Application No.: 11/553,339
`
`Docket No.: 638772000301
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`Neil P. DESAI et al.
`
`Application No.: 11/553,339
`
`Confirmation No.: 3605
`
`Filed: October 26, 2006
`
`For: COMPOSITIONS AND METHODS OF
`DELIVERY OF PHARMACOLOGICAL
`AGENTS
`
`Art Unit: 1656
`
`Examiner: M. Tsay
`
`DECLARATION OF NEIL P. DESAI PURSUANT TO 37 C.F.R § 1.132
`
`Commissioner for Patents
`
`P.O. Box 1450
`
`Alexandria, VA 22313-1450
`
`Dear Sir:
`
`I, Neil P. Desai, declare as follows:
`
`1.
`
`I am Senior Vice President of Global Research and Development at Abraxis
`
`BioScience, LLC ("Abraxis"), assignee ofthe above-referenced patent application. A copy of my
`
`biography is attached hereto as Exhibit 1.
`
`2.
`
`I have more than 17 years of experience in the research and development of drug
`
`delivery systems and biocompatible polymers. I was one of the individuals responsible for the
`
`development of Abraxis' nanoparticle-albumin bound (nab™) drug delivery platform and its
`
`product Abraxane®, one of the leading drugs for treating metastatic breast cancer in the United
`
`States.
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`3.
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`I am one of the named inventors of the above-referenced patent application and am
`
`familiar with the technical features of the invention and the amended claims.
`
`4.
`
`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
`
`Damascelli et al., Cancer, 2001, 92(10):2592-2602 ("Damascelli"), Ibrahim et al., Proc. Am. Soc.
`
`Clin. Oncol., 2000, 19:609F ("Ibrahim"), and one of Abraxis' earlier patents, U.S. Pat. No.
`
`6,537,579 ("the '579 patent"), on which I am also a named inventor. I have read and am familiar
`
`with these cited references.
`
`5.
`
`The claims as amended in the present patent application are generally directed to a
`
`pharmaceutical composition for injection comprising paclitaxel and a pharmaceutically acceptable
`
`carrier, wherein the pharmaceutically acceptable carrier comprises albumin, wherein the albumin
`
`and the paclitaxel in the composition are formulated as nanoparticles, wherein the nanoparticles
`
`have a particle size of less than about 200 nm, and wherein the weight ratio of albumin to paclitaxel
`
`in the composition is about 1:1 to about 9:1. In the sections below, I generally refer to a
`
`pharmaceutical composition for injection comprising paclitaxel and a pharmaceutically acceptable
`
`carrier, wherein the pharmaceutically acceptable carrier comprises albumin, wherein the albumin
`
`and the paclitaxel in the composition are formulated as nanoparticles, wherein the nanoparticles
`
`have a particle size of less than about 200 nm as an "albumin-based paclitaxel nanoparticle
`
`composition."
`
`6.
`
`In this declaration, I discuss unexpected results associated with the claimed
`
`albumin/paclitaxel ratio, including striking biological and clinical data relating to the ratio.
`
`An albumin/paclitaxel ratio of about 1:1 to about 9:1 unexpectedly shows increased cellular
`binding
`
`7.
`
`We have found, unexpectedly, that the ratio of albumin to paclitaxel in an albumin-
`
`based paclitaxel nanoparticle composition affects the ability ofpaclitaxel to bind to endothelial
`
`cells. Higher albumin/paclitaxel ratios are associated with poor cellular binding of paclitaxel, while
`
`lower albumin/paclitaxel ratios are associated with enhanced cellular binding ofpaclitaxel. We
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`have further unexpectedly found that the effect of albumin/paclitaxel ratio on the binding of
`
`paclitaxel changes dramatically at an albumin/paclitaxel ratio of about 9:1, as evidenced by an
`
`inflection point in the binding curve at an albumin/paclitaxel ratio of about 9:1. These unexpected
`
`results are provided in the present application as well as further data that I discuss below.
`
`8.
`
`The present application states,
`
`[T]he ratio of protein, e.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 this regard, higher ratios of protein to
