throbber
IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Attorney Docket No. ‘I‘i285.Di)55~OQ0£)C3
`
`PATENT
`
`in re Application of:
`
`Jenn R. Evans et ai.
`
`Application No; 121285387
`
`Fiied: October‘i*5,2008
`
`For:
`
`FORMULATKJN
`
`Commissioner for Patents
`$9.0. Box 1450
`
`Alexandria, VA 223’! 3~'i45G
`
`Sir:
`
`‘-..y\...r'V-o.»/w-u._v*«..J-..r-..,¢»..x\...z’~.._.rw..,a
`
`Group Art Unit: 1628
`
`E
`
`xaminer: HLH, San Ming R.
`
`Confirmation N0; 1199
`
`Mail Stcip REE
`
`‘WA EFS-WEB
`
`RE3PONSE TE) OFFICE ACTi0N, SUBMISSKJN UNDER 37 C.F.R. § 1.114,
`
`AND PETlTi0N FDR EXTENSION 0F TIME
`
`In repiy to the Finai Office Actipn mailed September 16, 2011 (“Office Action”),
`
`Applicants respectfutly request reconsideration of the claimed invention in View of the
`
`foilowipg amendments and remarks. This paper fulfilis the requirements pi‘ a
`
`submission under 37 C.F,R. § 1.114, and is flied tegether with 3 Request for Ceniinued
`
`Examination (REE).
`
`Applicants hereby petition for e one-month extension of time to respond to the
`
`Office Action, extending the period for resppnse to January 16, 2012. The requisite
`
`exiensien~of—-time fee is being paid ccincurrentiy with this filing.
`
`Amendments tn the Claims are reflected in the iisting of clairne, which starts on
`
`page 2 of this paper. Remarks foiiow the amendment sections at this paper and start
`
`an page T.
`
`Astrazeneca Ex. 2141 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01324
`
`

`
`Applicaticzin Na: 121285887
`Attorney Docket No; ‘l 1285r.O£l58-D0009
`
`1.
`
`Status of the claims and amendments
`
`REMARKS
`
`Upon entry of the instant amendments, Claims 24, 26, 27, 29, 30, 32, 34-36, 38,
`
`39, 41, 42, 44, 45, :37, and 54-57 will he pending in this appiieatien. Ciaime 25, 28, 3?,
`
`33, 37', 40, 43, 45, and 48-53 are cancelled in this Response without preiudice or
`
`disclaimer. New claims 545.? are added in this Response and find support, tar
`
`exampie, in the specification at 11 {@0531}
`
`Applicants amended ciaim 24 to recite a fermuiatioh comprising “about 50 mgmi—
`
`‘l at tulixestrant; about ‘i()‘’/-.» wfv of ethanoi; about 10% wfv of benzyi alcohel; and about
`
`15% wfv at benzyl benzoatef‘ Support for this amendment can be found, for exampie,
`
`in the specification at ‘M {Q9721-{G075}. Appiicante also amended claim 24 to recite that
`
`the method achieves a therapeutieaiiy significant bioed piaema fulveetrant cencerntration
`
`“for at least four weeks.” Suppert far this amendment can he found, for exampie, in the
`
`specification at 11 {0052]t Applicants amended ciairn 36 in a eimiiar manner ta eiaim 24,
`
`with supper’: in the same portions of the specification as the ameneimente to claim 24
`
`mentiened ahave. Appiicante amended ciaime 32, 34, «£4, and 46 to change their
`
`dependency because the claim from which each depended has been cenceileci in this
`
`Response. Mane of the claim amendments introduce new matter.
`
`Ciaime 24, 26, 27, 29, 30, 32, 34, 35, 54 and 55 are directed to methods for
`
`treating a hormenai dependent benign er malignant dieeaeeof the breast or
`
`it Uhieee etherwiee eeecitied, ail citatione to the instant specification refer to the
`eagination in the puhiisheci apeiicatien, US 201019152149.
`
`Astrazeneca Ex. 2141 p. 2
`
`

