[00:00:46] Speaker 02:
OK, the next argued case is number 191364, Biogen Incorporated against the director of the PTO, Ms.

[00:00:57] Speaker 02:
French Brown.

[00:00:59] Speaker 00:
Good morning, Your Honor.

[00:01:01] Speaker 00:
So we've reserved three times for rebuttal.

[00:01:04] Speaker 00:
May it please the court, I am Wanda French Brown on behalf of Appellant Biogen, the patent owner of the 873 patent.

[00:01:11] Speaker 00:
The board here made a number of errors in determining that all claims of the 873 patent

[00:01:16] Speaker 00:
are obvious in view of a five reference combination.

[00:01:19] Speaker 00:
The board erred in concluding that there was a motivation to combine, which constitutes a legal error and lacks substantial evidence.

[00:01:28] Speaker 00:
The board's decision that there was a reasonable expectation of success likewise constitutes legal error and lacks substantial evidence.

[00:01:36] Speaker 00:
Third, the board erred in finding that claim four is obvious because not one of these five references.

[00:01:42] Speaker 04:
Just to stop you before you go any further.

[00:01:43] Speaker 04:
You're saying the board's errors of motivation to combine and reasonable expectation of success are legal errors, but those are both questions of fact.

[00:01:50] Speaker 04:
So how is it that they're legal errors?

[00:01:53] Speaker 00:
So motivation to combine and reasonable expectation of success is viewed from the perspective of person, skill, and the art.

[00:01:59] Speaker 00:
The board did not do that here.

[00:02:01] Speaker 00:
And because it's viewed from the perspective of a person, skill, and the art, it's also a question of fact.

[00:02:06] Speaker 00:
And the experts here have factually testified consistently with each other with regards to motivation to combine that

[00:02:13] Speaker 00:
In order to combine these references, they would want to see evidence that a two treatment combination was better than a single treatment for DLCL patients over 60 before adding a third treatment.

[00:02:23] Speaker 04:
I guess I'm not understanding how that's a legal question as opposed to a factual one.

[00:02:27] Speaker 00:
Well, obviousness is a legal determination that's grounded in fact.

[00:02:33] Speaker 00:
I guess the root of the argument that it said.

[00:02:35] Speaker 04:
But we've expressly said on many, many cases that whether or not there is a motivation to combine and what that motivation to combine is is a question of fact.

[00:02:43] Speaker 00:
Yes, you're right.

[00:02:44] Speaker 00:
It's a question of fact because it's viewed from the perspective of person, skill, and art.

[00:02:48] Speaker 00:
The board ignored undisputed factual evidence in the record as what a person, skill, and art would say they would do to combine these references.

[00:02:56] Speaker 00:
And here, you know, Dr. Ozer's testimony at appendix 987

[00:03:01] Speaker 00:
Dr. Call's testimony in appendix 1125, they said that they would want to see that a two-treatment combination was better than a single treatment before adding a third treatment.

[00:03:10] Speaker 00:
Not one of the five references provides any clinical data or results comparing two treatments to one in patients over 60 with DLCL.

[00:03:21] Speaker 00:
This is undisputed.

[00:03:23] Speaker 01:
That would be a 102 reference, though.

[00:03:25] Speaker 01:
We're dealing with 103 here.

[00:03:28] Speaker 00:
Well, they combined five references.

[00:03:30] Speaker 00:
None of the references either collectively together compares a two treatment combination to one.

[00:03:37] Speaker 00:
A 102 reference would be comparing all three.

[00:03:40] Speaker 01:
The claim is just for treating DLCL in patients that are over 60.

[00:03:43] Speaker 01:
Is that right?

[00:03:45] Speaker 00:
That's right.

[00:03:45] Speaker 00:
Combining three treatment combinations.

[00:03:47] Speaker 01:
And it's not treating DLCL in patients over 60.

[00:03:54] Speaker 01:
That's better than just doing CHOP therapy alone.

[00:04:00] Speaker 00:
Is that right the claim doesn't isn't written that way the claim is not written that way but when you motivation can blind and viewed from the perspective of personal skill in the heart and what they've told us here in this case that in order to act before adding a third treatment to a very sensitive patient population of patients over 60 that were more prone to toxicity would chop alone compared to younger patients they would want to see a two treatments that were better than one and

[00:04:25] Speaker 00:
before adding yet a third treatment to the very sensitive patient population.

[00:04:29] Speaker 01:
Why would the hypothetical skilled artisan be motivated here when we have Link that actually did a test on humans combining CHOP with rituximab, or whatever it's called.

[00:04:48] Speaker 01:
And then we have another one, McNeil, that says,

[00:04:53] Speaker 01:
I am going to run a human clinical trial on patients over 60 using rituximab and CHOP chemotherapy.

[00:05:05] Speaker 01:
I mean, there's a question of whether a hypothetical skilled artisan would have been motivated.

[00:05:13] Speaker 01:
But then we have evidence of people actually doing it.

[00:05:16] Speaker 01:
I mean, that seems even stronger than

[00:05:19] Speaker 01:
the hypothetical question of one would have been motivated.

[00:05:22] Speaker 01:
People were actually doing it.

[00:05:24] Speaker 00:
LINC is not a study for patients over 60 with DLCL.

[00:05:28] Speaker 00:
LINC, and it's undisputed that LINC does not identify any patient.

[00:05:31] Speaker 01:
Right, the average age is 49 over there.

[00:05:33] Speaker 01:
But then we have McNeil, which is specifically talking about this looks good for people over 60.

