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`571-272-7822
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`Case IPR2015-01117, Paper No. 52
`Case IPR2015-01127, Paper No. 48
`September 9, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`PAR PHARMACEUTICAL, INC.,
`Petitioner,
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`v.
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`HORIZON THERAPEUTICS, INC.,
`Patent Owner.
`____________
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
`____________
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`Held: July 26, 2016
`____________
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`
`
`BEFORE: TONI R. SCHEINER, DEBORAH KATZ, and
`GRACE KARAFFA OBERMANN, Administrative Patent
`Judges.
`
`
`The above-entitled matter came on for hearing on Tuesday, July
`26, 2016, commencing at 10:02 a.m., at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
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`571-272-7822
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`Case IPR2015-01117, Paper No. 52
`Case IPR2015-01127, Paper No. 48
`September 9, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`PAR PHARMACEUTICAL, INC.,
`Petitioner,
`
`v.
`
`HORIZON THERAPEUTICS, INC.,
`Patent Owner.
`____________
`
`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
`____________
`
`Held: July 26, 2016
`____________
`
`
`
`BEFORE: TONI R. SCHEINER, DEBORAH KATZ, and
`GRACE KARAFFA OBERMANN, Administrative Patent
`Judges.
`
`
`The above-entitled matter came on for hearing on Tuesday, July
`26, 2016, commencing at 10:02 a.m., at the U.S. Patent and
`Trademark Office, 600 Dulany Street, Alexandria, Virginia.
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`ELIZABETH J. HOLLAND, ESQ.
`CYNTHIA LAMBERT HARDMAN, ESQ.
`Goodwin Procter LLP
`The New York Times Building
`620 Eighth Avenue
`New York, New York 10018
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`and
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`DAVID H. SILVERSTEIN, M.S., J.D.
`AZIZ BURGY, ESQ.
`Axinn, Veltrop & Harkrider LLP
`114 West 47th Street
`New York, New York 10036
`
`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`APPEARANCES:
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`ON BEHALF OF THE PETITIONER:
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`ON BEHALF OF PATENT OWNER:
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`ROBERT F. GREEN, ESQ.
`EMER SIMIC, ESQ.
`Green Griffith
`455 N. Cityfront Plaza Drive, Suite 3100
`Chicago, Illinois 60611
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`P R O C E E D I N G S
`- - - - -
`JUDGE OBERMANN: Please be seated.
`Good morning and welcome to the PTAB. This is a
`consolidated trial hearing in IPR2015-01117 and IPR2015-01127.
`Petitioner is Par Pharmaceutical, Inc., and Patent Owner is
`Horizon Therapeutics, Inc. I'm Judge Obermann, Judge Scheiner
`is on my right, and Judge Katz is on my left.
`Before we begin, I would just like to remind the parties
`that the hearing is open to the public, and a full transcript of it
`will become part of the public record. When you refer to an
`exhibit on the screen, please state the slide, the exhibit, or the
`page number to which you are referring for the record. That's
`important for clarity in the transcript.
`As you know from our order of July 18th, each party
`has one hour, in total, to present their argument. Because
`Petitioner has the burden to show unpatentability of the original
`claims, there's no motion to amend here, Petitioner will proceed
`first, followed by Patent Owner. Petitioner's counsel may reserve
`rebuttal time and divide the hour of time among the cases as it
`wishes.
`
`Now, in order to keep this case focused on the merits, I
`am going to ask counsel not to interrupt the other side to make
`objections. Any objections should be discussed during your own
`allotted argument time.
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`I have two preliminary matters that I wanted to discuss.
`The first, we sent the parties an email yesterday regarding paper
`47 in IPR '117 and paper 43 in IPR '127. Those are identified in
`our filing system as Petitioner's Reply in Support of the Motion to
`Exclude, but the actual papers appear to be duplicate copies of
`Petitioner's Supplemental Reply to Patent Owner's Corrected
`Response.
