[00:00:31] Speaker 03:
Next case for argument is 15-1962, Andrews Pharmaceuticals versus Celgene Corporation.

[00:00:41] Speaker 03:
Until everybody gets settled here.

[00:00:42] Speaker 03:
The bad news for you all is the clock is working.

[00:01:09] Speaker 02:
Good morning, may it please the court.

[00:01:13] Speaker 02:
This is a case involving combination chemotherapy, specifically a combination chemotherapy applying the ingredients of thalidomide and alkylating agents.

[00:01:27] Speaker 02:
The parties have a few claim construction disputes that are addressed in the briefing today.

[00:01:32] Speaker 02:
I'd like to focus on one of those terms as the enhanced term which the district court found

[00:01:38] Speaker 02:
indefinite and thereby dispositive.

[00:01:41] Speaker 02:
Obviously, I'm happy to answer questions on any of the terms, but I'll focus my limited time today.

[00:01:46] Speaker 02:
And your construction of enhanced is?

[00:01:49] Speaker 02:
Greater than additive.

[00:01:52] Speaker 02:
And that is based on?

[00:01:54] Speaker 02:
That's an excellent question on the intrinsic record.

[00:01:59] Speaker 02:
The term enhanced was introduced in the prosecution history in response to a 103 rejection.

[00:02:08] Speaker 02:
Examiner found that the claim combination would be obvious over a certain piece of prior art, the liverage patent, if it claimed only a combination of additive effect.

[00:02:20] Speaker 02:
Now the liverage patent is directed to an invention for a means of delivery of chemotherapy where the specification discloses a large menu of chemotherapeutic agents

[00:02:35] Speaker 02:
which the specification indicates may be administered alone or in combination.

[00:02:42] Speaker 02:
Therefore, the patent examiner said that a skilled artisan would be motivated to combine those elements, including the claimed elements in this patent, for their mere additive effect, but that if the patent owner could show

[00:03:00] Speaker 02:
a combination directed to greater than additive effect, then the 103 rejection would be overcome.

[00:03:09] Speaker 02:
The patentee Andrew Ellis responded by amending the claims to add the term enhance.

[00:03:14] Speaker 02:
The patentee vigorously disagreed with the assertion that liverage disclosed a combination showing the type of enhancement demonstrated by the claimed combination, and the patentee added

[00:03:30] Speaker 01:
I thought the vigorous disagreement was more about whether the reference actually taught or suggested a combination of litamide with one of these other anti-cancer agents.

[00:03:42] Speaker 02:
Well, I think those two points go together.

[00:03:43] Speaker 02:
I think the point is, I believe the record shows that the examiner pointed to liver seeds to show that any number of these chemotherapeutic agents could be combined.

[00:03:58] Speaker 02:
As the patentee argued, however, Liversidge did not focus on the specific claim combination, which distinguishes itself by having, we argue, greater than additive effect relative to the other combinations disclosed in Liversidge.

[00:04:13] Speaker 01:
Where in your remarks section in your response to the office action did the applicant actually say, you know, we have a greater than additive effect here?

[00:04:27] Speaker 02:
applicant attached in exhibit A that contains a series of materials that reflect the available science at that time.

[00:04:35] Speaker 02:
In particular, I would call the course attention to the first and last documents in that exhibit.

[00:04:46] Speaker 01:
And in your view, do any of those articles actually, teachers suggest that there's a greater than additive effect when you're combining these ingredients together?

[00:04:57] Speaker 01:
Because I didn't quite see that.

[00:04:59] Speaker 01:
I didn't see them say, there's something synergistic.

[00:05:03] Speaker 01:
You know, one plus one equals three.

[00:05:05] Speaker 01:
Right.

[00:05:06] Speaker 02:
Right.

[00:05:08] Speaker 02:
The articles do not claim that one plus one equals three in this case.

[00:05:12] Speaker 02:
That is true.

[00:05:12] Speaker 02:
What they do disclose is that, for instance, in the USA Today article, that the claimed combination, or in that case, the combination of thalidomide and carboplatin increased patients' lifespan

[00:05:24] Speaker 02:
remaining lifespan from 11 to 40 weeks, an increase of 363%.

