[00:00:00] Speaker 02: 2413, Board of Trustees versus Ariosa. [00:00:43] Speaker 02: Mr. Reinus, please proceed. [00:00:53] Speaker 03: Edward Reinus on behalf of Stanford and Professor Quake. [00:00:57] Speaker 03: May it please the court? [00:01:00] Speaker 03: The Patent Office decision invalidating Professor Quake and Christina Fan's patent is unsustainable because paragraph 72 of the low-priority reference [00:01:13] Speaker 03: does not disclose the sequencing of predefined subsequences required under the rigors of anticipation. [00:01:20] Speaker 03: What I'd like to focus the beginning of the discussion on is the relationship between paragraph 72, which is the relied upon paragraph by the board, and paragraph 77, 78, and 79. [00:01:33] Speaker 03: Paragraph 72 refers to three concepts for enrichment. [00:01:38] Speaker 03: One of them is enriching for shorter molecules because [00:01:44] Speaker 03: Fetal DNA, which is scarcer, tends to be shorter. [00:01:48] Speaker 03: Two is using formaldehyde, because that suppresses maternal DNA, therefore making the fetal DNA more prominent. [00:01:58] Speaker 03: And three, and what's relied on by the board, is enriching for chromosomes. [00:02:05] Speaker 03: And the reason I highlight these three different versions is because if you correspond them to paragraphs 77, 78, and 79 of low, [00:02:14] Speaker 03: and this is on JA 1015 and 1016. [00:02:17] Speaker 03: There's a direct correspondence and it's very clear. [00:02:19] Speaker 03: Paragraph 77 refers back to 72 and says it's mentioned before you can enrich. [00:02:25] Speaker 03: And then paragraph 77 corresponds to enrichment for fetal DNA that's shorter. [00:02:32] Speaker 03: 78 corresponds directly to suppressing maternal formaldehyde. [00:02:38] Speaker 03: And 79 corresponds directly to the chromosome approach. [00:02:43] Speaker 03: which is what's the basis for the invalidation of the patent. [00:02:48] Speaker 03: And if you look at that paragraph 79, again this is JA 1016, it makes two things ultra clear. [00:02:57] Speaker 03: One is that random sequencing is involved in that instance. [00:03:03] Speaker 03: And it says the enriched pools of nucleic acid would then be subjected to random sequencing, which is the antithesis of [00:03:13] Speaker 03: sequencing predefined subsequences. [00:03:15] Speaker 03: So that's the first important point. [00:03:17] Speaker 03: The second important point is that the definition of random sequencing in the low patent, and this is paragraph 47 of the low patent at JA 1013, the very definition of random sequences is that you have not specifically identified [00:03:39] Speaker 03: or targeted. [00:03:40] Speaker 01: So why is it that you think that paragraph 79, which begins alternatively, requires that whatever is described in paragraph 72, which is not all about enrichment as I read it, that that's only about using random sequencing? [00:04:03] Speaker 03: Just the architecture of the reference, the fact that paragraph 72 describes [00:04:09] Speaker 03: Three different concepts. [00:04:12] Speaker 01: Paragraph 77 says, as mentioned... Let's focus on 72. [00:04:17] Speaker 01: In another embodiment, we want the fraction. [00:04:21] Speaker 01: The fraction of the nucleic acid pool sequenced is further subselected. [00:04:25] Speaker 01: For example, hybridization-based techniques such as oligonucleotide array could be used to first subselect for nucleic acid sequences from certain chromosomes. [00:04:35] Speaker 01: And then it says, [00:04:37] Speaker 01: You know, another example. [00:04:39] Speaker 01: So why isn't that sentence alone, or I should say, why is that sentence alone tied to random sequencing? [00:04:46] Speaker 03: Because for two different reasons. [00:04:48] Speaker 03: One which I touched on, which is that paragraph 79 is tied to paragraph 72. [00:04:53] Speaker 03: It's in our briefs, but their expert admitted that 79 amplifies and describes that first concept in 72. [00:05:00] Speaker 03: But let me get to the technical reason, because I think that's what you're looking for. [00:05:03] Speaker 03: Not only the description and the patent. [00:05:07] Speaker 03: In the Morton Declaration 15, which is JA 3061, this is what's relied upon by the board to support the interpretation that you're giving, at least for the purpose of your questioning giving, and I trust that that's still being discussed. [00:05:26] Speaker 03: It's described, and