Case 2:17-cv-05901-KM-MAH Document 62-3 Filed 04/16/18 Page 1 of 18 PageID: 592
`
`John E. Flaherty
`Ravin R. Patel
`McCARTER & ENGLISH LLP
`Four Gateway Center
`100 Mulberry St.
`Newark, NJ 07102
`Telephone: (973) 622-4444
`
`Attorneys for Plaintiff Horizon
`Therapeutics LLC
`
`Robert F. Green
`Caryn C. Borg-Breen
`Ann K. Kotze
`Rachel C. Bell
`GREEN, GRIFFITH & BORG-BREEN LLP
`City Place
`676 N. Michigan Avenue, Suite 3900
`Chicago, Illinois 60611
`Telephone: (312) 883-8000
`
`Of Counsel for Plaintiff Horizon Therapeutics
`LLC
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`HORIZON THERAPEUTICS LLC,
`
`Plaintiff,
`
`v.
`
`Case No. 2:17-cv-5901-KM-MAH
`
`PAR PHARMACEUTICAL, INC.,
`
`Motion Date: See Dkt. No. 57
`
` Defendant.
`
`HIGHLY CONFIDENTIAL –
`PURSUANT TO THE DISCOVERY
`CONFIDENTIALITY ORDER
`
`DECLARATION OF INVENTOR BRUCE F. SCHARSCHMIDT, M.D., IN SUPPORT
`OF PLAINTIFF HORIZON’S OPPOSITION TO PAR’S MOTION FOR SUMMARY
`JUDGMENT OF INVALIDITY UNDER 35 U.S.C. § 101
`
`Horizon Exhibit 2020
`Lupin v. Horizon
`IPR2018-00459
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`HIGHLY CONFIDENTIAL – PURSUANT TO
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`INTRODUCTION .............................................................................................................. 1
`
`EDUCATION AND CAREER ........................................................................................... 1
`
`UREA CYCLE DISORDERS ............................................................................................ 2
`
`DEVELOPMENT OF RAVICTI® ..................................................................................... 6
`
`URINARY PAGN OUTPUT .............................................................................................. 8
`
`BLOOD AMMONIA LEVELS .......................................................................................... 9
`
`VII.
`
`THE PAA:PAGN RATIO................................................................................................. 11
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`I.
`
`INTRODUCTION
`
`1.
`
`I, Bruce F. Scharschmidt, M.D., submit this declaration on behalf of Horizon
`
`Therapeutics, LLC (“Horizon Therapeutics”) in support of its Opposition to Par’s Motion for
`
`Summary Judgment of Invalidity Under 35 U.S.C. § 101.
`
`2.
`
`I currently serve as a consultant to Horizon Pharma, Inc. (“Horizon Pharma”).
`
`Horizon Therapeutics, the plaintiff in this case, is a subsidiary of Horizon Pharma.
`
`3.
`
`I am one of the named inventors of U.S. Patent No. 9,561,1971 (“the ’197
`
`Patent”), entitled “Methods of Therapeutic Monitoring of Phenylacetic Acid Prodrugs” and
`
`issued on February 7, 2017.
`
`II.
`
`EDUCATION AND CAREER
`
`4.
`
`I completed my undergraduate and medical studies as part of Northwestern
`
`University’s Honors Program in Medical Education, an accelerated program that combined the
`
`traditional four years of undergraduate education and four years of medical education into a six-
`
`year degree. I graduated with my M.D. in 1970.
`
`5.
`
`6.
`
`I am Board Certified in Internal Medicine and Gastroenterology.
`
`After completing my residency and fellowship at the University of California, San
`
`Francisco, I continued my career there for the next 19 years, eventually serving as the Chief of
`
`Gastroenterology and a Professor of Medicine. During this time I also served as Editor-in-Chief
`
`of the Journal of Clinical Investigation and was elected President of the American Society for
`
`Clinical Investigation.
`
`7.
