DECLARATIIJN OF SANDRA MCLESKEY, Ph.D.
`
`1, Sandra McLeskey, declare as follows:
`
`I.
`
`Background
`
`1.
`
`I cameo 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
`
`1939.
`
`2.
`
`After obtaining my Ph.D., 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 cell 3. including research that led to the publication of the article
`
`Tamoxifen-resistamfibrobias-2‘ growthfac:or—rransfiecfed MCE7 cells are cross—resistant in viva
`
`to the ctnziesirogert IC1‘18'2. 780 and two aromatase inhibitors, Clin Cancer Res 4:697-"ill (1998)
`
`(“‘McLeskejz' 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.
`
`11.
`
`The McLeskey Publication
`
`4.
`
`The MeLeskey Publication discusses an academic research project aimed at
`
`elucidating the mechanism of cancer cell growth in tamoxifeneresistant 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 Ex. 2043 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01326
`
`
`
`1, Sandra McLeskey, declare as follows:
`
`I.
`
`Background
`
`1.
`
`I cameo 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
`
`1939.
`
`2.
`
`After obtaining my Ph.D., 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 cell 3. including research that led to the publication of the article
`
`Tamoxifen-resistamfibrobias-2‘ growthfac:or—rransfiecfed MCE7 cells are cross—resistant in viva
`
`to the ctnziesirogert IC1‘18'2. 780 and two aromatase inhibitors, Clin Cancer Res 4:697-"ill (1998)
`
`(“‘McLeskejz' 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.
`
`11.
`
`The McLeskey Publication
`
`4.
`
`The MeLeskey Publication discusses an academic research project aimed at
`
`elucidating the mechanism of cancer cell growth in tamoxifeneresistant 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 Ex. 2043 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01326
`
`
`
`in.
`
`The study was not designed to look at the treatment oflany disease with
`
`fulveetrarrt. Rather, We used fulvestraut as a tool to help us in examining a possible pathway of
`
`tamoxifen resistance. In feet, We used three different drugs (fulvestrent and two aromatase
`
`inhibitors) as tools to make sure that the estrogen receptor (ER) was not activated by small
`
`amounts of estro gen synthesized by the mouse’s liver and adrenal glands -nwith the goal being to
`
`determine 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 mice»-not trearmerrt of hurnaus. For example, we
`
`administered tatnoxifen 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 fonnulations of the other drugs were
`
`for use in mice subcutaneously for research, including the two different fulvesrrarlt forreulatiorrs:
`
`a peanut oil and a caetor oil formulation. As is clear fiom the paper, and in particular Figure 1,
`
`we treated the peanut oil and easier 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 irrclude plasma or blood levels of any of the drugs used,
`
`including ftrlvestrent, nor any information regarding the rate or extent of absorption of the drugs
`
`following subcutaneous adlrlinistration. This is not surprising, given that the study was designed
`
`to look at issues relating to basic: science and not drug formulation.
`
`Ix)
`
`Astrazeneca Ex. 2043 p. 2
`
`
`
`8.
`
`Far the same reason, our paper also does not specify whether the percentages in
`
`the caster oii fonnulati-an are in weightivoiume (W/V) units or in volume/volume {V/V) units (in
`
`fact, I assumed that the percentages were in WV units, because the components of the fomiuiation
`
`were iiquids).
`
`9.
`
`In my opinion, the M(:Leskey Puhiication clearly refiects that the purpose of our
`
`research was not to evaluate methods of treating any disease using fulvestrant. In fact; tn the
`
`extent that we discuss the effect of fulvestrant, the point is that it did not inhibit estrogen-
`
`independent tumor growth of FGF—expressing breast cancer celis, as we hypothesized.
`
`Specifically, the abstract states that the fcarmuiations “did not slow estrogen—independent growth
`
`er prevent metastasis of tumors produced by FGF-transfected MCF—7 cells in OV8I'i6Ct0l'I1iZ€d
`
`nude mice.” Additionatly, Figure 1 demonstrates and the figure caption explains that, “[g]rowth
`
`of FGF~transfec:ted MCFJ cells in ovariectomized nude misze is not inhibited by treatment with
`
`ICi 182380 {fu1vestrant}.” (See page 701).
`
`10.
`
`The McLeskey Publication was published in Clinical Cancer Research, which is 23.
`
`journal ofthe American Aseociatien for Cancer Research (AACR). The AACR is 21 professional
`
`nrganization of cancer researchers. The manuscript was submitted to Ciinical Cancer Research
`
`because that journai has an expressed interest in publishing research can mechanisms of drug
`
`sensitivity and resistance.
`
`11.
`
`In short, in my opinion, a scientist interested in developing a treatment for
`
`humans using‘ fulvestrant would not have looked to the McLeskey Publication for guidance given
`
`that it is directed to exploring a pathway of cancer gnwth different and independent of
`
`fiilvestranfs mechanism of action, and it prnvides no information about how to formulate an
`
`intramuscular preparation providing sustained release for humans. Moreover, the MeLeskey
`
`3
`
`Astrazeneca Ex. 2043 p. 3
`
`
`
`Publication appeared in a journal whose target readership is cancer researchers, and the
`
`fomxulaticms used were research formulations for use in mice.
`
`I hereby deciare that all of the statements made herein of my own knowledge are true and that all
`
`statements made on infmmation and belief are believed 10 be true.
`
`.
`'
`‘
`.
`ma/zffzgl
`Date:
`
`_
`2,
`if
`‘
`;_‘
`,::'Z?’xz”7p/_{xflg'72P:1§L. sflmaiaz. /,4?“
`Sandra McLeskey, Phi}.
`V‘
`
`4
`
`Astrazeneca Ex. 2043 p. 4
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