[00:05:39] Speaker 01:
This is what I'm going to do.

[00:05:41] Speaker 01:
I, McNeil, am motivated and am going to do this particular human clinical trial.

[00:05:47] Speaker 01:
So that sounds like pretty strong evidence when you actually have someone saying they're going to do it as evidence that people would be motivated because there was at least one person, McNeil, who was going to do it.

[00:06:02] Speaker 00:
Well, McNeil does not disclose any study design, any details, or any results.

[00:06:08] Speaker 00:
In fact, McNeil says that patients over 60 have been excluded from clinical trials.

[00:06:13] Speaker 00:
So we need to conduct this pilot study.

[00:06:15] Speaker 00:
Moreau, on its face,

[00:06:16] Speaker 00:
Says age was the most single prognostic factor and because of that there needs to be a study designed specifically for patients over 60 link has nothing to do with patients over 60 there And it's conceded that it's that doesn't identify any patients over 60 the board doesn't explain Why a person skilled in the art would nonetheless rely on link when patients over 60 weren't included in that study and

[00:06:40] Speaker 00:
And it's also undisputed that elderly patients react to treatment differently than younger DLCL patients.

[00:06:45] Speaker 00:
That's found in the record of Dr. Sulphur's deposition.

[00:06:47] Speaker 04:
And so, I mean, I understand your arguments with regard to LINC.

[00:06:51] Speaker 04:
But does that matter if McNeil otherwise expressly says to make this combination of CHOP and Rituxen?

[00:07:02] Speaker 00:
Yes, it matters.

[00:07:04] Speaker 00:
Because LINC is not a study of patients over 60.

[00:07:07] Speaker 00:
And McNeil says,

[00:07:08] Speaker 00:
We need to have a study for patients over 60, because they've been excluded.

[00:07:11] Speaker 00:
And they actually identify a presidential panel that criticizes current studies that didn't include the special patient populations of patients over 60.

[00:07:21] Speaker 00:
Also, LINC, even though the patients were under 60, identifies a significant number of toxicities.

[00:07:27] Speaker 00:
For example, at appendix 257, eight patients

[00:07:32] Speaker 00:
had grade four toxicities, which is the worst.

[00:07:34] Speaker 04:
Yes, but McNeil tells you to do this.

[00:07:37] Speaker 04:
I mean, why isn't it at least obvious to try after he's expressly said to do it?

[00:07:42] Speaker 00:
Well, I don't think Link expressly says to do it.

[00:07:46] Speaker 04:
McNeil does.

[00:07:47] Speaker 00:
McNeil suggests that there should be a study.

[00:07:49] Speaker 00:
And McNeil actually goes further to say that there should be a CHOP alone compared to CHOP and a second treatment.

[00:07:57] Speaker 00:
McNeil does not disclose that the study design

[00:08:00] Speaker 00:
It doesn't disclose details or results.

[00:08:02] Speaker 00:
And so the experts here, with regards to reasonable expectations of success, has testified consistently with each other that they would want to see study results that show that there's an improved prognosis.

[00:08:15] Speaker 00:
Now, going back to LINC, 14 patients had grade three toxicities.

[00:08:20] Speaker 00:
Eight had grade four.

[00:08:21] Speaker 00:
That's over 65% of younger patients experiencing toxicities.

[00:08:26] Speaker 00:
And experts have confirmed that elderly patients

[00:08:30] Speaker 00:
or more prone to toxicity.

[00:08:31] Speaker 01:
Well, didn't Link say its combination of rituximab and CHOP, quote, represents a tolerable therapy with serious adverse events occurring with a frequency similar to that seen with conventional CHOP therapy alone and may offer higher response rates?

[00:08:50] Speaker 00:
For those patients who were not over 60.

[00:08:54] Speaker 01:
But I thought now you were migrating over to an argument suggesting that this combination theory is more dangerous than doing CHOP therapy alone.

[00:09:07] Speaker 01:
And at least according to this quote, it sounds like, no, that's not what Link was saying.

[00:09:13] Speaker 01:
Link was saying it's no worse than doing CHOP therapy alone in terms of adverse events.

[00:09:19] Speaker 01:
But in addition to that, it may offer higher response rates.

[00:09:23] Speaker 00:
That's not for patients over 60 with I know we've got that through McNeil right so no make McNeil says that you need to have a study designed for patients over 60 because they respond to treatment differently so the experts have Testified consistently with each other that dl.

[00:09:39] Speaker 00:
So dl cl patients over 60 had worse response to treatment and was worse tolerability treatment Talks was top was more was the standard of care for coffee air

[00:09:51] Speaker 00:
Coffier was a study, a single study of Rituximab in patients over 60.

[00:09:55] Speaker 01:
Did you say Rituximab has significant activity in DLCL, including those above 60?

[00:10:05] Speaker 00:
Yes.

[00:10:05] Speaker 00:
So Coffier was a study, a monotherapy study for Rituximab administered to patients over 60.

[00:10:12] Speaker 00:
It was a single study.

[00:10:13] Speaker 00:
And even in that study, if you look at Appendix 261, 25% of arm A

[00:10:18] Speaker 00:
experience adverse events, and 31% in RMB experience adverse events.

[00:10:26] Speaker 00:
So going to the reasonable expectation.

[00:10:29] Speaker 01:
I'm reading at 8258, in this first trial of rituximab and DLCL, patients experienced a significant clinical activity with a low toxicity.

[00:10:39] Speaker 01:
Rituximab has a significant activity in DLCL and MCL patients and should be tested in combination with chemotherapy in such patients.

