IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`MYLAN PHARMACEUTICALS INC.
`Petitioner,
`
`v.
`
`3M COMPANY
`Patent Owner.
`
`U.S. Patent No. 6,743,413 to Schultz et al.
`Issue Date: June 1, 2004
`Title: Suspension Aerosol Formulations
`
`_____________________
`
`Inter Partes Review No.: IPR2015-_____
`
`
`
`DECLARATION OF HUGH SMYTH
`
`
`
`
`
`
`
`
`
`
`
`

`
`
`
` Inter Partes Review of USPN 6,743,413
`Declaration of Hugh Smyth
`
`
`Table of Contents
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II. MY EXPERIENCE AND QUALIFICATIONS ............................................. 2
`
`III. LIST OF MATERIALS CONSIDERED ........................................................ 4
`
`IV. PERSON OF ORDINARY SKILL IN THE ART (“POSA”) ......................... 5
`
`V.
`
`THE ’413 PATENT ......................................................................................... 7
`
`VI. STATE OF THE ART IN MAY OF 1992 ...................................................... 8
`
`VII. ANTICIPATION OF THE CLAIMS OF THE ’413 PATENT ...................... 9
`1.
`The ’011 Publication Discloses Claims 1-2, 4, 6-7, 10,
`12, 14-20, and 22-24 of the ’413 Patent ...................................10
`a)
`The ’011 Publication Discloses Claim 1 of the
`’413 Patent ......................................................................11
`The ’011 Publication Discloses Claim 4 of the
`’413 Patent ......................................................................19
`The ’011 Publication Discloses Claim 6 of the ’413
`Patent ..............................................................................22
`The ’011 Publication Discloses Claim 12 of the
`’413 Patent ......................................................................29
`The ’011 Publication Discloses Claim 14 of the
`’413 Patent ......................................................................34
`The ’011 Publication Discloses Claim 17 of the
`’413 Patent ......................................................................36
`The ’011 Publication Discloses Claims 20 and 22
`of the ’413 Patent ............................................................40
`The ’011 Publication Discloses Claim 2 of the
`’413 Patent ......................................................................45
`The ’011 Publication Discloses Claim 7 of the
`’413 Patent ......................................................................45
`The ’011 Publication Discloses Claim 10 of the
`’413 Patent ......................................................................47
`The ’011 Publication Discloses Claims 15, 16, 18,
`19, 23, and 24 of the ’413 Patent ....................................47
`
`b)
`
`c)
`
`d)
`
`e)
`
`f)
`
`g)
`
`h)
`
`i)
`
`j)
`
`k)
`
`i
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`MYLAN EX 1006, Page 2
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`

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`
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`2.
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` Inter Partes Review of USPN 6,743,413
`Declaration of Hugh Smyth
`
`
`b)
`
`c)
`
`The ’333 Publication Discloses Claims 1-5, 14, and 20-
`22 of the ’413 Patent .................................................................49
`a)
`The ’333 Publication Discloses Claim 1 of the
`’413 Patent ......................................................................50
`The ’333 Publication Discloses Claim 3 of the
`’413 Patent ......................................................................53
`The ’333 Publication Discloses Claim 4 of the
`’413 Patent ......................................................................55
`The ’333 Publication Discloses Claims 5 and 14 of
`the ’413 Patent ................................................................57
`The ’333 Publication Discloses Claims 20, 21, and
`22 of the ’413 Patent .......................................................61
`The ’333 Publication Discloses Claim 2 of the
`’413 Patent ......................................................................65
`
`d)
`
`e)
`
`f)
`
`VIII. OBVIOUSNESS OF THE CLAIMS OF THE ’413 PATENT .....................65
`1.
