UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`J KYLE BASS and ERICH SPANGENBERG,
`Petitioner
`
`
`
`v.
`
`
`
`FRESENIUS KABI USA, LLC
`Patent Owner
`
`
`Case No. IPR2016-00254
`U.S. Patent No. 8,476,010
`
`
`
`
`EXHIBIT 2036 - DECLARATION OF STANLEY S. DAVIS Ph.D.
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`J KYLE BASS and ERICH SPANGENBERG,
`Petitioner
`
`
`
`v.
`
`
`
`FRESENIUS KABI USA, LLC
`Patent Owner
`
`
`Case No. IPR2016-00254
`U.S. Patent No. 8,476,010
`
`
`
`
`EXHIBIT 2036 - DECLARATION OF STANLEY S. DAVIS Ph.D.
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`I, STANLEY DAVIS, Ph.D., hereby declare and state as follows:
`
`
`1.
`
`I submit this expert declaration at the request of counsel for patentee
`
`Fresenius Kabi USA, LLC (“Fresenius”) in the above-captioned matter. My
`
`compensation pertaining to this matter is not dependent on the outcome of this
`
`matter.
`
`I.
`
`QUALIFICATIONS AND EXPERIENCE
`
`2.
`
`I am an Emeritus Professor of Pharmacy at the University of
`
`Nottingham, United Kingdom. For over forty years, I have been active in the field
`
`of pharmaceutical science. I have taught courses, conducted research, written
`
`papers, edited books, and consulted for industry on a wide-range of topics, to
`
`include emulsion formulations and their use in drug delivery.
`
`3.
`
`I am the co-founder of three pharmaceutical companies and the
`
`recipient of awards relating to my research. I have authored or co-authored over
`
`750 scientific papers and have co-edited seven books relating to the pharmaceutical
`
`sciences. I am also a named inventor on several patents in the pharmaceutical area.
`
`4.
`
`I continue to provide consulting services relating to the development
`
`of pharmaceutical formulations and stay abreast of relevant scientific publications.
`
`5.
`
`I have consulted for various pharmaceutical companies all over the
`
`world on matters relating to pharmaceutical formulation, pharmaceutical analysis,
`
`processing, scale-up, material science, drug stability, controlled release, and other
`
`
`
`2
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`formulation issues. These companies have included: Abbott, Pharmaceutical
`
`Profiles, Hoechst, Alza, Synthelabo Pharma, Pierre Fabre, Jouveinal, Eli Lilly,
`
`Glycoform, Aradigm, Gene Medicine, Leopold, ICI Pharmaceuticals (Zeneca),
`
`Marion Merrell Dow, Fresenius, Baxter and Arakis. I was also a visiting scientist
`
`at Allergan, Syntex and Alza in the United States.
`
`6.
`
`I graduated from the School of Pharmacy at the University of London
`
`in 1964 with a Bachelor’s degree in Pharmacy. I continued my studies at the
`
`University of London and received a Ph.D. in 1967 for studies on emulsion
`
`systems. I was awarded a Doctor of Science degree (higher doctorate) in 1982 for
`
`my subsequent research work.
`
`7.
`
`In 1967, I was appointed to the faculty of the University of London
`
`and in 1968 I was awarded a one year Fulbright Scholarship to undertake
`
`postdoctoral studies with Professor Takeru Higuchi at the University of Kansas in
`
`the field of solution thermodynamics.
`
`8.
`
`In 1970, I moved to the University of Aston in Birmingham, UK, as
`
`Senior Lecturer and Head of the Pharmaceutics section where I developed an
`
`active research group in the field of drug delivery systems that included work on
`
`emulsions and other colloidal systems.
`
`9.
`
` In 1975, I became Lord Trent Professor of Pharmacy at the
`
`University of Nottingham. In this role, I ran a large research group specializing in
`
`
`
`3
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`the study of novel drug delivery systems including disperse systems such as
`
`emulsions, liposomes and microparticles for human and animal use.
