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, Ph.D. IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 1
`
`

`
`I.
`
`C.
`
`D.
`
`II.
`III.
`IV.
`V.
`VI.
`VII.
`
`TABLE OF CONTENTS
`QUALIFICATIONS AND BACKGROUND .....................................................................4
`A.
`Education and Experience; Prior Testimony ...........................................................4
`B.
`Bases for Opinions and Materials Considered .........................................................7
`SUMMARY OF OPINIONS ...............................................................................................8
`LEGAL STANDARDS .......................................................................................................9
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”) ...........................................10
`U.S. PATENT NO. 8,329,680 [Ex. 1001] .........................................................................12
`CLAIM CONSTRUCTION ...............................................................................................16
`SCOPE AND CONTENT OF THE PRIOR ART .............................................................18
`A.
`Fulvestrant Was Well Known in the Prior Art as a Pure Antiestrogen .................18
`B.
`The Prior Art Disclosed Fulvestrant Formulations ................................................18
`Castor Oil...................................................................................................19
`(a)
`Ethanol .......................................................................................................20
`(b)
`Benzyl Alcohol ...........................................................................................21
`(c)
`Benzyl Benzoate .........................................................................................22
`(d)
`Intramuscular Injection of Fulvestrant 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
`McLeskey [Ex. 1005].............................................................................................25
`A POSA Would Have Understood that the Formulation in
`(a)
`McLeskey Was Expressed in %w/v ............................................................28
`A POSA Would Have Known that the Formulation in McLeskey
`Was a Solution ...........................................................................................31
`Howell 1996 [Ex. 1006] .........................................................................................33
`F.
`EP 0 346 014 (“Dukes 1989”) [Ex. 1007] .............................................................34
`G.
`H. Wakeling 1991 [Ex. 1008] .....................................................................................35
`I.
`Wakeling 1992 [Ex. 1009] .....................................................................................36
`J.
`Dukes 1992 [Ex. 1025] ..........................................................................................37
`K.
`Dukes 1993 [Ex. 1026] ..........................................................................................38
`VIII. CLAIMS 1-20 OF THE ’680 PATENT WERE UNPATENTABLE ................................39
`A.
`Ground 1: Claims 1-20 of the ’680 Patent Were Obvious Over McLeskey .........39
`Independent Claim 1 Was Obvious Over McLeskey ..................................40
`(a)
`Independent Claim 9 Was Obvious over McLeskey ...................................45
`(b)
`
`E.
`
`(b)
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 2
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`

`
`Dependent Claims 2 and 10 Were Obvious Over McLeskey .....................47
`(c)
`Dependent Claims 3, 6, 11, and 14 Were Obvious over McLeskey ...........49
`(d)
`Dependent Claims 4, 7, 12, and 15 Were Obvious over McLeskey ...........50
`(e)
`Dependent Claims 5, 8, 13 and 16 Were Obvious over McLeskey ............51
`(f)
`Dependent Claims 17–20 Were Obvious over McLeskey ..........................52
`(g)
`Ground 2: All Claims of the ’680 Patent Were Obvious Over Howell 1996
`In View of McLeskey ............................................................................................53
`The POSA Would Have Been Motivated to Combine the Howell
`(a)
`1996 and McLeskey References .................................................................53
`Independent Claim 1 Was Obvious over Howell 1996 in view of
`McLeskey....................................................................................................54
`Independent Claim 9 Was Obvious over Howell 1996 in View of
`McLeskey....................................................................................................57
`Dependent Claims 2 and 10 Were Obvious Over Howell in View of
`McLeskey....................................................................................................59
`Dependent Claims 3, 6, 11, and 14 Were Obvious over Howell
`1996 in View of McLeskey .........................................................................61
`Dependent Claims 4, 7, 12 and 15 Were Obvious over Howell
`1996 in View of McLeskey .........................................................................61
`Dependent Claims 5, 8, 13 and 16 Were Obvious over McLeskey ............63
`(g)
`Dependent Claims 17–20 Were Obvious over McLeskey ..........................64
`(h)
`THE CLAIMS OF THE ’680 PATENT DID NOT ACHIEVE ANY
`UNEXPECTED RESULT .................................................................................................64
`A POSA Would Have Understood that Solubility of a Drug Does Not
`A.
`Depend Solely on Its Solubility in Each Solvent Individually ..............................65
`Examples of Increased Solubility of a Solute in a Mixture of
`(a)
`Solvents Were Disclosed in the Art ............................................................66
`A POSA Would Have Expected that the Addition of Benzyl Benzoate
`Would Improve the Solubility of Fulvestrant ........................................................67
`The Solubility of a Solute in a Solvent (or Mixture of Solvents)
`(a)
`Depends on Molecular Forces ...................................................................67
`Intermolecular Forces Between Fulvestrant and the Excipients in
`the ’680 Patent Claims Would Have Led a POSA to Predict that
`Adding Benzyl Benzoate Would Have Improved the Solubility of
`Fulvestrant .................................................................................................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 Performed Routine Solubility Calculations ............................70
`CONCLUSION ..................................................................................................................71
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`(f)
`
`(b)
`
`B.
`
`B.
`
`C.
`
`IX.
`
`X.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 3
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`