`The Claims of the ’413 Patent Would Have Been
`Obvious in View of the ’011 Publication Alone and/or in
`Combination with the Knowledge of a POSA ..........................67
`a)
`The Scope and Content of the Prior Art .........................67
`b)
`Differences Between the Claims of the ’413 Patent
`and the ’011 Publication .................................................68
` Claims 1, 2, and 4 of the ’413 Patent Would
`Have Been Obvious ..............................................68
` Claim 3 of the ’413 Patent Would Have
`Been Obvious .......................................................70
` Claims 5 and 14 of the ’413 Patent Would
`Have Been Obvious ..............................................73
` Claim 6 of the ’413 Patent Would Have
`Been Obvious .......................................................74
` Claim 7 of the ’413 Patent Would Have
`Been Obvious .......................................................79
` Claims 8-11 of the ’413 Patent Would Have
`Been Obvious .......................................................80
` Claim 12 of the ’413 Patent Would Have
`Been Obvious .......................................................82
` Claim 13 of the ’413 Patent Would Have
`Been Obvious .......................................................84
`
`ii
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`MYLAN EX 1006, Page 3
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`2.
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`
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`
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` Inter Partes Review of USPN 6,743,413
`Declaration of Hugh Smyth
`
`
`b)
`
`c)
`
`d)
`
`e)
`
`f)
`
`g)
`
`h)
`
` Claim 17 of the ’413 Patent Would Have
`Been Obvious .......................................................85
` Claim 20 of the ’413 Patent Would Have
`Been Obvious .......................................................86
` Claims 21 and 22 of the ’413 Patent Would
`Have Been Obvious ..............................................87
` Claims 15, 16, 18, 19, 23, and 24 of the ’413
`Patent Would Have Been Obvious .......................88
`The Claims of the ’413 Patent Would Have Been
`Obvious to a POSA in View of the ’333 Publication ...............93
`a)
`The Base Limitations of Every Claim Would Have
`Been Obvious ..................................................................94
`Equipping the Aerosol Canister with a Metering
`Valve Would Have Been Obvious .................................96
`Selecting Therapeutically Effective
`Amounts/Doses Would Have Been Obvious .................97
`The Redispersibility Limitation Would Have Been
`Obvious ...........................................................................99
`The Flocculation Limitation Would Have Been
`Obvious .........................................................................100
`Selecting a Micronized Drug Particulate, or a
`Particulate Drug wherein 90% or More of the
`Particles Have a Diameter of Less Than 10
`Microns Would Have Been Obvious ............................101
`Selecting a Formulation That Exhibits
`Substantially No Growth in Particle Size Would
`Have Been Obvious ......................................................102
`Using Formulations that Were Surfactant-Free or
`“Substantially Free of Surfactant” for the
`Treatment of Asthma or COPD Would Have Been
`Obvious .........................................................................104
`The ’333 Publication Discloses the Preamble
`Limitations Claims 12-14, 17, and 22 of the ’413
`Patent ............................................................................106
`
`i)
`
`
`
`iii
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`MYLAN EX 1006, Page 4
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`
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`I, Hugh Smyth, do hereby declare and say as follows:
`
`
`
`I have been asked to provide testimony as to what one of ordinary
`
`skill in the art would have understood with respect to the patent at issue and
`
`various prior art. I provide this testimony below:
`
`I.
`
`INTRODUCTION
`
`
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this Declaration.
`
`
`
`I have been retained on behalf of Petitioner, for the above-captioned
`
`inter partes review (“IPR”). I am being compensated for my time in connection
`
`with this IPR at my standard consulting rate, which is $650 per hour. My
`
`compensation does not depend in any way on the outcome of this IPR.
`
`
`
`It is my understanding that the petition for inter partes review in this
`
`matter involves U.S. Patent No. 6,743,413 (“the ’413 patent”) (EX1001), which
`
`issued June 1, 2004 from U.S. Application No. 08/455,280 (“the ’280
`
`application”), which was filed May 31, 1995 and was a division of U.S.
`
`Application No. 07/878,039 (“the ’039 application”), filed May 4, 1992. The ’039
`
`application was a continuation-in-part of U.S. Application No. 07/809,791 (“the
`
`’791 application”), filed December 18, 1991, which was a continuation-in-part of
`
`U.S. Application No. 07/810,401 (“the ’401 application”), also filed December 18,
`
`1991.
