[00:00:04] Speaker 03:
is INRAE MERC 171960.

[00:00:06] Speaker 03:
It is an appeal from the Patent Trial and Appeal Board in connection with the ex parte reexamination.

[00:00:39] Speaker 03:
Mr. Henter, you want five minutes for rebuttal?

[00:00:44] Speaker 00:
Yes.

[00:00:44] Speaker 00:
Okay.

[00:01:03] Speaker 00:
May it please the court, the most important question in this case is whether Van Eten at the single reference

[00:01:10] Speaker 00:
teaches or suggests that folate alone should be administered for improving enol-mediated endothelial-dependent vasomotor responses, which is a mouthful, but it really stands for whether it would dilate your veins or not.

[00:01:25] Speaker 00:
It's also called vasodilation.

[00:01:26] Speaker 03:
Is it your position that a prior art reference, that the board can never rely on the fact that a prior art reference impliedly contains a limitation?

[00:01:38] Speaker 03:
Or is it your position that they just got that wrong in this case?

[00:01:45] Speaker 00:
A reference can genuinely provide motivation by implied statements, by reading between the lines.

[00:01:53] Speaker 00:
It's whether it conveys to one an ordinary skill in the heart.

[00:01:56] Speaker 00:
In this case, our position is that there's clear data evidence contradicting the position of the patent office and that certain data was ignored

[00:02:06] Speaker 00:
dismissed as not significant.

[00:02:09] Speaker 00:
And instead, the reference was looked at all the generic statements, the mechanism of action of folates, which inform about how these drugs work in the body, but it does not inform about what the effect of folate alone would be.

[00:02:24] Speaker 03:
Why don't we conclude that your interpretation of Van Eten is reasonable, but the board's is also reasonable.

[00:02:33] Speaker 03:
Where does that leave you?

[00:02:36] Speaker 00:
Well, the burden is on the patent office to let applicants know that they have the burden of not providing a patent.

[00:02:45] Speaker 00:
I'm sorry, I'm not verbalizing that properly.

[00:02:48] Speaker 03:
Right, but the question is, if we assume that there is substantial evidence to support both conclusions, both readings, doesn't that mean that based on our review, we have to defer to the board's conclusion?

[00:03:01] Speaker 00:
I think that's probably correct.

[00:03:03] Speaker 00:
I think substantial evidence has to support the decision which we believe is not present based on the facts in this case.

[00:03:09] Speaker 03:
And that's all that's necessary even if we think your argument is the better one, right?

[00:03:13] Speaker 00:
I believe so.

[00:03:16] Speaker 00:
I know that we have the higher burden at this stage.

[00:03:20] Speaker 01:
Is there any difference

[00:03:24] Speaker 01:
between your use of, I think essentially the same material in Van Etten, very much concentrated on the left most trio of points on the graphs, which are all essentially overlapping.

[00:03:40] Speaker 01:
Is there any difference in your argument based on that as to motivation to combine teaching away and reasonable expectation of success?

[00:03:52] Speaker 00:
I'll feather those points.

[00:03:54] Speaker 00:
What Vanita shows is that at those points there is no effect of folate.

[00:04:01] Speaker 00:
And that, I believe, is the crux of the issue.

[00:04:04] Speaker 00:
If it tells you that there's no effect, somebody would not follow that path or expect success doing exactly what the reference tells you.

[00:04:12] Speaker 01:
Well, I guess what I'm wondering is whether there's some difference between the motivation question and the reasonable expectation question that is when

[00:04:23] Speaker 01:
Van Etten says, twice really, but at least once very clearly, this would be a really good idea to go and try something like this.

[00:04:33] Speaker 01:
And I know you have an interpretive question about some words that build in conditions, but that one at least seems pretty easy to read as a, this is worth looking at.

[00:04:46] Speaker 01:
I wonder if your argument is,

[00:04:49] Speaker 01:
somewhat stronger on what would be the reasonable expectation of success, because where would that come from, given the essentially overlapping three, is it, there are three lines on the graph?

[00:05:04] Speaker 01:
The three lines.

[00:05:04] Speaker 01:
Three, yeah, the leftmost one, the points are essentially at the same spot.

[00:05:11] Speaker 00:
Yes.

