`
`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.
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`Table of Contents
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`
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`I. QUALIFICATIONS ................................................................................................................ 4
`II.
`INFORMATION CONSIDERED ....................................................................................... 6
`III.
`SUMMARY OF OPINIONS AND EXPECTED TESTIMONY ........................................ 9
`IV. LEGAL STANDARDS ..................................................................................................... 10
`(i)
`Law of Obviousness ....................................................................................................... 10
`(ii)
`Person of Ordinary Skill in the Art ................................................................................ 12
`(iii) Claim Construction ........................................................................................................ 13
`V.
`BACKGROUND AND STATE OF THE ART ................................................................ 17
`(i)
`The Urea Cycle ............................................................................................................... 17
`(ii) Use of Nitrogen Scavenging Drugs ................................................................................ 20
`(iii) Overview of Applied Prior Art References .................................................................... 25
`a. The ’859 Publication .......................................................................................................... 25
`b. Simell ................................................................................................................................. 28
`c. Blau .................................................................................................................................... 29
`d. The Brusilow ’979 Patent .................................................................................................. 30
`VI. OVERVIEW OF THE ’278 AND ’966 PATENTS .......................................................... 30
`(i)
`The ’278 Patent Claims .................................................................................................. 34
`(ii)
`The ’966 Patent Claims .................................................................................................. 39
`VII. THE ’278 PATENT CLAIMS ARE OBVIOUS IN VIEW OF THE PRIOR ART .......... 44
`a. Ground 1: Claims 1-3 of the ’278 Patent Would Have Been Obvious Over the ’859
`Publication .................................................................................................................................... 44
`b. Ground 2: Claims 4-7 and 12-15 of the ’278 Patent Would Have Been Obvious Over Blau,
`Simell and the ’859 Publication .................................................................................................... 47
`i. Overview of Applied Prior Art .............................................................................................. 47
`ii. Motivation to Combine Applied Prior Art ............................................................................ 47
`iii.
`Independent Claim 4 .......................................................................................................... 50
`1. Claim 4, Part (a)..................................................................................................................... 54
`2. Claim 4, Part (b) .................................................................................................................... 56
`3. Claim 4, Part (c)..................................................................................................................... 57
`4. Claim 4, Wherein Clause ....................................................................................................... 59
`iv.
`Independent Claim 12 ........................................................................................................ 61
`v. Dependent Claims 5 and 13 ................................................................................................... 63
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`Dependent Claims 6, 7, 14 and 15 ..................................................................................... 64
`vi.
`c. Ground 3: Claims 8-11 of the ’278 Patent Would Have Been Obvious Over Blau, Simell,
`the ’859 Publication, and the Brusilow ’979 Patent ..................................................................... 65
`i. Overview of Applied Prior Art .............................................................................................. 65
`ii. Motivation to Combine Applied Prior Art ............................................................................ 65
`iii.
`Independent Claim 8 .......................................................................................................... 66
`iv.
`Dependent Claim 9 ............................................................................................................ 67
`v. Dependent Claims 10 and 11 ................................................................................................. 68
`VIII.
`THE ’966 PATENT CLAIMS ARE OBVIOUS IN VIEW OF BLAU, SIMELL, AND
`THE ’859 PUBLICATION ........................................................................................................... 68
`(i)
`Overview of Applied Prior Art ....................................................................................... 68
`(ii) Motivation to Combine Applied Prior Art ..................................................................... 68
`(iii)
`Independent Claims 1, 6, and 9 ...................................................................................... 71
`a. Part (a) of Independent Claims 1, 6, and 9 ........................................................................ 75
`b. Part (b) of Independent Claims 1, 6, and 9 ........................................................................ 77
`c. Part (c) of Independent Claims 1, 6, and 9 ........................................................................ 79
`(iv)
`Independent Claim 12 .................................................................................................... 82
`(v) Dependent Claims 2 and 3 ............................................................................................. 84
`(vi) Dependent Claims 4, 7, 10, and 13 ................................................................................ 85
`(vii) Dependent Claims 5, 8, 11, 14, and 15 .......................................................................... 87
`IX.
