[00:00:00] Speaker 01:
member of this panel.

[00:00:01] Speaker 01:
She was not able to be here today.

[00:00:04] Speaker 01:
She is listening to the argument.

[00:00:07] Speaker 01:
She does not plan to ask questions during the argument, but she is fully participating in the case.

[00:00:14] Speaker 01:
Okay, our first case this morning is number 17, 2304 ABV, Biotechnology Limited versus United States.

[00:00:23] Speaker 02:
Mr. Saunders.

[00:00:32] Speaker 02:
The claims are on a method, right?

[00:00:50] Speaker 05:
They're not on the actual antibody itself.

[00:00:54] Speaker 05:
The dosing, okay.

[00:01:05] Speaker 02:
And it's obvious it's going to be a serious...

[00:01:39] Speaker 01:
One of your main points is that the 0.5 milligram, kilogram dosage in these prior studies wasn't effective, right?

[00:01:57] Speaker 01:
And for example, on page four of your reply brief, I guess you collect the evidence here that deals with that.

[00:02:06] Speaker 01:
And you say, Rao disclosed that 58% of patients receiving 0.5, 0.5-milligram-kilogram never achieved an ACR 20 response at any point in time.

[00:02:20] Speaker 01:
But this strikes me as a bit misleading.

[00:02:23] Speaker 01:
Because, for example, if you look at Kimpenny at Appendix 2304, it shows a 70% response to the weekly 0.5 milligram.

[00:02:48] Speaker 01:
Yes, and then Rao also teaches 78% moderate response on 28085, but let's look first at 2704.

[00:03:02] Speaker 01:
which is compenny, and it says there's a weekly, this is, this is table two at the bottom.

[00:03:10] Speaker 01:
This says weekly 0.05 milligram to kilogram sub SC that is subcutaneous injections is an ACR 20 response of 70%.

[00:03:20] Speaker 02:
Oh, yeah, I understand.

[00:03:25] Speaker 02:
So that is weekly dosing.

[00:03:29] Speaker 02:
So the claims here are,

[00:03:32] Speaker 02:
every other week dosing.

[00:03:34] Speaker 02:
So when you're talking about 0.5 milligram-kilogram weekly dosing, you're talking about essentially double what we have in the claims here.

[00:03:45] Speaker 02:
And so the point is that to reach its obvious determination, the board was combining weekly subcutaneous doses from the Dean's P-7 study, the bandicoot references, with

[00:04:01] Speaker 02:
the, at least every other week, intravenous weight-based doses in the D3 study, which is mainly recorded in RAL.

[00:04:14] Speaker 02:
And the glaring problem with that was that, for the allegedly equivalent 0.5-millimeter-kilogram dose in that D3 study, you had persistent up-dose.

[00:04:27] Speaker 02:
Indeed, before you add the uncertainty

[00:04:36] Speaker 05:
You're referring to DE and then some number and, you know, you'll have to forgive me.

[00:04:42] Speaker 05:
The way I think about it is, you know, certain excerpts that I've read from certain references, for example, Kempene.

[00:04:49] Speaker 05:
I know Kempene is telling me that they were talking about how you can administer D2E7 bi-weekly intravenously at 0.5 milligrams per kilogram.

[00:05:02] Speaker 05:
which, as I understand it, people seem to agree is roughly 40 milligrams.

[00:05:08] Speaker 05:
So 40 milligrams taken every other week.

[00:05:11] Speaker 05:
And then I see here an explanation that that seems to have a pretty positive outcome.

[00:05:20] Speaker 05:
I understand that it says, for those who did not respond, got up dosed.

[00:05:25] Speaker 05:
But it's not so clear to me that that suggests

[00:05:30] Speaker 05:
Everyone that got 0.5 milligrams per kilogram did not respond well.

[00:05:39] Speaker 02:
For those who didn't respond well.

[00:05:42] Speaker 05:
Right, for those who didn't respond well.

[00:05:44] Speaker 02:
And then when you look at the reports from the same study in RAU 2000, and so that's a little brief of page 39.

[00:05:59] Speaker 02:
Undisputed that by week 12, after week 12, every single patient within on that dose was up-dosed.

[00:06:09] Speaker 01:
Yeah, but that says specifically they were up-dosed because it was a study to determine safety, and they wanted to give them the larger dose to measure safety.

[00:06:20] Speaker 02:
Well, the statement about why they were up-dosed was the statement in Campany that patients who, quote, did not respond well

[00:06:30] Speaker 01:
Yeah, but the purpose of it was to measure safety.

[00:06:34] Speaker 01:
It wasn't to measure efficacy.

[00:06:36] Speaker 01:
They weren't abandoning the thing because it wasn't efficacious.

[00:06:40] Speaker 01:
They were changing it at 12 weeks because they wanted to measure safety at the higher dose.

