IN THE 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.
`_________________
`
`DECLARATION OF KEITH VAUX, M.D.
`
`Horizon Exhibit 2052
`Lupin v. Horizon
`IPR2017-01159
`
`Page 1 of 46
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`

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`Table of Contents
`
`QUALIFICATIONS ................................................................................................... 4
`I.
`INFORMATION CONSIDERED .......................................................................... 6
`II.
`SUMMARY OF OPINIONS AND EXPECTED TESTIMONY ................... 9
`III.
`LEGAL STANDARDS ........................................................................................... 10
`IV.
`A. Law of Obviousness .................................................................................... 10
`B.
`Person of Ordinary Skill in the Art ............................................................. 12
`C. Claim Construction ...................................................................................... 13
`BACKGROUND AND STATE OF THE ART ................................................ 13
`V.
`A. The Urea Cycle ............................................................................................ 13
`B. Use of Nitrogen Scavenging Drugs ............................................................. 16
`C. The Metabolic Fate of PBA and PAA ......................................................... 19
`D. Overview of Applied Prior Art References ................................................. 21
`1. MacArthur ................................................................................................ 21
`2.
`Enns 2010 ................................................................................................. 23
`3.
`Thibault .................................................................................................... 25
`Piscitelli .................................................................................................... 26
`4.
`5.
`Zeitlin ....................................................................................................... 27
`6.
`Simell........................................................................................................ 28
`OVERVIEW OF THE ’197 PATENT ................................................................ 29
`VI.
`A. The ’197 Patent Claims ............................................................................... 31
`VII.
`THE ’197 PATENT CLAIMS ARE OBVIOUS IN VIEW OF THE PRIOR
`ART .............................................................................................................................. 31
`A. Claims 1 and 2 of the ’197 Patent Would Have Been Obvious Over Enns
`2010, MacArthur, and Piscatelli, in View of the Knowledge of a Person of
`Ordinary Skill in the Art ............................................................................. 31
`Overview of Applied Prior Art ................................................................ 31
`1.
`2. Motivation to Combine Applied Prior Art ............................................... 32
`3.
`Independent Claim 1 ................................................................................ 36
`4.
`Independent Claim 2 ................................................................................ 39
`
`Page 2 of 46
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`

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`5.
`VIII.
`
`There is No Teaching Away .................................................................... 43
`SIGNATURE ............................................................................................................. 45
`
`Page 3 of 46
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`

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`I, Keith Vaux, M.D., declare and state as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I am a medical doctor with specialty training in Pediatrics and Clinical
`
`Genetics. I am currently the co-founder of Point Loma Pediatrics, where I
`
`maintain a pediatrics practice.
`
`2.
`
`From 2009 through 2017, I was an Associate Professor and then
`
`Professor in the Division of Medical Genetics in the Department of Medicine at
`
`UC San Diego. From 2014 through 2017, I was the Clinical Chief and Director of
`
`the Division of Genetics in the Department of Medicine at UC San Diego. I also
`
`had an appointment as Professor of Neurosciences at UC San Diego from 2015
`
`through 2017. Since 1994, I have regularly diagnosed and treated patients with
`
`urea cycle disorders (“UCD”), and continue to do so today. In treating UCD
`
`patients, I regularly prescribe nitrogen scavenging drugs and treat patients who are
`
`maintained on therapy with nitrogen scavenging drugs.
`
`3.
`
`I received a B.A. in History, Philosophy and Social Studies of Science
`
`and Medicine from the University of Chicago in 1987, and an M.D. from the
`
`University of Chicago in 1994. I have an unrestricted license to practice medicine
`
`in the State of California.
`
`4.
`
`After medical school, I completed a three year residency in pediatrics,
`
`including a year as Chief Resident, from 1994-1997. The recognition, immediate
`
`Page 4 of 46
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`