[00:05:11] Speaker 00:
Well, the reasonable expected, let me try,

[00:05:18] Speaker 00:
The question is about reasonable expectation of success when there is some sort of general statement that we should research something further.

[00:05:25] Speaker 00:
It is quite usual for scientific papers to be forward-looking and say some general forward-looking, we should research this further.

[00:05:33] Speaker 00:
But here, those statements are actually quite clearly in the context.

[00:05:37] Speaker 00:
Actually, that paragraph refers to we show certain effects.

[00:05:42] Speaker 00:
And what has been shown is effect with serotonin together and folate, but no effect in the last

[00:05:47] Speaker 00:
most set of data.

[00:05:49] Speaker 00:
It also tells you that folate should be supplemented to the treatment.

[00:05:54] Speaker 00:
That's what's the recommendation.

[00:05:56] Speaker 00:
A supplementation in its normal customary usage doesn't mean give it alone, try it alone.

[00:06:02] Speaker 00:
It usually means supplement added to something.

[00:06:05] Speaker 00:
These patients have a lot of risk factors.

[00:06:09] Speaker 00:
They're usually medicated for various vasomotor response effects

[00:06:14] Speaker 00:
Indeed, one of the things mentioned here is that to isolate the effect of the folate here and the serotonin, medication was stopped four weeks before for this patient.

[00:06:26] Speaker 01:
Were the other medications vessel dilators?

[00:06:31] Speaker 00:
It probably were a variety of medications.

[00:06:33] Speaker 01:
So Mike's supplementation there means supplement the other medications that are not really vessel dilators, which I think... That would be excluded from our claims.

[00:06:45] Speaker 00:
I believe.

[00:06:46] Speaker 01:
I thought part of the board's claim construction on alone meant alone among vessel dilators, not among other drugs.

[00:06:57] Speaker 00:
Other unrelated drugs.

[00:06:58] Speaker 00:
That's correct.

[00:06:59] Speaker 00:
But what the reference did that they stopped all sort of medication before so that they would be able to isolate the effect of the serotonin, which is known to affect dilation, and see if the folate has an effect alone.

[00:07:14] Speaker 00:
because they did the first set of baseline tests, and then whether it would improve on the effectiveness of serotonin.

[00:07:23] Speaker 03:
So is it your position that the better analysis for the board would have been to say, even if Benetton appears to teach the use of folate in combination with serotonin, that it would have been obvious to try using folate alone?

[00:07:44] Speaker 00:
So obvious-to-try is definitely a factor to consider based on KSR, but there's teaching away in this case because it actually answers the very question whether you can expect success here.

[00:07:58] Speaker 00:
They tell you that the limited set of data, they have showed no effect, and it's clearly stated in Ben Eton on the page appendix 415 that there's no effect of folate alone.

[00:08:10] Speaker 00:
This obvious-to-try is

[00:08:14] Speaker 00:
still needs some level of obviousness to go in that direction.

[00:08:18] Speaker 00:
When there's a clear teaching away, pointing away from that path of research, I would submit that obviousness to try is not present.

[00:08:29] Speaker 03:
But the PTO expressly found that Van Etten does not teach away.

[00:08:36] Speaker 03:
And that's a finding of fact, correct?

[00:08:37] Speaker 00:
That's correct.

[00:08:38] Speaker 00:
And we are stating that it's not

[00:08:43] Speaker 00:
There's no substantial evidence in support of that finding.

[00:08:48] Speaker 00:
The PTO had got a lot of things wrong with this data.

[00:08:52] Speaker 00:
One thing is that they ignored the leftmost data point, and that's clear.

[00:09:00] Speaker 00:
Your statements.

[00:09:01] Speaker 00:
In the board hold, if you look at the board decision on page five, it says the data presented in Van Eetim is limited to the use of 5MTHF in combination with other compositions.

[00:09:12] Speaker 00:
This is a quote from the decision of the board.

[00:09:14] Speaker 00:
It is not limited.

[00:09:15] Speaker 00:
There is the leftmost data points.

[00:09:17] Speaker 00:
We are not in a combination of serotonin and folate, but it is an administration of folate alone.

[00:09:24] Speaker 03:
But what do you do with the board's finding that really the focus, at least on some of these experiments, was what's the impact of folate?

[00:09:32] Speaker 03:
With serotonin or without serotonin, but really the focus of the experiments was what's the impact of folate?

