Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LANNETT HOLDINGS, INC
`Petitioner
`v.
`ASTRAZENECA AB
`Patent Owner
`
`of U.S. Patent No. 6,750,237 to Dearn et al.
`
`Title: PHARMACEUTICAL FORMULATIONS CONTAINING ZOLMITRIPTAN
`
`Inter Partes Review No. Unassigned
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`DECLARATION OF SVEINBJORN GIZURARSON, PH.D.
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`TABLE OF CONTENTS
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`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`INTRODUCTION .............................................................................................................. 1
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`MY BACKGROUND AND QUALIFICATIONS ............................................................. 1
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`LIST OF DOCUMENTS I CONSIDERED IN FORMULATING MY OPINION ........... 3
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`PERSON OF ORDINARY SKILL IN THE ART .............................................................. 4
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`THE SPECIFICATION OF THE ‘237 PATENT ............................................................... 5
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`THE CLAIMS OF THE ‘237 PATENT ............................................................................. 5
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`VII.
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`PROSECUTION HISTORY OF THE ‘237 PATENT ....................................................... 9
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`VIII. STATE OF THE ART OF INTRANASAL PHARMACEUTICAL
`FORMULATIONS AS OF DECEMBER 9, 1999. .......................................................... 11
`
`A.
`
`B1.
`
`B2.
`
`C.
`
`D.
`
`E.
`
`F.
`
`Certain triptans, including zolmitriptan, were known for intranasal use .............. 11
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`It was Known to Provide Nasal Formulationsat pH below 7................................ 13
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`It was Known to Provide Triptan Nasal Formulations at pH below 7 .................. 16
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`Buffering of Formulations Intended for Nasal Administration Was Well
`Known ................................................................................................................... 20
`
`Buffering of Formulations Intended for Nasal Administration Using a Mixture
`Containing Disodium Phosphate and Citric Acid Was Well Known .................. 20
`
`Sterility Is Known For Intrnasal Formulations and is Inherent In Formulations
`Intended for A Intranasal Administration to Humans........................................... 22
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`Packaging Intranasal Formulations with Protection Against Light is Known
`and Obvious .......................................................................................................... 22
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`IX.
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`THE CLAIMS OF THE ‘237 PATENT ARE ANTICIPATED AND/OR OBVIOUS.... 23
`
`A.
`
`B.
`
`C.
`
`Anticipation Ground 1: Claims 1 - 8, 13, 15 and 16 Are Anticipated By
`Chauveau et al. ...................................................................................................... 24
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`Anticipation Ground 2: Claims 9, 10 and 13 Are Anticipated By Rudolf et al. ... 29
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`Anticipation Ground 3: Claims 1 and 3 – 15 Are Anticipated By Marquess et
`al. ........................................................................................................................... 30
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`X.
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`GROUNDS BASED ON OBVIOUSNESS ...................................................................... 36
`
`A.
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`B.
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`C.
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`D.
`
`E.
`
`F.
`
`G.
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`H.
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`I.
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`Obviousness Ground 1: Claims 1 - 16 Are Obvious over By Chauveu et al.
`alone and in view of Harris ................................................................................... 36
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`Obviousness Ground 2: Claims 1 - 16 Are Obvious over By Marquee et al.
`alone and in view of Harris ................................................................................... 38
`
`Obviousness Ground 3: Claims 1 - 16 Are Obvious over Rudolf alone and in
`view of Harris ....................................................................................................... 40
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`Obviousness Ground 4: Claims 1 - 16 Are Obvious over Iyengar et al. and in
`view of Watts and/or Harris .................................................................................. 41
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`Obviousness Ground 5: Claims 1 - 16 Are Obvious over Iyengar et al. and in
`view of Watts and/or Clark ................................................................................... 42
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`Obviousness Ground 6: Claims 1 - 16 Are Obvious over Iyengar et al. in
`view of Watts and/or Uda et al. as Evidenced By McIlvane ................................ 43
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`Obviousness Ground 7: Claims 1 - 16 Are Obvious over Oxford in view of
`Clark and in further view of Harris or Remington’s ............................................ 45
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`Obviousness Ground 8: Claims 1 - 16 Are Obvious over Craig in view of
`Johnson alone or in further view of Harris or Remington ................................... 46
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`Obviousness Ground 9: Claims 1 - 16 Are Obvious over Rudolf in view of
`Aikawa and optionally in view of McIlvaine ....................................................... 47
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`I.
