[00:00:04] Speaker 02:
We have five cases on the calendar this morning.

[00:00:09] Speaker 02:
Two cases from the Patent Office that are being argued together.

[00:00:15] Speaker 02:
A Veterans Appeal Patent Case from the District Court and a Government Employee Appeal.

[00:00:23] Speaker 02:
Our first case cases are Illumina Cambridge Limited versus Intelligent Biosystems.

[00:00:34] Speaker 02:
2015-11-23, 12-43.

[00:00:35] Speaker 02:
Mr. Zimmerman.

[00:00:46] Speaker 04:
Good morning, Your Honors.

[00:00:47] Speaker 04:
May it please the Court.

[00:00:49] Speaker 04:
The Board erred in its obvious analyses in both cases by focusing on the disulfide linkage limitation in isolation.

[00:00:58] Speaker 04:
And it's the disulfide that connects the label to the base.

[00:01:02] Speaker 04:
And this error is particularly apparent with respect to the issue of motivation to combine.

[00:01:07] Speaker 02:
Well, the disulfide linkage was what was added to the claims, right?

[00:01:13] Speaker 04:
It was.

[00:01:15] Speaker 04:
The original claims 6 had a disulfide linkage in a group of other ones for the cleavable linker.

[00:01:23] Speaker 04:
In the amendments, they narrowed it to just the disulfide out of that group and picked

[00:01:30] Speaker 04:
a particular connection point for the three prime protecting group.

[00:01:34] Speaker 04:
Now, in making that change, the original rejection by the board was one of anticipation.

[00:01:40] Speaker 04:
And the rejection that was sustained was an obviousness rejection.

[00:01:45] Speaker 04:
So they need to come up with a reason to use a disulfide linkage for the cleavable linker in combination with a three prime protecting group where both are cleavable under identical conditions.

[00:01:58] Speaker 04:
And if you parse the board's opinions carefully, they say Rabani teaches a disulfide linkage to attach a label to a base.

[00:02:07] Speaker 04:
Church teaches a disulfide linkage to attach a label to a base.

[00:02:11] Speaker 04:
Nobody disagrees with the teachings of those two references.

[00:02:15] Speaker 04:
What the board doesn't then do is give you any reason to use that linker in combination with a three prime protecting group and to make them cleavable under identical conditions.

[00:02:28] Speaker 04:
And importantly, the Church method didn't have three-prime protected nucleotides.

[00:02:34] Speaker 04:
So there was no reason to combine the two from Church.

[00:02:38] Speaker 04:
The Rabani reference teaches a three-prime protecting group.

[00:02:42] Speaker 04:
It separately teaches a disulfide linkage connecting the label to the base.

[00:02:47] Speaker 04:
But it doesn't give you any reason to put those two together.

[00:02:50] Speaker 04:
In fact, none of the nucleotides in Rabani, despite disclosing each piece, combine those two.

[00:02:57] Speaker 04:
And the board's opinion is bereft of any reason to actually put them together.

[00:03:01] Speaker 04:
And then when you look at what one of skill and the art would have known, there was actually a reason not to combine them.

[00:03:08] Speaker 04:
These nucleotides have one use, and that's sequencing by synthesis.

[00:03:13] Speaker 02:
And the record was clear.

[00:03:15] Speaker 02:
That's the point, isn't it?

[00:03:16] Speaker 02:
There are a small number of procedures and references, and so putting a couple of them together isn't so non-obvious.

[00:03:25] Speaker 04:
But that's the problem here.

[00:03:26] Speaker 04:
The board never said there's a small number of references.

[00:03:30] Speaker 04:
The board never said it's a limited universe.

[00:03:33] Speaker 02:
The board, with the direction of hindsight, said... In other words, you're picking on the language and the reasoning rather than really the basics of the two references.

[00:03:44] Speaker 04:
No.

[00:03:45] Speaker 04:
There was no reason to pick the disulfide linkage in the first instance from

[00:03:51] Speaker 04:
the myriad of other linkages that were available.

[00:03:54] Speaker 04:
Myriad is another case.

[00:03:58] Speaker 04:
The only reason we're focused on the disulfide linkage is because that's what was added by amendment.

[00:04:05] Speaker 04:
And if you look at the record there are three facts that are fundamental.

[00:04:10] Speaker 04:
The first one is you need to cleave the three prime protecting group with greater than ninety percent efficiency.

[00:04:18] Speaker 04:
Ninety percent is insufficient and

[00:04:21] Speaker 04:
That fact was undisputed.

[00:04:23] Speaker 04:
It comes from Rabbani, but IDS's expert, Dr. Brand Schoud, admitted, I agree that a person of skill in the art would want greater than 90% efficiency for cleaving the three prime protecting group.

