UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.
`Petitioner
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`v.
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`3M COMPANY et al.
`Patent Owner
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`Case IPR2015-02002
`Patent 6,743,413
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`PATENT OWNER 3M COMPANY’S
`RESPONSE
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`I. 
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`II. 
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`Case IPR2015-02002
`Attorney Docket No: 26368-0021IP1
`TABLE OF CONTENTS
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`INTRODUCTION ................................................................................ 1 
`
`BACKGROUND .................................................................................. 4 
`
`A. 
`
`In December 1991, There Were Two Types of Aerosol
`Formulations for Metered Dose Inhalers: Solution Aerosol
`Formulations and Suspension Aerosol Formulations ................ 5 
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`B. 
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`C. 
`
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`D. 
`
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`E. 
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`B. 
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`C. 
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`III.  THE ‘413 PATENT ............................................................................ 14 
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`IV.  CLAIMS 14-19 AND 22-24 ARE PATENTABLE OVER THE ‘011
`PCT APPLICATION .......................................................................... 16 
`
`A. 
`
`Suspension Aerosol Formulations are Physically Unstable
`Systems ....................................................................................... 7 
`
`Replacing CFC Propellants in Aerosol Formulations Was
`Challenging ................................................................................ 9 
`
`Formulators Believed That Suspensions Containing Only HFA
`134a and Drug Were Not Sufficiently Stable for Therapeutic
`Use ............................................................................................ 12 
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`Formulators Tried to Prepare Stable Suspensions with HFA
`134a by Adding Surfactants and/or Co-Solvents ..................... 13 
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`The only suspension formulations the ‘011 PCT application
`teaches as suitable for treating patients contain HFA 134a and
`surfactant-coated drug particles ............................................... 17 
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`The ‘011 PCT application’s teaching regarding surfactants is
`consistent with the understanding in the art in December 1991
`that suspension formulations containing only HFA 134a and
`drug were not therapeutically useful ........................................ 19 
`
`The controls of Formulations 7 and 8 of the ‘011 PCT
`application that lacked surfactant would not have taught a
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`Case IPR2015-02002
`Attorney Docket No: 26368-0021IP1
`formulator to treat patients with suspensions containing only
`HFA 134a and drug .................................................................. 22 
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`1.  A formulator would not have drawn conclusions regarding
`the therapeutic usefulness of Control Formulations 7 and 8
`based upon the Drug Deposition Potential (DDP) metric used in
`Example 1 ................................................................................. 23 
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`2.  Dr. Smyth’s statistical analysis of Formulations 7 and 8 is
`flawed ....................................................................................... 25 
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`3.  The only purpose of the controls in Example 1 of the ‘011
`PCT application is to establish a baseline for assessing the
`surfactant-containing test formulations .................................... 27 
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`The ‘011 application does not anticipate claims 14-19 and 22-
`24 .............................................................................................. 30 
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`The ‘011 PCT application does not render claims 14-19 and 22-
`24 obvious ................................................................................ 32 
`
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`D. 
`
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`E. 
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`CLAIMS 14-19 AND 22-24 ARE PATENTABLE OVER THE ‘333
`PCT APPLICATION .......................................................................... 36 
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`A. 
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`The ‘333 PCT application does not suggest that suspension
`formulations containing only HFA 134a and drug would have
`been therapeutically useful ....................................................... 40 
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`B.  Dr. Smyth’s declaration is flawed because he mischaracterized
`the ‘333 PCT application ......................................................... 42 
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`V. 
