[00:00:02] Speaker 02:
Our next case today is 2016-1155 Cumberland Pharmaceutical versus Mylon.

[00:00:44] Speaker 02:
Staffer, please proceed.

[00:00:46] Speaker 02:
Thank you, Your Honor.

[00:00:57] Speaker 04:
May it please the Court.

[00:00:59] Speaker 04:
The District Court failed to understand... Excuse me.

[00:01:02] Speaker 02:
No problem.

[00:01:04] Speaker 04:
The District Court failed to understand and apply the proper legal standards for obviousness and derivation.

[00:01:09] Speaker 04:
Its order should be reversed for two reasons.

[00:01:12] Speaker 04:
First, regarding obviousness.

[00:01:13] Speaker 04:
The district court erred in applying the wrong standard for reasonable expectation of success.

[00:01:18] Speaker 04:
Instead of considering what would be reasonably expected by a person of skill in the art, the district court applied a heightened and near absolute predictability of success in excluding EDTA from the prior art formulation.

[00:01:30] Speaker 04:
The district court also erred by finding that there was no motivation in the prior art to exclude EDTA from the existing formulation.

[00:01:38] Speaker 04:
By doing so, the district court improperly ignored the explicit motivation of the prior art from the FDA approval letter.

[00:01:45] Speaker 04:
Specifically, this prior art letter instructed Cumberland to exclude EDTA from the existing prior art formulation because FDA expected that EDTA was not necessary and was known to cause certain adverse effects, including fatalities.

[00:02:01] Speaker 04:
This is admitted in sworn statements under penalty of perjury made by Cumberland, the patentee itself, in a citizen petition

[00:02:07] Speaker 04:
where it said from the outset that FDA wanted Cumberland to reformulate a prior acetate product that it did not itself develop to exclude EDTA because of safety concerns.

[00:02:21] Speaker 01:
What is the evidence for the proposition that let's assume that the FDA suggested you go figure this out?

[00:02:32] Speaker 01:
What is the evidence for the additional proposition that, as I think you just said, the FDA expected the project to succeed, namely to get to a sufficiently stable pharmaceutical product without EDTA, putting aside the requirement without any chelating agents?

[00:02:56] Speaker 04:
Okay, so I think it's several-fold.

[00:02:59] Speaker 04:
First, from the very outset of the NDA approval process for the PriorArt acetate that included EDTA starting in December of 2002, FDA said you need to justify the presence of EDTA.

[00:03:12] Speaker 04:
And this was in part due to what was called quality by design, which is where formulators by the time of 2002 but not back in the 70s when this PriorArt product was initially developed elsewhere in the world, they were looking at

[00:03:25] Speaker 04:
all ingredients, inactive ones like EDTA, and saying what's its purpose.

[00:03:31] Speaker 04:
Particularly EDTA, which the court admitted was known to have adverse side effects, including fatality.

[00:03:37] Speaker 04:
And so unless there's a justification for something to be there, you take it out.

[00:03:41] Speaker 01:
But I think what you just said seems to me to point rather against an affirmative expectation on the part of the FDA that one could do without chelating agents.

[00:03:54] Speaker 01:
Rather, they have a new general policy that says anything that's in here, you've got to make sure it belongs.

[00:04:00] Speaker 01:
We don't know whether it belongs before we study it or not.

[00:04:06] Speaker 04:
Well, that was the original reason for the justification.

[00:04:09] Speaker 04:
But then within six days, FDA said you have to include data in your submission.

[00:04:13] Speaker 04:
And then throughout the next almost two years, you're 14 months.

[00:04:17] Speaker 04:
FDA is consistently saying you need to reformulate to take out EDTA.

[00:04:21] Speaker 04:
You need to study whether EDTA is doing anything in this formulation, and you need to remove it.

[00:04:29] Speaker 01:
But you just said in three sentences,

[00:04:32] Speaker 01:
quite different things.

[00:04:33] Speaker 01:
One is you need to study it.

[00:04:34] Speaker 01:
That was your second sentence.

[00:04:36] Speaker 01:
Sentence one and three were you need to take it out.

[00:04:39] Speaker 01:
Where's the evidence for that?

[00:04:41] Speaker 04:
That's in the chemistry review and the approval letter and in the contemporaneous internal communications within Cumberland as well as its sworn statement in the citizen petition where it said

[00:04:52] Speaker 04:
that FDA from the outset wanted acetidote to be reformulated to remove EDTA.

[00:05:00] Speaker 04:
That's a sworn statement that Cumberland, the patentee, made to FDA.

[00:05:03] Speaker 04:
Can you give me the joint appendix site for that, please?

[00:05:06] Speaker 04:
Yes.

[00:05:06] Speaker 04:
It's the citizen petition.

[00:05:14] Speaker 04:
Starting at A11688.

[00:05:15] Speaker 04:
11688.

[00:05:17] Speaker 04:
A11688.

[00:05:21] Speaker 04:
The sworn statement under penalty of perjury is at A 11697.

[00:05:25] Speaker 04:
And then the statements.

[00:05:31] Speaker 02:
Well, let's go a little slower.

