UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN INSTITUTIONAL INC.,
`Petitioner
`
`v .
`
`FRESENIUS KABI USA, LLC,
`Patent Owner.
`
`U.S. Patent No. 9,168,239 to Jiang et al.
`Issue Date: October 27, 2015
`Title: Levothyroxine Formulations
`
`Inter Partes Review No.: IPR2017-00644
`
`Petition for Inter Partes Review of U.S. Patent No. 9,168,239 Under
`35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`I.
`II.
`III.
`
`C.
`
`INTRODUCTION ......................................................................................... 1
`OVERVIEW.................................................................................................. 1
`STANDING (37 C.F.R. § 42.104(a); PROCEDURAL
`STATEMENTS)............................................................................................ 2
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))..................................... 3
`A.
`Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) .......................... 3
`B.
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2))............................. 3
`1.
`Judicial Matters ......................................................................... 3
`2.
`Administrative Matters.............................................................. 4
`Designation of Lead and Back-Up Counsel and Service (37
`C.F.R. §§ 42.8(b)(3), 42.8(b)(4), 42.10(a), and 42.10(b)): .................. 4
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(a))......................................... 5
`THE ’239 PATENT....................................................................................... 5
`A.
`Claim Construction.............................................................................. 5
`VII. PERSON OF ORDINARY SKILL IN THE ART & STATE OF THE
`ART ............................................................................................................... 8
`VIII. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) .................. 9
`IX.
`INVALIDITY ANALYSIS ......................................................................... 11
`A.
`The Scope and Content of the Prior Art ............................................ 11
`1.
`Instability of Levothyroxine Salt Compositions...................... 11
`2.
`Mannitol was the Most Commonly Used Bulking Agent
`and was Used in Lyophilized Levothryoxine Sodium
`Compositions........................................................................... 16
`
`V.
`
`VI.
`
`

`

`3.
`
`B.
`
`Mannitol’s Impact on the Stability of Lyophilized
`Levothyroxine Sodium Compositions was Known ................. 17
`Ground 1: Claims 1–15 Would Have Been Obvious over the
`Abbott Label, Brower, Baheti, and Collier........................................ 21
`1.
`Claim 1.................................................................................... 21
`a.
`A POSA Would Have Been Motivated to Reduce
`the Amount of Mannitol Below the 10 Milligrams
`Used in the Abbott label................................................ 21
`(i)
`Instability of Lyophilized Levothyroxine
`Compositions was Known .................................. 22
`(ii) Degradation of Levothyroxine by Mannitol
`was Known as was Reducing the Amount of
`Mannitol to Improve the Composition................ 23
`A POSA Would Have Had a Reasonable
`Expectation of Success.................................................. 26
`Patent Owner’s Arguments during Prosecution of
`the Parent ’289 Patent Do Not Support
`Patentability .................................................................. 28
`Claims 2–5: Amount of Levothyroxine Sodium
`Converted to Liothyronine ...................................................... 36
`a.
`Claims 2 and 3............................................................... 36
`b.
`Claims 4 and 5............................................................... 39
`Claim 6: Amount of Mannitol ................................................. 42
`Claims 7 and 8: Phosphate Buffer and 400 to 600
`Micrograms of Dibasic Sodium Phosphate ............................. 43
`a.
`Claim 7.......................................................................... 43
`b.
`Claim 8.......................................................................... 43
`Claim 9: Sodium Salt of Levothyroxine.................................. 45
`Claim 10: Pharmaceutically Acceptable Liquid Carrier.......... 46
`Claim 11: Concentration of Levothyroxine............................. 46
`Claim 12: pH ........................................................................... 47
`
`5.
`6.
`7.
`8.
`
`b.
`
`c.
`
`2.
`
`3.
`4.
`
`i
`
`

