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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.
`
`______________
`
`Case IPR2019-00345
`
`Patent 6,803,046
`
`______________
`
`Patent Owner’s Preliminary Response
`
`
`
`IPR2019-00345
`US Patent No. 6,803,046
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`Patent Owner’s Preliminary Response
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`Table of Contents
`
`I.
`
`II.
`
`INTRODUCTION ....................................................................................... 1
`
`BACKGROUND .......................................................................................... 4
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Sincalide (CCK-8), KINEVAC, and the ’046 Patent ........................ 4
`
`The Person of Ordinary Skill in the Art (“POSITA”) ...................... 7
`
`The Related District Court Litigation ................................................ 8
`
`37 C.F.R. § 1.56 .................................................................................. 9
`
`Petitioner’s Sincalide Patent Application ......................................... 9
`
`III. CLAIM CONSTRUCTION ...................................................................... 12
`
`IV. PETITIONER FAILS TO ADEQUATELY ADDRESS THE SCOPE
`AND CONTENT OF THE PRIOR ART AS REQUIRED BY
`GRAHAM ................................................................................................... 12
`
`A.
`
`B.
`
`C.
`
`D.
`
`Legal Standards ................................................................................ 12
`
`“surfactant” ...................................................................................... 14
`
`“a stabilizer” ..................................................................................... 20
`
`“a phosphate buffer” ........................................................................ 24
`
`V.
`
`THERE IS NO MOTIVATION TO USE THE TEACHINGS OF
`SATO WITH THE PDR ........................................................................... 25
`
`A.
`
`B.
`
`Petitioner’s Combination ................................................................. 26
`
`There is no motivation to use Sato to modify KINEVAC-1976 ...... 29
`
`VI. THERE IS NO REASONABLE EXPECTATION OF
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`SUCCESSFULLY ACHIEVING A STABLE SINCALIDE
`FORMULATION BASED ON THE PDR AND SATO ........................ 33
`
`VII. PETITIONER’S ARGUMENT IS ALSO AN UNSUPPORTED
`“OBVIOUS TO TRY” ARGUMENT ...................................................... 43
`
`VIII. CONCLUSION .......................................................................................... 45
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`
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`Page ii of x
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`Patent Owner’s Preliminary Response
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Apple Inc. v. Samsung Electronics Co., Ltd.,
`839 F.3d 1034 (Fed. Cir. 2016) .......................................................................... 13
`Interbulk USA LLC v. Global Strategies, Inc.,
`IPR2018-01197, Paper 7 (PTAB Jan. 11, 2019) ............................................ 3, 19
`Bausch & Lomb, Inc. v. Barnes-Hind/Hydrocurve, Inc.,
`796 F.2d 443 (Fed. Cir. 1986) ............................................................................ 13
`Bayer Schering Pharma AG v. Barr Laboratories,
`575 F.3d 1341 (Fed. Cir. 2009) .......................................................................... 44
`Bracco Diagnostics Inc. v. Maia Pharmaceuticals, Inc.,
`3:17-cv-13151-PGS-TJB (D. N.J. Dec. 15, 2017) ...................................... 8, 9, 41
`Daiichi Sankyo Co., Ltd. v. Matrix Labs.,
`619 F.3d 1346 (Fed. Cir. 2011) .......................................................................... 32
`Graham v. John Deere Co. of Kansas City,
`383 U.S. 1 (1996) .........................................................................................passim
`KSR v. Teleflex Inc.,
`550 US 398 (2007) ...................................................................................... 3, 7, 13
`In re Magnum Oil Tools,
`829 F.3d 1364 (Fed. Cir. 2016) .......................................................... 4, 12, 13, 21
`
`Oxford Nanopore Techs. Ltd. v. Univ. of Washington and UAB
`Research Found.,
`IPR2014-00513, Paper 51 (PTAB Feb. 26, 2016) ........................................ 33, 40
`Panduit Corp. v. Dennison Mfg. Co.,
`810 F.2d 1561 (Fed. Cir. 1987) .......................................................................... 14
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) .......................................................... 12
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`Page iii of x
