UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN PHARMACEUTICALS INC.
`
`Patitioner,
`
`v.
`
`ASTRAZENECA AB
`
`Patent Owner.
`
`
`Patent NC). 8,329,680
`
`DECLARATION OF LAIRD FORREST, FILL). IN SUPPORT OF
`PETITION FOR INTER RARTES REVIEW
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 1
`
`"I.
`Astrafleneca Exhibit 2092 p.
`InnoPharma Licensing LLC v. AstraZeneca AB [PENN-00900
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01913
`
`

`

`
`TABLE OF CONTENTS
`
`QUALIFICATIONS AND BACKGROUND ...................................................................4
`
`A.
`
`B.
`
`Education and Experience; Prim Testimony4
`
`Bases fer Opinions and Materials Considered ......................................................... 7
`
`SUMMARY OF OPINIONS ............................................................................................... 8
`
`LEGAL STANDARDS ...................................................................................................... 9
`
`PERSON OF ORDINARY SKILL [N THE ART (ROSA”) ........................................... 10
`US. PATENT NO” 8,329,680 [Ex 1001] ......................................................................... 12
`
`11‘
`
`[IL
`
`IV.
`
`VI,
`
`CLAIM CONSTRUCTION ............................................................................................... 16
`
`VII_
`
`SCOPE AND CONTENT OF THE PRIOR ART.~.H..18
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F
`
`G.
`
`Ht
`
`l
`
`J“
`
`K.
`
`‘Fulvestrant Was Well Known in the flier Art as a Pure Antiestrngen ................. 18
`
`The Print Art Disclnsed Fulvestrant Formulations ............................................... 18
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`Castor01119
`
`Etta-(moi ................................................. . ..................................................... 20
`
`Benzyl Alcohal ........................................................................................... 21
`
`Benz1;! Benztmte ......................................................................................... 22
`
`Intramuscular Injection of Fulvestrant Was Known as the Superior Route
`of Administration in the Prior Art......................................................................... 22
`
`Oil—lased Intramuscular Depot Inj ectitm Was Conventional in the Fri 0r
`Art .......................................................................................................................... 23
`
`McLeskey [Ex 1005] ............................................................................................. 25
`
`(a)
`
`(b)
`
`A POSA Would Have {Arderstnud that the trbrmulattan in
`MCLESIIQV Was Expressnd if? 913w i! ............................................................ 28
`
`A POSA Wank! Have Known that the Irbrnmlattan in McLeskey
`Was {It 50111th ........................................................................................... 31
`
`Howell 1996 [Est 1006] ................................... . ..................................................... 33
`
`EP 0 346 014 (“Dukes 1989“) [Ex 100?] ............................................................. 34
`
`Wakeling 1991 [Ex 1008] ..................................................................................... 35
`
`Wakeling 1992 [Ex 1009] ..................................................................................... 36
`
`Dukes1992[Ex 1025] 37
`
`Dukes 1993 [Ex 1026] ......................................................................................... 38
`
`VIII,
`
`CLAIMS 1—20 OF THE 680 PATENT WERE UNPATENTABLE ................................ 39
`
`A.
`
`Ground 1: Claims 1~20 fifthe 680 Patent Were Obvious Over McLeskey ......... 39
`
`(51)
`
`(13)
`
`Independent Claim 1 Was ()bvtntts Over McLets'key ..................................AU
`
`Independent Claim 9 Was Obvious over Mctieskey................................... 45
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 2
`
`Astraleneca Exhibit 2092 pt 2
`
`

