Application No.: 12/285,887
`Attorney Docket No.: 11285.0056—OOOOO
`
`54. Moreover, the examples above underscore the fact that efficacy of a given
`
`drug administered by a given route of dosing (e.g., intramuscular) cannot be known until
`
`appropriate comparative studies are performed in a suitable animal model. For some
`
`drugs, the desired effect might be achieved following a particular route of dosing, but for
`
`other drugs it might not. The rate and extent of drug absorption, and the associated
`
`pharmacodynamics (e.g., the achievement of a desired drug effect) may differ greatly
`
`depending on the properties of the drug, the choice of an animal model, and the site of
`
`drug administration.
`
`55.
`
`Consequently, one of ordinary skill in the art having the very limited
`
`experimental subcutaneous data from McLeskey would not have had an expectation
`
`that the intramuscular administration of fulvestrant using the McLeskey castor oil
`
`composition would have been effective following intramuscular administration, such as
`
`in the method described in the claims. This is especially true because McLeskey did
`
`not disclose plasma or blood levels of fulvestrant in mice after subcutaneous
`
`administration of the formulation, nor any information regarding the rate and/or extent of
`
`absorption of fulvestrant from the subcutaneous injection site. Additionally, the claims
`
`recite achieving a given therapeutic plasma concentration for at least four weeks, and
`
`there is no information in any of the references cited in the Office Action that would have
`
`suggested that such long—term efficacy associated with a single dose would be exhibited
`
`using the McLeskey castor oil composition by any route of administration.
`
`56.
`
`Thus, one of ordinary skill in the art would not have had an expectation
`
`that the castor oil composition disclosed in McLeskey, which was administered
`
`-20-
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 376
`
`

`
`Application No.: 12/285,887
`Attorney Docket No.: 11285.0056—OOOOO
`
`subcutaneously to mice, would have been therapeutically effective upon intramuscular
`
`administration of fulvestrant, for example, by following the method described in the
`
`claims.
`
`The composition of a formulation can have a significant effect on the efficacy
`
`observed when the formulation is administered
`
`57. Where a dosage form of a drug is being developed for intramuscular
`
`administration in humans, one of ordinary skill in the art typically relies upon the results
`
`of intramuscular dosing studies in suitable animal models where pharmacokinetic data
`
`are collected to characterize the absorption of the drug from its dosage form.
`
`58.
`
`Typically, during the development of an intramuscular dosage form for
`
`administration ofa drug in humans, one would have carried out, among other tasks,
`
`formulation studies to determine suitable compositions in which the drug of interest is
`
`dissolved, as well as initial intramuscular dosing experiments in animals (e.g., mice,
`
`rabbits, and/or dogs) under various conditions (e.g., different compositions, different
`
`solvents, varying the proportion of the components of the composition, different drug
`
`concentrations, etc.) in order to gain an understanding of the pharmacokinetics of
`
`fulvestrant before attempting human administration. The very existence of this
`
`generalized approach highlights the lack of expectation of success with respect to the
`
`extrapolation of the McLeskey disclosure of subcutaneous administration to mice,
`
`lacking any pharmacokinetic information, to human intramuscular administration.
`
`59. With respect to the importance of formulation studies, I have read the
`
`Declaration Under 35 U.S.C §1.132 of Dr. Paul Gellert filed on August 2008 (“the Gellert
`
`-21-
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 377
`
`

`
`Application No.: 12/285,887
`Attorney Docket No.: 11285.0056—OOOOO
`
`Declaration”, cited as “Gellert Dec|.” and enclosed here as Exhibit 16).
`
`I understand
`
`that the Gellert Declaration was submitted to the U.S. Patent and Trademark Office in
`
`Application No. 10/872,784 (as indicated by the caption on the first page of the
`
`declaration).
`
`60.
`
`As part of the discussion of the development of methods of treatment
`
`involving the administration of fulvestrant, the Gellert Declaration states that “the
`
`experienced formulator would want to minimize the amount of co—so|vents and
`
`excipients in any injectable formulation.” Gellert Decl. at 11 22.
`
`61.
`
`Thus, even if the McLeskey castor oil composition had been considered
`
`as a potentially useful formulation in the development of a method of treatment for
`
`humans, one of ordinary skill in the art would have performed additional formulation
`
`studies to obtain a composition with suitable characteristics for the desired route of
`
`administration. The Gellert Declaration explains one of the rationales to perform those
`
`additional studies:
`
`Ideally, it is best to select and use solvents that would maximize the
`solubility of the compound. Maximizing the solubility of a compound in a
`particular cosolvent system would result in lower total levels of the non-
`aqueous so|vent(s) being administered to the patient, thereby lowering the
`chance for potential side effects.