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`C.  A person of ordinary skill would read the ‘333 PCT application
`in the context of the state of the art, which taught that
`suspension formulations containing only HFA 134 and drug
`were not therapeutically useful ................................................ 43 
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`D.  Mylan ignores the state of the art ............................................. 44 
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`VI.  CONCLUSION .................................................................................. 45 
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`Case IPR2015-02002
`Attorney Docket No: 26368-0021IP1
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`LIST OF EXHIBITS
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`EX. 2004
`EX. 2005
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`EX. 2006
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`EX. 2007
`EX. 2008
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`EX. 2009
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`EX. 2010
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`Exhibit No. Description
`EX. 2001
`Johnson et al., U.S. 5,126,123 (“the Johnson ‘123 patent”)
`EX. 2002
`WO93/11743
`EX. 2003
`“CFC-Free Aerosols-The Final Hurdle,” Manufacturing
`Chemist, 63(7):22-23 (1992) (“Manufacturing Chemist”)
`Purewal et al., U.S. 5,225,183 (“the Purewal ‘183 patent”)
`Dalby, “Special Considerations in the Formulation of
`Suspension Type Metered Dose Inhalers,” Aerosol Age
`(Oct. 1990) (“Aerosol Age”)
`“Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations”,
`http://www.accessdata.fda.gov/scripts/cder/ob/newobpat.cf
`m (12/28/15)
`Statutory Disclaimer
`Sheila D’Souza, The Montreal Protocol and Essential Use
`Exemptions, J. Aerosol Med., 8 (Suppl 1): S13–S17 (1995).
`Richard N. Dalby et al., CFC Propellant Substitution: P-
`134a as a Potential Replacement for P-12 in MDIs, Pharm.
`Tech., March 1990 at 26.
`Richard N. Dalby et al., Medical Devices for the Delivery of
`Therapeutic Aerosols to the Lungs, in Inhalation Aerosols
`441 (1996).
`Declaration of Richard N. Dalby, Ph.D.
`Curriculum vitae of Richard N. Dalby, Ph.D.
`Excerpts from the prosecution history of EP 0493437
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`EX. 2011
`EX. 2012
`EX. 2013
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`EX. 2014
`EX. 2015
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`EX. 2016-
`2020
`EX. 2021
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`EX. 2022
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`EX. 2023
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`EX. 2024
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`Case IPR2015-02002
`Attorney Docket No: 26368-0021IP1
`Transcript of the deposition of Dr. Hugh Smyth (6/14/16)
`Boring, Edwin G. 1954. “The Nature and History of
`Experimental Control.” The American Journal of
`Psychology, 67(4):573-589 (“Boring”).
`Reserved
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`Crowder et al., “2001: An Odyssey In Inhaler Formulation
`and Design,” Pharmaceutical Technology, 99-113 (July
`2001).
`Smyth et al., “Alternative Propellant Aerosol Delivery
`Systems,” Critical Reviews™ in Therapeutic Drug Carrier
`Systems, 22(6):493–534 (2005),
`Smyth, “The Influence of Formulation Variables on the
`Performance of Alternative Propellant Driven Metered-Dose
`Inhalers,” Advanced Drug Delivery Reviews, 55:807-828
`(2003).
`Smyth, “Tuning Aerosol Particle Size Distribution of
`Metered-Dose Inhalers Using Cosolvents and Surfactants,”
`BioMed Research International, vol. 2013, pp. 1-7 (2013).
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`Case IPR2015-02002
`Attorney Docket No: 26368-0021IP1
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`I. INTRODUCTION
`U.S. Patent No. 6,743,413 (“the ‘413 patent”) claims methods of treating
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`patients suffering from, e.g., asthma or chronic obstructive pulmonary disease
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`(“COPD”), by administering a suspension aerosol formulation containing only
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`drug and the propellant HFA 134a (1,1,1,2-tetrafluoroethane). Before December
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`1991,1 persons of skill in the art believed that suspension formulations containing
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`only drug and HFA 134a were not sufficiently stable for use in pressurized metered
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`dose inhalers (“MDI’s”). The ‘413 patent reflects the inventors’ surprising
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`discovery that suspension formulations containing only drug and HFA 134a could
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`satisfactorily treat patients.
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`Claims 14-19 and 22-24 of the ‘413 patent are method of treatment claims.
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`These claims are listed in the FDA’s Orange Book for FLOVENT® HFA,
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`ADVAIR® HFA, and Ventolin® HFA. EX. 2006. The Board granted Mylan’s
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`petition at to claims 14-19 and 22-24 on the basis of two references: WO
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`1991/004011 (“the ‘011 PCT application;” EX. 1007) and WO 1990/007333 (“the
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`‘333 PCT application;” EX. 1011).
