[00:00:03] Speaker 04:
OK.

[00:00:04] Speaker 04:
First argued case this morning is number 181696, Duke University against Biomer and Pharmaceuticals.

[00:00:13] Speaker 04:
Mr. Zales.

[00:00:18] Speaker 01:
May it please the court, Steve Zaleson for Duke University.

[00:00:22] Speaker 01:
In its prior decision in this case, this court identified two errors in the board's original decision invalidating claim nine.

[00:00:32] Speaker 01:
First, the board applied an improper claim construction and treated the claim element that the GAA, the enzyme in question, quote, is a precursor as if it needed to only include or be part of a mixture of precursor and non-precursor forms.

[00:00:49] Speaker 01:
That was error number one.

[00:00:51] Speaker 01:
The second error

[00:00:52] Speaker 01:
was as the court pointed out in a footnote number two in its original decision that the presumption of nexus had not been properly applied by the board and that the board otherwise failed to give appropriate consideration to the objective indicia of non

[00:01:10] Speaker 01:
obviousness evidence that Duke had brought forward.

[00:01:14] Speaker 01:
On remand the board committed precisely the same two errors.

[00:01:19] Speaker 01:
First it read prior art disclosures and expert declarations that refer to quote precursor of

[00:01:26] Speaker 01:
as though they addressed GAA that is exclusively a precursor, when in fact, those references in that testimony referred to a mixture of precursor and non-precursor forms.

[00:01:39] Speaker 05:
But the board referred to testimony, including a Kukuchi study, which talked about greater than 90%.

[00:01:50] Speaker 05:
And this is an obviousness case.

[00:01:52] Speaker 01:
Yes.

[00:01:53] Speaker 05:
So we're getting close to exclusively precursor form.

[00:02:01] Speaker 01:
I agree it's close, Your Honor, but if we.

[00:02:03] Speaker 05:
And so we're reviewing whether the board heard.

[00:02:07] Speaker 01:
Yes, that's correct, Your Honor.

[00:02:09] Speaker 01:
But there was no testimony in the case.

[00:02:12] Speaker 01:
There was mistaken testimony by Biomarin's experts because they were applying the wrong claim construction that Kukuchi and Bijvoe and a number of other prior art preclinical studies had used the precursor form, they referred to it, when in fact it was a mixture.

[00:02:30] Speaker 01:
And Kukuchi is a mixture, although it is predominantly over 90%.

[00:02:36] Speaker 01:
Most of the other prior art references, for example, the Van Brie patent, which comes up quite a bit, it was preferably predominantly, namely, greater than 50%.

[00:02:47] Speaker 05:
More than 50, right.

[00:02:48] Speaker 05:
Well, more than 90 is quite a bit different from more than 50.

[00:02:51] Speaker 01:
In that particular animal model, that's what was described.

[00:02:55] Speaker 01:
But there is no disclosure or teaching there and no testimony from anybody in the record that a person of ordinary skill in the art would have read Kikuchi, which, by the way, is not a reference on which trial was instituted.

[00:03:09] Speaker 01:
The asserted combination on which trial was instituted is Reuser 771.

[00:03:16] Speaker 01:
uh... and uh... van hove nineteen ninety-seven not kukuchi but even taking kukuchi as relevant background there is no testimony uh... or evidence of any other sort that a person of ordinary skill

[00:03:32] Speaker 01:
arrived at the claimed invention of exclusively precursor derived from Cho cells by combining the asserted references of Reuser and Van Hove 1997.

[00:03:43] Speaker 03:
And to illustrate... Can I just ask this?

[00:03:45] Speaker 03:
Isn't part of what the board found with at least some places in the record that by the priority date, it was pretty well understood that the mechanism by which

[00:04:01] Speaker 03:
the RHEAA would get into the cells was one that depended on a portion of the molecule that was in the precursor but not in the, I guess, the truncated version.

[00:04:18] Speaker 03:
And therefore, why wouldn't, if you could get pure precursor, why wouldn't you use only that?

[00:04:28] Speaker 01:
A couple of points on that, Judge Toronto.

[00:04:30] Speaker 01:
First, there is no teaching in either of the asserted references or in the testimony that you could get purely precursor.

[00:04:39] Speaker 01:
No reference discloses that.

[00:04:41] Speaker 01:
Second, although you are correct,

[00:04:44] Speaker 01:
that there are a variety of prior art references that state that for efficient uptake into the cells, the precursor has the proper glycosylation and other markers to be recognized by the receptors.

[00:04:57] Speaker 01:
There is also teaching in the prior art that in the lysosomes, the other forms, the mature forms, are what are active.

[00:05:05] Speaker 01:
And we are talking about a disease that affects the entire body, skeleton muscle, heart muscle, liver, kidney, spleen, et cetera, et cetera.

