`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner,
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`Patent Owner.
`
`_____________________
`
`Case IPR2017-01768
`Patent 9,095,559
`_____________________
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
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`
`
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`
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`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`

`

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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1 
`The Board’s Findings in the Previous IPRs of the ’215 and ’559
`Patents Apply To the ’559 Patent. ................................................................... 2 
`  The Claims In Each Ground Rise and Fall Together. ..................................... 4 
`  The Board Need Not Construe “Upper Limit of Normal”. ............................. 4 
`Claims 1, 2, 4, 7-10, 12 and 13 Are Invalid for the Reasons Set Forth
`in Ground 1. ..................................................................................................... 5 
`Fernandes, the ’859 Publication, Lee and Lichter-Konecki
`Disclose All Claim Limitations. ............................................................ 5 
`The Prior Art Teaches and Suggests Increasing Drug
`Doses for Patients Having “Normal” Ammonia Levels. ............ 5 
`Horizon’s Arguments Are Premised on an Erroneous
`Claim Construction That Is Contrary to the Plain
`Language of the Claims. ............................................................. 8 
`The Prior Art Teaches and Suggests Using “Fasting”
`Plasma Ammonia Levels for Determining Drug Doses. ............ 9 
`The Prior Art Does Not Teach Away From Using Plasma
`Ammonia Levels in Therapeutic Decision-Making. ................ 12 
`Horizon Exaggerates the Risk of Overdose. ....................................... 16 
`The Prior Art Provides a Reasonable Expectation of Success. ........... 18 
`  Claim 5 is Obvious for the Reasons in Ground 2. ......................................... 20 
`The Prior Art Would Have Motivated a POSA to Target a
`Fasting Plasma Ammonia Level Below One-Half ULN. ................... 20 
`A POSA Would Have Had a Reasonable Expectation of
`Success in Obtaining Fasting Plasma Ammonia Level Below
`One-Half ULN. .................................................................................... 24 
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`i
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`
`  Claims 3, 6-9, 11, 14 and 15 Are Invalid for the Reasons Set Forth in
`Grounds 3 and 4. ............................................................................................ 26 
`  Dr. Sondheimer’s Opinions Are Admissible. ................................................ 28 
`
`ii
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`
`INTRODUCTION
`The ’559 patent claims were already found unpatentable by the Board in
`
`
`
`
`
`Lupin Ltd. v. Horizon Therapeutics, Inc., IPR2016-00829, Paper 42 (P.T.A.B.
`
`Sept. 26, 2017) (“the Lupin IPR”), and are essentially identical to those found
`
`unpatentable by the Board in Par Pharmaceutical, Inc. v. Horizon Therapeutics,
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`LLC, IPR2015-01127, Paper 49 (P.T.A.B. Sept. 29, 2016). As explained in Par’s
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`Petition and in those prior decisions, the art prior to the filing of the ’559 patent
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`disclosed that medical professionals diagnosing and treating patients with urea-
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`cycle disorders (“UCDs”) obtained fasting plasma ammonia levels and compared
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`those levels to an upper limit of normal (“ULN”) for plasma ammonia to make
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`dosing decisions. Those dosing decisions include adjusting a subject’s dosage if its
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`fasting plasma ammonia level was between one-half ULN and ULN. The prior art
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`teaches or suggests each element of the ’559 patent claims and thus renders them
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`obvious.
`
`Horizon’s Patent Owner’s Response relies on legally and factually flawed
`
`arguments that do not rebut Par’s showing that the challenged claims are
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`unpatentable. Indeed, Horizon relies on arguments already twice rejected by the
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`Board in previous IPRs involving the ’559 patent family. Horizon should not be
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`allowed to advance these arguments a third time. Horizon additionally ignores the
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`
`
`1
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`

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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`
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`express disclosures of the prior art, relies on a misreading of the claims that
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`excludes using biomarkers other than plasma ammonia levels to make dosing
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`decisions, relies on inaccurate assertions of teaching away, and meritless attacks on
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`Dr. Sondheimer’s testimony.
