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`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`________________
`
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.,
`
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, INC.,
`
`Patent Owner
`
`________________
`
`Case IPR2016-00829
`
`Patent 9,095,559
`
`________________
`
`HORIZON THERAPEUTICS, INC.’S PATENT OWNER RESPONSE
`
`
`
`

`

` 
`
`I.
`
`II.
`
`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`TABLE OF CONTENTS
`
`Introduction ...................................................................................................... 1
`
`Background ...................................................................................................... 7
`
`A. Prior Art at Issue ....................................................................................... 7
`
`B. Technical Background on UCD and the Complexity Involved in
`Treating UCD Patients .............................................................................. 7
`
`C. Overview of the ’559 Patent ................................................................... 13
`
`III. Lupin’s Definition of One of Ordinary Skill in the Art is Overly Broad ...... 15
`
`IV. Claim Construction ........................................................................................ 20
`
`A. “upper limit of normal” ........................................................................... 21
`
`B. “the subject” ............................................................................................ 22
`
`V.
`
`Claims 1-15 Would Not Have Been Obvious in View of the Asserted
`Prior Art ......................................................................................................... 23
`
`A. One of Ordinary Skill Would Have Had No Motivation to
`Combine the Teachings of the ’859 Publication with Those of
`Simell, Blau, or Brusilow ’84 ................................................................. 24
`
`1. Simell Concerns the Dosing of Different Drugs Than in the
`’859 Publication ........................................................................... 26
`
`2. Simell Concerns a Condition That Is Different from
`Classic Urea Cycle Disorder ....................................................... 27
`
`3. Simell, Blau, and Brusilow ’84 Do Not Address the Use of
`Normal Fasting Plasma Ammonia Levels to Treat UCDs .......... 29
`
`B. There Would Have Been No Motivation To Adjust the Dosage of
`a Nitrogen Scavenging Drug for Subjects with Plasma Ammonia
`Levels in the Normal Range .................................................................... 33
`
`1. Lupin’s Alleged Motivation is Unsupported ............................... 33
`i
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`
`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
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`2. The Prior Art as a Whole Taught That Normal Plasma
`Ammonia Levels Were Acceptable and Increasing Dosage
`Only When Levels Were Above Normal .................................... 38
`
`3. One of Ordinary Skill Would Not Have Adjusted Dosage
`Based on Normal Plasma Ammonia Levels ................................ 46
`
`C. The Prior Art Did Not Disclose Increasing or Initiating a Dosage
`of Glyceryl Tri-[4-phenylbutyrate] in a Patient With a Plasma
`Ammonia Level Between Half the ULN and the ULN .......................... 51
`
`D. Lupin Fails To Prove Any Reasonable Expectation of Success ............. 55
`
`E. The Prior Art Did Not Disclose or Suggest the Limitations of
`Claim 5 .................................................................................................... 57
`
`VI. Conclusion ..................................................................................................... 59
`
`
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`ii
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`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Federal Cases
`Allergan, Inc. v. Sandoz, Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) .......................................................................... 37
`
`Alza Corp. v. Mylan Labs, Inc.,
`464 F.3d 1286 (Fed. Cir. 2006) .......................................................................... 38
`
`Amgen Inc. v. F. Hoffmann-La Roche Ltd.,
`580 F.3d 1340 (Fed. Cir. 2009) .......................................................................... 55
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ............................................................................ 37
`
`Bell Communications Research, Inc. v. Vitalink Communications
`Corp.,
`55 F.3d 615 (Fed. Cir. 1995) .............................................................................. 23
`
`BioGatekeeper, Inc. v. Kyoto Univ.,
`IPR2014-01286, Paper 12 (PTAB Feb. 11, 2015) .............................................. 55
`
`Broadcom Corp. v. Emulex Corp.,
`732 F.3d 1325 (Fed. Cir. 2013) .......................................................................... 55
`
`Catalina Mktg. Int’l v. Coolsavings.com, Inc.,
`289 F.3d 801 (Fed. Cir. 2002) ............................................................................ 23
`
`In re Cyclobenzaprine Hydrochloride Extended Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .................................................................... 25, 55
`
`Daiichi Sankyo Co. v. Apotex, Inc.,
`501 F.3d 1254 (Fed. Cir. 2007) .......................................................................... 20
`
`Envtl. Designs, Inc. v. Union Oil Co.,
`713 F.2d 693 (Fed. Cir. 1983) ............................................................................ 18
`
` 
`
`iii
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`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
` 
`Gechter v. Davidson,
`116 F.3d 1454 (Fed. Cir. 1997) .......................................................................... 21
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .......................................................................................... 25, 29
`
`Kinetic Techs., Inc. v. Skyworks Solutions, Inc.,
`IPR2014-00529, Paper 8 (PTAB Sept. 23, 2014) ............................................... 29
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 55
`
`Leo Pharm. Prods. Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .............................................................. 38, 39, 46
`
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1372 (Fed. Cir. 2012) .......................................................................... 25
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 33
`
`Pitney Bowes, Inc. v. Hewlett-Packard Co.,
`182 F.3d 1298 (Fed. Cir. 1999) .......................................................................... 23
`
`Procter & Gamble Co. v. Teva Pharm. USA Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ............................................................................ 35
`
`Federal Regulations
`
`37 C.F.R. § 42.65(a) ........................................................................................... 31, 37
`
`
`
`
`
` 
`
`iv
`
`
`
`
`

