[00:00:45] Speaker 04:
OK, the next argued case is number 191368.

[00:00:50] Speaker 04:
So no favor, it is Deutschland against My Land Pharmaceuticals.

[00:00:55] Speaker 04:
Mr. Banks.

[00:00:56] Speaker 03:
Good morning, Your Honor.

[00:00:57] Speaker 03:
May it please the Court.

[00:00:59] Speaker 03:
A remand is required here at a minimum for the PTAB to correct a critical omission in its final written decisions.

[00:01:06] Speaker 03:
The PTAB failed to find, as required,

[00:01:09] Speaker 03:
that a glargine aggregation problem would have motivated an artisan to modify the FDA-approved and stability-tested glargine formulation by adding a surfactant.

[00:01:21] Speaker 03:
And the reason that that failure was critical here is because an artisan would have also understood that glargine depends, indeed requires, a certain amount of aggregation to work, that is to provide its long-acting effect.

[00:01:34] Speaker 03:
Instead of making findings about glargine aggregation or a glargine aggregation problem,

[00:01:39] Speaker 03:
the PTab made findings about aggregation involving naturally occurring insulins that, unlike Glargine, do not depend on beneficial aggregation to do their job.

[00:01:49] Speaker 03:
So ultimately, the PTab never addressed the critical question here about whether an artisan would have added a surfactant to address a Glargine aggregation problem.

[00:01:58] Speaker 03:
And that's what requires a remand here.

[00:02:01] Speaker 03:
And it's clear from this court's cases and from the precedent from KSR on through Nubasev that this court decided, and Magnam Oil and others,

[00:02:09] Speaker 03:
that the PTAB analysis must be thorough in searching, that there's a need for specificity in the PTAB's findings, that it cannot simply make a conclusory analysis.

[00:02:19] Speaker 03:
It cannot merely summarize the party's arguments and reject them without explaining why.

[00:02:24] Speaker 03:
But that's exactly what the PTAB did here with respect to this issue.

[00:02:29] Speaker 03:
And so.

[00:02:29] Speaker 01:
So tell me, I guess, tell me why the following is wrong as a characterization of what the board

[00:02:39] Speaker 01:
did, that the board looked at the evidence, including some passages in the specification, but not by any means only that, and said that evidence would have reasonably been read by relevant artisans to say, as a general matter, there's an aggregation risk with insolence.

[00:03:07] Speaker 01:
Sanofi came back and said, has evidence that tries to persuade us that glargine is really an exception to that general recognition of a risk.

[00:03:21] Speaker 01:
We're more persuaded by the opposite evidence that we don't think that glargine would have been understood by relevant artisans to be outside the category of aggregation risk insolence.

[00:03:37] Speaker 01:
And then pretty much similar on the surfactant is a recognized potential solution to that problem.

[00:03:45] Speaker 03:
So I have two responses to that, Judge Toronto.

[00:03:47] Speaker 03:
The first is if you look at the PTAB's actual decision at pages 38 and 39, that's where they consider or they purport to consider the issue I just described, which is the failure of

[00:03:59] Speaker 03:
An artisan's understanding that a surfactant could interfere with Glargine's unique mechanism of action that sets it apart from all the other insulins that it looked at.

[00:04:10] Speaker 03:
And if you look at those pages, you don't see that answer there because they didn't address that question.

[00:04:14] Speaker 03:
They didn't ever answer the question, why an artisan knowing that one of the key differentiations between Glargine and other insulins is the fact that it does precipitate upon injection and that needs that aggregation in order to work.

[00:04:27] Speaker 03:
why that would dissuade or would have told an artisan that a surfactant should not be added.

[00:04:32] Speaker 03:
They simply didn't make that finding or draw that conclusion.

[00:04:35] Speaker 03:
Their analysis, to the extent there was any, was that because surfactants had worked with other insulins, they would also work with glargine.

[00:04:43] Speaker 03:
But that doesn't answer the question about whether an artisan would have drawn that answer knowing the differences that we pointed out relating to glargine.

[00:04:52] Speaker 03:
And the second more general response I would have to that

[00:04:56] Speaker 03:
is that the PTAB's own findings in this regard, with respect to the propensities of insulins to aggregate, was that they're all of a matter of degree in the end.

[00:05:05] Speaker 03:
That an insulin of different types aggregates at different degrees.

[00:05:08] Speaker 03:
They made that finding.

[00:05:09] Speaker 03:
They also made a finding that the container matters, that the insulins aggregate more readily in pumps than in other devices.

[00:05:18] Speaker 03:
But they never made the finding, and this is, again, the critical point,

[00:05:22] Speaker 03:
that the amounts or degree of aggregation in Glargine would have been sufficient to motivate an artisan to modify the Glargine formulation, particularly given all of the other evidence that we know that an artisan would have understood about Glargine at the time.

[00:05:37] Speaker 03:
Number one, like I mentioned, that it depends on aggregation upon injection to work.

[00:05:41] Speaker 03:
But at the same time, the Lantus label tells you that it's clear and colorless in its solution.