[00:05:28] Speaker 02:
The patentee pointed to this as evidence satisfying the examiner's rejection.

[00:05:37] Speaker 02:
Even that article, however, notes that further clinical trials would be required to prove the effectiveness of the combination.

[00:05:50] Speaker 02:
And then that is consistent with the patentee's

[00:05:54] Speaker 02:
position in this case.

[00:05:55] Speaker 01:
Did the inventors do any of their own research and generate some results on their own?

[00:06:02] Speaker 02:
They worked in collaboration with among other researchers NYU and that's precisely what exhibit the first document and exhibit A to the amendment is.

[00:06:14] Speaker 02:
However, they themselves did not conduct a complete clinical trials.

[00:06:18] Speaker 02:
No, I would submit that

[00:06:21] Speaker 02:
patent law does not require the inventor to prove an invention and in accord with that, no.

[00:06:29] Speaker 02:
The patentee did not have the funds or the resources to conduct clinical trials and did not complete those.

[00:06:36] Speaker 01:
I guess I was wondering how did the inventors come up with the invention?

[00:06:40] Speaker 01:
Was it based on reading medical journals or something like that?

[00:06:46] Speaker 02:
Dr. Peter Androulis, the CEO of

[00:06:51] Speaker 02:
had been involved in research regarding thalidomide for quite a long time.

[00:06:57] Speaker 02:
He's been published in other fields regarding advances in thalidomide.

[00:07:05] Speaker 02:
A background point that's important to note here is that at the time of the invention, thalidomide was still

[00:07:17] Speaker 02:
in its, I shouldn't say its infancy, in its early stages, recovering as a drug being reintroduced to the scientific community.

[00:07:29] Speaker 02:
And thus, that is the context in which the invention was created.

[00:07:36] Speaker 02:
Dr. Andoulas researched many uses of thalidomide, and this was one of them.

[00:07:45] Speaker 02:
But to answer your original question, no, clinical trials were not completed.

[00:07:50] Speaker 01:
If we conclude, based on a review of the prosecution history, that there really isn't a fair way of reading enhanced to map on the examiner's statement of greater than additive, then where are we?

[00:08:06] Speaker 01:
Do we then arrive at a point where we cannot conclude that enhanced means greater than additive, and then therefore

[00:08:15] Speaker 01:
because that was the grounds for indefiniteness we should affirm?

[00:08:21] Speaker 02:
I don't think so.

[00:08:25] Speaker 02:
This is a good moment to address the district court's opinion.

[00:08:30] Speaker 02:
The district court, as the court knows, found that enhanced can mean additive greater than additive or less than additive, essentially any degree of enhancement.

[00:08:43] Speaker 02:
I would submit that there is

[00:08:45] Speaker 02:
no support in the record for a finding that enhanced in this patent means less than additive.

[00:08:53] Speaker 02:
And that is the point that we discussed at some length in our opening brief.

[00:08:59] Speaker 02:
The district court's opinion is significant among other respects for what it omits.

[00:09:04] Speaker 02:
It omits the clear and convincing standard of evidence, and it also omits any reference to

[00:09:10] Speaker 02:
supporting testimony on the perspective of a person of ordinary skill in the art.

[00:09:14] Speaker 02:
In this case, the district court expressly stated it was not relying on Celgene's expert, and nonetheless found that enhanced could mean any degree of enhancement, thus adopting the opinion of Celgene's expert.

[00:09:32] Speaker 02:
However, to be clear, a less than additive combination

[00:09:39] Speaker 02:
would have to mean that the components of the combination actually inhibit each other's effectiveness.

[00:09:46] Speaker 02:
That is, if you take one and one, each component is decreased to some value less than one.

[00:09:55] Speaker 02:
Strange credulity, I would submit that.