`SIGNATURE ..................................................................................................................... 88
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`I, Keith Vaux, M.D., declare and state as follows:
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`I. QUALIFICATIONS
`1.
`I am a medical doctor with specialty training in Pediatrics and
`
`Clinical Genetics. I am currently Professor and Clinical Chief of the Division of
`
`Medical Genetics in the Department of Medicine at UC San Diego. I also have an
`
`appointment as Professor of Neurosciences at UC San Diego, and I am a physician
`
`at Point Loma Pediatrics. 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.
`
`2.
`
`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.
`
`3.
`
`After medical school, I completed a three year residency in
`
`pediatrics, including a year as Chief Resident, from 1994-1997. The recognition,
`
`immediate and long-term management, and consideration of the long-term
`
`prognosis, of Urea Cycle Defects is a core competency for training and board
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`certification in Pediatrics. Following two years of isolated clinical pediatric
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`practice and critical care transport in Guam and two years as a practicing
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`pediatrician and faculty member at the Naval Medical Center, I completed a three-
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`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.
`
`4.
`
`I teach 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.
`
`5.
`
`A copy of my curriculum vitae, which sets forth my education and
`
`experience in further detail, is provided herewith as Exhibit 1023.
`
`6.
`
`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
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`standard consulting rate of $670/hour. My compensation in no way depends on the
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`outcome of this proceeding or the content of my opinions.
`
`7.
`
`In the previous four years, I have testified by trial or deposition in
`
`the following matters:
`
` Montgomery v. USS/Clicker; mediation; July 2012;
`
` Fields v. Eli Lilly and Company; October 2014;
`
` Schomake v. Eli Lilly and Company; November 2014;
`
` Brookes Issue; February 2015;
`
` Lupin Ltd. et al. v. Horizon Therapeutics LLC; January 2017.
`
`II.
`
`INFORMATION CONSIDERED
`8.
`
`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. 9,254,278 (the “’278 Patent”) (Ex. 1001);
`
`b. U.S. Patent No. 9,326,966 (the “ʼ966 Patent) (Ex. 1003);
`
`c. Brusilow, et al., Treatment of Episodic Hyperammonemia in Children
`
`with Inborn Errors of Urea Synthesis, 310 The New England Journal
`
`of Medicine, 1630-1634 (1984) (“Brusilow’84”) (Ex. 1004);
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`d. Simell, et al., Waste Nitrogen Excretion Via Amino Acid Acylation:
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`Benzoate and Phenylacetate in Lysinuric Protein Intolerance, 20
`
`Pediatric Research, 1117-1121 (1986) (“Simell”) (Ex. 1005);
`
`e. Blau, Duran, Blaskovics, Gibson (editors), Physician’s Guide to the
`
`Laboratory Diagnosis of Metabolic Diseases, 261-276 (2d ed. 1996)
`
`(“Blau”) (Ex. 1006);
`
`f. U.S. Patent Publication No. 2010/0008859, filed January 7, 2009,
`
`published January 14, 2010 (the “’859 Publication”) (Ex. 1007);
`
`g. Scientific Discussion for Ammonaps, EMEA 2005, available at
`
`http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
`
`_Scientific_Discussion/human/000219/WC500024748.pdf (“Scientific
`
`Discussion”) (Ex. 1008);
`
`h. Dixon, et al., Intercurrent Illness in Inborn Errors of Intermediary
`
`Metabolism, 67 Archives of Disease in Childhood, 1387-1391 (1992)
`
`(“Dixon”) (Ex. 1009);
`
`i. UMass Memorial Laboratories, Lab Updates, February 2007,
`
`Measurement of Ammonia in Blood (Ex. 1010);
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`j. Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle for
`