the picture at the bottom, a picture's worth a thousand words, describes how she interprets paragraph 72, the sentence that you focused on. [00:05:37] Speaker 03: And what you see from that is that a lot of the unbounded DNA is sequenced. [00:05:45] Speaker 03: Because when the probe in low captures the DNA, it's longer than the area of interest. [00:05:53] Speaker 03: So there might be like a 10-base pair area of interest. [00:05:55] Speaker 03: It captures a large piece of DNA. [00:05:57] Speaker 03: This is their expert. [00:05:58] Speaker 03: And then all of that is put between the adapters. [00:06:02] Speaker 03: And then sequencing is performed. [00:06:06] Speaker 03: Professor Morton explained in deposition at 3274 and 3275 that when you do that, you're not necessarily sequencing the captured portion. [00:06:19] Speaker 03: You may be capturing what she calls the contiguous portion. [00:06:23] Speaker 01: So you could be identifying the string of ATCGs and counting the stuff that's [00:06:31] Speaker 01: that's not attached but is swinging around. [00:06:33] Speaker 03: Right. [00:06:34] Speaker 03: So for example, if there's a 200 base pair strand, which is what I think is being depicted here, you can only sequence 30 base pairs with below equipment. [00:06:44] Speaker 03: And that's, again, their own expert testifies to this. [00:06:48] Speaker 03: And so if you're only grabbing 30 of the 200, just using those numbers as rough terms, the odds of you even getting the so-called arguable [00:06:58] Speaker 03: predefined is very low. [00:07:00] Speaker 03: That's why everyone considers that random sequencing, because you're throwing in a whole bunch of DNA, you don't know what you're going to get, and you figure it later informationally as compared to quake. [00:07:10] Speaker 03: So at JA3255, Professor Morton explains, random is if you are sequencing data that is not the selected sequence itself. [00:07:21] Speaker 03: So she's saying if you include this other material, and we can look at that if you want to that passage, [00:07:26] Speaker 03: that could be considered random. [00:07:29] Speaker 03: So basically, Quake describes using PCR to actually capture the specific sequence that you're targeting and then sequencing only that. [00:07:41] Speaker 03: And part of this goes to the entirely different philosophy. [00:07:45] Speaker 03: The philosophy of LO, this is in the background section, is that the fetal DNA is so scarce [00:07:52] Speaker 03: that you want to just get as much genetic information as you can. [00:07:55] Speaker 03: And then in the summary of the adventures is random sequencing gets you that. [00:07:59] Speaker 03: So it teaches you that. [00:08:01] Speaker 03: Quake, by contrast, in column 13 and 14 says, well, if you really focus down and you selectively capture only the predefined sequences, then you're saving yourself the burden of the extra sequencing. [00:08:13] Speaker 03: So their own expert, as compared to a lawyer just reading this, understands that in the capture approach, [00:08:21] Speaker 03: that's described by Lowe, you have so much additional DNA that you're what they're calling random sequencing. [00:08:28] Speaker 03: You're not only sequencing the predetermined sequence. [00:08:32] Speaker 03: Now, what's important also here to note, because this is the other half of the equation, Your Honor, is that we disagree on claim construction. [00:08:41] Speaker 03: I'm happy to talk more about that, and trust I will. [00:08:44] Speaker 03: But claim nine, the board itself held [00:08:49] Speaker 03: that it's limited to sequencing only the predefined sequence. [00:08:53] Speaker 03: This is a JA-12. [00:08:54] Speaker 03: Their own construction of the board, that it's only the predefined sequence is sequenced. [00:09:00] Speaker 01: So can you explain why claim nine isn't a basis for a claim differentiation argument, putting aside what we all know, which is that claim differentiation doesn't always control over everything else, but why in its terms does it not imply [00:09:19] Speaker 01: that the claim one, sequencing preselected sequences must be broader than an arrangement in which you already know the string of base pairs in what you're sequencing. [00:09:36] Speaker 03: I just think there's so much overwhelming evidence [00:09:38] Speaker 03: and just trying to explain it in terms of that. [00:09:42] Speaker 03: No, well, I mean, I was going to go to a