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`1.
`
`2.
`
`INTRODUCTION
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`I am over the age of eighteen (18) and otherwise competent to make this declaration.
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`I have been retained as an expert witness on behalf of LANNETT HOLDINGS, INC. (“Lannett”)
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`for the above-captioned Inter Partes Review.
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`3.
`
`I am being compensated for my time in connection with this IPR at my standard consulting rate,
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`which is $350 per hour. I understand that the IPR petition seeks cancellation of claims 1 – 16 of U.S. Patent No
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`6,750,237 to Dearn et al. ("the '237 patent"). I understand that the ‘237 patent resulted from US Application
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`10/129,773 (“the ‘773 application”), filed on November 28, 200 in the United States and alleging an earliest
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`possible priority date (“EPPD”) of December 3, 1999 based on a filing in Great Britain.
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`4.
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`In preparing this declaration, I have reviewed the ‘237 patent and considered each of the
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`documents cited therein, in light of general knowledge in the art as of the earliest possible priority date
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`("EPPD") for the ‘237 patent. In formulating my opinions, I have relied upon my experience, education and
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`knowledge in the relevant art, and I have considered the viewpoint of a person of ordinary skill in the art
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`(“POSITA”) (i.e., a person of ordinary skill in the field of pharmaceutical formulations and in particular
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`pharmaceutical formulations for use in nasal applications) prior to December 3, 1999.
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`II. MY BACKGROUND AND QUALIFICATIONS
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`5.
`
`I am an expert in the field of pharmaceutical formulation and have been since before December
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`1999. I have approximately 25 years of experience in the design of pharmaceutical formulations, including
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`particularly and especially pharmaceutical formulations adapted for administration by the intranasal route.
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`I received my M.Sc. in Pharmacy from the University of Copenhagen in 1986.
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`My M.Sc. thesis was entitled “Drug-protein binding interactions.”
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`I received my Ph.D. in biopharmaceutics from the University of Copenhagen in 1990.
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`
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`6.
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`7.
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`8.
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`9.
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` My Ph.D. thesis was entitled “Intranasal application of insulin. Pharmaceutical and
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`physiological factors affecting successful absorption of insulin..”
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`10.
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` I received in 1994 authorization from the Ministry of Health in Iceland to act as an expert in the
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`field of Clinical Pharmacokinetics and Biopharmaceutic.
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`11.
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`Throughout my career my research interests have included design, formulation, testing and
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`analysis of pharmaceutical products, including particularly products relating to administration of drugs by the
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`nasal route.
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`12.
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`From about 1987 to about 1990 I was a teaching assistant at the University of Copenhagen as a
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`member of the faculty of pharmaceutical sciences (Denmark). I lectured in the topics of bio pharmacy,
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`biopharmaceutical training and drug delivery systems. In about 1991 I became an assistant professor (lector) in
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`pharmaceutical sciences at the University of Iceland, Faculty of Pharmaceutical Sciences. In 1993 I became
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`associate professor (docent) and in 1998 I became full professor (tenure).
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`13.
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` From about 1995 until the present, I have been a member of the patent pending committee in
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`Iceland. As a member of this committee, it is my responsibility to reevaluate patent applications, when the
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`applicant(s) files a formal complaint after the patent application has been rejected.
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`14.
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`In 2002, I participated as a member of an expert committee formed by the United States FDA
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`relating to nose to brain, adverse reactions.
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`15.
`
`From 2006 to about 2010 I was a visiting lecturer at the University of Copenhagen, faculty of
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`pharmaceutical sciences (Denmark) in connection with advanced drug delivery systems.
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`16.
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`I am the author of over 250 publications and presentations on pharmaceutics, intellectual
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`property, dosage forms, intranasal administration of drugs, and similar topics.
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`17.
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`Accordingly, I am an expert in the field of pharmaceutical formulations, including particularly
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`and especially pharmaceutical formulations intended for delivery by the intranasal route, and I have been an
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`expert in this field for many years prior to December, 1999. My full professional background, experience,
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`publications, presentations and other work history is provided in my curriculum vitae (LAN1012).
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`18. My work experience is outlined below:
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`1990-1991 - I was a postdoctoral fellow at the National Institute of Health of Japan in Tokyo,
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`focusing on intranasal delivery of vaccines.
