Application No.: 11/553,339
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`Docket No.: 63877200030 1
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`In rc Patent Application of:
`Neil P. DESAI ct al.
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`Application No.: 11 /553,339
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`Confirmation No.: 3605
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`Filed: October 26, 2006
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`For: COMPOSITIONS AND METHODS OF
`DELIVERY OF PHARMACOLOGICAL
`AGENTS
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`Art Unit: 1656
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`Examiner: M. Tsay
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`DECLARATION O}~ NEIL P. DESAI P URSUANT TO 37 C.F.R § 1.132
`
`Commi ssioner for Patents
`
`P.O. Box 1450
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`Alexandria, VA 22313- 1450
`
`Dear Sir:
`
`I, Neil P. Desai, declare as fo llows:
`
`I.
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`T am Senior Vice President of Global Research and Development at Abraxis
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`BioScience, LLC ("Abraxis"), assignee of the above-referenced patent application. A copy of my
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`biography is attached hereto as Exhibit I.
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`2.
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`I have more than 17 years of experience in the research and development of drug
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`del ivery systems and biocompatible polymers. I was one of the indi viduals responsible fo r the
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`development of Abraxis' nanoparticle-albumin bound (nab™) drug del ivery platform and its
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`product Abraxane®. one of the leading drugs for treating metastatic breast cancer in the United
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`States.
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`Apotex v. Abraxis - IPR20 18-001 52, Ex. 1023, p.OI of61
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`