`
`Gellert Decl. at ‘H 22 (quoting directly from P.K. Gupta and G.A. Brazeau (eds),
`
`“|njectab|e Drug Development: Techniques to Reduce Pain and |rritation”Chapter 11,
`
`p. 217, lnterpharm Press, Denver, Colorado (1999)).
`
`62.
`
`Regardless of how high or low the cosolvent concentrations are in a given
`
`formulation, the preparation of formulations in which a drug such as fulvestrant can be
`
`-22-
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 378
`
`

`
`Application No.: 12/285,887
`Attorney Docket No.: 11285.0056—00O00
`
`solubilized is not sufficient to ensure the desired therapeutic effect when such
`
`formulation is administered to patients. As explained in the ’887 application “[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.”
`
`Exhibit 7 at 11 [0054]. Thus, suitable experiments are needed to determine the
`
`pharmacokinetic performance of any candidate formu|ation(s).
`
`63.
`
`In that regard, it is understood that an animal model for drug dosage form
`
`performance may provide some discrimination among candidate dosage forms in
`
`development. Thus, the plasma concentration profile should reflect changes in the
`
`release characteristics of the drug from the formulation. That type of pharmacokinetic
`
`data could be used to characterize important variables in the development of a suitable
`
`method of treatment. For drugs that are difficult to formulate, such as fulvestrant
`
`(Exhibit 7, at 11 [OO14]), the pharmacokinetic data could be useful to investigate the
`
`most promising formulation for the desired route of administration.
`
`64.
`
`For example, for fulvestrant, PCT Application Publication No.
`
`WO 03/006064 (“WO 03/006064”, attached here as Exhibit 17) shows pharmacokinetic
`
`results of intramuscular administration of fulvestrant to rabbits. Figure 1 shows
`
`differences in results when seven different formulations of fulvestrant, each containing
`
`100 mg/ml of the drug, but having different co—so|vent compositions, were closed
`
`intramuscularly in rabbits. The table related to Example 4 on page 30 of WO 03/006064
`
`reports the composition of each formulation, labeled F1 to F7. As can be seen, all of
`
`these fulvestrant formulations contained ethanol, benzyl alcohol, and benzyl benzoate in
`
`-23-
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 379
`
`

`
`Application No.: 12/285,887
`Attorney Docket No.: 11285.0056—OOOOO
`
`a castor oil vehicle; these are the same components of the fulvestrant composition
`
`recited in the claims, but with different proportions for each component.2
`
`65. W0 O3/006064 reports that “[p]lasma levels were more variable than
`
`Control over the first 30 days” following intramuscular administration of fulvestrant.
`
`WO 03/006064 at 30, I. 23. W0 03/006064 explains that “some differences in profiles
`
`were noted over the first 30 days such that they were divided into 2 groups (with
`
`Formulation F7 showing intermediate behaviour).” Id. at 30, II. 29-30. According to
`
`WO 03/006064, Group A demonstrates “rapid release early time points”, corresponding
`
`to formulations containing high benzyl benzoate and low castor oil concentrations, while
`
`Group B shows a ‘‘lower release, flatter profile” corresponding to formulations containing
`
`lower benzyl benzoate and higher castor oil concentrations.
`
`Id. at 30, II. 31-34.
`
`WO 03/006064 replotted the data from Figure 1 corresponding to those formulations in
`
`Group A as part of Figure 2A and the data corresponding to those formulations in Group
`
`B as part of Figure 2B.
`
`66.
`
`Therefore, based on W0 O3/0O6064’s own characterization of the
`
`differences in the pharmacokinetic profile of different fulvestrant formulations, higher
`
`benzyl benzoate concentrations in the formulation resulted in a more rapid initial release
`
`of fulvestrant, whereas lower benzyl benzoate concentrations resulted in a lower initial
`
`release, and a flatter plasma level profile. Depending on the overall objective of the
`
`administration of fulvestrant, some of the fulvestrant formulations tested in
`
`2 The right—hand column in this table appears to indicate the % w/v composition of
`castor oil. All the entries in this column should more properly be “to 100%”, as they are
`in the Tables provided in the preceding Examples 2 and 3.
`
`-24-
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 380
`
`

`
`Application No.: 12/285,887
`Attorney Docket No.: 11285.0056—00000
`
`WO 03/006064’s study would be more desirable than others for that given purpose and,
`
`based on the relevant pharmacokinetic profiles, one of ordinary skill in the art would be
`
`able to select one of those fulvestrant formulations for further development and/or
`
`testing.
`
`67.
