`
`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 IPR2017-01767
`Patent 9,254,278
`_____________________
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`

`

`
`
` 
`
` 
`
` 
`
` 
`
` 
`
` 
`
`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1 
`The Board’s Findings in the IPR of the ’215 and ’559 Patents
`Apply To the ’278 Patent. ................................................................................ 2 
`  The Claims In Each Ground Rise and Fall Together. ..................................... 4 
`  The Board Need Not Construe “Upper Limit of Normal”. ............................. 4 
`Claims 1-3 Are Anticipated by the ’859 Publication. ..................................... 4 
`  Claims 4, 6-8, 10-12, 14, and 15 Are Obvious For the
`Reasons Set Forth in Ground 3. ....................................................................... 6 
`Fernandes, the ’859 Publication, Lee and Lichter-
`Konecki Disclose All Claim Limitations. ............................................. 6 
`The Prior Art Teaches and Suggests Increasing
`Drug Doses for Patients Having “Normal”
`Ammonia Levels. ........................................................................ 6 
`Horizon’s Arguments Are Premised on an
`Erroneous Claim Construction That Is Contrary
`to the Plain Language of the Claims. .......................................... 9 
`The Prior Art Teaches and Suggests Using
`“Fasting” Plasma Ammonia Levels for
`Determining Drug Doses. ......................................................... 10 
`The Prior Art Does Not Teach Away From
`Using Plasma Ammonia Levels In Therapeutic
`Decision-Making. ...................................................................... 13 
`Horizon Exaggerates the Risk of Overdose. ....................................... 17 
`The Prior Art Provides A Reasonable Expectation of
`Success. ............................................................................................... 19 
`  Claims 1-3, 5, 9, and 13 Are Obvious For the Reasons in
`Grounds 2 and 4. ............................................................................................ 21 
`
` 
`
` 
`
` 
`
` 
`
`i
`
`

`

`
`
`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
` 
`
`The Prior Art Would Have Motivated a POSA to
`Target a Fasting Plasma Ammonia Level Below One-
`Half ULN. ............................................................................................ 22 
`A POSA Would Have Had a Reasonable Expectation
`of Success in Obtaining Fasting Plasma Ammonia
`Levels Below One-Half ULN. ............................................................ 26 
`  Dr. Sondheimer’s Opinions Are Admissible. ................................................ 27 
`
` 
`
`ii
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`INTRODUCTION
`The ’278 patent claims are drawn to methods that are essentially identical to
`
`
`
`
`
`those 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 have
`
`significant overlap with the claims found unpatentable by the Board in Par
`
`Pharmaceutical, Inc. v. Horizon Therapeutics, LLC, IPR2015-01127, Paper 49
`
`(P.T.A.B. Sept. 29, 2016). As explained in Par’s Petition and in those prior
`
`decisions, the art prior to the filing of the ’278 patent disclosed that medical
`
`professionals diagnosing and treating patients with urea-cycle disorders (“UCD”)
`
`obtained fasting plasma ammonia levels and compared those levels to an upper
`
`limit of normal (“ULN”) for plasma ammonia to make dosing decisions. Those
`
`dosing decisions include adjusting a subject’s dosage if its fasting plasma ammonia
`
`level was between one-half ULN and ULN. The prior art teaches or suggests the
`
`’278 patent claims and thus renders them 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
`
`unpatentable. Indeed, Horizon relies on arguments already twice rejected by the
`
`Board in previous IPRs involving the ’278 patent family. Horizon should not be
`
`allowed to advance these arguments a third time. Horizon additionally ignores the
`
`
`
`1
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`express disclosures of the prior art, relies on a misreading of the claims that
`
`excludes using biomarkers other than plasma ammonia levels to make dosing
`
`decisions, relies on inaccurate assertions of teaching away, and meritless attacks on
`
`Dr. Sondheimer’s testimony.
`
`For these reasons, and as discussed in the Petition, Dr. Sondheimer’s
`
`declarations, and below, Par submits that the Board should find the ’278 patent
`
`claims unpatentable as obvious.
`
`
`
`THE BOARD’S FINDINGS IN THE IPR OF
`THE ’215 AND ’559 PATENTS APPLY TO THE ’278 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
`
`applicable to this proceeding because the ’215 patent does not concern drug
`
`adjustments for patients having plasma ammonia levels between one-half ULN and
`
`ULN. (Paper 22, 17-18.) But, Horizon does not challenge that, other than this one
`
`limitation, the steps of the claims in the ’215 and ’278 patents are essentially
`
`identical, as set forth in Par’s Petition.