`

`UCD
`
`ULN
`
`LPI
`
`PAA
`
`PAGN
`
`UCDC
`
`HPN-100
`
`AUC
`
` 
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`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
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`TABLE OF ABBREVIATIONS
`
`Abbreviation
`
`Definition
`
`urea cycle disorder
`
`upper limit of normal
`
`lysinuric protein intolerance
`
`phenylacetic acid
`
`phenylacetylglutamine
`
`Urea Cycle Disorder Consortium
`
`glyceryl tri-[4-phenylbutyrate]
`
`area under the curve
`
`
`
`
`
`v
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` 
`I.
`
`Introduction
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`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`Lupin has failed to meet its burden of establishing that claims 1-15 of U.S.
`
`Patent No. 9,095,559 (“the ’559 patent”) are not patentable. Accordingly, Horizon
`
`respectfully requests that the Board affirm the patentability of these claims.
`
`The Board instituted inter partes review proceedings on obviousness
`
`grounds based on Lupin’s mischaracterizations of the prior art and Lupin’s reliance
`
`on an affidavit by a doctor who is not a qualified expert in the field of the claimed
`
`inventions. As demonstrated herein, one of ordinary skill in the art would not have
`
`been led to the claimed treatment methods based on the prior art that Lupin has
`
`identified. Indeed, Lupin’s obviousness position is nothing but a hindsight analysis
`
`of the prior art using the claimed inventions as a roadmap to concoct a theory as to
`
`how one would have allegedly arrived at these treatment methods. The Supreme
`
`Court and the Federal Circuit have repeatedly stated that this type of hindsight
`
`approach to obviousness is improper.
`
`The ’559 patent concerns an ingenious solution to one of the most
`
`perplexing problems in modern medicine, i.e., how to treat a patient suffering
`
`from a nitrogen retention disorder such as urea cycle disorder (“UCD”). And
`
`this solution was desperately needed. A nitrogen retention disorder involves
`
`the accumulation of potentially fatal levels of ammonia in one’s blood because
`
`1
`
`
`

