[00:00:00] Speaker 01:
We have several motions for admission to the bar today.

[00:00:09] Speaker 01:
Judge Schall is going to make the first motion.

[00:00:12] Speaker 03:
Yes.

[00:00:13] Speaker 03:
Thank you, Judge Wallach.

[00:00:15] Speaker 03:
And I would like to ask my law clerk, Jennifer Veen, to stand up, please.

[00:00:23] Speaker 03:
And I move the admission of Jennifer Veen

[00:00:28] Speaker 03:
who is a member of the bar and is in good standing with the highest courts of the Commonwealth of Virginia and the District of Columbia.

[00:00:37] Speaker 03:
I have knowledge of her credentials and am satisfied that she possesses the necessary qualifications.

[00:00:44] Speaker 03:
I would just like to very briefly add, in support of my motion, those are kind of the formal official words that have to be spoken.

[00:00:52] Speaker 03:
Just to put a teeny bit of gloss on it, I would say that

[00:00:56] Speaker 03:
Jen has been an excellent clerk.

[00:00:58] Speaker 03:
It's been a delight this year to have her in chambers.

[00:01:01] Speaker 03:
And I know that she will be an excellent addition to the bar of the court if my motion is granted.

[00:01:08] Speaker 03:
Thank you.

[00:01:10] Speaker 01:
Having conferred with Judge Strano, the motion is granted.

[00:01:17] Speaker 01:
Why don't you do them all together?

[00:01:20] Speaker 01:
And at this point, I have a motion, so I'm going to recuse myself from the vote.

[00:01:26] Speaker 01:
And I'll pass that on over to Judge Shaw.

[00:01:30] Speaker 01:
And I actually have a motion for two of my clerks, or two motions, depending on how you look at it.

[00:01:38] Speaker 01:
And I'd ask them to please rise, both please rise.

[00:01:43] Speaker 01:
And I'm going to move both of them separately, but I want to talk about them together.

[00:01:51] Speaker 01:
And that's because there's so many similarities.

[00:01:56] Speaker 01:
That includes that one of them speaks Turkish and the other speaks Arabic.

[00:02:00] Speaker 01:
They both speak fluent French.

[00:02:03] Speaker 01:
They were both editors of their respective law reviews.

[00:02:09] Speaker 01:
And having said that, I'll say a little bit more as I move them.

[00:02:16] Speaker 01:
I begin by moving the admission of Christopher Mullins Tipler, who is a member of the Bar and in good standing with the highest court of the district

[00:02:26] Speaker 01:
of the Commonwealth of Virginia and the District of Columbia.

[00:02:30] Speaker 01:
I have knowledge of his credentials and am satisfied that he possesses the necessary qualifications.

[00:02:38] Speaker 01:
Mr. Tipler is of course an outstanding lawyer.

[00:02:48] Speaker 01:
He has a particular interest in national security law.

[00:02:52] Speaker 01:
He was a soccer player at the University of the South.

[00:02:55] Speaker 01:
And he's a fine and interesting person, and I move that admission.

[00:03:04] Speaker 03:
We've considered the supporting papers and the presentation.

[00:03:09] Speaker 03:
The motion is granted.

[00:03:11] Speaker 01:
And now I move the admission of Leslie Ezbrook.

[00:03:22] Speaker 01:
who is a member of the bar and is in good standing with the highest court of New York.

[00:03:27] Speaker 01:
I have knowledge of her credentials, and I'm satisfied that she possesses the necessary qualifications.

[00:03:35] Speaker 01:
And Ms.

[00:03:37] Speaker 01:
Esbrook is a Chicago graduate of Yale Law School, and like me, likes to cook.

[00:03:50] Speaker 01:
She's a baker.

[00:03:51] Speaker 01:
Uh, and, uh, I, uh, moved the admission of, uh, Ms.

[00:03:56] Speaker 01:
Ezbrough.

[00:03:57] Speaker 01:
That motion, too, is happily granted.

[00:04:21] Speaker 01:
Thank you so much.

[00:04:25] Speaker 01:
Our first case is Kite Pharma v. Sloan Kettering Institute.

[00:04:31] Speaker 01:
Council ready to proceed?

[00:04:32] Speaker 00:
Yes, Your Honor.

[00:04:34] Speaker 01:
You're reserving three minutes.