`So, as we explained in our email yesterday, Petitioner,
`you may address that issue in your opening argument if you like,
`and, Patent Owner, you may respond during your allotted hour of
`time to the extent that the Petitioner has argued it in their case in
`chief.
`
`The second thing I'd like to do, I want to let you know
`that the Panel has considered the joint objections to
`demonstratives that were filed in both cases. We've determined
`that both parties may use their demonstrative exhibits today. We
`overrule Patent Owner's objections based on the timing of
`service. In that regard, we understand that Petitioner did file what
`they purported to be final exhibits the day before our order
`issued, but our order does trump the timing in this case. So, we
`will let the Petitioner use their demonstratives as served five days
`before.
`
`We take under advisement Petitioner's concerns that the
`Patent Owner's demonstratives include new evidence. We
`routinely disregard new evidence that's inserted into
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`demonstratives. They're not evidence in the trial, and we will
`focus only on content that has been made of record during the
`trial. We're adept at making that distinction. So, for that reason,
`we are not going to exclude any exhibits.
`We will also take under advisement Petitioner's second
`objection to Patent Owner's demonstratives in IPR '127, going to
`the content of slide 19. We will take that objection into account
`when we prepare our final written decision, but, again, Patent
`Owner is free to use slide 19 during the hearing.
`Do we have any questions from either side on either of
`
`those?
`
`MS. HOLLAND: No, Your Honor.
`JUDGE OBERMANN: Okay, thank you. With that,
`let's take a moment for counsel introductions. Who will be
`presenting argument for Petitioner today?
`MS. HOLLAND: Good morning, Your Honor.
`Elizabeth Holland of Goodwin Procter, LLP. We are actually
`counsel for Petitioner Lupin in the joint IPR, but I will be arguing
`today on behalf of both Lupin and Par.
`JUDGE OBERMANN: Okay. And it's Ms. Holland?
`MS. HOLLAND: Yes.
`JUDGE OBERMANN: Thank you very much.
`And for Patent Owner?
`MS. SIMIC: Emer Simic from Green Griffith,
`representing Horizon Therapeutics, Inc.
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`
`JUDGE OBERMANN: Thank you very much.
`Petitioner, would you like to reserve any time for
`rebuttal?
`MS. HOLLAND: Yes. I would like to reserve 30
`minutes for rebuttal.
`JUDGE OBERMANN: Okay. What I am going to do,
`then, is I'm going to allow you to approach the Bench, and for
`both counsel, your time will start when you begin speaking. I am
`going to do is put your time behind me on the clock. So, I will
`set the clock right now for 30 minutes for your opening argument,
`Petitioner.
`MS. HOLLAND: Thank you.
`JUDGE OBERMANN: Okay. When you begin
`speaking, I will start the clock, Ms. Holland. Thank you.
`MS. HOLLAND: Thank you.
`Good morning. The patents at issue in these two IPRs
`relate to what was admittedly a very standard treatment as of
`2008, the use of nitrogen-scavenging drugs to treat urea cycle
`disorders, which I will be referring to as UCDs. There's no
`dispute that the general methods claimed in these patents -- in
`other words, the use of urinary PAGN to select dosages for
`nitrogen-scavenging drugs as claimed in the '012 and the use of
`blood ammonia levels as claimed in the '215 patent -- that those
`were known generally in the prior art as of the priority dates here.
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
`
`
`What Patent Owner claims are really observations that
`the Patent Owner claims to have made based on particular data
`sets from particular patients that were tested in clinical trials.
`Petitioner's IPRs here are rooted in the testimony of Dr. Neal
`Sondheimer, who is an expert in the treatment of UCDs.
`Dr. Sondheimer explains the prior art here from the perspective of
`a person of ordinary skill in the art, which, of course, is what is
`required under the statute and under Federal Circuit law. It's
`telling in this case that Patent Owner did not submit any expert
`evidence, even though there was an invitation to do so in the
`institution decisions in this case.