[00:04:36] Speaker 04:
That's JA 3013.

[00:04:37] Speaker 01:
Although it's not claimed in your claim.

[00:04:41] Speaker 01:
The claims have no explicit

[00:04:43] Speaker 01:
reference for the 90% figure, right?

[00:04:46] Speaker 04:
The claims do not contain an efficiency requirement, but when you look at a reason to motivate to combine the prior art, you're looking at essentially, and although the board doesn't say it, we have to assume it's the Chen and the Jew reference, both of which teach three prime protected nucleotides and SBS processes.

[00:05:07] Speaker 04:
Both of those references make clear that you need quantitative

[00:05:11] Speaker 04:
And IBS's expert agreed 100% removal of the three prime protecting group.

[00:05:17] Speaker 04:
And so you wouldn't modify those references in a way that's going to make them worse.

[00:05:22] Speaker 04:
The only proffered motivation from IBS for modifying the prior art is to improve the processes of Ju and Chen, both of which require efficiency.

[00:05:33] Speaker 04:
So efficiency is part of the motivation for modifying the prior art, even though there isn't an efficiency element to the claim.

[00:05:41] Speaker 04:
You wouldn't want to modify the prior art in a way that made the existing art less efficient or that didn't work for its intended purpose of SPS.

[00:05:49] Speaker 00:
What about on pages JA 40 through 41?

[00:05:53] Speaker 00:
Here the board has a section titled reason to use a disulfide bond on nucleotides and says things such as Rabini would have given a skilled worker a reason to have used a cleavable linker with a disulfide bond.

[00:06:06] Speaker 00:
to ensure that the labeling moieties on the nucleotides will not interfere.

[00:06:10] Speaker 00:
Why isn't that sufficient?

[00:06:12] Speaker 04:
And I assume you're looking at the 128 case, which is the first appeal?

[00:06:16] Speaker 00:
Yes.

[00:06:17] Speaker 04:
OK.

[00:06:17] Speaker 04:
On pages 40 and 41, if you look at what the board is doing, they're giving you a reason to use a disulfide linkage that comes straight out of Rabani and straight out of church.

[00:06:27] Speaker 04:
What they don't give you is any reason to use it in combination with a three prime protected nucleotide

[00:06:34] Speaker 04:
where you make the disulfide linkage and the three prime group cleavable under identical conditions, which is what you would get if you combined Rabani or Church with Ju and Chen from the institution decision.

[00:06:46] Speaker 04:
So they give you a reason to use a disulfide linker in isolation, but not to combine it where you're going to cleave both groups under identical conditions.

[00:06:55] Speaker 01:
But CN gets you, I take it, to using the label cleavage

[00:07:03] Speaker 01:
and using the cleavage of the three prime OH group, the protecting group, under simultaneously, which in effect means under the same conditions.

[00:07:13] Speaker 04:
Yes.

[00:07:14] Speaker 01:
All right.

[00:07:14] Speaker 01:
So the only thing that's different between CN and the patent is the use of the disulfide bond, right?

[00:07:23] Speaker 01:
Yes.

[00:07:23] Speaker 01:
And that with respect to the cleaving, the linker to the label.

[00:07:28] Speaker 04:
Yes, Your Honor.

[00:07:29] Speaker 04:
And so you have references that teach a disulfide bond in different sequencing schemes that don't use a three prime protecting group.

[00:07:38] Speaker 04:
And the question is, why would you use a disulfide linker in Chen?

[00:07:43] Speaker 04:
And Chen teaches that you're sequencing nucleotides from 25 to 300 units in length.

[00:07:50] Speaker 04:
You need an efficiency to be able to do that kind of sequencing.

[00:07:55] Speaker 04:
Chen expressly teaches it, and Chen teaches

[00:07:59] Speaker 04:
that you need quantitative removal of the three prime protecting group.

[00:08:04] Speaker 01:
Now let me ask you a question that relates to Vermaas, the Vermaas experiment.

[00:08:11] Speaker 01:
That took place, I gather, long after the patent was, the initial patent was issued, right?

[00:08:19] Speaker 01:
Vermaas, I think, he doesn't say exactly when he did the experiment, but he said that he was hired in 2006.

[00:08:24] Speaker 01:
So presumably he did the experiment after that.

[00:08:29] Speaker 04:
I don't remember the exact date, but it was prior to the institution of the IPR.

[00:08:34] Speaker 01:
Right, but the initial patent issue, and he uses a specific cleavage agent, I think Tris-Hydroxymethylphosphine, which so far as I can tell wasn't alluded to anywhere in the patent.

