Filed: November 19, 2018
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`Filed on behalf of:
`Maia Pharmaceuticals, Inc.
`By: Benjamin B. Anger
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`Peter J. Law
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`KNOBBE, MARTENS, OLSON & BEAR, LLP
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`2040 Main Street, 14th Floor
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`Irvine, CA 92614
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`Tel.: (949) 760-0404
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`Fax: (949) 760-9502
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`Email: BoxMAIA@knobbe.com
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`
`MAIA PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`BRACCO DIAGNOSTICS INC.,
`Patent Owner
`
`
`
`
`
`
`
`
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`
`
`Case No. IPR2019-00345
`U.S. Patent No. 6,803,046
`
`
`
`
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`
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`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 6,803,046
`
`
`

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`TABLE OF CONTENTS
`
`Page No.
`
`I.
`II.
`
`SUMMARY OF ISSUE PRESENTED ........................................................... 1 
`INTRODUCTION AND STATE OF THE ART ............................................ 3 
`A. 
`The Sincalide Peptide ............................................................................ 3 
`B. 
`The Old Kinevac Formulation Had Known Drawbacks ....................... 5 
`C. 
`Sincalide’s Known Chemical and Physical Instability ......................... 7 
`1. 
`Sincalide’s Chemical Instability ................................................. 7 
`a. 
`Hydrolysis of the Sulfated Tyrosine Residue ................... 8 
`b. 
`Oxidation of the Methionine Residues ........................... 10 
`Sincalide’s Physical Instability ................................................. 13 
`2. 
`Stable Lyophilized Parenteral Formulations ....................................... 15 
`1. 
`Stabilizers .................................................................................. 18 
`2. 
`Surfactants/Solubilizers ............................................................ 23 
`3. 
`Chelators ................................................................................... 24 
`4. 
`Bulking agents/tonicity adjusters .............................................. 25 
`5. 
`Buffers ....................................................................................... 26 
`Person of Ordinary Skill in the Art (“POSA”) .................................... 27 
`E. 
`III. THE ’046 PATENT ....................................................................................... 28 
`A. 
`The ’046 Patent Specification ............................................................. 28 
`B. 
`The Independent Claims ...................................................................... 34 
`
`D. 
`
`i
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`

`

`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`The Dependent Claims ........................................................................ 35 
`C. 
`Prosecution History ............................................................................. 36 
`D. 
`IV. CLAIM CONSTRUCTION .......................................................................... 37 
`V.
`STATEMENT OF PRECISE RELIEF REQUESTED ................................. 37 
`A.  Grounds ............................................................................................... 38 
`B. 
`Status of References as Prior Art ........................................................ 39 
`VI. THE CHALLENGED CLAIMS ARE UNPATENTABLE .......................... 39 
`A.  Ground 1: 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 Are
`Unpatentable as Obvious Over the PDR in Combination
`with Sato .............................................................................................. 39 
`1. 
`Overview of the PDR ................................................................ 39 
`2. 
`Overview of Sato ...................................................................... 39 
`3. 
`Independent Claim 1 ................................................................. 41 
`a. 
`An Effective Amount of Sincalide ................................. 41 
`b. 
`At Least One Stabilizer ................................................... 42 
`c. 
`A Surfactant/Solubilizer ................................................. 45 
`d. 
`A Chelator ....................................................................... 46 
`e. 
`A Bulking Agent/Tonicity Adjuster ............................... 48 
`f. 
`A Buffer .......................................................................... 49 
`Independent Claim 21 ............................................................... 51 
`Independent Claim 40 ............................................................... 52 
`
`4. 
`5. 
`
`ii
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`

