[00:00:19] Speaker ?: Ah. [00:00:31] Speaker ?: Ah. [00:01:22] Speaker 00: The United States Court of Appeals for the Federal Circuit is now open and in session. [00:01:27] Speaker 00: God save the United States and the Congress. [00:01:30] Speaker 01: Good morning. [00:01:30] Speaker 01: Please be seated. [00:01:35] Speaker 01: The first three cases are going to be argued together and we appreciate that. [00:01:40] Speaker 01: We think it's the most expeditious way to do it. [00:01:43] Speaker 01: The cases are 141547, 141548, and 141550. [00:01:50] Speaker 01: Trustees of Columbia University versus Illumina. [00:01:54] Speaker 01: Mr. Wilson, 24 minutes to start whenever you're ready. [00:02:04] Speaker 05: Thank you, Your Honor, and may it please the Court. [00:02:06] Speaker 05: These appeals arise from Interparte's review of three related patents on aspects of DNA sequencing technology invented by Dr. Jingwei Zhu of Columbia University. [00:02:18] Speaker 05: Dr. Zhu invented novel nucleotides for use in the method of DNA sequencing, known as sequencing by synthesis. [00:02:25] Speaker 05: Now, the general concept of sequencing by synthesis was proposed in the late 1980s, but for 10 years after the idea was first proposed, researchers had made no progress in developing a nucleotide that would actually work. [00:02:40] Speaker 05: What researchers found was this was a highly unpredictable part, and each feature of the nucleotide potentially affected whether the nucleotide could be incorporated successfully by the polymerase. [00:02:52] Speaker 05: What Dr. Ju recognized was all of the elements that, in combination, were necessary for high-throughput, commercially viable sequencing by synthesis that would actually work. [00:03:05] Speaker 03: Let me just throw you a little housekeeping question to start, OK? [00:03:09] Speaker 03: In the red brace at 48, Illumina says Columbia waived its arguments for claims 11 and 12, because it didn't argue non-arviness in the inner public's review. [00:03:22] Speaker 03: Did you argue non-obviousness? [00:03:25] Speaker 05: We did, Your Honor. [00:03:26] Speaker 05: We argued, yes, we argued non-obviousness for 11 and 12. [00:03:31] Speaker 03: Where would that be in the record? [00:03:34] Speaker 05: I'll need to check the record. [00:03:35] Speaker 05: Okay. [00:03:36] Speaker 05: Let me know on that. [00:03:42] Speaker 05: To return, it was the complete combination of features that were necessary for sequencing by synthesis would actually work. [00:03:49] Speaker 05: A removable cap on the 3-prime OH group. [00:03:52] Speaker 05: and a label on the base, and a cleavable linker, and using a diazepurine to connect the linker to the purine base. [00:04:03] Speaker 04: So let me ask you, what do you say, I'm sure I'm mispronouncing it, do you know apetaminescene or cyene or whatever it is? [00:04:11] Speaker 04: Dr. Chen. [00:04:12] Speaker 04: Pardon? [00:04:12] Speaker 04: Dr. Chen. [00:04:13] Speaker 04: Okay, I had it wrong all the way. [00:04:15] Speaker 04: But what do you say that reference does not teach? [00:04:19] Speaker 05: Well, two things, that reference does not teach a nucleotide that has a combination of base labeling, cap on the 3-prime OH, and clevo length. [00:04:36] Speaker 05: So although Dr. Chen certainly does propose three different possibilities for sequencing by synthesis, you know, and his main focus is certainly on the 3-prime OH, not on the base labeling, he does mention the possibilities. [00:04:52] Speaker 04: But he does mention base labeling. [00:04:53] Speaker 05: He does, but he never puts those three elements in combination. [00:04:56] Speaker 05: And he certainly does not teach himself a Diazepurin. [00:05:00] Speaker 05: So the question is that I think where the board fundamentally went wrong. [00:05:04] Speaker 04: You get the Diazepurin from Prober, correct? [00:05:06] Speaker 05: Well, he did not. [00:05:07] Speaker 05: You say it's Sanger. [00:05:08] Speaker 05: He did not get the Diazepurin from Prober, exactly. [00:05:11] Speaker 05: He certainly cites Prober, and he also cites another reference, Sarfati, for saying it's possible to put labels on base in ways that might be useful. [00:05:24] Speaker 05: But the thing is you have to keep reading. [00:05:26] Speaker 05: And when you turn the page, you see he's getting what he's citing prover for is labeling Pyrimides. [00:05:34] Speaker 05: Well, he's not citing prover at all for labeling Purians. [00:05:37] Speaker 05: And in fact, when he talks about labeling Purians, he says, [00:05:40] Speaker 05: Oh, the best place to label a purine would be on the eighth position, not the seventh position, which is what Prober had proposed. [00:05:51] Speaker 05: And Prober, of course, had proposed that for a different technology, which is Sanger sequencing. [00:05:57] Speaker 05: Now, you have to think about [00:06:00] Speaker 05: What was the reason why Kroger was interested in the diazepurine? [00:06:05] Speaker 05: And the reason why he was interested is very different from the reason why Dr. Ju found the diazepurine to be very useful. [00:06:15] Speaker 05: Fundamentally, Dr. Ju found the diazepurine to be very useful for a spatial reason. [00:06:20] Speaker 05: That is, the researchers who had tried and failed during the 1990s to solve the problem of sequencing by synthesis [00:06:29] Speaker 05: There was a recognition that there was a spatial problem. [00:06:33] Speaker 05: That is, where were you going to put the label physically so that it wouldn't interfere with other reactions, either the... What was going on with the sugar? [00:06:43] Speaker 05: Right. [00:06:43] Speaker 05: Some people had tried putting on the sugar, and those efforts to put it on the sugar had continued well into the 1990s, and a few researchers had said, it's very strange. [00:06:56] Speaker 05: This seems like it ought to work, but for some reason it's not working. [00:06:59] Speaker 05: Notably, they did not say, since it's not working, let's try putting the label on the base, even though they were well aware of Dr. Chen's paper. [00:07:10] Speaker 05: They weren't drawing the lesson from those experiments that Illumina says they ought to have drawn from putting Chen and Kroger together. [00:07:19] Speaker 05: What they were saying is let's try something else, let's fiddle with the polymerase or let's do something else to the molecule, not putting the label on the base. [00:07:28] Speaker 04: What Dr. Chu recognized- In sort of the post-KSR world, if you will, doesn't the combination, at least in terms of the 6,9,8 pattern of Sheen [00:07:42] Speaker 05: That's how I pronounce it anyway. [00:07:48] Speaker 04: Doesn't that combination, that reference with prober gets you pretty far in terms of... I don't think that's right your honor because [00:07:56] Speaker 05: This is not a mechanical patent. [00:07:58] Speaker 05: In other words, we're dealing here with a very unpredictable heart. [00:08:02] Speaker 05: This is very advanced synthetic nucleotide chemistry. [00:08:06] Speaker 05: As Columbia's expert pointed out, any time you change any aspect of a nucleotide, you change [00:08:13] Speaker 05: I'll put the label here. [00:08:15] Speaker 05: I'll put the cap here. [00:08:16] Speaker 05: I'll change which cap I use. [00:08:18] Speaker 05: I'll change which cleavable linker I use. [00:08:20] Speaker 05: And Prover doesn't have a cleavable linker at all. [00:08:23] Speaker 05: That could alter the reactions. [00:08:25] Speaker 05: That could make the reactions, you know... I appreciate what you're doing. [00:08:29] Speaker 01: I appreciate your brief, very good background, helpful background. [00:08:33] Speaker 01: Seems to me though the reality you're living under is you've got a very, very, very detailed board of opinions. [00:08:39] Speaker 01: there and you're left so I mean is there anything here that you're arguing that doesn't get substantial evidence deference for the board in terms of its findings and can you identify there what went wrong because they go through I mean meeting the opinions they're very detailed they go through all of the expert testimony and they draw a very clear picture which just