UNITED STATES PATENT AND TRADEMARK OFFICE
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`______________________
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`
`
`IN THE UNITED STATES PATENT TRIAL AND APPEAL BOARD
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`______________________
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`
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`PAR PHARMACEUTICAL, INC.
`Petitioner
`
`v.
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`HYPERION THERAPEUTICS, INC.
`Patent Owner
`
`______________________
`
`CASE IPR: UNASSIGNED
`U.S. PATENT NO. 8,642,012
`______________________
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`DECLARATION OF NEAL SONDHEIMER, M.D., Ph.D
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`
`
`1
`
`
` LUPIN
`EX. 1002
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`
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`______________________
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`
`
`IN THE UNITED STATES PATENT TRIAL AND APPEAL BOARD
`
`______________________
`
`
`
`PAR PHARMACEUTICAL, INC.
`Petitioner
`
`v.
`
`HYPERION THERAPEUTICS, INC.
`Patent Owner
`
`______________________
`
`CASE IPR: UNASSIGNED
`U.S. PATENT NO. 8,642,012
`______________________
`
`DECLARATION OF NEAL SONDHEIMER, M.D., Ph.D
`
`
`
`1
`
`
` LUPIN
`EX. 1002
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`
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`I, Dr. Neal Sondheimer, M.D., Ph.D, do hereby declare and say:
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`1.
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`I am a medical doctor with specialties in Medical and Biochemical
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`Genetics. I am over the age of twenty-one (21) and competent to make this
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`declaration. I am also qualified to give testimony under oath. The facts and
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`opinions listed below are within my personal knowledge.
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`2.
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`I am being compensated for my time in this proceeding at my standard
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`consulting rate of $500/hour. My compensation in no way depends on the
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`outcome of this proceeding or the content of my opinions. I am not employed by,
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`nor receiving grant support from, Par Pharmaceutical, Inc., which I refer to as
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`“Par” or any related companies. I am receiving compensation from Par solely for
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`my time spent working on this matter and based only on my standard hourly
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`consulting fees.
`
`3.
`
`I have been asked to review U.S. Patent No. 8,642,012 (which I refer
`
`to as the ’012 Patent) (Ex. 1001) and the other documents that are exhibits to the
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`petition, and to provide my opinions on what those documents disclose. I was also
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`asked to review and provide opinions regarding U.S. Patent No. 8,404,215, and
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`have provided opinions specific to that patent in a separate declaration. I also
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`reviewed additional scientific literature references discussed in this declaration that
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`are not exhibits to the petition.
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`2
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`4.
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`Of particular relevance to the (cid:1932)012 Patent, I have reviewed and am
`
`familiar with, among others, the following documents:
`
`a. Simell, et al., Waste Nitrogen Excretion Via Amino Acid Acylation:
`
`Benzoate and Phenylacetate in Lysinuric Protein Intolerance, 20
`
`Pediatric Research, 1117-1121 (1986) (“Simell”), which is marked
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`as Ex. 1005.
`
`b. Fernandes, Saudubray Berghe (editors), Inborn Metabolic Diseases
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`Diagnosis and Treatment, 219-222 (3d ed. 2000) (“Fernandes”),
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`which is marked as Ex. 1011.
`
`c. Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle
`
`for Waste Nitrogen Excretion, 29 Pediatric Research, 147-150
`
`(1991) (“Brusilow ’91”), which is marked as Ex. 1012.
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`d. Kasumov, et al., New Secondary Metabolites of Phenylbutyrate in
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`Humans and Rats, 32 Drug Metabolism and Disposition, 10-19
`
`(2004) (“Kasumov”), which is marked as Ex. 1015.
`
`e. Sherwin, et al., The Maximum Production of Glutamine by the
`
`Human
`
`Body
`
`as Measured
`
`by
`
`the Output
`
`of
`
`Phenylacetylglutamine, 37 J. Biol. Chem., 113-119 (1919)
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`(“Sherwin”), which is marked as Ex. 1016.