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`and long-term management, and consideration of the long-term prognosis, of Urea
`
`Cycle Defects is a core competency for training and board certification in
`
`Pediatrics. Following two years of isolated clinical pediatric practice and critical
`
`care transport in Guam and two years as a practicing pediatrician and faculty
`
`member at the Naval Medical Center, I completed a three-year fellowship in
`
`dysmorphology and medical genetics with an additional certificate in teratology
`
`(environmentally induced birth defects) at UC San Diego from 2001 to 2004. I am
`
`Board Certified by the American Board of Pediatrics (received in 1997 and
`
`recertified in 2007 and 2015), am a Fellow of the American Academy of Pediatrics
`
`and serve on the AAP National Council on Children with Disabilities and Society
`
`on Genetics and Birth Defects. I am a member of the California Department of
`
`Public Health, Genetic Diseases Screening Program Biobank Committee which
`
`address policy issues surrounding metabolic screening in newborns.
`
`5.
`
`As a professor, I taught Medical Students, Medical and Pediatric
`
`Residents and Specialty Fellows in Genetics, Complex Care Pediatrics and
`
`Metabolic Diseases. I have published in peer-reviewed journals on metabolic
`
`disorders. I regularly speak at national and international conferences on a variety
`
`of genetic, metabolic and genomic medicine topics.
`
`Page 5 of 46
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`

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`6.
`
`A copy of my curriculum vitae, which sets forth my education and
`
`experience in further detail, is provided herewith as Exhibit 1021.
`
`7.
`
`I have been engaged as an expert on behalf of Petitioners Lupin, Ltd.
`
`and Lupin Pharmaceuticals, Inc. I am being compensated for my time at my
`
`standard consulting rate of $670/hour. My compensation in no way depends on the
`
`outcome of this proceeding or the content of my opinions.
`
`8.
`
`In the previous four years, I have testified by trial or deposition in the
`
`following matters:
`
`• Fields v. Eli Lilly and Company; October 2014;
`
`• Schomake v. Eli Lilly and Company; November 2014;
`
`• Brookes Issue; February 2015; and
`
`• Lupin Ltd. et al. v. Horizon Therapeutics LLC; January 2017.
`
`II.
`
`INFORMATION CONSIDERED
`
`9.
`
`In forming the opinions set forth herein, I have relied on my own
`
`experiences and knowledge. I have also considered the documents discussed
`
`herein, which include the following:
`
`a. U.S. Patent No. 9,561,197 (the “’197 Patent”) (Ex. 1001);
`
`b. Enns, G.M., Alternative waste nitrogen disposal agents for urea cycle
`
`disorders, 135-152 (Small Molecule Therapy for Genetic Disorders,
`
`Page 6 of 46
`
`

`

`Cambridge University Press, Jess G. Thoene, Ed. 2010) (“Enns
`
`2010”) (Ex. 1003);
`
`c. MacArthur, et al., Pharmacokinetics of sodium phenylacetate and
`
`sodium benzoate following intravenous administration as both a bolus
`
`and continuous infusion to healthy adult volunteers, 81 Molecular
`
`Genetics and Metabolism, S67-S73 (2004) (“MacArthur”) (Ex. 1004);
`
`d. Simell, et al., Waste Nitrogen Excretion Via Amino Acid Acylation:
`
`Benzoate and Phenylacetate in Lysinuric Protein Intolerance, 20
`
`Pediatric Research, 1117-1121 (1986) (“Simell”) (Ex. 1005);
`
`e. U.S. Patent Publication No. 2010/0008859, filed January 7, 2009,
`
`published January 14, 2010 (the “’859 Publication”) (Ex. 1007);
`
`f. Batshaw, et al., Alternative Pathway Therapy for Urea Cycle
`
`Disorders: Twenty Years Later, 138 J. Pediatrics, S46-S55 (2001)
`
`(“Batshaw”) (Ex. 1008);
`
`g. Thibault, et al., A Phase I and Pharmacokinetic Study of Intravenous
`
`Phenylacetate in Patients with Cancer, 54 Cancer Research, 1690-
`
`1694 (1994) (“Thibault”) (Ex. 1009);
`
`Page 7 of 46
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`