`
`Application No; 121285887
`Attorney Docket Nd: ‘l’l285,.O£i58-0430053
`
`reproductive tract comprising administering intramuscuiariy to a human in need of such
`
`treatment a formulation t:omprising various components. Claims 36, 38, 39, 41, 42, 44,
`
`46, 47', 56, and 57 are identical to claims 24, 26, 2?, 29, 30, 32, 34, 35, 54 and 55
`
`except that the phrase “formulation consisting essentiaiiy of’ replaces the phrase
`
`“formulation eomprising‘ the various components.
`
`1].
`
`Statement of Substance of interview under 37 (:.F-R. § 1.'¥33(b}
`
`Applicants wouid like to thank Examiner San Ming Hal for granting a personal
`
`interview to Appiicants an August 4, 2611. Applicants present this Statement of
`
`Substance of interview in connection with that interview soondueted between Examiner
`
`San Ming Hui, the undersigned, Dr. Patti R. Geilert (AstraZeneca Pharmaceuticals), and
`
`Mr. Ailen F. Gites {Astrazeneea Pharmaceuticals).
`
`During the interview, the undersigned and the Examiner discussed the then
`
`pending claims 24-53 and the disclosures of the toliowing references: a) Hawaii et ai.,
`
`“Pharmaeekineties, Pharmacological, and Anti-mmour Effects of the Specific Anti-
`
`Estregen iCl ’l82?'8C.i in Women with Advanced Breast Cancer,” Brit J. Cancer 74:300-
`
`308 (1996), a) European Patent Appiicatien No. EP 0 346 die, and Meteskey et ai.,
`
`“Tamoxifen-Resistant Fibroblast Growth Factor-Transfected MCF-7 Cells are Cross-
`
`Resistant in Vivo to the Antiestrogen {Cl 182,780 and Two Arornatase inhibitors," Clih.
`
`Cancer Res. 4:69?-Y1 '3 (1998).
`
`At the interview, the undersigned aise mentioned the status of the lawsuit
`
`between Astrazeneca Pharmaceuticals and ‘fairs Parenteral Medicines concerning a
`
`generic: product containing 50 mg/ml of fulvestrant, which was aiso mentioned in the
`
`information Disclosure Statement fiied on June 20 , 201i.
`
`-3-
`
`Astrazeneca Ex. 2141 p. 3
`
`

`
`Applicatinn No; 121285887
`Attorney Docket No; ‘l’i285..O£i58-D0009
`
`No agreement was reached and the Examiner indicated he would consider the
`
`information presented at the interview in the preparation of the next Office Action.
`
`Ill. Double Patenting Rejection
`
`The Office rejected claims 24-53 under the noneiatutory obviousnese-type
`
`double patenting doctrine as being unpatentabie over: (a) oiairns 1-8 of US.
`
`‘atent
`
`No. 6,774,122 (“the *1 22 patent”) and (b) claims 14 2 of LL8. Patent No. 7,456,‘i60 (“the
`
`WEB patent”).
`
`With the sole purpose of expediting prosecution, Applicants submit a Terminal
`
`Disclaimer concurrently with this Response, which shows common ownership of the
`
`instant application and the ‘i22 and ’160 patents and should obviate this rejection.
`
`Aooordingiy, Applicants respestfuiiy request that this retention be withdrawn.
`
`The filing oi‘ the Terminal Disclaimer is not an admission of the aileged
`
`obviousness of the instant siaims in light of the ciaims in the '1 22 and “:60 patents.
`
`See, e.g., M.P.E.P. § 8(}4.02.ii; Quad Environmental Teonnoiogies, Corp. if. Union
`
`Sanitary District, 946 F.2d 870, 874 (Fed. Cir. 1991).
`
`W. Errors in the specification
`
`Applicants wouici like to remind the Office of certain errors appearing in the
`
`instant specification. Applicants mentioned those errors in the Deciaration Under
`
`35 U.S.C §t.132 of Dr. Paul Getiert tited on August20t:18(“the Gellert Declaration"), in
`
`the parent appiication (Appiication No. “i0!8?2,784). Applicants iisted the Geliert
`
`Declaration in an inforrriation Disciosure Statement being filed oonourrentiy with this
`
`Response.
`
`Astrazeneca Ex. 2141 p. 4
`
`

