[00:00:07] Speaker 03: OK, the next case before the court is Stanford University versus Chinese University of Hong Kong, case number 152011. [00:00:17] Speaker 03: This was originally before the TTAB in connection with interference proceedings. [00:00:27] Speaker 03: The challenge to those or the appeal from those interference proceedings was filed originally as a 146th proceeding in district court. [00:00:36] Speaker 03: The district court has now transferred the case here in light of our Biogen decision. [00:00:43] Speaker 03: Mr. Reines, you want four minutes for rebuttal? [00:00:46] Speaker 03: Yes, Your Honor. [00:00:47] Speaker 03: Let's hope we can give you that. [00:00:49] Speaker 03: We'll see. [00:00:52] Speaker 03: Before you begin, can I ask where we are with respect to the transfer question? [00:00:57] Speaker 03: It seems that you sort of dropped that issue after the Biogen search. [00:01:01] Speaker 03: petition was denied. [00:01:02] Speaker 03: Is that off the table now? [00:01:04] Speaker 02: I think that isn't going to be the subject of oral argument, that's for sure. [00:01:07] Speaker 03: OK. [00:01:08] Speaker 03: And there's nothing we as a panel could have done about it anyway. [00:01:10] Speaker 03: That's correct, Your Honor. [00:01:13] Speaker ?: OK. [00:01:13] Speaker 02: All right. [00:01:13] Speaker 02: Go ahead. [00:01:13] Speaker 02: Thank you, Your Honor. [00:01:15] Speaker 02: Edward Ryan is on behalf of Stanford University. [00:01:17] Speaker 02: He may please the court. [00:01:19] Speaker 02: The board erred by invalidating Professor Quake and Dr. Christina Fann's patent. [00:01:25] Speaker 02: The 01 patent captured the inspired insight that Down syndrome [00:01:31] Speaker 02: the excess of chromosomes, 21, could be diagnosed without separating fetal DNA from internal DNA, without separating those two things, for nearly a decade after the discovery that fetal DNA was in the mother's cell-free blood, which we know about from the low case. [00:01:58] Speaker 02: For nearly a decade, the entire community, including Dr. Lowe, were off chasing an effort to separate fetal DNA to look at it to determine whether the chromosome could be there. [00:02:10] Speaker 02: Only Professor Quague and Christina Fan's insight that that's foolish. [00:02:17] Speaker 02: Universities everywhere, companies everywhere, this document, it's in this record, were searching for this. [00:02:23] Speaker 02: And it was foolish because you didn't need to get rid of the maternal background [00:02:27] Speaker 02: If you were careful in your molecular counting, you could see the overshoot on the 21 by including it all. [00:02:36] Speaker 02: And what he then did was he put a patent application together well before 21. [00:02:41] Speaker 00: Let me ask you, I think we're familiar with the history that you're reciting. [00:02:46] Speaker 00: Let's look at claim one. [00:02:48] Speaker 00: And this is element B of claim one. [00:02:53] Speaker 00: And we have conducted massively parallel DNA sequencing of DNA fragments randomly selected. [00:03:00] Speaker 00: Now, reading that, one would think, well, OK, this claim is directed to a randomly selected process. [00:03:09] Speaker 00: Then you go to the specification, and there's mention there. [00:03:15] Speaker 00: And I think we're going to get into the value or the weight of that [00:03:22] Speaker 00: with references, but why is there no significant structure that would support a randomly selected? [00:03:30] Speaker 00: It seems to me that most of the written description goes to targeted selecting and not randomly selected. [00:03:40] Speaker 02: OK. [00:03:40] Speaker 02: Well, first of all, let me deconstruct one piece of that, which is the vast majority of the specification, the preferred embodiment, is digital PCR, which is not sequencing. [00:03:52] Speaker 02: If that's what, I'm not sure if that's what you're referring to. [00:03:55] Speaker 02: That's separate. [00:03:56] Speaker 02: Then there's a section called sequencing, which starts in column nine, section four. [00:04:01] Speaker 00: Now, this digital PCR, does that involve both process of randomly selected and targeted selection? [00:04:10] Speaker 00: Isn't that mostly directed towards targeted selection? [00:04:14] Speaker 02: It just has nothing to do with sequencing. [00:04:18] Speaker 02: If you take the DNA and you see which [00:04:22] Speaker 02: which little you amplify it, and then you see which ones light up. [00:04:26] Speaker 02: I mean, this is the problem with looking at why one would feel the need or urge to import what's happening in digital PCR over to a sequencing disclosure makes no sense. [00:04:37] Speaker 02: What I would answer to you, because you asked the question which really begs the primary question in this appeal, is why is column 19 and 20 sufficient to disclose random sequencing? [00:04:49] Speaker 02: I think it's relatively simple. [00:04:50] Speaker 02: I was shocked. [00:04:52] Speaker 02: at the outcome of this. [00:04:54] Speaker 02: Off-the-shelf technology at the time that this was submitted was the Illumina system was a commercial product that was used for random sequencing routinely. [00:05:05] Speaker 02: No debate in the record. [00:05:06] Speaker 02: You won't find any debate. [00:05:07] Speaker 02: Routinely done. [00:05:08] Speaker 02: Random sequencing, no problem. [00:05:10] Speaker 02: That's what people do. [00:05:11] Speaker 02: They're expert, our expert, everybody. [00:05:15] Speaker 02: The record is also unambiguous that on the Illumina system, [00:05:20] Speaker 02: At best, there was some experimental work people were playing with to try and get it to work for targeted sequencing. [00:05:29] Speaker 02: Keep in mind, targeted sequencing is just a little bit on the technology is random sequencing is you sequence everything and then you go figure out which ones of those match to, call them some 21 after the fact. [00:05:44] Speaker 02: Targeted sequencing is you filter out so that you only have [00:05:49] Speaker 02: chromosome 21 and whatever control chromosome you're using. [00:05:52] Speaker 02: You only have those. [00:05:53] Speaker 02: You sequence those and you're done. [00:05:56] Speaker 02: None of this has to do with digital PCR. [00:05:58] Speaker 02: It's just irrelevant. [00:06:00] Speaker 00: There's no doubt that the RID description would disclose to one skill in the art that the patent is directed towards targeted sequencing. [00:06:12] Speaker 02: I don't understand that. [00:06:13] Speaker 02: It says [00:06:17] Speaker 02: It says randomly fragmented genomic DMAs put to a planar surface, and then you use the Illumina system. [00:06:24] Speaker 02: Where are you reading from? [00:06:25] Speaker 02: This is at column 19, line 61. [00:06:29] Speaker 01: I guess the point I hear Judge Raina making is that when you read all of the columns before column 19, the reader is getting conditioned in a very severe way that this patent, this invention, [00:06:47] Speaker 01: is devoted to differential detection of targeted sequencing using something known as digital analysis. [00:06:54] Speaker 01: You know, this yes-no result where you have thousands and thousands and thousands of wells and then you put in your target primer in them to try to figure out a yes-no result for each individual well. [00:07:08] Speaker 01: And so that's the, you know, it's almost like a jackhammer to your forehead for the first [00:07:16] Speaker 01: several columns. [00:07:17] Speaker 01: And then we get to column 19. [00:07:19] Speaker 01: And as I understand the patent board, they're saying these two paragraphs, column 19 and column 20, they are somewhat ambiguous in what they're trying to get at. [00:07:31] Speaker 01: There's a discussion of sequencing. [00:07:39] Speaker 01: There's discussions of a target-specific sequence, doing massive parallel sequencing, [00:07:45] Speaker 01: on millions of fragments of randomly fragmented genomic DNA, but what we don't know is, is each one of those random fragments getting sequenced, or is it possible that there's some kind of target primer being used in this particular section of the patent? [00:08:05] Speaker 02: I just don't get it. [00:08:06] Speaker 02: There's no step in here that says you're filtering out all the other chromosomes before you do it. [00:08:10] Speaker 02: It says you use random sequencing [00:08:13] Speaker 02: randomly fragmented genomic DNA, and you use the standard Illumina product. [00:08:18] Speaker 02: That's what it says in the specification. [00:08:21] Speaker 02: Within the ordinary skill in the art, they admit that massively parallel sequencing is well known by people with skill in the art. [00:08:30] Speaker 02: They ended up choosing that one would assume that you would do this targeted on this Illumina