[00:05:16] Speaker 01:
And in the earlier studies, what the data showed is that

[00:05:23] Speaker 01:
the mature form, the non-precursor form, was taken up by these other organs.

[00:05:29] Speaker 01:
Now, those other organs are affected in the disease.

[00:05:31] Speaker 01:
So it is not intuitively obvious or necessarily the right conclusion that you would want exclusively precursor.

[00:05:39] Speaker 01:
You might well want a mixture, which is what all of the other prior art references taught before the Chen patent taught and claimed exclusively precursor as the preferred embodiment to be administered to treat the disease.

[00:05:54] Speaker 03:
And in regard to the... Did some of what you just said about an affirmative benefit from having some, at least, of the mature form get testified to by the experts?

[00:06:10] Speaker 01:
There was no testimony by either party's experts on that subject.

[00:06:16] Speaker 01:
What we have is the prior art references which teach a mixture.

[00:06:22] Speaker 01:
and we have I would say a failure of proof on the part of the

[00:06:27] Speaker 01:
challenger here, Biomerin, challenging the patent to demonstrate that a exclusively precursor version of the enzyme was taught or suggested by the prior art and that there'd be a reasonable expectation of success in achieving the claimed invention, namely an effective treatment for the disease using that form of the enzyme.

[00:06:48] Speaker 03:
Did the parties have an opportunity on remand to submit anything?

[00:06:53] Speaker 01:
Yes, the opportunity exists because even before the adoption of the standard operating procedure and the board that permits that type of submission on remand, the board was permitting that.

[00:07:07] Speaker 01:
The board issued its decision on remand.

[00:07:10] Speaker 01:
Neither party requested the opportunity to submit additional evidence.

[00:07:14] Speaker 01:
Biomarin, having relied on expert declarations that were predicated on the wrong claim construction where a mixture was all that was required,

[00:07:23] Speaker 03:
And the board panel itself didn't provide a notice saying, here's the opportunity.

[00:07:30] Speaker 01:
It just went about its business.

[00:07:31] Speaker 01:
The board did not do that.

[00:07:32] Speaker 01:
It went about its business and one day a decision came in the mail.

[00:07:36] Speaker 01:
The last thing I wanted to point out on the

[00:07:39] Speaker 01:
references, Your Honor, is that it is demonstrably clear, and this is set forth in detail in our papers, that when biomerins experts were testifying about, quote, the precursor form, they were not referring to exclusively a precursor, but rather a mixture of precursor and non-precursor forms.

[00:07:58] Speaker 01:
For example, Dr. Krogan

[00:08:02] Speaker 01:
who, by the way, admitted he's not a person of ordinary skill and did not view the evidence through that lens, said Reuser, one of the two references, that the GAA, quote, produced in the examples of Reuser 771 from the milk of transgenic mammals and described in the 712 patent

[00:08:22] Speaker 01:
produced in Cho cells in Dr. Chen's lab have the same size of 110 kilodaltons, the precursor form.

[00:08:31] Speaker 01:
That's at page A722 of the appendix.

[00:08:34] Speaker 01:
That is simply not what Reuser says.

[00:08:37] Speaker 01:
Reuser describes a mixture of 110 and 76 kilodaltons, i.e.

[00:08:42] Speaker 01:
precursor and non-precursor forms.

[00:08:44] Speaker 01:
The only way these experts could have made statements like they did is by construing references to precursor as though they meant exclusively precursor, which is not, in fact, what the references say or what they teach.

[00:08:59] Speaker 01:
Turning then to the board's second error, the treatment or mistreatment of the objective indicia of non-obviousness.

[00:09:09] Speaker 01:
The evidence in this case, candidly, is off the charts.

[00:09:13] Speaker 01:
This invention provides the first and only effective approved treatment for a previously fatal disease, a breakthrough that had eluded scientists for decades.

[00:09:25] Speaker 03:
Before you talk about the specifics, did you ever say to the board, you should apply a presumption of nexus?

[00:09:37] Speaker 01:
We did not, Your Honor.

[00:09:40] Speaker 03:
Why isn't it a little hard to fault the board for not doing that?

[00:09:44] Speaker 01:
Well, because in its first opinion in this case, this court said that the board erred by failing to apply a presumption of nexus.

[00:09:56] Speaker 03:
I think the footnote says,

[00:09:58] Speaker 03:
This appears well taken.

[00:10:01] Speaker 03:
That doesn't quite say we hereby declare that something that you forfeited by not preserving is now legitimately at play.

[00:10:10] Speaker 01:
Well, the exact footnote says, notably, Duke's objection to the board's treatment of its evidence of objective indicia of non-obviousness, including its failure to apply a presumption of nexus, appear well taken.