`

`9.
`
`b.
`
`Claim 13: Method of Providing Levothyroxine to a
`Patient in Need ........................................................................ 49
`10. Claims 14 and 15: Dosage of Levothyroxine .......................... 49
`Ground 2: Claims 1–15 Would Have Been Obvious over the
`APP Label, Brower, Baheti, and Collier............................................ 51
`1.
`Claim 1.................................................................................... 51
`a.
`A POSA Would Have Been Motivated to Reduce
`the Amount of Mannitol Below the 10 Milligram
`Amount Used in Conventional Compositions............... 51
`A POSA Would Have Had a Reasonable
`Expectation of Success.................................................. 52
`Claims 2–5: Amount of Levothyroxine Sodium
`Converted to Liothyronine ...................................................... 54
`Claim 6: Amount of Mannitol ................................................. 55
`Claims 7 and 8: Phosphate Buffer and 400 to 600
`Micrograms of Dibasic Sodium Phosphate ............................. 55
`a.
`Claim 7.......................................................................... 55
`b.
`Claim 8.......................................................................... 56
`Claim 9: Sodium Salt of Levothyroxine.................................. 57
`Claim 10: Pharmaceutically Acceptable Liquid Carrier.......... 57
`Claim 11: Concentration of Levothyroxine............................. 58
`Claim 12: pH ........................................................................... 58
`Claim 13: Method of Providing Levothyroxine to a
`Patient in Need ........................................................................ 59
`10. Claims 14 and 15: Dosage of Levothyroxine .......................... 59
`Ground 3: Claims 1–15 Would Have Been Obviousness over
`the Abbott Label, APP Label, Brower, Baheti, and Collier............... 60
`1.
`Claim 1.................................................................................... 60
`
`2.
`
`3.
`4.
`
`5.
`6.
`7.
`8.
`9.
`
`C.
`
`D.
`
`ii
`
`

`

`a.
`
`2.
`
`3.
`4.
`
`A POSA Would Have Been Motivated to Reduce
`the Amount of Mannitol................................................ 61
`Claims 2–5: Amount of Levothyroxine Sodium
`Converted to Liothyronine ...................................................... 61
`Claim 6: Amount of Mannitol ................................................. 61
`Claims 7 and 8: Phosphate Buffer and 400 to 600
`Micrograms of Dibasic Sodium Phosphate ............................. 62
`a.
`Claim 7.......................................................................... 62
`b.
`Claim 8.......................................................................... 62
`Claim 9: Sodium Salt of Levothyroxine.................................. 63
`Claim 10: Pharmaceutically Acceptable Liquid Carrier.......... 64
`Claim 11: Concentration of Levothyroxine............................. 64
`Claim 12: pH ........................................................................... 64
`Claim 13: Method of Providing Levothyroxine to a
`Patient in Need ........................................................................ 65
`10. Claims 14 and 15: Dosage of Levothyroxine .......................... 65
`Objective Indicia of Non-Obviousness.............................................. 65
`1.
`No Unexpected Results Over the Closest Prior Art................. 66
`2.
`Commercial Success................................................................ 70
`CONCLUSION ........................................................................................... 70
`
`5.
`6.
`7.
`8.
`9.
`
`E.
`
`X.
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Altaire Pharms., Inc. v. Paragon Bioteck, Inc.,
`PGR2015-00011, Paper 48 (P.T.A.B. Nov. 14, 2016)...................................... 67
`Amneal Pharmaceuticals, LLC v. Supernus Pharmaceuticals, Inc.,
`IPR2013-00368, Paper 8 (P.T.A.B. Dec. 17, 2013).......................................... 65
`Biomarin Pharms. Inc. v. Genzyme Therapeutics Products Ltd.,
`IPR2013-00534, Paper 81 (P.T.A.B. Feb. 23, 2015) ................ 27, 45, 50, 54, 59
`Chi Mei Innolux Corp. v. Semiconductor Energy Lab. Co., Ltd.,
`IPR2013-00028, Paper 14 (P.T.A.B. Mar. 21, 2014)........................................ 10
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016)........................................................................................ 8
`Ethicon Endo-Surgery, Inc. v. Covidien,
`IPR2015-01274, Paper 25 (P.T.A.B. Nov. 30, 2016) ....................................... 35
`Gnosis S.P.A. v. S. Ala. Med. Sci. Found.,
`IPR2013-00116, Paper 68 (P.T.A.B. June 20, 2014).................................. 30, 33
`Graham v. John Deere Co. of Kansas City,
`383 U.S. 1 (1966).............................................................................................. 11
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955) ................................................................... passim
`In re Fout,
`675 F.2d 297 (C.C.P.A. 1982) .......................................................................... 44
`In re Harris,
`409 F.3d 1339 (Fed. Cir. 2005)......................................................................... 69
`In re Icon Health and Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007)......................................................................... 35
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009)................................................................... 25, 30
`
`iv
`
`