`
`10.
`
`I have supervised over 100 Ph.D. candidates and 20 post-doctoral
`
`fellows in different areas of pharmacy.
`
`11.
`
`In 2003, I became an Emeritus Professor of Pharmacy at the
`
`University of Nottingham.
`
`12.
`
`I have served on numerous committees and panels including the
`
`British and European Pharmacopoeias, the Medicines Commission (United
`
`Kingdom), and the Science & Engineering Research Council (United Kingdom).
`
`13.
`
`I am or have been a member of many learned pharmaceutical
`
`societies, including the Royal Pharmaceutical Society, Royal Institute of
`
`Chemistry, Society of Rheology, Society of Chemical Industry, American
`
`Association of Pharmaceutical Scientists, Controlled Release Society and the
`
`Society for Drug Research.
`
`14.
`
`I have served as an Editorial Board member for many journals dealing
`
`with the pharmaceutical sciences as well as the materials sciences.
`
`15.
`
`I have received awards from various organizations to include the
`
`Swedish Pharmaceutical Society, the Royal Pharmaceutical Society of Great
`
`Britain, and in 2005 I received the Høest-Madsen Medal for lifetime achievement
`
`in the pharmaceutical sciences from the International Pharmaceutical Federation
`
`
`
`4
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`(FIP).
`
`16.
`
`In 2008, I was awarded an honorary Doctor of Science degree from
`
`London University and in 2012 I was made a Fellow of University College
`
`London.
`
`17.
`
`I have more than 40 years of experience in development of
`
`commercial drug products in the pharmaceutical industry and academic research,
`
`with specific focus on drug product formulation development. Specifically, I have
`
`extensive personal research experience in the area of colloids and colloidal drug
`
`product formulations, including emulsions and suspensions, and in particular, oil-
`
`in-water emulsions containing propofol, including Diprivan®, and have authored
`
`or co-authored many reviewed publications and made numerous presentations in
`
`this area at scientific meetings. I have also authored or co-authored several
`
`scientific publications and book chapters on physicochemical properties of
`
`emulsions and emulsion stability, including propofol oil-in-water emulsions, large
`
`particle contaminants in intravenous emulsions (e.g. Davis et al., Encyclopedia of
`
`Emulsion Technology, Chapter 3, Applications). I am an author of the Han,
`
`Washington and Davis reference describing the physical stability of commercially
`
`marketed Diprivan® that is cited in Petitioner’s Expert Declaration (see Exh. 1002,
`
`Feinberg Declaration at ¶16).
`
`
`
`5
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`18. Attached hereto as Exhibit 2037 is a copy of my curriculum vitae
`
`setting out in detail my qualifications and professional expertise, including a list of
`
`publications which I have authored or co-authored.
`
`19.
`
`In forming my opinions expressed herein, I considered the materials
`
`cited in this Declaration (attached hereto as Exhibit 2036). I have further relied on
`
`my knowledge, education and training and my many years of experience in the
`
`field of pharmaceutical sciences, as reflected in my qualifications and credentials
`
`set forth above and in my curriculum vitae.
`
`20.
`
`I have reviewed U.S. Patent No. 8,476,010 (“the ’010 Patent”, Exh.
`
`1001). I have also reviewed the petition filed in this matter, the expert declaration
`
`by Dr. Feinberg (the “Feinberg Declaration”, Exh. 1002) filed by the Petitioner in
`
`support of the petition, and the references identified by the Petitioner. I have also
`
`reviewed the Patent Owner Preliminary Response filed by the patentee in response
`
`to the petition in this matter.