[00:06:46] Speaker 02:
For every 0.5-kilogram dose, there was up to a same dose.

[00:07:00] Speaker 02:
Well, what page of the appendix is this at?

[00:07:23] Speaker 05:
This is the, it's also on 28080, right?

[00:07:28] Speaker 05:
The companion is in the appendix twice.

[00:07:31] Speaker 01:
So what it says is to keep as many patients as possible in the study for the long-term evaluation of safety, patients who did not respond, et cetera, et cetera.

[00:07:44] Speaker 01:
It's focusing on a change in the dosage because they wanted to measure safety.

[00:07:52] Speaker 02:
The DE3 study that we talked about here is something about which you're only going to make determinations of safety.

[00:07:59] Speaker 01:
No, no, but I'm talking about the language.

[00:08:01] Speaker 01:
To keep as many patients as possible, the study for the long-term evaluation of safety, patients who did not respond well after 0.05 or one milligram received higher doses.

[00:08:15] Speaker 02:
But the discussion of safety is because these are the phase one clinical trials for which

[00:08:21] Speaker 02:
you're looking at safety, but the board's obviousness combination depends on relying on the efficacy.

[00:08:30] Speaker 01:
No, no, but the point is that they didn't take them off the 0.05 dosage because of lack of efficacy.

[00:08:37] Speaker 01:
They did it in order to measure safety, correct?

[00:08:40] Speaker 02:
I mean, we asked both of the other side's experts about this and said for a coherence expert, this is an appendix 6189,

[00:08:50] Speaker 02:
D2E7, are there any possible reasons for up-dosing other than the fact that patients were not responding well?

[00:08:58] Speaker 02:
Your answer was that would be speculation.

[00:09:00] Speaker 01:
But look, I'm reading the study itself.

[00:09:04] Speaker 01:
Forget about the characterizations.

[00:09:06] Speaker 01:
It says because they up-dosed them because they wanted to conduct a long-term evaluation of safety, right?

[00:09:15] Speaker 02:
They wanted to conduct a longer evaluation

[00:09:21] Speaker 02:
losing patients, the patients who were not responding well.

[00:09:26] Speaker 02:
And so they were up-dosing the patients and keeping them in the study rather than having to continue with the inadequate response.

[00:09:35] Speaker 01:
Well, it doesn't say that, but that's another issue.

[00:09:40] Speaker 01:
If you look at

[00:09:42] Speaker 01:
These tables, I guess they are four and five in RAL.

[00:09:53] Speaker 01:
These show that the 0.05 dose, in fact, after 12 weeks was about as effective as the higher doses, right?

[00:10:04] Speaker 02:
No, the undisputed after the test beyond that is these are

[00:10:07] Speaker 02:
That's highly misleading that these are averages.

[00:10:11] Speaker 02:
And so when you have a dosing like this, the other side of the expert was asking how many... Well, let's just take the charts for the moment, put aside the experts.

[00:10:21] Speaker 01:
These charts show that in terms of the measurement here of efficacy, it's about the same after 12 weeks, right?

[00:10:29] Speaker 01:
Or even perhaps a little better in chart five.

[00:10:34] Speaker 02:
These...

[00:10:36] Speaker 02:
The number that is being shown for the 25-month program, there's no way whatsoever of knowing how many patients are left.

[00:10:46] Speaker 02:
So you would be talking about a single patient.

[00:10:48] Speaker 01:
No, no, I'm not talking about after 12 weeks.

[00:10:50] Speaker 01:
I'm talking about at 12 weeks.

[00:10:52] Speaker 02:
No, no, at 12 weeks with up-dosing, as patients are dropping out.

[00:10:58] Speaker 02:
And I'll put you 31387 in the appendix, 31389.

[00:11:04] Speaker 02:
the other side's expert in the codes.

[00:11:07] Speaker 02:
I mean, he says, you know, I can't say for any of those points how many patients are liquid.

[00:11:15] Speaker 02:
And that's a big problem when you're looking at this.

[00:11:17] Speaker 02:
You know, we read in at 2949, put in the FDA guidance for rheumatoid arthritis drugs in 1999.

[00:11:27] Speaker 02:
And it talks about dropouts.

[00:11:38] Speaker 02:
of the patients originally amended.

[00:11:40] Speaker 01:
That may be, but the chart is the same thing that's true for all the dosages.

[00:11:46] Speaker 01:
And the chart shows that in terms of efficacy at week 12, it's about the same, right?

[00:11:54] Speaker 02:
All the other doses are showing averages across the patients.

[00:11:59] Speaker 02:
Where you have up-dose, you can't compare that because you're taking out, if you take out all the people who

[00:12:08] Speaker 01:
aren't succeeding, then the average is going to... What tells us that in this period up to the 12-week mark, that people were taken out of the study who were receiving the 0.5, 0.05?

[00:12:23] Speaker 02:
The description of up-dose.