`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A.
`
`1.
`
`Education and Experience; Prior Testimony
`
`My name is M. Laird Forrest, Ph.D. I have been retained by counsel
`
`for Mylan Pharmaceuticals Inc. (“Mylan”). I understand that Mylan intends to
`
`petition for inter partes review of U.S. Patent No. 8,329,680 (“the ’680 patent”)
`
`[Ex. 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 Ph.D. 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
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`

`
`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 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 2009, 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 (“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 Pharmacy, New
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 5
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`

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`Investigators Award (2007); and the PhRMA Foundation Postdoctoral Fellow
`
`(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 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 peer-reviewed journal articles and 5
`
`book chapters. I 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 formulation, 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
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`

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`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.
`
`b.
`
`c.
`
`Merck Sharp & Dohme Corp. v. Savior Lifetec Corp., No. 5:15-
`cv-00415-TWB (E.D.N.C.)
`
`Medac Pharma, Inc. et. al. v. Antares Pharma Inc. et al., No.
`1:14-cv-01498-JBS-KMW (D.N.J.), and
`
`vs. Breckenridge
`al.
`et
`Inc.
`Par Pharmaceutical,
`Pharmaceutical, Inc. et al., 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 amount 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.
`
`12.
`
`Bases for Opinions and Materials Considered
`
`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,
`
`M.D., and agree with her analysis as to the treatment aspects of the ’680 patent.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 7
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`

`
`II.
`
`SUMMARY OF OPINIONS
`
`14.
`
`It is my opinion that claims 1–20 of the ’680 patent were obvious over
`
`McLeskey [Ex. 1005]. Independent claims 1 and 9 of the ’680 patent relate to the
`
`administration of a certain fulvestrant formulation in an intramuscular (“i.m.”)
`
`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
`
`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 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 fulvestrant formulations in castor oil achieve long-acting 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 8
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`

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`the POSA a formulated fulvestrant 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 obviousness 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 of non-obviousness.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 9
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`

`
`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 IN 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
`
`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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`

`
`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
`
`pharmacokinetics. A POSA 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 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
`
`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
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`

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`pharmaceutical formulation,
`
`including pre-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 of pharmaceutical formulation.
`
`26. A POSA 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 NO. 8,329,680 [Ex. 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. Ex. 1001. The
`
`’680 patent also disclosed that it was a continuation of No. 10/872,784, 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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`