`pharmaceutical agent generally are associated with poor cell binding and transport of the
`pharmaceutical agent, which possibly is the result of competition for receptors at the cell
`surface.
`
`Paragraph [0041] ofthe present application.
`
`9.
`
`Example 45 ofthe present application provides additional information relating to the
`
`finding that increasing amounts of albumin inhibit the binding of paclitaxel to endothelial cells and
`
`a hydrophobic surface coated with albumin. Specifically, Example 45 states,
`
`Albumin was immobilized on a microtiter plate. Fluorescent paclitaxel 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. The 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 endothelial cells. This indicated that higher albumin concentration
`inhibited binding ofpaclitaxel. Thus invention compositions having lower amounts of
`albumin are preferred.
`
`Paragraph [0 149] of the specification.
`
`10.
`
`Exhibit 2 provides further evidence that the amount of albumin affects the ability of
`
`paclitaxel to bind to endothelial cells in a cell binding assay. In this experiment, the binding of
`
`fluorescent-labeled paclitaxel to human umbilical vein endothelial cells (HUVEC) was analyzed in
`
`the presence of various concentrations of albumin. As shown in Exhibit 2, as the albumin
`
`concentration increased, the binding of paclitaxel to the endothelial cells decreased, suggesting that
`
`an increase in the amount of albumin inhibits the binding of paclitaxel to the endothelial cells.
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`11.
`
`Exhibits 3 and 4 provide further evidence that the amount of albumin affects the
`
`ability of paclitaxel to bind to cells in an artificial system simulating a cell membrane in the milieu
`
`of albumin. In this experiment, binding of paclitaxel onto a hydrophobic surface coated with
`
`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
`
`simulate a cellular membrane in a milieu of albumin, such as endothelial cells exposed to albumin in
`
`the blood. Fluorescent-labeled paclitaxel and various concentrations of albumin were added to the
`
`albumin-coated hydrophobic surface. Binding ofthe paclitaxel to the albumin-coated hydrophobic
`
`surface was determined using a scanning fluorometer.
`
`12.
`
`Exhibit 3 shows the correlation between the binding ofpaclitaxel to the simulated
`
`cellular membrane with the concentration of albumin added to the simulated cellular membrane. As
`
`shown in Exhibit 3, as the concentration ofthe added albumin increased, the binding ofpaclitaxel
`
`decreased, suggesting that an increase in the amount of albumin added to the simulated cellular
`
`membrane inhibits the binding of paclitaxel to the simulated cellular membrane.
`
`13.
`
`The binding results discussed above were further analyzed by examining the
`
`correlation between the binding of paclitaxel with the weight ratio of albumin/paclitaxel added to
`
`the simulated cellular membrane. See Exhibit 4. As shown in Exhibit 4, as the albumin/paclitaxel
`
`ratio increased, the binding of paclitaxel to the simulated cellular membrane decreased, suggesting
`
`that an increase in the ratio of albumin/paclitaxel added to the simulated cellular membrane inhibits
`
`the binding ofpaclitaxel to the simulated cellular membrane.
`
`14.
`
`Surprisingly, we found that the effect of the albumin/paclitaxel ratio on the binding
`
`of paclitaxel changes dramatically at an albumin/paclitaxel weight ratio of about 9:1. Exhibit 4.
`
`Specifically, when the albumin/paclitaxel ratios were above about 9:1, the paclitaxel binding
`
`decreased linearly as the log ofthe albumin/paclitaxel ratio increased with a slope of -14. When the
`
`albumin/paclitaxel ratios were about 9: 1 or less, the paclitaxel binding decreased linearly as the log
`
`of the albumin/paclitaxel ratio increased with a slope of -95, a nearly seven fold increase in the
`
`slope. The two lines intersect creating an unexpected inflection point in the binding curve at an