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`1 December 18, 1991 is the earliest filing date of the ‘413 patent. However, 3M’s
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`characterization of the state of the art, supported by Dr. Dalby’s testimony and
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`contemporaneous documents, applies even if the ‘413 patent claims are entitled
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`only to a filing date of May 4, 1992. See Dalby Decl’n (EX. 2011), ¶ 9.
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`Case IPR2015-02002
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`The Board concluded that on the basis of the record before it, Mylan had
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`established a reasonable likelihood that claims 14-19 and 22-24 were unpatentable
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`under 35 U.S.C. §§ 102 and 103 over the ‘011 PCT application. In its Decision,
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`the Board focused exclusively on two surfactant-free experimental control
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`formulations shown in Example 1 of the ‘011 PCT application. Institution
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`Decision, Paper No. 8, pp. 14-18.
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`The Board also concluded, on the basis of the record before it, that Mylan
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`had established a reasonable likelihood that claims 14-19 and 22-24 were
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`unpatentable under 35 U.S.C. § 103 over the ‘333 PCT application. The Board
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`stated that the ‘333 PCT application disclosed a limited number of possible
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`formulations for treating patients, including formulations lacking surfactants and
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`co-solvents. Id., pp. 23-25.
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`The Board did not have any expert testimony from 3M when it rendered its
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`decision. 3M now submits the declaration of Richard Dalby, Pharm.D. (EX.
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`2011). Dr. Dalby is a leading expert in the field respiratory drug delivery systems,
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`including MDI’s. See Dalby Decl’n (EX. 2011), ¶¶ 1-8. Mylan’s expert, Dr.
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`Smyth, agreed that Dr. Dalby is well-qualified to comment on the state of the art as
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`it existed before December 1991. Smyth Deposition Transcript (EX. 2014),
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`118:13 – 119:1. Dr. Dalby was actively engaged in MDI-related research and
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`development during that time period. Dr. Dalby also published a number of key
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`papers discussing the substitution of HFA propellants for CFC propellants in
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`MDI’s. See Dalby Decl’n (EX. 2011), ¶¶ 2-5; Dalby curriculum vitae (EX. 2012).
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`Dr. Dalby places the ‘413 patent invention, as well as the ‘011 and ‘333 PCT
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`applications, in technical and historical context by reviewing the state of the art
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`before December 1991. Dalby Decl’n (EX. 2011), ¶¶ 10-28. Viewed in proper
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`context, both the ‘011 and ‘333 PCT applications are consistent with formulators’
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`belief in December 1991 that suspension formulations containing only HFA 134a
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`and drug were not sufficiently stable for therapeutic use. See Arkie Lures, Inc. v.
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`Gene Larew Tackle, Inc., 119 F.3d 953, 958 (Fed. Cir. 1997) (“The evidence that
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`the combination was not viewed as technically feasible must be considered, for
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`conventional wisdom that a combination should not be made is evidence of
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`unobviousness.”)
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` Mylan’s expert, Dr. Smyth, ignored the state of the art as of December
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`1991. Instead, Dr. Smyth improperly viewed the ‘011 and ’333 PCT applications
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`in a vacuum. See Shire LLC v. Amneal Pharms., LLC, 802 F.3d 1301, 1308 (Fed.
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`Cir. 2015) (“Thus, read in context, a person of skill in the art would not have any
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`reason to specifically select [the claimed compound]”).
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`Dr. Dalby’s testimony, which is consistent with contemporaneous evidence
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`in the form of patents and publications, contradicts Dr. Smyth. The evidence
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`exposes Mylan’s arguments as unsupported hindsight reconstructions guided by
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`the ‘413 patent itself. See In re Cyclobenzaprine Hydrochloride Extended-Release
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`Capsule Patent Litig., 676 F.3d 1063, 1070-71 (Fed. Cir. 2012) (cautioning against
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`“hindsight claims of obviousness”).
