[00:00:00] Speaker 04:
Our first case this morning is number 23-1404, Unicur, Bio Pharma, BV, Ruses, Pfizer, and Fleming.

[00:00:10] Speaker 01:
Good morning, and may it please the court, Mark Fleming together with Natalie Morrissey and Emily Whalen on behalf of Unicur.

[00:00:16] Speaker 01:
I'd like to address two points this morning.

[00:00:18] Speaker 01:
First, a cursory mention of a hypothetical variant without any data, mechanism of action, or other promising information about it does not show a reasonable expectation that the human body would express it or that it would show clotting activity.

[00:00:32] Speaker 01:
And second, this is a case where, as this court has said, objective indicia can be the most probative evidence of non-obviousness in the record.

[00:00:39] Speaker 01:
This field was and still is nascent and unpredictable.

[00:00:43] Speaker 01:
It was starved for a solution.

[00:00:45] Speaker 01:
Yet despite knowing of Stafford and Schuttrumpf and Manow, nobody even made, much less tested, the leucine variant until Dr. Simeone came along.

[00:00:54] Speaker 01:
He showed the human body would express the leucine variant, that it had vastly more activity than the other options that the art had tried, and that it would work with an adeno-associated viral vector.

[00:01:03] Speaker 01:
Nobody expected that.

[00:01:04] Speaker 01:
everyone praised it, the field shifted to it, and it is the only FDA approved gene therapy treatment for hemophilia B today.

[00:01:12] Speaker 01:
Unfortunately, the board used Dr. Simeone's patent as a roadmap or maybe a spotlight to illuminate one option out of hundreds that the prior art was not looking at.

[00:01:22] Speaker 03:
Is it your view that when we look at Stafford, you know, and I believe this comes from people from the University of North Carolina,

[00:01:31] Speaker 03:
And Stafford says, I have three preferred embodiments.

[00:01:36] Speaker 03:
One of them is alanine, and the other is leucine, and then there's the third one.

[00:01:40] Speaker 03:
Are you saying that it has no evidentiary weight, or that a fact finder, just by virtue of this inventor declaring in a patent application that the inventor has three preferred embodiments, one of them identifying leucine,

[00:02:01] Speaker 03:
Shouldn't be some indicia of what a person of ordinary skill in the art would think about and consider as something with some expectation that it would work?

[00:02:12] Speaker 01:
I think the OSI case is very instructive in answering this question, Judge Chen.

[00:02:16] Speaker 01:
In OSI, the Schnurr patent identified erlotinib as one of the preferred compounds for treating lung cancer.

[00:02:23] Speaker 01:
And then there was another reference, the 10K, that specifically said that erlotinib targeted non-small cell lung cancer.

[00:02:30] Speaker 01:
This court reversed the board and said that was not substantial evidence because the references did not give any data or any indication as to how these compounds would supposedly work.

[00:02:42] Speaker 01:
in fighting this disease.

[00:02:43] Speaker 01:
Stafford does name them.

[00:02:45] Speaker 01:
There's no question about that.

[00:02:46] Speaker 01:
But it doesn't say why it's naming them.

[00:02:49] Speaker 01:
It doesn't identify any mechanism.

[00:02:51] Speaker 03:
We're connecting multiple different pieces of evidence together.

[00:02:55] Speaker 03:
One is Stafford and its declaration of what its preferred embodiments are.

[00:03:00] Speaker 03:
Then there's, I guess, Dr. Peterson's testimony.

[00:03:05] Speaker 03:
building a bridge between R338A and R338L because of common properties and such.

[00:03:15] Speaker 03:
And we know R338A works very well.

[00:03:19] Speaker 03:
And then third is, I guess, the statement in your own patents, which talk about how there would be certain conservative substitutions.

[00:03:28] Speaker 03:
And it reads like there's an expectation that these kinds of conservative substitutions, they would work, and one of them being swap out the alanine for leucine.

[00:03:40] Speaker 03:
And so when you combine all these things together, we're not just dealing with only one of them in isolation.

[00:03:47] Speaker 03:
It's the combination of everything that maybe pushes the ball forward and says, well, at least for a reviewing court, that counts as substantial evidence.

[00:03:56] Speaker 01:
So there's a lot in that question, Judge Chan.

[00:03:58] Speaker 01:
I want to try to address all three of them.

[00:03:59] Speaker 01:
Let's start with Stafford.

[00:04:01] Speaker 01:
And by the way, Stafford is the only prior art reference that we have here that even mentions Lucy.

[00:04:05] Speaker 03:
I want to make sure that you understand

[00:04:08] Speaker 03:
A core part of my question is not looking at these pieces of evidence alone, but more like it's a broader picture.

[00:04:16] Speaker 03:
When you put it all together, doesn't it create something that makes it hard for us to get over the substantial evidence standard on to reverse here?

[00:04:26] Speaker 01:
Okay, well, I want to address them individually, because I think they individually have a number of problems that don't permit the kind of inference that you're talking about.

