[00:00:00] Speaker 02:
The first case is Amgen versus Sandoz et al.

[00:00:06] Speaker 02:
2022-11-47.

[00:00:07] Speaker 02:
Ms.

[00:00:08] Speaker 02:
Worker.

[00:00:12] Speaker 04:
Good morning.

[00:00:12] Speaker 04:
May it please the court for this

[00:00:16] Speaker 04:
For the starting, I'd just like to focus on two points.

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And they're both related to the 638 patent and their findings in the district court on motivation and reasonable expectation of success.

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So the district court made findings here that support a finding of motivation to separate the enantiomers of example 12, which is the example disclosed in the 358 patent.

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The district court found that the 358 patent teaches example 12.

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and that it has therapeutic utility.

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The court also found that the 358 patent teaches that the isomers

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of the compounds in the 358 patent are part of the invention of the 358 patent.

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And so therefore, the reasonable assumption is they would also have therapeutic utility.

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And that's what is needed to provide a motivation to separate the enantiomers of example 12 and determine which of the enantiomers has the therapeutic benefits.

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support in the record as well for the finding that there would be motivation to Come on to separate the enantiomers the FDA's policy in 1990 by 1992 which is ten years before the priority date here was to Separate enantiomers and figure out what the activity of the enantiomers was Dr. Davies the expert for Amgen also testified about his article in nice you about the

[00:01:49] Speaker 03:
the potential patent admission in the 638 patent?

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Yes.

[00:01:53] Speaker 03:
You started us there.

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That's a good starting point.

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It appears that the 638 patent admits that a primal ass, am I saying that right?

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Yes.

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A primal ass can be isolated through chiral salt formation.

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Is that correct that that's what the 638 patent is saying?

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That's what the 638 patent says, yes.

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Now is that true in the real world?

[00:02:13] Speaker 04:
In the real world, there's not any evidence that that would work.

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I think that record evidence is that you would not be able to separate a primelast from its racemic mixtures using chiral salt.

[00:02:27] Speaker 02:
Well, that's against your position, right?

[00:02:31] Speaker 04:
Yes, it's against my position.

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You're arguing that it would have been obvious.

[00:02:35] Speaker 02:
I'm sorry?

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You're arguing that it would have been obvious to separate them.

[00:02:40] Speaker 04:
Correct.

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It would have been obvious to separate them.

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There wasn't a technique taught in the 358 patent, as well as an admission in the 638 patent, that chirochromatography would work to separate the enantiomers.

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And there was testimony that it would, and there was no contrary testimony that it would not work to separate the enantiomers.

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While there was one method that might not work for a premelast, there was absolutely in the art disclosed a method that would work for a premelast, which is chiral chromatography.

[00:03:10] Speaker 02:
But wasn't it determined that the positive enantiomer was 20 times as active as the racemate?

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Isn't that an unexpected property that overcomes any obviousness argument?

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I would say it's a difference in degree, not in kind.

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And there is an admission in the record that a person of skill would expect a twofold increase.

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So they would expect a difference between the enantiomers.

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And I think that's enough to establish a difference in degree rather than in kind.

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While there was a large- You mean 20 times isn't an enormous difference over two times?

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It's a difference.

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It's definitely a difference.

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I think the issue is whether that would be a difference in degree or in kind.

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And the law says that a difference in kind is not enough to establish unexpected results.

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Is that maybe itself a fact question?

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At what point do we go from a difference in degree to a difference in kind?

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I think it might be a fact question in certain circumstances.

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But I think in this case, it's

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I don't think there was any finding that there was a difference in kind here.

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I think the finding was just that it was an unexpected result.

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So I would say the court does not need to defer to that as a fact finding.

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Let me just get back to that admission.

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I apologize that I'm focused on that.

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But it's something I want to hear more about.

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What is the import of the admission being inaccurate?

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Because I think when we talk about it, I think you're saying that is an admission in the 638 patent.

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But then it sounds like you're saying that it's not true in the real world.

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What is the import of inaccuracy there?

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I don't think there is any import in inaccuracy there, mostly because there wasn't any.

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This is not a case where there was testimony outside of the admission that something, that a premise specifically, was difficult to isolate.

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The testimony that was taken by the court was that, that enantiomers sometimes are difficult to isolate and that there are things that you might have to do in order, it might take you to some time.