[00:12:25] Speaker 02:
The patients who will be up-dosed will be switched to the 1-milligram or kilogram dose.

[00:12:31] Speaker 02:
And in addition, new patients will come in at week 6.

[00:12:36] Speaker 01:
Where does it say that?

[00:12:38] Speaker 02:
That says that the placebo patients are coming in on week six.

[00:12:42] Speaker 02:
That's at page 4593 of the appendix.

[00:12:46] Speaker 02:
The placebo patients came in.

[00:12:49] Speaker 01:
Wait, wait, 4596?

[00:12:50] Speaker 02:
4593 of the appendix.

[00:12:58] Speaker 01:
OK, where does it say that?

[00:13:11] Speaker 02:
What does that have to do with what I was asking about, which is the lower dose?

[00:13:41] Speaker 02:
I'm sorry I'm not understanding where you're getting that from the sentence you showed me had to do with patients who are receiving placebo right that is for the fact that

[00:14:10] Speaker 01:
But that's about placebo.

[00:14:12] Speaker 01:
That wasn't what my question was.

[00:14:14] Speaker 02:
No, no, this is patients who switch from placebo.

[00:14:16] Speaker 02:
So those are their structure.

[00:14:18] Speaker 02:
You have patients being dosed, and then connected with each of those, you have a placebo set of patients.

[00:14:24] Speaker 02:
And those continue together for week six.

[00:14:27] Speaker 02:
For week six placebo patients, it's switched on to the corresponding dose.

[00:14:33] Speaker 02:
So you have people going on to the 0.5-milligram-kilogram dose for the very first time,

[00:14:39] Speaker 01:
Well, that would be true of the other doses too.

[00:14:44] Speaker 01:
That sort of suggests that the chart doesn't show anything at all.

[00:14:51] Speaker 01:
But that's not an argument you've made.

[00:14:55] Speaker 01:
What you have argued is that these charts show superiority for the higher doses and what I'm

[00:15:02] Speaker 01:
pointing out to you is that that's true in the DE-001 study, which stops much earlier, but it's not true for the 12-week point on the chart.

[00:15:22] Speaker 02:
Where you're comparing apples to oranges, and where we have claims that are specifically requiring efficacy,

[00:15:32] Speaker 02:
we access the data.

[00:15:34] Speaker 02:
And I also say, this isn't my research, it's my description.

[00:15:37] Speaker 02:
VAL itself signals out, preys, the doses greater than one milligram per kilogram, and criticizes the doses at .500.

[00:15:48] Speaker 01:
Yes, but that's for the DE001 study, not for the 3 study, which takes up to 12 weeks.

[00:16:02] Speaker 01:
If you look at 28085, it talks about the 0.5 milligram over 12 weeks resulted in a moderate response in 78% of the patients, right?

[00:16:34] Speaker 02:
Okay, I don't want to take up all of your time.

[00:16:41] Speaker 01:
Why don't you move on to another subject unless Judge Chin has other questions.

[00:16:47] Speaker 01:
We'll give you some more, we'll give you a couple more minutes here.

[00:16:50] Speaker 01:
No, you don't need to sit down.

[00:16:51] Speaker 01:
You can talk now.

[00:17:09] Speaker 02:
We saw the same thing on the semen levels.

[00:17:14] Speaker 02:
These are the trough concentrations between doses where when you stretch a dose like this, you may be giving the same amount of doses, but it's understood that you get dips, larger dips between the doses.

[00:17:30] Speaker 02:
And the board's response to that was to say, well,

[00:17:40] Speaker 02:
But what if, as I understand the board, they had van de Booth, we haven't talked about that yet, which showed, albeit weekly administration, subcutaneously,

[00:18:04] Speaker 05:
20 milligrams, 40 milligrams, 80 milligrams, were all statistically superior over placebo.

[00:18:11] Speaker 05:
And likewise, they were all essentially equivalent in terms of their effectiveness.

[00:18:18] Speaker 05:
That's what van de Poot says.

[00:18:20] Speaker 05:
Now we go over to Campania and we see, OK, you can take a 40 milligram equivalent, 0.5 milligrams per kilogram,

[00:18:27] Speaker 05:
bi-weekly do it intravenously and what if we just accept for now that substantial evidence supports the idea that Campeni also supports that that would be give you a good enough response.

[00:18:43] Speaker 05:
Maybe not as good of a response as one milligram per kilogram or three milligrams per kilogram but nevertheless

[00:18:51] Speaker 05:
good enough that that would be something that would be considered a positive outcome.

[00:18:58] Speaker 05:
So when you look at all of that and then say, well, we already know that taking it bi-weekly is going to get you a decent result at roughly the same amount as 40 milligrams.

[00:19:13] Speaker 05:
That is to say, five milligrams per kilogram.

