UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`INNOPHARMA LICENSING, LLC.
`
`Petitioner
`
`V.
`
`ASTRAZENECA AB
`
`Patent Owner
`
`
`
`Case IPR2017-00905
`
`US. Patent 8,466,139
`
`
`DECLARATIONOF LISBETH ILLUM,Ph.D. INSUPPORT OF PATENT
`OWNER’S PRELIMINARY RESPONSE
`
`AstraZeneca Exhibit 2001 p. |
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00905
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01912
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`1
`
`TI)
`
`INTRODUCTION 00 eeceecceeeeeeeceeeeeeeseseeeneenseeneeseeenaeeneeeeeneeeneeneeeateees 1
`
`QUALIFICATIONS AND EXPERIENCE.......0.00cccccccccseesceseseeesseteeseneens 1
`
`WT) MY UNDERSTANDING OF THE PROCEEDING..........0..ccccccesesetteee 4
`
`IV) MY OPINIONS AND THEIR BASES00.00... ccccccccccecccseeteeteeenetneeeetseeeneees 4
`
`V)
`
`VI)
`
`DOCUMENTS CONSIDERED 0.000... ecceteeeeteeceteceeeeseeeesenseeeenenaey 5
`
`THE ’139 PATENT SPECIFICATION AND CLAIMS........cc cece 6
`
`VII) PERSON OF ORDINARYSKILL IN THE ART 0.0... cccceeteeeeseetetees 9
`
`VITD) LEGAL PRINCIPLES 0.000. .cccccecccccccccccccceescencseeeseceeessensesseenseessetaeenseeseensenes 10
`
`TIX) CLAIM CONSTRUCTIONoo .ccccccccccceccceceescesseeeceeeseenseeseesseeseeseseeinas 11
`
`X)
`
`STATE OF THE RELEVANTART ou... ccccccccccccc cece etseeteetseeteesseensnes 15
`
`A)—Formulation Background... cece cccecceecetceeeceeeeeeeeeeeeeeseeeneeenaeeees 15
`B)
`The Claimed Blood Plasma Levels Are Critical To The
`TMVENTIONS 02... cece cece cete cece eeseeeaeceseeseeeseeeseecseeeseecsaeenaeesseesseeenaeeees 15
`
`XI)
`
`Formulation Options 20.0.0... ccc ccccccccceeceeecesseceesseesseeesseesesseessreeensees 17
`C)
`REFERENCES CITED IN THE PETITION AND BURGESS
`DECLARATION(0... cecececeececeteeeceeeeeeeeseneeeseenseeseesecseesecaeenseeseeseeeeteseeneeees 20
`
` McLeskey (Ex. 1008)... cece cece cecsecesseecsseeeesesesseeestseenseenes 22
`A)
`1)|McLeskey Describes A “Treatment Failure”’........00000.e 23
`2)|McLeskey Did Not Test Formulations For Human Use........... 23
`3)|McLeskey Provides No Pharmacokinetic Data.........00.000.. 25
`4)—McLeskey Does Not Disclose The Units For The
`Excipient Percentages .......00..ccccccccccccececsseccecsseeeesseesetsseseesiees 25
`5)|McLeskey Does Not Disclose Any Solubility
`Information... cece cecceecceeeccseeseeeseeeseeeseeenseenaeenseeeneenseeeiees 30
`
`Howell 1996 (Ex. 1007) oo... cccceceseceseeseetecneenseteensenieenieees 33
`B)
` DeFriend (Ex. 1038) 0.0... cecccceeeeeseceneeetsseeeeeessieenseeetieeniees 36
`C)
`D)—Riffkin (Ex. 1033) occ ccccceccseeseeneeesecseeseetsenseesseesetseeseenees 39
`E)
`O’Regan (Exhibit 1009) ooo cece eecsseecseeessseeesseeessieenseenes 43
`F)
`Dukes 1989 (Ex. 1047)... ccc cceceteeesecnseeseeteeeeetseesenteenieees 45
`
`AstraZeneca Exhibit 2001 p. 2
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`G)
`
`Gellert Declaration (Ex. 1020) oo... cccccccte ect eeeeeeetteeetteeeniees 47
`1)
`Background Of The Gellert Declaration........0.0000..c ces 47
`2)
`The Gellert Declaration Describes Extensive
`Experimentation Based On Information Not KnownIn
`The Art oo. cccceccececccceceneeescesecsseceseeeeeeteeeeseesseeeseenseeteenines 48
`
`XII) THE SKILLED FORMULATOR’S APPROACH TO
`FORMULATING FULVESTRANT|... cccceccceceeeteeeteensetseensetteenseiees 59
`
`A)
`
`B)
`C)
`D)
`
`The Fulvestrant Art Taught Once-A-Day Administration And
`Once-A-Month Administration ....0...0..ccccccccccccceeececeeseeneeeneenseenseeees 59
`
`The Formulator Would Prefer Oral Fulvestrant Formulations........... 62
`The Formulator Would Not Have Excluded Oral Formulations........ 64
`The Formulator Would Be Concerned About Intramuscular
`Administration Of Fulvestrant .......000.0cccccccccccecssceeseceeseeeteeenseeeeees 70
`
`The Prior Art Disclosed NumerousFulvestrant Formulations........... 71
`E)
`XII) NON-OBVIOUSNESS OVER HOWELL (GROUND ONE)...............00054 74
`
`A)
`
`B)
`
`C)
`
`The Board Already Rejected The Same Argument Based On
`Routine Experimentation .........000 ccc ccccccsccccecsecececseeceeseeeeesseesenaeenas 75
