`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`
`MAIA PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`BRACCO DIAGNOSTICS INC.,
`Patent Owner
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Case No. IPR2019-00345
`U.S. Patent No. 6,803,046
`
`
`
`
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`
`
`
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`
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`
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`
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`DECLARATION OF CHRISTIAN SCHÖNEICH, PH.D. IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 6,803,046
`
`
`
`
`
`
`MAIA Exhibit 1003
`MAIA V. BRACCO
`IPR PETITION
`
`

`

`TABLE OF CONTENTS
`
`
`
`Page No.
`I. INTRODUCTION ................................................................................................ 1
`
`II. QUALIFICATIONS ........................................................................................... 6
`
`III. LEGAL BACKGROUND ................................................................................ 8
`
`A. Relevant Legal Standards ........................................................................... 8
`
`B. Person of Ordinary Skill in the Art .......................................................... 11
`
`IV. BACKGROUND OF THE TECHNOLOGY ................................................. 12
`
`A. Peptides and Proteins ............................................................................... 13
`
`B. Peptide and Protein Drug Products .......................................................... 14
`C. Cholecystokinin and Sincalide ................................................................. 15
`
`D. Sincalide’s Chemical and Physical Instability ......................................... 17
`
`1. Sincalide Chemical Instability: Sulfated Tyrosine Residue ............. 20
`
`2. Sincalide Chemical Instability: Methionine Residues ..................... 21
`
`3. Sincalide Physical Instability ........................................................... 25
`
`E. Stable Lyophilized Parenteral Formulations ............................................ 27
`
`1. Stabilizers ......................................................................................... 29
`
`a.
`Antioxidants ........................................................................ 30
`
`b.
`
`2. Surfactant/Solubilizers ..................................................................... 35
`
`3. Chelators ........................................................................................... 36
`
`4. Bulking Agents/Tonicity Adjusters .................................................. 37
`
`5. Buffers .............................................................................................. 38
`
`V. THE ’046 PATENT ........................................................................................ 39
`
`VI. THE CHALLENGED CLAIMS OF THE ’046 PATENT WOULD HAVE
`BEEN OBVIOUS ............................................................................................ 47
`
`A. Claims 1-4, 6-11, 13, 15, 16, 19, 21-24, 26-31, 33, 35, 36, 40-42, 44-49,
`51, 53, 55, and 104 Would Have Been Obvious Over the PDR in
`Combination with Sato ............................................................................. 47
`
`Amino Acids ........................................................................ 31
`
`
`
`i
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`

`

`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`1. Independent Claim 1 ........................................................................ 49
`
`An Effective Amount of Sincalide ...................................... 50
`
`
`
`
`
`ii
`
`At Least One Stabilizer ....................................................... 51
`
`A Surfactant/Solubilizer ...................................................... 54
`
`A Bulking Agent/Tonicity Adjuster .................................... 57
`
`A Buffer ............................................................................... 58
`
`A Chelator ........................................................................... 56
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`2. Independent Claim 21 ...................................................................... 61
`
`3. Independent Claim 40 ...................................................................... 62
`
`4. Independent Claim 104 .................................................................... 64
`
`5. Claims 2, 22 ...................................................................................... 65
`
`6. Claims 3, 4, 23, 24, 41, 42 ................................................................ 66
`
`7. Claims 6-9, 26-29, 44-47 .................................................................. 67
`
`8. Claims 10, 11, 13, 30, 31, 33, 48, 49, 51 ......................................... 67
`
`9. Claims 15, 16, 35, 36 ........................................................................ 68
`
`10. Claim 19 ........................................................................................... 69
`
`11. Claim 55 ........................................................................................... 69
`
`B. Ground 2: Claims 5, 12, 14, 17, 18, 25, 32, 34, 37, 38, 43 50, 52, and 54
`are unpatentable under 35 U.S.C. § 103(a) over the PDR in combination
`with Sato and Nema ................................................................................. 70
`
`1. Claims 5, 25, 43 ................................................................................ 70
`
`2. Claims 12, 32, 50 .............................................................................. 71
`
`3. Claims 14, 34, 52 .............................................................................. 73
`4. Claims 17, 37, 54 .............................................................................. 75
`
`5. Claims 18, 38 .................................................................................... 76
`
`
`

