UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.
`
`Petitioner,
`
`V.
`
`ASTRAZENECA AB
`
`Patent Owner.
`
`Patent No. 8,329,680
`
`DECLARATION OF LAIRD FORREST, PILD. IN SUPPORT OF
`PETITION FOR INTER PAR TES REVIEW
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 1
`
`AstraZeneca Exhibit 2092 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`
`

`

`TABLE OF CONTENTS
`
`1.
`
`QUALIFICATIONS AND BACKGROUND ................................................................. ,.4
`
`A.
`
`B.
`
`Education and Experience; Prior Testimony ......................................................... . .4
`
`Bases for Opinions and Materials Considered ....................................................... ..7
`
`[ll
`
`IV.
`
`V.
`
`VI.
`
`LEGAL STANDARDS ..................................................................................................... ..9
`
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”) ......................................... ..10
`
`U.S. PATENT N0. 8,329,680 [EL 1001]
`
`CLAIM CONSTRUCTION ............................................................................................. ..16
`
`VII.
`
`SCOPE AND CONTENT OF THE PRIOR
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`H.
`
`I.
`
`I.
`
`K.
`
`Fulvestrant. Was Well Known in the Prior Art as 3 Pure Antiestrogen ............... ..18
`
`The Prior Art Disclosed Fulvestrant Formulations .............................................. .. 18
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`Castor
`
`Ethano! ..................................................................................................... .20
`
`BenzylAlcohol
`
`Beozyl Bemoote ....................................................................................... .22
`
`Intramuscular Injection of Fulvestr-ant Was Known as the Superior Route
`of Administration in the Prior Art........................................................................ .22
`
`Oil-Based Intramuscular Depot Injection Was Conventional in the Prior
`Art ........................................................................................................................ .23
`
`MoLeskey [Ex
`
`(a)
`
`(b)
`
`A POSA WouldHave Understood that the Formulation in
`McLeskey Was Expressed in 9’wa ......................................................... ...28
`
`A POSA Would Have Keenan that the Formulation ioMcLeskey
`Was a Solution
`
`Howell 1996 [EL 1006] ....................................................................................... .33
`
`EP'O 346 014 (“Dukes 1939") [Ex. 1007] ........................................................... ..34
`
`Wakeling 1991 [Ex 1008-] ................................................................................... ..35
`
`Wakeling 1992 [EL 1009] ................................................................................... ..36
`
`Dukes 1992 [Ex1025] .................. .37
`
`Dukes 1993 [EL 1026] ........................................................................................ .38
`
`VIII. CLAIMS 1-20 OF THE ’680 PATENT WERE
`
`A.
`
`Ground 1: Claims 1-20 of the ’680 Patont Were Obvious Ovor MoLeskey.........39
`
`(3.)
`
`(b)
`
`Independent Claim 1 Was Obvious Over McLeskey................................ ..40
`
`Independent Claim 9 Was Obvious over
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 2
`
`AstraZeneoa Exhibit 2092 p. 2
`
`

