throbber
IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Attorney Docket No. 112850056-00000
`
`PATENT
`
`In re Application of:
`
`John R. Evans et al.
`
`Application No.: 12I285,887
`
`Filed: October 15, 2008
`
`For:
`
`FORMULATION
`
`Commissioner for Patents
`P.O. Box 1450
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`Alexandria, VA 22313-1450
`
`Sir:
`
`-«._r--_.J-_a-..a-_.r--.r-_r-._.rs_.a
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`Group Art Unit: 1628
`
`Examiner: HUI, San Ming R.
`
`C
`
`onfirmation No.2 1199
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`VIA EFS-WEB
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`DECLARATION UNDER 37 C.F.R.
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`1.132 OF RONALD J. SAWCHUK
`
`I, Ronald J. Sawchuk, declare as follows:
`
`Qualifications
`
`1.
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`My academic background and work experience are summarized in my
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`curriculum vitae, which is attached as Exhibit 1.
`
`2.
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`Currently, I am a Professor of Pharmaceutics, Emeritus, and Morse
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`Alumni Distinguished Teaching Professor.
`
`I am also the Director of the Bioanalytic and
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`Pharmacokinetic Services Laboratory at the University of Minnesota.
`
`3.
`
`I obtained a Bachelor of Science Degree in Pharmacy in 1963 from the
`
`University of Toronto.
`
`I also received a Masters of Science Degree in Pharmaceutics
`
`from the University of Toronto in 1966 and completed a Doctoral Degree (Ph. D.) in
`
`Pharmaceutical Chemistry (pharmacokinetics emphasis) at the University of California,
`
`San Francisco in 1972.
`
`Astrazeneca Ex. 2138 p. 1
`Mylan Pharms. Inc. V. AstraZeneca AB IPR2016-01324
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`

`
`Application No.: 12I285,887
`Attorney Docket No.: 1128513056-00000
`
`4.
`
`ljoined the University of Minnesota in 1971 as an Instructor in
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`Pharmaceutics, and served from 1972 to 1977 as an Assistant Professor of
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`Pharmaceutics, from 1977 to 1983 as an Associate Professor of Pharmaceutics, and as
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`a full Professor of Pharmaceutics from 1983 until my retirement in July of 2010.
`
`5.
`
`At the University of Minnesota, I sewed as a member of the graduate
`
`programs in Pharmaceutics, Neurosciences, and Experimental and Clinical
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`Pharmacology. From 1983 to 1989 and 1991 to 1994 I was the Director of Graduate
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`Studies in Pharmaceutics at the University. From 1998 to 1999 I served as the Head of
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`the Department of Pharmaceutics at the University of Minnesota.
`
`6.
`
`Also, from 1982 to 1995, I served as Director of the Clinical
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`Pharmacokinetics Laboratory at the College of Pharmacy at the University of
`
`Minnesota.
`
`7.
`
`During my career, I received several honors, scholarships and awards,
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`including the Weaver Medal of Honor in 2001, the Meritorious Manuscript Award from
`
`the American Association of Pharmaceutical Scientists in 1999 and the Hallie Bruce
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`Memorial Lecture Award in 1996.
`
`In 2007, I received the American Pharmacists
`
`Association (APhA) Research Achievement Award in the Basic Pharmaceutical
`
`Sciences.
`
`8.
`
`I am a member of numerous scientific and clinical societies.
`
`I am a Fellow
`
`of the American Association of Pharmaceutical Scientists and of the American
`
`Association for the Advancement of Science.
`
`I have been a member of the International
`
`Society of Anti—infective Pharmacology and the International Society for the Study of
`
`Astrazeneca Ex. 2138 p. 2
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`