[00:19:16] Speaker 05:
So therefore, there's a reasonable basis to go from that

[00:19:21] Speaker 05:
0.5 milligram per kilogram to a fixed 40-milligram dosage every other week.

[00:19:28] Speaker 02:
Right, so I think there are two issues with that.

[00:19:30] Speaker 02:
So even setting aside up dosing, when you're talking about numbers and bandwidth, we're talking about going to semen levels that are below anything we saw in bandwidth, even though the other side's expert said

[00:19:51] Speaker 02:
you go over to 0.5 mg per kilogram to try to give yourself that assurance, you have to remember that those are intravenous weight-based doses that then are being diverted over.

[00:20:07] Speaker 02:
You'd be saying, well, why are we taking those over to subcutaneous doses?

[00:20:14] Speaker 02:
you know, with the loss of vital availability that occurs when you, rather than injecting it straight into the bloodstream, injecting it under the skin, it has to be absorbed.

[00:20:25] Speaker 02:
And then also the claims are bringing together that with fixed doses, meaning you have to have a dose that is working across the patient population.

[00:20:35] Speaker 02:
It gives you less margin of error to say, I'm gonna go as low as possible when people are being individually dosed,

[00:20:44] Speaker 05:
Yeah, but it was known in the art to give a fixed dosage.

[00:20:50] Speaker 05:
Van de Poot is a clear example of that.

[00:20:52] Speaker 02:
Well, it may be known in other arts to give a fixed dosage.

[00:20:57] Speaker 02:
I think we should remember here, at this time, there was one antibody approved as the anti-TNF-alpha antibody, and it is dosed intravenously, weight-based doses.

[00:21:10] Speaker 02:
At this time, there are zero antibodies

[00:21:14] Speaker 02:
any kind, any condition, that are approved for subcutaneous administration.

[00:21:21] Speaker 02:
This is very, very, very early in this part here.

[00:21:27] Speaker 05:
And so the, like, a sort of abstract principle... Can Penny says, um, subcutaneous administration would be a promising approach?

[00:21:36] Speaker 05:
And says that they're comparable, the subcutaneous and the intravenous administrations.

[00:21:42] Speaker 02:
Talking about

[00:21:44] Speaker 02:
results achieved with different doses.

[00:21:48] Speaker 02:
I think one of the hard things here is you have claims that are bringing together both the dose that is absolutely on the low end, with subcutaneous administration, with the fixed dose, and with the longer dose.

[00:22:05] Speaker 02:
And so you can look, and this is one of the issues with the Board of Indian is you can look in isolation

[00:22:13] Speaker 02:
But it doesn't have to be equivalent, right?

[00:22:23] Speaker 01:
I mean, the claims only require

[00:22:27] Speaker 01:
some efficacy.

[00:22:28] Speaker 01:
It doesn't require a particular level of efficacy, saying use the most effective one.

[00:22:35] Speaker 01:
And your theory, I guess, is that in terms of motivation, it combines that you would use the higher dose to achieve the greater efficacy?

[00:22:46] Speaker 02:
Well, it's not necessarily rare, because it's ensuring that you would get efficacy.

[00:22:52] Speaker 02:
In the context of there being not

[00:22:58] Speaker 02:
in the sense that, you know, BI's expert.

[00:23:04] Speaker 01:
Yeah, but these studies show considerable efficacy at the .5 level.

[00:23:11] Speaker 01:
It may be slightly below at 12 weeks what you get from the higher dosage, but on the face, these things show efficacy at the .5 level at 12 weeks.

[00:23:27] Speaker 02:
I mean, let's enter in on 24-week claims.

[00:23:31] Speaker 02:
Rao and Kaveni don't have anything to teach about 25-kilogram dose at 24 weeks, because it's undisputed.

[00:23:42] Speaker 02:
Whatever the reason, it's completely discontinued.

[00:23:45] Speaker 05:
Wouldn't it be obvious to keep treating someone with rheumatoid arthritis past 12 weeks, then?

[00:23:50] Speaker 02:
Well, we have to talk about the reasonable expectations.

[00:23:56] Speaker 02:
look at the statements in Rao about the fact that the erythrocyte sedimentation rate, which is a measure of inflammation, is getting worse again after only one week.

[00:24:12] Speaker 02:
And the fact that there was up-dosing, and the fact that Rao talks about long-term treatment, it says, yes, we got long-term efficacy with the doses greater than one milligram per kilogram.

[00:24:25] Speaker 02:
So there's a complete absence of information reported in the prior, or there in the DEO3 study, as to how people are going to do it.

[00:24:39] Speaker 01:
Did you separately argue the 24-week point before the board?

[00:24:43] Speaker 02:
Yes, we did.

[00:24:45] Speaker 02:
I refer you to page 44822.

[00:24:53] Speaker 01:
Which volume is this?

[00:24:56] Speaker 01:
Which volume is this?