`
`1
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`MYLAN EX 1006, Page 5
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`
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`It is my understanding that the records of the USPTO indicate that the
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`current owner of the ’413 patent is 3M Company.
`
`II. MY EXPERIENCE AND QUALIFICATIONS
`
`
`
`I am an expert in the field of pharmaceutical formulations and drug
`
`delivery, particularly in the field of pulmonary delivery systems (“PDS”) for
`
`inhalable drugs, and I have been an expert in this field since at least 2003. I will
`
`refer to the relevant field of endeavor as PDS for inhalable drugs throughout the
`
`remainder of this Declaration. In forming my opinions, I have relied on my
`
`knowledge, training, and experience in the pertinent art.
`
`
`
`I am an Associate Professor of Pharmaceutics in the College of
`
`Pharmacy at the University of Texas at Austin. My research is focused on
`
`inhalation aerosols, including metered dose inhalers, and drug delivery. In the
`
`context of my research, I have formulated and evaluated metered dose inhalers. I
`
`have designed test methods for these inhalers and their formulations, and I have
`
`evaluated the results of this testing.
`
`
`
`I received a Bachelor of Pharmacy from the University of Otago, New
`
`Zealand in 1995. I also completed a post graduate diploma in Pharmaceutics at the
`
`University of Otago in 1997. I received a Ph.D. in Pharmaceutical Sciences from
`
`the University of Otago in 2000, and conducted two years of postdoctoral research
`
`at the University of North Carolina at Chapel Hill.
`
`2
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`MYLAN EX 1006, Page 6
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`
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`
`
`After completing my postdoctoral fellowship in 2003, I became a
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`Research Assistant Professor at the University of North Carolina in the School of
`
`Pharmacy’s Division of Drug Delivery and Deposition. In 2005, I became an
`
`Assistant Professor at the University of New Mexico’s College of Pharmacy. In
`
`2009, I accepted a position at the University of Texas at Austin as an Assistant
`
`Professor. In 2011, I was promoted to my current position of Associate Professor
`
`of Pharmaceutics with tenure. In addition, I have served as an Adjunct Associate
`
`Scientist at Lovelace Respiratory Research Institute since 2006.
`
`
`
`I have served on the editorial boards for several scientific journals.
`
`Currently, I am the Editor in Chief for Drug Development and Industrial Pharmacy
`
`and serve on the editorial board for several other journals. I am also a member of
`
`several professional societies, including the International Society for Aerosols in
`
`Medicine, the American Association of Pharmaceutical Scientists, and the
`
`Controlled Release Society. In 2007, I received the American Association of
`
`Pharmaceutical Scientists’ New Investigator Award in Pharmaceutics, Drug
`
`Delivery, and Pharmaceutical Technologies. I have been invited to present
`
`numerous scientific lectures and seminars at conferences and universities. These
`
`lectures and seminars have focused on various aspects of aerosol drug formulation.
`
`My research has contributed to the authorship of over 60 peer-reviewed articles; 17
`
`book chapters; 3 books, and 17 patent applications. A copy of my curriculum
`
`3
`
`MYLAN EX 1006, Page 7
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`

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`
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`vitae, which includes a complete description of my education, experience, and
`
`inventions, is attached hereto as EX1012.