`The Skilled Formulator Would Not Have Been Motivated To
`Combine The Howell Reference With The Specific Amounts
`Of Specific Excipients 0.0.0.0. cece cece cecscececseesecseesentseeseeaeeeesstees 77
`1)
`The Choices Of Potential Excipients Would Be Infinite.......... 77
`2)
`Routine Experimentation Would Not Lead To The
`Claimed Excipient AMOumS.0.....0...000 ccc cece cece ceeetseeeeeaeenes 84
`Dr. Burgess Fails To Address A Reasonable Expectation Of
`Success Regarding The Physiological Effects Of The
`Formulation .....0....0cccccccccccccccececeeeceeseecseeseeeseceseeeeseeeseeeseeeeeenseesseeenanas 88
`
`D)
`
`There Is No Way To Predict How A Formulation Will Behave
`Upon Injection 2... cccccccccccececseecsseeeeessseseesseeeeessesestseeeesaeenas 94
`XIV) NON-OBVIOUSNESS OVER HOWELL COMBINED WITH
`MCLESKEY (GROUND TWO))......ccccccccccccccescetsceteceeeeteetseesetseenseteenieiees 97
`
`A)—The Board Already Considered Howell As TheStarting Point
`And Correctly Denied Institution ........000.000 ccc ccccccccsceeesseeeesseeeaes 97
`No Reason To Combine Howell And McLeskey..........0..00 cece 98
`
`B)
`
`ii
`
`AstraZeneca Exhibit 2001 p. 3
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`1)|There Would Have Been No Reason To Assume That
`The Howell Formulation Was Disclosed In The Prior Art.......99
`
`2)
`
`The Skilled Artisan Would Not Choose A Formulation
`Based Solely On Fulvestrant Concentration ...........000.000.008 101
`3)|McLeskey Disparaged The Results Of Howell 1996............. 103
`4)
`The Formulator Would Not Have Found McLeskey.............. 104
`5)|McLeskey Described Fulvestrant As A “Treatment
`Fanlure”’ cece ccccececcccnseeeeecseceesseeeseeessseeetseseneesneeeness 105
`
`C)
`
`D)
`
`The Skilled Formulator Would Not View The Castor Oil-Based
`Formulation Of McLeskey As “Matching” Howell..........0..000000.0. 107
`Other Prior Art Formulations Were Closer To Howell Than
`McLeskey.0......cccccccccccccccscececseesecceeeeecseceseeeseesueesesseeesessaeseesseeeenseeens 111
`The Combination Of Howell 1996 And McLeskey Could Not
`Have Been Expected To Result In The Claimed Inventions. ........... 114
`1)|McLeskey Used Experimental Animal Formulations That
`Would Not Be Viewed As Suitable For Human Use............. 115
`
`E)
`
`3)
`
`4)
`
`2)|No Approved Product Used The Same Combination Of
`Excipients As McLeskey .........00cccccccccccccsscccssscesessseeeesseeeeees 116
`Making The McLeskey Formulation Would Introduce
`Additional Unpredictability ...0.0000000 ccc cccccceseeeesteeeees 117
`The McLeskey Formulation Would Not Be Expected To
`Work When Administered Monthly Instead Of Weekly......... 118
`5)|The McLeskey Formulation Would Not Be Expected To
`Work When Administered Intramuscularly Instead Of
`Subcutaneously ........000 cece cc cccceccccsseseeeeecsseeeeeeesesteeeeseeesaeess 119
`The Concentration/Castor Oil Theory Of Dr. BurgessIs
`Contradicted By The Literature 0.0.0.0... ccc cceeeeenee 123
`F)—The Gellert Declaration And The Sawchuk Declaration Are
`Consistent And Both Support The Patentability Of The
`Challenged Claims 2.0.0.0... ccc iccccc ccc ccecceccseeeeecsaeeecesseesesseeseessaeeeenes 131
`XV) NON-OBVIOUSNESS OVER HOWELL COMBINED WITH
`MCLESKEY AND O’REGAN (GROUND THREE)...........0cccccsceeeeee 135
`
`6)
`
`A)
`
` O’Regan Does NotFill The Fatal Gaps In InnoPharma’s
`Combination Of Howell And McLeskey..........0000ccccccceceeeeeeeeee 135
`
`ili
`
`AstraZeneca Exhibit 2001 p. 4
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`Page
`
`XVI) UNEXPECTED RESULTS ...0...occcccccccccccccccccceeccececseecseeeseecsasesseseasesaees 137
`
`The Unexpected Results Of The Claimed Inventions...............0.0.... 137
`A)
`B)—The Superior Solubility Of Fulvestrant In The Claimed
`Formulation Was Unexpected And Not Suggested By The Prior
`ALtle cece cence ecneeeeeeeenseeeeseecsneeessaeeesectseesesseeseeessieeeiseseteestiieensess 140
`
`XVIT) CONCLUSION|... ccc ccceccenececeseeenseecseeeeeesseesessesesseesesasenseeeeieeeay 143
`
`1V
`
`AstraZeneca Exhibit 2001 p. 5
`
`