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`For these reasons, and for the reasons discussed in the Petition,
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`Dr. Sondheimer’s declarations, and below, Par respectfully submits that the Board
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`should find each of the ’559 patent claims unpatentable as obvious.
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`
`
`THE BOARD’S FINDINGS IN THE PREVIOUS IPRS OF
`THE ’215 AND ’559 PATENTS APPLY TO THE ’559 PATENT.
`Horizon alleges that the Board’s findings in the Final Written Decision
`
`regarding the unpatentability of the ’215 patent (IPR2015-01127, Paper 49) are not
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`applicable to this proceeding because the ’215 patent does not concern drug
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`adjustments for patients having plasma ammonia levels between one-half ULN and
`
`ULN. (Paper 22, 16-17.) But, Horizon does not challenge that, other than this one
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`limitation, the steps of the claims in the ’215 and ’559 patents are essentially
`
`identical, as set forth in Par’s Petition.
`
`Horizon fails to provide any reason why it should not be bound by the
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`previous IPR decision. Nor can it, because it is estopped from doing so. In re
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`Freeman, 30 F.3d 1459, 1465 (Fed. Cir. 1994); Webpower, Inc. v. WAG
`
`Acquisition, LLC, IPR2016-01239, Paper 21, 27-28 (P.T.A.B. Dec. 26, 2017)
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`
`
`2
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
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`(applying collateral estoppel based on prior Board decision in an earlier IPR); 37
`
`C.F.R. 42.73(d)(3). First, in the ’215 IPR proceeding, the Board resolved identical
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`issues to those in this case, namely whether (1) Fernandes and the
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`’859 Publication teach making dosing decisions based on plasma ammonia levels
`
`and ULN; (2) Simell and Blau teach measuring fasting plasma ammonia levels; (3)
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`a POSA would have relied on fasting plasma ammonia levels to adjust doses; and
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`(4) a POSA would have combined Fernandes, Blau, Simell, and the ’859
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`Publication. (IPR2015-01227, Paper 49, 6-12, 15-20.)
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`Second, after Par’s Petition was filed, the Board issued its Final Written
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`Decision in Lupin’s IPR (IPR2016-00829, Paper 42), finding the
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`’559 patent claims unpatentable as obvious over Blau, Simell, the ’859 Publication,
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`and Brusilow ’84. In that proceeding, the Board found that (1) the ’859
`
`Publication teaches making dosing decisions based on plasma ammonia levels and
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`ULN; (2) maintaining normal plasma ammonia levels was a goal in the art; (3) a
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`POSA would have sought to achieve plasma ammonia levels below ULN because
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`doing so would result in effective treatment; (4) Simell and Blau teach measuring
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`fasting plasma ammonia levels; and (5) a POSA would have combined the ’859
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`Publication, Simell, and Blau with a reasonable expectation of success in achieving
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`
`
`3
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`

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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`
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`the methods claimed in the ’559 patent. (Id., 9-29.) Those findings are antithetical
`
`to Horizon’s assertions in this IPR.
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`These were disputed issues that were resolved in a final written decision,
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`which means Horizon had a fair opportunity to litigate them. (IPR2015-01227,
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`Paper 49, 6-12, 15-20; IPR2016-00829, Paper 42, 9-29.) Thus, Horizon’s attempt
`
`to resurrect resolved disputes should be rejected. Webpower, IPR2016-01239,
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`Paper 21 at 27-28; 37 C.F.R. 42.73(d)(3).
`
` THE CLAIMS IN EACH GROUND RISE AND FALL TOGETHER.
`Horizon does not separately argue the patentability of the claims challenged.
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`As such, the claims in each individual Ground rise and fall together.
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` THE BOARD NEED NOT CONSTRUE “UPPER LIMIT OF NORMAL”.
`Horizon asks the Board to construe the term “upper limit of normal.”
