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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN INSTITUTIONAL LLC,
`Petitioner,
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`v.
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`NOVO NORDISK A/S,
`Patent Owner.
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`Patent No. 8,114,833
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`Inter Partes Review IPR2020-00324
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`EXPERT DECLARATION OF LAIRD FORREST, PH.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,114,833
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`TABLE OF CONTENTS
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`Page
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`QUALIFICATIONS AND BACKGROUND ................................................ 6
`A.
`Education and Experience; Prior Testimony........................................ 6
`B.
`Bases for Opinions and Materials Considered ................................... 10
`C.
`Scope of Work .................................................................................... 10
`SUMMARY OF OPINIONS ........................................................................ 10
`LEGAL STANDARDS ................................................................................ 12
`PERSON OF ORDINARY SKILL IN THE ART ....................................... 14
`THE ’833 PATENT (EX. 1001) ................................................................... 15
`CLAIM CONSTRUCTION ......................................................................... 18
`BACKGROUND .......................................................................................... 19
`A. GLP-1 Agonists, Including Liraglutide, Were Well Known in
`the Art ................................................................................................. 19
`Parenteral Peptide Dosage Forms ...................................................... 19
`Stability of Peptide Formulations and Selection of Excipients ......... 30
`i.
`Use of Propylene Glycol in Peptide Formulations .................. 31
`ii.
`Propylene Glycol is Safe .......................................................... 33
`iii.
`Propylene Glycol’s Advantages Over Other Isotonic
`Agents ...................................................................................... 34
`SCOPE AND CONTENT OF THE PRIOR ART REFERENCES ............. 37
`A.
`Flink (Ex. 1004) ................................................................................. 37
`B.
`Betz (Ex. 1005) ................................................................................... 48
`C. Other Art that Informs the Person of Ordinary Skill’s
`Knowledge .......................................................................................... 51
`i.
`U.S. Patent No. 6,268,343 (“Knudsen I”) (Ex. 1006) ............. 51
`ii.
`Eur. Patent App. Pub. No. EP0923950 (“Ibaraki”) (Ex.
`1007) ........................................................................................ 52
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`B.
`C.
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`1.
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`2.
`3.
`4.
`5.
`6.
`7.
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`8.
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`TABLE OF CONTENTS
`(continued)
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`Page
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`vii.
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`iii.
`iv.
`v.
`vi.
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`Powell (Ex. 1008) .................................................................... 52
`Epperson (Ex. 1009) ................................................................ 53
`Jacobs (Ex. 1011) ..................................................................... 53
`Int’l Patent Pub. No. WO 1999/040788 (“Young”) (Ex.
`1025) ........................................................................................ 54
`Int’l Patent Pub. No. WO 03/072195 (“Khan”) (Ex.
`1014) ........................................................................................ 55
`Int’l Patent Pub. No. WO 95/022560 (“Dix”) (Ex. 1019) ....... 55
`viii.
`ix. U.S. Patent No. 6,458,924 (“Knudsen II”) (Ex. 1020) ............ 56
`x.
`Int’l Patent Pub. No. WO 00/037098 (Ex. 1021) .................... 56
`xi. Handbook of Pharmaceutical Excipients 2000, 2003
`(Exs. 1022-1023) ...................................................................... 57
`xii. Nail & Akers (Ex. 1024) .......................................................... 58
`xiii. Bontempo (Ex. 1026) ............................................................... 60
`xiv. Gatlin (Ex. 1027)...................................................................... 62
`xv. Remington’s 1990 (Ex. 1013) .................................................. 64
`xvi. Sturis (Ex. 1046) ...................................................................... 66
`xvii. Chang (Ex. 1059) ..................................................................... 67
`xviii. U.S. Patent No. 4,425,346 (“Horlington”) (Ex. 1063) ............ 67
`xix. U.S. Patent No. 6,207,684 (“Aberg”) (Ex. 1064) .................... 68
`xx. U.S. Patent No. 6,440,460 (“Gurny”) (Ex. 1065) .................... 68
`xxi. Additional Prior Art References and Knowledge .................... 69
`UNPATENTABILITY OF THE ’833 PATENT ......................................... 70
`A.