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`3
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`f. Shiple, et al., Synthesis of Amino Acids in Animal Organisms. I.
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`Synthesis of Glycocoll and Glutamine in the Human Organism, 44
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`J. American Chem. Society, 618-624 (1922) (“Shiple”), which is
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`marked as Ex. 1017.
`
`g. U.S. Patent No. 4,284,647 to Brusilow, et al., filed January March
`
`31, 1980, issued August 18, 1981 (“the ’647 Patent”), which is
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`marked as Ex. 1018.
`
`h. Comte, et al., Identification of phenylbutyrylglutamine, a new
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`metabolite of phenylbutyrate metabolism in humans, J. Mass.
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`Spectrom. 2002:37:581–90 (“Comte”), which is marked as Ex.
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`1025.
`
`i. U.S. Patent No. 5,968,979 to Brusilow, filed Feb. 7, 1995, issued
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`Oct. 19, 1999 (“the ’979 patent”), which is marked as Ex. 1026.
`
`j. Collins et al., Oral Sodium Phenylbutyrate Therapy
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`in
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`Homozygous (cid:533) Thalassemia: A Clinical Trial, 85 Blood 43 (1995)
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`(“Collins”), which is marked as Ex. 1027.
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`5.
`
`I provide my conclusions regarding the disclosures of the documents I
`
`reviewed as applied to the ’012 Patent below.
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`6.
`
`I was also asked to provide my opinion on the technical feasibility of
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`combining certain exhibits, and offer my opinion on the feasibility of these
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`4
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`combinations in this declaration. I have also offered my opinions about what a
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`person of skill in the art would understand about the combinations of documents.
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`7.
`
`I am not offering any conclusions as to the ultimate determinations I
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`understand the Patent Trial and Appeal Board will make in this proceeding.
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`Specifically, I am not offering opinions on ultimate issues of validity. I am simply
`
`providing my opinion on the technical aspects of the documents and on the
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`combinability of the concepts disclosed in those documents from a technical
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`perspective (i.e., from the perspective of one of ordinary skill in the relevant art).
`
`I. BACKGROUND
`8.
`A copy of my curriculum vitae is attached to this declaration as Ex.
`
`1003.
`
`9.
`
`I received my A.B. in Biology from Harvard University in 1994, my
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`Ph.D. in Molecular Genetics and Cell Biology from the University of Chicago in
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`2000, and my M.D. from the University of Chicago Pritzker School of Medicine in
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`2002. I also completed a postdoctoral fellowship at the University of Pennsylvania
`
`in Genetics in 2009.
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`10.
`
`I am currently an Attending Physician at The Children’s Hospital of
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`Philadelphia in the Division of Biochemical Genetics. I am also currently the
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`Training Director for Clinical Biochemical Genetics at The University of
`
`Pennsylvania, as well as the Program Director for Medical Genetics at The
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`5
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`Children’s Hospital of Philadelphia and at The University of Pennsylvania. I am
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`also currently an Assistant Professor of Pediatrics at The University of
`
`Pennsylvania School of Medicine.
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`11.
`
`I hold multiple specialty certifications including a certification from
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`the American Academy of Pediatrics (received in 2006), a certification from the
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`American Board of Medical Genetics - Clinical Genetics (received in 2007), and a
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`certification from the American Board of Medical Genetics - Clinical Biochemical
`
`Genetics (received in 2009). Additionally, I have had an unrestricted license to
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`practice medicine in the Commonwealth of Pennsylvania since 2004.
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`12.
`
`I have been involved in several research studies on the genetic causes,
`
`diagnosis, and treatment of urea cycle defects (“UCD”). In 2008, I was co-author
`
`of a study that identified a novel genetic mechanism causing a disorder that
`
`included a urea cycle defect (Deardorff et al., MGM, 2008). In 2013, I was co-
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`author of a study of methods for emergency management of neonates with UCDs
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`(Spinale et al., Peds. Neph., 2013). Also in 2013, I was the senior author on a
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`study for early detection methods for infants with UCDs (Vergano et al., MGM,
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`2013). Although these studies acknowledge the use of ammonia-scavenging
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`medications, I have never performed or been funded to perform research in the
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`area of management of patients with UCDs using ammonia scavenging
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`medications.