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`(Paper 22, 15-16.) The Board need not construe this term to resolve any dispute,
`
`as each of the Grounds are predicated on prior art that teaches plasma ammonia
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`levels below ULN—under any reasonable construction. Par does not concede that
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`Horizon’s proposed construction is correct for purposes outside this proceeding.
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`
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`4
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
` CLAIMS 1, 2, 4, 7-10, 12 AND 13 ARE INVALID
`FOR THE REASONS SET FORTH IN GROUND 1.
`
`Fernandes, the ’859 Publication, Lee
`and Lichter-Konecki Disclose All Claim Limitations.
`Horizon does not dispute that the prior art discloses most limitations in the
`
`claims challenged in Ground 1 as described in Par’s Petition. Horizon’s dispute
`
`regarding the disclosures of the prior art is limited to two limitations: (1) adjusting
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`doses in patients who have plasma ammonia levels between one-half ULN and
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`ULN; and (2) using “fasting” plasma ammonia levels in making decisions about
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`drug dosing.
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`
`
`The Prior Art Teaches and
`Suggests Increasing Drug Doses for
`Patients Having “Normal” Ammonia Levels.
`Fernandes expressly discloses that even if a patient has “normal” plasma
`
`ammonia levels below 80µmol/L, high glutamine levels would signal imminent
`
`risk of becoming unwell, and thus advises to “↑medicines” (i.e., increasing the
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`dosage). (EX1015, 220; EX1002, ¶59; EX1028, ¶5.) Although Horizon alleges
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`that Fernandes discloses only a single ULN of 50µmol/L (Paper 22, 23), Fernandes
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`expressly discloses that “[h]ealthy neonates have slightly higher values.”
`
`(EX1015, 217; EX1028, ¶5.) Blau describes hyperammonemia as being “plasma
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`ammonia >80 in newborns or >50 µmol/L after 28 days postnatally.” (EX1006, 5;
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`
`
`5
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
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`EX1028, ¶5.) Thus, a POSA would understand that 80µmol/L in Figure 17.2 is a
`
`reasonable ULN for some patients, e.g. newborns. (EX1028, ¶5.)
`
`Even if the ULN in Fernandes is 50µmol/L, the below 80µmol/L range in
`
`Fernandes’s Figure 17.2 fully subsumes “normal” plasma values. In view of the
`
`overlap of ranges between the prior art (below ULN) and the challenged claims
`
`(between one-half ULN and ULN), the claims are presumptively obvious. See,
`
`e.g., In re Applied Materials, Inc., 692 F.3d 1289, 1295 (Fed. Cir. 2012). Horizon
`
`has nowhere come forward with evidence to rebut this presumption (Paper 22, 21-
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`23), such as by arguing that the claimed range achieves unexpected results relative
`
`to Fernandes’s plasma ammonia ranges. In re Woodruff, 919 F.2d 1575, 1578
`
`(Fed. Cir. 1990) (where the claimed and prior art ranges overlap, Federal Circuit
`
`“cases have consistently held that…the [patentee] must show that the particular
`
`range is critical, generally by showing that the claimed range achieves unexpected
`
`results relative to the prior art range.”). Thus, Horizon has not rebutted the
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`presumption of obviousness.
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`Horizon’s allegation that no “recognition” existed in the prior art and that it
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`is a “mere possibility” that patients in the “normal range” of plasma ammonia
`
`required an increased dose of drug (Paper 22, 19-23) is contrary to the express
`
`disclosure of Fernandes. (EX1028, ¶6.) Figure 17.2 is reproduced below with a
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`
`
`6
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`

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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`
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`red box highlighting the branch of the treatment protocol for patients having
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`“normal” plasma ammonia:
`
`
`
`(EX1015, Fig. 17.2 (annotated).) Notwithstanding that these patients have normal
`
`plasma ammonia, Fernandes nevertheless recommends, in view of additional risk
`
`factors (“biomarkers” such as plasma glutamine and essential amino acid (“EAA”)
`
`levels), that medicine doses be increased. (Id.; EX1028, ¶6.)
