‘
`
`1
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`.
`g, S no
`39803
`‘
`°
`lllllllllllllllllllllllllll
`81/ 09/ ill
`
`Hon. Commissioner of Patents
`Washington, DC 20231
`
`Sir:
`
`REQUEST FOR FILING APPLICATION
`mie_rsi_:eeiaLi2)_8;i1i
`(No Fiiing Fee or Oath/Declaration)
`
`RULE 531!) NO DECLARATION
`Atty. Dkt.
`PM 275507
`W‘
`
`Date:
`
`January 9, 2001
`
`1. This is a Request for filing a new Patent Appiication(El Design
`Utility) entitled:
`2. (Complete) Title:
`FORMULATION
`
`Page 1 of2
`
`APPLiCATiON
`-j-
`
`PHM70635/US
`°"°"tRef
`
`o
`5'.
`"E
`:3
`
`3.
`
`4.
`
`W
`
`
`
`
`J a filing fee or Oath/Declaration but for which is enclosed the following:
`
`Abstract
`
`1
`
`page(s).
`
`22
`
`Pages of Specification (only spec. and claims);
`
`5. El Specification in non—English language
`
`Numbered claimls); and
`23
`Drawings:
`1
`sheet(s)
`
`Cl 1 set informal;
`
`8. El formal of size: A4 C111”
`
`DOMESTIC/lNTERNATlONAL priority is claimed under 35 USC ’l19(e)/120/365(c) based on the
`followin rovisional, nonrovisional and/or PCT international a lication s :
`
`
`Aplication No.
`Filin Date
`Application No. -
`
`
`
`
`
`
`
`
`
`
`
`iififiii1
`
`(3)
`(4 —
` —_
`'0.
`FOREIGN priority is claimed under 35 USC 119(a)—(d)/365(b) based on filing in
`Great Britain
`
`
`Filin Date-—
`Aplication No.
`Filin
`A lication No.
`(2)
`0000313.?
`Janua
`10, 2000
`0008837.?
`April 12, 2000
`(1)
`
`——
`
`— Cl See 3’ ae for additional riorifies
`
`
`
`
`11.
`
`2
`
`(No.) Certified copy (copies):
`in U.S. Application No.
`
`I
`
`attached;
`
`Cl previously filed (date)
`filed on
`
`1:] This is a reissue of Patent No.
`12.
`13. El See top first page re prior Provisional, National, international applicationls) (X box only if info is
`there and do not complete corresponding item 14 or 15.)
`14. Cl Amend the specification by inserting before the first line —— This is a D Continuation-in-Part
`}:l Divisional
`1:] Continuation
`l:l Substitute Application (MPEP 201.09) of:
`
`14(a)
`14(b)
`
`filed
`l:l National Appln. No.
`filed
`PCT!
`l:l
`|nternationalAppin.No.
`designated the U.S., and that international Appiication
`under PCT Article 21(2) in English.-—
`
`I
`
`.--(M#
`
`)
`
`Cl was D was not
`
`which
`published
`
`15.
`
`16.
`
`17.
`
`1:! Amend the specification by inserting before the first line: --This application
`claims the benefit of U.S. Provisional Application No. 60!
`, filed
`
`.--
`
`Extension to date:
`
`[:1 concurrently filed
`
`1] not needed
`
`E] previously filed
`
`E] Small Entity Status is claimed (pre-filing confirmation required)
`
`17(a)
`
`(No.) Small Entity Statement(s). (Since 9/8/00 Small Entity Statement go_t
`1:] Attached:
`essentiai to make claim)
`17(b) Cl See NONPUBLICATION REQUEST under Rule 213(a) attached (PAT—258)
`
`PAT-1 04 t ZIQG
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 1
`
`