`
`However, one of ordinary skill in the art would not have been able to
`
`determine whether a given fulvestrant formulation injected intramuscularly as in
`
`WO 03/006064 would have had the desired pharmacokinetic profile until such in vivo
`
`pharmacokinetic studies were carried out. The testing of various formulations having
`
`different compositions, as portrayed in Figures 1, 2A and 2B, would typically be
`
`undertaken during the development of a dosage form in order to ensure an optimal
`
`method of treatment using a drug that is difficult to formulate. Such studies would be
`
`expected to demonstrate differences in the blood plasma concentrations of a test drug,
`
`and would allow the investigators to identify factors that would enhance the
`
`performance of the formulation.
`
`68.
`
`Therefore, when considering the differences in pharmacokinetic profiles
`
`demonstrated in the example from WO 03/006064, it becomes clear that one of ordinary
`
`skill in the art knowing only the composition of a given formulation administered
`
`subcutaneously, but having no pharmacokinetic data following its intramuscular
`
`administration, would have had no expectation, one way or another, that the formulation
`
`would be effective when administered intramuscularly in a given method of treatment.
`
`69.
`
`In particular, one of ordinary skill in the art would not have had a
`
`reasonable expectation that the McLeskey castor oil composition would have been
`
`-25-
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 381
`
`

`
`Appiicat:i<:m Na: 123285.887
`Attorney Duckei Nu: ii 1285@Q<}5tS~00{}0O
`
`effective when gwen as an intramuscufiar injection, such as in the methcact. sf treatment
`
`recited in the tziaims.
`
`?‘{3.
`
`5 here.-by dezzlare ‘ma: aii fine statements made herein an‘ my awn kmswjledge
`
`are true and that aii statements made an inforznatian and befief are befieveci to be true;
`
`and further. that these statements are made with the knowiedge that wiiifui faise
`
`staiemenis so macfie are punishable by fine at imp.r~iacm~men§, car bath, under S-ecticm
`
`109’? m‘ Title 38 of the United States Code and that such wiiifui fatsa statements may
`
`jeopardize the vaifidity 0f the apgztiaaticn at any patent issuing therecrn.
`
`
`
`,38,
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 382
`
`

`
`Application No.: 12/285,887
`Attorney Docket No.: 11285.0056—00000
`
`Exhibit List for Declaration Under 37 C.F.R. § 1.132 of Ronald J. Sawchuk
`
`T2
`
`Curriculum Vitae of Ronald J. Sawchuk
`Office Action for U.S. Patent Application No. 12/285,887 dated
`September 16, 2011
`
`McLeskey et al., “Tamoxifen-resistant fibroblast growth factor—transfected
`MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI 182,780
`and two aromatase inhibitors”, Clinical Cancel Research 42697-711
`
`(1998) (“McLeskey/’)
`
`European Patent Specification No. EP 0 346 014, naming Michael Dukes
`as inventor (“Dukes”)
`
`Osborne et al., “Comparison of the effects of a pure steroidal
`antiestrogen with those of tamoxifen in a model of human breast cancer”,
`J. National Cancer Institute, 87(20):746-750 (1995) (“Osborne”)
`
`Abstract for Wakeling et al., “|C| 182,780, a new antioestrogen with
`clinical potential", J. Steroid Biochemistry & Molecular Biology, 43(1-
`3):173—177 (1992) “Wal<eling”)
`
`7
`
`U.S. Patent Publication No 2010/0152149
`
`Pending claims in U.S. Application No 12/285 887 with proposed
`amendments
`
`U.S. Patent No 3,164,520
`
`Riffkin et al., “Castor oil as a vehicle for parental administration of steroid
`hormones”, J. Pharma Sci., 53(8):891-895 (1964) (“Riffkin”)
`
`Nema et al., “Excipients and their use in injectable products”, PDA J
`Pharma Sci Tech., 51(4):166-171 (1977) (“Nema”)
`
`The Merck Index, 12th Ed., Merck & Co., Inc. (1996) (“the Merck Index”)
`
`Guerrini et al., “Pharmacokinetics of probenecid in sheep”, J Vet
`Pharmacol Ther., 8:128-135 (1985) (“Guerrini”)
`
`Lavy, et al., “Pharmacokinetics of clindamycin HC1 administered
`intravenously, intramuscularly and subcutaneously to dogs:, J Vet
`Pharmacol Ther., 22(4)261-265 (1999) (“Lavy/’)
`
`Ismail, “Disposition kinetics of difloxacin after intravenous, intramuscular
`and subcutaneous administration in calves”, Vet Res Commun.,
`
`31(4):467—476 (2007) (“Ismail”)
`
`_\ O5
`
`_\ N]
`
`Declaration Under 35 U.S.C §1.132 of Dr. Paul Gellert filed on August
`2008 in U.S. Application No. 10/872,784 (“the Gellert Declaration”)
`
`PCT Application Publication No. WO 03/006064
`
`.27.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 383
`
`

`
`
`
`Complete if Known
`
`12/285,887
`October 15,2008
`John R. EVANS
`1628
`
`HUL San Ming R-
`1 1285.0056-00000
`
`STATEMENT BY APPLICANT
`
`(Use as many sheets as necessary)
`
`Application Number
`Filing Date
`First Named Inventor
`)>R S.