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`Application No.: Il1553,339
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`2
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`Docket No.: 638772000301
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`3.
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`J am one of the named inventors of the above-referenced patent application and am
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`familiar with the technical features of the invention and the amended claims.
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`4.
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`I have reviewed the Office Action dated December 31, 2009. I understand that
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`previously pending claims in the present patent application are rejected as being obvious over
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`Damascelli et aI., Cancer, 2001, 92(10):2592-2602 ("Damascelli"), Ibrah im et al., Proc. Am. Soc.
`Clin. Onco1., 2000, 19:609F ("Ibrahim"), and one of Abraxis' earlier patents, U.S. Pat. No.
`
`6,537,5 79 ("the '579 patent"), on which I am also a named inventor. I have read and am familiar
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`with these cited references.
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`5.
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`The claims as amended in the present patent application are generally directed to a
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`pharmaceutical composition fur inj ection compris ing paclitaxel and a pharmaceutically acceptable
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`carrier, wherein the pharmaceutically acceptable carri er comprises albumin, wherein the albumin
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`and the paclitaxel in the composition art.:: fo rm ulUkd as nanoparticles, when:in the nanoparticles
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`have a particle size of less than about 200 nm, and wherein the weight ratio of albumin to paclitaxel
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`in the composition is about 1:1 to about 9: 1. In the sections below, I generally refer to a
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`pharmaceutical composition for injection comprising paclitaxel and a pharmaceutically acceptable
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`carrier, wherein the pharmaceutically acceptable carrier comprises albumin, wherein the albumin
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`and the paclitaxcl in thc composition are formulated as nanoparticles, wherein the nanoparticles
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`have a particle size of less than about 200 nm as an "albumin-based paclitaxel nanopartick
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`composition."
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`6.
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`In this declaration, I discuss unexpected results associated with the claimed
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`albuminlpaclitaxel ratio, including striking biological and clinical data relating to the ratio.
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`An albumin/paC/ilaxe/ ratio of about J: 1 to about 9:J unexpectedly shows increased ct<llular
`binding
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`7.
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`We have found, unexpectedly, that the ratio of albumin to pacl itaxcl in an albumin-
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`based paclitaxe I nanoparticie composition affects the abi lity of paclitaxt:! to bind to cndotht:lial
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`cells. Highcr albumin/paelitaxcl ratios arc associated with poor cellular binding ofpac!itaxcl, whilc
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`lower albumin/paclitaxel ratios are associated with enhanced cellular binding of pac lit axe!. We
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`Apotex v. Abraxis - IPR20 18-00 15 2, Ex. 1023 , p.02 of61
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`Application No.: 11 /553,339
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`Docket No.: 638772000301
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`have further unexpected ly found that the effect of album in/paclitaxel ratio on the binding of
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`paclitaxel changes dramatically at an albuminlpacl itaxel ratio of about 9: I , as evidenced by an
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`inflect ion point in the binding curve at an album inlpaclitaxel ratio of about 9:1. These unexpected
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`results are provi ded in the present appl ication as well as further data that I discuss below.
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`8.
`
`The present appl ication states,
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`[nhe ratio of protein, c.g., human serum albumin, to pharmaceutical agent in the
`pharmaceutical composition affects the ability of the pharmaceutical agent to bind and
`transport the pharmaceutical agent to a cell. In thi s regard, higher ratios of protein to
`pharmaceutical agent generally are associated with poor ce ll bind ing and transport of the
`pharmaceutical agent, which possibly is the resu It of competition for receptors at the cell
`surface.
`
`Paragraph [0041] of the present application.
`
`9.
`
`Example 45 anhe present application prov ides additional information relating to the
`finding that increas ing amounts of album in inhi bit the binding of paclitaxel to endothelial ce lls and
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`a hydrophobic surface coated with albumin. Specifically, Example 45 states,
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`Albumin was immobilized on a microliter plate. Fluorescent paclit.axel was added into the
`wells and the binding of paclitaxel was measured using a scanning fluorometer. Increasing
`amounts of albumin were added to the wells and the level of inhibition of paclitaxel binding
`to immobilized albumin was measured. T he data showed that as the amount of albumin
`added was increased, a corresponding decrease in binding was seen. A similar effect was
`seen with binding to endothel ial cells. Thi s indicated that higher albumin concentration
`inhibited binding ofpaclitaxel. Thus invention compositions having lower amounts of
`albumin are preferred.
`
`Paragraph [0149] of the specification.
`
`10.
`
`Exhibit 2 provides further evidence that the amount of albumin affects the abi lity of
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`paclitaxel to bind to endothel ial cells in a cell binding assay. In this experiment, the binding of
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`fluorescent-labeled paclitaxe l to human umbilical vein endothelial cells (HUVEC) was analyzed in
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`the presence of various concentrations of albumin . As shown in Exhibit 2, as the albumin
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`concentration increased, the binding ofpacl itaxel to the endothe lial cells decreased, suggesti ng that
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`an increase in the amount of album in inhibits the binding ofpaclitaxel to the endothelial cells.
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`Apotex v. Abraxis - IPR20 18-001 52, Ex. 1023, p.03 of61
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`Application No.: 11/553,339
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`Docket No.: 638772000301
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`I I.
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`Exhibits 3 and 4 provide further evidence that the amount of albumin affects the
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`ability of pac lit axel to bind to cells in an artificial system simulating a cell membrane in the milieu
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`of albumin. In this experiment, binding of pac lit axel onto a hydrophobic surface coated with
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`albumin in the presence of varying amounts of albumin added to the albumin-coated hydrophobic