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`1991-2005 - I founded Lyfjathroun Biopharmaceuticals together with several investors, an
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`intranasal R&D company focusing on nasal vaccines and nasal drugs, including triptans such as
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`sumatriptan and zolmitriptan. From 1999 I was the CEO.
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`2005 – present - I have been a consultant for several pharmaceutical companies, focusing on
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`various aspects of intranasal drug delivery, such as Teva (Israel), Roche (USA), Intranasal
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`Therapeutics Int. that became Ikano Therapeutics Int. (USA), Upsher-Smith Laboratories
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`(USA), Alza (Johnson & Johnson) (USA), Schwartz Bioscience (Germany), Novo Nordisk
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`(Denmark) and Kurve Technology (USA).
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`III. LIST OF DOCUMENTS I CONSIDERED IN FORMULATING MY OPINION
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`19.
`
` In formulating my opinions, I have considered the following documents:
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`• The ‘237 patent and its prosecution history
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`• Remington's Pharmaceutical Sciences, Mack 30 Publishing Company, Easton, Pennsylvania,
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`19th Edition, 1995
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`Petition for Inter Partes Review of USPN 6,750,237
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`• Remington's Pharmaceutical Sciences, Mack 30 Publishing Company, Easton, Pennsylvania,
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`17th Edition, 1985.
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`• Remington's Pharmaceutical Sciences, Mack 30 Publishing Company, Easton, Pennsylvania,
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`16th Edition, 1980
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`• The following patents: US 6,344,449 (Rudolf); US Patent 5,482,931 (Harris); WO 97/25988
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`(Iyengar); WO 98/47535 (Watts); US Patent 5,4443,833 (Clark); US Patent 4,504,470 (Uda);
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`WO1998/002186 (Penkler); EP 0636623 (Robertson); WO96/29074 (Johnson); US Patent
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`5,705,520 (Craig); US 4,502,616 (Meierhoefer); Japanese Laid Open Patent Publication No
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`3-115219 (Yano); Japanese Laid Open Patent Publication No 11-255654 (Aikawa); US
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`4,782,047 (Benjamin); US 5,397,771 (Bechgaard et al.); EP 0417930 (Fujioka); EP 0486854
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`(Bolasco); EP 0489217 (Tosi); WO 99/40900 (Alam).
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`• McIlvaine, Journal of Biological Chemistry 49, 183(1921)
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`• Yeh, S-Y, Lach J.L. Stability of Morphine in Aqueous Solution III - Kinetics of Morphine
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`Degradation in Aqueous Solution. Journal of Pharmaceutical Sciences, 1959
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`• Declaration of Dr. Ed Cahill dated November 11, 2005 submitted in US Application
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`10/854959 as a continuation of US Application 10/129,773
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`PERSON OF ORDINARY SKILL IN THE ART
`
`I understand that a POSITA is a hypothetical person presumed to be aware of all pertinent art,
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`IV.
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`20.
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`thinks along conventional wisdom in the art, and is a person of ordinary creativity. A POSITA in
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`pharmaceutical design, formulation and testing, especially for administration by nasal delivery, as of December
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`3, 1999, the EPPD of the '273 patent, would typically have a Bachelors or Master's degree in Pharmacy,
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`Chemistry or a related field with at least 5 years of experience with pharmaceutical design, formulation and/or
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`testing, including design, formulation and testing of pharmaceuticals intended for delivery by nasal
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`administration.
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`21.
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`A POSITA could have a Ph.D. in Pharmaceutics, Chemistry or a related field with 2-3 years of
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`experience with pharmaceutical design, formulation and testing, including for administration by nasal delivery.
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`A POSITA would typically have experience in the analytical characterization of drug formulations, including in
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`vitro testing of drug formulations, including as it relates to formulation stability. A POSITA may work as part
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`of a multi-disciplinary team and draw upon not only his or her own skills, but also take advantage of certain
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`specialized skills of others on the team, to solve a given problem.
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`V.
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`22.
`
`THE SPECIFICATION OF THE ‘237 PATENT
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`I have considered the disclosure and file history of the '273 patent in light of general knowledge
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`in the art as of the EPPD of the '273 patent, namely, December 9, 1999.
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`23.
`
`The ‘273 patent specification is directed generally to allegedly new pharmaceutical formulations
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`and their use in the treatment of disease. (LAN 1001, 1:13-17). The specification indicates that it is more
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`specifically directed to "pharmaceutical formulations of the anti-migraine drug zolmitriptan for nasal
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`application." Id.
