UNITED STATES PATENT AND TRADEMARK OFFICE
`_______
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS, INC.,
`Petitioners,
`
`v.
`
`HORIZON THERAPEUTICS, INC.,
`Patent Owner.
`_______
`
`Case No. IPR2016-00829
`Patent No. 9,095,559 B2
`_______
`
`Record of Oral Hearing
`Held: Friday, July 28, 2017
`
`
`
`
`
`
`BEFORE: TONI R. SCHEINER, LORA M. GREEN, and DEBORAH
`KATZ, Administrative Patent Judges.
`
`
`
`
`
`
`
`
`
`_______
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS, INC.,
`Petitioners,
`
`v.
`
`HORIZON THERAPEUTICS, INC.,
`Patent Owner.
`_______
`
`Case No. IPR2016-00829
`Patent No. 9,095,559 B2
`_______
`
`Record of Oral Hearing
`Held: Friday, July 28, 2017
`
`
`
`
`
`
`BEFORE: TONI R. SCHEINER, LORA M. GREEN, and DEBORAH
`KATZ, Administrative Patent Judges.
`
`
`
`
`
`
`
`
`
`
`Case No. IPR2016-00829
`Patent No. 9,095,559 B2
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`APPEARANCES:
`
`ON BEHALF OF THE PETITIONERS, LUPIN LTD. AND
`LUPIN PHARMACEUTICALS, INC.:
` ELIZABETH J. HOLLAND, ESQUIRE
` CYNTHIA LAMBERT HARDMAN, ESQUIRE
` GOODWIN PROCTER LLP
` The New York Times Building
` 620 Eighth Avenue
` New York, New York 10018
` (212) 813-8800
`
`
`ON BEHALF OF THE PATENT OWNER, HORIZON
`THERAPEUTICS, INC.:
` EMER SIMIC, ESQUIRE
` ROBERT GREEN, ESQUIRE
` GREEN, GRIFFITH & BORG-BREEN, LLP
` 455 North Cityfront Plaza Drive
` Suite 3100
` Chicago, Illinois 60611
` (312) 883-8000
`
`
`
`The above-entitled matter came on for hearing on Friday, July 28,
`2017, commencing at 10:00 a.m., at the U.S. Patent and Trademark
`Office, 600 Dulany Street, Alexandria, Virginia 22314.
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`P R O C E E D I N G S
` JUDGE KATZ: Please be seated. Welcome. Good
`morning. This is an oral argument in inter partes review,
`2016-00829. Petitioner is Lupin Pharmaceuticals, and Patent
`Owner is Horizon Therapeutics. I'm Judge Katz, and Judge
`Scheiner and Judge Green are also on the panel.
` Before we begin, a few housekeeping things.
`Hearing is open to the public, and a full transcript will
`become part of the public record. Each party will have
`30 minutes for your arguments in total. Petitioner will go
`first followed by the Patent Owner. And there's no motion to
`amend at issue in this case, so the burden -- Petitioner
`carries the burden, and you may reserve rebuttal time.
` Would you like to reserve rebuttal time?
` MS. HOLLAND: Yes, your Honor. I'd like to
`reserve 15 minutes.
` JUDGE KATZ: 15 minutes. Okay. Thank you.
` All right. Counsel should not interrupt each
`other to make objections. Any objections to demonstratives
`or otherwise should be discussed during your allotted time.
`When you refer to an exhibit, please state the side, the
`exhibit, or the page number that you're referring to, for the
`record so the record is complete and clear.
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` So counsel for Petitioner, can you introduce
`yourself and those with you, please?
` MS. HOLLAND: Yes. Good morning. My name is
`Elizabeth Holland. I'm with the firm of Goodwin Procter here
`for Petitioner. With me is Cynthia Hordman, also with
`Goodwin Procter.
` JUDGE KATZ: Thank you, and for Patent Owner.
` MS. SIMIC: Good morning. Emer Simic from Green
`Griffith and Borb-Breen. With me is Robert Green, the
`counsel for Patent Owner, Horizon Therapeutics.
` JUDGE KATZ: Okay. All right. I think we're
`ready to begin.
` Petitioner, if you'd like to. And -- I'm sorry.
`I have to figure out how to do this. Okay.
` When you're ready to begin.
` MS. HOLLAND: Thank you. Good morning.