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`albumin/paclitaxel ratio of about 9: 1. This suggests a dramatic change in the binding of paclitaxel
`
`that occurs at an albumin/paclitaxel ratio of about 9:1.
`
`15.
`
`Albumin-based paclitaxel nanoparticle compositions utilize the natural receptor-
`
`mediated albumin transportation process to facilitate the delivery of paclitaxel to tumor sites. See
`
`paragraphs [0045] and [0048] of the present application. Albumin mediates endothelial transcytosis
`
`of plasma constituents via albumin receptor gp60. It is believed that when an albumin-based
`
`paclitaxel nanoparticle composition is injected into the blood vessel, the albumin-bound paclitaxel
`
`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 albumin/paclitaxel
`
`ratio affects the binding of paclitaxel to endothelial cells and simulated cellular membrane, and 2)
`
`there is a dramatic change in the binding of paclitaxel that occurs at an albumin/paclitaxel ratio of
`
`about 9:1. These findings suggest a biological significance of albumin/paclitaxel ratio in an
`
`albumin-based paclitaxel nanoparticle formulation.
`
`The biological significance of albumin/paclitaxel ratio in the claimed composition could not be
`predicted based on the cited references
`
`The three references cited in the Office Action report earlier clinical studies either
`16.
`conducted or supported by Abraxis. 1 These references provide no indication of any biological
`
`significance of a albumin/paclitaxel ratio in a pharmaceutical composition. The biological
`
`significance of albumin/paclitaxel ratio could not be predicted based on these references.
`
`17.
`
`The albumin-based paclitaxel nanoparticle compositions used for the clinical studies
`
`reported in the cited references were provided by Abraxis and represent an old formulation
`
`developed by Abraxis prior to the filing of the present application (hereinafter referred to as "the old
`
`formulation"). The albumin/paclitaxel weight ratio in the old formulation was about 19:1.
`
`18.
`
`The old formulation allowed paclitaxel to be administered without using toxic
`
`organic solvents, thus avoiding allergic reactions and side effects caused by the organic solvents
`
`1 ABI-007 is a code name used by Abraxis to refer to an albumin-based paclitaxel nanoparticle composition, and is not
`tied to any particular formulation.
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`used in standard paclitaxel formulations. For example, premedication with steroid and
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`antihistamine was necessary for solvent-containing paclitaxel formulations in order to reduce
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`hypersensitivity reactions. Ibrahim reported that the old formulation could be safely administered
`
`without premedication and that it can be administered conveniently in a 30-miriute infusion, without
`
`causing any observable hypersensitivity reactions among the patients.
`
`19.
`
`The old formulation was also shown to be efficacious in treating cancers. For
`
`example, Damascelli reported a clinical study using the old formulation, and demonstrated that
`
`intraarterial administration of the old formulation had "acceptable toxicity" and at most dose levels
`
`"showed considerable antitumor activity (42 assessable patients with 80.9% complete and partial
`
`response)" in treating advanced head and neck cancer and recurrent anal canal squamous cell
`
`carcinoma. See Abstract ofDamascelli.
`
`20.
`
`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 and/or more efficacious formulation,
`
`much less to modify it for this purpose by reducing the albumin/paclitaxel ratio in the formulation.
`
`21.
`
`Further, it was believed that the formation of stable colloidal dispersions of albumin-
`
`based paclitaxel nanoparticle compositions is facilitated by the combination of electrical repulsion
`