[00:04:35] Speaker 01:
Yes, Your Honor.

[00:04:39] Speaker 00:
May it please the Court.

[00:04:43] Speaker 00:
Respectfully, the Board below erred in applying an overly restrictive legal standard for obviousness.

[00:04:49] Speaker 00:
The board rejected Kite's obviousness theory based on its finding that one skilled in the art would not have been motivated to improve upon the construct in Krauss, which was an antibody fragment attached to the CD28 signaling sequence that she disclosed, and making that into a three-part car by adding the CD3 zeta primary signal that was taught in Finney.

[00:05:15] Speaker 01:
In the blue brief.

[00:05:17] Speaker 01:
You argued that the PTAB's fact findings with respect to Keit's other rationales, which included the teaching away findings, quote, provide nothing that can salvage its lack of fact finding on the first rationale.

[00:05:32] Speaker 01:
Where in the brief did you challenge the PTAB's actual fact findings on the teaching away issue?

[00:05:39] Speaker 00:
We did not challenge that in the opening brief, Your Honor.

[00:05:43] Speaker 00:
We did not consider the teaching away findings to be relevant with regard to the rationale why.

[00:05:48] Speaker 01:
Well, then why isn't Sloan prejudiced, given that it's not had an opportunity to respond to your reply brief arguments?

[00:05:56] Speaker 00:
Your Honor, I believe that Sloan fully addressed the teaching away argument in their brief, in their respondent's brief.

[00:06:05] Speaker 00:
had the opportunity to ask the court for additional briefing if they thought they needed additional briefing on that.

[00:06:10] Speaker 00:
We believe that the issue is properly before the court.

[00:06:14] Speaker 00:
If I can explain the reason that we did not believe that the teaching away binding applied to rationale one, I think that's relevant here.

[00:06:21] Speaker 00:
Because I think at a very minimum, there was an ambiguity.

[00:06:24] Speaker 01:
Given that the PTAP says the teaching away finding supports its determination as to ground one, which is obvious since Albert Krauss, Binion,

[00:06:35] Speaker 01:
are a RUFO rather than Rationale 1, doesn't that indicate that its teaching away finding applies to all rationales underground 1?

[00:06:47] Speaker 00:
I don't think they ever said that they were applying the teaching away finding to Rationale 1, Judge Walke.

[00:06:52] Speaker 00:
What they said was, and their rationale was very brief, their explanation for their decision was very brief on Rationale 1.

[00:07:00] Speaker 00:
They said that Kite had not distinguished expressly between the advantages of Krauss's CD28 sequence versus Finney's, or explained why one of ordinary skill would have been motivated to retain Krauss's CD28 reference over Finney's when combining two references.

[00:07:15] Speaker 00:
This is at 13 and 14 of the appendix.

[00:07:19] Speaker 00:
And then when they did refer to the other rationales, what they specifically said is, if we impute the alleged advantages

[00:07:26] Speaker 00:
of Krauss's CD28 sequences discussed with regards to Rationals 2 and 3 to Rationale 1, then Rationale 1 rises or falls with Rationale 2.

[00:07:34] Speaker 01:
But at JA22, the PTAB begins its teaching away finding by saying, the foregoing subsections provide a sufficient basis on which to conclude that kite has not carried its burden of persuasion as to Ground 1, and that teaching away, paraphrasing, finding

[00:07:54] Speaker 01:
quote, is an additional related reason that further supports this conclusion.

[00:08:00] Speaker 00:
Well, there, Your Honor, they refer to ground one, but ground one encompassed the three rationales.

[00:08:06] Speaker 00:
They didn't specifically say that they're applying that finding with regard to the first rationale.

[00:08:12] Speaker 00:
And if I could take a moment to explain why this is not just a matter of- All rationales includes the first one.

[00:08:20] Speaker 00:
Ground one included all rationales.

[00:08:21] Speaker 00:
That's correct, Ron.

[00:08:23] Speaker 00:
But I think there's an important distinction between the two rationales that the board did not recognize, and is the reason that we had understood that the teaching away finding was not focused on rational one as opposed to rational two.

[00:08:36] Speaker 00:
Rational two, to some extent, was a more difficult showing that Kite had presented for itself, which was Finney had a three-part car that was disclosed.