different way, which is there's so much evidence that this claim is limited to targeted sequencing since everyone said it, both sides attorneys have said it. [00:09:51] Speaker 03: I don't think it's a fairly debatable issue. [00:09:53] Speaker 03: That's why I don't really want to focus on it too much in oral argument, although I'm happy to answer any questions. [00:09:57] Speaker 01: So I think it's the fact... Well, claim nine seems to me, at least I did, and my current thinking is significant on the claim construction question. [00:10:07] Speaker 03: Oh, okay. [00:10:09] Speaker 03: I mean, there is a way, you can understand claim nine two ways. [00:10:13] Speaker 03: You could understand it to refer to a type of sequencing, like a technique, that particular technique that's used. [00:10:19] Speaker 03: So there's a way to harmonize that. [00:10:21] Speaker 03: If you want to harmonize it, that's the way to harmonize it. [00:10:26] Speaker 03: But I just go back to the fact that everybody agreed in plain terms and quote after quote that claim one's the targeted sequencing. [00:10:35] Speaker 03: I just think that whatever guide it is is overwhelmed easily. [00:10:39] Speaker 01: And your, since targeted sequencing is a term that doesn't appear in the patent and has a kind of informality to it, can you describe it in extremely precise terms? [00:10:51] Speaker 01: Do you mean that you count, you have a pool of DNA floating about that you are identifying the base pair strings in all of that [00:11:05] Speaker 01: and counting them only those base pair strings that you have identified before, that you have written down in a list before you start this counting process? [00:11:17] Speaker 03: Certainly in the quake patent, the way it's claimed, yes. [00:11:19] Speaker 01: Only those. [00:11:21] Speaker 03: Only those. [00:11:21] Speaker 03: And that's what the board, but here the board can't have it both ways. [00:11:24] Speaker 03: I know your honor is concerned that we make sure the board gets it right where there's anomalies. [00:11:30] Speaker 03: And that's been, Ariosa argued that effectively in a recent appeal. [00:11:34] Speaker 03: And here, the board itself held at JA12 that the sequencing has to be limited to only the predetermined sequences in claim nine. [00:11:43] Speaker 03: So there's no way to harmonize that. [00:11:46] Speaker 03: And I know, and this being a court of review, I think that in order to rehash all that and figure that all out, if anything, that would go back down. [00:11:54] Speaker 03: But with the definition of low, the definition in low of random sequencing is that it's not predefined. [00:12:02] Speaker 03: and notes that enrichment can happen beforehand with paragraph 79 directly corresponding to 72. [00:12:10] Speaker 03: Your Honor may not think so. [00:12:11] Speaker 03: I think there's evidence in the record that their expert has said that, quoted in our brief or cited in our brief. [00:12:15] Speaker 01: Can one use a random sequencing method on a predefined sequence? [00:12:23] Speaker 03: That would, to me that's a, no, nobody would say that. [00:12:27] Speaker 03: I don't think. [00:12:29] Speaker 03: Those are the opposites. [00:12:30] Speaker 03: Targeting is a well-established concept. [00:12:32] Speaker 03: I mean, they used it to describe this patent as a targeted sequencing patent, right? [00:12:37] Speaker 03: Their expert did, their lawyers did. [00:12:39] Speaker 01: So it's not an odd... That all by itself doesn't put a completely well-defined and concrete thing into my head. [00:12:50] Speaker 03: Admittedly, admittedly. [00:12:51] Speaker 03: So I'm saying in the context of Quake, with the disclosure of PCR, the fact that it's preselected, [00:12:58] Speaker 03: And the fact that low refers itself to the use of additional DNA that's unknown on top of the predefined sequences is random sequencing. [00:13:08] Speaker 03: The fact that they're expert in this matter in the relied upon paragraph. [00:13:12] Speaker 01: I thought your distinction about claim nine was that preselected sequences has to do with identifying what you're sequencing. [00:13:22] Speaker 01: In Claim 9, selective sequencing has to do with how you go about the process of counting and identifying what's in some pool, which if you put those, if you maintain that distinction, what you're sequencing, how you're doing it, why can't you do random sequencing of a predefined sequence? [00:13:45] Speaker 