UNITED STATES PATENT AND TRADEMARK OFFICE
`————————————————
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`————————————————
`MYLAN PHARMACEUTICALS INC.
`Petitioner,
`v.
`ASTRAZENECA AB
`Patent Owner.
`————————————————
`Patent No. 8,466,139
`————————————————
`
`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 .....................................................................5
`A.
`Education and Experience; Prior Testimony ...........................................................5
`B.
`Bases for Opinions and Materials Considered .........................................................8
`SUMMARY OF OPINIONS ...............................................................................................9
`LEGAL STANDARDS .....................................................................................................10
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”) ...........................................11
`U.S. PATENT NO. 8,466,139 [Ex. 1001] .........................................................................13
`CLAIM CONSTRUCTION ...............................................................................................18
`SCOPE AND CONTENT OF THE PRIOR ART .............................................................20
`A.
`Fulvestrant Was Well Known in the Prior Art as a Pure Antiestrogen .................20
`B.
`The Prior Art Disclosed Fulvestrant Formulations ................................................21
`Castor Oil...................................................................................................22
`(a)
`Ethanol .......................................................................................................23
`(b)
`Benzyl Alcohol ...........................................................................................23
`(c)
`Benzyl Benzoate .........................................................................................24
`(d)
`Intramuscular Injection of Fulvestrant Was Known as the Superior Route
`of Administration in the Prior Art ..........................................................................25
`Oil-Based Intramuscular Depot Injection Was Conventional in the Prior
`Art ..........................................................................................................................26
`McLeskey [Ex. 1005].............................................................................................28
`A POSA Would Have Understood that the Formulation in
`(a)
`McLeskey Was Expressed in %w/v ............................................................30
`A POSA Would Have Known that the Formulation in McLeskey
`Was a Solution ...........................................................................................34
`Howell 1996 [Ex. 1006] .........................................................................................35
`F.
`EP 0 346 014 (“Dukes 1989”) [Ex. 1007] .............................................................36
`G.
`H. Wakeling 1991 [Ex. 1008] .....................................................................................37
`I.
`Wakeling 1992 [Ex. 1009] .....................................................................................38
`J.
`Dukes 1992 [Ex. 1025] ..........................................................................................39
`K.
`Dukes 1993 [Ex. 1026] ..........................................................................................40
`VIII. CLAIMS 1-20 OF THE ’139 PATENT WERE UNPATENTABLE ................................41
`A.
`Ground 1: Claims 1-20 of the ’139 Patent Were Obvious Over McLeskey .........41
`Independent Claim 1 Was Obvious Over McLeskey ..................................42
`(a)
`Independent Claim 11 Was Obvious over McLeskey .................................47
`(b)
`
`E.
`
`(b)
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 2
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`

`
`B.
`
`(b)
`
`(c)
`
`(d)
`
`Dependent Claims 2 and 12 Were Obvious Over McLeskey .....................49
`(c)
`Dependent Claims 3 and 13 Were Obvious Over McLeskey .....................51
`(d)
`Dependent Claims 4 and 14 Were Obvious Over McLeskey .....................52
`(e)
`Dependent Claims 5 and 15 Were Obvious Over McLeskey .....................55
`(f)
`Dependent Claims 6 and 16 Were Obvious Over McLeskey .....................55
`(g)
`Dependent Claims 7 and 17 Were Obvious over McLeskey ......................57
`(h)
`Dependent Claims 8 and 18 Were Obvious over McLeskey ......................59
`(i)
`Dependent Claims 9 and 19 Were Obvious over McLeskey ......................60
`(j)
`Dependent Claims 10 and 20 Were Obvious Over McLeskey ...................61
`(k)
`Ground 2: All Claims of the ’139 Patent Were Obvious Over Howell 1996
`In View of McLeskey ............................................................................................64
`The POSA Would Have Been Motivated to Combine the Howell
`(a)
`1996 and McLeskey References .................................................................64
`Independent Claim 1 Was Obvious Over Howell 1996 in View of
`McLeskey....................................................................................................65
`Independent Claim 11 Was Obvious Over Howell 1996 in View of
`McLeskey....................................................................................................70
`Dependent Claims 2 and 12 Were Obvious Over Howell in View of
`McLeskey....................................................................................................73
`Dependent Claims 3 and 13 Were Obvious Over Howell 1996 in
`View of McLeskey ......................................................................................74
`Dependent Claims 4 and 14 Were Obvious Over Howell 1996 in
`View of McLeskey ......................................................................................76
`Dependent Claims 5 and 15 Were Obvious Over Howell 1996 in
`View of McLeskey ......................................................................................78
`Dependent Claims 6 and 16 Were Obvious Over Howell 1996 in
`View of McLeskey ......................................................................................79
`Dependent Claims 7 and 17 Were Obvious over Howell 1996 in
`View of McLeskey ......................................................................................80
`Dependent Claims 8 and 18 Were Obvious Over Howell 1996 in
`View of McLeskey ......................................................................................82
`Dependent Claims 9 and 19 Were Obvious Over Howell 1996 in
`View of McLeskey ......................................................................................83
`Dependent Claims 10 and 20 Were Obvious Over Howell 1996 in
`View of McLeskey ......................................................................................84
`
`(k)
`
`(e)
`
`(f)
`
`(g)
`
`(h)
`
`(i)
`
`(j)
`
`(l)
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 3
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`