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`24.
`
` The ‘273 patent specification indicates that "[t]he present inventors provide a pharmaceutical
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`formulation suitable for intranasal administration which comprises zolmitriptan and a pharmaceutically
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`accepted carrier wherein the pH of the formulation is less than 7.0." (LAN 1001, 2:23-27).
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`THE CLAIMS OF THE ‘237 PATENT
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`The ‘237 patent includes a total of 16 claims, four (4) of which (claims 1, 9, 11 and 15) are
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`VI.
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`25.
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`independent.
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`26.
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`All of the independent claims are directed to pharmaceutical formulations and require only two
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`elements: (1) zolmitriptan and (2) a carrier (claims 1 – 15) or an aqueous solvent (claims 15 and 16). In
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`addition to these elements, the various claims add further limitations on the claims as follows:
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`CLAIM(s)
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`LIMITATION
`
`9
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`pH of the formulation is less than 7.0
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`1, 11 and 15
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`pH of the formulation is 4.5 to 5.5
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`2 (depending from 1) and
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`pH is 5
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`16 (depending from 15)
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`3 and 4 (depending from 1)
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`formulation is buffered
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`9 and 11
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`16
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`zolmitriptan in a buffer
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`9 and 11
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`the formulation is buffered by a
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`mixture of citric acid and disodium
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`phosphate.
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`5 – 8 (depending from 1)
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`formulation is sterile
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`CLAIM(s)
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`LIMITATION
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`10 (depending from 9)
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`12 (depending from 11)
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`13 (multiple dependent)
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`14 (depending from 13)
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`intranasal administration device
`containing the formulation
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`the formulation is packaged to be
`protected from light
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`27.
`
`As of the EPPD, compounds of the class known of triptans, including sumatriptan and
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`zolmitriptan, were known to a POSITA as compounds useful for treating migraine headaches.
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`28.
`
` As disclosed in LAN 1005 at page 50, zolmitriptan has the following basic chemical structure:
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`There is nothing in the specification or prosecution history of the ‘237 patent which suggests that the term
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`zolmitriptan used in the claims has a special meaning, and accordingly a POSITA would understand this term
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`to have the ordinary and accustomed meaning, which would be ordinarily understood to include
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`pharmaceutically active variations thereof, including ionically and covalently bonded variations of the above
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`structure which maintain zolmitriptan’s pharmaceutical activity in the formulation. This meaning is consistent
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`with the manner in which the term is used in the specification of the ‘237 patent. For example, the ‘237 patent
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`describes the preparation of zolmitriptan formulations according to one embodiment as follows:
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`The pharmaceutical formulations of this invention may be prepared by dissolving
`zolmitriptan in an acidic medium, for example aqueous citric acid, thereby
`forming the citrate salt of zolmitriptan...
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`(LAN 1001, 3:8-13). Thus, the term "zolmitriptan" would be understood by the POSITA as including
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`zolmitriptan per se and zolmitriptan ionically and/or covalently bonded to other atoms or compounds in such a
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`way as to preserve the pharmaceutical activity of the compound, and would specifically include zolmitriptan
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`citrate.
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`29.
`
`As of the EPPD, dissodium phosphate was a known compound having many uses and having the
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`following general structure:
`
`
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`This compound is also known by several other names, including: sodium hydrogen phosphate; disodium
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`hydrogen orthophosphate; sodium phosphate dibasic; and dibasic sodium phosphate. There is nothing in the
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`specification or prosecution history of the ‘237 patent which suggests that the term dissodium phosphate as
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`used in the claims has a special meaning, and accordingly a POSITA would understand this term to have the
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`ordinary and accustomed meaning as stated above.
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`30.
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`As of the EPPD, the terms “buffer” and “buffered” and “in a buffer” were understood by a
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`POSITA to refer to the ability of a pharmaceutical formulation, including particular formulations which include
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`aqueous solutions, to resist a change in pH on adding acid or alkali or on dilution with solvent. This meaning is
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`reflected, for example, in Remington’s 1995 edition. (LAN 1006, I:225). There is nothing in the specification
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`or prosecution history of the ‘237 patent which suggests that the terms “buffer” and “buffered” and “in a
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`buffer” as used in the claims has a special meaning, and accordingly a POSITA would understand these terms
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`to have their ordinary and accustomed meaning as stated above.
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`31.
