PATENT
`ATTORNEY DOCKET N11: EISfi291-Sllfisi-«Q1
`
`IN TEE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Confinnation N0.
`
`2093
`
`Group Art Unit:
`
`1617
`
`Examiner: Hui, Sairming R
`
`Dam: August 21, 2008
`
`) } ) 3 ) ) 3
`
`) 3
`
`In re PATENT APPLICAHOEQ of:
`
`EVANS et 31.
`
`Application l*~I=o.:
`
`10/872,784
`
`Filed:
`
`June 22, 2004
`
`FOR:
`
`FORMULATION
`
`AMENDMENT AND RESPONSE
`
`This is in mspcmse to the Acticsii mailed March 1”}, 2(}i)8, the time far responding to
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`which has %beenV isxtendeci to and including September 17, 2008 by ?atition and authorization for
`
`payment of fees subinitted hicrewith. Pleaae amand the claims as preaenied below.
`
`Table of Contents is presented an page 2 cofthis paper.
`
`Table of References discussed is presanted ma page 3 of this paper.
`
`Amendments to the Claims begin on page 4 ofihis paper.
`Remarksr’Argumt:nts begin an page 6 of this paper.
`
`Applicants wish in express {heir appreciation to the Examinar fer taking the iime far the
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`p¥3i'3OI13.1 interview on July 15, 2008, with the undersigned, Dr. Gellcri and two other
`
`repreaentatives of Applicants’ assignee, which iiiteririew will also be discussed furthszr iieiow.
`
`T313 Examin<~:r’5 attentiun is called to the accmmpanying Declaraiion of Dr. Paul Richarri
`
`Gelllert and Attashinents thereto (hereinafter “the Geller’: Declaration"), pmti-axis inf which were
`
`presented at the interview; and addiiional portions of which previcie further ‘factual and
`
`documentary suppoii for the pateriiaiiility arguments presented during the interview
`
`E: is believed that arguments presented in this respeiise and the factual and ,dOCL1IT1fZ:11iEiI'“_‘y‘
`
`supportLprovided by tbs: Geilert Declaration sstafilish the patemabiiity of the amended claims
`
`presented below and should place this appiicaficm in rm-niiiticin for allnwanca. Therefore early
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`and favorable consideration is respectfully requested. However, if any autatandiiig issues
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`nrzvizrthaless remain, it is respectfillly requested that the Examintiir ttslephonae the undersigned to
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`expedite the resolutiiin {if such issues and the ailowance of this applicatimn.
`
`I)Bl£’€u20‘?Crl63.l
`
`Astrazeneca Ex. 2133 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01324
`
`

`
`.»5£I"T(}RI~IEY DQCKET NO, : 056291-50t)4—m
`Application No; }();’872,734
`Page 2
`
`Far convenience of reference, the Rmnarks will be presented under the section headings
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`Iisted in the fcslktrwing Table :)fC0ntents, brsginning an the gage noted:
`
`TABLE OF CONTENT$
`
`TABLE ()F‘
`
`Section
`
`3
`
`.
`
`CLAIM AMENDMENTS ............................................................................................. ..
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`(I) Appficants’ Sumnzaiy 0fPersmml Interview Juiy I5, 2063 .............................. ..
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`(2) Intrnductirztx and Bad-zgrauna’ ............................................................................ ..
`
`(3) Disczassion ofC?:z£m Amendments
`
`(4) Ciaim Rejections «- 35 USC'§ I03 ....................................................................... 11
`
`(5) Applicants ’ Rasgpcmse, Arguntentx and Declamtian Supparffar the
`Pxztersmbiligy ofthe Prexentgz Pending Claims ‘V...................
`-..................
`
`(6) Corrections/Ciarijicatie:-‘us to Evans
`
`{7} Additianai Tests and Data in Attachment C .............................
`
`.... .
`
`......
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`(8) Fourth Information Disclowre Statement ......................................................... ..
`
`(9) Conclusion ........................................................................................................... ..
`
`4
`
`6
`
`8
`
`10
`
`13
`
`14
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`26
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`2?
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`29
`
`31
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`DB}!-&30?0l€:3J
`
`Astrazeneca Ex. 2133 p. 2
`
`

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`ATTORNEY DGCKET NS. : 0S6291—5l}[§4«0’1
`
`Applicaticm No; 1m372;734
`Page 3
`
`TABLE OF REFERENCES
`
`
`
`
`
`
`
` Mackey (1995)
`
`MA. Mackey, AJ. Canway and DJ. Hzmcialszman. Tttslerability cf’
`intrmnuscular injectitms of testostertmt; eater in oil vehicla. Hum.