[00:10:48] Speaker 00:
Right, so COFIER does not identify any responders being greater than age 60.

[00:10:54] Speaker 00:
I mean, there are some patients in that study that are over age 60, but it doesn't identify any responders that are over age 60.

[00:11:03] Speaker 00:
And that's even conceded by Dr. Sulfur and his deposition at Appendix 1801.

[00:11:09] Speaker 00:
Going back to reasonable expectation of success, the board failed to view the reasonable expectation of success

[00:11:17] Speaker 00:
the person's skill and the art.

[00:11:18] Speaker 00:
And so what the experts have testified consistently with each other here is that a reasonable expectations assessment is going to improve prognosis for patients over 60.

[00:11:28] Speaker 04:
And even petitioner and their where do the claims require that because I only understand the claims to recite treating DlCl in patients over 60 I don't understand the claims to suggest it has to improve that this particular method of treatment has to improve their prognosis Right so over individual therapies for example improved prognosis is not expressly written in a claim But reasonable expectation of success is viewed from the perspective of person skilled in art

[00:11:55] Speaker 00:
And in this case, all experts agree that a reasonable expectation of success meant to them an improved prognosis in patients over 60.

[00:12:03] Speaker 00:
For example, Dr. Sophia in his deposition at 1786 said, if we just talk about patients over the age of 60, successful treatment would mean improvement of prognosis of patients over 60.

[00:12:14] Speaker 00:
That's consistent with Dr. Ozer's testimony at Appendix 985.

[00:12:18] Speaker 00:
And as this court has recognized recently in OSIV Apotex, cancer treatment is highly unpredictable.

[00:12:25] Speaker 00:
So similar to OCI, here we have no clinical data to suggest that there's going to be an improved prognosis in patients over 60 with a two-treatment combination.

[00:12:34] Speaker 00:
And the lack of clinical data here is even more significant because we have that person's skill and art telling us what reasonable expectation of success meant to them.

[00:12:43] Speaker 00:
It meant an improved prognosis.

[00:12:46] Speaker 00:
And in fact, petitioners in their original petition for IPR at Appendix 120, they acknowledged that the general problem confronted

[00:12:54] Speaker 00:
But inventor before the invention was made was whether new therapies would have improved the prognosis for patients over 60 There's no evidence in the record.

[00:13:02] Speaker 04:
I have a stupid factual question, but when you're talking about improved prognosis so if you take two particular therapies to put together

[00:13:19] Speaker 04:
I can't say we put these two together.

[00:13:22] Speaker 04:
Are you talking about improvement over either one of them?

[00:13:26] Speaker 04:
Individually or improvement over something else individually.

[00:13:30] Speaker 00:
It's improvement over one of them individually so if you take top and retoxin They said that they want to see that toxin retoxin is better than Top alone before adding a third treatment for patients over 60 with dlcl

[00:13:46] Speaker 00:
So the board also erred in their determination that claim four is obvious.

[00:13:52] Speaker 00:
So claim four requires patients over 60 with DLCL that involves bone marrow involvement.

[00:14:02] Speaker 00:
And so McNeil, Moreau, and Link do not disclose any treatment of patients with bone marrow involvement.

[00:14:10] Speaker 00:
Kofir does not disclose whether any of the seven patients with bone marrow involvement were DLCL patients.

[00:14:17] Speaker 00:
And COFIR doesn't disclose treatment of elderly patients with bone marrow involvement.

[00:14:23] Speaker 00:
So what the board did is they really conflated and collapsed claim four into claim one, rather than looking at claim four requirements separately.

[00:14:32] Speaker 00:
There's no reasonable expectations of excess here that combining these references will somehow improve the prognosis of patients over 60.

[00:14:41] Speaker 01:
I didn't hear you say anything about Maloney.

[00:14:43] Speaker 00:
Yeah.

[00:14:44] Speaker 00:
Maloney.

[00:14:47] Speaker 00:
is a reference that it only had two patients with DLCL.

[00:14:54] Speaker 00:
And Maloney does not identify any of those patients as being greater than 60.

[00:14:59] Speaker 01:
Well, they have bone marrow involvement.

[00:15:01] Speaker 01:
Is that right?

[00:15:03] Speaker 00:
Maloney doesn't identify those patients that have bone marrow involvement that were over age 60.

[00:15:10] Speaker 00:
And that's the problem with Maloney.

[00:15:13] Speaker 00:
And that's actually recognized by Dr. Ozer in his deposition at appendix 1013, start net line 11, that all the responders who are patients, and all the responders in Maloney are patients with low-grade non-Hoskins lymphoma.

[00:15:30] Speaker 00:
And so the experts have testified consistently that identifying the greater lymphoma is going to dictate treatment.

[00:15:37] Speaker 00:
So the board didn't explain, despite the fact that

[00:15:40] Speaker 00:
low-grade lymphoma was disclosed in Maloney, why a person of skill and art would rely on that, when the experts say that identifying the type and grade of lymphoma dictates the treatment plan.

[00:15:51] Speaker 00:
And in this case, we're talking about a sensitive patient population over 60 with an aggressive form of lymphoma.

[00:16:00] Speaker 00:
So I believe my time is up.

[00:16:01] Speaker 02:
I have a question from the other side.

[00:16:02] Speaker 02:
We'll save you rebuttal time.

[00:16:04] Speaker 02:
Thank you.

[00:16:11] Speaker 02:
Ms.