`

`I, Lisbeth lum, Ph.D., do hereby make the following declaration:
`
`I)
`
`INTRODUCTION
`
`1.
`
`2.
`
`I am over the age of eighteen and competent to make this declaration.
`
`I have beenretained 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 £500 per hour for my consultation in connection with this
`
`proceeding. My compensation is in no way dependenton 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, 1s attached to this declaration as Exhibit A.
`
`I)
`
`QUALIFICATIONS AND EXPERIENCE
`
`3,
`
`My nameis Lisbeth IIlum, Ph.D.
`
`I am a Danish citizen, born in
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`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 asa 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 Exhibit 2001 p. 6
`
`

`

`Visiting Research Fellow in the Pharmacy Departmentat University of
`
`Nottingham during several periods between 1981 and 1990.
`
`5.
`
`I was made a Docent (Full 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 Departmentof
`
`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 ArchimedesLtd)
`
`(1989-1998), a company that specializes in development of drug delivery systems
`
`for pharmaceutical drugs, and when sold to West Pharmaceutical Services
`
`employed 45 scientists. In addition, I was the founder and Managing Director of
`
`Phaeton Research Ltd. (2003-2005) until it was sold and the CEO of Critical
`
`Pharmaceuticals Ltd, a drug delivery company based in BioCity in Nottingham
`
`from 2007-2011.
`
`I am presently the Founder and Director of Eurocage Ltd., a drug
`
`delivery consultancy company, the directors of which also act as pharmaceutical
`
`experts in litigation cases.
`
`7.
`
`Myresearch 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
`
`AstraZeneca Exhibit 2001 p. 7
`
`

