UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.
`
`Petitioner
`
`V.
`
`ASTRAZENECA AB
`
`Patent Owner
`
`Case IPR2016-01324
`
`U.S. Patent 7,456,160
`
`DECLARATION OF LISBETH ILLUM, Ph.D. IN SUPPORT OF PATENT
`OWNER’S PRELIMINARY RESPONSE
`
`AstraZeneca Ex. 2001 p. 1
`Mylan Pharms. Inc. V. AstraZeneca AB IPR2016-01324
`
`

`
`TABLE OF CONTENTS
`
`Page
`
`I)
`
`11)
`
`111)
`
`1\/)
`
`I/)
`
`\/1)
`
`\/11)
`
`\/111)
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`1><)
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`X)
`
`INTRODUCTION ......................................................................................... .. 1
`
`QUALIFICATIONS AND EXPERIENCE ................................................... ..1
`
`MY UNDERSTANDING OF THE PROCEEDING .................................... ..3
`
`MY OPINIONS AND THEIR BASES ......................................................... ..4
`
`DOCUMENTS CONSIDERED .................................................................... ..5
`
`THE ’16O PATENT SPECIFICATION AND CLAIMS .............................. ..5
`
`PERSON OF ORDINARY SKILL IN THE ART ........................................ ..9
`
`LEGAL PRINCIPLES ................................................................................... ..9
`
`CLAIM CONSTRUCTION ........................................................................ ..11
`
`STATE OF THE RELEVANT ART ........................................................... .. 14
`
`A)
`
`B)
`
`Formulation Background ................................................................... .. 14
`
`The Claimed Blood Plasma Levels Are Critical To The
`Inventions .......................................................................................... .. 14
`
`C)
`
`Formulation Options ......................................................................... .. 16
`
`)<1)
`
`REFERENCES CITED IN THE PETITION AND FORREST
`
`DECLARATION ......................................................................................... ..20
`
`A) McLeskey (Ex. 1005) ........................................................................ ..21
`
`1)
`
`2)
`
`McLeskey Does Not Disclose The Units For The
`Excipient Percentages ............................................................. ..25
`
`McLeskey Does Not Disclose Any Solubility
`Information .............................................................................. ..29
`
`B)
`
`C)
`
`Howell 1995 (EX. 1012) .................................................................... ..35
`
`Howell 1996 (Ex. 1006) .................................................................... ..36
`
`D) Wakeling 1991 (EX. 1008) ................................................................ ..38
`
`E) Wakeling 1992 (EX. 1009) ................................................................ ..39
`
`F) Wakeling 1993 (EX. 1028) ................................................................ ..40
`
`G)
`
`H)
`
`I)
`
`Osborne 1995 (EX. 1018) .................................................................. ..41
`
`Dukes 1992 (Ex. 1025) ...................................................................... ..41
`
`Dukes 1993 (Ex. 1026) ...................................................................... ..43
`
`AstraZeneca Ex. 2001 p. 2
`
`