[00:05:32] Speaker 02:
Why don't you tell me in, because 11688 is a wrong document.

[00:05:36] Speaker 02:
So tell me that's just a cover letter.

[00:05:39] Speaker 02:
So what?

[00:05:40] Speaker 02:
The citizen petition follows that.

[00:05:41] Speaker 02:
Right.

[00:05:42] Speaker 02:
So tell me where in the citizen petition you think is the express admission that the FDA

[00:05:48] Speaker 02:
instructed them to take out E. coli agents.

[00:05:55] Speaker 04:
That starts I believe well it's at least at A11693.

[00:06:02] Speaker 04:
From the outset FDA wanted Cumberland to investigate reducing or removing EDTA from acetidote.

[00:06:09] Speaker 04:
To investigate.

[00:06:11] Speaker 02:
Right.

[00:06:12] Speaker 02:
Because it was concerned with the safety.

[00:06:14] Speaker 02:
It was concerned about the safety.

[00:06:15] Speaker 02:
Yeah but that's not

[00:06:17] Speaker 02:
There are lots of additives in drugs that the FDA may question.

[00:06:22] Speaker 02:
Is this really necessary?

[00:06:23] Speaker 02:
Because it can have delirious deterioration, bad side effects.

[00:06:27] Speaker 02:
And so why is asking them to investigate whether this is really necessary, the conception of a drug that doesn't include it in a complete concepted form?

[00:06:42] Speaker 04:
Because at the time of the NDA approval,

[00:06:44] Speaker 04:
FDA spent lots of time investigating and looking at all of the manufacturing and the product information which included things like pH control and nitrogen in the headspace.

[00:06:55] Speaker 02:
You're saying, no, that's not helpful.

[00:06:57] Speaker 02:
Show me evidence in this record that, because this sentence doesn't do it, this sentence tells

[00:07:03] Speaker 02:
You said that there is evidence in this record that the FDA had a complete conception.

[00:07:08] Speaker 02:
So this sentence absolutely doesn't do it because all this sentence does is admit that the FDA wanted Cumberland to investigate removing EDTA by no means

[00:07:17] Speaker 02:
Does that demonstrate that somehow the FDA had the conception of the exact formulation of a drug that would not include any chelating agent?

[00:07:24] Speaker 02:
So where is that evidence?

[00:07:25] Speaker 02:
You rattled off a bunch of different evidence.

[00:07:27] Speaker 02:
This was the first piece.

[00:07:28] Speaker 02:
This doesn't do it.

[00:07:29] Speaker 02:
So take me to the second piece of evidence that you say does it.

[00:07:33] Speaker 04:
Well, if you look at the actual district court opinion on expectation of success, first, the district court cites unigine, and it cites it for an incorrect proposition that there has to be.

[00:07:43] Speaker 03:
Where?

[00:07:44] Speaker 04:
What page would you like me to look at?

[00:07:48] Speaker 04:
So if you go to A27 of the order, this is the only place where there's a discussion of the expectation of success.

[00:07:58] Speaker 04:
And it cites to four things.

[00:08:00] Speaker 04:
It cites to the background section of the patent that talks about other products, including EDTA.

[00:08:06] Speaker 04:
And then it cites to three portions.

[00:08:09] Speaker 04:
It credits three portions of Dr. Kent's appellant's expert's testimony.

[00:08:15] Speaker 04:
And it's clear by looking.

[00:08:17] Speaker 04:
at that portion of his testimony, that he testifies that there was a reasonable expectation, but the FDA wouldn't know for sure.

[00:08:25] Speaker 00:
And so, for example, if you go to... But don't require more than a reasonable expectation.

[00:08:33] Speaker 00:
I mean, it seems to me that our case law requires that the inventor, in this case the FDA, have a settled idea, a specific settled idea,

[00:08:45] Speaker 00:
And I don't see that in any of these communications.

[00:08:48] Speaker 00:
And I don't understand how a 2012 letter several years after the fact helps you.

[00:08:56] Speaker 04:
Well, the settled idea goes to derivation and whether the FDA had a proper conception.

[00:09:00] Speaker 04:
The reasonable expectation of success goes to whether or not the chemistry review and the printed publication approval letter render obvious the claim to invention.

[00:09:11] Speaker 04:
The approval letter and the package insert are printed publications under 102B.

[00:09:16] Speaker 04:
And the prior art acetidote product, which included every single claim element of all of the asserted claims, except that it included EDTA, is also 102B prior art.

[00:09:26] Speaker 04:
So then you look at whether the suggestion in the approval letter to study taking out EDTA and to remove it from the formulation of the drug product, which includes every other element, whether or not that would have been obvious to try in light of this express instruction and motivation expressed in the approval letter.

[00:09:45] Speaker 04:
And then you look at whether or not that would have had a reasonable expectation of success.

[00:09:50] Speaker 04:
And if you look at what the district court says on that, the district court applies a heightened standard.

[00:09:54] Speaker 04:
And then the district court specifically cites and credits testimony of Dr. Kent, where he says you would have had a reasonable expectation of success, but FDA wouldn't know for sure.