`(negative zeta potential), steric stabilization, and viscosity, all attributable to albumin. Because
`
`albumin has a net negative charge and is a macromolecule, a higher albumin/paclitaxel ratio in the
`
`formulation could lead to increased steric and electrostatic intermolecular repulsion as well as
`
`higher viscosity, and could thus create a favorable environment for nanoparticles. One would
`
`expect that, based on these favorable properties imparted by albumin, reducing the
`
`albumin/paclitaxel ratio in the albumin-based paclitaxel nanoparticle composition could destabilize
`
`the nanoparticle composition.
`
`22.
`
`Thus, there was no basis in the teaching of the cited references to further modify the
`
`old formulation by reducing the albumin/paclitaxel ratio in the formulation, and the biological
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`significance of albumin/paclitaxel ratio in the claimed composition could not be predicted based on
`
`the cited references.
`
`A nanoparticle composition having an albumin/paclitaxel ratio of about 9:1 showed higher
`therapeutic efficacy and substantially reduced toxicity compared with the old formulation
`
`23.
`
`Based on clinical studies, we have found unexpectedly that Abraxane®, an albumin-
`
`based paclitaxel nanoparticle composition having about 9: 1 albumin/paclitaxel weight ratio, is more
`
`efficacious than the old formulation (about 19:1 albumin/paclitaxel ratio) in treating cancer. We
`
`have further unexpectedly found that Abraxane® has substantially reduced toxicity compared with
`
`the old formulation.
`
`24.
`
`Abraxane®, also referred to as "Abraxane for Injectable Suspension (paclitaxel
`
`protein-bound particles for injectable suspension)," is a sterile filtered, injectable, and albumin
`
`stabilized nanoparticle formulation of paclitaxel. The average particle size of the nanoparticles in
`
`the formulation is about 130 nm. Each single-use vial of Abraxane® contains 100 mg paclitaxel
`
`and approximately 900 mg human albumin. See Exhibit 5.
`
`25.
`
`Two clinical studies using Abraxane® ("the 9:1 formulation") and the old
`
`formulation ("the 19:1 formulation") were conducted in China with cancer patients having various
`
`solid tumors. In the first study, twenty-two patients having different cancers were enrolled to be
`treated with the 19:1 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 enrolled to be treated with the 9:1 formulation
`at the dose 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 19:1
`
`formulation were evaluable for tumor shrinkage. All 104 patients treated with the 9:1 formulation
`
`were evaluable for tumor shrinkage.
`
`26.
`
`Among the 21 evaluable patients treated with the 19:1 formulation, 8 showed
`
`substantial tumor shrinkage upon treatment, leading to an overall response rate of 38%. Among the
`
`104 evaluable patients treated with the 9:1 formulation, 56 showed substantial tumor shrinkage
`
`upon treatment, leading to an overall response rate of 54%.
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`27. We further compared the response rates ofthe patients treated with the 19:1
`formulation 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 of260-350 mg/m2
`tumor shrinkage upon treatment, leading to an overall response rate of 25%. Among the 104
`evaluable patients treated with the 9:1 formulation at dose level of260 mg/m2
`
`• Among these 12 patients, 3 showed substantial
`
`, 56 showed
`
`substantial tumor shrinkage upon treatment, leading to an overall response rate of 54%, more than
`
`double the 25% response rate observed in the study with the 19:1 formulation.
`
`28. We further compared the toxicity profiles ofthe 9:1 formulation and the 19:1
`
`formulation by quantifying treatment-related adverse events of all grades based on National Cancer
`Institute Common Toxicity Criteria Adverse Events (NCI CTCAE). 2 Exhibit 5 lists adverse events
`
`commonly observed with the treatment ofpaclitaxel. As shown in Exhibit 5, for the majority of
`