platform because of the opposing Dr. Gabriel cited three references that taught [00:08:43] Speaker 02: targeted sequencing. [00:08:44] Speaker 02: That's the basis. [00:08:45] Speaker 02: They say that's the decision point. [00:08:47] Speaker 02: And with respect to those, those all relate to the 454 platform, which is obsolete, never went anywhere, it's not even sold anymore, supported anymore, instead of the wildly popular Lumina system that works on the basic random sequencing. [00:09:02] Speaker 02: Why would you not use random sequencing? [00:09:05] Speaker 02: And it's within the basic competence in their own statement of ordinary skill in the art [00:09:11] Speaker 02: that people would be fluent with massively parallel sequencing. [00:09:14] Speaker 00: Well, it could be that you can use random sequencing within the scope of the process described in the patent. [00:09:23] Speaker 00: But the question is, is that what the patent discloses? [00:09:26] Speaker 00: Is that what the patent possesses? [00:09:29] Speaker 02: Well, it discloses it in the sense that there's no dispute about enablement, nor could there be, because it's agreed that people would know routinely that if you get Illumina, you do random sequencing. [00:09:38] Speaker 02: That's undisputed. [00:09:40] Speaker 02: Decision survives that. [00:09:42] Speaker 02: To go find three articles about a different platform that shows some experimentation with targeted and saying, therefore, we're going to assume there's a step that's not disclosed in this specification that's done beforehand to filter out all the other chromosomes. [00:09:55] Speaker 02: Why are we working so hard to deprive this person of what he invented? [00:09:59] Speaker 01: But the question is, did the inventor here really disclose that he, they contemplated using [00:10:08] Speaker 01: random massive parallel sequencing to detect aneuploidy and that's less clear here because there's nothing here that says we're going to use the Illumina platform and then we're going to sequence, we're going to use random primers and we're going to sequence every single little fragment and then we're going to match up the fragments to the respective chromosomes and then we're going to [00:10:34] Speaker 01: count them and associate, you know, which chromosomes are bigger than other chromosomes to figure out how many we're going to expect for chromosome 21. [00:10:42] Speaker 02: But the Patent Office rules tell you not to put in all that kind of detail when it's so basically known. [00:10:47] Speaker 02: Literally in their description of a person of ordinary skill in the art, it states they will be fluent in massively parallel sequencing and they will know how to take the results of massively parallel sequencing and compare it to a reference genome, which only relates [00:11:02] Speaker 02: to random parallel sequencing. [00:11:04] Speaker 02: It doesn't relate to target. [00:11:06] Speaker 02: So they're saying in the basic competency of a person's skill in the art is random sequencing. [00:11:11] Speaker 02: You worked in the solicitor's offices. [00:11:13] Speaker 02: You know, why would you clutter up a patent application with the details when you cite a luminous product? [00:11:19] Speaker 02: You've got that as the person's skill in the art. [00:11:20] Speaker 00: Well, it could be you clutter up a patent because you want to make sure that you're supporting what you claimed. [00:11:26] Speaker 00: I mean, you're claiming something. [00:11:28] Speaker 00: Now we're looking at the written description. [00:11:30] Speaker 00: We're trying to see if these references that you point to is sufficient. [00:11:35] Speaker 00: Understood. [00:11:35] Speaker 00: That's fair enough. [00:11:36] Speaker 02: That's fair enough. [00:11:37] Speaker 02: But I guess the context, Your Honor, is the insight is that you don't worry about the maternal background. [00:11:43] Speaker 02: Then he has, I think, one of the interesting aspects of this is the outline of the section. [00:11:47] Speaker 02: And he lists detection and quantification. [00:11:49] Speaker 02: And he lists four different ways of doing it. [00:11:51] Speaker 02: And one of them is sequencing. [00:11:53] Speaker 02: So he says one way you do it is sequencing. [00:11:55] Speaker 02: Let's not deprive him of that. [00:11:57] Speaker 02: Did he disclose sequencing for this? [00:11:58] Speaker 02: Yes, he