`

` 
`one’s body is unable to remove excess nitrogen like most humans. This is a
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`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
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`genetic disorder that is extremely rare (only 113 new U.S. patients per year),
`
`difficult to diagnose, and, most alarmingly, has an extremely low survival rate
`
`(an estimated 65% mortality rate in newborns presenting with UCD).
`
`Fortunately, the inventors of the ’559 patent took a fresh look at this
`
`serious medical issue and went against the grain to pursue a treatment
`
`approach that defied common wisdom at that time. Namely, prior to the ’559
`
`patent, the prior art consistently taught that there was no need to change the
`
`course of treatment for a UCD patient if that patient’s plasma ammonia level
`
`was within the normal range. Moreover, as confirmed by internationally
`
`recognized UCD expert, Dr. Gregory Enns, treating clinicians did not target any
`
`specific plasma ammonia level within the normal range and did not take into
`
`account whether a plasma ammonia level was taken in a fasted or fed state when
`
`making treatment decisions. Instead, treating clinicians focused on avoiding
`
`extremely high plasma ammonia levels far above the normal range by making
`
`complex adjustments to a patient’s diet, using amino acid supplements, managing a
`
`patient’s overall health, and/or prescribing nitrogen scavenging drugs. And as to
`
`the latter, the prior art disclosed increasing the dose of a nitrogen scavenging drug
`
`2
`
`
`

`

` 
`dosage only when a patient’s plasma ammonia level was above the upper limit of
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`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
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`normal.
`
`The inventors of the ’559 patent, however, discovered that UCD
`
`treatment could be improved by making adjustments to the dosage of a
`
`nitrogen scavenging drug even when a patient’s plasma ammonia level was
`
`within the normal range. They also surprisingly determined that a fasting plasma
`
`ammonia level not exceeding half of the upper limit of normal was a clinically
`
`useful and practical target that was statistically predictive of average daily
`
`ammonia levels over twenty-four hours. These discoveries were critical for
`
`patients with rare and debilitating UCDs because they eliminated confusion over
`
`conflicting ammonia levels and provided a statistically reliable basis for adjusting
`
`the dosage of a nitrogen scavenging medication. Most importantly, they provided
`
`assurance that a patient would have an optimally controlled ammonia level and
`
`would be unlikely to suffer from hyperammonemia.
`
`The claimed methods of the ’559 patent embody these discoveries. They
`
`recite methods of treating UCD patients using a specific nitrogen scavenging drug
`
`known as glyceryl tri-[4-phenylbutyrate] (also known as “HPN-100”). They recite
`
`the administration of an increased or initial dosage of this particular drug to a
`
`patient having a plasma ammonia level that is between half the upper limit of
`
`3
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`

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`normal and the upper limit of normal. And dependent claim 5 recites a method
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`U.S. Patent No. 9,095,559
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`that involves targeting a plasma ammonia level that is below half the upper limit of
`
`normal.
`
`In its Institution Decision, the Board focused on Lupin’s contention that it
`
`would have been obvious for one of ordinary skill in the art to increase the dosage
`
`of a patient’s nitrogen scavenging medication even when that patient’s fasting
`
`plasma ammonia level was in the normal range because maintaining the plasma
`
`ammonia level within the normal range was the goal for treating UCD and it was
`
`known that plasma ammonia levels vary during the day, including after eating.
`
`Lupin, however, provided no credible support for this contention.
`
`First, none of the art that Lupin identified suggests modifying the treatment
`
`for a patient who has achieved a plasma ammonia level that is within the normal
`
`range. In other words, none of the art suggests that there is any need to continue to
`
`tinker with what has already been fixed and considered normal. To the contrary,
`
`the ’859 Publication (Ex. 1007) (and the prior art as a whole) teaches the opposite,
`
`i.e., that a normal plasma ammonia level is acceptable and indicative of an
`
`effective treatment. And it discloses increasing the dosage of a nitrogen
`
`scavenging medication only when the plasma ammonia level is above normal.
`
`4
`
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`