`

`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`C. Ground 3: Claims 77-88, 90-95, 97, 99, 100, and 105 are unpatentable
`under 35 U.S.C. § 103(a) in view of the PDR in combination with
`Sato and ENMS ........................................................................................ 77
`
`1. Independent Claim 77 ...................................................................... 77
`
`2. Claim 78 ........................................................................................... 79
`
`3. Claims 79-80 .................................................................................... 80
`4. Claims 81-82 .................................................................................... 80
`5. Claim 83 ........................................................................................... 81
`
`6. Claims 84-85 .................................................................................... 81
`
`7. Claims 86-88, 90-95, 97, 99, 100 ..................................................... 81
`
`8. Claim 105 ......................................................................................... 82
`
`D. Ground 4: Claims 89, 96, 98, 101, and 102 are unpatentable under 35
`U.S.C. § 103(a) in view of the PDR in combination with Sato, ENMS,
`and Nema ................................................................................................. 83
`
`VII. CONCLUSION ............................................................................................. 84
`
`
`
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`
`iii
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`
`
`I, Christian Schöneich, Ph.D. declare and state as follows:
`
`
`I. INTRODUCTION
`
`1. My name is Christian Schöneich, Ph.D. My findings, as set forth
`
`herein, are based on my education and background in the fields discussed below.
`
`2.
`
`I have been retained on behalf of Petitioner Maia Pharmaceuticals, Inc.
`
`(“Maia” or “Petitioner”) to provide this Declaration relating to U.S. Patent No.
`
`6,803,046 (“’046 patent,” MAIA1001). I understand that Bracco Diagnostics, Inc.
`
`(“Bracco”) is the Patent Owner in this inter partes review.
`
`3.
`
`I reserve the right to supplement this Declaration in response to
`
`additional evidence that may come to light. I am over 18 years of age. I have
`
`personal knowledge of the facts stated in this Declaration and could testify
`
`competently to them if asked to do so.
`
`4.
`
`I am not currently, nor have I ever been, employed by Maia, or any
`
`affiliates of Maia. To the best of my knowledge, I have no financial interest in Maia,
`
`or any affiliates.
`
`5.
`
`I am being compensated by Maia for my time, billed at my normal
`
`hourly rate, for time actually spent reviewing materials, and performing my analysis
`
`of the technical issues relevant to this matter. My compensation is in no way
`
`dependent on the opinions I formulate or offer below, nor will I receive any
`
`additional compensation based on the outcome of this proceeding.
`
`
`
`1
`
`

`

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`
`
`
`6.
`
`In preparing this Declaration, I considered the following materials:
`
`Exhibit No.
`
`Description
`
`1001
`
`U.S. Patent No. 6,803,046 to Metcalfe et al.
`
`1005
`
`Physicians’ Desk Reference For Radiology and Nuclear
`Medicine, 1977/78 (1977) (“PDR”)
`
`1006
`
`PCT Publication No. WO 00/5169 to Sato
`
`1007
`
`1008
`
`1009
`
`PCT Publication No. WO 00/5169 to Sato (English Translation
`with affidavit) (“Sato”)
`
`Bacarese-Hamilton et al., “Prevention of Cholecystokinin
`Oxidation During Tissue Extraction,” 448 Neuronal
`Cholecystokinin 571 (1985) (“Bacarese-Hamilton I”)
`
`Bacarese-Hamilton et al., “Oxidation/Reduction of Methionine
`Residues in CCK: A Study by Radioimmunoassay and Isocratic
`Reverse Phase High Pressure Liquid Chromatography,” 6
`Peptides 17 (1985) (“Bacarese-Hamilton II”)
`
`1010
`
`U.S. Patent No. 7,329,644 to Saviano et al. (“Saviano”)
`
`1011
`
`1012
`
`1013
`
`1014
`
`Rational Design of Stable Protein Formulations: Theory and
`Practice, Chapters 5 & 8 (Carpenter and Manning, ed., April 30,
`2002).
`
`Liddle, R. A., On the Measurement of Cholecystokinin, 44
`Clinical Chemistry 5 (1998) (“Liddle 1998”)
`
`Akers et al., “Peptides and Proteins as Parenteral Solutions,” in
`Pharmaceutical Formulation Development of Peptides and
`Proteins (2000) (“Akers”)
`
`DeLuca, et al., “Formulation of Small Volume Parenterals,” in
`Pharmaceutical Dosage Forms: Parenteral Medications Volume
`1 (1992) (“DeLuca”)
`
`2
`
`