`
`TABLE OF CONTENTS
`
`(continued)
`
`Page
`
`J)
`
`K)
`
`L)
`
`DeFriend (EX. 1027) .......................................................................... ..44
`
`Riffl<in (Ex. 1022) ............................................................................ ..46
`
`Lehmann 1976 (EX. 1019) ................................................................. ..48
`
`M)
`
`Lu 1998 (Ex. 1014) ........................................................................... ..49
`
`N)
`
`O)
`
`P)
`
`Q)
`
`R)
`
`Lu 1999 (Ex. 1030) ........................................................................... ..50
`
`Dukes 1989 (Ex. 1007) ...................................................................... ..50
`
`GB ’286 (EX. 1020) ........................................................................... ..52
`
`Neumann (EX. l04l) ......................................................................... ..53
`
`O’Regan (Exhibit l0l3) .................................................................... ..54
`
`XII) THE SKILLED FORMULATOR’S APPROACH TO
`FORMULATING FULVESTRANT ........................................................... ..55
`
`A)
`
`B)
`
`C)
`
`The Fulvestrant A11; Taught Once-A-Day Administration And
`Once-A-Month Administration ......................................................... ..55
`
`The Formulator Would Prefer Oral Fulvestrant Formulations ......... ..5 8
`
`The Formulator Would Be Concerned About Intramuscular
`Administration Of Fulvestrant .......................................................... ..63
`
`D)
`
`The Prior Art Disclosed Numerous Fulvestrant Formulations ......... ..65
`
`XIII) NON-OBVIOUSNESS OVER MCLESKEY (GROUND ONE) ............... ..68
`
`A)
`
`No Reason To Select McLeskey ....................................................... ..68
`
`B) McLeskey Teaches Away From Using Fulvestrant .......................... ..69
`
`C)
`
`D)
`
`E)
`
`F)
`
`The Skilled Formulator Would Not Have Modified McLeskey
`To Obtain The Claimed Inventions ................................................... ..7l
`
`The Formulator Would Not Have Found McLeskey ........................ ..73
`
`No Motivation To Modify McLeskey Nor Reasonable
`Expectation Of Success In Doing So ................................................ ..73
`
`There Is No Way To Predict How A Formulation Will Behave
`Upon Injection ................................................................................... ..80
`
`XIV) NON-OBVIOUSNESS OVER MCLESKEY AND HOWELL
`(GROUND TWO) ....................................................................................... ..83
`
`A) McLeskey Disparaged The Results of Howell 1996 ........................ ..85
`
`ii
`
`AstraZeneca Ex. 2001 p. 3
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`

`
`B)
`
`C)
`
`D)
`
`TABLE OF CONTENTS
`
`(continued)
`
`Page
`
`The Skilled Formulator Would Not View The Castor Oil-Based
`Formulation Of McLeskey As A “Match” To The Formulation
`Of Howell .......................................................................................... ..86
`
`Other Prior Art Formulations Were Closer To Howell Than
`McLeskey .......................................................................................... ..89
`
`The Combination Of Howell 1996 And McLeskey Could Not
`Have Been Expected To Result In The Claimed Inventions. ........... ..9l
`
`1)
`
`2)
`
`3)
`
`4)
`
`5)
`
`McLeskey Used Experimental Animal Formulations That
`Would Not Be Viewed As Suitable For Human Use ............. ..92
`
`No Approved Product Used The Same Combination Of
`Excipients As McLeskey ........................................................ ..92
`
`Making The McLeskey Formulation Would Introduce
`Additional Unpredictability .................................................... . . 93
`
`The McLeskey Formulation Would Not Be Expected To
`Work When Administered Monthly Instead of Weekly ......... ..94
`
`The McLeskey Formulation Would Not Be Expected to
`Work When Administered Intramuscularly Instead Of
`Subcutaneously ....................................................................... ..95
`
`XV) UNEXPECTED RESULTS ....................................................................... .. 100
`
`A)
`
`B)
`
`C)
`
`The Unexpected Results Of The Claimed Inventions ..................... .. 100
`
`The Unexpectedly Superior Solubility Of Fulvestrant In The
`Claimed Formulation Was Not Taught In The Prior Art ................ .. 103
`
`Additional Unexpected Properties Of The Inventions Were Not
`Taught In The Prior Art ................................................................... ..l08
`
`XVI) CONCLUSION .......................................................................................... .. l l l
`
`iii
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`AstraZeneca Ex. 2001 p. 4
`
`

`
`I, Lisbeth Illum, Ph.D., do hereby make the following declaration:
`
`1)
`
`INTRODUCTION
`
`1.
`
`2.
`
`I am over the age of eighteen and competent to make this declaration.
`
`I have been retained as an expert witness on behalf of AstraZeneca
`
`AB for the above-captioned Inter Partes Review (IPR).
`
`I am being compensated at
`
`my customary rate of £5 00 per hour for my consultation in connection with this
`
`proceeding. My compensation is in no way dependent on the outcome of my
`
`analysis or opinions rendered in this proceeding. A copy of my curriculum vitae,
`
`which includes my educational background, work / research history, and lists of
`
`selected publications and presentations, is attached to this declaration as Exhibit A.
`
`II)
`
`QUALIFICATIONS AND EXPERIENCE
`
`3.
`
`My name is Lisbeth Illum, Ph.D.
`
`I am a Danish citizen, born in
`
`Aalborg, Denmark in 1947. Currently, I am a resident of the United Kingdom, and
`
`have been since 1987.
`
`I gained my Danish A levels at Horsens Statsskole in 1966,
`
`my MPharm First Class Honours Degree from the Royal Danish School of
`
`Pharmacy in 1972, and my Ph.D. and D.Sc. in Pharmaceutical Sciences in 1978
`
`and 1987, respectively, both from the Royal Danish School of Pharmacy.
`
`4.
`
`I worked as a lecturer / senior lecturer in the Royal Danish School of
`
`Pharmacy between 1972 and 1990.
`
`I upheld a Postgraduate Scholarship between
`
`1975 and 1978 and a Senior Research Fellowship between 1982 and 1985.
`
`I was a
`
`AstraZeneca Ex. 2001 p. 5
`
`