`
`21. Based on my experience, I believe that a person of ordinary skill in
`
`the field of the invention described in the ’010 patent prior to July of 2003 would
`
`have been someone with substantial research or industry experience in
`
`pharmaceutical drug product formulation, including experience in drug product
`
`emulsions and their packaging, including chemical and physical characteristics of
`
`oil-in-water emulsion systems such as propofol emulsions, and having at least a
`
`
`
`6
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`master’s degree or doctorate in a related technical field, such as analytical, physical
`
`or organic chemistry, pharmaceutics or related subject matter having equivalent
`
`experience in such fields, or a bachelor’s degree in those related fields with at least
`
`three years of practical experience.
`
`II. BACKGROUND OF THE PROPOFOL OIL-IN-WATER
`EMULSION (DIPRIVAN®)
`
`22. Propofol (2,6-Diisopropylphenol), has been a widely used intravenous
`
`anesthetic agent since its introduction in 1989. Oil-in-water emulsion systems had
`
`previously been described for the delivery of lipophilic drugs such as propofol.
`
`(For a review, see Exh. 2038, S.S. Davis et al., Lipid emulsions as drug delivery
`
`systems Ann. NY Acad. Sci., 507 (1987), pp. 75–88.) Because propofol is a
`
`hydrophobic, water-insoluble oil, it cannot be safely delivered in a simple aqueous
`
`solution (Exh.1001 at Col. 1:20-25.) In order to overcome propofol’s solubility
`
`limitation, pharmaceutical compositions containing propofol are typically
`
`formulated as oil-in-water emulsions in which the propofol is dissolved in an oil
`
`solvent, and then emulsified with a suitable emulsifying agent and water for
`
`injection (see, id. at Col. 2:20-47.)
`
`23. Patent Owner’s Diprivan® product is an oil-in-water emulsion
`
`formulation containing 1% (w/v) propofol contained in an emulsion of soybean oil
`
`(10% w/v), glycerol and purified egg lecithin and a tonicity adjusting agent
`
`(glycerol). (See, id. at Col. 2:33-39.) The soybean oil, egg lecithin and glycerol
`
`
`
`7
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`components in the Diprivan® oil-in-water propofol emulsion are present in the
`
`same proportion as in a parenteral nutrition oil-in water emulsion known as
`
`Intralipid®. (Farinotti, Exh. 1007 at 453-454.)
`
`24. The ’010 patent states that the described propofol emulsions can be
`
`manufactured using terminal sterilization by autoclaving. (Exh. 1001 at Col. 7:31-
`
`34.) Filtration of Diprivan® emulsion is impractical. Instead, the manufacturing
`
`steps for marketed Diprivan® included terminal heat sterilization by autoclaving
`
`after filling into its storage container. (Exh. 1014 at Cols. 7-8.)
`
`25. Unlike a simple homogeneous single phase containing drug
`
`compounds dissolved in aqueous solutions, emulsions are a non-homogeneous,
`
`three-component mixture of oil, water, and a surfactant. The components are
`
`distributed in a multi-phase system consisting of at least two immiscible liquids.
`
`One liquid (known as the internal or discontinuous phase) is dispersed in the form
`
`of small droplets surrounded by a surfactant (also known as an emulsifying agent)
`
`throughout the other (known as the external or continuous phase). (See, e.g.,
`
`Merck Manuals, “Routes of Administration of Dosage Forms”, Exh. 2001.)
`
`26. Where oils are dispersed as particles or microdroplets in water or an
`
`aqueous solution, the resulting system is called an oil-in-water emulsion. Unlike
`
`homogeneous aqueous solutions, emulsions are, by nature, physically unstable.
`
`Although emulsifying agents such as lecithin are included to increase their physical
`
`
`
`8
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`stability, emulsions droplets nonetheless tend to coalesce into larger droplets or
`
`emulsions can separate into two distinct phases when subjected to physical stresses
`
`such as agitation, temperature or pH changes. (See, e.g., Exh. 1009.)