`

`h. Piscitelli, et al. Disposition of Phenylbutyrate and its Metabolites,
`
`Phenylacetate and Phenylacetylglutamine, 35 J. Clin. Pharmacol,
`
`368-373 (1995) (“Piscitelli”) (Ex. 1010)
`
`i. Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle for
`
`Waste Nitrogen Excretion, 29 Pediatric Research, 147-150 (1991)
`
`(“Brusilow ’91”) (Ex. 1011);
`
`j. Zeitlin, et al., Evidence of CFTR Function in Cystic Fibrosis after
`
`Systemic Administration of 4-Phenylbutyrate, 6 Mol. Ther., 119-126
`
`(2002) (“Zeitlin”) (Ex. 1012);
`
`k. McGuire, et al., Pharmacology and Safety of Glycerol Phenylbutyrate
`
`in Healthy Adults and Adults with Cirrhosis, 51 Hepatology, 2077-
`
`2085 (2010) (“McGuire”) (Ex. 1015);
`
`l. Excerpts from Molecular Genetics and Metabolism 105 (2012) 273-
`
`366 (March 2012) (Ex. 1016);
`
`m. BUPHENYL® label, Physician’s Desk Reference, 60th ed. (2006),
`
`3327–28 (“BUPHENYL Label”) (Ex. 1018);
`
`n. AMMONUL® label, Physician’s Desk Reference, 60th ed. (2006),
`
`3323–26 (“AMMONUL Label”) (Ex. 1019); and
`
`Page 8 of 46
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`

`

`o. Thompson et al., Pharmacokinetics of Phenylacetate Administered as
`
`a 30-min Infusion in Children With Refractory Cancer, 52 Cancer
`
`Chemother. Pharmacol. 417-423 (2003) (“Thompson”) (Ex. 1022).
`
`III.
`
`SUMMARY OF OPINIONS AND EXPECTED TESTIMONY
`
`10.
`
`I have reviewed the documents referenced above, in view of my own
`
`knowledge and experience concerning the treatment of UCD patients with nitrogen
`
`scavenging drugs. As explained in detail herein, it is my opinion that at the earliest
`
`priority for the alleged inventions (which I am advised is April 2012), a person of
`
`ordinary skill in the art would have been aware of and motivated to carry out
`
`methods of treating a urea cycle disorder in a subject having a plasma phenylacetic
`
`acid (“PAA”)1 to phenylacetylglutamine (“PAGN”) ratio outside of a specified
`
`1 The ’197 patent defines PAA as “phenylacetic acid.” (Ex. 1001 (’197 patent) at
`
`2:4-10; 2:38-55.) A person of ordinary skill in the art would understand that
`
`“phenylacetic acid” encompasses either phenylacetic acid or its conjugate base,
`
`phenylacetate. As used herein, PAA means either phenylacetic acid or
`
`phenylacetate. Similarly, a person of ordinary skill in the art would understand
`
`that “phenylbutyric acid” encompasses either phenylbutyric acid or its conjugate
`
`base, phenylbutyrate. As used herein, PBA means either phenylbutyric acid or
`
`phenylbutyrate.
`
`Page 9 of 46
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`

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`range with glyceryl tri-[4-phenylbutyrate] (also known as “HPN-100”) effective to
`
`achieve a plasma PAA to PAGN ratio within the range.
`
`11.
`
`In my opinion, the subject matter of each claim of the ’197 patent was
`
`obvious in view of the prior art, as discussed further below.
`
`IV. LEGAL STANDARDS
`A. Law of Obviousness
`12.
`I have been informed that if the differences between the subject matter
`
`claimed in a patent and the prior art are such that the claimed subject matter as a
`
`whole would have been obvious to a person of ordinary skill at the time of the
`
`alleged invention, then the patent claim is unpatentable as obvious. I understand
`
`that the following factors must be evaluated in determining whether the claimed
`
`subject matter is obvious: (1) the scope and content of the prior art; (2) the
`
`differences between the claim and the prior art; (3) the level of ordinary skill in the
`
`art at the time the patent was filed; and (4) any “secondary considerations” of
`
`nonobviousness.
`
`13.
`
`I have been informed that “secondary considerations” of non-
`
`obviousness include: (i) any long-felt and unmet need in the art that was satisfied
`
`by the invention of the patent; (ii) failure of others to achieve the results of the
`
`invention; (iii) commercial success of products and processes covered by the
`
`invention; (iii) unexpected results achieved by the claimed invention; (iv)
`
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`