[00:09:39] Speaker 03:
Absolutely.

[00:09:40] Speaker 03:
And they actually

[00:09:41] Speaker 03:
suggest that additional testing with respect to the impact of folate should be done?

[00:09:47] Speaker 00:
Yes, that is clearly what is taught by Van Eden.

[00:09:50] Speaker 00:
But in the context, it teaches that this impact was only observed in combination with NO-mediated vasodilation.

[00:09:59] Speaker 00:
Indeed, they did two sets of tests, which is figure two, with NO-independent, with nitroprusside.

[00:10:05] Speaker 00:
It actually teaches that folate in the combination of NO-independent drugs

[00:10:11] Speaker 00:
to affect dilation had no effect.

[00:10:13] Speaker 00:
So it guides you away from proceeding with research with NO-independent dilation.

[00:10:17] Speaker 00:
It also guides you away by having the first set of data points from not testing folate alone.

[00:10:24] Speaker 01:
The suggestions... And what's the sentence on 415 that you... 415?

[00:10:29] Speaker 01:
Yeah, 416 has the two graphs.

[00:10:32] Speaker 00:
Yeah, 415.

[00:10:34] Speaker 00:
No, 416 has the graph.

[00:10:36] Speaker 01:
Right.

[00:10:37] Speaker 01:
I think you referred to 415 before.

[00:10:38] Speaker 00:
415 has the statement that there's no effect of folate.

[00:10:41] Speaker 01:
Is that right at the bottom of the left hand column?

[00:10:44] Speaker 00:
It's two places.

[00:10:45] Speaker 00:
If the diabetic patient on the left bottom side, the last two lines state that the diabetic patient group who was given 5MTHF had no, that 5MTH had no effect on the baseline MC ratio in patients with type 2 diabetes.

[00:11:03] Speaker 00:
It also does the same thing for the control group.

[00:11:05] Speaker 00:
So everybody was tested whether

[00:11:07] Speaker 00:
folate would have an effect.

[00:11:08] Speaker 00:
And it also controls, in the next paragraph up front, that 5MTHF alone had no effect on the baseline ratio of the control group either.

[00:11:16] Speaker 00:
So what it teaches is that for folate to be effective, it does something mechanistically to enhance the effect of NO-mediated vessel dilators.

[00:11:26] Speaker 00:
It does not seem to work alone, based on this limited set of data.

[00:11:30] Speaker 00:
And it also shows that it doesn't work in the context of nitroproside, which uses a different mechanism of action to dilate vessels.

[00:11:37] Speaker 00:
So it clearly steers you direction, steers and directs one of us in a direction away from using folate alone or in the other direction of NO independent dilation.

[00:11:51] Speaker 00:
And certainly there's a lot of research to be done because there are various drugs that do the same type of things, different combinations.

[00:11:58] Speaker 00:
So this hopeful research, the way I read it,

[00:12:02] Speaker 00:
And I submit one award in skill and art would be that it directs one to figure out further research, what combinations would work, which would be effective for effectively helping diabetic patients or other patients with dilation issues.

[00:12:16] Speaker 03:
You're into your rebuttal time.

[00:12:18] Speaker 03:
Have you saved the rest of it?

[00:12:20] Speaker 00:
Oh.

[00:12:22] Speaker 03:
You don't have to.

[00:12:23] Speaker 03:
You can use it up if you want.

[00:12:26] Speaker 00:
There's one more thing I wanted to mention.

[00:12:30] Speaker 00:
And it is that the...

[00:12:33] Speaker 00:
I think the board also did not really appreciate the effect of the drugs here.

[00:12:37] Speaker 00:
If you look at the decision based on appendix 366 and 367, the board held that based on Van Eten, this is quote, figure one, serotonin alone does not actually improve NO-mediated endothelial dependent vessel motor responses.

[00:12:55] Speaker 00:
And the brief also mentioned this at least three different locations.

[00:12:59] Speaker 00:
Serotonin is the drug that does this.

[00:13:01] Speaker 00:
If you look at figure one and the graph, it shows you that the increasing administration of serotonin, there's clearly an effect of vasodilation.

[00:13:09] Speaker 00:
So holding a statement that it does not do it clearly is an error of how the data is interpreted.