`
`27. As an oil-in-water emulsion stabilized and dispersed by an
`
`emulsifying agent, lecithin, Diprivan® would be expected to have a greater
`
`propensity for removing silicone oil from a siliconized container closure, as
`
`compared to aqueous drug formulations without an emulsifier. To maintain
`
`stability of the Diprivan® emulsion, the soybean oil, which holds the bulk of the
`
`propofol active ingredient, is kept dispersed in the aqueous phase as extremely
`
`small oil droplets (mean droplet size 0.10- 0.30 µM) by the lecithin emulsifying
`
`agent. (See e.g., Exh. 2026 at 862-863; Exh 1009 at 208.) Lecithin contains both a
`
`polar hydrophilic group, and a lipophilic group whereby the oil-miscible
`
`hydrophobic end interacts with the soybean oil, and the hydrophilic end interacts
`
`with the aqueous phase. The lecithin molecules, therefore, bridge the interface
`
`between the propofol-containing oil droplets and the aqueous phase. (See Exh.
`
`2026 at 864 and Figure 4.) An electrical charge on the polar hydrophilic end of the
`
`lecithin molecules causes the oil droplets to repel each other, thereby reducing the
`
`tendency for the oil droplets to coalesce into larger droplets and thus to maintain
`
`the physical stability of the emulsion. (Id.) Since Diprivan® contains an excess of
`
`lecithin to ensure complete emulsification of the soybean oil droplets, the excess
`
`
`
`9
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`lecithin that is not associated with oil droplets could interact with and emulsify
`
`silicone oil when Diprivan® contacts rubber closures siliconized with silicone
`
`oil. The potential for hydrogenated lecithin emulsifier to emulsify silicone oil was
`
`already known in the prior art. (See Exhs. 2039, Bae et al. (2000) at Abstract, 526,
`
`527 (Figures 7 and 8) and 2058.) Further, the manufacturing process for
`
`Diprivan® utilizes a high shear mixing device to ensure that the emulsified
`
`propofol-containing soybean oil is dispersed as extremely small droplets in the
`
`aqueous phase of the emulsion. (See Exh. 1001 at Col. 7:31-34.) Because any
`
`silicone oil emulsified from siliconized rubber closures is not subjected to any
`
`mechanical homogenization process, it may form larger droplets relative to the
`
`droplets in Diprivan®.
`
`28. Emulsions are metastable systems, which means that they are
`
`thermodynamically unstable. After a period of time, the emulsion eventually
`
`separates into two phases: a water plus surfactant phase and an oil phase,
`
`depending strongly on the preparation method, the surfactant, and oil properties.
`
`The separation process involves coalescence of the droplets which grow as a
`
`function of time, which can vary significantly depending on the specific emulsion
`
`system. (See Exh. 2026.)
`
`29. Oil-in-water emulsions intended for intravenous use should have an
`
`extremely small droplet size and remain highly stable, since large droplets
`
`
`
`10
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`administered intravenously can lodge in blood vessels potentially leading to life-
`
`threatening side effects. Particles greater than 5 μM are generally considered
`
`unsafe in parenteral emulsions. (See Exh. 1009 at 208.)
`
`30. The physical stability of the oil-in-water emulsion drug formulations,
`
`such as Diprivan®, must be evaluated in terms of droplet particle size and
`
`distribution, impurity and foreign particle contaminant levels, and the degradation
`
`or loss of propofol potency. This can be done after the emulsion drug product is
`
`subjected to accelerated stability tests and real-time shelf-life evaluation over the
`
`proposed shelf-life, and to obtain data to confirm that the formulation is safe and
`
`effective for administration to patients.
`
`31.
`
`In order to be a safe and effective drug formulation, parenteral
`
`emulsions must, therefore, be formulated with adequate physical stability to
`
`prevent an increase in droplet size during the shelf-life storage of the
`
`pharmaceutical emulsion products. (Id.) In addition to the physical stability
`
`requirement for emulsions (not susceptible to coalescence or separation), it is
`
`important to maintain the stability of the active ingredient and/or excipients in the
`
`emulsion (stability to degradation and/or loss due to adsorption or absorption to the
`
`storage container components). (See Exh. 2051 at 168.)