`

`(c)
`
`(d)
`
`(e)
`
`(f)
`
`(g)
`
`Dependent C{aims 2 and ll) Were Obvious Over McLeskey ................... A?
`
`Dependent Claws 3, 6, l l, and 14 Were Obvious over McLeskey ..,........49
`
`Dependent Claims 4, 7, 12, and 15 Were Obvious over MeLeskey
`
`.......50
`
`Dependent Claims 5, 8, l3 and I6 Were Obvious over McLeskey-...........51
`
`Dependent Claims 17—20 Were Obvious over McLeskey ........................ .52
`
`E.
`
`Ground 2: All Claims of the ’680 Patent Were Obvious Over Howell 1-996
`
`In View of McLeskejy .......................................................................................... .53
`
`(a)
`
`(b)
`
`(0)
`
`(d)
`
`(e)
`
`(f)
`
`(g)
`
`(h)
`
`The POSA Would Have Been Motivated to Combine the Howell
`l996 and McLeskey Refirences ............................................................... . .53
`
`Independent Claim I Was Obvious over Howell 1996 in view of
`MoLeskey.................................................................................................. .54
`
`Independent Claim 9 Was Obvious over Howell l996 in View of
`McLeskey.................................................................................................. .57
`
`Dependent Claims 2 and 10 Were Obvious Over Howell in View of
`MoLeskey.................................................................................................. .59
`
`Depemlent Claims 3, 6, U, and 14 Were Obvious over Howell
`I996 in View ofMoLesliey ....................................................................... ..61
`
`Dependent Claims 4, 7, 12 and 15 Were Obvious over Howell
`1996 in View ochLeskey ....................................................................... ..61
`
`Dependent Claims 5, 8, 13 and 16 Were Obvious over McLeskey........,...63
`
`Dependent Claims l 7—20 Were Obvious over McLeskey ........................ ..64
`
`THE CLAIMS- OF THE ’680 PATENT DID NOT ACHIEVE ANY
`
`UNEXPECTED RESULT ............................................................................................... ..64
`
`A.
`
`B.
`
`C.
`
`A PO SA Would Have Understood that Solubility of a Drug Does Not
`Depend 501er on Its Solubility in Each Solvent Individually ........... .. ............... .155
`
`(3.)
`
`Examples oflncreased Solubiligz ofa Salute in a Mixture of
`Solvents Were Disclosedin the
`
`A PO SA Would Have Expected that the Addition of Benzyl Benzoate
`Would Improve the Solubility of Fulvestrant ...................................................... ..67
`
`(a)
`
`(b)
`
`The Solubility ofa Solute in a Solvent (or Mixture ofSolvents)
`Depends on Molecular Forces ................................................................. . .67
`
`Immoleoular Forces Between Fulveslranr and the Exeuiienis in
`the ’68:!) Patten! Claims Would'Have Led o POSA to Predict lhal
`
`Adding Benzyl Beneoale WouldHave Improved the Solubility of
`
`To C'onfin'n the PO-SA’s Expectation that the Addition of Benzyl Benzoate
`Would Increase the Solubility of Fulvestrant in the Solvent Mixture, the
`POSA Could Have Perfumed Routine Solubility Calculations .......................... "70
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 3
`
`AstraZeneea Exhibit 2092 p. 3'
`
`

`

`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A.
`
`1.
`
`Education and Experience; Prior Testimony
`
`My name is M. Laird Forrest, PhD.
`
`I have been retained by counsel
`
`for My'lan Pharmaceuticals Inc. (“Mylan”).
`
`I understand that Mylan intends to
`
`petition for inter parses review of US. Patent No. 8,329,680 (“the ’680 patent”)
`
`[Ba 1001], which is assigned to AstraZeneca AB.
`
`I also understand that Mylan
`
`will request that the United States Patent and Trademark Office cancel certain
`
`claims of the ’680 patent as unpatentable in that petition.
`
`I” submit this expert
`
`declaration in support of Mylan’s petition.
`
`2.
`
`I am Currently an Associate Professor
`
`in the Department of
`
`Pharmaceutical Chemistry at the University of Kansas in Lawrence, Kansas, a
`
`position I have held since 2013.
`
`I am also an Associate Professor in the
`
`Bioengineering Center, a position I have held since 2011, and an Associate
`
`Professor in the Department of Chemistry, a position I have held since 2011, both
`
`also at the University of Kansas.
`
`3.
`
`I received a Bachelor of Science in Chemical Engineering from
`
`Auburn University in 1998, a Master of Science in Chemical Engineering from the
`
`University of Illinois in 2001, and a PhD.
`
`in Chemical and Biomolecular
`
`Engineering from the University of Illinois in 2003.
`
`I was a Postdoctoral Fellow in
`
`the Division of Pharmaceutical Sciences at the University of Wisconsin, Madison
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 4
`
`Astra'Zeneca Exhibit 2092 p. 4
`
`

`

`from 2004 to 2006.
`
`In 2006, I became an Adjunct Assistant Professor in the
`
`Department of Pharmaceutical Sciences at Washington State University, a position
`
`I held tutti] 2011.
`
`In 2007, I accepted a position as Assistant Professor in the
`
`Department of Pharmaceutical Chemistry at the University of Kansas.
`
`I was
`
`promoted to Associate Professor at the University of Kansas in 2013.
`
`4.
`
`Since 20.09, I have been a Member of the Scientific and Medical
`
`Advisory Board of Exogenesis Corporation, which develops nanoscale surface
`
`modifications for implantable medical devices.
`
`I am the co—founder of Nanopharm
`
`LLC (d/b/a HylaPharm), founded in 2011, which specializes in formulation of anti-
`
`cancer chemotherapeutics. My research toward anti-cancer drug formulation has
`
`been competitively funded by multiple awards from the National Institutes of
`
`Health and the National Cancer Institute,
`
`the Food and Drug Administration
`
`(“FDA”), the American Cancer Society, the Department of Defense, Susan G.
`
`Komen Race for the Cure, and the Pharmaceutical Research and Manufacturers of
`
`America Foundation (‘ThRMA”), among others.
`
`5.
`
`'I have received numerous awards and honors, including the University
`
`of Kansas Leading Light award (2014-); the Japan Society for Promotion of Science
`
`Visiting Scholar Fellow (2010); the American Cancer Society Research Scholar
`
`(2.008 to 2012);
`
`the American Association of Colleges of Pharmacy, New
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 5
`
`Astra'Zeneca Exhibit 2092 p. 5
`
`