01: So for example, next Sunday at Santa Clara Stadium, there are going to be 70,000 people in the stadium. [00:13:51] Speaker 01: And I've got a predefined, and let's assume each person has a single fan loyalty, and each one if asked will identify the fan loyalty. [00:13:59] Speaker 01: So here's my predefined sequence. [00:14:01] Speaker 01: I want to know Jaguar fans and Titans fans. [00:14:05] Speaker 01: That's different from either asking everybody or from randomly selecting. [00:14:10] Speaker 01: But why can't you do a random selection of people to find [00:14:17] Speaker 01: Jaguar and Titans. [00:14:19] Speaker 03: I think you're operating ahead of me, but I think if you ask the people going to the stadium, who's Jaguar fans? [00:14:25] Speaker 03: Let's just take that. [00:14:26] Speaker 03: And you held them aside. [00:14:27] Speaker 03: And you just held them aside, and then you confirm to how many Jaguar fans by sequencing. [00:14:32] Speaker 03: I mean, we're getting a little far-field. [00:14:34] Speaker 03: What the approach is of Lo is, if you see a Jaguar fan, grab the whole row. [00:14:40] Speaker 03: and then see who all the people are and figure it out from there. [00:14:43] Speaker 03: And then at the end, we'll determine which ones were Jaguar fans and we'll count it up. [00:14:47] Speaker 03: I mean, they're just opposite points. [00:14:49] Speaker 03: I'm sorry I'm not being as responsive, but I do want to save some time. [00:14:52] Speaker 03: I realize that was gone a little longer here. [00:14:55] Speaker 02: Mr. Gindler? [00:15:05] Speaker 00: Good morning. [00:15:06] Speaker 00: David Gindler with my colleague, Sandro Herberni. [00:15:09] Speaker 00: Even if the claims are interpreted, as Stanford would interpret them, to require a molecular pre-selection step as part of sequencing predefined subsequences, Lowe anticipates. [00:15:21] Speaker 00: That is a finding of fact by the board. [00:15:24] Speaker 00: What a choir art reference discloses is a question of fact. [00:15:28] Speaker 00: Anticipation is a question of fact. [00:15:31] Speaker 00: The board resolved that question of fact, and that is reviewed under a substantial evidence standard by this court. [00:15:38] Speaker 00: I have not heard [00:15:39] Speaker 00: any argument that there is no evidence supporting what the board concluded. [00:15:44] Speaker 00: In fact, the board's reasoning is quite extensive. [00:15:48] Speaker 00: It spans over 10 pages, looking at all the evidence in the record. [00:15:52] Speaker 00: The court made clear that it looked over the declarations and deposition testimony of all of the experts. [00:15:59] Speaker 00: And based upon that, it reached its conclusion. [00:16:03] Speaker 02: Am I right that your opposing counsel kept referring to [00:16:07] Speaker 02: your expert's admission. [00:16:09] Speaker 02: But I'm looking at what I think he's referring to, which is JA3329, where your expert only says, well, and I guess 79 is a further discussion of. [00:16:19] Speaker 02: I mean, that seems like less than a clear and resounding basis for me to conclude there's no substantial evidence in this record. [00:16:28] Speaker 00: Too many words? [00:16:29] Speaker 02: Too many negatives? [00:16:30] Speaker 02: Should I rephrase? [00:16:30] Speaker 00: Could you? [00:16:31] Speaker 02: Because it's a friendly question. [00:16:33] Speaker 00: Yes, I understood that. [00:16:35] Speaker 00: And I think because I got that from the I guess part of the testimony. [00:16:39] Speaker 00: I don't think paragraph 79 can reasonably be read as requiring that you use, quote, random sequencing. [00:16:46] Speaker 00: In fact, if you look at the end of paragraph 72, it says in one embodiment, you can use random sequencing. [00:16:53] Speaker 02: But what I was trying to get you to focus on was the strength of the argument that he made with regard to the experts. [00:17:00] Speaker 02: supposed admission that 79 is tied to 72. [00:17:04] Speaker 02: And I thought that it was less than a resounding and clear admission, as you would like to have it. [00:17:10] Speaker 00: And I agree it is less than a resounding and clear admission. [00:17:13] Speaker 00: I think it's fair to say there is a connection between 79 and 72. [00:17:18] Speaker 00: But to say that either based upon her testimony or based upon the language of the low reference itself, that paragraph 79 is somehow... Limiting 