[00:00:00] Speaker 04:
16-11-06

[00:00:36] Speaker 04:
This term is a lesson.

[00:00:39] Speaker 01:
May I proceed, Your Honor?

[00:00:41] Speaker 01:
You may.

[00:00:42] Speaker 01:
May it please the court, Steve Zaleson for Helen Duke University.

[00:00:48] Speaker 01:
With the court's permission, given limited time, I'm going to focus my argument today on the two dependent claims that are developed in the briefing, claims nine and 19.

[00:00:59] Speaker 01:
Time permitting, I may make some comments about claim one as well.

[00:01:03] Speaker 01:
I'd like to begin with claim 19.

[00:01:05] Speaker 01:
which, as the court knows, has a rather unusual procedural history.

[00:01:10] Speaker 01:
This is a claim on the prophylactic use of an immunosuppressant to prevent the occurrence of an immune reaction to this enzyme that's the subject of this patent.

[00:01:23] Speaker 04:
Well, it's interesting that you're leading off with claim 19.

[00:01:27] Speaker 04:
And I understand why, and we'll let you get to that eventually.

[00:01:35] Speaker 04:
Claim 9 goes back to claim 1.

[00:01:41] Speaker 04:
And claim 1, which is certainly part of your appeal, deals with treating Pompey's disease with an enzyme obtained from Cho cells.

[00:01:54] Speaker 04:
That's correct, John.

[00:01:56] Speaker 04:
And why isn't this all in Van Brie?

[00:02:02] Speaker 01:
Van Brie, the 410 Van Brie patent,

[00:02:06] Speaker 01:
is entitled, I believe, a method or a... Yes, but we looked at more than the title.

[00:02:14] Speaker 04:
We looked at the description.

[00:02:15] Speaker 01:
Understood.

[00:02:15] Speaker 01:
Understood.

[00:02:16] Speaker 01:
There are a number of, I would say, passing references to Cho cells as an alternative source of enzyme to the transgenic mammals that are the focus of the Van Brie patent.

[00:02:30] Speaker 01:
Biomerins experts testify that they understood the disclosure in Van Brie.

[00:02:35] Speaker 01:
and the prophetic clinical trial and prophetic results in Van Brie to relate to the enzyme obtained from transgenic mammals.

[00:02:47] Speaker 01:
And to the extent there is a disclosure in Van Brie of Cho cells, it is essentially to criticize or belittle Cho cells as an inferior source of enzyme because, according to Van Brie, that source is more difficult to work with,

[00:03:04] Speaker 01:
It's not as efficient to propagate the enzyme in that fashion.

[00:03:08] Speaker 01:
There's other prior art that we've brought to the court's attention and we've brought to the board's attention, the Canfield 785 patent, which is much more important, I would say, because it showed that the CHO cell material had very little of this important glycosylation element, the mannose 6-phosphate, or M6P.

[00:03:31] Speaker 01:
And in this court's decision,

[00:03:33] Speaker 01:
last year in the related case of genzyme versus biomarin, the panel in that case recognized that M6P was absolutely critical to effective or therapeutic use of the enzyme.

[00:03:49] Speaker 01:
And the prior art that existed prior to Dr. Chen's 712 patent showed that the Cho enzyme had very little M6P.

[00:03:59] Speaker 04:
So it's our contention that... You may try to

[00:04:03] Speaker 04:
denigrate the quality of the disclosure, but a disclosure is a disclosure, and CHO cells are there as an alternative.

[00:04:12] Speaker 01:
I agree that they are there, your honor, but the question is whether a person of skill in the art, ordinary skill in the art, would have been motivated to substitute CHO cells in the therapeutic use of the enzyme for the

[00:04:31] Speaker 01:
what is claimed to be superior material.

[00:04:34] Speaker 03:
The question is not an anticipation question.

[00:04:37] Speaker 03:
It's not a motivation question.

[00:04:39] Speaker 03:
I think the question is whether when Van Bree says give a therapeutic dose of the mouse milk version of this and then says a couple of places you can get the same stuff from a different source that a skilled artisan would read that

[00:04:57] Speaker 03:
to disclose, among other things, the same process that Mambrie talks about with the mouse milk version as using the Cho version.

[00:05:09] Speaker 01:
That's correct, Your Honor.

[00:05:10] Speaker 01:
And I was answering from the standpoint of obviousness, but there is an anticipation finding.

[00:05:15] Speaker 01:
And on anticipation,

[00:05:17] Speaker 01:
I believe that the way this case was originally pled or petitioned to the board was that the Chocell element of claim one in the Chen patent was a so-called product by process claim, which essentially made it irrelevant.

[00:05:41] Speaker 00:
That's your ultra-various argument, which even if we agree with you, and it's

[00:05:44] Speaker 00:
pretty good argument, but it's one that we can't review anymore after the proposal, right?