`

`Investigators Award (2007); and the PhRMA Foundation Postdoctoral Fellow
`
`(2006); among others.
`
`6.
`
`I am curreme or have been in the past a member of various
`
`professional societies, including the American Association for Cancer Research,
`
`the American Association of Pharmaceutical Scientists, and the American Institute
`
`of Chemical Engineers.
`
`I serve or have served on numerous scientific review
`
`panels for the National Institutes of Health’s National Cancer Institute,
`
`the
`
`American Cancer Society, and the Association for International Cancer Research
`
`(United Kingdom).
`
`I am a standing member of the American Cancer Society
`
`review panel on Cancer Drug Development.
`
`7.
`
`I have authored more than 70 peervreviewed journal articles and 5
`
`book chapters.
`
`1 have also edited 2 special journal issues on drug delivery and a
`
`book on drug delivery and formulation. A list of all publications that I have
`
`authored is included in my curriculum vitae, attached as Exhibit A to this
`
`Declaration
`
`8.
`
`'I have taught drug fomrulation, including all aspects of drug excipient
`
`choice and the effects of excipient modification on drug chemical stability,
`
`solution solubility, dissolution, and pharmacokinetics,
`
`to clinical pharmacy
`
`students and graduate students studying pharmaceutical formulation since 2007.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 6
`
`Astra'Zeneca Exhibit 2092 p. 6
`
`

`

`9.
`
`I have experience in all aspects of parenteral and oral drug
`
`formulation through my research and teaching. Additionally, as part of my work
`
`with Nanopharm and Exogenesis, I have worked on pharmaceutical formulations
`
`for intramuscular, subcutaneous, intravenous, topical, and oral formulation.
`
`10.
`
`In the past six years, I have testified in the following litigations:
`
`a.
`
`Merck Sharp & Dohme Corp. v. Savior'LMetee Corp, No. 5:15-
`cv-OO415-TWB (E.D.N.C.)
`
`v. Antares Pharma Inc. at 511., No.
`b. Medea Pharma. Inc. et. al.
`1:14~cv-Dl498-JBS~KMW (D.N.J.), and
`
`c.
`
`Breckenridge
`vs.
`al.
`er
`Inc.
`Pharmaceutical,
`For
`Phamaceutieal, Inc. at 511., No. 1: 15~cv-00486~SLR (D. Del).
`
`11,
`
`I am being compensated for my time at my standard consulting rate of
`
`$595/hour. Neither the anme of my compensation nor the fact that I am being
`
`compensated has altered the. Opinions that I have given in this Declaration. My
`
`compensation is in no way dependent on the outcome of this proceeding.
`
`B.
`
`Bases. for Opinions and Materials Considered
`
`12.
`
`In addition to the materials cited herein,
`
`I have considered the
`
`materials. identified in Exhibit B, in addition to my experience, education, and
`
`training, in providing the opinions contained herein,
`
`13.
`
`I have also reviewed the expert declaration of Dr. Leslie Oleksowicz,
`
`MD, and agree with her analysis as to the treatment aspects of the ’680 patent.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 7
`
`Astra'Zeneca Exhibit 2092 p. 7
`
`