`
`surface was analyzed. The albumin-coated hydrophobic surface was an artificial system used to
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`simulate a ccllular membrane in a milieu of albumin, such as endothelial cells exposed to albumin in
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`the blood. Fluorescent-labeled paclitaxel and various concentrations of albumin were added to the
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`albumin-coated hydrophobic surface. Binding of the pac! itaxcl to the albumin-coated hydrophobic
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`surface was determined using a scanning fluorometer.
`
`12.
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`Exhibit 3 shows the correlation between the bind ing ofpaciitaxel to the simulated
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`cellular membrane with the concentration of albumin added to the simulated cellular membrane. As
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`shown in Exhibit 3, as the concentration of the added albumin increased, the binding ofpaciitaxel
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`decreased, suggesting that an increase in the amount of album in added to the simulated ccllular
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`membrane inhibits the binding of paciitaxe! to the simulated cellu lar membrane.
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`13.
`
`The binding resu Its discussed above were further analyzed by examining the
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`correlation bet\\'een the binding of paclitaxel with the weight ratio ofalbuminlpaclitaxcl added to
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`the simulated cellular membrane. See Exhibit 4. As shown in Exh ibil4, as the albumin/paclitaxel
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`ratio increased, the binding ofpaclitaxel to the simulated cellular membrane decreased, suggesting
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`that an increase in the ratio of album inlpaclitaxel added to the simulated cellular membrane inhibits
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`the binding ofpaclitaxel to the simu lated cellular membrane.
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`14.
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`Surprisingly, we found that the effect of the albuminlpaclitaxel ratio on the binding
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`ofpaclitaxel changes dramatically at an albumin/paclitaxel weight ratio of about 9: 1. Exhibit 4.
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`Specifically, when the albuminlpaclitaxel ratios were above about 9: I, the paclitaxel binding
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`decreased linearly as the log of the albuminlpaclitaxel ratio increased with a slope of -14. When the
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`albumin/paclitaxel ratios were about 9: 1 or less, the paclitaxel binding decreased lin early as the log
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`of the albumin/paclilaxel ratio increased with a slope of -95, a nearly seven fo ld increase in the
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`slope. The two lines intersect creating an unexpected inflection point in the binding curve at an
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`Apotex v. Abraxis - IPR2018-00152, Ex. 1023, p.04 of61
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`Application No.: 11/553,339
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`Docket No.: 638772000301
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`albumin/pacl itaxel ratio of about 9: I. This suggests a dramatic change in the binding ofpaclitaxel
`
`that occurs at an albumin/pac litaxel ratio of about 9: I.
`
`IS.
`
`Albumin-based pac litaxel nanoparticle compositions utilize the natural receptor-
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`mediated albumin transportation process to facilitate the delivery ofpaclitaxel to tumor sites. See
`
`paragraphs [0045] and [0048] of the present application. Albumin mediates endothel ial transcytosis
`
`of plasma constituents via albumin receptor gp60 . It is believed that when an albumin-based
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`pnclitaxel nanopnrticle composition is injected into the blood vessel, the albumin-bound paclitaxel
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`binds to gp60 on endothelial cells and is transported to the endothelial cells. See paragraph [0045]
`
`and [0048] ofthe present application. We have unexpectedly Found that 1) the albuminlpaclitaxel
`
`ratio affects the binding of pac lit axel to endothelial cells and simulated cellu lar membrane, and 2)
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`there is a dramatic change in the binding ofpacHtaxcl that occurs at an albumin/paclitaxel ratio of
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`about 9:1. These findings suggest a biological significance ofalbumin/paclitaxel ratio in an
`
`albumin-based paclitaxcl nanoparticlc formu lation.
`
`The biological significance of albuminlpaclitaxel ratio in the claimed composition could not be
`predicted based on the ciled references
`
`16.
`
`The three reFerences cited in the Office Action report earlier clinical studies either
`
`conducted or supported by Abraxis. I These references provide no indication of any biological
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`significance ofa albuminJpaclitaxel ratio in a pharmaceutical composition. The biologica l
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`significance of albumin/paclitaxel ratio could not be predicted based on these references.
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`17.
`
`The albumin-based paclitaxel nanoparticie compositions used for the clinical studies
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`reported in the cited references were provided by Abraxis and represent an old formulation
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`developed by Abraxis prior to the filing ofthe present application (hereinafter referred to as "the old
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`formulation''). The albumin/paclitaxel weight ratiu in the old Formulation was about 19: 1.
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`18.
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`The old formulation allowed paclitaxel to be administered without using toxic
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`organic solvents, thus avoiding allergic reactions and side effects caused by the organic solvents
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`I ABr-007 is a code name used by Abraxis to refer to an albumin-based paditaxel nanoparticle C(Jmposition, and is not
`tied to any particular formulation.
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`Apotex v. Abraxis - IPR2018-00152, Ex. 1023, p.05 of61
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`Application No.: 111553,339
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`Docket No.: 63877200030 1
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`used in standard paclitaxel formu lations. f or example, premedication with steroid and
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`anti histamine \ .... as neccssary for solvent-containing paclitaxel fo rmulations in order to reduce
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`hypersensitivity reactions. Ibrah im reported that the old formulation could be safely administered
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`without premedication and that it can be administered conveniently in a 30-m inute infusion, without
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`causing any observable hypersensitivity reactions among the patients.
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`19.
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`The old formu lation was also shown to be efficacious in treating cancers. For
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`example. Damascelli reported a clinical study using the old formulation, and demonstrated that
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`intraarterial administration of the old formu lation had "acceptable toxicity" and at most dose levels
