[00:00:00] Speaker 01:
I'll turn to Judge Still for a motion.

[00:00:04] Speaker 01:
I move for the admission of Michael J. Bulanco, who is a member of the bar and is in good standing with the highest court of Virginia.

[00:00:13] Speaker 01:
I have knowledge of his credentials and am satisfied that he possesses the necessary qualifications.

[00:00:20] Speaker 01:
I'm particularly pleased to move for Mike's admission today because he's my law clerk.

[00:00:26] Speaker 01:
In fact, he's one of my first law clerks.

[00:00:29] Speaker 01:
He has consistently demonstrated excellence in his legal work and dedication and passion in his legal work, as well as in his culinary skills in preparing spicy desserts for the annual La Posada celebration, not to mention his wonderful stagecraft skills.

[00:00:49] Speaker 01:
He has also brought much joy to our chambers by giving us our first grand clerk, Colin Belanco, who was born

[00:00:58] Speaker 01:
a year ago on Valentine's Day.

[00:01:00] Speaker 01:
Mike is a kind, hardworking, funny, and dedicated attorney, and I'm sure he will uphold the values of this court.

[00:01:10] Speaker 02:
We're delighted to grant your motion, Judge Still.

[00:01:14] Speaker 04:
Do you swallowingly swear that you will comport yourself as an attorney and counselor of this court?

[00:01:23] Speaker 04:
according to law, and that he will support the Constitution of the United States of America.

[00:01:28] Speaker 04:
I do.

[00:01:30] Speaker 02:
Congratulations.

[00:01:31] Speaker 04:
Congratulations.

[00:01:33] Speaker 02:
Thank you.

[00:01:33] Speaker 02:
The first case for argument this morning is 15-2095, NatQuest versus Lee.

[00:01:40] Speaker 02:
Mr. Heinrich, whenever you're ready.

[00:01:44] Speaker 04:
May it please the court, Alan Heinrich, on behalf of Appellant NatQuest.

[00:01:50] Speaker 04:
So this is an appeal from a section 145 action

[00:01:54] Speaker 04:
in which the district court granted summary judgment of obviousness to the PTO.

[00:01:59] Speaker 04:
In doing so, the district court resolved material factual disputes against Nantquest in violation of Rule 56.

[00:02:07] Speaker 04:
The district court rejected the opinions of Nantquest expert, Dr. Miller, without explanation.

[00:02:14] Speaker 04:
And the district court had a wholly conclusory analysis of obviousness.

[00:02:20] Speaker 04:
Now, the claims at issue here, they cover

[00:02:23] Speaker 03:
Can I ask you a question about the claims?

[00:02:25] Speaker 03:
Because it may not make any difference, but the claims as quoted in the district court opinion 2026 and 2027 seem to be different than as set forth in the appendix.

[00:02:40] Speaker 03:
What's the explanation for that?

[00:02:43] Speaker 04:
Frankly, Your Honor, I did not notice that.

[00:02:47] Speaker 04:
I believe that the recitation of

[00:02:53] Speaker 04:
Claim 20, for example, on page JA5 of the district court's order.

[00:03:01] Speaker 04:
I believe that's a correct recitation of the claims at issue here.

[00:03:08] Speaker 03:
Well, there's the reference, among other things, to the cell line, which doesn't appear in the claims as set forth in the appendix.

[00:03:17] Speaker 03:
But if you don't know the answer to that, please.

[00:03:22] Speaker 04:
The claims here, they claim the use of this cell line, NK92, in the in vivo treatment of a cancer.

[00:03:33] Speaker 04:
The NK92 cell line is actually a cancerous cell line of natural killer cells harvested from a particular patient who succumbed to the cancer.

[00:03:45] Speaker 04:
So what the claim is claiming here is the sort of paradoxical use of this cancerous cell line

[00:03:51] Speaker 04:
in a method of treating cancer in others.

[00:03:54] Speaker 03:
So basically your position is that the Miller Declaration creates a genunation material fact.

[00:04:02] Speaker 04:
The Miller Declaration as well as the 32 additional exhibits that were cited to the district court in this proceeding.

[00:04:12] Speaker 04:
And in fact, there are statements in the prior art itself that raise that.

