‘
`
`J
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Fayeton
`
`7
`_
`U s
`PTO
`35803
`‘
`iiiiiiiiiiiiiiiiiiii
`[11/09/01
`
`‘
`
`REQUEST FOR FILING APPLICATION
`Under Rule 53(a), (b)&{fl
`(No Filing Fee or Oattheclaration)
`Lg; e3; or
`
`se or
`
`esi n or
`
`tiiit A lications
`
`RULE 53 NO DECLARATION
`
`AppLiCATiQN
`——
`
`PM 275507
`PHM70635/US
`Mi"
`Gimme?
`
`Hon. Commissioner of Patents
`Washington, DC 20231
`
`Atty. Dkt.
`
`Sir:
`
`Date:
`
`January 9, 2001
`
`v—g
`our-g
`ENE"
`.‘DES
`“imam
`
`1. This is a Request for filing a newW(D Design
`Utility) entitled:
`FORMULATIONl
`2. (Complete) Title:
`
`=0
`
`M a filing fee or Oath/Declaration but for which is enclosed the following:
`
`3.
`
`4
`
`1
`
`page(s).
`
`Pages of Specification (only spec. and claims);
`
`5. D Specification in non-English language
`
`Abstract
`
`22
`
`Numbered ciaim(s); and
`23
`
`Drawings:
`1
`sheet(s) D 1 set informal;
`
`8. E] formal of size: A4 D11”
`
`
`DOMESTIC/INTERNATIONAL priority is claimed under 35 USC 119(e)/120/365(c) based on the
`
`foilowin rovisional, nonrovisional and/or PCT international a iication s :
`
`Aplication No.
`Filin Date
`Aplication No.m
`
`
`
`
`O.
`
`Apiication NO-m Application NO-m
`
`
`
`0000313.?
`Janua
`10,2000
`(2)
`0008837.?
`April 12, 2000
`(1)
`
`(3)
`(4)
`
`
`
`
`5)
`D See 3rd page for additionaifliorities
`
`11.
`2
`(N0.) Certified copy (copies):
`attached;
`D previously filed (date)
`in US. Application No.
`filed on
`
`FOREIGN priority is claimed under 35 USC 119(a)—(d)/365(b) based on filing in
`
`Great Britain
`
`
`
`I
`
`12. D This is a reissue of Patent No.
`13. D See top first page re prior Provisional, National, international application(s) (X box oniy if info is
`there and do not complete corresponding item 14 or 15.)
`14. D Amend the specification by inserting before the first line - This is a D Continuation-in—Part
`D Divisional
`D Continuation D Substitute Application (MPEP 201.09) of:
`
`filed
`14(a) D National Appln. No.
`filed
`PCT]
`14(b) D International Appln. No.
`designated the U.S., and that international Application D was D was not
`under PCT Article 21 (2) in English-—
`
`.- - (Mill!
`
`)
`
`I
`
`which
`pubiished
`
`15.
`
`16.
`
`17.
`
`D Amend the specification by inserting before the first line: --This application
`
`claims the benefit of US. Provisional Application No. 60/
`, filed
`
`.-—
`
`Extension to date: D concurrently filed D not needed
`
`D previously filed
`
`[3 Small Entity Status is claimed (Ere—filing confirmation required)
`
`(N0.) Small Entity Statement(s). (Since 9/8/00 Small Entity Statement go_t
`17(a) D Attached:
`essentiai to make claim)
`17(0) D See NONPUBL|CAT!ON REQUEST under Rule 213(a) attached (PAT-258)
`
`
`
`FAT~104 tZIOO
`
`InnoPharma Exhibit 1006.0001
`
`

`

`18. D Prior application is assigned to
`
`by Assignment recorded
`
`Reel
`
`Frame
`
`19.
`
`E] Attached:
`
`20. This application is made by the following named inventor(s)
`(Listing of inventor(s) n_ot a requirement, but list if known)
`
`(Double check instructions for accuracy.):
`
`PageZ 012
`
`_ EVANS
`.N
`Middlé‘inifia
`r
`UNITED
`.2;
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`éae‘:
`A
`.
`3322:»:
`C
`Alderle Park, Macclesfield
`8K1 0 4TG
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`(include Zip Code)
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`l2) Inventor
`
`UMTED km 66M"
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`" ”
`
`Charter Wa , Macclesfield,
`
`re, United Kindo
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`
`Fax: (202) 822-0944
`Tel: (202) 861-3027
`
`PAT-10412/D0
`
`InnoPharma Exhibit 1006.0002
`
`“265 l.
`
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`21. NOTE: FOR ADDITIONAL lNVENTORS, check box I:
`and attach sheet with same information regarding additional inventors.
`
`Pillsbury Winthrop LLP
`Intellectual Property Group
`
`By: Atty:
`
`Reg. No.
`
`1 100 New York Avenue, NW.
`Ninth Floot
`Washington) DC 20005-3918
`Tel: (202) 861-3000
`Atty/Sec: DJB/mhn
`
`Sig:
`
`V
`
`'
`
`>
`~/
`.
`NOTE: File in duplicate wijh’ post card receipts (PAT—103) & attachments
`
`