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`"showed considerable antitumor activity (42 assessable patients with 80.9%. complete and partial
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`response)" in treating advanced head and neck cancer and recurrent anal canal squamous cell
`carcinoma. See Abstract of Damas cell i.
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`20.
`
`Because the old fo rmulation was shown to be safe and ha\'e considerable antitumor
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`activity, there was no need or desirability based on the teaching of the cited re fere nces to further
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`modify the old formulation for the purpose of obtaining a safer and/or more efficacious formulation,
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`much less to mod ify it for th is purpose by reducing the a lbum in/paclitaxel ratio in the formulation.
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`21.
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`Further, it was believed that the fonnation of stable col loidal dispersions of albumin-
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`based paclitaxel nanoparticle compositions is fac ilitated by the combination of electrical repulsion
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`(negative zeta potential), steric stabilization, and viscosity, all attributable to albumin. Because
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`albumin has a net negative charge and is a macromolecu le, a higher albuminlpaclitaxel ratio in the
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`formulation could lead to increased steric and electrostatic intennolecular repulsion as well as
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`higher viscosity, and cou ld thus create a favorable environment for nanoparticles. One would
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`expect that, based on these favorable properties imparted by albumin, reducing the
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`albumin/paclitaxel ratio in the albumin-based paclitaxel nanopartic\e composition could destabilize
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`the nanopartici e composition.
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`Thus, there was no basis in the teaching of the cited references to further modify the
`22.
`old formulation by reducing the albumin/paclitaxcl ratio in the formulation, and the biological
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`Apotex v. Abraxis - IPR20 18-00 152, Ex. 1023 , p.06 of61
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`Application No.: 11 /553,339
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`Docket No.: 638772000301
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`significance of albumin/paclitaxcl ratio in the claimed composition could not bc predicted based on
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`the cited references.
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`A nanoparticle composition having an a/buminlpaclitaxe/ ratio of about 9:1 showed higher
`therapeutic efficacy and substantially reduced toxicity compared with the oldformulation
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`23.
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`Based on clinical studies, we have found unexpectedly that Abraxane®, an albumin-
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`based paclitaxel nanoparticle composition having about 9: I album in/pac1itaxel weight ratio, is more
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`efficacious than the old formulation (about 19:1 albuminlpac1itaxel ratio) in treating cancer. We
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`have further unexpectedly found that Abraxane® has substantially reduced toxicity compared with
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`the old formulat ion.
`
`24.
`
`Abraxane®, also referred to as "Abraxane for Injectable Suspension (paclitaxel
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`protein-bound particles for injectable suspension)," is a sterile filtered, injectable, and albumin
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`stabilized nanoparticle formulation ofpaclitaxel. The average particle size of the nanoparticles in
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`the formu lation is about 130 nm. Each single-use vial of Abraxane® contains 100 mg paclitaxe1
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`and approximately 900 mg human albumin. See Exhibit 5.
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`25.
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`Two clin ical studies using Abraxane® ("the 9: I formulation") and the old
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`formulation ("the 19:1 formulation'') were conducted in China with cancer patients having various
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`solid tumors. In thc first study, t\venty-two patients having different cancers were enrolled to be
`treated With the 19: I formulation at dose levels of 135-350 mg/m2 (mean dose of about 250 mg/m2
`).
`In the second study, 104 breast cancer patients were enro lled to be treated with the 9: 1 formulation
`at thc dosc level of260 mg/m2
`• In both studies, tumor shrinkage following treatment was evaluated
`using standard response criteria. Twenty one out of the 22 patients treated with the 19: I
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`formulation were evaluable for tumor shrinkage. All 104 patients treated with the 9: 1 formulat ion
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`wefC evaluable for tumor shrinkage.
`
`26.
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`Among the 2 1 evaluable patients treated with the 19: 1 formu lation, 8 showed
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`substantial tumor shrinkage upon treatment, leading to an overall response rate of38%. Among the
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`104 evaluable patients treated w ith the 9: 1 formulation, :56 showed substantial tumor shrinkage
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`upon treatment, leading to an overall response rate of 54%.
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`Apotex v. Abraxis - IPR2018-00152, Ex. 1023, p.07 of61
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`Application No.: 111553,339
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`Docket No.: 638772000301
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`27. We fUliher compared the response rates of the patients treated with the 19: I
`formulati on at a dose of260 mg/m2 or higher with those of patients treated with the 9: 1 formulation
`at a dose of260 mg/m2• Twelve out the 21 evaluable patients treated with the 19:1 formulation
`
`were treated at dose levels of 260-350 mg/m2. Among these 12 patients, 3 showed substantial
`tumor shrinkage upon treatment, leading to an overall response rate of25%. Among the 104
`evaluable patients treated with the 9: I formu lation at dose level of260 mg/m2, 56 showed
`substantial tumor shrinkage upon treatment, leading to an overall response rate of54%, more than
`double the 25% response rate observed in the study with the 19: 1 formulation.
`
`28. We further compared the toxicity profiles of the 9: 1 formulation and the 19: I
`
`formu lation by quantifying treatment-related adverse events of all grades' based on National Cancer
`Institute Common Toxicity Criteria Adverse Events (Nel CTCAE).2 Exhibit 5 lists adverse events
`
`commonly observed with the treatment of paclitaxcl. As shown in Exhibit 5, forthc majority of
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`these adverse events, the 9: I formulation showed substantially reduced number of incidents than the
`
`19: 1 formulation. These data demonstrate that the 9:1 formu lation has substantially reduced
`toxicity compared with the 19: 1 formulation.
`
`29.
`
`Our clinical data demonstrate that the 9: I formulation leads to a higher therapeutic
`
`efficacy than the old formulation. This result was unexpected. Since the amount of albumin in the
`
`pharmaceutical composition injected into the blood vessel is relatively small comparing to the high
`