`deliberate copying of the invention by others in the field; (v) taking of licenses
`
`under the patent by others; (vi) expressions of disbelief or skepticism by those
`
`skilled in the art upon learning of the invention; (vii) praise of the invention by
`
`others skilled in the art; and (viii) lack of contemporaneous and independent
`
`invention by others. I understand that evidence of potential secondary
`
`considerations must have a nexus to the claimed invention.
`
`14.
`
`I reserve the right to respond to any secondary considerations that
`
`Patent Owner may raise.
`
`15.
`
`I have been informed that in the context of this proceeding, a claim
`
`will be found unpatentable as obvious if a preponderance of the evidence indicates
`
`that the claim would have been obvious.
`
`16.
`
`I have been informed that a claim can be obvious in light of multiple
`
`prior art references. I have been informed, however, that a patent claim is not
`
`obvious merely by demonstrating that each of its elements was, independently,
`
`known in the prior art. To be obvious in light of a combination of prior art
`
`references, there must have been a reason, at the time of the alleged invention, for
`
`a person of ordinary skill in the art to have combined the teachings of two or more
`
`references in order to achieve the claimed invention. This reason may come from a
`
`teaching, suggestion, or motivation to combine, or may come from the reference or
`
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`

`references themselves, the knowledge or “common sense” of one skilled in the art,
`
`or from the nature of the problem to be solved, and may be explicit or implicit
`
`from the prior art as a whole.
`
`17.
`
`I have been informed that a claim can be obvious if it claims an
`
`optimized range by routine experimentation when the general conditions of the
`
`claim are disclosed in the prior art.
`
`18.
`
`I have been informed that the combination of familiar elements
`
`according to known methods is likely to be obvious when it does no more than
`
`yield predictable results. I also understand it is improper to rely on hindsight in
`
`making the obviousness determination.
`
`B.
`19.
`
`Person of Ordinary Skill in the Art
`
`I have been informed that a patent is not written for the general public,
`
`but instead is directed to a “person of ordinary skill” in the field of the patent. I
`
`have been informed that factors such as the education level of those working in the
`
`field, the sophistication of the technology, the types of problems encountered in the
`
`art, the prior art solutions to those problems, and the speed at which innovations
`
`are made, help establish the level of skill in the art.
`
`20.
`
`For purposes of this declaration, I have been asked to assume that the
`
`date of the inventions for the ’197 Patent is April 20, 2012.
`
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`21.
`
`In my opinion, a person of ordinary skill in the art with respect to the
`
`’197 Patent as of April 20, 2012 would have been a physician with a M.D. degree
`
`with a residency in pediatrics or internal medicine, and would have had specialized
`
`training in the treatment of inherited metabolic disorders, including UCDs and
`
`other nitrogen retention disorders.
`
`C. Claim Construction
`I have been informed that in inter partes review proceedings, each of
`22.
`
`the terms in the patent claims is given its broadest reasonable interpretation in light
`
`of the patent specification.
`
`23.
`
`In addition, I understand that each of the challenged claims contains
`
`the transition term “comprising.” I am informed that in the patent context, the term
`
`“comprising” signals that the claims require the claimed method steps, but do not
`
`exclude additional steps.
`
`V. BACKGROUND AND STATE OF THE ART
`A. The Urea Cycle
`24.
`In the human body, the urea cycle is the major pathway for the
`
`excretion of waste nitrogen. Enzymes and transporters within the urea cycle
`
`synthesize urea from ammonia, which is then excreted in urine to remove excess
`
`nitrogen. In a patient with a UCD, an enzyme or transporter in the urea cycle is
`
`deficient, and, therefore, the patient is not able to remove excess nitrogen. The
`
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`inability to remove excess nitrogen in these patients can lead to elevated plasma
`
`ammonia levels and hyperammonemia, which in turn can lead to lethargy, coma,
`
`brain damage, and death.
`
`25.
`
`In the human body, the urea cycle is the major pathway for the
`
`metabolism and excretion of waste nitrogen. Nitrogen enters the body as
`
`constituents of the amino acids in dietary protein. Amino acids that are not used
`
`for endogenous protein synthesis are broken down, forming pools of free amino
`
`acids, including glutamine and glycine. Ammonia is liberated during the
`
`breakdown of free amino acids and through the sequential actions of carbamoyl
`
`phosphate synthetase and the enzymes of the urea cycle, wherein two moles (a unit
`
`of measurement) of amino acid nitrogen (from free ammonia and aspartate) are
`
`converted into the two moles of nitrogen in urea. Urea is then excreted in urine,
`
`removing the excess nitrogen from the body. Each urea molecule removes two
`
`nitrogen molecules. The below schematic provides a simplified overview of the
`
`urea cycle:
`
`Page 14 of 46
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`