`
`32. The average particle size of the emulsion droplets in propofol oil-in-
`
`water emulsions is much less than 1 micron. The average particle size diameter of
`
`
`
`11
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`emulsion droplets for Diprivan® have been reported to be 150-200 nm (0.15 – 0.2
`
`M). (Exh. 1009 at 208.) It was known that both emulsion destabilization and
`
`loss of propofol due to adsorption-diffusion are risks associated with Diprivan®.
`
`(Exh. 1007 at Abstract.)
`
`33. Although testing methods to determine emulsion physical stability for
`
`emulsion drug formulations were known in the art, these were distinct and different
`
`from tests used to determine the stability of the drug active ingredient over the
`
`proposed shelf-life of the product. The Han reference, which I co-authored,
`
`reported a method of assessing physical stability used for Diprivan® “shaking,
`
`freeze-thaw cycling and thermal cycling, physical agitation.” (Exh. 1009 at 213.)
`
`The Han “shake testing” used a wrist-action shaker operating at 300 strokes/min. at
`
`room temperature for 2, 4, 6, 8, 10, 12 and 16 hours, after which the particulate
`
`size and particle distribution in the emulsion were analyzed with a variety of
`
`particle size measurement techniques. (Id. at 215-17.) The Han shaking test was
`
`designed to evaluate emulsion physical stability, and was not used nor intended for
`
`use in determining the content of the active ingredient in the emulsion. Han’s
`
`shaking test is unlike the closure compatibility testing described in the ’010 Patent.
`
`Notably, the Han shaking test did not combine an HPLC chemical analysis with
`
`the mechanical shake test for evaluating the loss of propofol active ingredient after
`
`mechanical agitation.
`
`
`
`12
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`III. BACKGROUND OF THE ‘010 PATENT INVENTION
`
`34. The ’010 patent to Desai, et. al. issued on July 2, 2013 from U.S.
`
`Appl. No. 10/616,709, which was filed on July 10, 2003. I understand that claims
`
`1, 13-15, 17, 18 20, and 24-28 have been challenged in this matter (the “challenged
`
`claims”) and alleged to be unpatentable as obvious. Claim 1 states:
`
`1. A sterile pharmaceutical composition of propofol in a
`container, comprising:
`a container which includes a closure and a composition
`in the container, and
`the composition in the container comprising from 0.5%
`to 10% by weight propofol and from about 0 to about
`10% by weight solvent for propofol,
`
`where when the composition in the container sealed
`with the closure is agitated at a frequency of 300-400
`cycles/minute for 16 hours at room temperature, the
`composition maintains a propofol concentration (w/v)
`measured by HPLC that is at least 93% of the starting
`concentration (w/v) of the propofol;
`
`where the closure is selected from the group consisting of
`siliconized bromobutyl rubber, metal, and siliconized
`chlorobutyl rubber.
`
`35. Claims 17 and 18, which depend from claim 1, require that the closure
`
`consist of closure that is inert to propofol. Claim 19, which depends from claim 18
`
`requires that the closure include siliconized bromobutyl rubber that is inert to
`
`propofol.
`
`36.
`
`I understand that the claims of the patent define the scope of the
`
`exclusionary rights the patentee is entitled to. Claim 1 is directed to a sterile
`
`
`
`13
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`propofol formulation stored in a container having a siliconized bromobutyl rubber,
`
`metal, and siliconized chlorobutyl rubber closure that retains at least 93% weight
`
`by volume of the initial propofol concentration in the formulation after being
`
`subjected to the specified accelerated stability test.