[00:10:05] Speaker 04:
So FDA is not going to approve a drug product.

[00:10:07] Speaker 04:
So for example, that is at 8816 and 8817.

[00:10:13] Speaker 04:
which is cited from the trial transcript in A27 is 673-22 through 674-4, where Dr. Kent testifies specifically.

[00:10:24] Speaker 04:
There's documents that support essentially the removal.

[00:10:26] Speaker 04:
There's no direct documents, but certainly a person of ordinary skill would realize that by removing EDTA, there is certainly an expectation that it would be stable.

[00:10:36] Speaker 04:
Then the district court also cites the testimony in response to the court's questions, where the court says,

[00:10:43] Speaker 04:
And this is at A8823 and A8824.

[00:10:52] Speaker 04:
And so the court says at line 18, they thought most likely it was superfluous, referring to FDA, thought that EDTA was superfluous.

[00:11:00] Speaker 04:
The witness says correct.

[00:11:02] Speaker 04:
The court, do you think the FDA opinion writers are persons of ordinary skill in the art?

[00:11:06] Speaker 04:
Witness says absolutely.

[00:11:07] Speaker 04:
Court, so they didn't know for sure that EDTA was superfluous.

[00:11:11] Speaker 04:
They thought it was superfluous.

[00:11:14] Speaker 04:
Witness, they see a lot.

[00:11:15] Speaker 04:
And the court says, so they were pretty sure.

[00:11:17] Speaker 04:
Court continues, EDTA seemed superfluous to them, but they didn't know for sure.

[00:11:22] Speaker 04:
Otherwise, what's the point of asking for a study, right?

[00:11:25] Speaker 04:
The witness, well, it's the FDA world.

[00:11:27] Speaker 04:
A person of ordinary skill sees enough information to certainly that it would be expected.

[00:11:32] Speaker 04:
But the FDA wants confirmation, because they are obviously not going to approve a change in a drug formulation without doing a full study.

[00:11:40] Speaker 01:
And so if you- Just to be clear, this is your witness, right?

[00:11:43] Speaker 01:
This is our witness, but this is the only... I'm sorry.

[00:11:46] Speaker 01:
So the district court, as I read this, is saying, I don't have to believe Dr. Kent's testimony went about, period.

[00:12:00] Speaker 01:
And one reason I don't have to believe it is that even he conceded there are no prior art references.

[00:12:07] Speaker 01:
All the stuff that you're just reciting from the testimony

[00:12:13] Speaker 01:
is stuff that the district court did not need to credit because there is not an objectively cited basis for it.

[00:12:20] Speaker 01:
But why do you think the district court had to accept these assertions?

[00:12:24] Speaker 04:
I think district court did credit it and assert it because that's all that's cited with respect to the expectation of success.

[00:12:31] Speaker 01:
If you look at the cited... The first sentence, no prior references with one possible exception taught or suggested a formulation would be safe without a chelating agent of some kind.

[00:12:44] Speaker 01:
and citing Dr. Kent saying, right, I can't actually cite to anything in the prior art, but I believe this.

[00:12:51] Speaker 01:
So why can't the district court say the absence of anything in the prior art is, to me, more persuasive than your assertion?

[00:12:57] Speaker 04:
Because this is an obviousness analysis.

[00:12:59] Speaker 04:
And so we're not claiming anticipation.

[00:13:01] Speaker 04:
We're claiming obviousness.

[00:13:02] Speaker 04:
And so it's obvious to try because the district court doesn't make a finding that there's no reasonable expectation of success.

[00:13:09] Speaker 04:
The district court just says that you can't predict

[00:13:12] Speaker 04:
Absolutely success.

[00:13:13] Speaker 04:
It cites the unigine, and then it cites to and credits this testimony.

[00:13:17] Speaker 04:
And the only thing that this testimony shows is that you would have had a reasonable expectation of success, but you wouldn't know for sure.

[00:13:24] Speaker 04:
You wouldn't have an approved drug product.

[00:13:26] Speaker 04:
And I think that that's where the standard is conflated.

[00:13:29] Speaker 02:
And I think it's conflated also in the opposing brief, where- Didn't he, the district court, didn't she compare Dr. Penn's testimony?

[00:13:38] Speaker 02:
Clearly, she didn't ignore it.

[00:13:40] Speaker 02:
She pointed to the exact sections that

[00:13:42] Speaker 02:
you would want us to look at in this regard, but then goes on to say, given all the prior art which taught EDTA or other chelating agents, chelating agents, they were necessary to stabilize the formulation, the court rejects the argument.

[00:13:58] Speaker 02:
I mean, that's the very next sentence after her discussion of Kent.

[00:14:02] Speaker 02:
The court rejects the argument.

[00:14:04] Speaker 02:
So the reason, it seems to me, that she's saying she rejects it is

[00:14:08] Speaker 02:
There is a large body of prior art that teaches the requirement of chelating agents for stability, and EDTA in particular.

[00:14:15] Speaker 02:
And so Mr. Kent may come along, but experts get paid to say a lot of things.