did. [00:11:59] Speaker 02: Then he discloses the main way you do it is you use an Illumina product whose basic process of use by the undisputed record is random. [00:12:07] Speaker 02: Then he discloses that if you have 30 base pairs of random sequencing information, you can go to the known genome and figure it out. [00:12:17] Speaker 02: Why would you disclose that if you were talking about targeted? [00:12:21] Speaker 02: He cites multiple references on random sequencing, which is known to be basic in the art. [00:12:27] Speaker 02: How much does he have to do to say sequencing? [00:12:29] Speaker 02: So I mean, look, if it was targeted sequencing, someone would come in and say he didn't disclose targeted sequencing. [00:12:35] Speaker 02: Why are we nitpicking something that's not at the center point of the invention? [00:12:40] Speaker 02: I just don't understand that. [00:12:42] Speaker 02: If it wasn't the basic. [00:12:43] Speaker 00: Well, you're making the claim, not us. [00:12:47] Speaker 00: The patent is issued, and the burden's on the other side. [00:12:50] Speaker 00: You're making a claim that the rent description supports the claim. [00:12:55] Speaker 00: That's what we're looking at. [00:12:56] Speaker 00: Call that nitpicking or whatever, but it's your case. [00:13:00] Speaker 00: True. [00:13:01] Speaker 02: And what I'm saying is that since it's basic skill in the art to use random sequencing, that's the baseline. [00:13:07] Speaker 02: And the only evidence in the record is that it's experimental to use targeted sequencing. [00:13:12] Speaker 02: when the inventor says, oh, and you can use other ways of counting molecular. [00:13:15] Speaker 02: I did my work in my university lab with digital PCR. [00:13:19] Speaker 02: But you know what? [00:13:19] Speaker 02: It wouldn't be limited to that. [00:13:21] Speaker 02: It could be emulsion. [00:13:22] Speaker 02: It could be microfluidic dilution. [00:13:24] Speaker 02: It could be sequencing. [00:13:25] Speaker 02: Oh, if you want to do sequencing, use the Illumina. [00:13:28] Speaker 02: Oh, everyone knows how to use that. [00:13:29] Speaker 02: It's in the ordinary skill in the art by both parties. [00:13:33] Speaker 02: Why would that not be covered? [00:13:35] Speaker 01: It's not that the invention... Dr. Gabriel said that the Illumina platform could be used either for targeted sequencing or random sequencing. [00:13:42] Speaker 02: Right. [00:13:42] Speaker 02: And the state of the record, this to me is the hinge point, the state of the record, especially when you go to their opposition, is, well, we kind of agree because Dr. Deder, who's our expert, said that that would be experimental at the time. [00:13:54] Speaker 02: And they say, well, he acknowledged that there could be some experimental work that's non-standard. [00:13:59] Speaker 02: It's a commercial product with kits sold for random sequencing. [00:14:02] Speaker 02: There's some experimentation that's been done [00:14:05] Speaker 02: on at that time period on Targeted. [00:14:11] Speaker 02: And the only references that shows anyone ever doing Targeted is on this 454 platform, which is not even cited as one of the platforms in here. [00:14:20] Speaker 00: I understand the reference to the Illumina product, and I believe I understand the Illumina product. [00:14:26] Speaker 00: What I'm struggling with is whether in a written description, you can footnote your way around to disclosures. [00:14:34] Speaker 00: You can bring in material that's not within the four corners of the written description by way of a footnote and then have us, then puts us in a situation where we have to go out there and try to understand what that footnote means. [00:14:51] Speaker 00: What's supposed to happen is that you're supposed to have that information in the written description, and that's what we're looking at. [00:14:59] Speaker 00: I know you're trying to shoehorn the references in here, and I'm trying to find out if your shoehorning is enough or not. [00:15:08] Speaker 02: You're allowed to incorporate by reference, but the real point, Your Honor, and I understand your frustration with it, I don't mean to be presumptuous about this in any way, but in the statement of the ordinary skill in the art that was included by their expert, it's like seven lines, it's a degree in this and fluency in [00:15:28] Speaker 02: massively parallel sequencing and