`
`III. LIST OF MATERIALS CONSIDERED
`
`
`
`In formulating my opinions, I have considered the following
`
`materials, and any other materials referenced in this Declaration or the Petition:
`
`Exhibit
`#
`
`Description
`
`1001
`
`U.S. Patent No. 6,743,413
`
`1002
`
`U.S. Patent Application Ser. No. 07/809,791
`
`1003
`
`U.S. Patent Application Ser. No. 07/810,401
`
`1004
`
`December 8, 1998 Request that an Interference Be Declared
`
`1005
`
`July 30, 2002 Amendment
`
`1007
`
`International Patent Application Publication No. WO 1991/004011
`
`1008
`
`RESERVED
`
`1009
`
`U.S. Patent No. 4,866,051
`
`1010
`
`Weir, D.C., et al. “Corticosteroid trials in non-asthmatic chronic
`airflow obstruction: a comparison of oral prednisolone and inhaled
`beclomethasone dipropionate.” Thorax 1990;45:112-117
`
`1011
`
`International Patent Application Publication No. WO 1990/007333
`
`1012
`
`Curriculum Vitae of Hugh Smyth
`
`1013
`
`RESERVED
`
`1014
`
`Joseph P. Remington, Remington’s Pharmaceutical Sciences 308-17
`(Alfonso R. Gennaro ed., 17 ed. 1985)
`
`4
`
`MYLAN EX 1006, Page 8
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`

`
`Exhibit
`#
`
`1015
`
`
`
`
`
`Description
`
`G. S. Banker and C. T. Rhodes, Eds., Modern Pharmaceutics,
`Second Edition 341 (Marcel Dekker, Inc., New York 1990)
`
`IV. PERSON OF ORDINARY SKILL IN THE ART (“POSA”)
`
`
`
`In preparing this Declaration, I have consulted the ’413 patent and its
`
`prosecution history as well as each of the documents cited herein in light of the
`
`general knowledge in the state of the art as of May 1992. In arriving at my
`
`opinions, I have relied on my experience in the relevant art and have considered
`
`the point of view of a person of ordinary skill in the art, that is, a person of
`
`ordinary skill in the field of pulmonary delivery systems for inhalable drugs.
`
`
`
`I understand that a POSA is a hypothetical person who, at the time of
`
`the invention, is presumed to know of all relevant art and is a person of ordinary
`
`creativity. With respect to the ’413 patent and its field of PDS for inhalable drugs,
`
`a POSA would have education and/or experience in particulate drug formulations
`
`and drug delivery via inhalation and knowledge of the scientific literature in the
`
`field.
`
` Although the education and experience levels may vary, a POSA
`
`would have had at least a bachelor’s degree in pharmacy or chemistry and work
`
`experience in the field of aerosol formulations and aerosol delivery systems for
`
`5
`
`MYLAN EX 1006, Page 9
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`

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`
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`medications, including working with propellant based systems. A POSA would
`
`also have had experience in the research and/or development of inhalers to
`
`administer various medications, including inhalers directed to the treatment of
`
`asthma and chronic obstructive pulmonary disease (“COPD”).
`
` A person holding only a Bachelor’s degree would be required to have
`
`had five to ten years of relevant work experience to qualify as a POSA, but a
`
`person with a more advanced degree, such as a master’s of science, could qualify
`
`as a POSA with fewer years of experience.
`
`
`
`I understand that a POSA is not necessarily limited to his or her own
`
`skills but also may work as part of a team and utilize specialized skills of other
`
`team members in order to solve a particular problem.
`
` A POSA’s knowledge of the scientific literature in the field, common
`
`sense, and skill in December 1991 would remain the same in May 1992 because
`
`this field is a slow-moving science where relatively few advancements would have
`
`been made during this 5-month time period.
`
` Based on my experience, I have an understanding of the capabilities
`
`of a person of ordinary skill in the relevant field. Although I would not have been
`
`considered a POSA at the time of the invention, over the past twenty years I have
`
`worked in this field. Thus, I have closely followed the scientific and patent
`
`literature of the field relevant to the ’413 patent both prior to, and after, the time of
`
`6
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`MYLAN EX 1006, Page 10
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`
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`the ’413 patent. All the opinions I express in this Declaration have been made
`
`from the standpoint of a POSA in the field of the ’413 patent at the time of the
`
`invention.
`
`V. THE ’413 PATENT
`
`
`
`I have reviewed and considered the ’413 patent in view of general
`
`knowledge in the relevant field measured from the time of the earliest possible
`
`priority date for the ’413 patent, which I understand to be May 4, 1992.1
`
` The ’413 patent specification is generically directed to pharmaceutical
`
`suspension formulations suitable for aerosol administration. (EX1001, 2:33-42).