`
`Application No: 121285887
`Attorney Docket No: ‘l’l285r.O£l58-D0009
`
`V. Rejections under 35 U.S.C. 103(3)
`
`The Office rejected claims 2463 under 35 U.S.C. iO3(a} as being unpateniatnie
`
`over it/icLesl<ey et ai,, Clinical Cancel Research 4:89?’-711 (i998) (“Mci_esirey’); in View
`
`of European Patent Specification No. EP 0 346 (314, which names Michael Dukes as
`
`inventor (“Du.i<:es"); Osborne ei all, Journal of National Cancer institute, 87(20}:7’45-750
`
`(i995) (“Osborne"}; and the abstract of Wakeling et al., “lCI ‘l82,?80, J. Steroid
`
`Biochemistry and Mclecuier Biology, -t~3(’l -3):? ?’3-~'i 7? (1992) (“Wakeling”). Office Action
`
`at 5.
`
`According to the Office, McLesl<ey teaches “a etuo[y] employing subcutaneous
`
`injection of fulvestrant to nude mice” and a “fuivestrant formuiaiion containiingfl Sfirngfmi
`
`in a vehicle of 10% ethanci, 15% benzyl benzoate, 10% benzyl alcohol brought to
`
`volume with castor oil." Id. The Office acknowieoges that McLesl<ey does not expressly
`
`teach “the use of tulvesirant in treating hormonal dependent diseases of breast”, “the
`
`dosing regimen in be once a month, intramuscuier administration”, “the volume
`
`administered”, or “the herein claimed serum concentration of fuivestrant." id.
`
`in the Oi‘fice’s view, Dukes teaches that “antiestrogen agent[s], including
`
`fulvestrant, via intramuscular route of administration may he used in a dosage of 50mg
`
`to 59 in vehicle comprising castor oil anti benzyi alcohol.” id. at 5-6.
`
`The Office cites Osborne as teaching that fuivestrani is “useful in treating human
`
`breast cancer" (to. etc) and Walrefing as teaching that “the administration of fullvestrant
`
`(H3! 182789} demonstrat[es} the antiestrogenic effect for over a “l month period.” In’.
`
`According to the Office “[i§t would have been obvious to one of ordinary Sklli in
`
`the art at the time the invention was made to employ fuivesiranl: in [Mctesirsy], in the
`
`-19-
`
`Astrazeneca Ex. 2141 p. 5
`
`

`
`Application No; 121285887
`Attorney Docket No; ‘l’l285i.O£i58-D0009
`
`herein ctaimed dosing regimen and dosage, for treating hormonat dependent diseases
`
`such as breast cancer and postmenopausal symptoms” because it is “known in the art
`
`that fuivestrant can be administered intramusouiarty and its antitumor effect can test for
`
`more than 1 month.” Id.
`
`The Office argues that “{e]rnptoying MoLeskey’.s formutation of tulvestrant for
`
`intrarnusouiar administration woutd be seen as obvious since administering a retative
`
`targe votome of fulvestrant (amt) woutd not be appropriate for subcutaneous
`
`administration.” to. The Cities further argues that “the optimization of resutt effectiivej
`
`earameters (e.g., dosing regimen, weight ratio of the actives and the excipients) is
`
`obvious as being within the stzili of the artisan." id. Applicants respeotfulty traverse this
`
`retention.
`
`A.
`
`Declaration of Dr. Ronald J. Sawchuk
`
`in support of Applicants’ statements regarding the state of the art and how one of
`
`ordinary stall: in the an wouto have unoerstooo the references cited in the Office Action
`
`prior to the earliest priority date for the instant appttsation (January ‘H3, 2000},
`
`Applicants submit concurrently with this Response 3 oeoiaration by Dr. Ronatcl J.
`
`Sawchuk (“Sawotiuk Dsotf’).
`
`B.
`
`The Office has not made the necessary factuai findings to support a
`conclusion of obviousness
`
`Applicants understand that the Offices rejection is based on at toast the ioilowing
`
`two impttctt assumptions: 1) that a person of ordinary skit! in the art ("’PCtSiTA”) would
`
`have chosen the tuivestrant composition disclosed in Mcteskey, from among aii other
`
`known compositions in which fuivestrant has been dissolved, for the devetopment of a
`
`-13-
`
`Astrazeneca Ex. 2141 p. 6
`
`

`
`Application No: 121285887
`Attorney Docket No; it285i.OQ58-D0009
`
`method of treating the diseases recited in the claims, and 2) that the POSETA would
`
`have had a reasonahte expectation that such a composition would have been
`
`successtui in those methods. Applicants respectfully submit that the Office has not
`
`provided support for those assumptions.
`
`Applicants respectfully remind the Office that the focus in an ohviousness
`
`regeotion is not on what one of ordinary skit! in the art couid have done, but rather “on
`
`what a person of ordinary skili in the pertinent art wontd have known at the time of the
`
`invention, and on what such a person wouid have reasonably expected to have been
`
`ebie to do in view of that knowtedge. M.P.E.P. § 2t41.ti (emphasis added}. Thus, two
`
`of the retevant questions in this rejection are: (1) whether the knowledge in the art woutct
`
`have suggested to a PO8iTA that McLesI<ey’s composition had some advantages over
`
`other known toivestrant oomposittons such that it wouid have been seteoted for the
`
`devetoprnent of a method of human treatment, and (2) even assuming that a POSiTA
`
`wouici have selected the tuivestrent M'cLeskey’s composition for the development of a
`
`method of treatment, whether in tight or the knowledge in the art prior to January 10,
`
`2000, one of ordinary skill in the art wouid have expected that the tuivestrant Moteskey
`
`composition cited by the Cttiice woutd have been successful in a method of treating as
`
`recited in the instant ciaims.
`
`Specificalty, regarding the second question, even after i-(SR, an obviousness
`
`rejection in whichthe Citfioe argues that the oieirned invention woutd have been the
`
`result of a combination of references requires that the Qtfice show that one of ordinary
`
`skill in the art would have had a reasonebie expectation of success when combining the
`
`references. M.P.E_P. § 2143.92; see also M. ’.E.P. § 2143.A (addressing the
`
`-12-
`
`Astrazeneca Ex. 2141 p. 7
`
`