[00:04:18] Speaker 03:
It strikes me that the Miller Declaration, to a significant extent, reads like illegal brief.

[00:04:24] Speaker 03:
And everyone knows that lawyers help witnesses write declarations.

[00:04:31] Speaker 03:
What exactly is a factual matter?

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Is there in the Miller Declaration that should cause us to say that there needs to be a trial here?

[00:04:44] Speaker 03:
I look at the Miller Declaration, one of the things that you rely on

[00:04:48] Speaker 03:
is the notion that inserting this NK92 in vivo into a patient might cause disease.

[00:05:02] Speaker 03:
And yet, I see the Miller declaration as resting on an incorrect claim construction in the sense that Miller says that the claims require unmodified cell lines.

[00:05:15] Speaker 03:
But that's not correct, is it?

[00:05:17] Speaker 04:
So we're not relying on that here, Your Honor.

[00:05:22] Speaker 04:
To answer your question, there are two sets of material facts that I want to focus on here.

[00:05:30] Speaker 04:
One is whether in vitro data, such as the in vitro data on NK92 in the Gang reference, would have given a person of ordinary skill a reasonable expectation of success that NK92

[00:05:47] Speaker 04:
could be used in an in vivo method of treating a cancer.

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And we're talking about an allogeneic therapy here.

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In other words, a therapy where we're using a cell line from a donor in a foreign host.

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And there are many problems with taking in vitro data and making assumptions about in vivo efficacy

[00:06:14] Speaker 04:
particularly in the circumstances we're talking about here with an allogeneic therapy.

[00:06:20] Speaker 04:
Dr. Miller described a number of these difficulties.

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One is there's a risk of what's called graft versus host disease, namely that the NK92 cell line will attack the patient's own cells upon the administration of this therapy.

[00:06:39] Speaker 04:
There's another risk that the host cells will attack the NK92 cells.

[00:06:45] Speaker 04:
To get into the weeds a little bit on a very specific factual point that Dr. Miller raised, NK cells, natural killer cells, at the time were known to be inhibited by MHC class I. There was a risk, and this was an important part of their function, it was believed, there was a risk that was recognized that if you take a foreign NK

[00:07:15] Speaker 04:
cell line, put it into another host, that as a result of the mismatch, the MHC mismatch between the host and the donor, that the NK cells would not, it was thought, respond to inhibitory signals, and as a result could indiscriminately kill the host cells.

[00:07:37] Speaker 03:
This would be an example of... These risks may have existed.

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The question is whether they are sufficient

[00:07:45] Speaker 03:
to defeat an obviousness finding.

[00:07:48] Speaker 03:
And you certainly agree that the NK92 cell was in vitro found to be effective.

[00:07:57] Speaker 03:
And you certainly have to agree that other NK cells had been found effective in vivo, right?

[00:08:05] Speaker 04:
So certainly Gong shows that the NK92 cell line is cytotoxic against a couple of

[00:08:14] Speaker 04:
cancerous cell lines.

[00:08:18] Speaker 03:
However... And Vunovič, or how are words pronounced?

[00:08:22] Speaker 03:
Vunovič actually says that you can't... it's very difficult to predict... I did find that a particular NK cell line, not NK92, was effective in treating cancer in vivo, right?

[00:08:37] Speaker 04:
No, no.

[00:08:38] Speaker 04:
The 955 application is the first

[00:08:42] Speaker 04:
first disclosure of the use of NK cells in any allogeneic therapy.

[00:08:50] Speaker 03:
And more than that... I didn't understand that to be true.

[00:08:53] Speaker 03:
I thought it was clear that, I mean, that Vonovich had two cell lines in Avivo, two NK cell lines in Avivo, one of which worked and one of which didn't.

[00:09:07] Speaker 04:
No, Your Honor.

[00:09:07] Speaker 04:
This is the first use of an NK cell line

[00:09:12] Speaker 04:
in vivo in an allogeneic therapy in the prior art.

[00:09:17] Speaker 04:
And in fact, this is the first use of NK cells solely in in vivo therapy.

[00:09:25] Speaker 03:
There was lack of... Look at appendix 9 to 61 on the right hand side in the last paragraph.

[00:09:36] Speaker 03:
The significant in vivo antitumor activity in

[00:09:40] Speaker 03:
in K, but not in a in K cells, blah blah blah.