`
`I spent the next ten years at Chiron Corporation, where, as Vice President of
`
`Clinical Development, I headed the clinical development, clinical operations and biostatistics
`
`1 Attached to the Declaration of Rachel C. Bell, Esq. (“Bell Declaration” or “Bell Decl.”),
`submitted contemporaneously, as Ex. A.
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`and clinical data management groups before being elevated to the corporate group as VP of
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`Scientific Affairs. Chiron was acquired by Novartis International AG in April 2006. I continued
`
`working at Novartis as a Vice President until April 2008.
`
`8.
`
`I served as the Chief Medical Officer and subsequently Chief Medical &
`
`Development Officer of Hyperion Therapeutics, Inc. (“Hyperion”) from April 2008 to May
`
`2015, at which time it was acquired by Horizon Pharma. I also served as a Senior Vice President
`
`at Hyperion.
`
`9.
`
`I was listed as an inventor on every patent application filed by Hyperion during
`
`my tenure there.
`
`10.
`
`I have authored over 200 scientific articles over the course of my career.
`
`III.
`
`UREA CYCLE DISORDERS
`
`11.
`
`The ’197 Patent generally is directed to an improved method of treating a patient
`
`with a urea cycle disorder (“UCD”). The method involves measuring the ratio of plasma
`
`phenylacetate (“PAA”) to plasma phenylacetylglutamine (“PAGN”) in the same blood sample of
`
`a UCD patient who has previously taken glycerol phenylbutyrate or another PAA prodrug, and,
`
`if the ratio is outside of the range from 1:1 to 2:1 (or, alternatively, outside of the range from 1:1
`
`to 2.5:1) and, in particular, if the PAA to PAGN ratio is above 2:1 or 2.5:1, administering to the
`
`UCD patient glycerol phenylbutyrate in an amount that is effective to cause the UCD patient to
`
`achieve a PAA to PAGN ratio that is within the target range.
`
`12.
`
`UCDs are a class of inherited metabolic diseases characterized by a partial or
`
`complete absence of one or more enzymes or transporters involved in the metabolic pathway for
`
`disposing of waste nitrogen from the human body in the form of urea, which is excreted in urine.
`
`Disruption of the urea cycle leads to an accumulation of waste nitrogen and a corresponding
`
`increase in ammonia in a patient’s bloodstream. Ammonia is a potent neurotoxin which, when
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`present in sufficiently high concentrations in the bloodstream, results in a clinical condition
`
`referred to as hyperammonemia. Hyperammonemia manifests as central nervous system
`
`dysfunction of varying severity up to and including irreversible neurological damage and death if
`
`left untreated. Symptoms of neurotoxicity associated with UCDs include the following:
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`somnolence (sleepiness), fatigue, lightheadedness, headache, irritability, poor feeding,
`
`hyperventilation, vomiting, disorientation, impaired memory, coma, irreversible neurological
`
`injury and death.
`
`13.
`
`Prior to the advent of drug therapy, patients severely affected by UCDs typically
`
`died. In one longitudinal study, two-thirds of the severely affected babies diagnosed with a UCD
`
`during the first month of life died by the age of 6, even with the administration of sodium
`
`phenylacetate/sodium benzoate 10%/10% rescue treatment (AMMONUL®) during
`
`hyperammonemic crises.2 With the development of newer chronic treatments, survival rates
`
`increased, but one out of five of severely affected newborns diagnosed with a urea cycle disorder
`
`within the first month of life still died from the condition within the first year of life.3
`
`14.
`
`Dietary restriction is a key component of managing treatment of a UCD patient.
`
`Physicians decrease a patient’s protein intake, thereby reducing the amount of waste nitrogen
`
`which must be cleared from the body through a genetically impaired urea cycle. With less waste
`
`nitrogen, patients are less prone to develop elevated blood ammonia levels. However, severe
`
`dietary protein restriction may also decrease the intake of essential amino acids below the levels
`
`2 Marshall Summar et al., Diagnosis, symptoms, frequency and mortality of 260 patients with
`urea cycle disorders from a 21-year, multicenter study of acute hyperammonaemic episodes, 97
`ACTA PAEDIATRICA 1420, 1423 & Fig. 3 (2008), attached as Exhibit B to the Bell Declaration.