[00:08:52] Speaker 01:
The patent doesn't seem to identify the cleavage agent.

[00:08:55] Speaker 04:
The patent talks about using reductive cleavage.

[00:08:59] Speaker 04:
Right, but that's just a very general... Exactly.

[00:09:01] Speaker 04:
And it does identify DDT as one potential cleavage.

[00:09:05] Speaker 01:
Right, but that was all over the prior argument.

[00:09:07] Speaker 01:
Yes.

[00:09:07] Speaker 01:
Right, so there's nothing there.

[00:09:08] Speaker 04:
Right.

[00:09:09] Speaker 01:
So my problem is that you're identifying Vermont as having achieved this close to 100% efficiency.

[00:09:20] Speaker 01:
But with a cleavage agent that isn't in the patent, so we're in the patent, is there anything that suggests something, some increased efficiency above what the prior art had achieved?

[00:09:32] Speaker 01:
Or a cleavage agent that would have achieved that?

[00:09:34] Speaker 04:
The patent doesn't teach you an expectation of better cleavage.

[00:09:39] Speaker 04:
What the patent tells you is pick disulfide.

[00:09:43] Speaker 04:
And once you pick disulfide as your linker, you can have the conditions that give you the cleavage with the three prime protecting group.

[00:09:51] Speaker 04:
That's not disputed, that picking them to cleave under identical conditions would have been within the skill of the art.

[00:09:59] Speaker 04:
The problem is there's nothing that tells you to pick disulfide in the first instance.

[00:10:04] Speaker 04:
And as for your difference in solvents, if you look at JA 3021, paragraph 53, it's Dr. Brand-Shoud.

[00:10:13] Speaker 04:
IBS's expert, he says that you should be able to get efficient cleavage with DTT, which is what's disclosed in the prior art.

[00:10:23] Speaker 04:
And so the choice of solvent shouldn't make a difference.

[00:10:27] Speaker 04:
And IBS never challenged before the board the choice of solvent.

[00:10:31] Speaker 04:
There's no argument from any expert that the choice of solvent should make a difference.

[00:10:36] Speaker 04:
And what Illumina was able to show with their unexpected results is that in 150 cycles, you get a 0.43% error, which is far better than had been achieved in the art.

[00:10:48] Speaker 04:
But I would like to go back to the efficiency argument for one moment.

[00:10:52] Speaker 04:
It was undisputed that 90% was insufficient for cleaving the three prime protecting group.

[00:10:59] Speaker 04:
Dr. Romsberg, Illumina's expert, testified that you wouldn't expect the three prime group

[00:11:05] Speaker 04:
to cleave with any better efficiency than the disulfide.

[00:11:10] Speaker 04:
That testimony was unchallenged.

[00:11:13] Speaker 04:
IBS's expert never said you would expect to get better three-prime cleavage.

[00:11:18] Speaker 04:
You would expect to cleave them at different rates.

[00:11:21] Speaker 04:
And so once you have those two unchallenged prongs and then the efficiency of the disulfide linkage, which was 86% or 87% based on Ruby or Herman, and then Herman does additional work

[00:11:34] Speaker 04:
where he gets about half.

[00:11:37] Speaker 04:
You just have wild variability with disulfide.

[00:11:40] Speaker 04:
And the Regus articles say there was variability.

[00:11:44] Speaker 04:
We didn't pursue disulfide linkages rigorously.

[00:11:48] Speaker 04:
So there was no reason to pick this linker that gave you variable cleavage and unpredictable results, pair it with a three prime group, and cleave them under identical conditions in a serial scheme where

[00:12:04] Speaker 04:
the efficiency of each round builds on the next one.

[00:12:08] Speaker 04:
It simply would have made Ju or Chen less efficient than they already were.

[00:12:15] Speaker 04:
And the board doesn't give you any reason to put those together.

[00:12:20] Speaker 01:
And you allude to this in your brief, but the focus of the disulfide, of course, is on the linking with the label, not the linking with the 3'O3 protecting group.

[00:12:34] Speaker 01:
The patent doesn't identify any bond that is used there, as I understand it, correct?

[00:12:41] Speaker 04:
Any bond for the three prime group?

[00:12:43] Speaker 04:
Right.

[00:12:44] Speaker 01:
It gives you a number of choices, but it doesn't pick out one in particular and say... Right, but the choices were just from, what is it, green and woods?

[00:12:52] Speaker 01:
Green and woods, and then a number of them are in... It's basically all over the priorities, your choices.

[00:12:56] Speaker 01:
There wasn't anything that the patent came up with and said, this is the bond to use and this is not.

[00:13:02] Speaker 04:
Right.