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`II. BACKGROUND
`The ‘011 and ‘333 PCT applications must be read in the context of the state
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`of the art existing in December 1991. Dr. Dalby supplies this crucial context.
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`Dr. Dalby explains that before the ‘413 patent’s effective filing date,
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`formulators believed that if a suspension formulation flocculated quickly, resulting
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`in drug inhomogeneity, the suspension formulation was unsatisfactory for treating
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`patients. Id., ¶¶ 21-23. With the objective of maintaining drug homogeneity for
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`an extended period of time in mind, Dr. Dalby then describes the challenges
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`formulators faced when attempting to substitute HFA propellants such as HFA
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`134a for existing CFC propellants in MDI’s. Id., ¶¶ 24-28.
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`Dr. Dalby notes that in December 1991, CFC-based suspension formulations
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`known to be safe and effective for therapeutic use were physically stable, meaning
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`that the drug particles remained homogeneously distributed for some extended
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`period of time following shaking. Id., ¶¶ 17 and 20. The same was not true of
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`HFA 134a-based suspensions, at least in part because surfactants typically included
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`in CFC formulations to stabilize the suspension were poorly soluble in HFA 134a.
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`Id., ¶ 18.
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`Before the ‘413 patent, formulators tried a number of approaches to prepare
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`stable HFA 134a-containing suspensions. Id., ¶¶ 25-28. These approaches
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`included using new surfactants that were soluble in HFA 134a; pre-coating
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`conventional surfactants that were insoluble in HFA 134a onto the drug particles
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`before dispersing the drug particles in HFA 134a; adding a co-solvent that could
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`dissolve conventional surfactants; and blending HFA 134a with one or more CFC
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`propellants. Id. Importantly, as Dr. Dalby points out, formulators rejected
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`suspension formulations containing only HFA 134a and drug because these
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`suspensions failed to re-create the appearance and performance of CFC-based
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`formulations known to be safe and effective for therapeutic use. Id., ¶¶ 24-25.
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`A. In December 1991, There Were Two Types of Aerosol Formulations
`for Metered Dose Inhalers: Solution Aerosol Formulations and
`Suspension Aerosol Formulations
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`A metered-dose inhaler (MDI) is a handheld device designed to deliver a
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`specific amount of medication in aerosol form. Dalby Decl’n (EX. 2011), ¶ 11. A
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`MDI consists of a liquefied propellant-pressurized canister sealed with a metering
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`valve that is attached to a plastic actuator incorporating a mouthpiece. Id. To use
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`an MDI, the patient presses on the base of the canister to discharge a metered dose
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`from the valve. Id. The dose exits the mouthpiece and is inhaled into the lungs.
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`Id.
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`As of December 1991, pharmaceutical aerosol formulations for MDI’s fell
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`into two categories: (1) solution formulations and (2) suspension formulations.
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`Dalby Decl’n (EX. 2011), ¶ 12; Aerosol Age (EX. 2005), p. 22 (“There are
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`basically two types of metered dose inhaler formulations available today. Those in
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`which the active constituent is dissolved, and those in which it is suspended.”).
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`Solution formulations for MDI’s included a propellant and a drug. The drug
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`dissolved in the propellant. Dalby Decl’n (EX. 2011), ¶ 12; Aerosol Age (EX.
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`2005), p. 22. Sometimes an adjuvant, also known as a co-solvent, was included to
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`aid solubilization of the drug. Aerosol Age (EX. 2005), p. 22. Surfactants also
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`could be included in solution formulations to aid solubilization. See the Purewal
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`‘183 patent (EX. 2004), 3:1-9 (“The presence of large amounts of solubilised
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`surfactant may also assist in obtaining stable solution formulations of certain
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`drugs.”).
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`In suspension formulations for MDI’s, substantially all of the drug was
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`suspended as fine particles in the propellant, rather than dissolved in the propellant.
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`Dalby Decl’n (EX. 2011), ¶ 12; the Johnson ‘123 patent (EX. 2001), 1:21-24
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`(“One widely used method for dispensing such an aerosol drug formulation
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`involves making a suspension formulation of the drug as a finely divided powder
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`in a liquefied gas known as a propellant.”).