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`Application No.: 12l285,887
`Attorney Docket No.: 112850056-00000
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`Xenobiotics (ISSX).
`
`I recently served as a member-at-large on the American
`
`Association of Pharmaceutical Scientists (AAPS) Executive Council.
`
`9.
`
`I have sewed on the editorial boards of scientific journals such as the
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`Journal of Pharmaceutical Sciences and the Saudi Pharmaceutical Journal.
`
`I am
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`currently on the Editorial Board of the AAPS Journal, and on the ISSX Journal,
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`Xenobiotica.
`
`I have also served on numerous advisory committees and review panels,
`
`10.
`
`I have participated in multiple research projects focused in the areas of
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`preclinical and clinical pharrnacokinetics, both publicly and privately funded. I am a
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`named author on over 100 refereed scientific publications, in addition to several book
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`chapters, a book that I co-edited on drug bioavailability, and over 170 abstracts which
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`have been presented at scientific meetings.
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`I have also given hundreds of invited
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`lectu res.
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`11.
`
`I have significant experience in the areas of pharmaceutical research,
`
`pharmacokinetics, and drug development. Therefore, I believe that I am qualified to
`
`render the opinions set forth in this declaration.
`
`12.
`
`I have read the Office Action dated September 16, 2011 (“Office Action”),
`
`which is attached as Exhibit 2. Among other rejections, I understand that the Office
`
`Action rejects the claims pending in the captioned application as unpatentable over the
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`following references:
`
`a.
`
`lv1cLeskey et al., “Tamoxifen-resistant fibroblast growth factor-transfected
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`MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI 182,780 and
`
`Astrazeneca Ex. 2138 p. 3
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`

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`Application No.: 121285887
`Attorney Docket No.: 112850056-00000
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`two aromatase inhibitors”, Clinical Cancel Research 4:697-711 (1998)
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`(“McLeskey’, attached hereto as Exhibit 3);
`
`b.
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`European Patent Specification No. EP 0 346 014, which names Michael
`
`Dukes as inventor (“Dukes”, attached hereto as Exhibit 4);
`
`c.
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`Osborne et aI., "Comparison of the effects of a pure steroidal antiestrogen
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`with those of tamoxifen in a model of human breast cancer", J. National
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`Cancer Institute, 87(20):746-750 (1995) (“Osborne”, attached hereto as
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`Exhibit 5); and
`
`d.
`
`the abstract of Wakeling et aI., “|Cl 182,780, a new antioestrogen with
`
`clinical potential", J. Steroid Biochemistry & Molecular Biology, 43(1-
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`3):1‘/3-177' (1992) (“Wakeli'ng", attached hereto as Exhibit 6);
`
`13.
`
`I have read the instant application (“the '88? application“), which I believe
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`corresponds to U.S. Application Publication No. US 201 0l0152149 (attached hereto as
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`Exhibit 7.)
`
`14.
`
`I attach hereto Exhibit 8, which I believe is a copy of the pending claims in
`
`the '88? application with proposed amendments.
`
`I understand the claims in Exhibit 8
`
`will be filed in the Patent and Trademark Office as part of the response to the Office
`
`Action.
`
`15.
`
`I understand that the earliest priority date for the ‘B87 application is
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`January 10, 2000.
`
`In the paragraphs below, I will refer to the state of the art in the
`
`areas of pharmaceutical research, pharmacokinetics, and drug development prior to
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`January 10, 2000.
`
`I will also explain how a person of ordinary skill in that art at that time
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`Astrazeneca Ex. 2138 p. 4
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`

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`Application No.: 121285.887
`Attorney Docket No.: 112850056-00000
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`would have understood the references cited in the Office Action and how such a person
`
`would have interpreted certain experimental results related to various fulvestrant
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`formulations.
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`Disclosure in McLeskey regarding the castor oil fulvestrant composition
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`16. Mcteskey discloses two fulvestrant compositions. One composition was
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`prepared by dissolving powdered drug in 100% ethanol and then spiking it into warmed
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`peanut oil to give a final concentration of 50 mg/ml (“the McLeskey peanut oil
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`composition"). MCLe.skey at 698, col. 2, under “Drugs”. The second composition is a
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`50 mg/ml fulvestrant composition “in a vehicle of 10% ethanol, 15% l:-enzyl benzoate,
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`10% benzyl alcohol, brought to volume with castor oil” (“the Mcl_eskey castor oil
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`composition”).
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`la‘. McLeskey does not specify whether the percentages in the castor oil
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`composition are in weightlvolume units (% wlv, as recited in the claims of the ’887
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`application) or in volume/volume units (% WV).
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`17.
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`In a liquid composition, when a solute or cosolvent is a liquid, it is often
`
`convenient to express its concentration as a volume percent, i.e., % vfv. For the
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`reasons that follow, I believe one of ordinary skill in the art would have concluded the
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`ll/lcl_eskey castor oil composition was described in volumelvolume units (% WV).
`
`18.
`
`For example, U.S. Patent No. 3,164,520 (“the '520 patent", attached as
`
`Exhibit 9) entitled “lnjectable Steroid Compositions Containing at least 75% Benzyl
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`Benzoate” discloses the preparation of parenteral injections of steroid drugs in
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`formulations containing benzyl benzoate, and often also containing Castor oil or sesame
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`oil. See, e.g., the working examples. The ’520 patent states: “The amount of benzyl
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`Astrazeneca Ex. 2138 p. 5
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`