[00:13:16] Speaker 00:
And this leads down the board to the wrong conclusion that the actual effect is due to folate, not serotonin.

[00:13:21] Speaker 01:
Just to see if I understand.

[00:13:23] Speaker 01:
And the reason that you think it's clear from the graph is that it... It goes up.

[00:13:27] Speaker 00:
There's an effect.

[00:13:28] Speaker 00:
The only thing that's from left to right that's different is the administration of serotonin.

[00:13:33] Speaker 00:
So the effect of serotonin improves dilation, so the graph for all groups, including the control group, goes up.

[00:13:39] Speaker 00:
Also, the abstract actually states that serotonin is a stimulator of nitric oxide dependent vessel dilation.

[00:13:47] Speaker 00:
For the board to hold that serotonin does not have this effect clearly shows that

[00:13:51] Speaker 00:
They didn't appreciate what's happening, what drug does what.

[00:13:55] Speaker 00:
And then the conclusion was jumped to, it was actually the poly that does this, which I don't think the data shows.

[00:14:03] Speaker 03:
OK, you'll have two minutes for them.

[00:14:04] Speaker 03:
Thank you.

[00:14:16] Speaker 02:
Good morning, Your Honor.

[00:14:17] Speaker 02:
May I please the court?

[00:14:18] Speaker 02:
We'd like to begin by addressing Judge O'Malley's first question about what standard of review we have here.

[00:14:24] Speaker 02:
And based on the board's and the examiner's factual findings of what the references taught, there is substantial evidence here that Van Etten does, in fact, render obvious representative claim 35.

[00:14:37] Speaker 02:
And that is because the board and the examiner's reading of Van Etten here is reasonable.

[00:14:42] Speaker 02:
And it's a reasonable conclusion.

[00:14:44] Speaker 02:
And it's one that the court can follow here.

[00:14:47] Speaker 03:
But how can we read Van Etten to disclose that folate alone had an effect on vasodilation when at least the tests seem to show that it didn't?

[00:14:58] Speaker 02:
So if you look at the data as a whole, which is what the examiner and the board did, it shows that serotonin, or I'm sorry, that folate in fact is what improved endothelial function.

[00:15:10] Speaker 02:
And that is because if you look at figure one, which is that APPX416,

[00:15:15] Speaker 02:
and you look at the graphical data that's depicted there, if you compare the control group along with the diabetic patients who were also administered folate, the folate actually normalized endothelial function there.

[00:15:31] Speaker 02:
The diabetic patients that were administered folate exhibited a very similar profile as to the control group who did not have diabetes.

[00:15:41] Speaker 03:
But in each they had

[00:15:43] Speaker 03:
The serotonin was also administered, right?

[00:15:45] Speaker 02:
The serotonin was also administered.

[00:15:47] Speaker 02:
But again, the examiner also made the finding that serotonin is an endogenous molecule that's within your body.

[00:15:54] Speaker 02:
And serotonin levels can vary over time.

[00:15:56] Speaker 02:
So the fact that the serotonin values, the fact that serotonin was administered was used as a signaling molecule in these studies

[00:16:09] Speaker 02:
to actually induce vasodilation, as it would normally with a body.

[00:16:14] Speaker 01:
And also... Was there endogenous serotonin at the 0.0 level, the left hand?

[00:16:22] Speaker 02:
At the 0.0 level... There must have been.

[00:16:24] Speaker 01:
I mean, presumably, if it's endogenous... There could be some endogenous serotonin, but because... And yet, these three data points overlap.

[00:16:36] Speaker 02:
These three data points overlap at that point.

[00:16:38] Speaker 02:
But again, within even a control subject, there could be low levels of serotonin at one point and higher levels at another point, which would induce vasodilation.

[00:16:47] Speaker 01:
And so in order to... Is your understanding of what the board meant by, I guess it's claim construction, about Foley alone, that includes any endogenous serotonin in the body, which is probably pretty hard to remove?

[00:17:00] Speaker 02:
That is correct.

[00:17:01] Speaker 02:
I think that is the... If they didn't get that some granite, right?

[00:17:04] Speaker 02:
That was not from Venetian.

[00:17:06] Speaker 02:
That was from the examiner's findings as with respect to the state of the art at the time.

[00:17:12] Speaker 03:
But you didn't use that other prior art reference as part of the combination.

