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`l, Sandra McLeskey, declare as follows:
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`I.
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`Background
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`1.
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`l earned a BS in chemistry from Duke University in 1963, a BSN in nursing from
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`George Mason University in 19829 and a PhD. in phannacology from Georgetoem University in
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`1989.
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`2.
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`After obtaining my Phil, I worked as a postdoctoral fellow in the laboratory of
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`Francis G. Kern in the Department of Biochemistry at the Lombardi Cancer Center, Georgetown
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`University. During that time, I conducted research on the mechanisms of cancer growth in
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`tamoxifen-resistant breast cancer cells? including research that led to the publication of the article
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`Tamoxifen-reststamfihmblasr growrhfactor—zmnsficicd MCF»? cells are cross—resistant in visa
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`in the anticslmgen 1C] 182, 780 and two aromatase inhibitors, Clin Cancer Res 4:697»7ll (1998)
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`(“McLeskey Publication”).
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`3.
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`I was the primary individual responsible for conducting the research discussed in
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`this article, as well as the first author of the publication.
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`11.
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`The McLeskey Publication
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`4.
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`The McLeskey Publication discusses an academic research project aimed at
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`elucidating the mechanism of cancer cell growth in tamoxifen-resistant breast cancer cells that
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`do not depend on estrogen for growth stimulation. This property is called estrogen
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`independence. These cells became estrogen independent and tamoxifen resistant when they were
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`engineered to express a fibroblast growth factor (FGF). In particular, the paper explores the
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`question of whether tamoxifen resistance is related to FGF signaling pathways.
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`5.
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`The study was not designed to look at the treatment of'any disease with
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`fulvestrant. Rather, we used fulvestrant as a tool to help us in examining a possible pathway of
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`tamoxifen resistance. In fact, we used three different drugs (fulvestrant and two aromatase
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`inhibitors) as tools to make sure that the estrogen receptor (ER) was not activated by small
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`amounts of estrogen synthesized by the mouse’s liver and adrenal glands “with the goal being to
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`determine if the activity of FGF (rather than estrogen) could drive tanner growth in tamoxifen-
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`resistant breast cancer cells. We hypothesized that, “[i]f FGF-mediated growth pathways bypass
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`the ER pathway to affect growth directly, we would expect that growth would he maffeeted by
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`hormonal treatments devoid of agonist activity.” (See page 698).
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`6.
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`The paper is clear that the formulations of these drugs were for research purposes
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`for subcutaneous administration to mice—not neatrnent of humans. For example, we
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`administered tamoxifen as sustained—release pellets implanted subcutaneously. Those pellets
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`were available eonnnereially for experimentation in mice and used for only that purpose--there is
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`no corresponding formulation for humans. Similarly, the formulations of the other drugs were
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`for use in mice subcutaneously for research} including the two different fiilvestrant formulations:
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`a peanut oil and a caster oil fonnulation. As is clear from the paper, and in particular Figure l:
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`we treated the peanut oil and caster oil formulations as interchangeable for the purpose of our
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`research and we did not draw any comparisons between the two formulations.
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`7’.
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`Our paper also does not include plasma or blood levels of any of the drugs used,
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`including fulvestrant, nor any information regarding the rate or extent of absorption of the drugs
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`following subcutaneous administration. This is not surprising, given that the study was designed
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`to look at issues relating to basic science and not drug formulation.
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`[Q
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`AstraZeneca Exhibit 2043 p. 2
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`8.
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`For the same reason, our paper also does not specify whether the percentages in
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`the caste: oii fonnulation are in weightfvolurne (w/v) units or in volume/volume (WV) units (in
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`fact, i assumed that the percentages were in V/V units, because the components of the formulation
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`were iiquids).
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`9.
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`In my opinion, the Moieskey Publication clearly reflects that the puipose of our
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`research was not to evaluate methods of treating any disease using fulvestrant. In fact. to the
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`extent that we discuss the effect of fab/€311?th the point is that it did not inhibit estrogen-
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`independent tumor growth ofFEW—expressing breast cancer cells, as we hypothesized.
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`Specifically, the abstract states that the formulations “did not slow estrogenwindependent growth
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`or prevent metastasis of tumors produced by FGF-transfccted MCF—7 cells in ovariectomized
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`nude mice.” Additionally, Figure 1 demonstrates and the figure caption explains that, “[ghowth
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`ot‘FGEtransfected MCP—i’ cells in ovariectomized nude mice is not inhibited by treatment with
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`lCi 1823780 {ftflvestrant}.” (See page 701).
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`10.
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`The McLeskey Publication was published in Clinicai Cancer Research, which is a
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`journal ofthe American Association for Cancer Research (AACR). The AACR is a professional
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`organization of cancer researchers. The manuscript was submitted to Ciinicaf Cancer Research
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`because that journal has an expressed interest in publishing research on mechanisms of drug
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`sensitivity and resistance.
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`11.
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`in Short. in my opinion, a scientist interested in developing a treatment for
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`humans using. fiilvestrant would not have looked to the McLeskey Publication for guidance given
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`that it is directed to exploring a pathway of cancer grown] different and independent of
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`fiilvestrant’s mechanism of action, and it provides no information about how to formulate an
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`intramuscular preparation providing sustained release for humans. Moreover. the McLeskey
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`3
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`AstraZeneca Exhibit 2043 p. 3
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`Publication appeared, in a joumal whose target readership is cancer researchers: and thc:
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`fonnulations used were research fonnuiations for use in mice.
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`I hereby deciare that all ofthe Statements made herein nf my Own knowledge are true and that all
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`statements made on information and belief are believed to be true.
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`Sandra McLeskey, PhD.
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`4
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`AstraZeneca Exhibit 2043 p. 4
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