`Reprod. 10: 863865 (1995)
`
`3
`Nana (1997)
`
`
`
`9*
`
`FDR (1973)
`
`10
`
`Powall (1998)
`
`ll
`
`Rifflcin (1964)
`
`12
`
`Striclszlegx I (1999)
`
`33
`
`Strickley H (2000)
`
`14
`
`Strickltey Ill (2000)
`
`15 Wat1g(l980)
`
`Physicians ’De3!t Reference {'27:}: editian). l277-l 278, 1350-31 354, l39l~
`1392 Medical Eccznomics Company, Qradgll, NJ (31973)
`
`M. F. Powell, T. Nguyen. and L. Baloian. Compendium of excipients for
`parenteral formulations. FDA J. Pkarm. Sci. Techno}. 521238611 [pages
`233-255 prcwidesrl] (2993)
`C. Riffllzin.
`Huber and CH. Keysstzt. Castor (Bill as a vehicle for
`parentaral adtninstation of stemid hormoneg. J.P1zarm,Sci. 53: 89l -5
`(1964)
`
`R. G. Strickley. Parenteral flmnulaticms of small molecule therapeutics
`marketed in the United States (1999) «Part E. PD;-I J. Pharm. Sci. Technoi.
`
`S3:324~w3-49 (1999)
`
`R. G. Stricklejr. Pramntcml formulatitmsof small molecule therapeutics
`marketed in the United States (1999) — Part ll PEA J. Pkarm. Sci.
`Tee}/anal. 54:+59»96 (2000)
`
`R. (3. tStricl<}ey. Parenteral fonnulations at‘ small malecule therapeutics
`ntarlmtcd in {ha United States (1999) — Part ill. PIM .1. Pkarm. Sci.
`Tecitnai. 54: 152-l 69 (2000)
`
`‘fr’,C‘. J. Wang and R. R. Kowal. Review of excipienta and pH’3 for
`parenteral products used in the United States. J. Parsntaral Drug Assoc.
`34:452-$.62 ( 198(3).
`
`t>B1.»ts2<>7t>m3.a
`
`Astrazeneca Ex. 2133 p. 3
`
`Reference Citationmatent
`Anthorflnventor
`Comelius (us ‘$53) Us Patent 4.212363
`
`Dukes (EP 1314)
`I E? 0 346 014 Al {tzorresponds to US Patent S,l 833,814)
`l Dukes (US ‘814;
`l US Patent 5,133,314 {corresponds to E? 0 346 013 Al}
`
`
`Gupta (1999)
`PK. Gupta and GA. Brazeau (eds). Injezizmble Drug
`Deve£0pmen:.'Teckniqm2s ta Reduce Pain tzmd Irritation. Chapters 1 1 8:
`17 lnterphann Ptesg. Danwr, Cralmado (1999)
`
`
`
`
`
`S. Nema, RJ. Washkuhn, and RJ. B-rendei. Excipients and their
`use in injectable pmducts. FDA .1. Plmrm. Sci. Technai. 51366571
`
`(2997)
`
`
`
`
`
`
`PQV. Lepatin, V. P. Safe-nmi. '1". P. Litvinova and L. M. Yakimenlto. Use
`ofnonaqtmous solvents to prepare. injection solutions. Pfzarm, Chem. J.
`6:’724~733 (1972)
`
`Huber (US $20}
`
`‘US Patent 3,164,520
`
`Lepatin (1972)
`
`

`
`ATTGRNEY DOCKET NO. : 056291-SW34-01
`
`Applicatimn Nu: 1fl1’87‘2,’784
`Page 4
`
`IN THE CLA1MS:
`
`This listing of claims will replace all prior versions and listing of claims in the application.
`
`Listing of the elaimx:
`
`Claims 1«3«-4 (cancelled).
`
`Claim 35 (new): A method of treating a. he-rmonal depcndent benign or malignant disease
`
`of the breast GI‘ reproductive tract by administration to a human in need of such treatrnent an
`
`imra—musr.:ular injecting of a pharinaceutical formulation comprising fulvesitrant, a mixtxxre of
`
`from 10 1:0 30 % wsight cf a mixmre of ethaml and benzyl alcohol per volums of fommlation
`
`and from 10120 25 % weight ofbenzyl benzoate per volume of fmzmulation and a sufficient
`
`amcnmt of 21 casmr mil vehicle, whrsicby a therapeutically significant blmd plasma fiflvszstrani
`
`concentration of at least 2.5ng*nl‘* is attained for at least 2 weekg after injectim.
