DECLARATION OF SANDRA MCLESKEY,Ph.D.
`
`IL, Sandra McLeskey, declare as follows:
`
`I.
`
`Background
`
`1.
`
`[ 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 Universityin
`
`1989.
`
`2.
`
`After obtaining my Ph.D., I worked as a post-doctoral fellow in the laboratory of
`
`Francis G. Kern in the Department of Biochemistry at the Lombardi Cancer Center, Georgetown
`
`University. During that time, ] conducted research on the mechanisms of cancer growth in
`
`tamoxifen-resistant breast cancer cells, including research that led to the publication ofthearticle
`
`Tamoxifen-resistantfibroblast growthfactor-transfected MCI-7 cells are cross-resistant in vivo
`
`to the antiestrogen ICT182,780 and two 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.
`
`Il.
`
`The McLeskey Publication
`
`4,
`
`The McLeskey 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 exploresthe
`
`question ofwhether tamoxifen resistance is related to FGF signaling pathways.
`
`AstraZeneca Exhibit 2043 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
`
`
`
`IL, Sandra McLeskey, declare as follows:
`
`I.
`
`Background
`
`1.
`
`[ 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 Universityin
`
`1989.
`
`2.
`
`After obtaining my Ph.D., I worked as a post-doctoral fellow in the laboratory of
`
`Francis G. Kern in the Department of Biochemistry at the Lombardi Cancer Center, Georgetown
`
`University. During that time, ] conducted research on the mechanisms of cancer growth in
`
`tamoxifen-resistant breast cancer cells, including research that led to the publication ofthearticle
`
`Tamoxifen-resistantfibroblast growthfactor-transfected MCI-7 cells are cross-resistant in vivo
`
`to the antiestrogen ICT182,780 and two 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.
`
`Il.
`
`The McLeskey Publication
`
`4,
`
`The McLeskey 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 exploresthe
`
`question ofwhether tamoxifen resistance is related to FGF signaling pathways.
`
`AstraZeneca Exhibit 2043 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
`
`
`
`5.
`
`The study was not designed to look at the treatmentofany 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 makesure 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 tumor 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 unaffected by
`
`hormonal treatments devoid of agonist activity.” (See page 698).
`
`6.
`
`The paperis clear that the formulations of these drugs were for research purposes
`
`for subcutancous administration to mice--not treatment ofhumans. 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--thereis
`
`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. Asis clear from the paper, and in particular Figure 1,
`
`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 plasmaor 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.
`
`bo
`
`AstraZeneca Exhibit 2043 p. 2
`
`
`
`8.
`
`For the same reason, our paper also does not specify whether the percentages in
`
`the castor oil formulation are in weight/volume (w/v) units or in volume/volume (v/v) units (in
`
`fact, | assumed that the percentages were in v/v units, because the componentsof the formulation
`
`were liquids).
`
`9.
`
`In my opinion, the McLeskey Publication clearly reflects that the purpose of our
`
`research was not to evaluate methodsof treating any disease using fulvestrant. In fact, to the
`
`extent that we discuss the effect of fulvestrant, the pointis that it did not inhibit estrogen-
`
`independent tumor growth ofFGF-expressing breast cancer cells, as we hypothesized.
`
`Specifically, the abstract states that the formulations “did not slow estrogen-independent growth
`
`of 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]rowth
`
`of FGF-transfected MCF-7cells in ovariectomized nude mice is not inhibited by treatment with
`
`ICI 182,780 [fulvestrant].” (See page 701).
`
`10.
`
`The McLeskey Publication was published in Clinical Cancer Research, whichis a
`
`journal ofthe American Association for Cancer Research (AACR). The AACRis a professional
`
`organization of cancer researchers. The manuscript was submitted to Clinical Cancer Research
`
`because that journal 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 treatmentfor
`
`humans usingfulvestrant would not have looked to the McLeskey Publication for guidance given
`
`that it is directed to exploring a pathway of cancer growth different and independent of
`
`fulvestrant’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 appearedin ajournal whosetarget readership is cancer researchers, and the
`
`formulations used were research formulations for use in mice.
`
`L hereby declare thatall ofthe statements made herein of my own knowledge are true and thatall
`
`statements made on information and belief are believed to be true.
`
`} | I;
`
`f
`
`Date:
`
`AMLitoobe ORezeCi, )
`
`Sandra McLeskey, Ph.D.
`
`AstraZeneca Exhibit 2043 p. 4
`
`
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