`
`Visiting Research Fellow in the Pharmacy Department at University of
`
`Nottingham during several periods between 1981 and 1990.
`
`5 .
`
`I was made a Docent (Professor equivalent) in the Department of
`
`Pharmaceutical Sciences, Royal Danish School of Pharmacy, in 1989.
`
`I was made
`
`a Special Professor at the University of Nottingham, UK, in the Department of
`
`Pharmaceutical Sciences in 1990, and in the Department of Chemistry in 2007.
`
`6.
`
`I was the founder, and for twelve years the Managing Director, of
`
`DanBioSyst UK Ltd. (later West Pharmaceutical Services, now Archimedes Ltd)
`
`(1989-1998), a company that specializes in development of drug delivery systems
`
`for pharmaceutical drugs. In addition, I was the founder and Managing Director of
`
`Phaeton Research Ltd. (2003-2005) and the CEO of Critical Pharmaceuticals Ltd, a
`
`drug delivery company based in BioCity in Nottingham from 2007-2011.
`
`I am
`
`also Director of Eurocage Ltd., a drug delivery consultancy company.
`
`7.
`
`My research expertise covers the area of novel drug delivery systems
`
`for difficult to formulate drugs such as peptides, proteins, polar and lipophilic
`
`small molecular weight compounds.
`
`I have extensive experience in novel
`
`approaches to the delivery of such drugs including the use of various routes of
`
`delivery such as oral, nasal, vaginal and parenteral.
`
`8.
`
`I have published more than 350 scientific papers (about 90 in the last
`
`ten years) and I am among the top 100 most cited scientists on pharmacology, with
`
`AstraZeneca Ex. 2001 p. 6
`
`

`
`an h index of ~ 57.
`
`I have co-edited four books related to drug delivery, drug
`
`therapy, and drug transport.
`
`I am the inventor on nearly fifty patent family
`
`applications on novel drug delivery systems.
`
`9.
`
`I have been the recipient of several scientific awards and have been
`
`elected a Fellow of the American Association of Pharmaceutical Scientists and of
`
`the Controlled Release Society.
`
`I have lectured throughout the world at
`
`conferences and workshops on drug delivery systems.
`
`I am or have been on the
`
`Editorial Boards of eleven pharmaceutical scientific journals, and a reviewer for
`
`many more journals.
`
`I was in 2008/2009 the President of the U.S.-based
`
`Controlled Release Society, with over 2000 members dedicated to the science of
`
`delivery of bioactive agents.
`
`10. A list of U.S. cases in which I have testified at trial or by deposition
`
`within the preceding four years is attached at Exhibit B.
`
`III) MY UNDERSTANDING OF THE PROCEEDING
`
`11.
`
`I have been informed that this proceeding is a petition for Inter Partes
`
`Review before the Patent Trial and Appeal Board of the United States Patent and
`
`Trademark Office (“the Board”). I have been informed that an Inter Partes Review
`
`is a proceeding to review the patentability of one or more issued claims in a United
`
`States patent on the grounds that the patent is the same as or rendered obvious in
`
`view of the prior art.
`
`AstraZeneca Ex. 2001 p. 7
`
`