`
`The ’413 patent describes “suspension aerosol formulations” as a formulation in
`
`which the drug is in particulate form and is substantially insoluble in the
`
`propellant. (EX1001, 3:27-29).
`
` The ’413 patent further indicates that when the claimed formulations
`
`are intended for oral inhalation into the lungs, the drug is preferably “micronized,”
`
`i.e., about 90 percent or more of the particles have a diameter of less than about 10
`
`microns. (EX1001, 3:55-60).
`
`
`1 As stated above, the opinions I express in this declaration would not change even
`
`if I were to provide them from the December 1991 time frame.
`
`7
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`MYLAN EX 1006, Page 11
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`
`
` The common base limitations of every claim of the ’413 patent
`
`generally involve aerosol formulations that contain a: (1) particulate drug; (2)
`
`1,1,1,2-tetrafluoroethane as propellant (also known as HFC-134a or HFA 134a);
`
`and (3) formulations that are either surfactant-free or “substantially surfactant
`
`free.”
`
` Additional limitations common throughout the claims of the ’413
`
`patent include, inter alia: (1) a therapeutically effective amount or a plurality of
`
`therapeutically effective doses of the drug, (2) utilizing the formulation with a
`
`metering valve or making a metered dose inhaler, (3) the formulation being
`
`substantially and readily dispersible, and upon redispersion, does not flocculate so
`
`quickly as to prevent reproducible dosing of the drug, and (4) utilizing the
`
`formulations for treatment of asthma or COPD. I will discuss these, and the other
`
`limitations of the ’413 patent throughout this declaration.
`
`VI. STATE OF THE ART IN MAY OF 1992
`
` Prior to May of 1992, it was well known in the art that particulate
`
`drugs, including various steroids, could be administered through inhaler PDS in
`
`order to treat bronchial diseases such as asthma and COPD.
`
` As of May 4, 1992, pharmaceutical suspension formulations
`
`containing a particulate drug, propellant, and no surfactant that were suitable for
`
`aerosol delivery had received approval from the FDA and were sold in the United
`
`8
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`MYLAN EX 1006, Page 12
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`
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`States. For example, Azmacort® (triamcinolone acetonide) was first approved in
`
`1982 and is administered as an aerosol via inhalation.
`
`VII. ANTICIPATION OF THE CLAIMS OF THE ’413 PATENT
`
` With regard to claim construction, I understand that in an inter partes
`
`review, claim terms are given their broadest reasonable construction in light of the
`
`specification of the patent in which they appear. I understand that under the
`
`broadest reasonable interpretation standard, claim terms are presumed to be given
`
`their ordinary and customary meaning as understood by one of ordinary skill in the
`
`art in the context of the entire disclosure at the time of the invention. I understand
`
`that one must be careful not to read a specific embodiment appearing in the written
`
`description into the claim if the claim language is broader than the embodiment. I
`
`further understand that any special definition for a claim term must be set forth
`
`with reasonable clarity, deliberateness, and precision. I have considered each of
`
`the claim terms using the broadest reasonable interpretation standard.
`
`
`
`I understand that anticipation requires that each and every element of
`
`the claimed invention be disclosed expressly or inherently in a single prior art
`
`reference. I also understand that an element may be inherent in the prior art where
`
`the prior art necessarily functions in accordance with or includes the claimed
`
`limitations.
`
`9
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`MYLAN EX 1006, Page 13
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`
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`I am also informed that inherency may exist even if a POSA would
`
`not appreciate or recognize the inherent characteristics of the prior art, as the
`
`discovery of a previously-unappreciated property does not make an old
`
`composition patentable.
`
`
`
`I also understand that a prior art reference must enable a POSA to
`
`make and use a claimed invention in order to anticipate a patent claim.
`
`
`
`I understand that it is appropriate to consider additional references in
`
`the context of analyzing anticipation where a reference is silent about an inherent
`
`characteristic and to determine whether the reference gives possession of the
`
`invention to a POSA.