`3 See Food & Drug Administration Division Director’s Summary Review of New Drug
`Application No. 203284 (the RAVICTI® (glycerol phenylbutyrate) NDA) at p. 3 of 33, attached
`as Exhibit C to the Bell Declaration.
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`necessary for normal growth and development, such that supplementation with amino acid
`
`mixtures or the concomitant use of nitrogen scavenging drugs is often necessary to adequately
`
`balance a UCD patient’s nutritional needs with good metabolic control. In severely affected
`
`patients, dietary management is typically not enough by itself and patients require drug therapy
`
`or other measures. More specifically, in addition to dietary protein restriction, treatment methods
`
`include ammonia-scavenging drugs (alternatively known as nitrogen-scavenging drugs or
`
`alternate pathway drugs) and, in severely affected patients who cannot be controlled by dietary
`
`management and nitrogen scavenging drugs, liver transplantation.
`
`15.
`
`Ammonia-scavenging drugs use a metabolic pathway other than the urea cycle to
`
`excrete excess nitrogen; hence the term alternate pathway drugs. Glycerol phenylbutyrate (GPB),
`
`for example, is a prodrug of PAA. A prodrug is an inactive precursor chemical compound of a
`
`drug, which is then converted to an active form through normal metabolic processes. Glycerol
`
`phenylbutyrate is hydrolyzed by pancreatic enzymes to yield phenylbutyrate (a prodrug of PAA),
`
`which undergoes beta oxidation by the fatty acid oxidation cycle to produce PAA. PAA, in turn,
`
`is converted to PAGN by an enzymatic reaction that conjugates PAA to the amino acid
`
`glutamine. PAGN incorporates two nitrogens and is excreted in the urine, in effect bypassing the
`
`urea cycle.
`
`16.
`
`Alternative pathway drug treatments have increased the survival rate for UCD
`
`patients but are not a cure. Patients with UCDs require daily treatment for life and are managed
`
`by a physician specializing in the disorder. Patient monitoring and treatment compliance is
`
`critically important in ensuring effective treatment of urea cycle disorders and preventing
`
`episodes of acute hyperammonemia.
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`17.
`
`Oral administration of drug treatment is widely considered preferable for daily
`
`maintenance of chronic illnesses like urea cycle disorders, as opposed to intravenous or
`
`parenteral administration. However, oral administration of drugs in whatever form – powders,
`
`tablets, capsules, or liquids – requires investigators to consider the taste, odor, and texture of a
`
`drug product during pharmaceutical development. These attributes are collectively referred to as
`
`the “palatability” of a drug product.
`
`18.
`
`Patient compliance is particularly challenging in treatment of pediatric UCD
`
`patients. Generally speaking, pediatric patients are especially sensitive to unpalatable drugs.4
`
`19.
`
`One of the earlier developed ammonia scavenging drugs is BUPHENYL®.5
`
`BUPHENYL® is a sodium phenylbutyrate drug product available in tablet or powder form for
`
`the long-term management of hyperammonemia caused by urea cycle disorders that cannot be
`
`managed by diet alone.6 Unfortunately, the sodium phenylbutyrate in BUPHENYL® is
`
`associated with palatability issues, thereby resulting in reduced patient compliance with
`
`treatment regimens. In one recent study7, 64% of patients reported that sodium phenylbutyrate is
`
`“difficult to take because of its taste and strong odor.” Similarly, nearly half of UCD patients and
`
`their caregivers who stopped sodium phenylbutyrate treatment reported that sodium
`
`4 See Bell Decl. Ex. C p. 29 of 33 (“[T]he product was being developed as [sic] more palatable
`formulation of phenylbutyrate, which would make the prescriber want to use it in young
`children.”).