[00:13:03] Speaker 04:
In terms of the pairing with the disulfide, no.

[00:13:05] Speaker 01:
No, no, not the disulfide.

[00:13:07] Speaker 01:
Well, you say pairing with it.

[00:13:08] Speaker 01:
That's how I'm talking about the three prime OH group linking.

[00:13:13] Speaker 04:
There are particular three prime groups that are the subject of other Illumina patents, but not in this patent, the 026 or the 346.

[00:13:21] Speaker 04:
Right.

[00:13:23] Speaker 04:
All right.

[00:13:23] Speaker 04:
And so going back to the efficiency of the disulfide, you said that the disulfide doesn't have to cleave with a particular efficiency.

[00:13:32] Speaker 04:
The problem is, on this record, it's undisputed that you need at least 90% and that 90% for the 3 prime group is probably insufficient.

[00:13:44] Speaker 01:
Well, but 90% for the three prime group isn't driven by the percent, I don't think, unless you, I mean, you may argue to the contrary, but I'd be interested in hearing what the argument is.

[00:13:55] Speaker 01:
But my understanding was that that's not driven by the percentage of accuracy, the percentage of cleavage of the disulfide bond

[00:14:07] Speaker 01:
to the label, correct?

[00:14:10] Speaker 01:
Or am I wrong about that?

[00:14:11] Speaker 04:
Well, and here's the issue on that.

[00:14:13] Speaker 04:
They are directly related in this appeal.

[00:14:16] Speaker 04:
If you look at Joint Appendix 3701 through 05, paragraphs 52, 55, 58, and 60, it's Dr. Romsberg, who is Illumina's expert.

[00:14:30] Speaker 04:
He said that the person of skill in the art wouldn't have expected the three prime group

[00:14:37] Speaker 04:
to cleave with any greater efficiency than the disulfide linker attaching the label to the base, in view of ruby-herman-short-rabani.

[00:14:48] Speaker 04:
IBS never challenged that.

[00:14:51] Speaker 04:
So you do have a direct link between the efficiency of disulfide cleavage and the efficiency of the three prime protecting group cleavage in this appeal.

[00:15:01] Speaker 04:
IBS's expert never said

[00:15:03] Speaker 01:
Why would that be as a matter of chemistry?

[00:15:05] Speaker 01:
That strikes me as peculiar.

[00:15:08] Speaker 01:
The disulfide may be a much stronger bond than what you would use for the other bond.

[00:15:17] Speaker 01:
I mean, why?

[00:15:19] Speaker 01:
Assuming it's not also a disulfide bond, why would it be necessarily equivalent?

[00:15:24] Speaker 04:
No, no.

[00:15:25] Speaker 04:
His testimony was you wouldn't expect the three prime group to cleave any better.

[00:15:29] Speaker 01:
Well, why?

[00:15:31] Speaker 01:
I mean, why is that true as a matter of chemistry?

[00:15:33] Speaker 01:
It would seem to me that if you have a weaker bond, it doesn't take as strong a cleavage agent to produce a higher rate of cleavage, right?

[00:15:46] Speaker 04:
It's not directly, it's not addressed in the record.

[00:15:52] Speaker 04:
The answer was apparently the positioning of the three prime group makes it such that you would expect the disulfide

[00:16:00] Speaker 04:
to be the limiting step, as explained.

[00:16:04] Speaker 04:
But that statement is not in the record.

[00:16:06] Speaker 04:
What is in the record is you wouldn't expect the 3-prime group to cleave with any better efficiency than the disulfide linker, and it's unchallenged.

[00:16:15] Speaker 04:
IBS's expert never said you could cleave the disulfide linkage at a lower rate and the 3-prime group at a higher rate.

[00:16:23] Speaker 01:
You gave us a citation to the appendix from Dr. Rumsberg, I think, just a moment ago.

[00:16:28] Speaker 01:
Could you repeat that?

[00:16:30] Speaker 04:
3701 to 05 and the paragraph numbers are 52, 55, 58, and 60 and this is from the 1123 appeal.

[00:16:42] Speaker 04:
I have it if you want it from the 12.

[00:16:44] Speaker 04:
If you've got the other one I can give it to you.

[00:16:45] Speaker 04:
No, I can get this one.

[00:16:50] Speaker 04:
Okay.

[00:16:51] Speaker 04:
It's 3711.

[00:16:51] Speaker 04:
3701.

[00:16:52] Speaker 04:
3701.

[00:16:52] Speaker 04:
Okay, thank you.

[00:16:55] Speaker 04:
And then the next piece is the board said

[00:16:58] Speaker 04:
Even if efficiency mattered, you could increase the efficiency of a disulfide linkage.