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But this is not a case like Forrest where there was testimony specifically directed to

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as a telepram and how difficult that particular isomer was to isolate.

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There's no testimony about a premelast specifically being difficult to isolate, so I don't think there's much import that would take away from the admission in the 638 specification that these were techniques that you could do in the art and they were techniques that were known and were routine.

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A person of skill in the art at the time would have been able to do

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These do these isolation techniques and maybe figure out the chiral salt acids won't work But that kind of and what's your best case that you're relying on with respect to the admission?

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Pharmacem therapeutics is the case I think that's the main case does far stem stamp or anything more than just we have to give

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credit in some way to the admission.

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Isn't that all it says?

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And yet you argue that this is somehow dispositive, I think.

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That's where I'm not quite clear on how Pharmastem gets you to this being a dispositive issue.

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I think the problem is the court didn't consider it at all.

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The court did not.

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I think you know that he recognized it in footnote 17.

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He recognized that there was an admission.

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He doesn't give it any weight at all.

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And I don't think there's any evidence in the record that he actually weighed the admission on any level or weighted it as part of the legal analysis for this.

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Why would we presume that he, in noting the admission, at least in a footnote, then gave it?

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If he gave it no weight, it was presumably because he found it merited no weight.

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I think it probably required some sort of an explanation for him as to why it was outweighed by the evidence that was put in the record.

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And again, this relates, it goes back to what the testimony was about a premelast and how difficult it was to, in particular, a premelast was to isolate.

[00:07:28] Speaker 04:
There is no testimony that a premelast in particular was difficult to isolate, only that enantiomers are generally difficult to isolate and that you

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would have to run some experimentation in order to determine whether or not you could do that.

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Are you familiar with the Nomiya case, the Judge Rich case?

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Are you familiar with that case?

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I am not familiar with that case.

[00:07:48] Speaker 04:
Sorry.

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So just to close out, because I'm running low on time.

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I think the other issue here is the misapplication, I think, of the lead compound analysis that the district court engaged in.

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The district court placed a lot of weight on Dr. Davies' testimony that a person still in the art would have to separate all 17 examples

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and the 358 patent and test them all to determine which ones had activity.

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Don't think that would be a lead compound analysis, and that is not required here.

[00:08:26] Speaker 04:
He correctly found that it wasn't required here.

[00:08:27] Speaker 00:
The district court said lead compound is not required, but you do have to start somewhere, don't you?

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I think under the case law, you start at example 12.

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That's what you start at.

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You would start at example 12.

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So you don't have to choose example 12 among the three.

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You don't have any burden to show that there's some reason to even think about example 12 as a starting point?

[00:08:51] Speaker 04:
Not under Aventus or UCB, for that matter.

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But I will reserve the rest of my time for both.

[00:08:57] Speaker 02:
We will hold it for you, Mr. Horowitz.

[00:09:00] Speaker 01:
Thank you, Your Honor, and may it please the Court.

[00:09:03] Speaker 01:
I want to pick up with a question that Judge Stark just asked, which is, can you just start with example 12?

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And I think it's clear across the law of obviousness, not merely in the lead compound context, that you need to put yourself in the shoes of the skilled artisan at the time of the invention who doesn't already know about the invention

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and identify some reason why that person would have plucked a given teaching out of the prior article in order to solve a problem.

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Now, lead compound analysis is one framework.

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The court is used to address that question.

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But there are many different frameworks.

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The fundamental inquiry is the same in each case, and it's critical for guarding against hindsight.

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Now, in this case, the framework that this court applied was exactly the one that defendants asked it to apply, the Aventa standard.

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But even there, they needed to show that there was a reason to believe that a desirable property of the mixture derived from Primalast in particular.

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Now, that's a factual question.

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And defendants lost on the facts under their own test base and factual findings, they do not actually challenge as clearly erroneous.

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Another factual question, though, is how difficult, if at all, would it have been, assuming you had some reason to do it, to actually isolate this isomer.

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In that regard, it seems like your patent admits

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it would be, at worst, routine experimentation.

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And it seems like the district court put a lot of weight on the contrary view of your expert that it might be challenging.

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What do we do with that?

[00:10:31] Speaker 01:
So what the patent teaches

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and we don't dispute it, is that once the inventors had isolated a prem last, they could teach the world it was possible to do so.