to be frank very candid with you you know strikes me as very complete and thorough so [00:09:06] Speaker 05: So I would say there were three fundamental errors that the board made. [00:09:13] Speaker 05: The first fundamental error is, I think, and this is most manifest in its treatment of the objective evidence, the board fundamentally is suffering from a kind of hindsight bias. [00:09:23] Speaker 05: And the board did not really treat the objective evidence in the case as sort of an independent [00:09:33] Speaker 05: way of looking at the evidence of obviousness and sort of really seeing was there, you know, you might see looking back on what had happened, you might say, oh, it was all laid out in a path by the technology, but the objective evidence tells a very different story. [00:09:49] Speaker 05: I mean, in particular, the licensing evidence, that tells us that when there was a report of Dr. Ju having solved [00:09:55] Speaker 05: the reversible terminator cleavable die issue, Illumina immediately sprang into action and said, we'd really like to license this. [00:10:04] Speaker 05: You know, we don't have a play in sequencing by synthesis. [00:10:07] Speaker 05: How can we talk to Dr. Ju? [00:10:09] Speaker 05: You know, we trust what Dr. Ju says if he says that he's solved this. [00:10:13] Speaker 05: And there were extensive negotiations with Columbia about licensing. [00:10:18] Speaker 05: Eventually, those negotiations didn't bear fruit because Columbia chose a different licensee. [00:10:23] Speaker 05: But there's certainly no indication [00:10:24] Speaker 05: that they didn't bear fruit because the parties valued the technology very differently. [00:10:30] Speaker 05: And there's no question that Illumina's effort to license this technology, it was about this technology. [00:10:35] Speaker 05: I mean, the parent patent to this is in the list of technology that Columbia provided Illumina under the, they had a confidential disclosure agreement. [00:10:47] Speaker 01: Do we know at the time of licensing whether Illumina knew about the Qian patent? [00:10:53] Speaker 05: Well, I mean, Chen, of course, Chen is a patent application, not a Chen patent. [00:10:58] Speaker 05: I mean, there's no indication. [00:11:00] Speaker 05: I mean, they certainly don't say in their email traffic, oh, this is what we're really interested in is the Chen type technology. [00:11:11] Speaker 05: I mean, I think to the contrary, since it was phrased as Dr. Zhu has solved the reversible terminator cleavable die issue, there was a recognition that the technology had [00:11:22] Speaker 05: that advances in the technology have stopped and there was a problem to be solved. [00:11:27] Speaker 05: And that problem was solved by Dr. Ju's insight, fundamentally his spatial insight. [00:11:33] Speaker 05: So you have the Illuminati eagerness to license the technology. [00:11:38] Speaker 05: You have the Illuminati commercial success. [00:11:43] Speaker 05: And here the board did make a fundamental legal error, which is the board did not apply the presumption of nexus that this court has stated in several opinions comes from when you have commercial success from a product that embodies the invention, there's a presumption that the commercial success is due to that invention, and the burden then shifts to Illumina, or then is, I should say, is on Illumina. [00:12:09] Speaker 01: And what did the board say here about the commercial success? [00:12:12] Speaker 05: Well the board says that the commercial success, the board says that Columbia has not shown that the commercial success was due to, you know, only to the Diazepurine and not to, you know, not to the technology that was in the prior art. [00:12:30] Speaker 05: The board didn't say it was due to [00:12:32] Speaker 05: you know, extraneous factors like customer service or something like that. [00:12:36] Speaker 05: But that is another, I think, basic error in the board's scope of its decision because you have to look at the invention as a whole. [00:12:44] Speaker 05: Yes, there were elements of the technology that had been discussed in disparate places. [00:12:48] Speaker 01: But whose burden is that? [00:12:49] Speaker 01: I mean, if there's some elements that were in the prior elements of the whole and there's one additional one, [00:12:54] Speaker 01: And the board concludes that you have, aren't you, isn't your obligation to show that for persons of commercial success that it was the inventive portion of that that led to the commercial success? [00:13:06] Speaker 05: Well, I think if we, I think if we, you know, we are entitled to a presumption that it is if we produce evidence. [00:13:12] Speaker 05: I mean, we certainly have a burden of production and we satisfied that burden of production by showing, you know, illuminate products embody the invention. [00:13:21] Speaker 05: There's not really a dispute. [00:13:22] Speaker 05: The board didn't really doubt that. [00:13:24] Speaker 05: Illumina has had commercial success with that invention. [00:13:27] Speaker 05: The board didn't really dispute that. [00:13:29] Speaker 05: You have to really look at the invention as a whole because it's not like the three pieces together were working. [00:13:40] Speaker 05: It's not like Illumina had a car and Columbia proposed to put a hood ornament on the car. [00:13:47] Speaker 05: The three pieces together, either separately or together, that Illumina says were in the prior art, [00:13:54] Speaker 05: the base label 3' OH cap and cleavable linker, those three creases together were never working together. [00:14:01] Speaker 05: There wasn't any commercial embodiment that together had been used what certainly was successful. [00:14:09] Speaker 05: It was with the addition of the diazepurine and diazepurine attached to the base by the cleavable linker that the whole thing really works and works dramatically well. [00:14:21] Speaker 05: So that I think is, I think, you know, the board said, [00:14:24] Speaker 05: Well, you have to see what was readily available in the prior art. [00:14:31] Speaker 05: But I think you can't just look to the theoretical possibility that there might have been things available in the prior art, because nothing was on the market. [00:14:40] Speaker 05: Nothing was actually working. [00:14:42] Speaker 05: So it's really again only putting together all the pieces, but not just putting together, actually synthesizing them from scratch. [00:14:53] Speaker 05: a mechanical art where it's just a question of taking a rotor off one place and putting it off another. [00:14:59] Speaker 05: As Columbia's expert explained, starting from the prior art and developing the chemistry that it would be necessary to get you from point A to point E was enormously complicated. [00:15:15] Speaker 05: One thing that the board didn't really resolve or appreciate was [00:15:22] Speaker 05: who is competent to testify about how complicated it would be to get from point A to point E. Columbia had a chemist who was able to explain all that. [00:15:35] Speaker 04: My sense was that both Dr. Treanor and Dr. Weinstock were both very qualified. [00:15:45] Speaker 04: Is this a sort of a Daubert issue? [00:15:48] Speaker 04: You're saying Dr. Weinstock wasn't qualified? [00:15:53] Speaker 05: Dr. Weinstock disclaimed the ability to talk to the chemistry that would be necessary to either synthesize the nucleotide, the brand new nucleotide. [00:16:07] Speaker 05: So he really was not able to talk to the question of how complex [00:16:13] Speaker 05: the chemistry would be. [00:16:14] Speaker 05: Now, Illumina's response to that is, well, if he had chemistry, a higher level of skill would have only meant it was more obvious. [00:16:21] Speaker 05: But I think what that argument really doesn't appreciate is, really, it's a person with the advanced chemistry who can really appreciate how unpredictable [00:16:32] Speaker 05: the chemistry is in synthesizing nucleotides and in synthesizing nucleotides that are not natural so that they're, you know, they're not analogous. [00:16:44] Speaker 04: Is your argument basically that somehow the Illumina's case is weaker because Dr. Weinstock didn't have, while he's