`

`In re Kwan,
`837 F.2d 1097 (Fed. Cir. 1987)......................................................................... 33
`In re Mayne,
`104 F.3d 1339 (Fed. Cir. 1997)............................................................. 43, 56, 63
`In re Mouttet,
`686 F.3d 1322 (Fed. Cir. 2012)......................................................................... 30
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2005).................................................................. passim
`In re Siebentritt,
`372 F.2d 566 (C.C.P.A. 1967) .......................................................................... 44
`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007)........................................................................... 8
`Jonsson v. Stanley Works,
`903 F.2d 812 (Fed.Cir.1990)....................................................................... 25, 28
`Karlin Technology, Inc. v. Surgical Dynamics, Inc.,
`177 F.3d 968 (Fed. Cir. 1999)............................................................................. 7
`Lupin Ltd. et al. v. Senju Pharmaceutical Co., Ltd.,
`IPR2015-01099, Paper 69 (P.T.A.B. Sep. 12, 2016) ........................................ 44
`Newell Cos., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988)........................................................................... 65
`Owens Corning v. Fast Felt Corp.,
`IPR2015-00650, Paper 9 (P.T.A.B. Aug. 13, 2015) ......................................... 10
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2008)......................................................................... 65
`
`Pharmacosmos A/S v. Luitpold Pharms., Inc.
`IPR2015-01490 Paper 54 (P.T.A.B. Jan. 4, 2017)...................................... 51, 56
`Praxair Distrib., Inc. v. Ino Therapeautics, LLC,
`IPR2015-00893, Paper 14 (P.T.A.B. Sept. 22, 2015) ....................................... 10
`
`v
`
`

`

`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012)......................................................................... 42
`Sharp Corp. v. Surpass Tech Innovation LLC,
`IPR2015-00021, Paper 10 (P.T.A.B. Mar. 18, 2015)........................................ 10
`Titanium Metals Corp. v. Banner,
`778 F.2d 775 (Fed. Cir. 1985)............................................................... 41, 45, 48
`Vandenberg v. Dairy Equip. Co.,
`740 F.2d 1560 (Fed. Cir. 1984)......................................................................... 70
`STATUTES
`35 U.S.C. § 102(a) ................................................................................................. 15
`35 U.S.C. § 102(b).......................................................................................... passim
`35 U.S.C. § 102(e) ................................................................................................. 12
`35 U.S.C. § 103.................................................................................................. 9, 25
`35 U.S.C. § 112, fourth paragraph ................................................................... 36, 40
`OTHER AUTHORITIES
`37 C.F.R. § 42.6(d) .................................................................................................. 9
`37 C.F.R. § 42.8(a) .................................................................................................. 3
`37 C.F.R. § 42.8(b) .............................................................................................. 3, 4
`37 C.F.R. § 42.10..................................................................................................... 4
`37 C.F.R. § 42.100(b) .......................................................................................... 6, 8
`37 C.F.R. § 42.104(a)............................................................................................... 2
`37 C.F.R. § 42.104(b) .............................................................................................. 9
`37 C.F.R. § 42.106(a)............................................................................................... 2
`37 C.F.R. § 42.65................................................................................................... 67
`37 C.F.R. § 42.65(b)(2).......................................................................................... 67
`
`vi
`
`

`

`37 CER.R. § 42.65(b)(5)ccccsssssessssssesssssevsscessevesssevscsssssecsssevecssuteesssuveceeaeecesneecesenveees 68
`37 C.F.R. § 42.65(b)(5).......................................................................................... 68
`37 C-F-R. §42.65(b)(5) ......................................................................... ..
`63
`
`vii
`vii
`Vii
`
`