`5 Hyperion acquired rights to BUPHENYL® in 2013.
`6 See FDA-approved BUPHENYL® Label, attached as Exhibit D to the Bell Declaration.
`7Oleg A. Shchelochkov et al., Barriers to drug adherence in the treatment of urea cycle
`disorders: Assessment of patient, caregiver and provider perspectives, MOLECULAR GENETICS &
`METABOLISM REPORTS 43 (2016), attached as Exhibit E to the Bell Declaration. I am listed as an
`author of this article.
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`phenylbutyrate’s taste was a factor contributing to their discontinuation of that course of
`
`treatment.8
`
`20.
`
`Consequently, Hyperion turned its attention to the development of glycerol
`
`phenylbutyrate, hoping to make available to patients a drug product that was biochemically
`
`similar to sodium phenylbutyrate while lacking its undesirable attributes including poor
`
`palatability and high sodium content.9
`
`IV.
`
`DEVELOPMENT OF RAVICTI®
`
`21.
`
`Upon joining Hyperion in 2008, I began working on the clinical trials comparing
`
`glycerol phenylbutyrate oral liquid with BUPHENYL®. The results of these clinical trials were
`
`submitted to the U.S. Food & Drug Administration (“FDA”) as part of Hyperion’s New Drug
`
`Application No. 203284 (“the RAVICTI® NDA”). Ultimately, Hyperion submitted clinical data
`
`from approximately 9 clinical studies for the FDA’s consideration. While the primary purpose of
`
`these clinical trials was to support the RAVICTI® NDA, I also recognized that we had acquired
`
`a large and unique data set and was therefore also interested in whether we could interrogate
`
`these clinical data so as to discover dosing biomarkers that would enable us to provide
`
`physicians with guidelines that could improve methods of treatment and dosage adjustment for
`
`their urea cycle disorder patients undergoing PAA prodrug treatment. In addition to developing a
`
`better drug product, my goal was to develop better guidelines for dose adjustment and
`
`monitoring that could improve outcomes for urea cycle disorder patients.
`
`22.
`
`At the time we were conducting the clinical trials, physicians did not have a
`
`reliable methodology available to help them evaluate the optimal dose of a PAA prodrug drug
`
`8 Id.
`9 U.S. Patent Appl. No. 2010/0008859 (“the ’859 Publication”) at ¶ [0065] (“[HPN-100] avoids
`the unpleasant taste associated with sodium PBA, and it reduces potentially harmful sodium
`intake . . . .”), attached as Exhibit F to the Bell Declaration.
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`product for an individual UCD patient. The available scientific literature provided little guidance
`
`to physicians trying to determine the most effective dose and/or adjust the dose to better suit the
`
`needs of a UCD patient. For example, the BUPHENYL® Label contained no guidance on how
`
`to calculate an effective dosage for an individual UCD patient other than including a
`
`recommended range of dosages based on body weight (e.g. 450-600 mg/kg/day) and/or body
`
`surface area of the patient.10 Furthermore, the BUPHENYL® Label provided no guidance on
`
`how to adjust the dosage within that range so as to minimize the risk of toxicity and optimize
`
`control of blood ammonia.11
`
`23.
`
`Because UCDs represent a collection of inherited disorders involving genes
`
`encoding for 6 different enzymes or transporters, and because each of these genes may be
`
`affected by as many as 40 or more different mutations, the UCD patient population is extremely
`
`heterogenous and each patient requires highly individualized treatment. Different UCD patients,
`
`even patients with the same defective gene, may have diseases of varying severity and require
`
`different treatment regimens, including different doses of the same drug. The pediatric
`
`population of UCD patients, particularly infants, tends to include patients with earlier onset and
`
`often more severe disease as well as slower conversion of PAA to PAGN. 12 As a result,
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`individualized treatment is particularly important in very young UCD patients.
`
`24.