`

`(c)
`
`(d)
`
`(e)
`
`(f)
`
`(g)
`
`Dependen! (31629733 2 and i0 Were Obvious Over McLeskev .....................47
`
`Dependem ('Tiuims 3, 6. i i! and 14‘ Were Obvious over MoLaskey ........... 49
`
`Dependefli (ll/aims 4, F, 12, and i5 Were Obvious over McLeSkey ........... SQ
`
`Dependent Claims 5. 8, i 3 and 16 Were Obvious over AJcLeskey ............ 51
`
`Dependent Claims 1 7—20 Wei-e thiow; over McLeskey.,...
`
`.
`
`.
`
`l
`
`.
`
`52
`
`B.
`
`Ground 2: All Claims of the ‘680 Patent Were Obvious Clver Howell 1996
`
`In View of McLeskey ............................................................................................ 53
`
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`(f)
`
`(g)
`
`(h)
`
`The P034 Would Have Been Axi'otivawd to Combine the Howell
`1996 and Mafileskev Rejérencex ................................................................. 53
`
`Irzdependeni Claim 1 W253 Ohvicms over Howell I996 in view of
`McLe.5*key.................................................................................................... 54
`
`independem Claim 9 WE” Obvious over Howell I996 in It’iew of
`McLeSkev............................................................................................... _.,. . ‘57
`
`Dependem Claims 2 mid 10 Were Obvious Over Hawaii in View of
`McLe.5*key.................................................................................................... 59
`
`Dependeni Claims 3, 61, LL and 1-“! Were Obvious over Howell
`1996 in View ofMcLeskey ......................................................................... 61
`
`Dependent Claims 4, 71 12 mm? 15 Were. Dblriozis over Howell
`i996 in View qucLeskey ........................................................................ :51
`
`Degendmi Claims 5, 8% i3 and 16 Were Obvious over McLeskey ............ 63
`
`Dependent Claims 1 ?—20 Were Obvious over McLeskey .......................... 64
`
`IX‘
`
`THE CLAIMS OF THE ’680 PATENT DID NOT ACHIEVE ANY
`
`UNEXPECTED RESULT ................................................................................................ 64
`
`A.
`
`B
`
`C;
`
`A POSA Would Have Understood that Solubility of a Drug Does Not
`Depend Solely on Its Solubility in Each Solvent Individually .............................. 65
`
`(a)
`
`Exaowles ofliwremed lS'm’zifizilfiy {gfa Soluie in a Mixizcre of
`Solvents Were Disclosed in the Ar? ............................................................ 66
`
`A POSA Would Have Expected that the Addition of Benzyl Benzoate
`Would Improve the Solubility uf‘Fulvestrant ...................................................... 67
`
`(a)
`
`(b)
`
`fire Solubiliiy qfa Sci/Hie in a Soivem (or Mixture cngohfiae'nm
`Depends on Molecular Forces ................................................................... 67
`
`Intermoleczdar Ii‘or'ces Ben-veer: Mill-*esirmit and the Ekemienix if?
`the V580 Paienl Claims Would Have Led 6: 1305A m Predict 1km
`
`Adding Benzyl Beneoaie Would Have Improved the Soi‘ubiiigv of
`Fulvestmn: ................................................................................................. 68
`
`To Confirm the POSA“S Expectation that the Addition of Benzyl Benzoate
`Would Increase the Solubility of Fulvestrant in the Solvent Mixture, the
`POSA Could Have Perfonned Routine Solubility Calculations ............................ 70
`
`CONCLUSION .................................................................................................................. 71
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 3
`
`Astraleneca Exhibit 2092 p. 3
`
`

`

`l.
`
`QUALIFICATIDNS AND BACKGROUND
`
`A.
`
`1.
`
`Education and Experience; Prior Testimony
`
`My name is M. Laird Forrest, PhD.
`
`I have been retained by counsel
`
`for Mylar: Phamiaceuticais inc. (“Mylan”).
`
`i understand that Mylan intends to
`
`petition for inter partes review of US, Patent No. 8329:6801 (“the ’680 patent”)
`
`[Es 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 unpatentahle in that petition.
`
`I submit this expert
`
`declaration in support of Mylatfs petition.
`
`2.
`
`I am currently an Associate Professor
`
`in the Department of
`
`Pharmaceutical Chemistiy 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 Chemisny, 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 200], and a PhD.
`
`in Chemical and Biomolecular
`
`Engineering from the University of Illinois in 2003.
`
`l was a Postdoctoral Fellow in
`
`the Division of Pharmaceutical Sciences at the University of Wisconsin, Madison
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 4
`
`Astraleneca Exhibit 2092 pt 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 until 201].
`
`In 20071 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 2009,
`
`l 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 Nanophann
`
`LLC (d/b/a Hylaphann), founded in 201], which specializes in formulation of anti»
`
`cancer chemotlierapcutics. 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 Phannaceutical Research and Manufacturers of
`
`America Foundation (“PhRMA”), 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
`
`(2008 to 2012);
`
`the American Association of Colleges of Phannacy, New
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 5
`
`Astraleneca Exhibit 2092 p. 5
`
`