[00:08:47] Speaker 00:
And the argument there was that a person of skill in the art would look at that and say, this isn't good enough.

[00:08:52] Speaker 00:
There's something that could be made better about it.

[00:08:54] Speaker 00:
And what can be made better is you can take out the CD28 sequence that Finney uses and replace it with another one.

[00:09:01] Speaker 00:
And that's where the board was talking about the issues of superiority and teaching away and why someone would be dissuaded from doing that.

[00:09:08] Speaker 00:
Rationale 1 was a different rationale, which started from Krauss, where Krauss was doing testing to show

[00:09:16] Speaker 00:
that she could, through her construct, obtain a vibrant co-stimulatory effect in natural T cells.

[00:09:25] Speaker 00:
And that's very important, because Finney did not test in natural T cells.

[00:09:28] Speaker 00:
So there are two aspects of the immune response.

[00:09:31] Speaker 00:
One of them is cytokine production, IL-2 production.

[00:09:34] Speaker 00:
One of them is proliferation of the cells.

[00:09:36] Speaker 00:
And one of them is survival of the cells, because if the cells are activated by a primary signal but don't get the secondary signal, they die.

[00:09:43] Speaker 00:
She tested each of the three of these.

[00:09:45] Speaker 00:
to see if when the CD28 sequence, instead of directly binding to its natural ligand, was instead attached to an antibody fragment that bound to a particular antigen, whether she could promote the same and provoke the same healthy response that you would get from the direct binding.

[00:10:05] Speaker 00:
And she found that.

[00:10:05] Speaker 00:
And she found that in healthy T cells.

[00:10:07] Speaker 00:
So Krauss was a very, very important reference for one of skill in the art, because it showed that the sequence that she used worked beautifully.

[00:10:15] Speaker 00:
There's no suggestion that there's anything wrong with that sequence.

[00:10:18] Speaker 00:
And for that rationale, the only issue was whether one would then be motivated to then take what she had done, which was a sequence that worked perfectly well.

[00:10:27] Speaker 00:
There's no suggestion in any of her reference that there's anything wrong with the sequence, and would think to then take Finney's suggestion that you can not only take a single signaling domain, but you can take both the primary and the secondary signaling domains, put them into

[00:10:45] Speaker 00:
a single chain attached to a variable fragment of an antibody and create a three-part car that will function properly.

[00:10:55] Speaker 00:
And the board, in its finding... Oh, wait a minute, though.

[00:10:58] Speaker 01:
OK, go ahead, and then I'll certainly do that with what you said about the finding.

[00:11:02] Speaker 00:
So the board didn't make any finding that one of skill and the art, at the time of the invention, would not have thought that that was an option that would work.

[00:11:10] Speaker 00:
But the board, in its teaching away finding,

[00:11:14] Speaker 01:
It says, I'm quoting, the prior art fails to provide a motivation to include the MYPPY motif found in Krause's CD28 sequence in a dual-signaled chimera TCR, and therefore found the prior art would have discouraged the ordinary skilled artisan.

[00:11:35] Speaker 01:
And in rationale one, the PTAB found Kite failed to demonstrate the posita in developing a dual-signaling chimera TCR ellipsis

[00:11:45] Speaker 01:
would have been motivated to retain Krause's CD28 or the Finneys when combining the two references.

[00:11:51] Speaker 01:
Why doesn't the PTAB's finding about a posita being discouraged from retaining CD28, which uses the MYPPY amino acid motif, directly tie into whether a posita would have retained Krause's CD28?

[00:12:12] Speaker 00:
Well, our understanding of the board's decision, and I'll answer your question as to what Kite understood in its opening brief.

[00:12:18] Speaker 00:
I'll then move on to the issue of the teaching away finding itself, if the court were to consider that on the merits.

[00:12:26] Speaker 00:
Our understanding was that there was a distinction in the rationales that was relevant to whether teaching away was something that the board was relying on or not, which was that

[00:12:40] Speaker 00:
And this goes back to the law that we cited, including the Bayer Watson case, 874 F.

[00:12:48] Speaker 00:
3rd, 1316, where the court held that obviousness does not require that motivation be the best option, only that it be a suitable option, from which the prior art does not teach away.

[00:12:59] Speaker 00:
For purposes of the second rationale, we clearly have the obligation to show that someone would have thought to change things, would have thought to.