`

`
`
`
`
`Exhibit No.
`
`Description
`
`1015
`
`U.S. Patent No. 3,937,819 to Ondetti et al. (“Ondetti”)
`
`1016
`
`1017
`
`Wang et al., “Review of Excipients and pHs for Parenteral
`Products Used in the United States,” 34 PDA J. Pharm. Sci and
`Tech. 452 (1980) (“Wang 1980”)
`
`Nema et al., “Excipients and Their Use in Injectable Products,”
`51 PDA J. of Pharma. Sci. and Tech. 166 (1997) (“Nema”)
`
`1018
`
`U.S. Patent Publication No. 2003/0104996 to Li et al. (“Li”)
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`Wang et al., “Parenteral Formulations of Proteins and Peptides:
`Stabilities and stabilizers,” 42 J. Parenteral Sci. and Tech. S4
`(1988) (“Wang 1988”)
`
`Wünsch, E., “Peptide Factors as Pharmaceuticals: Criteria for
`Application,” 22 Biopolymers 493 (1983) (“Wünsch”)
`
`Yagami, et al., “Stabilization of a tyrosine O-sulfate residue by a
`cationic functional group: formation of a conjugate acid-base
`pair,” 56 J. Peptide Res. 239 (2000) (“Yagami”)
`
`Huttner, W. B., “Determination and Occurrence of Tyrosine O-
`Sulfate in Proteins,” 107 Methods in Enzymology 200 (1984)
`(“Huttner”)
`
`Moroder et al., “Gastrin and Cholecystokinin, An Arduous Task
`for the Peptide Chemist” in Natural Product Chemistry (1986)
`(“Moroder”)
`
`Yoshioka, et al., “Stability of Peptide and Protein
`Pharmaceuticals” in Stability of Drugs and Dosage Forms (2002)
`(“Yoshioka”)
`
`Marseigne, et al., “Full Agonists of CCK8 Containing a
`Nonhydrolyzable Sulfated Tyrosine Residue,” 32 J. Med. Chem.
`445 (1989) (“Marseigne”)
`
`3
`
`

`

`
`
`
`
`Exhibit No.
`
`Description
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`Gorman et al., “Proton Affinities of the 20 Common α-Amino
`Acids,” 114 J. Am. Chem. Soc. 3986 (1992)
`
`Liddle, R. A., “Cholecystokinin Cells,” 59 Annu. Rev. Physiol.
`221 (1997) (“Liddle 1997”)
`
`Wang, Y.J., “Parenteral Products of Peptides and Proteins,” in
`Pharmaceutical Dosage Forms: Parenteral Medications Volume
`1 (1992) (“Wang 1992”)
`
`Package Insert for “KINEVAC® Sincalide for Injection,”
`November 1994 (“Kinevac 1994 Package Insert”)
`
`Essentials of Nuclear Medicine Science (Hladik, et al., eds.,
`1987) (“ENMS”)
`
`Uffelman, W., “Unexpected Shortfalls of Two Nuclear Medicine
`Pharmaceuticals,” 42 J. Nuc. Med. 16N (2001) (“Uffelman”)
`
`1032
`
`U.S. Patent No. 5,272,135 to Takruri (“Takruri”)
`
`1033
`
`1034
`
`1035
`
`1036
`
`FDA Approval Package for NDA Application Number 017697-
`S012.
`
`Fendler et al., “Hydrolysis of Nitrophenyl and Dinitrophenyl
`Sulfate Esters,” 33 J. Org. Chem. 10 3852 (1968) (“Fendler”)
`
`Handbook of Pharmaceutical Excipients, Third Edition, Arthur H.
`Kibbe, Ed. (2000) (“Handbook”)
`
`Jensen et al., “Metal-Catalyzed Oxidation of Brain-Derived
`Neurotrophic Factor (BDNF): Analytical Challenges for the
`Identification of Modified Sites,” 17 Pharm. Research 190 (2000)
`(“Jensen I”)
`
`4
`
`