`
`Claim 36 (new): A methcbd cf treating a honnenal clerpendent benign car malignant ciiseage
`
`cf the breast er reproductive tract by administratim ta a human in need of such treatment an
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`intra~muscular in} action cf 3 pharmacetmical fcsrmulatien mmprising fillvestrant, a mixture of
`
`from 10 to 30 % weight of a mixture of ethanol and benzyl alcohol per voluma of fonnulatian
`
`and frum 10 to 25 % weight of benxyl benzcaate per volume of fonnulation and a sufficicnt
`
`amount of a castor oil vehicle, whereby the fommlation cw:-mprises at least éfimgmfl of
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`fillvestrant.
`
`Claim 37 (new): The method as claimed in claim 35 or 36 wherein the formulation
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`comprises a mixture of from 15 to 25 % Waight of a mixture of ethanol and benzyl alcohol per
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`volume of fortnulaiion and from 12 to 20 % wcight csf bcnzyl benzzoate par mlume mf
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`fcmnulation.
`
`Claim 38 (mew): The methmi as claimed in claim 35 0: 36 wherein the forrnulation
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`caxnprises 3. mixture csf from 8.5 to 11.5 % wcigln of ethanol per volume of f0m1ulation, fmm
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`8.5 to 11.5 % weight ivflzsenzyl aicelml per ‘volume sf formulaticm and E2 is 18 % weight of
`
`DB l;a§ZC:‘i‘{3.i£r3.3.
`
`Astrazeneca Ex. 2133 p. 4
`
`

`
`ATTQRNEY DOCKET NO. : 056291-«50l}4~01
`Applicatian Na; 1f}f87f2,784
`Page 5
`
`benzyl benzoate per volume of fonnulatitm.
`
`Claim 39 (new): The method as claimed in claim 35 wherein the bleed plasmalfulveslrant
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`cuncentration is attained for at least 3 weeks after injaclion.
`
`Claim 40 (new): The method as claimed in claim 35 wherein the blood plasma fulvestrant
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`concentration is attained far at lsast 4 wcelzs after in} action,
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`Claim 41 (new): The mstlmd as. claimed in claim 35 wherein a therapeutically significant
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`blood plasma fulvestrant concentration cat” at least 3ngrnl" is attained for at least 2 weeks after
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`inj ectian.
`
`Claim 42 (new): The method as claimed in claim 35 wherein a therapeutically signifmant
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`blood plasma fulvestrant cmncentratian of at least Syfingml" is attained for at least 2 weeks after
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`inj actiim.
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`Claim 43 (new): The metlmci as claimed in claim 35 whensin a therapeutically significant
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`blond plasma fulvestrant ceneentration of at least 8.5ngml" is attained for at least 4 weeks afier
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`injection,
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`Claim 44 {new}: The methed as claimed in claim 35 01‘ 36 wherein the total volume sf
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`the fonnulaticen administcred to said human is ffoml 0.1‘ lags, and tha cztmcfirtttation of fillvestrant in
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`said formulaticm is at least 45mgml".
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`Claim 45 (new): The method as claimed in claim 35 or 36 wherein the total vcslume of
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`the forrnulation administered to said human is éml or less, and the total amount of fulaxestrant in
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`said mlums: sf fmmulatizm is 250mg or more.
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`Claim 46 (new): The method as claimed in claim 35 or 36 wlmrein the benign or
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`malignant disease is ljreagt calmer.
`
`DB l:v63(l7Ql63.l
`
`Astrazeneca Ex. 2133 p. 5
`
`

`
`ATTORNEY DOCKET Ni}. : 056291-S004-()1
`
`Application N23,: 1 01'872,7i§4
`Page 6
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`REMARKS
`
`This Amenément and Reeponse is being filed as a folioweup to the personal interview
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`with Examiner I-iui on July 15, 2008, in order to formaliy present the amended claims and the
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`patentabgiiity arguments that were ciiecussed at the interview, and to formally present and
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`supplement by means of the accompanying Ge11ertDeoIaration the factual and doszzumentary
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`support for the arguments presented at the interview.
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`(I) Applicatzts’ Summary 0_f.Personm' Interview .1111); I5, 2008
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`Applicants wish to thank the Examiner for extending a personal interview in this
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`Application on Juiy 15, 2908 to the undersigned and three represetttatives of Apoiioants’
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`assignee, Astrazeneca AB.
`
`Attending this interview on behalf of Applicants? in addition to the undersigned US
`
`attorney, were Dr. Paul Gellert, the declarant on the attached Gellert Declaration and a Senior
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`Principal Scientist for Astrazenecag Dr. Allen Giles, 3 European Patent Attorney with
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`Astrazeneea; and Dr. Bolvimter Mathamt a patent trainee for Astrazeneca, all working out ofthe
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`Asttaleneca facilities at Mereside, Alderley Park, Macciesfiled, England.