`

`Investigators Award (2007); and the PILRMA Foundation Postdoctoral Fallow
`
`(2006); among others.
`
`6.
`
`I am currently or have been in the past a member of various
`
`professional societies, including the American Association for Cancer Research,
`
`the American Association of Phannaceutical Scientists, and the American Institute
`
`of Chemical Engineers;
`
`l serve or have sewed on numerous scientific review
`
`panels for the National
`
`Institutes of Health’s National Cancer Institute,
`
`the
`
`American Cancer Society, and the Association for lntemational 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 peer~reviewed journal anticles and 5
`
`book chapters» I have also edited 2 special journal issues on drug delively and a
`
`hook on drug delivery and fonnulation. A list of all publications that l have
`
`authored is included in my curriculum vitae} attached as Exhibit A to this
`
`Declaration.
`
`8.
`
`I have taught drug formulation, including all aspects of drug excipient
`
`choice and the effects of excipient mdification on drug chemical stability,
`
`solution solubility, dissolution, and phannacokinetics,
`
`to clinical pharmacy
`
`students and graduate students studying pharmaceutical fonnul ation since 2007.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 6
`
`Astraleneca Exhibit 2092 p. 6
`
`

`

`9,
`
`I have experience in all aspects of parenteral and oral drug
`
`formulation through my research and teaching. Additionally, as pan of my work
`
`with Nanopharrn and Exogenesis, I have worked on phannaceutical formulations
`
`for intramuscular, subcutaneous, intravenous, topical, and oral formulation.
`
`10.
`
`In the past six years, I have testified in the following litigations:
`
`a.
`
`b,
`
`C,
`
`w[Liferole Sharp cli- Dohnra Corp. V. Savior Lifetec Corp, No. 5:15-
`CV~0041 S-TWB (E.D.N.C.)
`
`Adenine Pharma, [no at, Cd.
`12. Antares Pharma inc. at (11., No,
`1:l4—cv~fll498-JBS—KMW (D.N.J.), and
`
`Breckenridge
`vs,
`al.
`of
`Inc.
`Pharmaceutical,
`For
`Pharmaceutical, Inc. at (13., No. 1:15-cv-Di3486-SLR (D. Del).
`
`1 1.
`
`I am being compensated for my time at my standard consulting rate of
`
`$595/hour, Neither the amount of my compensation nor the fact that 1 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.
`
`I.
`
`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 ot‘Dr. Leslie Oleksowicz,
`
`Ml), and agree with her analysis as to the treatment aspects of the “680 patent.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 7
`
`Astraleneca Exhibit 2092 pt 7
`
`

`

`I].
`
`SUMMARY OF OPINlONS
`
`14.
`
`It is my opinion that claims l~20 of the ”680 patent were obvious over
`
`McLeskey [Ext 1005].
`
`Independent claims I and 9 of the ”680 patent relate to the
`
`administration of a certain fulvestrant formulation in an intramuscular (“int”)
`
`injection to humans to treat benign and malignant diseases of the breast or
`
`reproductive tract, such as breast cancer. A fonnulation falling squarely within the
`
`claimed 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, fulvestrant was known to be administered as an
`
`intramuscular injection
`
`15.
`
`It is also my opinion that claims l»20 of the ”680 patent would have
`
`been obvious over Howell 1996 [Era 1006] in View of McLeskey [Etc 1005].
`
`Howell 1996 disclosed fulvestrant fonuulations in a caster oil~hased depot
`
`injection to treat malignant breast cancer in women. Howell 1996 also disclosed
`
`that fulvestrant formulations in castor oil achieve longectingF effects. With Howell
`
`1996’s disclosure that fulvestrant administered in castor 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 3
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`Astraleneca Exhibit 2092 p, 8
`
`