`
`IX.
`
`X.
`
`THE CLAIMS OF THE ’139 PATENT DID NOT ACHIEVE ANY
`UNEXPECTED RESULT .................................................................................................87
`A POSA Would Have Understood that Solubility of a Drug Does Not
`A.
`Depend Solely on Its Solubility in Each Solvent Individually ..............................88
`Examples of Increased Solubility of a Solute in a Mixture of
`(a)
`Solvents Were Disclosed in the Art ............................................................88
`A POSA Would Have Expected that the Addition of Benzyl Benzoate
`Would Improve the Solubility of Fulvestrant ........................................................90
`The Solubility of a Solute in a Solvent (or Mixture of Solvents)
`(a)
`Depends on Molecular Forces ...................................................................90
`Intermolecular Forces Between Fulvestrant and the Excipients in
`the ’139 Patent Claims Would Have Led a POSA to Predict that
`Adding Benzyl Benzoate Would Have Improved the Solubility of
`Fulvestrant .................................................................................................91
`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 ............................92
`CONCLUSION ..................................................................................................................93
`
`B.
`
`C.
`
`(b)
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 4
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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. 8,466,139 (“the ’139 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 ’139 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 5
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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 6
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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 7
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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 ’139 patent.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 8
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`

`
`II.
`
`SUMMARY OF OPINIONS
`
`14.
`
`It is my opinion that claims 1–20 of the ’139 patent were obvious over
`
`McLeskey [Ex. 1005]. Independent claims 1 and 11 of the ’139 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 ’139 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 9
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`

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`the POSA a formulated fulvestrant product exactly as recited in the claims of the
`
`’139 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 10
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`

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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 11
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`

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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 ’139 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 ’139 patent was filed
`
`on January 10, 2000. Thus, I understand that the ’139 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 12
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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. 8,466,139 [Ex. 1001]
`
`27.
`
`I have read and understood the ’139 patent, entitled “Formulation.”
`
`The ’139 patent was filed on September 4, 2012, 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
`
`’139 patent also disclosed that it was a continuation of No. 12/285,887, filed on
`
`October 15, 2008, which is now U.S. Patent No. 8,329,680, which was a
`
`continuation of No. 10/872,784, filed on June 22, 2004, which is now U.S. Patent
`
`No. 7,456,160, which was a continuation of No. 09/756,291, filed on Jan. 9, 2001,
`
`which is now U.S. Patent No. 6,774,122. The ’139 patent issued on June 18, 2013,
`
`and names John R. Evans and Rosalind U. Grundy as inventors.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 13
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`

`
`28.
`
`The following table organizes each recitation in the claims by the
`
`claim(s) in which the recitation appears:
`
`Table 1. Claims of the ’139 Patent
`Fulvestrant Component
`As Claimed in the ’139 Patent
`Claims 1, 11: hormonal dependent benign or
`Indications for Fulvestrant
`malignant diseases of the human breast or
`reproductive tract
`Claim 5, 10, 15, 20: breast cancer
`Claims 1, 7, 11, 17: IM2 injection
`Claims 8, 18: once monthly
`Claims 9, 19: divided dose
`Claims 7, 17: 5 ml
`
`Route of Administration
`Frequency of Administration
`Fulvestrant Dose
`Volume of Formulated
`Fulvestrant Administered
`Fulvestrant Concentration
`Final Formulation of
`Fulvestrant
`
`Claims 1, 11: about 50 mg/ml
`Claims 1, 11:
`“comprising” (claim 1) / “consisting essentially
`of” (claim 11)
`about 50 mg/ml fulvestrant
`17–23% w/v ethanol and benzyl alcohol mixture
`12–18% w/v benzyl benzoate
`sufficient amount of a castor oil vehicle
`Claims 2, 12:
`“comprising” (claim 2) / “consisting essentially
`of” (claim 12)
`about 50 mg/ml fulvestrant
`19–21% w/v ethanol and benzyl alcohol mixture
`14–16% w/v benzyl benzoate
`sufficient amount of a castor oil vehicle
`Claims 3, 13:
`“comprising” (claim 3) / “consisting essentially
`of” (claim 13)
`about 50 mg/ml fulvestrant
`10% w/v ethanol
`10% w/v benzyl alcohol
`
`2 Intramuscular, also denoted “i.m.”
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 14
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`