`

`
`
`
`
`
`
`
`Exhibit No.
`
`Description
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`Jensen et al., “Metal-Catalyzed Oxidation of Brain-Derived
`Neurotrophic Factor (BDNF): Selectivity and Conformational
`Consequences of Histidine Modification,” 46 Cellular and
`Molecular Biology 685 (2000) (“Jensen II”)
`
`Swadesh, et al., “Sodium Sulfite as an Antioxidant in the Acid
`Hydrolysis of Bovine Pancreatic Ribonuclease A,” 141 Analytical
`Biochemistry 397 (1984) (“Swadesh”)
`
`Mattern et al., “Formulation of Proteins in Vacuum-Dried
`Glasses. II. Process and Storage Stability in Sugar-Free Amino
`Acid Systems,” 4 Pharm. Development and Tech. 199 (1999)
`(“Mattern”)
`
`Wang et al., “Lyophilization and Development of Solid Protein
`Particles,” 203 Int. J. of Pharm. 1 (2000) (“Wang 2000”)
`
`Bush et al., “A critical evaluation of clinical trials in reactions to
`sulfites,” 78 J. Allergy Clin. Immunol. 191 (1986) (“Bush”)
`
`Liddle, et al., “Cholecystokinin Bioactivity in Human Plasma,”
`75 J. Clin. Invest. 1144 (1985) (“Liddle III”)
`
`Konturek, et al., “Effect of Cholecystokinin Receptor Antagonist
`on Pancreatic Responses to Exogenous Gastrin and
`Cholecystokinin and to Meal Stimuli,” 94 Gastroenterology 1014
`(1988) (“Konturek”)
`
`Banga, A.K., “Structure and Analysis of Therapeutic Peptides and
`Proteins” in Therapeutic Peptides and Proteins: Formulation,
`Processing, and Delivery Systems, Chapter 2 (2006) (“Banga”)
`
`Graf, et. al., “Iron-catalyzed Hydroxyl Radical Formation,” 259 J.
`Bio. Chem. 3620 (1984) (“Graf”)
`
`1046
`
`U.S. Patent No. 6,238,664 to Hellerbrand et al. (“Hellerbrand”)
`
`5
`
`

`

`
`
`
`
`
`
`
`II. QUALIFICATIONS
`
`7. My Curriculum Vitae is attached hereto as exhibit MAIA1004, and it
`
`includes a listing of my prior experience. My background, education, and
`
`professional experiences are summarized below.
`
`8.
`
`I am currently the Chair of the Department of Pharmaceutical
`
`Chemistry at the University of Kansas. I have been Chair of that department since
`
`2005. I have been a professor in that department since 2003.
`
`9.
`
`In addition, I currently hold the position of Takeru Higuchi
`
`Distinguished Professor for Bioanalytical Chemistry. I also have an appointment as
`
`Courtesy Professor in the Department of Chemistry at the University of Kansas.
`
`From 1998 to 2003, I was an associate professor and from 1992 to 1998, I was an
`
`assistant professor in the Department of Pharmaceutical Chemistry at the University
`
`of Kansas.
`
`10. Prior to those appointments, I was a Postdoctoral Fellow in the same
`
`department from 1991 to 1992. I earned my Ph.D. in chemistry with honors from the
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`Technical University Berlin in 1990.
`
`11.
`
`I have been fortunate to receive a number of distinctions for my
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`research on free radical and oxidation chemistry including: “Young Investigator
`
`Award” of the Society For Free Radical Research (SFRR) in 1990 and 1994; the
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`
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`6
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`