`

`APPLICATION UNDER UNITED STATES PATENT LAWS
`
`Atty. Dkt. No.
`
`PM 275507/PHM 70635/US
`(M1?)
`
`Invention:
`
`FORMULATION
`
`Inventor (s):
`
`EVANS, John R.
`GRUNDY, Rosalind U.
`
`
`
`Pillsbury Winthrop LLP
`intellectual Property Group
`1100 New York Avenue, NW
`Ninth Floor
`
`Washington, DC 20005-3918
`Attorneys
`Telephone: (202) 861—3000
`
`This is a:
`
`El Provisional Application
`
`IX] Regular Utility Application
`
`El Continuing Application
`The contents of the parent are incorporated
`by reference
`
`DECIDE
`
`[J
`
`PCT National Phase Application
`
`Design Application
`
`Reissue Application
`
`Plant Application
`
`Substitute Specification
`Sub. Spec Filed
`in App. No.
`
`/
`
`Marked up Specification re
`Sub. Spec. filed
`in App. No
`
`/
`
`SPECIFICATION
`
`Documents
`
`PAT-100 TlDO
`
`
`
`InnoPharma Exhibit 1006.0003
`
`

`

`Z70635
`
`i
`
`‘
`
`-1-
`
`FORMULATION
`
`The invention relates to a novel sustained release pharmaceutical formulation adapted
`
`for administration by injection containing the compound
`
`5
`
`70L—[9-(4,4,5 ,5 ,5 -p entafluoropentylsulphinyl)nonyl]oestra— l ,3 , 5( l 0)—triene-3 , l 7f5—diol, more
`
`particularly to a formulation adapted for administration by injection containing the compound
`
`7a—[9-(4,4,5,5 ,5—pentafluoropentylsulphinyl)nonyl]oestra— l ,3 ,5(lO)—triene~3, l 7B-diol 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.
`
`10
`
`Oestro gen deprivation is fundamental to the treatment of many benign and malignant
`
`diseases of the breast and reproductive tract. In premenopausal women, this is achieved by
`
`the ablation of ovarian function through surgical, radiotherapeutic, or medical means, and, in
`
`postmenopausal women, by the use of aromatase inhibitors.
`
`An alternative approach to oestrogen withdrawal is to antagonise oestrogens with
`
`15 antioestrogens. These are drugs that bind to and compete for oestrogen receptors (ER) present
`
`in the nuclei of oestrogen-responsive tissue. Conventional nonsteroidal antioestrogens, such
`
`as tamoxifen, compete efficiently for ER binding but their effectiveness is often limited by the
`
`partial agonism they display, which results in an incomplete blockade of oestrogen-mediated
`
`activity (Furr and Jordan 1984, May and Westley 1987).
`
`
`
`
`
`20
`
`The potential for nonsteroidal antioestrogens to display agonistic properties prompted
`
`the search for novel compounds that would bind ER with high affinity without activating any
`
`of the normal transcriptional hormone responses and consequent manifestations of oestrogens.
`
`Such molecules would be “pure” antioestrogens, clearly distinguished from tamoxifen-like
`
`ligands and capable of eliciting complete ablation of the trophic effects of oestro gens. Such
`
`Is)L11
`
`compounds are referred to as Estrogen Receptor—Downregulators (E.R.D.). The rationale for
`
`the design and testing of novel, pure antioestrogens has been described in: Bowler et a1 1989,
`
`Wakeling 1990a, 1990b, 1990c. W'akeling and Bowler 1987, 1988,
`
`Steroidal analogues of oestradiol, with an alkylsulphinyl side chain in the 70c position,
`
`provided the first examples of compounds devoid of oestrogenic activity (Bowler et a1 1989).
`
`30 One of these, ‘7ot- [9-(4,4,5,5,S-pentafluoropentyl sulphinyl)nonyl]oestra—1,3,5 —(10)triene-
`
`3,17B-diol was selected for intensive study on the basis of its pure oestrogen antagonist
`
`activity and significantly increased antioestrogenic potency over other available
`
`
`
`InnoPharma Exhibit 1006.0004
`
`