`

`approachesto the delivery of such drugs including the use of various routes of
`
`delivery such asoral, nasal, buccal, pulmonary, vaginal and parenteral.
`
`8.
`
`I have published more than 350 scientific papers (about 90 in thelast
`
`ten years) and I am amongthe top 100 mostcited scientists on pharmacology, with
`
`an h index of more than 60.
`
`I have co-edited four booksrelated to drug delivery,
`
`drug therapy, and drug transport.
`
`I am the inventor or co-inventor on nearly fifty
`
`patent family applications on novel drug delivery systems. A large numberof
`
`patents has been granted worldwide from this patent portfolio.
`
`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 as one ofthe first recipients.
`
`I have lectured widely
`
`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 havetestified at trial or by deposition
`
`within the preceding four years is attached at Exhibit B.
`
`AstraZeneca Exhibit 2001 p. 8
`
`

`

`Il) MY UNDERSTANDING OF THE PROCEEDING
`
`11.
`
`IThave 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 groundsthat the patent is the same as or rendered obviousin
`
`view ofthe priorart.
`
`12.
`
`Jhave been informed that InnoPharma Licensing, LLC
`
`(“InnoPharma’’) filed a Petition requesting Inter Partes Review (“Petition”) of U.S.
`
`Patent No. 8,466,139 (“the 7139 Patent”), which issued to John R Evans and
`
`Rosalind U Grundy on June 18, 2013 andis assigned to AstraZeneca AB.
`
`I have
`
`reviewed the Petition, and understandthatit alleges that claims 1,3, 10, 11, 13, and
`
`20 of the ’139 Patent are unpatentable over Howell 1996 (Ex. 1007) and,
`
`alternatively, over the combination of Howell 1996 (Ex. 1007) with McLeskey
`
`(Ex. 1008), and the combination of Howell 1996 (Ex. 1007) with McLeskey(Ex.
`
`1008) and O’Regan(Ex. 1009),
`
`IV) MY OPINIONS AND THEIR BASES
`
`13.
`
`Ihave been asked to give my opinion on whether InnoPharmahas
`
`shown with reasonable likelihood that a person of ordinary skill in the art
`
`(“POSA”) would understand claims 1, 3, 10, 11, 13, and 20 of the 7139 Patent to be
`
`AstraZeneca Exhibit 2001 p. 9
`
`

`

`rendered obvious by: (1) Howell 1996 (Ex. 1007); (2) the combination of Howell
`
`1996 (Ex. 1007) with McLeskey (Ex. 1008); or (3) the combination of Howell
`
`1996 (Ex. 1007) with McLeskey (Ex. 1008) and O’Regan (Ex. 1009). Most of my
`
`opinions herein are a direct repeat of the opinions in my declaration submitted in
`
`support of AstraZeneca’s Preliminary Patent Owner Response in Mylan
`
`Pharmaceuticals Inc. v. AstraZeneca AB, Case IPR2016-01325 (see AstraZeneca
`
`Ex. 2001) attached hereto for the Board’s convenience as Ex. 2135 (Illum Decl.).
`
`14.
`
`As part of this opinion, I considered the level of ordinary skill in the
`
`art around January 2000, which representsthe filing date of GB 0000313, to which
`
`the °139 Patent claimspriority.
`
`15.
`
`For the reasons explained below,in my opinion, InnoPharmahas not
`
`shown that there is a reasonable likelihood that it would prevail in an inter partes
`
`review of claims 1, 3, 10, 11, 13, and 20 of the 7139 Patent.
`
`V)
`
`DOCUMENTS CONSIDERED
`
`16.
`
`The materials that I have considered, in addition to the exhibits to the
`
`Petition, are listed in Exhibit C. My opinionsasstated in this Declaration are
`
`based on the understanding of a POSA inthe art as defined above and in § 25,
`
`below.
`
`AstraZeneca Exhibit 2001 p. 10
`
`