`

`
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`Pfizer Research Scholar Award in 2001, 2002, 2003, and 2004; and Dolph Simons
`
`Award in Biomedical Sciences. For a full list of my awards and honors, please see
`
`my curriculum vitae, which is included as MAIA1004.
`
`12.
`
`I serve on the International Editorial Board of the journal Free Radical
`
`Biology and Medicine, and on the Editorial Advisory Board for the Journal of
`
`Pharmaceutical Sciences. I previously served on the Editorial Board of the journal
`
`Experimental Gerontology and on the Editorial Advisory Board of the journal
`
`Chemical Research in Toxicology. I am also a review editor for the journal Free
`
`Radical Research. As an editor, I routinely review scientific manuscripts concerning
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`free radical reactions, oxidation reactions, and the degradation of small and large
`
`molecules, including pharmaceuticals.
`
`13. My research interests include mechanisms of free radical reactions.
`
`This includes, for example, the oxidative post-translational modifications of
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`proteins, which are generally carried out by reactive oxygen species and/or reactive
`
`nitrogen species. Such oxidative modifications accompany physiological disorders
`
`associated with biological aging or disease. My research spans the behavior of
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`proteins and peptides in solution and the solid state, including stability of proteins
`
`and peptides in pharmaceutical formulations, mechanisms for protein instability in
`
`these formulations, and methods to stabilize proteins in these formulations.
`
`
`
`
`
`7
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`

`

`
`
`III. LEGAL BACKGROUND
`
`A. Relevant Legal Standards
`
`
`14.
`
`I have been asked to provide my opinion as to whether the claims of the
`
`’046 patent would have been obvious to a person of ordinary skill in the art at the
`
`time of the alleged invention, in view of the prior art.
`
`15.
`
`I am a pharmaceutical chemist by training and profession. The opinions
`
`I am expressing in this report involve the application of my training and technical
`
`knowledge and experience to the evaluation of certain prior art with respect to the
`
`’046 patent.
`
`16. Although I have been involved as a technical expert in patent matters
`
`before, I am not an expert in patent law. Therefore, the attorneys from Knobbe,
`
`Martens, Olson & Bear, LLP have provided me with guidance as to the applicable
`
`patent law in this matter. The paragraphs below express my understanding of how I
`
`must apply principles related to patent validity to my analysis.
`
`17.
`
`It is my understanding that in determining whether a patent claim is
`
`obvious in view of the prior art, the Patent Office construes the claim by giving the
`
`claim its plain and ordinary meaning consistent with the specification. Below I
`
`have considered the claim terms in a manner consistent with their plain and ordinary
`
`meanings and have not separately provided any claim construction. However, in the
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`8
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`