[00:13:08] Speaker 00:
That was an either-or proposition for the second rationale.

[00:13:13] Speaker 00:
You had to decide.

[00:13:13] Speaker 00:
You already had a sequence that was taught by Finney.

[00:13:16] Speaker 00:
There had to be motivation for somebody to say, that's not good enough.

[00:13:18] Speaker 00:
I need something else.

[00:13:19] Speaker 00:
And for that one, it really is a matter of you look at the two side by side.

[00:13:23] Speaker 00:
And what would someone of skill in ER think was better?

[00:13:25] Speaker 00:
And that's where we thought the teaching away finding went.

[00:13:29] Speaker 00:
But it's a little bit different.

[00:13:30] Speaker 00:
And your honor, I don't believe this is just semantics.

[00:13:33] Speaker 00:
I think there's a difference with rationale one, which is rationale one is if you start with

[00:13:38] Speaker 00:
with Krauss.

[00:13:40] Speaker 00:
And Krauss says, hey, what I've done works terrifically.

[00:13:43] Speaker 00:
It's great.

[00:13:44] Speaker 00:
And there's nothing in Krauss to suggest there's anything wrong with it.

[00:13:47] Speaker 00:
Then the question there was simply, would someone have thought to take this and then to try to add the primary signal and make this into a three-part car?

[00:13:58] Speaker 00:
And for that purpose, there was no suggestion that there was anything that would preclude someone from thinking that

[00:14:08] Speaker 00:
the Kraus sequence would work.

[00:14:11] Speaker 00:
For that purpose, it's not either or.

[00:14:13] Speaker 00:
For that purpose, CD28 sequence she used, it doesn't have to win a head-to-head battle against Finney's, which is the reasoning that the board used, which we believe was erroneous.

[00:14:23] Speaker 04:
The board seemed to suggest that- But why isn't the concern, which certainly has some evidence in the record to support it,

[00:14:35] Speaker 04:
the same concern that the board discussed in the teaching away section.

[00:14:41] Speaker 04:
Why would not that be obviously relevant to the Kraus's good?

[00:14:47] Speaker 04:
Maybe we can make it great, the rationale one.

[00:14:52] Speaker 04:
That is, maybe we can make it even better in this way if this way carries a risk of friendly fire.

[00:15:04] Speaker 00:
Well, your honor, our understanding of the board's decision was that what the board was saying when it was discussing the teaching away, it was that someone would be motivated not to have replaced or substituted the CD28 sequence with the one in Kraus because of the issues that the board addressed.

[00:15:21] Speaker 04:
But the way the board discusses rationale one, at least I understood to be, if you start with Kraus and you think, can we add

[00:15:33] Speaker 04:
the thing that's in Phinney but not in Kraus, then why would you keep the, is it, can one say My Puppy or?

[00:15:44] Speaker 00:
That's my Puppy or Mitmy.

[00:15:46] Speaker 04:
You've got to be able to say My Puppy, right?

[00:15:47] Speaker 04:
The My Puppy sequence.

[00:15:50] Speaker 04:
Instead of swapping out that piece of it for the version of CD28 that's found in Phinney and you would need a reason to, you know, to say

[00:16:02] Speaker 04:
I'm not going to do that.

[00:16:05] Speaker 04:
And all the teaching away stuff would bear on that reason, would it not?

[00:16:11] Speaker 00:
I believe, Your Honor, that it could have.

[00:16:14] Speaker 00:
But the way that the court, the way that the board described what it was doing, its reference to rationales two and three, it did say, and we consider this to be a somewhat ambiguous sentence, it says,

[00:16:32] Speaker 00:
if we impute the alleged advantages of Krauss's C28 sequence.

[00:16:37] Speaker 04:
Well, put aside the question of preservation of the argument.

[00:16:42] Speaker 04:
Just on the merits, why is rejection of rationale one not supportable on the board's reasoning as to teaching away?

[00:16:58] Speaker 04:
I'm using several short hands.

[00:17:00] Speaker 00:
I understand.

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

[00:17:01] Speaker 00:
And let me turn to that quickly.

[00:17:04] Speaker 00:
There are two reasons.

[00:17:05] Speaker 00:
One is that the board relied almost entirely upon post-invention date, priority, prior art.

[00:17:13] Speaker 00:
There were only two references that involved CD28 at all.