`
`Moreover, Horizon fails to provide any reason why it should not be bound
`
`by the previous IPR decision. Nor can it, because it is estopped from doing so.
`
`In re 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)
`
`
`
`2
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`(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
`
`issues to those in this case, namely whether (1) Fernandes and the ’859 Publication
`
`teach making dosing decisions based on plasma ammonia levels and ULN; (2)
`
`Simell and Blau teach measuring fasting plasma ammonia levels; (3) a POSA
`
`would have relied on fasting plasma ammonia levels to adjust drug doses; and (4) a
`
`POSA would have combined Fernandes, Blau, Simell, and the ’859 Publication.
`
`(IPR2015-01227, Paper 49, 6-12, 15-20.)
`
`Second, after Par’s Petition was filed, the Board issued its Final Written
`
`Decision in the Lupin IPR (IPR2016-00829, Paper 42), finding the related
`
`’559 patent claims unpatentable as obvious over Blau, Simell, the ’859 Publication,
`
`and Brusilow ’84. In that proceeding, the Board found that (1) the ’859
`
`Publication teaches making dosing decisions based on plasma ammonia levels and
`
`ULN; (2) maintaining normal plasma ammonia levels was a goal in the art; (3) a
`
`POSA would have sought to achieve plasma ammonia levels below ULN because
`
`doing so would result in effective treatment; (4) Simell and Blau teach measuring
`
`fasting plasma ammonia levels; and (5) a POSA would have combined the ’859
`
`Publication, Simell, and Blau and had a reasonable expectation of success in
`
`achieving the methods claimed in the ’559 patent. (Id., 9-29.) These findings are
`
`
`
`3
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`antithetical to Horizon’s assertions in this IPR.
`
`These were disputed issues that were resolved in a final written decision,
`
`which means that Horizon had a fair opportunity to litigate them. (IPR2015-
`
`01227, Paper 49, 6-12, 15-20; IPR2016-00829, Paper 42, 9-29.) Thus, Horizon’s
`
`attempt to again resurrect resolved disputes should be rejected. Webpower,
`
`IPR2016-01239, Paper 21, 27-28; 37 C.F.R. 42.73(d)(3).
`
` THE CLAIMS IN EACH GROUND RISE AND FALL TOGETHER.
`Within each Ground, Horizon does not separately argue the patentability of
`
`the claims challenged. As such, the claims in each individual Ground rise and fall
`
`together.
`
` THE BOARD NEED NOT CONSTRUE “UPPER LIMIT OF NORMAL”.
`Horizon asks the Board to construe the term “upper limit of normal.”
`
`(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
`
`levels below ULN—under any reasonable construction. Par does not concede that
`
`Horizon’s proposed construction is correct for purposes outside this proceeding.
`
` CLAIMS 1-3 ARE ANTICIPATED BY THE ’859 PUBLICATION.
`Horizon does not dispute that the ’859 Publication discloses each and every
`
`limitation of claims 1-3, except administering GPB to a subject with a fasting
`
`plasma ammonia level below half ULN. (Paper 22, 60-63.) Horizon’s argument is
`
`
`
`4
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`based on the incorrect premise that “a POSA would not understand Example 3 to
`
`disclose that Subject 1006 received an amount of GPB sufficient to produce a
`
`fasting plasma ammonia level that is necessarily less than half the ULN.” (Id., 60.)
`
`Horizon’s arguments are meritless for at least three reasons:
`
`1.
`
`The ’859 Publication discloses that the maximum plasma
`
`concentration (Cmax) of plasma ammonia levels in Subject 1006 was 13.0µmol/L.
`
`The ULN for the study sites was 26-35µmol/L. (EX1004, [0201]; EX1028, ¶5.)
`
`One-half ULN would be in the range of 13-17.5µmol/L. (EX1028, ¶5.) Thus,
`
`Subject 1006’s maximum plasma ammonia level was the same as the lowest end of
`
`the one-half ULN range (13µmol/L). (EX1004, [0201]; EX1028, ¶5.) Based on
`
`this result, at every other time point, Subject 1006 necessarily had a plasma
`
`ammonia level lower than one-half ULN. (EX1028, ¶5.) As such, Patent Owner’s
`
`efforts to dispute whether Subject 1006 had a plasma level less than 8.30µmol/L
`
`are irrelevant.
`
`2.
`
`Horizon’s argument is contrary to its admissions in this proceeding
`
`that the fasting plasma ammonia level would be one of the lowest values in a day,
`
`barring some unusual circumstance that Horizon does not contend is present in the
`
`’859 Publication examples. (Paper 22, 62.)