`

`11.
`
`SUMMARY OF OPINIONS
`
`14.
`
`It is my opinion that claims 1—20 of the ’680 patent were obvious over
`
`McLesltey [Era 1005].
`
`Independent claims 1 and 9 of the ’680 patent relate to the
`
`administration of a certain fiilvestrant formulation in an intramuscular (“im”)
`
`injection to humans to treat benign and malignant diseases of the breast or
`
`reproductive tract, such as breast cancer. A formulation falling squarely within the
`
`clairned excipient percentage ranges was expressly disclosed in McLeskey.
`
`Furthermore, fulvestrant was already long known in the art to be useful to treat
`
`breast cancer.
`
`Still further, fitlvestrant was known to be administered as an
`
`intramuscular injection.
`
`15.
`
`It is also my opinion that claims 1—20 of the ’680 patent would have
`
`been obvious over Howell 1996 [Ex 1006] in View of McLeskey‘ [Ex. 1005].
`
`Howell 1996 disclosed. fulvestrant formulations in a castor oil-based depot
`
`injection to treat malignant breast cancer in women. Howell 1996 also disclosed
`
`that fiilvestrant formulations in castor oil achieve long-acting effects. With Howell
`
`1996’s disclosure that fiilvestrant administered in caster oil—based depots was
`
`efficacious in the treatment of breast cancer, a person of ordinary skill in the art
`
`(“POSA”) would investigate prior art
`
`formulations of fulvestrant.
`
`This
`
`investigation would quickly uncover McLeskey, a reference that would reveal to
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 8
`
`Astra'Zeneca Exhibit 2092 p. 8
`
`

`

`the POSA a formulated fiilvestrant product exactly as recited in the claims of the
`
`’680 patent.
`
`III. LEGAL STANDARDS
`
`16.
`
`In preparing and forming my opinions set forth in this declaration, I
`
`have been informed of the relevant legal principles.
`
`I have used my understanding
`
`of these principles in forming my opinions. My understanding of these principles
`
`is summarized below.
`
`17‘
`
`I have been told that Mylan bears
`
`the. burden of proving
`
`unpatentability by a preponderance of the evidence.
`
`I am informed that this
`
`preponderance of the evidence standard means that Mylan must Show that
`
`unpatentability is more probable than not.
`
`I have taken these principles into
`
`account when forming my opinions in this case.
`
`18.
`
`.I have also been told that claims should be given their broadest
`
`reasonable interpretation in light of the specification from the perspective of a
`
`POSA.
`
`19.
`
`I am told that
`
`the concept of obviousnes-s involves four factual
`
`inquiries: (1) the scope and content of the prior art, (2) the differences between the
`
`claimed invention and the prior art, (3) the level of ordinary skill in the art. and (4)
`
`secondary considerations ofnon-obviousness.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 9
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`Astra'Zeneca Exhibit 2092 p. 9
`
`

`

`20..
`
`I am also informed that when there is some recognized reason to solve
`
`a problem, and there are a finite number of identified, predictable, and known
`
`solutions, a POSA has good reason to pursue the known options within his or her
`
`technical grasp. If such an approach leads to the expected success, it is likely not
`
`the product of innovation but of ordinary skill and common sense.
`
`In such a
`
`circumstance, when a patent simply arranges old elements with each performing its
`
`known function and yields no more than what one would expect from such an
`
`arrangement, the combination would have been obvious.
`
`21.
`
`I also understand that a whereby clause in a method claim is not given
`
`weight when it simply expresses the intended result of a process step positively
`
`recited. If the language in the whereby clause does not inform how the method is
`
`carried out, the whereby clause is generally not given patentable weight.
`
`IV.
`
`PERSON OF ORDINARY SKILL [N THE ART (“POSA”)
`
`22,
`
`I understand that the obviousness analysis is to be conducted from the
`
`perspective of a POSA at the time of the invention.
`
`I have applied that standard in
`
`the analysis in this declaration. When I discuss the teachings of the prior art, I
`
`discoss those teachings from the perspective of how the POSA would understand
`
`the prior art.
`
`23-.
`
`I also understand that in defining a POSA, the following factors may
`
`be. considered: (1) the educational level of the inventor, (2') the type of problems
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 10
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`AstraZeneca Exhibit 2092 p. 10
`
`

`

`encountered in the art, (3) prior art solutions to those problems, (4) rapidity with
`
`which innovations are made, and (5) sophistication of the technology and
`
`educational level of active workers in the field.
`
`24. As of the earliest possible priority date of the ’680 patent,1 a POSA
`
`would have had a pharmacy degree. or graduate degree in either pharmacy,
`
`pharmaceutics, chemistry, or a related discipline, or equivalent experience in drug
`
`development and formulation, and would also have familiarity with and knowledge
`
`of designing and formulating drug dosage forms. The POSA would have at least 2
`
`years
`
`of
`
`practical
`
`experience
`
`in
`
`pharmaceutical
`
`formulations
`
`and.
`
`phannacokinetics. A POS-A would collaborate with others having expertise in, for
`
`example, methods of treating disease and administering medicines.
`
`25-. A POSA would have a general understanding and knowledge of the
`
`basic principles of formulation development.
`
`In addition to experimental
`
`knowledge in fomiulation deveIOprnent, the POSA would have knowledge in
`
`theoretical aspects of formulation science and physical chemistry. The POSA
`
`would be familiar with general drug formulation strategies; procedures and tools of
`
`pharmaceutical
`
`formulation; and theoretic and experimental methodologies of
`
`1 I understand that the earliest application giving rise to the ’680 patent was filed
`
`on January 10, 2000. Thus, I understand that the ’680 patent is to be evaluated
`
`from the viewpoint of a person of ordinary skill in the art as of January 10, 2000.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 11
`
`AstraZeneca Exhibit 2092 p. l l
`
`