`

`the POSA a formulated fulvestrant product exactly as recited in the claims of the
`
`3680 patent.
`
`III. LEGAL STANDAS
`
`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 widerstanding
`
`of these principles in forming my opinions My understanding of these principles
`
`is summarized below.
`
`17.
`
`I have been told that Mylan hears
`
`the hnrden of proving
`
`mipatentability by a preponderance of the evidence.
`
`I am informed that this
`
`preponderance of the evidence standard means that Mylan must Show that
`
`nnpatentability 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 obviousness involves four factual
`
`inquiries: (l) 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 of non—ohvionsness.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 9
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`Astraleneca Exhibit 2092 p. 9
`
`

`

`2D.
`
`I am also informed that when there is some recognized reason to solve
`
`a problem, and there are a finite ntnnber of identified, predictable, and known
`
`solutions, a PQSA 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 0F 0RDINARY SKILL IN THE ART (“PISA”)
`
`22.
`
`I understand that the ohviousness analysis is to be conducted from the
`
`perspective of a POSA at the time of the invention.
`
`1 have applied that standard in
`
`the analysis in this declaration. When I discuss the teachings of the prior art, I
`
`discuss 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
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`

`

`encountered in the art, (3) prior art solutions to those problems, (4) rapidity with
`
`which iimovations 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 PQSA
`
`would have had a pharmacy degree or graduate degree in either pharmacy,
`
`phannaceutics, chemistry, or a related discipline, or equivalent experience in drug
`
`development and fonnulation, and would also have familiarity with and knowledge
`
`of designing and fonnulating drug dosage fonns. The POSA would have at least 2
`
`years
`
`of
`
`practical
`
`experience
`
`in
`
`phannaceutical
`
`formulations
`
`and
`
`phannacokinetics. A POSA would collaborate with others having expertise in, for
`
`example, methods of treating disease and administering medicines.
`
`25. A PDSA would have a general understanding and knowledge of the
`
`basic principles of fonnulation development.
`
`In addition to experimental
`
`knowledge in formulation development,
`
`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
`
`phannaceutical fonnulation; and theoretic and experimental methodologies of
`
`
`' I understand that the earliest application giving rise to the ”680 patent was filed
`
`On January 10, 2000. Thus, I Lmderstand 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
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`AstraZeneca Exhibit 2092 pt 1 l
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`

`

`pliannaceutical
`
`fonnulation,
`
`including pie-formulation 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 ofphannaceutical formulation.
`
`26-
`
`A POSA would also have both the tools and the ability to research
`
`prior art literanlre to find information on fulvestrant, its prior art fonnulations, and
`
`its prior art utility.
`
`v.
`
`US. PATENT No. 8,329,680 1122:. 1001]
`
`27.
`
`I have read and understood the "”680 patella entitled “Fonnulation.”
`
`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. 101872384; filed on
`
`June 22, 2004, which was now US. Patent No. 7,456,160. The "”680 patent issued
`
`on November 253 2008, and names John R. Evans and Rosalind U. Grundy as
`
`inventors.
`
`28.
`
`The following table organizes each recitation in the claims by the
`
`elai1n(s) in which the recitation appears:
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 12
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`AstraZeneca Exhibit 2092 p. 12
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`