` The claims in the ’559 Patent is a prior art drug,
`Glyceryl Tri-(4-phenylbutyrate), also known as HPN-100, for a
`prior art purpose -- maintaining normal plasma ammonia levels
`in patients with urinary cycle disorders.
` Now, the prior art teaching here is really clear
`from Patent Owner's own paper.
` So if we could put up slide 50, please.
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` This is from Patent Owner's response at 39, and
`Patent Owner says clearly, Using nitrogen-scavenging drugs to
`maintain plasma ammonia levels within the normal range has
`therefore been ammonia in the prior art for almost two
`decades.
` So how does the Patent Owner say that the claims
`of this patent, the '559, are different from the prior art?
` If we go to slide 6, it's really helpful to see
`this graphically. So what the Patent Owner says is that the
`prior art taught to adjust the dose of nitrogen-scavenging
`drugs when the plasma ammonia levels go above the upper limit
`of normal, which is the solid red line at the top of the
`chart here -- the graph.
` They say that the claims in this case cover
`adjusting the dose when the plasma ammonia levels go
`somewhere between half the upper limit of normal and the
`upper limit of normal. In other words, a range that abuts
`right up against the prior art range -- the admitted prior
`art range here, above the upper limit of normal. That's it.
`That's what the claimed invention is.
` JUDGE KATZ: So -- what -- there are a lot of
`these sort of words in the claim and in the prior art. What
`is the difference between, Upper limit of normal, and,
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`Normal, and -- can you talk to me about that?
` MS. HOLLAND: Sure. So the upper limit -- I'm
`starting with the upper limit of normal. The upper limit of
`normal would be the upper limit within the normal range, and
`as you've probably seen from the different prior art
`references, that's not a one -- you know, it's not like 40,
`and that's it.
` There's different prior references referring to
`the upper limit of normal in different ways, but that's what
`we're talking about. It's kind of the top of the normal
`range.
` And the prior art, at least according to -- to
`Patent Owner, teaches to administer above that range. And
`their claim here teaches to administer below that range.
`But, as you can see, there's no space between the prior art
`and what the Patent Owner is claiming here.
` So, you know, even if the Patent Owner were to
`correct on what the prior art teaches -- and I'm going to get
`to that in a minute -- and they're not, but even if they
`were, just on this basis of the abutting ranges here, the
`claims in this case should be found obvious.
` Now, getting to the prior art, the Patent Owner is
`incorrect when it says that the prior art was limited to
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`dosing only when the plasma ammonia was above the upper limit
`of normal. And there are references that make this clear.
`The references that are clear -- that patients were being
`dosed even when their plasma ammonia levels were within the
`normal range.
` So if we could start by going to slide 47 --
` JUDGE KATZ: So the normal range is below what was
`just on the graph there?
` MS. HOLLAND: The normal range is below the solid
`red line that was on top of the graph.
` JUDGE KATZ: Possibly considerably below, because
`that was the upper limit of normal, and there's half of the
`upper limit. There's, like, a range. That's the upper limit
`of normal, and then there's the range that's normal? Is
`that --
` MS. HOLLAND: There's a range -- anything below
`the upper limit of normal is normal.
` JUDGE KATZ: Okay.
` MS. HOLLAND: So I mean, I think that's the way
`the prior art views this -- is that there's the upper limit
`of normal, and you're either above or below it.
` JUDGE KATZ: Okay.
` MS. HOLLAND: And those are the two choices. So
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`that's why I say it's an abutting range. I mean, there's
`above and below, and there's no space, as I said, between the
`prior art and what's been claimed here.
` JUDGE KATZ: Okay.
` MS. HOLLAND: If we look at slide 47, there are
`two references mentioned in the '859 -- in the Berry
`reference. And what's interesting about the '859
`publication, which is our key prior art reference here, is
`that there is this distinction in the language in the
`specification between, Normal, and, Desired ammonia levels.
` So it's clear from the patent that there's -- you
`can be within the normal range, but there can be a desired
`level even within the normal range. If it is only normal,
`then it would just say, Normal. But it says, Normal, or
`Desired.
` And if we go to figure 12 of the '859 Patent,
`which is Exhibit 1007 and it's slide 38, you can really see
`this very explicitly from this graph that's in the '859
`Patent.
` What we have here on the screen is Exhibit 12.
`It's part of the Example 3 that's contained in the '859.
`Example 3 is on page 32 of Exhibit 1007, and it starts at
`paragraph 195.