[00:17:17] Speaker 00:
And both of them were several years after the 2002 claim date of the invention.

[00:17:23] Speaker 00:
The only prior art reference that the board relied on was CAPON.

[00:17:27] Speaker 00:
CAPON did not involve CD28.

[00:17:28] Speaker 00:
It didn't involve extracellular sequences.

[00:17:30] Speaker 00:
It just involved

[00:17:31] Speaker 00:
transmembrane proteins, and it talked about if you're making CAR T that you want to avoid having these transmembrane proteins.

[00:17:39] Speaker 00:
Remember, you're in your rebuttal time.

[00:17:41] Speaker 00:
You might want to talk fast.

[00:17:43] Speaker 00:
Thank you, Your Honor.

[00:17:45] Speaker 00:
But the other references, the Hombach reference does not involve CD28.

[00:17:52] Speaker 00:
And the Korchendorfer reference and the Koalak reference

[00:17:58] Speaker 00:
Neither of them say that there actually is a problem with binding with this extracellular domain.

[00:18:02] Speaker 00:
They postulate that there's a possibility that there might be.

[00:18:05] Speaker 00:
Korchendorfer actually goes on to say, we thought there might be a problem.

[00:18:08] Speaker 00:
We weren't sure, because you need a particular folding, a three-dimensional folding of the CD28 sequence to have this off-target binding.

[00:18:14] Speaker 00:
We tested it, and it wasn't there.

[00:18:16] Speaker 00:
So Korchendorfer later shows that there's no such problem.

[00:18:19] Speaker 00:
And we think that under the law, it has to be the case that the concern had to exist as of the time of the invention, because otherwise it could not have dissuaded someone of skill in the art.

[00:18:26] Speaker 00:
And I just very quickly want to make sure that I mention to the court.

[00:18:30] Speaker 00:
The board, as indication of the error that the board made in its teaching away finding, is there was evidence Kraus had done a test to see if she would get off target binding.

[00:18:41] Speaker 00:
And this is discussed at appendix 766 through 69 and 1230 through 1233.

[00:18:47] Speaker 00:
She had added her construct to T cells where she provoked the primary signal using the antibody for the CD3.

[00:18:55] Speaker 00:
But she didn't add the antibody that caused her construct to fire and to give the co-stimulatory sequence.

[00:19:03] Speaker 00:
So she tested that.

[00:19:03] Speaker 00:
And then she had it side by side in a culture where she did have the CD28 with the binding with the antibody receptor.

[00:19:13] Speaker 00:
And if there had been this off-target binding, she would have seen it.

[00:19:17] Speaker 00:
Because in that first example, where she didn't tie her CD28 construct to

[00:19:24] Speaker 00:
the antibody didn't have the antigen to which the antibody bound, it couldn't have bound to anything.

[00:19:30] Speaker 00:
That could not have been the cause of any signaling.

[00:19:32] Speaker 00:
The signaling would have resulted from this off-target binding that the board talked about.

[00:19:36] Speaker 00:
But as shown in Table 2 of her reference, there was no IL-2 production or presentation over and above that of a control that had no possibility of co-stimulatory binding.

[00:19:50] Speaker 00:
And the board simply ignored that evidence, which was itself

[00:19:53] Speaker 00:
demonstrative that there neither was a concern about off-target binding, and Krauss herself was evidence that off-target binding would not have dissuaded using her sequence.

[00:20:03] Speaker 00:
Thank you.

[00:20:03] Speaker 00:
Thank you, Ms.

[00:20:04] Speaker 00:
Pann.

[00:20:08] Speaker 02:
Mr. Chu.

[00:20:09] Speaker 02:
Nice tie.

[00:20:11] Speaker 02:
Thank you very much, Your Honor.

[00:20:13] Speaker 02:
May it please the Court, Morgan Chu, on behalf of the Sloan Kettering Institute for Cancer Research.

[00:20:22] Speaker 02:
Good morning.

[00:20:24] Speaker 02:
There was an extensive factual record before the board.

[00:20:27] Speaker 01:
If we find that Kite waived any challenge to the PTAB's teaching away rationale, is it appropriate for us to deny the motion to strike his mood?

[00:20:39] Speaker 02:
It could be, depending on the reasoning of this court on the other issues.