[00:04:35] Speaker 01:
I also want to make sure I get to objective indicia, because it is precisely in this situation, when it may look like the prior art discloses a bunch of different points that just need to be connected, that how the art actually reacted in real life to these disclosures is particularly important.

[00:04:52] Speaker 01:
And I'm happy to start there if you'd like.

[00:04:55] Speaker 01:
And with respect to column four of the patent, I think it is, I mean, first of all, to the extent you can even look at Dr. Simeone's own disclosure, he certainly doesn't say that you could substitute out anything for physician 338.

[00:05:09] Speaker 01:
And our expert Dr. Spiegel explained why.

[00:05:12] Speaker 03:
And that's because this... The patent identifies certain conservative substitutions, just a handful, and one of them being leucine.

[00:05:21] Speaker 01:
Well, it identifies certain properties that certain amino acids have in common, but it does not suggest that those substitutions would be permitted at all locations in the fixed protein, much less in this particular helix.

[00:05:36] Speaker 01:
And it cites the Bowie reference, and this is what Dr. Spiegel explains in detail in his declaration,

[00:05:41] Speaker 01:
and the board we think wrongly cast this aside and I can explain why in a moment but he explains that the Bowie reference itself says and a skilled artisan would have recognized that at some positions particularly those that are heavily involved in protein function which 338 is it is heavily involved in the interaction

[00:05:58] Speaker 01:
between factor 9 and factor 8, which is critical to the clotting function.

[00:06:03] Speaker 01:
That is a place where no substitutions might be allowed.

[00:06:06] Speaker 01:
Let's remember also, column 4 calls out certain differences between alanine and leucine.

[00:06:11] Speaker 01:
Alanine has a short side chain.

[00:06:12] Speaker 01:
It has the second shortest side chain of all the amino acids.

[00:06:15] Speaker 01:
Leucine does not.

[00:06:16] Speaker 01:
It has a longer side chain.

[00:06:17] Speaker 01:
It is much bigger in size.

[00:06:19] Speaker 01:
It is more hydrophobic than alanine is.

[00:06:22] Speaker 01:
Dr. Spiel explains this

[00:06:24] Speaker 01:
in paragraph 131 of his declaration at 13367 of the appendix.

[00:06:29] Speaker 01:
The board disregarded this, not because it assessed the science and thought he was wrong on the science, but because they thought that he hadn't addressed the properties of Alanine and Lucene.

[00:06:39] Speaker 01:
Of course, he did that.

[00:06:40] Speaker 01:
He did that at length.

[00:06:41] Speaker 01:
We cite the passages in our brief, and I'm happy to direct your honor to them.

[00:06:44] Speaker 01:
It also thought that he didn't address the structure of Factor IX at all.

[00:06:48] Speaker 01:
That's also incorrect.

[00:06:49] Speaker 01:
He discussed that at length.

[00:06:51] Speaker 01:
If the board had properly considered, addressed, and found fault with the merits of Dr. Spiegel's evidence, we might be in a substantial evidence world.

[00:06:59] Speaker 01:
But I think we're in a world like PPC, or like Provisor, or like VICOR, where the board simply failed for manifestly erroneous reasons to even engage with the merits of the testimony that we put before it.

[00:07:12] Speaker 04:
not absent those errors no we think that even on the evidence that the board looked at there's no substantial evidence but there's at the very least sounds like an argument that you would make before the board not so much like an argument that you'd make on appeal you're just disagreeing with the

[00:07:30] Speaker 01:
I don't think that's true, Judge Dyke, because the failure to even address the merits of the evidence that Dr. Spiegel gave at length in his declaration and in his deposition is an APA violation that this court frequently reverses and remands, as it did in PPC, as it did in Provisor, if I'm pronouncing that correctly.

[00:07:52] Speaker 01:
The mischaracterization or the misunderstanding of a party's argument, the failure to consider all the evidence of record,

[00:07:59] Speaker 01:
is an APA error.

[00:08:00] Speaker 04:
Well, that's why I asked you that absent those supposed errors, you lose.

[00:08:04] Speaker 04:
No, I... But you're arguing about the weight that the board gave to other evidence.

[00:08:09] Speaker 01:
I think we still have a substantial evidence appeal, the same as the one that succeeded in OSI.

[00:08:15] Speaker 01:
And that led to outright reversal of the board.

[00:08:18] Speaker 04:
OSI doesn't say that every time you're claiming a compound and there's an issue about prior art, that the prior art has to show testing.

[00:08:27] Speaker 04:
It doesn't say that.

[00:08:29] Speaker 01:
We don't argue that, Your Honor.

[00:08:30] Speaker 01:
It doesn't have to show testing.

[00:08:32] Speaker 01:
If it doesn't have data, then it needs to show some kind of indication or mechanism of action that would permit a skilled artisan, without hindsight, at the time of the prior art, not today, but at the time of the prior art, to extrapolate from whatever was known in the prior art to the claimed invention.