`
`Page2 012
`
`
`
`
`
`
`
`
`_.,;::"
`
`
`
`18. E] Prior application is assigned to
`
`by Assignment recorded
`
`Reel
`
`Frame
`
`19. D Attached:
`
`20. This application is made by the following named inventor(s)
`{Listing of invehtor(s) n_<>t a requirement, but list if known)
`
`(Double check instructions for accuracy.):
`
`
`
`
`
`
`minventor ID EVANS
`
`» ?$§
`“
`Macclesfield, Cheshire
`
`UNITED KINGDOM
`
`
`
`\)
`
`
`
`T
`
`GREAT BRITAIN
`
`Mailing Address
`(include Zip Code)
`
`~Stat‘e’Fo:ein,Com;
`Alderle Park, Macclesfield, Cheshire, United Kindom
`
`SK10 4TG
`
`
`
`GREAT BR!TAlN
`
`‘QTFCIEZSHS
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`
`
`
`GRUNDY
`
`
`
`UNITED
`
`
`
`
`
`Vi\/tailing Address
`
`V
`
`(2) Inventor
`
`Macclesfieid, Cheshire
`G!
`‘ Charter Wa , Macclesfield, Cheshire, United Kindom
`
`
`
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`21. NOTE: FOR ADDlTlONAL INVENTORS, check box El
`and attach sheet with same information regarding additional inventors.
`
`Pillsbury Winthrop LLP
`Intellectual Property Group
`.
`'
`
`V
`
`— I
`
`
`
`T
`
`I,
`
`.r
`
`e
`
`1100 New York Avenue, NW.
`Ninth Floor
`Washington, DC 20005-3918
`Tel: (202) 861-3000
`AttyfSec: DJB/mhn
`
`By: Atty:
`
`Sig:
`
`A
`e/’
`e
`NOTE: File in duplicate wijlr postcard receipts (PAT—103) & attachments
`
`Reg. No.
`
`25323
`
`
`
`Fax: (202) 822-0944
`Tel: (202)861-3027
`
`PAT-1 04 12/00
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 2
`
`

`
`Jr
`
`APPLICATION UNDER UNITED STATES PATENT LAWS
`
`Atty. Dkt. No.
`
`PM 275507/’PHl\«i{ 70635/US
`(M#)
`
`Invention:
`
`FORMULATION
`
`Inventor (s):
`
`EVANS, John R.
`GRUNDY, Rosalind U.
`
`Piilsbury Winthrop LLP
`intellectual Property Group
`1100 New York Avenue, NW
`Ninth Floor
`
`Washington, DC 20005-3918
`Attorneys
`Telephone: (202) 861-3000
`
`This is a:
`
`[:1 Provisional Application
`
`K4 Regular Utility Application
`
`{:1 Continuing Application
`The contents of the parent are incorporated
`by reference
`
`PCT National Phase Application
`
`Design Application
`
`D C
`
`I
`
`1:} Reissue Application
`
`1:] Plant Application
`
`U Substitute Specification
`Sub. Spec Filed
`in App. No.
`
`/
`
`E] Marked up Specification re
`Sub. Spec. filed
`in App. No
`
`I
`
`
`
`SPECIFICATION
`
`Docmtenw
`
`PAT-‘I00 7100
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 3
`
`

`
`Z70635
`
`»
`
`‘
`
`-1-
`
`FORMULATION
`
`The invention relates to a novel sustained release pharmaceutical formulation adapted
`
`for administration by injection containing the compound
`
`5
`
`7cc—[9-(4,435 ,5,5-pentafluoropentylsulphinybnonylloestra— l ,3 , 5( l 0)—triene-3, l 7£3-diol, more
`
`particularly to a formulation adapted for administration by injection containing the compound
`
`7oc—[9-(4,4,5,5 ,5—pentafluoropentylsnlphinyl)nonyl]oestra— l ,3,5(l0)—triene~3, 1 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
`
`Oestrogen 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
`
`is 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 efiiciently for ER binding but their effectiveness is often limited by the
`
`partial agonism they display, which results in an incomplete blockade of oestrogen-mecliated
`
`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 oestrogens. Such
`
`Ix)LIV
`
`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 al l989,
`
`Wakeling l990a, l990b, 1990c. Vlfakeling and Bowler 1987, l988.
`
`Steroidal analogues of oestradiol, with an alkylsulphinyl side chain in the 70:, position,
`
`provided the first examples of compounds devoid of oestrogenic activity (Bowler et al 1989).
`
`30 One of these, 7ot- (9-(4-,4,5,5,5-pentafluoropentyl sulphiny1)nonyl]oestra—l,3,5—(l(})triene-
`
`3,1713-diol was selected for intensive study on the basis of its pure oestrogen antagonist
`
`activity and significantly increased antioestrogenic potency over other available
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 4
`
`