[00:09:46] Speaker 03:
I mean, what am I missing?

[00:09:47] Speaker 04:
Let me just

[00:10:32] Speaker 04:
So I believe, Your Honor, we're talking about here lack cell therapy.

[00:10:43] Speaker 03:
I didn't read it that way.

[00:10:46] Speaker 03:
And it doesn't say that.

[00:11:02] Speaker 04:
Well, so it's certainly... Okay, so this is... I apologize.

[00:11:07] Speaker 04:
This is not an allogeneic therapy.

[00:11:10] Speaker 04:
We're talking about the activated NK cells of the patient, and it's not NK92.

[00:11:18] Speaker 04:
Well, it's certainly not NK92.

[00:11:21] Speaker 04:
And it's also not an allogeneic therapy here, where you're taking a foreign donor's cells and using them

[00:11:31] Speaker 04:
in a patient.

[00:11:33] Speaker 01:
You're saying this is their own NK cells.

[00:11:35] Speaker 01:
This is the patient's own NK cells.

[00:11:37] Speaker 01:
It's not the situation where you're taking them from elsewhere and putting them into the patient.

[00:11:42] Speaker 01:
Do I have that correct?

[00:11:43] Speaker 04:
Correct.

[00:11:47] Speaker 04:
So I want to get to a second point of disputed fact here, which is that according to the district court, and the premise of the district court's obviousness analysis is that the

[00:12:01] Speaker 04:
NK cells, NK92, and tall 104 cells were, quote, functionally similar.

[00:12:10] Speaker 04:
The district court just was making that.

[00:12:13] Speaker 04:
That was his own determination.

[00:12:15] Speaker 04:
And it appears that the only basis for that determination was that both NK92 and tall 104 were broadly cytotoxic in in vitro assays.

[00:12:29] Speaker 04:
The district court was looking at this at sort of a 50,000 foot level.

[00:12:34] Speaker 04:
Of course, the analysis here has to be from the perspective of a person skilled in the art.

[00:12:41] Speaker 04:
And a person skilled in the art would be looking at the very important details that Dr. Miller lays out in his declaration.

[00:12:49] Speaker 04:
Dr. Miller discusses the differences between NK92 and tall 104 with respect to antigen, surface antigen profile.

[00:12:59] Speaker 04:
target specificity, signaling pathways.

[00:13:03] Speaker 04:
And Dr. Miller states that those differences would have led a person of skill in the art to expect different immune responses and different cytotoxic functionality.

[00:13:16] Speaker 03:
So the question- He doesn't say that someone of skill in the art would have thought it wouldn't work, right?

[00:13:25] Speaker 04:
He says that a person of skill in the art would have had

[00:13:29] Speaker 04:
No basis to have a reasonable expectation of success.

[00:13:33] Speaker 03:
The answer to my question is yes.

[00:13:34] Speaker 03:
He doesn't say that someone's skill in the art would conclude that it wouldn't work.

[00:13:39] Speaker 04:
Did he would conclude that it wouldn't work?

[00:13:42] Speaker 04:
No.

[00:13:42] Speaker 04:
But he certainly says that a person of skill in the art would not have had a reasonable expectation of success, that it would work.

[00:13:51] Speaker 04:
And that's really the test here.

[00:13:54] Speaker 04:
So there are these two important constellations of disputed issues of fact.

[00:13:59] Speaker 04:
whether the Gong in vitro data was predictive of in vivo results, and whether there were differences between TAL 104 and NK92 that a person of skill would have recognized.

[00:14:16] Speaker 04:
The district court simply had a conclusion that this broad cytotoxic effect

[00:14:27] Speaker 04:
renders this combination obvious.

[00:14:30] Speaker 04:
The district court simply dismissed without explanation Dr. Miller's testimony.

[00:14:35] Speaker 03:
The basic question is, how confident do you have to be that it's going to work?

[00:14:39] Speaker 03:
I mean, it doesn't have to get to the level of certainty, right?

[00:14:44] Speaker 04:
Absolutely not.

[00:14:45] Speaker 04:
But there has to be a reasonable expectation of success.

[00:14:49] Speaker 04:
And there are simply disputed facts here that that's the case.