`
`
`INFORMATION DISCLOSURE
`
`
`
`
`U.S. PATENTS AND PUBLISHED U.S. PATENT APPLICATIONS
`Document Number
`issue or
`Name of Patentee or
`Pages, Columns, Lines, Where
`Publication Date
`Applicant of Cited Document
`Relevant Passages or Relevant
`MM-DD-YYYY
`Figures Appear
`
`Foreign patent Document
`
`Country Code’ Number‘ Kind Code5 (ifknown)
`
`Publication Date
`MM-DD-YYYY
`
`Pages, Columns, Lines,
`Name of Patentee or
`Applicant of Cited Document Where Relevant Passages
`or Relevant Figures
`
`
`
`Examiner
`Initials
`
`Cite
`No.‘
`
`
`
`Include name ofthe author (in CAPITAL LE'l'l'ERS), title of the article (when appropriate), title of the item
`(book, magazine, journal, serial, symposium, catalog, etc.), date, page(s), volume-issue number(s),
`publisher, city and/or country where published.
`
`NONPATENT LITERATURE DOCUMENTS
`
`
`
`
`
`
`
`
`Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through
`EXAMINER:
`citation if not in conformance and not considered.
`Include copy of this form with next communication to applicant.
`
`Considered
`
`
`
`The Merck Index, 12th Ed., Merck & Co., |nc., pgs. xiv, 189-190, 641-642 and 1715
`(1996).
`Guerrini, et al., “Pharmacokinetics of probenecid in sheep", J Vet Pharmacol Ther.,
`128-135 (1985).
`Lavy, et al., “Pharmacokinetics of clindamycin HCI administered intravenously,
`intramuscularly and subcutaneously to dogs”, J Vet Pharmacol Ther., 22(4):261-265
`(1999).
`
`Ismail, “Disposition kinetics of difloxacin after intravenous, intramuscular and
`subcutaneous administration in calves”, Vet Res Commun., 31(4):467-476 (2007).
`1
`Documents from the prosecution of European Application No. 0 900186.6 (EP 1 250
`138) from August 27, 2009 to December 15, 2011.
`Documents from the prosecution of European Application No. 10180667.7 (EP 2 266
`573) from November 23, 2010 to December 19, 2011.
`Documents from the prosecution of European Application No. 10180661.0 (EP 2 286
`818) from January 19, 2011 to December 19, 2011.
`Declaration Under 35 U.S.C §1.132 of Dr. Paul Gellert filed in August 2008 in U.S.
`Application No. 10/872,784.
`
`
`
`
`
`
`
`
`
`
`
`
`
`7
`
`Examiner
`Signature
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 384
`
`

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`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 385
`
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`iabci fmf E'.:2sim§e:\j}, and the 25"{f temperamm cmrresgzozads to *:h<: adminisizméon
`
`*:s:.m.;:ee:at§11'& {ziinhiem teiiaperzatiura). E11 a-tidétian, the Sgxacifieéu $i>iuhii§.iy vaéues on £3133
`
`Tabie 3 are 1'?£1€3I} vaiues aaicuiaéed fmm ana3.},r‘::is cf nspiic-‘cue sampies fi“{?i.’§‘§ One 9:‘ 1'§1(}i'€
`
`iriais.
`
`"§“ae iazaiixsiduai szaiues are shown in haaadxxmtiiig it: the aazzeixded §z'fi$1‘SiGfi esf Tabia 3
`
`ii: Atiszzckmzent A.
`
`in addiiifiil,
`
`appears ihat the mean vaiuea f€3§"1'§1:’3 East ihrezs
`
`cc-mgmsiiiens haaze ‘:2e:::1%n.cmr:—:c:‘.‘aycaicuiatszsi
`
`‘Em: e:oa'=.'cc%r:d zncan vahacs, tagsthssa‘ with
`
`{Erie c:<a:rea:‘:io§1 ef the ternpemime {$013 “Z5” ‘” his mad “4"{I”', are 2113:; shou./:2 in
`:
`
`§“;I2i:‘§s;§‘W£‘§?_i:1g in the zmazjmigd '<.5:3.:“s§e:m :3‘? Takée 3 in Atiachzncni 5%.