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`
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`7
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`

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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`
`
`
`Horizon’s Arguments Are Premised
`on an Erroneous Claim Construction That Is
`Contrary to the Plain Language of the Claims.
`Horizon’s arguments regarding combinability of and motivation to combine
`
`prior art references is based on an erroneous construction of the claims. Although
`
`Horizon argues at length that the prior art does not disclose using plasma ammonia
`
`levels alone to make decisions regarding drug dosing or as a target for treatment
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`(see, e.g., Paper 22, 21, 24), there is no claim limitation (and Horizon points to
`
`none) in the ’559 patent claims requiring that plasma ammonia levels be the only
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`“biomarker” or parameter used to determine nitrogen scavenging drug doses.1
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`Instead, the ’559 patent claims each recite the open-ended transitional phrase
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`“comprising.” They thus allow assessment of other biomarkers, including
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`glutamine and EAA levels in addition to the claimed plasma ammonia levels, to
`
`inform the appropriate drug doses. Invitrogen Corp. v. Biocrest Mfg., L.P., 327
`
`F.3d 1364, 1368 (Fed. Cir. 2003) (“The transition ‘comprising’ in a method claim
`
`indicates that the claim is open-ended and allows for additional steps.”). Indeed, in
`
`connection with the ’559 patent, the Board held the “comprising” transitional
`
`
`1 Horizon did not raise this claim construction issue in its response (Paper 22, 15-
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`16); Horizon’s argument is waived.
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`
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`8
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`
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`language meant that the claims are “open to additional steps.” (See the Lupin IPR,
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`Paper 42 at 23.)
`
`Horizon’s expert, Dr. Enns, admitted on cross-examination that he “do[es]
`
`not see a sentence or a description prohibiting the use of another biomarker.”
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`(EX1027, 132:1-2; see also id., 135:18-25.) And relying on plasma ammonia
`
`levels alone for patient care would be contrary to Dr. Enns’s clinical practice. (Id.,
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`138:7-21.) Thus, the undisputed evidence is that POSAs would understand these
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`claims do not require using plasma ammonia as the sole biomarker for making
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`drug dosing decisions.
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`
`
`The Prior Art Teaches and Suggests Using “Fasting”
`Plasma Ammonia Levels for Determining Drug Doses.
`Horizon again argues that the prior art does not disclose “fasting” plasma
`
`ammonia levels (Paper 22, 40-43), notwithstanding this argument was rejected by
`
`the Board in the prior IPR between Horizon and Par regarding the ’215 patent
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`(IPR2015-01127, Paper 49, 20-21 (finding Simell and Blau teach use of fasting
`
`ammonia levels)) and in Lupin’s IPR involving the ’559 patent (IPR2016-00829,
`
`Paper 42 , 24-26 (same)). Horizon should not be permitted to waste the Board’s
`
`and parties’ time by re-litigating the same issue a third time, notwithstanding that
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`Horizon has been fully heard and the Board has consistently and specifically
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`resolved this issue against Horizon.
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`
`
`9
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`

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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`
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`See Webpower, IPR2016-01239, Paper 21 at 27-28; see also 37 C.F.R.
`
`§ 42.73(d)(3)(i).
`
`As those rulings recognized, POSAs would understand that fasting plasma
`
`levels should be used in determining drug doses. For example, Fernandes and the
`
`’859 Publication disclose that plasma ammonia levels are affected by, among other
`
`things, protein intake (i.e., food intake). (EX1015, 217; EX1004, [0003]; EX1028,
`
`¶7.) Blau states that plasma levels should be analyzed at least four hours after a
`
`meal. (EX1006, 273.) Simell discloses measurement of plasma ammonia levels
`
`after an overnight fast (EX1007, 1118). Lee describes measurement of plasma
`
`ammonia levels prior to breakfast. (EX1010, Fig. 2 legend.)
`
`In view thereof, POSAs knew that fasting plasma ammonia levels should be
`
`used to avoid the variability in ammonia levels that were caused by food and other
`
`daily activities. (EX1002, ¶¶85-86, 90, 92; EX1028, ¶8.) Horizon’s suggestion
`
`that POSAs would simply disregard ammonia values because of variability ignores
`
`the significance of plasma ammonia values as evidenced by all record prior art.