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` What you can see clearly from this chart is that
`you have patients here. There are a number of patients that
`were being dosed in this study. Several of them were
`underneath the upper limit of normal, and they were being
`dosed. So you can see, for example, there are patients at
`the lower end. They're 20 or below. That's indisputably
`below the upper limit of normal in this case. They're being
`dosed; they're being given drugs. There's an explicit
`teaching in the prior art to dose even when you're below the
`upper limit of normal.
` And that is exactly what Dr. Vaux said in his
`declaration. He said that sometimes patients are treated
`with nitrogen-scavenging drugs, even though they are still in
`the normal range.
` Can we see slide 27, please?
` So this is what Petitioner's expert, Dr. Vaux,
`said. It's his declaration paragraph 51: A POSA would have
`the desire to maintain the patient at normal ammonia levels
`and would have known that variation in ammonia levels due to
`time of day and/or ingestion of food would potentially take
`the patient outside of normal levels.
` So in other words, if you want a patient to be
`maintained within normal levels, you are sometimes going to
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`have to dose when they're in the normal range, because the
`prior art is clear -- and I'll get to that in a moment -- but
`there's a lot of variation in ammonia levels over the course
`of the day based on things like how -- when the patient ate.
` If the patient ate protein, there's going to be a
`spike or a rise in the ammonia level over the course of the
`day. So if you want to keep the patient within the normal
`range, you are going to have to sometimes dose when the
`patient is still in the normal range to account for things
`like the patient may be eating in an hour. The patient might
`be at a different time of day where there's a different
`ammonia level.
` So if we look at the second bullet point on slide
`27, Dr. Vaux says: For a patient with fasting plasma ammonia
`levels approaching the upper limit of normal, a POSA would be
`motivated to increase the dose of the drug to lower the
`patient's baseline ammonia to ensure that the patient
`routinely stayed within normal plasma ammonia limits. If we
`think back to the graph that I had up earlier --
` Make sure we can put back up 6 --
` -- it's not hard to see how if you want the
`patient to stay at that -- you know, underneath that red
`line, and if they're right up again and approaching the red
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`line, and you have to assume they're going to be eating at
`some point during the day, you're going to have to dose when
`they're below the red line to make sure that they stay within
`the red line.
` Now, if we go to -- back to slide 47, the second
`bullet point there is from the Berry reference, another prior
`art reference, which also teaches to dose even when patients
`are within normal levels. What the Berry reference says --
`and it's Exhibit 1016 on page 4 -- is that if the patient has
`an acquired illness, ammonia-scavenging (sic) drugs should be
`administered if the plasma ammonia level is less than 100
`micromoles per liter.
` Now, the Patent Owner has, we believe,
`misinterpreted what the prior art says. They interpret this
`to say that you dose if it's greater than 100 micromoles per
`liter. But actually, when you look at the words in the
`reference, what the reference is saying is, If the plasma
`ammonia level is below 100 micromoles per liter anywhere
`within the range below, you should be dosing the patient if
`they have some kind of acquired illness.
` So that is the specific circumstance in the prior
`art where there's a teaching to dose within the -- the normal
`range, even if the plasma ammonia levels are within the
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`normal range.
` And I wanted to just talk very briefly about some
`of the references that really show this concept of the
`fluctuation of the plasma ammonia levels.
` So if we can put up slide 24.
` This is from the Blau reference. It's
`Exhibit 1006. And this talks about the reference values for
`ammonia level. But just to be clear, this is Exhibit 1006 at
`page 268 and Table 11.5.
` And if you look at the marks section, it says,
`Postprandially -- in other words, after eating -- 30 to 60
`micromoles per liter higher, depending on time and nitrogen
`load.
` So it very clearly says in this reference there's
`a huge fluctuation sometimes after eating. And so if you
`want to stay below the upper limit of normal, in that healthy
`range, you're going to have to dose sometimes within the
`healthy range to make sure that when you start eating you
`stay within that healthy range.
` Can we now -- let's go to slide 25.
` Sorry. It's a little hard to see. But this is
`from the Levin reference, Exhibit 1017 at 164, Table 2.
`Again, it's showing how the plasma ammonia levels fluctuate
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`with food intake. And just one more reference on slide 26,
`the Barsotti reference -- it's Exhibit 1015.
` Barsotti is quite explicit that there's a diurnal
`variation in blood ammonia levels and the results may differ,
`for example, depending on whether the sample was obtained
`before or after a meal.