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`6
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`13. Based upon my extensive knowledge and years of experience in this
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`field, I have an understanding of how nitrogen scavenging drugs were being used
`
`in medical treatment on or before August 29, 2008. My analysis on this matter, as
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`set forth below, is based on my personal experience and what was known, and in
`
`fact, considered to be standard, by one skilled in the art prior to August 29, 2008.
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`14. My opinions, explained below, are based on my education,
`
`experience, and background in the field discussed above, as well as my review of
`
`the references cited above.
`
`A. The ’012 Patent
`The ’012 Patent, titled “Methods of Treatment Using Ammonia-
`
`15.
`
`Scavenging Drugs,” provides a method for treating a patient having a urea cycle
`
`disorder (“UCD”) with a phenylacetic acid (“PAA”) prodrug. (Ex. 1001 at
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`Abstract.) I understand that the ’012 Patent claims a filing date back to August 29,
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`2008 (“the priority date”), which is when Provisional Application No. 61/093,234
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`was filed.
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`16.
`
`The ’012 Patent provides a method that includes determining a target
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`urinary phenylacetylglutamine (“PAGN”) output, administering a first dosage of a
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`PAA prodrug, determining urinary PAGN excretion, determining an effective
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`dosage of a PAA prodrug based on a mean conversion of PAA prodrug to PAGN
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`7
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`of about 60%, and administering the effective dosage to the patient. (Ex. 1001 at
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`42:16–25, 41–52.) Claim 1 recites the following:
`
`target urinary phenylacetyl glutamine
`
`A method of treating a patient having a urea cycle disorder
`comprising
`(a) determining a
`(PAGN) output
`(b) calculating an effective initial dosage of a phenylacetic acid
`(PAA)
`prodrug
`selected
`from
`glyceryl
`tri-[4-
`phenylbutyrate] (HPN-100) and phenylbutyric acid (PBA)
`or a pharmaceutically acceptable salt of PBA, wherein the
`effective dosage of PAA prodrug is calculated based on a
`mean conversion of PAA prodrug to urinary PAGN of
`about 60%; and
`(c) administering the effective initial dosage of PAA prodrug to
`the patient.
`Claim 8 recites the following:
`
`A method of administering a phenylacetic acid (PAA) prodrug
`selected
`from glyceryl
`tri-[4-phenylbutyrate]
`(HPN-100) and
`phenylbutyric acid (PBA) or a pharmaceutically acceptable salt of
`PBA to a patient having a urea cycle disorder comprising
`(a) administering a first dosage of the PAA prodrug;
`(PAGN)
`(b) determining urinary phenylacetyl glutamine
`excretion following administration of the first dosage of the
`PAA prodrug;
`(c) determining an effective dosage of the PAA prodrug based
`on the urinary PAGN excretion, wherein the effective
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`dosage is based on a mean conversion of PAA prodrug to
`urinary PAGN of about 60%; and
`(d) administering the effective dosage to the patient.
`
`17.
`
` The ’012 Patent describes in Example 9 the method by which the
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`PAGN excretion would be used to recalculate the dose of a PAGN prodrug if the
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`conversion rate was not 60%. It describes decreasing the dose if the conversion
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`rate is above 60% and increasing the dose if the conversion rate is below 60%. In
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`their own terms “if the doctor observes a higher output of urinary PAGN than
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`expected, the dosage of HPN-100 is reduced proportionally; thus if 21 g of urinary
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`PAGN per day is observed, the physician will reduce the dosage of HPN-100 to
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`(17/21)*19 g = 15 g.” It also provides a statement about increasing dosage by
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`proportionality for low conversion.1
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`
`
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`1 Example 9 is erroneous. This idea, however, violates the concept of steady-state
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`equilibrium. The relevant chemical equation could be written as: PAA + glutamine
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`(cid:198) PAGN. Per the Applicants of the ’012 patent, PAA and PAGN would always
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`be in a fixed proportion of 60% in this equation. By the definitions of this patent,
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`the actual and expected values for PAGN excretion cannot diverge. Even if the
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`patent did not fix conversion at 60%, the idea that giving more PAA would lead to
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`disproportionately more PAGN is an error.