`concentration of albumin present in the blood, it was further unexpected that reducing the
`
`albuminipaclitaxcl ratio in the a lbum in-based paclitaxel nanopartic1e composition would make any
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`difference in the therapeutic efficacy of tbe composition at all, much less result in the increased
`
`efficacy as we have observed in the clinical studies.
`
`30.
`
`Further, our data demonstrate that the 9: I formulation has substantially reduced
`
`toxicity compared with the old formulation. This result was unexpected . Since the amount of
`
`albumin in the pharmaceutical composition injected into the blood vessel is relatively small
`
`comparing to the high concentration of albumin present in the blood, it was further unexpected that
`
`~ CTCAE is a list ofadv~rs e event terms commonty used to assess drug toxicity in cancer treatment.
`
`Apotex v. Abraxis - IPR2018-00152, Ex. 1023 , p.08 of61
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`Application No.: 111553,339
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`9
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`Dockct No.: 638772000301
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`reducing the albuminlpaclitaxe1 ratio in the album in-based paclitaxel nanoparticle composition
`
`would lead to substantially reduced toxicity in the composition.
`
`Abraxane®
`
`31.
`
`Abraxam~® was approved in the United States in 2005 for treating metastatic breast
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`cancer based on its superior antihlmor effect and substantially reduced toxicity compared to the
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`FDA approved solvent-based paclitaxel fo rmulation, namely, Taxol®. In a randomized multicenter
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`phase III clinical trial conducted with 460 metastatic breast cancer patients, Abmxane® was shown
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`to produce an overall response rate of21.5%, nearly double the 11% response rate for patients
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`treated with Taxol®. Exhibit 6. Abraxane® also led to substantially longer tiine to disease
`
`progression ("TIP") compared to Taxol®, extending the ITP from 16.9 weeks (for Taxol®) to 23
`
`weeks (for Abraxane®). Gradishar et a!., Joumal of Clinical Oncology, 2005, 23(31):7794-7803
`(Exhibit 7). For patients receiving Abri1Xane® as a second line or greater therapy, Abraxanc® also
`showed significantly prolonged survival, with the risk for death being reduced by 28%. Exhibit 7.
`
`32. Within five years afier its initial approval in 2005, Abraxane® has become one of the
`
`lead ing drugs for treating metastatic breast cancer and has gained significant market share in the
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`taxane market. In 2009, it was estimated that the sale of Abraxane®accounts for about 37% of the
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`market share in taxane-based treatment of metastatic breast cancer, ranking No.1 along with the
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`well-established product Taxol®. For second-line and greater treatment of metastatic breast cancer,
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`the market share of Abraxane® surpassed that ofTaxol®, ranking No. I with a market share of
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`45%.
`
`33.
`
`In more recent studies, Abraxane® has also shown substantially improved
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`therapeutic efficacies in various clinical trials fo r treating difficult-te-treat cancers such as
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`pancreatic cancer, lung cancer, melanoma, and ovarian cancer. For example, Abraxane® has shown
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`remarkable results in treating pancreatic cancer when combined with gemcitabine. In a clinical trial
`
`treating metastatic pancreatic cancer using Abraxanc® and gemcitabine, it was (ound that the
`
`overall response rate for patients treated with the gemcitabinelAbraxanC® combination was 440/0.,
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`more than a five-fold increase over the reported 8% response rate for the gemcitabine monotherapy.
`
`Apotex v. Abraxis - IPR2018-00152, Ex. 1023 , p.09 of61
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`Application No.: 11 /553,339
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`The median time for progression free survival (PFS) was 6.9 months, and median time for overall
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`survival (OS) was 10.3 months, both of which nearly doubled those reported for the gemcitabinc
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`monotherapy (PFS 3.5 months; OS 6.0 months). These remarkable improvements are in stark
`
`contrast with the little or minimal improvements obtained when combining gemcitabine with many
`
`other therapeutic agents in the treatment of pallcreatic cancer.
`
`34.
`
`In a recent randomized Phase III clinical trial in combination with earboplatin for
`
`treating advanced non-small cell lung cancer (NSCLS), Abraxane® has shown significant
`
`improvement in overaJ1 response rate as compared to Taxol®.
`
`The advantages of the claimed compositions were unexpected
`
`35.
`
`In my opinion, the advantages of the compositions claimed in the present application
`
`were unexpected and could not be predicted based on the teaching of the cited references.
`
`36.
`
`As discussed above, the cited references prov ide no indication of the biological
`
`significance of albuminlpaclitax.el ratio in an albumin-based paclitaxel nanoparticle composition.
`
`Because the old formulation was shown to be safe and have considerable antitumor activity, there
`
`was no need or desirability based on the teaching of the cited references to further modify the old
`
`formulation for the purpose of obtaining a safer andlor more efficacious formulation, much less to
`
`modify it by reducing the albuminlpaclitaxel ratio in the formulation. Further, because albumin is a
`
`major contributing factor to the stability of an albumin-based paclitaxel nanoparticle composition,
`
`one would expect that reducing the albumin/pactitaxel ratio in the composition could destabilize the
`
`nanoparticle composition. There was therefore no reason to further modify the old fonnu lation by
`
`reducing the albuminlpaclitaxel ratio in the fonnu lation.
`
`37.
`
`Our finding that an increased album inlpaclitaxel ratio negatively alTects the binding
`
`ofpaclitaxel to endothelial cells was unexpected. Our finding that there is a dramatic change in the
`
`binding of paclitaxel that occurs at an albuminlpaclitaxel ratio of about 9: I was even more
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`surprising and unexpected.
`
`Apotex v. Abraxis - IPR2018-00152, Ex. 1023 , p. IO of6 1
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`38.
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`Furthermore. our find ing that a 9:1 formu lation shows higher therapeutic efficacy
`
`and reduced toxicity compared to the old fonnulation was unexpected. This is especially true in
`
`vicw ofthc relatively small amount of albumin in the pharmaceutical composition injected into the
`
`blood vessel compared to the high concentration of albumin already present in the blood.
`
`I hereby declare that all statements made herein of my own knowledge arc true and
`39.
`that all statements made 011 information and belief are believed to be true; and further that these
`
`statements were made with the knowledge that wi ll fu l false statements and the like so made aTC
`
`publishable by fine or imprisonment, or both, under Section 1001 of Title 18 ofthe United States
`
`Code, and that such willful false statt:ments may jeopardize the validity ufthe app lication, any
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`patent i~suing thereon, or any patent to which th is verified statement is directed.
`
`Ar.. /4, 'lO\D
`
`Date
`
`Apotex v. Abraxis - IPR20 18-0015 2, Ex. 1023, p. 11 of6 1
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`EXHIBIT 1
`EXHIBIT 1
`
`Apotex v. Abraxis -IPR201 8-001 52, Ex. 1023, p.12 of61
`Apotex v. Abraxis - IPR2018-00152, Ex. 1023, p.12 of61
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`

