UNITED STATES PATENT AND TRADEMARK OFFICE
`_________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_________________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`
`Petitioners,
`
`v.
`
`HORIZON THERAPEUTICS, LLC
`
`Patent Owner.
`_________________
`
`IPR2017-01159
`U.S. Patent No. 9,254,278
`
`
`
`PETITIONERS’ REPLY
`
`
`
`
`
`
`
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 22313-1450
`
`
`
`
`_________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_________________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`
`Petitioners,
`
`v.
`
`HORIZON THERAPEUTICS, LLC
`
`Patent Owner.
`_________________
`
`IPR2017-01159
`U.S. Patent No. 9,254,278
`
`
`
`PETITIONERS’ REPLY
`
`
`
`
`
`
`
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 22313-1450
`
`
`
`
`
`TABLE OF CONTENTS
`
`1.
`
`2.
`
`Page
`Horizon Is Collaterally Estopped from Arguing Unpatentability.................1
`
`Horizon Has Not Offered Any Evidence That Justifies Changing the Board’s
`
`Findings in the ’559 FWD or Those Reached at Institution ........................4
`
`3.
`
`Horizon Mischaracterizes the Prior Art ...................................................5
`
`(a) The Prior Art Does Not Teach Away From Adjusting Dosage When
`
`Plasma Ammonia Was at or Under the ULN ..................................5
`
`(b) POSAs Used Ammonia Levels to Adjust Drug Dosage ....................9
`
`Claims 1-3, 5, 9, and 13 Are Not Patentable .......................................... 12
`
`There Was Motivation to Combine the Cited Prior Art References ........... 14
`
`4.
`
`5.
`
`(a) Any Purported Differences Between the Nitrogen Scavenging Drugs
`
`in Simell and the ’859 Publication Are Irrelevant .......................... 14
`
`(b) LPI is a UCD ........................................................................... 16
`
`(c) A POSA Would Have Combined the Cited References .................. 17
`
`6.
`
`Horizon’s Arguments Regarding POSA Level and Dr. Vaux’s Qualifications
`
`Should be Rejected ............................................................................ 18
`
`7.
`
`Petitioners Have Shown a Reasonable Expectation of Success ................. 20
`
`
`
`8.
`
`8.
`
`Conclusion........................................................................................ 23
`
`Conclusion ........................................................................................ 23
`
`
`
`
`
`
`
`
`
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) .................................................................. 17
`Alza Corp. v. Mylan Labs, Inc.,
`464 F.3d 1286 (Fed. Cir. 2006) ................................................................ 21
`Black v. Office of Pers. Mgmt.,
`641 F. App’x 1007 (Fed. Cir. 2016) ............................................................ 3
`In re Freeman,
`30 F.3d 1459 (Fed. Cir. 1994) .................................................................... 1
`Innovation Toys, LLC v. MGA Entm’t, Inc.,
`637 F.3d 1314 (Fed. Cir. 2011) ................................................................ 17
`Iron Grip Barbell Co., Inc. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) ................................................................ 12
`Jet, Inc. v. Sewage Aeration Sys.,
`223 F.3d 1360 (Fed. Cir. 2000) .................................................................. 1
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................. 5
`Leo Pharmaceutical Products Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .................................................................. 9
`Liberty Mut. Ins. Co. v. FAG Bearings Corp.,
`335 F.3d 752 (8th Cir. 2003)...................................................................... 3
`In re Merck & Co.,
`800 F.2d 1091 (Fed. Cir. 1986) ................................................................ 17
`Nestle USA, Inc. v. Steuben Foods, Inc.,
`884 F.3d 1350 (Fed. Cir. 2018) .............................................................. 1, 2
`
`
`
`Ohio Willow Wood Co. v. Alps South, LLC,
`735 F.3d 1333 (Fed. Cir. 2013) .................................................................. 2
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ........................................................... 12, 13
`Pharmacia & Upjohn Co. v. Mylan Pharms., Inc.,
`170 F.3d 1373 (Fed. Cir. 1999) .................................................................. 3
`Other Authorities
`Charles Alan Wright et al., 18 Fed. Prac. & Proc. Juris. § 4426 (3d
`ed.)......................................................................................................... 4
`Charles Alan Wright et al., Federal Practice and Procedure § 4433 (2d
`ed. 2002) ................................................................................................ 3
`Restatement (Second) of Judgments § 13 (1982) ............................................... 3
`
`
`
`1. Horizon Is Collaterally Estopped from Arguing Unpatentability
`U.S. Patent 9,254,278 (the “’278 patent”) is a continuation of U.S. Patent
`
`9,095,559 (the “’559 patent”). After Petitioners filed the petition in this IPR, the
`
`Board issued a Final Written Decision (“FWD”) in IPR2016-00829, finding the
`
`’559 patent claims unpatentable over the same combination of prior art asserted
`
`here. (See Ex. 1028 at, e.g., 32.) Given the close similarity of the claims here to
`
`those in the ’559 patent, collateral estoppel prevents Patent Owner Horizon
`
`Therapeutics LLC (“Horizon”) from contesting unpatentability of the ’278 claims,
`
`and from re-litigating any issues it already lost before the Board.