[00:16:11] Speaker 02:
Craven, I guess I said the other side, but you're not the other side.

[00:16:15] Speaker 02:
What happened to the petitioner in this case?

[00:16:18] Speaker 03:
The petitioner dropped out, Your Honor.

[00:16:19] Speaker 03:
May it please the court.

[00:16:21] Speaker 03:
So the director, under their statutory authority, stepped in.

[00:16:26] Speaker 02:
Well, I'm not sure.

[00:16:28] Speaker 02:
The statute says that the director has the right to intervene, but it doesn't say the director has the right to take sides when the other side has dropped out.

[00:16:39] Speaker 02:
And I think this is a curious situation.

[00:16:43] Speaker 02:
in that here we have this board that is being treated like a tribunal.

[00:16:52] Speaker 02:
But isn't it curious for the decision-maker, the judge, to come in and to defend the decision when the winning party refuses to do so?

[00:17:06] Speaker 03:
Well, Your Honor, this Court has already decided and knows that the Director does have the statutory authority to step in in this situation.

[00:17:13] Speaker 03:
We are here to defend the board's decision just like we do in ex parte cases as part of the agency defending the agency's decision.

[00:17:21] Speaker 03:
And I think that it helps the court then to really understand the merits of the case to actually have two parties disputing them.

[00:17:29] Speaker 02:
I think we're trying to understand the role of the PTAP, which is

[00:17:35] Speaker 02:
doing its best to be treated like a tribunal.

[00:17:39] Speaker 02:
And yet, unlike any tribunal otherwise, if the winning party drops out for whatever reason, then the tribunal comes in to defend itself.

[00:17:53] Speaker 03:
Well, respectfully, Your Honor, we represent the agency.

[00:17:57] Speaker 03:
This is the director's decision through the PTAB.

[00:18:00] Speaker 02:
Yes, the tribunal is part of the agency.

[00:18:02] Speaker 02:
It's not a separate judicial branch

[00:18:05] Speaker 02:
activity is an agency activity.

[00:18:08] Speaker 03:
Right.

[00:18:08] Speaker 03:
And we're here to try and help your honors then to make the best decision based on what our understanding of the board's decision and to give you the other side of the story.

[00:18:18] Speaker 03:
So there's just Biogen here alone.

[00:18:20] Speaker 03:
And I understand your position, but this court in Knowles did say that we have the statutory authority to be here.

[00:18:27] Speaker 03:
And that isn't something we've briefed again in this case.

[00:18:31] Speaker 03:
So respectfully, I'd like to perhaps

[00:18:34] Speaker 03:
Continue then on the merits.

[00:18:36] Speaker 02:
Well, okay, all right, let's proceed with the merits.

[00:18:39] Speaker 02:
But on the merits, as long as I've interrupted you, I couldn't find anywhere in the prior art, in the record, a suggestion

[00:18:50] Speaker 02:
to make this combination.

[00:18:51] Speaker 02:
How do we distinguish what was actually done and viewing it in hindsight that, yeah, this is a good idea, and a suggestion in the prior art that this should be done and it will work?

[00:19:07] Speaker 02:
Not to go out and experiment.

[00:19:09] Speaker 02:
We know these are extraordinarily complex biological, physiological events that take place with antibodies and all this stuff.

[00:19:20] Speaker 02:
That's what I'm looking for.

[00:19:21] Speaker 02:
So help us if you're here to help us where there's a suggestion with likelihood of success.

[00:19:30] Speaker 02:
Not go out and do some experiments, but that this will work.

[00:19:35] Speaker 02:
Because the FDA doesn't seem to think so.

[00:19:38] Speaker 02:
They made them go through the whole FDA process for approval.

[00:19:44] Speaker 03:
Right.

[00:19:44] Speaker 03:
So there's a lot there, Your Honor.

[00:19:45] Speaker 03:
Let me see if I can unpack that and give you

[00:19:49] Speaker 03:
the answers that you require.

[00:19:51] Speaker 03:
So starting with just the primary reference here, Moreau, it has a therapy that it says... You can find these activities in separate references.

[00:20:02] Speaker 02:
I'm looking at the combination.

[00:20:04] Speaker 03:
Right.

[00:20:04] Speaker 03:
So Moreau teaches all the limitations of the claim, Your Honor, except the addition of the CD20 antibody.

[00:20:10] Speaker 03:
Rituximab.

[00:20:11] Speaker 03:
We can just call it the antibody.

[00:20:13] Speaker 03:
That might be easier for everyone.

[00:20:15] Speaker 03:
And Moreau already has a successful treatment for the exact patient population that's claimed, older patients that have DLCL.

[00:20:25] Speaker 03:
And the question then, the motivation question that your honor is getting at, is the motivation then to add the antibody to that method.

[00:20:34] Speaker 03:
That's how the board is framing the motivation to combine.

[00:20:37] Speaker 03:
And what the board looks at with the other prior art is, in fact,

[00:20:40] Speaker 03:
that there is explicit statements in the prior art to make the combination.

[00:20:46] Speaker 03:
LINC is a study that combines rituximid and CHOP in DLCL patients and shows an increased efficacy over CHOP alone, a 96% efficacy, without any increase in toxicity, which is suggesting to someone that you can get a better efficacy with adding rituximid without extra toxicity.

[00:21:09] Speaker 03:
And the older patients are the exact patient population that have this problem with toxicity with CHOP.

[00:21:15] Speaker 03:
What McNeil says is this is the patient population where we need alternative therapies.