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`Procter & Gamble Co. v. Teva Pharmaceuticals USA,
`566 F.3d 989 (Fed. Cir. 2009) ...................................................................... 26, 40
`Seabed Geosolutions (US), Inc. v. Fairfield Indus. Inc.,
`IPR2018-01269, Paper 11 (PTAB Jan. 7, 2019) ................................................ 19
`Simpson Strong-Tie Co. Inc. v. Oz-Post Int’l, LLC,
`IPR2018-01379, Paper 8 (PTAB Jan. 28, 2019) .......................................... 19, 23
`Travelocity.com L.P. v. Cronos Tech. LLC,
`CBM2014-00082, Paper 12 (PTAB Oct. 16, 2014) ........................................... 13
`In re Wesslau,
`353 F.2d 238 (CCPA 1965) ................................................................................ 13
`Statutes
`35 U.S.C. § 103 .................................................................................................... 8, 13
`Other Authorities
`37 C.F.R. § 1.56 ......................................................................................................... 9
`37 C.F.R. § 42.100(b) .............................................................................................. 12
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`Page iv of x
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`Exhibit
`No.
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`Patent Owner’s Preliminary Response
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`EXHIBIT LIST
`
`Description
`
`Petitioner’s Exhibits
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`
`1008
`
`
`
`1009
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`1010
`
`U.S. Patent No. 6,803,046 to Metcalfe et al. (“the ’046 Patent”)
`
`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”)
`
`PCT Publication No. WO 00/5169 to Sato
`
`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”)
`U.S. Patent No. 7,329,644 to Saviano et al. (“Saviano”)
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`Page v of x
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`Patent Owner’s Preliminary Response
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`Exhibit
`No.
`
`1011
`
`
`1012
`
`1013
`
`1014
`
`1015
`
`
`1016
`
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`Description
`
`Rational Design of Stable Protein Formulations: Theory and
`Practice, Chapters 5 & 8 (Carpenter and Manning, ed., April
`30, 2002) (“Carpenter”).
`
`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”)
`
`U.S. Patent No. 3,937,819 to Ondetti et al. (“Ondetti”)
`
`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”)
`
`U.S. Patent Publication No. 2003/0104996 to Li et al. (“Li”)
`
`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”)
`
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`Exhibit
`No.
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`Description
`
`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”)
`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”)
`
`U.S. Patent No. 5,272,135 to Takruri (“Takruri”)
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`Page vii of x
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`No.
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`Patent Owner’s Preliminary Response
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`Description
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`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”)
`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”)
`
`Page viii of x
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`Exhibit
`No.
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`Patent Owner’s Preliminary Response
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`Description
`
`
`1043
`
`1044
`
`1045
`
`1046
`
`2001
`
`2002
`
`2003
`
`2004
`2005
`2006
`2007
`2008
`2009
`2010
`
`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”)
`
`U.S. Patent No. 6,238,664 to Hellerbrand et al. (“Hellerbrand”)
`
`Patent Owner’s Exhibits
`Amended Joint Claim Construction and Prehearing Statement
`(December 26, 2018 - Case No. 3:17-cv-13151-PGS-TJB, Doc.
`28, “the Litigation”)
`Citizen Petition submitted by Patent Owner to the FDA on
`November 28, 2017
`Maia Pharmaceuticals Invalidity Contentions from the Litigation
`(April 26, 2018)
`Bracco Response to Invalidity Contentions from the Litigation
`(Redacted) (June 11, 2018)
`Bracco Opening Markman Brief (Redacted) (February 9, 2019)
`Bracco’s Expert Declaration concerning Bracco’s Opening
`Markman Brief (Redacted) (February 8, 2019)
`Maia’s Opening Markman Brief (Redacted) (October 9, 2018)
`Maia’s Expert Declaration concerning Maia’s Opening Markman
`Brief (Redacted) (October 8, 2018)
`U.S. Patent No. 5,574,136
`U.S. Patent Application Publication No. 2019/0060240 filed by
`Petitioner
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`Exhibit
`No.