`
`“Under the doctrine of issue preclusion, also called collateral estoppel, a
`
`judgment on the merits in a first suit precludes relitigation in a second [proceeding]
`
`of issues actually litigated and determined in the first suit.” In re Freeman, 30
`
`F.3d 1459, 1465 (Fed. Cir. 1994) (citing Lawlor v. National Screen Serv. Corp.,
`
`349 U.S. 322, 326 (1955)). The Federal Circuit has articulated a four-factor test in
`
`determining whether collateral estoppel attaches: “(1) identity of the issues in a
`
`prior proceeding; (2) the issues were actually litigated; (3) the determination of the
`
`issues was necessary to the resulting judgment; and (4) the party defending against
`
`preclusion had a full and fair opportunity to litigate the issues.” Jet, Inc. v. Sewage
`
`Aeration Sys., 223 F.3d 1360, 1366 (Fed. Cir. 2000). It is well-settled that
`
`collateral estoppel applies to PTAB decisions. Nestle USA, Inc. v. Steuben Foods,
`
`1
`
`
`
`Inc., 884 F.3d 1350, 1351 (Fed. Cir. 2018) (“[C]ollateral estoppel, also known as
`
`issue preclusion, applies in the administrative context.”) (quote and citation
`
`omitted).
`
`Here, all four factors are met. As to the first factor, in the ’559 IPR, the
`
`Board addressed the patentability of substantially similar claims over the same
`
`combination of prior art. Application of collateral estoppel does not require
`
`identical patent claims. Rather, “[i]f the differences between the unadjudicated
`
`patent claims and adjudicated patent claims do not materially alter the question of
`
`invalidity, collateral estoppel applies.” Ohio Willow Wood Co. v. Alps South, LLC,
`
`735 F.3d 1333, 1342 (Fed. Cir. 2013) (citations omitted); Nestle, 884 F.3d at 1352.
`
`Here, the ’278 claims are substantially similar to the ’559 claims, 1 and are obvious
`
`for the same reasons. The second through fourth factors are also easily met. The
`
`same art and arguments were addressed in the prior IPR; the Board’s determination
`
`of subsidiary issues such as level of skill in the art, scope and content of the prior
`
`1 Claims 4, 8, and 12 are substantially similar to claim 1 of the ’559 patent. Claims
`
`5, 9, and 13 are substantially similar to claim 5 of the ’559 patent. Claim 2 is
`
`substantially similar to claim 7 of the ’559 patent. Claims 3, 6, 7, 10, 11, 14, and
`
`15 are substantially similar to claims 12-14 of the ’559 patent. Claim 1 is
`
`substantially similar to claim 5 of the ’559 patent. (Compare claims of Ex. 1001
`
`with claims of Ex. 1030.)
`
`
`
`2
`
`
`
`art, and motivations of POSAs were necessary to the ultimate determination of
`
`unpatentability; and Horizon fully and fairly participated in the prior IPR,
`
`including through briefing and at oral hearing.
`
`The fact that the ’559 FWD is subject to appeal does not affect this analysis.
`
`The “vast weight of case law” follows “the established rule in the federal courts . . .