`

`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`Independent Claim 104 ............................................................. 54 
`6. 
`Claims 2, 22 .............................................................................. 55 
`7. 
`Claims 3, 4, 23, 24, 41, 42 ........................................................ 56 
`8. 
`Claims 6-9, 26-29, 44-47 .......................................................... 56 
`9. 
`10.  Claims 10, 11, 13, 30, 31, 33, 48, 49, 51 .................................. 57 
`11.  Claims 15, 16, 35, 36 ................................................................ 57 
`12.  Claim 19 .................................................................................... 58 
`13.  Claim 55 .................................................................................... 58 
`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 ............................ 59 
`1. 
`Claims 5, 25, 43 ........................................................................ 59 
`2. 
`Claims 12, 32, 50 ...................................................................... 60 
`3. 
`Claims 14, 34, 52 ...................................................................... 62 
`4. 
`Claims 17, 37, 54 ...................................................................... 63 
`5. 
`Claims 18, 38 ............................................................................ 65 
`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 ......................................... 65 
`1. 
`Independent Claim 77 ............................................................... 65 
`2. 
`Claim 78 .................................................................................... 68 
`3. 
`Claims 79-80 ............................................................................. 68 
`4. 
`Claims 81-82 ............................................................................. 68 
`
`iii
`
`B. 
`
`C. 
`
`

`

`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`Claim 83 .................................................................................... 69 
`5. 
`Claims 84-85 ............................................................................. 69 
`6. 
`Claims 86-88, 90-95, 97, 99, 100 ............................................. 70 
`7. 
`Claim 105 .................................................................................. 70 
`8. 
`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 ............................ 71 
`VII. SECONDARY CONSIDERATIONS ........................................................... 72 
`VIII. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8(A)(1) ...................... 72 
`A. 
`Real Parties-In-Interest (37 C.F.R. § 42.8(b)(1)) ................................ 72 
`B. 
`Related Matters Under 37 C.F.R. § 42.8(b)(2) ................................... 72 
`C. 
`Lead and Back-up Counsel Under 37 C.F.R. § 42.8(b)(3) ................. 73 
`D. 
`Service Information Under 37 C.F.R. § 42.8(b)(4) ............................. 73 
`IX. PAYMENT OF FEES ................................................................................... 73 
`X.
`REQUIREMENTS FOR REVIEW ............................................................... 74 
`XI. CONCLUSION .............................................................................................. 74 
`
`
`
`
`iv
`
`

`

`TABLE OF AUTHORITIES
`
`Page No(s).
`
`Leapfrog Enters. v. Fisher-Price, Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) .......................................................................... 72
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 18, 27
`Coalition For Affordable Drugs II LLC v. NPS Pharmaceuticals, Inc.,
`IPR2015-00990, Paper 68 (PTAB Oct. 21, 2016) .............................................. 27
`OTHER AUTHORITIES
`35 U.S.C. § 103 .................................................................................................passim
`37 C.F.R. § 42.8 ................................................................................................. 72, 73
`37 C.F.R. § 42.10 ..................................................................................................... 73
`37 C.F.R. § 42.15 ..................................................................................................... 73
`
`
`v
`
`

`

`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
`EXHIBIT LIST
`
`Exhibit No.
`
`Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`U.S. Patent No. 6,803,046 to Metcalfe et al.
`
`Prosecution History excerpts for the ’046 patent
`
`Declaration of Christian Schöneich, Ph.D.
`
`CV of Christian Schöneich, Ph.D.
`
`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
`
`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”)
`
`Exhibit List, Page 1
`
`

`

`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
`Exhibit No.
`
`Description
`
`1013
`
`1014
`
`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”)
`
`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
`
`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”)
`
`Exhibit List, Page 2
`
`

`

`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
`Exhibit No.
`
`Description
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`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”)
`
`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
`
`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”)
`
`Exhibit List, Page 3
`
`

`

`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
`Exhibit No.
`
`Description
`
`1036
`
`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”)
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`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”)
`
`Exhibit List, Page 4
`
`

`

`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
`Exhibit No.
`
`Description
`
`1045
`
`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”)
`
`
`
`Exhibit List, Page 5
`
`