`I'm going to start by talking about the '012 patent, so if
`we can go to slide 2, please, and let's go to slide 3. Thank you.
`Slide 3 has independent claim 1 of the '012 patent. The '012
`patent is Exhibit 1001. And there is really no dispute here that
`determining a target UPAGN output was known in the art;
`calculating an effective initial dosage of a PAA prodrug selected
`from HPN-100 or PBA or pharmaceutically acceptable salt of
`PBA was also known in the art; and under subpart (c),
`administering the effective dosage of PAA prodrug to the patient
`was also known in the art. That's all conceded in this case.
`The only dispute really relates to the wherein clause you
`see on the screen in independent claim 1, which says that the
`effective dosage of the PAA prodrug is calculated based on a
`mean conversion of PAA prodrug to urinary PAGN of about 60
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`percent. So, the first issue here is, what does "about 60 percent"
`mean.
`
`Can we go to slide 10, please. As Petitioners have
`argued in their papers, the broadest reasonable interpretation of
`"about 60 percent" in this case has to be at least 53 to 67 percent.
`Now, there's no dispute that the upper limit here has to be at least
`67 percent. That was conceded by Patent Owner in their papers,
`and, of course, they had to concede that because the Scharschmidt
`declaration that was submitted during prosecution had the mean
`conversion rate of 67 percent, and based on the information in
`that declaration, the claim of "about 60 percent" was allowed.
`So, certainly, it has to go up to at least 67 percent, but
`this is, of course, a claim term that says "about," which is a
`plus/minus term. If there are seven percentage points above 60,
`there need to be seven percentage points below 60. So, at a
`minimum, the claim has to range from 53 to 67 percent.
`Now, why do I say "at a minimum"? Because when
`you look at the patent, what the Patent Owner observed here in
`these clinical trials and what they attempt to claim in the patent is
`actually a lot broader than 53 to 67 percent. So, for example, if
`we look at the specification -- can we go to Exhibit 1001 at
`lines -- page 14, lines 28 to 29, please. I'm sorry, I wanted to look
`at the patent, Exhibit 1001 at page 14, lines 28 to 29. It's column
`14, lines 28 to 29. I apologize. Sorry for the slight interruption
`here.
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`
`Let me just read it while we wait for that to get on the
`screen. What Patent Owner says in column 14 is it has been
`found that between 50 and 85 percent of HPN-100 is converted
`into urinary PAGN, typically about 60 percent to about 75
`percent, and they refer to this as the conversion efficiency for
`HPN-100 in UCD patients. So, the actual observations that are
`discussed in the specification of the patent, based on what they've
`seen in clinical trials with UCD patients, ranges from 50 to 85
`percent. So, there is really quite a large range, quite a lot of
`intervariability among patients in terms of the percentage
`conversion of PAA prodrugs to PAGN in the urine.
`If we go to column 30 -- again, this is Exhibit 1001 --
`and we look at Example 2, what the patent says is that the mean
`percentage conversion of administered PAA into urinary PAGN
`began was about 75 percent. And can we blow up the table at the
`bottom of the page in the lower right-hand corner, please? So,
`this is the table at the bottom of column 30 of the '012 patent,
`Exhibit 1001. If you look at the line for mean range molar
`percent of dose ammonia scavenge, what you will see there is
`quite a large range of observed rates of conversion from PAA
`prodrug to PAGN, ranging in absolute terms from 58.2 to 85, but,
`of course, with very large standard deviations. So, again, we
`believe that the broadest reasonable construction here has to be at
`least 53 to 67 percent, but actually, based on the specification,
`can be broader than that.
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`
`Now, I'd like to start with Brusilow Exhibit '91. Could
`we go to slide 16, please. Brusilow '91 discusses conversion of
`PAA prodrug to PAGN in a patient with three different dosages,
`and what you can see clearly from Brusilow '91, Table 1, is that
`there was incomplete conversion of the prodrug to PAGN. You
`can see in period one, it was 83 percent; period two, 90 percent;
`period three, 80 percent. So, there is no question, based on the
`testing that was actually done in Brusilow '91, Exhibit 1012, that
`there was incomplete conversion of -- into PAGN in this patient.