`
`that a final judgment retains all of its res judicata consequences pending decision
`
`of the appeal.” Pharmacia & Upjohn Co. v. Mylan Pharms., Inc., 170 F.3d 1373,
`
`1381 (Fed. Cir. 1999) (citations omitted); Restatement (Second) of Judgments § 13
`
`(1982) (“The better view is that a judgment otherwise final remains so despite the
`
`taking of an appeal …”); Charles Alan Wright et al., Federal Practice and
`
`Procedure § 4433 (2d ed. 2002) (“The bare act of taking an appeal is no more
`
`effective to defeat preclusion than a failure to appeal.”). 2
`
`Collateral estoppel cannot be avoided based on purported new arguments or
`
`evidence. See Black v. Office of Pers. Mgmt., 641 F. App’x 1007, 1009 (Fed. Cir.
`
`2016) (“Both res judicata and collateral estoppel apply even if new evidence exists
`
`or the aggrieved party believes the earlier case was wrongly denied.”); Liberty
`
`Mut. Ins. Co. v. FAG Bearings Corp., 335 F.3d 752, 762 (8th Cir. 2003) (“[M]ere
`
`2 Some panels have refused to accord preclusive effect to a FWD before
`
`termination of all appeal rights, but these rulings do not comport with Federal
`
`Circuit precedent.
`
`
`
`3
`
`
`
`discovery of new evidence does not create a new issue… [L]itigants may not have
`
`a second opportunity to prove a fact or make an argument relating to an issue
`
`previously decided.”); Charles Alan Wright et al., 18 Fed. Prac. & Proc. Juris. §
`
`4426 (3d ed.) (“The introduction of new evidence on a matter previously resolved
`
`is not an exception to collateral estoppel.”) (quoting Oyeniran v. Holder, 672 F.3d
`
`800, 807 (9th Cir. 2012)).
`
`Accordingly, the Board should determine that Horizon is collaterally
`
`estopped from arguing the unpatentability of the ’278 claims in view of the ’559
`
`FWD, and from re-arguing any subsidiary issues already decided against it.
`
`2. Horizon Has Not Offered Any Evidence That Justifies Changing the
`Board’s Findings in the ’559 FWD or Those Reached at Institution
`Even if the ’559 FWD were not accorded preclusive effect, the Board should
`
`make the same findings in this case as it made there. Horizon’s Patent Owner
`
`Response (“POR”) and Dr. Enn’s declaration in this IPR do nothing more than
`
`parrot arguments the Board rejected in the ’559 IPR. As Horizon acknowledged in
`
`its Preliminary Response, “Dr. Enns’s trial testimony in the ’559 patent case is
`
`substantially the same as his preliminary testimony here.”3 (Paper 7 at 5.) Dr.
`
`Enns confirmed this similarity both in his declaration on the ’278 patent and during
`
`
`3 Horizon did not submit any additional expert testimony from Dr. Enns beyond
`
`Ex. 2006, which it submitted with its Preliminary Response.
`
`
`
`4
`
`
`
`deposition. (Ex. 2006 at, e.g., ¶¶68, 90, 116, 128, 131; Ex. 1029 at, e.g., 21:11-
`
`23:7; 23:16-24:5; 25:18-27:25; 29:6-30:8; 31:2-33:10; 37:13-20.)
`
`On re-direct, Horizon’s counsel pointed Dr. Enns to purported differences
`
`between his ’278 and ’559 declarations. (Ex. 1029 at, e.g., 55:8-59:9.) But Dr.
`
`Enns relied on the exact same prior art as he did in the ’559 IPR. Nothing in his
`
`declaration should cause the Board to depart from the ’559 FWD.
`
`Alternatively, the Board should reaffirm the findings in its institution
`
`decision. Post-institution, Horizon submitted only two new documents: a
`
`deposition transcript of Dr. Vaux, and a declaration by Dr. Vaux from a different
`
`IPR on a patent in a different family. As discussed below (see infra at 8-9, 22-23),
`
`this information in no way undercuts the Board’s initial findings of unpatentability.
`
`3. Horizon Mischaracterizes the Prior Art
`Turning to the merits of Horizon’s arguments, the challenged claims are to
`
`nothing more than “the predictable use of prior art elements according to their
`
`established functions,” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007),
`
`and should be cancelled as obvious.