`these adverse events, the 9:1 formulation showed substantially reduced number of incidents than the
`
`19:1 formulation. These data demonstrate that the 9:1 formulation has substantially reduced
`
`toxicity compared with the 19:1 formulation.
`
`29.
`
`Our clinical data demonstrate that the 9:1 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
`
`albumin/paclitaxel ratio in the albumin-based paclitaxel nanoparticle composition would make any
`
`difference in the therapeutic efficacy of the 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 9:1 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
`
`2 CTCAE is a list of adverse event terms commonly used to assess drug toxicity in cancer treatment.
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`reducing the albumin/paclitaxel ratio in the albumin-based paclitaxel nanoparticle composition
`
`would lead to substantially reduced toxicity in the composition.
`
`Abraxane®
`
`31.
`
`Abraxane® was approved in the United States in 2005 for treating metastatic breast
`
`cancer based on its superior antitumor effect and substantially reduced toxicity compared to the
`
`FDA approved solvent-based paclitaxel formulation, namely, Taxol®. In a randomized multicenter
`
`phase III clinical trial conducted with 460 metastatic breast cancer patients, Abraxane® was shown
`
`to produce an overall response rate of 21.5%, nearly double the 11% response rate for patients
`
`treated with Taxol®. Exhibit 6. Abraxane® also led to substantially longer time to disease
`
`progression ("TIP") compared to Taxol®, extending the TIP from 16.9 weeks (for Taxol®) to 23
`
`weeks (for Abraxane®). Gradishar et al., Journal of Clinical Oncology, 2005, 23(31 ):7794-7803
`
`(Exhibit 7). For patients receiving Abraxane® as a second line or greater therapy, Abraxane® also
`
`showed significantly prolonged survival, with the risk for death being reduced by 28%. Exhibit 7.
`
`32. Within five years after its initial approval in 2005, Abraxane® has become one ofthe
`
`leading drugs for treating metastatic breast cancer and has gained significant market share in the
`
`taxane market. In 2009, it was estimated that the sale of Abraxane® accounts for about 37% of the
`
`market share in taxane-based treatment of metastatic breast cancer, ranking No. 1 along with the
`
`well-established product Taxol®. For second-line and greater treatment of metastatic breast cancer,
`
`the market share of Abraxane® surpassed that ofTaxol®, ranking No. 1 with a market share of
`
`45%.
`
`33.
`
`In more recent studies, Abraxane® has also shown substantially improved
`
`therapeutic efficacies in various clinical trials for treating difficult-to-treat cancers such as
`
`pancreatic cancer, lung cancer, melanoma, and ovarian cancer. For example, Abraxane® has shown
`
`remarkable results in treating pancreatic cancer when combined with gemcitabine. In a clinical trial
`
`treating metastatic pancreatic cancer using Abraxane® and gemcitabine, it was found that the
`
`overall response rate for patients treated with the gemcitabine/Abraxane® combination was 44%,
`
`more than a five-fold increase over the reported 8% response rate for the gemcitabine monotherapy.
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`The median time for progression free survival (PFS) was 6.9 months, and median time for overall
`
`survival (OS) was 10.3 months, both ofwhich nearly doubled those reported for the gemcitabine
`
`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 pancreatic cancer.
`
`34.
`
`In a recent randomized Phase III clinical trial in combination with carboplatin for
`
`treating advanced non-small cell lung cancer (NSCLS), Abraxane® has shown significant
`
`improvement in overall response rate as compared to Taxol®.
`
`The advantages of the claimed compositions were unexpected
`
`35.
`
`In my opinion, the advantages ofthe 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 provide no indication of the biological
`
`significance of albumin/paclitaxel 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 and/or more efficacious formulation, much less to