[00:17:04] Speaker 04:
And that is unsupported by substantial evidence on this record.

[00:17:08] Speaker 00:
What about the expert testimony?

[00:17:10] Speaker 04:
The expert testimony is simply a statement from Dr. Brand Schaud.

[00:17:16] Speaker 04:
It's joint appendix 3016 paragraph 37.

[00:17:21] Speaker 04:
And it's a naked statement.

[00:17:24] Speaker 04:
The only support for it is Ruby and Herman

[00:17:28] Speaker 04:
which he relies on.

[00:17:29] Speaker 04:
And the Ruby reference, the board said, it teaches you all of these things and that could get you increased cleavage.

[00:17:36] Speaker 04:
But Ruby actually did the experiments.

[00:17:39] Speaker 04:
Ruby changed the concentration and the cleavage agent.

[00:17:43] Speaker 04:
And the best Ruby did was 86% after 100 minutes.

[00:17:48] Speaker 04:
There's nothing in the record to suggest you could do better than that.

[00:17:52] Speaker 02:
Mr. Zimmerman, you're into your rebuttal time?

[00:17:55] Speaker 04:
I thank you.

[00:17:59] Speaker 02:
Mr. Barron.

[00:18:11] Speaker 03:
May it please the Court, my name is Rob Barron.

[00:18:13] Speaker 03:
I represent Intelligent Biosystems.

[00:18:15] Speaker 03:
Judge Lurie, I want to turn to something you noted at the beginning of this, and I think it's exactly right.

[00:18:21] Speaker 03:
It's important to understand the context, which is that the nucleotide, as originally claimed, was found to be in the art and taught, and something that a person of skill in the art would know.

[00:18:31] Speaker 03:
The nucleotide that would have the label connected by a cleavable linker to the base and a protecting group protecting the three prime hydroxyl to be used, among other things, in an SBS process.

[00:18:45] Speaker 03:
Known.

[00:18:46] Speaker 03:
So they react to that by saying, OK, we're going

[00:18:49] Speaker 03:
cancel our claims, and we're going to instead add the disulfide.

[00:18:54] Speaker 03:
So on the one hand, to have some scrutiny of the disulfide makes sense in that perspective.

[00:19:00] Speaker 03:
If you're a person of skill in the art, you see what Ju and Chen had taught.

[00:19:05] Speaker 03:
And you want to build one of these nucleotides, and you would look to this ubiquitous art that should point to disulfide.

[00:19:14] Speaker 03:
And I think that's where the board was found

[00:19:18] Speaker 03:
The art was very substantial in that.

[00:19:21] Speaker 03:
And obviously, as you said, Judge Stoll, that they actually have a heading that is identifying their motivation based on Rabbani.

[00:19:29] Speaker 03:
And Rabbani is interesting because he says in the passages that identifies the disulfide linker, he cites to two things.

[00:19:36] Speaker 03:
One, he cites to Pierce, which is a catalog, which lists, and that's in the record, and that catalog lists

[00:19:46] Speaker 03:
and I can get you that site.

[00:19:49] Speaker 03:
It's at 2970 and 1795, or the actual peer site.

[00:19:53] Speaker 03:
It's a catalog where it lists a link or a disulfide link, or it says it's quantitatively cleavable with DTT.

[00:20:03] Speaker 03:
And so the point is that disulfide linkers are ubiquitous.

[00:20:08] Speaker 03:
And what Rabani says is this is attractive and I'm motivated to use this in part because they're commercially available.

[00:20:15] Speaker 03:
And that's a kind of a market motivation that KSR ratifies.

[00:20:20] Speaker 03:
And then in addition, he says, they seem to work.

[00:20:23] Speaker 03:
And he points to Ruby and the 87% for a very different experiment.

[00:20:30] Speaker 03:
And he says, this is an example of someone using a disulfide linker to connect a label to a nucleotide and cleaving it.

[00:20:41] Speaker 03:
The crux of their argument is, and of course there's a church which shows it being incorporated in an SBS process.

[00:20:48] Speaker 03:
So the crux of their argument is they try to take the 90%.

[00:20:52] Speaker 03:
And we'll live with it for purposes of this argument.

[00:20:55] Speaker 03:
I think that the board rightly put a lot of skepticism on the 90% for many different reasons that they articulate pretty well, particularly the 346 decision.

[00:21:04] Speaker 03:
But even if you do have a 90% requirement,

[00:21:11] Speaker 03:
It's their jump to applying it to the linker, because the 90% is for the cleavage at the 3'OH.

[00:21:19] Speaker 03:
So what their theory is, I mean, there's all this art that says, OK, the nucleotides, no.