[00:14:21] Speaker 02:
And Mr. Kent may have come along and said, it would have been reasonable not to include this.

[00:14:27] Speaker 02:
But all the prior art went the other way, all of it.

[00:14:30] Speaker 02:
And there's no prior art that went his way.

[00:14:32] Speaker 02:
So why isn't that?

[00:14:33] Speaker 02:
This was a bench trial, and this is a fact finding.

[00:14:37] Speaker 02:
Isn't that exactly the sort of thing that even if I were to agree with you, we leave to the district court?

[00:14:42] Speaker 04:
Because I think that to the extent she made a fact finding that no prior art considered taking out EDTA or not using EDTA, that's clearly erroneous because the approval letter, we think she didn't fully consider it, she cites it there, but she doesn't give any explanation anywhere in her opinion why the approval letter doesn't provide a motivation or suggestion under KSR to take out EDTA.

[00:15:02] Speaker 02:
I read the approval letter and we just went through parts of it, you know, and the approval letter just tells them to investigate removing it.

[00:15:11] Speaker 02:
That isn't a suggestion to take it out.

[00:15:14] Speaker 02:
It's a suggestion to do an investigation about whether it's necessary, whether it could be replaced with something different, whether it could be removed altogether, but that's...

[00:15:22] Speaker 02:
I'm sorry, but that is not adequate for me.

[00:15:25] Speaker 02:
So I don't know.

[00:15:28] Speaker 02:
I mean, I understand Dr. Kent testified very effectively exactly what you would need him to say in this circumstance.

[00:15:37] Speaker 02:
But it seems quite clear from this paragraph that she rejected that in light of the other evidence.

[00:15:41] Speaker 04:
Thank you.

[00:15:42] Speaker 04:
I think I'm almost out of my time, so.

[00:15:44] Speaker 02:
Oh yeah, I'm going to restore your bottle time.

[00:15:46] Speaker 02:
We've been asking you lots and lots of questions.

[00:15:48] Speaker 02:
Sorry.

[00:15:49] Speaker 02:
No, no, not a problem.

[00:15:50] Speaker 02:
Okay, so we'll hear from the closing counsel.

[00:15:53] Speaker 02:
I'm just going to ask you to tell me how to say your name.

[00:15:56] Speaker 03:
Mazurowski, Your Honor.

[00:15:57] Speaker 02:
Mazurowski.

[00:15:58] Speaker 02:
Very good.

[00:15:59] Speaker 02:
Ms.

[00:15:59] Speaker 02:
Mazurowski.

[00:16:02] Speaker 02:
And since we're going to restore her five minutes of her bottle time, this is a complicated case, if you need to go over, don't worry about the red light.

[00:16:09] Speaker 02:
Thank you, Your Honor.

[00:16:09] Speaker 03:
May it please the court?

[00:16:12] Speaker 03:
Mylan's appeal does not ask the court to revisit claim construction or the district court's findings and conclusions on anticipation.

[00:16:19] Speaker 03:
Rather, it argues de novo and asks the court to reweigh the evidence on who first proposed testing a formulation with no or lower EDTA, was the mere idea to test or a commitment to test a disclosure of all the limitations of the claimed method, i.e.

[00:16:36] Speaker 03:
treating,

[00:16:37] Speaker 03:
acetylcysteine overdose, excuse me, acetaminophen overdose with a stable aqueous acetylcysteine solution or formulation with a particular concentration and pH stable free of all chelating agents.

[00:16:52] Speaker 03:
I think, Your Honor, you asked a question about laying aside all those critical elements and that what's important to remember here is that

[00:17:00] Speaker 03:
The district court did find that those were critical elements, that none of the disclosures disclosed all of the limitations, and that those free of all chelating agents were key limitations.

[00:17:13] Speaker 01:
Is there a dispute in this record whether your product is acetidote?

[00:17:19] Speaker 01:
Acetidote.

[00:17:20] Speaker 01:
Acetidote meets the claim limitations, putting aside the chelating agent element.

[00:17:27] Speaker 03:
The prior art acetidote was made with EDTA and all of the claims of the 445 patent of the claim method of use require a formulation that is free of all chelating agents.

[00:17:39] Speaker 01:
Does the earlier version of acetidote meet all of the claim limitations of the patent that is issued here except

[00:17:56] Speaker 01:
for the free of chelating agent claim requirement?

[00:18:01] Speaker 03:
Your Honor, yes, it does.

[00:18:03] Speaker 03:
It has.

[00:18:03] Speaker 01:
So if the FDA had said, please take out EDTA from your existing product.

[00:18:15] Speaker 01:
We expect it to be a success.

[00:18:17] Speaker 01:
Don't put any other chelating agent back in place.

[00:18:22] Speaker 01:
You'd be in a tough spot.

[00:18:25] Speaker 03:
But yes, that would be true.

[00:18:27] Speaker 03:
But what the FDA did not say was don't put in any other chelating agents.

[00:18:31] Speaker 03:
And there was an admission that the district court relied on in making a specific finding that the approval letter did not anticipate because it didn't disclose all of the claim limitations.