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`In order to faciiitate the disouasion during the interview, the undersigned faxed to
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`Examiner Hui on July 14, 2008, at partial draft of the Geliert Declaration (having the substantive
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`content of paragaphs 1-9 ofthe attached Gellert Dociaratioo and Attachments A, 8 anti (3), and
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`3 partial draft ofthis Amentiment and Response, inch.1d:in,g the amended claims and the substance
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`of the “Introduction and B;a<:1<:gound” and “Chaim Amendment” portions of the present
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`Amendment and Response (Sections (2) and (3) ofthe Remarks).
`
`During the course of the interview the Examiner was also given at copy of a corrected
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`version of Table I from the present application with an attached expianation of the corrections
`
`(see Attachment D to the Cvellert Declaration); a two page document showing the xtmoture and
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`solubility of certain steroids in castot oil and sesame oil compared to the structure anti soiobility
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`of fulvestrant, and the Eolubility of certain steroicis in benzyi benzoate {see Attachment E to the
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`Geliert Declaration); and a copy of Huber (US ‘$20) referred to in Attachment E, which is
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`included as Tab 5 of the Compendium offltttachment F to the Gellert Deoiaration.
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`A1} of the abovemoted ctmfig and documents that were provided to Examiner Hui were
`
`D81:'t3Zi}?€}!:fv3,
`
`I
`
`Astrazeneca Ex. 2133 p. 6
`
`

`
`ATTORNEY DQCKET Nil : D5(i291~Sfl£)4~(l1
`
`Application Not:
`
`Il)f8‘72,‘78£¥
`Page 7
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`discussed during the interview, as were the subject application {as published), the present Action
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`and, generally, the applied references.
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`The undersigned briefly commented on the prior art cited in the ohvionsness rejection as
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`disclosing, separately or in various sub-combinations, each ofthe fitlvestrnnt, caster oil, ethanol,
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`benzyl alcohol and benzyl benzoate components of the formulation administered in the claimed
`
`method. Then the underslgnecl and Dr. Gellert went through a enrnmary of Applicants’ argument
`
`as outlined in the Introduction and Background portion of partial draft response and the
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`additional data presented with the draft portion of the Gellert Declaration that had been sent to
`
`the Examiner prior to the interview.
`
`In brief summary it was argued {and it is believed was cietnonstrated) that the skilled
`
`formulator tasked with developing an intramuscular (IM) injectable formulation for the sustained
`
`release of fnlvestrant, would have conducted a literature review for previously approved andfor
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`commercially marketed injeetable formulations to identify potential solvents and cosolvents
`
`meriting fizrther consideration. A preformulation solubility screen would then have been
`
`conducted to determine the solubility of fulvestrant separately in a range ofptzre solvents,
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`including potential Solvents and cosolvents identified in the literature review. Based on the
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`results of these preformulation investigations; the experienced fortnulator would ltave selected a
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`cantor oil based vehicle, but would have been led away from adding benzyl benzoate as a
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`eosolvent for fulvestrant when attempting to increase the fulvestrant concentration in the canto:
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`oil vehicle up to the target level. Many commercialized steroide were more soluble in benzyl
`
`benzoate than in the oil base of the vehicleas disclosed in Riftkin (19135), i and benzyl benzoate
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`could thus act as a cosolvent. Howevert fitlventrant is even less; soluble in benzyl benzoate than it
`
`is in castor oil and therefore its addition to Castor oil would have been expected (and has been
`
`shown) to furl/ter cfeerease the ability of the resulting eastor Bil-b3Si?>d vehicle to dissolve
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`fixlvestrant.
`
`It was therefore unexpected and surprising when Applicants found that tltteadclition of
`
`benzyl benzoate to a Castor oilfalcolaol mixture would increase the solubility of finltzestrant in the
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`formulation as presently clainted, permitting the target fulvestrant concentration to be attained
`
`I See Table of References at page 3 above; a copy of each referenee it: ineluded in Attachmelzt F to the Gellert
`fleelaration under the Tab number indicated in the Table of References.
`
`I313 ift§’.2iJ7{ll 63 .1
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`Astrazeneca Ex. 2133 p. 7
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`

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`A'l"'l“Ol"{NEZY DOCKET NO‘ : e5a291—5m}«4.e1
`
`Application No: 10;’S’?2,’?84
`Page 3
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`with a more desirable lower level of alcohol. cosolvent. It was pointed out at the interview that
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`this unexpected positive effect ofbenz-zyl henzoete on the eoluhility of fiilvestrant in the caster
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`oilfalcohol mixture is shown by the data in Table 3 of the Evans epecification. Moreover, the
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`data from the additional testing overseen by Dr. Gellert and presented in Attachment C to hie
`
`Declaration demonetrates that this unexpected positive henzyl henzoate effect is present across
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`the broader range of formulation composition as presently claimed.