[00:21:20] Speaker 03:
And that exact alternative therapy that McNeil suggests is CHOP with Rituximab.

[00:21:27] Speaker 03:
And a perspective, there's going to be a clinical study on that.

[00:21:31] Speaker 02:
And in retrospect, but it wasn't obvious to the regulatory agencies, to the FDA.

[00:21:38] Speaker 02:
So who are the judges to say, well, it's obvious to us, we know better?

[00:21:42] Speaker 03:
So the requirements for FDA approval are much more stringent in terms of

[00:21:48] Speaker 03:
They're just different requirements than for obviousness, right?

[00:21:50] Speaker 02:
They're stringent.

[00:21:51] Speaker 02:
Absolutely.

[00:21:52] Speaker 02:
And we're talking about really extraordinarily complex biological properties.

[00:21:58] Speaker 03:
But I don't know what your honor is referring to when you said the FDA hasn't approved this.

[00:22:04] Speaker 03:
We have FDA approval

[00:22:06] Speaker 03:
to do stem cell transplantation, which involves a CHOP therapy.

[00:22:10] Speaker 03:
And Rituximab is an FDA-approved therapy.

[00:22:15] Speaker 03:
And people are using them in clinical trials and finding that they're getting success in that they're having responses from patients with DLCL and including people who are older patients with DLCL.

[00:22:29] Speaker 03:
So I'm not sure what the regular agency has said about

[00:22:34] Speaker 03:
clinical trials for this particular combination.

[00:22:36] Speaker 03:
That's not in the record.

[00:22:38] Speaker 03:
But this court has repeatedly said whatever the standard is for an FDA trial, it's not what the standard is for obviousness.

[00:22:46] Speaker 03:
There's substantial evidence for the board's motivation to combine finding.

[00:22:51] Speaker 03:
We haven't even talked about Malhoney, which Malhoney is a study of rituximab.

[00:22:55] Speaker 04:
Is the pallet correct that all of the experts in this case agreed that reasonable expectation of success

[00:23:04] Speaker 04:
would hinge on an improved prognosis as compared to an individual drug, that you wouldn't add a third treatment until you knew adding two was better than just any one of them by themselves.

[00:23:16] Speaker 03:
So Pfizer's experts did make general statements to that effect, but they were not tied to the specific facts of this case.

[00:23:24] Speaker 03:
So I believe it was.

[00:23:26] Speaker 04:
Well, their expert definitely testified to it at 1257.

[00:23:29] Speaker 04:
And then I thought the Pfizer expert

[00:23:30] Speaker 04:
also did at 1785 to 1786.

[00:23:35] Speaker 04:
But I agree with what you're saying, that they're more generalized statements.

[00:23:38] Speaker 04:
But given that all of the experts seem to have said, and no experts contradicted the notion, that in general, you wouldn't think about adding a third drug in with this patient population, given the toxicity concerns, unless you were sure that the two you were already working with was better than either one of them individually.

[00:23:58] Speaker 03:
So two answers to that first.

[00:23:59] Speaker 03:
The claims don't require any improved prognosis.

[00:24:02] Speaker 03:
So for a reasonable expectation of success, it has to be a reasonable expectation of what is claimed, and that is treating DLCL.

[00:24:11] Speaker 03:
Experts can't change what the claims say through their expert testimony.

[00:24:15] Speaker 03:
And second, when the experts are saying this, I wouldn't add the third therapy.

[00:24:20] Speaker 04:
But it's a reasonable expectation of success in terms of reasonable expectation and motivation to combine really go hand in hand.

[00:24:28] Speaker 04:
I mean, we've said they're interrelated.

[00:24:30] Speaker 04:
Yes.

[00:24:30] Speaker 04:
So why would somebody be motivated to add a third treatment in, given the toxicity concerns in this patient population, if they weren't sure

[00:24:40] Speaker 04:
that two treatments taken together were any better than one.

[00:24:43] Speaker 04:
Those two concepts are intertwined for me.

[00:24:46] Speaker 03:
OK.

[00:24:47] Speaker 03:
So I think when Pfizer's experts said that, they was not saying it in the context of the specific facts of this case.

[00:24:55] Speaker 03:
And I believe Pfizer's expert understood this case based on the prior art that was reading that CHOP therapy as part of stem cell transplantation was already

[00:25:09] Speaker 03:
one conventional therapy for a certain population of patients with aggressive non-Hodgkin's lymphoma.

[00:25:15] Speaker 03:
So the motivation to combine issue was adding the antibody to what Moro says is already the treatment of choice for a particular patient population.

[00:25:26] Speaker 03:
And the toxicity concerns are laid because you don't see increased toxicity with rituximab.

[00:25:33] Speaker 03:
You don't see it increase the toxicity of CHOP in the LINC study.

[00:25:37] Speaker 03:
It's the same toxicity as CHOP alone.

[00:25:40] Speaker 04:
And so given that it's all- Well, maybe if it's the same toxicity as CHOP alone, but is it the same toxicity as what Moreau discloses, which is what CHOP plus?

[00:25:51] Speaker 03:
Transplantation.

[00:25:53] Speaker 03:
So both report not significant toxicity.

[00:25:57] Speaker 03:
There's no toxic deaths in Moreau.

[00:25:59] Speaker 03:
There's no organ toxicity.

[00:26:01] Speaker 03:
People do fail the trial with disease progression.

[00:26:05] Speaker 04:
But I think the point is I don't seem to understand it.

[00:26:09] Speaker 04:
I don't think the record includes, but please correct me, an articulation of toxicity for just CHOP versus toxicity for stem cell versus toxicity for the two of them together.