`
`Z70635
`
`r
`
`t
`
`-2-
`
`
`
`antioestrogens. In vitro findings and early clinical experience with
`
`7oc—[9~(4,4,5 ,5 ,5-pentafluoropentylsulphinyl)nonyl]oestra—l ,3 -5 (l0)—triene—3,l 7 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.
`
`5
`
`'70:-{9-(4,-4,5 ,5,5-Pentafluoropentylsulphinyl)nonyl]oestra- l ,3-5(l 0)-triene-3 , 1 7B-diol,
`
`or ICE 182,780, has been allocated the international non-proprietary name fulvestrant, which is
`
`used hereinafter. Wheii referring to fulvestrant we include pharrnaceutically-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 oestradiol in rats, mice and monkeys, and also blocks the
`
`uterotrophic activity of tamoxifen.
`
`Because fulvestrant has none of the oestrogen—lil<e stimulatory activity that is
`
`is characteristic of clinically available antioestrogens 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 l38 504 discloses that certain steroid derivatives
`
`are effective antioestrogenic agents. The disclosure includes information relating to the
`
`preparation of the steroid derivatives.
`
`ln particular there is the disclosure within Example 35
`
`of the compound 7oc~{9-(4,4,5,5,5 -pentafluoropentylsulphinyl)nonyl]oestra-
`
`3O l,3,5(l0)—triene-3,l7[3—cliol, 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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 5
`
`

`
`Z70635
`
`.
`
`‘
`
`-3-
`
`pharmaceutically—acceptable diluent or carrier. It is stated therein that the composition can be
`
`in a form suitable for oral or parenteral administration.
`
`Fulvcstrant shows, along with other steroidal based compounds, certain physical
`
`properties which make formulation of these compounds difficult. Fulvestrant is a parficularly
`
`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 inj ectable steroidal formulations
`
`which have been commercialised. Commonly these fonnulations use oil as a solvent and
`
`10 wherein additional excipients may be present. Below in Table l 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
`
`15
`
`release is achievable for periods from 1 to 8 weeks.
`
`20
`
`25
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 6
`
`

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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 7
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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 8
`
`
`

`
`2370635
`
`’
`
`-6-
`
`described which comprises 50mg of fulvestrant, 400mg of benzyl alcohol and sufficient castor
`
`oil to bring the solution to a Volume of 1 ml. 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 number of different solvents.
`
`Table 2 — SOLUBILITY OF FULVESTRANT
`
`SOLUBILITY
`
`(rngrnl“ at 25°C)
`
`0.001
`
`0.45
`
`0.5 8
`
`20
`
`3.06
`
`2.72
`
`1.25
`
`6. l 5
`
`0.80
`
`3.79
`
`>200
`
`>200
`
`
`
`SOLVENT
`
`Water
`
`Arachis oil
`
`Sesame oil
`
`Castor oil
`
`Miglyol 810
`
`Miglyol 812
`
`Ethyl oleate
`
`Benzyl benzoate
`
`lsopropyl rnyristate
`
`Span 85 (surfactant)
`
`Ethanol
`
`Benzyl Alcohol
`
`l0
`
`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 (Riftkin 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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 9
`
`

`
`Z7063S
`
`1
`
`‘
`
`-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 formulation to administer a dose
`
`significantly high enough for human therapy.
`
`5
`
`Currently guidelines recommend that no more than Smls 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 l0ml 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 rngrnll — see Table 3 below. The finding is surprising since the
`
`solubility of fulvestrant in r1on—aqueous ester solvents — see Table 2 above — is significantly
`
`lower than the solubility of fulvestrant in an alcohol. The solubility of fulvestrant 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°/fmrfv, 4-9°/ow/V, 4—8°/ow/'V,
`
`4—7%W/V, 4-6°/i)W'/V and most preferably at about 59/ow/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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 10
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`