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`Application No.: 121285.887
`Attorney Docket No.: 112850056-00000
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`benzoate which may be employed in the compositions of this invention while still
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`yielding satisfactory results has been found to range from about 75% to 100% by
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`volume of the pharmaceutical vehicle employed.” The ’520 patent at col. 2, II. 10-14.
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`In
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`addition, each of the four claims of the 520 patent refers to a parenteral steroid
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`formulation in a pharmaceutical vehicle or pharmaceutical carrier wherein at least 75%
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`by volume of said vehicle is benzyl benzoate.
`
`19.
`
`Raymond Huber, the named inventor of the '520 patent, is a co-author of a
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`similar publication in which parenteral formulations of steroid hormones in castor oil are
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`described. Riffkin, C., Huber, R., and Keysser, C.H., “Castor oil as a vehicle for
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`parenteral administration of steroid hormones“, J Pharm Sci, 53(8): 891 -95 (1964)
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`(“Riffkfn", attached as Exhibit 10). Riffkin lists the compositions of various vehicles
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`prepared in Tables IV to VI, which reference liquid components and their proportions in
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`the overall composition in terms of percentage units (“‘%"). Although Rfffkin does not
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`specifically state that those compositions are % vlv. one would understand them to be
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`% v/v because Riffkin refers to the concentrations of the solid solutes (the steroids) in
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`terms of w/V, (e.g., mg./ml_), whereas the concentrations of the liquid components are
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`simply reported in terms of “%” units. See, e.g., Tables V and VI. One would
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`reasonably assume that, had Riffkin intended the concentration of the liquid
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`components to be in terms of % wlv units, Riffkin would have explicitly indicated that
`
`fact, as it did for the solid components. Footnote 4 is another example of the use of the
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`above nomenclature. Footnote 4 refers to the concentration of estradiol valerate in the
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`injectable formulations, in terms of “mg./ml.“, but refers to a “%" value for the liquids-
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`Astrazeneca Ex. 2138 p. 6
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`

`
`Application No.: 12l285,887
`Attorney Docket No.: 1128510056-00000
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`castor oil, benzyl benzoate, and benzyl alcohol. Therefore, one would conclude that the
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`composition of the solvents in Riffkin’s vehicles is expressed as % viv.
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`20.
`
`Other publications also describe the composition of injectable formulations
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`comprising liquid solvents or co—solvents on a “by volume” basis. For example, a
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`published review tabulates various excipients included in the formulation of injectable
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`products marketed in the Unites States. Neema, S, Washkuhn, R.J., and Brendel, R.J.,
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`“Excipients and their use in injectable products", PDA J Pharm Sci’ Tech, 51 (4):‘l66-171
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`(1997)(“Neema”, attached as Exhibit 11). Neema lists liquid solvents, co-solvents, and
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`solubilizing agents, and identifies commercial products in which the content of such
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`liquid agents is described on a % vlv basis (e.g., benzyl benzoate, 20% v/v; PEG 40
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`castor oil, 11.5% vfv; sorbitol, 50% v/v). See, e.g., Tables I and II.
`
`21.
`
`Considering the above examples, and because all of the components of
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`the vehicle disclosed in Mcl_eskey are liquids, one of ordinary skill in the art would have
`
`concluded that the composition was described in terms of volumelvolume percent units
`
`(% WV).
`
`22.
`
`Therefore, one of ordinary skill in the art would have concluded that the
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`ll/lcLeskey castor oil composition on page 698 was reported in % vlv units and referred
`
`to a composition containing 10% glv ethanol, 15% 31v benzyl benzoate, and 10% 3/v
`
`benzyl alcohol in a castor oil vehicle. This composition is differentfrom a composition
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`containing 10% wlv ethanol, 15% ylv benzyl benzoate, and 10% gr/v benzyl alcohol in
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`a Castor oil vehicle.
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`Astrazeneca Ex. 2138 p. 7
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`