[00:20:48] Speaker 02:
So there was this extensive factual record, 256 exhibits, seven depositions, seven declarations, and other materials.

[00:20:56] Speaker 02:
And the board made findings of fact.

[00:20:58] Speaker 04:
Can I ask you what is the evidence from the prior art about the worry of off-target binding when you had this sequence sticking out into the extracellular domain?

[00:21:16] Speaker 02:
First, there was a clash among the experts, Dr. Brocker for Sloan Kettering and two experts for Kite, a book by Girov and Dr. Abkin.

[00:21:30] Speaker 02:
What the board found and credited Dr. Brocker with was a well-reasoned opinion based on references.

[00:21:40] Speaker 02:
Here are the references.

[00:21:41] Speaker 04:
There's the Capon reference.

[00:21:43] Speaker 04:
That's the one that I think your friend said is the soul that

[00:21:46] Speaker 04:
so one that predates the priority date?

[00:21:49] Speaker 02:
He said that, but there were other references of great importance that were in the prior art.

[00:21:56] Speaker 02:
There is the Carrick reference and the Greenfield reference.

[00:22:01] Speaker 02:
And what those two references stood for is that it was well known in the art that my puppy would bind to naturally occurring ligands in perfectly healthy cells

[00:22:16] Speaker 02:
B7-1 and B7-2.

[00:22:19] Speaker 02:
And why is that important here?

[00:22:22] Speaker 02:
T cells themselves have that ligand, B7.

[00:22:26] Speaker 02:
So a T cell might bind to itself and, importantly, might bind to its friendly soldiers, its neighboring T cells, and kill those neighboring T cells.

[00:22:43] Speaker 02:
So that's a very, very important point here.

[00:22:46] Speaker 02:
There is the question about the other three references.

[00:22:49] Speaker 04:
So I think you said that the prior art that you just mentioned recognized the affinity of My Puppy for the B7-1 and B7-2.

[00:22:59] Speaker 04:
Did it connect that to a problem of killing the T cells, or is that little bit what?

[00:23:08] Speaker 04:
Was it Brocker?

[00:23:09] Speaker 04:
Is that his name?

[00:23:10] Speaker 04:
Yes, Dr. Brocker.

[00:23:11] Speaker 04:
Is that what Brocker fills in, that a person of skill in the art would have understood

[00:23:16] Speaker 04:
that if it affiliated with, if it bound to B71, B72, then that would, of course, be this obvious problem.

[00:23:23] Speaker 04:
And nobody said it specifically, but everybody knew it.

[00:23:26] Speaker 04:
Yes.

[00:23:26] Speaker 02:
Is that the idea?

[00:23:27] Speaker 02:
Basically, yes.

[00:23:29] Speaker 02:
But we also have the concern expressed in K-PON.

[00:23:33] Speaker 02:
And then Dr. Brocker is also looking to ART that comes after the filing date of the 190 patent.

[00:23:40] Speaker 02:
So let me address an argument that was first made in the reply brief.

[00:23:46] Speaker 02:
The other side points to a board decision.

[00:23:49] Speaker 02:
So it's not a Federal Circuit decision trying to argue you can't look to anything post the filing date.

[00:23:56] Speaker 02:
So I'd like to cite a Federal Circuit decision.

[00:23:59] Speaker 02:
It's Monarch Knitting.

[00:24:01] Speaker 02:
It's 139 F3, 877.

[00:24:05] Speaker 02:
And the relevant pages start at 884.

[00:24:11] Speaker 02:
That involves a discussion of a reference that is not prior art.

[00:24:16] Speaker 02:
And then this court goes on to discuss skepticism and whether that reference can be considered, and then specifically says that teaching away is a certain brand of skepticism.

[00:24:33] Speaker 02:
So it's giving credit to a reference that is not prior.

[00:24:37] Speaker 04:
Can I ask, is there something, one version of the narrative from the other side?

[00:24:43] Speaker 04:
And maybe I may be unfairly characterizing it.

[00:24:46] Speaker 04:
is that before the priority date, this problem wasn't really recognized.

[00:24:50] Speaker 04:
It came to be recognized after.

[00:24:53] Speaker 04:
What might have changed on that narrative to create a recognition that might not have previously existed?

[00:25:00] Speaker 04:
And if your answer is nothing, then I guess I'm curious.