`
`(a) The Prior Art Does Not Teach Away From Adjusting Dosage
`When Plasma Ammonia Was at or Under the ULN
`Horizon asserts that the prior art “taught away” from the claimed methods
`
`because it purportedly “established that normal plasma ammonia values were
`
`acceptable and only addressed increasing the dosage of medication for plasma
`
`
`
`5
`
`
`
`ammonia levels well above the ULN [upper limit of normal].” (POR at 21.) The
`
`Board, however, already made a factual finding on this very same issue in the ’559
`
`FWD: “[W]e are persuaded that Petitioner has established that one of ordinary
`
`skill in the art would have had a reason to increase drug dosage for subjects whose
`
`plasma ammonia levels are less than the upper limit of normal.” (Ex. 1028 at 24.)
`
`This finding is entitled to preclusive effect.
`
`But even if this argument were considered on its merits, as in the ’559 IPR,
`
`Horizon points to no express instruction in the prior art directing POSAs to focus
`
`only on “high” ammonia levels, or to stop titrating drug dosage as soon as a
`
`patient’s plasma ammonia level hits the ULN.
`
`Horizon argues that the ’859 Publication teaches increasing dosage only
`
`when plasma ammonia levels are inadequate, which it equates with “above
`
`normal.” (POR at 24, 32.) But the ’859 Publication’s disclosure does not limit
`
`“inadequate” plasma ammonia levels to those “above normal.” Instead, it teaches
`
`POSAs to adjust dosage to “attain a normal or desired plasma ammonia level,
`
`e.g., a level below about 40 µmol/L.” (Ex. 1007 at [0226] (emphasis added).) It
`
`also makes clear that any value less than the ULN is appropriate: “a plasma
`
`ammonia level of less than about 40 µmol/L, or of not greater than 35 µmol/L
`
`would indicate that the treatment was effective.” (Ex. 1007 at [0074], [0085])
`
`(emphasis added). The ’859 Publication also teaches that a benefit of glyceryl tri-
`
`
`
`6
`
`
`
`[4-phenylbutyrate] is that it leads to average ammonia levels that are typically
`
`lower than those achieved with other nitrogen scavenging drugs. (Ex. 1007 at
`
`[0209].) This demonstrates that POSAs were not merely content to reach the ULN,
`
`but in fact recognized that lower ammonia levels are better.
`
`Horizon cites the ’157 Publication (Ex. 2012), for a purported teaching to
`
`adjust dosage only when ammonia is above the ULN. 4 (POR at 26-27.) But in the
`
`’559 FWD, the Board flatly rejected this reading of the reference. (Ex. 1028 at
`
`20.) Like the ’859 Publication, the ’157 Publication suggests adjusting drug
`
`dosage to attain “a normal or desired plasma ammonia level,” meaning that the
`
`disclosure is not limited to increasing dose only when ammonia is above the ULN.
`
`(Id. at [0299] (emphasis added).) Horizon also points to Brusilow ’84 (Ex. 1004),
`
`but as the Board previously found (Ex. 1028 at 18), treatment of a few patients
`
`4 Horizon also points to Häberle (Ex. 2019), which was published after the claimed
`
`September 30, 2011 priority date. Horizon argues that despite its late publication
`
`date, the development of the guidelines took place through August 2011. (POR at
`
`n.1.) This does not mean, however, that the guidelines were in the prior art. In any
`
`event, the Board previously found that Häberle “is not persuasive of the non-
`
`obviousness of the challenged claims.” (Ex. 1028 at 21 fn. 9) Häberle relates to
`
`crisis situations, whereas the issue here is routine management of UCD patients,
`
`who are not necessarily symptomatic. (Ex. 2019 at 8-10.)
`
`
`
`7
`
`
`
`with high plasma ammonia levels does not indicate that POSAs would always wait
`
`until plasma ammonia reached those levels.