[00:14:53] Speaker 04:
And then finally,

[00:14:54] Speaker 04:
the district court, in assessing this question of reasonable expectation of success, applied an improper claim construction.

[00:15:02] Speaker 04:
At JA 22, the district court states that a person of skill in New York would have had a reasonable expectation of success that NK 92 would lice one or more cancer cells in vivo.

[00:15:19] Speaker 04:
But that's not what the claim requires.

[00:15:21] Speaker 04:
The claim recites a method of treating a cancer.

[00:15:25] Speaker 04:
That preamble is limiting.

[00:15:27] Speaker 01:
That wasn't his claim construction, right?

[00:15:30] Speaker 01:
He had a different claim construction, but your point is that later when he actually analyzed it, he used the incorrect claim construction.

[00:15:37] Speaker 04:
Well, so his claim construction that he recited earlier in his opinion was also incorrect.

[00:15:45] Speaker 04:
But it doesn't make any difference, does it?

[00:15:46] Speaker 04:
I mean, it's summary judgment.

[00:15:47] Speaker 04:
We're not talking about findings of fact.

[00:15:50] Speaker 04:
It makes a big difference.

[00:15:52] Speaker 04:
There's a big difference between

[00:15:54] Speaker 03:
We're reviewing at de novo, what difference does it make?

[00:15:57] Speaker 04:
Well, on his finding about whether a person... No findings, it's summary judgment.

[00:16:02] Speaker 03:
Well, his conclusion, that a person of skill in the art... Well, we're reviewing at de novo, what difference does it make that he might have said something wrong?

[00:16:10] Speaker 03:
Well, because it goes to his analysis, your honor.

[00:16:13] Speaker 03:
No, but you're not answering my question.

[00:16:14] Speaker 04:
If it's de novo review, what difference does it make?

[00:16:17] Speaker 04:
Well, it goes to whether his analysis should be affirmed or not.

[00:16:22] Speaker 04:
The fact is the claim doesn't require just killing one cancer cell.

[00:16:25] Speaker 03:
But that's not the question on summary judgment is whether the district court's analysis should be affirmed.

[00:16:29] Speaker 03:
The question is whether the result that the district court reached on de novo review should be sustained.

[00:16:34] Speaker 03:
So I agree with that, Your Honor.

[00:16:36] Speaker 04:
But what the district court concluded here was simply that a person of ordinary skill would have expected that NK92 could kill just one or more cancer cells in vivo.

[00:16:48] Speaker 04:
That's simply an incorrect

[00:16:50] Speaker 04:
claim construction.

[00:16:51] Speaker 04:
The preamble sets forth the essence of this invention.

[00:16:55] Speaker 04:
So I'm going to reserve the rest of my time.

[00:16:58] Speaker 02:
You've already used all of your rebuttal, but we'll restore two minutes on rebuttal.

[00:17:02] Speaker 04:
Thank you.

[00:17:19] Speaker 00:
Good morning, your honors.

[00:17:20] Speaker 00:
May it please the court.

[00:17:22] Speaker 00:
We are here today because Dr. Klingman filed his patent application more than a year after he published his work on NK92 cells with Dr. Gong.

[00:17:33] Speaker 00:
The Gong publication, combined with Dr. Santoli's work in TL104 cells, render the claims on appeal unpatentable.

[00:17:41] Speaker 00:
To this day, there are only two types of cells that are known

[00:17:47] Speaker 00:
to recognize and lyse cancer cells, NK cells and T cells.

[00:17:53] Speaker 00:
Therefore, anybody looking to develop an adoptive immunotherapy to develop a cell line to administer to cancer patients to recognize and lyse cancer cells would have looked for a cell line derived from either T cells or NK cells.

[00:18:13] Speaker 00:
Dr. Santoli had shown that the TL104 cell line, both in vivo and in vitro, in vivo in mice and in dogs, had the ability to recognize and lyse cancer cells and actually successfully treat cancers in mice and dogs.

[00:18:37] Speaker 00:
As far as in vivo use of NK92 cells,

[00:18:44] Speaker 00:
No, that hadn't been shown prior to filing.

[00:18:46] Speaker 00:
What had been shown prior to filing is that NK92 cells work in vitro and that they work ex vivo.