`

`26.
`
`In UCD patients, enzymes or transporters in the urea cycle are
`
`deficient. This can cause excess dietary amino acids to be converted into ammonia
`
`that accumulates rather than get excreted, causing toxicity. There is no minimum
`
`level of blood ammonia that must be maintained for normal body function, and I
`
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`

`am not aware of any negative effects of ammonia levels that are low or even
`
`absent.
`
`B. Use of Nitrogen Scavenging Drugs
`27.
`Prior to April 20, 2012, using nitrogen scavenging drugs to treat
`
`nitrogen retention disorders such as hepatic encephalopathy and UCDs was well
`
`known. (See, e.g., Ex. 1009 (Thibault) at 1690; Ex. 1011 (Brusilow ’91) at 147;
`
`Ex. 1003 (Enns 2010) at 142, 144.) Nitrogen scavenging drugs provide an
`
`alternative pathway to the urea cycle for waste nitrogen excretion. These drugs
`
`were known to remove waste nitrogen in both normal individuals and UCD
`
`patients.
`
`28. Known nitrogen scavenging drugs as of April 20, 2012 included
`
`sodium benzoate, PAA, phenylbutyrate (“PBA”), sodium phenylbutyrate
`
`(“NaPBA,” sold as BUPHENYL), and HPN-100, or a combination of two or more
`
`of HPN-100, PBA, and sodium phenylbutyrate (“Na-PBA”). (See, e.g., Ex. 1003
`
`(Enns 2010) at 142, 144, 150; Ex. 1007 (’859 Publication) at [0022]; Ex. 1011
`
`(Brusilow ’91) at 147; Ex. 1018 (BUPHENYL Label); Ex. 1019 (AMMONUL
`
`Label).)
`
`29. Nitrogen scavenging drugs that are metabolized to PAA (which are
`
`also known as PAA prodrugs), provide an alternative mechanism for the clearance
`
`of glutamine in the form of PAGN, which like urea, carries nitrogen out of the
`
`Page 16 of 46
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`