79. [00:17:29] Speaker 00: The other thing that's very important to look at is the definition of random sequencing. [00:17:37] Speaker 00: In paragraph 47, because Lowe actually points out the answer to the question that you asked, Judge Toronto, that you asked counsel, which is, it says, in some embodiments of the present invention, [00:17:51] Speaker 00: random sequencing may be preceded by procedures to enrich a biological sample with particular populations of nucleic acid molecules sharing certain common features. [00:18:03] Speaker 00: Low answers the question of it's actually using random sequencing in a somewhat more generic way. [00:18:11] Speaker 00: Essentially, it can be used on a subpopulation, such as fragments from a particular chromosome, which have been subselected using an [00:18:21] Speaker 00: using an array as described in paragraphs 72 and 79 of the low reference. [00:18:28] Speaker 01: So you read that the second sentence of paragraph 72 to be a form of pre-defining your sequences is just that you're doing it for, to continue my football metaphor, the Broncos fans, which are going to be a whole lot bigger pool [00:18:48] Speaker 01: in Santa Clara on Sunday than the Jaguars fans. [00:18:52] Speaker 00: That's correct. [00:18:52] Speaker 00: Think of it this way. [00:18:53] Speaker 01: Massively parallel sequencing is essentially... The chromosome is just... If I remember the great brief, the gist of it was to say, that's just too big to do it for a whole chromosome. [00:19:08] Speaker 01: That's correct. [00:19:09] Speaker 01: What's your response to that? [00:19:12] Speaker 00: Actually, I'm not sure I followed that question. [00:19:13] Speaker 00: Would you try it one more time? [00:19:15] Speaker 01: This language in paragraph 72 is clearly doing something sequence-based to narrow the pool that you're then going to do counting and identification on. [00:19:28] Speaker 01: That's correct. [00:19:29] Speaker 01: That's a phrase I'm trying to use as a substitute for the confusing term sequencing. [00:19:34] Speaker 01: Okay. [00:19:34] Speaker 01: And I think in the great brief they said, chromosome, that's just too big really to be a predefined sequence within claim one. [00:19:45] Speaker 01: What's your answer to that? [00:19:48] Speaker 00: An entire chromosome would make no sense to be a predefined subsequence because what you're talking about in both the low patent and in the 076 patent is sequencing little bits of cell-free DNA which are found in the bloodstream of a pregnant woman. [00:20:07] Speaker 00: These are definitionally things that have floated outside of a cell and they're small. [00:20:13] Speaker 00: So you're never going to actually pull down an entire chromosome. [00:20:16] Speaker 00: That's sort of an oxymoron. [00:20:18] Speaker 00: That's never what you're dealing with here. [00:20:20] Speaker 01: So you read this sentence in paragraph 72 as not talking about getting the whole chromosome, but particular sequences that you know sit on particular chromosomes. [00:20:32] Speaker 00: Right. [00:20:32] Speaker 00: In fact, that's what goes on to say, that you're looking for nucleic acid sequences from certain chromosomes, e.g., a potentially anaploid chromosome, [00:20:42] Speaker 00: and other chromosomes not involved in the aneuploidy being tested. [00:20:46] Speaker 00: In other words, let's limit our sample not just to everything, the entire pool of all the chromosomes, but let's look at just, say, two chromosomes. [00:20:56] Speaker 00: One that you think might be aneuploid, and one that you know is just never aneuploid. [00:21:02] Speaker 00: Let's look at chromosome 21, and let's look at chromosome 12. [00:21:07] Speaker 00: And what we're gonna do is we're gonna find little bits. [00:21:10] Speaker 00: And how are we gonna find those little bits? [00:21:12] Speaker 00: we're going to use these probes which have a known sequence for the chromosomes of interest. [00:21:20] Speaker 01: And those, and those probes don't have to put it more positively. [00:21:24] Speaker 01: Those probes can be for only a portion of the, of the chromosome specific sequences that you will then identify. [00:21:34] Speaker 00: That's correct. [00:21:34] Speaker 00: They'll be short and they'll pick up the fragments, some of the fragments, [00:21:40] Speaker 01: which are in the sample. [00:21:44] Speaker 01: What this is making me think of, and maybe incorrectly, is the passage from, I