`

`
`
`
`
`Tab} 1Elaims;ni_tlie__i689”Fatent
`________________________________________
`Indications for Fulvestr‘ant
`Claims 1 9: heminiial dependent benign or
`
`
`
`malignant diseases of the human breast or
`
`reproductive tract
`Claim 3, 6, 11, 14: breast cancer
`
`Rnute andminiatratinn
`Claims 1, 4,, 71 9, 12, 15: 1M injecticn
`
`Frequency cf Administration
`Claims 5, 8, 13, 16: Once manila]
`Fulvest'rant Dose
`Claims 17—20: divided dese
`
`
`
`
`
`Volume 0f Farmulated
`Fulveatrant Administered
`Claims I, 9: abeut SO nag/ml
`Fulvestrant Concentration
`Final Formulation of Fulvestrant Claim 1:
`
`Claims 4, 7, 12, 15: 5 ml
`
`+
`
`“cemptising”
`about 50 mgnfl" cffiilvcstrant
`abnut 10% WW ethanol
`
`about 10% wtv benzyl alcchol
`abcut 15% WW beneyl benzoate
`
`sufficient 3111011111 at a caster nil vehicle
`
`Claim 9:
`
`“consisting essentially of”
`abcut 50 mgml'I cffiilvestrant
`abnut 10% wk ethane]
`
`about 10% WW benzyl alcchnl
`abcut 15% WW bene l benaeate
`
`Claims 1, 9: at least 2.5 ng/ml for at least 4
`
`weeks
`
`Blond Plasma Fnlvestrant
`Cnneentratinn Levels and Their
`
`Claim 2., 10: at least 8.5 rig/nil far at least 4
`Duratinns
`
`weeks
`
`29,
`
`I understand that Mylan is challenging claims L510. The ’680 patent
`
`includes 2 independent claims: claims 1 and 9.
`
`.
`.
`’3
`“ Intramuscular, alsn denoted “Lin.”
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 13
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`AstraZencca Exhibit 2092 pl 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: about 50 mgml"l of fiilvestrant; 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 thlvestrant
`
`concentration of at least 2.5 ngml'l 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
`
`consisting essentially of: about 50 mgml"I of fiilvestrant; about 10%
`
`w/v of ethanol; about 10% wiv 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” for at least four
`
`weeks.
`
`32.
`
`In comparing claims 1 and 9, the primary difference between them is
`
`that claim I
`
`recites that the formulation is “comprising” the listed elements,
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`whereas claim 9 recites that the formulation is “consisting essentially of" the listed
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`elements. Claim 1 also requires a “a sufficient amount of castor oil vehicle,“
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 14
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`AstraZeneca Exhibit 2092 pt 14
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`whereas claim 9 omits this requirement. The disclosed method is otherwise
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`identical between claims I and 9.
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`33. Dependent claims 2nd and 1748 depend directly cr indirectly from
`
`independent claim 1. Dependent claims 10—16 and 1920 depend directly er
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`indirectly frcrn independent claim 9.
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`3d. Dependent claims 2 and 10 depend frcm claims 1 or 2, respectively,
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`and alter the bleed serum ccncentraticn level to at least 8.5 ngml'] fer at least that
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`weeks.
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`35.
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`Dependent claims 3 and 11 depend frcm claims 1 0r 2, respectively,
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`and recite that the disease being treated is breast cancer. Dependent claims 6 and
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`14 depend indirectly from claims 1 or 2, respectively, and recite that the disease
`
`being treated is breast cancer.
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`36. Dependent claims 4 and 1.2 depend from claims 1 cr 2, respectively=
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`and recite that 5 ml of the fulvestrant fcrrnulaticn is administered intramuscularly
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`to a human. Dependent claims ’7 and 15 depend indirectly from claims 1 er 2.,
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`respectively, and recite that 5 ml of the fulvestrant formulation is administered
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`intramuscularly to a human.
`
`37.
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`Dependent claims 5 and 13 depend fmm claims 1, cr 2, respectively,
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`and recite that
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`the fulvestrant
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`fcnnulatien is administered cnce monthly.
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 15