knowing how to take the results of that and put that in alignment. [00:15:32] Speaker 02: So if it wasn't so basic that they have to acknowledge it in their own basic statement of skill in the art, I could see an argument. [00:15:41] Speaker 02: Wow, that's sort of inventive. [00:15:42] Speaker 02: It was cutting edge. [00:15:43] Speaker 02: It was different. [00:15:43] Speaker 02: Who would know? [00:15:44] Speaker 02: They're saying people walk into this. [00:15:46] Speaker 02: The first thing they know is random parallel sequencing. [00:15:49] Speaker 02: I should probably sit down. [00:15:51] Speaker 03: Thank you very much. [00:15:53] Speaker 03: We'll give you two minutes for rebuttal. [00:16:04] Speaker 04: May it please the court, I think it would help to focus on the questions from the bench to recognize that there are at least three really profound differences between doing this technique with predetermined unique sequences and doing it by massively parallel random sequencing. [00:16:26] Speaker 04: And the first is that with a predetermined target, [00:16:30] Speaker 04: It's easy to detect. [00:16:31] Speaker 04: The spec says you do it one of two ways. [00:16:33] Speaker 04: You can have a sequence-specific probe. [00:16:36] Speaker 04: It says, or you can sequence it. [00:16:37] Speaker 04: And it's easy to sequence. [00:16:39] Speaker 00: Council, I was really impressed by the credentials of the two experts in this case. [00:16:43] Speaker 00: And it's clear to me that the PASIDA, even though the PTAB didn't go and set out complete detail, but the PASIDA in this case is somebody, given the two experts that testified here, they're at a really high level. [00:17:00] Speaker 00: I mean, they understand DNA technology in the most fundamental way. [00:17:07] Speaker 00: Why is it that a posita, looking at the claim, and looking at that element B of claim one, and then seeing these references that are here, why wouldn't a posita say, aha, they've also captured random sequence, random selection? [00:17:26] Speaker 04: For a couple of reasons. [00:17:27] Speaker 04: The first is, [00:17:28] Speaker 04: that the fundamental difference between these two methods cascades through the whole method. [00:17:34] Speaker 04: When you use a predetermined sequence, you fix the ratio for eucloide at one to one. [00:17:39] Speaker 04: You know that there's only going to be one you find in one chromosome, and there's only going to be one you find in the other. [00:17:45] Speaker 04: And you see if the difference is one to one. [00:17:46] Speaker 03: But Dr. Gabriel said that Illumina could be used for targeting sequencing. [00:17:50] Speaker 03: But you don't dispute that at the time, that those of skill in the art did not think it was a useful mechanism for targeted sequencing. [00:17:59] Speaker 03: I mean, it was possible they were doing some experimentation, but it wasn't deemed to be efficient. [00:18:05] Speaker 03: It was deemed to be costly. [00:18:07] Speaker 03: I mean, isn't it true that Illumina really was an off-the-shelf product for random sequencing? [00:18:12] Speaker 04: It was, as was the 454 device at the time. [00:18:15] Speaker 04: And I think it's helpful [00:18:18] Speaker 04: If you take a look at page 4887 of the appendix of paragraph 13 of Dr. Gabriel's declaration, she explains what the difference in background is between her and Dr. Dieter. [00:18:28] Speaker 04: Dr. Gabriel is at the Broad Institute at Harvard and MIT, which is one of the biggest human genomic sequences enterprises in the world. [00:18:38] Speaker 04: And she said that she was deeply involved in human sequencing, including human sequencing with these devices, in 2006 and 2007. [00:18:47] Speaker 03: She points out that... But she also said that Craig came up with this targeted fetal DNA sequencing, right? [00:18:55] Speaker 04: He did indeed come up with the targeted sequencing. [00:19:00] Speaker 04: And her point is that in human genomic DNA work, these devices were regularly being used. [00:19:07] Speaker 04: or targeted sequencing, not for random sequencing. [00:19:11] Speaker 04: And that explains the difference in the opinion testimony. [00:19:14] Speaker 03: I don't see her saying that Illumina was regularly being used for this. [00:19:18] Speaker 03: I hear her saying that it was possible. [00:19:21] Speaker 04: I think if you look at 4890 paragraph 20, [00:19:36] Speaker 