[00:08:48] Speaker 04:
What the board concluded was present here was the evidence that would allow you to extrapolate.

[00:08:53] Speaker 01:
well that the board concluded the board stated that certainly but there was no prior art evidence supporting it just as there wasn't an OSI and if the court isn't with me on this and i would urge the court to look at the objective condition because

[00:09:12] Speaker 00:
lots of issues in your brief, but I don't know that I saw that one.

[00:09:15] Speaker 00:
Is that an issue in front of us?

[00:09:17] Speaker 01:
Yes, it's the failure to consider Dr. Spiegel's evidence, and we brief that at length in both our briefs.

[00:09:23] Speaker 00:
And you say that is a potentially reversible PPA violation?

[00:09:27] Speaker 01:
Oh, absolutely, and we cite PPC, and we cite Provisor, and we cite FICOR, all the cases where

[00:09:32] Speaker 01:
this court has remanded.

[00:09:36] Speaker 03:
Something about solvent exposure?

[00:09:38] Speaker 03:
Was that the point that you didn't feel like the board addressed Dr. Spiegel's position about solvent exposure?

[00:09:47] Speaker 01:
That was an additional problem and I'm happy to go to that.

[00:09:49] Speaker 01:
Judge Stark can answer your question.

[00:09:51] Speaker 01:
The APA argument begins on the bottom of 33 of the blue brief and then is picked up again in the reply.

[00:09:55] Speaker 04:
What is this that they ignored?

[00:09:59] Speaker 01:
They ignored Dr. Spiegel's evidence on the basis of his explanation that the common physical properties that Pfizer was putting forward as supposedly linking alanine and leucine together

[00:10:14] Speaker 01:
were not properties that the prior art, that a skilled artisan before the priority date would have used to extrapolate or to conclude that the leucine variant would either express in the human body or that it would be active in promoting clotting and fighting hemophilia.

[00:10:30] Speaker 01:
That that was hindsight.

[00:10:32] Speaker 01:
And the reason it was hindsight

[00:10:33] Speaker 01:
is because there was nothing in any of the prior references suggesting that any of these characteristics, being aliphatic, being hydrophobic, having a side chain of different lengths, that any of that was predictive of either expression or function, and he gives a number of counter examples.

[00:10:49] Speaker 01:
Leucine, which I'm sure Mr. Grossman will say is a good helix former, if you put it at position 3-3-3, close by to the 3-3-8 position that's at issue here, it causes hemophilia because it's not active.

[00:11:00] Speaker 01:
There are a number of other substitutions at 338 itself and nearby disclosed in the Stafford reference that are not active or that don't express and therefore cause hemophilia.

[00:11:12] Speaker 01:
There are plenty of counterexamples that refute Dr. Peterson's theory and Dr. Spiegel lays this out in detail.

[00:11:18] Speaker 01:
He explains starting at 13359 how alanine and leucine differ and how that made it impossible to predict what leucine would do at 338.

[00:11:26] Speaker 01:
He explains in detail why the statement in column four

[00:11:29] Speaker 01:
about conservative substitutions is not inconsistent with our position, because a skilled artisan would have read it in light of the Bowie reference which is cited.

[00:11:37] Speaker 01:
That's 1-3336 and 3-7 of the appendix.

[00:11:40] Speaker 01:
And he explains, Judge Chen, to the point, the question that you raised, that the 338 position is solvent-exposed, and because leucine is highly hydrophobic, much more hydrophobic than alanine,

[00:11:52] Speaker 01:
it would be counterintuitive for a skilled artisan to put leucine in there.

[00:11:56] Speaker 01:
The board said, well, Dr. Spiegel was wrong about that, because there are two other leucines in the helix.

[00:12:04] Speaker 01:
But Pfizer's own reference, the Mathura reference, which we cited in our surreply and pointed out to the board, says that those two occur in hydrophobic pockets.

[00:12:14] Speaker 01:
That's page 1359.

[00:12:15] Speaker 04:
What would the board say about Spiegel's testimony?

[00:12:17] Speaker 01:
If we look at page 39 of the appendix, that's where the board swipes away Dr. Spiegel's testimony.

[00:12:26] Speaker 01:
38 and 39.

[00:12:35] Speaker 01:
So it says, Dr. Spiegel's surface exposure opinion is undercut by Stafford's teaching that the 330-338 region contains two solvent-exposed leucines.

[00:12:46] Speaker 01:
But we explained by referring to the Mathur reference that those leucines are in hydrophobic pockets.

[00:12:52] Speaker 01:
I'm not sure ultimately that that is disputed.

[00:12:54] Speaker 01:
The board didn't address that.

[00:12:56] Speaker 01:
And then separately, Dr. Spiegel, the board recognized the testimony... When did the board mischaracterize this testimony?

[00:13:06] Speaker 01:
At the very top of 39, his opinions, so Dr. Spiegel, his opinions do not account for the knowledge of a person of ordinary skill in the art as to the properties of Alanine and Lucine and the structure of fix.