`
`37. The accelerated stability test required by claim 1 requires the propofol
`
`emulsion to maintain at least 93% of the initial concentration in the container as
`
`determined by HPLC after being subjected to agitation or ‘shaking’ at the specified
`
`frequency and time at room temperature. The patent specification describes the
`
`accelerated stability test as a “method for testing compatibility of propofol
`
`emulsions”, and states that the test was used for accelerated testing of propofol
`
`emulsions on propofol emulsion degradation or potency. (Exh. 1001 at Col. 23:17-
`
`37.) The specification further states that an HPLC assay of the propofol samples
`
`before and after the accelerated testing determined if there was any loss in the
`
`potency or concentration of propofol in the formulations, and that the testing
`
`method allowed the rapid testing of closure compatibility with different propofol
`
`formulations as well as emulsion stability.” (Id.) The specification further states
`
`“the degradation or loss in potency of propofol potency should be such that the
`
`propofol composition meets regulatory safety and efficacy standards. As a result,
`
`impurity levels, such as silicone oil, levels of degradation products and potency
`
`loss are within acceptable regulatory limits.” (Id. at 4:47-58.)
`
`
`
`14
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`38.
`
`I agree with the construction of “siliconized” adopted by the Board.
`
`The specification of the ’010 patent states that “[in] general the preferred closures
`
`are made with inert, non-reactive materials with little to no leachables. Preferred
`
`closures also include those that are coated or treated with inert materials such as
`
`siliconized polymer…” and that “[b]y way of example and not in limitation of the
`
`present invention, rubber closures that are suitable in the present invention include
`
`silicones, siliconized bromobutyl rubber…and siliconized chlorobutyl rubber.”
`
`(Id. at Col. 9:40 - Col. 10:3.) For example, the Glossary entry in Smith et al. (Exh.
`
`1004) states that the term “silicone” commonly refers to silicone fluid, which, in
`
`turn, is commonly used to describe a liquid silicone, including silicone oil. (See
`
`Exh. 1004 at S12.) The Smith reference also describes “silicone polymer” (i.e.
`
`polysiloxane) as a general term describing a silicon containing polymer whose
`
`silicon atoms are separated by oxygen atoms (contain si-O-Si bonds). (Id.) A
`
`person of ordinary skill in the art (POSA), based on the descriptions in the art,
`
`including Smith, would have known and understood that the term “siliconized” in
`
`the claims refers to a closure that is surface-treated, coated or manufactured with
`
`silicone or one or more siloxane polymers.
`
`39.
`
`I agree with the construction of “inert to propofol” adopted by the
`
`Board. The patent specification defines “inert to propofol” to mean that the
`
`closure itself is non-reactive to propofol such that it does “not cause significant
`
`
`
`15
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`degradation or loss of potency of the propofol formulation.” (Exh. 1001 at Col. 4:
`
`47-51 and Col. 8: 39-43.) A POSA would therefore, have understood the term
`
`“inert to propofol” to mean “does not interact or react with propofol to cause a loss
`
`in the potency or concentration of propofol.”1
`
`40. The ’010 patent inventors discovered that changes in propofol
`
`concentrations after agitation with a mechanical shaker (previously used to test
`
`only emulsion stability) correlated with the change in propofol concentration after
`
`real-time shelf stability testing as determined by HPLC analysis. The ’010 patent
`
`inventors concluded that when coupled with HPLC analysis for the active
`
`ingredient, “the shaker test, for which results could be obtained within 24 hours,
`
`was a suitable surrogate for accelerated testing in conventional shelf-stability
`
`chambers”, which took two months to complete. (Exh. 1001 at Col. 27:45-49.)
`
`Further, the inventors also surprisingly found that siliconized bromobutyl rubber
`
`closures maintained the concentration of propofol in the emulsion and the stability
`
`of the emulsion after subjecting it to accelerated stability testing, and that these
`
`advantages persisted over a wide range of soybean oil concentrations.
`
`41. The change in the level of the propofol active ingredient in the
`
`propofol oil-in-water emulsions (i.e. drug loss) after the ’010 patent inventors
`
`subjecting it to the “shaker test,” in my opinion, was most likely caused by the
`
`1 I understand that the Parties have agreed to the construction of the term
`“siliconized.”