`

`Z70635
`
`)
`
`t
`
`-2-
`
`antioestrogens. In vitro findings and early clinical experience with
`
`705-[9-(4,4, 5 ,5 ,5 -p entafluoropentylsulphinyl)nonyl]o estra—l ,3 —5(1 0)—triene—3 ,17 B—diol have
`
`promoted interest in the development of the drug as a therapeutic agent for oestrogen-
`
`dependent indications such as breast cancer and certain benign gynaecological conditions.
`
`U!
`
`7a-[9-(4,4,5 ,5,5-Pentafluoropentylsulphinyl)nony1]oestra— 1,3 -5 ( l 0)-triene-3, l 7B—diol,
`
`or [Cl 182,780, has been allocated the international non-proprietary name fulvestrant, which is
`
`used hereinafter.
`
`\Vhen referring to fulvestrant we include pharmaceutically—acceptable salts
`
`thereof and any possible solvates of either thereof.
`
`Fulvestrant binds to ER with an affinity similar to that of oestradiol and completely
`
`10 blocks the growth stimulatory action of oestradiol on human breast cancer cells in vitro; it is
`
`more potent and more effective than tamoxifen in this respect. Fulvestrant blocks completely
`
`the uterotrophic action of oestradi 01 in rats, mice and monkeys, and also blocks the
`
`uterotrophic activity of tamoxifen.
`
`Because fulvestrant has none of the oestrogen—like stimulatory activity that is
`
`15 characteristic of clinically available antioestro gens such as tamoxifen or toremifene, it may
`
`offer improved therapeutic activity characterised by more rapid, complete, or longer-lasting
`
`tumour regression; a lower incidence or rate of development of resistance to treatment; and a
`
`reduction of tumour invasiveness.
`
`In intact adult rats, fulvestrant achieves maximum regression of the uterus at a dose
`
`20 which does not adversely affect bone density or lead to increased gonadotrophin secretion. If
`
`also true in humans, these findings could be of extreme importance clinically. Reduced bone
`
`density limits the duration of oestrogen—ablative treatment for endometriosis. Fulvestrant does
`
`not block hypothalamic ER. Oestrogen ablation also causes or exacerbates hot flushes and
`
`other menopausal symptoms; fulvestrant will not cause such effects because it does not cross
`
`25 the blood-brain barrier.
`
`European Patent Application No. 0 138 504 discloses that certain steroid derivatives
`
`are effective antioestrogenic agents. The disclosure includes information relating to the
`
`preparation of the steroid derivatives. In particular there is the disclosure within Example 35
`
`of the compound 70t~[9-(4,4,5,5,5—pentafluoropentylsulphinyl)nonyl]oestra-
`
`30 1,3,5(10)—triene-3,l7B-diol, which compound is specifically named in Claim 4. It is also
`
`disclosed that the compounds of that invention may be provided for use in the form of a
`
`pharmaceutical composition comprising a steroid derivative of the invention together with a
`
`
`
`
`
`InnoPharma Exhibit 1006.0005
`
`

`

`Z70635
`
`r
`
`‘
`
`-3-
`
`pharmaceutically—acceptable diluent or carrier. It is stated therein that the composition can be
`
`in a form suitable for oral or parenteral administration.
`
`Fulvestrant shows, along with other steroidal based compounds, certain physical
`
`properties which make formulation of these compounds difficult. Fulvestrant is a particularly
`
`5
`
`lipophilic molecule, even when compared with other steroidal compounds, and its aqueous
`
`solubility is extremely low at around 10 ngml" (this is an estimate from a water/solvent
`
`mixture solute since measurements this low could not be achieved in a water only solute).
`
`Currently there are a number of sustained release injectable steroidal formulations
`
`which have been commercialised. Commonly these formulations use oil as a solvent and
`
`10 wherein additional excipients may be present. Below in Table 1 are described a few
`
`commercialised sustained release inj ectable formulations.
`
`In the formulations within Table l a number of different oils are used to solubilise the
`
`compound and additional excipients such as benzyl benzoate, benzyl alcohol and ethanol have
`
`been used. Volumes of oil needed to solubilise the steroid active ingredient are low. Extended
`
`release is achievable for periods from 1 to 8 weeks.
`
`15
`
`20
`
`25
`
`
`
`InnoPharma Exhibit 1006.0006
`
`