[00:18:55] Speaker 00:
Dr. Klingman also published a prior art abstract showing that NK92 cells work in ex vivo purging of cancer cells taken from the blood of a cancer patient.

[00:19:08] Speaker 02:
Well, why don't you address specifically your friend's point about dislodging

[00:19:13] Speaker 02:
or the incorrect conclusions here on summary judgment given Dr. Miller's report.

[00:19:19] Speaker 02:
Why isn't, specifically, why isn't Dr. Miller's report sufficient to at least raise a question of fact that would obviate summary judgment?

[00:19:28] Speaker 00:
It's not sufficient, first of all, because the points raised are not in dispute.

[00:19:34] Speaker 00:
And additionally, they're not material.

[00:19:38] Speaker 00:
All of the points that Dr. Miller raises

[00:19:42] Speaker 00:
For example, in the reasonable expectation of success about graft versus host disease, those are all related to whether something will be successful in the clinical setting, safe and effective in treating a cancer.

[00:20:00] Speaker 00:
The claims here state that treating a cancer is merely the killing, the recognition and lysis of cancer cells.

[00:20:07] Speaker 00:
The claims do not require that the

[00:20:12] Speaker 00:
cancer that we see a clinical result.

[00:20:16] Speaker 03:
And so... But doesn't his affidavit to some extent suggest that the efficacy in vitro can't be translated into in vivo efficacy?

[00:20:33] Speaker 00:
We don't dispute that.

[00:20:34] Speaker 00:
We don't dispute that everything that works in vitro works in vivo.

[00:20:39] Speaker 03:
And the law doesn't require it.

[00:20:41] Speaker 00:
Right.

[00:20:42] Speaker 00:
We're not saying that if it works in vitro, it will work in vivo, but the law doesn't require that either.

[00:20:49] Speaker 00:
This court has repeatedly said that that isn't required, and the PTO regularly will issue patents on in vivo methods based in certain situations on in vitro use.

[00:21:04] Speaker 00:
But in this case,

[00:21:06] Speaker 00:
If you look, for example, to the Yan publication, she said, oh, you know, Dr. Santoli showed in vitro and in vivo that these TL104 cells can recognize in lice cancer cells.

[00:21:20] Speaker 00:
So I'm going to do some head-to-head comparison, and NK92 cells work in vitro, so I'm going to do head-to-head comparisons to see, you know, which one would be really good in an adoptive immunotherapy to test whether NK92 cells will be similarly

[00:21:36] Speaker 00:
useful and adaptive immunotherapy.

[00:21:38] Speaker 00:
She goes on to say, well, this indicates that it would be, of course, we need to test this in vivo.

[00:21:46] Speaker 00:
But we have indication.

[00:21:48] Speaker 00:
This is a contemporaneous study and publication by someone of ordinary skill in the art who had a reasonable belief and reasonable expectation that NK92 cells would perform in vivo

[00:22:06] Speaker 00:
the way that TL104 cells had performed.

[00:22:12] Speaker 00:
And this court's case law doesn't require the prior art to have actually tested to make sure that there's in vivo activity.

[00:22:22] Speaker 00:
Essentially, what Dr. Miller is saying is that in order to render the claimed invention obvious, the prior art would have to anticipate the claimed invention, that

[00:22:36] Speaker 00:
The prior art would need to show, in his own words, that the use of NK92 cells were safe and effective if used in humans, or would be safe and effective in treating cancer in several, and this is his word, robust animal models.

[00:22:55] Speaker 00:
That's more than Dr. Klingman submitted to the USPTO in order to obtain his patent.

[00:23:03] Speaker 00:
what he's asking for, this novelty plus, that's not the standard, that's not the legal standard by which this court or the USPTO judges whether there's a reasonable expectation of success.

[00:23:18] Speaker 03:
Are you suggesting that the same test exists for patentability, for getting a patent and for obviousness?

[00:23:25] Speaker 03:
In other words, that if based on this accumulation of prior art showing

[00:23:30] Speaker 03:
in vitro efficacy, the other efficacy in vivo of these other L cells or whatever they are.

[00:23:45] Speaker 03:
If you could get a patent based on that, that would render the claims obvious?

[00:23:53] Speaker 00:
No, Your Honor, that's not what I'm suggesting.