`A person of ordinary skill in the art looking at Brusilow
`'91, as explained by Dr. Sondheimer in his declaration, would see
`that there's incomplete conversion here. This is, however, based
`on one patient. The person of ordinary skill in the art is going to
`want to look at the prior art as a whole to determine how much
`variability is there really in these determinations of conversion
`into PAGN, and what the person of ordinary skill in the art finds
`is the Sherwin '19 reference.
`If we can go to slide 19, please. Slide 19 is from the
`Sherwin '19 reference, Exhibit 1016, at page 116. It's Table 1.
`And, again, what we see is a range of conversion percentages into
`urinary PAGN, and you can see it ranges from 49.65 to 67.67.
`So, a person of ordinary skill in the art, looking at Sherwin '19,
`sees about 60 percent conversion within the meaning of the
`claims.
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`
`Dr. Sondheimer explained that a POSA would actually
`understand the percentages in Sherwin to be a little low because
`the subject wasn't dosed throughout the day; and in addition, this
`is a healthy subject, and the person of ordinary skill in the art
`would expect the conversion percentage to be a bit higher in a
`UCD patient.
`But the person of ordinary skill in the art would know,
`based on the Shiple reference, that basically the metabolism in a
`healthy person and in a UCD patient is the same, that the prodrug
`is going to be converted into PAGN in the same way. So, while
`there may be small differences in the amount of the conversion,
`generally the pathway is the same.
`Can we go to slide 25, please. When a person of
`ordinary skill in the art went to the prior art to look at the urinary
`PAGN conversion percentages, they would also see the 2002
`Comte reference, and this is -- on slide 25 is an excerpt from
`Comte, Exhibit 1025 at page 589. And what you see here, again,
`is very similar to what we saw in Sherwin in terms of the
`percentage conversion. What we see here is 53.4, plus or minus
`4.5 percent conversion.
`So, the person of ordinary skill in the art really sees a
`range in the prior art, sees a lot of variability, does see in
`Brusilow '91 the 80 -- approximately 80 to 90 percent; sees in
`other references approximately 53 percent, in Comte as well as in
`Sherwin '19; and understands that the prior art discloses about 60
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`percent as one range in the prior art for the PAGN conversion
`percentage.
`In addition, the person of ordinary skill in the art would
`know about the Simell reference, and this is Exhibit 1005. If we
`could put that up on the screen, please, at page 1121, and can we
`bring up the highlighted portion, please. This, again, is from the
`Simell reference. This reference tested five children who actually
`had UCD disorder. So, we're not talking about healthy patients in
`this reference; we're talking about UCD patients.
`And, again, what we find, very similar to what we saw
`in Sherwin '19, very similar to what we saw in Comte, we see 54
`percent of the PAA was excreted as urinary PAGN. So, the prior
`art really is coming to the consensus -- if you want to use that
`term, that's a term that Patent Owner used in their papers -- but if
`you really want to look at the prior art, the consensus more so is
`that the conversion rate was about 60 percent within the meaning
`of the claims.
`Now, if we can put up on the screen the chart that's on
`pages 6 to 7 of the reply, of Petitioner's reply, and that's paper
`number 30. What you can see here is really a wide -- just putting
`in one place the wide variety of percentages converted to
`UPAGN that we've seen in the prior art. Can we make that a little
`larger, please?
`So, starting with Brusilow '91, we see, as I've discussed
`already, 83 percent, 90 percent, 80 percent. In Sherwin '19,
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`Case IPR2015-01117, Patent 8,642,012 B2
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`again, we have this variability. We go 53 percent, 68 percent --
`can we continue to the next page? Thanks -- 50 percent, 52
`percent, 51 percent. Comte has the 54 percent. And Simell, as
`well, has the 54 percent.