`
`
`
`5
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`3.
`
`Horizon’s argument regarding variability is based purely on
`
`
`
`speculation and contrary to the specific data reported in the ’859 Publication.
`
`Indeed, a POSA would readily understand that the only way that the TN-AUC
`
`(AUC that is normalized based on values obtained throughout the course of the
`
`day) can be 8.30µmol/L with a Cmax of 13.0µmol/L for Subject 1006, is if there are
`
`other measured plasma ammonia levels throughout the course of the day that were
`
`lower than 8.30µmol/L. (EX1028, ¶6.)
`
` CLAIMS 4, 6-8, 10-12, 14, AND 15 ARE
`OBVIOUS FOR THE REASONS SET FORTH IN GROUND 3.
`
`Fernandes, the ’859 Publication, Lee
`and Lichter-Konecki Disclose All Claim Limitations.
`Horizon does not dispute that the prior art discloses most of the limitations
`
`in the claims challenged in Ground 3 as described in Par’s Petition. Horizon’s
`
`dispute regarding the disclosures of the prior art is limited to two limitations: (1)
`
`adjusting doses in patients who have plasma ammonia levels between one-half
`
`ULN and ULN; and (2) using “fasting” plasma ammonia levels in making
`
`decisions about drug dosing.
`
`
`
`The Prior Art Teaches and
`Suggests Increasing Drug Doses for
`Patients Having “Normal” Ammonia Levels.
`Fernandes expressly discloses to “↑medicines” (i.e., increasing dosage of
`
`medication) even if a patient has “normal” plasma ammonia levels below
`
`
`
`6
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`80µmol/L, high glutamine levels would signal that a patient is at imminent risk of
`
`becoming unwell, and thus advises to “↑medicines” (i.e., increasing dosage of
`
`medication). (EX1015, 220; EX1002, ¶73; EX1028, ¶9.) Although Horizon
`
`alleges that Fernandes discloses only a single ULN of 50µmol/L (Paper 22, 23),
`
`Fernandes expressly discloses that “[h]ealthy neonates have slightly higher
`
`values.” (EX1015, 217; EX1028, ¶9.) Blau describes hyperammonemia as being
`
`“plasma ammonia >80 in newborns or >50 µmol/L after 28 days postnatally.”
`
`(EX1006, 5; EX1028, ¶9.) Thus, a POSA would understand that 80µmol/L in
`
`Figure 17.2 is a reasonable ULN for some patients, such as newborns. (EX1028,
`
`¶8.)
`
`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-
`
`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, the Federal
`
`
`
`7
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`Circuit’s “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 presumption of obviousness.
`
`Horizon’s allegation that no “recognition” existed in the prior art and that it
`
`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, ¶10.) Figure 17.2 is reproduced below with a
`
`red box highlighting the branch of the treatment protocol for patients having in
`
`“normal” plasma ammonia:
`
`
`
`
`
`8
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`(EX1015, Fig. 17.2 (annotated).) Notwithstanding that these patients have normal
`
`plasma ammonia, Fernandes nevertheless recommends that, in view of additional
`
`risk factors (“biomarkers” such as plasma glutamine and essential amino acid
`
`(“EAA”) levels), that medicine doses should be increased. (Id.; EX1028, ¶10.)
`
`
`
`Horizon’s Arguments Are Premised
`on an Erroneous Claim Construction That Is
`Contrary to the Plain Language of the Claims.
`Horizon’s arguments regarding the combinability and motivation to combine
`
`prior art references is based on an erroneous claim construction. 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 (see,
`
`e.g., Paper 22, 21, 24), there is no claim limitation (and Horizon points to none) in
`
`the ’278 patent claims that require plasma ammonia levels be the only “biomarker”
`
`or parameter used to determine nitrogen scavenging drug doses.1
`
`Instead, the ’278 patent claims each recite the open-ended transitional phrase
`
`“comprising.” These claims thus allow assessment of other biomarkers including
`
`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
`
`
`1 As Horizon did not raise this claim construction issue in its response (Paper 22,
`
`15-16), Horizon’s argument is waived.
`
`
`
`9
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`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 nearly identical ’559 patent, the Board held that the
`
`“comprising” transitional language meant that the claims are “open to additional
`
`steps.” (See IPR2016-00829, Paper 42 at 23.)
`
`Indeed, 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.” (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., 138:7-21.) Thus, the undisputed evidence is that a POSA would
`
`understand these claims do not require using plasma ammonia as the sole
`
`biomarker for making drug dosing decisions.