`
`Table 1. Claims of the ’680 Patent
`Fulvestrant Component
`Indications for Fulvestrant
`
`As Claimed in the ’680 Patent
`Claims 1, 9: hormonal dependent benign or
`malignant diseases of the human breast or
`reproductive tract
`Claim 3, 6, 11, 14: breast cancer
`Claims 1, 4, 7, 9, 12, 15: IM2 injection
`Claims 5, 8, 13, 16: once monthly
`Claims 17–20: divided dose
`Claims 4, 7, 12, 15: 5 ml
`
`Route of Administration
`Frequency of Administration
`Fulvestrant Dose
`Volume of Formulated
`Fulvestrant Administered
`Claims 1, 9: about 50 mg/ml
`Fulvestrant Concentration
`Final Formulation of Fulvestrant Claim 1:
`“comprising”
`about 50 mgml-1 of fulvestrant
`about 10% w/v ethanol
`about 10% w/v benzyl alcohol
`about 15% w/v benzyl benzoate
`sufficient amount of a castor oil vehicle
`Claim 9:
`“consisting essentially of”
`about 50 mgml-1 of fulvestrant
`about 10% w/v ethanol
`about 10% w/v benzyl alcohol
`about 15% w/v benzyl benzoate
`Claims 1, 9: at least 2.5 ng/ml for at least 4
`weeks
`Claim 2, 10: at least 8.5 ng/ml for at least 4
`weeks
`
`Blood Plasma Fulvestrant
`Concentration Levels and Their
`Durations
`
`29.
`
`I understand that Mylan is challenging claims 1–20. The ’680 patent
`
`includes 2 independent claims: claims 1 and 9.
`
`2 Intramuscular, also denoted “i.m.”
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 13
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`

`
`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-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-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
`consisting essentially of: about 50 mgml-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-1 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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`

`
`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 from
`
`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 11 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 fulvestrant 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 fulvestrant formulation is administered
`
`intramuscularly to a human.
`
`37. Dependent claims 5 and 13 depend from claims 1 or 2, respectively,
`
`and recite that the fulvestrant formulation is administered once monthly.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 15
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`

`
`Dependent claims 8 and 16 depend indirectly from claims 1 or 2, respectively, and
`
`recite that the fulvestrant formulation is administered once monthly.
`
`38. Claims 17–18 depend directly or indirectly, respectively, from claim
`
`1, 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 Ex. 1001 at col. 11, ll. 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 ll. 51–53, col. 13 ll. 14–16, merely expresses an
`
`intended result of the administration of the fulvestrant formulation recited in the
`
`claims of the ’680 patent. Likewise, the term “wherein the method achieves a
`
`therapeutically significant blood plasma fulvestrant concentration [of] at least 8.5
`
`ngml-1,” Ex. 1001 at col. 12 ll. 54–56, col. 13 ll. 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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`

`
`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
`
`“therapeutically significant” is understood, based on the specification, to mean any
`
`blood plasma fulvestrant concentration of at least 2.5 ngml-1 (claims 1, 9) or 8.5
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`ngml-1 (claims 2, 10) that is attained for 4 weeks after injection. Ex. 1001 at col. 9,
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`ll. 24–28.
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`42.
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`To the extent the Board believes that any of the “wherein” terms
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`recited in paragraph 40 are entitled to any patentable weight, the term “attained” is
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`understood under the broadest reasonable interpretation of the term to mean
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`“achieved an average concentration (Cavg) in a patient over the specified time
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`period.” The term “attained” is never defined in the specification, and the patent
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`does not include any instructions on how the POSA would have maintained the
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`specified concentrations over the entire specified time periods (or why it would
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`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
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`plasma concentration that is, on average, at least 2.5 ngml-1 (claims 1, 9) or at least
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`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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`