[00:18:41] Speaker 01:
I just want to focus on what seems to me

[00:18:46] Speaker 01:
the aspect of the claims that matters here, which is the free of chelating agent aspect, not all this other stuff in the claims, because that was in the prior art acetidote.

[00:18:59] Speaker 03:
The court found that all of the elements of the claim are a unitary whole in a formulation.

[00:19:05] Speaker 03:
And the court found that you need to look at the composition as a unitary whole, that you can't treat the, based on expert testimony that she credited, that you cannot treat each of the elements separately

[00:19:16] Speaker 03:
that it makes a difference because all of the molecules interact.

[00:19:19] Speaker 03:
They're not like a bag of marbles that you can just kind of pick one out and expect the rest to stay the same.

[00:19:24] Speaker 03:
There was consistent expert testimony that the court credited.

[00:19:27] Speaker 03:
that these two formulations are entirely different formulations.

[00:19:30] Speaker 01:
And given the state of the prior art, and that's... There was only the most indirect reference, which surprised me, in the papers that we were given.

[00:19:39] Speaker 01:
So the answer to the question, did you guys get a new drug application, file a new drug application, and get one approved for the updated acetidose?

[00:19:51] Speaker 03:
Yes.

[00:19:51] Speaker 01:
Okay.

[00:19:52] Speaker 03:
When?

[00:19:54] Speaker 03:
In 2011.

[00:19:55] Speaker 01:
In January 2001... Is there some reason that's not in the record?

[00:20:02] Speaker 01:
It's very odd to me.

[00:20:03] Speaker 03:
I believe there was evidence, it may not have made it into the Joint Appendix, but there was evidence that in January 2011 the new product was approved and what is... And was that a whole new drug application or was that some... Was there some, I don't know, short form because it's making one change in an old one?

[00:20:26] Speaker 03:
It was done in a supplemental NDA because Cumberland had submitted a final report with all the data from its testing and that's how it was approved.

[00:20:42] Speaker 01:
Supplemental to the original?

[00:20:45] Speaker 03:
Yes, and both are approved and on the market today.

[00:20:47] Speaker 01:
Would that have been possible if

[00:20:52] Speaker 01:
a new chelating agent had been added in place of EDTA?

[00:20:56] Speaker 01:
Can I ask that question without having a particular view about why the answer might matter?

[00:21:00] Speaker 03:
I actually don't know about the regulatory aspect of it, but it may have been, like our product, a completely different product and may have required a different regulatory process.

[00:21:10] Speaker 03:
What's important to know about the date of the approval of our new product is that, but two months after that, Mylan internal formulation scientists

[00:21:20] Speaker 03:
when considering what product they were going to submit to be approved in an ANDA, wrote, we've learned about this new product, and we are concerned that, quote, removing EDTA will open up sensitivity to heavy metals at low levels.

[00:21:36] Speaker 03:
Possibly some testing or spiking studies should be done to, quote, define what needs to be in place to compensate for EDTA removal.

[00:21:44] Speaker 01:
And this is your part of the evidence for why success

[00:21:50] Speaker 01:
can be found not to have been reasonably expected, even if they didn't.

[00:21:54] Speaker 03:
Exactly.

[00:21:54] Speaker 03:
There was USV Adams type skepticism that even after knowing that the light bulb would keep burning, they didn't believe it.

[00:22:00] Speaker 03:
And they said that again in June of 2011.

[00:22:03] Speaker 03:
That's in that March 2011 skepticism is at A14346 to 47.

[00:22:08] Speaker 03:
And the same thing was said barely three months later.

[00:22:12] Speaker 03:
Iron in the glass may seep in and cause an issue with EDTA removal in June 2011 at A14562.

[00:22:20] Speaker 03:
We submit, Your Honor, that that further supports the district court's three core findings on the state of the art, which were germane to each of the issues she decided the way she did.

[00:22:30] Speaker 03:
First and foremost, that acetylcysteine is a highly unstable molecule.

[00:22:34] Speaker 03:
It oxidizes and degrades, loses its potency, and it becomes impure, the types of impurities that are at the tables in the patent at A100.

[00:22:43] Speaker 03:
Liu, prior to Liu, coined the phrase notorious instability and taught use of a chelating agent, such as EDTA, to stabilize it or to take it completely out of solution and lyophilize it.

[00:22:55] Speaker 03:
Likewise, Strobelo refers to its high reactivity.

[00:22:59] Speaker 03:
And Mylan's expert, Dr. Kent, at trial explained that it was well known that acetylcysteine's thiol group, which is important to its activity, also happens to be the group that is subject to oxidation.

[00:23:10] Speaker 03:
Quote, thiol groups are well known to oxidize.

[00:23:13] Speaker 03:
The district court relied on all of this in finding that it was well known in the art at A4 and A26 and 28 of her thorough opinion on this issue that stability was known to be a problem and because stability is part and parcel of safety and efficacy, as Mylan's expert explained, a drug of unknown stability would not even be a drug and no physician would administer it.