04: I think you'll see at the end of that, she cites the Pareka publication, which, not in the appendix, but when you look at it, you'll see that it was submitted in August 2007 at the end of an obviously lengthy period. [00:19:52] Speaker 04: What volume are you in? [00:19:54] Speaker 04: I am not sure. [00:19:55] Speaker 00: It is volume three. [00:19:57] Speaker 00: Volume three. [00:20:06] Speaker 00: Okay, go ahead. [00:20:19] Speaker 04: The Pareka publication actually deals with the Illumina device. [00:20:23] Speaker 04: The other publications here, essentially contemporaneous with the filing of the application, Bin Laden in 2007. [00:20:31] Speaker 04: the Dahl publication in 2007. [00:20:33] Speaker 04: If you look at those in the joint appendix, you'll see that those are in February or were submitted in February, essentially contemporaneous. [00:20:41] Speaker 04: And then she states, based on her experience with use of these devices for human work, which is what's relevant here, although the publication dates of Pareka and Dr. K, [00:20:54] Speaker 04: are after the filing date of the 686 application. [00:20:57] Speaker 04: They represent the type of work that was being routinely performed in sequencing laboratories in 2006 and 2007 based on her actual experience with exactly that kind of work. [00:21:09] Speaker 04: And if I may, the whole point here is no matter what Quake does, Quake has to do a whole bunch of experiments. [00:21:20] Speaker 04: The only way you get data you can use is by doing a whole bunch of experiments. [00:21:25] Speaker 04: When you do it with sequence-specific probes, they light up. [00:21:28] Speaker 04: If you're going to do it by sequencing, you're going to obviously have to do a whole bunch of sequencing, and it sure sounds like a good idea to have a machine. [00:21:35] Speaker 04: Let's have a machine. [00:21:36] Speaker 04: And he says there are machines that do a whole bunch of sequencing. [00:21:39] Speaker 04: He doesn't say use Illumina. [00:21:41] Speaker 04: He says use a platform based on this kind of machine. [00:21:46] Speaker 04: And what Dr. Gabriel testified to is that in the human area, [00:21:50] Speaker 04: Because the genome was so big and use of the machines was so expensive, they routinely would target the DNA by some kind of target-specific amplification before they put it on the device. [00:22:04] Speaker 04: And that certainly could have been done. [00:22:06] Speaker 04: And what the board found supported by substantial evidence is that's how a person of ordinary skill in the art would read it. [00:22:13] Speaker 04: Now, we've heard here, oh, you can just read into the patent [00:22:20] Speaker 04: Things that the person of ordinary skill in the art might have imagined that you didn't describe, and that's just not the law. [00:22:27] Speaker 04: The board cited Lockwood versus American Airlines, 107 F-3RD 1565 at 1572. [00:22:34] Speaker 04: The claim was to a whole system. [00:22:37] Speaker 04: The application was missing pieces of the system. [00:22:39] Speaker 04: And they said that the person of ordinary skill might speculate as to modifications the inventor didn't disclose doesn't fill the void. [00:22:46] Speaker 04: Ariad, the on-bound Ariad opinion. [00:22:49] Speaker 04: You know, vague reference and invitation for further research doesn't constitute written description, and went on to say, which is really what they're arguing. [00:22:58] Speaker 04: They're trying to say, well, somebody skilled in the art might have thought it was obvious from what we disclosed. [00:23:03] Speaker 04: And Lockwood says that's not enough. [00:23:05] Speaker 04: Ariad says at 1356, that's not enough. [00:23:08] Speaker 04: Citing UCV Lilly 119F3 at 1566 says that's not enough. [00:23:14] Speaker 04: The Enzo case makes the point, you have to have a description of the whole process. [00:23:18] Speaker 00: And the court recognized that this difference between using targets... Is that the case you have to have a description of the whole product or you have to have enough description that would lead a procedure to recognize the product? [00:23:34] Speaker 04: You have to have enough description that would lead a person of ordinary skill and the art to recognize that you were describing that product. [00:23:41] Speaker 00: Then why in this situation? [00:23:43] Speaker 00: going, again, we have two experts that are at