`
`12.
`
`I have been informed that Mylan Pharmaceuticals Inc. filed a Petition
`
`requesting Inter Partes Review (“Petition”) of U.S. Patent No. 7,456,160 (the ’ 160
`
`Patent”), which issued to John R Evans and Rosalind U Grundy on November 25,
`
`2008 and is assigned to AstraZeneca AB.
`
`I have reviewed the Petition, and
`
`understand that it alleges that claims 1-12 of the ’ 160 Patent are unpatentable over
`
`McLeskey (Ex. l005) and, alternatively, over the combination of Howell l996 (Ex.
`
`1006) with McLeskey
`
`1005).
`
`IV) MY OPINIONS AND THEIR BASES
`
`13.
`
`I have been asked to give my opinion on whether Mylan has shown a
`
`reasonable likelihood that a person of ordinary skill in the art (“POSA”) would
`
`understand claims 1-12 of the ’l60 Patent to be rendered obvious by: (l)
`
`McLeskey (Exhibit 1005); or (2) the combination of Howell 1996 (Ex. 1006) with
`
`McLeskey
`
`l005).
`
`14. As part of this opinion, I considered the level of ordinary skill in the
`
`art around January 2000, which represents the filing date of GB 0000313, to which
`
`the ’l60 Patent claims priority.
`
`15.
`
`For the reasons explained below, in my opinion, Mylan has not shown
`
`that there is a reasonable likelihood that it would prevail in an Inter Partes Review
`
`of claims 1-12 of the ’l60 patent.
`
`AstraZeneca Ex. 2001 p. 8
`
`

`
`V)
`
`DOCUMENTS CONSIDERED
`
`16.
`
`The materials that I have considered, in addition to the exhibits to the
`
`Petition, are listed in Exhibit C. My opinions as stated in this Declaration are
`
`based on the understanding of a POSA in the art as defined above and in 11 24,
`
`below.
`
`VI) THE ’160 PATENT SPECIFICATION AND CLAIMS
`
`17.
`
`I have been informed that the priority date of the ’160 Patent is
`
`January 10, 2000. The invention relates to “a novel sustained release
`
`pharmaceutical formulation adapted for administration by injection containing the
`
`compound [fulvestrant], more particularly to a formulation adapted for
`
`administration by injection containing the compound [fulvestrant] in solution in a
`
`ricinoleate vehicle which additionally comprises at least one alcohol and a non-
`
`aqueous ester solvent which is miscible in the ricinoleate vehicle.” Ex. 1001 at
`
`Abstract.
`
`18.
`
`The specification of the ’160 Patent explains that “[f] ulvestrant shows,
`
`along with other steroidal based compounds, certain physical properties which
`
`make formulation of these compounds difficult.” Ex. 1001 at 2:46-48.
`
`Specifically, “[f]ulvestrant is a particularly lipophilic molecule, even when
`
`compared with other steroidal compounds, and its aqueous solubility is extremely
`
`low at around 10 ngml’1.” Ex. 1001 at 2:48-52.
`
`AstraZeneca Ex. 2001 p. 9
`
`

`
`19.
`
`The inventors of the ’ 160 Patent “surprisingly found that the
`
`introduction of a non-aqueous ester solvent which is miscible in the castor oil and
`
`an alcohol surprisingly eases the solubilisation of fulvestrant into a concentration
`
`of at least 50 mgml'1.” Ex. 1001 at 5:60-64. This was surprising because “[t]he
`
`solubility of fulvestrant in non-aqueous ester solvents .
`
`.
`
`. is significantly lower
`
`than the solubility of fulvestrant in an alcohol” and “in castor oil.” Ex. 1001 at
`
`5:65 -6:3. In addition, the inventors noted that “[s]imply solubilising fulvestrant in
`
`an oil based liquid formulation is not predictive of a good release profile or lack of
`
`precipitation of drug after injection at the injection site.” Ex. 1001 at 9:38-40.
`
`20.
`
`Therefore, the inventors further found that the claimed inventions
`
`“provide, after intra-muscular injection, satisfactory release of fulvestrant over an
`
`extended period of time.” Ex. 1001 at 8:49-51. The specification of the ’16O
`
`Patent states that “[b]y use of the term ‘therapeutically significant levels’ we mean
`
`that blood plasma concentrations of at least 2.5 ngml'1, ideally at least 3 ngml'1, at
`
`least 8.5 ngml’1, and up to 12 ngml'1 of fulvestrant are achieved in the patient.” Ex.
`
`1001 at 9: 18-21. Further, the specification describes “extended release” as “at
`
`least two weeks, at least three weeks, and, preferably at least four weeks of
`
`continuous release of fulvestrant is achieved.” Ex. 1001 at 9:24-26. In addition,
`
`the inventors found that “the castor oil formulation showed a particularly even
`
`AstraZeneca EX. 2001 p. 10
`
`

