker 01: One, a basic point, which I think does show you at some level how far off the rails this whole PCAP analysis went. [00:38:41] Speaker 01: My friend Mr. Nimrod says that these other three systems that Judge Moore identified were failures. [00:38:46] Speaker 01: I'd like to give the court three sites to the record, each of which will demonstrate that these three systems were successful. [00:38:54] Speaker 01: The first, with respect to ribozymes, that's 5890. [00:38:58] Speaker 01: You'll see a quote from the relevant article, which talks about the consistently high levels of activity and the success with utility in medicine for that. [00:39:08] Speaker 01: If you look at riboswitches. [00:39:09] Speaker 02: Yeah, but page 5893 says, unfortunately, a number of factors intervene to prevent many engineered riboswitches from become useful genetic switches. [00:39:16] Speaker 02: For example, and it goes on to explain a multitude of problems that occurred to get from the eukaryotic. [00:39:23] Speaker 01: What problems? [00:39:24] Speaker 02: Which ones? [00:39:24] Speaker 02: Bacteria. [00:39:25] Speaker 01: prokaryotic. [00:39:26] Speaker 02: The number of problems between the prokaryotic to the eukaryotic. [00:39:29] Speaker 01: But 20 years ago and all solved and then with respect to riboswitches 5309, Dr. Simon admits successful with respect to group 2 introns. [00:39:39] Speaker 02: They were ultimately successful but after time and effort and innovation to figure out how to take them from the bacteria to the plant. [00:39:46] Speaker 01: Which I think gets to I think is the key point. [00:39:49] Speaker 01: Really the key point here which is that [00:39:52] Speaker 01: Based on that evidence, Dr. Simon hypothesized that a person of ordinary skill in the art in 2012 would have assumed that, with respect to CRISPR-Cas9, there would be similar needs for unique tailoring, and therefore it wouldn't have had a reasonable expectation of success. [00:40:12] Speaker 01: What the evidence at the PTAP did not consider at going to expectation of success, the evidence of what these six groups did, shows you that that is not what [00:40:21] Speaker 01: people of ordinary skill and the art thought at the time, because they made no effort to anticipate and design around those kinds of problems. [00:40:29] Speaker 01: And of course they would have if they thought that they were going to be an impediment to success, because this was like the California Gold Rush of 1848. [00:40:35] Speaker 01: People are trying to get there first on this. [00:40:39] Speaker 01: And they would of course try, if they really thought this was going to be a problem, an impediment to success, of course they would have designed around it. [00:40:46] Speaker 01: None of them did. [00:40:47] Speaker 01: The PTAB never considered that evidence as relevant [00:40:49] Speaker 01: to reasonable expectation of success. [00:40:52] Speaker 01: And I just think that's a key legal error. [00:40:54] Speaker 01: And I do also think, if I may just make one more point, it ties back to the whole specific instructions point two. [00:41:02] Speaker 01: The reason, and this is at, this is, you can see this at page 39 of the PTAP, the reason the PTAP said this was a situation in which specific instructions were necessary in order to have a reasonable expectation of success was because of the difficulties with these three prior systems. [00:41:19] Speaker 01: that given those difficulties and the need for unique conditions, unless there were specific instructions dealing with the unique conditions of CRISPR-Cas9, there wouldn't be a reasonable expectation of success. [00:41:29] Speaker 01: Again, the evidence of the six groups refutes that inference because all of them faced with this problem took the conventional off-the-shelf techniques, codon optimization, the NLS, all of the conventional techniques at the peak to final convention. [00:41:46] Speaker 02: And you know what they did with ribosomes and riboswitches? [00:41:48] Speaker 02: I'll tell you, because I know you don't. [00:41:49] Speaker 02: They started with conventional techniques. [00:41:52] Speaker 02: And guess what? [00:41:53] Speaker 02: They didn't work. [00:41:55] Speaker 02: So it took years and innovation. [00:41:56] Speaker 02: That's how science works, Mr. Varelli. [00:41:58] Speaker 02: You start with the conventional techniques, and then when they don't work, you spend the time, energy, and money coming up with a new technique. [00:42:05] Speaker 02: So the fact that they started with the easiest off-the-shelf stuff doesn't mean they thought it would work. [00:42:10] Speaker 02: It means it was what was most readily and easily available to them at the time, the least cost and the least effort. [00:42:16] Speaker 02: Let's rule out the easy stuff first before we spend the time and money designing around. [00:42:20] Speaker 01: Respectfully, Your Honor. [00:42:21] Speaker 02: But that's what the board found, Mr. Borrelli. [00:42:23] Speaker 02: And it's hard for me to say there's not substantial evidence for that. [00:42:26] Speaker 01: Respectfully, Your Honor. [00:42:27] Speaker 01: There is not. [00:42:28] Speaker 02: Don't interrupt me when I'm speaking. [00:42:29] Speaker 01: I apologize. [00:42:29] Speaker 01: Please go ahead now. [00:42:30] Speaker 01: I didn't mean to do that. [00:42:31] Speaker 01: I'm sorry. [00:42:32] Speaker 01: Mr. Borrelli, I didn't get the last page site. [00:42:35] Speaker 01: You gave 58.90, 53.09, and then there was one. [00:42:38] Speaker 01: 59.24. [00:42:39] Speaker 01: OK, thank you. [00:42:42] Speaker 03: We're going to conclude. [00:42:44] Speaker 03: Thank you. [00:42:44] Speaker 03: Thank you.