`_________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_________________
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`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
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`Petitioners,
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`v.
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`HORIZON THERAPEUTICS, INC.
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`Patent Owner.
`_________________
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`IPR2016-00829
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`DECLARATION OF KEITH VAUX, M.D.
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`Table of Contents
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`I. QUALIFICATIONS ................................................................................................................ 1
`II.
`INFORMATION CONSIDERED ....................................................................................... 3
`III.
`SUMMARY OF OPINIONS AND EXPECTED TESTIMONY ........................................ 6
`IV. LEGAL STANDARDS ....................................................................................................... 6
`(i)
`Law of Obviousness ......................................................................................................... 6
`(ii)
`Person of Ordinary Skill in the Art .................................................................................. 9
`(iii) Claim Construction .......................................................................................................... 9
`V.
`BACKGROUND ............................................................................................................... 12
`(i)
`The ʼ559 Patent .............................................................................................................. 12
`(ii)
`The Urea Cycle and Nitrogen Scavenging Drugs .......................................................... 18
`VI. CLAIMS 1, 2, 4, 5, 7–10, 12, AND 13 OF THE ’859 PATENT WOULD HAVE BEEN
`OBVIOUS OVER BLAU, SIMELL, AND THE ’859 PUBLICATION ..................................... 25
`(i)
`Overview of Applied Prior Art ....................................................................................... 25
`(ii) Combining Applied Prior Art ......................................................................................... 28
`(iii)
`Independent Claims 1 and 2 ........................................................................................... 31
`(iv) Dependent Claim 4 ......................................................................................................... 38
`(v) Dependent Claim 5 ......................................................................................................... 39
`(vi) Dependent Claim 7 ......................................................................................................... 40
`(vii) Dependent Claim 8 ......................................................................................................... 40
`(viii) Dependent Claim 9 ..................................................................................................... 41
`(ix) Dependent Claim 10 ....................................................................................................... 42
`(x) Dependent Claims 12 and 13 ......................................................................................... 43
`(xi) Summary of Claims 1, 2, 4, 5, 7-10, 12 and 13.............................................................. 43
`VII. CLAIMS 3, 6, 11, 14, AND 15 OF THE ’859 PATENT WOULD HAVE BEEN
`OBVIOUS OVER BLAU, SIMELL, THE ’859 PUBLICATION, AND BRUSILOW ’84 ........ 44
`(i)
`Overview of Applied Prior Art ....................................................................................... 44
`(ii) Combining Applied Prior Art ......................................................................................... 45
`(iii)
`Independent Claim 3 ...................................................................................................... 46
`(iv) Dependent Claim 6 ......................................................................................................... 51
`(v) Dependent Claim 11 ....................................................................................................... 52
`(vi) Dependent Claims 14 and 15 ......................................................................................... 53
`(vii) Summary of Claims 3, 6, 11, 14 and 15 ......................................................................... 54
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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
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`Clinical Genetics. I am currently Professor and Clinical Chief of the Division of
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`Medical Genetics in the Department of Medicine at UC San Diego. I also have an
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`appointment as Professor of Neurosciences at UC San Diego, and I am a physician
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`at Point Loma Pediatrics. Since 1994, I have regularly diagnosed and treated
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`patients with urea cycle disorders (“UCD”), and continue to do so today. In
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`treating UCD patients, I regularly prescribe nitrogen scavenging drugs and treat
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`patients who are maintained on therapy with nitrogen scavenging drugs.
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`2.
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`I received a B.A. in History, Philosophy and Social Studies of
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`Science and Medicine from the University of Chicago in 1987, and an M.D. from
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`the University of Chicago in 1994. I have an unrestricted license to practice
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`medicine in the State of California.
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`3.
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`After medical school, I completed a three year residency in
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`pediatrics including a year as Chief Resident from 1994-1997, and a three year
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`fellowship in dysmorphology and medical genetics with an additional certificate in
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`teratology (environmentally induced birth defects) at UC San Diego from 2001 to
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`2004. I am Board Certified by the American Board of Pediatrics (received in 1997
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`and recertified in 2007 and 2015), am a Fellow of the American Academy of
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`Pediatrics and serve on the AAP National Council on Children with Disabilities
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`and Society on Genetics and Birth Defects. I am a member of the California
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`Department of Public Health, Genetic Diseases Screening Program Biobank
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`Committee which address policy issues surrounding metabolic screening in
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`newborns.