`
`QB} "»32§}4?(>{‘z6.‘:
`
`kl
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 386
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`

`
`S7‘
`
`ihavgz evaluated zhe t1'a::s<:;'i§:»€éon 3:36. czsher ezrmrs 3g8,§i:1SZ the oiiginzfi zsgygxliezaiicr:
`
`disclosures and csxxciuéa mat ihese dz) moi; change. the uétizxxata c<3a1cEus;i<ms traaée from tin.-3
`
`dame: as szriginaiiy rezgzortazzi. The z:s:§di§:i0n sf E 5% WW baggy} Exenzoate to camgsasiiiens
`
`having iota} ;«;i<:<>l::<:>‘§, e;3a3m:€:t1‘E’raL‘%.€.ms
`
`in caster eii {sf 3€}% , 1.5%, 233% aszsi 38% wfv
`
`aznexpscieéiy ;3z'{:=vie:is:s a §30S§.fi¥'€ efilsmi an fi1Ev>:3s§ran%; S0§1:bfli*€_§?, significamiy increasing
`
`{ha ss:»§u‘:>i}§tj,: of fuivxtgxram, in {$33 costzpesitioxzs despite fuivafitrant having 3 Eower
`
`s0iubiiiLt§,' in Eaeznztyi benzuais: than in iii E312: aic<>‘s1<31 or e:23.:«:i£3r 0&1.
`
`7.
`
`additicsraai set ofexperin:e:1~‘:s11as beer. comiucéeé at 25°C under H13: gcaidance £0
`
`ohiain camsistant data with reduceai varia3:si3i£§,r {mm a singks
`
`0? riigazrousiy wnirofied
`
`sfiiubéiiéy experiments and to aiemazzstrate that the :mccX§e4:fs:€:d imtmase of sohlbiii‘-‘iy Gf
`
`mivssstrantt by adding 33-may}. %€fiZ0&t€
`
`into csarzipgsitians cesntainitzg 6:}: 3:10}, Ezxsnzyi
`
`aicshoi and czzsioz mi, is presexzé. acmss {Em bruzséer 1'a:1g:: {sf cumposition smzaéziipassed by
`
`the ciaims basing §31'(:S<:I2‘u$€3. with $.§i}iS Decsiarsaxiéon. The s<>Eub§3i%.y of fuivestrané: in iaenzyi
`
`benzoate 2:11:31 in easier oii was aZs~::- measured in ihe same set 0f€X§3€E‘§fl1€1’fiS
`
`uséag the
`
`same haich afbenzyi bsmzoaie and
`
`same: iazmzh
`
`casiasr (xii wen: useazi {:7 make up
`
`the cxzxngrmsétieszes, The Exp@rimes1ta§’1‘est Proceszium is éiescribed in Aiztaszzhment B.
`
`8.
`
`Tiraea results Exam {bass soiubiiity exgsetiments arc she:-wn in $312 rams in Afizschmmxt
`
`Teziififii resui
`
`shew aha: the s:)§’ubéiity of =.u3vs3s€Ia:ai
`
`in ¢:az«:ts327 oil aione (23 .4 mg;’m§.} is
`
`significaniiy greaier than the sehfisiiity sf fuivestrazzt in %::en:»:§*i §xen2c»at<: zziwrze {3 .8
`
`mg,/1:31} ami dem<>n:;£r.::te the uaexgoected increszses in fuivestrant .<§<3h§bi§§ty on $315: aéaiiiien
`
`cf 38, £5 am} 25% wfv ixrnzyi bexzzoate, in place of an equivalem; amoamt {sf caster @213, $0
`
`ciarxzpasétéons having {(313} aimhni concentrations in Castor mi of 353%, 15*.’/(as 29%, 335%
`
`and 3{é% wfv.