`
`Even Dr. Enns admits that to this day, plasma ammonia levels are “the best we’ve
`
`got” for making therapeutic decisions for UCD patients. (EX1027, 168:13-18.)
`
`Lee attributes significance to lower fasting plasma ammonia levels that
`
`would have motivated a POSA to focus on that biomarker in determining drug
`
`
`
`10
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`

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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`
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`doses. (EX1002, ¶98.) After noting that only 27.0% of ammonia values exceeded
`
`ULN while patients were taking GPB, in contrast to 39.6% while on PBA, Lee
`
`states that “[t]hese differences were attributable to lower ‘overnight’ ammonia
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`levels (12-24 h)….” (EX1010, 224 (emphasis added); EX1002, ¶98; Ex1028, ¶9)
`
`Although Horizon notes that the lowest mean ammonia values occurred
`
`30 minutes after breakfast, Horizon ignores that dietary protein is not immediately
`
`absorbed and metabolized and thus takes time to be reflected in plasma ammonia
`
`measurements. (See EX2046, 49:18-50:8 (explaining “an issue of the
`
`bioavailability of the protein”); EX1028, ¶10.) Furthermore, the lowest measured
`
`plasma ammonia level is at 24 hours – which would be a fasting ammonia level
`
`that preceded breakfast (EX1010, Fig. 2 legend; EX1028, ¶10).
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`Horizon also mischaracterizes the variability in ammonia values discussed
`
`by Dr. Sondheimer. (Paper 22, 41-42.) Dr. Sondheimer’s Initial Declaration
`
`explained that fasting plasma ammonia values are the least variable for a given
`
`patient. (EX1002, ¶38 (discussing “a patient’s plasma ammonia level”).) On the
`
`other hand, Horizon and Dr. Enns cite to the error bars depicted in Figure 2 of Lee.
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`(EX1027, 263:19-265:16.) But those error bars merely represent variation in the
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`population studied in Lee – i.e., variability between individual subjects—which is
`
`irrelevant here.
`
`
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`11
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`

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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`
`
`
`The Prior Art Does Not Teach
`Away From Using Plasma Ammonia
`Levels in Therapeutic Decision-Making.
`Horizon’s “teaching away” argument (Paper 22, 35-39) is both contrary to
`
`the law and contradicted by fact, which highlights the importance of plasma
`
`ammonia levels in therapeutic decision-making for UCD patients.
`
`None of the prior art “criticize[s], discredit[s] or otherwise discourage[s]”
`
`using plasma ammonia levels in determining drug doses. Galderma Labs., L.P. v.
`
`Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013). To the contrary, the prior art
`
`highlights its criticality. For example, Fernandes states that “[a]ll treatment must
`
`be monitored with regular quantitative estimation of plasma ammonia….”
`
`(EX1015, 219.) In fact, “[t]he most important diagnostic test in urea cycle
`
`disorders is measurement of the plasma ammonia concentration.” (Id., 217.) Lee
`
`states that “[c]ontrol of blood ammonia levels is the main objective of both acute
`
`and chronic management of UCD patients.” (EX1010, 222.)
`
`Similarly, far from discouraging the practice, the ’859 Publication expressly
`
`states that drug dosage adjustments can be made using plasma ammonia levels.
`
`For example, the ’859 Publication discloses a method having the step of
`
`“measuring blood ammonia to determine if the initial dosage is sufficient to control
`
`blood ammonia levels, or to establish a suitable average ammonia level,” and then
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`12
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
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`“adjusting” the dosage of the new drug as needed to a level “less than about
`
`40 µmol/L,” without limit to how low. (EX1004, [0095-0099]; see also id., [0088-
`
`0091]; EX1028, ¶23.) The Board also previously found that the ’859 Publication
`
`teaches that “plasma ammonia levels below a level considered to be normal were
`
`acceptable, even desirable” and that “a known goal of treatment is plasma levels
`
`that are below normal, not just below the upper limit of normal.” (IPR2016-00829,
`
`Paper 42, 10-11, 18.)