[00:05:46] Speaker 03:
Secondly, they would have known

[00:05:48] Speaker 03:
that if all the other vial formulations of insulin on the market, none of them contained a surfactant to address an aggregation problem.

[00:05:55] Speaker 03:
They would have known from the prior art that Myelin itself cited that insulin formulations in vials were uniformly stable and didn't require additional surfactants or anything else to stabilize them.

[00:06:07] Speaker 02:
I thought the motivation was the idea that it was known that other insulins had a problem with

[00:06:18] Speaker 02:
some kind of aggregation, that when you store them in glass vials, that those hydrophobic surfaces have a tendency to induce aggregation.

[00:06:30] Speaker 02:
Same with the air space that's in the vials.

[00:06:34] Speaker 02:
That when your insulin is acidic, there's a higher tendency to have aggregation.

[00:06:43] Speaker 02:
And when your insulin is

[00:06:47] Speaker 02:
more monomeric, then you're also going to be having a higher tendency for aggregation.

[00:06:56] Speaker 02:
And that's precisely how glare gene is stored and marketed.

[00:07:03] Speaker 02:
It's in a glass vial with some air space.

[00:07:05] Speaker 02:
It's acidic.

[00:07:06] Speaker 02:
It's got monomers running around in it.

[00:07:09] Speaker 02:
So therefore, when you put all that together, when knowing that even

[00:07:15] Speaker 02:
other insulins at the neutral pH have had problems with aggregation.

[00:07:22] Speaker 02:
And then the Lantus label says, definitely don't take this if it looks cloudy to you.

[00:07:28] Speaker 02:
There's enough of a collective concern through all those factors for the board to find, yeah, one would be motivated to try to

[00:07:39] Speaker 02:
address potential concerns that glare gene, just like all these other insulins, and we don't know of any other insulins that don't have any susceptibility to aggregation, we'd want to try to address this concern with glare gene.

[00:07:55] Speaker 03:
So my response to that, and I think there's several pieces of that evidence that I think, for example, the cloudiness issue that the board didn't end up relying on that.

[00:08:05] Speaker 03:
So that's not really a basis that this court can use to affirm.

[00:08:08] Speaker 03:
But with respect to the remainder of it, I think, again, the question is, what would an artisan have known at the time?

[00:08:13] Speaker 03:
And as to many of those factors, we showed that, for example,

[00:08:17] Speaker 03:
With the delivery device, there was no other insulin sold in a vial that had surfactant or addressed an aggregation problem.

[00:08:25] Speaker 03:
So again, it's a question of degree.

[00:08:27] Speaker 03:
With respect to the acidic pH, we showed that, yeah, it was designed to be acidic on purpose, because that allowed for glargine to aggregate once it was injected.

[00:08:39] Speaker 02:
But there was something in the prior art that suggested that acidic insulins are

[00:08:45] Speaker 02:
that have a higher tendency to aggregate?

[00:08:49] Speaker 03:
That's correct, but that was about prior art insulins and naturally occurring insulins, not glargine, which was designed fundamentally differently and was designed to be both clear in its solution and not aggregate in solution and to aggregate upon injection.

[00:09:03] Speaker 03:
And that's what an artisan would have understood about the invention of glargine at the time.

[00:09:07] Speaker 03:
But the PTAP never really found that

[00:09:11] Speaker 03:
Regardless of whether there was any propensity or tendency to aggregate based on all the factors that you mentioned, the PTEP understood it was a matter of degree, but never found that that degree would have motivated an artisan to modify enlarging.

[00:09:23] Speaker 03:
In particular, given its unique mechanism of action in which a surfactant was thought to disrupt and interrupt that mechanism.

[00:09:31] Speaker 03:
And that's a key finding that the board simply didn't make.

[00:09:35] Speaker 01:
But what do you make of the sentence right at the top of column three?

[00:09:41] Speaker 01:
that says, especially, and this is right after, this is a paragraph talking about glargine, right?

[00:09:48] Speaker 01:
This is, especially at acidic, because it's just said glargine gets injected at acidic, in an acidic solution.

[00:09:55] Speaker 01:
Especially at acidic pH, insulins, however, show a decreased stability and an increased proneness to aggregation on thermal and physical mechanical stress.

[00:10:07] Speaker 01:
which can make itself felt in the form of turbidity and precipitation particle formation.

[00:10:13] Speaker 01:
Citing something in 1997, which is before the priority date here.

[00:10:18] Speaker 03:
So two responses.

[00:10:19] Speaker 03:
Number one, the article that's cited here doesn't concern glargine.

[00:10:23] Speaker 03:
It concerns bovine insulin, if I'm not mistaken.

[00:10:26] Speaker 01:
But the specification is invoking this in talking about a problem that

[00:10:36] Speaker 01:
In talking about insulin, glargine, having just said, we've had some good luck with doing this because of glargine's properties with using an acidic solution, but now there's this other problem.

[00:10:50] Speaker 01:
And one of the ways we know there's this other problem is a 1997 article that says, mix insulin and acids.

[00:10:57] Speaker 01:
Not so good.