`
`release profile with no evidence of precipitation of fulvestrant at the injection site.”
`
`Ex. 1001 at 10:55-57.
`
`21.
`
`Independent claim 1 of the ’l60 Patent is provided below.
`
`1. A method of treating a hormonal dependent benign
`
`or malignant disease of the breast or reproductive tract by
`
`administration to a human in need of such treatment an
`
`intra-muscular injection of a pharmaceutical formulation
`
`comprising fulvestrant, a mixture of from 10% to 30%
`
`weight of ethanol and benzyl alcohol per volume of
`
`formulation and 10% to 25% weight of benzyl benzoate
`
`per volume of formulation and a sufficient amount of a
`
`castor oil vehicle, whereby a therapeutically significant
`
`blood plasma fulvestrant concentration of at least 2.5
`
`ngml'1 is attained for at least 2 weeks after injection.
`
`22.
`
`Independent claim 2 of the ’ 160 Patent is provided below.
`
`2. A method of treating a hormonal dependent benign or
`
`malignant disease of the breast or reproductive tract by
`
`administration to a human in need of such treatment an
`
`intra-muscular injection of a pharmaceutical formulation
`
`comprising fulvestrant, a mixture of from 10 to 30%
`
`weight of a mixture of ethanol and benzyl alcohol per
`
`volume of formulation and from 10 to 25% weight of
`
`benzyl benzoate per volume of formulation and a
`
`sufficient amount of a castor oil vehicle, whereby the
`
`formulation comprises at least 45 mgml'] of fulvestrant.
`
`AstraZeneca Ex. 2001 p. 11
`
`

`
`23. Dependent claims limit claim 1 and/or claim 2 to a method: wherein
`
`the formulation comprises a mixture of from 15 to 25% weight of a mixture of
`
`ethanol and benzyl alcohol per Volume of formulation and from 12 to 20% weight
`
`of benzyl benzoate per Volume of formulation (claim 3); wherein the formulation
`
`comprises a mixture of from 8.5 to 11.5% weight of ethanol per Volume of
`
`formulation and from 8.5 to 11.5% weight of benzyl a1cohol[l] per Volume of
`
`formulation an[d] 12 to 18% weight of benzyl benzoate per Volume of formulation
`
`(claim 4); wherein the blood plasma fulvestrant concentration is attained for at
`
`least 3 weeks after injection (claim 5); wherein the blood plasma fulvestrant is
`
`attained for at least 4 weeks after injection (claim 6); wherein a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 3 ngml'1 is attained
`
`for at least 2 weeks after injection (claim 7); wherein a therapeutically significant
`
`blood plasma fulvestrant concentration of at least 8.5 ngm1'1 is attained for at least
`
`2 weeks after injection (claim 8); wherein a therapeutically significant blood
`
`plasma fulvestrant concentration of at least 8.5 ngml'1 is attained for at least 4
`
`weeks after injection (claim 9); wherein the total Volume of the formulation
`
`administered to said human is 6ml or less; and the concentration of fulvestrant in
`
`said formulation is at least 45 mgml’1 (claim 10); wherein the total Volume of the
`
`formulation administered to said human is 6 ml or less; and the total amount of
`
`AstraZeneca Ex. 2001 p. 12
`
`