[00:23:36] Speaker 01:
Can I ask you a question that

[00:23:40] Speaker 01:
Maybe it doesn't matter because reasonable expectation of success is necessary here.

[00:23:46] Speaker 01:
But I want you to focus on the motivation to combine.

[00:23:50] Speaker 01:
If the FDA says, go and try this, is that always, sometimes, never enough for the motivation to go and try it?

[00:24:07] Speaker 03:
Which may not be legally sufficient because they may ask you to try things that you just have its complete guesswork as to whether it would succeed or not But just on the motivation to combine the FDA says go and try The context is what matters the factual context and the specific factual context here was Not only that a seal system was highly unstable but that for years every single commercial manufacturer of this treatment for

[00:24:36] Speaker 03:
IV use added EDTA.

[00:24:39] Speaker 03:
So there was a settled expectation.

[00:24:41] Speaker 03:
The accepted wisdom, as the court called it at A28, a general understanding in the scientific community that you would need.

[00:24:49] Speaker 01:
But what all of that says, it seems to me that goes to either of two things.

[00:24:54] Speaker 01:
One, it might, in fact, be ample to show no reasonable expectation of success.

[00:25:01] Speaker 01:
case over, but on the motivation to combine, maybe that says, had the FDA not said so, there would not have been a motivation to combine.

[00:25:11] Speaker 01:
But when the FDA says, go and try this, can't you check off, or can't the other side, check off the box?

[00:25:19] Speaker 01:
Okay, there was a motivation to combine after, combine, I mean to modify, to modify after the FDA said, go and do it.

[00:25:27] Speaker 01:
That's a pretty strong motivation.

[00:25:29] Speaker 03:
Your Honor, I believe the case law talks about there being a motivation to combine where there are a small number of reasonably successful options, not a limitless number of things that you would be able to do.

[00:25:40] Speaker 01:
Right, but the FDA told you to do one thing.

[00:25:43] Speaker 03:
That was a very small number.

[00:25:46] Speaker 03:
The FDA took our commitment to test EDTA.

[00:25:49] Speaker 03:
There was a lot of testimony in the record that there were myriad ways of testing

[00:25:54] Speaker 03:
whether or not EDTA had effects on stability.

[00:25:56] Speaker 03:
One could, for example, do this type of spiking studies that were done in Hamlo or that Mylan's scientists proposed after the fact in 2011.

[00:26:06] Speaker 03:
Those samples, those spiking type studies were quick and dirty studies that would have yielded information like Hamlo that yes, in fact, EDTA preserved stability.

[00:26:15] Speaker 03:
You could have varied many different parameters.

[00:26:18] Speaker 03:
Mylan's expert agreed in trial

[00:26:20] Speaker 03:
And this was the basis of the court's finding no anticipation that one of the parameters that you could have modified was adding another chelating agent.

[00:26:28] Speaker 03:
You could modify pH.

[00:26:29] Speaker 03:
You could modify concentration.

[00:26:30] Speaker 03:
Dr. Byrne testified that it was like asking to make 0.

[00:26:34] Speaker 03:
You would start from the ground up, and you would take any number of possibilities that a formulation scientist would consider so that the options were really quite limitless.

[00:26:44] Speaker 03:
Mr. Pablin himself testified that he considered lots of different options,

[00:26:48] Speaker 03:
kind of in the way that necessity is the mother of invention, he didn't have his own laboratory and he took a route that was elegant for the result and yielded a long study that, you know, some other formulation scientists might not have done that he designed that was scheduled to go out 3, 6, 12, 36 months.

[00:27:08] Speaker 03:
So I think the answer to your question, to answer your question, is that it really depends on... The number really wasn't one.

[00:27:14] Speaker 03:
that there really wasn't one.

[00:27:15] Speaker 03:
I mean, that question has to be answered in the context of the state of the art and the options available to the scientists at the time and the specific request.

[00:27:25] Speaker 03:
Here, the court also found that there was no directive or instruction to Mr. Pavlov as to what to test, what parameters to test, how to test.

[00:27:34] Speaker 03:
The only instruction there was was to conduct a test.

[00:27:37] Speaker 03:
And the type of test that everyone, even Mylan scientists, agreed that was most likely to be done

[00:27:42] Speaker 03:
was a small-scale bench test, testing like Mylan's scientists suggested, spiking and getting a result in a few weeks or a month.

[00:27:52] Speaker 00:
Could you address the derivation argument?

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

[00:27:57] Speaker 03:
So what the court found on derivation was that the letter which Mylan argued at trial, and I guess argues again on appeal, the December 10th letter that requested

[00:28:12] Speaker 03:
justification for EDTA's presence in the composition was really just that, just a request to provide information and not a instruction or direction to generate any test.

[00:28:26] Speaker 03:
The court found significant in looking at that document that a page later the FDA did ask for tests so that that was really not a request when it said please provide justification and a description of its properties.

[00:28:42] Speaker 03:
As a finding of fact, the court read the document and said that that's not a direction to conduct a test.

[00:28:50] Speaker 03:
And it couldn't meet all of the elements of the claim methods for several reasons.

[00:28:56] Speaker 03:
One, it was just a request for justification.