`
`Application No; 121285887
`Attorney Docket No; ‘l’l285r.O£i58-D0009
`
`requirements for a “combination of prior art eiernents” rationaie)- As wili be explained
`
`beiow, a crltioai review and analysis of the state of the art at the time the instant
`
`application was filed leads to the conclusion that no such expectation existed.
`
`Applicants wili expiain and discuss beiow the foilowing independent reasons
`
`supporting withdrawal of the instant oiziviousness rejection:
`
`(i)
`
`MeLeske_ir would not have suggested to a POSiT.~'?*~. the specific %w/v composition
`
`recited in the claims;
`
`(2)
`
`None of the cited references woolci have provioeo a PQSITA with information to
`
`select the tots/estrent composition oisoioeeo in Mcteskey over other known
`
`fuivestrant compositions;
`
`(3)
`
`The POSlTA would not have has a reasonable expectation that the Motesiiey
`
`composition wouici have been successfui in such a methoci. Applicants present
`
`two independent arguments to support a lack of expectation of success:
`
`a,
`
`One of ordinary skill in the art wouici have understood that resuits from
`
`subcutaneous administration, such as those in MoLeskey, cannot be
`
`extrapolated to intramuscular administration and, thus, a POSlTA wouicl
`
`not have a had an expectation as to whether the fulvestrant composition
`
`from Mcieskey would have been effective for intrarnusouiar delivery of
`
`fiiivestreni.
`
`b.
`
`Numerous variables affect the efficacy of an intramuscular forrnuiiation,
`
`among them the identity and proportion of each of its oosolvenis, and a
`
`POSITA understands that the resetting variability precludes a POSITA
`
`from having an expectation a priori that a given formulation wouio’ be
`
`-13-
`
`Astrazeneca Ex. 2141 p. 8
`
`

`
`Application No; 121285887
`Attorney Docket No; 1 1285r.OQ58-D0009
`
`successfut in a given method of treatment untii sotuat suitebte in vivo
`
`experiments are performed.
`
`1.
`
`lndegendent Reason 1, McLe.skeg woutd not have suggested
`to a POSITA the sgeoifio %w!v oomgosifion recited in the
`so
`
`Mcteskey ciisotoses two futvestrant compositions. Qne composition was
`
`prepared by oissoiving powdered drug in 180% ethanol and then spiking it into warmed
`
`peanut oi; to give a finet concentration of 50 mgfml (“the Mcteskey peanut oil
`
`composition"). MoLest<ey at 698, col. 2, under “Drugs”; Sawohuk Beet. etfl 16. The
`
`second composition is a 50 mg/mt tuivestrant composition “in s vehioie of t()% ethanoi,
`
`15% oenzyt benzoete, 10% benzyt sicohot, brought to votume with oastor-oil” (“the
`
`MoLeskey caster oit composition”).
`
`Id. The Office only refers to the Mctesatrey Castor oil
`
`composition in the critics Action, Office Action at 5.
`
`MoLeskey does not specify whether the percentages in the Motiesfrey Castor oit
`
`oomoosttion are in weightfvolome units (%w/vi, as recited in the instant otaimsj or in
`
`voiumelvotume units (%x/Iv). Sawchok Beet. at ii 16. Dr. Sswohuk states that “[i}Erz a
`
`tiquid composition, when a solute or oosotvent és a liquid, it is often convenient to
`
`express its concentration as a volume percent, i.e., “fa v/V.” to’. at 1] 17.
`
`Dr. Sawchuk provides various examoies of references in which the oorioentretion
`
`of iiquid components in s oomoosition is reported in terms of ‘ttiviv vetoes, whereas the
`
`oonoentratton of solid solutes is reported in terms of %w/v.
`
`Jo’. at ‘M 18-26.
`
`Dr. Sawchuk ooneiudes that “[b}eoeuse all of the components of the vehiote ctisotosed in
`
`Moteskey are liquids, one of ordinary stciit in the art wouict have oonotuoeo’ that the
`
`-14-
`
`Astrazeneca Ex. 2141 p. 9
`
`