`

`body. HPN-100, NaPBA, and PBA are PAA prodrugs. (See, e.g., Ex. 1007 (’859
`
`Publication) at [0022].) And because glyceryl tri-[4-phenylbutyrate] is converted
`
`in the body to PBA and then PAA, it is also referred to as a PAA prodrug, or a
`
`PBA prodrug. (Id. at [0022-23].)
`
`30.
`
`PAA prodrugs rapidly metabolize to PAA, and PAA in turn
`
`metabolizes to PAGN. PAGN, like urea, removes two nitrogen atoms from the
`
`body. (Ex. 1011 (Brusilow ’91) at 147; Ex. 1018 (BUPHENYL Label); Ex. 1019
`
`(AMMONUL Label).) The below schematic provides a simplified overview of the
`
`removal of nitrogen by PAA or a PAA prodrug:
`
`31. Nitrogen scavenging drugs greatly simplify the process of balancing
`
`dietary intake of nitrogen with bodily demand in patients with UCDs. These
`
`medications act prior to the release of free ammonia, providing a shunt away from
`
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`its formation. Nitrogen scavenging drugs remove excess nitrogen to bring the
`
`plasma ammonia value back to a normal range and avoid hyperammonemia, which
`
`is a metabolic disturbance characterized by an excess of ammonia in the blood.
`
`32.
`
`It was well known prior to April 2012 that treating patients with
`
`UCDs involved achieving a balance between diet, amino acid supplementation,
`
`and use of nitrogen scavenging drugs. (Ex. 1003 (Enns 2010) at 140, 141, 144.)
`
`The goal of treatment is to attain normal levels of plasma ammonia through the
`
`medication and diet. (Ex. 1004 (MacArthur) at S58; see also Ex. 1007 (’859
`
`Publication) at, e.g., [0182] (noting that subjects treated with HPN-100 can
`
`“achieve and maintain normal plasma ammonia levels”).)
`
`33. Given that excess ammonia can lead to short term health challenges,
`
`and long term intellectual compromise, one key in the long-term clinical treatment
`
`of UCD patients is maintaining plasma ammonia levels as low as possible given
`
`the need for growth and development, and ideally within or below the normal
`
`ranges. (See, e.g., Ex. 1018 (BUPHENYL Label) at 2 (“Laboratory Tests” section);
`
`Ex. 1007 (’859 Publication) at [0083], [0094].) Since many patients with UCDs
`
`still have intellectual challenges despite ammonia levels in the normal range,
`
`clearly the clinician caring for the child’s total health and development will ideally
`
`maintain the ammonia levels as low as possible.
`
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`34.
`
`Furthermore, it was well known prior to April 2012 that nitrogen
`
`scavenging drugs were being investigated for use in treating conditions other than
`
`UCDs, including cancer, cystic fibrosis, and hepatic encephalopathy. (See, e.g.,
`
`Ex. 1009 (Thibault); Ex. 1010 (Piscitelli); Ex. 1011 (Brusilow ’91) at 147; Ex.
`
`1012 (Zeitlin); Ex. 1015 (McGuire); Ex. 1022 (Thompson).) In cancer patients,
`
`PAA was thought to have multiple therapeutic roles, including reducing circulating
`
`glutamine through conversion of PAA to PAGN, which in turn reduces the amount
`
`of glutamine available to tumors, and modulating gene expression in tumors. (Ex.
`
`1010 (Piscatelli) at 368.) In cystic fibrosis patients, PBA modulates heat shock
`
`protein expression and restores maturation to a specific membrane protein. (Ex.
`
`1012 (Zeitlin) at 119.)
`
`C. The Metabolic Fate of PBA and PAA
`35. As noted above, prior to April 2012, PAA, or prodrugs of PAA like
`
`PBA and HPN-100, had been investigated for the treatment of UCDs and other
`
`conditions. (Ex. 1003 (Enns 2010) at 142, 144, 150; Ex. 1004 (MacArthur) at S67;
`
`Ex. 1005 (Simell) at 1117; Ex. 1007 (’859 Publication) at [0022]; Ex. 1009
`
`(Thibault) at 1690; Ex. 1010 (Piscatelli) at 368; Ex. 1011 (Brusilow ’91) at 147;
`
`Ex. 1012 (Zeitlin) at 119; Ex. 1018 (BUPHENYL Label); Ex. 1019 (AMMONUL
`
`Label).) As discussed above, it was known that PBA and PAA could be used to
`
`scavenge excess nitrogen by conversion of PAA to PAGN.
`
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`36.
`
`It was further known prior to April 2012 that PAA had certain
`
`drawbacks associated with its use. PAA itself has an unpleasant odor, which some
`
`patients are adverse to. (Ex. 1010 (Piscitelli) at 369; Ex. 1011 (Brusilow ’91) at
`
`147; Ex. 1003 (Enns 2010) at 146.) Using a prodrug of PAA minimizes this
`
`drawback, which led to the investigation and use of PBA and HPN-100. (Ex. 1010
`
`(Piscitelli) at 369.)
`
`37. More importantly, PAA was known to cause neurotoxicity at higher
`
`serum plasma concentrations. (Ex. 1004 (MacArthur) at S72; Ex. 1005 (Simell) at
`
`1020; Ex. 1009 (Thibault) at 1693-1694; Ex. 1012 (Zeitlin) at 120-121; Ex. 1018
`
`(BUPHENYL Label) at 3327; Ex. 1019 (AMMONUL Label) at 3325-26; Ex. 1003
`
`(Enns 2010) at 147.) PAA toxicity manifests with symptoms that include nausea,
`
`vomiting, headache, sleeplessness, sedation, fatigue, dysgeusia, and confusion.
`
`(Ex. 1004 (MacArthur) at S72; Ex. 1005 (Simell) at 1020; Ex. 1009 (Thibault) at
`
`1693-1694; Ex. 1012 (Zeitlin) at 120; Ex. 1018 (BUPHENYL Label) at 2; Ex. 1019
`
`(AMMONUL Label) at 4-5.) Two FDA-approved nitrogen scavenging drug labels
`
`specifically noted that PAA could cause neurotoxicity. (Ex. 1018 (BUPHENYL
`
`Label) at 2; Ex. 1019 (AMMONUL Label) at 4.) The BUPHENYL Label states:
`
`“Neurotoxicity was reported in cancer patients receiving intravenous
`
`phenylacetate, 250–300 mg/kg/day for 14 days, repeated at 4-week intervals.
`
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`