` So these three references -- they're in our
`papers. They really make clear this point that there's a
`variation. You have to compensate for that variation by
`sometimes administering nitrogen-scavenging drugs even when
`the patient is already within the normal range.
` Now, the Patent Owner disputes that a POSA would
`have wanted to maintain normal plasma ammonia levels
`throughout the day, but there really is an explicit teaching
`in the '859 Patent that you do want to maintain these plasma
`levels throughout the -- normal plasma levels throughout the
`day.
` This is in our reply on page 3, but it's paragraph
`46 in the '859 Patent that says explicitly that you want to
`maintain a stable level of plasma ammonia. And paragraph 182
`from the '859 talks about -- similarly talks about achieving
`and maintaining -- importantly, maintaining -- normal plasma
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` I'd like to touch briefly for a moment on Claim 5,
`which is one of the -- the claims where Patent Owner has
`argued separately for patentability.
` And let's put up slide -- Claim 5 on the screen,
`slide 35.
` So if we look at dependent Claim 5, what it says
`is that the method of Claim 4 further comprising repeating
`steps until the subject exhibits a fasting plasma ammonia
`level at or below half the upper limit of normal for plasma
`ammonia level.
` And that's what Patent Owner points to in this
`claim -- achieving the level at or below half the upper limit
`of normal for plasma ammonia level.
` First of all, if we go back to Figure 12 of the
`'859 Patent -- that was slide 38 -- although it's a little
`hard to see again, this -- at least one of the patients here,
`you can see, goes from a level of 70. It's the patient with
`the X, patient 1006. Goes from a level of about 70 down to a
`level below 10, which is less than half the upper limit of
`normal. So there is a teaching in the prior art of dosing a
`patient to a level below half the upper limit of normal.
` In addition, the prior art taught, generally, to
`maintain plasma ammonia levels below the upper limit of
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`normal; in other words, within a normal range. As I said
`earlier in response to a question from Judge Katz, that's the
`entire range below the upper limit of normal, and it
`includes -- it necessarily includes what is claimed here.
` What Patent Owner has done is taken the prior art
`range of, Below the upper limit of normal -- trying to keep a
`patient within the normal range, below the upper limit of
`normal -- and chose a specific piece within that range to
`claim.
` That is generally presumed to be something that is
`obvious. There has to be some showing of unexpected results,
`which we don't have in this case. And I would cite the
`federal circuit cases of Iron Grip and In re Peterson on that
`point. It cannot be separately patentable if it's within the
`prior art range and there's no showing that there's anything
`special about that range, as compared to the rest of the
`prior art range.
` JUDGE KATZ: Okay. Thank you.
` MS. HOLLAND: I think I have 37 seconds, so I'll
`sit down.
` JUDGE KATZ: Patent Owner?
` MS. SIMIC: Your Honors, may I approach with
`copies of the demonstrative slides? Would you like copies?
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` JUDGE GREEN: We have them already.
` JUDGE KATZ: We have them electronically. Have
`both sides given copies to the court reporter?
` MS. SIMIC: That's right.
` MS. HOLLAND: Yes.
` JUDGE KATZ: Okay. Ready?
` MS. SIMIC: May it please the Board.
` There are three fundamental deficiences in Lupin's
`petition that I'd like to address today. First is that Lupin
`has failed to demonstrate any motivation to pursue the
`methods disclosed in the patent claims, because normal plasma
`ammonia was not recognized as a problem to be solved in the
`prior art.
` Secondly, Lupin has failed to identify any
`objective evidence in support of its theory of obviousness.
`In fact, the '859 publication, its primary prior art
`reference, actually contradicts its theory.
` And finally, Dr. Vaux, Lupin's expert -- his
`testimony should not guide the Board in this instance,
`because it conflicts with the prior art and lacks any support
`and does not reflect the views of a person of skill.
` Now, if I could have slide 7. To my first point,
`let's take a step back and examine the state of the art prior
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`to September 30, 2011, which is the prior art date of the
`’559 Patent. Now, as the Board is well aware, urea cycle
`disorders are a rare, complex genetic disorder, and treatment
`of these patients is difficult. And that was true prior to
`2011.
` Prior to 2011, patients had been treated with
`nitrogen-scavenging medications -- excuse me -- medications
`for more than 20 years. And the variability of ammonia
`levels was known for those patients for just as long. But in
`all that time, nothing in the prior art taught or suggested
`that there was a problem with normal plasma ammonia levels.