a competent gentleman, [00:16:57] Speaker 04: didn't have, in your view, the particular expertise background that was necessary for the subtle issues in this case. [00:17:06] Speaker 05: He did not have the background, and he disclaimed the expertise to testify about issues that I think are at the core of this case, in particular, reasonable expectation of success in synthesizing the nucleotide and a reasonable expectation of success [00:17:24] Speaker 05: that the nucleotide would actually work, that it would actually be incorporated by a polymerase. [00:17:29] Speaker 05: And I think that the defect in the luminous argument is actually shown by the board's decision on those two very points, because the board's decision on reasonable expectation of success of a polymerase doesn't rely on Dr. Weinstock at all. [00:17:47] Speaker 05: I mean, the board really relies on what I might call its own expertise, which is really [00:17:53] Speaker 05: a kind of a burden shifting where they say, well, Columbia hasn't persuaded us that there are these two technologies that seem to be working separately, three-prime OH cap and labeling base. [00:18:10] Speaker 05: We dispute the premise of that, but even putting that aside, Columbia hasn't persuaded us that it wouldn't be perfectly sensible to put the two together and that they would work perfectly well together. [00:18:20] Speaker 04: One of the things that we seem to see, at least from time to time, is the argument that the board has gone too far in relying on what I think you just described or referred to as its own expertise. [00:18:35] Speaker 04: Do you see that as an issue? [00:18:37] Speaker 05: I see that as a very significant issue here. [00:18:39] Speaker 05: I think that's a kind of a fundamental issue. [00:18:41] Speaker 04: In what particular area do you say the board overstepped that band? [00:18:46] Speaker 05: I think you see it most salient in reasonable expectation of success. [00:18:53] Speaker 01: Because in reasonable expectation... Can we be a little more specific? [00:18:56] Speaker 01: Sure. [00:18:57] Speaker 01: Do you want to show us when you've got three or eight board opinions? [00:19:01] Speaker 05: I think around pages... [00:19:05] Speaker 03: Which one? [00:19:06] Speaker 05: Sorry, I'm looking at the appeal number 1547, which is the 698. [00:19:11] Speaker 01: And I've got commercial success at page A34. [00:19:15] Speaker 01: Right. [00:19:15] Speaker 05: So the first thing I would say is when you look at sort of page A26 and 27, so page A26, there's a, if you see there's an italicized, was there a basis for reasonably expecting [00:19:33] Speaker 05: that a nucleotide with a removable three primal wage caps, et cetera. [00:19:37] Speaker 05: I mean, one problem with this is the board actually doesn't even answer that question. [00:19:40] Speaker 05: If you read the second paragraph, it's talking about an argument that Columbia is making. [00:19:49] Speaker 05: And they say, opening line in the second paragraph, this argument is not persuasive, indicating to me that [00:19:55] Speaker 05: Essentially, they're placing the burden on Columbia to show why it's not obvious. [00:19:59] Speaker 05: But then if you look at the last paragraph, the last sentence, secondly, a preponderance of evidence establishes a reasonable expectation of success as addressed above. [00:20:08] Speaker 05: It isn't addressed above. [00:20:10] Speaker 05: There's just no analysis of reasonable expectation of success of incorporation by the preliminaries. [00:20:18] Speaker 00: I'm not one. [00:20:20] Speaker 05: I mean, I realize that. [00:20:21] Speaker 05: The other place where I think this is. [00:20:23] Speaker 01: Well, it says, I mean, before the quote that you had, the question, it says, in sum, the prominence of evidence establishes there was a reasonable expectation of success. [00:20:31] Speaker 01: So what precedes it, the analysis that precedes it, supports that conclusion, right? [00:20:35] Speaker 01: And they're talking about. [00:20:37] Speaker 05: If that's what the board means, Your Honor, then all that they're talking about here is arguments by Columbia that they've rejected. [00:20:45] Speaker 05: And they don't rely on any arguments. [00:20:47] Speaker 05: They don't rely on any evidence by Dr. Weinstock. [00:20:51] Speaker 05: And on the previous page, there's a, on A24 and A25, which is, I think, where you have principally the discussion of reasonable expectation of success and actually of incorporation by a polymerase. [00:21:09] Speaker 05: You know, they do, there's a lot of discussion about how Dr. Treanor didn't explain or Dr. Treanor didn't, Dr. Treanor didn't persuade us. [00:21:19] Speaker 05: There's no discussion at all of what Dr. Weinstock did, or what did Dr. Weinstock said. [00:21:24] Speaker 05: So I think these pages are examples of where the board's decision literally lacks substantial evidence because it doesn't rely on any evidence presented by Illumina. [00:21:37] Speaker 05: And we infer that it only could have been relying on its own expertise, which under decisions like Brandy Miller, [00:21:46] Speaker 05: is you know is not permissible on it can't be upheld. [00:21:49] Speaker 05: Excuse me you start off by saying there were three specific problems in the board's decision it was hindsight right and the second one is so the second one are the kind of burden shifting what you just described right burden shifting what I just described and I also think burden shifting you also see that in the in the hindsight and then the third I think is fundamentally the board's failure to [00:22:14] Speaker 05: really appreciate that the question here was about the invention as a whole. [00:22:20] Speaker 05: And I mean, that point sort of overlaps on some other points I mentioned, but the board sort of points to individual features of the prior art without appreciating the challenges of combining those features. [00:22:34] Speaker 05: No prior art, even Dr. Chen, suggested combining even the three features, base labeling, [00:22:43] Speaker 05: free-prime OH capping and cleavable linker into a single embodiment, and certainly no prior art suggested combining the fourth feature of a diazepurine, which was what made it very useful to attach the label by a cleavable linker. [00:23:03] Speaker 05: Now the board sort of dismissed a lot of those difficulties by saying, well, it would have been obvious, I mean, for example, you see in the board's discussion of Stempel and Anazawa, [00:23:13] Speaker 05: which is in the 1548 appeal. [00:23:16] Speaker 05: The board says, well, Anazawa is flawed. [00:23:20] Speaker 05: His chemical processes actually don't work. [00:23:23] Speaker 05: And the board says, well, some skilled in the art would have figured that out. [00:23:28] Speaker 05: They would have figured out how to use prover to fix Anazawa. [00:23:32] Speaker 05: There's no evidence of that. [00:23:34] Speaker 05: That's, first of all, burden shifting. [00:23:37] Speaker 05: And there's not any evidence of that in the record either. [00:23:40] Speaker 05: But fundamentally, I think, [00:23:41] Speaker 05: Going back to maybe an objective point, the board also sort of lost sight of the fact that Chen and Prober are from 1990 and 1991, and there's a 10-year gap where researchers are persistently trying the path that Chen laid out, which is put the label on the three-prime OH cap. [00:24:02] Speaker 05: That is, no question, his preferred embodiment. [00:24:05] Speaker 05: researchers tried that and researchers failed and they couldn't figure out what was wrong. [00:24:11] Speaker 05: They couldn't figure out what the solution to that was. [00:24:14] Speaker 05: I think the board, this loops back into hindsight bias, but the board fundamentally failed to sort of appreciate there's this long period of time where it just doesn't seem to be the right answer. [00:24:26] Speaker 04: And that I think is... Are you saying this is kind of a [00:24:29] Speaker 04: Quasi-secondary consideration or passage of time? [00:24:33] Speaker 05: It's kind of a long-felt needs type argument, but it's also, I think, a response to Illumina. [00:24:39] Speaker 05: I