[00:10:58] Speaker 03:
Sure.

[00:10:58] Speaker 03:
And so my understanding of this is the inventors are describing the problem that they've identified in our salt.

[00:11:04] Speaker 03:
And that's the reason why they

[00:11:05] Speaker 03:
they've connected here in the specification, the acidic.

[00:11:11] Speaker 02:
You don't think this portion of the background section is reporting out what this prior art reference branch at all is disclosing?

[00:11:21] Speaker 03:
Well, I agree that it's disclosing what branch is disclosing, or Brongay.

[00:11:25] Speaker 03:
Brongay.

[00:11:26] Speaker 03:
But I've made that mistake many times.

[00:11:28] Speaker 03:
That's fine.

[00:11:31] Speaker 03:
But again, it wasn't disclosing anything about glargine.

[00:11:33] Speaker 03:
And so what the inventors here are doing is linking a disclosure in the prior art relating to other insulins to glargine, which has never been done before in any of the prior art cited anywhere in this matter.

[00:11:45] Speaker 03:
And so that's what the contributions here and in the next paragraph of this spec are doing.

[00:11:48] Speaker 03:
They're the inventors invoking their own knowledge and their own contributions to connect what the prior art said might happen

[00:11:55] Speaker 02:
with certain other insulins to glargine when, you know, that was an unexpected result based on all... There seems to be evidence in the record that there were other insulins that had trouble with aggregation.

[00:12:06] Speaker 02:
And then there were certain factors that were known to cause those aggregation problems.

[00:12:13] Speaker 02:
Is there evidence in the record that there were still other insulins that

[00:12:18] Speaker 02:
never had any problem with aggregation.

[00:12:21] Speaker 02:
And so therefore, what we've got on our hands is kind of a mixed record where, OK, we've got some insulins that have an aggregation problem, and that was known.

[00:12:30] Speaker 02:
And so there's perhaps reason to believe that clarygine as an insulin would also share that aggregation problem.

[00:12:37] Speaker 02:
But no, there's actually a lot of other insulins out there that have never any reported aggregation problem.

[00:12:43] Speaker 03:
So my response to that is that the market of insulins that were sold in a vial like glargine did, none of them had a surfactant to address any problem with aggregation.

[00:12:53] Speaker 03:
And so an artisan would have been especially reluctant to add a surfactant to glargine, especially given what it knew about what glargine needed in terms of the desirable aggregation to work.

[00:13:03] Speaker 03:
And so I don't know the answer that whether there was anything that definitively said there was no aggregation problem.

[00:13:08] Speaker 03:
But an artisan looking at the available market said, none of these other vile insulins have done anything about an aggregation problem to add anything that's necessary.

[00:13:16] Speaker 03:
And so an artisan would be especially reluctant to modify an already approved, already stability tested

[00:13:23] Speaker 03:
formulation to add something additional when it thought that something additional could be a counterindication for the actual operation of the molecule.

[00:13:32] Speaker 03:
I see I'm into my rebuttal time.

[00:13:34] Speaker 04:
Let's hear from the other side.

[00:13:35] Speaker 04:
Thank you.

[00:13:36] Speaker 00:
Mr. Karsten.

[00:13:46] Speaker 00:
Thank you, Your Honor.

[00:13:47] Speaker 00:
Good morning, and may it please the Court.

[00:13:50] Speaker 00:
What we have here

[00:13:51] Speaker 00:
Well, let me first answer the question that my learned friend didn't answer for you, Judge Chen, and that is there is no evidence in the record of an example of an insulin that has no aggregation.

[00:14:02] Speaker 00:
Certainly, if there were such evidence in the record, my friend would have been able to point to a chapter and verse readily and was unable to.

[00:14:11] Speaker 00:
What Sanofi's position here is,

[00:14:13] Speaker 00:
They don't think that the board below paid enough attention to the fact that they think that glargine is special, that glargine is different.

[00:14:22] Speaker 00:
That's a factual determination.

[00:14:24] Speaker 00:
And there was ample record evidence presented below that led to three, I think, fundamental and critical

[00:14:33] Speaker 00:
factual findings below that are supported by more than a mere scintilla of evidence.

[00:14:38] Speaker 00:
And I think Judge Chan and Judge Duronto, both of you identify some of those factual findings in the context of your questions.

[00:14:47] Speaker 01:
You're not relying on the proposition that anything that is more than a mere scintilla suffices, are you?

[00:14:53] Speaker 00:
No, I think there's certainly all of these.

[00:14:55] Speaker 00:
I think that's the legal standard through which.

[00:14:58] Speaker 01:
I'm not sure that is the legal standard.

[00:15:01] Speaker 01:
Substantial evidence first has to be more than a scintilla, and then it also has to reasonably support.

[00:15:07] Speaker 01:
So the scintilla thing is doing no work.

[00:15:09] Speaker 01:
It has to reasonably support the conclusion.

[00:15:11] Speaker 00:
Fair enough.

[00:15:11] Speaker 00:
And I think, Judge Stronto, we do have more than ample evidence which absolutely supports each of these critical factual findings.