`2011
`2012
`2013
`
`Description
`U.S. Provisional Patent Application No. 62/550,484 filed by
`Petitioner
`Original (as-filed) claims of US2019/0060240
`Response to Office Action filed February 19, 2019, in
`US2019/0060240
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`I.
`
`INTRODUCTION
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`
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`Patent Owner’s Preliminary Response
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`Patent Owner Bracco Diagnostics Inc. (“Patent Owner”) submits the following
`
`Preliminary Response (“POPR”) to the Petition for Inter Partes Review (the
`
`“Petition”) filed by Maia Pharmaceuticals, Inc. (“Petitioner”) regarding Claims 1-19,
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`21-38, 40-55, 77-102, and 104-105 (“the Challenged Claims”) of U.S. Patent No.
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`6,803,046 (“the ’046 Patent”). As shown in detail below, the Petition should be
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`denied because, inter alia, a POSITA would not have been motivated to use the
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`teachings of Sato (the secondary reference) to solve the stability problems associated
`
`with sincalide (the claimed peptide), and Petitioner fails to show that there was a
`
`reasonable expectation of success in achieving the claimed stable sincalide
`
`formulations. Further, Petitioner’s own cited prior art controverts its obviousness
`
`allegations.
`
`As one example, Petitioner asserts a POSITA would have used a surfactant to
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`achieve the claimed invention based on general teachings in the art. (Petition at 23-
`
`24, 45.) However, Petitioner’s own cited prior art shows that, prior to the ’046 Patent,
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`it was believed that surfactants were not needed and should not be used with the
`
`claimed peptide. For instance, Petitioner cites the textbook “Rational Design of
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`Stable Protein Formulations,” (Ex. 1011 or “Carpenter”) to support many of its
`
`contentions, but completely ignores the book’s “rational” teachings regarding
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`surfactants:
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`“For the current discussion it is sufficient to stress that a surfactant
`should not be included in a lyophilized product, unless there is direct
`evidence that [it] increases recovery of native protein in the
`rehydrated sample.” (Ex. 1011 at 127.)
`
`Thus, although Petitioner relies on Carpenter for other teachings, it conveniently
`
`ignores Carpenter when its teachings diverge from Petitioner’s results-oriented
`
`analysis. Petitioner cannot simply pick and choose disclosures it likes from the art
`
`while ignoring relevant teachings of the same art that undercut Petitioner’s
`
`arguments, particularly when it fails to explain why, even in view of Carpenter’s
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`teachings, a person of ordinary skill in the art would have used a surfactant with the
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`claimed peptide.
`
`Even more egregious is Petitioner’s failure to address the following surfactant-
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`related teaching that specifically relates to sincalide1:
`
`“The CCK-PZ-octa- [CCK-8] and decapeptides were long believed to
`possess higher activity than CCK-PZ-33 or its variant 39. It is now
`known that this difference is mainly attributable to adsorption on
`laboratory glassware.” (Ex. 1020 at 503 (emphasis added).)
`
`Petitioner simply glosses over this teaching (Petition at 23, 45), never acknowledging
`
`that the above statement specifically shows that sincalide (CCK-8) does not have a
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`
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`1 As detailed below, “CCK-8” is another name for sincalide.