`

`Exhibit #
`1001
`
`1002
`
`1003
`
`1004
`1005
`1006
`1007
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`Petitioner’s Exhibit List
`
`Description
`U.S. Patent No. 9,006,289 to Jiang et al., “Levothyroxine
`Formulations”
`U.S. Patent No. 9,168,238 to Jiang et al., “Levothyroxine
`Formulations”
`U.S. Patent No. 9,168,239 to Jiang et al., “Levothyroxine
`Formulations”
`Declaration of James E. Kipp, Ph.D.
`Curricula Vitae of James E. Kipp, Ph.D.
`Abbott Synthroid® Prescribing Information
`APP Levothyroxine Sodium for Injection Prescribing Information
`Rowe et al., “Mannitol,” Handbook of Pharmaceutical
`Excipients, 5th Ed. (2006) pp. 449-453
`Collier et al., “Influence of Formulation and Processing Factors
`on Stability of Levothyroxine Sodium Pentahydrate,” APPS
`PharmSiTech 11(2), 2010, 818-825
`Baheti et al., Excipients Used in Lyophilization of Small
`Molecules, J. Excipients and Food Chem. 1 (1), 41-54 (2010)
`U.S. Patent App. Pub. No. 2012/0190748 to Haren Treasurer,
`“Greater Utility with Thyroid hormone”
`Markman Opinion in Fresenius Kabi USA, LLC v. Fera
`Pharmaceuticals, LLC, et al., No. 15-cv-3654-KM-MAH, ECF
`No. 327 (D.N.J. Sep. 20, 2016)
`Declaration of Arunya Usayapant dated December 23, 2014 filed
`in U.S. Patent App. No. 13/597,884
`Declaration of Jiang et al., dated August 7, 2013 filed in U.S.
`Patent App. No. 13/597,884
`Declaration of Leonard J. Chyall dated June 5, 2014 filed in U.S.
`Patent App. No. 13/597,884
`Shah et al., Stability Indicating Validated HPLC Method for
`Quantification of Levothyroxine with Eight Degradation Peaks in
`the Presence of Excipients, International Journal of
`Pharmaceutics 360 (2008) 77–82
`Chong Min Won, Kinetics of Degradation of Levothyroxine in
`Aqueous Solution and in Solid State, Pharm. Res. Vol. 9 No.,
`131–137 (1992)
`
`viii
`
`

`

`Exhibit #
`1018
`
`1019
`
`1020
`1021
`1022
`1023
`1024
`1025
`
`1026
`
`1027
`1028
`1029
`1030
`1031
`1032
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`Description
`Brower et al., Determination of Sodium Levothyroxine in Bulk,
`Tablet, and Injection Formulations by High-Performance Liquid
`Chromatography, J. Pharm. Sci. 73:1315-1317 (1984)
`Glass et al., Stability Considerations in Liquid Dosage Forms
`Extemporaneously Prepared from Commercially Available
`Products, J Pharmacy & Pharma. Sci. 9 (3): 398-426 (2006)
`Reserved
`Physician’s Desk Reference, 25th Ed., 1971, p. 716
`Reserved
`Reserved
`Reserved
`Carpenter et al., Rational Design of Stable Lyophilized Protein
`Formulations: Some Practical Advice, Pharm. Research, Vol. 14,
`No. 8, 1997
`Amendment and Response dated December 23, 2014 filed in U.S.
`Patent App. No. 13/597,884
`U.S. Provisional Application No. 61/529,084
`Reserved
`Reserved
`Reserved
`Reserved
`Reserved
`Byrn et al., Chemical Reactivity in Solid-State Pharmaceuticals:
`Formulation Implications, Advanced Drug Delivery Reviews 48
`(2001) 115-136
`Prescribing Information of Levothyroxine Sodium, Fresenius
`Kabi USA, LLC (December 2013)
`Amendment and Response dated June 6, 2014 filed in U.S. Patent
`App. No. 13/597,884
`Richard J. Lewis, Sr., Hawley’s Condensed Chemical Dictionary
`15th Ed. (2007) 1153-1154
`Amendment and Response dated August 9, 2013 filed in U.S.
`Patent App. No. 13/597,884
`Sznitowska et al., The Physical Characteristics of Lyophilized
`Tablets Containing a Model Drug in Different Chemical Forms
`and Concentrations, Drug Research, Vol. 62 No. 1 pp. 25-29
`(2005)
`
`ix
`
`