`

`VI THE ’139 PATENT SPECIFICATION AND CLAIMS
`
`17.
`
`Ihave been informed that the priority date of the ’139 Patentis
`
`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-
`
`aqueousester solvent which is miscible in the ricinoleate vehicle.” Ex. 1001 at
`
`Abstract.
`
`18.
`
`The specification of the 139 Patent explains that “[fJulvestrant shows,
`
`along with other steroidal based compounds,certain physical properties which
`
`make formulation of these compoundsdifficult.” Ex. 1001 at 2:46-48.
`
`Specifically, “[fJulvestrant is a particularly lipophilic molecule, even when
`
`compared with other steroidal compounds, and its aqueous solubility is extremely
`
`low at around 10 ngml'.” Ex. 1001 at 2:48-51.
`
`19.
`
`The inventors of the °139 Patent “surprisingly found that the
`
`introduction of a non-aqueousester 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'.” Ex. 1001 at 5:57-61. This was surprising because “[tJhe
`
`solubility of fulvestrant in non-aqueousester solvents .
`
`.
`
`. is significantly lower
`
`AstraZeneca Exhibit 2001 p. 11
`
`

`

`than the solubility of fulvestrant in an alcohol” and “in castor oil.” Ex. 1001 at
`
`5:62-67. 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 9:19-21.
`
`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 8:34-36. The specification of the °139
`
`Patent states that “[b]y use of the term ‘therapeutically significant levels’ we mean
`
`that blood plasma concentrationsofat least 2.5 ngml’, ideally at least 3 ngml',at
`
`least 8.5 ngml', and up to 12 ngm!"of fulvestrant are achieved in the patient.” Ex.
`
`1001 at 9:1-5. 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 9:6-8. In addition, the inventors
`
`found that “the castor oil formulation showed a particularly even release profile
`
`with no evidence of precipitation of fulvestrant at the injection site.” Ex. 1001 at
`
`10:30-32.
`
`21.
`
`Independent claim 1 of the *139 Patent is provided below.
`
`1. A method for treating a hormonal dependent benign
`
`or malignant disease of the breast or reproductivetract
`
`comprising administering intramuscularly to a human in
`
`need of such treatment a formulation comprising:
`
`AstraZeneca Exhibit 2001 p. 12
`
`

`

`about 50 mgml" 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 castor oil vehicle;
`
`wherein the method achieves a blood plasma
`fulvestrant concentration ofat least 2.5 ngmlfor
`
`at least two weeks.
`
`22.
`
`Claims 3 and 13 limit claims 1 and 11, respectively, to a method
`
`wherein the formulation comprises:
`
`about 10% w/v of ethanol;
`
`about 10% w/v of benzyl alcohol; and
`
`about 15% w/v of benzyl benzoate.
`
`23.
`
`Claims 10 and 20 limit claims 3 and 13, respectively, to a method
`
`wherein the hormonal dependent benign or malignant disease of the breast or
`
`reproductive tract is breast cancer and the blood plasma fulvestrant concentration is
`
`attained for at least 4 weeks.
`
`24.
`
`Independent claim 11 of the 7139 Patent is provided below.
`
`11. A methodoftreating a hormonal dependent benign
`
`or malignant disease of the breast or reproductivetract
`
`comprising administering intramuscularly to a human in
`
`need of such treatment a formulation consisting
`
`essentially of.
`about 50 mgml"of fulvestrant;
`
`AstraZeneca Exhibit 2001 p. 13
`
`