`
`'"§"n:-.33, zhs resuks that were ebtained {mm exgsefinzaxzzs cmaducted 1313§'<3§' n2g<3musEy
`
`camamiied cea1c§i§§e3ns amii with an exgmazded range Of campositions, as shcwn in
`
`.A§‘tas;:h:1r3e:1 C, Ceilfiffil $212 uitimate cmaciusiang drawn fmrarx tbs resuiis S}}{}W§’1 in Tabiar
`
`sf this £§§ig:“;a;:§ z1;z>'g3ii€:a€;i{3n
`
`dé:»:::§:3su:'e§ 3f:as:z.s§y ‘sh
`
`.‘:3(‘1d%$.’iQ§} {Bf L§{3% to
`
`wfv Ersmaytyi
`
`DB? ?f'3L?C14Z’.{~.(‘:é'>. 1
`
`3
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 387
`
`

`
`‘hezzmaie :9 i’..’€}},”i‘i§3{3S§‘{i€)}lS havéeag totai aicohai e::mc.ez1:1'atiens in caster aii cf between
`
`§.{‘:"/in to 36% vfiv 1:z:e:2;pec:e3<:§§.‘y‘ provideg a gmsitive efiécz on ‘-.‘i2iv“esi;‘a§1i: s0.§ub:i§it};,
`
`sig::if1s:a1:t1jg«' increasing €316
`
`s0E;:‘b§}i§y {Bf faivestmrzi in ‘ihe cempositiens fisrspiie
`
`fuivestrzzni Exzwiragg 23 ‘flows: soiuhiiia * in benzyi ‘aetzzoate man in €ti’£§3.SY aiczahcsi or casts:
`
`{KL
`
`1%}. Dxzring {he ~:c<>urse crf .513}: sméy csffize ¥3.Va'as Appiicaiicsn and 1312 12:1é1»::s'§yii:;g smxrce
`
`maiciriais ii was drawn to my 2.=E§e:;ii0r1 that somc efthfi c01fapr;;siE:£<m data gives. far
`
`Dcicstraagen and Deiaiutin s<3m<:h<:>*»>'~.* had
`
`shifis:<%£ mane: c<>Ea1n1n.m the right. Thus, rfor
`
`}[}e.E<estrogez::, the '73‘?/e ami :3-8% figures Shawn umier the BEBE. ceiunaxx shmlié have bean
`
`‘gmcier the GEL cczimmx; the 2&3‘?/£3 and 48% figures; Shawn muier the 8210?? column slmuid
`
`have been midst: the B232 ccaiumn; and the 2% figures sheswn umiazr E5:/(SE-IL she-uici have
`
`‘mean under ‘$15: 828 H cniunm. S§m%iar3y far §3::iaEu£%m the “tag: to 2%” shown urder the
`
`BEECH C<}11m3,t; silcszxid have 3333:: Laizder irhe E2533 coksxsm. This {aim-: repcmts ‘that ihe
`
`source of this data was 3.P§1a.:’:I:.Sci (19641?) 53(3) 891, which is Riffégin (1964) eisawhere
`
`refesrreci to in £11.35 L‘>e:.:Earati<3:1, 3313 K
`
`aiso V::::71§'ie<;§‘ the cesrraaeéed xi. ‘:3 fawn she entries
`
`for Beiaiuién and Deiesircgen in PEER (1973). A i?E}3§fy' ofTah'ie 1 from if-rze Evans
`
`Appiicatican £8 rcmaducad
`
`Attachmeizi‘ B, {:13 which these C{}§f§'i:C’5;i{}I3S haw: bsan made
`
`in handw3'it'§;:2g, ané I have: additirmaiiy more: correciiy amteé {Chat _'€)<~:Ea'§2,1§§:':
`
`is 1’:’—hys:Ir0xy
`
`p§<3gc3sir3m§:r3 céaproaie, zrmd that Ehs “COM ”’ de.s.ig1:a§i<>n for De.1223.=;;ti:1 should be “‘BMS”
`
`{Brisi::>§~Myr:r:< Squibb). Aiiaemizzem D also iETLC§.E.1%.'§£S 3 (3333 §(}1~i§,'€ ¢:>:pE:~ma:§0n of £116:
`
`::<3r;r:3<.’::.i<m,s: to this; Tabie E,
`
`ii. in ahmgtt sari}! 2630, 2: pffifiiflil r§2:»:§::a>nsi.b3:: fer deveiaaping 21 szxstamssd micasa irzjatctabi-it
`
`fiammiaiiwn suitabie fest a.<i*s§2i:;i5Zra:i0‘s1 ts} Emmans for new si:s~3:'ei<ia} Ltimrzpoumi such as
`
`fiaivasirana, ws:3u}Q§ hzwe heist} specé.=.':3L§2e<i training and tixperience in dexse?-aping
`
`phanazacetzticai famzz.‘-iaticzmz ami ineihods fast their 3f§I3Tii3}iSEZ'3i§G}1. in :3‘e‘\:eE<:s§3i;::g S‘:i{.‘3§Tz 2:
`
`f0.s‘muEati0n for fisivcssimslt, ihe asigtsetive wuuiai have ham: E13 famluiaie an imramuzscuizzr
`
`{EM} injaciiorx ihai wmxid garmzidc far the saiisfacmrgr‘ s:.:s:aé:1s3dzf::§<::;2s<: cf fzxivesgagai ovsx
`
`parieci ofai 3:233: twat: Wccks mid p2:*::fs:*rai>Ey eves‘ :3 period of 3‘; ieasé £23m“ ‘»Vr3€}{S to
`
`radzzsge fizz: :Frx3;:g;s:3;1c}; of ads':1§:1és;‘£:‘ai:§&r:, am} vmgakfi Emvei a target fuhsestmnt zzmsiem sf 3:
`
`333 1/6Z€}42<'>i}(>.E
`
`4
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 388
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`

`
`3635? 4:3 mgfnii. so as Em pa'0vi.<:i£-: 3 fu1ves£:“a:1‘{ dose ofa: Eaast .Z*"‘G mg in :2: singie :?«6 ml.