[00:24:57] Speaker 02:
That should be in line three.

[00:25:06] Speaker 01:
Well, unless Judge Chin has further questions at this point, why don't we?

[00:25:10] Speaker 05:
Just one more.

[00:25:11] Speaker 05:
Go ahead.

[00:25:12] Speaker 05:
When it comes to this combination of Bandit Put and Campany, there's

[00:25:18] Speaker 05:
two board decisions that are discussing that combination.

[00:25:22] Speaker 05:
One is the Co-Harris IPR.

[00:25:24] Speaker 05:
The other one is the Boehringer IPR.

[00:25:29] Speaker 05:
And I don't recall seeing in your blue brief a retort to the Boehringer rationale for combining Kimpenny and Vandeput.

[00:25:45] Speaker 02:
I think it was just taking the same references and running them in the opposite direction.

[00:25:53] Speaker 05:
There seemed to be a routine optimization theory expressed in the...

[00:25:58] Speaker 05:
in the Boehringer IPR that wasn't necessarily articulated in the Coheras IPR or board final written decisions.

[00:26:08] Speaker 05:
So that's why I'm wondering that maybe there's something of a delta between the two board decisions and how they combined these two references.

[00:26:17] Speaker 02:
But I don't think in either of those board decisions that the idea that the board is itself accepting a routine population theory

[00:26:25] Speaker 02:
And one of the reasons here is, in my dispute, we talked about 96 different kinds of action just on the basis of what's the slowest in the environment.

[00:26:35] Speaker 02:
And so we don't have a sort of small number of easily traversed things to try here.

[00:26:45] Speaker 02:
We have 96 different ways you can go.

[00:26:48] Speaker 02:
And the board's own reasoning said the way you're going to do this is you're going

[00:26:58] Speaker 02:
between for the gene optimization.

[00:27:00] Speaker 02:
This is unpredictable chemistry.

[00:27:02] Speaker 02:
This is chemistry where we try 80 milligrams monthly.

[00:27:07] Speaker 02:
Failure, no better than placebo.

[00:27:10] Speaker 02:
Unpredictable dosing first in the FDA.

[00:27:15] Speaker 01:
OK, well, I think we're out of time.

[00:27:16] Speaker 01:
We'll give you two minutes or above.

[00:27:20] Speaker 01:
Mr. Matej?

[00:27:29] Speaker 05:
Are there two different rationales for the combination of Van de Poot and Ken Penny and the two different IPR board decisions?

[00:27:37] Speaker 04:
Your Honor, yes, and may it please the Court.

[00:27:39] Speaker 04:
I think you can look at the prior in this case in one of two ways.

[00:27:43] Speaker 04:
I think you can either say you take the DE7, which is a Van de Poot preference, with the 20 milligrams and 40 milligrams weekly, and you stretch that out to every two weeks.

[00:27:56] Speaker 04:
There's a very clear rationale and motive for a person to do that because no one likes being injected more frequently than they have to be, so patients would want to be injected less frequently.

[00:28:07] Speaker 04:
Alternatively, you could look at the DE3 reference and say, well, we have- When you say DE3 reference, do you mean Kim Penney?

[00:28:14] Speaker 04:
Yeah, Kim Penney and Rao.

[00:28:15] Speaker 04:
Sorry, you're under the Kim Penney and Rao report.

[00:28:17] Speaker 04:
The early DE3 study, Van de Peut reports the later DE7 study.

[00:28:23] Speaker 04:
Or you could look at that dose and modify that and say, well, subcutaneous is more convenient.

[00:28:30] Speaker 05:
In the Coherence IPR, the board rejected that first theory you just expressed, right?

[00:28:37] Speaker 05:
The idea of taking van de Poot and stretching it out from a weekly dosage to a biweekly dosage?

[00:28:44] Speaker 04:
I don't think that's exactly what the board was up to.

[00:28:48] Speaker 04:
The board looked at the

[00:28:51] Speaker 04:
the two-week half-life and said that that alone would not counsel in favor of the two-week dosing regimen.

[00:29:01] Speaker 04:
I think that's what the board was saying.

[00:29:03] Speaker 04:
But they later said in the Boehringer IPRs that it was a factor.

[00:29:08] Speaker 04:
And in fact, in the coherence IPRs, I think if you

[00:29:10] Speaker 04:
look at what they actually said, they sort of hint that it was a factor, which I suspect is probably why Bollinger made that argument.

[00:29:18] Speaker 05:
I'm confused.

[00:29:20] Speaker 05:
I'm just talking about the coherence IPR final written decision.

[00:29:24] Speaker 04:
No, I understood, Your Honor.

[00:29:25] Speaker 04:
So in that decision.

[00:29:27] Speaker 05:
There's only one theory, and it's based on leading with Kim Penney.

[00:29:32] Speaker 04:
It leads with Kim Penney.

