[00:00:00] Speaker 03:
as pharmaceuticals.

[00:00:37] Speaker 03:
All right, good morning.

[00:00:57] Speaker 03:
All right.

[00:00:58] Speaker 03:
Can I just ask a question about is this chart and what I guess you're asking the deputy clerk to hand out to us, is this something that's in the briefs?

[00:01:07] Speaker 02:
This is in the briefs.

[00:01:14] Speaker 02:
This is just a summary.

[00:01:28] Speaker 02:
It's just in the abstract without looking at it.

[00:01:31] Speaker 02:
But it might be helpful to the court.

[00:01:33] Speaker 02:
If it's not helpful to the court, I don't need to use that because it was just there as an agent.

[00:01:40] Speaker 02:
Should I begin?

[00:01:53] Speaker 03:
Yeah, please.

[00:01:54] Speaker 02:
May it please the court.

[00:01:56] Speaker 02:
The 886 patent essentially claims formulations of GLP2 are an analog, particularly GLI2-GLP2 histidine to stabilize the peptide, a phosphate buffer for physiological pH, and mannitol or sucrose as a bulking agent for lyophilization.

[00:02:12] Speaker 02:
The board made errors of law and errors of fact in finding the challenge claims obvious.

[00:02:17] Speaker 02:
First, the board erred in using hindsight to find the predictability required by KSR in combining Drucker with Osterberger-Kornfeld.

[00:02:26] Speaker 02:
Second, the board erred by focusing on superficial similarities between the prior archleukogon and GLP2, not the material differences as required by Graham v. Deer.

[00:02:37] Speaker 02:
Third, the board erred by summarily dismissing secondary considerations when the invention made Gadex a viable commercial product, just as in the horse decision in Millennium versus Sandoz this past July.

[00:02:49] Speaker 02:
Each error requires reversal.

[00:02:52] Speaker 02:
The board misread Osterberg and Kornfeld and then applied its erroneous findings, readings, to find predictable obviousness.

[00:03:00] Speaker 03:
It seems to me one of the difficulties you have, so maybe you can incorporate responding to this and what you're about to tell us, but you've got a battle of the experts here.

[00:03:10] Speaker 03:
And it seems like Dr. Palmieri, which was the other side's expert, right?

[00:03:14] Speaker 03:
Yes.

[00:03:14] Speaker 03:
The board seemed to credit

[00:03:17] Speaker 03:
what he said, his observations, and his conclusions.

[00:03:20] Speaker 03:
Now, you may disagree with that, and your expert might have disagreed with that, but on a substantial evidence review here, if the board has credited what this expert has said, it's kind of hard to get by that.

[00:03:34] Speaker 03:
So can you just factor that in?

[00:03:36] Speaker 03:
Because I know there's stuff on the record that you can make an argument, as you did to the board,

[00:03:43] Speaker 03:
about Dr. Palmieri's conclusions, but the board chose to credit him, and it's kind of hard to get by that.

[00:03:49] Speaker 02:
Well, Dr. Palmieri's conclusions were all based upon hindsight.

[00:03:52] Speaker 02:
There's nothing in the record that he could rely on other than his own opinion that would lead one to where he went without hindsight.

[00:04:02] Speaker 02:
For example, Osterberg talks about generally amino acids as being general stabilizers.

[00:04:08] Speaker 02:
And there, from that statement alone, you can't predict which amino acid will work for any particular protein.

[00:04:14] Speaker 02:
Osterberg is all about L-histidine.

[00:04:17] Speaker 02:
Osterberg is about L-histidine.

[00:04:18] Speaker 02:
There was a sort of oversimplification of Osterberg.

[00:04:24] Speaker 02:
The reasons to pick Osterberg, to pick histidine, from among the other amino acids that Osterberg talks about, because Osterberg, in the first page of Osterberg, says that amino acids and or sugars are general protein stabilizers.

[00:04:38] Speaker 02:
But Osterberg stands for the proposition that you pick histidine out of the hundred of differences of amino acids if you need its two other properties.

[00:04:49] Speaker 02:
That's what distinguishes histidine from all the other amino acids.

[00:04:53] Speaker 02:
He doesn't say that histidine will work for any particular peptides except for metalloproteins, factors eight and nine.

[00:04:59] Speaker 03:
But you're requiring a conclusion.

[00:05:02] Speaker 03:
I mean, there's an obvious to try, whether there's a motivation.