[00:05:49] Speaker 00:
Understood, but... Those two were stuck with the fact that they took it, despite the fact that it was a product by process reference in the petition.

[00:06:01] Speaker 01:
Right.

[00:06:02] Speaker 00:
Then what?

[00:06:03] Speaker 01:
Then you're left with the question, I think, of whether a passing and denigrating reference in a single reference, now Van Bree,

[00:06:13] Speaker 01:
We're not talking about other references that describe CHO cells and the ability to produce them efficiently, but a passing and denigrating reference in Vandrie to CHO cells is anticipatory of therapeutic use of enzyme derived from CHO cells to produce a cure or rather a treatment for a previously untreatable disease.

[00:06:37] Speaker 01:
And I would say that that is simply not an adequate

[00:06:40] Speaker 01:
disclosure of, there's no disclosure in BanBri of a therapeutic use of Cho cells periodically at an administration interval to treat effectively this disease.

[00:06:59] Speaker 00:
Assuming, just for the sake of argument, that disclosure, that passing reference disclosure of Cho cells is enough,

[00:07:09] Speaker 00:
Is there in Van Brie any disclosure of precursor-only methodology as described in Claim 9?

[00:07:19] Speaker 01:
No.

[00:07:19] Speaker 01:
And so in Claim 9, which was invalidated on both anticipation and obviousness grounds, you have a statement in Van Brie that the enzyme is preferentially, predominantly, that is greater than 50% in the precursor form.

[00:07:37] Speaker 01:
There is no disclosure.

[00:07:39] Speaker 01:
of what the board agreed with Appellant Duke University was the claim, the essence of claim nine, which is that the enzyme is an exclusively precursor form.

[00:07:51] Speaker 04:
Claim nine doesn't say exclusively.

[00:07:53] Speaker 01:
It says is a precursor, Your Honor.

[00:07:55] Speaker 04:
A precursor.

[00:07:56] Speaker 01:
Is a precursor.

[00:07:57] Speaker 04:
A precursor.

[00:07:59] Speaker 04:
And as you read column 13, lines 48 or thereabouts 49 describes a precursor.

[00:08:07] Speaker 01:
In Van Brie?

[00:08:09] Speaker 01:
and then bring yes but but your honor that the way the board ultimately constricted but you're saying that and breed describes a precursor only in combination form correct it's a mixture it describes a mixture of precursor and non-creep precursor it does not describe a pure one hundred percent or exclusively precursor and to take the phrase and claim nine uh... which was quote is a precursor and read it as the board did

[00:08:36] Speaker 01:
to say is or is not a precursor, is not a logical or sustainable interpretation.

[00:08:43] Speaker 01:
And the board's rationale was predicated on the preamble, if you will, to claim one, which was, it's a method claim, obviously, that includes a number of steps, and it uses the word comprising to introduce those steps.

[00:08:59] Speaker 01:
And when we get to claim nine, which adds a narrow limitation, is a precursor,

[00:09:05] Speaker 01:
The board said, well, the introductory preamble to claim one, from which nine depends, begins with this open language of comprising, and that allows for additional method steps, including the co-administration or simultaneous administration of non-precursor form.

[00:09:24] Speaker 04:
I forget to claim 19 that I think you wanted to address.

[00:09:28] Speaker 01:
If I could just finish on this one point on claim nine.

[00:09:31] Speaker 01:
So this court and both Judge Lurie and Judge Toronto have both written opinions in the last year on this issue of comprising and how it does not open up.

[00:09:42] Speaker 01:
It's not a weasel word that opens up.

[00:09:44] Speaker 01:
Comprising is decades old.

[00:09:46] Speaker 01:
Exactly.

[00:09:47] Speaker 01:
So the law here, which I believe that the board simply got wrong, is that that word comprising does not allow for the performance of that particular method step

[00:10:00] Speaker 01:
where the enzyme is a precursor to be performed by administering both precursor and non-precursor.

[00:10:06] Speaker 01:
You could perform it by a number of other means, injecting it with a hypodermic needle, but you can't perform that step with non-precursor enzyme along with precursor.

[00:10:18] Speaker 01:
So now I'll return with the court's permission to claim 19 on the prophylactic use of immunosuppressant.

[00:10:26] Speaker 01:
So as the court knows, in the original final written decision, the board unanimously invalidated that claim as obvious over primarily a reference called Brady, which had to do with the immunosuppressive... And then re-hearing this at, oops, let's forget about Brady.

[00:10:44] Speaker 03:
Correct.

[00:10:45] Speaker 03:
that since using an immunosuppressant when you see a problem is something everybody would do uh... if collectively you see enough of the problems that you would start giving it to everybody ahead of time correct that's uh... and they said it's a it's a predictable variation or it's common sense so so let's look at what the state of the art and on this enzyme was because uh... in brady it is said but you said it can't answer this for me uh...