[00:09:58] Speaker 01:
Is it possible that they have overlapping impacts to a certain degree such that you don't get necessarily a one plus one equals two, but because they both somehow are

[00:10:10] Speaker 01:
operating on the same item or mechanism or something like that, then therefore you end up with something a little bit less than additive.

[00:10:20] Speaker 02:
Yes, in the abstract that is possible.

[00:10:24] Speaker 02:
I don't believe that's what this patent claims.

[00:10:27] Speaker 02:
Both the specification states and the inventor testified that the invention is directed to

[00:10:39] Speaker 02:
combinations of agents that have different mechanisms of action and combine in a way that, as the prosecution history shows, have an effect that is greater than the generically disclosed additive combinations of liver-sage.

[00:10:56] Speaker 02:
So yes, we come back to the liver-sage patent.

[00:11:01] Speaker 02:
But to find that the

[00:11:07] Speaker 02:
patent claims a less than additive combination would be to find that there was no invention at all.

[00:11:15] Speaker 02:
In other words, it would be contrary, it would be difficult to read in light of the record that the patentee intended to cite Exhibit A showing the results that blew away the investigators at NYU, that those results were claiming a less than additive combination that

[00:11:36] Speaker 02:
our invention is something that diminishes the effectiveness of each of the components.

[00:11:42] Speaker 02:
That would not be consistent with anything in the record.

[00:11:46] Speaker 01:
Is that what less than additive means?

[00:11:47] Speaker 01:
Because I was under the impression it would mean that the combination of the ingredients yields some kind of benefit above and beyond using any of the ingredients alone.

[00:12:02] Speaker 01:
Well, it would mean that... And so therefore, you would have

[00:12:06] Speaker 01:
some kind of plus advantage in using the combination rather than any of the ingredients alone?

[00:12:12] Speaker 02:
Right.

[00:12:13] Speaker 02:
I don't think that the parties are in disagreement regarding the definition of less than additive.

[00:12:19] Speaker 02:
That is, a less than additive combination would be 1 plus 1 equals 1.5.

[00:12:28] Speaker 02:
So in other words, each component would be diminished, but the net effect would be greater than a single component.

[00:12:35] Speaker 02:
That is correct.

[00:12:45] Speaker 02:
I'd like to note before I move on quickly here that Solzhen's argument that enhances an indefinite term of varying degree does not, or excuse me,

[00:13:10] Speaker 02:
is not consistent entirely with this course prior jurisprudence.

[00:13:15] Speaker 02:
We know from biosig that terms of degree are not inherently indefinite.

[00:13:20] Speaker 02:
And I would further note that Halliburton, the case that Celgene cites throughout the briefing, in fact, states that a person of ordinary skill in the art is likely to conclude that the definition of a term does not encompass that which is expressly distinguished as prior art.

[00:13:36] Speaker 02:
This case

[00:13:38] Speaker 02:
somewhat uniquely presents an instance where the patentee and the patent examiner expressly address that situation in the prosecution history where they distinguish the liversage of prior art in narrowing the claims by amending them and adding the term enhanced.

[00:13:52] Speaker 02:
And thus I submit that the term should be read consistent with that prosecution history.

[00:13:59] Speaker 03:
You're into your rebuttals.

[00:14:02] Speaker 03:
Let's hear from the other side.

[00:14:13] Speaker 00:
May it please the court.

[00:14:21] Speaker 00:
There is no special definition of enhanced in this intrinsic record, and the rule is conceded, moreover.

[00:14:30] Speaker 01:
What's wrong with just thinking of the word enhanced as improved?

[00:14:35] Speaker 01:
Some benefit, some benefit above and beyond any of the ingredients by itself.

[00:14:41] Speaker 00:
There's nothing wrong with it.

[00:14:42] Speaker 01:
Would that be an indefinite usage of the word enhanced in a claim?

[00:14:47] Speaker 00:
Yes.

[00:14:48] Speaker 00:
Yes, it would.

[00:14:48] Speaker 00:
And there's nothing wrong with, I think the district court viewed the term.

[00:14:53] Speaker 01:
In terms of debris like that are in claims all the time.

[00:15:01] Speaker 00:
There's several problems with this particular one.