mean, one thing that Illumina has said is, you know, really the three-prime OH cap label approach was, I think they use the term fading alternative. [00:24:47] Speaker 05: everybody knew that the, everybody had recognized that the base labeling was really the more promising thing. [00:24:53] Speaker 05: But that's when you look at the evidence Illumina points to and when you look at the researchers who are working in this field in the 1990s, they're all trying, they are trying to put, they're not all put aside Anazawa, but the others, Welch, Metzger, they are trying to put the label on the three prime OH cap well into the 1990s. [00:25:13] Speaker 05: They're trying and they're failing and they don't [00:25:17] Speaker 05: They don't draw from their failure the answer that Dr. Ju drew, which is put the label on the base with a cleavable linker attached to the purine through a diatapurine. [00:25:45] Speaker 02: Edward Reinitz on behalf of Illumina. [00:25:48] Speaker 02: May it please the court. [00:25:50] Speaker 02: First, to address the housekeeping issue, there was no defense of claims 11 and 12 in the patent owner's response, which is at A2167. [00:26:00] Speaker 02: Moving to the more fundamental question, what the board found and did it have substantial evidence, where the board started is, I think, where we should start today and is on the substance the right place to start, which is [00:26:15] Speaker 02: What was the interest level in the art in capping the sugar and labeling the base? [00:26:20] Speaker 02: Because that's really what they're claiming is the advantage of doing sequencing by synthesis, where you cap the sugar, but you put the base not on the sugar. [00:26:28] Speaker 02: I mean, label not on the sugar, but on the base. [00:26:32] Speaker 02: And we've heard here nobody showed it. [00:26:34] Speaker 02: We've heard all kinds of arguments about how this was disfavored and so forth. [00:26:38] Speaker 02: And the board said, we hear you. [00:26:41] Speaker 02: You're articulate, but that's not what the evidence shows. [00:26:44] Speaker 02: What the evidence shows in Dower, Stample, and Shen is that that combination was taught. [00:26:53] Speaker 02: And in fact, one of the last things the council stated was that clearly in Shen, it was a disfavored version of the invention. [00:27:02] Speaker 02: Not true. [00:27:03] Speaker 02: You'll find nothing in there that says that it's any less favored. [00:27:06] Speaker 02: In fact, if you read the summary of the invention, if you just take a fresh document and read Shen's summary of the invention, he says we want to move away from electrophoresis, so we're doing sequencing by synthesis, and there's a number of ways you can do it. [00:27:18] Speaker 04: Let me ask you one question. [00:27:19] Speaker 04: I wasn't something Mr. Wolfson said, and this is a gap in my technology understanding, I will confess. [00:27:27] Speaker 04: Prober, he said, is directed to pyrimidines. [00:27:32] Speaker 02: Yes, the purine versus pyrimidine. [00:27:35] Speaker 04: What is the significance of that distinction? [00:27:39] Speaker 02: The significance of that distinction is that they're making an argument that you wouldn't be motivated to use diagrapurine with the combination of the cap on the sugar and the base label because [00:27:57] Speaker 02: In Shen, I mean really the better form of the argument which we didn't really hear today is that Shen said use the eight position to attach the cleavable label when you use it on the base and the claim requires that the adipurin is the seven. [00:28:13] Speaker 02: There is an avalanche of reasons behind that. [00:28:18] Speaker 02: I could start with this. [00:28:21] Speaker 01: we don't want to break up you know let me just let me just one question thank you i'd like to go back to the point you were making about the discussion board recognized that [00:28:30] Speaker 01: Columbia may be right that Chen didn't say that the base labeling was the most favored, but what it said, which I think is the correct statement of law, is that that didn't constitute a teaching away. [00:28:42] Speaker 01: And just because there was a preference for one thing in Chen does not mean that the other disclosures in Chen weren't useful or necessary. [00:28:50] Speaker 02: Spot on. [00:28:51] Speaker 02: And I think, to put it the way I think of it, real common sense level, it's part of his invention. [00:28:58] Speaker 02: He's saying, I made an invention, and one way you can use my invention is to cap the sugar and label the base. [00:29:05] Speaker 02: So why would that be something you wouldn't want to do if someone's... What about the licenses? [00:29:10] Speaker 01: I mean, that's good evidence, is it not? [00:29:13] Speaker 02: I don't think it's much evidence at all. [00:29:16] Speaker 02: I mean, first of all, it's unconsummated. [00:29:18] Speaker 02: I don't think there's ever been a case by this court where an unconsum... [00:29:22] Speaker 02: Respect for the patent is you're licensing it. [00:29:25] Speaker 02: I think having prevailed in a re-exam after refusing to acquiesce to a charge of infringement is the opposite of respect. [00:29:33] Speaker 02: We're sort of here because we didn't license it. [00:29:35] Speaker 02: So it's sort of backwards to say that we're respecting the patent by our conduct. [00:29:40] Speaker 02: What happened was there was initial license discussions. [00:29:44] Speaker 02: Importantly, we ended up licensing this technology from Solexa, which invented. [00:29:49] Speaker 02: There's a simultaneous invention. [00:29:50] Speaker 02: The evidence is in the record. [00:29:51] Speaker 02: There's no real contest about that. [00:29:53] Speaker 02: So we got the technology that we used. [00:29:57] Speaker 02: These claims didn't exist when they began. [00:29:59] Speaker 02: And then what you see is after 2007, 2008, is Columbia's approaching Illumina about that and saying, look, if we have this patent, do you want a license? [00:30:07] Speaker 02: And we basically said, we found a better solution. [00:30:09] Speaker 02: I mean, it's an uncontamated license. [00:30:11] Speaker 02: It hardly shows respect. [00:30:13] Speaker 02: It's not tied to any of the patents. [00:30:17] Speaker 02: It's not tied to any of the claims. [00:30:20] Speaker 02: And it's not tied to the feature that they say is inventive. [00:30:22] Speaker 02: I mean, the reality is, by the time you get through this record, they can't say that capping the sugar and labeling the base is theirs, because Dauer, Stempel, and Shen all show it, and they don't even really contest that. [00:30:35] Speaker 02: Now, one thing they do say, I mean, the most they can say about Shen in this embodiment is you have to cobble together. [00:30:41] Speaker 02: It's sort of a little bit of one from column A and one from column B, and you'd be befuddled. [00:30:46] Speaker 02: Their own expert at page 83794 states that Chen discloses an alternative nucleotide analogs which include a label attached to the base and the possibility of the label being attached to the nucleotide analogs by means of a cleavable tether. [00:31:03] Speaker 02: That's paragraph 28, 83794. [00:31:07] Speaker 02: And the board pointed that out. [00:31:09] Speaker 02: and said, your own guy acknowledges that Chen teaches it, as his invention. [00:31:13] Speaker 02: And there was no arguments about dour, and there was no arguments about steppe. [00:31:16] Speaker 02: So any idea that there's this fundamental teaching that they have, that you can cap the sugar and label the base, just doesn't go anywhere, because it's fully disclosed in the art. [00:31:27] Speaker 01: What about the combination with Provo? [00:31:29] Speaker 02: OK, so let's talk about the Diaz edition. [00:31:33] Speaker 02: So the reality is that everyone agrees that during the course of the 90s, [00:31:38] Speaker 02: the azapurines were ubiquitous. [00:31:42] Speaker 02: That's the word their own attorney used before the board. [00:31:46] Speaker 02: That's what the board was entitled to rely on, that they're ubiquitous. [00:31:49] Speaker 02: The azapurines were so ubiquitous, you could buy them from a manufacturer made