`Manifestations were predominately somnolence, fatigue, and lightheadedness; with
`
`less frequent headache, dysgeusia, hypoacusis, disorientation, impaired memory,
`
`and exacerbation of a pre-existing neuropathy.” (Ex. 1018 (BUPHENYL Label) at
`
`2.)
`
`38.
`
`PAA toxicity was known to be associated with the build-up of PAA in
`
`vivo, which is impacted by the amount of PAA or prodrug given to patients and the
`
`elimination of PAA by conversion to PAGN. (Ex. 1004 (MacArthur) at S72; Ex.
`
`1005 (Simell) at 1020; Ex. 1009 (Thibault) at 1693-1694; Ex. 1012 (Zeitlin) at 120-
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`121; Ex. 1018 (BUPHENYL Label) at 2; Ex. 1003 (Enns 2010) at 147.)
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`Optimizing the dose regimen by reducing the amount of drug given or dividing the
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`dose out into more administrations over time generally improved the tolerability of
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`treatment. (Ex. 1012 (Zeitlin) at 120; Ex. 1009 (Thibault) at 1690, 1694; see also
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`Ex. 1004 (MacArthur) at S67, S72.)
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`D. Overview of Applied Prior Art References
`1. MacArthur
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`39. MacArthur published in 2004. (Ex. 1004 (MacArthur).) MacArthur
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`reports the results of a study where healthy volunteers were infused with sodium
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`phenylacetate/sodium benzoate (“NAPA/NABZ”). (Id. at S67.) Subjects received
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`either a bolus dose of 5.5 g/m2 (n=3) or 3.75 g/m2 (n=17) of NAPA/NABZ
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`followed by a wash-out period, then followed by another bolus dose of the same
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`amount, and finally a continuous infusion of the same amount over the course of
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`24 hr. The authors noted that the subjects who received 5.5 g/m2 experienced
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`significant nausea, vomiting, and somnolence during the infusion phase, “and as a
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`result no additional volunteers were treated at this dose level.” (Id. at S69.)
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`40.
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`Plasma levels of PAA, benzoate (“BZ”), PAGN, and hippurate (the
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`metabolite of BZ) were measured over a 24-hr. period. (Id. at S67.)
`
`41. MacArthur also discusses the known adverse events associated with
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`PAA use, including somnolence, fatigue, headache, lightheadedness, dysgeusia.
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`(Id. at S72.) MacArthur suggests that keeping the levels of PAA below a threshold
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`should reduce the risk of toxicity. (Id.) Further, MacArthur states that the
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`“administration of [PAA] needs to be optimized to lessen the risk of attaining
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`inappropriately high plasma [PAA] levels, while maximizing its conversion to
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`[PAGN].” (Id.) In other words, MacArthur specifically taught to optimize dose of
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`the nitrogen scavenging drug to optimize PAGN formation (and thus nitrogen
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`removal) while minimizing PAA toxicity.
`
`42. MacArthur further teaches that dose optimization is necessary to
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`minimize the risk of PAA toxicity while maximizing nitrogen removal. (Id. at
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`S67, S72.) MacArthur discloses that PAA displays “saturable, non-linear
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`elimination, with a decrease in clearance with increased dose,” and that higher
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`doses should be avoided unless blood monitoring can be performed. (Id.)
`
`43.
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`Figures 1 and 2 of MacArthur discloses blood plasma concentrations
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`of PAA and PAGN vs. time in subjects that received bolus doses of NAPA/NABZ
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`at different concentrations. (Id. at S69-S70.) In both cases, PAA spikes upon
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`administration of the bolus, leading to high concentrations of PAA and lower, but
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`rising, concentrations of PAGN. Over time, the PAGN concentration increases as
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`PAA is converted to PAGN. During the 24-hours after the bolus is administered,
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`the ratio of PAA to PAGN, which is well above 2, comes down. In both cases,
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`PAA concentration eventually falls below PAGN concentration, as PAA is
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`eliminated and no additional drug is supplied. In both figures, the ratio of PAA to
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`PAGN goes from over 2 to below 1.
`
`2.
`
`Enns 2010
`
`44.
`
`Enns 2010, which published in 2010, provides an overview of the
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`natural history of urea cycle disorders and medications used for treating them. (Ex.