`
`modify it by reducing the albumin/paclitaxel 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/paclitaxel ratio in the composition could destabilize the
`
`nanoparticle composition. There was therefore no reason to further modify the old formulation by
`
`reducing the albumin/paclitaxel ratio in the formulation.
`
`37.
`
`Our finding that an increased albumin/paclitaxel ratio negatively affects the binding
`
`of paclitaxel to endothelial cells was unexpected. Our finding that there is a dramatic change in the
`
`binding of paclitaxel that occurs at an albumin/paclitaxel ratio of about 9:1 was even more
`
`surprising and unexpected.
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`38.
`
`Furthermore, our finding that a 9:1 formulation shows higher therapeutic efficacy
`
`and reduced toxicity compared to the old formulation was unexpected. This is especially true in
`
`view of the 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.
`
`39.
`
`I hereby declare that all statements made herein of my own knowledge are true and
`
`that all statements made on information and belief are believed to be true; and further that these
`
`statements were made with the knowledge that willful false statements and the like so made are
`
`publishable by fine or imprisonment, or both, under Section 1001 ofTitle 18 ofthe United States
`
`Code, and that such willful false statements may jeopardize the validity of the application, any
`
`patent issuing thereon, or any patent to which this verified statement is directed.
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`EXHIBIT 1
`EXHIBIT 1
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`BIOGRAPHY
`NEIL 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 the development ofthe company's intellectual property portfolio. These responsibilities include
`the development of products from the early discovery phase through preclinical testing, late stage clinical
`studies and development for commercial manufacturing. Dr. Desai is an inventor of ABI's nanotechnology
`and nanoparticle-albumin bound (nabTM) drug delivery platform, was primarily responsible for the
`development of its nanotechnology drug, Abraxane® and the discovery of the novel targeted biological
`pathway utilized by nab™-drugs. This platform has been proven to enhance the efficacy and 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 class of nanotherapeutics for the treatment of metastatic breast cancer.
`
`Prior to joining ABI, Dr. Desai was Senior Director of Biopolymer Research at VivoRx, Inc where he
`developed novel encapsulation systems for living cells and was part of the team that performed the world's
`first successful encapsulated islet cell transplant in a diabetic patient.
`
`Dr. Desai has more than 17 years of experience in the research and development of novel drug delivery
`systems and biocompatible polymers. He holds over 40 issued US patents, has authored over 30 peer(cid:173)
`reviewed publications, made over 60 presentations at scientific meetings and is also active in the research
`community having organized and chaired several symposia in the areas of biocompatible polymers and
`nanotechnology-based delivery systems.
`
`DESAI, Page 1/9
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`EXHIBIT2
`EXHIBIT 2
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`Exhibit 2.
`
`Inhibition of paclitaxel binding to cell-surface of human umbilical vein
`endothelial cells (HUVEC) with increase in albumin
`
`-+- HUVEC
`
`100
`
`80
`
`.-..
`?fl.
`._.
`
`0') c ·-"'C c ·-al
`
`0 1
`0.001
`
`I
`0.01
`
`I
`I
`1
`0.1
`HSA%
`
`I+~
`10
`
`I
`100
`
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`EXHIBIT3
`EXHIBIT 3 -
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`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
`.._...
`en 60
`.~ 50
`
`-g 40 m 3o
`•
`•
`10 -1~rr-~·==---~·&-------_:
`
`20
`
`0
`
`I
`I
`20
`10
`Albumin Concentration (%)
`
`I
`30
`
`CIPLA EXHIBIT 1023
`Page 17 of 61
`
`

