[00:00:00] Speaker 01:
is case 20-1875, Onyx Therapeutics versus CIPLA Limited.

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Mr. O'William, whenever you're ready.

[00:00:11] Speaker 00:
Good morning, Your Honors.

[00:00:12] Speaker 00:
My name is Gurpreet Singh Balia from the Lawful Facial Boards, representing CIPLA USA and CIPLA Limited.

[00:00:20] Speaker 00:
The 112 Patent Claim Number 31 to Anarchist Formulation... Sir, this is Judge Proce.

[00:00:25] Speaker 01:
Could you speak up just a little?

[00:00:27] Speaker 00:
I'm sorry, Your Honor.

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The 112 patent claim number 31 to an aqueous formulation of carfilzomib is invalid for obviousness double patenting.

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The earlier claim of the 125 patent provided for an aqueous formulation of carfilzomib.

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The district court found that the only patentable distinction in claim number 31 of the 112 patent over the aqueous formulation of the earlier patent was, number one, the specification of a pH of 3.5.

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And number two, the 10 million more concentration of citric acid that achieves that pH.

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The pH of 3.5 is the pH that is necessary to make castlezomib water soluble.

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Mr. Wallia.

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Yes, your honor.

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Thank you.

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In the blue braids at 55 to 57, you argue that formulating zomib at a pH of 3.5

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was obvious because, quote, optimization of pH ranges is routine, first of all, is within the range of what the prior art taught was acceptable for intravenous injection.

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Where'd you make that argument in the record below?

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Your Honor, it was in the

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record below, I can try and find that in a minute.

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But we did cite extensively to the Henderson-Hasselbalch equation, and we used it for the premise that it was a known prior art, the Henderson-Hasselbalch equation was known prior art, and that the use of it was routine.

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The Henderson-Hasselbalch equation has been routinely taught to pharmacy students, and it was well known in the art.

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Mr. Walia, in the gray brief at 13, you argued that the Henderson-Hasselbalch equation allows a person of skill, quote, to see that a pH of 3.5 provides 97% protonation.

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Sorry, Dr. Amidji's testimony at JA 4468.

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But at 4468, counsel asked Dr. Imigi whether a person of skill in the art would, quote, continue to use PHs below 3 if they were formulating carfazomib, to which Dr. Imigi responded, no, not in my opinion, because you are already getting 97% ionization.

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Why didn't we get that complete citation?

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I believe it was in the appendix, Your Honor, but we do refer to it numerous times in the brief submitted to Your Honor.

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And it is actually a fact that at 3.5 pH, 97% of Calfazomib will be solubilized, will be protonated, which will lead to 97% solubilization.

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and that has been referred to extensively in our briefs.

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What Dr. Meaty mentioned about the rule of thumb, about being two, that was just a red herring.

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He did mention that the Henderson-Hesbeck equation has been used extensively, and a person with a skill in the art would use the Henderson-Hesbeck equation, and to go below the PKA to find the optimization

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pH for the solubility.

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The problem of the prior art was solubility, the YU-101, which was the closest compound to it.

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You argue in the blue brief at 14 that Dr. Radewski's testimony that an acid pH below seven would degrade the warhead, you say, quote, was in fact wrong.

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Because, quote, routine testing could easily establish

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that the warhead does not degrade at 3.5 pH.

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Where is that fact that it doesn't degrade at 3.5 pH found in the record?

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Your Honor, it was never disputed by the latest expert claimed that it would disintegrate the epoxy-ketone warhead, but it was never approved.

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The formulation used is 3.5 pH, and that's below the pKa.

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And it does not degrade at that point.

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May I continue, Yana?

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Yes.

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So the pH of 3.5 is the pH that is necessary to make carfazome of water soluble so that it can be made into an aqueous formulation and the citric acid concentration of 10 millimoles if that's needed.

[00:05:43] Speaker 01:
Let me just be, I'm sorry, this is Judge Prouse, but I mean there are several different claims here.