`
`Even references that Horizon cites and identifies do not discourage using
`
`plasma ammonia levels, but instead describe its ongoing significance to physicians.
`
`For example, Häberle states that “[l]aboratory monitoring must include plasma
`
`ammonia determination in venous samples (target level <80 µmol/L[]).” (EX2019,
`
`18 (emphasis added); EX1028, ¶24.) Barsotti2 highlights a need for better
`
`ammonia measurement methods, stating that “[a]lternative methods are still sought
`
`that are noninvasive or require a small catheter in a peripheral vein but provide a
`
`
`2 Barsotti notes only that “certain centers” are moving away from using plasma
`
`ammonia (EX1022, S19), but as described herein, as a whole, Barsotti and other
`
`prior art describe the continuing importance of plasma ammonia levels (EX1028,
`
`¶25).
`
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`13
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
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`continuous monitor of blood ammonia levels.” (EX1022, S15; EX1028, ¶25.) The
`
`“Consensus Statement” recommends that “[b]oth the plasma ammonia level and
`
`the clinical picture should be considered when choosing therapy.” (EX2025, S3;
`
`EX1028, ¶25.) Broomfield states “[p]lasma ammonia can be used both as part of
`
`diagnostic investigations and for monitoring of efficacy of treatment….”
`
`(EX2015, 73-75; EX1028, ¶26.) Blau discloses the proper conditions for obtaining
`
`plasma ammonia levels and highlights the need for “frequent monitoring during
`
`treatment.” (EX1006, 262, 268; EX1028, ¶26.)
`
`Although the ’157 Publication highlights the difficulty of “routine” ammonia
`
`level determinations (i.e., multiple measurements throughout the course of a single
`
`day), the application recites an alternative embodiment of the method which
`
`includes the step of “adjusting dietary protein and/or drug dosage as appropriate
`
`based upon measurement of blood ammonia…” such that plasma levels are “less
`
`than 40 µmol/L” or “not greater than 35 µmol/L, without limitation to how low.”
`
`(EX2012, [0104, 0115, 0134-0137]; see also id., [0127-0131]; EX1028, ¶27.)
`
`These disclosures, therefore, contradict Horizon’s teaching away argument. At
`
`most, PAGN-based dose adjustments are one of several alternative embodiments,
`
`not a “teaching away.” (EX2012, [0022].) See In re Ethicon Inc., 844 F.3d 1344,
`
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`14
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
`
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`1351 (Fed. Cir. 2017) (description of a “more desirable” embodiment does not
`
`teach away from a less desirable alternative embodiment).
`
`Although Lichter-Konecki states that random values for plasma ammonia
`
`are of limited utility, it then explains that ammonia values should be obtained and
`
`“drawn at a constant time in relation to meals and medication for monitoring of
`
`treatment.” (EX1017, 328 EX1028, ¶28;.) And, while noting the variability in
`
`plasma ammonia levels over the course of a day, Lee acknowledges that plasma
`
`ammonia levels are of “clinical importance,” and that using urinary PAGN is still
`
`“preliminary” and “deserves further exploration.” (EX1010, 226-27; EX1028,
`
`¶29.)
`
`Thus, even Horizon’s prior art teaches using ammonia levels in therapeutic
`
`decision-making. At most, Horizon has cited out-of-context statements that are
`
`legally insufficient to be a “teaching away.” Allied Erecting & Dismantling Co. v.
`
`Genesis Attachments, LLC, 825 F.3d 1373, 1382 (Fed. Cir. 2016).