`
`A POSITA would have understood that the remaining terms used in the claims of the ‘237
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`patent are plain on their face. Thus, I have given the other terms their plain and ordinary meaning under a
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`broadest reasonable interpretation in light of the specification.
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`VII. PROSECUTION HISTORY OF THE ‘237 PATENT
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`32.
`
`The ‘237 patent, which issued on June 15, 2004, was filed on August 28, 2002, as U.S.
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`Application No. 10/129,773 ("the '773 application"). The ‘773 application is the U.S. national stage entry of
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`International Application No. PCT/GB00/04528 (“the PCT application”), filed November 28, 2000, which
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`claims priority from Great Britain Patent Application No. 9928578.5, filed on December 3, 1999. The ‘237
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`patent is assigned on its face to AstraZeneca AB.
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`33.
`
`The as-filed PCT application had 14 claims, of which claims 1 and 6-14 were independent. The
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`as-filed '773 application had 20 claims, of which claims 1 and 13-20 were independent.
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`34.
`
`In an Office Action mailed August 26, 2003, the U.S. Patent and Trademark Office (“PTO”)
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`stated that 14 claims were pending in the application, claim 12 was allowed, claims 1-4, 11, 13, and 14 were
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`rejected, and claims 5-10 were objected to. Specifically, claim 12 was allowed because the PTO alleged that the
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`prior art did not teach or suggest the instant composition/solution comprising disodium phosphate, or the
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`instant composition/solution buffered at a pH of 4.5 to 5.5; claims 13 and 14 were rejected under 35 U.S.C. §
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`102(b) as being anticipated by Robertson et al. (European Patent Application Publication No. 0636623,
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`hereinafter “Robertson”); claims 13 and 14 were also rejected under 35 U.S.C. § 102(b) as being anticipated by
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`Penkler et al. (PCT Application No. PCT/GB97/01872, hereinafter “Penkler”); claims 1, 3, and 11 were
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`rejected under 35 U.S.C. § 103(a) as being obvious in view of Robertson; claims 1, 3, and 11 were also rejected
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`under 35 U.S.C. § 103(a) as being obvious in view of Penkler; claims 5-10 were objected to under 37 CFR
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`1.75(c), and thus were not treated on the merits, as being in improper form because a multiple dependent claim
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`cannot depend from another multiple dependent claim; and claims 2 and 4 were objected to as being dependent
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`upon a rejected base claim, but would be allowable if rewritten in independent form to include all of the
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`limitations of their base claim.
`
`35.
`
`On November 28, 2003, the Applicants filed remarks stating that claims 1-20 were pending, and
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`the Applicants alleged that the PTO appeared to have examined the 14 claims of the PCT application rather
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`than the 20 claims of the ‘773 application. Further, Applicants canceled claims 14, 17, 19, and 20, added new
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`claim 21, and amended claims 1, 2, 5, 6, 15, 16, and 18. Specifically, the Applicants amended claim 1 to
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`incorporate the claim language of the allowed claim 12 of the PCT application, i.e., a formulation in the pH
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`range of 4.5 to 5.5, thus overcoming the rejection 35 U.S.C. § 103(a) over Robertson or Penkler; Applicants
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`noted that claims 5-10 in the PCT application had been rewritten or canceled in the ‘773 application, thus
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`overcoming the PTO’s objection to those claims; Applicants submitted that claims 13 and 14 of the PCT
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`application, allegedly anticipated by Robertson or Penkler, had been canceled; Applicants alleged that claim 18
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`of the ‘773 application corresponded to claim 12 of the PCT application, and thus was allowable; and
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`Applicants asserted that new claim 21 was a dependent claim of claim 18 of the ‘773 application.
`
`36.
`
`37.
`
`
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`On February 27, 2004, the PTO mailed a Notice of Allowance, allowing all pending claims.
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`The ‘773 application issued on June 15, 2004, as U.S. Patent No. 6,750,237.
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`VIII. STATE OF THE ART OF INTRANASAL PHARMACEUTICAL
`FORMULATIONS AS OF DECEMBER 9, 1999.
`
`A.
`
`Certain triptans, including zolmitriptan, were known for intranasal use
`
`38.