`

`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
`
`Maia Pharmaceuticals, Inc. (“Petitioner” or “Maia”) requests inter partes
`
`review of claims 1-19, 21-38, 40-55, 77-102, and 104-105 (“Challenged Claims”)
`
`of U.S. Patent No. 6,803,046 (“the ’046 patent,” MAIA1001), purportedly owned
`
`by Bracco Diagnostics Inc. (“Patent Owner” or “Bracco”).
`
`I. SUMMARY OF ISSUE PRESENTED
`
`The claims of the ’046 patent generally recite a formulation for sincalide, a
`
`peptide drug that is administered by injection. Independent claim 1, for example,
`
`claims 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 insubstantial variations of this basic formulation, claiming the
`
`formulation as a kit (claim 40), or as a method of making the formulation by
`
`mixing the excipients (claim 21), or as a method of imaging a patient by first
`
`administering the formulation (claims 77, 104). The dependent claims narrow the
`
`extremely broad excipient classes to common subclasses and common compounds,
`
`or list common techniques for administering the drug, or imaging a patient.
`
`The ’046 patent admits that old sincalide formulations had various
`
`drawbacks. Indeed, sincalide’s potency and stability drawbacks were well-known
`
`and well-documented in the art. The ’046 patent explains the obvious need
`
`resulting from the drawbacks to make “sincalide formulations having improved
`
`1
`
`

`

`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
`
`stability and/or potency over previous formulations.” MAIA1001, 3:37-39. The
`
`inventors of the ’046 patent purportedly solved the known drawbacks with the
`
`simple and obvious “selection of excipients that provide certain desired functions.”
`
`Id., 3:35-36.
`
`But selecting these broad excipient classes for their desired and known
`
`functions was not patentable when Bracco filed its patent application in August
`
`2002. By that time, using functional classes of excipients according to their
`
`desired function—to stabilize unstable injectable drug products and improve
`
`potency—was well known. For example, Wang in 1980, and Nema in 1997,
`
`published lists of the functional classes of excipients to use in injectable
`
`formulations—the exact excipient classes claimed in the ’046 patent. MAIA1016,
`
`453-458 (Table I); MAIA1017, 167-169 (Tables II-VII). DeLuca instructed that
`
`these same excipient classes be used to “provide safe, efficacious, and elegant
`
`parenteral dosage forms.” MAIA1014, 192.
`
`Sato, in particular, disclosed all the excipient classes claimed in the ’046
`
`patent for use in peptide formulations, and expressly taught using these excipients
`
`in unstable cholecystokinin formulations. MAIA1007, 7-11. Sincalide is a
`
`cholecystokinin peptide. MAIA1010, 1:18-32.
`
`Sato was not before the Examiner during examination. Had Sato, and the
`
`other highly relevant—and invalidating—prior art references, been applied by the
`
`2
`
`

`

`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
`
`Examiner, Bracco’s claims would not have issued. The ’046 patent slipped
`
`through the PTO with only a later-retracted restriction requirement, followed by a
`
`Notice of Allowance. The Board should rectify this error by canceling the
`
`Challenged Claims. Additional support for this Petition is included in the
`
`Declaration of Christian Schöneich, Ph.D. MAIA1003.
`
`II. INTRODUCTION AND STATE OF THE ART
`
`A. The Sincalide Peptide
`
`Sincalide is the sole active ingredient in Bracco’s reformulated Kinevac
`
`product, which Bracco gained FDA approval to market in 2002. MAIA1033, 22.1
`
`The reformulated Kinevac product is the subject of the ’046 patent. Sincalide was
`
`also the sole active ingredient in Bracco’s old Kinevac formulation, first marketed
`
`in 1976, that exhibited the potency and stability drawbacks. MAIA1001, 1:17-20,
`
`1:27-28.
`
`Sincalide is an eight-amino acid peptide having the following sequence:
`
`
`MAIA1001, 1:11-16; MAIA1010, 1:25-32. Sincalide’s two methionine residues
`
`and its sulfated-tyrosine residue (highlighted above) are essential for biological
`
`1 The citations to MAIA1033 are to new page numbers added to the document, in
`
`light of the document’s inconsistent internal page numbering.
`
`3
`
`