a very high level. [00:23:48] Speaker 00: When they look at the claim and then look at the references in the written description, why is that not enough for an expert to go? [00:23:55] Speaker 00: I'm assuming, and I think this is a fair assumption, that a placida, at the time we're talking about, would understand the difference between targeted and random selection. [00:24:08] Speaker 04: Absolutely. [00:24:08] Speaker 00: OK. [00:24:10] Speaker 00: So why wouldn't a placida read [00:24:13] Speaker 00: this RIN description and the claimant says, oh, look, they're also claiming a random sequencing. [00:24:22] Speaker 04: At best, they have a suggestion to use one of these massively parallel systems in doing their targeted work. [00:24:30] Speaker 03: The essence of doing- Well, that's not- I mean, there's more to it. [00:24:33] Speaker 03: They actually use the word random sequencing more than once, right? [00:24:38] Speaker 04: No, they say random fragments. [00:24:41] Speaker 04: And when you make these things, you chop up the DNA. [00:24:44] Speaker 04: And whether that DNA is something that's been amplified first with target-specific sequences or taken out of the patient, you chop it up and you put it on the device to sequence it. [00:24:56] Speaker 03: OK, so your contention is that there's no disclosure of random sequencing at all in this set, in the written description. [00:25:06] Speaker 04: Our position, as ably articulated by Dr. Gabriel, is these devices were known to be useful both ways. [00:25:15] Speaker 04: And when you read this statement in the context of the entire specification, and you see that there's no description of the other steps of the method, no description of mapping the random sequences to the genome, and no description of the fact that the ratio is no longer one-to-one. [00:25:31] Speaker 04: Because when you don't have a preselected sequence, [00:25:34] Speaker 04: There are different numbers of unique sequences you're going to find, depending on the size of the chromosome. [00:25:39] Speaker 04: And you have to do some fancy statistics to figure that out. [00:25:42] Speaker 04: And that's nowhere discussed in this. [00:25:45] Speaker 04: There is no all the rest of the process this deficiency cascades into. [00:25:51] Speaker 01: This claim, it wasn't filed with the original application, right? [00:25:56] Speaker 01: Absolutely not. [00:25:58] Speaker 01: many years after the original filing date. [00:26:02] Speaker 01: So we can't just look at the claim and say that's its own written description. [00:26:07] Speaker 04: Absolutely. [00:26:07] Speaker 04: And in fact, I think we laid out in our brief history here objectively supports that this is the kind of case that routinely raises these written description issues. [00:26:15] Speaker 04: The original application was filed in 2007, described as using known sequences. [00:26:22] Speaker 04: When Quake finally hit on using random sequencing, so-called shotgun sequencing, filed an entirely separate patent application. [00:26:31] Speaker 04: in September of 2008 in which he referred to this disclosure saying it related to digital PCR and what happened then Lowe's competing patent application was published in 2009 showing a priority date before Quake's random sequencing case and only then four years almost four years later is a claim to random sequencing presented here and [00:26:59] Speaker 04: You have to simply work too hard to try to piece this together out of their disclosure. [00:27:06] Speaker 04: And certainly do not have disclosure of all of the elements or description of all of the elements needed to perform this method. [00:27:15] Speaker 04: You have the description of all the elements you need if it's targeted. [00:27:18] Speaker 04: Why? [00:27:19] Speaker 04: It's a one-to-one ratio if it's targeted. [00:27:22] Speaker 04: All you need are the simple statistics that he has an example. [00:27:25] Speaker 04: You can do the sequencing in a targeted manner, even on these machines. [00:27:28] Speaker 04: And it all seems to make sense. [00:27:31] Speaker 04: And candidly, we have a situation where, at best, there are two reasonable conflicting interpretations that could be drawn from the evidence. [00:27:44] Speaker 04: And in circumstances like that, the Moutet case that we cited in our brief says that's the epitome of substantial evidence. [00:27:54] Speaker 04: And we submit that