`
`Application No; 121285887
`Attorney Docket No; ‘l’l285.0£l58-D0009
`
`composition was described in terms of volumehrolume percent units (% w'v).” Id. at
`
`13’ 2 t .
`
`Based on that information, Dr. Sawchuk states that “one of ordinary skill in the art
`
`would have concluded that the ll/lcLeskey Castor oil composition on page 698 was
`
`reported in % WV units and referred to a composition containing 30% yjv ethanoi,
`
`15% giv benzyt benzoate, and 10% git: oenzyi alcohol? in a caetor oil vehicle.
`
`to’. at
`
`1f 22. This composition is different from a oomooettion containing 10% ___ily_!v ethanol,
`
`15% _u_v_.’v ‘oenzyl benzoate, and 10% gfv benzyt alcohol in e caetor oil vehicle.
`
`Id. The
`
`units ofthe futvestrant compoeitton recited tn the instant cteirns are %w;‘v.
`
`Dr. Sawohuk converted the %v!~..r values that McLeskey would have suggested to
`
`a POSITA into %wl’v values, which would aliow 3 direct comparison between the
`
`McLeekey castor oil composition and the composition recited in the instant claims.
`
`id.
`
`at Tm 23-27. Table ‘l below shows the results of the oaicuiation, with Coiumn E having
`
`the firlai concentration trainee in ‘lfuwlv units for each component in the McLes1rey caator
`
`oil composition.
`
`Id. atfil 2?.
`
`Table 1.
`
`information for 100 mi of the fulveetrant McLeskey caetor oil composition
`
`Component
`
`% Viv
`
`to Benzyl
`
`Ethanol
`
`Benzoete
`Benzyt
`Amohm
`
`15
`
`ti}
`
`’l,D4‘f5B
`
`According to Dr. Sewchuk, a POSITA “reading McLeakey wouio have concluded
`
`that McI_e3key described a composition containing about 8.1% wit: ethanol, about
`
`-15-
`
`Astrazeneca EX. 2141 p. 10
`
`

`
`Application No; 121285887
`Attorney Docket No: ‘l’l285l.O£l58-D0009
`
`18.4% wlv benzyl eleohol, and about 16.3 “/2 wlv benzyl eenzoate in e eeetor oil
`
`vehicle.” id. at ‘[1 29. Therefore, McLeskey wouici not have suggested the fuiveefrant
`
`composition recited in the cieims comprising about 19% W/V of ethane}; about 10% wfv
`
`of benzyi eicohot; and about 1.5% w/V of benzyi benzoate.
`
`In Dr.8awohul¢’e op-inien, none of the references cited in the Office Action
`
`contain any disclosure “that wouio have suggested to one of ordinary ekiil in the art the
`
`meoifieation of a composition Containing aoout 8.1% wiv ethanol, about 36.8 % w/v
`
`benzyl benzoate, and about 10.4% wiv benzyi alcohol tie, the Mcteskey caster oii
`
`composition) in an attempt to eroduce e comoositien as recited in the claims containing
`
`about 10% wiv ethanol, about 15% w/v benzyi benzoete, and about 16% V/V benzyl
`
`eioohol”.
`
`id. atfii 30.
`
`For et least this reason, the cited references, either aione or in combination, faii
`
`to meet all of the limitations of the ciaime, and Appiloants respectfully request that this
`
`rejection be withdrawn.
`
`.2.
`
`Indegendent Reason 2. The (mice has not shown that a
`POSITA would have selected the MeLeekez caster oil
`com};oeition for the oeveiogment of a method of treating
`involving intramuscular administration as instantly claimed
`
`Applicants remind the Office that “ioibviousneee requires more than a mere
`
`ehowing that the prior art lnciuoee separate references covering eeeh separate
`
`lim,l§8Il{3f‘,i in a claim under examination.” Unigene Laboratories, Inc. v. Apotex, Ina, No.
`
`20104005, eiip op. at ‘I3 (Fed. Cir. Aug. 25, 2011) (intemai citations omitted). Indeed,
`
`the Federei Circuit explained that:
`
`-15-
`
`Astrazeneca EX. 2141 p. 11
`
`