`
`Dr. Cielle-It atlditionally commented at the interview on certain transcription and other
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`errors in Tables 3 and l ofthe Evens Application relative to the underlying laboratory notebook
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`data and other source materials, and provided clarification by means of handwritten notations on
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`copies of these 'l‘ahler., which are Attachments A and D to his Declaration.
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`At the conclusion of the interview Exantiner Hui indicated that the allowehility of the
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`amended claims would he viewed favorably in light of the factual preeentation of the draft
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`Gellert Declaration and the argmnents preheated at the interview. ‘the recitations and
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`Attaelnnents to the draft Gellert Declaration rlircussed at the interview have been retained in the
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`executed Gellert Declaration submitted herewith, The executed Ciellert Declaration also ineluties
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`additional support for the enehviousness of the presently elaimeé invention, hacked up hy
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`literature and patent riocumente in the Compericlium and discussion further below.
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`(2) Introduction and Background
`
`The invention as presently claimed and disclosed in the sub} eet application is broadly
`
`directed toward a method of treating a hormonal dependent benign or malignant disease of the
`
`breast or reproductive tract in a human by administration of an intramuscular injection ofa
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`sustained releaee ‘phartnaceutieal formulation compri sing fulvestrant.
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`Even relative to other difficult to formulate steroidal based eornpetmds, fulvestrant is 21
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`particularly lipephilis: molecule having extremely low aqueous solnhility. The invention
`
`therefore addresses the olljectitse of defining (21) a pharmaeeutically acceptable solvent or mixture
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`of solvente (3)) that will diseolve e snffieient quantity of fulvestrant [at least 256 mg} (:2) to form a
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`small enough volume of formulation that is acceptable for injection {6 ml or less} and will
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`previée (cl) 2: fiilvestrant concentration of at least 4:3mgml'l {claim 36} astdfor (e) the sustained
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`DEl.‘t32{l?{}l 153. l
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`Astrazeneca Ex. 2133 p. 8
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`

`
`ATTORNEY DOCKET NO, : 056291-5i)04—l}1
`
`Application No; 1l)i‘372,734
`Page 9
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`release of fiilvesiranr whereby a therapeutically significant blood plasma fiilveatrani
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`concentration of at least 2.5ng3:nl”3 is attained for at least 2 weeks {claim 35].
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`The person of ordinary skill in the art irwolvecl in developing fonnularions for the
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`parenteral arlminiarrafiion of new, clifficulrly soluble compounds such as fiilvcsrrant would be a
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`person having specialized training and experience in developing oharmaceutical formulations
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`and methods for their administration. Such person would be aware of commercialized sustained
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`release injectable steroidal fonnulations, such as those included in Table l oftlie Evans
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`specification, which commonly use oil to solnbilize the compound and may have various
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`afldirional errcipients. The Evans specification acknowledges, as relevant here, that such known
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`formulations include oils such as motor oil and may include one or more other crrcipients such as
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`benzyl alcohol, ethanol and benzyl benzoate. However, such person woulrl begin the
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`development of er suitable formiilation for fulvcstrant by determining the solubility of fulvcstrant
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`in various single solvents that have previously been used in injectablc formulations.
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`A selection ofsuch solubility data for fLll‘\s"6Sll‘3nl is listed in Table 2 of the Evane
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`specification, from which it can be Seen that fiilvestrani is aigiificantly more soluble in caster oil
`
`than any of the other oils rested. However, as noted in paragraph {O01 ‘ll of the Evans
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`specification, 2 the solubility of fiilvcstranr in cantor oil alone would not meet the above criteria.
`
`Table 2 shows a very high solubility of fulvcstrant in benzyl alcohol and ethanol, and adding an
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`alcohol component to the cantor oil would be seen as a clear choice to the slrillerl person. Dukes
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`(US ‘8 14) took this approach in his Example 3, where his formulation contained 50 mg of
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`fiilveatreni, 400 mg ofbenzyl alcohol and sufficient castor oil to bring the solution to a volume
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`of 1 ml, or about 40% wfv benzyl alcohol. While this may have provided acceptable solubility of
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`liilveslrant in an experimental quantity of formulation to dcmonsirate selective oestrogen therapy
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`in rare, the Evans specification in paragraph [901 5} notes that this very high alcohol
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`concentration would complicate manufacture on a commercial scale, and that there is a need to
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`lower the alcohol concentration Whilst preventing precipitation of fulvesrranr from the
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`formulation. Moreover, the skilled person would want to reduce the level of alcohol Cosolventa
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`to minimize their potential to arlverscly impact performance including toierability.
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`3 Reference made licrcin and in thc Gelicri; Declaration to paragraphs ofrlie Evans specification roller to {he
`numbered paragrapha of the pnlili;-rhecl application: US 2i3(}5.-"{lifi4,32fiS Al, publiahcd Fclnmary 24: 2005.