`
`As of the EPPD, compounds of the class known of triptans, including sumatriptan and
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`zolmitriptan, were known to a POSITA as compounds useful for treating migraine headaches. At the time of
`
`the EPPD, although the group of compounds that were within the group of triptans generally, there were a
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`relatively small number of triptans that were well known for treating migrane headaches. For example,
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`WO1998/002186, issued to Penkler (LAN1014), published on January 22, 1998 and generally discloses the
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`following group of six (6) triptans as being useful for the treatment of migranes: sumatriptan; naratriptan,
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`rizatriptan, zolmitriptan, eletriptan and almotriptan. (LAN 1014, 1: 3 – 7). (emphasis added). Furthermore,
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`Penkler discloses that such triptans can be contained in pharmaceutical compositions “…particularly for oral or
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`nasal mucosal delivery.” (LAN 1014, 1: 3 – 7).
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`39.
`
`Another example of disclosure in the prior art of zolmitriptan for nasal formulations is EP
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`0636623 issued to Robertson (LAN1015), which published on February 1, 1995. Robertson, like Penkler,
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`generally describes compositions and formulations relating to indole derivatives as 5-HT-1 agonists for the
`
`prophylaxis and treatment of migraine. (LAN 1015, 4:13 - 22). Robertson discloses N,N-dimethyl-2-[5-(2-oxo-
`
`1
`
`,3-oxazolidin-4-yl-methyl)-1 H-indol-3-yl]ethylamine, which
`
`is an alternative chemical name for
`
`zolmitriptan, and physiologically acceptable salts thereof. Id. In addition, zolmitriptan is disclosed as being one
`
`of two triptans “having exceptional properties for the treatment and prohylaxis of migraine.” (Id.). Robertson
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`teaches intranasal application of formulations comprising these compounds. (LAN 1015, 5:2-5)
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`40. WO96/29074 in the name of Johnson (LAN 1018), which was published in 1996, also is related
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`to compounds and formulations containing active compounds that are known as 5-HT agonists that can be used
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`to help in the treatment of migraines, among other disorders. (LAN 1018, 2:1– 4). Johnson references certain
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`triptans as being effective in this regard as follows:
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`[Subtype-selective] compounds are especially preferred in the methods of the present
`invention.
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`One example of such a compound is sumatriptan, a compound having the structure
`
`
`
`and the chemical name, 342-(dimethylamino)ethyll-N-methy1-1Hindole-5-
`methanesulfonaraide. This compound …[s]umatriptan is selective for the 5-HT1 receptor
`subtypes.
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`An additional serotonin agonist which is specific for the 5-HT1 class of receptors is:
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`
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`having the designation 311C90 and the chemical name (S)-41[342-
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`(dimethylamino)ethy11-1H-indo1-5-yllmethy11-2-oxazolidinone.
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`(LAN 1018, 10:12 – 11:8)
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`41.
`
`This second of the two molecules identified by Johnson above is zolmitriptan. Thus, Robertson
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`and Johnson illustrate that sumatriptan and zolmitriptan have very similar molecular structures and share
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`similar pharmaceutical activity for the treatment of migraine headaches and, are identified as preferred
`
`compounds of the invention. Johnson also discloses that
`
`These compositions can be administered by a variety of routes
`including…intranasal. …Such compositions are prepared in a manner
`well known in the pharmaceutical art and comprise at least one active.
`See. e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16th 15
`ed. 1980).
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`42.
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`Another example is US Patent 5,705,520 – Craig (LAN 1019), which was patented in 1998 and
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`discloses the use of sumatriptan (“3-[2-(dimethylamino)ethyl-N-methyl-1H-methanesulphonamide sulphate salt
`
`(2:1)” for migraine treatment. Craig discloses that sumatriptan is particularly preferred for “intranasal
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`administration.” (LAN 1019, 1:34-39).
`
`43.
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`Intranasal pharmaceutical formulations containing zolmitriptan are also disclosed in each of the
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`following items which were published before, filed before and/or patented before the ‘237 patent: US Patent
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`6,326,401 - Chauveu et al (LAN 1004A); WO 99/64044 - Marquess (LAN 1005); US 6,344,449 - Rudolf (LAN
`
`1007); WO 97/25988 - Iyengar (LAN 1009). Intranasal formulations based on sumatriptan (“3-[2-
`
`(dimethylamino)ethyl-N-methyl-1H-methanesulphonamide”) are also disclosed in US 5,037,845 – Oxford
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`(LAN 1029).
`
`B1.
`
`It was Known to Provide Nasal Formulationsat pH below 7
`
`44.