`Claims 1-15 of the ’833 patent were anticipated by or would
`have been obvious over Flink ............................................................. 70
`i.
`Claim 1 was Anticipated by or Would Have Been
`Obvious Over Flink .................................................................. 70
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`9.
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`TABLE OF CONTENTS
`(continued)
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`Page
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`ii.
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`v.
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`x.
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`ii.
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`Claims 2-4 were Anticipated by or Would Have Been
`Obvious Over Flink .................................................................. 81
`iii. Claims 5-7 were Anticipated by or Would Have Been
`Obvious Over Flink .................................................................. 82
`iv. Claims 8 and 9 were Anticipated by or Would Have Been
`Obvious Over Flink .................................................................. 82
`Claim 10 was Anticipated by or Would Have Been
`Obvious Over Flink .................................................................. 83
`vi. Claim 11 was Anticipated by or Would Have Been
`Obvious Over Flink .................................................................. 83
`vii. Claim 12 was Anticipated by or Would Have Been
`Obvious Over Flink .................................................................. 84
`viii. Claim 13 was Anticipated by or Would Have Been
`Obvious Over Flink .................................................................. 85
`ix. Claim 14 was Anticipated by or Would Have Been
`Obvious Over Flink .................................................................. 85
`Claim 15 was Anticipated by or Would Have Been
`Obvious Over Flink .................................................................. 86
`Claims 1-31 of the ’833 patent would have been obvious over
`Flink in view of Betz .......................................................................... 87
`i.
`Claims 1-15 Would Have Been Obvious Over Flink in
`View of Betz ............................................................................ 87
`Claim 16 Would Have Been Obvious Over Flink in View
`of Betz ...................................................................................... 96
`iii. Claims 17-19 Would Have Been Obvious Over Flink in
`View of Betz ............................................................................ 97
`iv. Claims 20-22 Would Have Been Obvious Over Flink in
`View of Betz ............................................................................ 98
`Claims 23, 26, and 29 Would Have Been Obvious Over
`Flink in View of Betz ............................................................... 98
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`v.
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`B.
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`TABLE OF CONTENTS
`(continued)
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`Page
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`vi. Claims 24, 27, and 30 Would Have Been Obvious Over
`Flink in View of Betz ............................................................... 99
`vii. Claims 25, 28, and 31 Would Have Been Obvious Over
`Flink in View of Betz ............................................................. 102
`10. NO SECONDARY CONSIDERATIONS OVERCOME PRIMA
`FACIE OBVIOUSNESS OF THE CLAIMED INVENTIONS ................. 102
`A.
`The Methods Recited in the ’833 Patent Produce No
`Unexpected Results. ......................................................................... 102
`There Was No Long-Felt But Unmet Need ..................................... 104
`There Was No Industry Skepticism ................................................. 104
`Copying by Generic Drug Makers Is Irrelevant ............................... 104
`A Blocking Patent Existed at the Time of the Claimed
`Invention ........................................................................................... 105
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`B.
`C.
`D.
`E.
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`1. My name is Laird Forrest, Ph.D. I have been retained by counsel for
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`Mylan Institutional LLC (“Mylan”). I understand that Mylan intends to petition for
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`inter partes review (“IPR”) of U.S. Patent No. 8,114,833 (“the ’833 patent”), Ex.
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`1001, which is assigned to Novo Nordisk A/S. I also understand that, in the IPR
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`petition, Mylan will request that the United States Patent and Trademark Office
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`cancel all claims of the ’833 patent as unpatentable. I submit this expert declaration
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`to address and support Mylan’s IPR petition for the ’833 patent.
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`1. QUALIFICATIONS AND BACKGROUND
`A. Education and Experience; Prior Testimony
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`2.
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`I am currently a Professor in the Department of Pharmaceutical
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`Chemistry at the University of Kansas in Lawrence, Kansas, a position I have held
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`since 2017. I am also Professor in the Bioengineering Center, a position I have held
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`since 2011, and Professor in the Department of Medicinal Chemistry, a position I
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`have held since 2015, both also at the University of Kansas. I have been a faculty at
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`the University of Kansas since 2007.
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`3.