[00:15:04] Speaker 00:
And so in other words, the notion here is this combination is better.

[00:15:10] Speaker 00:
It's better.

[00:15:11] Speaker 00:
And what does that mean?

[00:15:13] Speaker 00:
We don't know.

[00:15:15] Speaker 00:
They argued that the results they got in Exhibit A in their amendment were not achieved by the prior art, but nobody knows what level of enhancement, what level of better those results are.

[00:15:31] Speaker 01:
Do you have to claim with specificity the utility you get from any kind of combination patent?

[00:15:40] Speaker 01:
combination patents have some utility, and now we're asking patent drafters to be very specific in how it claims the utility?

[00:15:51] Speaker 00:
Your Honor, I don't think you have to claim utility.

[00:15:55] Speaker 00:
Of course, you do have to have utility, but this is not a utility issue that we have here.

[00:16:01] Speaker 00:
They wrote enhanced into the claim, and so the meets and bounds of what

[00:16:07] Speaker 00:
that enhanced combination is has to be known with reasonable certainty by persons of skill in the art.

[00:16:15] Speaker 00:
These claims don't have a reasonably certain scope.

[00:16:17] Speaker 00:
They do not provide the notice function the claims have to provide as to what's in and what's out.

[00:16:23] Speaker 00:
A competitor wanting to stay away from these claims, wanting to not fringe, has no means by which they can do that with any reasonable certainty and know

[00:16:36] Speaker 00:
I'm in or I'm out when I do something.

[00:16:39] Speaker 01:
And so, for example, in the... And I would just read the claim as any therapeutically effective amount of the two recited ingredients in combination would meet the claim.

[00:16:53] Speaker 00:
That claim was rejected.

[00:16:55] Speaker 00:
And so what they put into the claim was an enhanced therapeutically effective amount, not merely an effective amount.

[00:17:06] Speaker 00:
Enhanced was added to specify an amount, but it is an indefinite amount and it's an indefinite level of enhancement or the combination.

[00:17:18] Speaker 00:
There's no question that under these claims, you can use an unenhanced combination.

[00:17:26] Speaker 00:
If you're an unenhanced combination, you do not infringe these claims.

[00:17:29] Speaker 00:
They put in a level of enhancement that has to be achieved, an indefinite level of enhancement that has to be achieved.

[00:17:36] Speaker 00:
into the claim.

[00:17:37] Speaker 00:
If they had simply said, let me put this in perspective of a situation one often finds in pharmaceutical cases, whether it's a combination claim or not, when there's an obviousness debate about whether a given drug, it could be a combination, is effective or is non-obvious or not,

[00:18:03] Speaker 00:
Sometimes a patentee will put in evidence of, for example, synergy to try to establish non-obviousness.

[00:18:09] Speaker 00:
They'll put it in as a secondary consideration.

[00:18:12] Speaker 00:
And the examiner may find, in view of the synergy showing as a secondary consideration, that the claim is allowable.

[00:18:20] Speaker 00:
And they will allow the claim as an effective amount of A in combination with an effective amount of B. And in that situation, we know that

[00:18:31] Speaker 00:
You know, the patent specifies effective amounts for A, effective amounts for B. You know what your method, you know whether you're practicing the method or not when you use 50 mgs of A, 50 mgs of B, you're treating disease C, and so you know you're within the scope of the claim.

[00:18:52] Speaker 00:
And the showing of synergy in that instance was used to get the claim allowed to establish non-obviousness.

[00:18:58] Speaker 00:
That is not what we have here.

[00:18:59] Speaker 00:
They wrote a level of enhancement into the claim.

[00:19:02] Speaker 00:
And so you have to practice this invention.

[00:19:05] Speaker 00:
One has to achieve some level of enhancement.

[00:19:09] Speaker 00:
And the problem we have is we don't know what level of enhancement that is.

[00:19:13] Speaker 00:
That's the problem.

[00:19:14] Speaker 01:
Maybe what we have here is a narrower question in that all that the district court was confronted with was the specific question of whether this word enhanced necessarily means greater than additive.