already. [00:31:57] Speaker 02: I don't know why you need a chemical degree to do that. [00:32:00] Speaker 02: Applied Biosystems is mentioned in the record, others are mentioned in the record. [00:32:04] Speaker 02: On top of that, [00:32:06] Speaker 02: our expert, Dr. Weinstock, explained that the adverbases were used in the context of sequencing by synthesis, in the context of a cleavable linker. [00:32:20] Speaker 02: That's a paragraph 44 at A3177. [00:32:22] Speaker 02: So if you could just buy them off the shelf and attach them, it just makes it stronger. [00:32:32] Speaker 02: It's chemistry, but we can explain it relatively simply. [00:32:34] Speaker 02: It says instead of using on the base the nitrogen, which has three bonds, replace it with a carbon with four bonds. [00:32:40] Speaker 02: It's stronger. [00:32:41] Speaker 02: And it's not like that's a discovery. [00:32:44] Speaker 02: It was ubiquitous. [00:32:45] Speaker 02: Everybody was moving to Diaz's, because when you put the label on the base, it would be stronger. [00:32:50] Speaker 04: One of the things that Mr. Wilson focused on in his argument was this 10 year gap that you heard him describing that. [00:33:01] Speaker 04: What do you have to say? [00:33:03] Speaker 04: That's an interesting point. [00:33:04] Speaker 04: What do you have to say about that? [00:33:06] Speaker 02: It's sort of intriguing. [00:33:09] Speaker 02: I must admit that when I looked at this record, that's the question that comes to me because I actually think of all the things kind of long felt need can sometimes be a helpful tool to why people do it. [00:33:21] Speaker 02: The answer is A, people did do it because [00:33:24] Speaker 02: What that ignores is that you're treating Shen in isolation, not the record that's here, which is Stempel and Dower. [00:33:30] Speaker 02: That's at least two others that did everything. [00:33:32] Speaker 02: Keep in mind, in these PTAB proceedings, they're still looking at reference by reference. [00:33:36] Speaker 02: We had numerous, numerous references. [00:33:39] Speaker 02: And you just have to narrow it down at some point. [00:33:42] Speaker 02: So there's three places where they have that combination. [00:33:47] Speaker 02: But even more to the point, and the one that just sort of said, all right, there's nothing to this argument, in my mind, is [00:33:53] Speaker 02: The commercial success that they're claiming, right, really started in 2008, which is almost 10 years after they came up with their so-called invention. [00:34:05] Speaker 02: You know, it sort of led to go back to first principles, right? [00:34:07] Speaker 02: That's always the useful thing to do. [00:34:09] Speaker 02: We start getting caught into who's burden and burden of persuasion and proof and it's going forward and all that legalese. [00:34:16] Speaker 02: When you ask yourself the common sense question of what's commercial success supposed to show, it says, well, if there's this big [00:34:23] Speaker 02: golden ring that you can grab. [00:34:26] Speaker 02: Why wouldn't anyone have done it? [00:34:27] Speaker 02: Wouldn't people have been motivated to grab the ring? [00:34:30] Speaker 02: Well, if the ring was grabbed in 1999 or 2000 when Jews came up with a paper patent, how come it took 10 more years to make it something that was worthwhile and commercial? [00:34:43] Speaker 02: And the answer to the question is, [00:34:45] Speaker 02: Experimentally, people knew that this was something you could do. [00:34:48] Speaker 02: They knew that you could demonstrate it. [00:34:50] Speaker 02: But to scale it up, there's so much more. [00:34:52] Speaker 02: And this goes to why the whole commercial success argument doesn't work. [00:34:55] Speaker 02: You need the arrays. [00:34:57] Speaker 02: You need a lot about the prep. [00:34:59] Speaker 02: There's actually a ton of technology in how you prepare these arrays with so many different parallel polynucleotides. [00:35:07] Speaker 02: So there's so much to that and the optics and everything else that you have to get right for it. [00:35:12] Speaker 02: that everyone wasn't sitting around waiting for Jew to resolve this in 2000 to get this done. [00:35:18] Speaker 02: And Amersham was doing the same. [00:35:20] Speaker 04: You're saying that there were a lot of issues not related to this invention that were impeding the process, if you will, of making it a high-throughput commercial goldmine. [00:35:34] Speaker 02: That didn't happen until the record will show. [00:35:37] Speaker 02: There's some claim that 2007 or something like that is really 2008 before they have actual evidence of any large-scale sales bias. [00:35:47] Speaker 02: But the other point is, you would think if it was a long-felt need and this person broke through because they had the stroke of genius, which is sort of the implication they're trying to give you, then why would Amersham did it at the same time? [00:36:00] Speaker 02: Selexa did it at the same time? [00:36:02] Speaker 02: Dower did it. [00:36:03] Speaker 02: Stempel did it around the Stempel's 1999. [00:36:05] Speaker 02: It's prior art, but it's right beforehand. [00:36:07] Speaker 02: So other people did it. [00:36:10] Speaker 02: And there's just no basis. [00:36:12] Speaker 02: And interestingly, in simultaneous invention, everyone used the ASIS. [00:36:16] Speaker 02: So when you look at the Amersham technology, you look at Selexa, which is what we licensed in. [00:36:20] Speaker 02: Everyone used the ASIS because that makes the stronger bond. [00:36:24] Speaker 02: But one thing I want to get back to was the motivation to use the ASIS because [00:36:32] Speaker 02: It became pretty clear from the board's initial institution decision that their central invention, if you read their patent what they say the invention is, I mean if you read the patent what the invention is, is the capping of sugar and labeling base. [00:36:47] Speaker 02: That's what they're saying the invention is. [00:36:49] Speaker 02: And then we came back with this avalanche of evidence, like three different anticipatory references, more, but at least three, and they just said, all right, well, [00:36:56] Speaker 02: And they dropped back and they said, well, it's the addition of the Diaz and they had a dependent claim. [00:37:00] Speaker 02: That's not what the summary of the invention is telling you they invented. [00:37:03] Speaker 02: So that's why there's a little bit of a, when you hear dissonance from the other side of the argument, that's what it is. [00:37:08] Speaker 02: So they're now trying to say it's the Diaz. [00:37:12] Speaker 02: And we put in pages of evidence, I think about it, 20 paragraphs from Weinstock nailing this issue. [00:37:21] Speaker 02: that the Diaz avoids GC-rich problems, that the Diaz just makes a more stable linker that you'd want, and that you could buy it on the street. [00:37:30] Speaker 02: All that stuff's just of record. [00:37:32] Speaker 02: So now what's happened is, on appeal, when they lost on that attempt to rely on the Diaz as the real true nature of the invention, they're shifting back to other things. [00:37:42] Speaker 02: And none of the three arguments that they've made is at all persuasive. [00:37:46] Speaker 02: I can go through the three errors that they're saying and won't [00:37:50] Speaker 02: repeat myself because I know how important everyone's time is. [00:37:53] Speaker 02: But starting with the objective evidence, there is no more, the commercial success, the way I think about it, the commercial success of Illumina is no more of a story of greatness for the Jew invention as it is for Dower or Stample or Shen. [00:38:11] Speaker 02: Because all of them have the combination of capping the sugar and labeling the base. [00:38:17] Speaker 02: So what the board says is, well, if your addition of the diazza, which is what distinguishes you from those references, look, there's anticipation references here, right? [00:38:27] Speaker 02: We didn't hear anything about that, and there's really what, like a paragraph of argument where they make the argument like in Shen that you have to cobble it together. [00:38:34] Speaker 02: They don't really contest