`
`Z70635
`
`-
`
`'
`
`-3-
`
`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%
`
`Qareferably at least 5% or ideally 10%) Weight of a pharrnaoeutically-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 45mgrnl" 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 fiirther illustration
`
`3’:
`7
`
`lrnl
`
`I
`
`J
`
`9
`
`20%
`
`10%
`
`5%
`
`1%
`
`200mg
`
`100mg
`
`50mg
`
`10mg
`
`Preferred pharmaceutical formulations of the invention are as described above
`
`wherein:
`
`20
`
`1.
`
`The total Volume of the formulation is 61111, or less, and the concentration of
`
`fulvestrant is at least 45mgml" .
`
`2.
`
`The total amount of fulvestrant in the formulation is 250mg, 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 Voluine of
`
`25
`
`the formulation is 5—5.25ml.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 11
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`

`
`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 Sml dose is required it would be appreciated that an excess of up to 0251111, preferably
`
`up to 0.1 Srnl will 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 pharrnaceutically-acceptable alcohol present in any of the
`
`above formulations are; at least 3%w/V, at least 5%w/V, at least 79/ow/V, at least 10% W/V, at
`
`least ll% w/V, at least 12% W/V, at least 13% wfv, at least 14% W/"V, at least 15% W/V and,
`
`10 preferably, at least l6% wfv. Preferred maximal concentrations of pharmaceutically-
`
`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; 3-359/ow/V, 4-35“/ow/V, 5—35%w/V, 5-32%W/V, 7—32%w/‘V, l0-30%W/V, 12-
`
`15 28%W/V, l5—25%w/V, 17-23"/{aw/V, 18-22%w/V and ideally 19-21"/ow/V.
`
`The pharrnaceutica1ly—acceptable alcohol may consist of one alcohol or a mixture of
`
`two or more alcohols, preferably a mixture of two alcohols. Preferred pharmaceutically-
`
`acceptable alcohols for parenteral administration are ethanol, benzyl alcohol or a mixture of
`
`both ethanol and benzyl alcohol, preferably the ethanol and henzyl 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 pharmaceutically—acceptable non-aqueous ester solvent may consist of one or a
`
`mixture of two or more pharmaceutica1ly—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
`
`palrnitate 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 phaimaceutically—acceptable
`
`alcohol will be of a quality such that it will meet pharrnacopoeial standards (such as are
`
`described in the US, British, European and Japanese pharmacopoeias) and as such will contain
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 12
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`

`
`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 l5.56°C. Dehydrated alcohol in the US Pharmacopeia contains not less than
`
`99.5% ethanol by Volume when measured at l5.56°C.
`
`5
`
`10
`
`Preferred concentrations of the pharrnaceutically-acceptable non-aqueous ester solvent
`
`present in any of the above formulations are; at least 5% W/V, 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% VVIV and at least 20% W/V. Preferred maximal
`
`concentrations of the pharmaceutically-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% wiv or less and
`
`25% W./V or less. A preferred concentration is 15% wfv. Preferred ranges of pharmaceutically-
`
`acceptable non-aqueous ester solvent present in any of the above formulations are selected
`
`from any rninimum or maximum Value described above and preferably are; 5-60%w/V, 7-
`
`55%W/V, 8-50%wfv, 10-50%w/V, 10-45%W/v, 10-40%w/V, 10-35%w/V, 10-30%w/V, 10-
`
`15 25°/ow/V, 12-259/ow/V, 12-22%W," 7, 12-20%w/V, 12-180/o‘W/V, l3-17%wfV and ideally 14-
`
`1 6%W/V. Preferably the ester solvent is benzyl benzoate, most preferably at about l5%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:
`
`
`
`
`ideally 14-16.
`
`I Pharmaceutically-acceptable
`
`Pharmaceutically-acceptable non-aqueous
`
`alcoho1(°/ow/V)
`
`ester (%wlv)
`
`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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 13
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`