`
`Application No: 121285887
`Attorney Docket No; ‘l’l285i.O£l58-D0009
`
`itiizhviouaness requires the additional showing that a person of ordinary
`sitilt at the time of the invention would have selected and combined these
`
`prior an‘ elements in the normal course of research and deveiooment to
`yieid the claimed invention.
`
`id. (internal citations omitted, itaiics added). Thus, in the instant retention, the Office
`
`needs to identify reasons why a PQSlTA would have: a) selected and then b) combined
`
`the elements the Office argues are disoiosed in the cited references. For exampie, the
`
`Office needs to explain why a POSITA would have selected the it/lcieskey Castor oil
`
`composition (comprising ethanol, benzyi alcohol, and benzyi benzoate), from among the
`
`known tulvestrant formulations at the time of filing, to develop a method of treatment as
`
`instantly ciairned.
`
`Dr. Sawchult exoiains that Mcl_es1<:ey provides no information that would have
`
`suggested to a POSITA the desirability of any of its two tulveatrant compositions over
`
`other known fulvestrant formulations. Sawchuk Deal. at if 31. For exampie,
`
`Dr. Sawohuk points out that antitumor treatment with fulvestrant was ineffective in the
`
`MoLeske3r experiments.
`
`to’. at 1t 33.
`
`in addition, with respect to the two formulations
`
`disclosed in Mcteakey, Dr. Sawchuk highiights that Moteskey “cicl not provide any
`
`experimental data that wouici have ailoweo one of ordinary aititl it the art to compare
`
`any aspect of the performance of the two tuhrestrant compositiors for the treatment of
`
`cancerous tumors." Id. at 1] 31.
`
`Therefore, in Dr. Sawchuhs ooinion, “because of the lack of fuivestrant efficacy
`
`and the absence of pharmacoitinetio data in Mcteskey, one of ordinary sttili in the art
`
`would have been unable to conclude whether either of the two fulvestrant Moieakey
`
`compositions (peanut oii or castor oil} was able to deliver a close of toivestrant that had
`
`-17-
`
`Astrazeneca EX. 2141 p. 12
`
`

`
`Application No; 121285887
`Attorney Docket No; i1285,.O£i58-D0009
`
`an antitumor therapeutic effect in the mice when administered subcutaneously.” id. at
`
`11‘ 35.
`
`in tight of those circumstances, Dr. Sawchuir conctuctee that “McLeskey provides
`
`no information that would have ted one of ordinary sttiil in the art to have a preference
`
`for either the peanut oii or the castor oii fulveetrant compositions over the other one, or
`
`even a preference for one of the two Mcteskey fuiveetrant compositions over other
`
`fuiveetrerrt compositions known in the art prior to January 10, 2000.“ id. at 1] 36.
`
`Regarding fuivestrant compositions known in the art different from the Mr:Lestre_y
`
`Castor oil composition, Dr, Sawchuk iiste various compositions diectosed in the
`
`references cited by the Office.
`
`id. at ‘W 3739. Among those formulations, Dr. Sewchuk
`
`mentions fuiveetrant in an oii suspension (Wakeiing), fulveetrant in a Castor oil
`
`composition (Osborne), ioltrestrent in a mixture of propylene
`
`giycol:ethanot:water:poloxamer 407 (Dukes), and tuhxestrant in 460 mg of benzyi
`
`aioohol and sufficient caster oii to bring the soiution to a volume of 1 mi (Dukes), in
`
`addition to the peanut oil tutveetrant composition from Mr.:Leskey. Sawchuk Decl. at
`
`1! 37-39.
`
`Therefore, Dr. Sawchuit concludes, “one of ordinary skill in the art had other
`
`choices besides the Mcteskey ceetor oii composition with respect to potential
`
`tulvestrent tormutations that could have been further investigated for the cleveiooment of
`
`a method of treating humans with intramuscuter fulveetrant.” Id. atfi 40. However, in
`
`Dr. Sawchok’ opinion, “none of the references cited in the Office Action provides any
`
`information that woutct have guided one of ordinary skit! in the art to select the
`
`Moteekey oaetor oti composition, over any of the other tuiveetrent compositions
`
`-13-
`
`Astrazeneca EX. 2141 p. 13
`
`

`
`Application No; 121285887
`Attorney Docket No; ‘l’l285.0£i58-D0009
`
`mentioned above,” for the potentiai development of a method of treatment as recited in
`
`the instant claims.
`
`id’.
`
`in this regard, the Federal Circuit has explained that:
`
`When afield is unreduced by direction of the prior art, and when prior art
`gives no indication of which parameters were ortticai or no direction as to
`which of many possible choices is likely to be successful, an invention is
`not obvious to try.
`
`Unigene, slip op. at 15 (internal citation omitted).
`
`in this case, the Office has not explained how the cited art directs a PDSlTA to
`
`select the Mrieskey castor oil composition from among all other known fulvestrant
`
`compositions to clevetop a method as claimed.
`
`indeed, according to Dr. Sawchutt,
`
`“none of the references cited by the Examiner provides any guidance as to the retevant
`
`factors to consider when selecting a formulation for the potential development of a
`
`method of treatment as recited in the instant claims.” Sawchuk Deal. at ‘ll 41.
`
`Nonetheless, in Dr. Sewchuke opinion, and imaging soiely on the basis of
`
`efficacy, “the McLeskey Castor oil composition would have been among the least
`
`favored compositions to select for further oevetoprnent from among the tuivestrant
`
`compositions discussed above because one of ordinary skit! in the art woutcl not nave
`
`been able to conclude from the information in McLeskey whether fulveetrant, using that
`
`cornposttion, was sutticientiy bioavaiiabte to have an antitumor effect.” Id. Rather,
`
`according to Dr. Sawchuk and based on only efficacy, “the tulvestrant oil suspension
`
`from Wakeling would have been among the most favored formutattons to select for
`
`further development from among those discussed above because at least that
`
`_-go-
`
`Astrazeneca EX. 2141 p. 14
`
`