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`I received a Bachelor of Science in Chemical Engineering from Auburn
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`University in 1998, a Master of Science in Chemical Engineering from the
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`University of Illinois in 2001, and a Ph.D. in Chemical and Biomolecular
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`Engineering from the University of Illinois in 2003. I was a Postdoctoral Fellow in
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`the Division of Pharmaceutical Sciences at the University of Wisconsin, Madison,
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`from 2004 to 2006. In 2006, I became Adjunct Assistant Professor in the Department
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`of Pharmaceutical Sciences at Washington State University, a position I held until
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`2011. In 2007, I accepted a position as Assistant Professor in the Department of
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`Pharmaceutical Chemistry at the University of Kansas. I was promoted to Associate
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`Professor at the University of Kansas in 2013. I was then promoted to the rank of
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`Professor in 2017.
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`4.
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`Since 2009, I have been a Member of the Scientific and Medical
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`Advisory Board of Exogenesis Corporation, which develops nanoscale surface
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`modifications for implantable medical devices. I am the co-founder of HylaPharm
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`LLC, founded in 2011, which specializes in reformulation of anti-cancer
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`chemotherapeutics by modification of the delivery route and pharmacokinetics.
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`Also, I am a co-founder of Hafion LLC, founded in 2016, which specializes in
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`development of vaccines, and Aerobyx LLC, founded in 2017, which specializes in
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`the development of medications for treatment of neurological and metabolic disease.
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`In addition, I am a co-founder of Vesarex, founded in 2018, which specializes in the
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`development of ultrasound imaging devices and contrast agents. My research toward
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`drug formulation has been competitively funded by multiple awards from the
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`National Institutes of Health and the National Cancer Institute, the National Institute
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`of Allergy and Infectious Disease, the American Cancer Society, the Department of
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`Defense, Susan G. Komen Race for the Cure, and the Pharmaceutical Research and
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`Manufacturers of America Foundation (“PhRMA”), among others. In addition, I
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`have been funded by the Food and Drug Administration (“FDA”) to develop
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`methodologies for the in vitro determination of bioequivalence in follow-on complex
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`botanical and biosimilar drug formulations.
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`5.
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`I have received many awards and honors, including the Baxendale
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`Innovation Award (2016), the University of Kansas Leading Light award (2014), the
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`Japan Society for Promotion of Science Visiting Scholar Fellow (2010), the
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`American Cancer Society Research Scholar (2008 to 2012), the American
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`Association of Colleges of Pharmacy, New Investigators Award (2007), and the
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`PhRMA Foundation Postdoctoral Fellow (2006), among others.
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`6.
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`I am currently or have been in the past a member of various professional
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`societies, including the American Association for Cancer Research, the American
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`Association of Pharmaceutical Scientists, and the American Institute of Chemical
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`Engineers. I serve or have served on numerous scientific review panels for the
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`National Institutes of Health, the American Cancer Society, and the Association for
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`International Cancer Research (United Kingdom). I am a standing member of the
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`American Cancer Society review panel on Cancer Drug Development.
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`7.
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`I have authored more than 90 peer-reviewed journal articles and 5 book
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`chapters. I have also edited 2 special journal issues on drug delivery and a book on
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`drug delivery and formulation.
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`8.
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`I have taught drug formulation and biopharmaceutics, including all
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`aspects of drug excipient choice and the effects of excipient modification on drug
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`pharmacokinetics, ionic equilibrium, drug chemical stability, drug dissolution, and
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`drug absorption, to clinical pharmacy students and graduate students studying
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`pharmaceutical sciences since 2007.
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`9.
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`I have experience in all aspects of parenteral, topical, and oral drug
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`formulation and pharmacokinetics through my research and teaching. Additionally,
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`as part of my work with HylaPharm, Exogenesis Inc., Atrin Pharmaceutics, and
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`Akari Therapeutics Inc., I have worked on pharmaceutical formulations for
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`intramuscular, subcutaneous, intravenous, topical, and oral formulation.
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`10.