[00:23:55] Speaker 00:
What I'm saying is that the prior art in an obviousness rejection

[00:24:00] Speaker 00:
shouldn't have to show more than the applicant is showing to get his patent.

[00:24:05] Speaker 03:
It sounds as though it's the same thing that I'm saying, that if you could get a patent based on this, for these claims, then that would render it obvious.

[00:24:17] Speaker 03:
Never mind, if you don't understand what I'm saying.

[00:24:19] Speaker 00:
I think that's what Dr. Miller is trying to say.

[00:24:22] Speaker 00:
In some ways, I think Dr. Miller is trying to say this.

[00:24:30] Speaker 00:
maybe we are cross-communicating.

[00:24:34] Speaker 00:
The simple point is that those sort of factual disputes about whether there would be graft versus host disease or host versus graft disease or whether you would see regression of tumor cell growth or successful cancer treatment

[00:24:56] Speaker 00:
He's arguing that those things are required to show reasonable expectation of success for the prior art to render these claims obvious.

[00:25:05] Speaker 00:
So what he's asking for is that the prior art actually tested the claimed invention and not only tested the claimed invention, that would be anticipation, but tested the claimed invention and found positive results.

[00:25:17] Speaker 00:
So he's really asking for novelty plus.

[00:25:20] Speaker 00:
And so those things that he says are material

[00:25:24] Speaker 00:
really aren't material to the question before the court.

[00:25:27] Speaker 00:
And the court did find that there were no material at A-12, there were no material factual disputes that would preclude summary judgment.

[00:25:37] Speaker 00:
With respect to the motivation to combine and the other differences... Isn't teaching away a question of fact?

[00:25:44] Speaker 01:
And doesn't Miller take a position that there's teaching away?

[00:25:48] Speaker 01:
How do you respond to that?

[00:25:52] Speaker 00:
I want to make sure that we're talking about the same thing.

[00:25:54] Speaker 00:
So Dr. Miller appears to say, oh, look, there are all these differences between T cells and NK cells and TL cells and NK-104 cells and NK-92 cells.

[00:26:07] Speaker 00:
Oh, they have different cell surface receptors.

[00:26:09] Speaker 00:
One uses MHC.

[00:26:11] Speaker 00:
The other one doesn't.

[00:26:13] Speaker 03:
I thought the teaching away argument was based on the notion that it might cause disease in the patient and that he's abandoned that argument this morning.

[00:26:22] Speaker 00:
Okay, is that also your question?

[00:26:24] Speaker 01:
Well, everything he has in his declaration, there's quite a bit in there about the differences and also about how one of her near-nearly-skilling art might be reluctant to do this because of the reasons of the graft disease and whatnot.

[00:26:40] Speaker 01:
Again, and because it's a question of fact, that would be a concern.

[00:26:44] Speaker 01:
I mean, you've generally talked about Mr. Miller's declaration and how it doesn't

[00:26:49] Speaker 01:
create a general issue of material fact because it's not material, but you have a specific response on this teaching away point.

[00:26:59] Speaker 00:
If we're talking about the host versus graft disease and graft versus host disease allegedly causing a teaching away, there's no dispute that those things might happen.

[00:27:14] Speaker 00:
So there's not an issue there where in agreement those things might happen.

[00:27:19] Speaker 00:
The issue is whether those things are material to the question before the court.

[00:27:23] Speaker 01:
Do you think somebody would give it a try anyway, given the teachings in his own prior reference?

[00:27:30] Speaker 00:
Right, because there are only these two types of cells that recognize and analyze cancer cells.

[00:27:35] Speaker 00:
It was true then, it's true now.

[00:27:37] Speaker 00:
And because we've already seen T cell line, the TL104 cells that worked in vivo and ex vivo, and we already saw

[00:27:47] Speaker 00:
that the NK92 cells work in vitro and ex vivo.

[00:27:51] Speaker 00:
The next logical step, and this was recognized by the Yen reference, the next logical step is go ahead and test it in an animal and see, does it really work?

[00:28:00] Speaker 00:
And that would be the next step is to test it, and that's anticipation.

[00:28:06] Speaker 00:
Obviously, Yen had the idea that this was the way to go.

[00:28:11] Speaker 00:
And I would assert that in the Clingmans

[00:28:15] Speaker 00:
abstract that he published with the ex vivo purging studies, that's where he was going.