`
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`event any claim construction is needed during the course of the inter partes review,
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`I will provide a construction when requested by counsel to do so.
`
`18.
`
`It is my understanding that a claim is “obvious,” and therefore
`
`unpatentable, if the claimed subject matter as a whole would have been obvious to a
`
`person of ordinary skill in the art at the time of the alleged invention. I also
`
`understand that an obviousness analysis takes into account the scope and content of
`
`the prior art, the differences between the claimed subject matter and the prior art,
`
`and the level of ordinary skill in the art at the time of the invention.
`
`19.
`
`In determining the scope and content of the prior art, it is my
`
`understanding that a reference is considered appropriate prior art if it falls within the
`
`field of the inventor’s endeavor. In addition, a reference is prior art if it is reasonably
`
`pertinent to the particular problem with which the inventor was involved. A
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`reference is reasonably pertinent if it logically would have commended itself to an
`
`inventor’s attention in considering his problem. If a reference relates to the same
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`problem as the claimed invention, that supports use of the reference as prior art in
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`an obviousness analysis.
`
`20. To assess the differences between prior art and the claimed subject
`
`matter, it is my understanding that the law requires the claimed invention to be
`
`considered as a whole. This “as a whole” assessment requires showing that one of
`
`ordinary skill in the art at the time of invention, confronted by the same problems as
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`9
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`
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`the inventor and with no knowledge of the claimed invention, would have selected
`
`the elements from the prior art and combined them in the claimed manner.
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`21.
`
`It is my further understanding that the law recognizes several rationales
`
`for combining references or modifying a reference to show obviousness of claimed
`
`subject matter. Some of these rationales include: combining prior art elements
`
`according to known methods to yield predictable results; simple substitution of one
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`known element for another to obtain predictable results; a predictable use of prior
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`art elements according to their established functions; applying a known technique to
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`a known device (method or product) ready for improvement to yield predictable
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`results; choosing from a finite number of identified, predictable solutions, with a
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`reasonable expectation of success; and some teaching, suggestion, or motivation in
`
`the prior art that would have led one of ordinary skill to modify the prior art reference
`
`or to combine prior art reference teachings to arrive at the claimed invention.
`
`22.
`
`I also understand that an obviousness analysis must consider whether
`
`there are additional factors that would indicate that the invention would not have
`
`been obvious. These factors include whether there was: (i) a long-felt need in the
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`industry; (ii) any unexpected results; (iii) skepticism of the invention; (iv) a teaching
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`away from the invention; (v) commercial success; (vi) praise by others for the
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`invention; and (vii) copying by other companies. I am not aware of any evidence
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`that would suggest that the claims of the ’046 patent would have been non-obvious.
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`10
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`

`
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`To the extent Bracco submits evidence for any of these factors during the course of
`
`the inter partes review, I may provide my opinion on such evidence if asked to do
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`so by counsel.
`
`B.
`
`
`Person of Ordinary Skill in the Art
`
`23.
`
`It is my understanding that when evaluating the claims of the ’046
`
`patent, I must do so based on the perspective of a person of ordinary skill in the art
`
`(“POSA”) at the time of the alleged invention.
`
`24. Based on my review of the ’046 patent, including its specification and
`
`claims, and the prior art references cited in this Declaration, it is my opinion that a
`
`POSA would have had (1) a Ph.D. in Chemistry, Biochemistry, or Pharmaceutical
`
`Chemistry, or in a related field in the chemical sciences, and at least about two years
`
`of experience in formulating peptide or protein pharmaceutical compositions; or (2)
`
`a Master's degree in these same fields with at least about five years of the same
`
`experience. A POSA may have also worked as part of an interdisciplinary team,
`
`including, for example, a molecular biologist and a clinician specializing in
`
`hepatobiliary imaging.
`
`25.
`
`I am able to make this assessment based on the years of research I have
`
`conducted and the publications I have published in the field of pharmaceutical
`
`chemistry, particularly focused on the stability of protein and peptide drug products,
`
`as further described in my CV. MAIA1004. I have reviewed hundreds if not
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`11
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`

`
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`thousands of publications addressing formulation techniques for stabilizing unstable
`
`protein and peptide molecules, including proteins and peptides encountering the
`
`oxidative and hydrolytic instability problems, as well as the physical instability,
`
`encountered by sincalide.
`
`26. Because I published extensively and collaborated with, and reviewed
`
`the works of, those publishing on the issues of stabilizing peptide and protein
`
`formulations prior to 2002, I know how these chemists would interpret and
`
`understand the claims of the ’046 patent, and how they would understand the
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`disclosures in the prior art discussed herein.
`
`27.
`
`In my opinion, as set forth in more detail below, a person of ordinary
`
`skill in the art at the time of the alleged invention would have considered the claimed
`
`formulation in the ’046 patent to be obvious in view of the prior art.
`
`IV. BACKGROUND OF THE TECHNOLOGY
`28. The claims of the ’046 patent relate generally to a sincalide formulation
`
`including certain functional excipient classes. Independent claim 1, for example,
`
`recites a sincalide formulation that includes the following standard classes of
`
`excipients, defined by their function: at least one stabilizer, a surfactant/solubilizer,
`
`a chelator, a bulking agent/tonicity adjuster, and a buffer. The other independent
`
`claims are simple variations of this basic formulation, claiming the formulation as a
`
`kit (claim 40), as a method of making the formulation by mixing the excipients
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`
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`12
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`