`Waste Nitrogen Excretion, 29 Pediatric Research, 147-150 (1991)
`
`(“Brusilow ’91”) (Ex. 1011);
`
`k. Yajima, et al. Diurnal Fluctuations of Blood Ammonia Levels in
`
`Adult-Type Citrullinemia, 137 Tokohu J. Ex/ Med, 213-220 (1982)
`
`(“Yajima”) (Ex. 1012);
`
`l. Batshaw, et al., Treatment of Carbamyl Phosphate Synthetase
`
`Deficiency with Keto Analogues of Essential Amino Acids, 292 The
`
`New England J. Medicine, 1085-90 (1975) (“Batshaw”) (Ex. 1013);
`
`m. Kasumov, et al., New Secondary Metabolites of Phenylbutyrate in
`
`Humans and Rats, 32 Drug Metabolism and Disposition, 10-19 (2004)
`
`(“Kasumov”) (Ex. 1014);
`
`n. Barsotti, Measurement of Ammonia in Blood, 138 J. Pediatrics, S11-
`
`S20 (2001) (“Barsotti”) (Ex. 1015);
`
`o. Berry, et al., Long-term management of patients with urea cycle
`
`disorders, Journal of Pediatrics, Vol. 138, No. 1, S56–S61 (2001)
`
`(“Berry”) (Ex. 1016);
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`p. Levin, et al., Hyperammonaemia A Variant Type of Deficiency of
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`Liver Ornithine Transcarbamylas, Arch. Dis. Childh. 1969, 44, 162
`
`(1968) (“Levin”) (Ex. 1017);
`
`q. Prosecution History of U.S. Patent No. 8,404,215 (Ex. 1018);
`
`r. Excerpt from Stedman’s Medical Dictionary (Lippincott Williams &
`
`Wilkins 2006) (Ex. 1019);
`
`s. BUPHENYL® label, Physician’s Desk Reference, 60th ed. (2006), at
`
`3327–28 (Ex. 1020);
`
`t. AMMONUL® label, Physician’s Desk Reference, 60th ed. (2006), at
`
`3323–25 (Ex. 1021);
`
`
`
`u. U.S. Patent No. 5,968,979 (“Brusilow ’979 Patent”) (Ex. 1025)
`
`III. SUMMARY OF OPINIONS AND EXPECTED TESTIMONY
`9.
`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 time of
`
`the alleged inventions (September 2011), a person of ordinary skill in the art would
`
`have been aware of and motivated to carry out methods of using a patient’s fasting
`
`plasma ammonia levels to guide treatment decisions with nitrogen scavenging
`
`drugs (including glyceryl tri-[4-phenylbutyrate]), including in patients who have a
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`plasma ammonia level between half the upper limit of normal and the upper limit
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`of normal for plasma ammonia.
`
`10. In my opinion, the subject matter of each claim of the ’278 and ’966
`
`patent was obvious in view of the prior art.
`
`IV. LEGAL STANDARDS
`(i)
`Law of Obviousness
`11. 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.
`
`12. 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
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`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.
`
`13. I have been informed that at this time, Patent Owner has not identified
`
`any secondary considerations of nonobviousness. I reserve the right to respond to
`
`any secondary considerations that Patent Owner may raise.
`
`14. I have been informed that in the context of this proceeding, a claim will
`
`be found unpatentable as obvious if the preponderance of the evidence indicates
`
`that the claim would have been obvious.
`
`15. 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
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`a person of ordinary skill in the art to have combined the teachings of two or more
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`references in order to achieve the claimed invention. This reason may come from a
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`teaching, suggestion, or motivation to combine, or may come from the reference or
`
`references themselves, the knowledge or “common sense” of one skilled in the art,
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`or from the nature of the problem to be solved, and may be explicit or implicit
`
`from the prior art as a whole.
`
`16. 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.
`
`(ii)
`Person of Ordinary Skill in the Art
`17. 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.
`
`18. For purposes of this declaration, I have been asked to assume that the
`
`date of the inventions for both the ’966 Patent and the ’278 Patent is September 30,
`
`2011.