[00:28:21] Speaker 00:
Because these things do proceed, the testing proceeds along a sort of normal path.

[00:28:27] Speaker 00:
You go from in vitro with cancer cell lines to in vitro with primary tumor cells to ex vivo to in vivo in animals and then in vivo in humans.

[00:28:42] Speaker 00:
There's no dispute that that's how these things happen.

[00:28:46] Speaker 00:
And all those facts that Dr. Miller says lead to a teaching away or no reasonable expectation of success, those things all relate to what we don't know for sure, with 100% accuracy, that if you put these in humans, these bad things aren't going to happen.

[00:29:05] Speaker 01:
How do you distinguish the Ganga-Haram case, I don't know if I'm saying that correctly, where we reverse the board's obviousness finding because the prior art cautioned about predicting that something that was used

[00:29:16] Speaker 01:
in vivo could be used in vitro.

[00:29:19] Speaker 01:
Or I think I've got them reversed.

[00:29:23] Speaker 00:
What I would say is the facts in that case are different than the facts here.

[00:29:28] Speaker 00:
The facts here are that NK cells, not a cell line, but in the LAC studies that were conducted in the 1980s had shown that NK cells do recognize in N life tumor cells, and successfully so with renal tumors and melanoma tumors,

[00:29:47] Speaker 00:
that they do that in vivo.

[00:29:49] Speaker 00:
And so here, there's much more evidence that would lead someone of ordinary skill of the art to believe.

[00:29:57] Speaker 01:
You're saying the host's own cells.

[00:29:59] Speaker 01:
We know that the host's own cells do that.

[00:30:02] Speaker 01:
Is that what you're saying?

[00:30:05] Speaker 01:
Like the person's NK cells in vivo.

[00:30:07] Speaker 01:
I thought that it was established that prior to this invention, there were no foreign NK cells that were inputting cells.

[00:30:14] Speaker 00:
Correct, Your Honor, and thank you for making that clear.

[00:30:17] Speaker 00:
if I hadn't done so.

[00:30:19] Speaker 00:
Yes, these are the patient's own NK cells.

[00:30:26] Speaker 00:
These have been shown by Dr. Rosenberg and others that if you activate those NK cells, just like Vujatovic had found, that those NK cells would then go out and recognize and lyse tumor cells.

[00:30:43] Speaker 00:
You could do that either in vivo where you just give interleukin-2 to activate the cells to the patient and you cause the NK cells to respond this way.

[00:30:53] Speaker 00:
Or you could take the patient's blood cells out and then add the IL-2 that's called ex vivo and then put it back into the patient.

[00:31:02] Speaker 00:
And now those cells would go on to recognize and lyse cancer cells.

[00:31:09] Speaker 00:
And that that was successful in treating renal carcinoma

[00:31:14] Speaker 00:
And melanoma, it was found, however, that the IL-2, which the claims on appeal permit as well, if you do a lot of that, the IL-2 will be cytotoxic to cells, but the fact remains that NK cells in vivo will recognize and lyse tumor cells.

[00:31:41] Speaker 00:
Again, there's all of this evidence about what T cells and NK cells, and TL104 cells and NK92 cells, about their ability to recognize and lyse cancer cells.

[00:31:55] Speaker 00:
And all of the other differences between how they recognize and lyse cancer cells don't matter in face of the fact that they do recognize and lyse cancer cells.

[00:32:10] Speaker 00:
The fact that they may do it through different mechanisms, it doesn't change the fact that they have this proven ability.

[00:32:17] Speaker 00:
And that proven ability would recommend to a person with ordinary skill and art, let's go try this in vivo.

[00:32:24] Speaker 00:
And that's a reasonable expectation of success.

[00:32:27] Speaker 00:
An unreasonable expectation of success is, hey, you've got to test it.

[00:32:32] Speaker 00:
Not only do you have to test it, you have to show it safe and effective, and that nothing is going to go wrong.

[00:32:37] Speaker 00:
That's not the right standard.

[00:32:39] Speaker 00:
And so Dr. Miller's ultimate opinion on the reasonable expectation of success and the facts he brings forward to support that just do not make a material dispute.