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`9
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`The Urea Cycle
`B.
`In the human body, the urea cycle is the major pathway for the
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`18.
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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 two moles of amino acid
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`nitrogen (from free ammonia and aspartate) are converted into the two moles of
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`nitrogen in urea. Urea is then excreted in urine, removing the excess nitrogen from
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`the body. Each urea molecule excreted represented the removal two ammonia
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`molecules. The urea cycle works as follows:
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`10
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`11
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`19.
`
`In a patient with a urea cycle disorder, a defect in a required enzyme
`
`or transporter for urea cycle substrate is present. In these patients, excess dietary
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`amino acids are converted into ammonia that will accumulate, causing toxicity.
`
`Medications
`
`that are metabolized
`
`to phenylacetate
`
`(including
`
`sodium
`
`phenylbutyrate and glycerol triphenylbutyrate or HPN-100) provide an alternative
`
`mechanism for the clearance of glutamine in the form of phenylacetylglutamine,
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`which contains two mole of nitrogen like urea. Similarly hippurate can be formed
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`from the conjugation of glycine and benzoate to excrete one mole of nitrogen per
`
`mole of hippurate. These medications greatly simplify the process of balancing
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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 hyperammonemia2, which in turn can lead to
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`lethargy, coma, brain damage, and death.
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`20. A group of medicines called nitrogen scavenging drugs provide an
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`alternative pathway to the urea cycle for waste nitrogen excretion. These drugs
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`were known remove waste nitrogen in both normal individuals and UCD patients.
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`Known nitrogen scavenging drugs as of 2008 included sodium benzoate,
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`2 Hyperammonemia is a metabolic disturbance that is characterized by an excess
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`of ammonia in the blood.
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`12
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`phenylacetic acid (“PAA”) and PAA prodrugs: phenylbutyrate (“PBA”), sodium
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`phenylbutyrate (“NaPBA”), and glycerol phenylbutyrate (“HPN-100”). (See e.g.,
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`Ex. 1012 at 147–48; Ex. 1015 at 10–11, 13.) It was known that each equivalent of
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`PAA in a PAA prodrug could be converted to phenylacetyl glutamine (“PAGN”)
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`and remove two ammonia ions upon excretion, like urea does. (Ex. 1012 at 147;
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`Ex. 1016 at 113, 116; Ex. 1017 at 623; Ex. 1018 at 1:57–61.) In this case, the
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`conversion of a PAA prodrug to PAGN varies with individual patients, and even
`
`from time to time those patients. The removal of nitrogen by a PAA prodrug
`
`works as follows:
`
`Glutamine
`(2 moles N)
`
`PAA
`
`PAGN
`(2 moles of N)
`
`(cid:574)-oxidation
`
`PAA prodrug
`
`
`
`21.
`
`In the body, the processing and excretion of nitrogenous waste is like
`
`a river. Nitrogen enters the river in the form of dietary protein and, after running
`
`its course through the urea cycle, flows out through the urine in the form of urea.
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`For most individuals, this river flows smoothly because the capacity to handle
`
`nitrogenous waste is greater than the flow of nitrogen-containing dietary protein
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`13
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`into the river. In urea cycle defect patients, however, the river gets backed up
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`downstream – a condition known as hyperammonemia. As a result, dangerous
`
`accumulations of ammonia can occur.