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It doesn't say, through routine experimentation x ante, you could have.

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That's not what it says.

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And it teaches a specific method of doing it in columns 21 to 22.

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But you're right.

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It is a factual question.

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And it's a factual question as to which the district court said, it's a battle of the experts.

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I have Dr. Davis explaining why it's quite difficult, and I have Dr. Gribble explaining why it's quite easy.

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And he found Dr. Davis more persuasive than Dr. Gribble in this regard.

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As Dr. Davis said, ex-ante, yes, you knew about general techniques.

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You knew chirochromatography was a technique you could try.

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You'd have to pick one of 50 possible columns, any number of solvent systems, you'd have to adjust the pH, the temperature, the flow rate.

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And as Dr. Davis testified, all you could do is vary these parameters, put your compound on the column, and hope.

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Hope that you got the separation.

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But until these inventors did it, you didn't know it was possible.

[00:11:32] Speaker 03:
So I'm going to take you down some of the same lines of questions that I took the other counsel down, if you're ready for them.

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So first up, are you familiar with the Nomea case?

[00:11:41] Speaker 01:
I'm not.

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I don't believe we cited it.

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So I believe Pharma STEM cites Nomea.

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It's a judge-rich opinion.

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And in particular, and I think multiple of our cases say something to the effect of that

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the patent's admission in the prior art would be binding on patentees.

[00:11:56] Speaker 03:
What is your response to that and that sort of line of cases?

[00:12:00] Speaker 01:
So we take no issue with the admission that it is possible to isolate a primelast.

[00:12:06] Speaker 01:
What it says in column 9 is compound A can be isolated from the racemic compound by techniques known in the art.

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That is a teaching of the inventors, and we don't take issue with it.

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We accept it as true.

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And in fact, the inventors did teach how to do it.

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They taught a specific method in columns 21 to 22.

[00:12:23] Speaker 01:
The difference in PharmaStem, applying that Nomiya case, was that the

[00:12:28] Speaker 01:
Patentee was trying to dispute a fact about what was in the prior art.

[00:12:32] Speaker 01:
The patentee said, no one knew that cord blood contained stem cells.

[00:12:36] Speaker 01:
But the patent said cord blood has been shown to be in stem cells, citing prior art that taught that.

[00:12:42] Speaker 01:
So again, we take no issue with the so-called admission.

[00:12:46] Speaker 01:
We take it as it is.

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But the disclosure of general techniques, and even the disclosure that general techniques can work, is not an admission that a person of ordinary skill at the time of the invention in 1999 would reasonably expect to be able to isolate a primelast from a racemic mixture.

[00:13:02] Speaker 01:
And the district court found exactly the opposite, crediting Dr. Davis' testimony over Dr. Gribble's.

[00:13:09] Speaker 01:
So that's as far as it goes.

[00:13:10] Speaker 01:
It's just a factual question.

[00:13:12] Speaker 01:
Similarly, with respect to

[00:13:15] Speaker 01:
on the objective evidence, Judge Stark, you were mentioning, isn't a 20 to 1 versus 2 to 1 difference

[00:13:21] Speaker 01:
First of all, it sounds quite surprising and different.

[00:13:24] Speaker 01:
But on top of that, isn't it a factual question?

[00:13:26] Speaker 01:
Defendants own case on this subject, the Merck case, the one they point to for degree versus kind.

[00:13:31] Speaker 01:
You read further down on the same page, and what you'll see is sometimes a difference in degree is so substantial that it's truly unexpected.

[00:13:38] Speaker 01:
When is that?

[00:13:39] Speaker 01:
That's a factual question, a factual question reserved for the district court and resolved in our favor, along with numerous other factual questions on the objective evidence, which the district court said strongly supported a conclusion of non-obviousness.

[00:13:52] Speaker 01:
They don't even challenge the fact that there was skepticism towards apremlast, both at the FDA and in industry, that others wouldn't take a license to apremlast even after seeing the outstanding properties that had been showed.

[00:14:05] Speaker 01:
They don't take issue with the fact that Otesla, the commercial embodiment of the claimed invention, satisfied a long felt but unmet need for an improved treatment for psoriasis.

[00:14:13] Speaker 01:
There is no challenge to any of this.

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This court has never held that an enantiomer was obvious overarasmate in the presence of a finding of unexpected results.