`
`In an attempt to suggest a hesitancy to increase drug dosage, Horizon posits
`
`that clinicians typically use the lowest possible drug dosage to minimize side
`
`effects. (POR at 27-28.) But as the Board found in the ’559 FWD, Horizon points
`
`to evidence of massive overdoses, but has not provided evidence “that slight
`
`increases in HPN-100 would have been considered to be dangerous.” (Ex. 1028 at
`
`22-23.) On the contrary, at the dosage levels at issue here, the prior art showed
`
`that the drug “exhibits no indications of toxicity.” (Ex. 1007 at [0086]; see also
`
`[0203]-[0204]; Ex. 2009 at 4 (“[A]lternative pathway therapies have been found to
`
`be remarkably nontoxic in humans at the doses recommended to treat patients with
`
`urea cycle disorders.”).) Indeed, Horizon does not dispute that nitrogen
`
`scavenging drugs are generally well-tolerated. Accordingly the Board was “not
`
`persuaded by [Horizon’s] arguments regarding the risks of toxicity of nitrogen
`
`scavenging drugs.” (Ex. 1028 at 23.)
`
`Horizon attempts to argue that Dr. Vaux’s declaration in the ’197 IPR
`
`supports their position here. But it does no such thing. Dr. Vaux simply gave the
`
`unremarkable testimony that POSAs would optimize dosage regimens of nitrogen
`
`scavenging drugs to balance PAA efficacy and toxicity concerns. (Ex. 2052, ¶64.)
`
`As Dr. Vaux testified, in certain patients even the labeled amount of 60 grams of
`
`
`
`8
`
`
`
`Ravicti would produce PAA blood levels that could lead to adverse events, but as a
`
`general matter “you would be able to increase [dosage] significantly without major
`
`side effects.” (Ex. 2051 at 33:1-19.) Indeed, while Dr. Enns testifies that “even
`
`small increases in dosage” can cause unpleasant side effects, he does not testify
`
`that these side effects, or a concern over PAA toxicity, prevents any dose increase
`
`whatsoever. (Ex. 2006, ¶114.)
`
`Horizon’s efforts to liken this case to Leo Pharmaceutical Products Ltd. v.
`
`Rea, 726 F.3d 1346 (Fed. Cir. 2013), where the inventors were the first to
`
`recognize and then solve a problem, are unavailing. (POR at 22-23.) Horizon fails
`
`to articulate exactly what problem was purportedly recognized and solved. In any
`
`event, as Dr. Vaux explained, POSAs were aware that even patients with normal
`
`ammonia levels could experience events that routinely take them outside of normal
`
`limits, which was contrary to the goal of maintaining stable levels under the ULN.
`
`(Ex. 1002 at ¶80; Petition at 26-27.) Accordingly, Horizon was by no means the
`
`first to recognize that the inherent variability of ammonia levels presented an
`
`obstacle to maintaining stable plasma ammonia levels, even in seemingly well-
`
`controlled patients.
`
`(b) POSAs Used Ammonia Levels to Adjust Drug Dosage
`Horizon lists several purported drawbacks of using ammonia as a biomarker,
`
`but none of the purported drawbacks deterred POSAs from actually using ammonia
`
`
`
`9
`
`
`
`levels when adjusting drug dosage. As the Board found in the ’559 FWD: “[T]he
`
`’859 publication teaches. . . that measuring blood ammonia was a known step in
`
`adjusting drug dosages.” (Ex. 1028 at 11.) This finding is entitled to preclusive
`
`effect.
`
`In any event, the claimed methods fail to address these purported
`
`drawbacks. For example, Horizon contends that inherent difficulties with the
`
`interpretation of blood ammonia “undermined its usefulness as a diagnostic tool”
`
`(POR at 9), but the ’278 claims do not cover using a specific numerical value of
`
`ammonia to diagnose diseases. Thus Horizon did not solve this purported
`
`problem.
`
`Nor have the ’278 patent claims solved any of the other purported problems
`
`with ammonia that Horizon raised, including diurnal fluctuation and the impact of
`
`diet, exercise, infection, or pregnancy. (POR at 9.) The prior art disclosed all of
`
`these issues with ammonia, yet POSAs still used ammonia levels to adjust drug
`
`dosage. (See, e.g., Ex. 1007 at [0232] (“[D]ose adjustment would be based on
`
`repeated measurement of urinary PAGN as well as assessment of dietary protein
`
`and plasma ammonia.”).)
`
`Horizon appears to suggest that given the variability of plasma ammonia
`
`levels (even fasting levels), POSAs would have used them only to merely measure
`
`a therapy’s clinical effectiveness, not to adjust drug dosage. (POR at 31-33.)