[00:26:21] Speaker 04:
And wouldn't you need to know that before you're going to add a third in, which could further exacerbate the toxicity concerns?

[00:26:29] Speaker 03:
Right.

[00:26:29] Speaker 03:
I think the framing, though, is when there is no stem cell transplantation toxicity

[00:26:35] Speaker 03:
alone, because as Biogen's argument concedes, you do the chemotherapy as part of the stem cell transplantation.

[00:26:43] Speaker 03:
And if you don't respond to CHOP, you're not going to go on to the transplantation of the cells, the harvesting and all that.

[00:26:50] Speaker 03:
And the toxicity associated with that entire therapy is what Moreau says is actually tolerable in the exact patient population that's claimed, DLCL patients who are an older population.

[00:27:04] Speaker 03:
So the toxicity concern is of adding Rituximab to that combination.

[00:27:09] Speaker 03:
It has some toxicity, yes, but no toxic deaths, no organ toxicity.

[00:27:15] Speaker 03:
And Rituximab, as a monotherapy, doesn't have those toxicity concerns.

[00:27:19] Speaker 04:
I guess here's the problem.

[00:27:20] Speaker 04:
These two things in Moreau, when taken together, were deemed tolerable.

[00:27:27] Speaker 04:
that doesn't, tolerable, right, could be like just borderline on the edge of, oh my god, don't do it again.

[00:27:33] Speaker 04:
You know, we don't know where that toler, I don't understand from Moreau precisely where something would cross the line.

[00:27:39] Speaker 04:
There seems to be no doubt that the additional treatment would increase toxicity.

[00:27:44] Speaker 04:
The question is, by how much?

[00:27:46] Speaker 03:
I don't think there, I mean, I don't think people do think adding Rituximab would increase toxicity, because Link says.

[00:27:52] Speaker 04:
But it increases, it causes toxicity in and of itself, by itself.

[00:27:57] Speaker 03:
The toxicity is, there's not a lot of adverse effects with rituximid.

[00:28:01] Speaker 03:
There's some adverse effects with infusion.

[00:28:04] Speaker 03:
So it's true.

[00:28:04] Speaker 04:
There's going to be- No, but doesn't the record show that there is some toxicity caused by rituximid?

[00:28:10] Speaker 03:
That doesn't overlap with the toxicity of CHOP.

[00:28:13] Speaker 03:
So when you give them- That wasn't what I asked you.

[00:28:14] Speaker 04:
What I asked you is, doesn't this record show that rituximid has some attention to toxicity?

[00:28:20] Speaker 03:
It has some toxicity, but it's minor toxicity, and it's mostly- Yes, but minor.

[00:28:26] Speaker 03:
When the water is about to cross over the dam even one more drop might be too much right and I think the thing is Chop therapy is the more toxic therapy and in link study it didn't increase the toxicity with you said what you had with chop and McNeil says the problem we have with older patients is that chop is very toxic in them and we're looking for alternatives so we can dial back the chop and one of the recommend one thing that McNeil freshly says we are going to do is

[00:28:54] Speaker 03:
is tested with rituximab for the older patient population.

[00:28:58] Speaker 04:
But that's the problem.

[00:28:59] Speaker 04:
We know CHOP is probably the large cause of the toxicity concern.

[00:29:07] Speaker 04:
Moreau says it added in the stem cell, and then it was tolerable.

[00:29:12] Speaker 04:
But it doesn't tell you whether it increased toxicity above what CHOP alone would have had.

[00:29:18] Speaker 04:
We only know it's tolerable.

[00:29:20] Speaker 04:
Tolerable to me seems like borderline.

[00:29:22] Speaker 04:
Tolerable doesn't seem like what you want to hear if you're hoping for a happy ending.

[00:29:27] Speaker 04:
It's just tolerable means, OK, this is going to suck, but I'm not going to die.

[00:29:32] Speaker 04:
And so then you're talking about adding something which has been established by this record to increase toxicity, even if it's only in a minor way.

[00:29:40] Speaker 04:
And I guess my concern is when you're in this patient population, which is definitely sensitive,

[00:29:47] Speaker 04:
And you're talking about such a large number of references combining in such an unpredictable area.

[00:29:55] Speaker 04:
I am sort of not confident in what you've done.

[00:30:01] Speaker 03:
All right.

[00:30:01] Speaker 03:
Two answers.

[00:30:02] Speaker 03:
One, I think reading the tolerable therapy, we are talking about a very aggressive disease that these patients have.

[00:30:09] Speaker 03:
And 50% of them are surviving, which is what Moreau is saying.

[00:30:15] Speaker 03:
This is a treatment of choice.

[00:30:17] Speaker 03:
for salvage therapy for certain group of patients who don't have a good prognosis.

[00:30:23] Speaker 03:
The review in the record says that CHOP therapy alone is the standard of care for people with poor prognosis, with good prognosis, and people who have poor prognosis are going to intensify with stem cell transplantation because they're not going to respond to CHOP alone.

[00:30:38] Speaker 03:
So yes, there's some toxicity associated, and definitely with the transplantation, but the problem is

[00:30:44] Speaker 03:
This is the therapy we have for these patients.

[00:30:47] Speaker 03:
The CHOP chemotherapy is part of all the stages you're going to do for stem cells.

[00:30:51] Speaker 04:
I know, but that's the thing.

[00:30:52] Speaker 04:
I mean, you got the one level with this CHOP.