[00:17:19] Speaker 02:
No, the other prior reference was not used as part of the combination, but it was also known within the art that humans have endogenous serotonin and that serotonin values can differ over time.

[00:17:32] Speaker 02:
and that certain values of serotonin would induce vasodilation.

[00:17:36] Speaker 03:
So how can we say that Van Etten taught the use of folate alone when its ultimate conclusion was we should do some studies to see what the impact of folate is?

[00:17:46] Speaker 02:
Well, I think what we can look at is the reference as a whole teaches that folate improves endothelial function and further that Van Etten specifically suggests the study of folate for that very purpose.

[00:17:59] Speaker 03:
Although the test, or although the data here- Isn't that then more, isn't that evidence more appropriate for an examination of whether it would be obvious based on a modification of Van Etten rather than to say Van Etten actually teaches it?

[00:18:17] Speaker 02:
Well, I think that's why this is a 103 rejection as opposed to a 102 rejection here because- The board never made the findings though.

[00:18:24] Speaker 02:
Well, the board made the finding that folate here did actually improve endothelial function.

[00:18:29] Speaker 02:
That is what the data shows at figure one.

[00:18:32] Speaker 02:
And further, the entire purpose of the Van Etten study was to study folate on endothelial function.

[00:18:39] Speaker 02:
And because serotonin is a known endogenous vasodilator and also has a known dose-dependent response, serotonin was used to induce vasodilation to actually study the effect of a folate on whether or not it improved that endothelial function in diabetic patients.

[00:18:58] Speaker 02:
And what the data shows is that in fact it did.

[00:19:00] Speaker 02:
At figure one it shows that the slopes of the control group as well as the diabetic patients who were given folate exhibited very similar profiles.

[00:19:09] Speaker 02:
And what that shows is that folate indeed did improve and have that functionality.

[00:19:15] Speaker 03:
What's your response to Merck's argument that at best it showed that folate restored or improved the effectiveness of the vasodilator

[00:19:28] Speaker 03:
not vasodilation itself?

[00:19:30] Speaker 02:
Well, again, serotonin is endogenous in the human body.

[00:19:34] Speaker 02:
And serotonin itself does induce vasodilation in the human body.

[00:19:39] Speaker 02:
But diabetic patients, and this is in Venet, and diabetic patients have impaired serotonin functionality.

[00:19:45] Speaker 02:
And so by studying what the effect of folate would be on a series of patients who are all given the same amount of baseline serotonin, they could study what the effect would be on vasodilation

[00:19:58] Speaker 02:
based on folate itself.

[00:20:01] Speaker 02:
And again, the claim is directed to improving that vasodilation function.

[00:20:07] Speaker 02:
And that is what folate does here.

[00:20:09] Speaker 02:
Folate actually improves the vasodilation function of diabetic patients.

[00:20:14] Speaker 02:
And the conclusion of the Van Etten study was to specifically suggest further study of folate alone.

[00:20:22] Speaker 02:
And that's what the entire purpose of this study was.

[00:20:26] Speaker 02:
Van Etten also indicates that

[00:20:28] Speaker 02:
These studies had already been done in vitro.

[00:20:31] Speaker 02:
And so this was basically a further study done in vivo to confirm the in vitro findings that were found already to be the case.

[00:20:41] Speaker 01:
Then it refers to the predecessor in vitro.

[00:20:44] Speaker 02:
It does.

[00:20:45] Speaker 02:
And that is at APPX.

[00:20:47] Speaker 02:
It's in the abstract at APPX 413, but it's also at APPX 414.

[00:20:54] Speaker 01:
I see.

[00:20:57] Speaker 02:
And it's in the paragraph on the left that begins, of interest, amelioration of enose function can also be achieved by using folic acid.

[00:21:13] Speaker 02:
And here it's also clear that there would have been a motivation to use folate because

[00:21:22] Speaker 01:
What do you think that the word supplementation means in the crucial sentence?

[00:21:27] Speaker 02:
Sure.

[00:21:28] Speaker 02:
I think you already alluded to this when you were asking my friend questions about what supplementation means.

[00:21:33] Speaker 02:
Here, diabetic patients are already taking a multitude of medications, and a folate supplement would simply be... Is this specifically about diabetic patients or cardiovascular?

[00:21:43] Speaker 02:
Well, this is specifically... The Van Etten study is specifically about diabetic patients.