that Dower, Stempel, and Shen disclose everything but the diazza. [00:38:41] Speaker 02: You wouldn't get that from the argument, but if you look at the anticipation rejections, that's what you get, because they don't have an argument. [00:38:47] Speaker 04: That's how you know. [00:38:48] Speaker 04: The Diasprine comes from Prober. [00:38:51] Speaker 02: Well, there's multiple combinations and I'm glad you asked that question. [00:38:56] Speaker 02: The Diasprine comes from Prober, but it also comes from the level of skill in the art. [00:39:00] Speaker 02: The fact that you could buy one on the street, the fact that it was ubiquitous, the fact that Siela, which is another combination, so one of the references before the board was the combination of Shen and Siela, [00:39:15] Speaker 02: And the name of it is the 7-diazepurine patent from the 80s. [00:39:20] Speaker 02: And in there, they say, this is great. [00:39:23] Speaker 02: It makes a stronger label and it prevents secondary structures, this GC ridge problem. [00:39:28] Speaker 02: Go on. [00:39:29] Speaker 02: I mean, it's a whole patent. [00:39:29] Speaker 02: It's about using diaza in your DNA. [00:39:32] Speaker 02: And then they say, use it for anything where you're having a DNA sequencing reaction. [00:39:39] Speaker 02: Not limited to Sanger. [00:39:41] Speaker 02: They will tell you that it's limited to Sanger. [00:39:44] Speaker 02: Their argument depends on them. [00:39:46] Speaker 02: How can they win otherwise? [00:39:49] Speaker 04: Well, it was focused on Sanger in Prober. [00:39:51] Speaker 04: That was the focus of it. [00:39:53] Speaker 02: But I'm now talking about Fielder. [00:39:56] Speaker 02: All Fielder says, forget all Fielder says, Prober is a landmark reference that taught [00:40:02] Speaker 02: Terminators and had a whole bunch of technology in it. [00:40:04] Speaker 02: It's the reason they cited it. [00:40:06] Speaker 02: It's such a fundamental reference. [00:40:07] Speaker 02: Everyone goes back to this program. [00:40:09] Speaker 02: But CELA, in many ways, is a more interesting combination. [00:40:11] Speaker 02: Because CELA's just U70 as is their grape for base labeling. [00:40:19] Speaker 02: And I think what's important to understand in CELA is that in CELA, they do not limit themselves to saying, or they say, anything with DNA sequencing reaction. [00:40:29] Speaker 02: Well, this is a DNA sequencing reaction. [00:40:31] Speaker 02: And it's no different. [00:40:33] Speaker 02: In Sanger, you had a cap that was not removable on the sugar. [00:40:38] Speaker 02: Here you have removable, and that technology is trivial, making it cleavable versus non-cleavable. [00:40:43] Speaker 02: They don't even argue about that. [00:40:50] Speaker 02: So, that already had the adjustment here and said, use the 7-diassa here for a firmer base. [00:40:57] Speaker 02: What's the difference? [00:40:58] Speaker 02: removable or non-removable. [00:41:01] Speaker 02: And it says, if you're using a polymerase, an enzyme, to incorporate the nucleotide, we're a good option for you. [00:41:07] Speaker 02: And that's in the 80s. [00:41:08] Speaker 02: That's the sealer effort. [00:41:10] Speaker 02: That is one of the combinations. [00:41:11] Speaker 02: And on prober, let me go through, I think it's worth discussing going through prober and how that's referred to in Shen. [00:41:24] Speaker 02: In Shen, [00:41:30] Speaker 02: At page 28, on this occasion it's kind of easier to use the internal paging rather than the appendix, but for reference in appeal 1547, this is A3029. [00:41:44] Speaker 02: It states at page 28, Prober shows, at line 17, Prober shows enzymatic incorporation of fluorescent DDNTPs by reverse transcriptase and sequinase. [00:41:58] Speaker 02: You talk about your reasonable expectation of success. [00:42:04] Speaker 02: In Shen, he's saying, when you label the base, look at Prober, because Prober was labeling the base and it was incorporating just fine. [00:42:15] Speaker 02: And he also had a cap on the sugar. [00:42:21] Speaker 02: And they say, this works fine. [00:42:23] Speaker 02: It's directing you. [00:42:24] Speaker 02: So what would one skill in the art do? [00:42:26] Speaker 02: One skill in the art would look [00:42:28] Speaker 02: at Prober to understand what worked. [00:42:33] Speaker 02: And that would be the Diaz's design. [00:42:35] Speaker 02: And again, they didn't really develop this argument in front of the panel, but it's sort of the best thing they got on Diaz's. [00:42:42] Speaker 02: I just say, to accept this argument, you'd have to ignore that as ubiquitous, ignore all the Weinstock evidence that's more than sufficient evidence alone, ignore the Siela combination, and ignore Siela's teaching, and ignore [00:42:57] Speaker 02: you know, a lot of other things that are documented in our briefs about why someone would use a diazo. [00:43:02] Speaker 02: But they argue on page 29, which is the very next page, that the C8 position of the purine structure presents an ideal position. [00:43:10] Speaker 02: So that's what Shen likes. [00:43:13] Speaker 02: But that doesn't nullify the idea of using a diazo, especially since, as everyone points out, there is... I know there's a difference, but what is the significance in the science [00:43:23] Speaker 04: between your being on a C7 or a C8 position, generally. [00:43:29] Speaker 04: I just don't have a sense as to whether that makes a lot of difference or not. [00:43:34] Speaker 02: I don't know if it makes a lot of difference, but the C7 position is where you can substitute the nitrogen for the carbon and therefore get a stronger bond. [00:43:44] Speaker 02: But you can't do it at the C8 position? [00:43:46] Speaker 02: I don't know if you can. [00:43:48] Speaker 02: I don't know that people explored that. [00:43:51] Speaker 02: But like I say, the real point is [00:43:54] Speaker 02: Over the course of the 90s, everyone moved to Diaz's. [00:43:57] Speaker 02: I mean, so their own, as I said, their argument isn't that Diaz's weren't ubiquitous. [00:44:04] Speaker 02: Their argument isn't that when you base label, everyone was using Diaz's and you could buy them commercially. [00:44:09] Speaker 02: Their own expert trainer acknowledges that, and he has to. [00:44:14] Speaker 02: Their argument is somehow, if it was great and standard for Sanger sequencing to get a really strong label, [00:44:25] Speaker 02: of the base to the label in Sanger, that wouldn't translate over to sequencing by synthesis. [00:44:32] Speaker 02: That's the best form of the argument. [00:44:35] Speaker 02: But the problem with that, among other problems, in the fact that they've never explained a reason why anyone would care about that difference. [00:44:47] Speaker 02: You hear it's all unpredictable. [00:44:48] Speaker 02: It's chemistry unpredictable. [00:44:50] Speaker 02: I mean, this panel's too experienced to fall for that kind of, I mean, all chemistry isn't [00:44:55] Speaker 02: In fact, we've established here that they, I mean, maybe the most important fact on this, and maybe this is the right, maybe where I should have started, and maybe I'll regret it when I re-listen to this, is that Jew himself, when he wants to describe the use of the adipurine, says this is just well established, and refers to Provert, and refers to Lee, and refers to Hobbes, and doesn't explain how to do it. [00:45:21] Speaker 02: This is this unpredictable science. [00:45:22] Speaker 02: He just says, well, it's all well established. [00:45:24] Speaker 02: You know what it is. [00:45:26] Speaker 02: Your people say, that's binding, as this court knows. [00:45:30] Speaker 02: But it's also just common sense. [00:45:31] Speaker 02: If he doesn't want to have to describe how to do it, then how unpredictable is it? [00:45:35] Speaker 02: And if he's just saying, this is described as well established, and then cites three different references. [00:45:42] Speaker 02: Now, they make arguments. [00:45:43] Speaker 02: And I thought some of them did border on more weak than you'd like to see. [00:45:50] Speaker 02: was that, well, because there's three different references cited for how well established it