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`laboratory glass adsorption issue -- Ex. 1020’s reference to “higher activity” is a
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`Patent Owner’s Preliminary Response
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`
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`reference to activity in the body, i.e., the chemical was successfully parenterally
`
`administered, so it did not adsorb on the glassware. When a protein or peptide does
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`not have surface adsorption issues, there is no reason to use a surfactant. (Carpenter
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`at 127; Ex. 1013 at 160-161.) Accordingly, Petitioner fails to carry its evidentiary
`
`burden under § 314(a) and Supreme Court precedent:
`
`“Under § 103, the scope and content of the prior art are to be
`determined; differences between the prior art and the claims at issue
`are to be ascertained; and the level of ordinary skill in the pertinent
`art resolved. Against
`this background,
`the obviousness or
`nonobviousness of the subject matter is determined.”
`
`KSR v. Teleflex Inc., 550 US 398, 406 (2007) (emphasis added), citing Graham v.
`
`John Deere Co. of Kansas City, 383 U.S. 1, 17-18 (1996). A Petition fails to
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`adequately explain the “the scope and content of the prior art” when it selectively
`
`cites portions of the prior art while ignoring relevant teachings of that same art.
`
`Interbulk USA LLC v. Global Strategies, Inc., IPR2018-01197, Paper 7 at 21 (PTAB
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`Jan. 11, 2019) (noting that a petitioner’s approach to obviousness was “difficult to
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`distinguish from hindsight reconstruction” where the petitioner “appear[ed] to
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`picking and choosing aspects of the prior art without explanation”). Failure to meet
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`the threshold evidentiary requirements of § 314(a) and Graham means that a
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`Petitioner cannot meet the preponderance of the evidence standard required for
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`institution in these proceedings. In re Magnum Oil Tools, 829 F.3d 1364, 1376 (Fed.
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`Patent Owner’s Preliminary Response
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`
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`Cir. 2016). Accordingly, the Petition should be rejected.
`
`II. BACKGROUND
`A.
`
`Sincalide (CCK-8), KINEVAC, and the ’046 Patent
`
`The ’046 Patent was filed August 16, 2002. (Ex. 1001.) As noted in the
`
`Background of the ’046 Patent, the ’046 Patent relates to improved formulations
`
`comprising sincalide, which is an octapeptide of the formula: Asp-Tyr(SO3H)-Met-
`
`Gly-Trp-Met-Asp-Phe-NH2. (Ex. 1001 at 1:9-40.) The chemical structure of
`
`sincalide is illustrated below.
`
`
`
`(Id. at FIG. 1.) Sincalide is also known as CCK-8, the C-terminal octapeptide of
`
`cholecystokinin. (Id. at 14-15.) Sincalide is formulated into a drug product for
`
`parenteral administration for uses that include stimulating gallbladder contractions
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`for use in tandem with various methods of diagnostic imaging for analysis of
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`cholesterol, bile salts, phospholipids, and crystals. (Ex. 1029 at 1.)
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`Patent Owner’s Preliminary Response
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`However, and as noted in the ’046 Patent and various prior art references cited
`
`in the Petition, the original formulation used to administer sincalide (KINEVAC-
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`1976)2 had issues such as potency variability. (Id. at 28-31.) Despite approving
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`KINEVAC-1976, the FDA was aware of the problems with KINEVAC-1976 and
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`requested that its developer, E.R. Squibb & Sons, Inc. (“Squibb”) investigate the
`
`issues and propose a solution. Squibb was not able to reformulate sincalide into a
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`safe parenteral drug before transferring the ownership rights of KINEVAC-1976 to
`
`Patent Owner (Bracco) in 1994. (Ex. 2002 at 3.) After much research and
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`development, Patent Owner developed a formulation that solved the stability and
`
`other issues associated with sincalide and KINEVAC-1976. The new formulation
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`remains stable through 24 months, whereas the prior formulation would significantly
`
`degrade within 18 months. (Id. at 3-4.) This stable formulation is the subject of the
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`’046 Patent.
`
`Patent Owner was not the first to endeavor to produce a more stable sincalide
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`formulation. Even though many knew of the reasons the sincalide formulation was
`
`likely unstable, the community was unable to deliver the much needed solution to
`
`
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`2 KINEVAC (sincalide for injection, USP) was approved for use by the FDA in 1976,
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`hence the usage of KINEVAC-1976.