[00:19:29] Speaker 01:
And if it doesn't necessarily mean greater than additive, then all the parties agreed that the claim would be indefinite.

[00:19:35] Speaker 01:
That is correct.

[00:19:36] Speaker 01:
On that narrow question, the district court said what it said, and that's what we have to review.

[00:19:42] Speaker 00:
Your Honor, that is the situation that we have.

[00:19:44] Speaker 00:
That is absolutely the case.

[00:19:48] Speaker 00:
Your Honor asked a question of my opponent as to what is less than additive.

[00:19:53] Speaker 00:
And there was a discussion about what less than additive is.

[00:19:55] Speaker 00:
I think that would be useful to discuss right now.

[00:19:59] Speaker 00:
in this context.

[00:20:02] Speaker 00:
If I have drug A that has a cure rate of 20% and drug B has a cure rate of 20%, and then when I combine the two, I get a cure rate of 35%.

[00:20:17] Speaker 00:
That's a nice improvement.

[00:20:20] Speaker 00:
It's increased, which is what Your Honor indicated is a possible definition of an enhancement.

[00:20:26] Speaker 00:
I think that, Your Honor, actually is

[00:20:28] Speaker 00:
what the trial judge regarded as the general meaning of enhanced.

[00:20:32] Speaker 00:
Clearly, this less than additive combination is improved.

[00:20:36] Speaker 00:
It's increased.

[00:20:37] Speaker 00:
And on page 29 of Andrew Ellis's opening brief, they even say that an alternative definition that they would accept is consistent with the intrinsic record.

[00:20:47] Speaker 00:
This is stated on page 29 of the brief, is a better outcome with the combination than with either drug used alone.

[00:20:58] Speaker 00:
In my hypothetical, the combo that achieves a 35% cure rate is clearly a better outcome than either drug alone.

[00:21:06] Speaker 00:
It is fully within this broad notion of enhanced, of a better outcome as described, even in their own alternative definition.

[00:21:17] Speaker 00:
They conceded that this claim, when extended to these less than additive effects, which are certainly not excluded by the claim,

[00:21:28] Speaker 00:
Um, is indefinite and that's judge, um, Andrew's relied on that representation relied on that concession that they made to him.

[00:21:37] Speaker 00:
And I think the situation we have is exactly as your honor described.

[00:21:42] Speaker 00:
Um, uh, and, and to elaborate, uh, I guess, uh, a little further on this, uh, there was a mention of this USA Today article, which has become, uh, kind of the,

[00:21:56] Speaker 00:
foundation really of their arguments that this claim does not extend to less than additive effects.

[00:22:03] Speaker 00:
And this argument wasn't made to the district court.

[00:22:06] Speaker 00:
It's made for the first time in their brief on appeal here.

[00:22:08] Speaker 00:
But they said, we know that what I think it was Dr. Gruber in the USA Today article, we know when he said he was blown away by the results.

[00:22:27] Speaker 00:
that it can't be less than additive because you wouldn't be blown away by a less than additive effect.

[00:22:34] Speaker 00:
Well, that's sheer speculation.

[00:22:37] Speaker 00:
That's just attorney argument.

[00:22:38] Speaker 00:
Personally, as a patient and perhaps as a doctor, in my hypothetical, when you get a 35% cure rate instead of a 20, as a patient, I would like that much better.

[00:22:49] Speaker 00:
And I like my odds better, and I would be perhaps blown away by that.

[00:22:53] Speaker 00:
Does that mean that it's no longer less than additive just because I'm blown away by it?

[00:22:57] Speaker 00:
And I'm thinking of this court's statement in interval licensing where it said that a claim is indefinite if you leave the skilled artisan to consult the unpredictable vagaries of any one person's opinion.

[00:23:16] Speaker 00:
And that's what we have here.

[00:23:18] Speaker 00:
We have the patentee

[00:23:21] Speaker 00:
consulting the vagaries of Dr. Gruber's opinion is reported in a USA Today article.