is to use Diazas and how easy the chemistry is, that it's some combination of the three, which is complicated. [00:46:00] Speaker 02: I actually argued that, I think, in the reply brief. [00:46:02] Speaker 02: It's like, come on. [00:46:04] Speaker 02: They're giving you three references from a long time ago that all show it's well established. [00:46:09] Speaker 02: So their invention is the addition of a Diaza, which their own inventor described as not his invention, but well established. [00:46:17] Speaker 02: But beyond that, in case that wasn't enough, [00:46:20] Speaker 02: At paragraph 59, at A3178, and this is Weinstock, Weinstock specifically says, he just nails that he has an issue, but he says, their argument is what I just described, because it's the only thing that- As you mentioned, Dr. Weinstock, at least I had a little bit of a colloquy with Mr. Wolfson about this issue, about the credentials. [00:46:41] Speaker 04: Well, it's not really the credentials. [00:46:42] Speaker 04: I mean, I think both sides would agree that [00:46:45] Speaker 04: uh... dr trainer dr wine stocker very educated and competent so forth but this argument i think mister woulson is making that there's at least for purposes of this case there's a little bit of a gap uh... in dr wine stocks expertise is true that dr wine stock did candidly make some admissions for you what's your response to that very very fair question i want first aid and or echoing [00:47:15] Speaker 02: observations made previously that the board was thorough in this matter. [00:47:20] Speaker 02: They looked at the qualifications, and that's at A3, and concluded him qualified as I think your honor did too. [00:47:26] Speaker 02: But let me get directly to the question. [00:47:29] Speaker 02: His job, he was at, there's three main genome centers in the United States. [00:47:35] Speaker 02: There's one at Harvard, one at George Washington, and one at Baylor. [00:47:37] Speaker 02: He worked at two of them as director. [00:47:40] Speaker 02: The job at those genome centers, they got large scale. [00:47:42] Speaker 02: This is a human genome project and follow on work. [00:47:45] Speaker 02: His job was to go around, in his declaration, to go around and evaluate advanced DNA sequencing technologies to know what was out there, what was new, what was going to work, and be a beta site and interact with. [00:47:58] Speaker 02: I can't think of a better position person to understand. [00:48:03] Speaker 04: Well, maybe Mr. Wolfson would say, and I don't want to put words in his argument, but maybe he would say, well, that's fine. [00:48:09] Speaker 04: He obviously has an important position. [00:48:11] Speaker 04: He's very accomplished. [00:48:12] Speaker 04: But it's not a hands-on type. [00:48:16] Speaker 04: type of thing in the chemistry like Dr. Traynor or maybe other people are. [00:48:21] Speaker 02: Okay. [00:48:21] Speaker 04: Maybe I'm misinterpreting his argument. [00:48:23] Speaker 02: He did say with hands on, my point is if you're looking at what the new sequencing technologies are, you need to have an interdisciplinary, obvious, I mean, it's obvious, you need to have knowledge of physics, biochem. [00:48:33] Speaker 02: He was a biophysics degree. [00:48:35] Speaker 02: He did his postdoc work at Stanford in biochemistry. [00:48:39] Speaker 02: He was not unsophisticated in what was needed to know. [00:48:42] Speaker 02: The point, really the point getting directly at what the concern is, which is almost [00:48:47] Speaker 03: Well, the board, in addition, the board had the opportunity to test the expertise of both of these winners. [00:48:54] Speaker 02: They were cross-examined for hundreds and hundreds of pages, and that was all briefed and argued for long periods. [00:49:01] Speaker 02: But the underlying concern, I don't think, really is a qualification of Dr. Weinstock. [00:49:07] Speaker 02: I mean, he's a professor. [00:49:08] Speaker 02: In other words, it's not a downward issue. [00:49:09] Speaker 02: The question is, is the organic chemistry the tough stuff here that's really the invention? [00:49:14] Speaker 02: I think that's what it is as compared to will it incorporate. [00:49:18] Speaker 02: If you cap the sugar, label the base, would you want to use the diazza and would it work? [00:49:23] Speaker 02: Let's not overcomplicate things. [00:49:25] Speaker 02: And the answer is, with respect to the addition of the diazza, which is where they're saying the invention is, their own patent doesn't say that it's any chemistry. [00:49:35] Speaker 02: It says go look at these old references. [00:49:38] Speaker 02: 10 years plus old, you can proportion, and you can find this chemistry. [00:49:43] Speaker 02: So it wasn't a synthetic chemistry problem because it was so old and the patent doesn't add it. [00:49:48] Speaker 02: On the linker, I think this is interesting, on the linker, and this comes up in 869, it's not so important to what's being questioned here directly, but secondarily it is, there's claims where they refer to three different ways to cleave the label when you're moving to the next base. [00:50:08] Speaker 02: actually claim more than that. [00:50:09] Speaker 02: They claim using photography, using heat, using physical means, and using chemical means. [00:50:15] Speaker 02: The only thing they disclose in their expert admitted deposition is photo, using light to disassociate it. [00:50:24] Speaker 02: They don't explain, they claim it, but they don't explain how you use a linker for chemical [00:50:32] Speaker 02: cleaving. [00:50:32] Speaker 02: They don't describe how you do it physically to get rid of the label when you need to get rid of it. [00:50:39] Speaker 02: But they claimed it all, and claimed 12. [00:50:41] Speaker 02: And all they showed was the use of light to eliminate it. [00:50:45] Speaker 02: So the linger can't be the fancy chemistry, because they don't give you any embodiment, but they claim it four different or five different ways. [00:50:52] Speaker 02: I think they even include physical chemistry. [00:50:54] Speaker 02: They don't have any embodiment in there. [00:50:57] Speaker 02: The capping the sugar, you would have heard argument from counsel [00:51:01] Speaker 02: formidable as he is, that, well, capping the sugar, that's hard. [00:51:05] Speaker 02: How do you do that? [00:51:06] Speaker 02: You didn't hear any argument that there's a challenge there. [00:51:09] Speaker 02: So there's no challenge in organic chemistry. [00:51:14] Speaker 02: And I don't like the sense that there's hand waving there, because that's the only place left to go when you understand that the azzes are every day and the rest of it's in reference after reference, undisputed based on anticipation rejections with not much of any kind of contest. [00:51:31] Speaker 02: So if there's not real chemistry to do, what you really want is someone to say, well, can you put these pieces together, and then we'll incorporate it with an enzyme in biophysics, in biochemistry, in microbiology. [00:51:41] Speaker 04: You're saying what you're making the argument is I understand that Dr. Weinstock, maybe at the point in time that we're dealing with here, wasn't as hands-on in terms of the laboratory. [00:51:54] Speaker 04: What's relevant to this case, he had more than enough expertise. [00:51:58] Speaker 02: Absolutely. [00:51:58] Speaker 02: And the board self-found. [00:52:01] Speaker 02: judge wallach planet more than sufficient evidence of that i mean uh... you know this this appeal is turning into sort of an argument on the other side of the novel level because we didn't really a legal argument so i'm kind of contesting them i think everything i'd say it's got to be through the lens of sufficient evidence i'm not particularly worried about that because it's overwhelming i hope i've laid out where the heart starts and the minor addition that they're claiming and and how weak that is [00:52:29] Speaker 02: as we've described. [00:52:30] Speaker 02: Now I want to make sure that I've covered his three arguments. [00:52:33] Speaker 02: The one stock unqualified I addressed. [00:52:36] Speaker 02: The objective evidence, I don't know if there's