`
` The danger posed by ammonia
`
`accumulation is exacerbated by the accumulation of glutamine, which is one of the
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`principal amino acids that donates to the ammonia pool. PAA prodrugs address
`
`the problem caused by the backup by creating a shunt pathway through which
`
`glutamine can be diverted. Glutamine diverted in this way, in the form of PAGN,
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`is removed from the body through the urine and never forms ammonia. Reducing
`
`the levels of glutamine thus decreases the amount of ammonia formed, resolving
`
`hyperammonemia.
`
`22.
`
`It was well known before the August 29, 2008 priority date of the
`
`’012 Patent that when the PAA prodrug is converted into PAGN, there is not 100%
`
`conversion. Instead, it was well known that the conversion rate varied between
`
`50%–67%. (Ex. 1016 at 114, Table 1.) It was also well known before the priority
`
`date of the ’012 Patent that this conversion rate, along with the patient’s target
`
`urinary PAGN excretion, could be used to determine an effective dosage of the
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`PAA prodrug to administer to the patient. (Ex. 1012 at 147.)
`
`II. LEVEL OF SKILL IN ART
`23.
`I understand that one of the relevant factors in this proceeding is the
`
`level of skill in the pertinent art. I understand that the pertinent dated for this
`
`14
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`determination is the date of the alleged invention. For purposes of this declaration,
`
`I have been asked to assume that the date of the invention for the ’012 Patent is the
`
`August 29, 2008 priority date.
`
`24.
`
`In my opinion, a person of ordinary skill in the art as of August 29,
`
`2008, would have been a physician or scientist with a Ph.D. or M.D. degree and
`
`had specialized training in the diagnosis or treatment of inherited metabolic
`
`disorders, such as urea cycle disorders (“UCDs”) and other nitrogen retention
`
`disorders. Today, such a person may have post-graduate training to fulfill the
`
`requirements of the American Board of Medical Genetics and Genomics in
`
`Clinical Genetics, Clinical Biochemical Genetics, or Medical Biochemical
`
`Genetics.
`
`III. INTERPRETATIONS OF THE ’012 PATENT CLAIMS AT ISSUE
`25.
`I have been informed by counsel that, for purposes of my analysis
`
`each term appearing in a patent claim should be interpreted according to its
`
`“broadest reasonable construction in light of the specification of the patent in
`
`which it appears.” I further understand that the words of the claims should be
`
`given their plain meaning unless that meaning is inconsistent with the patent
`
`specification.
`
`26.
`
`I also understand that the words of the claims should be interpreted as
`
`they would have been interpreted by a person of ordinary skill in the art at the time
`
`15
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`the invention was made (not today). For my analysis, I was instructed to use the
`
`priority date of the ’012 Patent, August 29, 2008, as the point in time for claim
`
`interpretation purposes.
`
`27.
`
`I have reviewed the correspondence between the patent office and the
`
`applicant for the ’012 Patent. (Ex. 1021.) The examiner rejected the claims in the
`
`application leading to the ’012 Patent over Brusilow ’91and other references. The
`
`examiner would not grant a patent to the claimed methods until after applicant
`
`submitted test data showing a mean percent conversion of 67%, and the examiner
`
`narrowed the claims to a mean percent conversion of about 60%. Because “mean
`
`percent conversion of about 60%” includes 67%, it is my opinion that a person of
`
`ordinary skill in the art would interpret the patent term “mean conversion . . . of
`
`about 60%” as meaning at least 53–67%
`
`IV. LEGAL PRINCIPLES
`28.
`I have been informed that a patent claim is invalid as “obvious” under
`
`35 U.S.C. § 103 in light of one or more prior art references if it would have been
`
`obvious to one of skill in the art at the time the invention was made, taking into
`
`account (1) the scope and content of the prior art, (2) the differences between the
`
`prior art and the claims, (3) the level of ordinary skill in the art, and (4) any so-
`
`called “secondary considerations” of non-obviousness, which include: (i) “long felt
`
`need” for the claimed invention, (ii) commercial success attributable to the claimed
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`16
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`invention, (iii) unexpected results of the claimed invention, and (iv) “copying” of
`
`the claimed invention by others.