`

`Exhibit #
`1039
`
`1040
`1041
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`1056
`
`Description
`Richard J. Lewis, Sr., Hawley’s Condensed Chemical Dictionary
`15th Ed. (2007) 1035-1036
`Reserved
`Reserved
`Michael J. Akers, Sterile Drug Products, Formulation, Packaging,
`Manufacturing, and Quality, Informa Healthcare (2010) 138-139,
`154-168
`U.S. Patent No. 6,399,101 to Frontanes et al., “Stable Thyroid
`Hormone Preparations and Method of Making Same”
`Amendment and Response dated July 13, 2015 filed in U.S.
`Patent App. No. 14/658,058
`Rowe et al., “Sodium Phosphate,” Handbook of Pharmaceutical
`Excipients, 5th Ed. (2006) pp. 693-698
`Merck Index 14th Ed. (2006) pp. 1488-1489
`Appeal Brief of Defendants-Appellants filed in Fresenius Kabi
`USA, LLC v. Fera Pharmaceuticals, LLC, et al., No. 2017-1099,
`ECF No. 24 (Fed. Cir. Dec. 27, 2016)
`Kim et al., The Physical State of Mannitol after Freeze-Drying:
`Effects of Mannitol Concentration, Freezing Rate, and a
`Noncrystallizing Cosolute, 87 J. Pharm. Sci. 931-935 (1998)
`Yu et al., Existence of a Mannitol Hydrate during Freeze-Drying
`and Practical Implications, 88 J. Pharm. Scis. 196-198 (1999)
`Torrado et al., Characterization of Physical State of Mannitol
`after Freeze-Drying: Effect of Acetylsalicylic Acid as a Second
`Crystalline Cosolute, Chem. Pharm. Bull. 50(5) 567-570 (2002)
`Synthroid, Announcements: Postgraduate Medicine, 1969 Vol.
`46, No. 4, p. 18
`U.S. Patent No. 6,284,277 to Bouloumie et al., “Stable Freeze-
`Dried Pharmaceutical Formulation”
`Bedford Laboratories, Levothyroxine Sodium for Injection Rx
`Only
`Herman et al., The Effect of Bulking Agent on the Solid-State
`Stability of Freeze-Dried Methylprednisolone Sodium Succinate,
`Pharm. Res., 11:1467-1473 (1994)
`Reserved
`Smith R.M., Martell A.E., Critical Stability Constants, Vol. 4:
`Inorganic Complexes, Springer Science, New York, 1976, pp. 56-
`74
`
`x
`
`

`

`Exhibit #
`1057
`
`Description
`Brown T.L., Lemay H.E. Jr., Bursten B.E., Chemistry, the Central
`Science 8th Rev. Ed., Prentice-Hall, Inc., New Jersey, 2002, pp.
`644-647, 650
`
`xi
`
`