[00:05:07] Speaker 03:
You don't need proof here.

[00:05:09] Speaker 03:
The other site didn't need proof that it would absolutely 100% work, and the result was entirely there.

[00:05:17] Speaker 03:
We're just talking about whether or not there would have been a motivation to try based on these results.

[00:05:22] Speaker 02:
Right.

[00:05:22] Speaker 02:
And what we're saying, it was not predictable based upon what Osterberg told you about histidine and what

[00:05:30] Speaker 02:
Kornfeldt told you about glucagon.

[00:05:33] Speaker 02:
It was not predictable that histidine would function as a stabilizer in a formulation that already had a buffer, that already had a lyophilization aid, because... Didn't Paul Mary conclude otherwise?

[00:05:49] Speaker 02:
Yes, he did, and he was incorrect.

[00:05:51] Speaker 02:
And I'll explain to you why.

[00:05:52] Speaker 00:
That gets to the substantial evidence question.

[00:05:54] Speaker 00:
No, it gets actually to the fact that... You can stand up here and say that the expert is wrong, but

[00:05:59] Speaker 00:
That's not our job to make a fact finding about whether the expert was right or wrong.

[00:06:05] Speaker 00:
That's up to the board.

[00:06:06] Speaker 02:
It gets to the point that the findings that the board made were clearly erroneous based upon what the... That's the wrong standard.

[00:06:15] Speaker 00:
It's not clearly erroneous.

[00:06:16] Speaker 00:
It's substantial evidence.

[00:06:17] Speaker 02:
Well, there is substantial evidence going the other way.

[00:06:20] Speaker 00:
The substantial evidence... You lose.

[00:06:23] Speaker 00:
I mean, substantial evidence going the other way doesn't help you if there's substantial evidence to support what the board did.

[00:06:29] Speaker 02:
There isn't substantial evidence to support with the board.

[00:06:31] Speaker 02:
That's the problem.

[00:06:32] Speaker 02:
Dr. Palmieri relied upon superficial similarities between glucagon and GLP-2 rather than looking at the differences.

[00:06:41] Speaker 03:
I mean, we're here as a court of review.

[00:06:44] Speaker 03:
That's the job of the board.

[00:06:46] Speaker 03:
You bring in your expert, they bring in their expert, and you each make your arguments, and the board evaluates those two and picks between them or comes up with some combination of them.

[00:06:56] Speaker 02:
But the error of law was that he did not do what Grandiere said was to look at the differences between the prior art and the present invention.

[00:07:04] Speaker 02:
What he looked at were superficial similarities.

[00:07:07] Speaker 02:
The differences are overwhelming in favor of the fact that it's not obvious.

[00:07:12] Speaker 02:
The similarities were irrelevant.

[00:07:14] Speaker 02:
They were irrelevant in fact and they were irrelevant in law under Grandiere.

[00:07:19] Speaker 02:
Didn't he recognize that there were some similarities?

[00:07:22] Speaker 02:
He recognized some similarities, yes, but the similarities were irrelevant.

[00:07:26] Speaker 02:
He recognized similar name, similar family, similar number of amino acids.

[00:07:33] Speaker 02:
That's all he recognized.

[00:07:34] Speaker 02:
However, the differences that he did not recognize and didn't explore, he even testified he did not go to them, were differences in optimum pH, differences in solubility.

[00:07:46] Speaker 02:
And you had an expert that outlined that.

[00:07:48] Speaker 02:
Yes, absolutely, Dr. Carpenter.

[00:07:50] Speaker 02:
Dr. Comperer outlined all those differences, and he did not look at the degradation pathways.

[00:07:55] Speaker 02:
He did not look at the dissimilarities between the two peptides, glucagon and Li2-GLP2.

[00:08:03] Speaker 02:
The white amino acids are the dissimilarities, the differences.

[00:08:07] Speaker 02:
There are many more.

[00:08:08] Speaker 02:
He didn't look at the differences in degradation of susceptible amino acids.

[00:08:12] Speaker 02:
They're in color.

[00:08:13] Speaker 02:
There are differences in position and in place.

[00:08:16] Speaker 01:
What is it that you can point us to as evidence

[00:08:20] Speaker 01:
Something that's evidence-based that can tell us that the board was wrong here because it was quite clear to one of ordinary skill in the art at the time the invention was made that these differences, whatever differences you want to point at, would make a critical difference to a skilled artisan in choosing what kind of amino acid, what kind of excipient to add to the active ingredient in order to stabilize it for long-term storage.