`
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`(claim 21), and as a method of imaging a patient by first administering the
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`formulation, followed by imaging the patient (claims 77 and 104). The dependent
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`claims add limitations regarding the common subclasses and compounds within the
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`functional excipient classes, common techniques for administering the drug, and
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`common techniques for imaging the patient.
`
`A.
`
`
`Peptides and Proteins
`
`29. Peptides and proteins are polymer molecules made up of amino acids
`
`linked together by peptide bonds, where peptide length and order of these amino
`
`acids define the peptide’s or protein’s structure and function. MAIA1028, 284-285.
`
`Chains of amino acids on the order of 50 or fewer amino acids in length are generally
`
`referred to as peptides or polypeptides. MAIA1044, 34-35. Importantly, all proteins
`
`are technically polypeptides; however, researchers sometimes find it useful to
`
`differentiate between proteins and peptides, and use the term protein for peptides
`
`having a chain length greater than 50 amino acids. Id.
`
`30. The presence and order of individual amino acids (also known as amino
`
`acid “residues”) in a peptide or protein define the molecule’s primary structure. Id.
`
`at 35. In a peptide chain there is always an N-terminal amino acid residue and always
`
`a C-terminal amino acid residue. Id. Because of their larger size, proteins also have
`
`a secondary, tertiary, and quaternary structure due to intra- and inter-molecular
`
`
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`13
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`
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`interactions, which together define the molecule’s three-dimensional structure. Id.
`
`at 35-38; MAIA1028, 284-285.
`
`B.
`
`
`Peptide and Protein Drug Products
`
`31. Like drugs of low molecular weight, peptides and proteins experience
`
`chemical degradation, but additionally may undergo physical degradation.
`
`MAIA1024, 187. Prior to 2002, chemical and physical instability of peptides and
`
`proteins had been studied extensively. Id. It was understood that many peptide and
`
`protein drug products did not exhibit sufficient stability in aqueous solution to allow
`
`a shelf stable liquid formulation to be developed. MAIA1011, 188. For this reason,
`
`as of 2002 it was reported that “[m]ost protein pharmaceuticals currently on the
`
`market are sold as lyophilized formulations.” Id. at 184; MAIA1013, 146 (majority
`
`of commercial and clinical protein drug products are freeze-dried powders).
`
`32. And by 2002 the requirements for making stable lyophilized drug
`
`products were well developed:
`
`Our understanding of the basic requirements for obtaining a stable
`lyophilized protein formulation is relatively well developed. The
`question then is what combination of excipients will allow such a
`formulation to be prepared. The minimal composition includes a buffer
`species, an additive capable of forming an amorphous glassy state and
`inhibiting lyophilization-induced unfolding in which the protein
`remains entrapped, a bulking agent to provide cake stability, and
`
`
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`14
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`
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`possibly a surfactant to retard surface-induced damage and/or promote
`refolding.
`MAIA1011, 188. As the quotation above indicates, a stable lyophilized formulation
`
`should include, at a minimum, a buffer species, a bulking agent, and a possibly a
`
`surfactant. As I explain below in Section IV. E, by 2002 researchers would have
`
`known to use these and other functional classes of excipients to stabilize an unstable
`
`sincalide formulation.1
`
`C. Cholecystokinin and Sincalide
`
`
`33. Cholecystokinin (CCK) is a family of peptide molecules of varying
`
`amino acid chain length. A prior art patent assigned to Bracco explains:
`
`Cholecystokinins (CCKs) are a family of peptide molecules whose
`biological action is performed as a hormone and a neurotransmitter. All
`the CCKs originate from a process of fragmentation which takes place
`on a pre-hormone consisting of 115 amino acid residues, followed by a
`post-translational process of alpha-amidation of the C-terminal
`phenylalanine residue and sometimes, sulphation of the tyrosine
`residue contained in the C-terminal portion. The cholecystokinins
`therefore exist in various molecular forms; the most important ones
`have a sequence of 58, 39, 33 or 8 amino acid residues, and they all
`have the same C-terminal sequence of 8 amino acid residues:
`
`
`1 The quotation also refers to inclusion of an additive to inhibit protein unfolding,
`
`which would not be of concern in developing a peptide formulation.
`
`
`
`15
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`