`
`1.
`
`The ’011 Publication Discloses Claims 1-2, 4, 6-7, 10, 12, 14-
`20, and 22-24 of the ’413 Patent
`
`
`
`International Patent Application Publication No. WO 1991/004011
`
`(“the ’011 publication”) (EX1007) anticipates Claims 1-2, 4, 6-7, 10, 12, 14-20,
`
`and 22-24 of the ’413 patent.
`
`
`
`I understand that the ’011 publication, entitled “Medicinal Aerosol
`
`Formulations” published on April 4, 1991, is prior art with respect to the ’413
`
`patent.2
`
`
`2 It is my understanding that the ’011 publication was listed on the face of the ’413
`
`patent, but it was not cited in an Office Action or referred to during prosecution.
`
`10
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`MYLAN EX 1006, Page 14
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` The ’011 publication describes medicinal aerosol formulations that are
`
`suitable for pulmonary, nasal, buccal or topical administration. (Id. at p. 1, ll. 1-6).
`
`a)
`
`The ’011 Publication Discloses Claim 1 of the ’413
`Patent
`
` Claim 1 is reproduced below:
`
`1. A pharmaceutical suspension formulation suitable for aerosol
`
`administration consisting essentially3 of:
`
`(i) particulate drug; and
`
`(ii) 1,1,1,2-tetrafluoroethane as propellant,
`
`wherein the formulation is further characterized in that it contains no
`
`surfactant.
`
`(EX1001 at 15:61-67).
`
` The ’413 patent explains that “[t]he term ‘suspension aerosol
`
`formulation’ as used herein refers to a formulation in which the drug is in
`
`particulate form and is substantially insoluble in the propellant.” (EX1001 at
`
`3:27-29). The ’011 publication states: “[d]esirably the finely divided solid
`
`
`3 I have been informed that the phrase “consisting essentially of” signals that an
`
`invention includes the components recited in the claim and is only open to additional
`
`unlisted ingredients that do not materially affect the basic and novel properties of
`
`the invention. I have applied this understanding in performing my analysis.
`
`11
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`MYLAN EX 1006, Page 15
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`
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`materials should be substantially insoluble in both the liquefied propellant and
`
`the surface-active agent.” (EX1007 at p. 10, ll. 3-5). A POSA would
`
`understand the disclosure of “substantially insoluble” drugs in the ’011
`
`publication to be synonymous with the “particulate drug” described in the ’413
`
`patent. Thus, the ’011 publication therefore clearly teaches pharmaceutical
`
`suspension formulations containing particulate drugs.
`
` Example 1 of the ’011 publication describes the production of seven
`
`separate “control” pharmaceutical aerosol suspension formulations containing
`
`1,1,1,2-tetrafluoroethane (Propellant 134a) and one of several drugs without the
`
`use of any surfactant. A POSA would understand that 1,1,1,2-tetrafluoroethane is
`
`the same as HFC-134a, just as the ’011 publication describes that the two terms are
`
`interchangeable. See EX1007 at p. 2, ll. 6-11 (“It is disclosed that 1,1,1,2 –
`
`tetrafluoroethane, hereinafter referred to as Propellant 134a…”).
`
` Example 1 of the ’011 publication is reproduced below:
`
`Example 1
`
`Method for Determining the Drug Deposition Potential of
`the Formulations
`
`The formulations were evaluated by the following protocol
`to demonstrate the improvement brought about by coating
`the micronised drug particles with a suitable surfactant in
`accordance with the invention. The quantification of the
`improvement was expressed as the drug deposition
`potential of a given formulation and was determined as
`follows: -
`
`12
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`MYLAN EX 1006, Page 16
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`

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`
`
`(a) The surfactant coated drug was prepared as described
`above from micronised drug in dehumidified conditions.
`The control comprising the same formulation but
`omitting the surfactant was subjected to the same
`procedure.
`
`(b) 69 mg of the coated drug (or control) was added to
`each of several 10 ml capacity aluminium aerosol cans.