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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
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`A.
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`Fulvestrant Was Well Known in the Prior Art as a Pure
`Antiestrogen
`
`43.
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`Fulvestrant, the compound that is the subject of the claims of the ’680
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`patent, is known chemically as (cid:26)(cid:302)-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]
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`oestra-1,3,5(10)-triene-(cid:22)(cid:15)(cid:20)(cid:26)(cid:533)-diol. It is also known by its code name ICI 182,780.
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`Fulvestrant has the following chemical structure:
`
`44.
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`Fulvestrant was known in the prior art to be a pure antiestrogen that
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`has high binding affinity for the estrogen receptor and no residual estrogen
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`stimulating activity. See, e.g., Ex. 1008 at 5. Because of their mechanism of
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`action, antiestrogens are known to be effective in the treatment of breast cancer.
`
`B.
`
`45.
`
`The Prior Art Disclosed Fulvestrant Formulations
`The prior art disclosed a number of fulvestrant formulations. See,
`
`e.g., Exs. 1005 (McLeskey); 1006 (Howell 1996); 1007 (Dukes 1989); 1008
`
`(Wakeling 1991); 1009 (Wakeling 1992); 1012 (Howell 1995); 1013 (O’Regan
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 18
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`1998); 1014 (Lu 1998); 1018 (Osborne 1995); 1025 (Dukes 1992); 1026 (Dukes
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`1993); 1027 (Defriend 1994); 1028 (Wakeling 1993); 1030 (Lu 1999). These
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`formulations used conventional excipients, e.g., castor oil, benzyl alcohol, benzyl
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`benzoate, and ethanol, for their known purposes to achieve a formulated product.
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`McLeskey, as one example, disclosed a fulvestrant formulation with 10% ethanol,
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`10% benzyl alcohol, 15% benzyl benzoate and a sufficient amount of a castor oil
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`vehicle. Ex. 1005 at 2.
`
`46.
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`The excipients used in prior art fulvestrant formulations are
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`conventional excipients often used in injectable depots. The POSA would
`
`understand that a fulvestrant formulation containing excipients as disclosed in
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`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
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`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, ll. 21–26;
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`1007 (Dukes 1989) at 5; 1020 (GB ’286) at 1; 1022 (Riffkin) at 2–4; 1040
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 19
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`(Schülze) at col. 7, ll. 42–43. It was known in the art to formulate both steroidal
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`and non-steroidal antiestrogens in castor oil. See, e.g., Ex. 1041 (Neumann) at col.
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`9, ll. 22–29 (discussing the formulation of both non-steroidal and steroidal
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`antiestrogens in castor oil suitable for i.m. injection).
`
`49. Castor oil differs from corn, peanut, and most other vegetable oils in
`
`that castor oil has significant quantities of ricinoleic acid. Ex. 1022 (Riffkin) at 3.
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`Ricinoleic acid has a hydroxyl functional 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.
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`In other words, castor oil is a
`
`particularly good solvent for pharmaceutical applications.
`
`50. Castor oil is frequently used to create long-acting pharmaceutical
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`formulations. This is because castor oil persists longer in the tissue than some
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`other pharmaceutically acceptable oils. See, e.g., id. at 1.
`
`(b)
`
`Ethanol
`Ethanol was a common conventional excipient used in prior art oil-
`
`51.
`
`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.
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`It is
`
`typically included in formulations as an antimicrobial agent, id., but it can also be
`
`used as a solvent.
`
`The POSA would understand that a product for i.m.
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 20
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`administration can contain 5–50% alcohol. See Ex. 1010 (Spiegel & Noseworthy)
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`at 8 (referring to the United States Pharmacopeia standard and giving examples of
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`drug formulations containing 50% ethanol or less and administered intramuscularly
`
`or intravenously).
`
`(c)
`
`Benzyl Alcohol
`52. Benzyl alcohol was also included in prior art formulations of
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`fulvestrant. See, e.g., Exs. 1005 (McLeskey) at 2; 1007 (Dukes 1989) at 7, 9; 1016
`
`(Poyser) at 2. The prior art disclosed that solvents such as benzyl alcohol can be
`
`used to increase the solvent power of oils. Exs. 1022 (Riffkin) at 2; 1041
`
`(Neumann) at col. 9, ll. 27–29 (“To increase solubility [of the non-steroidal or
`
`steroidal antiestrogen in an oily solution, such as a solution in castor oil], it is also
`
`possible to add solubilizers, for example, benzyl benzoa