[00:13:19] Speaker 01:
He addressed both the properties of Alanine and Lucine and the structure of fix in great detail.

[00:13:25] Speaker 01:
And there is no engagement with it.

[00:13:27] Speaker 01:
The board, I don't know how they could reach this conclusion that he didn't account for it because just two pages earlier, in summarizing our case,

[00:13:36] Speaker 01:
They specifically explain that he testified that a skilled artisan would have considered, among other things, this is the middle of 37, that increased size and hydrophobicity of, they say an alanine variant, I think they mean a leucine variant, would negatively affect stability and solubility.

[00:13:51] Speaker 01:
And they specifically cite the pages of Dr. Spiegel's declaration, which is exhibit

[00:13:55] Speaker 01:
2101 at Paragas 41 to 57 and then 131 to 35.

[00:14:00] Speaker 01:
So they knew the material was there.

[00:14:02] Speaker 04:
We do argue that there's a nexus, most certainly.

[00:14:08] Speaker 01:
We don't argue there's a presumption of nexus, but we argue that we carried our burden to prove it.

[00:14:13] Speaker 01:
We do not argue a presumption.

[00:14:14] Speaker 01:
We never have argued a presumption of nexus.

[00:14:16] Speaker 01:
We argue that we proved a nexus

[00:14:19] Speaker 01:
the board mistakenly held us to the higher standard for a presumption.

[00:14:24] Speaker 01:
It absolutely does, Judge Chen, most certainly.

[00:14:28] Speaker 01:
It doesn't go to the leucine variant sitting in a dish somewhere.

[00:14:32] Speaker 01:
It goes to the recognition that Dr. Simeone had after he observed it in a human being, that it has significantly greater activity than anything else the prior art had tried, that it successfully expresses in the human body, and that it can therefore be used with an adeno-associated viral vector

[00:14:47] Speaker 01:
to treat hemophilia B. That is the complete invention.

[00:14:51] Speaker 01:
That is what was praised.

[00:14:53] Speaker 01:
That is what had unexpected results.

[00:14:55] Speaker 00:
Show me your best example of where that, your invention, was praised.

[00:15:00] Speaker 00:
Because it seemed to me like what was praised was the substitution, which is not your invention.

[00:15:06] Speaker 01:
So, well, it's part of the invention, obviously.

[00:15:09] Speaker 00:
It's claimed.

[00:15:09] Speaker 00:
But it's not commensurate.

[00:15:11] Speaker 01:
If you look at 12.001, the Vanden Dresche article specifically says the improvement in vector performance, vector performance can be ascribed to the use of a modified transgene encoding a hyperactive mutant.

[00:15:25] Speaker 01:
It was putting it all together.

[00:15:27] Speaker 01:
The mutant used in a vector improved the vector.

[00:15:31] Speaker 01:
The Cancio and Nathwani paper on 13817, this so-called padua mutation has been shown to provide AAV vectors with enhanced potency.

[00:15:42] Speaker 01:
12196, Dr. Wang's 2019 study, their own expert, padua mutation significantly improved the efficacy of gene targeting.

[00:15:50] Speaker 00:
I was putting them all together.

[00:15:51] Speaker 00:
I appreciate those sites.

[00:15:53] Speaker 00:
At 27, at the end of all of the survey of the secondary consideration evidence, the board basically

[00:16:01] Speaker 00:
Is there not substantial evidence?

[00:16:04] Speaker 00:
They didn't have to call it weak, but in the end they said it's weak.

[00:16:08] Speaker 00:
And we have to take pretty deferential view of that assessment of that evidence.

[00:16:13] Speaker 00:
Why would we not say there's substantial evidence for the finding that it's weak?

[00:16:16] Speaker 01:
because first of all there were legal errors that the board made on the way there.

[00:16:19] Speaker 01:
The first was holding us to the standard of a presumption.

[00:16:21] Speaker 01:
The second was wrongly thinking that our argument was inconsistent with a prior judgment on the board that rested on a disclaimer only and not on any merits.

[00:16:33] Speaker 01:
Pfizer doesn't even try to defend that.

[00:16:34] Speaker 01:
It's clearly a legal error.

[00:16:36] Speaker 01:
And it's manifestly prejudicial because they thought we were making an argument that the board had already rejected, which of course is not true.

[00:16:42] Speaker 01:
And third, the board erroneously thought we had to compare the unexpected results of Dr. Simeone's invention

[00:16:50] Speaker 01:
with supposed hypothetical results that did not exist in the prior art about the leucine variant by itself.

[00:16:56] Speaker 01:
That's the error that this court corrected in the Millennium case, where Millennium had claimed a mannitol ester of bortezomib, said this is much better than bortezomib, and the district court said, no, no, no, you had to compare it

[00:17:07] Speaker 01:
to the results from a glycerol ester, because there was a reference that mentioned it as a possibility, even though it had never been tested in the prior art.

[00:17:15] Speaker 01:
And this court said, that's not correct.