`

`BIOGRAPHY
`NElL PRAFULLA DESAI
`
`Vice President, Research and Development
`Abraxis Bioscience, Inc.
`Los Angeles, CA
`
`Neil Desai is currently Vice President of Research and Development at Abraxis Bioscience, Inc .. in Los
`Angeles, California, USA, where he is responsible for the development of the company's growing product
`pipeline and tht development or lhe company's intellectual property portfolio. These responsibilities include
`the dcvelopm~nt of proollClS from the early d iSC{lvery phase tIlrough preclinical testing, laic stage clinical
`studies and development for commer"illl manuf<lcluring. Dr. Desai is an inventor of ASl's nanotechnology
`and nanoparticle-albumin bound (nabn<) drug delivery platfonn, was primarily responsible for the
`development of its nanotechnology drug, AbraxanelP and the diSC(lvery of the nove! targeted biological
`pathway utilized by nabThi-d rugs This platform has ~n proven to enhance the efficacy Bnd safety of
`cytotoxic drugs though the novel targeted biological pathway. Abraxane was Approved by the fDA in
`January 2005 as the first in a new elass of mmotherapeutics for the treatment of metastatic brea~t cancer.
`
`Prior to jOining Am, Dr. Desai was Senior Dilcctor of Biopolymcr Research at VivoRx, Inc where he
`developed novel encapsulation systems for living cells and was part of the team that performed the world's
`fim successful encapsulated islClI cell transplant in a diabetic patient
`
`Dr. Desai has more than 17 years. of eJ<perience in the res<::arch and developrnenl of novel drug delivery
`systems and biocompatibJe polymers. HI' holds over 40 issued US plllents, has authored over 30 peer(cid:173)
`reviewed puhlications, made over 60 pre'lentatiOlls at scientific meetings lind is also active in the re5eaIT.h
`community having organized a nd chaired several symposia in the areas of biocompatible polymers a nd
`nanotechnology-based deJivct}' systems.
`
`DESAI, Page 1/9
`
`Apotex v. Abraxis - IPR201 8-00 152, Ex. 1023, p. 13 of6 1
`
`