`
`fulvestrant in said volume of formulation is 250 mg or more (claim ll); wherein
`
`the benign or malignant disease is breast cancer (claim 12).
`
`VII) PERSON OF ORDINARY SKILL IN THE ART
`
`24.
`
`I have been asked to provide my opinion on the novelty and
`
`obviousness of the asserted claims from the perspective of a person of ordinary
`
`skill in the relevant art. The skilled person with respect to the patents—in—suit is a
`
`person having a bachelor’s or advanced degree in a discipline such as pharmacy,
`
`pharmaceutical sciences, endocrinology, medicine or related disciplines, and
`
`having at least two years of practical experience in drug development and/or drug
`
`delivery, preclinical models, or the clinical treatment of hormone dependent
`
`diseases of the breast and reproductive tract. Because the drug discovery and
`
`development process is complicated and multidisciplinary, it would require a team
`
`of individuals including, at least, medical doctors, pharrnacokineticists, and
`
`formulators.
`
`25. As considered from the perspective of the forrnulator member of that
`
`team, the inventions of the asserted claims are novel, and not obvious, for the
`
`following reasons.
`
`VIII) LEGAL PRINCIPLES
`
`26.
`
`I am not a lawyer.
`
`I have relied on the explanations of counsel for an
`
`understanding of certain principles of U.S. patent law that govern the
`
`AstraZeneca EX. 2001 p. 13
`
`

`
`determination of patentability. The discussion set forth below regarding the law of
`
`obviousness is intended to be illustrative of the legal principles I considered while
`
`preparing my declaration, and not an exhaustive list.
`
`27.
`
`I understand that to institute an Inter Partes Review Mylan must show
`
`that there is a reasonable likelihood that it would prevail in an Inter Partes Review.
`
`I am informed by counsel that there is no presumption of validity. If an IPR is
`
`instituted, Mylan must show unpatentability by a preponderance of the evidence,
`
`and preponderance of the evidence means “more probable than not.”
`
`28.
`
`I am informed by counsel that for a patent claim to be invalid as
`
`anticipated by a prior art reference, that reference must disclose every limitation of
`
`the claim. Thus, if the limitations of a patent claim were already disclosed, in their
`
`entirety, by a single prior art reference, that claim is anticipated and not novel.
`
`29.
`
`I am informed by counsel that for an invention to be obvious, the
`
`patent statute requires that the differences between the invention and the prior art
`
`be such that the “subject matter as a whole would have been obvious at the time
`
`the invention was made to a person of ordinary skill in the art to which such
`
`subj ect matter pertains.”
`
`30.
`
`I understand that the obviousness evaluation must be from the
`
`perspective of the time the invention was made. In the current proceeding, I
`
`understand that the relevant date is considered to be the earliest priority date of the
`
`AstraZeneca EX. 2001 p. 14
`
`

`
`applications, which is January 10, 2000. The obviousness inquiry must guard
`
`against slipping into use of hindsight.
`
`31.
`
`I understand that even in circumstances where each component of an
`
`invention can be found in the prior art, there must have been an apparent reason to
`
`combine the known elements in the fashion claimed by the patent at issue. For an
`
`invention to be found obvious, to protect against the distortion caused by hindsight
`
`bias, there must be a reason that would have prompted a person of ordinary skill in
`
`the relevant field to combine the elements in the way the claimed new invention
`
`does.
`
`32.
`
`To be obvious, the claimed method of treatment must have been
`
`among a finite number of identified, predictable solutions to the problems at hand.
`
`IX) CLAIM CONSTRUCTION
`
`33.
`
`In independent claim 1, the term “whereby a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 2.5 ngml'1 is attained
`
`for at least 2 weeks after injection” is a claim limitation entitled to patentable
`
`weight. Independent claim 1 does not specify the total amount of fulvestrant to
`
`administer to the patient. Instead, the desired blood plasma level of fulvestrant, for
`
`example, limits the method of claim 1 to an amount of fulvestrant that achieves and
`
`maintains 2.5 ngm1'1 for at least 2 weeks after injection. The claimed methods
`
`cannot be practiced without knowing the target blood plasma levels, which then
`
`AstraZeneca EX. 2001 p. 15
`
`