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`4.
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`I teach Medical Students, Medical and Pediatric Residents and
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`Specialty Fellows in Genetics, Complex Care Pediatrics and Metabolic Diseases. I
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`have published in peer reviewed Journals on metabolic disorders. I regularly speak
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`at national and international conferences on a variety of genetic, metabolic and
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`genomic medicine topics.
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`5.
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`A copy of my curriculum vitae, which sets forth my education and
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`experience in further detail, is provided herewith as Exhibit 1003.
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`6.
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`I have been engaged as an expert on behalf of Petitioners Lupin, Ltd.
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`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.
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`7.
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`In the previous four years, I have testified by trial or deposition in
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`the following matters:
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` Montgomery v. USS/Clicker; mediation; July 2012;
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` Fields v. Eli Lilly and Company; October 2014;
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` Schomake v. Eli Lilly and Company; November 2014;
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` Brookes Issue; February 2015.
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`INFORMATION CONSIDERED
`8.
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`In forming the opinions set forth herein, I have relied on my own
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`
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`II.
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`experiences and knowledge. I have also considered the documents discussed
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`herein, which include the following:
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`a. U.S. Patent No. 9,059,559 (the “ʼ559 Patent) (Ex. 1001);
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`b. Brusilow, et al., Treatment of Episodic Hyperammonemia in Children
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`with Inborn Errors of Urea Synthesis, 310 The New England Journal
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`of Medicine, 1630-1634 (1984) (“Brusilow’84”) (Ex. 1004);
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`c. Simell, et al., Waste Nitrogen Excretion Via Amino Acid Acylation:
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`Benzoate and Phenylacetate in Lysinuric Protein Intolerance, 20
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`Pediatric Research, 1117-1121 (1986) (“Simell”) (Ex. 1005);
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`d. Blau, Duran, Blaskovics, Gibson (editors), Physician’s Guide to the
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`Laboratory Diagnosis of Metabolic Diseases, 261-276 (2d ed. 1996)
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`(“Blau”) (Ex. 1006);
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`e. U.S. Patent Publication No. 2010/0008859, filed January 7, 2009,
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`published January 14, 2010 (the “’859 Publication”) (Ex. 1007);
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`f. Scientific Discussion for Ammonaps, EMEA 2005, available at
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`http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
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`_Scientific_Discussion/human/000219/WC500024748.pdf (“Scientific
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`Discussion”) (Ex. 1008);
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`g. Dixon, et al., Intercurrent Illness in Inborn Errors of Intermediary
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`Metabolism, 67 Archives of Disease in Childhood, 1387-1391 (1992)
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`(“Dixon”) (Ex. 1009);
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`h. UMass Memorial Laboratories, Lab Updates, February 2007,
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`Measurement of Ammonia in Blood (Ex. 1010);
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`i. Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle for
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`Waste Nitrogen Excretion, 29 Pediatric Research, 147-150 (1991)
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`(“Brusilow ’91”) (Ex. 1011);
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`j. Yajima, et al. Diurnal Fluctuations of Blood Ammonia Levels in
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`Adult-Type Citrullinemia, 137 Tokohu J. Ex/ Med, 213-220 (1982)
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`(“Yajima”) (Ex. 1012);
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`k. Batshaw, et al., Treatment of Carbamyl Phosphate Synthetase
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`Deficiency with Keto Analogues of Essential Amino Acids, 292 The
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`New England J. Medicine, 1085-90 (1975) (“Batshaw”) (Ex. 1013);
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`l. Kasumov, et al., New Secondary Metabolites of Phenylbutyrate in
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`Humans and Rats, 32 Drug Metabolism and Disposition, 10-19 (2004)
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`(“Kasumov”) (Ex. 1014);
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`m. Barsotti, Measurement of Ammonia in Blood, 138 J. Pediatrics, S11-
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`S20 (2001) (“Barsotti”) (Ex. 1015);
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`n. Berry, et al., Long-term management of patients with urea cycle
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`disorders, Journal of Pediatrics, Vol. 138, No. 1, S56–S61 (2001) (Ex.