`
`Appiiceiion No; 12128538?
`Attorney Docket No; 1128533356-80800
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`23.
`
`it is possible to convert % WV values for a given component in a liquid
`
`composition into % W/V vaiues by calculating the weight of the corresponding volu me of
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`that component in the composition. As a first approximation, the weight of tie
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`component can be caicuieteci by multipiying the volume of the component by its density.
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`24.
`
`in order to facilitate this calculation, l assumed the preparatien of 100 ml
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`of the ii/l‘cLesi<ey caetor oil cempesition and reported the associated volume and weight
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`trainee in Table ‘i heiow, using densiiies reported or calculated at 25°C.. The reeuitiog ‘ii;
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`wlv vetoes are independent of the choice of a particular voiume of the McI_eel<ey castor
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`oil composition for this oelcuiation. However, at voiume of 100 ml of the easier oil
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`composition was selected for simpiicity to Show the corresponding volumes and
`
`weights. The differences between % WV and % wlv compositions for each of the three
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`components can be seen by comparing the values in Columns A and E.
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`it shooid be
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`mated that although these rzompositiens are identical, they are described differently; in
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`Column A, the composition is described on a percentage “by volume“ {% V/V} basis, and
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`in Column E, the composition is described on a percentage “by weight” (“/9 wiv) basis.
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`Astrazeneca Ex. 2138 p. 8
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`

`
`Application No.: 121285138‘/’
`Attorney Docket No.: 112850056-00000
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`Table 1. Information for 100 ml of the fulvestrant McLeskey castor oil composition‘
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`Component
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`Ethanol
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`1 D4156
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`Benzyl
`Benzoate
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`Benzyl
`Alcohol
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`25.
`
`In Table 1, Column A represents the concentration of each component in
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`the ll/lcLeskey castor oil composition in ‘/u 1/v units (i.e., as one of ordinary skill in the art
`
`in would have understood the Mcl_eskey disclosure). Column B represents the volume
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`in milliliters (ml) of each component necessary to prepare 100 ml of the McLeskey
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`Castor oil composition.
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`26.
`
`Column C represents the density of each component in g/ml at 25°C,
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`reported or calculated from published relative density data from the Merck Index,
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`Exhibit 12. The Merck Index reports specific gravity values for liquid substances as the
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`ratio of the density of the substance at a given temperature relative to the density of
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`water at a reference temperature. Exhibit 12 at p. xiv (entry for “d"). Regarding the
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`benzyl benzoate and benzyl alcohol values, their densities were reported at 25°C and
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`1 Mcl_eskey does not indicate whether the ethanol used in its castor oil fulvestrant
`composition is dehydrated ethanol or the binary azeotropic ethanol composition
`containing about 96% ethanol by volume (see entry no. 3806 for ethanol in the Merck
`Index, 12th Ed., Merck 8; Co., Inc. (1996) at pp. 641-642 (“the Merck Index", relevant
`copies attached as Exhibit 8)). The value in Table 1 for the density of ethanol
`corresponds to the density of the azeotropic ethanol composition. The density of
`dehydrated ethanol is 0.789 mg/ml at 20°C (Exhibit 8), which would produce an even
`lower w/v% value for ethanol than that reported in Table 1.
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`Astrazeneca Ex. 2138 p. 9
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`

`
`Application No.: 121285887
`Attorney Docket No.: 112850056-00000
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`the density of water was reported at 4°C (Exhibit 12 at entries no. 1159, 1162;
`
`pp. 189-190). Because the density of water at 398°C is 1.0000 g/ml (Exhibit 12 at
`
`entry 10175; p. 1715), the values reported in the Merck Index for benzyl benzoate and
`
`benzyl alcohol were used in Table 1 as the corresponding densities in mgiml
`
`(considering that 398°C is 4°C for purposes of this calculation). For ethanol, the Merck
`
`Index reports a specific gravity of 0.810 at 25°C with respect to the density of water at
`
`25°C (Exhibit 12 at entry no. 3806; p. 642). Thus, to obtain the density of ethanol (the
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`binary azeotrope) at 25°C, I multiplied the density of water at 25°C, 0.997 mgfml
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`(Exhibit 12 at entry no. 10175; p. 1715), by the specific gravity reported in the Merck
`
`Index (0.810) to produce a value of 0.808 mglml for the density of ethanol at 25°C.
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`27.
`
`Column D represents the weight of each component, obtained by
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`multiplying the volume of each component (Column B) by its density (Column C).
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`Column E represents the concentration of each component in the McLeskey castor oil
`
`composition in wlv% units. which is the weight of each component (Column D) in 100 ml
`
`of solution (the total volume of the composition) after rounding the value to a single
`
`decimal place.
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`28.
`
`Accordingly, based on the values in Table 1, a composition containing
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`10% vfv ethanol, 15% v/v benzyl benzoate, and 10% vfv benzyl alcohol translates into a
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`composition containing about 8.1% w/v ethanol, about 16.8 % w/v benzyl benzoate, and
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`about 10.4% w/v benzyl alcohol.
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`29.
`
`Thus, one of ordinary skill in the art reading ll/lcl_eskey would have
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`concluded that Mcl_eskey described a composition containing about 8.1% w/v ethanol,
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`-10-
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`AstraZeneca Ex. 2138 p. 10
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`