[00:10:24] Speaker 04:
I don't understand the fuss about the presumption.

[00:10:34] Speaker 04:
a relationship, a substantial benefit.

[00:10:38] Speaker 04:
Why do you need a presumption?

[00:10:40] Speaker 01:
We actually don't.

[00:10:41] Speaker 04:
Are you saying that it can't be shown without the presumption?

[00:10:45] Speaker 04:
It would not be found?

[00:10:48] Speaker 01:
So the law on this says, as I understand it, and this is from the Alexam case and the Centricut case, that where the patent owner proves that the commercial embodiment, quote, is the patented invention.

[00:11:03] Speaker 01:
And we prove that with undisputed evidence, that the drugs, myozyme and lumozyme, that are marketed for the purpose of treating the disease with an exclusively precursor enzyme,

[00:11:15] Speaker 01:
are the invention in claim nine and they are administered by doctors according to the instructions in claim one which is from which claim nine depends so once that is established

[00:11:30] Speaker 01:
And we did have an economist, Mr. Green, who put in an extensive declaration tying the commercial success, praise, success in solving the long-felt need, et cetera, to these products and the practice claims.

[00:11:46] Speaker 05:
To exclusively precursor?

[00:11:50] Speaker 05:
Yes.

[00:11:50] Speaker 05:
Or to HGAA, because the material

[00:11:59] Speaker 05:
was in the prior art.

[00:12:02] Speaker 05:
In fact, some of it was by your own inventor.

[00:12:05] Speaker 05:
And so the board said, we find that Patent Honor does not provide evidence sufficient to permit a determination as to what long-felt need was met by any alleged novel feature, which means exclusively as opposed to, say, 50% or 90%.

[00:12:24] Speaker 01:
Correct.

[00:12:25] Speaker 01:
And there is no prior art teaching of exclusively precursor.

[00:12:30] Speaker 01:
We went over that.

[00:12:31] Speaker 01:
And there is undisputed evidence.

[00:12:34] Speaker 05:
But there is prior art teaching of the use of this material.

[00:12:36] Speaker 01:
Yes.

[00:12:37] Speaker 01:
And we are not saying that we discovered precursor.

[00:12:40] Speaker 01:
That is not our point.

[00:12:42] Speaker 01:
What we are saying is that this is the first teaching in the prior art of treating the disease with exclusively a precursor form of the enzyme.

[00:12:50] Speaker 03:
Right.

[00:12:50] Speaker 03:
But let me just, I guess, frame the question that's in my mind.

[00:12:54] Speaker 03:
why in this case the presumption might make a difference.

[00:12:59] Speaker 03:
There was remarkably little evidence from either side about whether there would have been comparable success from, let's say, Van Brie, which is just before this, and the only difference between Van Brie and this is exclusivity.

[00:13:19] Speaker 03:
If there's no evidence on that question, the presumption may decide it.

[00:13:23] Speaker 03:
But if there is no presumption and you had to show the nexus of exclusivity to success, that is, that only because of the exclusivity was their success, whereas 90% wouldn't have been successful, doesn't really sound that plausible on its face.

[00:13:44] Speaker 03:
without some evidence saying why exclusivity would make a giant difference in whether there was going to be a successful product, then the presumption might make all the difference.

[00:13:57] Speaker 03:
That's, I guess, just addressed.

[00:13:58] Speaker 01:
Yes, and Your Honor, the marketed form of the drug, the only approved version of the drug anywhere in the world,

[00:14:05] Speaker 01:
and the only one that's ever been successfully given to a patient to treat the disease is the exclusively precursor form.

[00:14:14] Speaker 03:
But why does that necessarily establish that, for example, if Van Bree was also owned by Genzyme, is that right?

[00:14:24] Speaker 01:
It was, by the time.

[00:14:25] Speaker 03:
Right, so Zhengzheng now has Van Brie in its quiver, and it has this, and it says, let's do this one.

[00:14:31] Speaker 03:
Let's not pursue Van Brie.

[00:14:33] Speaker 03:
But the nexus question is, maybe somebody else had owned Van Brie, would have pursued Van Brie, and gotten FDA approval.

[00:14:41] Speaker 03:
These are unknowns, because the record is remarkably thin.

[00:14:46] Speaker 01:
Fair enough.

[00:14:47] Speaker 01:
It is an unknown, and that's what the board said.

[00:14:49] Speaker 01:
They can't conclude on the record whether the commercial success is truly attributable to the exclusively precursor feature or Van Bree.

[00:15:00] Speaker 01:
That's the one they explicitly cited.

[00:15:02] Speaker 01:
That, Your Honor, is a failure of proof on Biomarin's part.

[00:15:06] Speaker 01:
They had the burden.