[00:15:19] Speaker 00:
The first is at the final written decision at page 32.

[00:15:22] Speaker 00:
Where the the panel the board below says the record supports that an ordinarily skilled artisan would not have suspected insulin Glargine to behave differently than other insulins due to differences in amino acids between them when exposed to hydrophobic surfaces That's on page.

[00:15:38] Speaker 00:
That's a page 32 a ppx 32 and page 32 of the final written decision as it pertains to one of the two they are

[00:15:45] Speaker 00:
essentially identical, but for these two patents.

[00:15:49] Speaker 00:
So this notion that the board didn't even consider this idea or this factual presentation by Sanofi that insulin glargine is special is just incorrect.

[00:16:00] Speaker 00:
They just disagree with what the board did.

[00:16:03] Speaker 00:
Secondly, the board at the final written decision on page 36 went further and said, we find that a person of ordinary skill in the art would have had an additional reason to be concerned about aggregation in the insulin-glargine formulations that the Lantus label and Owens disclosed.

[00:16:19] Speaker 00:
This is again, final written decision, page 36.

[00:16:23] Speaker 00:
they did consider insulin glargine specifically and rendered a factual determination supported by ample record evidence to say, no, no, no, it's not different.

[00:16:35] Speaker 00:
And then furthermore, if you look at page 35 of the final written decision, APPX 35, the board considered that to the extent that glargine was different, that that difference actually led to an enhanced risk

[00:16:50] Speaker 00:
of potential aggregation.

[00:16:53] Speaker 00:
This is on the Jones reference.

[00:16:55] Speaker 00:
They say, rather, we consider Jones for what it would have taught the ordinary artisan, that insulin glargine is more monomeric than other insulin preparations.

[00:17:06] Speaker 00:
And Your Honor, Judge Chen, you're absolutely right to point out that that's one of the risk factors identified by the branch or Brangue reference that we talk about.

[00:17:15] Speaker 00:
There's two Brangue references, our exhibits 1014

[00:17:20] Speaker 00:
and 1015.

[00:17:21] Speaker 00:
They appear in the record.

[00:17:23] Speaker 00:
It's the first page of 6760 and 6797.

[00:17:27] Speaker 00:
The Bronga 97 reference that that specification reference, column three, pointed to is the Bronga reference, exhibit 1015, which starts at page 6797.

[00:17:39] Speaker 00:
While these Bronga references don't identify Glargian specifically, they do talk about the risk factors

[00:17:45] Speaker 00:
that relate to aggregation of insulins generally.

[00:17:49] Speaker 00:
And if you look further on column 3 of the specification, at column 3, I think it's lines 32 through 37, and this would be for the 652 patent at APPX 1006, you'll see that Sanofi themselves, in the context here, didn't distinguish glargine at all.

[00:18:14] Speaker 00:
They said the present invention was thus based on the object of finding preparations for acid soluble insulins.

[00:18:22] Speaker 00:
Insulins.

[00:18:23] Speaker 00:
Not this is something magic and specific to insulin glargine.

[00:18:27] Speaker 00:
They themselves were lumping glargine in together.

[00:18:30] Speaker 00:
And if you don't want to look at the specification to render that conclusion, you need look no further than the Lantis label itself, which is one of the primary references that Mylon relied upon below.

[00:18:43] Speaker 00:
Did the board rely on it?

[00:18:44] Speaker 00:
The board did.

[00:18:45] Speaker 01:
I think Mr. Banks said, I think in response to one of Judge Chen's questions, that the Lantus label warned patients not to use vials in which the liquid was cloudy, which makes clear that there's some recognition of a potential

[00:19:09] Speaker 01:
for cloudiness, which I assume everybody agrees in this context, equates to aggregation.

[00:19:16] Speaker 01:
I believe that's correct.

[00:19:18] Speaker 01:
But I think he said the board did not rely on that.

[00:19:21] Speaker 00:
The board, at various points in its decision, says based upon the record as a whole in its analysis.

[00:19:28] Speaker 00:
And in the front piece of the board's decision, and here I'm at APPX 19, in which they're describing the import of the various prior art materials that were cited.

[00:19:41] Speaker 00:
And this is bridging pages 18 to 19 about the Lantis label itself.

[00:19:46] Speaker 00:
Lantis was originally on the market in a formulation without a surfactant for some period of time.

[00:19:53] Speaker 00:
And that label acts as prior art here.

[00:19:55] Speaker 00:
At page 19, Lantis label instructs that Lantis, quote, must only be used if the solution is clear and colorless with no particles visible, close quotes.

[00:20:04] Speaker 01:
Can I ask you, is there something in the record that answers the following question?

[00:20:10] Speaker 01:
And if not, what do you know about it?

[00:20:12] Speaker 01:
Is this an absolutely standard

[00:20:14] Speaker 01:
thing to put on the label of anything that's being marketed in a vial so that it doesn't actually imply recognition of a problem.

[00:20:25] Speaker 00:
I don't know the answer to that question directly.