`
`
`
`10
`
`
`
`However, as the Board previously recognized, this argument is meritless because it
`
`is contrary to the art. (Ex. 1028 at 23.) For example, the ’859 Publication
`
`expressly provides a method to adjust the dose of a nitrogen scavenging drug,
`
`including “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” and then “adjusting the dosage of the new drug as needed . . . .”
`
`(Ex. 1007 at [0095-99] and [0088-91].) And as the Board recognized (Ex. 1028 at
`
`23-24), because high ammonia levels can be toxic (see Ex. 1002, ¶29, Ex. 2006
`
`¶35), POSAs would have considered ammonia variability a reason to increase drug
`
`dosage when plasma ammonia levels approach the ULN. (Ex. 1002, ¶¶78, 89, 120,
`
`133.)
`
`Horizon repeatedly argues that there is no teaching in the prior art to
`
`increase drug dosage for subjects whose plasma levels are less than the ULN.
`
`(POR, passim.) However, the Board has previously rejected this argument:
`
`In light of the teachings in the prior art regarding measuring plasma
`ammonia levels in a fasting state and using this information to adjust
`drug dosages, along with Dr. Vaux’s testimony, we are persuaded that
`Petitioner has established that one of ordinary skill in the art would
`have had a reason to increase drug dosage for subjects whose plasma
`ammonia levels are less than the upper limit of normal.
`
`
`
`11
`
`
`
`(Ex. 1028 at 24.) The Board should give this finding preclusive effect or again
`
`adopt this rationale.
`
`4.
`
`Claims 1-3, 5, 9, and 13 Are Not Patentable
`
`Claims 5, 9, and 13 recite repeating the steps of the independent claims until
`
`the subject exhibits a fasting plasma ammonia level at or below half the ULN.
`
`(See, e.g., POR at 50.) Horizon contends that the prior art did not suggest
`
`“target[ing]” any specific plasma ammonia level below the ULN, including below
`
`half the ULN as recited in these claims. (Id.) But the Board previously found that
`
`POSAs “would have had reason to target any level below the [ULN].” (Ex. 1028
`
`at 29-30.) This finding is entitled to preclusive effect. (See also Ex. 1002, ¶98
`
`(noting that there is no minimum level of blood ammonia level that must be
`
`maintained for normal body function).)
`
`The prior art clearly taught POSAs to administer drug to obtain normal
`
`ammonia levels, i.e. any value under the ULN, which includes values less than half
`
`the ULN. (See, e.g., Ex. 1007 at [0085], [0226], [0074]; Ex. 1016 at 3 (“The goal
`
`of treatment is to maintain normal levels of plasma ammonia . . . . includ[ing] a
`
`plasma ammonia level of <40 µmol/L . . . .”).)
`
`Because the prior art teaches a range that includes the claimed plasma
`
`ammonia level, the claimed values are prima facie obvious. See Iron Grip Barbell
`
`Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1321-22 (Fed. Cir. 2004); In re
`
`
`
`12
`
`
`
`Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). Although it had the burden to do
`
`so, Horizon has not submitted any evidence that the claimed values exhibit
`
`unexpected results over the prior art disclosure of ammonia values that are less
`
`than the ULN. See In re Peterson, 315 F.3d at 1330; Petition at 21-22; Ex. 1028 at
`
`30.
`
`With respect to claim 1, 5 Horizon additionally notes that the ’859
`
`Publication does not “single out” the patient who achieved an ammonia level that
`
`was less than half the ULN, and that all nine patients in the clinical study were
`
`characterized as “better controlled” with HPN-100 as compared to NaPBA. (POR
`
`at 52-54.) But Horizon never argues that a POSA would therefore have ignored
`
`patient 1006 because of this. Indeed, as Dr. Vaux points out, in view of the
`
`motivation to keep fasting plasma ammonia levels low and the fact that there is no
`
`minimum level of blood ammonia that must be maintained for normal body
`
`function, this patient would have been of interest to POSAs. (Ex. 1002, ¶¶64-64;
`
`see also infra n.7, addressing Dr. Vaux’s comments on the clinical study.)
`
`Horizon also notes that “the ’859 Publication does not disclose the use of
`
`fasting plasma ammonia levels.” (POR at 54.) This argument is irrelevant because
`
`5 Horizon does not separately argue the patentability of dependent claims 2 and 3,
`
`and their additional limitations over claim 1 do not render them patentable. See
`
`Petition at 21.