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`In the past six years, I have testified in the following litigations:
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`• Merck Sharp & Dohme Corp. v. Savior Lifetec Corp., No. 5:15-cv-
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`00415-TWB (E.D.N.C.);
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`• Medac Pharma, Inc. et al. v. Antares Pharma Inc. et al., No. 1:14-cv-
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`01498-JBS-KMW (D.N.J.);
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`• Halozyme, Inc. v. Joseph Matal (on behalf of USPTO), No. 1:16-cv-
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`1580 (E.D. Va.);
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`• Bracco Diagnostics v. Maia Pharm., Inc., No. 3:17-cv-13151 (D.N.J.);
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`and
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`• Horizon Medicines LLC v. Dr. Reddy’s Labs. Inc., No. 2:15-cv-03324-
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`SRC-CLW (D.N.J.) (consolidated).
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`11. My curriculum vitae, which describes my experience and background
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`in more detail, is attached as Exhibit A.
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`B.
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`Bases for Opinions and Materials Considered
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`12. Exhibit B includes a list of the materials I considered, in addition to my
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`experience, education, and training, in providing the opinions contained in this
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`declaration.
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`C.
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`13.
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`Scope of Work
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`I have been retained by Mylan as a technical expert to provide various
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`opinions regarding the ’833 patent. I am being compensated for my time at my
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`standard consulting rate of $600/hour. Neither the amount of my compensation nor
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`the fact that I am being compensated has altered the opinions that I have given in
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`this Declaration. My compensation is in no way dependent on the outcome of this
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`proceeding. I do not have any current or past affiliation with Novo Nordisk A/S, or
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`any of its affiliates presently known to me, or the named inventors on the ’833 patent.
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`2.
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`SUMMARY OF OPINIONS
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`14.
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`In my view, claims 1-15 of the ’833 patent were anticipated by
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`International Patent Publication No. WO 2003/0002136 to Flink et al. (“Flink”) (Ex.
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`1004), as described in detail below. Flink’s claim 14 disclosed, in the context of the
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`specification, each element of the inventions claimed in claims 1-15 of the ’833
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`patent.
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`15. Also, claims 1-15 of the ’833 patent would have been obvious over
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`Flink, as described in detail below. In short, to the extent Flink would have been
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`viewed as not anticipating the inventions claimed in the ’833 patent, the inventions
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`would have been obvious to a person of ordinary skill in the art because the POSA
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`would have been motivated to combine the claimed elements with a reasonable
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`expectation of success.
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`16. Additionally, claims 1-31 of the ’833 patent would have been obvious
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`over Flink in view of International Patent Publication No. WO 2004/0004781 to Betz
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`and Stevens (“Betz”) (Ex. 1005), as described in detail below. To the extent Flink
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`would have been viewed as neither anticipating nor rendering obvious the claims of
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`the ’833 patent, a POSA would have understood from Betz to use propylene glycol
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`in the GLP-1 formulation disclosed in Flink, with a reasonable expectation of
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`success.
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`17. Finally, there are no apparent secondary considerations supporting
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`nonobviousness of the claims. There is no evidence of unexpected results in view
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`of the prior art, which also satisfied any need for the claimed invention. Further,
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`there is no evidence of industry skepticism of the claimed invention, and any
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`allegation that the invention is nonobvious because it was copied does not weight in
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`this context. Finally, a blocking patent existed at the time of the claimed invention,
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`which would have dissuaded anyone from developing the claimed formulations and
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`methods, and reduces the weight to be given to any secondary considerations
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`asserted in favor of patentability. I reserve the right to address any secondary
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`considerations put forth by Patent Owner in any later response to this declaration or
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`the petition it accompanies.
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`3.
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`LEGAL STANDARDS
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`18.
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`In preparing and forming my opinions set forth in this report, counsel
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`has informed me regarding the relevant legal principles.
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`19. Counsel informed me that Mylan bears the burden of proving
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`unpatentability by a preponderance of the evidence. Counsel informed that this
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`“preponderance of the evidence” standard means that Mylan must show that
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`unpatentability is more probable than not. I have taken these principles into account
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`when forming my opinions in this case.
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`20.
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`I have also been told that claims should be given their plain and
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`ordinary meaning in light of the specification from the perspective of a person of
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`ordinary skill in the art.