[00:21:50] Speaker 02:
But it's also talking about how it addresses cardiovascular risk.

[00:21:56] Speaker 02:
So yes, the teachings of Van Etten can be further addressed to also using folate as a supplement to help patients who have cardiovascular problems.

[00:22:11] Speaker 02:
But a supplement just means adding or using an additional

[00:22:17] Speaker 02:
like vitamin, or like pregnant women take folic acid supplements when they're pregnant.

[00:22:23] Speaker 02:
I mean, it does not mean that it's necessarily given with an additional vasodilator.

[00:22:27] Speaker 02:
That's not what Van Etten states in its conclusion.

[00:22:31] Speaker 03:
And what about the teaching way?

[00:22:32] Speaker 03:
I mean, as he points out at 415, it says that folate had no effect on the baseline MC ratio in patients with type 2 diabetes.

[00:22:41] Speaker 02:
But again, I think you have to look at Van Etten's data as a whole.

[00:22:44] Speaker 02:
And what Benetton's data as a whole shows is that folate is what improved functionality of endothelial function.

[00:22:50] Speaker 02:
Even though the baseline at figure one shows that there wasn't an effect on endothelial function at that data point, at the subsequent data points, it does show that folate actually improved endothelial function.

[00:23:04] Speaker 01:
And again, the examiner pointed to... But what that graph shows is that you see the improvement when there is

[00:23:14] Speaker 01:
serotonin added to whatever the background is in the patient's body.

[00:23:18] Speaker 01:
How does that tell you that you would see an improvement without such supplemental serotonin?

[00:23:26] Speaker 02:
Well, again, the human body has endogenous serotonin.

[00:23:29] Speaker 01:
That's right.

[00:23:29] Speaker 01:
It referred to supplemental serotonin.

[00:23:31] Speaker 02:
Which is different than supplemental serotonin, but within the body itself, serotonin levels vary.

[00:23:36] Speaker 02:
And so this study, all that it was doing was bringing up the serotonin value to a base level where there

[00:23:43] Speaker 02:
is vasodilation.

[00:23:45] Speaker 02:
And so in the control subjects, once serotonin is administered, even in the control subjects.

[00:23:51] Speaker 01:
I guess that makes me want to ask you the same question I asked.

[00:23:55] Speaker 01:
I don't think it was you.

[00:23:56] Speaker 01:
I think it was your opposite number.

[00:23:57] Speaker 01:
At the 0.0 level, there is endogenous serotonin.

[00:24:02] Speaker 01:
So in some patients, there is going to be some dilating effect from endogenous serotonin.

[00:24:08] Speaker 01:
Otherwise, this whole reference to endogenous serotonin is a red herring.

[00:24:13] Speaker 03:
And yet they still found no effect.

[00:24:15] Speaker 02:
Well, at zero, there is still some effect of endogenous serotonin, but even, like I said, the serotonin levels may vary within the body.

[00:24:24] Speaker 02:
And so even at a low serotonin value, there may not be enough of a signaling molecule to induce vasodilation.

[00:24:33] Speaker 03:
Right, but there's no finding that the serotonin levels would be at the level that Van Etten is contemplating with supplemental serotonin.

[00:24:42] Speaker 03:
There's nothing in the record that would indicate that.

[00:24:44] Speaker 03:
We all have a lot of levels of certain things in our body, but rarely are they high enough.

[00:24:50] Speaker 03:
So he's talking about a supplemental serotonin.

[00:24:55] Speaker 02:
Well, what they're trying to do is study the effect of folate on a particular function.

[00:24:59] Speaker 02:
And what they want to study is NO-mediated vasodilation.

[00:25:04] Speaker 02:
And the reason serotonin is administered is because it has a known dose-dependent response.

[00:25:10] Speaker 02:
And so you can study

[00:25:12] Speaker 02:
You can compare what the vasodilation will be in a control group as well as in a diabetic group.

[00:25:20] Speaker 02:
And in the diabetic group, it shows that over time, the vasodilation is not improved.

[00:25:28] Speaker 02:
It's not increased.

[00:25:29] Speaker 02:
But with the administration of folate, it is improved and it is increased.

[00:25:36] Speaker 02:
The application of serotonin was simply used as a known control parameter to study the effect of folate.