[00:25:04] Speaker 02:
Yes.

[00:25:05] Speaker 02:
Yes.

[00:25:06] Speaker 02:
There was no trigger.

[00:25:07] Speaker 02:
There was no reason for persons of extraordinary skill in the art to say, by the way,

[00:25:15] Speaker 02:
We know that B71 and B72 naturally occur.

[00:25:19] Speaker 02:
They knew that.

[00:25:21] Speaker 02:
There was no reason, as established by the references I've already cited, that my puppy would bind to them.

[00:25:27] Speaker 02:
And that, of course, would create a problem.

[00:25:32] Speaker 02:
Can I ask you?

[00:25:33] Speaker 04:
Yes, please.

[00:25:33] Speaker 04:
I think this probably turns quite heavily on some specifics.

[00:25:38] Speaker 04:
So can you address the portion of

[00:25:43] Speaker 04:
his argument, as I understand it, that says there's something actually in Krauss, an experiment, that shows by the absence of certain sorts of results that this really would not have been a problem.

[00:25:56] Speaker 04:
And since Krauss is prior art, then there's something in the prior art that actually suggests that you shouldn't be worried about this.

[00:26:03] Speaker 02:
Right.

[00:26:04] Speaker 02:
So this is a reference to table two in Krauss.

[00:26:10] Speaker 02:
The board?

[00:26:11] Speaker 04:
Do you happen to have the page where I can look at that?

[00:26:14] Speaker 02:
Yes.

[00:26:17] Speaker 02:
It's at 361?

[00:26:21] Speaker 02:
Yeah.

[00:26:22] Speaker 02:
OK.

[00:26:23] Speaker 02:
The discussion of Table 2 actually starts on the prior page.

[00:26:28] Speaker 02:
But first, let me just give the big picture.

[00:26:30] Speaker 02:
Let's remember what Krauss is doing.

[00:26:33] Speaker 02:
It's not redirecting a T cell.

[00:26:36] Speaker 02:
to a new human-specified target.

[00:26:39] Speaker 02:
That's what Finney does.

[00:26:41] Speaker 02:
Krauss is leaving signal one alone.

[00:26:43] Speaker 02:
It's leaving the T cell to identify for itself its target.

[00:26:50] Speaker 02:
Krauss is now only looking at signal two and asking, how can we make signal two better?

[00:26:59] Speaker 02:
So the way it works for a normal T cell with no changes to it, signal one identifies the target.

[00:27:07] Speaker 02:
binds to the target.

[00:27:08] Speaker 02:
And then there's a separate second binding of signal two.

[00:27:13] Speaker 02:
In that circumstance and in Krauss, there is no safety concern.

[00:27:19] Speaker 02:
Because the safety concern for a chimeric TCR with a single binding event is that that receptor may bind to something it doesn't want to bind to.

[00:27:35] Speaker 02:
And that would be off target.

[00:27:37] Speaker 02:
binding.

[00:27:38] Speaker 02:
So Krauss is doing an experiment just saying, how do I, or what has occurred with respect to signal two?

[00:27:52] Speaker 02:
And it's an in-vitro experiment.

[00:27:56] Speaker 02:
So it's putting things in a dish.

[00:27:57] Speaker 02:
It's not inside the human body.

[00:28:00] Speaker 02:
And that's what she's looking at.

[00:28:02] Speaker 02:
She is not studying whether the my puppy

[00:28:08] Speaker 02:
motif in her signal two receptor is or is not binding.

[00:28:17] Speaker 02:
And in fact, the board directly addresses this at appendix 22 through 24.

[00:28:25] Speaker 02:
And here's what the board says.

[00:28:28] Speaker 02:
There is this clash on the kite side, bar giraffes and apkin, and Dr. Brocker on the other side.

[00:28:37] Speaker 02:
I think the key passage is at the second half of Appendix 23.

[00:28:45] Speaker 02:
And the board finds that Dr. Atkin admitted that endogenous CD28 is in this mix.

[00:28:59] Speaker 02:
That's at the bottom of that page.

[00:29:01] Speaker 02:
And then at the top of the following page, the board says,

[00:29:06] Speaker 02:
Dr. Apkin also admitted that this could cause the signaling.

[00:29:13] Speaker 02:
There's a quote to the effect of, it can, but it's not proven.