`
`allows administration of an appropriate amount of fulvestrant to reach those levels.
`
`Hence, the blood plasma levels absolutely inform how the method of administering
`
`the fulvestrant formulation to a human patient is carried out.
`
`34.
`
`The formulator would understand “whereby a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 2.5 ngml'1 is attained
`
`for at least 2 weeks” to mean that the blood plasma fulvestrant concentration of at
`
`least 2.5 ngml'1 is achieved and maintained for at least two weeks. The plain
`
`meaning of the words “attained” and “at least” indicate to the formulator that the
`
`patient’s blood plasma level must remain at or above 2.5 for the entire specified
`
`time period. This understanding is also supported by authoritative treatises in the
`
`art. EX. 2080 (Remington’s Ch. 91) at 6 (“The objective in designing a sustained-
`
`release system is to deliver drug at a rate necessary to achieve and maintain a
`
`constant drug level”) (emphasis added); see also EX. 1011 (Order by Judge Bumb
`
`of the District of New Jersey).
`
`35.
`
`The specification indicates that a goal of the invention is sustained
`
`release. The specification describes the problem of formulating fulvestrant: “when
`
`using the best oil based solvent, castor oil, we have found that it is not possible to
`
`dissolve fulvestrant in an oil based solvent alone so as to achieve a high enough
`
`concentration to dose a patient in a low volume injection and achieve a
`
`therapeutically significant release rate.” EX. 1001 at 5:37-41. The inventors noted
`
`AstraZeneca EX. 2001 p. 16
`
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`that “[s]imply solubilising fulvestrant in an oil based liquid formulation is not
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`predictive of a good release profile or lack of precipitation of drug after injection at
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`the injection site.” Ex. 1001 at 9:38-40. Thus, the inventors faced the problem not
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`only of dissolving a sufficient amount of fulvestrant in a formulation but also
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`determining a therapeutically significant release rate and duration and furthermore
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`developing a formulation that could provide such a pharmacokinetic profile
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`without causing precipitation at the injection site.
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`36.
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`The inventors “surprisingly found that the introduction of a non-
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`aqueous ester solvent which is miscible in the castor oil and an alcohol surprisingly
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`eases the solubilisation of fulvestrant into a concentration of at least 50 mgml'1.”
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`EX. 1001 at 5:60-64. The inventors further found that the claimed formulations
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`“provide, after intra-muscular injection, satisfactory release of fulvestrant over an
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`extended period of time.” Ex. 1001 at 8:49-51. In addition, Table 4 of the patent
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`showed that the claimed methods avoid precipitation that occurred in other
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`fulvestrant formulations. Ex. 1001, Table 4. The inventors concluded that “the
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`castor oil formulation showed a particularly even release profile with no evidence
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`of precipitation of fulvestrant at the injection site.” Ex. 1001 at 10:55-57.
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`37. Despite Dr. Forrest’s claims, see Ex. 1003 at 111] 38-39, the blood
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`plasma limitations of the ’160 Patent, including the term “whereby a
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`therapeutically significant blood plasma fulvestrant concentration of at least 2.5
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`AstraZeneca EX. 2001 p. 17
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`ngml'1 is attained for at least 2 weeks,” are critical to the invention, as discussed
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`further below. In addition, Dr. Forrest provides no explanation or support for
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`reading an average concentration limitation into the claims. See EX. 1003 at 11 41.
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`Indeed, there is no support in the claims or specification for such an interpretation.
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`X)
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`STATE OF THE RELEVANT ART
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`A) Formulation Background
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`38.
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`“The development of an optimum formulation is not an easy task, and
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`many factors readily influence formulation properties.” Ex. 2081 (Remington’s
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`Ch. 75) at 5. Such factors include biopharmaceutical considerations, drug factors,
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`and therapeutic considerations. Ex. 2082 (Aulton Ch. 1) at 5.
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`39. A successful formulation of an active pharmaceutical ingredient must
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`deliver the active ingredient in such a way that it is biologically effective. This
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`often requires meeting certain parameters, such as blood plasma concentrations
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`and/or duration. EX. 2083 (Ansel Ch. 4) at 5 (“The magnitude of the response is
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`related to the concentration of the drug achieved at the site of its action”). In such
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`cases, the delivery method and formulation must ensure that a sufficient amount of
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`the active ingredient enters the circulation when introduced into the body to deliver
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`the active ingredient to the site of action (normally via the bloodstream).
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`B) The Claimed Blood Plasma Levels Are Critical To The Inventions
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`40.
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`The skilled formulator would know that the release profile of a drug
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`from the formulation and its absorption into the blood stream are critical factors
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`AstraZeneca EX. 2001 p. 18