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`1003 (Enns 2010).) In terms of nitrogen scavenging drugs that were F.D.A.
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`approved at the time of its writing, Enns 2010 discusses AMMONUL and
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`BUPHENYL. (Id. at 142, 144, 147.) Enns 2010 also discloses that “[b]oth
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`phenylacetate and benzoate demonstrate saturable, nonlinear elimination, with a
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`decrease in clearance with increased dose. Therefore, following established
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`treatment protocol dosing guidelines is important to avoid an overdose.” (Ex. 1003
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`(Enns 2010) at 144.) It also discusses glycerol phenylbutrate [glyceryl tri-(4-
`
`phenylbutyrate)], which it describes as a new oral medication that was in clinical
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`trials for hyperammonemia control. (Ex. 1003 (Enns 2010) at 150.)
`
`45. Glyceryl tri-(4-phenylbutyrate), a triglyceride of phenylbutyrate, can
`
`be depicted as follows:
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`One molecule of glyceryl tri-(4-phenylbutyrate) is metabolized to three PBA
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`molecules in vivo, giving one molecule of glyceryl tri-(4-phenylbutyrate) the
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`capacity to sequester 3 times the amount of nitrogen that one PBA molecule can.
`
`46.
`
`Enns 2010 points out several advantages of glyceryl tri-(4-
`
`phenylbutyrate) over PBA and PAA. Glyceryl tri-(4-phenylbutyrate) does not
`
`have the odor that PAA exhibits or the noxious taste of NA-PBA. (Id. at 146,
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`150.) It is also more convenient for patients. Approximately three teaspoons (~
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`17.4 mL) of glyceryl tri-(4-phenylbutyrate), a liquid, deliver the same amount of
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`PBA as 40 tablets of Na-PBA. (Id. at 150.) Further, a typical Na-PBA dose was
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`known to result in large amounts of sodium intake for patients. (Ex. 1018
`
`(BUPHENYL Label) at 2.) A person of ordinary skill in the art would have
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`appreciated that glyceryl tri-(4-phenylbutyrate) is not a sodium salt, thus
`
`eliminating the issue of excessive salt exposure associated with Na-PBA.
`
`47.
`
`Enns 2010 describes a clinical study in which ten adult UCD subjects
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`were switched to glycerol phenylbutyrate from Na-PBA. (Ex. 1003 (Enns 2010) at
`
`150.) Compared to treatment with Na-PBA, glycerol phenylbutyrate treatment
`
`resulted in approximately 30% lower plasma ammonia levels, and fewer adverse
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`events were reported during the glycerol phenylbutyrate period of the trial. (Id.)
`
`3.
`
`Thibault
`
`48.
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`Thibault, which published in 1994, discloses the administration of
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`PAA to 17 patients with advanced solid tumors. (Ex. 1009 (Thibault) at 1690.)
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`Thibault used i.v. administration of PAA, and noted that in some patients,
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`continuous i.v. administration resulted in serum PAA concentrations that exceeded
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`the patient’s capacity to eliminate PAA, leading to rapid drug accumulation and
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`“dose-limiting toxicity.” (Id.) Thibault reports that PAA serum concentrations of
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`over 900 µg/mL were associated with neurotoxicity. Thibault further notes that
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`adapting the dose of PAA in each patient enabled safe dosing of PAA that also
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`resulted in clinical improvements. (Id.)
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`Piscitelli
`4.
`Piscitelli, which published in 1995, discloses the use of PBA to treat
`
`49.
`
`fourteen patients with cancer. (Ex. 1010 (Piscitelli) at 368.) In Piscitelli, patients
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`received either 600, 1200, or 2000 mg/m2 of PBA via a 30-minute infusion. (Id.)
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`Among other assays, PBA, PAA, and PAGN were measured from patient blood
`
`samples. (Id.) Piscitelli describes PAA as exhibiting non-linear, saturable
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`pharmacokinetics. (Id. at 369.) Furthermore, Piscitelli discloses that PAA has an
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`unpleasant odor that may limit its use. (Id. at 369.)
`
`50.
`
`Figure 2 of Piscitelli reports concentrations of PBA, PAA, and PAGN
`
`in three representative patients measured over time after administering doses of
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`600, 1200, or 2000 mg/m2 of PBA via a 30-minute infusion. (Id. at 370, 372.) The
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`authors note that the doses of PBA used in these trials were small compared to
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`phase I trials with PBA for treating cancer. (Id.) Further, the doses are low
`
`enough that the conversion of PAA to PAGN was not saturated. (Id.) At the
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`lowest dose