`
`29.
`
`For purposes of my analysis above, unless otherwise stated, I have
`
`applied a date of September 30, 2011, as the date of invention, in my obviousness
`
`analyses, although in many cases the same analysis would hold true even at an
`
`earlier time than September 30, 2011.
`
`30.
`
`I have been informed that a claim can be obvious in light of a single
`
`prior art reference or multiple prior art references. To be obvious in light of a
`
`single prior art reference or multiple prior art references, there must be a reason to
`
`modify the single prior art reference, or combine two or more references, in order
`
`to achieve the claimed invention. This reason may come from a teaching,
`
`suggestion, or motivation to combine, or may come from the reference or
`
`references themselves, the knowledge or “common sense” of one skilled in the art,
`
`or from the nature of the problem to be solved, and may be explicit or implicit
`
`from the prior art as a whole.
`
`31.
`
`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.
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`32.
`
`I have been informed that a patent claim composed of several
`
`elements is not obvious merely by demonstrating that each of its elements was,
`
`independently, known in the prior art. I have been further informed that it can be
`
`important to identify a reason that would have prompted a person of ordinary skill
`
`in the relevant field to combine the elements in the way the claimed new invention
`
`does.
`
`V. THE PRIOR ART REFERENCES MEASURING PAA TO PAGN
`CONVERSION
`
`A. Brusilow ’91
`Brusilow ’91 teaches a method for calculating an effective dosage of
`
`33.
`
`PAA prodrug (NaPBA) to treat UCD, using the daily protein intake of a patient to
`
`calculate dietary nitrogen intake. (Ex. 1012 at 147–48.) This dietary nitrogen
`
`intake was used to calculate the required waste nitrogen excretion, which was used
`
`to determine the target amount of urinary PAGN to be excreted in a UCD patient.
`
`(Id.) Brusilow ’91 used this target amount of urinary PAGN to calculate the dose
`
`of NaPBA to be administered to the patient. (Id.)
`
`34.
`
`The experiment in Brusilow ’91 involved treating a 7 1/2 year old
`
`UCD patient over three periods. In the first period, the author administered sodium
`
`phenylacetate, hypothesizing a mean conversion of 100% to PAGN, but observing
`
`a conversion of 83%.
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`18
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`35.
`
`In the second period, the author administered a 12 g dose of the PAA
`
`prodrug, NaPBA. This dose was calculated to be sufficient to cause the excretion
`
`of 193 mmol of PAGN, which provided the desired nitrogen excretion based on the
`
`patient’s diet (Period II). (Id. at 147–48, 148 (Table 1).)
`
`
`
`36. After administering the 12 g/day dose, he measured the urinary PAGN
`
`excreted, which showed a 90% conversion rate of NaPBA to PAGN. (Id.) Based
`
`on the prior rates of conversion in Period I and Period II, Brusilow increased the
`
`NaPBA dose to 14 g/day in Period III. (Id.) Again, this dose was calculated to
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`create an excretion of 193 mmol of PAGN with the new assumption that PAGN
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`excretion after the administration of NaPBA was lower. However, as seen in Table
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`1, the 14 g/day dose resulted in an 80% conversion of NaPBA to PAGN. (Id. at
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`148 (Table 1).)
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`B. Sherwin
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`37.
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`Sherwin, published in 1919, studied the conversion of PAA into
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`PAGN by administering varying doses of PAA to a normal healthy volunteer. (Ex.
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`1016 at 114.) The subject ingested varying doses of PAA ranging from 2.5–15.0
`19
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`grams, and each dose was taken all at once over 3–5 minutes. (Id.) His urine was
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`collected in 24 hour periods beginning at the time of ingestion of the dose. (Id.)
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`Urinary PAGN was measured and a percent conversion from PAA to PAGN was
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`calculated. (Id. at 114 & 116 (Table I).)