`

`Moreover, the unsupported testimony of Dr. Vaux does not cure this
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`U.S. Patent No. 9,095,559
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` 
`
`deficiency. Indeed, a close examination of the citations in his affidavit reveals that
`
`the material that Dr. Vaux cites often does not even discuss, let alone support, the
`
`point for which he is citing that material. Furthermore, given the rarity,
`
`complexity, and life-threatening nature of UCDs, only a limited number of
`
`specialized medical experts (such as Horizon’s expert, Dr. Enns) have the
`
`qualifications to treat these genetic disorders, and, with all due respect to Dr. Vaux,
`
`he is not qualified to provide an expert opinion regarding how such specialists
`
`would treat UCDs.
`
`In addition, Dr. Vaux fails to address that the prior art upon which he relies
`
`would have discouraged the skilled artisan from combining these items as he
`
`proposes. For example, Simell (Ex. 1005) discusses the intravenous administration
`
`of sodium benzoate and phenylacetate to treat acute hyperammonemia, whereas the
`
`’859 Publication discusses the administration of a different drug (glyceryl tri-[4-
`
`phenylbutyrate) through a different route of administration (oral) for a different
`
`purpose (chronic management of UCD). Dr. Vaux does not address the critical
`
`differences between these drugs, their mechanisms of metabolism, routes of
`
`administration, or treatment indications. Furthermore, contrary to his declaration,
`
`5
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`

`

` 
`Dr. Vaux admitted at his deposition that Simell concerns an experiment on patients
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`U.S. Patent No. 9,095,559
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`with lysinuric protein intolerance, not UCD.
`
`In view of these many differences, Simell is not relevant to the claimed
`
`methods directed to the oral administration of increased or initial dosages of
`
`glyceryl tri-[4-phenylbutyrate] to patients with normal plasma ammonia levels, and
`
`Lupin and Dr. Vaux have provided no credible motivation for the skilled artisan to
`
`combine the Simell teachings with that of the ’859 Publication. Similarly, Blau
`
`relates only to the diagnosis of metabolic diseases and not their treatment, and
`
`Lupin and Dr. Vaux have provided no motivation for the skilled artisan to combine
`
`its teachings with that of the ‘859 Publication.
`
`As discussed, Lupin and Dr. Vaux also have not identified any prior art
`
`indicating that there is any concern with a patient having a plasma ammonia level
`
`in the normal range, let alone that one should increase the dosage of a nitrogen
`
`scavenging drug for a patient with such a normal plasma ammonia level as in
`
`independent claims 1-3. Nor has Lupin identified any prior art that would have led
`
`a skilled artisan to target a plasma ammonia level below half the upper limit of
`
`normal as recited in dependent claim 5.
`
`Finally, Lupin has failed to present any evidence that one of ordinary skill in
`
`the art would have had a reasonable expectation of success in treating UCD (i.e.
`
`6
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`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
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`reducing the incidence and frequency of hyperammonemia) based onthe priorart.
`
`Indeed, Lupin’s Petition does not even mention this required element of an
`
`obviousness analysis, nor does Dr. Vaux provide any discussion of this element.
`
`Consequently, on this basis alone, Lupin has failed as a matter of law to establish
`
`that the subject matter of claims 1-15 would have been obvious.
`
`Il.
`
`Background
`
`A.
`
`Prior Art at Issue
`
`The Board instituted this IPR based on the °859 Publication (Ex. 1007),
`
`Simell (Ex. 1005), Blau (Ex. 1006), and Brusilow ’84 (Ex. 1004) in the following
`
`manner:
`
`1, 2, 4, 5, 7-10, 12, and 13
`
`Blau, Simell, and the ’859 Publication
`
`Blau, Simell, the °859 Publication, and Brusilow ’84
`
`3, 6, 11, 14, and 15
`
`B.
`
`Technical Background on UCD and the Complexity Involved in
`Treating UCD Patients
`
`In conducting an obviousness analysis one must consider the state of the art
`
`at the time of the claimed inventions. Asnoted, a patient with a nitrogen retention
`
`disorder such as UCD cannot remove excess nitrogen from her body, and this
`
`