`

`EXHIBIT 4
`EXHIBIT 4
`
`CIPLA EXHIBIT 1023
`
`Page 18 of 61
`
`CIPLA EXHIBIT 1023
`Page 18 of 61
`
`

`

`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_
`
`100
`
`80
`
`-";f:. 60 -Ol
`
`t: ·-"0
`t: ·-OJ
`
`Region of ratio
`~about9:1
`
`Inflection point in
`the binding data
`occurs at a ratio of
`about 9:1
`
`--.---·
`
`0 I
`0
`
`>9 ratio
`~I
`1
`
`,.....
`
`I
`2
`Log (Albumin: paclitaxel ratio)
`
`I
`3
`
`I
`4
`
`CIPLA EXHIBIT 1023
`Page 19 of 61
`
`

`

`EXHIBIT 5
`EXHIBIT 5
`
`CIPLA EXHIBIT 1023
`
`Page 20 of 61
`
`CIPLA EXHIBIT 1023
`Page 20 of 61
`
`

`

`Exhibit 5
`
`Treatment-related Adverse Events of All Grades by NCI CTCAE
`Term
`
`NCI CTCAE Term
`(Reported Adverese
`Event)
`
`9:1 formulation
`260 mg/m 2
`q3 Weeks (n=104)
`
`19:1 formulation
`135-350 mg/m 2
`(mean dose about 250 mg/m2)
`q3 Weeks (n=22)
`
`Neurology: Neuropathy:
`Sensory
`Blood/Bone Marrow:
`Lymphopenia
`Blood/Bone Marrow:
`Leukocytopenia
`Blood/Bone Marrow:
`Hemoglobinemia
`Blood/Bone Marrow:
`Neutropenia
`Pain: Myalgia
`Pain: Arthralgia
`Gastrointestinal:
`Anorexia
`Gastrointestinal: Diarrhea
`Gastrointestinal: Nausea
`Dermatology/Skin:
`Rash/Desquamation
`Dermatology/Skin:
`Pruritus/Itching
`Constitutional
`Symptoms: Fatigue
`
`79 (76%)
`
`6 (6%)
`
`67 (64%)
`
`16 (15%)
`
`72 (69%)
`
`40 (38%)
`23 (22%)
`19 (18%)
`
`16(15%)
`24 (23%)
`27 (26%)
`
`22 (21%)
`
`16 (15%)
`
`19 (86%)
`
`8 (36%)
`
`18 (82%)
`
`17 (77%)
`
`14 (64%)
`
`10 (45%)
`6 (27%)
`16 (73%)
`
`5 (23%)
`8 (36%)
`9 (41%)
`
`5 (23%)
`
`8 (36%)
`
`CIPLA EXHIBIT 1023
`Page 21 of 61
`
`

`

`EXHIBIT6 W
`
`CIPLA EXHIBIT 1.023 ’
`
`Page 22 of 61
`
`CIPLA EXHIBIT 1023
`Page 22 of 61
`
`

`

`Version: September 2009
`
`Rx Only
`
`ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for
`injectable suspension)
`(albumin-bound)
`
`(Patient Information Enclosed)
`
`WARNING
`
`ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for
`injectable suspension) should be administered under the supervision of a
`physician experienced in the use of cancer chemotherapeutic agents.
`Appropriate management of.complications is possible only when adequate
`diagnostic and treatment facilities are readily available.
`
`ABRAXANE therapy should not be administered to patients with metastatic
`breast cancer who have baseline neutrophil counts ofless than 1,500 cclls/mm 3
`In order to monitor the occurrence of bone marrow suppression, primarily
`neutropenia, which may be severe and result in infection, it is recommended
`that frequent peripheral blood cell counts be performed on all patients
`receiving ABRAXANE.
`
`•
`
`Note: An albumin form of paclitaxel may substantially affect a drug's
`functional properties relative to those of drug in solution. DO NOT
`SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.
`
`DESCRIPTION
`
`ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable
`
`suspension) is an albumin-bound form of paclitaxel with a mean particle size of approximately
`
`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 reconstitution with
`
`20 mL of0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use
`
`vial contains 100 mg ofpaclitaxel and approximately 900 mg of human albumin. Each milliliter
`
`(mL) of reconstituted suspension contains 5 mg paclitaxel. ABRAXANE is free of solvents.
`
`CIPLA EXHIBIT 1023
`Page 23 of 61
`
`

`

`The active agent in ABRAXANE® is paclitaxel, a natural product with antitumor activity.
`
`Paclitaxel is obtained from Taxus media. The chemical name for paclitaxel is 5~,20-Epoxy-
`
`1,2a,4, 7~, I 0~, 13a-hexahydroxytax-ll-en-9-one 4, I 0-diacetate 2-benzoate 13-ester with (2R,3S)(cid:173)
`
`N-benzoyl-3-phenylisoserine.
`
`Paclitaxel has the following structural formula:
`
`Paclitaxel is a white to off-white crystalline powder with the empirical formula C47Hs1N014 and
`
`a molecular weight of853.91. It is highly lipophilic, insoluble in water, and melts at
`
`approximately 216°C to 2l7°C.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`
`ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable
`
`suspension) is an antimicrotubule agent that promotes the assembly of microtubules from tubulin
`
`dimers and stabilizes microtubules by preventing depolymerization. This stability results in the
`
`inhibition of the normal dynamic reorganization of the microtubule network that is essential for
`
`vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or "bundles"
`
`of microtubules throughout the cell cycle and multiple asters ofmicrotubules during mitosis.
`
`Human Pharmacokinetics
`
`The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of ABRAXANE
`at dose levels of 80 to 3 75 mg/m2 were determined in clinical studies. Dose levels of mg/m 2 refer
`
`to mg ofpaclitaxel in ABRAXANE. Following intravenous administration of ABRAXANE,
`
`p