guess, the Morton Declaration that has the little drawing at the bottom where there's discussion. [00:21:55] Speaker 01: Mr. Reinus was talking about how the probe can, if I have a DNA fragment sitting like this, the probe can bind just to this. [00:22:03] Speaker 01: And then it'll get the whole pen, even though it's stuck to only the cap, [00:22:08] Speaker 01: And the sequencing will then go on for the whole pen. [00:22:12] Speaker 00: The sequencing will always be something you know, which is you know that sequence comes from the chromosome you've chosen. [00:22:18] Speaker 01: You don't know the ATCG string in the whole pen. [00:22:23] Speaker 01: Well, you actually would. [00:22:25] Speaker 01: It's not part of the probe, right? [00:22:26] Speaker 01: The probe is just the cap. [00:22:28] Speaker 00: That's correct. [00:22:28] Speaker 00: But on the other hand, you do know [00:22:31] Speaker 00: what flanks the probe on each side. [00:22:34] Speaker 00: Because we've sequenced the human genome, that's why we can even make these probes. [00:22:37] Speaker 00: We know what chromosome 21 looks like. [00:22:40] Speaker 00: That's why we can create a probe with a certain number of base pairs. [00:22:44] Speaker 00: And we actually know what's on each side of the probe. [00:22:48] Speaker 00: But the important thing is the probe is going to pick up what fragments there are in the sample for the chromosome we're looking for. [00:22:57] Speaker 00: Think of it sort of this way. [00:23:02] Speaker 00: We're an intact chromosome. [00:23:04] Speaker 00: In the bloodstream of a pregnant woman, essentially this is what there is. [00:23:10] Speaker 00: Little fragments like this. [00:23:13] Speaker 00: And we have probes that will look for a portion of the fragment. [00:23:18] Speaker 00: But we know that all of them are from chromosome 21. [00:23:20] Speaker 00: So we've subselected our population down. [00:23:24] Speaker 00: We sequence and we engage in some very interesting computational processes to figure out [00:23:30] Speaker 00: Is there too much of chromosome 21? [00:23:32] Speaker 01: So do you, because we now have a, as I understand it, a kind of full human genome map, do you think all sequencing is sequencing predefined subsequences because we know what they all are? [00:23:45] Speaker 00: Your Honor, that question is beyond my scientific knowledge and I think it's beyond the record. [00:23:50] Speaker 01: Right, but I'm not sure, I'm not sure it's beyond the record, put aside the scientific knowledge. [00:23:58] Speaker 01: Doesn't the phrase selecting predefined subsequences in order to have meaning have to exclude the possibility that everything you're sequencing is something that's predefined because you could look it up in a genome map? [00:24:15] Speaker 00: I think this is the answer to your question, if I'm understanding it correctly. [00:24:22] Speaker 00: There is an extraordinary amount of information as a result of the Human Genome Project about the sequence of [00:24:28] Speaker 00: all the chromosomes. [00:24:30] Speaker 00: That is the entire basis for engaging in the sequencing. [00:24:33] Speaker 00: You can now actually look at a random sample where you don't know beforehand whatever's in there. [00:24:41] Speaker 00: It could be little bits of chromosome 1, 9, 14, 16. [00:24:45] Speaker 00: That's called shotgun sequencing. [00:24:47] Speaker 00: And using an Illumina sequencer, for example, you can figure out exactly what is in your sample. [00:24:54] Speaker 00: The sequencing knowledge is so precise [00:24:57] Speaker 00: at even having no knowledge beforehand, you can use shotgun sequencing. [00:25:02] Speaker 00: And in fact, a lot of Lo talks about, and a lot of the 076 patent talks about what's called shotgun sequencing, where you have no idea before you begin to sequence what's in your sample. [00:25:14] Speaker 00: But we have such detailed knowledge, you can actually then figure out by referencing back to a reference genome, [00:25:23] Speaker 00: what it is that you've sequenced. [00:25:24] Speaker 01: So what in your view is the meaning of the phrase that is at issue here, the sequencing predefined subsequences? [00:25:36] Speaker 01: I think I've got the phrase. [00:25:36] Speaker 00: So as you know, there are two competing constructions. [00:25:41] Speaker 00: The way the board looked at it is it being informationally predefined. [00:25:45] Speaker 01: What does that