`
`BB l:’fi3i}7£,”9 l 63. l
`
`Astrazeneca Ex. 2133 p. 9
`
`

`
`ATTORNEY DQCKET NO. :
`
`l}5fi291«5§}ll4—{31
`
`Application No;
`
`l(lf8?2,734
`Page 10
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`The focus of the present invention, therefore, resulted from the discovery by Applieanio
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`of the unexpected poeitive effect ofbcnzzyl ‘oenzoale in significantly increasing fire sohabifizy of
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`fxilvcetrant when added to a caste: oilfalcoliol mixture, whereby the needed therapeutic amount
`
`of fulvestranr could be dissolved in a small enough volume of formulation for injection without
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`need for an excessive amount of alcohol. This was truly surprising since the solubility of
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`fiilvestrant in benzyl benzoate is significantly lower than the solubility of fulvesrrant either in the
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`alcohol component or in castor oil. See Table 2 and specification paragraphs W819} and [0051]
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`of the Evans Application. This positive efiect of benzyl benzcate in significantly increasing
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`fiilvestranl: solubility in the eartor oilfalcohol mixture is demonstrated by the data i‘ne'l‘ai:ole 3 of
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`the specification, and is confirmed and amplified by the further evirlence presented in the Gellert
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`Declaration and tabulated in Attachment C’ thereto.
`1
`The ,:xamincr will note that the claims presented above cover a broader range oftotal
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`alcohol and benzyl benzoate content than the rcjccrecl previously pending claims. However, it
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`will be apparent from the above summary and the following discussion that the inventive step
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`(non—obviousness) of the present invention does not reside in any particular range of solvent
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`concentration; but lies in Applicants’ cos.mter~intuitive addition ofbenzyl henzoate to the
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`fulvestrant formulatiorr, and the unexpected positive effect of this benrtyl benzoate addition on
`
`increasing fulvestrant solubility. The fiirther data provided by the Geller’: Declaration confirms
`
`that the addition of bcnzjwl benzoate unexpectedly Significantly increasee the solubility of
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`folvesrranl over the broader range of fonmxlation composition as presently claimed.
`
`(3) Discussion of Claim Ametzdments
`
`Claims 24-34 are newly cancelled above (claims L23 having been previously cancelled}
`
`and replaced by new claims 35-46. The cancellation of these claims is without disclaimer or
`
`prejudice to Applicanfs right to prosecute any eubject matter Ilia: may have been deleted thereby
`
`in one or more continuing applications.
`
`As with cancelled claims 2434, new claims 3546 are directed toward a method of
`
`treating a homional dependent beni g1 or malignant disease of the breast or reproductive tract by
`
`administration to a human in need of such treatment an intro-muscular injection of a
`
`DB l.-62(l'?(l l 633}
`
`Astrazeneca EX. 2133 p. 10
`
`

`
`(}56291»50l}4-{)1
`ATTORNEY DOCKET MO. :
`Application E10,: 19f872.,784
`Page ll
`
`pharmaceutical forrnulation as recited in the various elaims. As in cancelled claim 24, the
`
`method of new independent claim 35 provides that “a therapeutically significant blood plasma
`
`fiilvestrant concentration of at leaet 2.5ngml”’ is attained for at least 2 weeks after injection.” A3
`
`in cancelled claim 29, the method of new independent claim 36 provides a fonnuletionthat
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`“comprises at least 45rng,rnl'1 of fnlvestrant.” A3 in cancelled claims 26 and 31, new dependent
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`claim 46 is specifically directed toward the method wherein the hormonal dependent benign or
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`malignant disease is breast cancer.
`
`The particular ranges of formulation composition or other charactcri stios recited in new
`
`claims 3546 find support in the specification as follows:
`
`I
`
`Support for the recitation in new independent claime 35 and 36 of’”from ii) to 30 %
`
`weight of a mixture of ethanol and benzyl alcohol per volume of formulation and from 10
`
`to 25 % weight of henzyl bcnzoate per volorne of formulation” is. found in the published
`
`specification, inter aiicz, at line 13 of paragraph [UEBI] and at line l6 of paragraph [G036].
`
`4!
`
`Support for the recitation in new dependent claim 37 of “frorn 15 to 25 ‘I4: weightof £1
`
`niixture of ethanol and henzyl alcohol per volume of formulation and firorn 12 to 20 ‘E’/E;
`
`weight of hcnzyl benzene: per volume of formulation” is found in the puhliehcd
`
`specification, inter atin, at line l3 cfparagmph [0031] and at line 17’ ofpa1*agaph{(}036}.