`
`Horizon’s “teaching away” arguments cannot be reconciled with
`
`Dr. Enns’s admission that, to this day, he and other POSAs use plasma ammonia
`
`levels in treating patients. (EX1027, 168:13-18.) He further admitted that no prior
`
`art condemning the use of plasma ammonia levels to determine or adjust the dose
`
`of nitrogen scavenging drugs, stating that “[t]hat specific statement I don’t recall in
`
`
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`15
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
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`the prior art that I have been using.” (EX1027, 169:8-14.) Indeed the prior art
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`cannot be said to “teach away” from or even to “discourage” using plasma
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`ammonia for drug dose decision-making as Horizon contends, as the prior art like
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`Fernandes and the ’859 and ’157 Publications specifically discuss drug dose
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`adjustment in view of plasma ammonia levels, and this process remains the
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`standard of care as “the best we’ve got.” (EX1027, 161:17-162:6.)
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` Horizon Exaggerates the Risk of Overdose.
`Horizon’s concerns regarding “massive overdoses” with nitrogen scavenging
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`drugs are divorced from the prior art and clinical practice for treating UCD
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`patients.
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`First, the reports regarding overdoses and unpleasant side effects (Paper 22,
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`33) do not even relate to GPB. (See EX1006, 262 (phenylbutyrate); EX2013, 105
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`(phenylacetate, phenylbutyrate); EX2018, 10 (phenylbutyrate); EX2019,
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`Table 4 (phenylacetate, phenylbutyrate); EX2031, 564 (phenylbutyrate); EX2032,
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`S79 (phenylacetate and phenylbutyrate)). As such, these concerns are irrelevant,
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`particularly when the prior art states that GPB has a “much higher” tolerability
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`than other prior art drugs. (EX1004, [0086]; EX1028, ¶14; see also IPR2016-
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`00829, Paper 42 at 22; EX1028, ¶13.)
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
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`Second, although Horizon focuses on massive overdoses, Horizon does not
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`address the risks associated with only slight drug dosage adjustments. Neither
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`Horizon nor Dr. Enns provide data regarding any dangers associated with slight
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`dosage adjustments. Furthermore, if a patient is initially treated with a dose of
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`nitrogen-scavenging drug doses below the maximum recommended dose, an
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`increased dose can continue to remain within the range of safe and effective FDA-
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`approved drug doses. (EX1028, ¶14.) The prior art, such as Lee, further
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`demonstrates that patients are not always given the maximum labeled dose of a
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`nitrogen-scavenging drug, stating that “8 of 10 patients were given below-
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`maximum label NaPBA doses. (EX1010, 226; EX1028, ¶15.) Such patients could
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`receive slight increases of drug and remain within the ranges recommended in the
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`approved product labeling, and thus not be a “massive overdose.” (EX1028, ¶15.)
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`Third, the claims do not specify how much greater the adjusted dosage of
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`GPB should be, and can include clinically-irrelevant small increases. (EX1001,
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`24:61-63; 25:6-10; EX1027, 278:9-279:1.)
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`Fourth, Dr. Enns’s opinions are predicated on hypersensitive patients
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`(EX1027, 279:18-280:6) without any evidence regarding the proportion of patients
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`who are hypersensitive. Dr. Enns’s opinions ignore that “[s]ome children have
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`tolerated medications relatively well” (id.) and the prior art such as the
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
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`’859 Publication describes that GPB is generally better tolerated than other
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`nitrogen scavenging drugs, as discussed above. Horizon has not provided any
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`evidence that non-hypersensitive patients could not tolerate small increases in drug
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`doses.
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`Fifth, side effects are a concern for any drug with an increased dose. Neither
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`Horizon nor Dr. Enns has provided any evidence that GPB is more toxic than other
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`drugs, particularly with respect to small increases within the range of prior art
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`doses that were tolerated by patients and subjects.
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`The Prior Art Provides a Reasonable Expectation of Success.
`Horizon’s argument that there is no reasonable expectation of success is
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`based on mischaracterizations of the record.
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`First, the prior art (e.g., Fernandes) already described increasing the drug
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`doses for patients having “normal” plasma ammonia levels. Because the claimed
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`method merely follows the prior art to obtain the same results disclosed by the
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`prior art, a POSA would necessarily have an expectation of success. See
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`PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1363-64 (Fed. Cir.