`

`270635
`
`PRODUCT NAME
`
`STEROID
`
`DOSE
`
`TYPE
`
`
`COMP’.
`SOURCE
`QIL
`Bsz
`
`BgLQfi
`
`EQH DQSE DOSING
`
`Table 1 — OIL BASED LONG~ACTING INTRAMUSCULAR INJECTIONS
`
`SUSTANON 100
`
`PROLUTON
`DEPOT
`
`Testosterone proprionate
`Testosterone
`phenylproprionate
`Testosterone isoeaproate
`Testosterone deeanoate
`Hydroxy progesterone
`hexanoate
`
`TOCOGESTAN
`
`Hydroxy progesterone
`errantate
`Progesterone
`a«Tocopher01
`TROPHOBOLENE Estraprpnieate
`Nandrolone undeeanoate
`Hydroxyprogesterone
`heptanoate
`Norethisterone
`oenanthoate
`
`NORISTERAT
`
`Estradiol
`BENZO—
`hexahydrobenzoate
`GYNOESTRYL
`PROGESTERONE Hydroxy progesterone
`-RETARD
`caproate
`GRAVIBINAN
`Estradiol 17—[3-valerate
`Hydroxyprogesterone
`eaproate
`
`.
`
`«
`
`30mg Androgen
`60mg
`
`Organon
`
`ABPI Data
`Sheet
`Comp. 1999
`
`Araehis
`
`0.1rr11
`
`1ml
`
`3 weeks
`
`60mg
`100mg
`250mgrr11‘I
`
`Progestogen
`
`200mg Progestogen
`
`50mg
`250mg
`1,3mg Mixed
`50mg
`80mg
`
`Sehering
`HC
`
`ABPI Data
`Sheet
`Comp. 1 999
`Theramax Diet. Vidal
`1 999
`
`Castor
`
`Ethyl
`oleate
`
`11p to
`46%
`
`*40%
`
`Theramax Diet. Vidal
`1997
`
`Olive
`
`45%
`
`1 or
`21111
`
`2ml
`
`lml
`
`1 week
`
`< lweek
`
`15 to 30
`days
`
`200mg Contraceptive
`
`Schering
`HC
`
`5mg Estradiol
`
`Roussel
`
`250mg1nl"I
`
`Progestogen
`
`Pharlon
`
`Srngml'1 Mixed
`250mgml‘]
`
`Sehering
`HC
`
`ABPI Data
`Sheet
`Comp. 1999
`Diet, Vidal
`1 998
`Diet. Vidal
`1999
`Diet. Vidal
`1995
`
`Castor
`
`YES
`
`lml
`
`8 weeks
`
`Ame-his
`
`Castor
`
`YES
`
`Castor
`
`YES
`
`1m]
`
`1 or
`2m]
`1 or
`2m]
`
`1 week
`
`1 week.
`
`1 ~ 2
`weeks
`
`
`
`InnoPharma Exhibit 1006.0007
`
`

`

`Z70635
`
`
`
`PARABOLAN
`
`Trenbolone
`
`76mg Androgen
`
`Negma
`
`DELESTROGEN
`
`Estradiol
`valerate
`
`ZOmgml'l Estradiol
`4On‘1gml'1
`
`BMS
`
`DELALUTIN
`
`l7—Hydroxy
`progesterone
`
`zsomgml"
`
`Progestrogen
`
`DMS
`
`Dict. Vidal
`1997
`
`J .Phann.
`Sci
`
`(1964)
`53(8) 891
`J.Pharmi
`
`Sci.( 1964)
`53(8) 891
`
`Arachis
`
`Castor
`
`75 mg
`
`45mg
`
`1.5ml
`
`2 weeks
`
`78%
`58%
`
`20%
`40%
`
`2%
`2%
`
`Castor
`
`YES
`
`YES
`
`up to
`2%
`
`= ethanol Dict. Vidal : Dictionnaire Vidal
`EtOH
`Bsz = benzylbenzoate BZOH = benzylalcohol
`S % are W/V and * approximate as measured directly from a single sample
`
`
`
`InnoPharma Exhibit 1006.0008
`
`

`

`Z70635
`
`1
`
`-6-
`
`described which comprises 50mg of fulvestrant, 400mg of benzyl alcohol and sufficient castor
`
`oil to bring the solution to a volume of 1 m1. Manufacture at a commercial scale of a
`
`formulation as described in US 5,183,814 will be complicated by the high alcohol
`
`concentration. Therefore, there is a need to lower the alcohol concentration in fulvestrant
`
`5
`
`formulations Whilst preventing precipitation of fulvestrant from the formulation.
`
`Table 2 shows the solubility of fulvestrant in a numb er of different solvents.
`
`Table 2 - SOLUBILITY OF FULVESTRANT
`
`SOLUBILITY
`
`(mng" at 25°C)
`
`0.001
`
`045
`
`0.58
`
`20
`
`3.06
`
`2.72
`
`1.25
`
`6.15
`
`0.80
`
`3.79
`
`>200
`
`>200
`
`
`
`SOLVENT
`
`W’ater
`
`Arachis oil
`
`Sesame oil
`
`Castor oil
`
`Miglyol 810
`
`Miglyol 812
`
`Ethyl oleate
`
`Benzyl benzoate
`
`Isopropyl myristate
`
`Span 85 (surfactant)
`
`Ethanol
`
`Benzyl Alcohol
`
`10
`
`As can be seen fulvestrant is significantly more soluble in castor oil than any of the
`
`other oils tested. The greater solvating ability of castor oil for steroidal compounds is known
`
`and is attributed to the high number of hydroxy groups of ricinoleic acid, which is the major
`
`constituent of the fatty acids within the triglycerides present in castor oil - see (Rifflcin et.al. J.
`
`15 Pharm. Sci, (1964), 53, 891).
`
`However, even 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
`
`
`
`InnoPharma Exhibit 1006.0009
`
`