[00:29:34] Speaker 05:
You're telling me there's a second theory in there?

[00:29:36] Speaker 04:
No.

[00:29:37] Speaker 04:
So the argument for motivation to combine them

[00:29:40] Speaker 04:
was one of the theories that was offered in the coherence IPR was that if you look at the half life of the drug, it was known to be about two weeks.

[00:29:51] Speaker 04:
And so a lot of skill in the art will have said, well, a two week dosing regimen based on that fact.

[00:29:56] Speaker 04:
would have been obvious.

[00:29:58] Speaker 05:
The board rejected the idea that Half-Life alone was sufficient to get you from... Right, but the board didn't adopt any second theory that led with Vandeput in the co-Harris IPR final written decision.

[00:30:13] Speaker 05:
Am I right?

[00:30:15] Speaker 04:
I don't think so.

[00:30:16] Speaker 05:
Okay, so then where did it say, yes, you could start with van de Poot and you could legitimately, reasonably expect that it would, you could extend it out from a weekly to biweekly dosage.

[00:30:32] Speaker 04:
In the cohericite?

[00:30:34] Speaker 04:
Right.

[00:30:35] Speaker 05:
That's what we've been talking about.

[00:30:36] Speaker 04:
So I'm not sure that the board necessarily had to decide which one you would start with because the reasoning was that from the combination of the two, you would have gotten there.

[00:30:52] Speaker 04:
And in all events, the board clearly did find that in the Boehringer IPRs and found the same claims invalid.

[00:31:00] Speaker 04:
So even if the board didn't find that there,

[00:31:03] Speaker 05:
Well, they didn't find it there.

[00:31:08] Speaker 05:
There was only one theory in coherence.

[00:31:11] Speaker 05:
It was leading with compenny and then switching over from 0.5 milligrams to kilogram to a fixed dosage of 40 milligrams and then changing over from intravenous to subcutaneous and relying on van der Poet for those two things.

[00:31:30] Speaker 05:
The coherence IPR

[00:31:33] Speaker 05:
made any kind of finding of motivation to extend van de Poot's weekly dosages to a bi-weekly and then double up in the Coherence IPR?

[00:31:46] Speaker 05:
In the Boehringer IPR, yes, but I've been talking to you for the past three minutes about the Coherence IPR.

[00:31:54] Speaker 04:
So in the Coherence IPR, the board said Campania expressly discloses a dose that is equivalent to the recited subcutaneous 40-milligram dose

[00:32:03] Speaker 04:
Kim Penney also teaches bi-weekly administration.

[00:32:05] Speaker 04:
Accordingly, Kim Penney explicitly provides motivation for converting bandipute's weaker dosing regimen from DE7 into a bi-weekly dosing regimen.

[00:32:14] Speaker 04:
That's an appendix 78 and 71.

[00:32:18] Speaker 04:
Does that answer the question, Your Honor?

[00:32:22] Speaker 05:
Go ahead and go on.

[00:32:24] Speaker 04:
So I think I'd also like to address what my colleague on the other side said regarding the patients being shifted off the dose.

[00:32:32] Speaker 04:
I think that's a little misleading because of the breadth of these claims.

[00:32:37] Speaker 04:
Because these claims cover treatment of any patient, the fact that even some patients were still having success with the dose as of week 12 would teach these claims.

[00:32:50] Speaker 01:
So in title... What does the record show about patients being shifted off of doses?

[00:32:55] Speaker 04:
I think it reflects what your honor was discussing with my colleague on the other side is that it's a little unclear exactly why they were shifted off.

[00:33:07] Speaker 01:
You do point to the... I think there are two different issues here.

[00:33:13] Speaker 01:
One is where patients shifted off of doses before 12 weeks and then after 12 weeks.

[00:33:21] Speaker 01:
Shortly after 12 weeks.

[00:33:23] Speaker 01:
the patients receiving the .5 milligram dose were shifted off or were up dosed according to the thing to test safety.

[00:33:36] Speaker 01:
But I thought there was a suggestion that there was shifting off the .5 dose before 12 weeks.

[00:33:44] Speaker 01:
Did that happen?

[00:33:46] Speaker 04:
I believe it did, but I think the record's unclear.

[00:33:50] Speaker 01:
I think the point is that... Well, why were they shifted off before the 12 weeks when this determination was made to conduct the safety analysis?

[00:34:00] Speaker 04:
Again, I don't think the record discloses that, but what I would say is that it doesn't matter for these claims.

[00:34:07] Speaker 01:
No, but I'm just trying to understand what the record does show about it.

[00:34:09] Speaker 01:
Does it show that before 12 weeks people were shifted off the 0.5 dose?

[00:34:14] Speaker 04:
I don't think the record is clear about that.

[00:34:17] Speaker 04:
It says some were up-dosed,

[00:34:20] Speaker 00:
Before 12 weeks.