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`B. Suspension Aerosol Formulations are Physically Unstable Systems
`Suspension formulations containing only drug and propellant are inherently
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`physically unstable systems. Dalby Decl’n (EX. 2011), ¶ 13; Banker (EX. 1015),
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`p. 3. Aggregated, flocculated, or discrete drug particles can float to the surface of
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`the propellant or sink to the bottom of the canister. Dalby Decl’n (EX. 2011), ¶ 13.
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`Whether a particle sinks or floats depends on its density relative to the liquefied
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`propellant. Id. Generally, the larger the aggregate, the floccule, or the discrete
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`particle, the more quickly the mass will either float to the top or sink to the bottom.
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`Id.; Aerosol Age (EX. 2005), p. 26.
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`Dr. Dalby explains that as of December 1991, formulators believed that
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`suspension aerosol formulations that flocculated quickly after shaking, resulting in
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`drug inhomogeneity, were unsatisfactory for treating patients. Dalby Decl’n (EX.
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`2011), ¶ 21. Formulators believed that if a formulation flocculated quickly, the
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`MDI would not reliably deliver the target dose of medication to the patient. Id.
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`As Dr. Dalby further explains, suspensions in which the particles quickly
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`floated to the top or sunk to the bottom displayed a non-uniform concentration of
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`medication throughout the liquefied formulation. Id. Formulators believed the
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`non-uniform concentration of medication presented an obstacle to achieving
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`reproducible dosing because the valve of the MDI extracts a specific volume of
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`formulation from the bottom. Id. The product of the valve volume and the
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`concentration of drug in the formulation (in the vicinity of the valve) determines
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`the nominally emitted dose. Id. Dr. Smyth agreed that suspension stability is
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`critical to MDI performance. Smyth Deposition Transcript (EX. 2014), 71:12-22.
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`To create a stable, homogeneous, aerosol suspension, formulators typically
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`dissolved a surfactant in the propellant to prevent the drug particles from
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`agglomerating or flocculating. See Dalby Decl’n (EX. 2011), ¶ 18. For example,
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`the Johnson ‘123 patent (EX. 2001) explains:
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`To minimize or prevent the problem of aggregation of fine particles,
`compounds known as surface active agents, or surfactants, are used to
`coat the surfaces of the fine particles and assist in wetting the particles
`with an aerosol propellant. The use of surfactants in this way to
`maintain substantially uniform suspensions is said to “stabilize” the
`suspensions. An ideal surfactant should have a relative high affinity
`for the suspended drug formulation and be chemically and physically
`compatible with the propellant as well as the drug formulation. If it
`does not have these properties, the surfactant can possibly destabilize
`the suspension. Additionally, it must be essentially nontoxic.
`Id., 1:59 to 2:3.
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`Surfactants were also included to lubricate the valve in MDI’s containing
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`suspension formulations. See, e.g., Dalby Decl’n (EX. 2011), ¶ 18; Aerosol Age
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`(EX. 2005), p. 34 (“adequate valve lubrication and reduction of inter-particulate
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`aggregation must be provided by surfactants incorporated into the [suspension]
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`formulation”); WO 93/11743 (EX. 2002), p. 2 (“Surfactants are generally
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`recognized by those skilled in the art to be essential components of aerosol
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`formulations, required not only to reduce aggregation of the medicament but also
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`to lubricate the valve employed, thereby ensuring consistent reproduction of valve
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`actuation and accuracy of dose dispensed.”). Conventional surfactants used in
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`aerosol suspension formulations included sorbitan trioleate (SPAN 85), oleic acid,
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`and lecithins. See, e.g., the Purewal ‘183 patent (EX. 2004), 5:15-44.
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`C. Replacing CFC Propellants in Aerosol Formulations Was
`Challenging
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`As of December 1991, MDI’s contained chlorofluorocarbon (“CFC”)
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`propellants. See Dalby Decl’n (EX. 2011), ¶ 14; the Johnson ‘123 patent (EX.