`So, based on the prior art as a whole, we see every
`element of the claims of the patent, the '012 patent. We see,
`based on Brusilow '91, administration to a UCD patient. We see
`conversion rates falling within the claims in many references,
`Sherwin '19, Comte, and Simell.
`I'm going to move on now to the '215 patent, unless
`there are any questions. So, turning to the '215 patent, unlike for
`'012 patent, Patent Owner did give a detailed response on the
`substantive issues in this case in its -- that had been raised in the
`petition. After considering the Patent Owner's arguments and the
`evidence, the Board found that there was a reasonable likelihood
`that the Petitioner would prevail in this case, but the full trial
`record here is very, very similar to what it was at that stage.
`As I mentioned earlier, Patent Owner hasn't submitted
`any expert evidence to rebut anything that Dr. Sondheimer has
`said. So, Petitioners respectfully submit that the Patent Owner
`here has given the Board really no reason to deviate or to come to
`a different decision than the one that was reached at the
`institution stage.
`Can we go to slide 48, please. Slide 48 is independent
`claim 1 of the '215 patent, and these elements are all in the prior
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`art. The Fernandes reference that's discussed in our papers
`teaches measuring a fasting blood ammonia level. It teaches
`comparing the fasting -- I'm sorry, it teaches measuring of blood
`ammonia level, it teaches comparing the blood ammonia level to
`the upper limit of normal, and it teaches administering the
`adjusted dosage of the nitrogen-scavenging drug where the
`dosage is greater than the initial dosage if the blood ammonia
`level is greater than half the upper limit of normal. There's really
`no way to read that reference and not see all those claim
`elements. The one thing that is not explicit in that reference is to
`look for fasting blood ammonia levels, but that was clearly in the
`prior art as well.
`If we turn first -- let's look first a little bit more deeply
`at the Fernandes reference. Can we go to slide 62, please. Thank
`you. So, slide 62 is Figure 17.2 from the Fernandes reference,
`Exhibit 1011, and this is a flow chart that's provided in Fernandes
`to teach persons of ordinary skill in the art how to manage
`treatment of patients with UCD disorders.
`And as Dr. Sondheimer stated, clearly the central
`decision factor here is plasma ammonia. You can see that at the
`top of the decision tree. It's the first thing that the clinician -- the
`person of ordinary skill in the art has to look at, and as
`Dr. Sondheimer says, this Figure 17.2 in Fernandes really does
`give a very realistic picture of how physicians manage patients
`with UCD disorders.
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`
`JUDGE KATZ: Can I stop you and ask you a question
`about the figure? So, the plasma ammonia level is a decision, but
`it seems like you can get to treatment whether you have either
`less than 80 -- whatever it is -- micromoles, molar, or more than
`80. How do you explain that that makes a decision, then?
`MS. HOLLAND: Clearly on the chart, the first thing
`that the physician looks at is the plasma ammonia level. You are
`correct that there are two decision branches there that could go in
`either direction based on the 80, but clearly one of the decision
`branches is based on greater than 80, which is greater than the
`upper limit of normal, which falls within the claim.
`And if you go down -- maybe it's easiest if we look at
`slide 66 to show exactly that particular branch I'm talking about.
`If we go to slide 66, you see the first is a decision point. You see
`one possibility of that first point is greater than 80 micromoles
`per liter, and if you follow that down, one of the outcomes there
`is to increase the level of medicine, of nitrogen-scavenging drug.
`So, while there are different treatment methods within
`this one figure, one of them is one that falls within the claims of
`the patent, and, you know, there can be others on this chart, but
`the question is, is there -- does this chart teach one way of getting
`to the claims in the patents, and it does.