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`this long felt need. As one example, in 1983 Wünsch ascribed sincalide’s stability
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`Patent Owner’s Preliminary Response
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`
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`issues to the facile hydrolysis of the tyrosine-O-sulfate moiety and the oxidation of
`
`its two methionine groups. (Ex. 1020 or “Wünsch” at 503.) Wünsch also proposed
`
`two solutions to these problems: (a) add complex forming cations Ca2+ or Ba2+, and
`
`(b) replace the oxidation prone methionine groups with norleucine.3
`
`“It may well be possible that similar stabilizing effects can be
`produced by the complex forming cations Ca2+ or Ba2+ added to the
`octa- [CCK-8] and decapeptides.
`
`Our studies on CCK-related peptides have shown that biological
`activity is fully retained on substitution of methionine-28 with
`threonine … and of methionine-31 with norleucine. The CCK-
`nonapeptide analog, as lypophilizate, was found to be perfectly stable
`in the cold for three years… and biological activity was fully retained.
`
`Replacement of methionine with norleucine seems to be of general
`utility. In fact, norleucine-analogs retain the biological potency of the
`parent methionine peptides, and excluding inactivation via oxidation
`of the methionine thioether function, may represent a useful bypass
`to stabilize peptide factors for their use in medicine.” (Id.)
`
`
`
`3 Consistent with its failure to meaningfully address the scope and content of the
`
`prior art, neither Petitioner nor Petitioner’s expert address Wünsch’s proposed
`
`solutions to the sincalide stability issues.
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`Nonetheless, no viable replacement for KINEVAC was put forth from 1976 until
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`Patent Owner’s Preliminary Response
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`2002 when Patent Owner introduced KINEVAC-2002. (Ex. 2002 at 3-4.)
`
`Now, nearly 17 years after the ’046 Patent was filed, Petitioner seeks to piggy-
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`back off Patent Owner’s inventive efforts. As shown below, the Petition must be
`
`rejected, and for several reasons. First and foremost, Petitioner fails to adequately
`
`consider and explain the prior art as a Petitioner must do under KSR and Graham.
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`Second, Petitioner cannot carry its burden because a POSITA would not have
`
`believed that Sato’s teachings would solve sincalide’s stability issues. Third,
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`Petitioner’s own cited prior art and its own recent sincalide formulation patent
`
`application shows that there was no reasonable expectation of successfully achieving
`
`a stable sincalide formulation. Fourth, Petitioner’s “obvious to try” argument must
`
`fail because the prior art provides no indication as to which parameters are critical
`
`and provides no guidance as to which of many possible choices is likely to be
`
`successful.
`
`B.
`
`The Person of Ordinary Skill in the Art (“POSITA”)
`
`Petitioner proposes that a POSITA is a hypothetical person that would
`
`“typically have had (i) a Ph.D. in Chemistry, Biochemistry, or Pharmaceutical
`
`Chemistry, or in a related field in the chemical sciences, and have at least about two
`
`years of experience in formulating peptide or protein pharmaceutical compositions;
`
`or (ii) a Master's degree in the same fields with at least about five years of the same
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`Page 7 of 45
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`US Patent No. 6,803,046
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`experience.” (Petition at 28.) For purposes of this POPR, Patent Owner does not
`
`Patent Owner’s Preliminary Response
`
`
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`currently disagree with this definition. Nonetheless, if a trial is instituted, Patent
`
`Owner reserves the right to submit a different POSITA definition than that proposed
`
`by Petitioner.
`
`Petitioner also proposes the following: “Also, a POSA may have worked as
`
`part of a multidisciplinary team and drawn upon not only his or her own skills, but of
`
`others on the team, including, for example a molecular biologist and a clinician
`
`specializing in hepatobiliary imaging.” (Id.) Patent Owner disagrees with this
`
`portion of Petitioner’s proposed POSITA definition because it appears to allow for
`
`multiple different people working together to create a POSITA. Patent Owner is
`
`unaware of any authority authorizing multiple different POSITAs when the statute
`
`expressly only allows one “person of ordinary skill in the art.” 35 U.S.C. § 103.