[00:21:23] Speaker 03:
A person's skill in the art will look at Jun Chen.

[00:21:26] Speaker 03:
Jun Chen say, hey, I recommend you look into chemical cleavers.

[00:21:30] Speaker 03:
All they need to be is easy to cleave.

[00:21:32] Speaker 03:
Chen says, which he referenced, Chen says, they need to be non-acidically cleaved, 2 to 20 atoms.

[00:21:38] Speaker 03:
And he says, I encourage you to look at other things.

[00:21:41] Speaker 03:
So disulphide fits right within that.

[00:21:44] Speaker 03:
And so there's all these examples of being used successfully, including in SBS.

[00:21:50] Speaker 03:
Their point is a person of scale in the art, because of the three prime OH cleaving efficiency requiring 90%, would use that as a litmus test for a disulphide linker when they would look at the reported efficiencies of Ruby and Herman.

[00:22:08] Speaker 03:
I think that's incorrect.

[00:22:10] Speaker 03:
Their theory is incorrect in a couple of ways, and the board noted them.

[00:22:13] Speaker 03:
And first, as you said, Judge Stolich, in your discussion, there's no evidence that a person's skill in the art will look at those numbers and think that they're written in stone.

[00:22:25] Speaker 03:
And I disagree, respectfully, with Mr. Zimmerman.

[00:22:30] Speaker 03:
The board actually found that it was Rosenberg who was unsupported, correctly so, on the issue of Ruby.

[00:22:39] Speaker 03:
They found that Dr. Brand-Schod was supportive.

[00:22:44] Speaker 03:
And that was at 46 of the decision.

[00:22:50] Speaker 03:
And that's because of Ruby.

[00:22:53] Speaker 03:
They said, well, look, a couple things here.

[00:22:57] Speaker 03:
Dr. Brand-Schod, that's the IBS expert, made it clear, and the board picked up on this and held this, that those references aren't doing SBS.

[00:23:08] Speaker 03:
So as a first instance, they're not motivated to keep on experimenting until they get to 90, some magical 90.

[00:23:14] Speaker 03:
And you're right, Judge.

[00:23:16] Speaker 03:
The 90 is not in that.

[00:23:19] Speaker 03:
And I think we need to remember that.

[00:23:21] Speaker 03:
90% sign.

[00:23:22] Speaker 03:
Not only is it not in the claim, it's not in the specification, which is important when it's a motion to amend.

[00:23:26] Speaker 03:
So a person of skill in the art wouldn't look at Ruby and Herman, which is looking at elution percentages of connecting something to a column and seeing how much drops out.

[00:23:38] Speaker 03:
And Ruby, in fact, says that the percentages I'm reporting are not dependent only on cleaving the disulfide linkers.

[00:23:46] Speaker 03:
There are other things in what I'm doing that could affect that negatively.

[00:23:52] Speaker 03:
So they would look at that, and they would say, A, I could get better, and B, Ruby teaches by optimizing conditions such as pH, such as temperature, the concentration of the cleaving,

[00:24:08] Speaker 03:
agent elongation of the linker itself which worked in Herman that you could optimize.

[00:24:17] Speaker 00:
How do you respond to Mr. Zimmerman's argument that the best he did was 86% even after modifying all of those things and that your expert's testimony at page JA3016 isn't supported?

[00:24:31] Speaker 03:
Well I think it is supported.

[00:24:33] Speaker 03:
I think the board found it was supported.

[00:24:36] Speaker 03:
I think that he said

[00:24:37] Speaker 03:
based on the fact that Dr. Ruby and his team was not doing SBS.

[00:24:44] Speaker 03:
Number one, they didn't have to keep on experimenting to hit 90.

[00:24:49] Speaker 03:
That's number one.

[00:24:50] Speaker 03:
Number two, there's no evidence in Ruby, if you look at it, that 86 is a limit.

[00:24:57] Speaker 03:
He just reports it.

[00:24:58] Speaker 03:
He says, he actually at one point says, we didn't get a chance to try two millimolars of concentration.

[00:25:04] Speaker 03:
It was working for its purpose, which was to

[00:25:07] Speaker 03:
elute an RNA strand off an affinity column, not SBS.

[00:25:12] Speaker 03:
And so it worked for its purpose.

[00:25:14] Speaker 03:
What the board said was Dr. Romesberg, which just said, I don't think he can get any higher than that, he didn't have anything else other than his opinion to back him up.

[00:25:23] Speaker 03:
That's what the board found.

[00:25:25] Speaker 03:
I think going to Dr. Romesberg, another key point I think here is that basically what they're saying is there's no evidence that a POSA would look to the disulfide,

[00:25:38] Speaker 03:
They say that an opposer would look at the disulfide linker and say, I'm cooked.