[00:15:07] Speaker 01:
We established, as the law required us to do, that the success

[00:15:13] Speaker 01:
uh... derives from the commercial success and other uh... indicia uh... derived from the use and sale of the exclusively precursor form they could have had an expert say it's really due to van bree all they did is say maybe it's due to van bree and that's not good enough under alexandre setra cutt and other cases decided by the court i see him past my rebuttal time we will save your rebuttal let's hear from the other side thank you

[00:15:49] Speaker 04:
Mr. Murphy.

[00:15:50] Speaker 04:
Yes.

[00:15:51] Speaker 00:
May it please the court.

[00:15:51] Speaker 00:
My name is Gerald Murphy, representing BioMarine Pharmaceuticals.

[00:15:56] Speaker 00:
I have a few points I'd like to make.

[00:16:00] Speaker 00:
The first is we disagree with the argument that all of the prior art teaches a mixture.

[00:16:08] Speaker 00:
I think there's a word game going on here.

[00:16:11] Speaker 00:
I think some of the prior art that had actually been used in certain early experiments.

[00:16:18] Speaker 00:
Early, I'm talking about three or four or five years before the filing date.

[00:16:26] Speaker 03:
Van Bree is roughly 95.

[00:16:29] Speaker 00:
Yeah, right around that time, from the 95 to 2000 date.

[00:16:34] Speaker 00:
They used what they had at the time, and they hadn't necessarily all purified it to the level that they might need to get FDA approval, which is basically highly pure product.

[00:16:44] Speaker 00:
They were research articles.

[00:16:47] Speaker 00:
They hadn't necessarily put it in humans yet, but the whole idea

[00:16:53] Speaker 00:
purifying this active compound, it was all over the place.

[00:16:57] Speaker 00:
And in terms of specific teachings, the two main references, I'll just point to what they actually teach.

[00:17:04] Speaker 00:
Reusser states, restoration of the endogenous alpha-glucosidase activity by alpha-glucosidase isolated from mouse milk was as efficient as restoration from the same drug from Cho cells.

[00:17:23] Speaker 00:
appendix six dash seven six and seven five thirty six

[00:17:29] Speaker 00:
And it's also, which is page 28, lines 10 to 14 of Roycer.

[00:17:33] Speaker 00:
Also, Dr. Krogan, who was our expert that spent the most time talking about purification, stated that Roycer teaches that the precursor should be, quote, highly purified.

[00:17:45] Speaker 00:
That's cited at BioLuren's brief page 4, citing APPX 642, paragraph 58 of the declaration.

[00:17:55] Speaker 00:
Turning to Van Hove 97, which is the other main reference,

[00:17:59] Speaker 00:
It says that the precursor 110 acid alpha glucosidase isolated from tissue culture medium.

[00:18:07] Speaker 00:
So it isolated doesn't say the words of the claim construction exclusively, but it's certainly isolated and there's been a lot of discussion about Van Hove and I won't go over it again.

[00:18:17] Speaker 00:
It's important that

[00:18:19] Speaker 00:
Duke ignores two important references that talk about a purifying the drug to homogeneity that were argued in our brief.

[00:18:30] Speaker 00:
And specifically, the two references are Vanbrief 410 and Fuller.

[00:18:38] Speaker 00:
And we've discussed Fuller on pages six to seven of our brief.

[00:18:42] Speaker 00:
And I'll just read a couple of quotes.

[00:18:44] Speaker 03:
Can I just ask you?

[00:18:45] Speaker 00:
Sure.

[00:18:45] Speaker 03:
What do you make of Duke's point that purification means?

[00:18:52] Speaker 03:
I guess I'll put it as two points.

[00:18:57] Speaker 03:
Never mind whether Duke makes these or not.

[00:18:59] Speaker 03:
One is purification is getting rid of what you would call impurities as opposed to getting only the precursor and not the mature.

[00:19:11] Speaker 03:
And second, even if you purify, why would you necessarily use only the purified form?

[00:19:18] Speaker 03:
Maybe you get a nice pure batch of precursor and you decide

[00:19:21] Speaker 03:
I'm going to use that mixed with 10% of mature so that the heart gets the benefit of what we think the mature one is doing.

[00:19:34] Speaker 00:
Well, all of the evidence teaches that the active form is the precursor form.

[00:19:42] Speaker 00:
The fact that once it gets to where it's supposed to be, it gets broken down into the mature form.

[00:19:47] Speaker 03:
What's the best evidence that says the only active form is the precursor form?

[00:19:54] Speaker 03:
It's everywhere.

[00:19:56] Speaker 03:
Then it should be really easy.

[00:19:57] Speaker 00:
OK.

[00:19:59] Speaker 00:
Let's see.

[00:20:00] Speaker 03:
I've seen a lot of quotes that say efficiency is greater or things like that.