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`AstraZeneca Exhibit 2092 p. 15
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`Dependent claims 8 and lo depend indirectly from claims 1 or 2, respectively, and
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`recite that the fiilvestrant formulation is administered once monthly.
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`38.
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`Claims 1748 depend directly or indirectly, respectively, from claim
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`I, and 19-~20 depend directly or indirectly, respectively, from claim 9, and recite
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`that the fulvestrant formulation is administered in a divided dose.
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`VI. CLAIM CDNSTRUCT [ON
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`39.
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`The term “sufficient amount of a castor oil vehicle” is understood,
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`based on the specification: to mean that for a given volume of formiflation: after
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`the addition of fitlvestrant, ethanol: benzyl alcohol; benzyl benzoate, and any
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`further optional excipients, the remaining volume of the formulation would he
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`castor oil, See BX, 100] at col. 11,11. 640.
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`4C).
`
`The term “wherein the method achieves a therapeutically significant
`
`blood plasma fulvestrant concentration of at least 2.5 ngml'] for at least four
`
`weeks,“ Ex. 1001 at col, 12 ll. Slm53, col. 13 11. 1-446, merely expresses an
`
`intended result of the administration of the fiilvestrant fonnulation recited in the
`
`claims of the 3680 patent Likewise, the term “wherein the method achieves a
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`therapeutically significant blood plasma fiilvestrant concentration [of] at least 8.5
`
`ngml'i,” Ex. 1001 at col. 12 11. 5466, col. 13 11. 17349, merely expresses the
`
`intended result of the administration of the fulvestrant fonnulation recited in the
`
`claims of the ”680 patent. None of this language informs how the method of
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 16
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`AstraZeneca Exhibit 2092 pt 16
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`administering the fulvestrant formulation to a human patient
`
`is carried out.
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`Therefore, it is my Lmderstanding that this phrase is not to be given any patentahle
`
`weight.
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`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
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`‘dlierapeutically significant” is understood, based on the specification, to mean any
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`blood plasma fulvestrant concentration of at least 2.5 ligml'] ("claims 1, 9) or 8.5
`
`ngrnl'I (claims 2, 10) that is attained for 4 weeks afier injection. BX. 100] at col. 9,
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`l]. 2,4ng
`
`42.
`
`To the extent the Board believes that any of the “wherein” terms
`
`recited in paragraph 40 are entitled to any patentahle 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 PQSA would have maintained the
`
`specified concentrations over the entire specified time periods (or why it wordd
`
`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 25 ngml‘l (claims 1, 9) or at least
`
`85 nng (claims ‘2, 10) for 4 weeks afier injection.
`
`I understand a district court
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 17
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`AstraZeneca Exhibit 2092 pl 17
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`has construed attained as “achieved and maintained.” See Ex. 1011 at 2-3. My
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`opinions are unchanged even if the Board were to adopt this construction.
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`VII. SCOPE AND CONTENT OF THE PRIOR ART
`
`A.
`
`Ful‘vestrant Was Well Known in the Prior Art as a Pure
`
`Antiestrogen
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`43.
`
`Fulvestrant, the compound that is the subject of the claims of the ”680
`
`patent, is known chemically as 7o-[9-(414isa55—pentafluoropentylsulphinyl)nonyl]
`
`oestra—l,3,5(lD)-triene~3,ITS—dict
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`It is also known by its code name ICI 182,780.
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`Fulvestrant has the following chemical smicture:
`
`
`