[00:25:43] Speaker 03:
I can't use that for this nucleotide because I have two things that reported under 90, even though it's working, because I need 90% for the 3 prime OH.

[00:25:54] Speaker 03:
And Mr. Zimmerman talked about how Mr. Romsberg or Dr. Romsberg had uncontradicted testimony about how, quote, you wouldn't expect that a person would think a protecting group could be cleaved

[00:26:08] Speaker 03:
faster than the disulfide linker.

[00:26:10] Speaker 03:
And you talk, Judge Price, about the citation.

[00:26:17] Speaker 03:
And I think it's important to look at those citations.

[00:26:19] Speaker 03:
And I'm sure this Court has.

[00:26:21] Speaker 03:
To be very clear, Dr. Romesberg does not say that.

[00:26:26] Speaker 03:
Dr. Romesberg was a paid expert.

[00:26:30] Speaker 03:
And he could have said, as an expert with a lot of experience in the field,

[00:26:36] Speaker 03:
It's my feeling, and others would also believe that there's no, under these conditions, there would be no protecting group that could be cleaved any faster.

[00:26:44] Speaker 03:
What he does is he goes through each of the references, Ruby, Rabani, Church, and he says, I've looked at Church.

[00:26:54] Speaker 03:
Church does not report a three-pine OH protecting group and a disulfide linker cleavable under identical conditions

[00:27:06] Speaker 03:
wherein there's evidence that the protecting group could be cleaved under greater efficiency than the disulfide linker.

[00:27:13] Speaker 03:
It's so carefully crafted in those paragraphs that it's clear that all he's really testifying to is those references do not provide anticipation.

[00:27:23] Speaker 03:
But he certainly had the opportunity to make that testimony.

[00:27:28] Speaker 03:
He did not.

[00:27:29] Speaker 03:
So I think that what you see the board doing is on this what I'll call the proxy point.

[00:27:36] Speaker 03:
that the 90% as it relates, if you look at something, the percentage that you look at for the disulfide linker can be proxied over, imported over, and be a good proxy for what would happen with the protecting group.

[00:27:49] Speaker 03:
I think there's no evidence on this.

[00:27:51] Speaker 03:
And the only way we can figure out that they would be the same as to your point, Judge, is if they were the same material.

[00:28:03] Speaker 03:
And they're not.

[00:28:03] Speaker 03:
The claims don't require that.

[00:28:07] Speaker 03:
I also want to, in talking about the claims and the claim requiring a 3-prime OH protecting group and a disulfide linker, cleavable under identical conditions, the board construed that to the point where they said it's not required that the linkage for the protecting group and the linker be the same, be disulfide.

[00:28:33] Speaker 03:
So just the act of construction is

[00:28:37] Speaker 03:
Mr. Zimmerman said the board improperly focused on the disulfide.

[00:28:44] Speaker 03:
I don't think that's right.

[00:28:45] Speaker 03:
I think if you read the board, they framed the issues properly.

[00:28:49] Speaker 03:
They identified all the limitations.

[00:28:53] Speaker 03:
And in fact, they even construed the key phrase with the 3-prime OH protecting group and the disulfide linker, cleavable disulfide linker, wherein the two are cleavable under identical conditions for the one patent or cleavable

[00:29:07] Speaker 03:
under the same chemical conditions for the other.

[00:29:11] Speaker 03:
So they construe it.

[00:29:12] Speaker 03:
So they're obviously paying attention to it as a whole.

[00:29:15] Speaker 03:
And actually, interestingly, in the secondary considerations point, one of the many reasons that the board found that there was not evidence of unexpected results was they said you didn't provide evidence that it was the nucleotide that gave the result versus the disulfide molecule.

[00:29:37] Speaker 03:
So the board actually called- Versus the cleavage agent, right?

[00:29:41] Speaker 03:
They made several points.

[00:29:42] Speaker 03:
You're right, Your Honor.

[00:29:44] Speaker 03:
First, they said there's nothing on kind of a nexus argument.

[00:29:47] Speaker 03:
There's nothing that, on the nexus argument, which was the primary observation, they said there's nothing here that would prove that it was this quote unquote unexpected result was due to the bond as opposed to

[00:30:02] Speaker 03:
the cleaving agent, because they used a different cleaving agent than had been used previously.

[00:30:05] Speaker 03:
That's exactly right.

[00:30:06] Speaker 03:
And that is totally supported by the record of substantial evidence.

[00:30:11] Speaker 03:
But they also, towards the end, they made what I'll call an inherency or latency observation in Ray Baxter, where they said, and they called out Illumina for saying, look, for it to be, you didn't provide any evidence that the nucleotide with all of its limitations is what

[00:30:32] Speaker 03:
created this, you just focused on the bond.