`Can we go to slide 67, please. So, what we've just
`looked at is this method of adjusting dosages based on the
`upper -- above half the upper limit of normal, and as I mentioned
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`earlier, the one thing that's not explicit in Fernandes is this fasting
`blood level, but that's also very clear in the prior art, and as
`Dr. Sondheimer explains, very, very clearly what the person of
`ordinary skill in the art understands based on the prior art and
`based on their clinical practice.
`So, this is from the Blau reference, Exhibit 1006, and as
`Dr. Sondheimer explained, this is a companion reference to the
`Fernandes reference, and this goes towards laboratory diagnosis
`of metabolic diseases. It's a physician's guide not to necessarily
`what happens in the clinic, but what happens in the laboratory.
`And what Blau says is when you are testing for
`ammonia, the precondition is that it's at least four hours after the
`end of the last meal or stopping intravenous AA supply from a
`central vein or artery; in other words, fasting blood levels.
`And this is -- as we've seen in many of the references
`here, it's -- persons of ordinary skill in the art understand that they
`need to monitor these blood ammonia levels for the patient
`consistently, and when they take a specimen from a patient, to
`measure the blood ammonia level. When they do it, they do it in
`a fasting state.
`And if you think about it, that makes a lot of sense, as
`Dr. Sondheimer explained. It's the optimum way to determine
`ammonia level because you don't have the variations in ammonia
`level that happen if you take a sample after a meal, for example.
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`And if you want to be consistent, the way to do that is to take
`fasting blood ammonia levels.
`Can we go to slide 74. Thank you. This is another
`prior art reference that we discussed in our papers, the '859
`publication. It's Exhibit 1008. And, again, this is a method that's
`set forth in the '859 publication for identifying a suitable starting
`dose or a dosage for a UCD patient and adjusting that dosage.
`And if you look at paragraph 98 in Exhibit 1008, the
`'859 publication, what you see is that it clearly states "optionally
`measuring blood ammonia to determine if the initial dosage is
`sufficient to control blood ammonia levels, or to establish a
`suitable average ammonia level." So, a clear teaching here. It's
`one method of practicing what's in the '859 patent, one teaching
`of the '859 patent, is to measure blood ammonia levels to
`determine if the initial dosage is sufficient.
`Can we now go to slide 73, please. In the '859
`publication, what we see is the upper limit of normal described as
`between 26 and 36 micromoles for the subjects, and then it says
`generally below about 40 micromoles. And what we see in the
`prior art is, you know, similar to what we see in the '012 patent in
`terms of conversion percentages, there's variability here. So, in
`other words, if you're looking at a neonate, the upper limit of
`normal is going to be higher. It's going to be maybe in the range
`of 80 micromoles, which is what we saw in Fernandes. If you're
`looking at adults or older children, you are going to see
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`something lower, but that is known and standard to the person of
`ordinary skill in the art, as Dr. Sondheimer explains.
`So, again, based on the '859 publication, Fernandes,
`Blau, we contend here that these claims, the claims of the '215
`patent, are obvious and that they should be cancelled.
`Are there any questions or else I will reserve the rest of
`my time?
`JUDGE OBERMANN: Thank you very much.
`MS. HOLLAND: Thank you.
`JUDGE OBERMANN: So, I am going to put five
`minutes to your rebuttal time, if that's all right.
`MS. HOLLAND: Thank you very much.
`JUDGE OBERMANN: When you are ready, I will start
`your time. I am just going to put the clock up to 60 minutes for
`you.
`
`(Pause in the proceedings.)
`MS. SIMIC: May it please the Board.
`Prior to the inventions that are claimed in the '012
`patent, it is undisputed that physicians were making dosing
`recommendations for patients with urea cycle disorders assuming
`complete or 100 conversion of PAA to PAGN. Now, the inventor
`of the '012 patent discovered, upon analyzing a set of clinical data
`from urea cycle disorder patients, that, in fact, conversion of PAA
`to PAGN was, in fact, incomplete and as low as about 60 percent.