`

`phamiaceutical
`
`formulation,
`
`including pre~fonnulation studies,
`
`formulation
`
`screening, optimization, and experimental design The POSA would have also
`
`been generally familiar with commonly used textbooks and reference manuals in
`
`the field of formulation development and would have general knowledge of printed
`
`publications and relevant references in the field of pharmaceutical formulation.
`
`26. A PDSA would also have both the tools and the ability to research
`
`prior art literature to find information on fulvestrant, its prior art formulations, and
`
`its prior art utility.
`
`V.
`
`U.S. PATENT N0. 8,329,680 [EL 1001]
`
`27,
`
`I have read and understood the ’680 patent, entitled “Formulation.”
`
`The ’680 patent was filed on October 15, 2008, and claims priority to two foreign
`
`patent applications: GB Patent Application No. 0000313, filed January 10, 2000;
`
`and GB Patent Application No. 0008837, filed April 12, 2000. BX. 100]. The
`
`’680 patent also disclosed that it was a continuation of No.
`
`1' 01872384, filed on
`
`June 22, 2004, which was now U.S. Patent No. 7,456,160. The ’680 patent issued
`
`on November '25, 2008, and names John R. Evans and Rosalind U. Grundy as
`
`inventors.
`
`28.
`
`The following table organizes each recitation in the claims by the
`
`claim(s) in which the recitation appears:
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 12
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`AstraZeneca Exhibit 2092 p. 12
`
`

`

`-
`_-_ — o)
`‘
`'
`'-.
`.'
`i r73; 5“
`El." :1- ,1r-}
`
`-
`
`n
`'
`||. “4.
`
`f
`
`benign or
`‘
`f Cla I
`malignant diseases of the human breast or
`A . oductive tract
`
`Volume of Formulated
`Fulvestrant Administered
`
`Claims 4, 7, 12', 15: 5 ml
`
`Final Formulation of'Fulvestrant Claim 1':
`
`“comprising”
`about 50 mgml'I of fiilvestrant
`about 10% W/‘V ethanol
`
`about 10% w/v benzyl alcohol
`about 15% w/v benzyl benzoate
`sufficient amount ofa castor oil vehicle
`
`Claim 9:
`
`“consisting essentially of”
`abOut 50 mgrnl’1 of fulvestrant
`about 10% WW ethanol
`
`about 10% wfv benzyl alcohol
`about 15% WW be
`I benzoate
`
`
`
`Blood Plasma Fulvestrant.
`Concentration Levels and Their
`
`Claims 1., 9: at least 2.5 ngxml for-at least 4
`weeks
`
`Durations
`
`Claim 2, 10: at least 8.5 ng/ml for at least 4
`weeks
`
`29.
`
`I understand that Mylan is. challenging claims 1—20. The ’680 patent
`
`includes 2 independent claims: claims 1 and 9.
`
`2 Inhamuscflar, also denoted “int”
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 13
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`AstraZeneca Exhibit 2092 p. 13'
`
`

`

`30.
`
`Independent claim 1 recites:
`
`A method for treating a hormonal dependent benign or malignant
`
`disease of the breast or reproductive tract comprising administering
`
`intramuscularly to a human in need of such treatment a formulation
`
`comprising: aboat 50 mgml'I of fulvestrant; about 10% w/v of
`
`ethanol; about 10% w/v .of benzyl alcohol; about 15% w/v of benzyl
`
`benzoate; and a sufficient ainoimt of a castor oil vehicle, wherein the
`
`method achieves a therapeutically significant blood plasma fulvestrant
`
`concentration of at least 2.5 ngrnl'1 for at least four weeks.
`
`31.
`
`Independent claim 9 recites:
`
`A method for treating a hormonal dependent benign or malignant
`
`disease of the breast or reproductive tract comprising administering
`
`intramuscularly to a human in need of such treatment a formulation
`
`censisting essentially of: about 50 n:1grn1'1 of fulvestrant; about 10%
`
`w/v of ethanol; about 10% w/v of benzyl alcohol; about 15% w/v of
`
`benzyl benzoate; and a sufficient amount of a castor oil vehicle,
`
`wherein the method achieves a therapeutically significant blood
`
`plasma fulvestrant concentration of at least 2.5 ngml‘l for at least four
`
`weeks.
`
`32.
`
`'In comparing claims 1 and 9, the primary difference between them is
`
`that claim 1
`
`recites that the formulation is “comprising” the listed elements,
`
`whereas claim 9 recites that the formulation is “consisting essentially of” the listed.
`
`elements. Claim 1 also requires a “a sufficient amount of castor oil vehicle,”
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 14
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`AstraZeneea Exhibit 2092 p. 14
`
`