[00:17:17] Speaker 01:
The patentee does not need to compare results to results that didn't exist in the prior art.

[00:17:21] Speaker 01:
You compare it to what was known.

[00:17:23] Speaker 01:
And the only results that were known in the prior art were the MANO testing of wild-type fix.

[00:17:29] Speaker 01:
Our results were eight to nine times better in terms of activity.

[00:17:32] Speaker 01:
And the Schutrimf test in mice

[00:17:34] Speaker 01:
of the alanine variant.

[00:17:35] Speaker 01:
Ours were still better.

[00:17:36] Speaker 01:
That one was at most six times.

[00:17:38] Speaker 01:
I appreciate the Court's attention.

[00:17:41] Speaker 01:
Thank you, Your Honor.

[00:18:05] Speaker 02:
Good morning, Your Honors, and may it please the Court.

[00:18:07] Speaker 02:
On behalf of Appellee-Fizer, we respectfully request that the Court affirm the findings of unpatentability of the Patent Trial and Appeal Board.

[00:18:16] Speaker 02:
I'd like to start with a colloquy that counsel had with Judge Dyke about whether this case is about substantial evidence and the arguments that Unicure is making here.

[00:18:30] Speaker 02:
The Board considered all of the evidence that Unicure is raising here.

[00:18:34] Speaker 02:
The board rejected that evidence.

[00:18:37] Speaker 02:
Their arguments here are fundamentally not directed to, is there a lack of substantial evidence?

[00:18:42] Speaker 02:
They're fundamentally directed to, we think the board should have found differently based on the evidentiary record, but not that there was no evidence to support its findings.

[00:18:50] Speaker 04:
OK.

[00:18:50] Speaker 04:
But they're also arguing that there are some legal errors here.

[00:18:54] Speaker 04:
And I think it would be helpful if you addressed that argument.

[00:18:58] Speaker 02:
Sure.

[00:18:58] Speaker 02:
I think the one legal error that they point to.

[00:19:03] Speaker 04:
Well, they point to two.

[00:19:05] Speaker 04:
Oh, they point to one in connection with the prima facie case, the Spiegel testimony.

[00:19:12] Speaker 04:
And then they claim there were errors in connection with the assessment of the secondary consideration.

[00:19:17] Speaker 02:
Sure.

[00:19:18] Speaker 02:
So with respect to the consideration of Dr. Spiegel's testimony, they absolutely consider Dr. Spiegel's testimony.

[00:19:25] Speaker 02:
That is on pages 38 to 39 of the board's decision of the appendix.

[00:19:32] Speaker 02:
as counsel pointed out, number one.

[00:19:34] Speaker 03:
They addressed all of Dr. Spiegel's testimony.

[00:19:37] Speaker 03:
And did they correctly understand Dr. Spiegel's testimony?

[00:19:39] Speaker 02:
I believe they did.

[00:19:40] Speaker 03:
But those are the two arguments.

[00:19:43] Speaker 02:
I believe the board is not required to address every single thing in 40 pages of Dr. Spiegel's testimony.

[00:19:50] Speaker 02:
But they did address the two key points that he made.

[00:19:53] Speaker 02:
One was whether or not there was any such thing as a conservative substitution in this context.

[00:19:59] Speaker 02:
And the board flatly rejected that.

[00:20:01] Speaker 02:
Number one, in light of the discussion in column four of the patent.

[00:20:05] Speaker 02:
And number two, in light of the Stafford reference, which highlights alanine and leucine as the most two preferred variants, and that reflects a conservative substitution.

[00:20:16] Speaker 02:
The other argument that they addressed of Dr. Spiegels was whether the leucine variant would express.

[00:20:22] Speaker 02:
And there was extensive evidence about why, based in part on this conservative substitution and the data for the alanine variant, as Your Honor Judge Shen pointed to, that the leucine invariant would likewise be expected to express and to express at the same levels as the wild type.

[00:20:38] Speaker 02:
The issue about whether or not

[00:20:42] Speaker 02:
the leucine would be solvent exposed, which the board also addressed, is secondary to whether something would express or not.

[00:20:50] Speaker 02:
Because whether or not something is solvent exposed only goes to the question of whether or not the leucine variant would express.

[00:20:58] Speaker 02:
And the board pointed to ample evidence as to why

[00:21:01] Speaker 02:
there would be a reasonable expectation here that the leucine variant would in fact express.

[00:21:06] Speaker 02:
The board rejected Dr. Spiegel's testimony on that because that was compared to a different protein.

[00:21:14] Speaker 02:
The argument about hydrophobic pockets

[00:21:17] Speaker 02:
was an attorney argument that they made in surreply, but I will add that the board rejected that argument for two reasons.

[00:21:26] Speaker 02:
Well, they rejected the argument because Stafford itself said that the helix, where the leucine is, is surface exposed.

[00:21:33] Speaker 02:
number one.

[00:21:34] Speaker 02:
And number two, as we pointed out in our briefing, Dr. Spiegel's testimony is directly contradicted by the testimony of UNICURES other expert Dr. Doering.