[00:20:27] Speaker 00:
I've not scoured the art to see if each and every vile pharmaceutical product contains that.

[00:20:33] Speaker 00:
I know that certainly for protein products and for insulins, which are injectables, it is common to have an instruction not to inject anything into your body that contains particulate matter for obvious reasons.

[00:20:48] Speaker 00:
You don't want to inject anything particulate into your body, into your bloodstream, et cetera, that could cause deleterious effects.

[00:20:54] Speaker 00:
Having said that though, the presence here recognizes that there is a potential for aggregation, that there is a potential to have particulate matter develop in a vial of this particular formulation.

[00:21:11] Speaker 01:
That's why I guess I asked the question.

[00:21:13] Speaker 01:
It seems to me that if this is standard, maybe not universal, but close to universal or standard, then maybe it doesn't actually

[00:21:21] Speaker 01:
reflect a recognition of the potential.

[00:21:24] Speaker 01:
It's just that you always say that including on labels of vials where there is no possibility because who knows?

[00:21:34] Speaker 00:
Well, I think there's no record evidence that no insulins avoid aggregation altogether.

[00:21:42] Speaker 00:
And so I would submit it's a different issue.

[00:21:44] Speaker 00:
It's not that this particular vial doesn't have a risk of aggregation because it's just like all the others.

[00:21:52] Speaker 00:
I put it differently, and that is this vial does have a risk of aggregation, and so you need to check it just like all the others.

[00:22:01] Speaker 00:
I mean, I think that Sanofi has said somewhere here that it's one in 10,000, one in, I don't know where exactly the record evidence of this, but, you know, sure, maybe it's a minor problem.

[00:22:11] Speaker 01:
This is the that's something about when it started getting reports from from patients and was quite surprised about this.

[00:22:20] Speaker 00:
That's they claim they were quite surprised about this.

[00:22:22] Speaker 00:
Of course, the board's findings below the factual funds, which are entitled to deference.

[00:22:27] Speaker 00:
suggest and tell a very different story.

[00:22:30] Speaker 00:
And moreover, to the extent that we saw in Sanofi's reply, etc., that we didn't identify or the board didn't identify a motivation, you don't need to have the same motivation to solve the problem that the inventors had.

[00:22:46] Speaker 00:
Maybe the inventors were

[00:22:47] Speaker 00:
were motivated by having a particular vial or a particular report past their desk.

[00:22:54] Speaker 00:
Whereas here, we have a generalized understanding by people of skill in the art that this is a risk factor.

[00:23:01] Speaker 00:
And in fact, there's fact findings by the board that this risk factor, which applies to insulins generally, specifically implies in an enhanced way here.

[00:23:10] Speaker 04:
But you also have a clear statement of enhanced ability

[00:23:15] Speaker 04:
with temperature and time and so on with this particular surfactant.

[00:23:21] Speaker 04:
And isn't that really the problem to be resolved in this case?

[00:23:27] Speaker 00:
I don't believe so.

[00:23:28] Speaker 00:
I don't believe that there is this enhanced stability presentation here, Your Honor.

[00:23:33] Speaker 04:
The record, the specification, the patents provide data.

[00:23:38] Speaker 04:
Are you saying that that's flawed?

[00:23:40] Speaker 00:
Well, I'm not quibbling with the data.

[00:23:43] Speaker 00:
I'm making an obvious analysis.

[00:23:45] Speaker 00:
And so I am not looking at the particularized data to see if the acclaimed invention solved the problem.

[00:23:52] Speaker 00:
Certainly, I think that there's record evidence.

[00:23:55] Speaker 00:
We had Professor Langer provide 20 examples of insulins being stabilized by addition of acerfactins.

[00:24:05] Speaker 04:
How did your reciting at some length

[00:24:08] Speaker 04:
the problems that were being experienced with this particular insulin.

[00:24:15] Speaker 04:
I agree.

[00:24:15] Speaker 04:
I think the question is one of obviousness.

[00:24:19] Speaker 04:
At what stage, other than with hindsight, do we say, well, just put in some polysorbate and it's over?

[00:24:26] Speaker 00:
I think there was absolutely no hindsight here at all.

[00:24:29] Speaker 00:
The factual findings of the board below look specifically at primary references, those two Bronga articles, for example, the Lantus label itself.

[00:24:39] Speaker 00:
And they all identify, as well as another Sanofi product in a pump, which required the inclusion of a surfactant.

[00:24:48] Speaker 00:
And the board made a specific factual finding about that, crediting Mylan's experts over Sanofi's experts here, saying that it was the exposure to the hydrophobic surface that was the cause of concern for aggregation.

[00:25:02] Speaker 00:
It was not the particular delivery system.

[00:25:04] Speaker 04:
So if this product doesn't solve any special problem, or any old surfactant would do, what is your client's interest, all this pressure, to be able to

[00:25:18] Speaker 04:
affect the patent structure for this product?

[00:25:21] Speaker 00:
Well, so there are two, there's a product on the market and under FDA guidance and analysis we are required to duplicate, essentially duplicate the formulation that is the brand product here.