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We've got the compound claims and the formulation claims.

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So the argument, just so I'll be clear, there are a lot of issues in this case.

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The argument you're making on obviousness double patenting goes only to the formulation claim.

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Yes, Your Honor.

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Okay.

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I'd like to address also the compound patents

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The selection of bortezomib was a legal error because there was nothing in the prior art which showed how to improve it.

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It had very serious toxicity problems.

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The elite compound is one that a person of ordinary skill would select as most promising to modify in order to improve upon its activity and obtain a compound with better activity.

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And the hypothetical person of ordinary skill in the art is not an inventor.

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He does not seek to innovate.

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He just follows conventional wisdom.

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He knows all the prior art.

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I take your, I take your points and we've all read your briefs.

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It seems to me that the real hurdle you have in this case is you have a very detailed district court opinion based on a bench trial where he made numerous, numerous findings of fact.

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Now, maybe a reasonable person could have gone the other way too, but that's not sufficient to establish clear error on the part of the district court.

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On this point, for instance, he rejected that POSA would know how to improve YU-101.

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And he also rejected that the only problem with YU-101 was solubility.

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And to be just completely out front with you, I have a hard time seeing how we can dislodge those findings based on his review of the record.

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He disregarded why you want a lead compound because he said it's an irreversible inhibitor.

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But irreversible inhibitors were in the prior rot, and the compound patent suit do mention, they refer to voxymysin, which was in the prior rot, as use, they depend on that as use for anti-cancer treatment.

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So he also disregarded YU-101 as being toxic.

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But there's no, toxicity is not part of the claims.

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It's not part of the claimed invention here.

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So because of that reason, YU-101 should have been at least one compound to have been selected as a lead compound.

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And it was well known in the prior art

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And there was no evidence in the prior art of the bautism which he selected, that there was nothing in the prior art to show that it could be improved.

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So a person who is still in the art would not choose a compound which he could not improve.

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He's not an inventor.

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So he had to have a starting point.

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And a starting point, the most promising starting point was YU-101.

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It was well-known in the art.

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studies showing that it was useful for cancer.

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It was the most potent, it was the most specific compound at the protease inhibitors, as a protease inhibitor.

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And the problem of the solubility was the way to, it had a problem with solubility.

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And the way to overcome the solubility problem was known in the app of using morpholine.

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And morpholine, the district court below accepted as a fact that morpholine

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is a weak base which can be used to help solubility.

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It's known in the prior art in the CPC handbook, and using morpholine was just an obvious way of increasing its solubility.

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And that's the reason why, and attaching it again to the air terminus was the most obvious place to put it, because that was the only place which was most

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was not active in its function.

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The epoxy ketone warhead and the side chains were hydrophobic and they were necessary for its binding to the proteasome.

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So therefore N-terminus being the only logical place to attach this was, and using morpholino as one of the obvious choices of improving solubility would be the way

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for a person or any skill to use it.

[00:10:27] Speaker 01:
Okay, why don't we reserve the remainder of your rebuttal and hear from Mr. Groombridge.

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Thank you.

[00:10:32] Speaker 01:
Thank you.

[00:10:34] Speaker 02:
Thank you, Chief Judge.

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This is Nicholas Groombridge on behalf of ONIX, and I'd like to just pick up with the lead compound issue here.

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So in our view, it is exactly

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as your honor stated, that there are extensive fact findings all amply supported by the evidence.

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And the court would have to find clear error, we believe, as to five separate factual issues in order to find structural obviousness here.

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Those are the selection of the lead compound, the motivation to modify it, specifically where to modify it, the interminus, and what to modify it with a morpholino group.

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whether there would be any reasonable expectation of success, that all of those things are factual questions that were extensively addressed below and resolved by the district court.

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And there's no clear error in that.

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So with respect to the selection of YU-101, the district court noted the facts, the positive attributes that Mr. Wilier mentioned.

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that it was more potent and that it was specific for the so-called CTL site.

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But then went on to address all of the shortcomings that YU 101 had.