[00:30:34] Speaker 03:
And therefore, the disulfide linkage, this has been known.

[00:30:38] Speaker 03:
So I think that you're just talking about, to the extent it was unexpected, that it was something that was an inherent property of an already known thing.

[00:30:50] Speaker 03:
I mean, the fact is, since the 90s, the disulfide linker was known, was known to be, was ubiquitous, easy to get.

[00:31:01] Speaker 03:
known to be mildly cleavable, was shown to incorporate by the polymerization process by Church, who their expert admitted was one of the greatest minds in DNA, and was also shown in Rabani, where there was a 3-prime OH.

[00:31:19] Speaker 03:
He even recognizes the 90% issue, and he still goes to Ruby and a disulfide linker.

[00:31:26] Speaker 03:
So we think that they certainly recognize the limitations.

[00:31:32] Speaker 03:
If there's, is there anything else I can help you with?

[00:31:39] Speaker 02:
Apparently not, Mr. Barron.

[00:31:40] Speaker 02:
No one loses points for not using up all your time.

[00:31:45] Speaker 02:
Thank you very much.

[00:31:47] Speaker 02:
Thank you.

[00:31:47] Speaker 02:
Mr. Zimmerman has some rebuttal time.

[00:31:54] Speaker 04:
Thank you, Your Honor.

[00:31:55] Speaker 04:
I'd just like to make three quick points.

[00:31:59] Speaker 04:
The first one is that

[00:32:00] Speaker 04:
The characterization of Dr. Romsberg's testimony in paragraphs 52, 55, 58, and 60 as carefully crafted, he looks at each reference that was before the board and says, this reference wouldn't give a person of skill in the art the expectation that you would cleave the disulfide and the three prime protecting group under identical conditions and get above 90 for the three prime group.

[00:32:27] Speaker 04:
The testimony was straightforward.

[00:32:30] Speaker 04:
If there were any ambiguity that this was carefully crafted or that a person of skill in the art would have said, no, no, no, the expectation is different, I assume their expert would have said it somewhere.

[00:32:41] Speaker 04:
The statements from Dr. Romsberg are completely unchallenged on this record.

[00:32:47] Speaker 04:
The second point goes to Judge Stoll's discussion about, could you improve disulfide cleavage based on Ruby and Herman?

[00:32:56] Speaker 04:
Those are the only two references Dr. Brandschild relied on.

[00:32:59] Speaker 04:
They're the only two references the board relied on.

[00:33:02] Speaker 04:
If you look at Ruby, Ruby actually did the experiments, varied pH, varied concentration, varied the cleavage agent, and he got 86% after 100 minutes.

[00:33:15] Speaker 04:
We're talking about, if you use this for SBS, a serial scheme, that 100 minutes means to do five bases

[00:33:24] Speaker 04:
You're talking 500 minutes.

[00:33:27] Speaker 04:
There's no expectation that you could improve this, and the board didn't give us any.

[00:33:32] Speaker 04:
Then on the Herman references, the original cleavage of Herman was 87%.

[00:33:38] Speaker 04:
Two years later, they said, we got virtually all of it, but there's no data in that paper.

[00:33:44] Speaker 04:
Two years after that, they provide the data, and it's 50%.

[00:33:48] Speaker 04:
There's no basis for the board to say you could routinely

[00:33:54] Speaker 04:
enhanced cleavage efficiency with an expectation of success.

[00:33:58] Speaker 04:
There just isn't substantial evidence to support that point.

[00:34:02] Speaker 04:
And for the board to say wildly variable cleavage gives you an expectation of success we think was erroneous.

[00:34:09] Speaker 04:
And the last point is we heard from Mr. Barron that the disulfide linkages are ubiquitous and that they were out there in the art.

[00:34:18] Speaker 04:
There isn't a single reference that suggests

[00:34:23] Speaker 04:
you put a disulfide linkage with a three prime protecting group, and you cleave them under identical conditions.

[00:34:29] Speaker 04:
If you read both boards' opinions, there is not a statement anywhere in there that says you put them together because.

[00:34:37] Speaker 04:
And so at the end of the day, you are left with, what is the motivation to combine these?

[00:34:43] Speaker 04:
And although we can all try to come up with one, there isn't one in the board's opinion, and therefore it's insufficient.

[00:34:50] Speaker 02:
Thank you.

[00:34:50] Speaker 02:
Thank you.

[00:34:50] Speaker 02:
Mr. Zimmerman will

[00:34:51] Speaker 02:
Take the case under advisement.