DECLARATION OF SANDRA MCLESKEY, Ph.D.
`
`l, Sandra McLeskey, declare as follows:
`
`I.
`
`Background
`
`1.
`
`I earned a BS in chemistry from Duke University in 1963, a BSN in nursing from
`
`George Mason University in 1982, and a Ph.D. in pharmacology from Georgetown University in
`
`1989.
`
`2.
`
`After obtaining my Ph.D., I worked as a postdoctoral fellow in the laheratcry of
`
`Francis G. Kern in the Department of Biochemistry at the Lcmhardi Cancer Center, Georgetown
`
`University. During that time, I conducted research on the mechanisms of cancer growth in
`
`tamexifen-resistant breast cancer cells. including research that led to the publication of the article
`
`Tamoxifen-reststamfiiiroblasr grawIhfactar—z7'ar:sfecied MCF3/" cells are cr0.s‘s—re5i5ranz‘ in viva
`
`re the cmtieszragerr IC1‘f82, ?'8t’} and twe aromazase inhibitors, Clin Cancer Res 4:697-7ll (1998)
`
`(“l‘v‘lcLeske3z' Publication”).
`
`3.
`
`I was the primary individual responsible for conducting the research discussed in
`
`this article, as well as the first author of the publication.
`
`II.
`
`The McLeskey Publication
`
`4.
`
`The Mclleskey Publication discusses an academic research prcject airned at
`
`elucidating the mechanism of cancer cell growth in tamoxifen-resistant breast cancer cells that
`
`do not depend on estrogen for growth stimulation. This property is called estrogen
`
`independence. These cells became estrogen independent and tamoxifen resistant when they were
`
`engineered to express a fibroblast growth factor (FGF).
`
`in particular, the paper explores the
`
`question of whether tamexifen resistance is related te FGF signaling pathways.
`
`Astrazeneca Ex. 2043 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01325
`
`
`
`l, Sandra McLeskey, declare as follows:
`
`I.
`
`Background
`
`1.
`
`I earned a BS in chemistry from Duke University in 1963, a BSN in nursing from
`
`George Mason University in 1982, and a Ph.D. in pharmacology from Georgetown University in
`
`1989.
`
`2.
`
`After obtaining my Ph.D., I worked as a postdoctoral fellow in the laheratcry of
`
`Francis G. Kern in the Department of Biochemistry at the Lcmhardi Cancer Center, Georgetown
`
`University. During that time, I conducted research on the mechanisms of cancer growth in
`
`tamexifen-resistant breast cancer cells. including research that led to the publication of the article
`
`Tamoxifen-reststamfiiiroblasr grawIhfactar—z7'ar:sfecied MCF3/" cells are cr0.s‘s—re5i5ranz‘ in viva
`
`re the cmtieszragerr IC1‘f82, ?'8t’} and twe aromazase inhibitors, Clin Cancer Res 4:697-7ll (1998)
`
`(“l‘v‘lcLeske3z' Publication”).
`
`3.
`
`I was the primary individual responsible for conducting the research discussed in
`
`this article, as well as the first author of the publication.
`
`II.
`
`The McLeskey Publication
`
`4.
`
`The Mclleskey Publication discusses an academic research prcject airned at
`
`elucidating the mechanism of cancer cell growth in tamoxifen-resistant breast cancer cells that
`
`do not depend on estrogen for growth stimulation. This property is called estrogen
`
`independence. These cells became estrogen independent and tamoxifen resistant when they were
`
`engineered to express a fibroblast growth factor (FGF).
`
`in particular, the paper explores the
`
`question of whether tamexifen resistance is related te FGF signaling pathways.
`
`Astrazeneca Ex. 2043 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01325
`
`
`
`5.
`
`The study was not designed to look at the treatment ofany disease with
`
`fulvestrant. Rather, we used fulvestrant as a tool to help us in examining a possible pathway of
`
`tamoxifen resistance. In fact, we used three different drugs (fulvestrant and two aromatase
`
`inhibitors) as tools to make sure that the estrogen receptor (ER) was not activated by small
`
`amounts of estrogen synthesized by the Inouse’s liver and adrenal glands «with the goal being to
`
`cleterniine if the activity of FGF (rather than estrogen) could drive tumor growth in tamoxifen-
`
`resistant breast cancer cells. We hypothesized that, “[i]f FGF-mediated growth pathways bypass
`
`the ER pathway to affect gowth directly, we would expect that growth would be unaffected by
`
`hormonal treatments devoid of agonist activity.” (See page 698)
`
`6.