[00:08:51] Speaker 02:
Clellan tells you that the most important thing to look at, the most important thing to look at for any kind of stabilization, any kind of formulation for a peptide is degradation, degradation pathways.

[00:09:01] Speaker 02:
Dr. Palmieri testified that he never, ever, ever looked at that.

[00:09:06] Speaker 02:
It wasn't important to him.

[00:09:08] Speaker 02:
The prior art showed him that histidine would work and therefore the patent showed that it worked and therefore it worked.

[00:09:14] Speaker 01:
Trouble I have with the case is that

[00:09:19] Speaker 01:
The board looked to Osterberg, which came after Clayland.

[00:09:23] Speaker 01:
It was published after Clayland.

[00:09:25] Speaker 01:
And Osterberg could be read broadly as to say, you know, we all know we need to stabilize these proteins for long-term storage.

[00:09:36] Speaker 01:
And now I'm going to study L-histadine to add.

[00:09:42] Speaker 01:
And L-histadine seems to do well as a stabilizer.

[00:09:46] Speaker 01:
It also works as a buffer, too.

[00:09:48] Speaker 01:
But there's advantages to using L-histidine.

[00:09:51] Speaker 01:
And it doesn't in any way say, well, don't use L-histidine for certain kinds of proteins that have certain kinds of physical characteristics, which glucagon-like protein too happens to have.

[00:10:05] Speaker 01:
But that's the concern I have is that here the board relied on a teaching from Osterberg.

[00:10:13] Speaker 01:
It seems kind of broad, the teaching, arguably.

[00:10:16] Speaker 01:
And then Kornfeldt,

[00:10:18] Speaker 01:
clearly teaches the use of histidine along with mannitol to stabilize glucagon.

[00:10:27] Speaker 01:
And so now we have, we also know that there's an important goal to stabilize glucagon-like peptide 2, your active ingredient, and so there is some reason to believe that you would use

[00:10:43] Speaker 01:
the histidine, taught by Osterberg and also taught by Kornfield.

[00:10:47] Speaker 02:
And this is where the board misread Osterberg when saying it's an oversimplification of Osterberg.

[00:10:52] Speaker 02:
The first thing Osterberg says in general, which is what you alluded to, is sugars and or amino acids are often included in formulations to prevent inactivation during freeze-drying and to stabilize the protein during long-term storage.

[00:11:04] Speaker 02:
That's in appendix 247.

[00:11:06] Speaker 02:
However, histidine is one of

[00:11:09] Speaker 02:
hundreds of amino acids, because even Kornfeld uses non-naturally occurring amino acids and dipeptide amino acids.

[00:11:15] Speaker 02:
So now, what else does Osterberg say?

[00:11:19] Speaker 02:
Osterberg adds that histidine, histidine in particular, is useful if you need one of two other properties, each of which is irrelevant here.

[00:11:29] Speaker 02:
The two other properties that Osterberg talks about with histidine is that it may act as a buffer, that's Appendix 2247, and that it may

[00:11:38] Speaker 02:
work to stabilize metalloproteins, factors 8 and 9, by being a metal ion scavenger, and that's at appendix 2253.

[00:11:46] Speaker 02:
That's why it calls histidine multifunctional, and that's why it says histidine may be particularly good.

[00:11:52] Speaker 02:
Now, let's go back to the other priority.

[00:11:54] Speaker 02:
Drucker taught using a phosphate buffer with GLP2, and that's exactly what the 886 patent uses.

[00:12:00] Speaker 02:
There's no need for another buffer, the histidine buffer property.

[00:12:04] Speaker 02:
There's no need for that with GLP2.

[00:12:07] Speaker 02:
As a matter of fact,

[00:12:08] Speaker 02:
at appendix 5135 and 5137, you'll find that Dr. Carpenter testified that buffer competition would teach away from using histidine in combination with phosphate or any other buffer, because buffers can interact with one another and offset one another.

[00:12:23] Speaker 02:
Now Drucker also taught that lyophilization of Gly2-GLP2 can be done without an amino acid, because Drucker talked lyophilized GLP2 without an amino acid.

[00:12:36] Speaker 02:
So there's no need, according to Drucker, to have an amino acid in this formulation to help in lyophilization.

[00:12:44] Speaker 02:
The present formulations also do not include any metal ions.