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`
`If I can turn to slide 2. So, the inventor of the '012
`patent, Bruce Scharschmidt, translated his discovery into a
`method of improving dosing in urea cycle disorder patients that
`focused on calculating an effective dose based on that mean
`conversion of PAA prodrug to PAGN of about 60 percent.
`Claim 1 deals with the situation where you're
`calculating an initial dose, whereas claim 8 deals with the
`situation where you are calculating an adjusted dose, and under
`those circumstances, you administer an initial dose, you measure
`the amount of PAGN being excreted by the patient, and then you
`calculate an effective dose based on the amount excreted by the
`patient and bearing in mind the mean conversion data that was
`already known.
`So, there are three primary points I'd like to make in
`response to Petitioner's arguments. The first is -- and turning to
`slide 6. Turning to slide 6, Brusilow '91 actually teaches away
`from the claimed inventions. The express conclusion in Brusilow
`is that conversion of PAA to PAGN is, in fact, complete or nearly
`complete in the patients that he studied.
`Second of all, with respect to claim 8, Brusilow
`specifically did not teach or suggest calculating an effective
`dosage based on the urinary PAGN that was excreted by the
`patient. Instead, he simply predetermined the doses and
`measured how much PAGN came out.
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`
`And finally, a person of ordinary skill in the art would
`not have combined the Brusilow '91 disclosure with Sherwin '19
`for a number of reasons. First of all, Brusilow taught away from
`a combination with an additional reference concerning
`incomplete conversion because it taught the conversion was
`complete; but second of all, Sherwin '19 was, in fact, discredited
`in a later paper by the same author who found that the method of
`extraction of PAGN from the urine was, in fact, unreliable and
`led to incomplete -- or, rather, led to the conclusion of incomplete
`conversion.
`Now, the secondary references that counsel mentioned,
`Comte and Simell, do not cure the deficiencies of Brusilow '91 in
`that respect. They don't contain any relevant disclosure of overall
`PAA to PAGN conversion. And I'll note for the record that the
`Simell reference is, in fact, a reference that was not the subject of
`the institution decision. It has appeared in Petitioner's reply.
`Patent Owner has not had an opportunity to respond to the
`argument based on Simell, and we would object to the use of that
`reference in this IPR.
`Now, moving on to my first point, which is really the
`key to this issue, Brusilow '91 clearly teaches that conversion of
`PAA to PAGN was complete. His conclusion is based on the
`data in his article. The data is not limited to Table 1, which I can
`bring up, but, in fact, was based on the overall data that was
`collected for the individual patient.
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`
`So, just to give the Board a little background on the
`experiment, Brusilow administered 10, 12, and 14 grams of a
`PAA prodrug -- two different drugs, in fact -- to a seven-year-old
`boy and then collected the amount of -- collected urine over 24
`hours as best they could for that patient and measured how much
`PAGN essentially appeared and was recovered from the urine.
`So, with respect to the recovery that was found in the urine that
`was collected, they determined that between 83 and 90 percent
`had been recovered.
`However, that's not the whole story. The reason
`Brusilow concluded that conversion was nearly complete in the
`patient was based upon the fact that no unconverted drug was
`found in the urine. So, less than 1 percent of the dose was found
`unconverted in the urine, and there was no accumulation in the
`overnight plasma for the patient. So, that led Brusilow to his
`conclusion, which was that conversion was, in fact, complete or
`substantially -- or significantly complete, up to 100 percent, in
`that patient.
`So, counsel's argument that Table 1 shows incomplete
`conversion is, in fact, incorrect, and it conflicts with the express
`conclusions in Brusilow '91, which -- if I just may refer to slide
`7 -- Brusilow concludes that phenylbutyrate appears to be
`completely oxidized to phenylacetate and that phenylacetate is
`completely or nearly so conjugated with glutamine, and that
`complete conjugation occurs may be further adduced by the
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`Case IPR2015-01117, Patent 8,642,012 B2
`Case IPR2015-01127, Patent 8,404,215 B1
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`insignificant amount of unchanged drug or their esters
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