`

`EXHIBIT 2
`EXHIBIT 2
`
`Apotex v. Abraxis - IPR20 18-00 152, Ex. 1023 , p. 14 of6 1
`Apotex v. Abraxis — 1PR2018-00152,EX. 1023, p.14 of61
`
`

`

`Exhibit 2.
`
`Inhibition of paclitaxel binding to cell-surface of human umbilical vein
`endothelial cells (HUVEC) with increase in albumin
`
`100-
`
`80
`
`..... HUVEC
`
`~
`
`60
`
`:::!<
`0 -
`07
`C .-'tl 40
`
`c
`to
`
`20
`
`0
`0.001
`
`0.01
`
`0.1
`1
`HSA%
`
`10
`
`100
`
`Apotex v. Abrax is -IPR201 8-00152, Ex. 1023, p.15 of6 1
`
`

`

`EXHIBIT 3
`EXHIBIT 3
`
`Apotex v. Abrax is - IPR20 18-00 152, Ex. 1023, p.16 of 6 1
`Apotex v. Abraxis - IPR2018-00152, Ex. 1023, p.16 0f61
`
`

`

`Exhibit 3.
`
`Inhibition of paclitaxel binding to simulated cell membrane (hydrophobic
`surface coated with albumin) with increasing amounts of albumin
`
`110
`100
`90
`~ 80
`70
`~ c
`-
`60
`.~ 50
`'tl 40
`c: .-
`30
`D'l 20
`10
`0
`-10
`
`•
`
`•
`
`0
`
`20
`10
`Albumin Concentration (%)
`
`30
`
`Apotex v. Abraxis - IPR20 18-00 152, Ex. 1023 , p.l? of 6 1
`
`

`

`EXIDBIT4
`EXHIBIT 4
`
`Apotex v. Abrax is -I PR20 IS-00 152, Ex. 1023, p. IS of6 1
`Apotex v. Abraxis - IPR2018-00152, Ex. 1023, p.18 0f61
`
`

`

`Exhibit 4.
`
`Paclitaxel binding to simulated cell membrane (hydrophobic surface coated with
`albumin) showing an inflection point at an albumin: paclitaxel ratio of about 9:1
`
`Slope = -95
`
`Region of ral io
`~abouI9 : 1
`
`Inflection poinl in
`the binding data
`occurs at a ratio of
`about 9:1
`
`~
`
`,,11 • ~
`Cl c:
`'5
`c:
`iii
`
`>9 ratio
`
`Slope = -14
`~ ..
`•
`
`o
`
`1
`
`2
`Log (Albumin :paclitaxel ratio)
`
`3
`
`4
`
`Apotex v. Abraxis - IPR20 18-00 152, Ex. 1023 , p.19 of 6 1
`
`

`

`EXHIBITS
`EXHIBIT 5
`
`Apotex v. Abraxis - IP R20 18-00 152, Ex. 1023, p.20 of 6 1
`Apotex v. Abraxis — IPR2018-00152, Ex. 1023, p.20 01°61
`
`