[00:20:07] Speaker 00:
Well, just Van Brie 410.

[00:20:11] Speaker 00:
Van Brie indicates that a small amount of impurities can be tolerated.

[00:20:15] Speaker 00:
I guess it depends on how you interpret impurities.

[00:20:18] Speaker 00:
But basically up to about 5% can be tolerated.

[00:20:22] Speaker 00:
And the current batches are greater than 95% pure.

[00:20:26] Speaker 00:
Van Brie itself actually talks about purity of greater than 95%.

[00:20:30] Speaker 00:
That's cited in our brief.

[00:20:33] Speaker 03:
Right, but let me just try to focus.

[00:20:35] Speaker 03:
I'm interested in the question of what the mechanism of successful action in the body is.

[00:20:42] Speaker 03:
What art says the only form of the RHGAA or any form of the GAA that will do anybody any good is the precursor form.

[00:20:56] Speaker 03:
as opposed to it will do more good to have more of it.

[00:21:01] Speaker 00:
Every study that measured the activity of the precursor versus mature form found no activity, because they did actually separate them out, found no activity when the mature form was used.

[00:21:14] Speaker 00:
In fact, the very earliest study from the 1960s, and it's cited in our brief, they used a form that they didn't realize at the time was the mature form, and nothing happened.

[00:21:24] Speaker 00:
There was no benefit to the patient.

[00:21:26] Speaker 00:
I think the patient probably died.

[00:21:27] Speaker 00:
This was back in the 60s.

[00:21:29] Speaker 00:
So there was a long-felt need.

[00:21:31] Speaker 00:
But by about 1990, there was a seminal article.

[00:21:35] Speaker 00:
I don't remember which one it is right now, but we have it on our brief.

[00:21:39] Speaker 00:
They said, ah, now we know why those earlier studies failed, because they were using the mature form.

[00:21:48] Speaker 05:
And the mature form was missing something.

[00:21:50] Speaker 00:
Yeah, it's missing a piece off the end.

[00:21:52] Speaker 00:
It's an incomplete molecule.

[00:21:55] Speaker 00:
It's like you have this great drug, and if you cut the end of it off, this protein, it doesn't work anymore.

[00:22:01] Speaker 00:
And they didn't realize that back in the 60s, but that was reported in the early 90s.

[00:22:06] Speaker 00:
And then all of a sudden, about 95, there was article after article after article came out saying, hey, this is it.

[00:22:14] Speaker 00:
This is where we're going to go.

[00:22:15] Speaker 00:
We're either going to go with producing it in

[00:22:18] Speaker 00:
mammals, which is Van Bree, or Chocells, which is all of Dr. Chen's work.

[00:22:26] Speaker 00:
There's seven or eight probably publications of Dr. Chen.

[00:22:29] Speaker 00:
including press releases, everybody's working on the precursor form towards the end.

[00:22:37] Speaker 00:
And the two references, I'd like to point out that they were kind of ignored in Duke's briefs.

[00:22:46] Speaker 00:
Van Bree says, most preferably the object species is purified to essential homogeneity.

[00:22:53] Speaker 00:
The object species is obviously the precursor in the context of the invention.

[00:22:58] Speaker 00:
And then Fuller at APPX 3844 and 3839 mentions that the precursor recombinant GAA was purified to homogeneity, had a molecular mass, dot, dot, dot.

[00:23:14] Speaker 00:
So everybody, I mean there may be individual studies where they didn't know that it was homogenous, they didn't know how pure it was.

[00:23:21] Speaker 00:
But clearly everybody, Fuller specifically talks about purifying it to homogeneity.

[00:23:27] Speaker 00:
as well as Van Hove 1997.

[00:23:30] Speaker 00:
So, I mean, I think everything says use the purified molecule and our witnesses testified to that and we argued that at the board.

[00:23:39] Speaker 05:
Purified which?

[00:23:40] Speaker 05:
Precursor?

[00:23:41] Speaker 00:
Yeah, purified precursor all by itself.

[00:23:45] Speaker 00:
That's where everybody was going.

[00:23:50] Speaker 00:
So I think it's all in the briefs.

[00:23:52] Speaker 00:
There's not one scintilla of evidence that says the mature form might give some benefit.

[00:24:01] Speaker 00:
All the evidence says the precursor is where you get your benefit.

[00:24:04] Speaker 04:
That's where they were going, but nobody actually did it, produced it, put it through the system?

[00:24:10] Speaker 00:
Yeah, it hadn't gotten through FDA yet.

[00:24:12] Speaker 00:
Right.

[00:24:12] Speaker 00:
I mean, it was all in the art.

[00:24:14] Speaker 00:
It was all in the prior art.

[00:24:15] Speaker 00:
This is the good stuff, the highly purified stuff.