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It was not drug-like.

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It was not well-studied.

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There was almost no data on its solubility or bioavailability or stability.

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That even though it had high specificity for the CTL site, that did not necessarily equate to

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specificity for the proteasome.

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In other words, there could very easily be off-tissue targeting where it bound to the CTL site in other undesired places.

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Of course, that it was irreversible and that there was a strong industry prejudice against irreversible molecules.

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And, of course, also low solubility.

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But low solubility was by no means the only shortcoming.

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And the district court made a point of rejecting that argument, which is repeated here throughout the blue brief.

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and said, no, when you view all this on balance, looking at this through the eyes of the person of ordinary skill, then that person would not have selected YU101.

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And it was not only more likely, it was far more likely that the person of ordinary skill would have selected Bortezomib.

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And in addition, even apart from Bortezomib, there were at least three other candidates that would be ahead of YU101 on the list.

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And so in our view, there's simply no clear error in that.

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There's ample evidence.

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And it's correct that YU-101 would not be a lead, that the people who made this invention, Proteolex, were, as the district court pointed out, idiosyncratically motivated because one of their founders was the developer of YU-101 and they had a license to that compound.

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But when you look at the, you survey the art and the knowledge of the person of ordinary skill, you would not have picked YU-101.

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Even if you did pick it,

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you would then need to decide how to modify it.

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And again, there's a factual finding that the N-terminus would not have necessarily have been the logical place.

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There's evidence in the record that it was known in the ARP that modifications at the N-terminus could decrease potency by 90% or perhaps as much as a factor of 30.

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And that if potency was the reason for picking YU101 in the first place, then you wouldn't want to make a modification that severely compromised its potency.

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And these are all fact findings by the district court based on some evidence presented to him, correct?

[00:14:12] Speaker 02:
Exactly, Your Honor.

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Not just some evidence, but these were central disputed issues that were the focal point of the venture.

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Mr. Browridge, before your time runs out, your friend started with the formulation claim and the obviousness double patenting.

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And doesn't it strike you a little strange that pH is enough for patentability here?

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You've got the 125 and pH for that claim would be limited to the 3 to 5 pH range, right?

[00:14:48] Speaker 02:
No, you're right.

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The reference claim in the 125 patent is completely silent about pH, simply doesn't mention it.

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A pharmaceutical composition, so what would the pH for that claim possibly be?

[00:15:04] Speaker 02:
Well, it's unstated.

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And there was evidence that for injectable pharmaceuticals, they can fall in the range 2 to 12, which is, of course, a huge part of the potential range of 0 to 14.

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And so there's a very wide range.

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And once again, and I'm happy to go into this, Your Honor, and also picking up on some of Judge Wallach's questions, in the trial court,

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The argument in support of our business type double patenting was based on this reported rule of thumb that someone would formulate picking a pH that was approximately two pH units below the so-called PKA value.

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And the district court rejected that making credibility determinations and said it simply didn't accept that such a rule of thumb existed.

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On appeal, the argument has now been retold to rely on the so-called Henderson-Hasselbalck equation.

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And as I understand the argument, it is to the effect of, well, if you know the PKA, then you can determine that at a pH of 3.5, 97% of the species would be protonated and therefore soluble.

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Again, one of the flaws, the first flaw in that is that the district court made a fact finding that the person of ordinary school would not know the PKA value for carfilzomib.

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was not known in the prior art.

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The skilled person wouldn't be able to calculate it and would have found it very difficult to measure precisely because carfilzomib is such an unstable molecule.

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And then so if you don't have the pKa value, then the supposed teaching to go to a pH value in the range of 3 or 3.5 just disappears.

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And there was testimony that was credited by the district court that the warhead here

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the part that's going to bind and have the biological effect is an extremely unstable structure.

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It's depicted as a kind of triangular moiety.

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And the chemical bonds are very tightly constrained, also because oxygen is involved there.

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It's vulnerable to hydrolysis.

