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`1, Sandra McLeskey, declare as follows:
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`I.
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`Background
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`1.
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`I cameo a BS in chemistry from Duke University in 1963, a BSN in nursing from
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`George Mason University in 1982, and a Ph.D. in pharmacology from Georgetown University in
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`1939.
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`2.
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`After obtaining my Ph.D., 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 cell 3. including research that led to the publication of the article
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`Tamoxifen-resistamfibrobias-2‘ growthfac:or—rransfiecfed MCE7 cells are cross—resistant in viva
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`to the ctnziesirogert IC1‘18'2. 780 and two aromatase inhibitors, Clin Cancer Res 4:697-"ill (1998)
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`(“‘McLeskejz' 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 MeLeskey Publication discusses an academic research project aimed at
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`elucidating the mechanism of cancer cell growth in tamoxifeneresistant 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).
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`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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`in.
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`The study was not designed to look at the treatment oflany disease with
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`fulveetrarrt. Rather, We used fulvestraut as a tool to help us in examining a possible pathway of
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`tamoxifen resistance. In feet, We used three different drugs (fulvestrent 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 estro gen synthesized by the mouse’s liver and adrenal glands -nwith the goal being to
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`determine if the activity of FGF (rather than estrogen) could drive tumor 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 gowth directly, we would expect that growth would be unaffected 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 trearmerrt of hurnaus. For example, we
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`administered tatnoxifen as sustained—release pellets implanted subcutaneously. Those pellets
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`were available commercially for experimentation in mice and used for only that purpose--there is
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`no corresponding formulation for humans. Similarly, the fonnulations of the other drugs were
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`for use in mice subcutaneously for research, including the two different fulvesrrarlt forreulatiorrs:
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`a peanut oil and a caetor oil formulation. As is clear fiom the paper, and in particular Figure 1,
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`we treated the peanut oil and easier 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 irrclude plasma or blood levels of any of the drugs used,
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`including ftrlvestrent, nor any information regarding the rate or extent of absorption of the drugs
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`following subcutaneous adlrlinistration. 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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`Ix)
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`8.
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`Far the same reason, our paper also does not specify whether the percentages in
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`the caster oii fonnulati-an are in weightivoiume (W/V) units or in volume/volume {V/V) units (in
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`fact, I assumed that the percentages were in WV units, because the components of the fomiuiation
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`were iiquids).
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`9.
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`In my opinion, the M(:Leskey Puhiication clearly refiects that the purpose of our
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`research was not to evaluate methods of treating any disease using fulvestrant. In fact; tn the
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`extent that we discuss the effect of fulvestrant, the point is that it did not inhibit estrogen-
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`independent tumor growth of FGF—expressing breast cancer celis, as we hypothesized.
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`Specifically, the abstract states that the fcarmuiations “did not slow estrogen—independent growth
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`er prevent metastasis of tumors produced by FGF-transfected MCF—7 cells in OV8I'i6Ct0l'I1iZ€d
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`nude mice.” Additionatly, Figure 1 demonstrates and the figure caption explains that, “[g]rowth
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`of FGF~transfec:ted MCFJ cells in ovariectomized nude misze is not inhibited by treatment with
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`ICi 182380 {fu1vestrant}.” (See page 701).
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`10.
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`The McLeskey Publication was published in Clinical Cancer Research, which is 23.
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`journal ofthe American Aseociatien for Cancer Research (AACR). The AACR is 21 professional
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`nrganization of cancer researchers. The manuscript was submitted to Ciinical Cancer Research
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`because that journai has an expressed interest in publishing research can 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‘ fulvestrant 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 gnwth different and independent of
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`fiilvestranfs mechanism of action, and it prnvides no information about how to formulate an
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`intramuscular preparation providing sustained release for humans. Moreover, the MeLeskey
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`Publication appeared in a journal whose target readership is cancer researchers, and the
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`fomxulaticms used were research formulations for use in mice.
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`I hereby deciare that all of the statements made herein of my own knowledge are true and that all
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`statements made on infmmation and belief are believed 10 be true.
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