[00:24:19] Speaker 04:
So it would still reside in the scientific literature.

[00:24:23] Speaker 04:
Maybe even prizes would be awarded.

[00:24:25] Speaker 04:
It wouldn't be available to the public because the final proof, which

[00:24:31] Speaker 04:
is the philosophy for why the FDA has such rigorous requirements hadn't been achieved.

[00:24:39] Speaker 04:
So now, in retrospect, we say, well, that was obvious.

[00:24:43] Speaker 04:
Anybody could have done that.

[00:24:45] Speaker 04:
But if so, why are those rigorous requirements in the system?

[00:24:52] Speaker 00:
Well, that's for the safety of the patients, basically.

[00:24:55] Speaker 00:
They want to make sure it works.

[00:24:56] Speaker 00:
It's safe and effective.

[00:24:58] Speaker 00:
But just because you get FDA approval, maybe because you're the first one to get FDA approval, doesn't mean you should.

[00:25:05] Speaker 00:
It's a patentable invention where it's all over the prior art.

[00:25:09] Speaker 00:
It's just somebody's got to get the approval first.

[00:25:11] Speaker 04:
Well, it's hard to tell because the FDA statutes and all the rest have a good deal to say about patents and Orange Book and all of the...

[00:25:22] Speaker 04:
paragraph or certifications and so on.

[00:25:24] Speaker 04:
So it isn't as if these systems are operating in an unrelated matter.

[00:25:30] Speaker 04:
I'm trying to figure out how the public interest of providing products to the public ways in determining the objective obviousness.

[00:25:44] Speaker 00:
Well, so the public interest, I mean, patents are in the public interest, but there's multiple patents on this product.

[00:25:51] Speaker 00:
The Roycer got a patent.

[00:25:52] Speaker 00:
The same Roycer reference that we're talking about as a PCT publication, they got a patent.

[00:25:57] Speaker 00:
They got FDA exclusivity.

[00:25:59] Speaker 00:
They got patent term extension.

[00:26:03] Speaker 00:
That was listed as covering the product.

[00:26:04] Speaker 00:
This is all in our brief.

[00:26:06] Speaker 00:
The two Van Brie patents

[00:26:09] Speaker 00:
We're also listed as covering that patent.

[00:26:12] Speaker 05:
Are you arguing that the precursor, exclusively precursor molecule lacks novelty?

[00:26:19] Speaker 00:
Oh, yeah.

[00:26:20] Speaker 00:
Yes.

[00:26:21] Speaker 00:
I mean, right here, the molecule itself is purified to homogeneity right here in Fuller.

[00:26:26] Speaker 00:
It's in our brief.

[00:26:29] Speaker 00:
And you can see they talked about purified to homogeneity.

[00:26:32] Speaker 00:
This is from Cho cells.

[00:26:33] Speaker 00:
APX3844 and 3839.

[00:26:38] Speaker 05:
The Cho cell's limitation is critical because that's in claim 29.

[00:26:42] Speaker 05:
Sure.

[00:26:43] Speaker 05:
Sure.

[00:26:44] Speaker 00:
Yeah.

[00:26:45] Speaker 00:
That's important.

[00:26:46] Speaker 00:
One thing I'd also like to point out is that the board said that they didn't feel that Duke even

[00:26:58] Speaker 00:
prove that their product is covered by the claims of the patent.

[00:27:07] Speaker 00:
We talk about nexus.

[00:27:09] Speaker 00:
I think regardless of whether there's a presumption or no presumption, to get that presumption, you at least need to show that your claims cover your product.

[00:27:19] Speaker 00:
And I'm going to point to the board's statement

[00:27:28] Speaker 00:
in the supplemental final written decision on page 18.

[00:27:32] Speaker 00:
And I believe they may have said this twice, and I have a quote here.

[00:27:36] Speaker 00:
Just give me a moment, please.

[00:27:55] Speaker 05:
Are you assuring to in particular the record before us does not elucidate adequately the impact of the patent as compared to other relevant patents on licensing revenues?

[00:28:08] Speaker 00:
That's not what I was looking for.

[00:28:10] Speaker 00:
On page 18 of the supplemental final written decision, joint appendix page 18, patent owner does not show adequately that my... Top, bottom, where?

[00:28:21] Speaker 02:
Pardon me?

[00:28:22] Speaker 02:
Top, bottom, where?

[00:28:23] Speaker 00:
Oh, so middle of the first full paragraph.

[00:28:26] Speaker 02:
Yeah.

[00:28:27] Speaker 00:
Patent owner does not show adequately that myozyme and lumozyme are the invention disclosed and claimed in claim nine.

[00:28:35] Speaker 00:
We have, if you look at the three expert declarations, none of the three experts of Duke ever talked about administering substantial, the language here on the claim construction, exclusively the precursor.