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`Application No.: 12l285,887
`Attorney Docket No.: 112850056-00000
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`about 15.8 % w/v benzyl benzoate, and about 10.4% w/v benzyl alcohol in a castor oil
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`vehicle.
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`30.
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`Neither Mcl_eskey nor any of the references cited in the Office Action
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`contain any disclosure that would have suggested to one of ordinary skill in the art the
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`modification of a composition containing about 3.1% wfv ethanol, about 16.8 % w/v
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`benzyl benzoate, and about 10.4% w/v benzyl alcohol (i.e., the McLeskey castor oil
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`composition) in an attempt to produce a composition as recited in the claims containing
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`about 10% wlv ethanol, about 15% w/v benzyl benzoate, and about 10% w/v benzyl
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`alcohol.
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`Disclosure in McLeskey regarding administration of fulvestrant compositions
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`31.
`
`As mentioned above, Mcteskey disclosed two different fulvestrant
`
`compositions, the peanut oil composition and the castor oil composition. McLeskey at
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`698. Mcl_esl<ey, however, did not provide any experimental data that would have
`
`allowed one of ordinary skill in the art to compare any aspect of the performance of the
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`two fulvestrant compositions for the treatment of cancerous tumors. Therefore,
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`Mcl_esltey provided no information that would have suggested to one of ordinary skill in
`
`the art the desirability of either of its fulvestrant compositions over other known
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`fulvestrant formulations.
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`32. McLeskey did not disclose plasma or blood levels of fulvestrant in mice
`
`after subcutaneous administration of either the peanut oil or the castor oil compositions.
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`Thus, no information regarding the rate and/or extent of absorption of fulvestrant from
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`-11-
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`AstraZeneca Ex. 2138 p. 11
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`

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`Appiicetion No; 121285.88?’
`Attorney Docket No; 11285.0G56-80800
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`the subcutaneous injection site is available to one of ordinary ekiii in the art for either
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`composition.
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`33. Moteekey oonciuded that treatment with tuivestrent (10! 182,780}, using
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`either of the disclosed compositions was not effective in that it “did not slow estrogen-
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`iridependent growth or prevent metastasis of tumors produced by FGF—trenstet:ted
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`MCF-7 oeile in overiectornizsd nuoe mice.” ii/IcLeei<ey at Abstract. Thee. one of
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`zorciinary skit! in the art wouid not have been informed aboutthe usefulness of either
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`tuiveetrent formuietioh when administered eubcuteneoueiy to a mouse for the treatment
`
`of cancerous tumors.
`
`34.
`
`McI_es!re_y also reports that fulvestrerit “retained activity" based on the
`
`reeuite from injecting tulvestrent into “repro»:iur:tiveiy intact ternaie mice for two
`
`weeks .
`
`.
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`. at theeerne doses need in the above experiment” and the uteri subsequeniiy
`
`harvested from those mice “weighed ieee than those from control mice and exhibited a
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`cornpieie tack of endornetriei giariduiar structures (data not shown)? Id. at ‘[1 bridging
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`7D’i—?’02. Liotortimeteiy, Mcieskey does not specify which of the two fuivestrant
`
`forrhuiations, if any, (the peanut oii oernpoeition or the Castor oii composition), was used
`
`in these experiments. Mc!_ee!<ey does not disclose the route of administration
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`(subcutaneous, intremueeutar, intreperitoneei, etc.) for the injection of fuhreetrent into
`
`those “reprodeotively intact femate mice." Thus, one of ordinary skit! in the art reading
`
`McLes!«tey cannot draw any conciueione regarding the extent to which fuivestrant
`
`administered subcutaneously beoerne absorbed, if at ail. when using the peanut oil or
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`the easier on compositions.
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`-12-
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`Astrazeneca EX. 2138 p. 12
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`