`
`
`
`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 that this argument was rejected
`
`by the Board in the prior IPR between Horizon and Par relating to the ’215 patent
`
`(IPR2015-01127, Paper 49, 20-21 (finding Simell and Blau teach use of fasting
`
`ammonia levels)) and in the Lupin IPR relating to the related ’559 patent
`
`(IPR2016-00829, Paper 42, 24-26 (same)). Horizon should not be permitted to
`
`
`
`10
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`waste the Board’s and parties’ time by re-litigating the same issue in some cases
`
`for a third time, notwithstanding that Horizon has been fully heard and the Board
`
`has consistently and specifically resolved this issue against Horizon. See
`
`Webpower, IPR2016-01239, Paper 21, 27-28; see also 37 C.F.R.
`
`§ 42.73(d)(3)(i).
`
`As those decisions recognized, a POSA 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, ¶11.) Blau states that plasma levels should be analyzed at least
`
`four hours after the end of 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 of the above, 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, ¶¶106-107, 110, 112; EX1028, ¶12.)
`
`Horizon’s suggestion that POSAs with experience with UCDs would simply
`
`disregard ammonia values because of variability ignores the significance of plasma
`
`
`
`11
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`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
`
`doses. (EX1002, ¶116.) 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 levels (12-24 h)....” (EX1010, 224 (emphasis added); EX1002, ¶116;
`
`EX1028, ¶13.)
`
`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, ¶14.) 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, ¶14).
`
`Horizon also mischaracterizes the variability in ammonia values discussed
`
`by Dr. Sondheimer. (Paper 22, 41-42.) Dr. Sondheimer’s Initial Declaration
`
`
`
`12
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`explained that fasting plasma ammonia values are the least variable for a given
`
`patient. (EX1002, ¶36 (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.
`
`(EX1027, 263:19-265:16.) But those error bars merely represent variation in the
`
`population studied in Lee – i.e., variability between individual subjects—which is
`
`irrelevant here.
`
`
`
`The Prior Art Does Not Teach
`Away From Using Plasma Ammonia
`Levels In Therapeutic Decision-Making.
`Horizon’s “teaching away” argument (Paper 22, 35-40) is both contrary to
`
`the law and contradicted by the prior art, 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; EX1028, ¶25.) In fact, “[t]he most important diagnostic test in urea
`
`cycle disorders is measurement of the plasma ammonia concentration.” (EX1015,
`
`217; EX1028, ¶25.) Lee states that “[c]ontrol of blood ammonia levels is the main
`
`
`
`13
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`objective of both acute and chronic management of UCD patients.” (EX1010, 222;
`
`EX1028, ¶26.)
`
`Similarly, 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 “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, ¶27.) 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 at 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,
`
`
`
`14
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`18 (emphasis added); EX1028, ¶28.) 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
`
`continuous monitor of blood ammonia levels.” (EX1022, S15; EX1028, ¶29.) The
`
`“Consensus Statement” recommends that “[b]oth the plasma ammonia level and
`
`the clinical picture should be considered when choosing therapy.” (EX2025, S3;
`
`EX1028, ¶29.) 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, ¶30.) Blau discloses the proper conditions for obtaining plasma
`
`ammonia levels and highlights the need for “frequent monitoring during
`
`treatment.” (EX1006, 262, 268; EX1028, ¶30.)
`
`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
`
`
`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,
`
`¶29).
`
`
`
`15
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`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, ¶31.)
`
`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,
`
`1351 (Fed. Cir. 2017) (description of a “more desirable” embodiment does not
`
`teach away from a less desirable 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, ¶32.) 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,
`
`¶33.)
`
`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
`
`
`
`16
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`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
`
`the prior art that I have been using.” (EX1027, 169:8-14.) Indeed, the prior art
`
`cannot be said to “teach away” from or even to “discourage” using plasma
`
`ammonia for drug dose decision-making as Horizon contends, as the prior art like
`
`Fernandes and the ’859 and ’157 Publications specifically discuss drug dose
`
`adjustment in view of plasma ammonia levels, and this process remains the
`
`standard of care as “the best we’ve got.” (EX1027, 161:17-162:6.)
`
` Horizon Exaggerates the Risk of Overdose.
`Horizon’s concerns regarding “massive overdoses” with nitrogen scavenging
`
`drugs are divorced from the prior art and clinical practice for treating UCD
`
`patients.