`

` 
`results in elevated blood ammonia levels. (Ex. 1001 at 1:15-20; Ex. 2006 at ¶¶ 31-
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`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
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`32.) This genetic disorder is extremely rare and difficult to diagnose. (Ex. 2006 at
`
`¶¶ 28, 32, 33.) It is estimated that one out of only 35,000 live births have this
`
`disorder, resulting in only 113 new patients in the U.S. per year. (Ex. 2042 at 1-2;
`
`Ex. 2006 at ¶¶ 28, 33; see also Ex. 2019 at 1-2.) Even experienced metabolic
`
`physicians may only manage fewer than a total of 50 UCD patients during their
`
`career. (Ex. 2006 at ¶ 28; see Ex. 2044 at S86.) Symptoms of this disorder often
`
`appear within 24 to 48 hours after a normal birth when a newborn begins to exhibit
`
`progressive lethargy, hypothermia, and apnea. (Ex. 2006 at ¶ 34; Ex. 2033 at 1;
`
`Ex. 2019 at 2.) Onset of symptoms, however, can appear at any age. (Ex. 2006 at
`
`¶ 34; Ex. 2019 at 2.) Unfortunately, survival in patients with a UCD is extremely
`
`low because high levels of ammonia (hyperammonemia) are extremely toxic to the
`
`brain. (Ex. 2006 at ¶¶ 33-34; Ex. 2008 at 1; Ex. 2020 at 21.) Between 1982 and
`
`2003, patients presenting with hyperammonemia within the first 30 days of life had
`
`only a 35% survival rate (65% mortality rate). (Ex. 2006 at ¶¶ 28, 34; Ex. 2043 at
`
`1423; see also Ex. 2017 at S66.) High ammonia levels primarily cause stupor,
`
`convulsions, and if left untreated, coma and death. (Ex. 2006 at ¶¶ 33, 34; Ex.
`
`2016 at 1605S-1606S.)
`
`8
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`