[00:34:22] Speaker 04:
It says some were up-dosed, and I think it's ambiguous on that point.

[00:34:28] Speaker 04:
I don't think it says one way or the other.

[00:34:30] Speaker 04:
It says some were up-dosed, but I don't think it explicitly says that they were up-dosed along the way.

[00:34:37] Speaker 05:
That's clearly an abuse position, but I don't think it matters because... What about all patients that were initially getting .5?

[00:34:49] Speaker 05:
Were they all

[00:34:50] Speaker 04:
So that's the inference from the chart in RAU that when we get to 12 weeks because it ends there, that there was no one any longer on that dose.

[00:35:03] Speaker 04:
But again, I don't think that matters because if you look at the chart, it clearly shows that there's substantial success.

[00:35:10] Speaker 04:
They improved 30% from baseline.

[00:35:12] Speaker 04:
42% of them at some point had received an ACR 20 response,

[00:35:19] Speaker 04:
And if you look at 151, the board petitioner argued in the board notes that Remicade, which was the competitor drug, was only doing between 30 and 38 percent ACR 20 response.

[00:35:31] Speaker 04:
So it's hard to say that something that was more successful than the competitive drug that was down on the market.

[00:35:36] Speaker 04:
is not adequately successful for claims that admittedly cover even something that doesn't improve a patient's health but just slows their decline.

[00:35:46] Speaker 04:
And so the fact that some patients were being up-dosed because they weren't performing well, however that's defined, and it's not clear from the record, but whatever that means, the fact that some patients were receiving benefit from the drug, which is all that's necessary to

[00:36:07] Speaker 04:
And I think it might be helpful to look at the court's decision in Tyco, where there was in the prior art, there were higher doses disclosed in the prior art, and then there was one teaching of the claimed lower dose for a subset of patients.

[00:36:21] Speaker 04:
Because the claims in that case weren't limited to a particular subset of patients, this court found that sufficient to disclose it as obvious.

[00:36:31] Speaker 04:
This court has generally treated these dosing

[00:36:37] Speaker 04:
within a range because as the board found at 31 and 37, what doctors do in these circumstances is tailor particular doses to particular patients.

[00:36:52] Speaker 03:
So if you're looking for 31 and 37, the board said that a skilled artisan designing a dosing regimen through clinical trials would have

[00:37:07] Speaker 01:
So the fact that there was... If you look at RAL at 28085, where it says patients with 0.05 milligram body weight over 12 weeks resulted in a moderate DAS response in 78% of the patients, is there something wrong with that figure?

[00:37:44] Speaker 05:
Is that teaching success with 0.5 milligram per kilogram?

[00:37:48] Speaker 04:
I would say that's teaching success.

[00:37:51] Speaker 04:
What you're all appointed to in Campeni actually covers 0.5 to 10 milligrams.

[00:37:58] Speaker 04:
That's like the same 78% figure.

[00:38:07] Speaker 04:
the 42%.

[00:38:08] Speaker 01:
And on 2704, which is in compenny in table two, it reports weekly 0.5 milligram is receiving an ACR 20 response, 70% of them, right?

[00:38:33] Speaker 04:
Yes, Your Honor.

[00:38:35] Speaker 04:
weekly 0.5 subcutaneous injection.

[00:38:38] Speaker 04:
So that's the maximum ACR response, ACR 20 response.

[00:38:43] Speaker 04:
So there's also how they were doing over the course of time, which I think might account for the difference there.

[00:38:50] Speaker 04:
So if at some point you had 70% getting an ACR 20 response, but then that later declined, and I think that might account for RALS, RALS disclosure of 42%

[00:39:04] Speaker 04:
at any given time.

[00:39:06] Speaker 01:
But I thought the short four and five in round 28087 and 28088 showed that at 12 weeks, the 0.5 is about the same as the other dosages, right?

[00:39:31] Speaker 04:
No, I think that's right very clearly.

[00:39:36] Speaker 04:
lines for the 0.5 milligram per kilogram dose is not substantially different than the other ones, which is why I don't think it's appropriate to attribute the up-dosing whenever it occurred to a overall lack of efficacy.

[00:39:54] Speaker 05:
Just to understand those graphs a little better, is it possible that what's going on

[00:40:01] Speaker 05:
in the latter half of that 12-week cycle with the 0.5 milligrams, is that those data points are now including people that have been moved from placebo to the 0.5 milligram dosage?

[00:40:17] Speaker 04:
That may be.

[00:40:20] Speaker 04:
I don't think I'd consider that possibility, but that could be.

[00:40:25] Speaker 01:
Were they also moving people from the placebo to the higher doses?

[00:40:30] Speaker 04:
Yes, so there were people in the placebo group that were, that there were, you know, the one milligram per kilogram placebo group that they would have been put onto that at that point as well.

