UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`INNOPHARMA LICENSING, LLC.
`
`Petitioner
`
`V.
`
`ASTRAZENECA AB
`
`Patent Owner
`
`
`
`Case IPR2017-00900
`
`US. Patent 8,329,680 B2
`
`
`DECLARATION OF LISBETH ILLUM, Ph.D. IN SUPPORT OF PATENT
`OWNER’S PRELIMINARY RESPONSE
`
`AstraZeneca Exhibit 2001 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00900
`Fresenius—Kabi USA LLC V. AstraZeneca AB IPR2017-01913
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`I)
`
`II)
`
`INTRODUCTION ........................................................................................... 1
`
`QUALIFICATIONS AND EXPERIENCE ..................................................... 1
`
`III) MY UNDERSTANDING OF THE PROCEEDING ...................................... 4
`
`IV) MY OPINIONS AND THEIR BASES ........................................................... 4
`
`V)
`
`DOCUIVIENTS CONSIDERED ...................................................................... 5
`
`VI)
`
`THE ’680 PATENT SPECIFICATION AND CLAIMS ................................ 6
`
`VII) PERSON OF ORDINARY SKILL IN THE ART .......................................... 8
`
`VIII) LEGAL PRINCIPLES ..................................................................................... 9
`
`IX) CLAIM CONSTRUCTION .......................................................................... 11
`
`X)
`
`STATE OF THE RELEVANT ART ............................................................. 14
`
`A)
`
`B)
`
`Formulation Background ..................................................................... 14
`
`The Claimed Blood Plasma Levels Are Critical To The
`Inventions ............................................................................................ 1 5
`
`C)
`
`Formulation Options ........................................................................... 17
`
`XI) REFERENCES CITED IN THE PETITION AND BURGESS
`DECLARATION ........................................................................................... 20
`
`A) McLeskey (EX. 1008) .......................................................................... 21
`
`1)
`
`2)
`
`3)
`
`4)
`
`5)
`
`McLeskey Describes A “Treatment Failure” ............................ 23
`
`McLeskey Did Not Test Formulations For Human Use ........... 23
`
`McLeskey Provides No Pharmacokinetic Data ........................ 25
`
`McLeskey Does Not Disclose The Units For The
`Excipient Percentages ............................................................... 25
`
`McLeskey Does Not Disclose Any Solubility
`Information ................................................................................ 29
`
`B)
`
`C)
`
`D)
`
`E)
`
`F)
`
`Howell 1996 (EX. 1007) ...................................................................... 33
`
`DeFriend (EX. 1038) ............................................................................ 36
`
`Riffl<in (EX. 1033) .............................................................................. 38
`
`O’Regan (Exhibit 1009) ...................................................................... 42
`
`Dukes 1989 (EX. 1047) ........................................................................ 44
`
`AstraZeneca Exhibit 2001 p. 2
`
`

`

`TABLE OF CONTENTS
`
`(continued)
`
`G)
`
`Gellert Declaration (Ex. 1020) ............................................................ 46
`
`1)
`
`2)
`
`Background Of The Gellert Declaration ................................... 47
`
`The Gellert Declaration Describes Extensive
`Experimentation Based On Information Not Known In
`The Art ...................................................................................... 48
`
`Page
`
`XII) THE SKILLED FORMULATOR’S APPROACH TO
`FORMULATING FULVESTRANT ............................................................. 59
`
`A)
`
`B)
`
`C)
`
`D)
`
`The Fulvestrant Art Taught Once-A-Day Administration And
`Once-A-Month Administration ........................................................... 60
`
`The Formulator Would Prefer Oral Fulvestrant Formulations ........... 62
`
`The Formulator Would Not Have Excluded Oral Formulations ........ 65
`
`The Formulator Would Be Concerned About Intramuscular
`Administration Of Fulvestrant ............................................................ 70
`
`E)
`
`The Prior Art Disclosed Numerous Fulvestrant Formulations ........... 72
`
`XIII) NON-OBVIOUSNESS OVER HOWELL (GROUND ONE) ...................... 75
`
`A)
`
`B)
`
`C)
`
`D)
`
`The Board Already Rejected The Same Argument Based On
`Routine Experimentation ..................................................................... 76
`
`The Skilled Formulator Would Not Have Been Motivated To
`Combine The Howell Reference With The Specific Amounts
`Of Specific Excipients ......................................................................... 78
`
`1)
`
`2)
`
`The Choices Of Potential Excipients Would Be Infinite .......... 78
`
`Routine Experimentation Would Not Lead To The
`Claimed Excipient Amounts ..................................................... 85
`
`Dr. Burgess Fails To Address a Reasonable Expectation Of
`Success Regarding The Physiological Effects Of The
`Formulation ......................................................................................... 89
`
`There Is No Way To Predict How A Formulation Will Behave
`Upon Injection ..................................................................................... 95
`
`XIV) NON-OBVIOUSNESS OVER HOWELL COMBINED WITH
`MCLESKEY (GROUND TWO) ................................................................... 98
`
`A)
`
`The Board Already Considered Howell As The Starting Point
`aAnd Correctly Denied Institution ...................................................... 98
`
`B)
`
`No Reason To Combine Howell And McLeskey ............................... 99
`
`ii
`
`AstraZeneca Exhibit 2001 p. 3
`
`