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`2007) (method claims obvious where inventors “merely used routine research
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`methods to prove what was already believed to be the case”). And, as noted above,
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
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`Horizon nowhere contends that the claimed methods provide any unexpected
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`results over the prior art.
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`Second, as discussed above, Lee attributed reductions in fasting ammonia
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`levels to improved ammonia control throughout the day, as evidenced by a
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`decreased incidence of excursions of plasma ammonia levels above ULN and thus
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`provides a motivation to reduce even “normal” plasma ammonia levels.
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`Third, contrary to Horizon’s argument (Paper 22, 45-46), Petitioner and Dr.
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`Sondheimer do not claim that “to improv[ing] neurological outcome[s]” is a
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`rationale to combine references. Nowhere in the rationale to combine section does
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`the Petition mention improving neurological outcomes. (Paper 3, 54-56; EX1002,
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`¶¶124-126.) Instead, Horizon fabricates a criticism by citing to Dr. Sondheimer’s
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`discussion of Lee, a reference that itself tied lower plasma ammonia levels to
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`improved neurological outcomes. (Paper 22, 45.)
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`Fourth, although Horizon alleges that its method leads to
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`“reduc[ed]…frequency and incidence of hyperammonemia,” (Paper 44, 57)
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`nothing in the claims require that this result be obtained. As Dr. Enns notes, the
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`claims encompass nominal increases in drug doses that would be therapeutically
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`meaningless. (EX1027, 271:21-25, 279:2-11.) Moreover, as discussed, Lee
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
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`already recognized that lower overnight ammonia levels resulted in better
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`ammonia control. (See supra Section V.A.3.)
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`Fifth, Horizon’s criticisms that Dr. Sondheimer could not explain why
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`Subject 1006 had low plasma ammonia levels is legally irrelevant and Horizon has
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`identified no law imposing such a requirement. See In re O’Farrell, 853 F.2d 894,
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`902 (Fed. Cir. 1988) (rejecting patentee’s argument belittling the predictive value
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`of prior art where reference proved that claimed method could be performed).
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` CLAIM 5 IS OBVIOUS FOR
`THE REASONS IN GROUND 2.
`In addition to the reasons discussed above in Section IV, Par should prevail
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`on Ground 2 for at least the following reasons.
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`The Prior Art Would Have Motivated a POSA to Target
`a Fasting Plasma Ammonia Level Below One-Half ULN.
`Horizon misleadingly argues that the prior art is “completely silent”
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`regarding “any particular ammonia level within the normal range let alone the
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`claimed target.” (Paper 22, 50.) As discussed above, the prior art discloses plasma
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`ammonia levels that overlap with the claimed ranges. For example, the
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`’859 Publication discloses that “a plasma ammonia level of less than about
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`40 µmol/L, or of not greater than 35 µmol/L would indicate the treatment was
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`effective.” (EX1004, [0074].) Fernandes similarly states that “[t]he aim [of
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`treatment] is to keep plasma ammonia levels below 80 µmol/L….” (EX1015, 219;
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`IPR2017-01768
`Patent No. 9,095,559
`Petitioner’s Reply to Patent Owner’s Response
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`EX1028, ¶17.) And thus, contrary to Horizon’s bald claims of “hindsight” (e.g.,
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`Paper 22, 53), the prior art consistently discloses that maintaining plasma ammonia
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`levels below ULN was desirable. (EX1028, ¶17.) Further, because the prior art
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`sets no lower bound, the prior art necessarily expressly includes that range of at or
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`below half the ULN. Where the prior art range overlaps with the claimed range,
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`obviousness is presumed. Applied Materials, 692 F.3d at 1295. And Horizon has
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`nowhere come forward with evidence that this claimed target plasma ammonia
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`levels achieves unexpected results. Woodruff, 919 F.2d at 1578.
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`Furthermore, Horizon takes isolated statements out of context from both
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`Lichter-Konecki and the ’859 Publication to argue that a POSA would not