`

`I.
`
`INTRODUCTION
`
`Mylan Institutional Inc. (“Petitioner”) petitions for Inter Partes Review
`
`(“IPR”), and seeks cancellation of Claims 1–15 (“challenged claims”) of U.S. Patent
`
`No. 9,168,239 (“the ’239 patent”) (EX1003), which is assigned to Fresenius Kabi
`
`USA, LLC (“Patent Owner”).
`
`II. OVERVIEW
`
`Patent Owner admits that
`
`lyophilized compositions with levothyroxine,
`
`mannitol and a buffer were well-known before the filing date of the ’239 patent.
`
`Nevertheless, the ’239 patent purports to cover these same prior art lyophilized
`
`compositions merely with lower amounts of mannitol.
`
`The Board need look no further than the Background section to understand
`
`the well-known nature of the subject matter:
`
`Conventional formulations of levothyroxine sodium for injection are
`preservative-free lyophilized powders containing synthetic crystalline
`levothyroxine sodium and the excipients mannitol, tribasic sodium
`phosphate, and sodium hydroxide. These conventional formulations
`typically contain 10 milligrams (mg) of mannitol, 700 μg of tribasic
`sodium phosphate, and either 200 μg or 500 μg of levothyroxine
`sodium.
`
`EX1003, 2:3–14. Petitioner agrees.
`
`Faced with Patent Owner’s recognition of these prior compositions, Patent
`
`Owner is left to assert that reducing the amount of mannitol unexpectedly improved
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,168,239
`
`the stability of levothyroxine. EX1003, 3:41–46. This too fails. The prior art is
`
`replete with teachings that mannitol leads to instability of lyophilized levothyroxine
`
`compositions. EX1007, 15; EX1006, 4, 9. Thus, a person of ordinary skill in the
`
`art (“POSA”) would have been motivated to increase stability of such compositions
`
`by simply decreasing the amount of mannitol.
`
`Petitioner is mindful that certain of the relied upon references herein were
`
`before the Examiner during the prosecution of the ’239 patent. Nevertheless, that
`
`does not change the obviousness of the alleged invention and should not deter the
`
`Board from instituting this IPR, particularly in light of the new prior art, evidence,
`
`and arguments presented herein. As explained herein, and by Petitioner’s expert Dr.
`
`Kipp (EX1004), decreasing mannitol from 10 milligrams to 2 to 4 milligrams (or 3
`
`milligrams) would have been obvious as well as the other remaining limitations.
`
`For these reasons, this Petition ultimately boils down to whether lowering
`
`mannitol in prior art compositions, when mannitol was known to increase instability,
`
`was novel. It was not.
`
`III.
`
`STANDING (37 C.F.R. § 42.104(a); PROCEDURAL STATEMENTS)
`
`Petitioner certifies that: (1) the ’239 patent is available for IPR; and (2)
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the ’239
`
`patent on the grounds identified herein. This Petition is filed in accordance with 37
`
`C.F.R. § 42.106(a). Filed herewith are a Power of Attorney and an Exhibit List
`
`2
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,168,239
`
`pursuant to § 42.10(b) and § 42.63(e). The required fee is paid through an online
`
`credit card, and the Office is authorized to charge any fee deficiencies and credit
`
`overpayments to Deposit Acct. No. 160605 (Customer ID No. 00826).
`
`IV. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))
`
`Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1))
`A.
`Mylan Institutional Inc., Mylan Inc., and Mylan N.V.
`
`B.
`
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`
`Judicial Matters
`1.
`The ’239 patent is currently the subject of the following litigations: Fresenius
`
`Kabi USA, LLC v. Fera Pharmaceuticals, LLC, Docket No. 17-01099 (Fed. Cir. Oct
`
`24, 2016); Fresenius Kabi USA, LLC v. Innopharma Licensing, LLC et al., No. 2:15-
`
`cv-03655-KM-MAH (D.N.J.); Fresenius Kabi USA, LLC v. Fera Pharmaceuticals,
`
`LLC, No. 2:15-cv-03654-KM-MAH (D.N.J.); Fresenius Kabi USA, LLC v. Par
`
`Sterile Products, LLC et al., No. 2:15-cv-03852-KM-MAH (D.N.J.); Fresenius Kabi
`
`USA, LLC v. Dr. Reddy’s Laboratories, Inc. et al., No. 1:16-cv-00169-GMS (D.
`
`Del.); Fresenius Kabi USA, LLC v. Dr. Reddy’s Laboratories, Inc. et al., No. 2:16-
`
`cv-01542-KM-MAH (D.N.J.); Fresenius Kabi USA, LLC v. Maia Pharmaceuticals,
`
`Inc., No. 1:16-cv-00237-GMS (D. Del.); Fresenius Kabi USA, LLC v. Dr. Reddy’s
`
`Laboratories, Inc. et al., No. 2:16-cv-03316-KM-MAH (D.N.J.); and Fresenius
`
`Kabi USA, LLC v. Maia Pharmaceuticals, Inc., No. 2:16-cv-03315-KM-MAH
`
`3
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,168,239
`
`(D.N.J.).
`
`Administrative Matters
`2.
`At least the following related ’239 patent family members exist: U.S. Patent
`
`No. 9,006,289 (“the ’289 patent”) (EX1001); U.S. Patent No. 9,168,238 (“the ’238
`
`patent) (EX1002); and U.S. App. No. 14/866,521.
`
`C.
`
`Designation of Lead and Back-Up Counsel and Service (37 C.F.R.
`§§ 42.8(b)(3), 42.8(b)(4), 42.10(a), and 42.10(b)):
`
`Lead Counsel
`Jitendra Malik, Ph.D.
`Reg. No. 55,823
`ALSTON & BIRD LLP
`4721 Emperor Boulevard, Suite 400
`Durham, North Carolina 27703-8580
`919.862.2200
`jitty.malik@alston.com
`
`Back-Up Counsel
`H. James Abe
`Reg. No. 61,182
`ALSTON & BIRD LLP
`333 South Hope Street, 16th Floor
`Los Angeles, CA 90071
`213.576.1000
`james.abe@alston.com
`
`Lance Soderstrom
`Reg. No. 65,405
`ALSTON & BIRD LLP
`90 Park Avenue, 15th Floor
`New York, New York 10016-1387
`212.210.9400
`lance.soderstrom@alston.com
`
`Alissa Pacchioli
`Reg. No. 74,252
`ALSTON & BIRD LLP
`4721 Emperor Boulevard, Suite 400
`Durham, North Carolina 27703-8580
`919.862.2200
`alissa.pacchioli@alston.com
`
`Petitioner consents to email service.
`
`4
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`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,168,239
`
`V.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(a))
`
`Petitioner requests IPR and cancellation of Claims 1–15 of the ’239 patent.
`
`Petitioner’s full statement of the reasons for the relief requested is set forth in detail
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`below.
`
`VI. THE ’239 PATENT
`
`The ’239 patent has one independent claim. Independent Claim 1 is directed
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`to a lyophilized solid composition comprising three components: (1) between 100
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`and 500 micrograms of a salt of levothyroxine; (2) a buffer; and (3) between 2 and