`

`Z70635
`
`r
`
`‘
`
`-7-
`
`
`
`significant release rate. To achieve a therapeutically significant release rate the amount of
`
`fulvestrant needed would require the formulation volume to be large, at least 10 ml. This
`
`requires the doctor to inject an excessively large volume of fonnulation to administer a dose
`
`significantly high enough for human therapy.
`
`Ul
`
`Currently guidelines recommend that no more than Snils of liquid is injected
`
`intramuscularly in a single injection. Pharmacologically active doses required for a 1 month
`
`long acting depot formulation of fulvestrant is around 250mg. Therefore, when dissolved in
`
`just castor oil, fulvestrant would need to be administered in at least 10ml of castor oil.
`
`The addition of organic solvents in which fulvestrant is freely soluble, and which are
`
`10 miscible with castor oil, may be used, such as an alcohol. With the addition of high
`
`concentrations of an alcohol concentrations of >50mgml" of fulvestrant in a castor oil
`
`formulation is achievable, thereby giving an injection volumes of <5ml - see Table 3 below.
`
`We have 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
`
`15
`
`a concentration of at least 50 mgrnl'] - see Table 3 below. The finding is surprising since the
`
`solubility of fulvestrant in non—aqueous ester solvents — see Table 2 above — is significantly
`
`lower than the solubility of fulvestrant in an alcohol. The solubility of fiilvestrant is also lower
`
`in non—aqueous ester solvents than is the solubility of fulvestrant in castor oil.
`
`Therefore, we present as a feature of the invention a pharmaceutical formulation
`
`20 comprising fulvestrant (preferably fulvestrant is present at 3—10%W/v, 4—9%W/v, 4—8%w/v,
`
`4—7%w/v, 4—6%w/v and most preferably at about 5%w/v) in a ricinoleate vehicle, a
`
`pharmaceutically acceptable non-aqueous ester solvent, and a pharmaceutically acceptable
`
`alcohol wherein the formulation is adapted for intramuscular administration and attaining a
`
`therapeutically significant blood plasma fulvestrant concentration for at least 2 weeks.
`
`25
`
`Another feature of the invention is a pharmaceutical formulation comprising
`
`fiilvestrant in which the formulation is adapted for intra-muscular injection into a human and
`
`which is capable after injection of attaining a therapeutically significant blood plasma
`
`fulvestrant concentration for at least 2 weeks.
`
`Further features of the invention include a pharmaceutical formulation adapted for
`
`30
`
`intra—muscular injection comprising fulvestrant, 30% or less weight of a pharmaceutically-
`
`acceptable alcohol per volume of formulation, at least 1% weight of a pharmaceutically—
`
`acceptable non-aqueous ester solvent miscible in a ricinoleate vehicle per volume of
`
`
`
`InnoPharma Exhibit 1006.0010
`
`

`

`Z70635
`
`I
`
`‘
`
`-8-
`
`formulation and a sufficient amount of a ricinoleate vehicle so as to prepare a formulation
`
`which is capable after injection of attaining a therapeutically significant blood plasma
`
`fulvestrant concentration for at least 2 weeks.
`
`Further features of the invention include a pharmaceutical formulation adapted for
`
`5
`
`intra—muscular injection comprising fulvestrant; 35% (preferably 30% and ideally 25%) or less
`
`weight of a pharmaceutically—acceptable alcohol per volume of formulation, at least 1%
`
`(preferably at least 5% or ideally 10%) weight of a phannaceutically-acceptable non-aqueous
`
`ester solvent miscible Within a ricinoleate vehicle per volume of formulation and a sufficient
`
`amount of a ricinoleate vehicle so as to prepare a formulation of at least KJrSmgirnl‘1 of
`
`10
`
`fulvestrant.
`
`For the avoidance of any doubt when using the term % weight per volume of
`
`formulation for the constituents of the formulation we mean that Within a unit volume of the
`
`formulation a certain percentage of the constituent by weight will be present, for example a
`
`1% weight per volume formulation will contain within a 100ml volume of formulation 1 g of
`
`15
`
`the constituent. By way of further illustration
`
`byggeigbtgapersvoium’7
`
`20%
`
`10%
`
`5%
`
`1%
`
`1 0mg
`
`3i
`‘
`
`lrnl bf’férfiiifiii: ’ i
`
`200mg
`
`100mg
`
`50mg
`
`
`
`
`
`Preferred pharmaceutical formulations of the invention are as described above
`
`wherein:
`
`20
`
`l.
`
`The total volume of the formulation is 6ml, or less, and the concentration of
`
`fiilvestrant is at least 45mng'1 .
`
`2.
`
`The total amount of fulvestrant in the formulation is 25 0mg, or more, and the total
`
`volume of the formulation is 6ml, or less.
`
`3.
`
`The total amount of fulvestrant in the formulation is 250mg and the total volume of
`
`25
`
`the formulation is 5—5.25m1.
`
`InnoPharma Exhibit 1006.0011
`
`