[00:11:13] Speaker 03:
Why, I guess, why does it matter whether anybody thought it was going to be likely or not very likely that a large number of the recipients of this enzyme would have antibody problems?

[00:11:32] Speaker 03:
But why isn't it enough for the board to say,

[00:11:39] Speaker 03:
There are two options here.

[00:11:40] Speaker 03:
You either give the immunosuppressant as a prophylactic matter or you don't.

[00:11:44] Speaker 03:
You do when, after you've given this enzyme to a sufficient number of people, it is clear that quite a lot of them get the antibody problem, and then you would do it prophylactically.

[00:11:58] Speaker 03:
Either or choice.

[00:12:00] Speaker 03:
We don't know if the second option is going to come to fruition, but if it does, this is what everybody will do.

[00:12:07] Speaker 01:
So, and the logic would seem straightforward, Your Honor, but we have to remember a number of things.

[00:12:15] Speaker 01:
First, immunosuppressants are serious drugs that have serious side effects.

[00:12:19] Speaker 01:
You don't simply give them lightly as prophylaxis.

[00:12:22] Speaker 01:
Second, immune reactions to recombinant proteins were rare and incurred in, quote, very few patients.

[00:12:31] Speaker 01:
That's the prior art according to Brady, and there's no contrary prior art

[00:12:36] Speaker 01:
Third, as of the time of this invention, there's no record, there's no prior art of any administration of this enzyme, recombinant choform enzyme, to any patient or any other recombinant, GAA, to any patient on earth.

[00:12:50] Speaker 01:
Dr. Chen is the first person, first physician to do that.

[00:12:54] Speaker 01:
And in his, it's only three studies, excuse me, three patients described in his specification, the study was eventually expanded, but he sees in patients one and two

[00:13:06] Speaker 01:
not only immune responses, but a quick onset within three weeks, which is very different from Brady.

[00:13:12] Speaker 01:
Brady, the patient, didn't even develop the antibodies for a year and wasn't administered in an immunosuppressive regimen until two years later.

[00:13:20] Speaker 01:
So Dr. Chen sees this.

[00:13:22] Speaker 01:
He puts it in the specification, quick onset of immune response and antibody titers, and lack of efficacy as those antibody titers rise.

[00:13:34] Speaker 01:
And he concludes that this is a serious issue with this enzyme and this disease.

[00:13:39] Speaker 01:
And he teaches the medical community about both of those things.

[00:13:43] Speaker 01:
And he proposes a solution.

[00:13:45] Speaker 01:
Let's pre-medicate them with immunosuppressant, even though there's no prior art disclosure whatsoever to do that in this context.

[00:13:53] Speaker 01:
That is, enzyme replacement therapy or elsewhere.

[00:13:56] Speaker 01:
There's absolutely no disclosure anywhere in the prior art of that.

[00:14:00] Speaker 01:
And it works.

[00:14:01] Speaker 01:
So if that's not an invention, really, what is?

[00:14:04] Speaker 01:
He discovered a problem that was not known to exist, and he found a solution for it.

[00:14:09] Speaker 01:
And on this record, as Judge Bonilla said, Judge Bonilla, of course, was the author of the original majority opinion, which she said, and I think quite correctly, that there's nothing other than empty conclusory statements in the record to support a conclusion that this was

[00:14:27] Speaker 01:
either obvious or practical, you know, a predictable variation on the priority.

[00:14:32] Speaker 03:
Can I ask you one informational question which may or may not be relevant?

[00:14:36] Speaker 03:
Does the product label here say anything about prophylactic immunity?

[00:14:44] Speaker 01:
I believe it certainly describes immune reactions and I believe it does describe co-administration or pre-administration.

[00:14:52] Speaker 01:
So this is a gift from Duke University and Dr. Chen to the medical community, which the community has relied upon.

[00:15:01] Speaker 01:
It's a bona fide invention.

[00:15:02] Speaker 01:
And this court has said a number of times that while common sense has its role, obviously, in patent law, it has its limits as well.

[00:15:11] Speaker 01:
And it's very unusual that it can substitute for prior art when we're talking about two things.

[00:15:17] Speaker 01:
Number one, a missing limitation from the prior art, and that's prophylactic use of the immunosuppressant.

[00:15:23] Speaker 01:
And number two, the essence of the invention, which that is, the essence of claim 19.

[00:15:28] Speaker 01:
It may not be the essence of claim one, obviously, but for claim 19, the essence is prophylactic use.

[00:15:34] Speaker 01:
That is absent from the prior art.

[00:15:37] Speaker 01:
Common sense is not a substitute for that type of an invention.

[00:15:41] Speaker 04:
Counsel, you've consumed what you wanted to save for rebuttal, but we'll give you three minutes back anyway.

[00:15:48] Speaker 01:
Thank you, Your Honor.