[00:30:54] Speaker 04:
You got the stem cell, which adds more.

[00:30:57] Speaker 04:
And then you say we should add a third.

[00:30:58] Speaker 04:
But the only reason to add a third is because there's some study out there that says number one and number three might be a good idea to add together.

[00:31:06] Speaker 04:
But what it doesn't suggest is one and two, with the already more vulnerable population, already with the increased toxicity,

[00:31:13] Speaker 04:
is a good idea to add with three.

[00:31:15] Speaker 04:
And that's, I mean, I think you understand my concern.

[00:31:17] Speaker 03:
Yeah, I understand your concern.

[00:31:19] Speaker 03:
I will note that Malhoney does suggest once with the rituximid to combine it with chemotherapy and stem cell transplantation.

[00:31:28] Speaker 03:
And you already have that therapy working in the exact patient population claimed.

[00:31:33] Speaker 01:
And the idea is you're adding the rituxen at the same time you're reducing the CHOP therapy.

[00:31:40] Speaker 03:
That's the idea.

[00:31:40] Speaker 03:
So Moreau's therapy reduces the six cycles to three cycles at the induction phase.

[00:31:47] Speaker 03:
And the idea is older patients can't handle the six cycles.

[00:31:49] Speaker 03:
We reduce, chop.

[00:31:51] Speaker 03:
If we add Rituximab, Link tells us we are looking at a high level of efficiency in DLC patients.

[00:31:58] Speaker 03:
And in theory, then, it would also work in older patients because there's nothing, Rituximab is already safe and effective in that older patient population.

[00:32:09] Speaker ?:
OK.

[00:32:10] Speaker 02:
Okay.

[00:32:11] Speaker 02:
Thank you.

[00:32:12] Speaker 02:
Thank you, Ms.

[00:32:12] Speaker 02:
Craven.

[00:32:21] Speaker ?:
Let's see.

[00:32:21] Speaker ?:
Yeah.

[00:32:21] Speaker 02:
Okay.

[00:32:22] Speaker 02:
Ms.

[00:32:22] Speaker 02:
French-Brown.

[00:32:23] Speaker 00:
Thank you.

[00:32:23] Speaker 00:
Teyon, I think the record is very clear that the experts have said what a reasonable expectation of success is in this case.

[00:32:30] Speaker 00:
It wasn't in a general sense.

[00:32:31] Speaker 00:
For example, Dr. Sophia at his deposition, Appendix 1797, starting at Line 5, he says, often times oncologists would be motivated

[00:32:40] Speaker 00:
to add a new drug, in this case, rituxan, for a regimen that you've established and you think is safe to improve outcomes.

[00:32:48] Speaker 00:
Dr. Ozer, similarly in his deposition at appendix 985, starting at line 11, states the purpose of using multiple drugs together is to increase both the efficacy, but unfortunately, it also may carry increased toxicity when they are used together.

[00:33:07] Speaker 00:
And this is consistent with biogenics expert Dr. Call.

[00:33:09] Speaker 01:
I guess I'm trying to understand, though, how to understand all of that in the context of patent law and trying to understand what is a reasonable expectation of success for accomplishing the claimed invention.

[00:33:23] Speaker 01:
And I can't tell if that testimony is linked to trying to understand how to, the words of the claim treating DLCL patients that are over 60.

[00:33:35] Speaker 00:
Well, in the context of this case, the experts said, I'm not talking about in Patmore Journal, but the experts have read the claims, and they understand the field of the invention at the time of the priority.

[00:33:46] Speaker 01:
I understand their concerns as scientists and trying to find the next solution, but I'm also

[00:33:56] Speaker 01:
in a court of law where I have to give deference to the fact findings made by the fact finder below and then also understand how to apply the law here on obviousness and specifically reasonable expectation of success of the claimed invention.

[00:34:12] Speaker 01:
How to fit all of that within what these witnesses were testifying to.

[00:34:19] Speaker 00:
So reasonable expectation of success is viewed from the person's skill in the art.

[00:34:24] Speaker 00:
The experts have told us what that is.

[00:34:26] Speaker 01:
The reasonable expectation of success is a claimed invention.

[00:34:28] Speaker 00:
Right.

[00:34:28] Speaker 00:
And they said this is a method of treatment claim.

[00:34:31] Speaker 00:
And from their perspective, as persons of skill and art, method of treatment may improve outcomes.

[00:34:37] Speaker 01:
I'm just wondering, is there any case law where we have as a default rule that when it's a method of treating patients, the reasonable expectation of success requires and mandates that the claimed treatment is some quantum

[00:34:54] Speaker 01:
better than prior art treatments.

[00:34:58] Speaker 00:
I don't think there's any bright line rule, or if there's any case law as a matter of law, that this should be the standard.

[00:35:04] Speaker 00:
We're talking about in the context of this patent, in the context of these claims, the factual record does not support the board's finding.

[00:35:10] Speaker 00:
The board didn't review the evidence from the perspective of person skill and the art, which means an improved prognosis.

[00:35:17] Speaker 00:
There's not one reference that suggests.

[00:35:19] Speaker 04:
I was about to run out with your permission.

[00:35:21] Speaker 04:
I'd like to ask a question.

[00:35:23] Speaker 04:
Of course.

[00:35:25] Speaker 04:
I mean you're obviously much smarter and well understood on all these technology things that I am and you've done a great job in that regard today explaining it to me but my issues which I think you may have heard in my dialogue with opposing counsel

[00:35:41] Speaker 04:
I don't think hinge on me having to agree with you that a reasonable expectation of success involves increased prognosis as opposed to any individual therapy.