[00:29:00] Speaker 03:
Two, it didn't provide any definition or instruction on how to conduct a test, what test to conduct.

[00:29:07] Speaker 03:
It left much open to the imagination.

[00:29:10] Speaker 02:
Suppose that the FDA had said investigate whether EDTA can be removed and not replaced with any chelating agents.

[00:29:22] Speaker 02:
Suppose that had been the instruction so that it was much clearer.

[00:29:27] Speaker 02:
We want you to investigate whether EDTA can be removed and not replaced with any other chelating agents.

[00:29:33] Speaker 02:
If that had been the FDA mandate, how would this case come out?

[00:29:39] Speaker 03:
Had the FDA said those words that you cannot use any chelating agents?

[00:29:48] Speaker 02:
Because they said the first part.

[00:29:49] Speaker 02:
They just didn't say and replace it with nothing.

[00:29:53] Speaker 03:
Again, in the context of the state of the art, knowing that metal catalysis was such a problem for this composition, for this molecule, a formulation scientist would have looked at other parameters, other

[00:30:06] Speaker 03:
Measures that would have adjusted for finding something for stability since the expectation was you needed something for stability given this particular concentration and pH the Analysis again would have been the same there are multiple options the FDA hasn't given you specific direction The question being asked or is close the direction really was specific You have a product.

[00:30:35] Speaker 01:
It's on the market

[00:30:37] Speaker 01:
Go and test that product with one change.

[00:30:42] Speaker 01:
Take out the EDTA.

[00:30:43] Speaker 01:
Don't put anything else back as a substitute.

[00:30:46] Speaker 01:
Make that one change.

[00:30:49] Speaker 01:
And the FDA is the one who had thought about that, the hypothetical.

[00:30:54] Speaker 01:
Forget about obviousness.

[00:30:57] Speaker 01:
Does that provide a derivation ground?

[00:31:04] Speaker 03:
No, because the FDA could not have appreciated that for these, remember, these are method claims that needs to be stable for human administration.

[00:31:12] Speaker 03:
And given the understanding of the state of the art, that it would not have been stable and a conception requires a conception, an embodiment of all of the elements.

[00:31:23] Speaker 01:
Stable is actually in the claim, is it not?

[00:31:24] Speaker 03:
Yes.

[00:31:25] Speaker 03:
And the stable is in and suitable for IV administration is in the claims.

[00:31:30] Speaker 03:
So it would not have been a full conception of all of the elements since the expectation is without test, without any key leading agents, it would have been unstable and therefore unsuitable for its intended purpose.

[00:31:42] Speaker 01:
So.

[00:31:42] Speaker 01:
And if the FDA had said exactly what we're talking about and said, we're pretty sure this will be stable.

[00:31:53] Speaker 03:
Had they said, we know, in fact, it will be stable.

[00:31:58] Speaker 01:
No, they don't know.

[00:31:58] Speaker 01:
Because for conception, they don't actually have to confirm it, do they?

[00:32:02] Speaker 03:
Had the state of the art been different, and there could have been an expectation that it would have been stable, the answer might be different.

[00:32:09] Speaker 03:
But under these facts, and this record, and this state of the art, that would not have been the expected expectation.

[00:32:16] Speaker 03:
OK, thank you very much.

[00:32:20] Speaker 03:
Thank you for my additional time, Your Honor.

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

[00:32:22] Speaker 02:
Stafford, you will restore your five minutes of rebuttal time.

[00:32:25] Speaker 02:
Thank you very much.

[00:32:26] Speaker 02:
Appreciate that.

[00:32:28] Speaker 04:
So I'd like to start off with the approval letter.

[00:32:30] Speaker 04:
I think there's a misconception.

[00:32:31] Speaker 04:
It's not just an invitation to investigate.

[00:32:35] Speaker 04:
It's actually a commitment that was entered into after a 14-month negotiation between Cumberland and FDA in which Cumberland, and it does call out specifically the test that has to be done, they have to evaluate the potential benefit of EDTA on the stability of the drug product.

[00:32:51] Speaker 04:
was uncontested at trial by Mr. Pavlov and Cumberland that when it talks about the drug product, it's referring to the prior acetate drug product that is the subject of the NDA that was approved.

[00:33:03] Speaker 04:
And so it's saying you have to look at the drug product formulation and you have to compare the stability of that versus a concentration of lower EDTA and no EDTA.

[00:33:15] Speaker 04:
And the fact that that is exactly what the parties understood

[00:33:18] Speaker 04:
is borne out by the actual study that Mr. Pavlov did, and it's also confirmed by the chemistry review, where it says you are to look at the effect of EDTA on the stability in the formulation.

[00:33:30] Speaker 04:
Now, it can't be an invention for Mr. Pavlov, who admitted that the stability study that he designed, that he paid BioNiche to implement, and then he evaluated the studies.

[00:33:40] Speaker 04:
He said none of that is inventive.