[00:21:46] Speaker 02:
And this is at page 13721 of the record where he said, quote unquote, for factor nine, helix 338 is entirely solvent exposed, which directly contradicts this idea that there is any

[00:22:01] Speaker 02:
weights to be given to this potential hydrophobic pockets that my colleague was pointing to.

[00:22:07] Speaker 04:
So for purposes of the APA... There are even at the top of page 39 of the board's decision that they mischaracterized Dr. Segal's testimony.

[00:22:16] Speaker 04:
What's your comment on that?

[00:22:17] Speaker 02:
I don't think they mischaracterized Dr. Spiegel's testimony at all.

[00:22:21] Speaker 02:
I think that they rejected Dr. Spiegel's testimony because Stafford said that there are two solvent-exposed leucines, and they also rejected it, saying it lacks credibility because it was based on the protein hemoglobin S, which is not factor 9.

[00:22:36] Speaker 02:
So there is no APA.

[00:22:37] Speaker 00:
They say that Dr. Spiegel's opinions did account, that is they, your friends on the other side, they say Dr. Spiegel did account for the knowledge of the person of ordinary skill in the art as to the properties of Alanine and Lucine and therefore the board statement at the top of 39 simply can't be defended.

[00:22:54] Speaker 02:
Well, I think the board correctly rejected Dr. Spiegel's testimony in that regard.

[00:22:59] Speaker 02:
This is, I believe, on 38, if I may.

[00:23:02] Speaker 00:
At the top of 39.

[00:23:04] Speaker 00:
It's the end of the sentence.

[00:23:05] Speaker 00:
They're saying it's just a reversibly horrendous mischaracterization of Dr. Spiegel's testimony.

[00:23:14] Speaker 00:
And I won't understand your response to that.

[00:23:15] Speaker 02:
I think the response, and if I may, I think it actually goes back to the discussion of his testimony earlier on page 38, where they're talking about Alanine and Lucy.

[00:23:25] Speaker 02:
And what he is saying there is that there's no such thing as conservative substitutions.

[00:23:35] Speaker 02:
They rejected that on page 38, where he does not account for the knowledge of the skilled artisan, which begins

[00:23:46] Speaker 02:
on page 39, but it comes from the paragraph on 38.

[00:23:49] Speaker 02:
And what he was saying on 38 is, as they noted, there's no such thing as conservative amino acid substitutions here.

[00:23:56] Speaker 02:
And they did not find that credible in light of Stafford and other information, including the admission and their patent.

[00:24:02] Speaker 03:
Do you understand this statement by the board, the top of A39, to be really getting at?

[00:24:07] Speaker 03:
a conclusion that, in the board's view, Dr. Spiegel just did not wrestle with certain pieces of evidence of what would be the knowledge of a person of ordinary skill.

[00:24:19] Speaker 03:
That's the problem, not that Dr. Spiegel didn't account for any of the knowledge of a person of ordinary skill.

[00:24:27] Speaker 02:
I think that's a very fair characterization of the problem with Dr. Spiegel's testimony.

[00:24:32] Speaker 03:
Has this court ever tried to wrestle with

[00:24:36] Speaker 03:
a deeper explanation of what the law means when it requires a reasonable expectation of success.

[00:24:45] Speaker 03:
I mean, we all know it doesn't demand absolute predictability, but reasonable expectation of success can also be

[00:24:54] Speaker 03:
kind of a mushy impressionistic kind of finding.

[00:25:00] Speaker 03:
And so I'm wondering, can you provide a little more insight on what you think reasonable expectation of success demands?

[00:25:11] Speaker 02:
I think a reasonable expectation of success has to be measured with respect to the claimed invention.

[00:25:17] Speaker 02:
I think that's obviously a fixed point of law.

[00:25:20] Speaker 02:
And the question then becomes,

[00:25:23] Speaker 02:
I don't know that the court has delved into the level of reasonableness required, if that's your honor's question.

[00:25:31] Speaker 02:
I do think in the context of the examples that were given in both OSI and Strathclyde, there is an indicator here, as the board found.

[00:25:43] Speaker 02:
There is, in the words of Strathclyde, evidence or promising information.

[00:25:46] Speaker 02:
There's even data in the form of the Allen and Barry.

[00:25:50] Speaker 02:
Where exactly that line is?

[00:25:54] Speaker 02:
for how reasonable it needs to be.

[00:25:55] Speaker 02:
I couldn't cite a case for you for what that means, but I do think even under their cited cases, the standard is met here.

[00:26:04] Speaker 02:
And what I think they're really trying to argue at bottom is really rhetorically, how could it be?

[00:26:11] Speaker 03:
Would you agree it's harder to meet that standard in a recognized, unpredictable field of art?

[00:26:22] Speaker 02:
I think it depends on the information and the art.

[00:26:24] Speaker 02:
I think there are a lot of fields that are unpredictable, and the court routinely finds inventions obvious because there was a reasonable expectation of success.