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`2001), 2:4-16. CFC propellants were well-suited to suspension formulations
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`because conventional surfactants are soluble in CFC propellants. See Dalby
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`Decl’n (EX. 2011), ¶ 18. However, scientists became concerned that CFC’s were
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`depleting the ozone layer. Dalby Decl’n (EX. 2011), ¶ 14; the Johnson ‘123 patent
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`(EX. 2001), 2:16-18. The Montreal Protocol, an international treaty signed in
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`1987, called for a series of decreasing limits on CFC use and production. Dalby
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`Decl’n (EX. 2011), ¶ 15.
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`Because of the impending phase-out of CFC’s, formulators attempted to
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`develop formulations with propellants other than CFC’s that replicated the
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`appearance and performance of CFC-based formulations known to be safe and
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`effective for therapeutic use. Dalby Decl’n (EX. 2011), ¶ 17. One of those
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`propellants was HFA 134a. Id., ¶ 15.
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`In the case of suspension formulations, replicating the physical properties of
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`the CFC-based formulations meant producing stable homogeneous suspensions
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`that resisted flocculation and/or aggregation for some extended period of time
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`following shaking. Dalby Decl’n (EX. 2011), ¶ 24. In CFC-based formulations
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`known to be safe and effective for therapeutic use, the drug was readily re-
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`dispersed by shaking; thus the target dose of drug could be reliably sprayed into
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`the lungs of the patient. Id., ¶ 22.
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`As of December 1991, formulators believed that if a suspension aerosol
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`formulation showed significant flocculation within a minute after shaking, the
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`suspension aerosol formulation was incapable of producing accurate and
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`reproducible dosing. Dalby Decl’n (EX. 2011), ¶ 23; Aerosol Age (EX. 2005),
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`Figs. 2 and 3. This is further confirmed in the Johnson ‘123 patent (EX. 2001),
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`which defined “stable” suspensions as suspensions in which the drug particles
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`remained suspended in the propellant for at least 30 seconds following shaking:
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`[I]t is now possible with the present invention to prepare aerosol
`formulations of inhalation drugs with P 134a which have sufficient
`stability for the purposes of this invention to deliver the active drug in
`the desired way as presently marketed MDI’s, but without the
`environmental problems associated with CFC’s. As used herein the
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`term “sufficient stability” means that the aerosol drug formulation
`remains as a suspension after shaking at least long enough to allow
`activation of MDI and administration by the patient. The time
`between shaking and administration is typically about 10 sec and
`generally for the formulations of this invention the period of stability
`is at least about 30 sec.
`The Johnson ‘123 patent (EX. 2001), 3:1-14.
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`The aerosol industry devoted substantial resources to developing HFA 134a-
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`based formulations, including forming consortia consisting of a number of major
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`industry players. See, e.g., Manufacturing Chemist (EX. 2003), p. 1. Initially,
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`formulators attempted to substitute HFA 134a in place of a CFC propellant or
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`blend of CFC propellants in existing suspension formulations—a straightforward
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`“drop-in” approach. See Dalby Decl’n (EX. 2011), ¶¶ 17-18. However,
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`formulators soon discovered that simple replacement of HFA 134a for the CFC
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`propellant, or blends of CFC propellants, did not to re-create the appearance and
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`performance of CFC-based suspension formulations known to be safe and effective
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`for therapeutic use. That was because the surfactants previously used in CFC-
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`based suspension formulations to stabilize those formulations were not soluble in
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`HFA 134a. Id.; EX. 2009, p. 26 (Dr. Dalby 1990 article describing the differences
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`in properties between HFA 134a and CFC’s that were expected to make a simple
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`“drop-in” approach infeasible).
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`D. Formulators Believed That Suspensions Containing Only HFA 134a
`and Drug Were Not Sufficiently Stable for Therapeutic Use
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`Dr. Dalby explains that as of December 1991, formulators believed that
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`suspensions containing only HFA 134a and drug flocculated too quickly to be
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`therapeutically useful. Dalby Decl’n (EX. 2011), ¶ 24. For example, the Johnson
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`’123 patent (EX. 2001), reported that a suspension formulation containing only
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`albuterol and HFA 134a displayed significant flocculation in less than 2 seconds.