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`19. In my opinion, a person of ordinary skill in the art with respect to the
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`
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`’966 and ’278 Patents as of September 30, 2011 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.
`
`(iii)
`Claim Construction
`20. I have been informed that in the context of the current proceedings,
`
`each of the terms in the patent claims is given its broadest reasonable interpretation
`
`in light of the patent specification. I have reviewed the specifications of the ʼ966
`
`and ’278 patents, and I interpret the below claim terms under this standard, as
`
`follows.
`
`21. According to the specification, “upper limit of normal” (“ULN”), which
`
`appears in each of the challenged claims of both patents, means “the highest level
`
`in the range of normal values.” (Ex. 1001 at 12:7-8)1
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`22. Independent claims 1, 6, 9, and 12, and dependent claims 4, 7, 19, and
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`13 of the ’966 Patent, and independent claims 1, 4, 8, and 12, and dependent
`
`
`1 I understand that the ’278 and ’966 Patents are related as “continuations,” and
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`thus share the same specification. For convenience, I will cite to only the ’278
`
`specification.
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`claims 5, 9, and 13 of the ’278 Patent, recite a “fasting” plasma ammonia level.
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`The plain and ordinary meaning of the term “fast” in the medical context means
`
`abstaining from at least food. See, e.g., Stedman’s Medical Dictionary (Lippincott
`
`Williams & Wilkins 2006) (Ex. 1019).
`
`23. The specification of the patents makes clear that fasting means
`
`abstaining from at least food for a minimum of four hours:
`
`In certain embodiments of the methods disclosed
`
`herein, the fasting period for obtaining a fasting blood
`
`ammonia level is overnight. In certain embodiments,
`
`the fasting period is 4 hours or more, 5 hours or more,
`
`6 hours or more, 7 hours or more, 8 hours or more, 9
`
`hours or more, 10 hours or more, 11 hours or more, or
`
`12 hours or more, and in certain embodiments the
`
`fasting period is 4-8 hours, 6-8 hours, or 8-12 hours.
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`(Ex. 1001, 10:21–27.) The specification also makes clear that fasting means that
`
`the subject preferably does not ingest any food, and in certain embodiments, some
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`non-food substances (such as certain supplements, beverages, etc.):
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`During the fasting period, the subject preferably does
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`not ingest any food. In certain embodiments, the
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`subject may also refrain from ingesting certain non-
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`food substances during the fasting period. For
`
`example, in certain embodiments the subject does not
`
`ingest any supplements and/or nitrogen scavenging
`
`drugs during the fasting period. In certain of these
`
`embodiments, the subject may nonetheless ingest one
`
`or more drugs other than nitrogen scavenging drugs
`
`during the fasting period. In certain embodiments, the
`
`subject does not ingest any high calorie liquids during
`
`the fasting period. In certain of these embodiments, the
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`subject does not ingest any liquids other than water
`
`during the fasting period. In other embodiments, the
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`subject may ingest small amounts of low calorie
`
`beverages, such as tea, coffee, or diluted juices.
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`
`
`(Id. at 10:28–41.) In view of the specifications and the plain and ordinary meaning
`
`of the term fasting, “fasting” plasma ammonia level means the plasma ammonia
`
`level in a person who has not eaten food for at least four hours.
`
`24. Claims 1, 6, and 9 of the ’966 Patent, and claims 4, 8, and 12 of the
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`’278 Patent, require that the “adjusted dosage” is “greater than the initial dosage.”
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`With regard to an adjusted dosage of glyceryl tri-[4-phenylbutyrate] that is greater
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`than the initial dosage, the specification states: “Increasing the dosage of a
`
`nitrogen scavenging drug may refer to increasing the amount of drug per
`
`administration (e.g., an increase from a 3 mL dosage to a 6 mL dosage), increasing
`
`the number of administrations of the drug (e.g., an increase from once-a-day
`
`dosing to twice- or three-times-a-day), or any combination thereof.” (Id. at 10:8–
`
`13.) Based on this disclosure, an adjusted dosage that is “greater than the initial
`
`dosage” means a dosage that increases the amount of drug per administration, an
`
`increased number of administrations of the drug, or any combination thereof.