`
`Application No: 121285887
`Attorney Docket No; ‘l’l285.0£l58-043009
`
`formulation, when given as 3 single iniection, showeci a therapeutic entitumor effect in
`
`mice for over a one-month perioci.” Id.
`
`Accordingly, at least because the Office has fsiied to expisin why a POSITA
`
`would have seiecteo the Mcieskey caster oii composition from among those fulveslrant
`
`compositions known in the art at the time of fiiing to develop e method of treatment as
`
`claimed, the Qffice has not made 3 crime tecie case of obviousness. Thus, Appiicsnts
`
`respectfoily request that this rejection be withdrawn.
`
`3.
`
`One of ordinagg skill in the art would not have had an
`exgectetion that the formulation disclosed in McLeskey_',
`administered subcutaneously to mice, wouid have been
`successfui for intramuscular administration as instantly
`recited
`
`The POSITA would not have had a reasonable expectation that the McLes1<ey
`
`cestor oil composition would have been effective to administer fulvestrant
`
`intrarnuscuieriy to achieve a therapeutic effect for at iesst four weeks, as instantly
`
`recited. Two independent reasons are set forth below supporting a lack of expectation
`
`of success for the combination of the references cited by the Office.
`
`a)
`
`mdegendeni Reason 3. A POSITA would not have had
`an exgctation that the resuits from subcutaneous
`injection in Mcieskeg would have been agglicabie to the
`intramuscular administration of fuivestrant
`
`One of ordinary sitili in the art wouid have understood that resoits from
`
`subcutaneous administration, such as those reported in M‘ci_eskey, cannot be
`
`extrapolated to iniiramoscuier administration. Sewchuk: Deci. at ‘ll 42.
`
`in Dr. Sswcholfs
`
`view, “one of ordinary skili in the en: would not have had an expectation as to whether
`
`the Mcieskey caster oil composition would have had e therapeutic effect when
`
`-29-
`
`Astrazeneca EX. 2141 p. 15
`
`

`
`Application No: 121285887
`Attorney Docket No; ‘l’l285..O£i58-D0009
`
`administered intramusoulany before actuaily performing soitabie in vivo experiments.”
`
`Id.
`
`Dr. Sswchuk cites a few exarnpies in which comparison of the resuits from
`
`subcutaneous administration yielded significant differences with respect to those from
`
`intramuscular administration. For examoie, a study of administration of probenecid in
`
`ewes showed that administration of the same dose of probenecid, a drug which may be
`
`used to oroiong the hair-life of eorne antibiotics in anirneis. resulted in significant
`
`differences in absorption and bioavaiisbiiity of the drug when administered
`
`suboutaneousily or intrernuscuiariy. Guerrini V.H., Fiiipoicn i_.J., English P.B., Schneider
`
`J., Can 6. end Bourne D.W.A., “Pharmaookinetics of orooeneoid in sheep”, J Vet
`
`Phsrmaoo Their. 8(2):'l28~35 (i985) {“Guerri'm‘”}; Siawchuk Desi. at 11 44.
`
`Sr. Sawchuk comments that in Guerrini the intramuscular dose was absorbed
`
`more rapidly and more oompietely than the subcutaneous dose, whereas the
`
`subcutaneous administration resulted in 3 “higher and more proionged piesrns
`
`orobenecid concentration”. Sawcnuk Desi. at 1} 43. Due to the overail characteristics
`
`associated with subcutaneous administration, Guerrini reports that such a mode of
`
`administration is preferred over intramuscuiar administration under the conditions of its
`
`study.
`
`In. at 46. Dr. Sewsnuk concludes that “this is an example where subcutaneous
`
`administration achieves a certain desires’ resuir out where intramuscular administration
`
`does not acoomoiish the same resuir." id. (italics added}.
`
`in contrast to the phannacokinetic profiles observed in Guerrini, in another study,
`
`subcutaneous administration of olindsrnyoin, an antibiotic, resulted in faster absorption
`
`compared to intrarnuscuisr injection.
`
`I avy ‘j ?iv G, Shem-Tov M, Giiekman A, Dey A,
`
`-23-
`
`Astrazeneca EX. 2141 p. 16
`
`