`
`It was generally known and accepted at the time of EPPD that pharmaceutical formulations for
`
`intranasal administration should be formulated with pH values less than 7.
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`45.
`
`For example, Remington's Pharmaceutical Sciences, Mack 30 Publishing Company,
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`Easton, Pennsylvania, 19th Edition, 1995 (LAN 1006) states that:
`
`Nasal solutions are prepared so that they are similar in many respects to nasal
`secretions, so that normal ciliary action is maintained. Thus, the aqueous nasal
`solutions usually are isotonic and slightly buffered to maintain a pH of 5.5 to
`6.5.
`
`
`
`(LAN 1006, Vol II:1502) (emphasis added).
`
`46.
`
`In addition to adjusting the pH of nasal formulations to be consistent with and relatively non-
`
`irritating to the nasal cavity, it was known that the pH of formulations should be adjusted to values below 7 in
`
`order to enhance the stability of the formulations. This concept was well known in the art at the time of the
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`EPPD, as illustrated for example by the following teaching from US 5,443,883 issued to Clark in 1995 (LAN
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`1011) relating to formulations intended for intranasal administration:
`
`Although physiological pH is about 7.4, we prefer the pH of the solution to be in the
`range 3.5 to 6, preferably 4 to 5.5. In this range of pH, the stability of the solution is
`enhanced, surprisingly with no deleterious effects such as undue tissue irritation.
`
`
`(LAN 1011, 3:61-65)
`
`47.
`
`Another example of the accepted use of pH below 7 for nasal formulations is provided in
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`Japanese Laid Open Patent Publication No 3-115219 in the name of Yano (“Yano”, LAN 1021(including the
`
`English language translation thereof), which was laid open on May 16, 1991. Yano discloses nasal
`
`formulations having denopamine as an active ingredient and indicates that “pH of the formulation is preferably
`
`in a range of 4 to 6.” (LAN 1021, 3:¶4).
`
`48.
`
`Another example of the accepted use of pH below 7 for nasal formulations is provided in
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`Japanese Laid Open Patent Publication No 11-255654 in the name of Aikawa (“Aikawa”), LAN 1022
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`(including the English language translation thereof), which was laid open on September 21, 1999. Aikawa
`
`discloses nasal formulations having a “buffer solution having a pH of 3-6…[that] has the capability of
`
`regulating and keeping the pH of nasal mucus on the nasal mucous membrane in a slightly acidic condition.”
`
`(LAN 1022, 6:¶0009).
`
`49.
`
`Another example of the accepted use of pH below 7 for nasal formulations is provided in US
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`4,782,047 to Benjamin, which issued November 1, 1988 (“Benjamin”, LAN 1023). Benjamin discloses a
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`“…stable, preservable, substantially non-stinging aqueous anti-inflammatory steroid formulation suitable for
`
`nasal administration…” (LAN 1023, 1:63 – 65). The formulation is disclosed as having a pH of “between
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`about 3.5 and about 7…” (LAN 1023, 2:8 – 12). A preferred species is described as “the nonstinging aqueous
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`Declaration of Sveinbjorn Gizurarson
`Petition for Inter Partes Review of USPN 6,750,237
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`anti-inflammatory steroid formulation suitable for nasal administration… wherein the pH of the resulting
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`solution is adjusted to about 5.2.” (LAN 1023, 2:28–46).
`
`50.
`
`Another example of the accepted use of pH below 7 for nasal formulations is provided in US
`
`5,397,771 to Bechgaard et al., which issued March 14, 1995 (“Bechgaard”, LAN 1024). Bechgaard discloses
`
`the preferred use of “…carrier compositions…in pharmaceutical preparations for systemic administration
`
`through the mucosa of the nose…e.g. as a nasal spray.” (LAN 1024, 9:1 -5). The examples indicate that the
`
`compositions are “…adjusted to a pH in the physiological range of 4 – 7.5 using phosphate buffer.” LAN
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`1024, 32:41-47).
`
`51.
`
`Another example of the accepted use of pH below 7 for nasal formulations is provided in EP
`
`0417930 to Fujioka et al., which published March 20, 1991 (“Fujioka”, LAN 1025). Fujoika discloses nasal
`
`formulations which have a preferred pH of from “2 to 7 in consideration of the stability of [the active]” (LAN
`
`1025, 3:37 – 38). Examples 1 – 7 are all nasal preparations which have the pH of the formulation adjusted to 5.
`
`52.
`
`Another example