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In this case, you see 20 to 1 difference in potency.

[00:14:27] Speaker 01:
In Forest Labs, 2 to 1 was enough to be unexpected.

[00:14:30] Speaker 02:
You're saying it's not a question of difference in kind versus degree.

[00:14:35] Speaker 02:
It's unexpectedness.

[00:14:37] Speaker 01:
It's unexpectedness.

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It's simply a question of fact.

[00:14:38] Speaker 01:
What would a person of skill in the art expect?

[00:14:42] Speaker 01:
The testimony at trial was that not that 2 to 1 was expected, to be clear, but that 2 to 1 is the most that you could reasonably expect, because that's a situation where one enantiomer has all the activity, and the other one has nothing.

[00:14:55] Speaker 03:
In this situation, we have- I want to go back to that statement that you made right before Judge Laurie's question.

[00:14:59] Speaker 03:
You said something to the effect of the court has never held.

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Can you repeat that?

[00:15:03] Speaker 03:
I want to maybe explore that.

[00:15:05] Speaker 01:
The court has seen a lot of enantiomer cases.

[00:15:07] Speaker 03:
And in no case- You say a lot.

[00:15:09] Speaker 03:
Can we put a number on that?

[00:15:12] Speaker 01:
Sanofi, Forest Labs, UCB, Henry May.

[00:15:18] Speaker 02:
At least a half a dozen.

[00:15:19] Speaker 01:
At least a half a dozen.

[00:15:21] Speaker 01:
And there are a couple of cases in which obviousness was shown.

[00:15:24] Speaker 01:
In no case was obviousness established in circumstances where there was a finding of unexpected results.

[00:15:31] Speaker 03:
But those are all very fact-specific, right?

[00:15:33] Speaker 03:
There's no per se rule that you're saying our court has said in that regard.

[00:15:37] Speaker 01:
Absolutely.

[00:15:38] Speaker 01:
100% agree.

[00:15:39] Speaker 01:
Each case is fact-specific.

[00:15:40] Speaker 01:
That's what Sanofi teaches.

[00:15:42] Speaker 01:
In this case, we have factual findings resolved across the board in our favor.

[00:15:47] Speaker 01:
With the remaining time, I'd like to turn, if I may, to the 541 patent.

[00:15:50] Speaker 01:
Now, this patent claims a very specific dosing schedule.

[00:15:55] Speaker 01:
And the problem is that the district court simply failed to make findings to explain why a person of ordinary scale would have been motivated to make the very specific choices reflected in that schedule.

[00:16:05] Speaker 02:
And a lot of the choices were counter to- Isn't that ordinary experimentation?

[00:16:09] Speaker 02:
After all,

[00:16:11] Speaker 02:
drug developers always have to determine the proper doses of a proposed drug?

[00:16:19] Speaker 02:
And was it the PAP reference here illustrated that?

[00:16:27] Speaker 01:
The point is that there is a very specific set of choices reflected in that schedule, in the claim schedule that's different from PAP.

[00:16:34] Speaker 01:
And those choices, as compared to PAP, go against a lot of the intuitions of a skilled artisan at the time.

[00:16:39] Speaker 01:
And if you didn't already know what the invention is, there is no explanation in the court's findings as to how you get to several of these specific choices, and certainly not all of them together.

[00:16:49] Speaker 01:
So for example.

[00:16:50] Speaker 01:
The prior art already taught the schedule.

[00:16:52] Speaker 01:
It was eight days long and got the 40 milligrams maintenance dose.

[00:16:55] Speaker 01:
We're trying to get to 60.

[00:16:56] Speaker 01:
Now, the question is, if the prior art schedules weren't sufficient to manage the dose-dependent tolerability concerns, why would you go backwards to six days as opposed to do the typical thing, as the testimony established, which is titrate over weeks or months, as was done with many other psoriasis medications at the time, such as acetretin or methotrexate?

[00:17:17] Speaker 01:
There's no explanation as to that choice.

[00:17:19] Speaker 01:
Or, for example, why do you sometimes have the same dose morning and afternoon, but other times different doses, what we call asymmetric doses?

[00:17:29] Speaker 01:
There was literally nothing in the prior art that had a single day of asymmetric dosing.

[00:17:33] Speaker 01:
Pat, same morning and evening.