mean? [00:25:46] Speaker 00: Well, what the board said [00:25:48] Speaker 00: is, and I'll just read you what the board said. [00:25:51] Speaker 01: I remember the phrase, you don't have to know the base pair strings, but you have to in some way have it informationally identified. [00:25:59] Speaker 00: Right. [00:25:59] Speaker 00: What the board did is look back and it said, in the patent, the word predefined is also used in this concept of predefined windows. [00:26:08] Speaker 00: And the board looked at this and said, this actually is a subset [00:26:14] Speaker 00: of the information that's available. [00:26:16] Speaker 00: We don't care about the entire chromosome. [00:26:19] Speaker 00: We actually are going to create some windows along each chromosome of interest. [00:26:24] Speaker 01: Isn't the windowing just a process of making sure that you have essentially the same length in each pool that you're testing so that you don't compare [00:26:39] Speaker 01: the numbers you get from something like this to something you get like this? [00:26:43] Speaker 00: It's a little more complicated than that. [00:26:45] Speaker 00: I think the windows do at least several things. [00:26:48] Speaker 00: The first is they exclude something which is not very interesting. [00:26:51] Speaker 00: If you don't care about the centromere, you don't care about the exon. [00:26:54] Speaker 00: So first, let's take those out of the equation. [00:26:56] Speaker 00: The second is there's a phenomenon called GC bias, where if you have portions of the chromosome which are rich in guanine and cytosine, [00:27:08] Speaker 00: they get read more frequently. [00:27:10] Speaker 00: And the problem is you have to account for that because otherwise it looks like you've got too many hits along one particular chromosome when in fact it's not overrepresented. [00:27:21] Speaker 00: So it's a way basically of engaging some with a pattern called normalization. [00:27:25] Speaker 00: So you can actually have some smart statistical processing. [00:27:30] Speaker 00: So the board looked at this and said, you can define what you're looking for informationally. [00:27:36] Speaker 00: I don't care about the whole chromosome. [00:27:38] Speaker 00: just care about what's in these predefined windows. [00:27:42] Speaker 00: But of course, as the board found, even under the interpretation advanced by Stanford, which is, by the way, exactly the opposite of what it said to the district court, even under that interpretation, Low anticipates. [00:27:58] Speaker 00: Because Low in paragraph 72 and Low in paragraph 79 discloses the preselection step. [00:28:05] Speaker 00: That's explained by Dr. Morton [00:28:07] Speaker 00: in her declaration is discussed in paragraph 15 at some length. [00:28:11] Speaker 00: That paragraph is in fact cited in the board's decision. [00:28:16] Speaker 00: And that's entitled to review under a substantial evidence test. [00:28:20] Speaker 00: The question is, could no reasonable person find that evidence to support the board's decision? [00:28:28] Speaker 00: I think the answer to that question is clear. [00:28:29] Speaker 00: A reasonable person could find that evidence sufficient to support the board's decision. [00:28:35] Speaker 00: It's not a matter whether or not somebody could argue the case differently. [00:28:38] Speaker 00: Somebody can always argue the case differently. [00:28:40] Speaker 00: That's why there are lawyers. [00:28:42] Speaker 00: But here, this is a decision which has strong support. [00:28:46] Speaker 00: I want to add one more thing, which is this is a case where a judicial estoppel applies. [00:28:53] Speaker 00: It applies whether the broadest reasonable [00:28:56] Speaker 00: interpretation standard applies here, or the Phillips standard were to apply here. [00:29:02] Speaker 00: What happened in the district court, what happened in the district court was that Stanford argued vociferously that the claims the 076 patent... I may just be having a memory lapse, but is there judicial estappel in here? [00:29:19] Speaker 00: Yes, there is. [00:29:22] Speaker 00: It is discussed at some length. [00:29:25] Speaker 00: Stanford argued that the claims are not limited to the embodiment. [00:29:30] Speaker 01: Oh, OK. [00:29:30] Speaker 01: I was thinking different estoppel, not like 315 estoppel or something. [00:29:33] Speaker 00: No. [00:29:34] Speaker 01: Oh. [00:29:36] Speaker 00: OK. [00:29:36] Speaker 