[00:33:42] Speaker 04:
And this clearly, to the extent that you believe there's not an express motivation, although we believe there is,

[00:33:46] Speaker 04:
This clearly falls within KSR where there is a market need and a design need and a market pressure that is put forth by FDA saying you need to look at getting rid of and removing EDTA and there's a limited number of options and the most obvious one to try is just to take out EDTA because FDA was aware and by this time the industry was aware that there

[00:34:10] Speaker 04:
There wasn't an issue with metal ions in the Priorart acetidote formulation.

[00:34:14] Speaker 04:
It had specifications.

[00:34:15] Speaker 04:
This metal ions issue was a hearing.

[00:34:17] Speaker 04:
It's not discussed in the assorted patents.

[00:34:20] Speaker 04:
And in fact, if you look at the specifications for the Priorart acetidote product, adding EDTA added more metal ions to the Priorart drug product than everything else combined.

[00:34:30] Speaker 04:
And so if you're concerned about metal ions and you're concerned about adding EDTA and FDA wants it removed,

[00:34:37] Speaker 04:
then the easiest way to do that, the most obvious way to do that, is to take out the EDTA, which includes metal ions.

[00:34:43] Speaker 04:
So it's not just a suggestion.

[00:34:45] Speaker 04:
And they did actually tell them exactly what they did to do, what they needed to do.

[00:34:50] Speaker 04:
Now this suggestion that there was an admission by plaintiff's experts that you could have changed other things and fallen within the commitment that's spelled out in the approval letter, I think that's incorrect.

[00:35:02] Speaker 04:
If you look at that, I believe they're referring to the testimony of Dr. Civalotti, which is at the appendix at A8328 and A8329.

[00:35:11] Speaker 04:
And all he says there is that you could change other things to achieve a stable aqueous acetylcysteine formulation that would be EDTA-free.

[00:35:20] Speaker 04:
He's not being asked about what the approval letter commitment was.

[00:35:24] Speaker 04:
He's just saying there are lots of ways that you can make acetylcysteine EDTA-free.

[00:35:29] Speaker 04:
And that's also supported by a water

[00:35:31] Speaker 04:
Waterman actually lists at page A14428 a list of things that you can do to prevent oxidation for protein products like N-acetylcysteine.

[00:35:45] Speaker 04:
And it talks about the first one is you can store it in the refrigerated conditions.

[00:35:48] Speaker 04:
You can optimize the formulation of pH, which is the second one.

[00:35:52] Speaker 04:
You can apply a nitrogen headspace.

[00:35:54] Speaker 04:
Then it says you can remove excipients that are suspected of introducing transition metals.

[00:35:59] Speaker 04:
All of those first three things

[00:36:01] Speaker 04:
Clearly, the first two are speaking to what was done in the prior acetidote formulation that was controlled for by somebody else that developed that drug.

[00:36:11] Speaker 04:
The removing or replacing excipients that are expected of introducing transition metals tells you that if you want to get rid of EDTA, the most effective and efficient way to do that is just to remove it.

[00:36:21] Speaker 04:
And that also removes your metals and your source of metals.

[00:36:25] Speaker 01:
Can I ask you the most trivial and sensible question, just to confirm something?

[00:36:29] Speaker 01:
Sure.

[00:36:29] Speaker 01:
The district court said at A11 that

[00:36:31] Speaker 01:
The BioNiche was Mylan's predecessor company, is that it?

[00:36:35] Speaker 04:
Yes, that is true.

[00:36:37] Speaker 04:
So the Prior Art Acetidote product that is being talked about here was actually developed by a company that Mylan owns.

[00:36:43] Speaker 04:
It was developed long before Cumberland became involved.

[00:36:47] Speaker 04:
And so as I believe council admitted, the Prior Art Acetidote product included every single element.

[00:36:53] Speaker 04:
It included the method of use, all the components, all the properties of all of the claims of the assertive patents, with one exception.

[00:37:00] Speaker 04:
It omitted EDTA.

[00:37:01] Speaker 04:
And all it did, all that Mr. Pavlov, the alleged inventor, did in response to this commitment that FDA put down in the approval letter, is he told BioNiche.

[00:37:11] Speaker 04:
He said, go make your prior acetidote product exactly like you make it for us, but just don't add EDTA.

[00:37:19] Speaker 04:
And then conduct a stability study, just like you conduct all the other stability studies that you've done in the last decade and that we have made subject to approval, and then send me the results.

[00:37:29] Speaker 04:
And then he testified that he didn't have an invention until he saw those results.

[00:37:32] Speaker 04:
Those are industry standards tests.

[00:37:35] Speaker 04:
It cannot be an invention.

[00:37:37] Speaker 04:
To take the suggestion and the direction and the commitment that FDA gives you, to take out EDTA, to do nothing else, to not create anything, and then to read a stability study to test results three months in and say, gee, I guess it wasn't needed.

[00:37:52] Speaker 04:
I have an invention.

[00:37:53] Speaker 04:
That is not an invention.

[00:37:56] Speaker 02:
OK.

[00:37:56] Speaker 02:
Thank you, Ms.

[00:37:56] Speaker 02:
Stafford.

[00:37:56] Speaker 02:
Thank you, Your Honor.