`Polyethylene terephthalate (PET) aerosol containers may
`be substituted where appropriate. An aerosol valve was
`crimped into place before addition of Propellant 134a
`(7.9g). Once crimping had been effected cans could be
`removed from the dehumidified environment.
`
`(c) The contents of each can were homogenized by
`immersion in an ultrasonic bath for five minutes.
`
`(d) The cans were subjected to the following conditions,
`designed to promote drug deposition: -
`
`Each can was placed on its side on an electric rolling
`apparatus such that it is in a position to rotate about an axis
`parallel with its axis of rotational symmetry, i.e. its
`longitudinal axis. The apparatus was programmed to be
`alternately switched on for 15 minutes and then off for 15
`minutes, for a total of 15 hours operation time (30 cycles).
`
`Each can subjected to intermittent rolled storage was
`chilled for 30 minutes at -50°C.
`
`Immediately prior to decrimping the valve, the can was
`inverted to ensure that undeposited drug particles are
`dispersed. The valve was decrimped and the can contents
`discarded.
`
`(e) The deposits from each can were rinsed with a suitable
`solvent, ensuring quantitative transfer of the washings, into
`a volumetric flask. Where appropriate the flask contents
`were made up to the required volume with solvent, before
`u.v. spectro-photomeric analysis of the drug. Where
`
`13
`
`MYLAN EX 1006, Page 17
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`
`
`necessary samples were diluted to provide an absorbance
`within the linear range of the Beer-Lambert Law.
`
`(f) The amount of drug deposited from each preparation
`(including the control) was determined and the results
`expressed as follows: -
`
`
`
`A value of less than 1.0 for the drug deposition potential
`indicates an improvement due to the pre-coating of the
`micronised drug particles with the surfactant.
`
`(EX1007 at pp. 12-13) (emphasis added).
`
` The applicants of the ’011 publication examined the formulations
`
`created during Example 1 and set forth the results in a table, reproduced below:
`
`
`
`14
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`MYLAN EX 1006, Page 18
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`(EX1007 at p. 14).
`
` The table for Example 1 reports the values for a “Drug Deposition
`
`Potential” (“DDP”) of each of the seven formulations. Step (f) of Example 1 from
`
`the ’011 publication identifies the DDP as:
`
`
`
`(EX1007 at p. 13, ll. 17-20).
`
` A POSA would understand that the Applicants of the ’011 publication
`
`had to make at least seven corresponding control formulations that omitted the
`
`surfactant using the various drugs and containers reported in the table in order to
`
`generate the DDP values. In other words, a POSA would understand that Example
`
`1 of the ’011 publication describes at least seven formulations designated as
`
`“controls” that include one of the seven particulate drugs listed in the Table on
`
`page 14 of the ’011 publication (e.g., beclomethasone dipropionate,
`
`betamethasone, ergotamine tartrate, salbutamol B.P., sodium cromoglycate B.P.,
`
`salbutamol sulphate, or salbutamol sulphate B.P.) and 1,1,1,2-tetrafluoroethane
`
`(i.e., Propellant 134a) without any surfactant.
`
` The ’011 publication explains that “[a] value less than 1.0 for the
`
`[DDP] indicates an improvement due to the pre-coating of the micronised drug
`
`particles with the surfactant.” (EX1007 at p. 13, ll. 22-26). The ’011 publication
`
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`further explains that the DDP of Salbutamol B.P. is 0.92, and the DDP of
`
`Salbutamol Sulphate B.P. is 0.85. (EX1007 at p. 14). Although the ’011
`
`publication does not provide statistical variance of these ratios, Example 2 of the
`
`same publication provides an indication of the variability in the DDP measurement
`
`because each result represents a determination on a separate can.
`
` Regardless of whether surfactants were pre-coated or physically
`
`mixed, the percentage coefficient of variation of the average is around 18%.4
`
`Thus, a POSA would interpret 0.92 and 0.85 in light of this variability, and
`
`understand that these would not be statistically different from 1. A POSA would
`
`understand that including surfactant in these formulations resulted in no
`
`meaningful (if any) improvement in DDP because the reported values are likely
`
`not statistically different. That is, the Salbutamol B.P. and Salbutamol Sulphate
`
`B.P. “control” formulations were nearly as effective as the surfactant-containing
`
`formulations.