`
`
`Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-amide.
`
`The form containing this sequence only is known as CCK8.
`
`MAIA1010, 1:18-32; see also MAIA1012, 903. Thus, peptides in the CCK family
`
`vary in size, but all biologically-active CCK peptides have the same eight-amino
`
`acid C-terminal sequence. Id. Thus, cholecystokinin is a family of peptides, which
`
`specifically includes the CCK-8 peptide.
`
`34. Since its discovery, CCK has been called by different names due to its
`
`multi-functional role in the body:
`
`Cholecystokinin (CCK) was discovered in 1928 by Ivy & Oldberg
`based on the ability of intestinal extracts to stimulate gallbladder
`contraction when infused into dogs (1). In 1943, Harper & Raper
`recognized that similar intestinal extracts also stimulated pancreatic
`enzyme secretion and proposed the name pancreozymin (2). It was not
`until the active substance was purified and the amino acid sequence
`determined that CCK and pancreozymin were proven to be the same
`hormone that now goes by the name cholecystokinin (3).
`
`MAIA1027, 221. As the quotation explains, the literature historically referred to the
`
`cholecystokinin peptide family as pancreozymin. The literature also previously
`
`abbreviated the peptide as PZ or CCK-PZ. MAIA1020, 503.
`
`35. The CCK-8 peptide is also referred to by its non-proprietary chemical
`
`name, sincalide. MAIA1001, 1:9-16; MAIA1029, 1. Like most peptides and
`
`proteins, sincalide is susceptible to chemical and physical instability that may lead
`
`
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`16
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`
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`to its degradation, potency variability, and loss of bioactivity. MAIA1019, S4-S8;
`
`MAIA1024, 187-203 (identifying protein and peptide degradation pathways). The
`
`sincalide peptide has two methionine residues and one sulfated tyrosine residue
`
`(highlighted in the sequence peptide below).
`
`
`
`As discussed in detail below, the sulfated tyrosine and methionine residues are
`
`required for sincalide’s biological activity, but they also make sincalide chemically
`
`unstable in solution.
`
`36. Sincalide has been used as a pharmaceutical drug product for decades
`
`to stimulate gall bladder contraction in a patient to allow the physician to more easily
`
`image the patient’s gallbladder with x-ray imaging or another imaging modality.
`
`MAIA1005, 154; MAIA1015, 1:14-17.
`
`D.
`
`
`Sincalide’s Chemical and Physical Instability
`
`37.
`
`In a 1983 study of peptide pharmaceutical drug products, Wünsch
`
`reported that CCK had been studied for years because of its well-known instability:
`
`A peptide hormone, studied for years particularly because of its well-
`known instability, is pancreozymin-cholecystokinin (CCK-PZ). The
`instability of the CCK-PZ-tritriacontapeptide amide, as well as of its
`C-terminal fully active octa- and decapeptides with concomitant loss
`of biological activity, is mainly due to two factors: (1) facile hydrolysis
`of the tyrosine-O-sulfate moiety and (2) the strong tendency of the two
`
`
`
`17
`
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`

`
`
`methionine residues to oxidize. In fact, HPLC of ampuled CCK-PZ-
`octapeptide (Scincalide) [sic], as well as of the bulk materi