`
`25. Claim 12 of the ’966 Patent requires that the “adjusted dosage” is the
`
`same as the initial effective dosage or is an “increased dosage.” As discussed
`
`above, with regard to an adjusted dosage of glyceryl tri-[4-phenylbutyrate] that is
`
`increased, the specification states: “Increasing the dosage of a nitrogen
`
`scavenging drug may refer to increasing the amount of drug per administration
`
`(e.g., an increase from a 3 mL dosage to a 6 mL dosage), increasing the number of
`
`administrations of the drug (e.g., an increase from once-a-day dosing to twice- or
`
`three-times-a-day), or any combination thereof.” (Id. at 10:8–13.) Based on this
`
`disclosure, an adjusted dosage that is an “increased dosage” means a dosage that
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`increases the amount of drug per administration, an increased number of
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`administrations of the drug, or any combination thereof.
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`26. 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
`(i) The Urea Cycle
`27. 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,
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`brain damage, and death.
`
`28. 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
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`for endogenous protein synthesis are broken down, forming pools of free amino
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`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 urea cycle works as follows:
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`Amino Acids
`
`Gm&Gw
`
`4:(:
`
`03>.95‘
`
`Carbamoyl P04
`
`1
`
`aspartate
`
`63>
`
`fumarate
`
`0
`
`JL
`
`urea
`
`NH2
`
`H2N
`
`
`
`
`
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`

`

`29. 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 am not
`
`aware of any negative effects of ammonia levels that are low or even absent.
`
`(ii) Use of Nitrogen Scavenging Drugs
`30. Prior to September 2011, using nitrogen scavenging drugs to treat
`
`nitrogen retention disorders such as hepatic encephalopathy and UCDs was well
`
`known. (See, e.g., Ex. 1004 at 1631; Ex. 1005 at 1118.) Nitrogen scavenging
`
`drugs provide an alternative pathway to the urea cycle for waste nitrogen excretion.
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`These drugs were known to remove waste nitrogen in both normal individuals and
`
`UCD patients.
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`31. Known nitrogen scavenging drugs as of September 2011 included
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`sodium benzoate, phenylacetic acid (“PAA”), phenylbutyrate (“PBA”), sodium
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`phenylbutyrate (“NaPBA,” sold as BUPHENYL®), and glyceryl tri-[4-
`
`phenylbutyrate] (also known as “HPN-100”), or a combination of two or more of
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`HPN-100, phenylbutyrate, and sodium phenylbutyrate. (See, e.g., Ex. 1004 at
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`1631; Ex. 1011 at 147–48; Ex. 1014 at 10–19, 13; Ex. 1020; Ex. 1021.)
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`32. Nitrogen scavenging drugs that are metabolized to PAA (which are also
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`
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`known as PAA prodrugs), provide an alternative mechanism for the clearance of
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`glutamine in the form of phenylacetylglutamine (“PAGN”), which like urea,
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`carries nitrogen out of the body. NaPBA is a PAA prodrug. (Ex. 1007 at [0022].)
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`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].)
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`33. PAA prodrugs rapidly metabolize to PAA, and PAA in turn metabolizes
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`to PAGN. PAGN, like urea, removes two nitrogen molecules from the body. (Ex.
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`1011 at 147; Ex. 1015 at S13, S16; Ex. 1020; Ex. 1021.) The removal of nitrogen
`
`by a PAA prodrug works as follows:
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` 
`
`β‐oxidation 
`
`
`
`PAA prodrug 
`
`  
`
`Glutamine
`(2 moles N) 
`
`
`
` PAA 
`
` 
`
`PAGN 
`(2 moles of N) 
`
` 
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`34. Nitrogen scavenging drugs greatly simplify the process of balancing
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` 
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`dietary intake of nitrogen with bodily demand in patients with UCDs. These
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`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
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`plasma ammonia value back to a normal range and avoid hyperammonenmia,
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`which is a metabolic disturbance characterized by an excess of ammonia in the
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`blood.