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`21. Counsel informed me that the question of whether the claims of a patent
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`are anticipated by, or obvious in view of, the prior art is to be considered from the
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`perspective of the person of ordinary skill in the art (“POSA”). Counsel further
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`informed me that the answer to this question is determined as of the time the
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`invention was made. I understand from counsel that the concept of patent
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`obviousness involves four factual inquiries: (1) the scope and content of the prior
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`art; (2) the differences between the claimed invention and the scope and content of
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`the prior art; (3) the level of ordinary skill in the art; and (4) whether there are
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`additional factors present that may argue against a conclusion of obviousness (i.e.,
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`“secondary considerations”) such as unexpected results attributable to the invention,
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`or whether the invention met a long-felt but unmet need.
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`22. Counsel informed me that an invention may be found obvious when
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`there is some recognized reason to solve a problem, and there are a finite number of
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`identified, predictable, and known solutions, and a person of ordinary skill in the art
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`has good reason to pursue the known options within his or her technical grasp. If
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`such an approach leads to the expected success, it is likely not the product of
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`innovation but of ordinary skill and common sense. In such a circumstance, when a
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`patent simply arranges old elements with each performing its known function and
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`yields no more than what one would expect from such an arrangement, the
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`combination is obvious.
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`23. Counsel informed me that a prior art reference anticipates a claimed
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`invention if the prior art reference disclosed each of the claimed elements of the
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`invention either expressly or inherently. A claim element is inherent in the
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`anticipating reference if that element, or characteristic, is the natural result that flows
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`from the reference’s explicit limitations. In this regard, counsel informed me that a
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`reference can anticipate a claim even if the reference does not expressly spell out all
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`the limitations arranged or combined as in the claim, if a person of skill in the art,
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`reading the reference, would at once envisage the claimed arrangement or
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`combination. Counsel has informed me that if a patent claims a composition in terms
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`of a function, property, or characteristic, and the composition itself is in the prior art,
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`then the claim may be anticipated or obvious in view of the prior art reference
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`disclosing the composition.
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`4.
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`PERSON OF ORDINARY SKILL IN THE ART
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`24.
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`I have been informed by counsel that the obviousness analysis is to be
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`conducted from the perspective of a person of ordinary skill in the art (a “person of
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`ordinary skill” or “skilled artisan”) at the time of the invention.
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`25.
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`I have also been informed by counsel that in defining a person of
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`ordinary skill the following factors may be considered: (1) the educational level of
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`the inventor; (2) the type of problems encountered in the art; (3) prior art solutions
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`to those problems; (4) rapidity with which innovations are made; and (5)
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`sophistication of the technology and educational level of active workers in the field.
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`26. Thus, in this report, unless stated otherwise, I opine from the
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`perspective of the person of ordinary skill in the art at the time of the invention
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`(POSA). The POSA is (1) a Pharm. D., or a Ph.D. in pharmacy, chemical
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`engineering, bioengineering, chemistry, or related discipline; with (2) at least two
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`years of experience in the area of protein or peptide therapeutic development and/or
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`manufacturing; and (3) experience with the development, design, manufacture, or
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`formulation of therapeutic agents, and the literature concerning protein or peptide
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`formulation and design.
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`27. For purposes of this declaration, my opinion is based on the knowledge
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`or understanding of a POSA as of the earliest possible priority date claimed on the
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`cover of the ’833 patent, November 20, 2003 (see below, ¶28), unless specified
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`otherwise.
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`5.
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`THE ’833 PATENT (EX. 1001)
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`28.
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`I have read the ’833 patent, entitled “Propylene glycol-containing
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`peptide formulations which are optimal for production and for use in injection
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`devices.” According to its cover page, the ’833 patent was filed on May 17, 2006 as
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`U.S. Patent Application No. 11/435,977, a continuation application of No.
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`PCT/DK2004/000792, filed on November 18, 2004. U.S. Patent Application No.
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`11/435,977 also claims priority to U.S. Provisional Application No. 60/524,653,
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`filed on November 24, 2003, as well as a Danish application filed November 20,
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`2003.
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`29.
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`I understand that Mylan is challenging claims 1-31 of the ’833 patent
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`as unpatentable. The ’833 patent includes five independent claims: claims 1, 16, 23,
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`26, and 29.
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`30.