[00:28:51] Speaker 00:
None of those three witnesses said that in their declarations.

[00:28:57] Speaker 00:
And none of them had first-hand knowledge of it.

[00:28:59] Speaker 00:
I mean, they basically said, oh, the claims cover the product.

[00:29:03] Speaker 00:
OK?

[00:29:04] Speaker 00:
So what does that mean?

[00:29:05] Speaker 00:
I mean, I think there wasn't really any real proof there that what is the approved product?

[00:29:12] Speaker 00:
do cat knows what the approved product is they never came in and even showed it they didn't have their witnesses say they're what they criticize our witnesses for not talking about the claim construction when they gave their opinions and gave their testimony and what the art teaches their witnesses didn't either they just said claim all the claims cover it they didn't there was no discussion of claim nine and what that means in terms of

[00:29:40] Speaker 00:
um, their opinions.

[00:29:41] Speaker 04:
So I think it's just, you know- But that wasn't challenged on cross-examination, was it, as to these distinctions among the claims?

[00:29:51] Speaker 00:
Uh, I don't see- it's not in the brief by either party, so I don't think it was covered in cross-examination.

[00:29:58] Speaker 04:
Well, then how can you criticize it as being somehow unsupported or rejected?

[00:30:06] Speaker 00:
I'm saying the board said patent owner does not adequately, does not show adequately that myozyme and lumizine are the invention disclosed and claimed in claim nine.

[00:30:15] Speaker 00:
That's why we're here.

[00:30:15] Speaker 00:
Yeah, right, right.

[00:30:17] Speaker 00:
I don't think that they showed it.

[00:30:19] Speaker 00:
But even if they did show it, there's four patents that covered it that were based on earlier filed work that are all listed as covering it.

[00:30:27] Speaker 00:
And there's no attempt to break down claim nine and show why claim nine is important.

[00:30:33] Speaker 00:
And there's no attempt by any of their

[00:30:35] Speaker 04:
Well, if no one challenged it, why do they have to do it?

[00:30:38] Speaker 00:
Okay.

[00:30:38] Speaker 00:
Let's go to the next thing, what was challenged.

[00:30:41] Speaker 00:
The past.

[00:30:42] Speaker 00:
That's my question.

[00:30:43] Speaker 00:
Okay.

[00:30:44] Speaker 04:
As a matter of trial procedure.

[00:30:47] Speaker 04:
Okay.

[00:30:48] Speaker 04:
If they make a statement and no one challenges it, now you're telling us that statement is not supported?

[00:30:54] Speaker 00:
I was just reporting.

[00:30:55] Speaker 00:
I was just stating what the board said.

[00:30:57] Speaker 00:
So they said they didn't adequately prove it.

[00:31:00] Speaker 00:
Their witnesses didn't break it down and talk about it like what's in the claim.

[00:31:05] Speaker 05:
Is that a fact finding to which we owe deference, what the board said?

[00:31:12] Speaker 00:
Yeah, I would say it is.

[00:31:13] Speaker 00:
The claim interpretation is legal, but whether or not they prove that it actually falls within the claim, that would be fact-finding.

[00:31:21] Speaker 03:
Is the FDA label or other FDA information in A, the record, B, the joint appendix?

[00:31:31] Speaker 03:
Yes, and so I do that.

[00:31:32] Speaker 03:
Does that say whether all of the RHGAA in the product is precursor?

[00:31:39] Speaker 00:
The answer is no, it doesn't.

[00:31:40] Speaker 00:
And I looked at the several times the evidence cited by Duke where they said, oh, we did prove it.

[00:31:48] Speaker 00:
And they cited several things from the labels or draft labels for the two products.

[00:31:54] Speaker 03:
Are those in the joint appendix?

[00:31:56] Speaker 00:
Yes.

[00:31:56] Speaker 00:
I can give you the page numbers.

[00:32:02] Speaker 00:
I believe it's joint appendix 3815 to 3817 for myozyme and 3830 to 3831 for lumozyme prescribing information.

[00:32:15] Speaker 00:
And it's not there.

[00:32:16] Speaker 00:
They didn't quote that it's there.

[00:32:19] Speaker 00:
They didn't try to say, use the language of the claim.

[00:32:22] Speaker 00:
And I looked for it.

[00:32:23] Speaker 00:
I didn't see it.

[00:32:24] Speaker 00:
It's not pointed out anywhere.

[00:32:26] Speaker 03:
And I think you said, you made a reference to the material Duke cited.

[00:32:33] Speaker 03:
Yes.

[00:32:34] Speaker 03:
What is the sum total of that material?

[00:32:36] Speaker 00:
Well, I think in their brief, the material they cited relating to the FDA is, I believe, only 3815 to 17 and 3830 to 31, maybe a page before or after that.