[00:25:35] Speaker 00:
And so we are required to include a surfactant in our formulation.

[00:25:40] Speaker 00:
And I'm not quibbling in saying that the surfactant does nothing to stabilize the formulation.

[00:25:44] Speaker 00:
In fact, I think the reasonable expectation of success to an artisan is that it would enhance the stability of the formulation.

[00:25:53] Speaker 00:
But it's a business decision, ultimately.

[00:25:56] Speaker 00:
whether a person of skill in the art decides to add the surfactant or not in a situation where you've got a problem.

[00:26:04] Speaker 04:
A business decision if it's known or demonstrated.

[00:26:08] Speaker 04:
I don't think anyone's quibbled that adding the surfactant, adding the polysorbate has enhanced the stability to temperature and storage.

[00:26:19] Speaker 00:
I believe that's correct, Your Honor.

[00:26:21] Speaker 00:
I believe that there is a benefit to adding the surfactant.

[00:26:24] Speaker 00:
And that's one of the reasons, among the others, including the FDA requirements here, that my client wants to provide a product.

[00:26:32] Speaker 01:
What can you tell me about the timing of the FDA requirements?

[00:26:35] Speaker 01:
At what point did the FDA say the Glarging product, the Lantus product, now needs to include a surfactant?

[00:26:44] Speaker 00:
So the FDA never, as far as I can tell,

[00:26:47] Speaker 00:
Based on the record before us, the FDA never said you have to.

[00:26:51] Speaker 00:
My understanding is, and perhaps my learned friend representing Sanofi can provide further color to the extent it's not in the record, there were reports that were made to FDA and or Sanofi about some amount of aggregation.

[00:27:08] Speaker 00:
They went ahead and reformulated

[00:27:10] Speaker 00:
to identify if they could solve the problem of aggregation by including a surfactant.

[00:27:18] Speaker 00:
They sought approval with the FDA.

[00:27:19] Speaker 00:
The FDA granted approval.

[00:27:23] Speaker 00:
And then a year later, after Sanofi had continued selling the old non-reformulated, non-surfactant-containing material for over a year after the approval, only then was there a switch to the reformulated surfactant-containing product.

[00:27:40] Speaker 00:
So I don't know that it was an FDA crackdown that said, no, no, no, you have to do this.

[00:27:46] Speaker 01:
Do you remember even roughly what years you're talking about?

[00:27:49] Speaker 01:
So I believe that the original Lantus came on the market, I think, 2001.

[00:27:53] Speaker 00:
Yes.

[00:27:53] Speaker 00:
And then what?

[00:27:54] Speaker 00:
I believe that the reformulated product was approved in 2004 or 2005, and it entered the market in 2005 or 2006.

[00:28:06] Speaker 00:
I remember the year delta between the approval

[00:28:09] Speaker 00:
and the introduction to cell material.

[00:28:12] Speaker 00:
So, Your Honor, Judge Newman, I do agree that I think that the addition of the surfactant was beneficial, and I think that the evidence of record, the 20-odd references that Professor Langer identified, suggest and make a reasonable expectation that you're going to succeed here.

[00:28:30] Speaker 00:
A final point,

[00:28:32] Speaker 00:
There's this tension or notion, and I've heard Sanofi sort of say, well, there's desired aggregation and non-desired aggregation.

[00:28:40] Speaker 00:
Those are very different things, and those are explained pretty clearly and understood by a person of ordinary skill in art.

[00:28:46] Speaker 01:
In the vial versus under the skin.

[00:28:48] Speaker 00:
Exactly.

[00:28:49] Speaker 00:
And that's understood.

[00:28:50] Speaker 00:
And the formation of hexamers, the proper, the desirable sort of agglomeration, so the desired form of insulins,

[00:29:01] Speaker 00:
is a hexameric structure, and that's what you want.

[00:29:05] Speaker 00:
It's when these insulin molecules are in monomeric form and can expose a little bit of a hydrophobic surface that they tend to agglomerate and just sort of crash out of solution in an irreversible, non-reversible way.

[00:29:20] Speaker 00:
Those are very different mechanisms, very different mechanisms.

[00:29:24] Speaker 00:
I see that I'm nearly out of my time.

[00:29:27] Speaker 00:
I understand that one of their

[00:29:30] Speaker 02:
the patent owner's arguments is that your expert said something about how a surfactant can inhibit aggregation from monomer to hexamer and it will act as

[00:29:57] Speaker 02:
I don't know, some instrument of enhancing absorption.

[00:30:03] Speaker 02:
And so therefore, the argument goes that, well, this therefore is some kind of proof that the introduction of a surfactant will actually undo the desired native agglomeration once you inject

[00:30:24] Speaker 02:
the monomeric solution into the human tissue.

[00:30:32] Speaker 00:
So what's your answer to that?

[00:30:34] Speaker 00:
So the panel did consider that argument.

[00:30:36] Speaker 00:
They recognized it at page 31.