`

`Z70635
`
`-
`
`'
`
`-9-
`
`It is appreciated that in the formulation an excess of formulation may be included to
`
`allow the attendant physician or care giver to be able to deliver the required dose. Therefore,
`
`when a 5ml dose is required it would be appreciated that an excess of up to 0.25rnl= preferably
`
`up to 0.15mlwill also be present in the formulation. Typically the formulation will be
`
`5 presented in a vial or a prefilled syringe, preferably a prefilled syringe, containing a unit
`
`dosage of the formulation as described herein, these being further features of the invention.
`
`Preferred concentrations of a pharmaceutically-acceptable alcohol present in any of the
`
`above formulations are; at least 3%w/v, at least 5%W/V, at least 7%w/v, at least 10% W/v, at
`
`least 11% w/v, at least 12% w/v, at least 13% w/v, at least 14% W/V, at least 15% W/v and,
`
`10 preferably, at least 16% wfv. Preferred maximal concentrations of pharrnaceutically—
`
`acceptable alcohol present in the formulation are ;28% W/v or less, 22% w/v or less and 20%
`
`W/V or less.. Preferred ranges of pharmaceutically—acceptable alcohol present in any of the
`
`above formulations are selected from any minimum or maximum value described above and
`
`preferably are' 3-35%W/v, 4—35%W/V, 5—35%w/v, 5—32%W/v, 7—32%w/’v, 10-30%W/v, 12-
`
`15 28%w/v, 15-25%W/V, 17-23%w/v, 18-22%w/v and ideally 19—21%W/v.
`
`The pharmaceutically-acceptable alcohol may consist of one alcohol or a mixture of
`
`two or more alcohols, preferably a mixture of two alcohols. Preferred phannaceutically—
`
`acceptable alcohols for parenteral administration are ethanol, benzyl alcohol or a mixture of
`
`both ethanol and benzyl alcohol, preferably the ethanol and benzyl alcohol are present in the
`
`20 formulation in the same W/v amounts. Preferably the formulation alcohol contains 10% w/v
`
`
`
`ethanol and 10% W/v benzyl alcohol.
`
`The phannaceutically—acceptable non—aqueous ester solvent may consist of one or a
`
`mixture of two or more pharmaceutically—acceptable non-aqueous ester solvents, preferably
`
`just one. A preferred pharmaceutically—acceptable non—aqueous ester solvent for parenteral
`
`25 administration is selected from benzyl benzoate, ethyl oleate, isopropyl myristate,isopropyl
`
`palmitate or a mixture of any thereof.
`
`The ricinoleate vehicle should preferably be present in the formulation in a proportion
`
`of at least 30% weight per volume of the formulation, ideally at least 40% or at least 50%
`
`weight per volume of formulation.
`
`30
`
`It will be understood by the skilled person that the pharmaceutically—acceptable
`
`alcohol will be of a quality such that it will meet pharmacopoeial standards (such as are
`
`described in the US, British, European and Japanese pharmacopoeias) and as such will contain
`
`
`
`InnoPharma Exhibit 1006.0012
`
`

`

`Z70635
`
`-10-
`
`some water and possibly other organic solvents, for example ethanol in the US Pharmacopeia
`
`contains not less than 94.9% by volume and not more than 96.0% by volume of ethanol when
`
`measured at 15.56°C. Dehydrated alcohol in the US Pharmacopeia contains not less than
`
`99.5% ethanol by volume when measured at 15.56°C.
`
`5
`
`10
`
`Preferred concentrations of the pharmaceutically—acceptable non—aqueous ester solvent
`
`present in any of the above formulations are; at least 5% WW, at least 8% w/v, at least 10%
`
`w/v, at least 11% w/v, at least 12% W/V, at least 13% w/v, at least 15% w/V, at least 16% w/v,
`
`at least 17% W/V, at least 18% W/v, at least 19% w/v and at least 20% WW. Preferred maximal
`
`concentrations of the pharmaceutical ly—acceptable non-aqueous ester solvent are; 60% w/v or
`
`less, 50%w/v or less, 45% W/V or less, 40% w/v or less, 35% w/v or less, 30% W/v or less and
`
`25% w/v or less. A preferred concentration is 15% W/V. Preferred ranges of pharmaceutically—
`
`acceptable non—aqueous ester solvent present in any of the above formulations are selected
`
`from any minimum or maximum value described above and preferably are; 5—60%w/v, 7-
`
`55%W/V, 8-50%w/v, 10-50%W/v, 10-45%W/v, 10—40%w/V, 10-35%W/v, 10—30%w/V, 10—
`
`15 25%W/v, 12—25%W/v, 12~22%W/V, 12~20%W/V, 12—18%W/V, 13—17%W/v and ideally l4—
`
`16%W/v. Preferably the ester solvent is benzyl benzo ate, most preferably at about 15%W/v.
`
`It will be understood by the skilled person that the pharmaceutically—acceptable non-
`
`aqueous ester solvent will be of a quality that it will meet pharmacopoeial standards (such as
`
`described in the US, British, European and Japanese pharmacopoeias).
`
`20
`
`Preferred combinations of pharmaceutically-acceptable alcohol and pharmaceutically—
`
`acceptable non~aqueous ester solvent in the formulation are set out below:
`
`
`
`
`
`
`
`‘ Pharmaceutically-acceptable
`
`g Pharmaceutically-acceptable non-aqueous
`
`alcohol(%W/v)
`
`10-30
`
`ester (%W/v)
`
`5—60, 7-55, 8—50, 10—50, 10—45, 10—40, 10—35, 10-
`
`30,10—25, 12-25, 12—22, 12—20, 12—18, 13—17 and ‘
`
`ideally 14—16.
`
`InnoPharma Exhibit 1006.0013
`
`