`
`I A3 with cancelled claime 24 and 29, support for the recitation in new dependent claim 38
`
`of “from 8.5 to ll.5 9/Ea weight of ethanol per volume of fonmilatinn” and “fiaom 8.5 to
`
`11.5 % weight ofhcnzyl alcohol per volume of formulation” is found in the published
`
`specification, {riser alto, at lines 9&4 of paragraph [0031] wherein one oflhc preferred
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`ranges ofpharmaceuticallyecceptahle alcohol {total} is “l7-23%wfx/” at line 14. The
`
`immediately following paragraph [(3032], lines 3»-73 discloses that the phannacenticallgp
`
`acceptable alcohol is “preferably a mixture of two alcohols,” specifically noting 3
`
`mixture of ethanol and benzyl alcohol, and that “preferably the ethanol and lzeenzyl
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`alcohol are present in the fommlation in the S31Il8‘Wf.V aniountn." Support for the
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`recitation of “E2 to 18 “/3 weight of henzyl licnzoate per volume of formulation” is found?
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`inter aiia, at line I?’ of paragraph [0€)36}.
`
`-
`
`Support for the recitation in new dependent claim 39 of “wherein the blood plasma
`
`DB1 z'f2T’.{3?t)l {$31
`
`Astrazeneca EX. 2133 p. 11
`
`

`
`ATTORNEY DQCKET NO, : 056291-51394-01.
`
`Application N13,: 10l872,‘?84
`Page 12
`
`fulvesirani coiicentraiion is aitainad for at least 3 weeks after inji*—;ction” is found in the
`
`published specification, infer cilia, at linas l-2 Bf paragraph [O0-48].
`
`Support for the reciiatimi in new deyendcni claim 40 {if “whr3rein the blood plasma
`
`fuiirestrant concantratian is attained far at least -4 Weeks aiiier in3;ecti0n” is found in the
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`published specification, imier afia, at lines 2-3 cf paragraph {G048}.
`
`Suppiirt for the recitation in new dcpcnricnt claim 41 oimwlierein a tharapeuticaliy
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`sigiificant bland plasma fiilvestrant ccinceiitration afat least Zingml“ is attained" is found
`
`in the published spccificatinn, inter aim, at line 3 of paragraph $3047].
`
`Support ft»? the recitation in new dependent claim 42 {if “wherein Z! therapeutically
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`sigiificant bleed plasma fulvestrant ccinceniration of at least 8.5ngrnl‘1 is attained” is
`
`found in ihe published specification, inter aim, at line 3 of paragraph {{}()4’?].
`
`Suppoii for the reciiatian in rm-W depczndcnt claim 43 of “wherein a therapeutically
`
`SigI1lfiCaI‘:tblQQd plasma fulvestramt concentration mi‘ at least 8.5ng;ml“ is attained for at
`
`least 4 weeks after iI1jBBil(5l}””lS‘f0Ill}d in the published specification, infer afia, at line 3
`
`of paragraph {@047} and at lines 2-3 mi" paragraph {(3048},
`
`Support fur the recitation in flaw dependent claim 44 cf “wherein the {mat volume of the
`
`formulation administered to said human is fiml or less:, and the concentration of
`
`fiilimsirant in said formulation is at least 4Smgml'1” is found in the published
`
`specification in paragraph {(l{l2‘?'].
`
`Support for the recitation in new dependent claim 45 {if “wlierein the mtal volume iii’ the
`
`fomiulaiicxn administered to said human is 61211 01‘ less, and the lam} '£i1T1{}l1l’1lL of fiilvesirani
`
`in said volume Of forimilation is 250mg or morrs" is fmmd in the published specificaiion
`
`in paragaph {G023}.
`
`Suppcirt for the recitation in new dependent claim 46 of “wherein the benign or malignant
`
`disease is breast cancer" is found in the published specification, inter aim, at lineg 1-? (if
`
`paragraph [(3038) anal in paragraph {(1062}.
`
`It should be clear fmm {ha above paragraphsi all limitations (if new claims 35-46 finii
`
`support in the specification, and these neiw ciaims are believed to be in proper fflflh in all
`
`£’£3§§pi’:iZ:l:S. Accordingly, entry sf l'.i1fiS€’: amizndments is believed to he in iirder and ii: respecifiilly
`
`mas ‘62I.’}70 i :33}
`
`Astrazeneca EX. 2133 p. 12
`
`

`
`ATTORNEY DOCKET NC) :
`
`[iS6291-S[l[J4--Cl1
`
`firpplicatian 3‘$t:«.: 10/872,384
`Page l3
`
`requested. Follewing entry of tlfzese amendments} claims 35~46remain pending in this
`
`application.
