DECLARATION OF SANDRA MCLESKEY, Phil.
`
`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 1932. and a PhD. in phannacology from Georgetown University in
`
`1989.
`
`2.
`
`After obtaining my Phil, I worked as a postdoctoral fellow in the laboratory of
`
`Francis G. Kern in the Department of Biochemistry at the Lombardi Cancer Center, Georgetown
`
`University. During that time, I conducted research on the mechanisms of cancer growth in
`
`tamoxifen-resistant breast cancer cells. including research that led to the publication of the article
`
`Tamoxifen-reststamfihmblasr growrhfacror—meficicd MCFJ cells are cross—resistant in viva
`
`to the antieslrogen 1C] 182, 780 and Mo aromatase inhibitors, Clin Cancer Res 4:697»711 (1998)
`
`(“McLeSkey 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 MeLeskey Publication discusses an academic research project aimed 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 tamoxifen resistance is related to FGF signaling pathways.
`
`AstraZeneca Exhibit 2043 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00900
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01913
`
`
`
`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 1932. and a PhD. in phannacology from Georgetown University in
`
`1989.
`
`2.
`
`After obtaining my Phil, I worked as a postdoctoral fellow in the laboratory of
`
`Francis G. Kern in the Department of Biochemistry at the Lombardi Cancer Center, Georgetown
`
`University. During that time, I conducted research on the mechanisms of cancer growth in
`
`tamoxifen-resistant breast cancer cells. including research that led to the publication of the article
`
`Tamoxifen-reststamfihmblasr growrhfacror—meficicd MCFJ cells are cross—resistant in viva
`
`to the antieslrogen 1C] 182, 780 and Mo aromatase inhibitors, Clin Cancer Res 4:697»711 (1998)
`
`(“McLeSkey 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 MeLeskey Publication discusses an academic research project aimed 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 tamoxifen resistance is related to FGF signaling pathways.
`
`AstraZeneca Exhibit 2043 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00900
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01913
`
`
`
`5.
`
`The study was not designed to look at the treatment of'any 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 mouse’s liver and adrenal glands “with the goal being to
`
`determine if the activity of FGF (rather than estrogen) could drive honor growth in tamoxifen-
`
`resistant breast cancer cells. We hypothesized that, “[i]f FGF-mediated growth pathways bypass
`
`the ER pathway to affect growth directly, we would expect that growth would be imaffected 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 mice—not neatrnent of htnnans. For example, we
`
`administered tamoxifen as sustained—release pellets implanted subcutaneously. Those pellets
`
`were available eonnnereially for experimentation in mice and used for only that purpose-there is
`
`no corresponding formulation for humans. Similarly, the fonnulations of the other drugs were
`
`for use in mice subcutaneously for research} including the two different fiilvestrant formulations:
`
`a peanut oil and a castor oil formulation. As is clear from the paper, and in particular Figure 13
`
`we treated the peanut oil and caster oil formulations as interchangeable for the purpose of our
`
`research and we did not draw any comparisons between the two formulations.
`
`37’.
`
`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 Exhibit 2043 p. 2
`
`
`
`8.
`
`For the same reason, our paper also does not specify whether the percentages in
`
`the caste: oii fonnulation are in weightfvoiume (w/v) units or in volume/volume (WV) units (in
`
`fact, i assumed that the percentages were in V/V units, because the components of the termination
`
`were iiquids).
`
`9.
`
`In my opinion, the Moleskey Publication clearly reflects that the puipose 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 fitlvesttantz. the point is that it did not inhibit estrogen-
`
`independent tumor growth ofFEW—expressing breast cancer ceiis, as we hypothesized.
`
`Specifically, the abstract states that the fonnulations “did not stow estrogen—independent 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, “[ghowth
`
`ot‘FGFuransfected MCP—i’ cells in ovariectomized nude mice is not inhibited by treatment with
`
`iCi 1823780 {ftilvestrant}.” (See page 701).
`
`10.
`
`The McLeskey Publication was published in Clinicat Cancer Research, which is a
`
`journal ofthe American Association for Cancer Research (AACR). The AACR is a professional
`
`organization of cancer researchers. The manuscript was submitted to Ciinicaf Cancer Research
`
`because that journai has an expressed interest in publishing research on mechanisms of drug
`
`sensitivity and resistance.
`
`11.
`
`In short. in my opinion, a scientist interested in developing a treatment for
`
`humans using. fiilvestrant would not have looked to the McLeskey Publication for guidance given
`
`that it is directed to exploring a pathway of cancer grown] different and independent of
`
`fifltfestrant’s mechanism of action, and it provides no information about how to formulate an
`
`intramuscular preparation providing sustained release for humans. Moreover. the McLeskey
`
`3
`
`AstraZeneca Exhibit 2043 p. 3
`
`
`
`Publication appeared, in a joumal whose target readership is cancer researchers: and thc:
`
`fomulations used were research fomnuiations for use in mice.
`
`I hereby deciare that all ofthe atatemems made herein af my avm knowledge are true and that all
`
`statements made on information and belief are believed to be true.
`
`.
`'
`: m}:
`
`‘
`//
`
`'
`I]
`
`Date:
`
`*‘
`’
`I”
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`
`Sandra McLeskey, PhD.
`
`AstraZeneca Exhibit 2043 p. 4
`
`
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