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`38. As seen in Table I, although the conversion ranged from about 50–
`
`67%, therapeutic doses (10 grams daily or above) only began at day 13. (Id.) In
`
`my opinion, a person of ordinary skill in the art would emphasize the conversion in
`
`therapeutic doses, which showed conversions of 51–52%. (Id.) Taken together,
`
`these two values can provide a mean conversion. A person of ordinary skill in the
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`art reviewing Sherwin would understand that the 51–52% figures are probably too
`
`low because the subject was not dosed throughout the day, but instead, given a
`
`single large dose of PAA. Sherwin itself acknowledges this: “It is probable that
`
`more of the [PAGN] would have appeared in the urine after each dose of the acid,
`
`had the acid been ingested at regular intervals covering a period of 10 or 12 hours.”
`
`(Ex. 1016 at 118.) The following table from Sherwin shows the percentage
`
`conversion to PAGN, the relevant column of which is outlined.
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`C. Shiple
`
`39.
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`Individuals without UCDs provide useful information about the
`
`conversion of PAA to PAGN in patients with UCDs because the administration of
`
`PAA prodrugs, by their design, divert most of the burden of waste nitrogen away
`
`from the urea cycle. Shiple, published in 1922, found that when an individual with
`
`a urea cycle defect subject consumed PAA, urea production was substantially
`
`suppressed. (Ex. 1017 at 620 (Table II), 623–24.) Shiple studied the effect that
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`varying doses of PAA had on urea production in a single healthy volunteer. (Id. at
`
`619–20, 623–24.) After treatment with 4 g and 6 g doses of phenylacetate, doses
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`21
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`which would be relevant to PAA prodrug dosage for a patient of this size, urea
`
`production as a measure of total nitrogen excretion declined to 12% from values of
`
`74–77% prior to the administration of phenylacetate. Thus, person of ordinary
`
`skill in the art would understand that the percentage conversion of PAGN in a
`
`UCD patient would be similar to if not greater than a normal patient. Because UCD
`
`patients typically have elevated glutamine levels, there is more glutamine for a
`
`PAA prodrug to scavenge, resulting in a higher conversion. Glutamine is the
`
`principal donor to the circulating ammonia pool, and elevations in glutamine will
`
`push the reaction that conjugates glutamine to PAA prodrugs (shown below) to
`
`increase the conversion of PAA to PAGN.
`
`Glutamine + PAA ——> PAGN
`
`D. Comte
`
`40.
`
`In Comte, the authors administered an oral dose of 5 grams of
`
`NaPBA to seven healthy volunteers who were drug naïve and in a fasted state.
`
`This dose closely approximates relevant dosing in UCD patients.3 Urine was
`
`collected for only 8 hours. This study was specifically designed to calculate the
`
`3 Comte used a single dose of NaPBA only. In a patient, the dosage is 9–13
`
`g/m2/d divided into 3–6 daily doses (per Buphenyl package insert). In an average
`
`sized adult of 1.75m2 this gives a total daily dose of 16–22 g. Thus a 5g dose
`
`would be appropriate generally for administration 4 times daily.
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`22
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`values of both PAGN and phenylbutyrylglutamine (PBGN). PBGN is formed
`
`from the acylcation of glutamine by PBA that has not undergone (cid:533)-oxidation to
`
`PAA. PBGN provides identical ammonia-scavenging capacity to PAGN. Comte
`
`reported a 33% conversion of NaPBA to PAGN and a 22% conversion of NaPBA
`
`to PBGN during their 8-hour recovery. In my opinion, a person of ordinary skill in
`
`the art would recognize that the summed value (54%) of glutamine-conjugated
`
`excretion understates the excretion had the urine sample been collected for 24
`
`hours to allow complete metabolism.
`
`E. Collins
`
`41.
`
`In Collins, the authors administered oral doses of NaPBA to patients
`
`with thalassemia using a dosing regimen that approximated that used for patients
`
`on Buphenyl (10.6–13.8 g/m2/d) divided into three daily doses for 21 days.