[00:32:51] Speaker 00:
And it's not there.

[00:32:53] Speaker 00:
There's no statement that it's homogeneous or only the precursor.

[00:33:00] Speaker 00:
It's just not there.

[00:33:04] Speaker 04:
Okay, any more questions for Mr. Murphy?

[00:33:08] Speaker 04:
Thank you.

[00:33:08] Speaker 04:
Okay, this is Allison for your rebuttal.

[00:33:15] Speaker 01:
Thank you, your honor.

[00:33:16] Speaker 01:
Let me start where we just left off.

[00:33:19] Speaker 01:
The evidence that Duke put forward as to whether the claim nine is practiced consists of declarations by doctors Wasserstein and Cummings, which can be found at page 1888 through 89 of the appendix in the case of Wasserstein and 2009 of the appendix in the case of Cummings.

[00:33:41] Speaker 01:
And what they both said is they both went through all the claims that were in dispute and said every one of these claims except claims five through seven, which deal with particular dosages that clinical practice showed were not high enough to provide the desired benefit, said all the other claims are practiced.

[00:34:00] Speaker 01:
So that would include, clearly, claim nine.

[00:34:03] Speaker 01:
Myomerin never disputed or challenged that.

[00:34:05] Speaker 01:
Second, the labeling

[00:34:07] Speaker 01:
Uh, that Mr. Murphy refers to says explicitly, uh, I'm reading for the case of my enzyme, which is at page three eight one six of the appendix.

[00:34:19] Speaker 01:
Uh, GAA is a glycoprotein with a calculated mass of.

[00:34:24] Speaker 01:
excuse me, a total mass of 110 kilodaltons, including carbohydrates.

[00:34:29] Speaker 01:
That is the precursor.

[00:34:30] Speaker 03:
I'm sorry.

[00:34:30] Speaker 03:
Just tell me what page you read.

[00:34:32] Speaker 01:
It's the first text that appears on page 3816 of the appendix.

[00:34:37] Speaker 01:
It says it's 110 kilodaltons.

[00:34:39] Speaker 01:
That is the precursor.

[00:34:41] Speaker 01:
The exact same statement appears for lumizyme at page 3831 of the appendix in the first full paragraph.

[00:34:48] Speaker 01:
Except it says 109,000 kilodaltons, which is

[00:34:53] Speaker 01:
nine kilodaltons.

[00:34:55] Speaker 01:
That's, again, the precursor form.

[00:35:00] Speaker 01:
Purification.

[00:35:02] Speaker 01:
I believe, quite honestly, that there's some confusion here about going on with respect to what is meant by purification and clearly what Biomarin's experts meant by it.

[00:35:14] Speaker 01:
Dr. Krogan, their expert, for example, said

[00:35:17] Speaker 01:
that purification referred to, quote, removing contaminants such as CHO proteins, DNA, and endogenous retrovirus, as well as adventitious virus from the finished product.

[00:35:30] Speaker 01:
That's at page 713 through 14 of the appendix.

[00:35:34] Speaker 01:
When there's a description of purified to homogeneity,

[00:35:38] Speaker 01:
There is nothing in the reference and certainly in the testimony that says that that means purifying the precursor form to homogeneity as opposed to isolating the GAA enzyme in whatever form from the medium in which it's produced, whether it's rabbit milk in the case of the transgenic mammals or cell culture medium in the case of CHO cells.

[00:36:02] Speaker 01:
Finally, with respect to Judge Newman's questions about FDA approval and what have you, this is the long felt need story in a nutshell.

[00:36:12] Speaker 01:
No one had discovered or proved an effective treatment for this disease until Dr. Chen did it with exclusively precursor material in the clinic.

[00:36:25] Speaker 01:
And that is a revolutionary invention in the treatment of this previously fatal disease for infants and children.

[00:36:31] Speaker 01:
that there is no teaching of the prior art that pointed to or suggested that, and certainly no testimony from Biomarin's experts that a person of ordinary skill in the art would have come to that invention by combining Reuser 771 with Van Hove 1997.

[00:36:49] Speaker 01:
Neither of those references contains a teaching of exclusively precursor,

[00:36:54] Speaker 01:
or suggests it, and there's no evidence that a person of ordinary skill would have gotten there.

[00:36:59] Speaker 01:
And so on that record, just like there was no sufficient evidence on claim 19, the one that this court reinstated the last time this case was before you, claim nine should be reinstated.

[00:37:09] Speaker 01:
There is no evidence from which the court can conclude that biomerin met its burden to show obviousness.

[00:37:18] Speaker 04:
Thank you.

[00:37:20] Speaker 04:
Thank you both.

[00:37:21] Speaker 04:
The case is taken under submission.