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`1016);
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`o. Levin, et al., Hyperammonaemia A Variant Type of Deficiency of
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`Liver Ornithine Transcarbamylas, Arch. Dis. Childh. 1969, 44, 162
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`(1968) (“Levin”) (Ex. 1017);
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`p. Prosecution History of U.S. Patent No. 8,404,215 (Ex. 1018);
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`q. Excerpt from Stedman’s Medical Dictionary (Lippincott Williams &
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`Wilkins 2006) (Ex. 1019);
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`r. BUPHENYL® label, Physician’s Desk Reference, 60th ed. (2006), at
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`3327–28 (Ex. 1020);
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`s. AMMONUL® label, Physician’s Desk Reference, 60th ed. (2006), at
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`3323–25 (Ex. 1021);
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`t. Prosecution History of U.S. Patent No. 9,095,559 (Ex. 1022) (part 1
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`of 2); and
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`u. Prosecution History of U.S. Patent No. 9,095,559 (Ex. 1023) (part 2
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`of 2).
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`III. SUMMARY OF OPINIONS AND EXPECTED TESTIMONY
`9.
`I have reviewed the documents referenced above, in view of my own
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`knowledge and experience concerning the treatment of UCD patients with nitrogen
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`scavenging drugs. As explained in detail herein, it is my opinion that at the time of
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`the alleged invention (September 2011), that a person of ordinary skill in the art
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`would have been aware of and motivated to carry out methods of using a patient’s
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`fasting plasma ammonia levels to guide treatment decisions with nitrogen
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`scavenging drugs (including glyceryl tri-[4-phenylbutyrate]), including in patients
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`who have a plasma ammonia level between half the upper limit of normal and the
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`upper limit of normal for plasma ammonia.
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`10. As of September 2011, it was also known that one could calculate an
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`effective dosage glyceryl tri-[4-phenylbutyrate]) based on a mean conversion of
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`glyceryl tri-[4-phenylbutyrate]) to urinary PAGN of 60 to 75%.
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`IV. LEGAL STANDARDS
`(i)
`Law of Obviousness
`11. I have been informed that if the differences between the subject matter
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`claimed in a patent and the prior art are such that the claimed subject matter as a
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`whole would have been obvious to a person of ordinary skill at the time of the
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`alleged invention, then the patent claim is unpatentable as obvious. I understand
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`that the following factors must be evaluated in determining whether the claimed
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`subject matter is obvious: (1) the scope and content of the prior art; (2) the
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`differences between the claim and the prior art; (3) the level of ordinary skill in the
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`art at the time the patent was filed; and (4) any “secondary considerations” of
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`nonobviousness.
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`12. I have been informed that “secondary considerations” of non-
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`obviousness include: (i) any long-felt and unmet need in the art that was satisfied
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`by the invention of the patent; (ii) failure of others to achieve the results of the
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`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
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`under the patent by others; (vi) expressions of disbelief or skepticism by those
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`skilled in the art upon learning of the invention; (vii) praise of the invention by
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`others skilled in the art; and (viii) lack of contemporaneous and independent
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`invention by others. I understand that evidence of potential secondary
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`considerations must have a nexus to the claimed invention.
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`13. I have been informed that at this time, Patent Owner has not identified
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`any secondary considerations of nonobviousness. I reserve the right to respond to
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`any secondary considerations that Patent Owner may raise.
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`14. I have been informed that in the context of this proceeding, a claim will
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`be found unpatentable as obvious if the preponderance of the evidence indicates
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`that the claim would have been obvious.
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`15. I have been informed that a claim can be obvious in light of multiple
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`prior art references. I have been informed, however, that a patent claim is not
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`obvious merely by demonstrating that each of its elements was, independently,
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`known in the prior art. To be obvious in light of a combination of prior art
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`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
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`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
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`from the prior art as a whole.
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`16. I have been informed that the combination of familiar elements
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`according to known methods is likely to be obvious when it does no more than
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`yield predictable results. I also understand it is improper to rely on hindsight in
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`making the obviousness determination.