`
`C. The Related District Court Litigation
`
`Patent Owner hereby provides notice that the parties are in concurrent District
`
`Court litigation relating to the ’046 Patent stylized as Bracco Diagnostics Inc. v. Maia
`
`Pharmaceuticals, Inc., 3:17-cv-13151-PGS-TJB (D. N.J. Dec. 15, 2017) (“the
`
`Litigation”). Out of an abundance of caution, Patent Owner includes some
`
`potentially pertinent documents from the Litigation with this POPR (listed in the
`
`Exhibit Table).
`
`Page 8 of 45
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`D.
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`37 C.F.R. § 1.56
`
`
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`Patent Owner’s Preliminary Response
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`In the Litigation, Petitioner has submitted invalidity contentions. While Patent
`
`Owner believes such invalidity contentions are cumulative and, therefore, not
`
`material, out of an abundance of caution Patent Owner includes Petitioner’s invalidity
`
`contentions with this filing as Ex. 2003 in an effort to comply with any Rule 56
`
`obligations associated with this proceeding. Patent Owner is not aware of any other
`
`non-cumulative, material prior art that should be brought to the Board’s attention.
`
`(37 C.F.R. § 1.56.)
`
`E.
`
`Petitioner’s Sincalide Patent Application
`
`Patent Owner notes that Petitioner has recently filed its own patent application
`
`to sincalide formulations. (Ex. 2010; US2019/0060240 (“the ‘240 application”).)4
`
`Petitioner’s patent application discusses the ’046 Patent (Ex. 2010 at ¶¶0005, 0111),
`
`and several portions of Petitioner’s patent application are remarkably similar to (if
`
`
`
`4 Patent Owner’s discussion of the ’240 application herein is solely for purposes of
`
`making the Board aware of Petitioner’s lack of credibility and to show that
`
`Petitioner’s IPR against the ’046 Patent should be rejected. For the record, Patent
`
`Owner also notes that nothing in the ’240 application is patentable at least in view
`
`of the ’046 Patent and/or other prior art.
`
`Page 9 of 45
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`not verbatim copies of) the ’046 Patent. (Compare, e.g., FIG 1 of the ’046 Patent to
`
`Patent Owner’s Preliminary Response
`
`
`
`FIG. 1 of the ’240 application; the “Buffering Agents” of the ’046 Patent (Ex. 1001
`
`at 9:45-65) to the “Buffers” of the ’240 application (Ex. 2010 at ¶78); the
`
`“Surfactants/Solubilizers/Surface Active Agents” of the ’046 Patent (Ex. 1001 at
`
`11:27-63) to the “Surfactants/Solubilizers” of the ’240 application (Ex. 2010 at ¶79),
`
`among many others.) Original claims 1 and 15 of the ’240 application are remarkably
`
`broad:
`
` A solid composition comprising sincalide, wherein the
`“1.
`composition does not contain a dibasic potassium phosphate buffer,
`and wherein the composition is stable in storage.” (Ex. 2012 at 1.)
`
`sincalide and a
`liquid composition comprising
`“15. A
`pharmaceutically acceptable carrier, wherein the composition is
`storage stable.” (Id. at 3.)
`
`Similarly, original claim 13 recites:
`
`“13. A method of making a storage stable solid sincalide composition
`comprising:
`
`(1) mixing:
`
`(a) sincalide, and
`
`(b) an excipient consisting essentially of (i) a stabilizer, (ii) a
`bulking agent/tonicity adjuster, (iii) a chelator, or (iv) any
`combination of (i), (ii) and (iii), and
`
`(c) water
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`Page 10 of 45
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`(2) adjusting the pH of the mixture to 6.5 to 7.5, and
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`
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`Patent Owner’s Preliminary Response
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`(3) lyophilizing the pH-adjusted mixture,
`
`wherein the storage stable sincalide composition does not contain a
`buffer having a pKa within one unit of the pH.” (Id. at 2-3.)