`
`Similarly, because UCDs impair a patient’s ability to excrete waste nitrogen
`
`resulting from break down of dietary protein, the manifestation of a patient’s disease also
`
`10 See Bell Decl. Ex. D at p. 5 of 8, § DOSAGE AND ADMINISTRATION; see also Bell Decl.
`Ex. C at p. 15 of 33 (“[T]he Buphenyl label is not precise in recommending an initial dose . . .
`.”).
`11 See Bell Decl. Ex. D. at p. 5 of 8, § DOSAGE AND ADMINISTRATION.
`12 Bell Decl. Ex. C at p. 15 of 33 (“[I]n children over the age of 2 years, there was higher
`variability and higher concentrations of PAA than in adults.”).
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`depends on their diet. Much like diabetes, this means that the manifestation of a UCD patient’s
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`disease may change from day to day, and even throughout the day, as a result of diet or a
`
`concurrent illness such as an infection.13
`
`25.
`
`Thus, as in to diabetes, I hoped to discover dosing biomarker(s) that would allow
`
`physicians to more effectively tailor the dosing of a phenylbutyrate drug product to the needs of
`
`an individual patient.14 A biomarker is defined as “a characteristic that is objectively measured
`
`and evaluated as an indicator of normal biologic processes, pathogenic processes, or
`
`pharmacologic responses to a therapeutic intervention.”15
`
`26.
`
`Therefore, my colleagues and I undertook extensive analyses of Hyperion’s
`
`uniquely large data set derived from controlled clinical trials to see if it was possible to identify
`
`biomarkers that would help physicians do a better job of treating urea cycle disorder patients.
`
`V.
`
`URINARY PAGN OUTPUT
`
`27.
`
`Initially, our analyses examined the possibility that we could evaluate the efficacy
`
`of glycerol phenylbutyrate by measuring the amount of PAGN excreted over 24 hours in a
`
`patient’s urine. Since PAGN excretes waste nitrogen in place of urea, PAGN does in effect
`
`function as a biomarker of drug effect.
`
`28.
`
`The consensus in the relevant scientific community at this time was that PAA was
`
`completely or almost completely converted to urinary PAGN in UCD patients.16 Through
`
`13 See U.S. Patent No. 9,095,559 at col. 4 ll. 29-64, attached as Exhibit G to the Bell Declaration.
`14 For example, in the diabetes context, HbA1c is an industry-standard biomarker for evaluating
`the efficacy of new drugs and treatments. By contrast, urea cycle disorders have no such agreed-
`upon biomarker by which to evaluate the efficacy of new or existing drugs.
`15 Biomarkers Definitions Working Group, Biomarkers and surrogate endpoints: preferred
`definitions and conceptual framework, 69 CLINICAL PHARMACOLOGY THERAPY 89 (2001)
`attached as Exhibit H to the Bell Declaration.
`16 See, e.g., Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle for Waste Nitrogen
`Excretion, 29 Pediatric Research, 147-150 (1991) attached as Exhibit I to the Bell Declaration.
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`analyzing the clinical data we had collected to support the RAVICTI® NDA, we discovered that
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`contrary to this consensus, only approximately 60% of the PAA prodrug is converted to urinary
`
`PAGN. Discovering this incomplete and variable conversion rate allowed us to develop more
`
`accurate dosing methods for physicians using PAA prodrugs to treat UCD patients and had
`
`critical implications for UCD treatment.
`
`29.
`
`This research resulted in the issuance of U.S. Patent No. 8,642,012, entitled
`
`“Methods of Treatment Using Ammonia-Scavenging Drugs.”
`
`30.
`
`However, several practical considerations stemming from the need for timed urine
`
`collections are inherent to this dosing approach. In adults, timed 24-hour urine collections are a
`
`nuisance and often incomplete. In infants, timed urine collected requires bladder catheterization,
`
`which is an invasive procedure. Thus, we further analyzed the clinical trial data to develop a
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`method whereby PAGN concentration in urine could be used to guide dosing of glycerol
`
`phenylbutyrate. Moreover, I continued to analyze the data from Hyperion’s clinical trials in my
`
`effort to further optimize UCD treatment methods.