`

`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 castor oil vehicle;
`
`wherein the method achieves a blood plasma fulvestrant
`
`concentration of at least 2.5 ngml-1 for at least two
`
`weeks.
`
`VID) PERSON OF ORDINARYSKILL IN THE ART
`
`25.
`
`J 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 ?139 Patent is a
`
`person having a bachelor’s or advanced degree in a discipline such as pharmacy,
`
`pharmaceutical sciences, endocrinology, medicineor 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
`
`developmentprocess is complicated and multidisciplinary, it would require a team
`
`of individuals including, at least, medical doctors, pharmacokineticists, and
`
`formulators.
`
`26. Asconsidered from the perspective of the formulator memberofthat
`
`team, the invention of the ’139 Patent is novel, and not obvious, for the following
`
`reasons.
`
`AstraZeneca Exhibit 2001 p. 14
`
`

`

`VIII) LEGAL PRINCIPLES
`
`27.
`
`Iam notalawyer.
`
`I have relied on the explanations of counsel for an
`
`understanding of certain principles of U.S. patent law that govern the
`
`determination of patentability. The discussion set forth below regarding the law of
`
`obviousness1s intended to be illustrative of the legal principles I considered while
`
`preparing my declaration, and not an exhaustivelist.
`
`28.
`
`I understandthat to institute an inter partes review, InnoPharma 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
`
`inter partes review 1s instituted, InnoPharma must show unpatentability by a
`
`preponderance of the evidence, and preponderanceof the evidence means “more
`
`probable than not.”
`
`29.
`
`Iam informed by counselthat for a patent claim to be invalid as
`
`anticipated by a priorart 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.
`
`30.
`
`Iam informed by counsel that for an invention to be obvious, the
`
`patent statute requires that the differences between the invention and the priorart
`
`be such that the “subject matter as a whole would have been obviousat the time
`
`10
`
`AstraZeneca Exhibit 2001 p. 15
`
`

`

`the invention was madeto a person of ordinary skill in the art to which such
`
`subject matter pertains.”
`
`31.
`
`J 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
`
`applications, which is January 10, 2000. The obviousness inquiry must guard
`
`against slipping into use of hindsight.
`
`32.
`
`J understand that even in circumstances where each componentof an
`
`invention can be foundin the priorart, there must have been an apparent reason to
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`combine the known elements in the fashion claimed by the patent at issue. For an
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`invention to be found obvious, to protect against the distortion caused by hindsight
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`bias, there must be a reason that would have prompted a person of ordinary skill in
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`the relevant field to combine the elements in the way the claimed new invention
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`does.
`
`33.
`
`To be obvious, the claimed method of treatment must have been
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`among a finite numberof identified, predictable solutions to the problemsat hand.
`
`IX) CLAIM CONSTRUCTION
`
`34.
`
`In independent claims | and 11, the term “wherein the method
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`achieves a blood plasmafulvestrant concentration of at least 2.5 ngml" for at least
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`two weeks”is a claim limitation entitled to patentable weight. Independent claims
`
`11
`
`AstraZeneca Exhibit 2001 p. 16
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`

`

`1 and 11 do not specify the total amount of fulvestrant to administer to the patient.
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`Instead, the desired blood plasmalevel of fulvestrant, for example, limits the
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`methods of claim 1 and 11 to an amountof fulvestrant that achieves and maintains
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`2.5 ngml’ for at least two weeksafter injection. The claimed methods cannotbe
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`practiced without knowingthe target blood plasmalevels, which then allows
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`administration of an appropriate amount of fulvestrant to reach thoselevels.
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`Hence, the blood plasma levels absolutely inform how the method of administering
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`the fulvestrant formulation to a humanpatient is carried out.
`
`35.
`
`The formulator would understand “wherein the method achieves a
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`blood plasmafulvestrant concentration ofat least 2.5 ngml'' for at least two
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`weeks” to mean that the blood plasma fulvestrant concentration of at least 2.5
`
`ngml' is achieved and maintainedfor at least two weeks. The plain meaning of
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`the words “‘achieves” and “at least” indicate to the formulator that the patient’s
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`blood plasma level must remain at or above 2.5 for the entire specified time period.
`
`This is consistent with the Board’s finding in Mylan Pharmaceuticals Inc. v.
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`AstraZeneca AB, Case IPR2016-01325, Paper No. 11 (Dec. 14, 2016) (Ex. 1011)
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`(“PTAB Decision”) which InnoPharmadoesnot dispute. Ex. 1011 (PTAB
`
`Decision) at 18 (“[W]e interpret ‘achieves’ in the wherein clauses as meaningthat
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`the concentration of fulvestrant in a patient’s blood plasmais at or above the
`
`specified minimum concentration for the specified time period.”); Petition at 18.
`
`12
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`AstraZeneca Exhibit 2001 p. 17
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`