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`(ii)
`Person of Ordinary Skill in the Art
`17. I have been informed that a patent is not written for the general public,
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`but instead is directed to a “person of ordinary skill” in the field of the patent. I
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`have been informed that factors such as the education level of those working in the
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`field, the sophistication of the technology, the types of problems encountered in the
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`art, the prior art solutions to those problems, and the speed at which innovations
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`are made, help establish the level of skill in the art.
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`18. For purposes of this declaration, I have been asked to assume that the
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`date of the invention for the ’559 Patent is September 30, 2011.
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`19. In my opinion, a person of ordinary skill in the art as of September 30,
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`2011 would have been a physician with a M.D. degree with a residency in
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`pediatrics or internal medicine, and would have had specialized training in the
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`diagnosis or treatment of inherited metabolic disorders, such as UCDs and other
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`nitrogen retention disorders.
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`(iii)
`Claim Construction
`20. I have been informed that in the context of the current proceedings,
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`each of the terms in the patent claims is given its broadest reasonable interpretation
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`in light of the patent specification. I have reviewed the specification of the ʼ559
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`patent, and I interpret the below claim terms under the “broadest reasonable”
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`standard, as follows.
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`21. According to the specification, “upper limit of normal” (“ULN”), which
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`appears in each of the challenged claims, means “the highest level in the range of
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`normal values.” (Ex. 1001 at 12:11–12.)
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`22. Each of independent claims 1, 2, and 3, as well as dependent claims 5,
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`6, and 8, recite a “fasting” plasma ammonia level. The plain and ordinary meaning
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`of the term “fast” in the medical context means abstaining from at least food. See,
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`e.g., Stedman’s Medical Dictionary (Lippincott Williams & Wilkins 2006) (Ex.
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`1019). The specification of the ’559 patent makes clear that fasting means
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`abstaining from at least food for a minimum of four hours:
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`In certain embodiments of the methods disclosed
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`herein, the fasting period for obtaining a fasting blood
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`ammonia level is overnight. In certain embodiments,
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`the fasting period is 4 hours or more, 5 hours or more,
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`6 hours or more, 7 hours or more, 8 hours or more, 9
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`hours or more, 10 hours or more, 11 hours or more, or
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`12 hours or more, and in certain embodiments the
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`fasting period is 4-8 hours, 6-8 hours, or 8-12 hours.
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`(Ex. 1001, 10:23–29.) The specification also makes clear that fasting means that
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`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
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`example, in certain embodiments the subject does not
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`ingest any supplements and/or nitrogen scavenging
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`drugs during the fasting period. In certain of these
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`embodiments, the subject may nonetheless ingest one
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`or more drugs other than nitrogen scavenging drugs
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`during the fasting period. In certain embodiments, the
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`subject does not ingest any high calorie liquids during
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`the fasting period. In certain of these embodiments, the
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`subject does not ingest any liquids other than water
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`during the fasting period. In other embodiments, the
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`subject may ingest small amounts of low calorie
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`beverages, such as tea, coffee, or diluted juices.
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`(Id. at 10:30–44.) In view of specification and the plain and ordinary meaning of
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`the term fasting, “fasting” plasma ammonia level means the plasma ammonia level
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`in a person who has not eaten food for at least four hours.
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`23. Claims 1, 2, and 6 require that the “adjusted dosage” is “greater than the
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`initial dosage.” With regard to an adjusted dosage of glyceryl tri-[4-
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`phenylbutyrate] that is greater than the initial dosage, the specification states:
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`“Increasing the dosage of a nitrogen scavenging drug may refer to increasing the
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`amount of drug per administration (e.g., an increase from a 3 mL dosage to a 6 mL
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`dosage), increasing the number of administrations of the drug (e.g., an increase
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`from once-a-day dosing to twice- or three-times-a-day), or any combination
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`thereof.” (Id. at 10:20–25.) In view of this disclosure, an adjusted dosage that is
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`“greater than the initial dosage” means a dosage that increases the amount of drug
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`per administration, an increased number of administrations of the drug, or any
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`combination thereof.
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`24. In addition, I understand that each of the challenged claims contains the
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`transition term “comprising.” I am informed that in the patent context, this term
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`signals that the claims require the claimed method steps, but do not exclude
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`additional steps.