`
`35. It was well known prior to September 2011 that treating patients with
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`UCDs involved achieving a balance between diet, amino acid supplementation,
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`and use of nitrogen scavenging drugs. (Ex. 1016 at S56.) “The goal of treatment
`
`is to maintain normal levels of plasma ammonia through the use of the low-protein
`
`diet and medication while allowing for normal growth.” (Ex. 1016 at S58; see also
`
`Ex. 1007 at, e.g., [0182] (noting that subjects treated with HPN-100 can “achieve
`
`and maintain normal plasma ammonia levels”).)
`
`36. 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. 1004 at 1631; Ex. 1008 at 10; Ex. 1020 at 3327
`
`(“Laboratory Tests” section); Ex. 1007 at [0083], [0094]; Ex. 1016 at S58.) Since
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`many patients with UCDs still have intellectual challenges despite ammonia levels
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`in the normal range, clearly the clinician caring for the child’s total health and
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`development will ideally maintain the ammonia levels as low as possible. Careful
`
`monitoring of patients with UCDs involved regularly measuring their plasma
`
`ammonia levels and comparing them to the ULN. (See, e.g., Ex. 1004 at 1631; Ex.
`
`1007 at [0083], [0094]; Ex. 1008 at 10.) It was well known that the ULN of
`
`plasma ammonia levels will vary depending exactly on how it was measured, but
`
`that some clinical tests showed a normal range of less than 35 μM, which would
`
`place the ULN at 35 μM. (See, e.g., Ex. 1004 at 1632 (Fig. 1); Ex. 1007 at [0063],
`
`Fig. 13, [0094], [0201].)
`
`37. In practice, when measuring a patient’s plasma ammonia levels to
`
`compare it to the ULN, it was recommended to measure a fasting plasma ammonia
`
`level. (Ex. 1005 at 1118; Ex. 1006 at Table 11.9; Ex. 1015 at S11; Ex. 1010.) This
`
`fasting plasma ammonia level is important, as a person’s daily ammonia level will
`
`vary throughout the day, and in response to protein intake during meals. (Ex. 1006
`
`at 268, Table 11.5; Ex. 1012 at 213; Ex. 1015 at S19.) However, it was known that
`
`a fasting plasma ammonia level will typically be lower than the daily average
`
`plasma ammonia level in the patient and would show a smaller fluctuation within
`
`an individual. (Ex. 1012 at 214.)
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`38. In practice, it was also well known prior to September 2011 that
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`
`
`ammonia levels may be markedly influenced by the manner in which the sample
`
`was obtained (phlebotomy with and without a tourniquet, for example), the
`
`condition of the patient (crying or quiet), or the manner in which the sample was
`
`handled and processed after being drawn. (See, e.g., Ex. 1015 at S12.)
`
`39. It was also well known prior to September 2011 that the level of
`
`ammonia in patients with UCD may have a diurnal variation, which can be based
`
`upon age, the underlying genetic condition, the feeding schedule used, and the
`
`degree of metabolic control present. (See, e.g., Ex. 1012 at 213, 214; Ex. 1015 at
`
`S19.) Diurnal variation would cause one of a set of repeated daily measurements
`
`to regularly approximate the lowest or highest value. (Ex. 1013 at 1086–87.) Due
`
`to diurnal variation, a person of ordinary skill in the art would have recognized the
`
`possibility that the ammonia levels at other points in the day would fluctuate from
`
`the value observed at another point in the day, such as a fasted level.
`
`40. In a UCD patient, if the measured plasma ammonia level is greater than
`
`half the ULN, then one treatment option is to administer nitrogen scavenging drugs
`
`such as sodium be