`Indeed, the contrary was the case.
` Now, Dr. Enns, Horizon's expert and a recognized
`expert in urea cycle disorder treatment, testified that --
`with respect to the prior art -- because treating a patient
`with urea cycle disorder involved a difficult balance between
`diet, ammonia acid supplements, nitrogen-scavenging drugs,
`and the patient's health, the prior art viewed a subject with
`a normal plasma ammonia level as a rousing success.
` JUDGE KATZ: How would you achieve a normal plasma
`ammonia level if you didn't treat when you were about to be
`outside of the normal plasma -- of the normal level? Would
`you wait until the patient was -- it's the word, Normal, that
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`I have problems with. If the patient was about to not be
`normal, why wouldn't you treat them?
` MS. SIMIC: Your Honor, the prior art did not draw
`a bright line for dosage adjustment at the upper limit of
`normal as suggested by Petitioner. Instead, the prior art
`tolerated variability in ammonia levels that actually brought
`patients somehow above the upper limit of normal, because
`there are those variability -- or that variability to be
`acceptable because it wasn't dangerous for those patients.
` JUDGE KATZ: So sort of the, Above the upper limit
`of normal, is normal?
` MS. SIMIC: Indeed.
` JUDGE KATZ: That's kind of the argument?
` MS. SIMIC: If I may just turn to the testimony of
`Dr. Enns on that point. It's at slide -- slide 17.
` Now, Dr. Enns testified that with these patients,
`because of the difficulty of controlling the ammonia levels
`and difficulty treating these patients, acceptable plasma
`ammonia levels often included those two to three times the
`upper limit of normal. Dr. Enns' testimony is supported by
`the prior art.
` Two references that Lupin fails to address
`anywhere in its papers and that its expert failed to address,
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`both teach that the aim of long-term therapy with these
`patients has been to maintain metabolic control with plasma
`ammonia concentrations less than twice normal. So there's a
`clear recognition in the prior art that the Petitioners
`ignore that at levels above the upper limit of normal were
`actually deemed to be acceptable.
` Now, if I could have slide 18 --
` JUDGE KATZ: But it does say, Less than twice
`normal or -- I can't see what the other one is. But, Less
`than twice normal, includes, Below normal; is that correct?
` MS. SIMIC: Indeed. Normal ammonia levels,
`without any specificity as to a -- without any distinction as
`to a specific range within normal were all considered
`indicative of highly effective treatment for these patients.
` So if a patient had a lower or a higher level of
`ammonia within the normal limits, that was considered a
`rousing success and indicative of highly effective treatment
`in the prior art. And I think --
` Actually, slide 19, please.
` A good example of this is the disclosure in the
`Häberle reference concerning treatment based on ammonia
`levels. And Dr. Enns testified that Häberle exemplifies
`prior art treatment practices with respect to urea cycle
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`disorder patients. And what we can see from Häberle is it's
`telling here and directly contradicts Lupin's theory, because
`there is no suggested action to take for a patient who has a
`normal plasma ammonia level.
` In fact, even when the plasma ammonia level rises
`above the upper limit of normal, Häberle, again, does not
`suggest any action to take it with respect to dosing.
`Instead, it's just that other treatment adjustments may be
`made, such as restricting protein intake or administering IV
`glucose.
` Now, consistent with Dr. Enns' testimony, only if
`ammonia levels are greater than 100 micromoles per liter,
`well above -- in fact, often two times above the upper limit
`of normal, does Häberle suggest that dosage adjustment or
`administration of a dose needs to be performed in these
`patients.
` JUDGE KATZ: So --
` MS. SIMIC: And so -- pardon me?
` JUDGE KATZ: I guess a lot of our argument is
`based on expressly what the prior art says. But this is a
`question of obviousness.
` So is there a way to sort of bridge what the prior
`art says to what one of skill in the art would have found
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`obvious even if it's not expressly taught in the prior art?
`Because it doesn't really have to be.
` MS. SIMIC: Understood, Your Honor. This is a
`situation where the Petitioners have not made out a prima
`facie case of obviousness, because there was no known problem
`to be solved in the art with respect to normal ammonia
`levels.