[00:17:35] Speaker 01:
Shet, single dose most of the time, but at the maintenance level, same morning and evening as an option.

[00:17:40] Speaker 01:
The 536 pattern, which they call a key reference, teaches evenly divided dosing.

[00:17:46] Speaker 01:
What explains this particular choice?

[00:17:48] Speaker 01:
It was incumbent upon the district court to make a finding to explain how a person of skill would have been motivated to make the choices that arrived at the invention.

[00:17:56] Speaker 01:
Didn't make that explanation.

[00:17:58] Speaker 01:
Or take another.

[00:17:58] Speaker 02:
Every developer is motivated to experiment and determine the proper dose.

[00:18:03] Speaker 02:
And whatever comes out, comes out.

[00:18:06] Speaker 01:
So Judge Laurie, in terms of the maintenance dose, figuring out where your target is, I don't dispute it.

[00:18:12] Speaker 01:
It was already established.

[00:18:13] Speaker 01:
60 milligrams is the maintenance dose.

[00:18:15] Speaker 01:
The claim is not figure out the proper maintenance dose.

[00:18:18] Speaker 01:
The claim is 10 milligrams in the morning, day one, nothing in the evening.

[00:18:22] Speaker 01:
Then 10 and 10, 10 and 20, et cetera.

[00:18:25] Speaker 01:
It's got a lot of specific limitations.

[00:18:27] Speaker 01:
Which were simply not addressed.

[00:18:28] Speaker 03:
Was the eight day schedule for psoriasis, or was it for something different?

[00:18:31] Speaker 01:
The eight day schedule was for psoriatic arthritis.

[00:18:34] Speaker 01:
If you want to look at the PAP schedule, even then, which is the psoriasis schedule, there's another choice that's not explained.

[00:18:41] Speaker 01:
So in PAP, you hold the same dose constant for at least two days at a time.

[00:18:45] Speaker 01:
Two days of 10 and 10, two days of 20 and 20.

[00:18:49] Speaker 01:
In SHET, which is the psoriatic arthritis, you hold it for three days and then four days.

[00:18:53] Speaker 01:
Dr. Gilmour holds it for 20 days at one point.

[00:18:56] Speaker 01:
So why do you make the choices to go from holding it constant for two days to increasing it every single day?

[00:19:04] Speaker 01:
If the goal was to manage tolerability concerns, to ease into that maintenance dose, there's absolutely no reason explained in the findings of fact as to why you choose increase every single day as opposed to every other day in PAP, every third or fourth day in SHED,

[00:19:20] Speaker 01:
Or, as I said, conventionally, you'd go to the doctor.

[00:19:23] Speaker 01:
You'd get your first dose.

[00:19:24] Speaker 01:
You'd come back a month later.

[00:19:26] Speaker 01:
The doctor would say, how's it going?

[00:19:28] Speaker 02:
And then you'd adjust.

[00:19:28] Speaker 02:
Was there evidence that these doses produced unexpected results over time?

[00:19:39] Speaker 02:
a simpler dose of regimen.

[00:19:42] Speaker 01:
We did not rely on objective evidence at trial.

[00:19:44] Speaker 01:
But with respect to motivation, it's the same test for this.

[00:19:46] Speaker 02:
You're asking for unexpected evidence to be given primacy on your main argument.

[00:19:56] Speaker 02:
But you don't have it here.

[00:19:57] Speaker 01:
I don't think the absence of unexpected results means that the invention is obvious.

[00:20:03] Speaker 01:
I certainly believe that the unexpected results with respect to the 638 are sufficient all by themselves to justify a firmance.

[00:20:10] Speaker 03:
What if your best case were strong?

[00:20:13] Speaker 03:
unexpected results outweigh an overall strong obviousness case.

[00:20:18] Speaker 03:
What's your best case in pointing to?

[00:20:20] Speaker 01:
I mean, I think the most relevant case in this context is the Sanofi case.

[00:20:23] Speaker 01:
In that case, the district court actually had presumed a prima facie case.

[00:20:26] Speaker 01:
And nonetheless, there was a finding of non-obviousness based on the unexpected results.

[00:20:30] Speaker 01:
So again, we're in this world of enantiomers and racemates.

[00:20:34] Speaker 01:
And it's a really consistent thread.

[00:20:35] Speaker 01:
If you go back to the old cases, Henry May, Adamson, et cetera, the one consistent thing you'll see is when there's unexpected results, no obviousness.