`

`TABLE OF CONTENTS
`
`(continued)
`
`Page
`
`1)
`
`2)
`
`3)
`
`4)
`
`5)
`
`There Would Have Been No Reason To Assume That
`The Howell Formulation Was Disclosed In The Prior Art ..... 100
`
`The Skilled Artisan Would Not Choose A Formulation
`Based Solely On Fulvestrant Concentration ........................... 102
`
`McLeskey Disparaged The Results Of Howell 1996 ............. 103
`
`The Formulator Would Not Have Found McLeskey .............. 105
`
`McLeskey Described Fulvestrant As A “Treatment
`Failure” .................................................................................... 105
`
`C)
`
`D)
`
`E)
`
`The Skilled Formulator Would Not View The Castor Oil-Based
`Formulation Of McLeskey As “Matching” Howell .......................... 107
`
`Other Prior Art Formulations Were Closer To Howell Than
`McLeskey .......................................................................................... 1 1 1
`
`The Combination Of Howell 1996 And McLeskey Could Not
`Have Been Expected To Result In The Claimed Inventions. ........... 114
`
`1)
`
`2)
`
`3)
`
`4)
`
`5)
`
`6)
`
`McLeskey Used Experimental Animal Formulations That
`Would Not Be Viewed As Suitable For Human Use ............. 116
`
`No Approved Product Used The Same Combination Of
`Excipients As McLeskey ........................................................ 116
`
`Making The McLeskey Formulation Would Introduce
`Additional Unpredictability .................................................... 1 17
`
`The McLeskey Formulation Would Not Be Expected To
`Work When Administered Monthly Instead of Weekly ......... 118
`
`The McLeskey Formulation Would Not Be Expected To
`Work When Administered Intramuscularly Instead Of
`Subcutaneously ....................................................................... 1 19
`
`The Concentration/Castor Oil Theory Of Dr. Burgess Is
`Contradicted By The Literature .............................................. 124
`
`F)
`
`The Gellert Declaration And The Sawchuk Declaration Are
`Consistent And Both Support The Patentability Of The
`Challenged Claims ............................................................................ 132
`
`XV) NON-OBVIOUSNESS OVER HOWELL COMBINED WITH
`MCLESKEY AND O’REGAN (GROUND THREE) ................................ 135
`
`A)
`
`O’Regan Does Not Fill The Fatal Gaps In InnoPharma’s
`Combination Of Howell And McLeskey .......................................... 135
`
`iii
`
`AstraZeneca Exhibit 2001 p. 4
`
`