`
`Application No.: 12l285,887
`Attorney Docket No.: 112850056-00000
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`35.
`
`Indeed, because of the lack of fulvestrant efficacy and the absence of
`
`pharmacokinetic data in Mcl_eskey, one of ordinary skill in the art would have been
`
`unable to conclude whether either of the two fulvestrant McLeskey compositions
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`(peanut oil or castor oil) was able to deliver a dose of fulvestrant that had an antitumor
`
`therapeutic effect in the mice when administered subcutaneously, nor any insight about
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`fulvestrant absorption characteristics (rate and extent) when administered via the
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`intramuscular route in any species, including humans.
`
`36.
`
`Thus, Mcl_eskey provides no information that would have led one of
`
`ordinary skill in the art to have a preference for either the peanut oil or the castor oil
`
`fulvestrant compositions over the other one, or even a preference for one of the two
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`McLeskey fulvestrant compositions over other fulvestrant compositions known in the art
`
`prior to January 10, 2000.
`
`37. While I have not performed a search for fulvestrant compositions known in
`
`the art prior to January 10, 2000, I note that some of the references cited by the
`
`Examiner in the Office Action do disclose other fulvestrant compositions. For example,
`
`Osborne discloses experiments in which a composition of fulvestrant “in Castor oil" was
`
`injected subcutaneously to female nude mice. Osborne (Exhibit 5) at 747, col. 1.
`
`Based on the positive results of those experiments, Osborne concludes that fulvestrant
`
`“is a more effective estrogen antagonist than tamoxifen in the MCF-7 tumor cell/nude
`
`mouse model system.’ Osborne at Abstract.
`
`38.
`
`The fulvestrant composition in Wakeling is described as having fulvestranl
`
`“in oil suspension" for parenteral administration to mice. Wakeling (Exhibit 6) at
`
`-13-
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`AstraZeneca Ex. 2138 p. 13
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`

`
`Application No.: 121285.887
`Attorney Docket No.: 112850056-00000
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`Abstract. Wakeling reports that, “over a 1 month period, a single injection of
`
`[fulvestrantl in oil suspension achieved effects comparable with those of daily tamoxifen
`
`treatment." Id.
`
`39.
`
`Dukes discloses two different fulvestrant compositions for intramuscular
`
`injection, one containing fulvestrant dissolved "in a mixture of propylene glycol: ethanol:
`
`water: poloxamer 407" administered daily by intramuscular injection to rats. Dukes
`
`(Exhibit 4) at Example 2, p. 8. The second composition contained 50 mg of fulvestrant,
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`"400 mg of benzyl alcohol and sufficient castor oil to bring the solution to a volume of 1
`
`ml.” id. at Example 3, p. 9. For each composition, Dukes reports that “at all doses
`
`tested the compound [fulvestrant] selectively inhibits the action of the animals’
`
`endogenous oestrogen on their uteri." id. at Examples 2 & 3, pp. 8-9.
`
`40.
`
`Thus, it is clear that one of ordinary skill in the art had other choices
`
`besides the McLeskey Castor oil composition with respect to potential fulvestrant
`
`formulations that could have been further investigated for the development of a method
`
`of treating humans with intramuscular fulvestrant. However, none of the references
`
`cited in the Office Action provides any information that would have guided one of
`
`ordinary skill in the art to select the ll/lcteskey castor oil composition, over any of the
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`other fulvestrant compositions mentioned above, for the potential development of such
`
`a method of treatment.
`
`41. Moreover, none of the references cited by the Examiner provides any
`
`guidance as to the relevant factors to consider when selecting a formulation for the
`
`potential development of a method of treatment as recited in the instant claims.
`
`-14-
`
`AstraZeneca Ex. 2138 p. 14
`
`