[00:20:43] Speaker 01:
And when it's exactly as expected in Aventus, then there was obviousness.

[00:20:47] Speaker 01:
That's the basic dividing line in those cases.

[00:20:50] Speaker 00:
Can I ask a question on the 101 patent?

[00:20:53] Speaker 00:
Sure.

[00:20:53] Speaker 00:
Do you contend that the 515 provisional patent application actually did disclose the form B?

[00:21:03] Speaker 00:
Or do you need the expert to say the form B is in there?

[00:21:09] Speaker 01:
So I think the answer to the question is yes to both in a way.

[00:21:12] Speaker 01:
There's no question that the inventors of the 101 patent, at the time of the filing of the provisional application, possessed the solid form that was recrystallized at the end of the reaction in example two.

[00:21:24] Speaker 01:
And that's what's claimed ultimately in the 101 patent.

[00:21:27] Speaker 01:
It's claimed with respect to certain properties that were inherent in it.

[00:21:31] Speaker 01:
So it discloses that form.

[00:21:33] Speaker 01:
The factual dispute that required an expert is the testimony that that form was necessarily always inherently form B, and that's what it is.

[00:21:42] Speaker 01:
So yes, the 515 discloses form B. It doesn't say the words form B. It doesn't have the XRPD peaks that are characteristic of form B. But it inherently discloses those because it discloses that the inventors possessed what was recrystallized.

[00:21:56] Speaker 02:
But 112 requires disclosure, not inherency.

[00:22:05] Speaker 02:
prior application, there must be disclosure.

[00:22:09] Speaker 02:
Now, the district court looked at all the evidence here and found that the 515 application did, in fact, disclose Form B.

[00:22:21] Speaker 02:
But that's sort of a better argument for you, isn't it?

[00:22:26] Speaker 01:
Yes.

[00:22:26] Speaker 02:
Inherency?

[00:22:28] Speaker 01:
I think inherency explains where the properties are.

[00:22:32] Speaker 01:
But absolutely, the dish work found that it disclosed corn feed.

[00:22:34] Speaker 02:
It's not a question of properties.

[00:22:35] Speaker 02:
It's a question of the substance.

[00:22:37] Speaker 01:
Yes.

[00:22:37] Speaker 01:
The substance was disclosed absolutely.

[00:22:39] Speaker 01:
And that's the finding.

[00:22:40] Speaker 01:
And that's exactly going back to the CCPA.

[00:22:42] Speaker 01:
That's what happens in Edwards, for example.

[00:22:44] Speaker 01:
It was disclosed that they had this reaction, and they had the product of the reaction, and they later claimed it by name.

[00:22:50] Speaker 01:
And that wasn't an issue.

[00:22:52] Speaker 01:
I'd like to reserve the balance of my time for a bottle if I may.

[00:22:54] Speaker 02:
All right.

[00:22:54] Speaker 02:
And of course, that's only for the cross-appeal if there's something to reply to.

[00:23:03] Speaker 02:
We have six minutes.

[00:23:06] Speaker 04:
So just briefly on the 638 patent, the disclosure in the patent, in the 638 patent itself, actually teaches specific prior art methods.

[00:23:16] Speaker 04:
It lists several references here that disclose prior art methods for

[00:23:22] Speaker 04:
resolving the enantiomers.

[00:23:24] Speaker 04:
So it's not, that's not an inventor's own teaching there.

[00:23:27] Speaker 04:
That's actually a concession at the prior.

[00:23:30] Speaker 00:
Is that a fact question or a question of law, whether it's the inventor's own contribution or whether it was not?

[00:23:38] Speaker 04:
I would say it's a question of law based on a reading of the specification itself.

[00:23:43] Speaker 04:
But to the 541 patent, I think there's a couple of things.

[00:23:47] Speaker 04:
First of all, PAP, the psoriasis study, is the closest prior art, not the 40 milligrams psoriatic arthritis study.

[00:23:55] Speaker 04:
And I think that was conceded in the district court by Amgen's expert.

[00:24:02] Speaker 04:
I think the argument that the court was required to make findings about why a person of skill in the art would select the prior art method over something that was not supported in the prior art is the basis for their argument.

[00:24:16] Speaker 04:
And I don't think that actually has any weight in the case law or in the facts of this case.