the judgment below should be affirmed for that reason. [00:28:07] Speaker 04: I could go on at length. [00:28:10] Speaker 04: Okay. [00:28:10] Speaker 04: Thank you. [00:28:10] Speaker 04: Thank you. [00:28:16] Speaker 02: In response to Judge O'Malley's question, the answer was yes, kits were standard for random sequencing on off-the-shelf products. [00:28:24] Speaker 02: there was experimentation done for targeted sequencing. [00:28:27] Speaker 02: And then he cites post-filing documents. [00:28:30] Speaker 02: Those two sites to Illumina are post-filing documents that talk about experimentation with targeted sequencing, which wouldn't have been known by people skilled in the art. [00:28:38] Speaker 02: What people skilled in the art would know is they could go to Illumina, buy a system, buy kits, and do [00:28:44] Speaker 03: And what about the fact that Dr. Gabriel said those post-filing documents aren't just reflective of what we knew pre-filing? [00:28:52] Speaker 02: I think one thing that this oral argument hasn't focused on sufficiently is the basis for the decision by the board. [00:28:57] Speaker 02: The board said the reason that they were going with, Gabriel said, was because of what she said about the 454, which makes no sense because Illumina is what's disclosed. [00:29:06] Speaker 02: 454 isn't mentioned, and council concedes that point. [00:29:10] Speaker 02: It's directing you to the system that's used for random sequencing. [00:29:14] Speaker 02: The second point, because there's this little bit of what I would call FUD about one-to-one ratio, that relates to step four. [00:29:21] Speaker 02: That's the statistical stuff at the bottom, which essentially fell away. [00:29:26] Speaker 02: It wasn't the basis for the board's decision. [00:29:28] Speaker 02: The board's decision was that you would think targeted sequencing, because there wasn't sufficient detail, because the board believed Gabriel based on the 454 documents. [00:29:42] Speaker 02: That doesn't make sense. [00:29:43] Speaker 02: At A2008, it's that there was no kits available for targeted sequencing. [00:29:47] Speaker 02: So if you went to Illumina, you couldn't even get one. [00:29:51] Speaker 02: And the final point I'd like to make on this is the board's decision acknowledges that people skilled in the art would have known random sequencing based on MPS. [00:30:06] Speaker 02: And I would say to you that [00:30:09] Speaker 02: If you apply the standard that's being applied, which is every step be spelled out, is every step for targeted sequencing spelled out on column 19? [00:30:17] Speaker 02: Do you see anywhere where they'd say, it says you randomly fragment, which opposing counsel agreed was you put them all on there, and then it says, and you put them on the device, and then you use the Illumina system. [00:30:30] Speaker 02: There's no middle step. [00:30:32] Speaker 02: This is at the bottom of column 19. [00:30:33] Speaker 02: There's no step of, OK, now you go filter them out. [00:30:36] Speaker 02: So it wouldn't be written described for targeted sequencing either, even though this is all just, oh, by the way, another way you can do the molecular counting is off-the-shelf stuff that people know about. [00:30:47] Speaker 02: That just doesn't make sense. [00:30:49] Speaker 02: It's almost like the board was saying, that's the problem. [00:30:55] Speaker 01: These two paragraphs are ambiguous. [00:30:58] Speaker 01: in isolation, now you read them in the context of the entire patent, the best reading leans this way rather than that way. [00:31:05] Speaker 02: The definition of ordinary skill in the art is one of ordinary skill in the art should understand both the operation and application of massively parallel sequencing and have significant direct experience in performing and applying these techniques. [00:31:16] Speaker 02: Further, one of skill in the art would understand and have experience with techniques for aligning sequencing reads generated by massively parallel sequencing to a reference genome. [00:31:25] Speaker 02: It's saying in the skill of art, [00:31:27] Speaker 02: is random sequencing. [00:31:30] Speaker 02: It's disclosed here, you use random sequencing. [00:31:32] Speaker 02: Aluminum off the shelf is only random sequencing if you have your kit, unless you're experimenting after the filing date. [00:31:40] Speaker 03: Okay. [00:31:41] Speaker 03: Thank you.