`

`Over the years, genetic specialists have developed emergency protocols to
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`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
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` 
`
`treat patients undergoing acute episodes of hyperammonemia. (Ex. 2006 at ¶ 24;
`
`see, e.g. Ex. 2023; see also Ex. 2025.) These protocols include discontinuing
`
`protein intake, intravenous infusions of sodium benzoate and phenylacetate, and
`
`dialysis. (Ex. 2006 at ¶ 34; Ex. 2025 at S2; Ex. 2017 at S65-66; Ex. 2023.) But
`
`even when plasma ammonia levels are brought back down to normal, the prior
`
`periods of high ammonia levels often cause irreversible damage to the central
`
`nervous system, leaving patients with severe neurological and developmental
`
`disabilities. (Ex. 2006 at ¶ 34; Ex. 2016 at 1605S-06S; Ex. 2017 at S68 (reporting
`
`that only 21% of patients ages 12-74 months had an IQ over 70; Ex. 2019 at 2.)
`
`A UCD diagnosis therefore presents a patient and one’s family with a life-
`
`time of coordinating a complex therapeutic regimen that involves promoting a
`
`child’s growth/development while concurrently trying to avoid the potentially
`
`devastating consequences of a hyperammonemic crises. (Ex. 2006 at ¶¶ 35-36, 41;
`
`Ex. 2017 at S67; Ex. 2018 at 104; Ex. 2033 at 46; Ex. 2008 at 8; Ex. 2021 at 32;
`
`Ex. 1001 at 4:29-36; Ex. 2019 at 12.) This coordination is a complicated balance
`
`made even more difficult by numerous external factors, such as stress and illness,
`
`which cause increases in a patient’s plasma ammonia levels. (Ex. 2006 at ¶ 43; Ex.
`
`1010 at 4; Ex. 2021 at 33.) Chronic UCD treatment also requires a balanced
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`9
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`therapeutic regimen involving low-protein diets, amino acid supplementation, and
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`Case No. IPR2016-00829
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`alternative pathway therapy with nitrogen scavenging drugs. (Ex. 2006 at ¶¶ 36-
`
`40; Ex. 2019 at 12; Ex. 2017 at S67-68.) Because of the rarity and complexity of
`
`UCD, it requires the supervision of specialists in metabolic genetic disorders rather
`
`than general practitioners. (Ex. 2006 at ¶¶ 27-29; Ex. 2017 at S66, S69 (discussing
`
`the importance of specialized metabolic centers and the increase in survival of
`
`UCD patients when treated in specialized metabolic centers); Ex. 2040 at S33
`
`(“Newborns with UCDs should be treated by a team of experienced personnel and
`
`in facilities with special resources. The community physicians should be aware of
`
`these facilities and how to reach them.”); Ex. 2044 at S87 (stressing the need to
`
`transport patients to a dedicated UCD facility).) Even Dr. Vaux, who was retained
`
`by Lupin, noted in a book review of Clinical Guides to Inherited Metabolic
`
`Diseases that for most clinicians a patient with an inborn error of metabolism
`
`remains “intimidating.” (Ex. 2037.)
`
`Dietary treatment is the “cornerstone of therapy” for UCD patients because
`
`minimizing protein intake will decrease the nitrogen load on the urea cycle. (Ex.
`
`2006 at ¶ 37; Ex. 2019 at 12-13.) But protein restriction decreases the nutrients
`
`needed for growth and normal development that are essential for a growing child.
`
`(Ex. 2006 at ¶ 37; Ex. 2019 at 12-13.) Therefore supplementation with essential
`
`10
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`amino acid mixtures or the use of nitrogen scavenging drugs is often necessary to
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`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
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`achieve good metabolic control. (Ex. 2006 at ¶ 37; Ex. 2021 at 32-33; Ex. 2019 at
`
`12-13; Ex. 2025 at S3-S4.)
`
`Nitrogen scavenging drugs use a different pathway than the urea cycle to
`
`excrete excess nitrogen. (Ex. 2006 at ¶ 38; Ex. 1001 at 1:54-63.) One such
`
`nitrogen scavenging drug is glyceryl tri-[4-phenylbutyrate] (“HPN-100”), which is
`
`a pre-prodrug of phenylacetic acid (“PAA”). (Ex. 2006 at ¶ 38; Ex. 1001 at 1:64-
`
`2:46.) It undergoes beta oxidation by the fatty acid oxidation cycle to produce
`
`PAA, which converts in vivo to phenylacetylglutamine (“PAGN”). (Ex. 2006 at
`
`¶ 38; Ex. 1001 at 1:64-2:46.) PAGN is then excreted in the urine, bypassing the
`
`urea cycle. (Ex. 2006 at ¶ 38; Ex. 1001 at 1:64-2:46.) Each molecule of glutamine
`
`contains two nitrogen atoms, allowing the body to eliminate two waste nitrogen
`
`atoms for every molecule of PAGN excreted. (Ex. 2006 at ¶ 39; Ex. 1001 at 1:64-
`
`2:46.)
`
`In addition to a therapeutic regimen for controlling plasma ammonia levels,
`
`a UCD patient also must endure the lifelong monitoring of the patient’s growth and
`
`development, use of dietary assessments, and laboratory testing of plasma
`
`glutamine levels, plasma ammonia levels, and amino acid profiles. (Ex. 2006 at
`
`¶¶ 41-42; Ex. 2025 at S3-S4; Ex. 2019 at 17-18; Ex. 2010 at 925; Ex. 2015 at 73.)
`
`11
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`