[00:24:21] Speaker 02:
You're not addressing 20 times, which was unexpected.

[00:24:27] Speaker 04:
So I would, again, maintain that that's a difference in degree, not in kind, Your Honor.

[00:24:35] Speaker 02:
But that's not the issue.

[00:24:36] Speaker 02:
Unexpectedness is what carries the day with known obviousness.

[00:24:42] Speaker 04:
And I agree with you, but I think that this Court has held that a difference in degree

[00:24:48] Speaker 04:
versus a difference in kind is the standard for how to determine whether something is unexpected.

[00:24:53] Speaker 02:
What is the dividing line between the difference in degree and the difference in kind?

[00:24:58] Speaker 04:
I think in the type of difference it is.

[00:25:02] Speaker 04:
If it's a difference that produces something that's not.

[00:25:07] Speaker 04:
So we have a concession here that there would be an expected difference between the two enantiomers, expected twofold.

[00:25:13] Speaker 04:
difference between the two enantiomers.

[00:25:14] Speaker 04:
And in that case, then we're talking about 2 versus 20 is a difference in degree, not in content.

[00:25:19] Speaker 02:
If you have a claimed compound, and it's close structurally to a prior odd compound with the same activity, and the claimed compound has 100 times the activity of the prior odd compound, that doesn't carry the day because it's just a difference in degree.

[00:25:40] Speaker 04:
I would say that's the difference in degree.

[00:25:42] Speaker 04:
Now, if it's an unexpected difference in degree, I guess that would be a question.

[00:25:47] Speaker 02:
Well, that's the point.

[00:25:49] Speaker 04:
Unexpectedness.

[00:25:50] Speaker 04:
Understood.

[00:25:51] Speaker 04:
So just to discuss the 541 briefly, there was plenty of evidence in the record to support the court's decision here.

[00:26:00] Speaker 04:
The claims here are to a dosing titration schedule where you give 10.

[00:26:04] Speaker 04:
Then 10 and 20, and 20 and 20, and 20 and 30, and then 30 and 30.

[00:26:09] Speaker 00:
How about the asymmetric dosing on a particular day?

[00:26:12] Speaker 00:
Was that in the prior art?

[00:26:13] Speaker 04:
Asymmetric dosing was not in the prior art.

[00:26:15] Speaker 04:
But the testimony that would lead you to asymmetric dosing, I should just add, there's no evidence at all that asymmetric dosing does anything.

[00:26:26] Speaker 04:
What there is evidence of is that patients were administered 10, 20, and 30 milligram doses.

[00:26:31] Speaker 04:
in patients, not healthy subjects.

[00:26:35] Speaker 04:
We're talking about patients that actually had psoriasis.

[00:26:37] Speaker 04:
We administered those three.

[00:26:39] Speaker 04:
That a person with skill in the art would understand from the PAP trial that there were still some adverse events happening in the first couple weeks and would want to slow down the titration there.

[00:26:48] Speaker 04:
And that a normal way to do that, a perfectly reasonable way to do that would be to increase

[00:26:54] Speaker 04:
the dose titration by 10 milligrams every day rather than 20 milligrams.

[00:26:59] Speaker 04:
So you started a lower dose, which their expert conceded would be expected to produce fewer side effects.

[00:27:05] Speaker 04:
You started 10 milligrams.

[00:27:07] Speaker 04:
And then you increased by 10 milligrams every day instead of 20 milligrams every two days.

[00:27:12] Speaker 04:
That would lead you to asymmetric dosing.

[00:27:15] Speaker 04:
Given the dosing types that you had, the 10, 20, and 30, that's the only way to get you to increasing 10 milligrams a day.

[00:27:24] Speaker 04:
up to day six.

[00:27:26] Speaker 04:
That's how you get exactly to the schedule.

[00:27:28] Speaker 04:
And that's what the judge found.

[00:27:30] Speaker 04:
In this case, he relied on the testimony of Dr. Gilmour, and he gave deference.

[00:27:35] Speaker 03:
I want to make sure I get your take on this secondary considerations or objective indicia point.

[00:27:46] Speaker 03:
I assume that you agree that they must, of course, be taken into account, but they don't necessarily control the obviousness determination.

[00:27:53] Speaker 03:
Is that true?

[00:27:54] Speaker 03:
That's correct, yes.