`
`First, the reports regarding overdoses and unpleasant side effects (Paper 22,
`
`33) do not even relate to GPB. (See EX1006, 262 (phenylbutyrate); EX2013, 105
`
`
`
`17
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`(phenylacetate, phenylbutyrate); EX2018, 10 (phenylbutyrate); EX2019,
`
`Table 4 (phenylacetate, phenylbutyrate); EX2031, 564 (phenylbutyrate); EX2032,
`
`S79 (phenylacetate and phenylbutyrate).) As such, these concerns are irrelevant,
`
`particularly when the prior art states that GPB has a “much higher” tolerability
`
`than other prior art drugs. (EX1004, [0086]; EX1028, ¶17; see also IPR2016-
`
`00829, Paper 42 at 22.)
`
`Second, although Horizon focuses on massive overdoses, Horizon does not
`
`address the risks associated with only slight drug dosage adjustments. Neither
`
`Horizon nor Dr. Enns provided data regarding any dangers associated with slight
`
`dosage adjustments. Furthermore, if a patient is initially treated with a dose of
`
`nitrogen-scavenging drug doses below the maximum recommended dose, an
`
`increased dose can continue to remain within the range of safe and effective FDA-
`
`approved drug doses. (EX1028, ¶18.) The prior art, such as Lee, further
`
`demonstrates that patients are not always given the maximum labeled dose of a
`
`nitrogen-scavenging drug, stating that “8 of 10 patients” were given below-
`
`maximum label NaPBA doses. (EX1010, 226; EX1028, ¶19.) Such patients could
`
`receive slight increases of drug and remain within the ranges recommended in the
`
`approved product labeling, and thus not be a “massive overdose.” (EX1028, ¶19.)
`
`
`
`18
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`Third, the claims do not specify how much greater the adjusted dosage of
`
`
`
`GPB should be, and can include clinically-irrelevant small increases. (EX1001,
`
`24:41-45; 24:66-25:3; EX1027, 278:9-279:1.)
`
`Fourth, Dr. Enns’s opinions are predicated on hypersensitive patients
`
`(EX1027, 279:18-280:6) without any evidence regarding the proportion of patients
`
`who are hypersensitive. Dr. Enns’s opinions ignore that “[s]ome children have
`
`tolerated medications relatively well” (id.) and the prior art such as the
`
`’859 Publication describes that GPB is generally better tolerated than other
`
`nitrogen scavenging drugs, as discussed above. Horizon has not provided any
`
`evidence that non-hypersensitive patients could not tolerate small increases in drug
`
`doses.
`
`Fifth, side effects are a concern for any drug with an increased dose. Neither
`
`Horizon nor Dr. Enns has provided any evidence that GPB is more toxic than other
`
`drugs, particularly with respect to small increases within the range of prior art
`
`doses that were tolerated by patients and subjects.
`
`
`The Prior Art Provides A Reasonable Expectation of Success.
`Horizon’s argument that there is no reasonable expectation of success is
`
`based on mischaracterizations of the record.
`
`
`
`19
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`First, the prior art (e.g., Fernandes) already described increasing the drug
`
`
`
`doses for patients having “normal” plasma ammonia levels. Because the claimed
`
`method merely follows the prior art to obtain the same results disclosed by the
`
`prior art, a POSA would necessarily have an expectation of success. See
`
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1363-64 (Fed. Cir.
`
`2007) (method claims obvious where inventors “merely used routine research
`
`methods to prove what was already believed to be the case”). And, as noted above,
`
`Horizon nowhere contends that the claimed methods provide any unexpected
`
`results over the prior art.
`
`Second, as discussed above, Lee attributed reductions in fasting ammonia
`
`levels to improved ammonia control throughout the day, as evidenced by a
`
`decreased incidence of excursions of plasma ammonia levels above ULN and thus
`
`provides a motivation to reduce even “normal” plasma ammonia levels.
`
`Third, contrary to Horizon’s argument (Paper 22, 45-46), Petitioner and
`
`Dr. Sondheimer do not claim that “improv[ing] neurological outcome[s]” is a
`
`rationale to combine references. Nowhere in the rationale to combine section does
`
`the Petition mention improving neurological outcomes. (Paper 3, 54-56; EX1002,
`
`¶¶124-126.) Instead, Horizon fabricates a criticism by citing to Dr. Sondheimer’s
`
`
`
`20
`
`

`

`IPR2017-01767
`Patent No. 9,254,278
`Petitioner’s Reply to Patent Owner’s Response
`
`
`discussion of Lee, a reference that itself tied lower plasma ammonia levels to
`
`improved neurological outcome