[00:15:49] Speaker 01:
Actually, if the court doesn't have any other questions at this time, I will

[00:15:52] Speaker 01:
Oh, I'm sorry, I used my entire... Who have used your time?

[00:15:56] Speaker 01:
Okay, I misread the clock.

[00:16:00] Speaker 01:
I gratefully accept your gift of the three minutes.

[00:16:03] Speaker 01:
Thank you, Your Honor.

[00:16:04] Speaker 04:
After Mr. Murphy speaks.

[00:16:27] Speaker 02:
Okay, maybe I'll just start with claims.

[00:16:29] Speaker 02:
Excuse me.

[00:16:29] Speaker 02:
My name is Gary Murphy.

[00:16:32] Speaker 02:
I represent BioMarine Pharmaceuticals.

[00:16:35] Speaker 02:
And I would like to start with claim 19, take it the reverse order that we had earlier, if that's okay.

[00:16:45] Speaker 02:
So on the immunosuppressant issue, counsel even acknowledged that the logic of using an immunosuppressant is straightforward.

[00:16:53] Speaker 02:
And Dr. Pastores laid that out in his declaration very clearly.

[00:16:58] Speaker 02:
He had a whole section of his declaration, talks about immunosuppressants.

[00:17:04] Speaker 02:
The record is clear that immune responses were observed with other therapeutic proteins.

[00:17:12] Speaker 02:
It's a very common problem, even Duke's own witnesses admitted it during cross-examination

[00:17:19] Speaker 02:
during depositions.

[00:17:20] Speaker 02:
Well, first let me start.

[00:17:21] Speaker 00:
Judge Benioff did lay this out in a lot of detail.

[00:17:25] Speaker 00:
First of all, it is true that this new predictable variation theory is really one that is adopted suespante by the board.

[00:17:34] Speaker 00:
I mean, the petitioner never urged it.

[00:17:35] Speaker 00:
You never urged that theory.

[00:17:37] Speaker 00:
Well, actually... You said Brady did it.

[00:17:41] Speaker 00:
You said it was in Brady.

[00:17:42] Speaker 02:
Early on, yes.

[00:17:43] Speaker 02:
Early on, but as the record developed, we did actually urge it prior to that decision.

[00:17:49] Speaker 02:
I can point to the record where the issue was raised specifically.

[00:17:53] Speaker 02:
If you could give me two seconds here.

[00:18:00] Speaker 00:
Because the majority did not dispute that it wasn't raised.

[00:18:05] Speaker 00:
They just said, well, we can do it anyway.

[00:18:07] Speaker 02:
OK.

[00:18:07] Speaker 02:
So let me just go back to was it raised or not.

[00:18:11] Speaker 02:
And the first point is the board noted

[00:18:14] Speaker 02:
that the patent owner had previously argued that a person of ordinary skill in the art, I'm quoting a person of ordinary skill in the art, could not have predicted that an immunosuppressant could be useful when the actiform of Cho GAA is used to treat Pompe patients.

[00:18:30] Speaker 02:
That's A9.

[00:18:31] Speaker 02:
So the board actually noted that the patent owner raised that argument, referring to A9, citing the petitioner's reply and the patent owner's response.

[00:18:42] Speaker 02:
And then in Biomarin's opposition to Duke's request for rehearing, Biomarin argued, and this is on A404, when there are a finite number of identified predictable solutions, it is obvious to select a particular dosing schedule.

[00:19:01] Speaker 02:
See Hoffman-LaRose versus Apotec citing KSR.

[00:19:05] Speaker 02:
That's an A404.

[00:19:06] Speaker 04:
Mr. Murphy, tell us about claim one.

[00:19:09] Speaker 04:
Your opposing counsel has disparaged the reference to Cho cells.

[00:19:16] Speaker 02:
That's not true at all.

[00:19:17] Speaker 02:
I mean, if you look at it, we're talking about Van Brie.

[00:19:20] Speaker 04:
Van Brie.

[00:19:21] Speaker 02:
Right.

[00:19:21] Speaker 02:
So Van Brie claims a method, discloses and claims a method for treating Pompe disease using the exact same enzyme that's the subject of the patented issue.

[00:19:33] Speaker 02:
If you look at the actual work that they did, they made it.

[00:19:37] Speaker 02:
But from a different source.

[00:19:39] Speaker 02:
Pardon me?

[00:19:39] Speaker 02:
But from a different source.

[00:19:40] Speaker 02:
Yeah, so if you look at the actual experiments, they made it from transgenic animals.

[00:19:46] Speaker 02:
So the actual work, hands-on work they did, they made that enzyme, and that was what their laboratory was working with.

[00:19:55] Speaker 02:
And they used it to set up their clinical trials.

[00:19:58] Speaker 04:
But of course, one doesn't need

[00:20:00] Speaker 04:
production to practice to be a disclosure.

[00:20:03] Speaker 02:
Absolutely.