`

`TABLE OF CONTENTS
`
`(continued)
`
`Page
`
`XVI) NON-OBVIOUSNESS OVER HOWELL COMBINED WITH
`MCLESKEY AND O’REGAN AND DEFRIEND (GROUND FOUR)....137
`
`A)
`
`B)
`
`The Skilled Formulator Seeking To Develop A Long-Acting
`Formulation Would Not Include DeFriend In A Combination ......... 137
`
`DeFriend Encourages The Skilled Formulator To Develop A
`Daily Administration Method Of Fulvestrant ................................... 138
`
`XVII) UNEXPECTED RESULTS ......................................................................... 13 8
`
`A)
`
`B)
`
`The Unexpected Results Of The Claimed Inventions ....................... 138
`
`The Superior Solubility Of Fulvestrant In The Claimed
`Formulation Was Unexpected And Not Suggested By The Prior
`Art ...................................................................................................... 142
`
`XVIII)
`
`CONCLUSION ................................................................................. 144
`
`iv
`
`AstraZeneca Exhibit 2001 p. 5
`
`

`

`I, Lisbeth Illum, 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 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 £500 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 PhD. 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 Exhibit 2001 p. 6
`
`

`

`Visiting Research Fellow in the Pharmacy Department at 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 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, 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.
`
`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
`
`AstraZeneca Exhibit 2001 p. 7
`
`

`

`approaches to the delivery of such drugs including the use of various routes of
`
`delivery such as oral, nasal, buccal, pulmonary, 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
`
`an h index of more than 60.
`
`I have co-edited four books related 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 number of
`
`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 of the 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 US. cases in which I have testified at trial or by deposition
`
`within the preceding four years is attached at Exhibit B.
`
`AstraZeneca Exhibit 2001 p. 8
`
`

`

`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.
`
`12.
`
`I have been informed that InnoPharma Licensing, LLC
`
`(“InnoPharma”) filed a Petition requesting Inter Partes Review (“Petition”) of US.
`
`Patent No. 8,329,680 (“the ’680 Patent”), which issued to John R Evans and
`
`Rosalind U Grundy on December 11, 2012 and is assigned to AstraZeneca AB.
`
`I
`
`have reviewed the Petition, and understand that it alleges that claims 1-3 and 6 of
`
`the ’680 Patent are unpatentable over Howell 1996 (EX. 1007) and, alternatively,
`
`over the combination of Howell 1996 (EX. 1007) with McLeskey (EX. 1008), the
`
`combination of Howell 1996 (EX. 1007) with McLeskey (EX. 1008) and O’Regan
`
`(EX. 1009), and the combination of Howell 1996 (EX. 1007) with McLeskey (EX.
`
`1008), O’Regan (EX. 1009), and DeFriend (EX. 1038).
`
`IV) MY OPINIONS AND THEIR BASES
`
`13.
`
`I have been asked to give my opinion on whether InnoPharma has
`
`shown with reasonable likelihood that a person of ordinary skill in the art
`
`AstraZeneca Exhibit 2001 p. 9
`
`

`

`(“POSA”) would understand claims 1-3 and 6 of the ’680 Patent to be rendered
`
`obvious by: (1) Howell 1996 (Ex. 1007); (2) the combination of Howell 1996 (Ex.
`
`1007) with McLeskey (Ex. 1008); (3) the combination of Howell 1996 (Ex. 1007)
`
`with McLeskey (Ex. 1008) and O’Regan (Ex. 1009); or (4) the combination of
`
`Howell 1996 (Ex. 1007) with McLeskey (Ex. 1008); O’Regan (Ex. 1009); and
`
`DeFriend (Ex. 1038). 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 represents the filing date of GB 0000313; to which
`
`the ’680 Patent claims priority.
`
`15.
`
`For the reasons explained below; in my opinion; InnoPharma has not
`
`shown that there is a reasonable likelihood that it would prevail in an inter partes
`
`review of claims 1-3 and 6 of the ’680 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 opinions as stated in this Declaration are
`
`AstraZeneca Exhibit 2001 p. 10
`
`

`

`based on the understanding of a POSA in the art as defined above and in 11 23,
`
`below.
`
`VI) THE ’680 PATENT SPECIFICATION AND CLAIMS
`
`17.
`
`I have been informed that the priority date of the ’680 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 ’680 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'l.” Ex. 1001 at 2:48-51.
`
`19.
`
`The inventors of the ’680 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
`
`AstraZeneca Exhibit 2001 p. 11
`
`