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`Independent claim 1 recites:
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`1. A pharmaceutical formulation comprising at least one GLP-1
`agonist, a disodium phosphate dihydrate buffer and propylene
`glycol, wherein said propylene glycol is present in said
`formulation in a final concentration of from about 1 mg/ml to
`about 100 mg/ml and wherein said formulation has a pH of from
`about 7.0 to about 10.0.
`31. Dependent claims 2-15 depend from claim 1. Dependent claims 2-4
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`relate to the concentration of propylene glycol in the formulation. Dependent claims
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`5-7 relate to the pH of the formulation. Dependent claims 8-9 recite that the
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`formulation contains a preservative, and identifies its concentration, respectively.
`
`Dependent claims 10-15 relate to the identity of the GLP-1 agonist.
`
`32.
`
`Independent claim 16 recites:
`
`16. A method of preparing a GLP-1 agonist formulation suitable
`for use in an injection device, said method comprising preparing
`a formulation containing a GLP-1 agonist, propylene glycol, a
`disodium phosphate dihydrate buffer, and a preservative,
`wherein said propylene glycol is present in a concentration from
`about 1 mg/ml to about 100 mg/ml, and wherein said formulation
`has a pH from about 7.0 to about 10.0, and wherein said GLP-1
`agonist, said propylene glycol and said buffer and preservative
`are mixed together to produce said formulation as follows:
`a) preparing a first solution by dissolving preservative, propylene
`glycol and buffer in water;
`
`
`
`
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`-16-
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`b) preparing a second solution by dissolving the GLP-1 agonist
`in water;
`c) mixing the first and second solutions; and
`adjusting the pH of the mixture in c) to a pH of from about 7.0 to
`about 10.0.
`33. Dependent claims 17-22 depend from claim 16. Dependent claims 17-
`
`19 relate to the concentration of propylene glycol in the formulation. Dependent
`
`claims 20-22 relate to the pH of the formulation.
`
`34.
`
`Independent claim 23 recites:
`
`23. A method for reducing deposits on production equipment
`during production of a GLP-1 agonist formulation, said method
`comprising replacing the isotonicity agent previously utilized in
`said formulation with propylene glycol at a concentration of
`between 1-100 mg/ml, and wherein said GLP-1 agonist
`formulation comprises a disodium phosphate dihydrate buffer.
`35. Dependent claims 24 and 25 depend from claim 23. Dependent claim
`
`24 recites that the reduction in deposits is measured by a simulated filling
`
`experiment. Dependent claim 25 recites the group of isotonicity agents that could
`
`be replaced.
`
`36.
`
`Independent claim 26 recites:
`
`26. A method for reducing deposits in the final product during
`production of a GLP-1 agonist formulation, said method
`comprising replacing the isotonicity agent previously utilized in
`said formulation with propylene glycol at a concentration of
`between 1-100 mg/ml, and wherein said GLP-1 agonist
`formulation comprises a disodium phosphate dihydrate buffer.
`
`
`
`
`
`-17-
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`37. Dependent claims 27 and 28 depend from claim 26. Dependent claim
`
`27 recites that the reduction in deposits is measured by the number of vials and/or
`
`cartridges that must be discarded due to deposits. Dependent claim 28 recites the
`
`group of isotonicity agents that could be replaced.
`
`38.
`
`Independent claim 29 recites:
`
`29. A method for reducing the clogging of injection devices by a
`GLP-1 agonist formulation, said method comprising replacing
`the isotonicity agent previously utilized in said formulation with
`propylene glycol at a concentration of between 1-100 mg/ml, and
`wherein said GLP-1 agonist formulation comprises a disodium
`phosphate dihydrate buffer.
`39. Dependent claims 30 and 31 depend from claim 29. Dependent claim
`
`30 recites that the reduction in clogging is measured by a simulated in use study.
`
`Dependent claim 31 recites the group of isotonicity agents that could be replaced.
`
`6.
`
`CLAIM CONSTRUCTION
`
`40.
`
`I understand that the claim terms used in the ’833 patent are to be
`
`understood according to their ordinary and customary meaning in light of the
`
`specification of the patent in which they appear. I further understand that Petitioner
`
`is not seeking to construe differently any terms in the claims of the ’833 patent,
`
`although Petitioner does argue that the preambles of certain claims should be
`
`construed as not limiting the scopes of those claims.