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`V. BACKGROUND
`(i) The ʼ559 Patent
`25. The ʼ559 Patent, titled “Methods of Therapeutic Monitoring of
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`Nitrogen Scavenging Drugs,” provides a method for evaluating daily ammonia
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`exposure based on a single fasting ammonia blood level measurement, as well as
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`methods that utilize this technique to adjust the dosage of a nitrogen scavenging
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`drug, determine whether to administer a nitrogen scavenging drug, and treat
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`nitrogen retention disorders. (Ex. 1001 at Abstract.) I understand that the ’559
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`Patent claims a filing date back to September 30, 2011 (“the priority date”), which
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`is when Provisional Application No. 61/542,100 was filed.
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`26. Specifically, the ’559 Patent claims a method for adjusting the dosage
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`of the nitrogen scavenging drug glyceryl tri-[4-phenylbutyrate] in a patient who
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`has a fasting plasma ammonia level less than the ULN for plasma ammonia, which
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`involves measuring the patient’s fasting plasma ammonia level, comparing it to the
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`ULN, and administering more drug if the fasting plasma ammonia level is greater
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`than half the ULN. (Ex. 1001 at claim 1.)
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`27. The ’559 Patent also claims a method of administering glyceryl tri-[4-
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`phenylbutyrate] to a UCD patient, which involves measuring a first fasting plasma
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`ammonia level, comparing it to the ULN, and administering drug if the fasting
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`plasma ammonia level is greater than half the ULN and less than the ULN. (Ex.
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`1001 at claim 3.)
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`28. The ’559 Patent claims read:
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`1. A method for adjusting the dosage of glyceryl tri-[4-
`phenylbutyrate] in a subject being treated for a urea cycle
`disorder who has previously been administered an initial
`dosage of glyceryl tri-[4-phenylbutyrate] and who has a
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`fasting plasma ammonia level less than the upper limit of
`normal for plasma ammonia level, the method
`comprising:
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`(a) measuring a fasting plasma ammonia level for
`the subject;
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`(b) comparing the fasting plasma ammonia level to
`the upper limit of normal for plasma ammonia
`level; and
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`(c) administering an adjusted dosage of glyceryl
`tri-[4-phenylbutyrate], wherein the adjusted dosage
`is greater than the initial dosage if the fasting
`plasma ammonia level is greater than half the
`upper limit of normal for plasma ammonia level.
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`2. A method of treating a subject with a urea cycle
`disorder who has previously been administered an initial
`dosage of glyceryl tri-[4-phenylbutyrate] and who has a
`fasting plasma ammonia level less than the upper limit of
`normal for plasma ammonia level, the method
`comprising:
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`(a) measuring a fasting plasma ammonia level for
`the subject;
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`(b) comparing the fasting plasma ammonia level to
`the upper limit of normal for plasma ammonia
`level; and
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`(c) administering an adjusted dosage of glyceryl
`tri-[4-phenylbutyrate] that is greater than the initial
`dosage if the fasting plasma ammonia level is
`greater than half the upper limit of normal for
`plasma ammonia level.
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`3. A method of administering glyceryl tri-[4-
`phenylbutyrate] to a subject having a urea cycle disorder,
`the method comprising:
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`(a) measuring a first fasting plasma ammonia level
`for the subject;
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`(b) comparing the first fasting plasma ammonia
`level to the upper limit of normal for plasma
`ammonia level; and
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`(c) administering an initial dosage of glyceryl tri-
`[4-phenylbutyrate] to the subject if the fasting
`plasma ammonia level is greater than half the
`upper limit of normal for plasma ammonia level
`and less than the upper limit of normal for plasma
`ammonia level.
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`4. The method of claim 1 or 2, wherein administering the
`adjusted dosage of glyceryl tri[4-phenylbutyrate]
`produces a normal average daily ammonia level in the
`subject.
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`5. The method of claim 4, further comprising repeating
`steps (a) to (c) until the subject exhibits a fasting plasma
`ammonia level at or below half the upper limit of normal
`for plasma ammonia level.