`
`Applicatien Ne: 121285887
`Attorney Docket No; ‘l1285r.OQ58-D0009
`
`“Phannaeekinetice at clindamyetn HG: administered intraveneualy, intramuecularly and
`
`subcutaneously to tinge”, J Vet Pharmacet Thar. 22(4):26'l—5 (1999) (“Levy”); Sawehuk
`
`Decl. at 1[ 47. Nevertheless, the pharmacekinetic profiles in Levy were such that
`
`subcutaneous administration maintained a therapeutic piaama concentration for a
`
`icnger period of time than intramuscular administration. Sawchuk Deci. at ‘ll 49, Based
`
`can the reautte from Levy, Dr. Sawchuk concludes that in that case, “cone of ordinary atriii
`
`in the art wnulci net have been ante tn refy an date from subcutaneous administration tn
`
`predict results of intramuscutar administration because intramuacuiar administration
`
`wouici not have prcelucecl the same ievei of fang-term efficacy achieved by
`
`subcutaneous administration.” Id‘. {itaiice added).
`
`in yet another study highiighting the lack at ccrretation between subcutaneous
`
`and intramuacutar administration, Dr. Sawchuh gives an exarnpie where, in contrast to
`
`the results from Levy, the absorption of the drug was mere rapid and complete feliewtng
`
`intrarnuacniar dosing than after subcutaneous injection. {email M, “Disposition kinetics
`
`of diftcsxacin after intravenous, intramuscular and subcutaneous administration in
`
`calves”, Vet Res t3arnmun., 31 (4):46T—76 (2037) Wamaii”); Sawchuk Deni. at fl 50.
`
`Dr. Sawchuk states that for the purposes in ismaif, the intramuaputar adrnintstratien was
`
`preferred to subcutaneous administration. Sawchuk Deni. at ‘H 52. Dr. Sawchuk
`
`explains that “tan this case, centrary tn the two examptes abcve, the intramuecutar
`
`administration was considered to be associated with greater clinical efficacy." id.
`
`Dr, Sawchuk summarizes that “ltlhese three examples ahpve show that there are
`
`significant differences in the rate and extent of absorption of a drug given by the
`
`intramuscular and subcutaneous route, even when given to the same animals in a
`
`-22-
`
`Astrazeneca EX. 2141 p. 17
`
`

`
`Application No; 121285887
`Attorney Docket No; ‘l’l285.0£i58-D0009
`
`crossover study.” Id. at Ti 53. Dr. Sawohuk ooneiudee that “ieie a result, it cannot be
`
`predicted a oriori whether intramuscular or subcutaneous dosing wiil result in more rapid
`
`and/or oompieie drug absorption, as examples of both cases are found in the scientific
`
`iitereture.“ Id. Dr. Sawchuia further explains that the exemoiee above “underscore the
`
`feet that efficacy of a given drug administered by a given route of dosing {e.g.,
`
`intramusouiar) cannot be known until appropriate comparative studies are izaerformeol in
`
`a suitetsie animal model.” Id. at ii 54 (emphasis added). Dr. Sewohuk indicates that
`
`“[t]or some ciruge, the desired effect might be eohieveo foiiowing a particular route of
`
`dosing, but for other drugs it might not," which underiies the ieok of expectation that
`
`results from subcutaneous administration oouid be indioetive of results obtained from
`
`intramuscular administration.
`
`to‘.
`
`With respect to the specific results from McLes.l<ey, Dr. Sewohuk conoiuoes that
`
`“one of ordinary eizili in the art having the very limitedlexpenmeritai subcutaneous data
`
`from Mcteskey would not have had an expectation that the intramuscular administration
`
`of tulueetrent using the Mzieekey Castor oil composition wouid heve been effective
`
`toilowing intramuscular administration, such as in the method described in the claims."
`
`lo’. at ii 55.
`
`For at leaet this additional reason, the irietant cieirns arenot obvious in light of
`
`the cited references and Applicants respeoituliy request that this reieotlon be withdrawn.
`
`-23-
`
`Astrazeneca EX. 2141 p. 18
`
`

`
`Application No; 121285887
`Attorney Docket No; ‘l’l285.0Q58-D0009
`
`b}
`
`lndegendent Reason 4. Numerous variables affect the
`
`effioaci of an intramuscular formulation e.
`. . icientlt
`
`and Qrogorfion of oosolvents} and a PGSETA would have
`understood that the resulting variability greoludee a
`POSITA from having an exg

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