anything more on that. [00:52:38] Speaker 02: If it was such a great invention and he turned the key that opened the door, how come it took so many years for someone else to do it based on different license technology? [00:52:48] Speaker 02: I think I addressed the licensing. [00:52:51] Speaker 02: And then the final thing with this invention as a whole. [00:52:58] Speaker 02: You know, I think the invention as a whole, yes, of course you have to look at the invention as a whole, but what the reality is, you know, and we learned this from Graham, is that you have to look at the difference between the art and what's claimed, at least for the obvious. [00:53:14] Speaker 02: And really this comes about because they want to ignore that feature and the board just wasn't due. [00:53:21] Speaker 02: The board, I think, safely concluded that [00:53:26] Speaker 02: The disclosure of the cap on the sugar and the label on the base was well known on multiple references. [00:53:35] Speaker 02: Are there any questions or anything else I can help with? [00:53:39] Speaker 02: Okay, thank you very much. [00:53:55] Speaker 05: I want to start by addressing Judge Wallach's question about claims 11 and 12. [00:54:01] Speaker 05: As you recall, we actually proposed substitute claims in our motion to amend. [00:54:06] Speaker 05: We argued the non-obviousness of proposed claims in 25 and 26. [00:54:12] Speaker 05: They were substitutes for claims 11 and 12. [00:54:15] Speaker 05: The argument appears [00:54:16] Speaker 05: on page 82191 of the 698 appendix. [00:54:22] Speaker 05: Dr. Treanor's relevant testimony is at page 82191. [00:54:30] Speaker 05: Dr. Treanor's relevant testimony is at page A3855, and this also is treated in page 22 and 23 of our reply brief. [00:54:44] Speaker 03: Let me just throw one more question. [00:54:46] Speaker 03: Sure. [00:54:47] Speaker 03: You're addressing mine. [00:54:50] Speaker 03: Mr. Reinus said, was talking about licensing. [00:54:53] Speaker 03: And he raised something I'd like you to answer, and that is, where in the licensing negotiations is there a tie to any of the features or inventions on what he lists? [00:55:05] Speaker 05: So, I mean, I think you start with [00:55:09] Speaker 05: that the first email that starts this, which is an email from between two of Illumina's chief scientists, which says, Dr. Ju has solved the problem that has spied us all. [00:55:24] Speaker 05: So he's solved the problem. [00:55:25] Speaker 05: And then you get a back and forth between Illumina and Columbia. [00:55:31] Speaker 05: There's an agreement to, and this appears, the key email is a page, [00:55:39] Speaker 05: 3993 of the 698 appendix. [00:55:43] Speaker 05: This is appeal 1547. [00:55:44] Speaker 05: And, you know, later on you see, you know, or farther down in the email chain, actually it's earlier, you know, somebody from Illumina says, we don't have a specific project or initiative to do sequencing. [00:55:57] Speaker 05: by synthesis. [00:55:57] Speaker 05: And then somebody else says, currently, Illumina doesn't have a play in this area. [00:56:02] Speaker 05: Now, Mr. Ryan said, well, this is unsuccessful licensing. [00:56:07] Speaker 05: This is attempted licensing, not consummated licensing. [00:56:09] Speaker 05: That's true. [00:56:11] Speaker 05: But there's certainly no doubt that this is a respect for the invention. [00:56:15] Speaker 05: I mean, the whole theme of this is, if you continue reading a couple of pages later, the whole theme of this is, if Dr. Ju says he solved it, I would believe him. [00:56:25] Speaker 05: is what is the back and forth between the folks in Illumina and then you have, and this is not just in 2005, 2006, 2006 the negotiations break down, Columbia licenses somebody else, Illumina jumps into the market by acquiring another company and immediately has success [00:56:43] Speaker 05: with the products that embody this invention. [00:56:45] Speaker 05: And yet, interestingly, well into 2008, 2009, 2011, there were still discussions, Illumina still saying, you know, we would have really liked to license the Columbia patent, but [00:56:58] Speaker 05: We have a problem with the fact that you licensed somebody else. [00:57:02] Speaker 05: There's some more discussions. [00:57:04] Speaker 05: Oh, I'd love to come and see your lab. [00:57:09] Speaker 05: Let me fly from San Diego to Boston. [00:57:12] Speaker 05: I'll be there as soon as I can. [00:57:14] Speaker 05: This is definitely respect for the invention. [00:57:16] Speaker 05: I mean, no question. [00:57:19] Speaker 05: If I could answer just one technical point about the purines and the pyrimidines and the C7 and the C8, [00:57:26] Speaker 05: So there are four bases, of course, in DNA. [00:57:29] Speaker 05: Two of them are purines. [00:57:30] Speaker 05: Two of them are pyrimidines. [00:57:32] Speaker 05: The two purines are larger. [00:57:34] Speaker 05: They're double rings. [00:57:35] Speaker 05: And so that creates part of the problem about putting the, you know, where to put the label by the cleavable linker so it doesn't get in the way. [00:57:43] Speaker 05: What Dr. Chen thought was mistakenly [00:57:46] Speaker 05: was that the eight position was the right one, but the eight position is not the right one because of spatial consideration. [00:57:54] Speaker 05: In order to make it work best, you have to put it at a seven. [00:57:57] Speaker 05: The problem is the seven in a natural purine is a nitrogen, and that's not good for the bond of holding the [00:58:05] Speaker 05: the cleavable linker. [00:58:06] Speaker 05: So you have to change the nitrogen to a carbon. [00:58:10] Speaker 05: You have to make one, I should say, that has a carbon rather than a nitrogen, and that helps with the bond. [00:58:16] Speaker 05: Now, Mr. Ryan said, well, everybody knew diazepurines were great. [00:58:20] Speaker 05: Diazepurines were used in Sanger sequencing. [00:58:24] Speaker 05: I mean, they were used for two different reasons that are completely irrelevant to sequencing by synthesis. [00:58:29] Speaker 05: The first reason they were used, and this is CELA, had to do with the fact that when you're sequencing bases that have a lot of GC, GC, GC, they tended to kind of clump together, and for some reason people were trying to fix that, and CELA figured out that the adipurines [00:58:49] Speaker 05: switching into a diazepurine from a regular purine would solve that problem. [00:58:53] Speaker 05: That has nothing to do with the problem that Dr. Ju was facing. [00:58:57] Speaker 05: That has solely to do with the process of electrophoresis, which is under sanguine sequencing, which wasn't satisfying to people because it takes a really long time and it can't be automated the way that sequencing by synthesis can be. [00:59:12] Speaker 05: The other was a separate problem that Dr. Hrober figured out, and this was a significant advance, no question, in Sanger sequencing, which was [00:59:22] Speaker 05: You have to keep a, he figured out you put the label on the base. [00:59:26] Speaker 05: The problem with his electrophoresis is a very kind of harsh process. [00:59:29] Speaker 05: And what he figured out was when you were sort of playing out all the strands, if you use a diazepurine instead of a natural purine, the label will stay on. [00:59:38] Speaker 05: And his label is an un-cleavable linker. [00:59:43] Speaker 05: So it's totally different from the whole, you know, there's no question, you know, Prober made an advance in Sanger sequencing, but the whole problem, the problems that they're trying to solve are totally different from the ones that Dr. Zhu was solving, which is where would the label fit so that it could, so that it [01:00:01] Speaker 05: could not get in the way of everything else. [01:00:04] Speaker 05: And it has to be cleavable because when you detect the label, there's a cap, you detect the label, and then the cap and the label have to fall off so that you can then repeat the process. [01:00:17] Speaker 05: If all of those put together, that fundamentally are what made SPS work as well as it has, and fundamentally all those put together are what Dr. Ju conceived. [01:00:27] Speaker 01: Thank you.