`
`
`
`13
`
`
`
`the only active step recited in claim 1 is “administering” drug; the claim does not
`
`require actual use of a fasting blood level. But even if it did, use of fasting plasma
`
`ammonia levels was routine in the art. (See Petition at 25-26 and n.4; see also Ex.
`
`1005 at 2; Ex. 1006 at 17; Ex. 1015 at 1; Ex. 1010 at 4; Ex. 2033 at 47; Ex. 2024 at
`
`35, Table 8 (see *); Ex. 2020 at 6; Ex. 2034 at 41:17-25.)
`
`5.
`
`There Was Motivation to Combine the Cited Prior Art References
`Horizon retreads arguments about a purported lack of motivation to combine
`
`the ’859 Publication with Blau or Simell. 6 (POR at 40-50.) The Board previously
`
`rejected these same arguments. (Ex. 1028 at 24-26.)
`
`(a) Any Purported Differences Between the Nitrogen Scavenging
`Drugs in Simell and the ’859 Publication Are Irrelevant
`According to Horizon, differences in the routes of administration and
`
`indications between the sodium benzoate and phenylacetate used in Simell and the
`
`glyceryl tri-[4-phenylbutyrate] used in the ’859 Publication would have
`
`discouraged POSAs from combining these references. (POR at 42-43.) But the
`
`Board rejected this very same argument in the ’559 FWD and found that “those of
`
`skill in the art would have considered it obvious to modify the teachings of the
`
`
`6 Horizon also makes a perfunctory note of the Brusilow ’979 Patent (POR at 49),
`
`but never specifically addresses the teachings on which Petitioner relies in this
`
`document (see, e.g., Petition at 44-48.)
`
`
`
`14
`
`
`
`’859 publication by using fasting serum ammonia levels as taught in at least Simell
`
`and Blau.” (Ex. 1028 at 26.) This finding is entitled to preclusive effect.
`
`As in the ’559 IPR, Horizon fails to establish why the purported differences
`
`between the drugs have any bearing on this issue. And as the Board has previously
`
`recognized, even if Simell and Blau are not directed to the exact same aspects of
`
`urea cycle disorders (“UCDs”) as the ’859 Publication, they reflect POSA’s
`
`knowledge with respect to measuring fasting plasma ammonia levels. (Ex. 1028 at
`
`25-26.) The use of fasting plasma ammonia levels is well-supported in the prior
`
`art. (See supra at 14.)
`
`Horizon further contends that Petitioners have not identified anything
`
`indicating that the dosing of sodium benzoate or phenylacetate is “interchangeable
`
`with glyceryl tri-[4-phenylbutyrate].” (POR at 43.) Even if interchangeable
`
`dosing mattered to the way Simell is being used here (which it does not), Horizon
`
`ignores that glyceryl tri-[4-phenylbutyrate] is metabolized to phenylacetate. (Ex.
`
`1007 at [0021].) The prior art provides straightforward methods of converting a
`
`patient to glyceryl tri-[4-phenylbutyrate] based on the patient’s current dosage of
`
`phenylacetate. (See, e.g., Ex. 1007 at [0116]-[0119].) Given the teachings of the
`
`prior art, any purported differences between these drugs would not have been an
`
`obstacle to combining Simell with the ’859 Publication.
`
`
`
`15
`
`
`
`Horizon’s contention that the drugs in Simell and the ’859 Publication have
`
`different indications (POR at 42-43) should also be rejected as based solely on
`
`post-art. RAVICTI was approved in 2013 (Paper 7 at 4), long after the priority
`
`date, making any differences in the indications for the drugs in Simell and the ’859
`
`Publication irrelevant to obviousness.