[00:20:04] Speaker 00:
And they said, you know, this is, of course, this is what we have to look at Van Bree from the perspective of one of skill in the art.

[00:20:10] Speaker 00:
Yes.

[00:20:11] Speaker 00:
Right.

[00:20:11] Speaker 00:
So where did you present or did the board rely on expert testimony to say what one of skill in the art would have understood Van Bree to dispose?

[00:20:22] Speaker 02:
So our, uh, witnesses, our witnesses did not testify about Van Bree.

[00:20:28] Speaker 02:
that for that 102 ground, they testified on obviousness.

[00:20:31] Speaker 00:
So how do we allow a 102 obviousness when there is no one to say what one of skill in the art would interpret Van Breda mean, except the experts who said one of skill in the art would not interpret Van Breda mean this.

[00:20:45] Speaker 02:
So our experts gave both experts, we had a production expert, Dr. Krogan, who gave, you know, pages and pages of declaration testimony.

[00:20:56] Speaker 00:
Was that one of the ones that

[00:20:57] Speaker 00:
that they moved to exclude?

[00:21:00] Speaker 02:
I don't think they moved to exclude Dr. Krogan's.

[00:21:03] Speaker 00:
They might have, but... There were two experts at the board that specifically said they weren't going to rely on at all.

[00:21:11] Speaker 00:
Two of yours.

[00:21:13] Speaker 02:
They weren't going to rely on that part of the testimony, I guess.

[00:21:17] Speaker 02:
Dr. Krogan?

[00:21:17] Speaker 02:
I don't remember about the motion to exclude right now.

[00:21:20] Speaker 00:
But you're conceding that you did not put in any expert testimony on Van Brie and what one of Skill in the Art would understand Van Brie to say.

[00:21:28] Speaker 02:
So we didn't put in expert testimony on Van Brie.

[00:21:30] Speaker 02:
But our experts did provide a lot of factual information to educate the board from a production expert and from Dr. Pastores, who's a medical doctor.

[00:21:41] Speaker 02:
He was our main expert on a person of ordinary skill in the art.

[00:21:45] Speaker 02:
So we had plenty of

[00:21:47] Speaker 02:
testimonial evidence and evidence to inform the board of what the state of the art was and help them read the prior art through the eyes of an ordinary person, a person of ordinary skill.

[00:21:57] Speaker 00:
But if you really thought a person of ordinary skill in the art would believe Van Brie anticipated, why didn't you put your expert on to say that?

[00:22:06] Speaker 02:
Because we focused on the 103.

[00:22:08] Speaker 02:
We had him focus on the 103.

[00:22:09] Speaker 00:
He must have been pretty surprised when the board came up with the 103.

[00:22:12] Speaker 02:
Not at all, because that was our first grounds of invalidation.

[00:22:15] Speaker 04:
Not at all.

[00:22:17] Speaker 04:
A 102 reference speaks for itself, whereas obviousness has a lot of motivation issues.

[00:22:25] Speaker 02:
I mean, yeah, the PTAB judges are used to reading patents.

[00:22:28] Speaker 02:
I mean, you can see it right there.

[00:22:32] Speaker 03:
So I mean, I'm sorry, the right there is column... In Van Brie.

[00:22:36] Speaker 03:
The bottom, there's a lot of Van Brie.

[00:22:39] Speaker 03:
The bottom of column 13.

[00:22:41] Speaker 03:
Is that what we're looking at?

[00:22:42] Speaker 03:
Okay.

[00:22:43] Speaker 03:
Therapeutic methods.

[00:22:44] Speaker 03:
The present invention provides effective methods of treating pompase disease.

[00:22:49] Speaker 03:
We're going to give this glucosidase, the human acid alpha-glucosidase.

[00:22:56] Speaker 03:
Such human acid alpha-glucosidase is provided from, for example, the transgenic animal described in the examples, preferably predominantly precursor.

[00:23:07] Speaker 03:
And then it says, given the successful results with human acid alpha glucosidase in the transgenic animals discussed in the examples, it is possible that other sources of human alpha glucosidase, such as resulting from cellular expression systems, can also be used, for example, CHO.

[00:23:27] Speaker 02:
I don't have that.

[00:23:28] Speaker 02:
Yeah, there's multiple references to CHO cells.

[00:23:31] Speaker 02:
Yes, that's one of them for certain.

[00:23:32] Speaker 03:
There's a later one that refers to certain in vitro

[00:23:36] Speaker 03:
tests and says something about Cho having that the restoration of the endogenous acid glucosidase activity is the same Cho.

[00:23:48] Speaker 02:
Yeah, and we laid it all out in our brief, but basically Van Bree clearly teaches that Cho cells are an alternative.

[00:23:54] Speaker 02:
I think the record is clear.

[00:23:55] Speaker 02:
80% of all therapeutic proteins that are ever made were made in Cho cells.

[00:24:00] Speaker 02:
This teaching of Van Bree, they kind of went off on their own.