[00:30:39] Speaker 00:
They say, among other things, and then they identify a string of things that they use air quotes around the wood could in characterizing some of Sanofi's arguments about why a person of ordinary skill in the art.

[00:30:52] Speaker 02:
It seemed to me the board

[00:30:54] Speaker 02:
just summed it up by saying, well, you don't need absolute predictability in an obviousness inquiry.

[00:31:01] Speaker 02:
You just need a reasonable expectation of success.

[00:31:04] Speaker 02:
And so therefore, some unpredictability or uncertainty doesn't defeat a reasonable expectation of success.

[00:31:14] Speaker 00:
Well, I think that's true.

[00:31:16] Speaker 00:
And I think also the board did go ahead and analyze.

[00:31:20] Speaker 00:
So this was essentially what Sanofi had presented these arguments.

[00:31:25] Speaker 00:
And the board was taking them seriously and considered them all.

[00:31:29] Speaker 00:
And for several of those arguments, concluded a significant analysis, including one about potential interference of a surfactant with another additive, metacresol.

[00:31:40] Speaker 00:
and found in there, I think, page 38 or 39 of the final written decision that there was no merit to that argument.

[00:31:49] Speaker 00:
And then went ahead and issued a conclusory paragraph at, I think, page 39, saying, we find unpersuasive Patinona's arguments that an ordinarily skilled artisan would not have reasonably expected success.

[00:32:04] Speaker 00:
So they did absolutely consider those arguments.

[00:32:07] Speaker 00:
In addition to that, Your Honor,

[00:32:08] Speaker 00:
I think there is record evidence that suggests and supports the notion that or the idea that the existence of a surfactant doesn't interfere with formation of hexamers generally in connection with other insulins, not specific to glargine, but with insulins generally.

[00:32:25] Speaker 00:
And I think I would cite the panel, the board to, the panel to

[00:32:30] Speaker 00:
The article Thoreau 6906 is the appendix site, and there's a pin site at page 6910 in the third full paragraph.

[00:32:41] Speaker 00:
It says, if I may read it, since the genepal PF10 content of a neutral insulin solution does not change after removing the insulin by precipitation with zinc ions, we assume there is no significant interaction between insulin and genepal.

[00:32:56] Speaker 00:
The genepal is a paloximer surfactant.

[00:32:58] Speaker 00:
And what that describes is they use zinc to form these hexamers of insulin.

[00:33:04] Speaker 00:
This is the desired pathway, not the undesirable pathway of aggregation that's irreversible and unwanted, which the surfactant is designed to protect against.

[00:33:15] Speaker 00:
And they knew how much surfactant they had in the solution.

[00:33:19] Speaker 00:
They precipitated out the insulin in hexameric form

[00:33:23] Speaker 00:
And they found that the same amount of surfactant was still in the solution above.

[00:33:28] Speaker 00:
Therefore, they concluded that there's no interference with the surfactant.

[00:33:32] Speaker 00:
I am well over time.

[00:33:33] Speaker 00:
I apologize.

[00:33:38] Speaker 04:
You've been able to avoid the blinking light.

[00:33:42] Speaker 00:
I've gotten the glaring eyes instead.

[00:33:44] Speaker 04:
We need to hear what you have to say.

[00:33:48] Speaker 04:
Are there any more questions?

[00:33:50] Speaker 04:
Any more questions?

[00:33:51] Speaker 00:
Thank you very much, Your Honor.

[00:33:52] Speaker 00:
I appreciate it.

[00:33:56] Speaker 03:
Thank you, Your Honor.

[00:33:57] Speaker 03:
I have three quick points I'd just like to make on rebuttals.

[00:34:00] Speaker 03:
Just picking up where we left off with the desirable versus undesirable aggregation, I think, Judge Chen, you hit it exactly right, which was that Mylan's own expert has testimony that surfactant would have been expected to interfere with the native formation of the hexamers that are vital to the glyrogene's mechanism of action once it's injected to form the precipitates necessary to give it its long-acting effect.

[00:34:26] Speaker 02:
And again, I think if you look... My understanding of the way the glare gene precipitates once it's injected, it's because the glare gene, while it's sitting in a vial in a solution, it's acidic.

[00:34:43] Speaker 02:
But then once you inject it into a human, the tissue is pH neutral at a 7.

[00:34:51] Speaker 02:
And then glare gene, as we know, doesn't handle itself very well at a neutral pH.

[00:34:57] Speaker 02:
It ends up becoming unstable, and then it precipitates like that.

[00:35:02] Speaker 03:
It precipitates like that, but into hexagonal formations.

[00:35:05] Speaker 02:
I guess what I'm just trying to figure out, whether the statement that you got out of the other side's expert, whether that's

[00:35:17] Speaker 02:
in the right context of what's going on in terms of the mechanism of action and glare gene, which is going from an acidic pH solution to a neutral pH human.

[00:35:29] Speaker 03:
So, Your Honor, I think that both parties agree on how the mechanism works.

[00:35:32] Speaker 03:
And if you look at 6509, for example, in the appendix, that's Dr. Yelkowski.

[00:35:36] Speaker 03:
There are experts

[00:35:37] Speaker 03:
description of how it works.