`

` 
`Moreover, although the prior art notes that clinicians must monitor a patient’s
`
`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`clinical status and blood ammonia level to track the effectiveness of a treatment,
`
`there are inherent difficulties with the interpretation of blood ammonia levels that
`
`have undermined its usefulness as a diagnostic tool. (Ex. 2006 at ¶¶ 41-43; Ex.
`
`2015 at 75; Ex. 2012 at [0047], [0090]; Ex. 2020 at 22; Ex. 1006 at 275.) With any
`
`given individual, ammonia values undergo a several-fold fluctuation throughout
`
`the day. (Ex. 2006 at ¶ 43; Ex. 2012 at [0090].) While a fasting value may be the
`
`lowest value for a patient over the course of a day, it may also be artificially high if
`
`a patient is in a catabolic state because of reduced protein intake. (Ex. 2006 at
`
`¶ 43; Ex. 1012 at 214, Fig. 2, 219; Ex. 2015 at 75, Box 1.) In addition to diet,
`
`factors such as infection, routine surgery, pregnancy, medication, and exercise, can
`
`cause an increase in plasma ammonia levels. (Ex. 2006 at ¶ 43; Ex. 2016 at 1608S;
`
`Ex. 2021 at 33; Ex. 2015 at 75, Box 1.)
`
`Given the unpredictable fluctuations of ammonia values, clinicians did not
`
`use normal plasma ammonia levels prior to the ’559 patent as a basis to adjust a
`
`patient’s treatment. (Ex. 2006 at ¶ 43.) Clinicians only considered plasma
`
`ammonia levels well above the upper limit of normal as cause to take further
`
`action. (Ex. 2006 at ¶ 43, 111-121; Ex. 2019 at 9, Table 4 (action taken when
`
`above the upper limit of normal); Ex. 2009 at S51 (“aim of long-term therapy has
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`been to maintain metabolic control with plasma ammonia concentrations less than
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`twice normal”) (emphasis added).)
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`C. Overview of the ’559 Patent
`The ’559 patent addresses the limitations in the art noted above. For
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`example, the ’559 patent explains that the dosing of nitrogen scavenging drugs is
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`usually based upon the clinical assessment and measurement of ammonia, but such
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`assessment and treatment are confounded by the fact that individual ammonia
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`values vary over the course of a day and are impacted by the timing of the blood
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`draw. (Ex. 1001 at 4:36-43; Ex. 2006 at ¶ 44.) The inventors of the ’559 patent
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`therefore identified a need for improved methods of determining the appropriate
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`dose of nitrogen scavenging drugs such as glyceryl tri-[4-phenylbutyrate] to use in
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`subjects having nitrogen retention disorders. (Ex. 1001 at 2:58-62; Ex. 2006 at
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`¶ 44.)
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`In response to this need, the inventors investigated the previously unknown
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`relationship between a fasting ammonia level and daily ammonia exposure. (Ex
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`1001 at 4:64-5:53, Example 1; Ex. 2006 at ¶ 45.) They discovered that a fasting
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`ammonia level correlated with daily ammonia exposure. (Ex 1001 at 4:64-5:53,
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`Example 1; Ex. 2006 at ¶ 45.) Based on this correlation, the inventors determined
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`that an ammonia value that does not exceed half of the upper limit of normal is a
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`clinically useful and practical target that is statistically predictive of average daily
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`ammonia values over twenty-four hours. (Ex. 1001 at 5:2-18, 5:54-67; Ex. 2006 at
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`¶ 45.) They used this data to develop methods for adjusting the dosage of a
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`nitrogen scavenging drug. (Ex. 1001 at 2:66-3:12; Ex. 2006 at ¶ 45.) These
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`patented methods provide significant advantages over previous dosing methods by
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`eliminating the confusion over conflicting ammonia levels, assuring ammonia
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`control, and providing a statistical basis for the adjustment of glyceryl tri-[4-
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`phenylbutyrate] dosages. (Ex. 1001 at 5:13-18, 15:11-15; Ex. 2006 at ¶ 45.)
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`Example 1 of the ’559 patent details the inventors’ analysis of the
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`relationship between fasting ammonia levels and the profile of ammonia levels
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`over twenty-four hours. (Ex. 1001 at 14:60-15:15; Ex. 2006 at ¶ 46.) The
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`inventors looked at steady-state and fasting ammonia data from sixty-five patients
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`across two Phase 2 studies and one Phase 3 study. (Ex. 1001 at 15:16-65; Ex. 2006
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`at ¶ 46.) They observed a positive and strong relationship between the fasting
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`ammonia levels and the area under the curve (AUC) over twenty-four hours. (Ex.
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`1001 at 16:10-14; Ex. 2006 at ¶ 46.) By employing modeling with Generalized
`
`Estimating Equations, they were able to predict the average daily or highest
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`achieved ammonia level based on this fasting plasma ammonia value. (Ex. 1001 at
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`16:15-17:55, Table 2; Ex. 2006 at ¶ 46.) Based on the results of this modeling, the
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`inventors concluded with 95% confidence that the true probability of having an