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`4 milligrams of mannitol. EX1003, 12:14–18. A complete analysis of the claims,
`
`as well as application of the relevant prior art is presented below.
`
`A.
`
`Claim Construction
`
`In the corresponding district court litigation, the District of New Jersey
`
`provided the following constructions:
`
`Term
`Buffer
`
`Dibasic sodium
`phosphate
`Converted to
`liothyronine
`
`Construction
`A system that resists changes in pH when acid or base is
`added.
`Anhydrous Na2HPO4 and the hydrate forms associated with
`Na2HPO4.
`Turned into liothyronine
`
`Fresenius Kabi USA, LLC v. Fera Pharmaceuticals, LLC, et al., No. 15-cv-3654-
`
`KM-MAH, ECF No. 327 (D.N.J. Sep. 20, 2016) (“Markman Opinion”) (EX1012) at
`
`5
`
`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,168,239
`
`18–19. While Petitioner maintains that these claim terms should be given their
`
`broadest reasonable interpretation (“BRI”) in this proceeding, the BRI should at least
`
`encompass the district court’s constructions. 37 C.F.R. § 42.100(b).
`
`The district court determined that “phosphate buffer” (see, e.g., Claim 7 of the
`
`’239 patent) did not require further construction in light of the construction of
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`“buffer” (EX1012, 18). Petitioner submits that “phosphate buffer” should be given
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`its BRI, however, to explain the obviousness analysis below which involves prior art
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`teachings of different phosphate buffers, Petitioner submits that the term “phosphate
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`buffer” is not limited to a specific phosphate buffer and thus includes, e.g., tribasic
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`phosphate, dibasic phosphate, and monobasic phosphate buffers. The claims,
`
`specification, and prosecution history all support this construction.
`
`First, under the ordinary and customary meaning, as would have been
`
`understood by a POSA at the time, the term “phosphate” buffer was not limited to
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`any particular type thereof (e.g., dibasic, tribasic, etc.), or even to any particular salt
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`form (e.g., sodium, potassium, etc.) or hydrate (e.g., anhydrous, heptahydrate, etc.).
`
`EX1004, footnote 21; EX1036, 1153 (defining sodium phosphate as “sodium
`
`metaphosphate; sodium phosphate, dibasic; sodium phosphate, monobasic; sodium
`
`phosphate (P-32); sodium phosphate,
`
`tribasic; sodium polyphosphate; sodium
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`pyrophosphate; sodium pyrophosphate, acid; sodium tripolyphosphate”); EX1039,
`
`1035 (listing potassium phosphate dibasic, monobasic, and tribasic).
`
`6
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`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,168,239
`
`The doctrine of claim differentiation also supports Petitioner’s construction.
`
`Dependent Claim 8 recites that “the phosphate buffer is dibasic sodium phosphate,”
`
`therefore, the claim term “phosphate buffer” recited by Claim 7 includes more than
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`just dibasic sodium phosphate. Karlin Technology, Inc. v. Surgical Dynamics, Inc.,
`
`177 F.3d 968, 971–72 (Fed. Cir. 1999) (“[D]ifferent words or phrases used in
`
`separate claims are presumed to indicate that the claims have different meanings and
`
`scope.”).
`
`Second, the specification does not explicitly exclude any particular phosphate
`
`buffer—such as tribasic sodium phosphate—from the term “phosphate buffer.”
`
`Although the ’239 patent states that tribasic sodium phosphate is not included in the
`
`preferred embodiment, the Federal Circuit has held that “[t]he general rule, of
`
`course, is that the claims of a patent are not limited to the preferred embodiment,
`
`unless by their own language.” Karlin Technology, Inc., 177 F.3d at 973; EX1003,
`
`4:42–48.
`
`Third, during prosecution of the parent ’289 patent, one of the named
`
`inventors filed a declaration (“Usayapant Decl.”) (EX1013) in which the prior art
`
`composition containing tribasic sodium phosphate was described as having “a
`
`phosphate buffer.” EX1013, ¶ 14. Accordingly, the term “phosphate buffer” should
`
`not be limited to specific phosphate buffers.
`
`7
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`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,168,239
`
`All remaining claim terms should be given their BRI, i.e., their ordinary and
`
`customary meaning as would have been understood by a POSA at the time, in the
`
`context of the entire patent disclosure.1 37 C.F.R. § 42.100(b); Cuozzo Speed Techs.,
`
`LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016); In re Translogic Tech., Inc., 504 F.3d
`
`1249, 1257 (Fed. Cir. 2007).
`
`VII. PERSON OF ORDINARY SKILL IN THE ART & STATE OF THE
`ART
`
`The earliest possible priority date of the ’239 patent is August 30, 2011.2 As
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`of that time, a POSA in the relevant field would have had education and/or
`
`experience in the field of drug delivery systems, with knowledge of the scientific
`
`literature concerning the same,
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`including some understanding of lyophilized
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`pharmaceutical compositions and injectable preparations. The education and
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`1 The ’239 patent also explicitly defines certain terms: “mass ratio,” “lyophilizing,”
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`and “spans the range.” EX1003, 2:62–3:16. To the extent necessary, Petitioner
`
`applies the definitions provided in the patent specification.
`
`2 The’239 patent is a continuation of U.S. Patent App. Ser. No. 13/597,884 filed on
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`August 29, 2012, which issued as the ’289 patent, which in turn claims priority to
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`U.S. Provisional App. No. 61/529,084 (“the ’084 provisional application”)
`
`(EX1027), which was filed on August 30, 2011. EX1003, 1:5–9.
`
`8
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`