`

`Z70635
`
`- 11 _
`
`5-60, 7-55, 8-50, 1050,1045, 10-40, 10-35, 10-
`
`30, 10-25, 12-25, 12-22, 12-20, 12-18, 13-17 and
`
`
`ideally 14-16.
`
`3-35, 4-35, 5-35, 5-32, 7-32, 10-30, 12-
`
`10-35
`
`preferably each at about 10%
`
`28, 15-25, 17-23, 18-22 and ideally 19-
`
`' 3-35, 4-35, 5-55, 5-32, 7-32, 10-30, 1.2-
`
`28, 15-25, 17-23, 18—22 and ideally 19—
`
`21.
`
`
`ethanol and benzyl alcohol, most
`
`benzyl benzoate, most preferably at about 15%
`
`
`
`
`
`By the use of the term ricinoleate vehicle we mean an oil which has as a proportion (at
`
`least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% W/V) of its composition as
`
`5.
`
`triglycerides of ricinoleic acid. The ricinoleate vehicle may be a synthetic oil or conveniently
`
`is castor oil, ideally of pharnlacopoeial standards, as described above.
`
`We have surplisingly found that the above formulations of the invention provide, after
`
`intra—muscular injection, satisfactory release of fulvestrant over an extended period of time.
`
`This finding is indeed surprising for the following reasons.
`
`10
`
`1.
`
`Previously tested by the applicants have been intra—muscular injections of fulvestrant
`
`in the fom1 of an aqueous suspension. We have found extensive local tissue irritation at the
`
`injection site as well as a poor release profile. It is believed that the tissue
`
`irritation/inflammation was due to the presence of fulvestrant in the form of solid particles.
`
`The release profile appeared to be determined by the extent of inflammation/irritation present
`
`15
`
`at the injection site and this was variable and difficult to control. Also the fulvestrant release
`
`rate was not sufficiently high to be clinically significant.
`
`2.
`
`Our findings from studies using ‘40 labelled benzyl alcohol show that it dissipates
`
`rapidly from the injection site and is removed from the body Within 24 hours of
`
`administration.
`
`20
`
`It would be expected that ethanol will dissipate at least as quickly, if not more rapidly,
`
`from the injection site.
`
`
`
`InnoPharma Exhibit 1006.0014
`
`

`

`Z70635
`
`‘
`
`’
`
`-12-
`
`It is known that benzyl benzoate is metabolised by conjugation to glycine to form
`
`hippuric acid by the human liver and excreted into the urine - Martindale: The Extra
`
`Pharmacopoeia 32“(1 edition page 1103, and, therefore, it is unlikely that benzyl benzoate,
`
`when used, is present at the injection site during the whole of the extended release period.
`
`U1
`
`We have found that despite the rapid elimination of the additional solubilising
`
`excipients, i.e. the alcohol and pharmaceutically—acceptable non—aqueous ester solvent, from
`
`the formulation vehicle and the site of inj ection after inj ection of the formulation, extended
`
`release at therapeutically significant levels of fulvestrant over an extended period can still
`
`achieved by the formulation of the invention.
`
`10
`
`By use of the term “therapeutically significant levels” we mean that blood plasma
`
`concentrations of at least 2.5 ngrnl'], ideally at least 3 ngml'l, at least 8.5 ngrnl'l, and up to 12
`
`ngml'E of fulvestrant are achieved in the patient. Preferably blood plasma levels should be less
`
`than 15 ngml".
`
`By use of the term “extended release" we mean at least two weeks, at least three
`
`weeks, and, preferably at least four weeks of continuous release of fulvestrant is achieved. In a
`
`
`
` preferred feature extended release is achieved for 36 days. Preferably extended release of
`
`
`fulvestrant is for at least 2— 5 weeks and more preferably for the following periods (weeks)
`
`2.5—5, 2.5-4, 3-4, 3.5—4 and most preferably for at least about 4 weeks.
`
`It will be understood that the attendant physician may Wish to administer the
`
`20 intramuscular injection as a divided dose, i.e. a 51111 formulation is sequentially administered
`
`in two separate injections of 2.5ml, this is a firrther feature of the invention
`
`Simply 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.
`
`Table 3 shows the solubility of fulvestrant in a castor oil vehicle additionally
`
`25 containing alcohols ethanol and benzyl alcohol with or Without benzyl benzoate. The results
`
`clearly Show the positive effect of benzyl benzoate on fulvestrant solubility in castor oil,
`
`despite fulvestrant having a lower solubility in benzyl benzoate than in either alcohol or castor
`
`oil.
`
`InnoPharma Exhibit 1006.0015
`
`