[00:24:03] Speaker 02:
They did their thing.

[00:24:04] Speaker 02:
They actually found another way to make it, which was in transgenic animals.

[00:24:09] Speaker 02:
But you can't rewrite history.

[00:24:10] Speaker 02:
80% of all therapeutic proteins ever approved by the FDA were made in show cells.

[00:24:16] Speaker 02:
And Van Brie acknowledged, oh, you can make them in show cells also.

[00:24:19] Speaker 03:
But that doesn't mean that for this particular enzyme, what has a therapeutic effect, which is a claim requirement, is independent of the source of the enzyme, does it?

[00:24:33] Speaker 03:
How do we know that?

[00:24:34] Speaker 02:
Yeah, because Van Brie tells you that they're the same.

[00:24:36] Speaker 02:
And you were just reading some of the disclosures from Van Brie.

[00:24:39] Speaker 03:
It's possible that you could do the same thing with the

[00:24:44] Speaker 03:
the enzyme from a different source.

[00:24:46] Speaker 02:
Right.

[00:24:48] Speaker 02:
And it also says that the activities, as best they could tell, as best they had studied, were the same.

[00:24:53] Speaker 02:
The activities between both sources, there's the specific quotes in Van Brie.

[00:24:59] Speaker 04:
What about claim nine?

[00:25:01] Speaker 02:
Claim nine?

[00:25:01] Speaker 04:
Claim nine.

[00:25:03] Speaker 04:
The question is whether the disclosure of precursor, which is only predominantly

[00:25:14] Speaker 04:
anticipates Claim 9, which refers to a pre-cursor.

[00:25:22] Speaker 02:
So we're talking about Van Bree, right?

[00:25:24] Speaker 02:
Claim 9?

[00:25:24] Speaker 02:
OK.

[00:25:28] Speaker 04:
That's the argument your opposing counsel made.

[00:25:31] Speaker 04:
Right.

[00:25:32] Speaker 00:
The board found that Claim 9 requires exclusively pre-cursor.

[00:25:35] Speaker 00:
Right.

[00:25:36] Speaker 00:
Does Van Bree dispose exclusively pre-cursor?

[00:25:39] Speaker 02:
First of all, I hope you don't think we're conceding that claim 9 should be interpreted narrowly.

[00:25:43] Speaker 02:
We rely on our brief, and we think that the board got the claim interpretation right.

[00:25:48] Speaker 02:
It should not be narrowly interpreted.

[00:25:51] Speaker 02:
There's no case law on that point.

[00:25:52] Speaker 02:
But let's assume, for purposes of discussion, the court wants to interpret claim 9 narrowly.

[00:25:59] Speaker 02:
I will point to A476, which is the Van Brie patent, column 4, lines 24 to 28.

[00:26:06] Speaker 02:
It says,

[00:26:08] Speaker 02:
And it teaches purification of the drug.

[00:26:11] Speaker 02:
This is well known prior to Van Brie.

[00:26:14] Speaker 02:
Van Brie teaches purification of the drug.

[00:26:16] Speaker 00:
What lines again?

[00:26:18] Speaker 02:
A476, column 4, lines 24 to 28.

[00:26:23] Speaker 02:
Most preferably, the object species is purified to essential homogeneity.

[00:26:30] Speaker 02:
Then at A481, small amount of impurities could be tolerated.

[00:26:35] Speaker 02:
That's column 13, lines 13 to 20.

[00:26:38] Speaker 02:
And then if you look for any examples, detailed purification procedures are reported in example three on A484.

[00:26:48] Speaker 02:
So Van Brie has a lot of disclosure about purification.

[00:26:54] Speaker 03:
I'm sorry.

[00:26:56] Speaker 03:
Maybe this is so obvious.

[00:26:58] Speaker 03:
I should note the answer.

[00:26:59] Speaker 03:
What is the relationship between purification and precursor?

[00:27:03] Speaker 02:
So I guess in the context of

[00:27:08] Speaker 02:
Claim 9, if you interpret Claim 9 to be limited to only the pure precursor and no other forms of the protein, you're going to want to purify the precursor.

[00:27:20] Speaker 02:
I mean, if that's the way you interpret it, then Van Brie clearly teaches that the precursor is the active form.

[00:27:27] Speaker 02:
Van Brie, all of the prior art, all across the whole record, teaches that the precursor is the active form.

[00:27:34] Speaker 02:
When you're developing a drug,

[00:27:36] Speaker 02:
You want to purify the active form and give it to the patient.

[00:27:39] Speaker 02:
You don't want to give them something.

[00:27:40] Speaker 03:
Is there such a thing as a purified precursor?

[00:27:44] Speaker 02:
So let me just do a visual here.

[00:27:48] Speaker 02:
So the molecule is a protein.

[00:27:52] Speaker 02:
It's a long protein.