`
`ingexzsticm. Froin :11}! pazarsonai e.:«;;:v::'ie§1cxit ans‘: knawiegige <:rfth:3 §i§€i‘3iEf€
`
`at ahout {hat
`
`iime, beiieve that such an exgefianaed f{3§‘§}‘1‘si§.3{0Z' wouid §i§;eiy have Ei§}§31”G£E<§:}}§5e1§ the
`
`cf cieveiaping
`
`‘f:_x;1.fzmi22.‘u2.::»;3 fiil.’ fi§‘m:str:a1‘;‘4; in abazui ihe faiimssisagg mamaexr.
`
`32» Given €113 fo:‘£~>g0'mg <3bj{*.ctivr:, the: cxpesriencasefg faxmuiatgr wouki hsavrs appreaziateé that
`
`the éraiiiiieiizxi a?dmmist:r2a*;i0:1 apiions Y0 m:p§01'e VJSIS iI1‘£1"£:£E‘m:sC1§§3i‘ (Lad; izljcciiszz sf 2:
`
`su:«:ia..inez} mitzasez aqueuais C91‘ 3%} suspémsizm or an ei1—b:a:s<::.§ soiuiimx {de:p0E.} cmrziaining 211.
`
`£635: 25% mg 0f’fu1Ve3s%:ra31t in a Voiume of'Ve§izicE:3 tfirzat is ieierabie fez‘ inj; eciian, .:'.e., {:0
`
`mare than 5 <31" 6 mL,
`
`3.3“ Be:;:aus<: cf the ex. \ amxzziy Em ' seiubiiiéy at‘ fiiivestram in Wain‘, 3 reasonable starting §3Gi.E§‘T.
`
`wmzid §:a“<;e §}£?€t'£}
`
`€43
`
`investigate i§;::‘a::auscu1a1"iagectioig 9%‘ an aqmrous 02‘ {xii suspension of
`
`§"uive:s£1'z-:nt. Em-s«*s;~:v::r_, fin: §’0s;1m,:f;2~:E=;sr avmaid have fsazsmi £3122’: i11jec*:ion sf am zaquesus
`
`suspensiun sf fuEv<::~:i=;a.n% rcsuiicd in c:».:i;<:nsiv:;: iocai tissuéx i37:'i?.a%i~m1 3% the injectiawn site
`
`wefi as a proof rreiease profiie, Such as reporter? in pa§agrag:si§ {G342} exfme Evans
`
`Appiicaiicra. Since susperzskms
`
`were ms’:
`
`accagxtahie optim: fer fuévezstranij
`
`experieaiced fonmfiamz‘ wmuid ‘gtxave mcsved on :0 f?.§E':fh€¥ ex;:aL:>1‘s: whether 25$} mg of
`
`‘fuivestram covld be 5:312/:Ti:3iEis<;3d
`
`no more than Sufi 113.. 01‘ an <3’:E—bas<3-:3 vehicie, §.e._, :0
`
`achieve the targez fuivestram ::em;e:1Erat%a>11 of at 2533: 45 mg;’n1§_...
`
`14. in ihe p2'ef:rrmu§afi<3n phase, the experienced fcsrmulatxsr wouizi have catzducied as
`
`iiieratme I'€Vi8W'
`
`01* sifizemrise wauid hawé become: familiar with c:<>mm<e1’c§.a3Ey ;r¥s:«:1'§<z:ie<*1
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`énjeciabie forsnuiatimis, §)E3I‘ii€311’§?:I1}~’iI!j8Cta?L'%.§€
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`stxsiainsd reiaase f0x'mu1a-Lticsns af siercsids
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`O1‘ ether reiaiiveiy i1'1sa§=.1‘r;«Ee cumpmmds such as»:
`
`‘Lh{}i~2E3 Eiséed in Tame i of the Evans
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`Ap§3§L§catéonL, with the oitsjctctive {sf éd$n.tifying;p0%e;1t3a3 0%? v{:hi.c.§r3s, cc-~so§v:~:§1ts am? other
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`rzxcipiams {hat a§i'€2aa;‘:y had baa} foimd {:3 be §<31s::'a‘i-;it:i zn:3d;"0§' :9 have passed §h£'C¥{1gh
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`reguiatory ratview, anci whicia might ‘be caytzéidates far fu1*£7§3<::* e;:e;ms§<i<v:1‘3.T:i<m am? testing fur
`
`the fu§.vestrant fmmmiation. This: review aiso wcsuki have ;::;'<:>Vids.=.é gu‘§(§23:;£e with .=:es§r::ct
`
`to czimcezxtratioia Eeveis ofsuch cwsoivesais ami oihet’ e‘xe:i§>iez1ts {hat geizeraéb-' had best;
`
`foimsf: agsegsizaiaia in
`
`reitizzsct <;tei§L~%:aV:acd ini?a3“;:e1::s§:r.1§23r ifiestiazas a<it:1;f.msicre{i £0
`
`B3156 ?.{E4f/I-f3-.’}:3 .‘:
`
`(J:
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 389
`
`

`
`mamaafas. ’,‘s"his 0bj€:<:=:§vz:
`
`is <;{311fim3<:z3, for examjpie, in Natma {‘§9‘3’I’} at page 1236:
`
`G»:23*1¢a“aii§«; a kixawiizsige 0f'w§3.ic}3 er=~;c‘ip:§::mts ‘nave: ‘csczten dammed
`by the FDA 0: Ems: aaiready’ §‘}i“ES€‘§1‘{
`in 2: iriarketeé ;31"-0:32:31
`prexiiées .£I:::1'ea.§e<5Z asszzxztnccz ts: ’£he fstnnmiator $13?