`

`whereas claim 9 omits this requirement. The disclosed method is otherwise
`
`identical between claims 1 and 9.
`
`33.
`
`Dependent claims 2—8 and 17—18 depend directly or indirectly fi‘om
`
`independent claim 1. Dependent claims 10—16 and 19-20 depend directly or
`
`indirectly from independent claim 9.
`
`34. Dependent claims 2 and 10 depend from claims 1 or 2, respectively,
`
`and alter the blood serum concentration level to at least 8.5 ngml”1 for at least four
`
`Weeks.
`
`35. Dependent claims '3 and 1'] depend from claims 1 or 2, respectively,
`
`and recite that the disease being treated is breast cancer. Dependent claims. 6 and
`
`14 depend indirectly from claims 1 or 2, respectively, and recite that the disease
`
`being treated is breast cancer.
`
`36. Dependent claims 4 and 12 depend from claims 1 or 2, reSpectively,
`
`and recite that 5 ml of the fiflvestrant formulation is administered intramuscularly
`
`to a human Dependent claims 7 and 15 depend indirectly from claims 1 or 2,
`
`respectively, and recite that 5 ml of the fiilvestrant formulation is administered
`
`intramuscularly to a human
`
`37. Dependent claims 5 and 13 depend from claims 1 or 2, respectively,
`
`and recite that
`
`the fillvestrant
`
`formulation is administered once monthly.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 15
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`AstraZeneca Exhibit 2092 p. 15
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`Dependent claims 8 and 16 depend indirectly from claims 1 or 2, respectively, and
`
`recite that the firlvestrant formulation is administered once monthly.
`
`38.
`
`Claims 17—18 depend directly or indirectly, respectively, from claim
`
`I, and 19—20 depend directly or indirectly, respectively, from claim 9., and recite
`
`that the fulvestrant formulation is administered in a divided dose.
`
`VI. CLAIM CONSTRUCTION
`
`39.
`
`The term “sufficient amount of a castor oil vehicle” is understood,
`
`based on the specification, to mean that for a given volume of formulation, after
`
`the addition of fulvestrant, ethanol, benzyl alcohol, benzyl benzoate, and any
`
`further optional excipients, the remaining volume of the formulation would be
`
`castor oil. See BX. 100] at col. 11,11. 6—10.
`
`40.
`
`The term “wherein the method achieves a therapeutically significant
`
`blood plasma fulvestrant concentration of at least 2.5 ngml‘1 for at least four
`
`Weeks,” Ex. 1001 at "col. 12 11. 51—53, col. 13 11. 14—16, merely expresses an
`
`intended result of the administration of the firlvestrant formulation recited in the
`
`claims of the ’680 patent. Likewise, the term “wherein the method achieves a
`
`therapeutically significant blood plasma fulvestrant concentration [or] at least 8.5
`
`ngml'l,” Ex. 1001 at col, 12 11. 54—56, col. 13 11. 17—19, merely expresses the
`
`intended result of the administration of the fulvestrant formulation recited in the
`
`claims of the ’680 patent. None of this language informs how the method of
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 16
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`AstraZeneca Exhibit 2092 p. 16
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`administering the fulvestrant formulation to a human patient
`
`is carried out.
`
`Therefore, it is my understanding that this phrase is not to be given any patentable
`
`weight.
`
`41.
`
`To the extent the Board believes that any of the “wherein” terms
`
`recited in paragraph 40 are entitled to any patentable weight,
`
`the term
`
`mtherapeutically significant” is understood, based on the- specifieation, to mean any
`
`blood plasma fillvestrant concentration of at least 2.5 ngmlq (claims 1, 9) or 8.5
`
`ngml’1 (claims 2, 10) that is attained for 4 weeks after injection. Ex. 1001 at col. 9,
`
`I]. 24—28.
`
`42.
`
`To the extent the Board believes that any of the “wherein” terms
`
`recited in paragraph 40 are entitled to any patentable weight, the term “attained” is