`
`The paper is clear that the formulations of these drugs were for research purposes
`
`for subcutaneous administration to rnice»-not treatment of humans. For example, we
`
`administered tamoxifen as sustained—release pellets implanted subcutaneously. Those pellets
`
`were available commercially for experimentation in mice and used for only that purpose--there is
`
`no corresponding formulation for humans. Similarly, the formulations of the other drugs were
`
`for use in mice subcutaneously for research including the two different fulvestrant formulations:
`
`a peanut oil and a Castor oil formulation. As is clear fi'on1 the paper, and in particular Figure 13
`
`we treated the peanut oil and castor oil formulations as interchangeable for the purpose of our
`
`research, and we did not draw any comparisons between the two formulations.
`
`‘.7’.
`
`Our paper also does not include plasma or blood levels of any of the drugs used,
`
`including fulvestrant, nor any information regarding the rate or extent of absorption of the drugs
`
`following subcutaneous administration. This is not surprising, given that the study was designed
`
`to look at issues relating to basic science and not drug formulation.
`
`[Q
`
`Astrazeneca Ex. 2043 p. 2
`
`
`
`8.
`
`For the same reason, our paper also does not specify whether the percentages in
`
`the caste: eii fcrinulaticn are in weightfvolume (W/V) units or in vclume/volume (Viv) units (in
`
`fact, i assumed that the percentages were in V/V units, because the components of the fcrmuiaticu
`
`were iiquids).
`
`9.
`
`in my opinion, the McLesl<ey Publication clearly reflects that the purpose of our
`
`research was not to evaluate methods of treating any disease using fulvestrant. In fact, to the
`
`extent that we discuss the effect of fulvestrant, the point is that it did not inhibit estrogen-
`
`independent tumor growth ofFGF-expressing hreast cancer cells, as we hypothesized.
`
`Specifically, the abstract states that the fermulations “did net slew estrogemindependent growth
`
`or prevent metastasis of tumors produced by FGF-transfected MCF—7 cells in ovariectomized
`
`nude mice.” Additionally, Figure 1 demonstrates and the figure caption explains that, “[g]rcwth
`
`ct"FGF~transfected MCF5! cells in ovariectcmized nude mice is not inhibited by treatment with
`
`ICI 182,780 {fulvestIant}."" (See page 701).
`
`10.
`
`The McLeskey Publication was published in Clinical Cancer Research, which is a
`
`journal ofthe American Associaticn for Cancer Research (AACR). The AACR is a professional
`
`organization of cancer researchers. The manuscript was submitted to Ciinicaf Cancer Research
`
`because that journal has an expressed interest in publishing research on mechanisms of drug
`
`sensitivity and resistance.
`
`1 1.
`
`ln short, in my opinion, a scientist interested in developing a treatment for
`
`humans using fulvestrant would not have looked to the McLeskcy Publication for guidance given
`
`that it is directed to exploring a pathway of cancer growth different and independent of
`
`fulvestranfs mechanism of action, and it presides no information about how to formulate an
`
`intramuscular preparation providing sustained release for humans. Moreover, the McLesi<ey
`
`3
`
`Astrazeneca Ex. 2043 p. 3
`
`
`
`Publicativzm appeared in a journal whose target readership is cancer researchers, and the
`
`formulations used were research formulations for use in mice.
`
`I hereby deciare that all ofthe atatements made herein cf my own knowledge are true and that all
`
`statements made on infonnation and belief are believed to be true..
`
`'
`
`_
`,: F‘
`
`‘
`«
`J; I’
`
`Date:
`
`"
`
`::.:;z»,? xx 53:), »§f)g‘;’\.,«5T~gi,»{£4«ei¢::.,LX,§
`
`,1
`
`fl.‘
`
`£5?
`
`Sandra McLeskey, Ph.D.
`
`4
`
`Astrazeneca Ex. 2043 p. 4
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