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`influencing the action of the drug on the patient. Ex. 2083 (Ansel Ch. 4) at 43
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`(“[T]he objective of pharmacokinetic dosing is to design a dosage regimen that
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`will continually maintain a drug’s therapeutic serum or plasma concentration
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`within the drug’s therapeutic index, i.e., above the minimum effective
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`concentration but below the minimum toxic level”); Ex. 2080 (Remington’s Ch.
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`91) at 5 (“The goal of any drug delivery system is to provide a therapeutic amount
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`of drug to the proper site in the body to achieve promptly, and then maintain, the
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`desired drug concentration”).
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`41. Depot fonnulations are particularly challenging. For instance, if too
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`much drug is released immediately from the formulation, the blood plasma
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`concentration may reach the minimum toxic level and cause side effects. Ex. 2080
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`(Remington’s Ch. 91) at 5. Additionally, if too much of a drug reaches the blood
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`stream immediately after the injection and is eliminated, insufficient drug will be
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`left at the depot to sustain the therapeutic levels over the long term. On the other
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`hand, if too little drug reaches the blood stream immediately after injection, the
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`therapeutic effect of the treatment could be delayed or be limited. Ex. 2080
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`(Remington’s Ch. 91) at 5. If the release rate is inconsistent and plasma levels
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`spike and plummet, the biological threshold necessary to trigger a therapeutic
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`response may not be reached at all.
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`AstraZeneca Ex. 2001 p. 19
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`42.
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`The inventors surprisingly discovered a treatment method that
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`combined a specific pharmacokinetic profile (fulvestrant blood plasma levels over
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`a particular time) with a specific administration method for therapeutic action.
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`From my perspective as a forrnulator, the fulvestrant blood plasma levels in the
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`claims are a clear limitation on the frequency of administration (every 2 weeks, 3
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`weeks, or 4 weeks) and of the amount of fulvestrant to be dosed. That the claims
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`differ make that clear. The entire combination of the invention ensures that the
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`level of fulvestrant in the patient’s blood plasma is consistent, steady, and
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`maintained over a relatively long period of time at therapeutically effective levels.
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`The successful use of the benzyl benzoate ingredient was particularly surprising in
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`that the addition of benzyl benzoate to the formulation would have been predicted
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`to be associated with a lower fulvestrant solubility in the formulation, leading to a
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`greater chance of precipitation. In sum, the claimed inventions (and, with that, the
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`use of benzyl benzoate) surprisingly achieved and maintained therapeutically
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`significant fulvestrant plasma levels, as compared to other fulvestrant formulations.
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`C) Formulation Options
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`43. A person wishing to formulate a highly lipophilic molecule, such as
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`fulvestrant, for administration to humans on a commercial basis, had many choices
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`for each step of the process. The field of drug formulation was wide open, replete
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`with multi-variable and interconnected possibilities, and lacking clear guideposts
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`AstraZeneca EX. 2001 p. 20
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`to suggest a particular direction. Most importantly, there was (and currently is) no
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`“one size fits all,” or single best approach to formulation. Thus, a forrnulator
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`would be aware of the many options available for formulating an active
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`pharmaceutical ingredient.
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`44.
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`Each active pharmaceutical ingredient has unique characteristics. For
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`each active ingredient, there will be many potential choices for administration
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`route, dosage form, and formulation. “Physical and chemical properties of drug
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`substances important in dosage form design,” include organoleptic properties,
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`particle size, surface area, solubility, dissolution, partition coefficient, ionization
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`constant, crystal properties, polymorphism, and stability. EX. 2082 (Aulton Ch. 1)
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`at 10.
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`45.
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`“Drugs may be administered by a variety of dosage forms and routes
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`of administration.” Ex. 2083 (Ansel Ch. 4) at 24. Examples of routes of
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`administration are oral, buccal, sublingual, nasal, pulmonary, transdermal, vaginal,
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`rectal, and parenteral. Ex. 2082 (Aulton Ch. 1) at 5-9; EX. 2083 (Ansel Ch. 4
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`1999) at