[00:12:48] Speaker 02:
So you don't need a metal scavenger.

[00:12:50] Speaker 02:
And the present formulation is not a metalloprotein.

[00:12:53] Speaker 02:
So you don't need an amino acid that stabilizes metals.

[00:13:00] Speaker 02:
There's nothing there that says, out of all the amino acids,

[00:13:04] Speaker 02:
that are often included in formulations to prevent inactivation during freeze drying and stabilize proteins use histidine with the kind of protein or peptide that you have GLP2.

[00:13:15] Speaker 02:
Now let's go over to Kornfeld.

[00:13:19] Speaker 02:
Kornfeld is directed specifically to glucagon.

[00:13:23] Speaker 02:
The only reason why you would take the teachings of Kornfeld and apply them to GLP2 or Gly2-GLP2

[00:13:33] Speaker 02:
is if you found some substantial similarity, or that the differences between glucagon and GLP-2 are not significant, are not material.

[00:13:43] Speaker 02:
But that's not the case.

[00:13:45] Speaker 02:
Dr. Palmieri found simply superficial similarities.

[00:13:50] Speaker 02:
Same names.

[00:13:51] Speaker 02:
That's nonsense.

[00:13:52] Speaker 02:
Same family.

[00:13:54] Speaker 02:
So what?

[00:13:54] Speaker 02:
There are 15 other proteins in that family also.

[00:13:58] Speaker 02:
No one could testify.

[00:13:59] Speaker 02:
Dr. Palmieri could not testify.

[00:14:01] Speaker 01:
They could stay below.

[00:14:02] Speaker 01:
I guess you're saying, why would you?

[00:14:04] Speaker 01:
I mean, another way of asking the question is, why wouldn't you?

[00:14:08] Speaker 02:
Because if you put another buffer in, then you have buffer competition.

[00:14:14] Speaker 02:
You may ruin the buffering capability of phosphate.

[00:14:17] Speaker 02:
And if you put an ion scavenger in there, there's a very strong statement by Dr. Carpenter

[00:14:24] Speaker 02:
that you can't add excipients to a formulation willy-nilly.

[00:14:40] Speaker 02:
There needs to be data to show that adding that excipient will aid the formulation.

[00:14:46] Speaker 02:
There was no data at all that showed

[00:14:50] Speaker 02:
that anything adding histidine would aid that formulation.

[00:14:53] Speaker 02:
There was data that showed that histidine might hurt that formulation by acting as a competing buffer.

[00:14:59] Speaker 02:
So you wouldn't go to histidine.

[00:15:02] Speaker 02:
And even if you would try, there's no expectation of success.

[00:15:04] Speaker 02:
But that's precisely right.

[00:15:05] Speaker 02:
And also, it was explained in the Carpenter article and in the Carpenter book chapter that you needed a detailed knowledge of the protein as a prerequisite to making choices for excipients.

[00:15:18] Speaker 02:
In other words, even if you had this list of excipients,

[00:15:20] Speaker 02:
And histidine was the greatest stabilizer in the world, which it isn't.

[00:15:25] Speaker 02:
It's like everything else for anything that we might use it for.

[00:15:28] Speaker 02:
So there's hundreds of them.

[00:15:30] Speaker 02:
But if you want to use it as a buffer, that's a good indication to use it.

[00:15:33] Speaker 02:
If you want to use it as a metal ion scavenger, that's a good indication to use it.

[00:15:36] Speaker 02:
But without detailed knowledge of the protein itself, which is GLP2 here, and that was not anywhere in the prior art.

[00:15:44] Speaker 02:
That was in our patent.

[00:15:46] Speaker 02:
There was no way to tell whether a protein would cooperate.

[00:15:50] Speaker 02:
Now Dr. Carpenter said in his article that it was unpredictable whether a protein would cooperate in formulation and would be illogical or would be illogical or inconsistent.

[00:16:01] Speaker 02:
That's in appendix 3176.

[00:16:02] Speaker 02:
That's the essence of unpredictability.

[00:16:05] Speaker 02:
So you have no indication to use histidine from Osterberg for GLP2 or in this formulation because you don't need histidine as a buffer and you don't need histin

[00:16:19] Speaker 02:
Histidine is an ion scavenger, and you have no indication at all.

[00:16:23] Speaker 01:
You need it as a stabilizer, and it was used in Kornfeldt as a stabilizer.