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`The Johnson ‘123 patent (EX. 2001), 6:1-40 (Table 1). The Johnson ‘123 patent
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`concluded that this formulation was not therapeutically useful: “[i]f significant
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`flocculation occurs, that is, a cognizable coarseness and/or clear region can be
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`observed, in less than about 15 sec., the suspension is deemed not stable enough
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`for a practical aerosol inhalation drug formulation.” Id., 5:49-54. Similarly, the
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`Purewal ‘183 patent (EX. 2004) stated that “use of [HFA] 134a and drug as a
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`binary mixture … does not provide formulations having suitable properties for use
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`with pressurised inhalers.” The Purewal ‘183 patent (EX. 2004), 2:58-62.
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`Both the Johnson ‘123 patent and the Purewal ‘183 patent reflect the belief
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`at the time that a suspension formulation containing only HFA 134a and drug
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`would not be unsatisfactory for therapeutic use. Dalby Decl’n (EX. 2011), ¶ 24.
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`E. Formulators Tried to Prepare Stable Suspensions with HFA 134a by
`Adding Surfactants and/or Co-Solvents
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`The pharmaceutical industry recognized that replacing CFC’s with HFA
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`134a as the propellant in suspension aerosol formulations would be complicated.
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`Dalby Decl’n (EX. 2011), ¶ 16; Smyth Deposition Transcript (EX. 2014), 63:24-
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`66:2. The task was so difficult that in 1994, seven years after the Montreal
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`Protocol, CFC-based MDI formulations were granted essential use exemptions
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`from the Protocol through 1997. Id.; D’Souza (EX. 2008), p. S-13.
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`Researchers pursued a number of different approaches to address the
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`formulation challenge that HFA 134a presented for suspension aerosol
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`formulations. Dalby Decl’n (EX. 2011), ¶ 25. The goal of each approach was to
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`re-create the appearance and properties of CFC-based suspension formulations
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`known to be safe and effective for therapeutic use. Id.
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`One approach, described in the Johnson ‘123 patent, involved using new
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`classes of surfactants (e.g., fluorosurfactants). The Johnson ‘123 patent (EX.
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`2001), 2:54-57; Dalby Decl’n (EX. 2011), ¶ 25. A second approach, described in
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`the ‘011 PCT application (Mylan’s EX. 1007), was to pre-coat surfactants directly
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`onto the drug particles before dispersing the drug particles in HFA 134a. ‘011
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`PCT application (EX. 1007), 3:1-16; Dalby Decl’n (EX. 2011), ¶ 26. A third
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`approach, described in the Purewal ‘183 patent, added co-solvents having higher
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`polarity than HFA 134a to allow use of conventional surfactants. The Purewal
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`‘183 patent (EX. 2004), 2:14-36; Dalby Decl’n (EX. 2011), ¶ 27. A fourth
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`approach, which Dr. Dalby himself attempted, was to try blends of CFC and HFA
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`134a propellants. Dalby Decl’n (EX. 2011), ¶ 28. Before December 1991,
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`however, no formulator suggested that suspensions containing only HFA 134a and
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`drug were suitable for treating patients.
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`III. THE ‘413 PATENT
`The inventors of the ‘413 patent discovered that satisfactory aerosol
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`suspension formulations based on HFA 134a could be successfully incorporated in
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`MDI’s and used to treat patients even though the HFA 134a-based suspensions
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`lacked the appearance and performance of CFC-based formulations known to be
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`safe and effective for therapeutic use. Dalby Decl’n (EX. 2011), ¶ 29. In
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`particular, the inventors found that even though suspension formulations
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`containing only HFA 134a and drug had a tendency to flocculate, upon shaking the
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`surfactant-free formulations nevertheless remained sufficiently homogeneous to
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`form “satisfactory formulations for use with a metered dose inhaler.” See, e.g., id.;
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`the ‘413 patent, 7:49-55.