[00:40:40] Speaker 04:
So you would have seen a similar thing.

[00:40:41] Speaker 05:
You mean there were people going from placebo straight to one milligram?

[00:40:45] Speaker 05:
Yeah.

[00:40:45] Speaker 05:
People going straight from placebo to three milligrams?

[00:40:49] Speaker 04:
Yes, yes.

[00:40:49] Speaker 04:
There were people that were receiving three milligrams of placebo and then those people were brought into their, into their ordinary cohort.

[00:40:56] Speaker 04:
at the point where they took the patients off the placebo.

[00:41:00] Speaker 04:
And so if you were on the 3 mg per kilogram placebo, then you would have been brought into the 3 mg per kilogram dose range once they ended the placebo portion of the study.

[00:41:17] Speaker 05:
What about the lower bioavailability concern with adjusting from intravenous to subcutaneous administration?

[00:41:27] Speaker 05:
It appears that the board was relying on the idea that, well, 0.5 milligram per kilogram is the equivalent of a fixed dosage of 40 milligrams.

[00:41:35] Speaker 05:
Campeni, you could just take that and go to a subcutaneous bi-weekly administration, and then we would arrive at the claims.

[00:41:45] Speaker 04:
So I think that's right, Your Honor, so before the board.

[00:41:49] Speaker 05:
But then the counter argument to that is, well, you're going to get a lower bioavailability by administering subcutaneously.

[00:41:57] Speaker 05:
So you're not going to get the same effect as you would by administering intravenously.

[00:42:04] Speaker 04:
So that's, as a general proposition, that's right, but in 28081, at the very end of Campini, Campini says that that's not the case for Jimera here.

[00:42:17] Speaker 04:
And as for the convertibility of fixed and weight-based doses, the patent owner conceded before the board the equivalent of a 0.5 milligram per kilogram and a 40 milligram dose because the average patient is about 80 kilograms.

[00:42:35] Speaker 04:
So we need to be able to take care of approximately the same.

[00:43:15] Speaker 04:
Oh, I'm sorry, at the bottom of the roundup of the paragraph, investigators included that DE, that D2E said to bring this up spontaneously was safe and as effective when administered intravenously.

[00:43:28] Speaker 01:
Okay.

[00:43:29] Speaker 03:
Unless you're most important for the questions.

[00:43:32] Speaker 01:
Okay, thank you.

[00:43:34] Speaker 01:
Mr. Sanders, you have two minutes.

[00:43:49] Speaker 02:
about this intravenous comparison.

[00:43:53] Speaker 02:
A study of study that has no intravenous here.

[00:43:56] Speaker 02:
Question, is no intravenous arm in that study correct?

[00:43:58] Speaker 02:
Answer, as far as I know, there is not.

[00:44:00] Speaker 02:
Questions, what does the intravenous administration refer to in that statement?

[00:44:05] Speaker 02:
Answer, I don't know.

[00:44:07] Speaker 02:
But what we do see is on the face of RAL 2000, on the main references here, an express statement

[00:44:15] Speaker 02:
2809 in the appendix, they quote, intravenous administration gives advantages.

[00:44:21] Speaker 02:
Statement that the board never addressed.

[00:44:25] Speaker 02:
Signing back to up-thrusting from the end of it.

[00:44:29] Speaker 02:
Judge Gazzoni put it that the statement about 78% that's being, they were talking about on the first page of RAL, as a statement about the DEO4 study, is the weekly study, not the weekly study.

[00:44:44] Speaker 02:
at least every other week study that's being relied on for obviousness.

[00:44:48] Speaker 02:
And on up-dosing, I think if one thing has come clear from this argument today is the sheer amount of uncertainty from the basis of these references.

[00:44:59] Speaker 02:
Our experts talked about up-dosing and their interpretation of it.

[00:45:09] Speaker 02:
The question is put to BI's expert, where does the telescope figure is how many patients will be dosed at 0.5 milligram per kilogram?

[00:45:18] Speaker 02:
The answer, it doesn't tell you how many patients were there.

[00:45:21] Speaker 02:
It tells you that those were all the patients that were there at that dose level.

[00:45:25] Speaker 02:
And it goes on to say, some were offered higher doses, yes, but it was up dosing.

[00:45:31] Speaker 02:
But if the up dosing is going to be dismissed on the ground, that this was just converting people for reasons of safety.

[00:45:40] Speaker 02:
or on the ground, I think, contrary to the record that didn't happen after 12 weeks, where the Lord's findings were.

[00:45:46] Speaker 02:
He didn't make those findings.

[00:45:47] Speaker 02:
He left that uncertainty hanging and counted against us as a pattern of error, which was improper.

[00:45:54] Speaker 01:
Okay.

[00:45:54] Speaker 01:
Thank you, Mr. Senator.

[00:45:55] Speaker 01:
May both counsel the case is submitted.