00: So Stanford argued the claims were not limited to what's in column 14. [00:29:41] Speaker 00: And here, their argument is 100% the claims the 076 patent are limited to column 14. [00:29:49] Speaker 00: And you should just basically ignore most the rest of the patent, and in particular, every single embodiment [00:29:55] Speaker 00: and every single example. [00:29:57] Speaker 00: So the claim construction issue really comes down to one question, which is, do the claims cover all of the preferred embodiments or just column 14? [00:30:08] Speaker 00: And I think the answer is they cover all the embodiments and not just column 14. [00:30:13] Speaker 00: Thank you. [00:30:16] Speaker 02: Thank you, Mr. Gendler. [00:30:19] Speaker 03: Thank you. [00:30:19] Speaker 03: I'd like to make two points. [00:30:21] Speaker 03: First, claim nine, as I noted, is [00:30:24] Speaker 03: held by the board to limit it to only sequencing the predetermined sequences themselves. [00:30:29] Speaker 03: And I don't even think with whatever skepticism there is or anything else that anyone saying that Lowe is teaching you only sequence the predetermined sequence. [00:30:37] Speaker 03: Their own expert, as I pointed out in the paragraph, relied upon the board says otherwise. [00:30:42] Speaker 03: This could be an error from the fact that the board said that none of the individual claim elements were argued separately. [00:30:49] Speaker 03: So they didn't consider claim nine separately. [00:30:52] Speaker 03: But that was clearly preserved at JA 613. [00:30:54] Speaker 03: The PTAB asked, you know, are you arguing anything separately? [00:30:59] Speaker 03: And it says, depending on how you do the construction, if you construct it the way Ariosa would like, then yes, we're asserting claim nine is narrower, for the reason that I just described. [00:31:08] Speaker 03: So that's one very straightforward path that I think requires at minimum remand, but probably reversal. [00:31:15] Speaker 03: Second reason why I think so is... What JA page did you say that's on? [00:31:20] Speaker 03: Oh, yes, Your Honor. [00:31:21] Speaker 03: It's JA 613 is the interchange on that. [00:31:25] Speaker 03: So that's one very clear path. [00:31:27] Speaker 03: The second one is, and I will note counsels equated 72 and 79, is regardless of what the expert said, I think that's the way you read this patent. [00:31:36] Speaker 03: And I think the important point is when you were going through the definition of random sequencing, what Lowe made clear, which is consistent with the expert testimony, [00:31:45] Speaker 03: is that when you enrich and you narrow down to specific things like the chromosome level, that when you then sequence at the chromosome level, that that's random sequencing. [00:31:56] Speaker 03: That's what that paragraph says. [00:31:59] Speaker 03: That is random sequencing. [00:32:01] Speaker 03: And so the point being that whether you look at 79 and they refer to as random sequencing is then done, or you look at the definition of random sequencing, [00:32:11] Speaker 03: In all of those things, if you separate out so you have the entire chromosome, which is what Mr. Gindler correctly described, then you have random sequencing. [00:32:21] Speaker 03: Finally, what I'd like to say on this question of now that we know the human genome is all sequencing predefined, the answer to that is pretty straightforward, which is absolutely not, and it's all over the record. [00:32:33] Speaker 03: There's a concept of alignment, which is done, and that's how sequencing is done. [00:32:37] Speaker 03: That's normal sequencing. [00:32:39] Speaker 03: sequence things and then you align them with the known genome and then you say, okay, this bit is from this portion or this chromosome or whatever test you're doing. [00:32:49] Speaker 03: That's how random sequencing is done. [00:32:51] Speaker 03: So the alignment process is that knowledge of how the whole genome is the layout of the whole genome. [00:32:58] Speaker 03: That's informational after the fact determination of what the sequence is as compared to physical before the fact segregation. [00:33:05] Speaker 03: There shouldn't be mystery to that. [00:33:08] Speaker 03: That one is random. [00:33:09] Speaker 02: We're well over your time. [00:33:10] Speaker 02: Thank you very much. [00:33:12] Speaker 02: I thank both counsel. [00:33:13] Speaker 02: The case is taken under submission.