[00:25:42] Speaker 03:
Wouldn't this absence also be a known control parameter then?

[00:25:46] Speaker 02:
Well, if the endogenous serotonin never rose to a level to actually induce vasodilation, then no.

[00:25:54] Speaker 02:
Then all of the data might all be flat because there may never be enough serotonin in the patient at that time to induce vasodilation.

[00:26:05] Speaker 03:
Right, wasn't that my point before?

[00:26:07] Speaker 02:
Well, no, because at different times of the day, your body will have a higher level of serotonin.

[00:26:15] Speaker 02:
And at that higher level of serotonin, vasodilation would be induced.

[00:26:19] Speaker 02:
And so in order to trigger that higher level of serotonin for the purpose of this experiment, Van Etten studied the curvature with serotonin at certain levels.

[00:26:32] Speaker 02:
So they know that

[00:26:33] Speaker 02:
at that level, the body would naturally be vasodilating at a certain level.

[00:26:39] Speaker 02:
And what it showed is that diabetic patients who have impaired endothelial function, their body normalize with the administration of folate.

[00:26:48] Speaker 01:
Can I ask you, is there any significance to the fact that the MC ratio at the y-axis is not 1, but is 1.3 or 1.2?

[00:27:02] Speaker 02:
I think that is significant.

[00:27:03] Speaker 02:
What's the significance?

[00:27:05] Speaker 02:
The significance is that there is still some effect.

[00:27:08] Speaker 02:
There is still some basodilation.

[00:27:10] Speaker 02:
And I think because it's a little above one, there was still some effect from just the baseline level of serotonin that was available at that time in those patient groups.

[00:27:27] Speaker 02:
And so I think that shows that

[00:27:30] Speaker 02:
that folate is what is actually causing the improvement here.

[00:27:34] Speaker 02:
Because with folate, the functionality of the diabetic patients who are administered that folate, their endothelial function was normalized.

[00:27:57] Speaker 02:
And just to go back to the

[00:28:00] Speaker 02:
the examiner's discussion of that, that's at pages APPX 365 to 367, actually, till 369.

[00:28:08] Speaker 02:
It discusses that serotonin itself is an endogenous molecule found in the body and can vary over time.

[00:28:15] Speaker 02:
If there are no further questions, I will yield the rest of my time.

[00:28:22] Speaker 00:
Thank you.

[00:28:26] Speaker 00:
Two minutes.

[00:28:26] Speaker 00:
For the endogenous serotonin question,

[00:28:29] Speaker 00:
For the data to make sense, one would have to assume that 23 patients and 21 control subjects were flatlined with serotonin exactly when this test was done.

[00:28:37] Speaker 00:
You'd think there would be some variation of endogenous serotonin in some of these people to show some effect.

[00:28:43] Speaker 00:
Yet the conclusion drawn was that there's no effect of folate alone.

[00:28:47] Speaker 00:
So endogenous doesn't seem to make a difference.

[00:28:49] Speaker 00:
The other thing you may ask about is that why is it a little bit above one?

[00:28:55] Speaker 00:
Well, we can second-guess whether there was a little bit of dilation.

[00:28:59] Speaker 00:
We can also assume that the judgment of the authors here, that there's no effect controls.

[00:29:05] Speaker 00:
But it could be a little bit higher, because you're actually infusing drugs into the veins, which has some volume.

[00:29:11] Speaker 00:
It may dilate just a little bit, because there is additional stuff flowing through, which is not the effect of folate, but just the extra volume of material being titrated.

[00:29:21] Speaker 00:
certain amount per minute, it's actually the amount of blood that's being pushed into your vein.

[00:29:25] Speaker 00:
So the no effect, this could be the little difference that makes, dilates your blood, but the authors said they did not see an effect from folate alone.

[00:29:35] Speaker 00:
And this was on patients and control subjects, which apparently were alive and had some level of endogenous serotonin.

[00:29:42] Speaker 00:
We don't know if this was done in the daytime, evening, afternoon, or various times.

[00:29:46] Speaker 00:
Opposing counsel said different times of the day, different results would be obtained.

[00:29:51] Speaker 00:
Here, same result and conclusion was drawn by the authors.

[00:29:58] Speaker 00:
There's no effect.

[00:30:01] Speaker 03:
Thank you.

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