[00:27:55] Speaker 03:
OK.

[00:27:55] Speaker 03:
Just because some of your communications back and forth with my colleagues, I felt like you were almost conceding that you thought one given secondary consideration would control the obviousness determination.

[00:28:08] Speaker 04:
I don't think one given secondary consideration.

[00:28:11] Speaker 04:
If I made that mistake, I apologize.

[00:28:15] Speaker 04:
I do not think one unexpected result controls the, or one objective indicia controls the obvious determination.

[00:28:23] Speaker 04:
I don't think that's been the law in this circuit ever.

[00:28:26] Speaker 02:
If it was commercial success and maybe upper secondary indicia weren't there,

[00:28:34] Speaker 04:
There were other objective indicia.

[00:28:36] Speaker 04:
They were all related to not really comparing a permalase to the racemic mixture of example 12.

[00:28:42] Speaker 04:
They were comparing a permalase to other drugs on the market.

[00:28:47] Speaker 04:
They were comparing it to, I think most of them were comparing it to other drugs on the market.

[00:28:53] Speaker 02:
But it was a real success.

[00:28:56] Speaker 04:
It certainly was.

[00:28:56] Speaker 04:
I mean, there was a 358 patent in the way.

[00:28:59] Speaker 04:
I mean, there were patents.

[00:29:00] Speaker 02:
That's why you wanted it.

[00:29:02] Speaker 04:
There were other things that would create this wall that would make it difficult for someone to enter the market.

[00:29:10] Speaker 04:
And one of them was a 358 patent was in the way.

[00:29:13] Speaker 04:
And that was not an issue in this case, but that's one patent that was in the way.

[00:29:18] Speaker 04:
But just to round out the 541 before I run out of time, the court's decision was

[00:29:25] Speaker 04:
And these specific things like asymmetric dosing and doing one dose on the first date was all just a natural result of taking the steps one at a time rather than two at a time, which is testimony that the judge specifically credited and was supported in the record.

[00:29:47] Speaker 02:
Thank you.

[00:29:48] Speaker 02:
Thank you, counsel.

[00:29:49] Speaker 02:
Mr. Hurwitz has about a minute of rebuttal left on the cross-appeal.

[00:29:54] Speaker 00:
Has this court reviewed, for obviousness, a titration dose schedule patent?

[00:30:01] Speaker 00:
And if so, what was the outcome?

[00:30:04] Speaker 01:
Well, the endopharmaceuticals case is a kind of a dose titration type of case.

[00:30:09] Speaker 01:
It's a dosing case adjusting to get to the maintenance dose, and it involved an affirmance of non-obviousness in that case.

[00:30:14] Speaker 01:
So that's the one I point to.

[00:30:18] Speaker 01:
I'd just like to start by pointing out that, as this court held in mince, obviousness requires a form of amnesia, where you forget about the invention and think about what a person of skill would do, what would they be motivated to do, not knowing what the invention is.

[00:30:32] Speaker 01:
Counsel just admitted that asymmetric dosing wasn't even known in the prior art at all.

[00:30:38] Speaker 01:
That's the record.

[00:30:40] Speaker 01:
So it was incumbent upon the district court to at least explain

[00:30:43] Speaker 01:
How is it that a person of skill would be motivated to do something that no one had done before?

[00:30:48] Speaker 01:
Now, what counsel just said was, well, that's the only way to get there given the dosage forms available.

[00:30:54] Speaker 01:
She didn't cite a finding of the district court, because no such finding exists.

[00:30:58] Speaker 01:
And it's inconsistent with the record.

[00:31:00] Speaker 01:
It's not as if Otezla was on the market, and you're going to the pharmacy and picking up your 10, 20, and 30 milligram dosage forms.

[00:31:06] Speaker 01:
The partner art taught 5, 10, 15, 20, 25.

[00:31:10] Speaker 01:
All of that is at page 10607 of the joint appendix in column 13 of the 536 patent, a key reference.

[00:31:18] Speaker 01:
And Dr. Alexis testified similarly.

[00:31:21] Speaker 01:
In light of your absence of findings, we'd ask the court to at least vacate.

[00:31:25] Speaker 01:
But we think you should reverse outright the judgment with respect to the 541.

[00:31:29] Speaker 02:
Thank you to both counsel and cases submitted.