`13:12 eXc§.g:s%£::a€5
`wifé probaiaiy‘ be safe fi}1‘ih€ii' new drug proxiaci.
`Reguiamry
`‘nesriies
`vimv an :3x<:§pi<:mt p3‘m'im1s§y :5q*;§=r<2vr.°.»;§V in an injectabie
`dasage fem": fax-'01‘;§biy, and WEE} f:'equ.em§y :‘eq*uire 1:335. safefy éaizi.
`
`The purgese oftiqis Nema pap:-:1‘ was thus
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`r..',~,
`:0 presseni ihe va1'ioas axcipierxts ihat have
`
`bsan inc‘zu:§ea:i in the fsnmaiaiicaza {sf injectahie *;o:'m:E::::ts sz:aa:E<e*£eai in the USA.“ Séizztfiar
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`cfigjectives were iimtended 3423 be servefi ‘:33’ the <:0mpiiati0ns of czmmzifzersiai f0:':r3’u.iax:ioLz::s in
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`Sirici<;k:y 1 {£999}, Siriszkisy ii (200%) §:‘:Yi(§ SiIie;:k§ey' 31 {E808}:
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`This co-mgaiiaiiam xvii} afisae be usefui far these énteresied én
`.i<::1c:wing what ad<iԤtivc:s are: czxm-sntiy used in insjeciabis pmducts
`ami at what c<mc:i:ntratim1:s 31:35; am zzdminisstered in praatice. This
`::tcs11:1;,:i.ZiV2ati,0:3 eniy fcacaxses an rz13.t‘§<:s:‘iea:§ f0a'zm::§a‘:§.€a3.1s and {flees $1232:
`iieives imo we subject of precéinicsi or (hug
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`phannaczudynamics, wfmare tisza fomxuiazian scientist is my; Emund
`by :'egu§a’ia3ry c<>:1s::'ai:3.t$.
`
`{$tz'i::§<.§£: If {E 999) at 324}.
`
`Pewesii {£993} simiiariy states ai
`
`238
`
`reggae’: ta ifis C{)1‘}’.‘£§i§at§{}fi_ of eaznfinlerciaiiy
`
`used exciments:
`
`Tixua the f01‘muIatie3n scieniisfi is offer} faced with Ei éiiexzima «-
`
`whéch excapients are truiy avaiiaiaie far use {based on what has
`{teen zzsed previeusiy), 2:31:11 whix:h are £106? And at What
`c0n,c:e1m7;3$,§0n$, and $3.! W333? a‘s:sut::‘.7"
`H€rs::‘in art: Eistcsi the excipienis fceund in mass: 037 $316: appmveai
`and mar}-ietrsszi parargtmsai fcsmiuiatimas, given systematiczzéiy by
`excigaiem mama. in ihig famiat ii is easy ‘at: éeiermine what
`co:1ce:1trai;i0ns were used, {he mute {sf adminésirarziam, the main
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`the drug that was
`z"a‘::i»:ma§c for aafzditiim 0% ma: <~:.x<:ipi€mt,
`fgsxmulatezifi she rxxzmufaaszttirer, brand name, sic.
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`ES. Fran} the §’i‘€?:‘:i'£i'{11f€i'€3‘Vi€\&’,
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`the §‘13rrn::§:r£(3§*w<>‘u1:i havs mated raference to a n§1m‘z3er of
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`inmzmuscuiar i:1j<:x::a.bEz:% Sustzmaed reisase U-i'Z~§>2*:.se:§ s§iemid;a§ fO?'.E‘£}1i§ai§G!”tS that ‘had been
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`':hat the new chug §3f0‘\§L1€:{ wifi be safs
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