`
`Appiicetlon No; 12128538?
`Attorney Docket No; 1128533356-80800
`
`However, judging soiely on the basis of efficacy, the Mates-key Castor oil composition
`
`wouio have been among the least favored compositions to select for further
`
`development from the fulveetrant compositions discussed above because the McLesi«:ey
`
`experiments were ineffective and one of ordinary skill in the art wouiol not have been
`
`able to conclude from the information in McLes.ltey whether fulvestrant, using that
`
`composition, wee sufficiently bioeveiieble to have an entitumor effect.
`
`In this regard,
`
`and considering only efficacy, the fuivestrant oil suspension from Wskeiing would have
`
`been among the most favored formulations to select for further development from
`
`among those discussed above because at least that formulation, when given as a singie
`
`injection, showed a therapeutic antitumor effect in mice for over a one—month period.
`
`Lack of cliseiosure in McLeskey regarding intramuscular efficacy of either
`
`fuiveetrant composition cliscloeed therein
`
`42.
`
`The mode of administration of a {true (e.g., oral, intramuscular,
`
`subcutaneous, etc.) and the dose administered effects the reieese profile of the drug.
`
`fine of ordinary skill in the art would have understood that resuits from subcutaneous
`
`administration in general, and inclocling those reporteo in MoLesl»:ey, oennot be
`
`extrapolated to intramuscular eciminietration. As e result one of ordinary ekiil in the en
`
`wouio not have heel an expectation as to whether the Mcieskey oeetor oil composition
`
`would have had a therapeutic effect when administered intremoeoulsrly before actually
`
`performing suitable in vivo experiments.
`
`43.
`
`There is abundant evidence in the scientific literature that the
`
`intramuscular and subcutaneous administration of a drug to the same animal or human
`
`-15-
`
`Astrazeneca EX. 2138 p. 15
`
`

`
`Application No.: 12I285,887
`Attorney Docket No.: 112850056-00000
`
`may produce very different plasma level curves. and therefore very different
`
`pharmacologic effects. These effects include the desired effects (effioacy) and those
`
`that are not desired (adverse events, or side effects).
`
`If a drug is poorly absorbed from
`
`the injected site, (e.g., too slowly, or to only a modest extent) the drug may show no
`
`effects whatsoever.
`
`44.
`
`For example, a study in sheep using probenecid, a drug which may be
`
`used to prolong the half-life of some antibiotics in animals, demonstrates significant
`
`differences in the absorption of intramuscular and subcutaneous injections of
`
`probenecid. Guerrini V.H., Filippich L.J., English P.B., Schneider J., Cao G.R. and
`
`Bourne D.W.A., “Pharmacokinetics of probenecid in sheep", J Vet Pharmacol Ther.
`
`s(2):123—35 (1935) (“Guerrinr", attached as Exhibit 13).
`
`45.
`
`Those investigators administered probenecid to ewes in doses of 1 gram
`
`by both intramuscular and subcutaneous injection. Guerrini at 129. The study shows
`
`that the absorption of probenecid is more rapid and complete following intramuscular
`
`injection, compared to subcutaneous injection.
`
`to‘. at Abstract. Guerrini reports that the
`
`bioavailability of the intramuscular dose was 135% of that of the subcutaneous dose
`
`(corresponding to an average bioavailability of 46% for intramuscular injection
`
`compared with an average bioavailability of 34% for subcutaneous injection).
`
`Id. The
`
`subcutaneous dose was also absorbed more slowly, with average plasma levels of the
`
`drug peaking at 1.5 hr, compared to 0.6? hr for the intramuscular dose. Id. at 131.
`
`Because of this slower absorption following subcutaneous dosing, probenecid plasma
`
`concentrations remained higher after 2 hours when the drug was administered
`
`-15-
`
`AstraZeneca Ex. 2138 p. 16
`
`

`
`Application No.: 12I285,887
`Attorney Docket No.: 112850056-00000
`
`subcutaneously than when it was administered intramuscularly.
`
`lo‘. at 135. Consistent
`
`with these observations, the rate constant for absorption for the intramuscular dose was
`
`41% greater than for the subcutaneous dose (5.45 vs. 3.8? hr ").
`
`Id. at 133.
`
`46.
`
`In this case, despite the overall higher bioavailability of intramuscular
`
`probenecid, the “higher and more prolonged plasma probenecid concentration"
`
`following subcutaneous administration resulted in "similar plasma concentrations to
`
`those found in man after oral administration." Id. at 135. Guerrini concludes that “[t]he
`
`s.c. [subcutaneous] administration of probenecid in animals is preferred [to
`
`intramuscular administration] because muscle damage is avoided and it provided useful
`
`plasma concentrations.” ld. Thus, this is an example where subcutaneous
`
`administration achieves a certain desired result but where intramuscular administration
`
`does not accomplish the same result.
`
`47.
`
`Another study shows that, contrary to the pharmacokinetic profiles
`
`observed in Guerrini, subcutaneous administration resulted in faster absorption
`
`compared to intramuscular injection. Lavy E, Ziv G, She-m—Tov M, Glickman A, Dey A.,
`
`“Pharmacokinetics of clindamycin HCI administered intravenously, intramuscularly and
`
`subcutaneously to dogs", J Vet Pharmacol Ther. 22(4):261-5 (1999) (“Law/‘, attached
`
`as Exhibit 14).
`
`48.
`
`Levy reports that when a 10 mgfkg dose of clindamycin HCI, an antibioitic,
`
`was given subcutaneously to dogs, the average maximum blood serum concentration
`
`(Cmax) of clindamycin was 20.8 pg/ml, and the time when this maximum occurred
`
`(Tmax) averaged 46.7 min. Lavy at Table 3. When the same dose was given
`
`-17-
`
`AstraZeneca Ex. 2138 p. 17
`
`