`

`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
`
`activity, but they are also susceptible to chemical degradation, resulting in
`
`sincalide’s instability. Section II.C.1, infra.
`
`Sincalide is sometimes called “CCK-8” because it is the sulfated C-terminal
`
`octapeptide of cholecystokinin (CCK). MAIA1001, 1:11-16. Sincalide is one of
`
`many peptide molecules in the cholecystokinin (CCK) family. MAIA1010, 1:18-
`
`32. CCK peptides vary in amino acid chain length, but all biologically-active CCK
`
`peptides share the same eight-amino acid C-terminal sequence that makes up
`
`sincalide. MAIA1010, 1:18-32; MAIA1012, 903; MAIA1003, ¶¶33-34.
`
`Sincalide has been used for decades to stimulate gall bladder contraction,
`
`which allows a physician to more easily image the patient’s gallbladder with x-ray
`
`imaging or another imaging modality in order to diagnose gallbladder conditions.
`
`MAIA1005, 154 (1977/78 Kinevac PDR entry); MAIA1015, 1:14-17, MAIA1029,
`
`1-3 (1994 Kinevac Package Insert). Sincalide is administered to the patient as a
`
`parenteral drug (i.e., by injection). MAIA1005, 154; MAIA1029, 1. It is often
`
`accompanied by separate administration of an imaging agent that further enhances
`
`gall bladder visibility during
`
`imaging.
`
` MAIA1030, 126-127 (describing
`
`administration of radiopharmaceutical agents with sincalide to enhance visibility of
`
`the hepatobiliary system, including the gall bladder).
`
`4
`
`

`

`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
`
`B.
`
`The Old Kinevac Formulation Had Known Drawbacks
`
`Like most peptide and protein molecules, sincalide is prone to instability and
`
`loss of biological activity in aqueous solution, making it difficult to formulate as a
`
`shelf-stable liquid formulation.
`
` Section II.C, infra; MAIA1003, ¶¶37-39.
`
`Unstable peptides and proteins have been historically formulated as lyophilized
`
`(freeze-dried) powders in an attempt to stabilize the active ingredient and retain
`
`biological activity. MAIA1014, 217 (“Substances that degrade in solution become
`
`candidates for freeze-drying.”); MAIA1013, 146 (majority of commercial and
`
`clinical protein drug products are freeze-dried powders); MAIA1003, ¶31.
`
`In 1976, E.R. Squibb (“Squibb”) patented a method of purportedly
`
`“enhancing the stability” of sincalide during storage by lyophilizing it with sodium
`
`chloride. MAIA1015, 2:60-4:2, Abstract. That same year, Squibb began
`
`marketing this two-ingredient lyophilized sincalide product under the tradename
`
`Kinevac. MAIA1001, 1:17-20; MAIA1005, 154. Bracco acquired Kinevac from
`
`Squibb in 1994. MAIA1033, 39.
`
`This Kinevac formulation (herein “the old Kinevac formulation”) was
`
`packaged in vials containing the lyophilized powder in amounts of 5 micrograms
`
`of sincalide and 45 milligrams of sodium chloride. MAIA1005, 154. The user was
`
`instructed to reconstitute the lyophilized powder with 5 mL of sterile water prior to
`
`administering the sincalide solution to the patient via injection. MAIA1030, 154;
`
`5
`
`