`

`of at least 50 mgml'l.” Ex. 1001 at 69-13. 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
`
`6:13-18. 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 9:42-44.
`
`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 8:59-60. The specification of the ’680
`
`Patent states that “[b]y use of the term ‘therapeutically significant levels’ we mean
`
`that blood plasma concentrations of at least 2.5 ngml'l, ideally at least 3 ngml'l, at
`
`least 8.5 ngml'l, and up to 12 ngml'1 of fulvestrant are achieved in the patient.” Ex.
`
`1001 at 9:24-27. 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 9:29-31. 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.1001at10:49-51.
`
`21.
`
`Independent claim 1 of the ’680 Patent is provided below.
`
`AstraZeneca Exhibit 2001 p. 12
`
`

`

`1. 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 mng'1 of fulvestrant;
`
`about 10% w/v of ethanol;
`
`about 10% w/v of benzyl alcohol;
`
`about 15% w/v of benzyl benzoate; and
`
`a sufficient amount of castor oil vehicle;
`
`wherein the method achieves a therapeutically
`
`significant blood plasma fulvestrant concentration of
`
`at least 2.5 ngml'1 for at least four weeks.
`
`22.
`
`Claim 2 limits claim 1 to a method wherein the therapeutically
`
`significant blood plasma fulvestrant concentration is at least 8.5 ngml'l. Claims 3
`
`and 6 limit claims 1 and 2; respectively; to a method wherein the hormonal
`
`dependent benign or malignant disease of the breast or reproductive tract is breast
`
`cancer.
`
`VII) PERSON OF ORDINARY SKILL IN THE ART
`
`23.
`
`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 ’680 Patent is a
`
`person having a bachelor’s or advanced degree in a discipline such as pharmacy;
`
`pharmaceutical sciences; endocrinology; medicine or related disciplines; and
`
`AstraZeneca Exhibit 2001 p. 13
`
`

`

`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
`
`forrnulators.
`
`24.
`
`As considered from the perspective of the forrnulator member of that
`
`team, the invention of the ’680 Patent is novel, and not obvious, for the following
`
`reasons.
`
`VIII) LEGAL PRINCIPLES
`
`25.
`
`I am not a lawyer.
`
`I have relied on the explanations of counsel for an
`
`understanding of certain principles of US. patent law that govern the
`
`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.
`
`26.
`
`I understand that 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 is instituted, InnoPharma must show unpatentability by a
`
`AstraZeneca Exhibit 2001 p. 14
`
`

`

`preponderance of the evidence, and preponderance of the evidence means “more
`
`probable than not.”
`
`27.
`
`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.
`
`28.
`
`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
`
`subject matter pertains.”
`
`29.
`
`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
`
`applications, which is January 10, 2000. The obviousness inquiry must guard
`
`against slipping into use of hindsight.
`
`30.
`
`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
`
`10
`
`AstraZeneca Exhibit 2001 p. 15
`
`

`

`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.
`
`31.
`
`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
`
`32.
`
`In independent claim 1, the term “wherein the method achieves a
`
`therapeutically significant blood plasma fulvestrant concentration of at least 2.5
`
`nng'1 for at least four weeks” 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 ngml'1 for at least four weeks after inj ection. The claimed methods
`
`cannot be practiced without knowing the target blood plasma levels, which then
`
`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.
`
`33.
`
`The forrnulator would understand “wherein the method achieves a
`
`therapeutically significant blood plasma fulvestrant concentration of at least 2.5
`
`nng'1 for at least four weeks” to mean that the blood plasma fulvestrant
`
`ll
`
`AstraZeneca Exhibit 2001 p. 16
`
`