[00:27:54] Speaker 02:
And the precursor, at one end of the protein, there are these sugar and phosphate groups.

[00:28:01] Speaker 02:
And the precursor form, it's the whole molecule.

[00:28:04] Speaker 02:
It has a certain molecular weight.

[00:28:06] Speaker 02:
Now, if the drug, after it's expressed and certain things happen to it, it can fall apart.

[00:28:15] Speaker 02:
And enzymes can clip it off.

[00:28:17] Speaker 02:
And so this is the precursor initially.

[00:28:20] Speaker 02:
Enzymes can come along and ruin it.

[00:28:22] Speaker 02:
And they can chop off parts off the end.

[00:28:25] Speaker 02:
So then you might end something.

[00:28:26] Speaker 02:
The mature form would not have this little important part on the end.

[00:28:30] Speaker 02:
So the precursor was the end.

[00:28:33] Speaker 02:
active form, and you want to purify that.

[00:28:35] Speaker 02:
You don't want to give the patient the inactive form, the mature part that's been cleaved off.

[00:28:40] Speaker 00:
All right.

[00:28:41] Speaker 00:
So where in the record did you present expert testimony that said that you have to understand that once there's this reference to Cho being a possibility, that therefore you have to go back and figure out that if you're going to have any purification, that therefore it would also mean that you would purify it so as to use a precursor only.

[00:29:03] Speaker 02:
I mean, that's a pretty big leap.

[00:29:06] Speaker 02:
Both of our witnesses testified that when you're developing a drug, you're going to get the active form and you're going to purify it.

[00:29:13] Speaker 02:
The precursor is the active form.

[00:29:18] Speaker 02:
It's in Van Brie.

[00:29:21] Speaker 02:
It's in Roycer.

[00:29:22] Speaker 02:
It's in both of our expert declarations.

[00:29:26] Speaker 03:
Did the board find that Van Brie shows a precursor only

[00:29:33] Speaker 03:
treatment mechanism or just say that's not?

[00:29:36] Speaker 03:
I thought the board said it's not necessary because we read the comprising language.

[00:29:41] Speaker 02:
They didn't go the extra step.

[00:29:42] Speaker 02:
They didn't think it was necessary to delve into that all the way because they were interpreting the claim broadly to include administering both the precursor form and a non-precursor form.

[00:29:52] Speaker 02:
As long as you have an effective amount of the precursor, it doesn't matter if there's something else in there.

[00:29:57] Speaker 02:
In the ideal world, you're going to purify it.

[00:30:00] Speaker 02:
The FDA is going to want you to purify it.

[00:30:02] Speaker 02:
So they didn't go the extra step and go through Van Brie and point to the other parts.

[00:30:08] Speaker 04:
Claim 9 says 8-precursive.

[00:30:11] Speaker 04:
And however the board construed it, that's a question of law, which we can review de novo.

[00:30:24] Speaker 02:
Sorry.

[00:30:24] Speaker 02:
Yes.

[00:30:26] Speaker 04:
And column 13 of Van Brie discloses 8-precursive.

[00:30:40] Speaker 02:
So I'm not sure what was the question.

[00:30:42] Speaker 04:
I was commenting.

[00:30:43] Speaker 04:
OK.

[00:30:44] Speaker 04:
I was commenting.

[00:30:47] Speaker 04:
You have a little time left if you wish to finish up.

[00:30:53] Speaker 02:
So I guess on the, I'm surprised that this purification issue has come up.

[00:30:59] Speaker 02:
So I'm going to just explain that a little bit more if I could.

[00:31:02] Speaker 02:
So claim nine, it's irrelevant whether it's purified completely or not, if you accept the board's interpretation of claim nine.

[00:31:09] Speaker 02:
Because the is argument and the precursor argument is all about purification.

[00:31:14] Speaker 02:
You get the active form.

[00:31:15] Speaker 02:
Everybody, both sides agree that the precursor is the active form in the enzyme.

[00:31:20] Speaker 02:
All the testimony of all the witnesses.

[00:31:23] Speaker 02:
And you can see it right in Banbury.

[00:31:24] Speaker 02:
You can see it right in Roycer.

[00:31:25] Speaker 02:
And you can see it in both declarations of our witnesses, probably the declarations of their witnesses also.

[00:31:32] Speaker 02:
So the precursor is the active form.

[00:31:36] Speaker 02:
If you accept the board's interpretation that it doesn't have to be completely pure, then we don't need to worry about this purification issue.

[00:31:44] Speaker 02:
If you take a very narrow interpretation of claim nine, then the question is, does Van Bree actually teach purification?

[00:31:52] Speaker 02:
And I pointed to where it says you purify the act of form, which is the precursor to essential homogeneity.

[00:31:58] Speaker 02:
You want the drug to be pure.

[00:32:00] Speaker 02:
You don't want the bad stuff in there.