[00:23:26] Speaker 00:
No data.

[00:23:27] Speaker 00:
No data to tell us whether that is greater than additive, additive, or less than additive.

[00:23:33] Speaker 00:
It's actually even more opaque than that in that very article.

[00:23:39] Speaker 00:
In the same page that Dr. Gruber's blown away statement occurs, on the left-hand column there's reports from Dr. Fine

[00:23:48] Speaker 00:
of his studies on using thalidomide alone in the same cancer.

[00:23:51] Speaker 00:
And he had a patient who survived for 18 months after treatment with thalidomide alone.

[00:23:59] Speaker 00:
So that's 72 weeks, as opposed to the 40 weeks median that Dr. Gruber had.

[00:24:05] Speaker 00:
So is Dr. Gruber talking about something that is additive, less than additive?

[00:24:12] Speaker 00:
I mean, it's a complete mystery.

[00:24:17] Speaker 00:
Judge Andrews was entitled properly to rely on the concession that Andrews was made before the district court.

[00:24:25] Speaker 00:
He interpreted the claims correctly and consistent with the intrinsic record.

[00:24:30] Speaker 00:
They did not make any statements indicating when they made their amendment that Hans somehow meant synergy or greater than additive.

[00:24:39] Speaker 00:
In fact, if they had thought that that's what it meant, they almost certainly would have said this mooted

[00:24:44] Speaker 00:
this mooted the 103 rejection that the examiner made, rather than argue that they had vigorous disagreement with the examiner.

[00:24:57] Speaker 00:
Your Honor, I think that those are the critical points that I would like to make.

[00:25:03] Speaker 00:
If the Court has any questions, I've got time remaining, but I would

[00:25:09] Speaker 00:
happily surrender it to the court.

[00:25:12] Speaker 00:
I'd like to make just a couple of quick points.

[00:25:24] Speaker 02:
One, a point of correction.

[00:25:26] Speaker 02:
Andrews did not concede before the district court that if enhanced does not mean greater than additive, that is indefinite.

[00:25:34] Speaker 02:
Rather, Andrews did concede.

[00:25:36] Speaker 02:
that if it means any degree of enhancement, therefore less than additive, additive or greater than additive, then it is indefinite.

[00:25:45] Speaker 02:
And that was a significant point as outlined in our opening brief.

[00:25:52] Speaker 02:
I'd like to touch on one other point very quickly in my one and a half minutes here.

[00:25:58] Speaker 02:
You heard my colleague, Mr. Griffith, talk a bit about how to read these claims as a patient, as a doctor,

[00:26:07] Speaker 02:
And I think that calls to mind the problem that we have here, that we do not have the perspective of a person of ordinary skill in the art in the record before the district court.

[00:26:17] Speaker 02:
And that was an omission that I submit was reversible error by the district court.

[00:26:26] Speaker 02:
Candidly, I'm a chemotherapy patient myself, and I submit that if the court were to consult

[00:26:37] Speaker 02:
a medical oncologist and ask them what is the objective of combination chemotherapy.

[00:26:46] Speaker 02:
It would not be long before the word synergy comes up.

[00:26:49] Speaker 02:
This is a term that has common usage in the field of medical oncology and is one that medical oncologists, persons of ordinary skill in the art would understand.

[00:26:59] Speaker 02:
By analogy, this court has held before that person of ordinary skill in the art in the pharmaceutical context

[00:27:05] Speaker 02:
would understand the meaning of effective amounts.

[00:27:09] Speaker 02:
That regardless of the fact that effective could mean any number of things in the abstract, yet still a person of ordinary skill in the art, a medical oncologist, would understand what an effective amount of a drug is.

[00:27:20] Speaker 02:
They would understand the concept of effectiveness.

[00:27:22] Speaker 02:
And likewise, they would understand the concept of synergy in this case.

[00:27:27] Speaker 02:
And if the court has any other questions, I'm happy to answer them.

[00:27:30] Speaker 02:
Thank you.

[00:27:30] Speaker 02:
We thank both counsel and the cases submitted.