`
`VI.
`
`BLOOD AMMONIA LEVELS
`
`31.
`
`Next, I considered whether measuring the concentration of ammonia in a patient’s
`
`blood was an effective way to evaluate whether that patient was receiving an effective dosage of
`
`a PAA prodrug. Many of the expert physicians with whom we worked in the clinical trials did
`
`not routinely check blood ammonia, in part because of the inherent variability in ammonia
`
`measurements taken at random times. Moreover, we learned from our studies that blood
`
`ammonia values often varied several-fold throughout the day, even among the well-controlled
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`individual UCD patients enrolled in our trials. Specifically, we observed that blood ammonia
`
`tended to be lowest in the morning before breakfast and tended to peak in the late afternoon or
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`early evening. These findings raised the question of exactly when blood ammonia should be
`
`drawn in UCD patients.
`
`32.
`
`In the Hyperion clinical trials, blood samples were frequently drawn “around the
`
`clock,” i.e., at multiple times during the day and night over 24 hours in order to assess daily
`
`ammonia exposure or burden. In routine clinical practice, such “around the clock” blood draws
`
`are impractical and rarely performed. Thus, we had at our disposal a unique data set that
`
`permitted us to gain insights never before appreciated.
`
`33. We discovered through extensive statistical analyses of the clinical data that there
`
`is a strong correlation between a patient’s fasting plasma ammonia level and that patient’s
`
`overall daily ammonia exposure. This was an important finding. It meant “around the clock”
`
`blood draws are not needed to assess daily ammonia exposure and average blood ammonia
`
`levels. Instead, physicians can assess daily blood ammonia exposure based on fasting blood
`
`ammonia, i.e., the first blood draw of the morning before patients eat breakfast or take their first
`
`daily dose of any drugs.
`
`34.
`
`Using that correlation, we next discovered that an individual patient’s likelihood
`
`of experiencing a normal daily ammonia exposure is enhanced if drug therapy is adjusted so as to
`
`maintain a fasting ammonia value that does not exceed half the upper limit of normal (“ULN”).
`
`We further discovered that keeping fasting ammonia levels to within half the upper limits of
`
`normal decreases both the risk and frequency of hyperammonemic crises.17 These discoveries
`
`allow us to develop a methodology whereby physicians could adjust the dose of a nitrogen-
`
`17 Lee et al., Blood ammonia and glutamine as predicators of hyperammonemic crises in patients
`with urea cycle disorder, Genetics in Medicine, 17(7):561-568 (2015) at 561, 563-565, attached
`as Exhibit J to the Bell Declaration.
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`scavenging drug based on measuring a fasting blood ammonia level and comparing it to the
`
`ULN, where a fasting level that is greater than half the ULN requires an increased dosage.
`
`35. We filed two provisional patent applications disclosing our method of adjusting
`
`treatment of a patient with a urea cycle disorder based on that patient’s blood ammonia level
`
`from a fasting blood draw in the fall of 2011. These applications eventually led to U.S. Patent
`
`Nos. 8,404,215; 9,095,55918; 9,254,278; and 9,326,966.
`
`36.
`
`However, although we had developed the above improved methods of
`
`determining an effective dose of a PAA prodrug to treat UCD patients, we were still concerned
`
`about the potential risk of neurotoxicity due to elevated levels of PAA that might result from too
`
`high a dosage of phenylbutyrate. This concern was based on reports by Thibault et al. in the
`
`context of cancer patients that reversible neurotoxicity was associated with plasma PAA levels
`
`exceeding ~500 µmol/L.19 We continued to examine the clinical data in the hopes of locating a
`
`biomarker that would indicate the optimal dose of phenylbutyrate to a physician treating a UCD
`
`patient.
`
`VII. THE PAA:PAGN RATIO
`
`37. We decided to look at the relative concentrations of PAA and PAGN in blood.
`
`38.