[00:32:02] Speaker 02:
And that's the same voice or has the same teachings.

[00:32:06] Speaker 02:
You always purify a drug.

[00:32:07] Speaker 02:
And there's plenty of testimony on that point.

[00:32:09] Speaker 02:
I think the board didn't go the extra step because they didn't think they needed to.

[00:32:16] Speaker 04:
Thank you, counsel.

[00:32:18] Speaker 04:
Mr. Zellessen has some rebuttal time.

[00:32:23] Speaker 01:
Thank you very much, Your Honor.

[00:32:25] Speaker 01:
Just a couple of points.

[00:32:26] Speaker 01:
On claim one and Van Brie, to be clear, there is no disclosure in Van Brie of therapeutic efficacy

[00:32:36] Speaker 01:
any data demonstrating therapeutic efficacy of GAA from any source.

[00:32:42] Speaker 01:
It's a prophetic disclosure.

[00:32:44] Speaker 01:
The only human testing that's described is volunteer normal testing for safety and dose ranging.

[00:32:51] Speaker 04:
So to me... Well, Van Bree says it's for treatment of patients with Pompe disease.

[00:32:56] Speaker 01:
He says that.

[00:32:57] Speaker 01:
He does.

[00:32:58] Speaker 01:
As to the transgenic mammal material... That's a statement of...

[00:33:04] Speaker 01:
Exactly.

[00:33:04] Speaker 01:
That matches what's in your claim.

[00:33:07] Speaker 01:
Well, what's in our claim is the therapeutic treatment, effective therapeutic treatment, using CHO material administered periodically.

[00:33:16] Speaker 04:
You're saying that Bree didn't prove it.

[00:33:19] Speaker 01:
He didn't prove it.

[00:33:19] Speaker 01:
He didn't describe it for CHO.

[00:33:21] Speaker 01:
That's not necessary for a description.

[00:33:22] Speaker 01:
He does not describe therapeutic efficacy using CHO material.

[00:33:28] Speaker 01:
I would say he doesn't even do it for the other material, but he doesn't do it for CHO.

[00:33:33] Speaker 01:
On claim nine, just to pick up on some of the panel's questions, there is no finding by the board.

[00:33:42] Speaker 01:
of a disclosure either in Van Brie or elsewhere of any GAA use in exclusively precursor form.

[00:33:54] Speaker 03:
Did the petitioner argue that to the board?

[00:33:57] Speaker 01:
No, I did not see any such argument.

[00:33:59] Speaker 03:
That might make a difference in whether if we were to disagree with the board's claim construction

[00:34:06] Speaker 03:
which is a legal issue, whether there's anything to remand on the question or whether it would be an outright reversal on claim nine.

[00:34:13] Speaker 01:
So two things, Your Honor.

[00:34:15] Speaker 01:
On the issue of anticipation, there was no argument below that there's a disclosure of exclusively precursor.

[00:34:24] Speaker 01:
There was also no contrary claim construction

[00:34:27] Speaker 01:
put forward in response to Duke's proposal, which was adopted by the board, that it required exclusively precursor.

[00:34:34] Speaker 01:
So on the anticipation finding, I believe that that argument is waived and there is no basis for remand.

[00:34:40] Speaker 03:
What about the obviousness?

[00:34:42] Speaker 01:
On the obviousness, one could make the argument that, as they found with claim 19, that if Van Brie discloses preferably, predominantly precursor,

[00:34:55] Speaker 01:
that you could go the rest of the distance and fill in the blank.

[00:34:59] Speaker 03:
I'm sorry.

[00:35:00] Speaker 03:
Van Brie is not part of the obviousness analysis.

[00:35:02] Speaker 01:
I'm sorry.

[00:35:03] Speaker 01:
I'm sorry.

[00:35:03] Speaker 01:
You're right.

[00:35:04] Speaker 01:
But for Roycer, I believe, same disclosure.

[00:35:07] Speaker 01:
Same disclosure.

[00:35:08] Speaker 01:
Same disclosure.

[00:35:09] Speaker 01:
So if Roycer advocates predominantly precursor, one could argue you could... Did the petitioner make that argument?

[00:35:17] Speaker 01:
I do not believe the petitioner made that argument, Your Honor, because they did not address the issue of exclusively precursor.

[00:35:24] Speaker 01:
either in the petition or in their reply.

[00:35:27] Speaker 01:
So there's just no showing on that.

[00:35:29] Speaker 01:
And in fact, to remand for that purpose would put us in essentially the identical position we're in on claim nine, where they'd be trying to rely on common sense to fill in a key missing claim limitation that's the essence of the invention.

[00:35:45] Speaker 01:
And we believe that would not be appropriate or necessary.

[00:35:48] Speaker 01:
It should be a straight reversal.

[00:35:50] Speaker 04:
Thank you.

[00:35:51] Speaker 04:
Thank you, Your Honor.