`

`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
`
`MAIA1015, 2:57-58. The reconstituted sincalide solution could also be diluted in
`
`a physiological acceptable fluid (for example Sodium Chloride Injection USP,
`
`0.9%) prior to administration. MAIA1029, 3.
`
`But simply lyophilizing the formulation with sodium chloride did not solve
`
`sincalide’s instability problems. The ’046 patent recognizes that since its
`
`introduction in 1976, the old Kinevac formulation suffered from “various
`
`drawbacks” related to sincalide’s instability. MAIA1001, 1:27-28 (emphasis
`
`added). It describes the potency variability and loss of bioactivity in the old
`
`Kinevac formulation due to sincalide degradation. Id., 1:29-30 (“the two-
`
`ingredient formulation suffers from potency variability”); 1:34-36 (“This bioassay
`
`was unable to distinguish between bioactivity of sincalide and bioactivity of
`
`sincalide degradants.”). To compensate for this degradative loss, the ’046 patent
`
`acknowledges that the old Kinevac formulation required a “20% overage of
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`sincalide” to maintain its required potency and bioactivity. Id., 1:35-37 (emphasis
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`added).
`
`Before Bracco ever filed for the ’046 patent, it was well documented that
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`sincalide’s potency variability and loss of bioactivity—that is, its drawbacks—
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`were due to its chemical and physical instability. Section II.C, infra. Likewise, the
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`obvious solutions to these drawbacks were well documented in the literature, also
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`before Bracco ever filed for the ’046 patent. Section II.D, infra. Bracco simply
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`IPR Petition – U.S. Patent No. 6,803,046
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`claimed in the ’046 patent the broad functional excipient classes that the prior art
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`instructed a POSA to use for stabilizing unstable peptides, like sincalide.
`
`C.
`
`Sincalide’s Known Chemical and Physical Instability
`
`Like most peptides and proteins, sincalide is susceptible to chemical and
`
`physical instability that, if left unchecked, leads to sincalide’s degradation, potency
`
`variability, and loss of bioactivity. MAIA1019, S4-S8 (identifying protein and
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`peptide degradation pathways); MAIA1024, 187-203 (same); MAIA1003, ¶¶37-
`
`54. The specific causes of sincalide’s chemical and physical instability were well
`
`known before August 2002.
`
`1.
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`Sincalide’s Chemical Instability
`
`In 1983, Wünsch reported that CCK had been studied for years “because of
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`its well-known instability.” MAIA1020, 503. Wünsch’s analysis via HPLC found
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`that most of the sincalide in the old Kinevac formulation had been destroyed due to
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`sincalide chemical
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`instability: “HPLC of ampuled CCK-PZ-octapeptide
`
`(Scincalide) [sic], as well as of the bulk material (Squibb Laboratories), clearly
`
`revealed that in the ampule form, most of the active material was destroyed.” Id.
`
`(emphasis added).
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`Wünsch taught that the two main factors contributing to sincalide’s chemical
`
`instability were hydrolysis of its sulfated tyrosine residue and oxidation of its
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`methionine residues:
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`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
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`The instability of the CCK-PZ-tritriacontapeptide amide, as well as of
`its C-terminal fully active octa- and decapeptides [sincalide] 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 methionine residues to oxidize.
`
`Id. (emphasis added).2 These factors are discussed below.
`
`a. Hydrolysis of the Sulfated Tyrosine Residue
`
`The first main factor contributing to sincalide’s chemical instability is
`
`hydrolysis of sincalide’s sulfated tyrosine residue. MAIA1020, 503; MAIA1003,
`
`¶¶40-43. Sincalide’s sulfated tyrosine residue is at the two amino acid position in
`
`the peptide, highlighted below:
`
`
`An excerpt of Fig. 1 from the ’046 patent shows the sulfated tyrosine residue:
`
`
`2 The peptide family that researchers more recently have called cholecystokinin,
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`had historically been called pancreozymin (PZ) or pancreozymin-cholecystokinin
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`(CCK-PZ). See MAIA1027, 221; MAIA1020, 503. Thus, the peptide that Wünsch
`
`calls the “C-terminal fully active octa-[]peptide” of CCK-PZ is sincalide.
`
`MAIA1020, 503; MAIA1003 ¶¶34, 37.
`
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`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
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`MAIA1001, Fig. 1 (excerpted). Hydrolysis of the sulfated tyrosine simply means
`
`that the tyrosine-O-sulfate ester bond is broken by reaction with water and the
`
`sulfate (-SO3, circled) moiety is cleaved from the tyrosine residue:
`
`
`
`
`
`
`
`MAIA1021, Figure 1 (excerpted, annotated); MAIA1003, ¶41.
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`Hydrolytic reactions are highly pH dependent, where a more acidic
`
`environment drives the reaction. See MAIA1019, S4 (“The formulation factor that
`
`most influences the hydrolytic rate is solution pH.”); MAIA1003, ¶42. Yagami
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`explained that “[i]t is well known that Tyr(SO3H) residues tend to rapidly desulfate
`
`to Tyr under acidic conditions.” MAIA1021, 240. Huttner also stated “[o]ne of
`
`the most remarkable properties of tyrosine sulfate is the lability of the ester bond in
`
`acid and its stability in alkali.” MAIA1022, 203. Tyrosine desulfation is catalyzed
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`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
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`by protons and accelerated under nonpolar conditions. MAIA1021, 240. Yagami
`
`disclosed that shorter CCK peptides are more susceptible to tyrosine desulfation in
`
`acidic conditions than longer chain CCK peptides, making CCK-8 (sincalide) the
`
`most susceptible among biologically-active CCK peptides
`
`to hydrolytic
`
`degradation. Id., 243; MAIA1003, ¶¶40-43.
`
`Not all tyrosine residues in peptides or proteins are sulfated, but sincalide’s
`
`tyrosine residue must be sulfated for it to be biologically active. MAIA1012, 903
`
`(“Sulfation of the tyrosine residue at position seven from the carboxyl terminus of
`
`CCK is critical for biological activity.”). Marseigne reported the biological
`
`activity of cholecystokinin is “dependent on the sulfation of tyrosine since the
`
`sulfated form was about 250 times more potent than the unsulfated one.”
`
`MAIA1025, 445. Liddle likewise reported that sulfation “is critical for biological
`
`potency of CCKs” and found that the “unsulfated form of CCK is ∼1000-fold less
`
`active than its sulfated counterpart.” MAIA1027, 224. Wang 1988 explained that
`
`“hydrolysis of the tyrosine-O-sulfate moiety was responsible for inactivation of
`
`cholecystokinin.” MAIA1019, S5 (emphasis added); MAIA1003, ¶40.
`
`b. Oxidation of the Methionine Residues
`
`The second main factor contributing to sincalide’s chemical instability is
`
`oxidation of its methionine residues. MAIA1020, 503. MAIA1003, ¶¶44-50.
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`IPR Petition – U.S. Patent No. 6,803,046
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`Sincalide’s methionine residues at the three and six amino acid positions are
`
`highlighted below:
`
`
`
`Although methionine residues in any peptide or protein can be susceptible to
`
`degradation (see, e.g., MAIA1019, S4, MAIA1013, 153), Bacarese-Hamilton I
`
`indicated in 1985 that “[c]holecystokinin (CCK) is particularly susceptible to
`
`oxidation of its methionine residues (of which CCK-33 has three, and CCK-8
`
`two).” MAIA1008, 571. Also in 1985, Bacarese-Hamilton II illustrated the
`
`mechanism of methionine oxidation in CCK and explained that the methionine
`
`degradation byproducts on the methionine residue are methionine sulfoxide and
`
`methionine sulfone:
`
`MAIA1009, 18. The ’046 patent acknowledges that sincalide’s methionine
`
`oxidation was well understood: “Methionine has been identified as one of the most
`
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`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
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`easily oxidizable amino acids, which degrades to its corresponding sulfoxide and,
`
`under more strenuous oxidation conditions, its sulfone.” MAIA1001, 10:12-15.
`
`Figure 4 of the ’046 patent shows the methionine residues oxidized to the
`
`sulfoxides:
`
`Id., Fig. 4.
`
`
`
`Akers stated that the oxidation of methionine to the sulfoxide occurs with
`
`peptide exposure to “the solvent and environmental conditions such as the presence
`
`of oxygen, light, high temperature, metal ions, and various free radical initiators.”
`
`MAIA1013, 153; see also MAIA1014, 200; MAIA1024, 192; MAIA1003, ¶48.
`
`Again, the ’046 patent acknowledges the mechanisms of sincalide’s methionine
`
`oxidation were known in the art: “The mechanisms of oxidation appear to be
`
`highly dependent on the reactive oxygen species under consideration: peroxide,
`
`peroxyl radicals, singlet oxygen, and hydroxyl radical have all been shown to
`
`oxidize methionine residues to sulfoxides and other products.” MAIA1001, 10:15-
`
`20.
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`Maia v. Bracco
`IPR Petition – U.S. Patent No. 6,803,046
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`Any oxidation at sincalide’s methionine residues is problematic because the
`
`resulting sulfoxide is highly polar, which “alters the non-polar characteristic of the
`
`side chain thereby interfering with (or even destroying) biological activity.”
`
`MAIA1009, 18 (emphasis added); see also MAIA1012, 903 (“Oxidation of CCK
`
`reduces its biological activity 100- to 1000-fold.”); MAIA1008, 571 (oxidation of
`
`methionine in CCK-8 “can cause loss both of immunoreactivity and biological
`
`potency”); MAIA1003, ¶49.
`
`Thus, in 2002 a POSA would have known that sincalide is chemically
`
`unstable due to hydrolysis of its sulfated tyrosine residue and oxidation of its
`
`methionine residues, and that this instability leads to loss of potency and a
`
`reduction in biological activity. MAIA1003, ¶50. A POSA would have been
`
`motivated to develop a sincalid