`
`
`
`
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`-18-
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`7.
`
`BACKGROUND
`
`A. GLP-1 Agonists, Including Liraglutide, Were Well Known in the
`Art
`
`41. Human GLP-1 is a 37-amino acid peptide hormone (“GLP-1(1-37)”)
`
`originating from preproglucagon. Processing of preproglucagon, yields two shorter
`
`forms of GLP-1: GLP-1(7-36)amide and GLP-1(1-37). Ex. 1006, 4:17-24. GLP-
`
`1(7-36) and GLP-1(1-37) have the following sequence:
`
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-
`Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-
`Gly-Arg-X
`where X is H2 for GLP-1(7-36) and X is Gly for GLP-1(7-37). Ex. 1006, 4:50-60.
`
`42. By the priority date, GLP-1 agonists were well known in the art. The
`
`’833 patent itself identifies numerous disclosures of prior art GLP-1 agonists. See
`
`Ex. 1001, 4:38-52
`
`(citing WO93/19175, WO99/43705, WO 99/43706,
`
`WO99/43707, WO98/08871, WO02/46227, WO99/43708, WO99/43341,
`
`WO87/06941, WO90/11296, WO91/11457, WO98/43658, EP0708179,
`
`EP0699686, and WO01/98331) (Exs. 1031-1045, respectively); see also Ex. 1006
`
`(U.S. Patent No. 6,268,343) at 268:15-16 (claim 23) (claiming liraglutide).
`
`B.
`
`Parenteral Peptide Dosage Forms
`
`43. Parenteral dosage forms are medicinal preparations that are intended to
`
`be given by injection into subcutaneous or muscular tissues, veins or arteries, joints,
`
`the spinal canal and other routes that are para enteron (Greek for “beside the
`
`
`
`
`
`-19-
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`intestine”). Ex. 1013 at 157-58, 354. In contrast, non-parenteral formulations are
`
`designed to be taken orally, topically, vaginally, via the rectum, and generally routes
`
`that require the medicament to pass through protective mucosal membranes. Ex
`
`1013 at 157-58, 203, 354.
`
`44. A POSA would understand that parenteral dosage forms have
`
`advantages in treating a patient for certain circumstances and conditions. Ex. 1013
`
`at 157-58. For example, oral drugs pass through the stomach and into the intestines
`
`before they are absorbed into the blood, a process that can delay the time at which
`
`therapeutic levels in the blood are reached by as long as several hours. Ex. 1013 at
`
`157-60; Ex. 1012 at 29-39. In contrast, the POSA would know that parenteral dosage
`
`forms are designed for more rapid distribution throughout the body, and
`
`consequently, earlier onset of pharmacological and therapeutic effects. Ex. 1013 at
`
`157-58; Ex. 1012 at 109-11, 247-48. In the case of subcutaneous and intramuscular
`
`routes, the onset of action is not as rapid as intravenous delivery, but generally these
`
`routes still avoid many of the disadvantages of the oral administration. Ex. 1013 at
`
`158; Ex. 1012 at 110-12, 248-50. In addition, the POSA would also know that
`
`parenteral dosages avoid “first-pass” metabolism—the hepatic metabolism and
`
`clearance of drug molecules from the portal venous blood (i.e. blood from gastro
`
`intestinal tract, gall bladder, pancreas and spleen)—which can limit systemic
`
`
`
`
`
`-20-
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`exposure to the drug and precludes the development of some drugs as oral
`
`medicaments. Ex. 1013 at 157, 177-78, 200-01; Ex. 1012 at 41-44, 109-14, 126.
`
`45. The POSA would have also known that parenteral dosage forms offer
`
`similar advantages for peptide-based drugs. Ex. 1053 (Zhou) at 8. Like proteins,
`
`peptide-based drugs are composed of amino acids, which are broken down by gastric
`
`acid and proteolytic enzymes in the gastrointestinal tract when ingested orally,
`
`resulting in the drug being absorbed with other nutrients, eliminating their
`
`therapeutic activity. Id. at 2, 8; Ex. 1013 at 296-303. The POSA would recognize
`
`that delivering a protein or peptide-based drug by parenteral administration would
`
`maximize the amount of drug that reaches the blood, and t