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`The inventors’ discovery was contrary to conventional wisdom in the field.
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`See Dalby Decl’n (EX. 2011), ¶ 29.Dr. Dalby wrote a paper in 1990 in which he
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`described tracking homogeneity over a full hour as a metric of formulation stability
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`in his research. Dalby Decl’n (EX. 2011), ¶ 29 and EX. 2005, p. 23. Similarly, the
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`Johnson ‘123 patent described experiments where flocculation was evaluated over
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`4 minutes as a metric of suitability. Dalby Decl’n (EX. 2011), ¶ 29 and EX. 2001
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`(Table 1). The ‘413 patent, on the other hand, concluded that “the drug substances
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`… can be formulated in HFA 134a alone” after observing them to be visually
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`acceptable for only 10 and 30 seconds after shaking. The ‘413 patent (EX. 1001),
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`7:24-51. According to Dr. Dalby, formulators in December 1991 were surprised
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`that formulations that were visually homogeneous for such a short period of time
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`could reliably deliver reproducible doses of drug to patients. Dalby Decl’n (EX.
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`2011), ¶ 29.
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`Claims 14-19 and 22-24 are method claims that require treating a mammal
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`having a condition capable of treatment by inhalation. Claims 15, 18, and 23
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`specifically define the condition as asthma, while claims 16, 19, and 24 define the
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`condition as COPD. Each of the claims recites formulations consisting essentially
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`of (1) a particulate drug and (2) HFA 134a propellant, which the claims sometimes
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`refer to by its chemical name (1,1,1,2-tetrafluorethane). Claims 14-16 further
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`require the formulation to be “substantially free of surfactant,” while claims 17-19
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`and 22-24 require the formulation to be “free of surfactant or contain[s] less than a
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`stabilizing amount of surfactant.” Each claim reflects the inventors’
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`counterintuitive discovery that suspension formulations containing only HFA 134a
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`and drug could be used to treat patients suffering from conditions such as asthma
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`or COPD.
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`IV. CLAIMS 14-19 AND 22-24 ARE PATENTABLE OVER THE ‘011
`PCT APPLICATION
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`The ‘011 PCT application does not anticipate claims 14-19 and 22-24, nor
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`does it render these claims obvious. The ‘011 PCT application does not teach or
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`suggest using the surfactant-free formulations of Formulations 7 and 8 shown in
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`Example 1 of the ‘011 PCT application to treat patients. In Example 1, these
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`surfactant-free formulations were used as controls in the experiment. ‘011 PCT
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`application (EX. 1007), pp. 12-14.
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`The ‘011 PCT application describes preparing HFA 134a-based suspension
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`aerosol formulations by coating surfactant onto the drug particles before dispersing
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`the drug particles in the HFA 134a propellant. The sole purpose of the controls
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`that lacked surfactant was to provide a baseline for assessing the performance of
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`the surfactant-containing test formulations. Id.; Dalby Decl’n (EX. 2011), ¶ 39.
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`The experimental results reported in the ‘011 PCT application for Formulations 7
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`and 8 would not have taught a formulator anything about the controls, let alone
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`their suitability for treating patients.
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`Before December 1991, a person of ordinary skill would have read the ‘011
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`PCT application consistent with the state of the art as disclosing that suspension
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`formulations containing only HFA 134a and drug were not therapeutically useful.
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`Each of the surfactant-containing suspension formulations that the ‘011 PCT
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`application tested outperformed the control formulations containing only HFA
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`134a and drug, as measured by a metric the ‘011 PCT application defined and
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`called the “Drug Deposition Potential.”
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`The ‘011 PCT application taught the importance of including the surfactant,
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`The ‘011 PCT application did not teach the possibility of omitting it in favor of
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`suspension formulations containing only HFA 134a and drug for treating patients.
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`A. The only suspension formulations the ‘011 PCT application teaches
`as suitable for treating patients contain HFA 134a and surfactant-
`coated drug particles
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`The ‘011 PCT application states that its invention is an “aerosol composition
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`comprising at least 0.001% by weight of a finely-divided solid