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`6. The method of claim 3, further comprising:
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`(d) measuring a second fasting plasma ammonia
`level for the subject;
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`(e) comparing the second fasting plasma ammonia
`level to the upper limit of normal for plasma
`ammonia level; and
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`(f) administering an adjusted dosage of glyceryl
`tri-[4-phenylbutyrate] that is greater than the initial
`dosage if the second fasting plasma ammonia level
`is greater than half the upper limit of normal for
`plasma ammonia level and less than the upper limit
`of normal for plasma ammonia level.
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`7. The method of any of claims 1-3, wherein the upper
`limit of normal for plasma ammonia level is 35 µmol/L.
`8. The method of any of claims 1-3, wherein the upper
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`limit of normal is specific to the laboratory in which the
`fasting plasma ammonia level is measured.
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`9. The method of any of claims 1-3, further comprising
`the step of determining an upper limit of normal for
`plasma ammonia level for the subject prior to step (b).
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`10. The method of claim 1 or 2, wherein the adjusted
`dosage is calculated by: (i) measuring urinary
`phenylacetyl glutamine (P AGN) output; and (ii)
`calculating an effective adjusted dosage of glyceryl tri-
`[4-phenylbutyrate] based on the urinary P AGN output,
`wherein the effective adjusted dosage is calculated based
`on a mean conversion of glyceryl tri-[4-phenylbutyrate]
`to urinary PAGN of 60 to 75%.
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`11. The method of claim 3, wherein the initial dosage is
`calculated by: (i) determining a target urinary
`phenylacetyl glutamine (P AGN) output; and (ii)
`calculating an effective initial dosage of glyceryl tri-[4-
`phenylbutyrate] based on a mean conversion of glyceryl
`tri-[4-phenylbutyrate] to urinary PAGN of 60 to 75%.
`12. The method of claim 1, wherein the adjusted dosage
`of glyceryl tri-[4-phenylbutyrate] is administered orally.
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`13. The method of claim 2, wherein the adjusted dosage
`of glyceryl tri-[4-phenylbutyrate] is administered orally.
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`14. The method of claim 3, wherein the initial dosage of
`glyceryl tri-[4-phenylbutyrate] is administered orally.
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`15. The method of claim 6, wherein the adjusted dosage
`of glyceryl tri-[4-phenylbutyrate] is administered orally.
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`
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`(ii) The Urea Cycle and Nitrogen Scavenging Drugs
`29. Prior to September 2011, using nitrogen scavenging drugs to treat
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`nitrogen retention disorders was well known. (See, e.g., Ex. 1004 at 1631; Ex.
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`1005 at 1118.) These drugs included phenylbutyrate, phenylacetate, sodium
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`phenylbutyrate (sold as BUPHENYL®), sodium benzoate, glyceryl tri-[4-
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`phenylbutyrate] (“HPN-100”), or a combination of two or more of HPN-100,
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`phenylbutyrate, and sodium phenylbutyrate. (See, e.g., Ex. 1004 at 1631; Ex.
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`1014 at 10–19; Ex. 1020; Ex. 1021.)
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`30. Nitrogen retention disorders that may be treated with these nitrogen
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`scavenging drugs include hepatic encephalopathy and UCDs. In the human body,
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`the urea cycle is the major pathway for the excretion of waste nitrogen. Enzymes
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`and transporters within the urea cycle synthesize urea from ammonia, which is then
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`excreted in urine to remove excess nitrogen. In a patient with a UCD, an enzyme
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`or transporter in the urea cycle is deficient, and, therefore, the patient is not able to
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`remove excess nitrogen. The inability to remove excess nitrogen in these patients
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`can lead to elevated plasma ammonia levels and hyperammonemia, which in turn
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`can lead to lethargy, coma, brain damage, and death.
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`31. In the human body, the urea cycle is the major pathway for the
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`metabolism and excretion of waste nitrogen. Nitrogen enters the body as
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`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
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`breakdown of free amino acids and through the sequential actions of carbamoyl
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`phosphate synthetase and the enzymes of the urea cycle, wherein two moles (a unit
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`of measurement) of amino acid nitrogen (from free ammonia and aspartate) are
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`converted into the two moles of nitrogen in urea. Urea is then excreted in urine,
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`removing the excess nitrogen from the body. Each urea molecule removes two
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`nitrogen molecules. The urea cycle works as follows:
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`21 of 57
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`32. In UCD patients, enzymes or transporters in the urea cycle are deficient.