[00:35:53] Speaker 04:
I think I can still conclude a reasonable expectation of success in this case is just over no treatment at all theoretically.

[00:36:00] Speaker 04:
But I think whether it's through the mechanism of motivation to combine a reasonable expectation of success which are intertwined

[00:36:07] Speaker 04:
Did you understand my arguments?

[00:36:09] Speaker 04:
Do you think I have to agree with you on this question you have about reasonable expectation of success?

[00:36:16] Speaker 04:
in order to have the concern I do?

[00:36:18] Speaker 04:
Because I don't think I do.

[00:36:20] Speaker 04:
I think I can conclude you're wrong about that, but actually still may be finding your favor, because I think reasonable expectation of success may not have been at all reasonable in light of the toxicity concerns.

[00:36:33] Speaker 04:
And I think that's independent of this argument that you're discussing now on rebuttal.

[00:36:38] Speaker 04:
But am I wrong?

[00:36:39] Speaker 04:
Is it not independent of that?

[00:36:40] Speaker 04:
Can you tell me?

[00:36:41] Speaker 04:
Are these things intertwined in some way that I don't understand?

[00:36:46] Speaker 00:
We take the position that a reasonable expectation says is viewed from the person's skill and the art.

[00:36:51] Speaker 04:
We don't think the board should come in and say what... I understand what your position is, but do you understand the questions I have, which is I don't know why a skilled artisan would add a third in this patient population when the first two together were only tolerable and the third definitely increases toxicity.

[00:37:09] Speaker 04:
Given that they don't know, I don't think that's the same as the argument you're making.

[00:37:16] Speaker 04:
I think you made this argument on toxicity clearly in your brief, but it's not the one that you're talking about now, I think.

[00:37:23] Speaker 00:
So I agree with you.

[00:37:25] Speaker 00:
Even if you don't agree with our reasonable expectation success standard, the board's decision of reasonable expectation success is not supported by substantial evidence.

[00:37:33] Speaker 00:
Because you have Moreau, who does not say CHOP plus stem cell was the conventional treatment, CHOP alone

[00:37:39] Speaker 00:
was the conventional treatment.

[00:37:40] Speaker 00:
And Morell states at Appendix 265 that stem cell transplantation was usually restricted in patients less than 60 because patients older 60 could not tolerate it.

[00:37:52] Speaker 00:
And Morell does not compare CHOP and stem cell with CHOP alone.

[00:37:57] Speaker 01:
So what in the record tells us that or suggests that the combination with this antibody is

[00:38:08] Speaker 01:
going to have a worse toxicity outcome?

[00:38:13] Speaker 00:
Well, that's the problem.

[00:38:15] Speaker 00:
There's no references that compare CHOP alone with CHOP plus for toxin.

[00:38:20] Speaker 04:
No, but the PTO agreed that the antibody therapy alone does have a degree of toxicity to it.

[00:38:31] Speaker 04:
So if you're, I don't know if you're adding toxicity from CHOP plus stem cell, and then you're adding on a treatment that in and of itself has toxicity, I don't see how that wouldn't increase the toxicity.

[00:38:42] Speaker 04:
Am I missing something?

[00:38:43] Speaker 00:
No, our position is that we agree with you.

[00:38:45] Speaker 00:
In fact, Pfizer's expert.

[00:38:48] Speaker 01:
What about LINC though?

[00:38:49] Speaker 01:
Didn't LINC say the toxicity issue is no worse with the combination of rituximab and CHOP therapy?

[00:38:58] Speaker 00:
Link was not a study for DLCL patients over 60, and Dr. Ozard in his deposition.

[00:39:03] Speaker 01:
But it says what it says about when you combine these two with those patients, average age 49, and I get that.

[00:39:11] Speaker 01:
But if I just step aside from that, on its face it says there's no worse adverse events compared to just using CHOP therapy alone.

[00:39:22] Speaker 00:
I don't think Link provides any data comparing

[00:39:25] Speaker 00:
And it was not a study that compared to it.

[00:39:28] Speaker 00:
I'm just saying what it says.

[00:39:29] Speaker 01:
I mean, that is, in fact, what it says.

[00:39:31] Speaker 00:
That's what it says.

[00:39:31] Speaker 00:
But as Dr. Ozar recognized, that length does not state that there is no overlap between a toxicity of a tuxen and a toxicity of a chop.

[00:39:40] Speaker 00:
And if you look at the great three and four toxicities, 21 patients out of 31 experience toxicities.

[00:39:46] Speaker 00:
And these are younger patients.

[00:39:47] Speaker 00:
So from what the experts tell us, that you're going to see even more so an incidence of toxicities in patients over 60.

[00:39:55] Speaker 00:
So it's our position that a person with skill and art wouldn't even apply LINC to this combination.

[00:40:00] Speaker 04:
Just to be clear, am I understanding right that your argument is that because LINC only deals with younger patients, the fact that they didn't have a worse adverse effect doesn't mean that wouldn't be true for older people?

[00:40:14] Speaker 04:
Correct.

[00:40:17] Speaker 04:
Thank you, Your Honor.

[00:40:18] Speaker 02:
Anything else you want to ask?

[00:40:19] Speaker 02:
Anything else?

[00:40:20] Speaker 02:
Thank you.

[00:40:21] Speaker 02:
Thank you.

[00:40:22] Speaker 02:
Thank you both.

[00:40:22] Speaker 02:
Case is taken under submission.