`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, tag, Ex. 1.008 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 Fulvestrant Formulations
`
`45.
`
`The prior art disclosed a number of fiilvestrant formulations. See,
`
`rag, Exs. 1005 (McLeskey); 1006 (Howell 1996); 1007 (Dukes 1989); 1008
`
`(Wakeling 1991); 1009 (Wakeling 1992); 1012 (Howell 1995); 1013 (D’Regan
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 18
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`AstraZeneca Exhibit 2092 pt 18
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`1998); 1014 (Lu 1998); 1018 (Qshorne 1995); 1025 (Dukes 1992.); 1026 (Dukes
`
`1993); 1027 (Defrienri 1994); 1028 (Wakeling 1993); 1030 (Lu 1999). These
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`fonnulations used conventional escipients, ego, castor oil, henzyl alcohol, benzyl
`
`benzoate, and ethanol, for their known purposes to achieve a formulated product.
`
`McLeskey, as one example, disclosed a fulvestrant fonnulation with 10% ethanol,
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`10% benzyl alcohol, 15% benzyi benzoate and a sufficient amount of a castor oil
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`vehicle. Ex. 1005 at2.
`
`46.
`
`The excipients used in prior art
`
`fulvestrant
`
`formulations are
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`conventional cxcipients often used in injectable depots.
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`The PQSA would
`
`understand that a fulvestrant formulation containing excipients as disclosed in
`
`McLeskey and other prior art
`
`references were suitable and appropriate for
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`intramuscular injection in humans.
`
`(a)
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`Castor Oil
`
`47. Many prior art publications disclosed fulvestrant formulated in castor
`
`oil. See, eg, 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.
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`Castor oil has long been known as a conventional pharmaceutical
`
`carrier for steroid hormones. See, Lag, Exs. 1019 (Lehtnann) at col. 1, 11. 2146;
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`1007 (Dukes 1989) at 5; 1020 (GB ”286) at 1; 102:2 (Rifr’kin) 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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`(Schttlze) at col. 7, 1]. 42—43 It was known in the art to formulate both steroidal
`
`and non-steroidal antiestrogens in castor oil. See rang, Ex. 1041 (Neuniann) at col.
`
`9,
`
`II. 2249 (discussing the fornmlation of both non—steroidal and steroidal
`
`antiestrogens in castor oil suitable for im. injection)
`
`49.
`
`Castor oil differs from corn, peanut, and most other vegetable oils in
`
`that castor oil has significant quantities of ticinoleic acid Ext 1022 (Riffldn) at 3.
`
`Ricineleic acid has a hydroxyl fiinctional group that increases the oil’s hydrogen
`
`bonding and polarity character compared to other vegetable oils. See id. This in
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`turn increases the solvent power of the oil. M.
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`In other wards, caster oil is a
`
`particularly good solvent for pharmaceutical applications!
`
`50.
`
`Castor oil
`
`is frequently used to create long—acting phannaceutical
`
`fonnulations. This is because castor oil persists longer in the tissue than some
`
`other phamiaceutically acceptable oils. See, e.g., id. at l.
`
`(h)
`
`Ethanol
`
`51.
`
`Ethanol was a common conventional excipient used in prior art oil—
`
`based fiilvestrant
`
`tonnulations.
`
`See. alga Exs. 1005 (McLeskey) at 2; 1008
`
`(Wakeling 1991) 312. Ethanol was and is one of the most common solvents used
`
`in phamiaceutical tbnnulations.
`
`See. e.g., Ex. 1021 (Remington’s) at 7.
`
`It is
`
`typically included in fonnulations as an antinucrohial agent, id, but it can also he
`
`used as a solvent.
`
`The. POSA would understand that a product
`
`for im.
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 20
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`AstraZeneca Exhibit 2092 p. 20
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`administration can contain 5—5094“: alcohol. See Ex. 1010 (Spiegel & Noseworthy‘)
`
`at 8 (referring to the United States Phannacopeia standard and giving examples of
`
`drug formal ations containing 50% ethanol or less and administered intramuscularly
`
`or intravenously).
`
`(c)
`
`Bengt/l Alcohol
`
`52.
`
`Benzy] alcohol was also included in prior art
`
`fonnnlations of
`
`fiilvestrant. See, eg, Exs. 1005 (McLeskey)a12; 1007 (Dukes 1989) at 7, '9; 1016
`
`(Poyser) at 2. The prior art disclosed that solvents such as benzyl alcohol can he
`
`used to increase the solvent power of oils.
`
`Exs. 1022 (Riflkin) at 2; 1041
`
`(Neumann) at col, 9, 11. 27429 (“To increase solubility [of the non—steroida