[00:32:53] Speaker 00:
And the same is true for all of the differences between the cells that he discusses that were also discussed before the board and the examiner and rejected by the board and the examiner.

[00:33:07] Speaker 00:
Thank you.

[00:33:08] Speaker 00:
Thank you.

[00:33:14] Speaker 04:
So just three points.

[00:33:16] Speaker 03:
I just want to be clear about the significance of your answer to my earlier question.

[00:33:20] Speaker 03:
My understanding was that you were saying we're not relying on the teaching away because of the risk of spreading disease.

[00:33:28] Speaker 04:
So I thought I was answering a different question, which was whether the claim

[00:33:35] Speaker 04:
encompasses modified and K-92.

[00:33:40] Speaker 03:
So your witness said it required that they be unmodified.

[00:33:45] Speaker 03:
That's not correct, right?

[00:33:48] Speaker 04:
In terms of what the claim requires, that's correct.

[00:33:50] Speaker 04:
But we're not abandoning teaching away.

[00:33:51] Speaker 04:
What he said is not correct, right?

[00:33:54] Speaker 04:
I agree with that, Your Honor.

[00:33:56] Speaker 03:
So if he made a wrong claim construction in that respect, then why should we pay any attention to what he said about the risk of spreading disease?

[00:34:05] Speaker 04:
Well, because it goes to the difference between these two cell lines.

[00:34:10] Speaker 04:
So example two of the Santoli patent shows that the unmodified tall 104 spread disease when engrafted in mice.

[00:34:24] Speaker 03:
I don't think you're answering my question.

[00:34:25] Speaker 03:
My question is, he said there's a risk of spreading disease because you have unmodified cells.

[00:34:31] Speaker 03:
He's wrong about the claim construction.

[00:34:33] Speaker 03:
So why should we pay attention to that?

[00:34:36] Speaker 04:
Well, because it's another example of a difference between these two cell lines.

[00:34:40] Speaker 04:
I don't understand what you're saying.

[00:34:42] Speaker 03:
I don't think you're addressing my question.

[00:34:44] Speaker 03:
If the risk of spreading disease only exists with respect to unmodified cell lines, in other words, not treated by radiation or whatever,

[00:34:57] Speaker 03:
and the claims don't require unmodified cell lines, why do we worry about the spreading of disease?

[00:35:03] Speaker 04:
Well, so the district court said these were functionally similar cell lines.

[00:35:09] Speaker 04:
There are a number of differences between them.

[00:35:10] Speaker 03:
You don't seem to be addressing my question.

[00:35:12] Speaker 03:
My question is, why should we pay any attention to the risk of spreading disease if he's got the wrong claim construction?

[00:35:19] Speaker 03:
And there's no question that you can irradiate the cells and prevent the spreading of disease.

[00:35:24] Speaker 04:
I agree with your honor that that's not relevant for the claim language.

[00:35:29] Speaker 04:
But it is relevant still scientifically, because it speaks to another difference between these cell lines.

[00:35:38] Speaker 04:
Now, we're not abandoning a teaching away argument.

[00:35:42] Speaker 04:
Just to give you one example, Santoli herself teaches away from the notion that in vitro results are a reliable indicator

[00:35:54] Speaker 04:
of in vivo results.

[00:35:56] Speaker 04:
Her own data shows this, and this is at JA 220.

[00:36:02] Speaker 04:
Counsel's suggestion that, well, as long as you have in vitro results, then one is we'll just try in vivo, and that's enough to render a claim such as this to a method of treatment in vivo obvious.

[00:36:18] Speaker 04:
Well, that's a very sweeping proposition, and the in-ray

[00:36:24] Speaker 04:
Ganderham case that was referenced earlier, the Henry Carroll case are both contrary to that.

[00:36:32] Speaker 04:
This is a question that turns on facts, whether on the facts of this case, the Gong in vitro results would have given a person of ordinary skill a reasonable expectation that NK92 could successfully be used in an in vivo therapy

[00:36:51] Speaker 04:
There are just many disputed facts concerning that, including the very big differences between these two cell lines that the district court ignored.

[00:37:02] Speaker 02:
Thank you.

[00:37:03] Speaker 02:
Thank you.

[00:37:03] Speaker 02:
Thank you.

[00:37:03] Speaker 02:
We thank both sides, and the case is submitted.