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`This can cause excess dietary amino acids to be converted into ammonia that
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`22 of 57
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`accumulates rather than get excreted, causing toxicity. It was well known prior to
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`September 2011 that treating patients with UCDs involved achieving a balance
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`between diet, amino acid supplementation, and use of nitrogen scavenging drugs.
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`(Ex. 1016 at S56.) Nitrogen scavenging drugs that are metabolized to
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`phenylacetate (including sodium phenylbutyrate and glyceryl tri-[4-
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`phenylbutyrate] or HPN-100) provide an alternative mechanism for the clearance
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`of glutamine in the form of phenylacetylglutamine (“PAGN”), which like urea,
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`carries two nitrogen out of the body. Similarly, hippurate can be formed from the
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`conjugation of glycine and benzoate to excrete one mole of nitrogen per mole of
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`hippurate.
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`33. Nitrogen scavenging drugs provide an alternative pathway to the urea
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`cycle for waste nitrogen excretion. These drugs were known to remove waste
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`nitrogen in both normal individuals and UCD patients. Known nitrogen
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`scavenging drugs as of September 2011 included sodium benzoate, phenylacetic
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`acid (“PAA”), and PAA prodrugs phenylbutyrate (“PBA”), sodium phenylbutyrate
`
`(“NaPBA,” sold as BUPHENYL®), and glycerl tri-[4-phenylbutyrate] (also known
`
`as “HPN-100”). (See, e.g., Ex. 1011 at 147–48; Ex. 1014 at 10–11, 13; Ex. 1020;
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`Ex. 1021.)
`
`34. It was known that PAA prodrugs rapidly metabolize to PAA, and that
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`PAA in turn metabolizes to PAGN. PAGN, like urea, removes two nitrogen
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`23 of 57
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`molecules from the body. (Ex. 1011 at 147; Ex. 1015 at S13, S16; Ex. 1020; Ex.
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`1021.) The removal of nitrogen by a PAA prodrug works as follows:
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`
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`β‐oxidation
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`
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`PAA prodrug
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`
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`
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`Glutamine
`(2 moles N)
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`
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` PAA
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`
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`PAGN
`(2 moles of N)
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`
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`35. 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. The inability to remove excess ammonia in these patients can lead to
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`elevated plasma ammonia levels and hyperammonemia,1 which in turn can lead to
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`lethargy, coma, brain damage, and death.
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`36. Nitrogen scavenging drugs remove excess nitrogen to bring the plasma
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`ammonia value back to a normal range. Further, it was taught in the prior art that
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`1 Hyperammonemia is a metabolic disturbance that is characterized by an excess of
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`ammonia in the blood.
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`24 of 57
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`the conversion rate of PAA prodrugs into PAGN is 60%–75% in the body, and that
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`this conversion rate can also be used to determine an effective dose of PAA
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`prodrug to administer to a UCD patient. (Ex. 1007 at [0020], [0043], [0223].)
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`37. Prior to September 2011, it was well known that the goal of treating
`
`UCD patients is to maintain plasma ammonia levels within normal ranges. (See,
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`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.) This involved regularly
`
`measuring a patient’s plasma ammonia levels and comparing them to the ULN.
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`(See, e.g., Ex. 1004 at 1631; Ex. 1007 at [0083], [0094]; Ex. 1008 at 10.) It was
`
`also 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.
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`1004 at 1632 (Fig. 1); Ex. 1007 at [0063], Fig. 13, [0094], [0201].)
`
`38. In practice, when measuring a patient’s plasma ammonia levels to
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`compare it to the ULN, it was recommended to measure a fasting plasma ammonia
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`level. (Ex. 1005 at 1118; Ex. 1006 at Table 11.9; Ex. 1015 at S11.) This fasting
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`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
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`268, Table 11.5; Ex. 1012 at 213; Ex. 1015 at S19.) However, it was known that a
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`fasting plasma ammonia level will typically be lower than the daily average plasma
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`25 of 57
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`ammonia level in the patient and would show a smaller fluctuation within an
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`individual. (Ex. 1012 at 214.)
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`39. 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
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`was obtained (phlebotomy with and without a tourniquet, for example