`

`Exhibit 5
`
`Treatment-related Adverse Events of All Grades by NCI CTCAE
`Term
`
`NCI crCAE Ter m
`(Report ed Adve rcse
`Event)
`
`9:1 formulation
`260 mg/ml
`q3 Weeks (n.,.104)
`
`19: 1 formulation
`135-350 mgtml
`(mean dose a bout 150 mg/m2)
`q3 Weeks (n==ll)
`
`Neurology: Neuropathy:
`Sensory
`BloodlBone Marrow:
`Lymphopenia
`Bloodl13one Marrow:
`Leukocytopenia
`B1oodlBone Marrow:
`Hemoglobinemia
`OloodlBone Marrow;
`Neutropenia
`Pain: Myalgia
`Pain: Arthralgia
`G astrointestinal:
`Anorexia
`Gastrointestinal: Diarrhea
`G astroinltlstinal; Nausea
`DermatologylSki n:
`Rash/Desquamlition
`Derm atologyfSkill:
`Pru ritusl1tching
`Constitutional
`Symptoms: Fatigue
`
`79 (16%)
`
`6 (6%)
`
`61 (64%)
`
`16(15%)
`
`72 (69%)
`
`40 (38%)
`23 (22%)
`19 ( 18%)
`
`16 (1 5%)
`24 (23%)
`27 (26%)
`
`22(21%)
`
`16(15%)
`
`19 (H6%)
`
`8 (36%)
`
`1 g (82%)
`
`11 (11%)
`
`14 (64%)
`
`I() (45%)
`6 (27"10)
`16 (13%)
`
`S (23%)
`8 (36o/. )
`9 (4 1%)
`
`S (23% )
`
`8 (36%)
`
`Apotex v. Abraxis - IPR20 18-00 152, Ex. 1023 , p.2 1 of6 1
`
`

`

`EXHIBIT 6
`EXHIBIT 6
`
`Apotex v. Abraxis -IPR201 8-00152, Ex. 1023, p.22 of6 1
`Apotex v. Abraxis — IPR2018-00152, Ex. 1023, p.22 0f61
`
`

`

`Version: September 2009
`Rx Only
`
`ABRAXANE® for Injectable Suspens~on (paclitaxel protcin. bound particles for
`injectable suspension)
`(a lbumin·bound)
`
`(Patient Information Enclosed)
`
`WARNING
`
`ABRAXANR for Injectable SU5pension (paclitaxel protein-bound particles for
`injecta ble suspension) should be administered und er the supervision ofa
`physician experienced in the use of cancer chemotherapeutic ageuts.
`App ropriate ma nagement of .complications is possible only when adequate
`diagnostic a nd treatmcnt facilities arc readily available.
`
`ABRAXANE therapy shou ld not be ad ministered to patients with metastatic
`b reast ca ucer who have ba~dinc neutrophil counb of less Ihan 1,500 ccllshum3.
`I n or der to monitor the occurrence of bone ma rrow suppression, primarily
`neu tropenia, which may be severe and r esult in infection, it is r ecommended
`that freq uent peripheral blood cell counts be performed Oll alllJfltients
`receiving ARRAXANE.
`
`Note: An albumin form of pa clitaxcl may substa ntially aITect a drug'S
`functional p ropertie~ relative to t hose of drug in solu tion. DO NOT
`SUBSTITUTE FOR OR WIUI OTHER PACLITAXEL FORl\tIULATIONS.
`
`DESCRIPTION
`
`ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable
`
`suspension) is an albumin·bound form of pac lit axel with a mean particle size ofapproximately
`
`130 nanometers. Paclitaxel exists in the particles in a non.crystalline, amorphous state.
`
`ABRAXANE is supplied as a white to yellow, sterile, lyophilized powder for reconsUtution with
`20 mL oFO.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each singlt::-ust!
`vial contains 100 mg o fpaclitax~ l and approximately 900 mg of human albumin. Each millil iter
`
`(mL) of reconstituted suspension contains 5 mg paclitaxel. ABRAXANE is free of solvents.
`
`Apotex v. Abraxis - IPR2018-00152, Ex. 1023 , p.23 of6 1
`
`

`

`The active agent in ABRAXAN~ is paclitaxel, a natural product with antitumor activity.
`Paclitaxel is obtained from Taxus media. The chemical name for paclitaxel is 5p,20-Epoxy-
`1,2a.,4, 7P, lOp, 13o.-hexahydroxytax-l l-en-9-one 4, I O-diacetate 2-benzoate 13-ester with (2R,3S)(cid:173)
`N-benzoyl-3-phenylisoserine.
`
`Paclitaxel has the fo llowing structural form ula:
`
`o
`
`Paclitaxel is a white to off-white crystalline powder with the empirical formula C(7HslNOI4 and
`a molecular weight of 85).91. It is highly lipophilic, insoluble in water, and melts at
`approximately 216"C \0 217°C.
`
`CLINICAL PHARMACOLO