`
` Moreover, the drugs disclosed in Example 1 on p. 14 would be the
`
`type of drugs used for pulmonary, nasal, buccal, or topical administration
`
`administered by aerosol administration. (EX1007 at p. 1, ll. 2-6). (“[t]his
`
`invention relates to medicinal aerosol formulations and in particular to
`
`
`4 Percent coefficient of variation = (stand deviation/mean) x 100.
`
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`MYLAN EX 1006, Page 20
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`formulations suitable for pulmonary, nasal, buccal or topical administration which
`
`are at least substantially free of chlorofluorocarbons.”). Furthermore, the drugs
`
`described in Example 1 of the ’011 publication are added to an aluminum aerosol
`
`can and then equipped with an aerosol valve before adding the propellant, HFC-
`
`134a, and therefore teaching that the compositions should be “suitable for aerosol
`
`administration” preamble limitation. (EX1007 at p. 12, ll. 19-23).
`
` As shown in the chart below, a POSA would find that every element
`
`of Claim 1 of the ’413 patent is present in the ’011 publication, namely the control
`
`formulations prepared as part of Example 1:
`
`’413 patent Claim 1
`
`Disclosure in ’011 publication
`
`1. A pharmaceutical
`suspension formulation
`suitable for aerosol
`administration consisting
`essentially of:
`
`(i) particulate drug; and
`
`“This invention relates to medicinal aerosol
`formulations and in particular to formulations
`suitable for pulmonary, nasal, buccal or topical
`administration . . . .” (EX1007 at p. 1, ll. 2-4).
`
`“[d]esirably the finely divided solid materials
`should be substantially insoluble in both the
`liquefied propellant and the surface-active
`agent.” (EX1007 at p. 10, ll. 3-5).
`
`“69 mg of the coated drug (or control) was
`added to each of several 10 ml capacity
`aluminum aerosol cans. Polyethylene
`terephthalate (PET) aerosol containers may be
`substituted where appropriate. An aerosol
`valve was crimped into place before addition of
`Propellant 134a (7.9g).” (EX1007 at p. 12, ll.
`18-23).
`“[d]esirably the finely divided solid materials
`should be substantially insoluble in both the
`
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`
`’413 patent Claim 1
`
`Disclosure in ’011 publication
`
`(ii) 1,1,1,2-tetrafluoroethane
`as propellant,
`
`wherein the formulation is
`further characterized in that it
`contains no surfactant.
`
`liquefied propellant and the surface-active
`agent.” (EX1007 at p. 10, ll. 3-5).
`
`EX1007 at p. 14, Table, listing formulations
`with seven different particulate drugs.
`“It is disclosed that 1,1,1,2-tetrafluoroethane,
`hereinafter referred to as Propellant 134a, may be
`employed as a propellant for aerosol
`formulations used in combination with a
`compound having a higher polarity than
`Propellant 134a.” (EX1007 at p. 2, ll. 6-11).
`
`“The invention is particularly useful in that it
`allows acceptably stable dispersions to be
`attained using Propellant 134a as the aerosol
`propellant.” (EX1007 at p. 3, ll. 29-31).
`
`“An aerosol valve was clamped into place before
`addition of Propellant 134a (7.9g).” (EX1007 at
`p. 12, ll. 21-23).
`“The surfactant coated drug was prepared as
`described above from micronised drug in
`dehumidified conditions. The control
`comprising the same formulation but omitting
`the surfactant was subjected to the same
`procedure.” (EX1007 at p. 12, ll. 13-17).
`
`EX1007 at p. 14, reflecting DDP values of
`formulations compared to control formulations
`without surfactant, specifically the DDP of
`Salbutamol B.P. as 0.92, and the DDP of
`Salbuta