`
`PAA and PAGN have comparatively short circulating half-lives. Therefore,
`
`because PAA and PAGN levels in a patient’s blood vary many-fold over the course of the day
`
`depending on when the sample is drawn in relation to drug dosing, random blood PAA values as
`
`might be drawn during a routine clinic visit are of limited utility in determining whether that
`
`18 See, e.g., Bell Decl. Ex. G.
`19 See, e.g., Alain Thibault et al., Phase I Study of Phenylacetate Administered Twice Daily to
`Patients with Cancer, 75 CANCER 2932, 2937 (1995), attached as Exhibit K to the Bell
`Declaration; see also Bell Decl. Ex. D at p. 4 of 8, § CLINICAL ADVERSE EVENTS.
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`patient might, at some point during the day, experience levels sufficiently high as to be
`
`associated with neurologic adverse events. Consequently, clinicians did not consider a patient’s
`
`blood PAA or PAGN levels to be useful in determining whether a patient was receiving the
`
`correct dose of a phenylbutyrate drug.20
`
`39.
`
`Although it had previously been established that PAGN was a metabolite of PAA,
`
`the relationship between these two metabolites in relation to drug dosing was not appreciated in
`
`the prior art. The published research at that time provided no indication that the relative
`
`concentrations of PAA and PAGN could provide useful clinical information of any type, let
`
`alone provide definitive dosing guidelines regarding a patient’s risk of neurotoxicity.
`
`40.
`
`Based on our analysis of the clinical data, we theorized that the enzymatic
`
`conversion of PAA to PAGN, which is rate-limiting in overall metabolism, might at some point
`
`become saturated. We further theorized, based on the Michaelis-Menten model of enzyme
`
`kinetics which describes the reaction process in which an enzyme converts a substrate into a
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`product, that an elevated ratio of precursor (i.e., PAA) to substrate (i.e., PAGN) might serve as a
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`biomarker indicating that PAA to PAGN conversion was saturated or approaching saturation;
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`20 See, e.g., Uta Lichter-Konecki et al., Ammonia Control in Children with Urea Cycle Disorders
`(UCDs): Phase 2 Comparison of Sodium Phenylbutyrate and Glycerol Phenylbutyrate, 103
`Molecular Genetics and Metabolism 323, at 328 Table 3 (2011) (“[B]lood levels of PBA, PAA
`and PAGN all varied widely over the course of the day. . . .”), attached as Exhibit L to the Bell
`Declaration; Brendan Lee et al., Phase 2 Comparison of a Novel Ammonia Scavenging Agent
`with Sodium Phenylbutyrate in Patients with Urea Cycle Disorders: Safety, Pharmacokinetics
`and Ammonia Control, 100 Molecular Genetics & Metabolism 221, at 226 Table 3 (2010),
`attached as Exhibit M to the Bell Declaration; U.S. Patent Appl. No. 2012/0022157 at [004]
`(“[M]easuring the blood level of the prodrug (e.g., PBA) or of PAA formed from it is unreliable
`in assessing drug effect . . . .”), attached as Exhibit N to the Bell Declaration; Bell Decl. Ex. F at
`[0023], [0070], & [0072] (“[S]ystemic levels of PAA or PBA are not reliably correlated with the
`efficacy of HPN-100 as an ammonia scavenger.”); see also Bell Decl. Ex. A col. 10 ll. 4-7
`(“Since PAA, PAGN, and ammonia levels do not provide the information necessary to determine
`whether a subject is effectively converting PBA to PAGN (i.e., effectively utilizing the PAA
`prodrug) . . . .”).
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`i.e., had reached its maximum level. For a patient whose PAA to PAGN conversion was
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`approaching saturation, prescribing additional phenylacetate prodrug (i.e., glycerol
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`phenylbutyrate or sodium phenylbutyrate) would not result in further formation of
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`phenylacetylglutamine and thereby removal of waste nitrogen, but could result instead in
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`elevation of circulating PAA levels that could put the patient at risk of toxicity.