`

`Further, these limitations give meaning to and provide defining characteristics of
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`the method of treatment.
`
`36.
`
`Indeed, as the Board previously held, “rather than merely stating the
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`result of intramuscularly administering the recited formulation, [] the wherein
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`clause dictates both the administration duration and dose of the formulation,1.¢., an
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`amount sufficient to provide a therapeutically significant blood plasma fulvestrant
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`concentration ofat least 2.5 ngml”for at least four weeks.” Ex. 1011 at 17 (citing
`
`Ex. 2136 (Robertson Decl.) at J] 37-39, Ex. 2135 (lum Decl.) at {9 33-37. And,
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`“[t]hat these parameters are further limited in claim 2, [] further indicates that the
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`wherein clauses provide defining characteristics.” /d. (citing Ex. 2133 (Sawchuk
`
`Decl.) at § 60).
`
`InnoPharmadoesnotdispute this finding. Petition at 18. This
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`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 a/so Ex. 1010 (Order by Judge Bumb ofthe District
`
`of New Jersey).
`
`37.
`
`The specification indicates that a goal of the invention is sustained
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`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
`
`13
`
`AstraZeneca Exhibit 2001 p. 18
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`

`

`concentration to dose a patient in a low volumeinjection and achieve a
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`therapeutically significant release rate.” Ex. 1001 at 5:36-40. 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
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`the injection site.” Ex. 1001 at 9:19-21. Thus, the inventors faced the problem not
`
`only of dissolving a sufficient amountof fulvestrant in a formulation but also
`
`engineering a therapeutically significant release rate and duration and furthermore
`
`developing a formulation that could provide such a pharmacokinetic profile
`
`without causing precipitation at the injectionsite.
`
`38.
`
`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 [in] an alcohol
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`surprisingly eases the solubilisation of fulvestrant into a concentration ofat least
`
`50 mgml’.” Ex. 1001 at 5:57-61. The inventors further foundthat the claimed
`
`formulations “provide, after intra-muscular injection, satisfactory release of
`
`fulvestrant over an extended period of time.” Ex. 1001 at 8:34-36. In addition,
`
`Table 4 of the patent showed that the claimed methods avoid precipitation that
`
`occurred in other fulvestrant formulations. Ex. 1001, Table 4. The inventors
`
`concludedthat “the castor oil formulation showed a particularly even release
`
`profile with no evidenceof precipitation of fulvestrant at the injection site.” Ex.
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`1001 at 10:30-32.
`
`14
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`AstraZeneca Exhibit 2001 p. 19
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`

`

`X)
`
`STATE OF THE RELEVANT ART
`
`A) Formulation Background
`
`39.
`
`“The development of an optimum formulation is not an easy task, and
`
`manyfactors readily influence formulation properties.” Ex. 2081 (Remington’s
`
`Ch. 75) at 5. Such factors include biopharmaceutical considerations, drug factors,
`
`and therapeutic considerations. Ex. 2082 (Aulton Ch. 1) at 5.
`
`40. A successful formulation of an active pharmaceutical ingredient must
`
`deliver the active ingredient in such a waythatit is biologically effective. This
`
`often requires meeting certain parameters, such as blood plasma concentrations
`
`and/or duration. Ex. 1091 (Ansel Ch. 4) at 5 (‘The magnitude of the response is
`
`related to the concentration of the drug achievedat the site of its action.”). In such
`
`cases, the delivery method and formulation must ensure that a sufficient amount of
`
`the active ingredient enters the circulation when introduced into the body to deliver
`
`the active ingredient to the site of action (normally via the bloodstream).
`
`B) The Claimed Blood Plasma Levels Are Critical To The Inventions
`
`41.
`
`The skilled formulator would know that the release profile of a drug
`
`from the formulation, its absorption into the blood stream and henceits
`
`pharmacokinetic profile are critical factors influencing the action of the drug on the
`
`patient. Ex. 1091 (Ansel Ch. 4) at 43 (“[T]he objective of pharmacokinetic dosing
`
`is to design a dosage regimenthat will continually maintain a drug’s therapeutic
`
`serum or plasma concentration within the drug’s therapeutic index,1.¢., above the
`
`15
`
`AstraZeneca Exhibit 2001 p. 20
`
`