`
`understood under the broadest reasonable interpretation of the term to mean
`
`“achieved an average concentration (Cam) in a patient over the specified time
`
`period.” The term “attained” is never defined in the Specification, and the patent
`
`does not include any instructions on how the POSA would have maintained the
`
`specified concentrations over the entire specified time periods (or why it would
`
`even be necessary to do so). Absent these instructions, under a broadest reasonable
`
`construction, the POSA would understand attained to mean the patient has a blood
`
`plasma concentration that is, on average, at least 2.5 ngml‘1 (claims 1, 9) or at least
`
`8.5 ngml.‘1 (claims 2, 10) for 4 weeks after injection.
`
`I understand a district court
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 17
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`AstraZeneca Exhibit 2092 p. 17
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`has construed attained as “achieved and maintained.“ See Ex. 1011 at 2—3. My
`
`opinions are unchanged even if the Board were to adopt this construction.
`
`VII. SCOPE AND CONTENT OF THE PRIOR ART
`
`A.
`
`Fulvestrant Was Well Known in the Prior Art as 3 Pure
`
`Antiestrogen
`
`43.
`
`Fulvestrant, the. compound that is the subject of the claims of the ’680
`
`patent, is known chemically as 70t-[944,4,5,5;S-pentafluoropentylsulphinyl)nonyl]
`
`oestra—l,3,5(10)—triene-3,17B-diol.
`
`It is also known by its code name ICI 182,780.
`
`Fulvestrant has the following chemical structure:
`
`
`
`44.
`
`Fulvestrant was known in the prior art to be a pure antiestrogen that
`
`has high binding affinity for the estrogen receptor and no residual estrogen
`
`stimulating activity. See, ag, Ex. 1008 at 5. Because of their mechanism of
`
`action, antiestrogens are known to be effective in the treatment of breast cancer.
`
`B.
`
`The Prior Art. Disclosed Fu-lvestrant. Formulations
`
`45.
`
`The prior art disclosed a number of fulvestrant fomiulations. See.
`
`e.g., Exs‘. 1005 (McLeskey); 1006 (Howell 1996); 1007 (Dukes 1989); 1008
`
`(Wakeling 1991); 1009 (Wakeling 1992); 1012 (Howell 1995); 1013 (O’Regan
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 18
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`AstraZeneca Exhibit 2092 p. 18
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`1998); 1014 (Lu 1998); 1018 (Osborne 1995);. 1025 (Dukes 1992); 1026 (Dukes
`
`1993); 1027 (Befriend 1994); 1028 Makeling 1993); 10.30 (Lu 1999). These
`
`formulations used conventional excipients, e.g., castor oil, benzyl alcohol, benzyl
`
`benzoate, and ethanol, for their known purposes to achieve a formulated product.
`
`McLeskey, as one example, disclosed a fulvestrant formulation with 10% ethanol,
`
`10% benzyl alcohol, 15% benzyl benzoate and a sufficient amount of a castor oil
`
`vehicle. Ex. 1005 at 2.
`
`46.
`
`The excipients used in prior art
`
`fulvestrant
`
`formulations are
`
`conventional excipients often used in injectable depots.
`
`The POSA would.
`
`understand that a fulvestrant fonnulation containing excipients as disclosed in
`
`McLeskey and other prior art references were suitable and appropriate for
`
`intramuscular injection in humans
`
`(a)
`
`Castor Oil
`
`47, Many prior art publications disclosed fulvestrant formulated in castor
`
`oil. See, e.g., Exs. 1006 (Howell 1996) at 2', 1005 (McLeskey) at 2; 1007 (Dukes
`
`1989) at 7, 9; 1025 (Dukes 1992) at 3, 6; 1026 (Dukes 1993) at 2; 1018 (Osborne
`
`1995) at 2; 1030 (Lu 1999) at 7.
`
`48.
`
`Castor oil has long been known as a conventional pharmaceutical
`
`carrier for steroid hormones See, e.g., Exs. 1019 (Lehmann) at col. 1, 11. 21—26;
`
`1007 (Dukes 1989) at 5; 1020 (GB 286) at 1; 1022 (Riflkin) at 2—4; 1040
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 19
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`AstraZeneca Exhibit 2092 p. 19