`
`Blood Plasma Fulvestrant
`Concentration Levels and Their
`Durations
`
`15% w/v benzyl benzoate
`sufficient amount of a castor oil vehicle
`Claims 1, 11: at least 2.5 ng/ml for at least 4
`weeks
`Claim 4, 14: at least 8.5 ng/ml for at least 2
`weeks
`Claim 6, 10, 16, 20: at least 2.5 ng/ml for at
`least 4 weeks
`
`29.
`
`I understand that Mylan is challenging claims 1–20. The ’139 patent
`
`includes 2 independent claims: claims 1 and 11.
`
`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; a mixture of from 17–
`23% w/v of ethanol and benzyl alcohol; 12–18% w/v of benzyl
`benzoate; and a sufficient amount of a castor oil vehicle, wherein the
`method achieves a blood plasma fulvestrant concentration of at least
`2.5 ngml-1 for at least two weeks.
`
`31.
`
`Independent claim 11 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; a mixture of
`from 17–23% w/v of ethanol and benzyl alcohol; 12–18% w/v of
`benzyl benzoate; and a sufficient amount of a castor oil vehicle,
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 15
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`

`
`wherein the method achieves a blood plasma fulvestrant concentration
`of at least 2.5 ngml-1 for at least two weeks.
`
`32.
`
`In comparing claims 1 and 11, the only 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. The disclosed method is otherwise identical between claims 1 and 11.
`
`33. Dependent claims 2–10 depend directly or
`
`indirectly
`
`from
`
`independent claim 1. Dependent claims 12–20 depend directly or indirectly from
`
`independent claim 11.
`
`34. Dependent claims 2 and 12 depend from claims 1 or 11, respectively,
`
`and narrow the percentage ranges of the excipients from 17–23% w/v to 19–21%
`
`w/v of ethanol and benzyl alcohol, and from 12–18% w/v to 14–15% w/v of benzyl
`
`benzoate.
`
`35. Dependent claims 3 and 13 depend from claims 1 or 11, respectively,
`
`and further narrow the percentage ranges of the excipients from 17–23% w/v of a
`
`mixture of ethanol and benzyl alcohol to “about 10% w/v of ethanol” and “about
`
`10% w/v of benzyl alcohol,” and from 12–18% w/v to “about 15%” w/v of benzyl
`
`benzoate.
`
`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 16
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`