[00:35:38] Speaker 03:
And one of the ways it works is that it does precipitate into these hexamer forms and that these slowly dissociate over time and then are absorbed into the bloodstream to deliver the long-acting effect.

[00:35:49] Speaker 03:
The testimony he gave at his deposition, which he was summarizing in an article that he had written, says that a surfactant slows down or speeds up that absorption process.

[00:36:01] Speaker 03:
So it inhibits the formation of the aggregates.

[00:36:04] Speaker 03:
and it slows their, or increases, sorry, their absorption into the bloodstream, both of which would counteract the long-acting intention of the bar gene.

[00:36:13] Speaker 02:
And I think- Your expert, Dr. Trout, he seemed a little equivocal about the possibilities of a surfactant affecting the so-called native aggregation, agglomeration.

[00:36:30] Speaker 02:
He said, well, it could.

[00:36:32] Speaker 02:
And so it sounded somewhat speculative when you actually read the text of his declaration.

[00:36:40] Speaker 03:
So I think this comes into a hindsight issue in some ways, because we know that it actually works fine in the solution.

[00:36:47] Speaker 03:
Now it does, right?

[00:36:50] Speaker 03:
So the question is, what would an artisan have thought at the time?

[00:36:52] Speaker 03:
And I think that's the challenge.

[00:36:53] Speaker 03:
And we don't have to show, obviously, that it wouldn't have worked, because we know that it does.

[00:36:56] Speaker 03:
The challenge is to show there's some likelihood, some reasonable likelihood that it would.

[00:36:59] Speaker 03:
And that's what we showed.

[00:37:02] Speaker 03:
And I'd like to direct, again, the court's attention to what the board actually said about this.

[00:37:07] Speaker 03:
And this is on 39.

[00:37:07] Speaker 03:
And I think my colleague described it as conclusory.

[00:37:10] Speaker 03:
And that's exactly our point.

[00:37:12] Speaker 03:
Because the way that they answered this particular point was to say, because surfactants work for everything else, they work for glargine.

[00:37:18] Speaker 03:
And that simply doesn't contend with the question that was presented here about whether the mechanism of action would be disrupted based on

[00:37:26] Speaker 03:
Based on this fact being added if I may just address a couple of more points that that came up in my Council's or my colleagues argument as to the warning label There is evidence that we put into the record Saying that the use only when cloudy is a very common thing and addresses other types of problems including microbial contamination the like and that's 14 286

[00:37:50] Speaker 03:
And then if you look at Appendix 726, that is of the board's institution decision, where they pretty much agree with us.

[00:37:58] Speaker 03:
What page was that?

[00:38:00] Speaker 03:
Sorry, it's 726.

[00:38:00] Speaker 03:
And that's the board's institution decision, where they essentially agree that patent owners' argument regarding Lantus labels patient mourning has merit.

[00:38:09] Speaker 03:
And they go on to talk about other evidence, but I think it's a good indication of why they didn't rely on it.

[00:38:14] Speaker 03:
in the second time around.

[00:38:16] Speaker 03:
And the passage my colleague read was merely a recitation of what the label says and not really the evidence that they were relying on.

[00:38:23] Speaker 03:
And that brings me to the third point I'd like to briefly touch on was my colleague brought up Dr. Langer's declaration and the additional references that he cited.

[00:38:35] Speaker 03:
And we have this in our brief, but just to make the point, those were references that Mylan introduced for the first time in connection with its reply brief.

[00:38:44] Speaker 03:
that we weren't allowed to respond to with evidence.

[00:38:46] Speaker 03:
And in fact, the board used that declaration and those references to discredit our expert without giving our expert or Santa Fe an opportunity to respond to it.

[00:38:55] Speaker 03:
That was improper.

[00:38:57] Speaker 03:
It was a matter of fairness.

[00:38:59] Speaker 03:
We should have had the opportunity to put on evidence.

[00:39:01] Speaker 02:
Is this the case where the patent owner filed two CIR replies?

[00:39:05] Speaker 03:
We did, but they weren't on this issue, Your Honor.

[00:39:08] Speaker 03:
The board did not allow us to apply

[00:39:12] Speaker 03:
at arguments or evidence or anything of the sort on these particular issues or to respond to this particular evidence.

[00:39:19] Speaker 03:
We should have had the opportunity to do that.

[00:39:21] Speaker 03:
This was evidence that MyLink could have and should have introduced with its petition.

[00:39:26] Speaker 03:
It introduced it for the first time on reply.

[00:39:29] Speaker 03:
And it is prejudicial because we know from the board's own language, and this is at page 33 of their decision, they used Dr. Langer to discredit our own expert who was replying to their first expert and didn't get a chance to

[00:39:41] Speaker 03:
To reply to dr. Langer and in fact, I think it's quite telling that the tribunal or the panel used the new expert to discredit our Expert instead of the first there in a mileage first expert.

[00:39:54] Speaker 03:
I see I'm out of time.

[00:39:54] Speaker 04:
So Thank you, thank you