`
`(b) LPI is a UCD
`Simell shows the use of a fasting plasma ammonia level in a protocol that
`
`uses a nitrogen scavenging drug to reduce plasma ammonia level. (Ex. 1005 at 1-
`
`2.) Horizon contends that POSAs would not have considered Simell because the
`
`patients suffered from lysinuric protein intolerance (“LPI”), which Horizon
`
`contends is not a UCD. (POR at 43-45.) Simell however, unambiguously refers to
`
`LPI as a UCD: “We studied metabolic changes caused by these substances and
`
`their pharmacokinetics in a different urea cycle disorder, lysinuric protein
`
`intolerance (LPI) . . . .” (Ex. 1005 at 1 (Abstract) (emphasis added).) At least
`
`eight of Horizon’s own exhibits do the same, many of which even discuss or cite
`
`Simell. See, e.g., Ex. 2022 at 6, 8; Ex. 2009 at 2, 3; Ex. 2018 at 5; Ex. 2016 at 2,
`
`Table 1; Ex. 2013 at 1-2; Ex. 2023 at 2; Ex. 2015 at 3, Table 2; Ex. 2044 at 2,
`
`Table 1.
`
`In any event, the Board specifically rejected this argument in the ’559 FWD.
`
`(Ex. 1028 at 25-26.) Simell teaches the use of nitrogen scavenging drugs to reduce
`
`
`
`16
`
`
`
`plasma ammonia levels—subject matter squarely related to the claims.
`
`Accordingly, Horizon’s attacks on the relevance of Simell should be rejected. See
`
`Innovation Toys, LLC v. MGA Entm’t, Inc., 637 F.3d 1314, 1321 (Fed. Cir. 2011)
`
`(“A reference is reasonably pertinent if . . . it is one which, because of the matter
`
`with which it deals, logically would have commended itself to an inventor’s
`
`attention in considering his problem.”) (citation omitted).
`
`(c) A POSA Would Have Combined the Cited References
`Horizon disputes the motivation to combine because the references do not
`
`“suggest reliance on normal fasting plasma ammonia levels to adjust the dosage of
`
`nitrogen scavenging drug.” (POR at 46.) Horizon improperly focuses on what
`
`each reference teaches separately, not on “the teachings of the prior art as a
`
`whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986); see also
`
`Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 964 (Fed. Cir. 2014) (warning against
`
`“taking an overly cramped view of what the prior art teaches” where
`
`“motivation to combine may be implicit in the prior art”).
`
`Horizon’s attempt to distinguish Simell by arguing that it discloses choosing
`
`a dosage based on body weight, not plasma ammonia (POR at 46), is misleading.
`
`While the prior art (and the ’278 claims) use ammonia values as a factor in
`
`considering whether to adjust the dosage of the nitrogen scavenging drug, neither
`
`
`
`17
`
`
`
`posits a quantitative relationship between the value of the ammonia level and drug
`
`dosage.
`
`Horizon also argues that there is no motivation to combine because Simell
`
`does not address treatment for a patient who already has normal ammonia levels.
`
`(POR at 46-47.) This again overlooks the larger context. As discussed here and in
`
`the Petition, POSAs were well aware of good reasons to maintain patients at
`
`normal ammonia levels, and would have been aware of these reasons whether or
`
`not these two references disclose treatment of patients with normal levels.
`
`Horizon again argues that Blau is concerned only with UCD diagnosis, not
`
`treatment. (POR at 47-48.) As Dr. Vaux testified, treatment and diagnosis are
`
`intimately intertwined. (Ex. 2034 at 23:20-24:14.) Moreover, Petitioners cite Blau
`
`for its disclosure of using fasting plasma ammonia levels, which, as noted above,
`
`was well-known in the prior art.
`
`In sum, Horizon’s arguments regarding lack of motivation to combine are
`
`not persuasive because they do not address Petitioners’ proposed combination.
`
`6. Horizon’s Arguments Regarding POSA Level and Dr. Vaux’s
`Qualifications Should be Rejected
`In the ’559 FWD, the Board made a finding specifically rejecting the
`
`definition of a POSA that Horizon offers in this case. (Ex. 1028 at 15.) The Board
`
`similarly rejected Horizon’s arguments about Dr. Vaux’s qualifications, finding
`
`that “Dr. Vaux is qualified to provide opinions about the motivations,
`
`
`
`18
`
`
`
`understandings, and actions of one of ordinary skill in the art.” (Id. at 15-16.)
`
`These findings are all entitled to preclusive effect, and the evidence, in any event,
`
`fully supports Dr. Vaux’s qualifications to provide expert testimony in this case
`
`(See Ex. 1002 at ¶¶1-4; Ex. 2034 at 7:3-17.)
`
`Horizon’s argument that the
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