[00:29:18] Speaker 02:
That, I think, when an expert is trying to speak for one side or the other, amounts to an admission.

[00:29:24] Speaker 02:
So Krauss was not trying to measure the binding.

[00:29:30] Speaker 02:
It's all made up lawyer argument, and second,

[00:29:34] Speaker 02:
There are no controls in Krauss to measure the binding of my puppy.

[00:29:45] Speaker 02:
So I just want to give the overall context, because I think it's very helpful in support of the board's finding.

[00:29:54] Speaker 02:
Let's start with Finney.

[00:29:56] Speaker 02:
Finney has human beings that say, we're going to change the antigen target for this T cell.

[00:30:03] Speaker 02:
We're going to specify it.

[00:30:06] Speaker 02:
And we're going to change what signaling will occur for signal one.

[00:30:15] Speaker 02:
Second, what we're going to do is not have two separate binding events, but a single binding event.

[00:30:22] Speaker 02:
And that's what gives rise to the safety concern.

[00:30:26] Speaker 02:
Because if that receptor might bind to a friendly cell,

[00:30:32] Speaker 02:
or a cell that's not being targeted, it can be a real problem.

[00:30:37] Speaker 02:
In contrast, here's Krauss.

[00:30:39] Speaker 02:
Leave alone signal number one.

[00:30:41] Speaker 02:
We're going to rely on the T cell's natural ability to identify a specific antigen target.

[00:30:49] Speaker 02:
And number two, how do we improve signal number two only?

[00:30:54] Speaker 02:
And therefore, there's no safety concern.

[00:30:56] Speaker 02:
Because the safety is provided by signal one.

[00:30:59] Speaker 02:
You have to have both to trigger

[00:31:02] Speaker 02:
the robust response of the T cells.

[00:31:06] Speaker 02:
So it doesn't really matter whether the argument is start with Krauss, start with Finney, combine the two.

[00:31:14] Speaker 02:
But the board specifically found that there wasn't a motivation to start with Krauss.

[00:31:20] Speaker 02:
And in addition, found there was a teaching away, no matter how you mixed and matched, rationales one, two, and three.

[00:31:27] Speaker 02:
And here's the problem.

[00:31:29] Speaker 02:
Known in the art.

[00:31:30] Speaker 02:
as testified to by Dr. Brocker, supported by key references, boy, you would stay away from putting my puppy into a Finney-like T-cell, because that could bind to B71, B72, naturally occurring ligands.

[00:31:53] Speaker 02:
It could bind to itself.

[00:31:55] Speaker 02:
It could bind to its fellow soldiers that look exactly like it.

[00:31:59] Speaker 02:
and kill those T cells, as well as other cells not intended to be targets.

[00:32:06] Speaker 02:
Those were factual findings that were well-supported, if there were no other questions.

[00:32:15] Speaker 02:
Thank you, Mr. Chief.

[00:32:16] Speaker 02:
Thank you very much.

[00:32:19] Speaker 01:
Well, Mr. Dean, you used up your time, and you knew you were using it up.

[00:32:24] Speaker 01:
I'll give you one minute.

[00:32:26] Speaker 01:
Thank you very much, Your Honor.

[00:32:28] Speaker 00:
When that red light goes on, stop.

[00:32:30] Speaker 00:
Just very quickly, your honor, to show that the board did not understand the experiment in Kraus on appendix 24, the board says that there is endogenous CD28 that could bind to B7 on neighboring T cells and concludes it is impossible to discern from Kraus whether the co-stimulatory signaling is from endogenous CD28 alone or both endogenous CD28 and the MIPI motif from the construct.

[00:32:57] Speaker 00:
What they're suggesting there is if she found co-stimulatory signaling, you wouldn't be able to tell what the binding was that caused it.

[00:33:06] Speaker 00:
That's a misunderstanding of the data.

[00:33:08] Speaker 00:
And at appendix 767 in the expert declaration, it's reflected there that the 3G6 CD28 and 3G6 CD28TR, which the CD828TR was a control that could not have stimulated co-stimulatory signaling, had the same amount of IL-2R expression

[00:33:27] Speaker 00:
as the CD28, so there was no costimulatory signaling that she found.

[00:33:31] Speaker 00:
Thank you.

[00:33:32] Speaker 00:
The matter will stand submitted.