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`41. We believed that if an elevated ratio of PAA to PAGN was a biomarker of
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`saturation, then we might be able to identify a specific value of the PAA:PAGN ratio that would
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`tell us when the enzymatic reaction was saturated. More specifically, we hoped we could identify
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`a ratio of PAA:PAGN above which the risk of phenylacetate toxicity was substantially increased
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`and develop a biomarker more useful than the highly variable individual levels of PAA and
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`PAGN.
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`42.
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`Our extensive review of Hyperion’s clinical data revealed, to our surprise, that
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`while the individual concentrations of PAA and PAGN fluctuated widely throughout the day, a
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`patient’s ratio of PAA:PAGN remained comparatively constant.
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`43. We were also surprised to find that the utility of the ratio of PAA:PAGN blood
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`levels was largely consistent among individual patients as well as patient populations, despite the
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`heterogeneous nature of the UCD patient population. As we explained in the ’197 patent: 21
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`The excess of PAA over PAGN, indicated by larger ratios as PAA increases, was
`evident across all dosage groups, disease populations, and types of treatment in
`UCD patients (i.e., applies to both NaPBA and HPN-100). This finding suggests
`that analysis of the precursor (PAA) to product (PAGN) ratio may be predictive
`of the efficiency of conversion among patients with or without liver
`dysfunction . . . and independently of dose.
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`21 Bell Decl. Ex. A at col. 24 ll. 22-30.
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`44.
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`Ultimately, we concluded that a ratio of PAA:PAGN above 2:1 in a patient’s
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`fasting blood draw indicated that the metabolic reaction converting phenylacetate to
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`phenylacetylglutamine may have become saturated. We confirmed through statistical analysis
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`that patients with a ratio of PAA:PAGN greater than 2:1 (or, alternatively, greater than 2.5:1)
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`were at a dramatically higher risk of experiencing neurotoxic side effects from receiving too high
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`of a dose of glycerol phenylbutyrate. 22 Consequently, a ratio of PAA:PAGN above 2:1 informed
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`the treating physician that the patient’s dose of glycerol phenylbutyrate needed to be reduced, or,
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`if that patient was also experiencing elevated blood ammonia levels which made dose reduction
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`problematic, alteration of dosing schedule.
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`45.
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`Similarly, we concluded that a ratio of PAA:PAGN below 1:1 in a patient’s
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`fasting blood draw could indicate that the dosage of nitrogen scavenging medication was
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`potentially insufficient. Consequently, a ratio of PAA:PAGN below 1:1 suggests to the treating
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`physician that the UCD patient’s dose of glycerol phenylbutyrate may need to be increased, and
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`that such increase could be safely made, if also warranted by the subject’s clinical status
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`including ammonia level, with minimal risk of triggering high PAA levels.23
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`46.
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`In the Hyperion clinical trials, just as was the case for ammonia, PAA and PAGN
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`levels were drawn ‘around the clock’ in order to assess maximum PAA levels. In clinical
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`practice, ‘around the clock’ blood draws are impractical and, as described above, random PAA
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`blood draws as might be done at a routine visit, are of little utility. By contrast, the comparative
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`constancy of the PAA:PAGN ratio renders it useful in the context of routine clinical practice for
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`22 Id. at col. 27 ll. 38-40 (“Furthermore, ratios between 2.0-2.5 were associated with significantly
`higher PAA levels than ratios less than 2.0 (p<0.001).”)
`23 Id. at col. 18 ll. 39-43 (“In certain of these embodiments where the target range is 1 to 2.5, a
`PAA:PAGN ratio below 1 indicates the PAA prodrug dosage is unlikely to be effective and
`needs to be adjusted upwards.”).
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`purposes of assessing that patient’s risk of PAA toxicity individualizing dosing irrespective of
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`the specific genetic cause of a patient’s urea cycle disorder. For the first time, there was a
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`relatively straightforward blood test that allowed a clinician to adjust a p