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And that a skilled person would have strongly believed that this warhead would be unstable in an acidic environment.

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and would have avoided using a pH on the acid side.

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And of course, 3.5 is quite acidic.

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The midpoint is 7.

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And so the skilled person would have tried to formulate in some other way.

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And the district court made an explicit fact finding.

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That's fact finding number 176.

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The person of ordinary skill would have known that there were numerous other solubilization techniques.

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So I think we need to be careful to avoid falling into the

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hindsight trap that pH is the only way to address solubility.

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It's not.

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And even in the reference claim, solubility is addressed by the presence of the cyclodextrin.

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And therefore, we would submit that it's perfectly plausible reading that if a skilled person were presented with the reference claim, that person would conclude that solubility has been addressed not through pH, but through the use of the cyclodextrin whose sole purpose

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is to promote solubility.

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And so we think, again, the district court was abundantly correct.

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There's certainly no clear error in finding that the skilled person would have been concerned about going to a low pH, would have looked for a pH probably in the range 7 to 11 or certainly above 5, and would have used other tools in the toolbox to try to formulate this product.

[00:18:48] Speaker 02:
And so there really is no obviousness type double patenting.

[00:18:52] Speaker 02:
And just to wrap up on that, the way we would look at it, we don't see it as being just about pH.

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We think that the district court correctly found that what's going on here is a formulation taken as a whole.

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And that there are various things working together to make this difficult to formulate molecule actually usable in a pharmaceutical context.

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And that would include the cyclodextrin.

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It would include the selection of the citric acid and so on.

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And we can't be in a place just by saying, well, if some of the elements of the claim were known, therefore, the claim taken as old must be obvious in the district court.

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And have you applied that very longstanding principle correctly to say it's not obvious?

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And so I guess with that, I would pause and see if there are any other areas as to which the court has questions.

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I can certainly go on.

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and address other issues, but I don't want to simply be speaking for the sake of it.

[00:19:59] Speaker 01:
Hearing none, I think we have your argument, Mr. Groombridge.

[00:20:07] Speaker 02:
Thank you.

[00:20:07] Speaker 01:
Great.

[00:20:10] Speaker 01:
Thank you.

[00:20:11] Speaker 01:
Mr. Walia, you've got some time left on rebuttal, please.

[00:20:15] Speaker 00:
Yes, Your Honor.

[00:20:16] Speaker 00:
Can you hear me?

[00:20:17] Speaker 00:
Your Honor, first of all,

[00:20:19] Speaker 00:
regarding bortezomib, it was a legal error because there was nothing in the prior art to guide a person of ordinary scale to select bortezomib.

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There was no way to improve it in the prior art.

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And therefore, selection of bortezomib was wrong.

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Selection of YU-101 was the right selection for a lead compound because of its non-in vivo in vitro properties

[00:20:46] Speaker 00:
and because it was the most specific and most important known in the prior art.

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The fact that it was rejected by the court below was a legal error.

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It was rejected because it was irreversible binder.

[00:21:04] Speaker 00:
In the patent suit, in suits themselves admit there's no data of in vivo function of the compound patents.

[00:21:13] Speaker 00:
They refer back to the prior art

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in 1992 article, which gives the benefits of epoxy mysin, which is the parent compound of YU-101, and it says because that irreversible inhibitor was effective for cancer, therefore, carfilzoma was effective for cancer.

[00:21:35] Speaker 00:
At best, they only talk of an enzyme inhibition test in their compound.

[00:21:43] Speaker 00:
Clearly, YU-101 should have been picked up as at least one lead compound.

[00:21:48] Speaker 00:
The irreversible, excuse me, the insolubility problem of YU-101 was very well known in the art.

[00:21:55] Speaker 00:
The way to solve that problem was well known in the art by using a morpholino substituent at the N-terminus.

[00:22:03] Speaker 00:
N-terminus, and this was acknowledged by the court below, the N-terminus was the most, was the best place to put it at because the epoxy ketone warhead

[00:22:13] Speaker 00:
was used for binding.