`

`concentration of at least 2.5 nng'1 is achieved and maintained for at least four
`
`weeks. The plain meaning of the words “achieves” and “at least” indicate to the
`
`forrnulator that the patient’s blood plasma level must remain at or above 2.5 or 8.5
`
`for the entire specified time period. This is consistent with the Board’s finding in
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`Mylan Pharmaceuticals Inc. v. AstraZeneca AB, Case IPR2016-01325, Paper No.
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`11 (Dec. 14, 2016) (EX. 1011) (“PTAB Decision”) which InnoPharma does not
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`dispute. EX. 1011 (PTAB Decision) at 18 (“[W]e interpret ‘achieves’ in the
`
`wherein clauses as meaning that the concentration of fulvestrant in a patient’s
`
`blood plasma is at or above the specified minimum concentration for the specified
`
`time period.”); Petition at 17. Further, these limitations give meaning to and
`
`provide defining characteristics of the method of treatment.
`
`34.
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`Indeed, as the Board previously held, “rather than merely stating the
`
`result of intramuscularly administering the recited formulation, [] the wherein
`
`clause dictates both the administration duration and dose of the formulation, i.e., an
`
`amount sufficient to provide a therapeutically significant blood plasma fulvestrant
`
`concentration of at least 2.5 nng'1 for at least four weeks.” EX. 1011 at 17 (citing
`
`EX. 2136 (Robertson Decl.) at W 37-39, EX. 2135 (Illum Decl.) at 1111 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.” Id. (citing EX. 2133 (Sawchuk
`
`Decl.) at 11 60). InnoPharma does not dispute this finding. Petition at 18. This
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`AstraZeneca Exhibit 2001 p. 17
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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 also EX. 1010 (Order by Judge Bumb of the District
`
`of New Jersey).
`
`35.
`
`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
`
`concentration to dose a patient in a low volume injection and achieve a
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`therapeutically significant release rate.” EX. 1001 at 5:54-58. The inventors noted
`
`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 9:42-44. 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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`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 injection site.
`
`36.
`
`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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`AstraZeneca Exhibit 2001 p. 18
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`

`

`surprisingly eases the solubilisation of fulvestrant into a concentration of at least
`
`50 mgml'l.” EX. 1001 at 6:9-12. The inventors further found that the claimed
`
`formulations “provide, after intra-muscular injection, satisfactory release of
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`fulvestrant over an extended period of time.” EX. 1001 at 8:59-60. In addition,
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`Table 4 of the patent showed that the claimed methods avoid precipitation that
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`occurred in other fulvestrant formulations. EX. 1001, Table 4. The inventors
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`concluded that “the castor oil formulation showed a particularly even release
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`profile with no evidence of precipitation of fulvestrant at the injection site.” EX.
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`1001 at 10:49-51.
`
`X)
`
`STATE OF THE RELEVANT ART
`
`A) Formulation Background
`
`37.
`
`“The development of an optimum formulation is not an easy task, and
`
`many factors 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.
`
`38. A successful formulation of an active pharmaceutical ingredient must
`
`deliver the active ingredient in such a way that it 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 achieved at the site of its action”). In such
`
`14
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`AstraZeneca Exhibit 2001 p. 19
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`

`

`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 T0 The Inventions
`
`39.
`
`The skilled formulator would know that the release profile of a drug
`
`from the formulation, its absorption into the blood stream and hence its
`
`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 pharrnacokinetic dosing
`
`is to design a dosage regimen that will continually maintain a drug’s therapeutic
`
`serum or plasma concentration within the drug’s therapeutic index, i.e., above the
`
`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 proper site in the body to achieve promptly, and
`
`then maintain, the desired drug concentration”).
`
`40. Depot formulations are particularly challenging. For instance, if too
`
`much drug 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
`
`15
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`AstraZeneca Exhibit 2001 p. 20
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`

`

`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 is inconsistent and plasma levels
`
`spike and plummet, the biological threshold necessary to trigger a therapeutic
`
`response may not be reached at all.
`
`41.
`
`The inventors surprisingly discovered a treatment method that
`
`combined a specific pharrnacokinetic profile (fulvestrant blood plasma levels
`
`maintained over a particular time) with a specific administration method for
`
`therapeutic action. From my perspective as a formulator, the fulvestrant blood
`
`plasma levels in the claims are a clear limitation on the frequency of administration
`
`(every four 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
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`level of fulvestrant in the patient’s blood plasma is consistent, steady, and
`
`maintained over a relatively long period of time at therapeutically effective levels.
`
`The successful use of the benzyl benzoate ingredient was particularly 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
`
`greater 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.
`
`16
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`AstraZeneca Exhibit 2001 p. 21
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`

`

`C) Formulation Options
`
`42. A person wishing to for