[00:26:33] Speaker 02:
And I will add here, and I think this is worth thinking about, because their unpredictability arguments are really about gene therapy, but in their reply, they actually

[00:26:44] Speaker 02:
effectively concede that gene therapy is not the issue.

[00:26:48] Speaker 02:
On page eight of their reply, they say, finally, the board's statement that factor nine levels correlate well with clinical symptomology is not substantial evidence of a particular mutation's expected activity.

[00:27:02] Speaker 02:
It at most suggests that factor nine mutations known or reasonably expected to be active could have predictable clinical effects.

[00:27:13] Speaker 02:
Here, the clinical symptomology finding of the board, which they don't actually dispute, is well supported by substantial evidence, including the Hasbrock reference statement at 1588, which was the basis for it.

[00:27:26] Speaker 02:
So it really comes back to this question of, would the poster reasonably expect that the leucine variant would be active?

[00:27:36] Speaker 02:
And I think, as the colloquy came out with Your Honor Judge Chen and my colleague earlier,

[00:27:42] Speaker 02:
They keep trying to point to individual pieces of evidence without looking at the evidence as a whole.

[00:27:47] Speaker 02:
And the evidence as a whole here certainly supports, as the board found, that the post would reasonably expect the leucine variant to be active, just as Stafford said it would be.

[00:27:57] Speaker 02:
And that then, once you move on to the clinical phase, makes this ample evidence of reasonable expectation of success.

[00:28:08] Speaker 02:
I just want to make sure I sufficiently address the APA issue.

[00:28:11] Speaker 04:
But what about their alleged errors in connection with the secondary consideration?

[00:28:15] Speaker 02:
Sure.

[00:28:16] Speaker 02:
I will say a couple of things about that.

[00:28:18] Speaker 02:
First of all, the board thoroughly analyzed all of the objective evidence that was presented and correctly found that no matter what standard was applied, whether it was coextensive or recently commensurate, there was not any nexus.

[00:28:34] Speaker 02:
And it further found

[00:28:36] Speaker 02:
And this is why I think this is really a factual issue that they're trying to argue is a legal one, that any evidence of Nexus was weak.

[00:28:45] Speaker 02:
And when they made that finding, they talked about how Nexus, and this is under both the Rao case and the Merck CIE case, that Nexus has to come from what's claimed and what's novel in the claim.

[00:28:58] Speaker 02:
And all of their evidence that they point to was really about the factor 9 variant.

[00:29:04] Speaker 02:
And I will add that the evidence from the Vandresha reference at 12,001 that my colleague pointed to about vector performance, as we pointed out in our briefing, was about in vitro studies, in cells.

[00:29:15] Speaker 02:
It had nothing to do with a claim to use in humans, which is what they are talking about.

[00:29:21] Speaker 02:
And there is other evidence in that same article on pages 12,001 and 12,002

[00:29:27] Speaker 02:
that the board cited to, supported that when it came to humans, there were a lot of variations that could impact the performance and the results in a clinical trial.

[00:29:39] Speaker 02:
And I will further note that on the question of objective evidence and the breadth of the claim, because this is something that I don't think they really engage with, the problem is they drew a massively broad claim.

[00:29:51] Speaker 02:
And as their own expert pointed out, there are

[00:29:55] Speaker 02:
thousands of AAV vectors.

[00:29:57] Speaker 02:
There are 10,000 promoters.

[00:30:00] Speaker 02:
And there are claims here, claim one permits at least 70% amino acid identity.

[00:30:06] Speaker 02:
That's 30% change is not even limited to conservative substitutions.

[00:30:11] Speaker 02:
And their evidence, which they try to say, oh, this goes out to the extent of AAV vectors, even if you credit that, and by the way, the board correctly found that AAV factor nine was disclosed in the prior art, disclosed in Stafford, so that's also not new.

[00:30:24] Speaker 02:
But even if you were to credit that argument, they do nothing to deal with the breadth of the claims on promoters.

[00:30:30] Speaker 02:
and nothing to do with the breadth of the claim on 70% identity.

[00:30:33] Speaker 02:
And in fact, their arguments about unexpected properties being commensurate with the scope of the claim is fundamentally contradicted by their own experts' arguments that there's no such thing as conservative substitutions here, and a single amino acid change can result in hemophilia.

[00:30:49] Speaker 02:
So there is no way here they could ever carry that burden, which is correctly why the board found it.

[00:30:54] Speaker 02:
And all of that was observed, which is why by the board in its discussion.

[00:30:59] Speaker 03:
So how would they ever get secondary consideration evidence to count in your view?

[00:31:03] Speaker 03:
Do they have to claim AAV5 all the way down to the last detail?

[00:31:12] Speaker 02:
I couldn't say exactly what they would need to claim, but it wouldn't be the claims that they have here.

[00:31:17] Speaker 02:
which are far too broad.

[00:31:19] Speaker 02:
Let me maybe put it slightly differently, because my colleague did talk about Dr. Simeone's contribution here.