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`ammonia value AUC in the desired normal range when a fasting ammonia level is
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`less than or equal to half the upper limit of normal is on average 84% and as high
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`as 93%. (Ex. 1001 at 17:56-60; Ex. 2006 at ¶ 46.) The ability to predict with such
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`statistical confidence the highest potential ammonia a patient may experience
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`during the day and the average twenty-four hour ammonia from a single
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`measurement was previously unknown and has important practical implications for
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`nitrogen scavenging drug dosing guidelines and patient management. (Ex. 1001 at
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`15:11-15; Ex. 2006 at ¶¶ 47-49.)
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`III. Lupin’s Definition of One of Ordinary Skill in the Art is Overly Broad
`The definition of one of ordinary skill in the art is particularly important in
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`the present case given the rarity and complexity of nitrogen retention disorders
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`such as UCD. And this is even more so given that the ’559 patent claims address
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`methods of administering and adjusting the dosage of a nitrogen scavenging
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`medication in subjects being treated for urea cycle disorder, a complex genetic
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`condition. (Ex. 1001 at 24:20-26:21; Ex. 2006 at ¶ 27.) Importantly, the ‘559
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`patent is not about merely diagnosing that a patient is suffering from UCD, but
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`rather is directed to the complicated treatment of such patients. (Ex. 2006 at ¶ 27.)
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`Accordingly, based on the subject matter of the ’559 patent claims, a person of
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`ordinary skill in the art would have been someone who had: (a) an M.D. or
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`equivalent degree; (b) at least three years of residency/fellowship training in
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`Medical Genetics, including Biochemical Genetics, followed by certification in
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`Clinical Genetics and Clinical Biochemical Genetics by the American Board of
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`Medical Genetics and Genomics; and (c) at least five years of experience treating
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`patients with nitrogen retention disorders, including UCD. (Ex. 2006 at ¶ 26.)
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`Horizon’s expert Dr. Enns meets this definition. (See Ex. 2006 at ¶¶ 5-16.)
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`He is a Professor of Pediatrics-Medical Genetics at the Lucile Salter Packard
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`Children’s Hospital of Stanford University and is an internationally recognized
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`expert in UCD treatment. (Ex. 2006 at ¶¶ 8-9; Ex. 2007 at 1.) He completed a
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`three-year residency in medical genetics at the University of California, San
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`Francisco, and is board certified in Clinical Genetics and Clinical Biochemical
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`Genetics. (Ex. 2006 at ¶¶ 6-7; Ex. 2007 at 2.) These certifications demonstrate
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`that he possesses, inter alia, “the ability to integrate clinical and genetic
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`information and understand the uses, limitations, interpretation, and significance of
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`specialized laboratory and clinical procedures.” (See generally, Ex. 2026; Ex. 2006
`
`at ¶ 7.) He also has much more than five years of experience treating patients with
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`UCD, maintains an active clinical practice focused on the ongoing management of
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`patients with inborn errors of metabolism, has treated approximately one hundred
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`UCD patients over the course of his career, and currently provides treatment for
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`approximately forty UCD patients. (Ex. 2006 at ¶¶ 6, 9-11; Ex. 2007.) This is a
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`significant number given that many experienced metabolic physicians may only
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`ever manage far fewer than 50 UCD patients. (Ex, 2044 at S86.)
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`Dr. Enns also has published a number of articles in peer-reviewed journals
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`regarding UCD treatment, has authored book chapters and reviews on alternative
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`pathway therapies, and has served on the editorial boards of major journals in the
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`field of medical genetics. (Ex. 2006 at ¶¶ 12-13; Ex. 2007 at 10-45; see also Ex.
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`2017.) Dr. Enns testifies that Horizon’s definition of one of ordinary skill is
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`appropriate for the claimed subject matter and that he meets (and exceeds) this
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`definition. (See Ex. 2006 at ¶¶ 17, 26.)
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`Lupin, in contrast, proposes that one of ordinary skill in the art would have
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`been a physician with an M.D. degree, a residency in pediatrics or internal
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`medicine, and specialized training in the diagnosis or treatment of inh