`

`Petition for Inter Partes Review
`of U.S. Patent No. 9,168,239
`
`experience levels may vary between POSAs, with some having a bachelor’s degree
`
`in the chemical or pharmaceutical arts plus five years of relevant work experience,
`
`or with others holding more advanced degrees—e.g., Ph.D. or Pharm.D.—while
`
`having fewer years of experience. EX1004, ¶45.
`
`VIII. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
`
`Petitioner respectfully requests IPR of Claims 1–15 of the ’239 patent on each
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`specific ground of unpatentability outlined below. Per 37 C.F.R. § 42.6(d), copies
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`of the references are filed herewith. In support of the proposed grounds, this Petition
`
`includes the declaration of a technical expert, James E. Kipp, Ph.D. (EX1004),
`
`explaining what the art would have conveyed to a POSA as of the priority date of
`
`the ’239 patent.
`
`Ground
`
`References
`
`1
`
`2
`
`3
`
`Abbott Label, Brower, Baheti, and
`Collier
`APP Label, Brower, Baheti, and
`Collier
`Abbott Label, APP Label, Brower,
`Baheti, and Collier
`
`Basis
`
`35 U.S.C. §
`103
`35 U.S.C. §
`103
`35 U.S.C. §
`103
`
`Claims
`Challenged
`1–15
`
`1–15
`
`1–15
`
`Prior art references in addition to the primary references listed above provide
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`further background in the art, motivation to combine the teachings of these
`
`references, and/or support for why a