`
`Z70635
`
`- 1 1 _
`
`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.
`
`benzyl benzoate, most preferably at about 15% preferably each at about 10%
`
`3-35, 4-35, 5-35, 5-32, 7-32, 10-30, 12-
`
`28, 15-25, 17-23, 18-22 and ideally 19-
`
`‘ 3-35, 4-35, 5-35, 5-32, 7-32, 10-30, 12-
`
`28, 15-25, 17-23, 18-22 and ideally 19-
`
`21.
`
`ethanol and benzyl alcohol, most
`
`
`
`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 pharniacopoeial standards, as described above.
`
`We have surprisingly 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 form 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 inflannnation/irritation present
`
`15
`
`at the injection site and this was variable and difficult to controi. Also the fulvestrant release
`
`rate was not sufficiently high to be clinically significant.
`
`2.
`
`Our findings from studies using MC 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 wiil dissipate at least as quickly, if not more rapidly,
`
`from the injection site.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 14
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`

`
`Z70635
`
`«
`
`’
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`-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“ edition page 1103, and, therefore, it is unlikely that benzyl henzoate,
`
`when used, is present at the injection site during the whole of the extended release period.
`
`(J1
`
`We have found that despite the rapid elimination of the additional solubilising
`
`excipients, ie. the alcohol and pharmaceutically~acceptable non—aqueous ester solvent, from
`
`the formulation vehicle and the site of injection after injection of the formulation, extended
`
`release at therapeutically significant levels of fulvestrant over an extended period can still
`
`achieved by the fonnulation 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 ngnill, at least 8.5 ngml", and up to 12
`
`ngmli‘ of fiilvestrant are achieved in the patient. Preferably blood plasma levels should be less
`
`than 15 ngrnl".
`
`By use of the term “extended release” we mean at least two weel<s, at least three
`
`13 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, 3.54 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 further 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 ofbenzyl benzoate on fulvestrant solubility in castor oil,
`
`despite fiilvestrant having a lower solubility in benzyl benzoate than in either alcohol or castor
`
`oil.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 15
`
`

`
`m2.3.
`
`
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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 16
`
`
`

`
`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.
`
`Table 4
`
`Solubility comparisons of fulvestrant in oil based formulations with and without
`alcohols
`
`Fulvestrant Solubility mg ml'1 @ 25 °C
`
`Complete Vehicle
`
`Vehicle minus alcohols
`
`Formulation la)
`
`Castor oil based
`
`;\/liglyol 812-N based
`
`8 l .2
`
`86.8
`
`Sesame seed/Castor oil (1:1) based
`
`70.1
`
`Sesame seed oil based
`
`Arachis oil based
`
`45.7
`
`40.2
`
`12.6
`
`L?
`
`4.4
`
`0.7
`
`< 0.2
`
`l0
`
`20
`
`
`
`25
`
`(a) Complete Vehicle Formulations comprised ethanol {96%](l0%), 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 "‘
`
`Formulation Fl
`castor oil based
`
`35
`
`Forrnulation 1:2
`Miglyol 812-N based
`
`40
`
`Formulation F3
`sesame seed oil/Castor
`oil based
`
`2
`
`0
`
`3
`
`0
`
`4
`
`0
`
`Days
`
`7
`
`0
`
`10
`
`0
`
`30
`
`U
`
`++ "
`
`+++
`
`+++
`
`-l—F+
`
`+++
`
`++
`
`+ °
`
`4+
`
`++
`
`+++
`
`++
`
`+
`
`5 l
`
`0
`
`0
`
`+
`
`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
`° Small needles and/or sheafs of crystals
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 17
`
`

`
`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 viva 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 fulvestrant
`
`content using lc—rns/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 further 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 volume of formulation and sufficient amount of a ricinoleate vehicle, taking into account the
`
`addition of any fiirther optional pharmaceutically—acceptable excipients, so as to prepare a
`
`formulation of at least 45mgml“ of fulvestrant.
`
`A further feature of the invention is a pharmaceutical fonnu