`
`
`
`16
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`partitioning of propofol, a highly hydrophobic compound, by the bromobutyl
`
`rubber stopper, whereby propofol is adsorbed on the surface of the stopper, and
`
`may subsequently be absorbed into the stopper material. While the siliconization
`
`of bromobutyl rubber stoppers were traditionally used in container-filling
`
`processes as a lubricant to prevent stoppers from sticking to one another in drug
`
`product fill lines, siliconization of bromobutyl rubber stoppers was not typically
`
`used to reduce drug loss in a formulation. In my opinion, a POSA, therefore,
`
`would not have siliconized bromobutyl rubber stoppers to combat the issue of
`
`propofol loss in propofol oil-in-water emulsions due to surface adsorption onto or
`
`absorption into the stopper material.
`
`IV. PARENTERAL DRUG PRODUCT PARTICLE
`CONTAMINATION FROM SILICONIZED VIAL CLOSURES
`
`42. Problems associated with siliconization of container closures were
`
`well known and documented in the art long before July 2003. The Smith
`
`reference2 (Exh. 1004), which published in 1988, states that although hydrophobic
`
`silicone lubricants such as silicone oil (polydimethoxysilane (PDMS)) were used
`
`generally in pharmaceutical packaging closures - because they were not generally
`
`expected to mix with homogeneous aqueous drug solutions - “[h]eavy application
`
`of PDMS to rubber closures …could result in the formation of silicone oil globules
`
`
`2 The Smith reference was cited by Petitioner’s expert. (Exh. 1002, Feinberg Decl.
`at, e.g. ¶10.)
`
`
`
`17
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`suspended in the formulation”, and that “[e]ven low application levels could result
`
`in suspended particles due to vial agitation…” (Exh. 1004 at S11.)
`
`43. By July of 2003, it was already well known in the art that silicone oil
`
`or other lubricants used in closures for storage containers introduced undesired
`
`large particle contaminants (e.g. particle size >10 M) into pharmaceutical drug
`
`products that raised potential concerns with respect to regulatory requirements for
`
`permissible levels of such large particle contaminants in injectable parenterals.
`
`44. U.S Patent 5,163,919 (Exh. 2024) stated that a water-based medical
`
`preparation after contact with the silicone oil treated elastomeric seal contained a
`
`relatively large quantity of silicone oil droplets in emulsified state. (Exh. 2024,
`
`Col. 2:42-29.) The ’919 patent disclosed that high particle contamination from
`
`rubber closures covered with a silicone layer (50,000 particles per mL of
`
`contacting fluid with particle size ≥ 2M) was observed compared to non-
`
`siliconized rubber seal (2000 particles per mL with particle size ≥ 2M) after
`
`contacting the rubber seals under steam sterilization conditions of 121oC for 30
`
`minutes. (Id. at Col. 5:37-54, Cols. 8-9.) The ’919 patent disclosed an alternative
`
`surface treatment for rubber closures with halogen or elementary halogen such as
`
`fluorine resulted in significantly lower particle contaminants (500 particles with
`
`particle size ≥ 2M) and similar friction coefficient as silicone oil treatment and
`
`easy processing in packaging equipment. (Id.)
`
`
`
`18
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`45. U.S. Patent 4,973,504 (Exh. 2040) stated that although the use of
`
`silicone oil improved the lubricity of rubber closures, it created additional
`
`problems of increased particle counts in various drug solutions during inspection.
`
`(Exh. 2040 at Col. 2:6-27.) The ’504 patent also stated that the FDA evaluated
`
`pharmaceutical manufacturing processes by counting the total number of particles
`
`present in the drug product, regardless of the source or nature of the particles. (Id.)