`
`Application No.: 121285.887
`Attorney Docket No.: 112850056-00000
`
`intramuscularly to the same animals, the corresponding values for Cmax and Tmax
`
`were 4.4 pg/ml and 73 min, exhibiting a very much slower rate of absorption.
`
`Id.
`
`In
`
`addition, the exposure of the dogs to clindamycin, assessed through an analysis of the
`
`plasma serum area under the curve (AU C) was 2.9 times greater for the subcutaneous
`
`dose than for the intramuscular dose.
`
`lo‘. This means that the bioavailability of the
`
`subcutaneous dose of this drug is 2.9 times that of the intramuscular dose.
`
`49.
`
`Based on the differences in pharmacokinetic profiles for subcutaneous
`
`and intramuscular administration, Lavy concludes that “it appears from the present
`
`study that the s.c. [subcutaneous] route is superior to the i.m. [intramuscular] in practical
`
`terms by permitting a longer treatment interval.“ id. at 265. This is another example in
`
`which subcutaneous administration is able to fulfill certain design criteria (maintain a
`
`therapeutic plasma concentration for a longer period of time) better than intramuscular
`
`administration. Therefore, under these circumstances, one of ordinary skill in the art
`
`would not have been able to rely on data from subcutaneous administration to predict
`
`results of intramuscular administration because intramuscular administration would not
`
`have produced the same level of long-term efficacy achieved by subcutaneous
`
`administration.
`
`50.
`
`There are other reports in the literature that show that, in contrast to the
`
`results from Levy, the absorption of a drug is more rapid and complete following
`
`intramuscular closing than after subcutaneous injection. For example, when the
`
`fluoroquinolone antimicrobial agent difloxacin was given by these routes to the same
`
`calves in a crossover study, the rates of absorption differed greatly, with intramuscular
`
`-13-
`
`AstraZeneca Ex. 2138 p. 18
`
`

`
`Application No.: 12I285,887
`Attorney Docket No.: 1128513056-00000
`
`injection showing higher and earlier peak plasma concentrations, confirming much more
`
`rapid absorption.
`
`Ismail M., “Disposition kinetics of difloxacin after intravenous,
`
`intramuscular and subcutaneous administration in calves“, Vet‘ Res Commun.,
`
`31(4):467—76 (2007) (“fsmarT’, attached as Exhibit 15).
`
`51.
`
`After intramuscular and subcutaneous dosing, maximum plasma
`
`concentrations (Cmax) of 3.38 and 2.18 pglml were observed after (Tmax) 1.22 and 3.7
`
`hr, respectively.
`
`Ismail at Abstract. The time for half of the dose to be absorbed when
`
`given by intramuscular injection was only 0.38 hr, whereas the corresponding time for
`
`absorption of the subcutaneously injected dose was 2.1 hr, over 5 times as long.
`
`id. at
`
`473.
`
`52.
`
`Under the conditions of its study, lsmail concludes that “the doses of
`
`difloxacin used in this study are likely to involve better pharmacodynamic characteristics
`
`that: are associated with greater clinical efficacy following i.m. [intramuscular]
`
`administration than following s.c. [subcutaneous] administration.” id. at Abstract.
`
`In this
`
`case, contrary to the two examples above, the intramuscular administration was
`
`considered to be associated with greater clinical efficacy.
`
`53.
`
`These three examples above show that there are significant differences in
`
`the rate and extent of absorption of a drug given by the intramuscular and
`
`s

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