[00:22:14] Speaker 00:
The difference between the YU-101 and carfilzomib was, sorry, the difference between epoxy of mycin and YU-101 was that Dr. Cruz had modified the side chains to make them more hydrophobic for attachment.

[00:22:30] Speaker 00:
So therefore that left the N-terminus for attaching the morpholino, which was the obvious choice.

[00:22:37] Speaker 00:
Now regarding the formulation pattern, Your Honor,

[00:22:40] Speaker 00:
The PKA, it's well known that to determine the pH, where the solubility of a compound is going to be, the PKA has to be determined.

[00:22:52] Speaker 00:
Once you determine the PKA, it's simply a matter of plugging in into the Henderson-Hasselbalch equation to see at what percentage you get a high solubility of the aqueous solution.

[00:23:08] Speaker 00:
The second thing is,

[00:23:09] Speaker 00:
Citric acid is added to titrate it to that particular pH.

[00:23:14] Speaker 00:
There's no invention here.

[00:23:16] Speaker 00:
It's using the known elements for the known uses to get to this.

[00:23:22] Speaker 00:
And to use a combination, the quote below also aired by saying, well, all the three things were in this combination.

[00:23:30] Speaker 00:
You're going into an anticipation argument.

[00:23:33] Speaker 00:
The obviousness just requires

[00:23:35] Speaker 00:
you to look at the prior art and see if it's been used for its intended purpose.

[00:23:41] Speaker 00:
And here we believe it was being used for its intended purpose.

[00:23:45] Speaker 00:
And the termination of, oh yeah, and then the fact that the epoxy ketone ring, there was nothing in the evidence which showed, as claimed by the plaintiffs,

[00:24:02] Speaker 00:
that the epoxy ketone ring would break apart at such a low pH.

[00:24:06] Speaker 00:
There was just a claim.

[00:24:07] Speaker 00:
There was no evidence provided that the epoxy ketone ring would break up at 3.5.

[00:24:13] Speaker 00:
So the fact that they're claiming that at 3.5 was some kind of an invention, it's not an invention.

[00:24:22] Speaker 00:
It's just using routine prior art for its usual purposes.

[00:24:31] Speaker 00:
They claim that the pKa was difficult to calculate.

[00:24:34] Speaker 00:
Well, they never showed that it's impossible.

[00:24:37] Speaker 00:
Their expert just said the pKa was difficult to calculate of carfizoma, but it was never shown as such during the trial.

[00:24:47] Speaker 00:
A calculation of pKa is routine, routinely taught to pharmacy students.

[00:24:53] Speaker 00:
Even though if it's difficult, it does not make it impossible.

[00:24:57] Speaker 00:
And it's routinely done to determine

[00:25:00] Speaker 00:
to get to the aqueous formulation of a compound.

[00:25:04] Speaker 00:
So these are unsupported assertions made by the plaintiffs.

[00:25:11] Speaker 01:
The range... You can finish your thought, Mr. Walia.

[00:25:17] Speaker 00:
Thank you, Your Honor.

[00:25:22] Speaker 00:
The plaintiff argues that pH of 3.5,

[00:25:29] Speaker 00:
is some kind of an invention.

[00:25:32] Speaker 00:
It is not.

[00:25:33] Speaker 00:
It's just a pH which is, number one, acceptable for injectables, and it's an optimization using the well-known Harrison-Hasselbalch equation to find at which optimum level the Caffezoma would be soluble.

[00:25:51] Speaker 01:
Okay.

[00:25:51] Speaker 01:
Thank you.

[00:25:52] Speaker 00:
Thank you, Your Honor.

[00:25:52] Speaker 01:
We thank both sides, and the case is submitted.

[00:25:55] Speaker 01:
That concludes our proceeding for this morning.

[00:25:57] Speaker 01:
Thank you all.

[00:25:58] Speaker 03:
Thank you, Your Honor.

[00:26:00] Speaker 03:
The Honorable is adjourned from day to day.