`
`The ’504 patent further stated:
`
`“Silicone oil in small amounts is normally not an
`undesirable contaminant in medicine but its use still adds to the
`count of particles and, therefore, detracts from the overall
`acceptance of its use in processing equipment”;
`
`“[E]ven though the amount of silicone oil is minimal,
`being only that amount necessary to prevent the individual
`stoppers from sticking to one another, silicone oil is not able to
`adequately lower the coefficient of friction of rubber stoppers
`for use in high speed capping equipment so as to give uniform
`faster movement, particularly with centrifugal feeding
`systems”; and
`
`“[R]ubber stoppers which have been treated by the use of
`silicone oil are not any more effective in surviving chemical
`tests concerning the compatibility with and contamination of
`material contained in the vials.”
`
`(Id.)
`
`
`46. The ’504 patent disclosed a non-silicone alternative coating for rubber
`
`stoppers containing polyparaxylylene, and demonstrated that that polyparaxylylene
`
`coated stoppers produced significantly reduced particle contamination levels
`
`
`
`19
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`compared to siliconized rubber stoppers. (Exh. 2040, Col. 5:4-24, Col. 8:56 - Col.
`
`9:2.) The ’504 patent further disclosed that after remaining in contact with an
`
`aqueous solution for 30 minutes, both untreated rubber stoppers and those treated
`
`with the polyparaxylylene coating produced less than 300 particles per stopper
`
`having a particle size of ≥ 5M, whereas siliconized rubber stoppers produced
`
`more than 10,000 particles of that size per stopper. (Exh. 2040, Col 9:3-23.) The
`
`’504 patent also disclosed that paraxylylene coated stoppers exhibited lower
`
`coefficient of friction than siliconized rubber closures thereby allowing silicone oil
`
`to be eliminated in processing, and that paraxylylene polymer coated rubber could
`
`be manufactured from conventional rubber material and formed into rubber
`
`stoppers. (Exh. 2040 Col. 5:6-8, 20-21.)
`
`47. A 1992 reference by Mannermaa et al. (Exh. 2041) disclosed that
`
`siliconized rubber stoppers produced significantly higher number of particulate
`
`contaminants in aqueous solution after being subjected to autoclave heat
`
`sterilization compared to non-siliconized stoppers. (See Exh. 2041, Abstract.)
`
`Specifically, Mannermaa reported that siliconized rubber stoppers produced as
`
`much as a 600% increase of particles between 5M and 32M (~1200 to 4500
`
`particles per mL of aqueous solution) after being sterilized by autoclaving at 121oC
`
`for 15 minutes compared to corresponding stoppers that were not autoclaved (~200
`
`to 900 particles per mL). (Exh. 2041, comparing stoppers 1-3 and 5-7 with
`
`
`
`20
`
`Fresenius Ex. 2036
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`
`
`stoppers 8-10 and 12-14, respectively, in Figure 3 at 75.) Mammeraa further
`
`reported that non-siliconized rubber stoppers produced a significantly lower
`
`number of 5M and 32M particles(~ 500 particles) after sterilization by autoclave
`
`. (Id.) Siliconized stoppers thus produced between about 120% to 900% more
`
`particles compared to the non-siliconized stopper. (See id.) Mannermaa also
`
`disclosed that the number of particles released from siliconized rubber stoppers
`
`after sterilization by autoclaving varied considerably between different stoppers
`
`(i.e. by manufacturer) and even between different batches of the same stopper.
`
`(See, id. at Abstract.)
`
`48. Significantly, Mannermaa disclosed that the only non-siliconized
`
`stopper evaluated in their study “performed better” (i.e. produced lower particle
`
`count) compared to all other siliconized stoppers tested. (Exh. 2041 at 74-76,
`
`Figures 2 and 3.) Mannermaa concluded that absence of surface siliconization may
`
`have contributed to the superior performance of the non-siliconized rubber stopper,
`
`and that the increased number of large particle contaminants from the siliconized
`
`stoppers “might indicate that silicone oil droplets shed from the stoppers have a
`
`significant effect on the number of particles generated by stoppers during
`
`sterilization.” (Exh. 2041 at 77.)
`
`49. A 1992 reference by Cape
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