`

`minimum effective concentration but below the minimum toxic level.”’); Ex. 2080
`
`(Remington’s Ch. 91) at 5 (“The goal of any drug delivery system is to provide a
`
`therapeutic amount of drug to the propersite in the body to achieve promptly, and
`
`then maintain, the desired drug concentration.”’).
`
`42. Depot formulations are particularly challenging. For instance,if too
`
`muchdrug is released immediately from the formulation, the blood plasma
`
`concentration may reach the minimum toxic level and cause side effects. Ex. 2080
`
`(Remington’s Ch. 91) at 5. Additionally, if too much of a drug reaches the blood
`
`stream immediately after the injection and is eliminated, insufficient drug will be
`
`left at the depot to sustain the therapeutic levels over the long term. On the other
`
`hand,if too little drug reaches the blood stream immediately after injection, the
`
`therapeutic effect of the treatment could be delayed or be limited. Ex. 2080
`
`(Remington’s Ch. 91) at 5. If the release rate 1s inconsistent and plasmalevels
`
`spike and plummet, the biological threshold necessary to trigger a therapeutic
`
`response maynot bereachedatall.
`
`43.
`
`The inventors surprisingly discovered a treatment method that
`
`combineda specific pharmacokinetic profile (fulvestrant blood plasma levels
`
`maintained overa particular time) with a specific administration method for
`
`therapeutic action. From myperspective as a formulator, the fulvestrant blood
`
`plasmalevels in the claims are a clear limitation on the frequency of administration
`
`16
`
`AstraZeneca Exhibit 2001 p. 21
`
`

`

`(every two weeks) and of the amount of fulvestrant to be dosed. That the claims
`
`differ make that clear. The entire combination of the invention ensures that the
`
`level of fulvestrant in the patient’s blood plasmais consistent, steady, and
`
`maintained overa relatively long period of time at therapeutically effective levels.
`
`The successful use of the benzyl benzoate ingredient wasparticularly surprising in
`
`that the addition of benzyl benzoate to the formulation would have been predicted
`
`to be associated with a lower fulvestrant solubility in the formulation, leading to a
`
`ereater chance of precipitation. In sum, the claimed inventions (and, with that, the
`
`use of benzyl benzoate) surprisingly achieved and maintained therapeutically
`
`significant fulvestrant plasma levels, as compared to other fulvestrant formulations.
`
`C) Formulation Options
`
`44. A person wishing to formulate a highly lipophilic molecule, such as
`
`fulvestrant, for administration to humans on a commercial basis, had many choices
`
`for each step of the process. The field of drug formulation was wide open,replete
`
`with multi-variable and interconnected possibilities, and lacking clear guideposts
`
`to suggest a particular direction. Most importantly, there was (and currently is) no
`
`“one size fits all,” or single best approach to formulation. Thus, a formulator
`
`would be aware of the many options available for formulating an active
`
`pharmaceutical ingredient.
`
`17
`
`AstraZeneca Exhibit 2001 p. 22
`
`

`

`45.
`
`Each active pharmaceutical ingredient has unique characteristics. For
`
`each active ingredient, there will be many potential choices for administration
`
`route, dosage form, and formulation. Physical and chemical pr