[00:16:27] Speaker 02:
It was used in Kornfeldt as a stabilizer, but histidine is used in many formulations of stabilizer.

[00:16:33] Speaker 02:
Why would you go from glucagon to GLP2?

[00:16:36] Speaker 02:
There's no rational reason to go from glucagon to GLP2 other than the fact that they have the same name and come from the same family.

[00:16:44] Speaker 02:
Now, even Dr. Palmieri, who said, oh, there's sequence similarity,

[00:16:47] Speaker 02:
He ran away from that.

[00:16:48] Speaker 02:
He disavowed that.

[00:16:50] Speaker 02:
And that's in the brief.

[00:16:51] Speaker 02:
He absolutely disavowed it.

[00:16:52] Speaker 02:
He said, I'm not relying on that.

[00:16:53] Speaker 02:
The reason why you would go is it's one of ordinary skill in the art where the formulation scientists went to look at these two peptides here and said, look at the degradation pathways.

[00:17:04] Speaker 02:
They're all different, different places, different amino acids, different similarities in sequence.

[00:17:09] Speaker 02:
Now, there's one other thing that Dr. Palmieri talked about, and that was you need to stabilize an alpha helix.

[00:17:16] Speaker 02:
An alpha helix is essential to stability.

[00:17:18] Speaker 02:
And that was his mantra all the way through.

[00:17:20] Speaker 02:
You've got to stabilize them because both glucagon, the similarity, unsimilarity, was glucagon and GLP2 both have an alpha helix.

[00:17:29] Speaker 02:
That is totally unsupported by the evidence.

[00:17:31] Speaker 02:
Totally unsupported.

[00:17:34] Speaker 02:
Knudsen said, Knudsen at 21, 28, and 30, said that glucagon has structural heterogenicity in liquid or lyophilized form.

[00:17:42] Speaker 02:
No alpha helix.

[00:17:43] Speaker 02:
Knudsen said that GLP2

[00:17:45] Speaker 02:
is expected to be highly flexible and unstable.

[00:17:48] Speaker 02:
Blendel said that receptor-induced secondary structure is absent from a formulation.

[00:17:53] Speaker 02:
Fang said maintaining secondary structure is not a prerequisite for glucagon in stability in lyophilized form.

[00:18:02] Speaker 02:
Everything said that everything that Dr. Palmieri relied upon for similarities didn't mean a thing, and he never, ever looked at integration pathways, which were very important.

[00:18:14] Speaker 02:
He could not show, we have to look at the differences between glucagon and GLP-2, and he never ever said that the differences were not significant.

[00:18:23] Speaker 01:
This is just my last question.

[00:18:25] Speaker 02:
Sure.

[00:18:28] Speaker 01:
What is the evidence in the record that tells me that the degradation pathway is so critical?

[00:18:35] Speaker 01:
I understand that Dr. Carpenter says the distinction in degradation is critical to choosing what stabilizer to pick, but what

[00:18:44] Speaker 01:
else besides him saying it?

[00:18:46] Speaker 02:
Cleland.

[00:18:48] Speaker 02:
Cleland at 3118.

[00:18:50] Speaker 02:
Cleland says degradation pathways are extremely important.

[00:18:54] Speaker 02:
That's known.

[00:18:54] Speaker 02:
Can I say one other thing before we leave?

[00:18:57] Speaker 02:
Secondary considerations real quickly.

[00:18:59] Speaker 02:
The secondary considerations here, the board disregarded secondary considerations because the board did not give any credit to the fact that there was a long felt need

[00:19:13] Speaker 02:
or that there was commercial success.

[00:19:17] Speaker 02:
However, the Millennium case that this court decided in July clearly shows that, it's right on point, and that this was, this invention, the 86 patent made Gatix a commercially viable product.

[00:19:32] Speaker 02:
It was not viable alone.

[00:19:34] Speaker 02:
The Act of Alone was not a viable product.

[00:19:36] Speaker 02:
Liophilization alone was not a product.

[00:19:38] Speaker 02:
The commercialization

[00:19:40] Speaker 02:
the commercial success and the long felt need are attributable to the formulation.

[00:19:44] Speaker 02:
And the board completely disregarded that.

[00:19:47] Speaker 03:
Thank you.

[00:19:48] Speaker 02:
Thank you.

[00:19:49] Speaker 03:
We have your argument.

[00:19:50] Speaker 03:
The case is submitted.

[00:19:51] Speaker 02:
Thank you.