`
`Buphenyl contains NaPBA. Collins was designed to evaluate the role of NaPBA
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`in activating the expression of fetal hemoglobin for the purpose of treating sickle
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`cell disease. This strategy was used in an attempt to promote the synthesis of an
`
`alternative form of hemoglobin. Urine samples were collected in 24-hour periods
`
`for 9 patients and the excretion of PAA prodrug as PAGN was determined to be
`
`23
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`76±13%.
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`VI. BRUSILOW ’91 IN VIEW OF SHERWIN AND SHIPLE (CLAIMS 1,
`3, 4, 7, 8, 10, AND 12)
`Technical Reasons to Combine Brusilow ’91, Sherwin, and Shiple
`
`A.
`
`42.
`
`It is my opinion that a person of ordinary skill in the art considering
`
`UCD treatment with PAA prodrugs before August 29, 2008 would have been
`
`motivated to combine the teachings of Brusilow ’91 with Sherwin and Shiple. A
`
`person of ordinary skill in the art reading Brusilow ’91’s clinical study using
`
`NaPBA (a PAA prodrug) (Ex. 1012 at 147) would have been motivated to look to
`
`both Sherwin and Shiple because each discusses the conversion of PAA to PAGN.
`
`(Ex. 1016 at 113, 116 (Table I), 117–18; Ex. 1017 at 623.) In my opinion, a person
`
`of ordinary skill in the art would have been motivated to combine the teachings of
`
`the prior art to arrive at the subject matter of claims 1, 3, 4, 7, 8, and 10 with a
`
`reasonable expectation of success in treating UCD patients.
`
`43. Because Brusilow ’91 involved a single subject and observed a range
`
`of conversion rates (80–90%), a person of ordinary skill in the art would have been
`
`motivated to look to other references, such as Sherwin, to find more information on
`
`conversion rates. A person of ordinary skill in the art would have then been able to
`
`better assess the specific amount of PAA or a PAA prodrug to eliminate a specific
`
`amount of waste nitrogen based on prior art published conversion rates.
`
`44. A person of ordinary skill in the art would also consider Shiple to
`
`ascertain any difference between UCD patients and normal subjects taking PAA,
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`24
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No. 8,642,012
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`and whether PAA administration impacts urea production in a normal person with
`
`a functioning urea cycle. Because Brusilow ’91 studied the conversion of the PAA
`
`prodrug, NaPBA, to PAGN in a UCD patient, and Sherwin studied the conversion
`
`of PAA to PAGN in a normal patient, a person of ordinary skill in the art would
`
`have looked to Shiple to determine if administering PAA to normal patients caused
`
`different waste nitrogen excretion than in UCD patients. Shiple teaches that
`
`administering PAA suppresses urea production (Ex. 1017 at 620 & 623), and
`
`therefore, a person of ordinary skill in the art reading Shiple and Sherwin would
`
`have understood that the conversion rate of PAA presented in Sherwin would also
`
`apply to the UCD patient in Brusilow ’91, because both the normal patient fed
`
`PAA and the UCD patient experienced suppressed urea production. (Ex. 1016; Ex.
`
`1017.)
`
`45. A person of ordinary skill in the art interested in UCD treatment with
`
`nitrogen scavenging drugs would have referred to Brusilow ’91’s clinical study
`
`regarding PAGN production using the PAA prodrug, NaPBA, with Sherwin’s and
`
`Shiple’s clinical studies into the effects of PAA treatment on patients.
`
`46. As discussed above, Brusilow’91 teaches treating a patient with
`
`NaPBA, which is a PAA prodrug. (Ex. 1012 at 147.) Brusilow’91 also teaches the
`
`determination of a target (predicted) urinary PAGN excretion. (Ex. 1012 at 147 &
`
`148 (Table 1).) In Table 1, Brusilow’91 calculates that if 12 g/day of NaPBA was
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`25
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`Declaration of Dr. Neal Sondheimer Regarding U.S. Patent No.
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