`
`(4) Claim Rejections - 35 836 § M3
`
`Claims 2434 have been rejected under 35 USC § ¥Q3(a) as being unpatentable over
`
`Dukes, EP 0 345 014 (hereinafter “Dulczes (E? ‘lIll4)”)3 in view 91‘ Lehmann ex :21, US Patent Re
`
`28,690 (hereinafrer “Lel1mann”)§ GB 1 569 286 (hereinafier “(EB ‘Z845; Osbcome er all, Journal
`
`of Natimnal Cancer Institute, 1995;87(l O);746-£750 (hereinafter “"Oslmme” , and Remi:egron’s
`
`Plrarrnacerrtical Sciences {hereinafter “Rernir:gtcm”). The Emrrliner applies these references to
`
`the rejection as follower
`
`1» Dukeslis said tr; reach that arltiesrmgen agents, ineludinglfxglvestrantg are ueeful in treating
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`pastmennpausal symptoms such as urogenital atrophy affecting the vagina (airing page 3;.
`
`lines 56-page 4, line 1; also page 7, line 2S~29). Dukes is said to further reach that
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`antiestrcsgen agents, inclucling fiflvestrant, may be used in a dosage of Slilmg to rig in
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`vehicle comprising easmr oil and benzyl alcohal {citing page 7,, 20-24).
`
`-v Lehmann er al. is eaid to {each that benzyl benzoare and easier oil are welbknown salvent
`
`usefill as crmventiconal carriers for steroids (citing cal. 1? line 21 ~26).
`
`4: GB ‘"286 (also by Lehmann) is saici to teach an intramuscular injection oftestoetemne
`
`cierivalive containing eaemr oilfbenzoate in ihe ratio of 6:4 {siting page 1, line l7’).
`
`- Osborne er al. is said 1:0 ‘reach fulvestrant as useful in treating human breast cancer (citing
`
`pagee ?47-?48).
`
`1: Remington is said to teach that ethane} is one cf the mast mmmonly used solvents in
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`pharmaczeutical li’lC1l.1S§l‘}’ (citing page 219).
`
`‘flue Examiner cczmcluded at page 4 efthe Aclgicsn that combining one or mere agents,
`
`which are known to be useful as commenly used selvents, such as benzyl benzoate, ethanol,
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`castor oil, and benzyl alcohol, together anri incorporating such combination with an estrclgen
`
`derivative, fizivesrrant, would be reasemably expected tr) be useful in formulating a
`
`3 This Dukes reference (Dukes; {EP 1314)} is the Izlumpean cmmterparr of {ES 5, l 83r8l4 [Dukes {US ‘é§l4}} nmeri in
`paragraph {£312} 1 4} ml’ the published specification.
`
`DB lI‘62'£}7ll I 63.1
`
`Astrazeneca EX. 2133 p. 13
`
`

`
`ATTORNEY DOCKET NQA :
`
`(356291-Sill)-4-I31
`
`Applicaticn 1539.: 1l}1S’}.2,’l8d
`Page 14
`
`pharmaceutical compositicn; and that cmploying such fulvcstrant-«containing composition to treat
`
`urogenital atrophy wtznlizl be reasonably expected to be effective.
`
`The Examiner further concluded that the optimization of parameters such as: the amcutit
`
`of cxcipicnts, dcsagc range, and dosing regimcna, is “cbvicug as being within the 3kill cf the
`
`artisan, absent cviclcncc to the contrary," and that maintaining the plasma ccnccntration cfthc
`
`active compound as claimed would he ctmsidcred “obvimzts as being within the purview of the
`
`skilled artisan, absent evidence to. the contrary.”
`
`Applicants respectfully traverse this obvicusricss gound for mjcctien based on the
`
`fcllcwing arguments and the suppcrt therefore pmvidcd by the Gellcrt Dcclaratitm.
`
`(5) Applicants’ Resjpanse, Arguments; and Decfamrian Supper!
`for tire Patentaiiiligy offhc Presently Pending Claims
`
`The invention as disclosed anal prcscntly claimed in the subject application is broadly
`
`directed toward a method cf treating a hcnncnal depcnrlent bcnigt 01‘ malignant discasc cf the
`
`breast or reproductive tract in a human by administration of an intramuscular HM} injection cf a
`
`sustained release pharmaceutical fgnmtlation ccmprising fulvcstratit. Fulixcstrant is the man-
`
`proprictary name for the subscqucntly approved and commcrcializcci drug ncxw known as
`
`Faslcdcxm.
`
`The invention is fccused in particular on the discovery cf a naval and uriolwicuc
`
`fcrmulaticn for this extremely difficult to fcrnittlatc mclcculc, which fcrtnulaticn £3 suitable for
`
`intramuscular injection to 3 human patient and is capablc of dissolving the therapeutic target
`
`amount of fulvcetrant in a sznall enough vclumc for IM administration, and which formulation
`
`provides for the satisfactcry s