`
`36. Dependent claims 4 and 14 depend from claims 1 or 11, respectively,
`
`and recite a blood plasma fulvestrant concentration of 8.5 ng/ml for two weeks,
`
`rather than 2.5 ng/ml for two weeks as in claims 1 and 11.
`
`37. Dependent claims 5 and 15 depend from claims 1 or 11, respectively,
`
`and recite that the disease being treated is breast cancer. Dependent claims 10 and
`
`20 depend indirectly from claims 1 or 11, respectively, and also recite that the
`
`disease being treated is breast cancer.3
`
`38. Dependent claims 6 and 16 depend from claims 1 or 11, respectively,
`
`and recite a blood plasma fulvestrant concentration of 2.5 ng/ml for four weeks,
`
`rather than for two weeks as in claims 1 and 11. Dependent claims 10 and 20
`
`3 Claims 10 and 20 depend from claims 3 or 13, respectively. A POSA would
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`understand the full claim 10 or 20 to read:
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`A method for treating a hormonal dependent benign or malignant disease of the
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`breast or reproductive tract comprising administering intramuscularly to a human
`
`in need of such treatment a formulation comprising [or consisting essentially of]:
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`about 50 mgml-1 of fulvestrant, about 10% w/v of ethanol, about 10% w/v of
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`benzyl alcohol, about 15% w/v of benzyl benzoate, and a sufficient amount of a
`
`castor oil vehicle, wherein the hormonal dependent benign of malignant disease of
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`the breast of reproductive tract is breast cancer and the blood plasma fulvestrant
`
`concentration is attained for at least 4 weeks.
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 17
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`depend indirectly from claims 1 or 11, respectively, and also recite a blood plasma
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`fulvestrant concentration of 2.5 ng/ml for four weeks, rather than for two weeks as
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`in claims 1 and 11.
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`39. Dependent claims 7 and 17 depend from claims 1 or 11, respectively,
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`and recite that 5 ml of the fulvestrant formulation is administered intramuscularly
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`to a human.
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`40. Dependent claims 8 and 18 depend from claims 1 or 11, respectively,
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`and recite that the fulvestrant formulation is administered once monthly.
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`41. Claims 9 and 19 depend from claims 1 or 11, respectively, and recite
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`that the fulvestrant formulation is administered in a divided dose.
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`VI. CLAIM CONSTRUCTION
`
`42.
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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 formulation, after
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`the addition of fulvestrant, ethanol, benzyl alcohol, benzyl benzoate, and any
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`further optional excipients, the remaining volume of the formulation would be
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`castor oil. See Ex. 1001 at col. 10, ll. 41–45.
`
`43.
`
`The term “wherein the method achieves a blood plasma fulvestrant
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`concentration of at least 2.5 ngml-1 for at least two weeks,” Ex. 1001 at col. 12
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`ll.20–22, 57–59, col. 13 ll. 14–16, merely expresses an intended result of the
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`administration of the fulvestrant formulation recited in the claims of the ’139
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 18
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`patent. Likewise, the terms “wherein the [2.5] ngml-1 blood plasma fulvestrant
`
`concentration is attained for at least four weeks,” Ex. 1001 at col. 12 ll. 35–36, col.
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`13 ll. 6–7; see also col. 12 ll. 44–47, col. 13 ll. 15–18 (similar), and “wherein the
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`blood plasma fulvestrant concentration is at least 8.5 ngml-1 [for two weeks],” Ex.
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`1001 at col. 12 ll. 30–31, col. 13 ll. 1–2, merely express intended results of the
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`administration of the fulvestrant formulation recited in the claims of the ’139
`
`patent. None of this language informs how the method of 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.
`
`44. Claims 1 and 11 uses the term “achieves” to describe reaching a
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`specified blood plasma fulvestrant concentration; similarly, claims 6, 10, 16, and
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`20 use the term “attained” to describe reaching a specified blood plasma
`
`fulvestrant concentration. To the extent the Board believes that any of the
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`“wherein” terms recited in paragraph 43 are entitled to any patentable weight, the
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`broadest reasonable interpretation of “attained”/“achieves” to a POSA as of the
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`priority date is “achieved or attained an average concentration (Cavg) in a patient
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`over the specified time period.” Ex. 1003 at ¶¶ 43–44; Ex. 1004 at ¶ 35. The term
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`“achieved”/”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
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 19
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`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, 16, 10, 11,
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`16, 20) or at least 8.5 ngml-1 (claims 4, 14) for either 2 weeks (claims 1, 4, 11, 14)
`
`or 4 weeks (claims 6, 10, 16, 20) after injection. I understand a district court has
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`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.
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`Fulvestrant Was Well Known in the Prior Art as a Pure
`Antiestrogen
`
`45.
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`Fulvestrant, the compound that is the subject of the claims of the ’139
`
`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:
`
`46.
`
`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
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`MYLAN PHARMS. INC. EXHIBIT 1003 PAGE 20
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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.
`
`47.
`
`The Prior Art Disclosed Fulvestrant Formulations
`The prior art disclosed a number of fulvestrant formulations. See,
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`e.g., Exs. 1005 (McLeskey); 1006 (Howell 1996); 1007 (Dukes 1989); 1008
`
`(Wakeling 1991); 1009 (Wakeling 1992); 1012 (Howell 1995); 1013 (O’Regan
`
`1998); 1014 (Lu 1998); 1018 (Osborne 1995); 1025 (Dukes 1992); 1026 (Dukes
`
`1993); 1027 (Defriend 1994); 1028 (Wakeling 1993); 1030 (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.
`
`48.
`
`The excipients used in prior art fulvestran