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`(Schulze) at col. ‘7', 11. 42—43.
`
`It was known in the art to formulate both steroidal
`
`and non—steroidal antiestrogens in castor oil. See, sag, Ex. 1041 (Neurnann) at col.
`
`9,
`
`II. 22—29 (discussing the formulation of both non-steroidal and steroidal
`
`anticstrogens in castor oil suitable for i.m. injection).
`
`49.
`
`Castor oil differs from com, peanut, and mast other vegetable oils in
`
`that castor .oil has significant quantifies of r'icinoleic acid. Ex. 1022 (Riffldn) at 3.
`
`Ricinoleic acid has a 'hydroxyl fimctional group that increases the. oil’s hydrogen
`
`bonding and polarity character compared to other vegetable oils. See id. This in
`
`turn increases the solvent power of the oil.
`
`Id.
`
`In other words, castor oil is a
`
`particularly good solvent for phannaceutical applications.
`
`50.
`
`Castor oil
`
`is frequently used to create long—acting pharmaceutical
`
`formulations. This is because castor oil persists longer in the tissue than some
`
`other pharmaceuticwa acceptable oils. See, e.g., id. at 1.
`
`(b)
`
`Ethanol
`
`51.
`
`Ethanol was a common conventional excipient used in prior art oil-
`
`based fulvestrant formulations.
`
`See, e.g., Exs. 1005 (McLeskey) at 2; 1008
`
`(Wakeling 1991) at 2. Ethanol was and is. one of the most common solvents used
`
`in pharmaceutical formulations. See. e.g., Ex. 1021 (Remington’s) at 7'.
`
`It is
`
`typically included in formulations as an antimicrobial agent, (at, but it can also be
`
`used as a solvent.
`
`The POSA would understand that a product for in.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 20
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`AstraZeneca Exhibit 2092 p. 20
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`administration can contain 5—50% alcohol. See Ex. 1010 (Spiegel & Noseworthy)
`
`at 8 (referring to the United States Phannacopeia standard and giving examples of
`
`drug formulations containing 50% ethanol or less and administered intramuscularly
`
`or intravenously).
`
`(c)
`
`BenzylAIcokot
`
`52.
`
`Benzyl alcohol was also included in prior art
`
`fonnulations of
`
`fillvestrant. See. ag, Exs, 1005 flVcheskey) a1 2; 1007 (Dukes 1989) at 7, 9; 1016
`
`(Peyser) at 2. The prior art disclosed that solvents such as benzyl alcohol can be
`
`used to increase the solvent power of oils,
`
`Exs. 1022 (Rifildn) at 2; 1041
`
`(Neumann) at cell 9, 1L 27—29 (“To increase solubility [of the non—steroidal or
`
`steroidal antiestrogen in an 0in solution, such as a solution in castor oil], it is also
`
`possible to add solubilizers, for example, benzyl benzoate or benzyl alcohol”); see
`
`also Ex. 1040 (Schulze) at col. 7,11. 43—45.
`
`53, Benzyl alcohol has other beneficial properties that often wanant its
`
`inclusion in pharmaceutical fonnulations. For example, benzyl alcohol is known
`
`to reduce the viscosity of oil—based formulations and to act as a local anesthetic for
`
`injectables. See, e.g.., Ex. 1022 (Riffkin) at 4 (noting that the addition of benzyl
`
`alcohol and benzyl benzoate to castor oil resulted in a more favorable viscosity,
`
`which made the fonnulation easier to inject, and benzyl alcohol was an effective
`
`preservative and local anesthetic).
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 21
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`AstraZeneca Exhibit 2092 p. 21
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`(d)
`
`Benzyl Benzoate
`
`54.
`
`Benzyl 'benzoate is a conventional synthetic solvent often used for
`
`steroid hormones. See Exs. 1005 (Mchskey) at 2; 1019 (Lehmann) at col. 1, 11.
`
`14—36; 1020 (GB ’286) at 1; see also Ex. 1040 (Schfilze) at col. 7, 11. 43—45, 52—
`
`53.
`
`55.
`
`Benzyl benzoate is commonly used as a solubilizing agent and non-
`
`aqueoos
`
`solvent
`
`in miramuscular
`
`injections.
`
`Ex.
`
`1023
`
`(Handbook of
`
`Pharmaceutical Excipients) at 9; see also Ex. 1010 (Spiegel & Noseworthy) at 2—3.
`
`Be