` If I may have slide 4, we've provided a graphic
`depiction of the range -- the target range for dosage
`adjustment as set out in the ’559 Patent. And as we can see
`here, what the inventors of the ’559 Patent discovered is
`that the -- a patient having a fasting plasma ammonia level
`greater than half the upper limit of normal but less than the
`upper limit of normal -- that patient's ammonia level was not
`good enough. That patient's ammonia level actually needed to
`be reduced to below half the upper limit of normal.
` The inventors found out that those patients,
`indeed, were at risk, and the prior art disclosed nothing
`concerning a disadvantage or a concern about having a normal
`plasma ammonia level. Instead, it was indicative of highly
`dosing.
` JUDGE KATZ: So let me ask you the same thing that
`I asked Petitioner's counsel.
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` What is the difference between, The upper limit of
`normal, and, Normal?
` MS. SIMIC: The upper limit of normal is a
`laboratory value that's determined for a given -- when a
`patient is -- when an ammonia level is measured for a
`patient, the laboratory provides an upper limit of normal
`based on the age of the patient and the sex of the patient.
`And that number can vary.
` And in general terms, upper limit of normal refers
`to the highest level within the range of normal. And we
`don't disagree that -- with Petitioners about the definition
`of the upper limit of normal. What we disagree about was
`what was acceptable in the prior to when it came to --
` JUDGE KATZ: But what about, Normal? What about
`the definition of, Normal? Is, Normal, anything that's even
`de minimus below the upper limit of normal? Or do you have
`some other understanding of, Normal?
` MS. SIMIC: No. The understanding of, Normal,
`when we use it, refers to the -- if we say the upper limit of
`normal -- the highest range within normal levels.
` And our position is that normal or near normal --
`so meaning levels above the upper limit of normal were also
`acceptable in the prior art because they weren't considered
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`dangerous for these patients. And, in fact, patients were so
`difficult to control -- their ammonia levels were so
`difficult to control with nitrogen-scavenging medication,
`that levels that were even above the upper limit of normal
`were considered acceptable. And that's exemplified by the
`Häberle reference that we just discussed, Exhibit 2019.
` Now, if I may address Lupin's primary prior art
`reference, which is -- let's turn to slide 9.
` Lupin's primary reference in the prior art is the
`'859 publication, which is actually authored by the same
`individual as the inventor of the ’559 Patent. The teachings
`of the '859 publication are directly contradictory to Lupin's
`theory of obviousness here. Because the '859 publication
`teaches, without qualification, that a plasma ammonia level
`that was normal would indicate that treatment was effective
`and that plasma ammonia levels are acceptable when they're at
`or below a level considered normal for the subject.
` And Dr. Enns' testimony was that these teachings
`are directly counter -- or increasing the dose, rather, when
`plasma ammonia levels were within normal limits for these
`patients -- that's directly countered to these teachings in
`the '859 publication. And Dr. Enns' testimony on this point
`is it's unrebutted by Dr. Vaux's.
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` Next slide, please.
` Now, the '859 publication does acknowledge that
`ammonia levels vary for these patients. And, in fact, it
`acknowledges that ammonia levels vary a good deal even when
`relatively well controlled based on meal timing, drug timing,
`and various other factors.
` But even with that knowledge in this 2010
`publication, the authors only suggested that ammonia -- that
`dosing may need to be increased if ammonia control is
`inadequate. And in this instance, both experts agree that,
`Inadequate, here is confined to levels above normal for these
`subjects.
` Next slide, please.
` Now, Lupin has suggested that the '859 publication
`would have motivated a person of skill in the art to pursue
`lower levels within the normal range, including at or below
`half the upper limit of normal. But that's not disclosed in
`the '859 publication. In fact, the clinical study in the
`'859 publication directly contradicts Lupin's theory.
` Example 3 discusses 10 patients who were stable
`patients. That were being administered nitrogen-scavenging
`medications. And after one week's treatment with either
`sodium phenylbutyrate or HPN-100, which is glyceryl
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`phenylbutyrate, those patients had plasma ammonia
`measurements determined.
` And the results are telling here, because 9 out of
`10 of those patients had ammonia levels that were above half
`the upper limit of normal. 4 out of 10 were even above the
`upper limit of normal. At the same time, the study authors
`were aware that the maximum daily ammonia levels for these
`patients were well above the upper limit of normal. In fact,
`for 9 out of 10 they were above, and for 4 out of 10 they
`were more than two times the upper limit of normal.
` But with that information, the study authors
`concluded that those patients were well controlled. In fact,
`had superior ammonia control to the patients tak
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