`
`Petitioner has also recently submitted an office action response in the ’240
`
`application. (Ex. 2013.) In this response, Petitioner argues that there was no
`
`reasonable expectation of successfully achieving its stable sincalide formulations.
`
`(Id. at 13-19.) Yet, Petitioner takes the exact opposite position in its Petition, arguing
`
`that its combination of prior art leads to the stable sincalide formulations of the ’046
`
`Patent, and that there was a reasonable expectation of success in achieving such
`
`formulations. (Petition at 40, 44-51, 61-63.)
`
`
`
`Patent Owner submits that this is a remarkable set of circumstances, which can
`
`only lead to the conclusion that Petitioner has failed to establish any Challenged
`
`Claim is obvious. Fifteen years after the ‘046 Patent was filed, Petitioner files its
`
`own patent application to what it must believe is novel and non-obvious subject
`
`matter.5 In doing so, Petitioner asserts that its formulations, which contain fewer
`
`excipients, are patentable because there was no reasonable expectation of
`
`successfully achieving them. Petitioner cannot credibly argue that the stable
`
`
`
`5 The priority date of the ’240 application is August 25, 2017. (Ex. 2010 at 1.)
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`Page 11 of 45
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`sincalide formulations of the ’046 Patent are easily predicted, yet in its next breath
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`Patent Owner’s Preliminary Response
`
`
`
`argue that its formulations (which contain fewer excipients) are patentable.
`
`Accordingly, Petitioner’s argument that there was a reasonable expectation of
`
`achieving the claimed inventions of the ’046 Patent is not credible and must be
`
`rejected. Indeed, as shown in detail below, Petition has failed to carry its burden on
`
`several fronts.
`
`III. CLAIM CONSTRUCTION
`The present IPR is subject to the Phillips standard since the Petition was filed
`
`after November 13, 2018. 37 C.F.R. § 42.100(b); 83 Fed. Reg. 51340 (Oct. 11,
`
`2019); Phillips v. AWH Corp., 415 F.3d 1303, 1312-14 (Fed. Cir. 2005) (en banc).
`
`Petitioner proposed no express claim constructions. (Petition at 37.) For purposes
`
`of this POPR, Patent Owner also believes that no express claim constructions are
`
`necessary. However, if a trial is instituted, Patent Owner reserves the right to argue
`
`any necessary claim construction(s).
`
`IV. PETITIONER FAILS TO ADEQUATELY ADDRESS THE SCOPE
`AND CONTENT OF THE PRIOR ART AS REQUIRED BY GRAHAM
`A. Legal Standards
`
`The burden to prove a challenged claim obvious always lies with a Petitioner.
`
`“Where, as here, the only question presented is whether due consideration of the four
`
`Graham factors renders a claim or claims obvious, no burden shifts from the patent
`
`challenger to the patentee.” In re Magnum Oil Tools, 829 F.3d 1364, 1376 (Fed. Cir.
`Page 12 of 45
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`2016) A Petitioner cannot carry its burden to show obviousness if it fails to make an
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`Patent Owner’s Preliminary Response
`
`
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`adequate showing under KSR and Graham. “Importantly, we have repeatedly
`
`emphasized that an obviousness inquiry requires examination of all four Graham
`
`factors and that an obviousness determination can be made only after consideration
`
`of each factor.” Id. (citing Nike, Inc. v. Adidas Ag, 812 F.3d 1326, 1335 (Fed. Cir.
`
`2016). “A determination of whether a patent claim is invalid as obvious under § 103
`
`requires consideration of all four Graham factors, and it is error to reach a conclusion
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`of obviousness until all those factors are considered.” Apple Inc. v.
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