`

` Z70635
`
`Table 3 - EFFECT OF BENZYL BENZOATE ON FULVESTRANT SOLUBlLITY IN CASTOR OIL AT 250C
`
`Table 3
`
`5
`
`5
`
`Ethanol
`
`(96%)
`
`Benzyl
`
`Alcohol
`
`Benzyl
`
`Benzoate
`
`10
`
`5
`
`5
`
`5
`
`15
`
`% w/v
`
`10
`
`5
`
`15
`
`10
`
`10
`
`15
`
`15
`
`10
`
`10
`
`15
`
`15
`
`15
`
`15
`
`‘
`
`Castor Oil,
`
`to 100
`
`Fulvestrant
`
`27
`
`tolOO
`
`36
`
`to 100
`
`to 100
`
`to 100
`
`to 100
`
`to 100
`
`to 100
`
`46
`
`54
`
`45
`
`65
`
`76
`
`102
`
`Solubility
`
`[mng1 ]
`
`
`
`InnoPharma Exhibit 1006.0016
`
`

`

`Z70635
`
`«
`
`'
`
`-14-
`
`The following Table 4 shows the solubility of fulvestrant in a range of oil based
`
`formulations which contain the same amounts of alcohol and benzyl benzoate but in which the
`
`oil is changed. The data also shows solubility of fulvestrant after removal of the alcohols.
`
`E1123
`
`5 Solubility comparisons of fulvestrant in oil based formulations with and Without
`alcohols
`
`Fulvestrant Solubility mg ml‘1 @ 25°C
`Complete vehicle
`Vehicle minus alcohols
`
`10
`
`Formulation (a)
`
`Castor oil based
`
`15 Miglyol 812—N based
`
`81.2
`
`86.8
`
`Sesame seed/Castor oil (lzl) based
`
`70.1
`
`Sesame seed oil based
`
`20 Arachis oil based
`
`45.7
`
`40.2
`
`12.6
`
`1.7
`
`4.4
`
`0.7
`
`< 0.2
`
`25
`
`(a) Complete Vehicle Formulations comprised ethanol [96%](10%), benzyl alcohol (10%) and benzyl benzoate
`( 15%) made to volume with the stated oil. Excess fulvestrant was added to each solvent mixture and solubility
`determined.
`
`Effect of formulation on precipitation of fulvestrant at the injection site
`
`30
`
`Formulation a
`
`Formulation Fl
`castor oil based
`
`35
`
`Formulation F2
`
`Miglyol 812-N based
`
`4o Formulation F3
`sesame seed oil/castor
`oil based
`
`2
`
`0
`
`3
`
`0
`
`4
`
`O
`
`Days
`
`7
`
`0
`
`10
`
`O
`
`3 0
`
`0
`
`
`1
`l
`l
`1
`+1
`
`
`
`—— C
`
`
`
`4+
`
`——+
`
`+l—+
`
`+++
`
`+++
`
`++
`
`———:—
`
`
`
`——
`
`5 l
`
`0
`
`0
`
`+
`
`45
`
`0, + , ++, +++ * Degree of precipitation (None detected: Mild, Moderate, Severe)
`a Formulations comprised fulvestrant (5%), ethanol [96%] (10%), benzyl alcohol (10%) and benzyl benzoate
`(15%) made to volume with the stated oil.
`Mainly large needle shaped crystals
`07
`Small needles and/or sheafs of crystals
`
`
`
`
`
`InnoPharma Exhibit 1006.0017
`
`

`

`Z70635
`
`-15-
`
`Precipitation of fulvestrant and the release profile was determined with the above
`
`formulations in an in viva rabbit study.
`
`Figure 1 shows the release profile in vivo of the four formulations from the second part
`
`of Table 4 and shows the effect of the fixed oil component on fulvestrant plasma profile over
`
`5
`
`five days following intramuscular administration in rabbits (data normalised to 50mg per 3kg;
`
`mean given; number of animals per timepoint = 8: plasma samples assayed for fiilvestrant
`
`content using lc—ms/ms detection following solvent extraction). As can be seen the castor oil
`
`formulation showed a particularly even release profile with no evidence of precipitation of
`
`fulvestrant at the injection site.
`
`10
`
`Therefore we present as a fiirther feature of the invention an extended release
`
`pharmaceutical formulation adapted for intramuscular injection comprising fulvestrant; 35%
`
`(preferably 30% or ideally 25%) or less weight of a pharmaceutically—acceptable alcohol per
`
`volume of formulation, at least 1% (preferably at least 5% or ideally 10%) weight of a
`
`pharmaceutically—acceptable non—aqueous ester solvent miscible in a ricinoleate vehicle per
`
`15 volmne of formulation and sufficient amount of a ricinoleate vehicle, taking into account the
`
`
` 20
`
`addition of any fin’ther optional pharmaceutically—acceptable excipients, so as to prepare a
`
`formulation of at least 45mgrnl“ of ful