[00:31:30] Speaker 02:
Dr. Simeone found that the leucine variant existed in a human.

[00:31:35] Speaker 02:
He published an article about that in the New England Journal of Medicine.

[00:31:39] Speaker 02:
That is an interesting scientific finding, worthy of publication.

[00:31:43] Speaker 02:
That is not worthy of a patent.

[00:31:45] Speaker 02:
And it's certainly not worthy of the patent that they have here, which is all they're doing is saying, oh, yeah, what Dr. Stafford published 10 years ago, now I'm going to say I'm going to try to claim that again.

[00:31:55] Speaker 02:
He did no gene therapy work.

[00:31:58] Speaker 02:
He relies on the mano reference.

[00:31:59] Speaker 02:
That goes back to your question about predictability here.

[00:32:02] Speaker 02:
I mean, everything has to be based on what was in the prior art

[00:32:07] Speaker 02:
on gene therapy studies, which is presumably why they made that admission on page 8 of their reply brief, that this really isn't about the gene therapy.

[00:32:17] Speaker 02:
And it's just about, is a variant that is a conservative, structurally similar variant to something that was disclosed and shown to be active going to be reasonably expected to be active?

[00:32:27] Speaker 02:
And on that question, there is certainly substantial evidence to support the board's decision.

[00:32:31] Speaker 00:
To address $12,113,817 was also mentioned by Mr. Fleming as apparently industry praise of their invention.

[00:32:40] Speaker 00:
What's your response to that?

[00:32:42] Speaker 02:
I'd have to go look that up, but I believe that was also directed to the Lucene variant.

[00:32:45] Speaker 00:
Is it your view that they presented no secondary consideration evidence that is commensurate with the scope or for which there's a nexus, or that maybe they presented some but the board adequately weighed it?

[00:32:57] Speaker 02:
I don't think they presented any evidence to show that what their evidence was, what was new in the claim.

[00:33:06] Speaker 02:
And the board correctly weighed that to show that it was weak.

[00:33:13] Speaker 04:
OK.

[00:33:24] Speaker 01:
Thank you, your honor.

[00:33:27] Speaker 01:
We didn't say there's no such thing as conservative substitutions.

[00:33:29] Speaker 01:
I would invite the court to look at 13335, paragraph 72.

[00:33:34] Speaker 01:
No, no.

[00:33:35] Speaker 01:
Well, 13335, paragraph 72.

[00:33:37] Speaker 01:
Here's what he said.

[00:33:38] Speaker 01:
To that end, particularly in the context of protein domains that are relevant to a protein's activity or specific interactions with other proteins,

[00:33:47] Speaker 01:
there is

[00:34:01] Speaker 01:
is relevant to protein activity and specific interactions with other proteins, namely the factor VIII protein.

[00:34:06] Speaker 01:
The board notes this on page 38.

[00:34:08] Speaker 01:
They recognize that Dr. Spiegel said substitution is context dependent.

[00:34:13] Speaker 01:
They don't say that that's wrong.

[00:34:15] Speaker 01:
They just say that somehow he didn't account for

[00:34:18] Speaker 01:
the difference between Alanine and Lucine and the structure of fix.

[00:34:21] Speaker 01:
He clearly did that.

[00:34:22] Speaker 01:
I don't think anyone can read his declaration starting at 13309, then again at 13335, 13341, and 13359.

[00:34:31] Speaker 01:
One cannot read those passages in those discussions and think he didn't account for them.

[00:34:35] Speaker 01:
If the board thought that he got something wrong on the signs, it wasn't incumbent on them to explain what.

[00:34:40] Speaker 01:
Judge Chen, regarding the standard for reasonable expectation of success,

[00:34:43] Speaker 01:
I think the standard is what this court said in OSI, which is there either needs to be some data or there needs to be some indication or mechanism of action that permits someone to extrapolate that the experiment will work.

[00:34:55] Speaker 03:
And no basis... A bridge in hindsight by looking at chemical properties that no one in the priority...

[00:35:05] Speaker 01:
Well, Stafford didn't mention the chemical properties.

[00:35:07] Speaker 01:
Stafford didn't say, you know, I expect these other ones to work.

[00:35:09] Speaker 01:
Remember, Stafford didn't even know why alanine worked.

[00:35:12] Speaker 01:
The very one that they tested, they tried.

[00:35:14] Speaker 03:
You look at 1300 to 1301, they tried to account for it.

[00:35:22] Speaker 01:
Well, and they would have had no answer because they would also note that Stafford looked at Vailene and claimed that is preferred as well.

[00:35:29] Speaker 01:
I would urge the court, either now or in repose, to look at the chart on page 10 of the blue brief, because that shows how the field was reacting to all this art in real time.

[00:35:39] Speaker 01:
This is a small... I think we're out of time.

[00:35:42] Speaker 01:
I will let page 10 rest on its own merits then.

[00:35:44] Speaker 01:
I thank the court for its attention.