Trials@uspto.gov
`571-272-7822
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` Paper No. 7
` Entered: October 11, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ACTAVIS LLC,
`Petitioner,
`
`v.
`
`ABRAXIS BIOSCIENCE, LLC,
`Patent Owner.
`____________
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`
`
`Case IPR2017-01100
`Patent 8,853,260 B2
`____________
`
`
`Before JEFFREY N. FREDMAN, RAMA G. ELLURU, and
`SUSAN L. C. MITCHELL, Administrative Patent Judges.
`
`MITCHELL, Administrative Patent Judge.
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
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`IPR2017-01100
`Patent 8,853,260 B2
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`INTRODUCTION
`I.
`Actavis LLC (“Petitioner”) requests an inter partes review of claims
`1–27 of U.S. Patent No. 8,853,260 B2 (“the ’260 patent,” Ex. 1001).
`Paper 2 (“Pet.”). Abraxis Bioscience, LLC (“Patent Owner”) filed a
`Preliminary Response. Paper 6 (“Prelim. Resp.”).
`We have authority to determine whether to institute an inter partes
`review. 35 U.S.C. § 314(b); 37 C.F.R. § 42.4(a). We may not institute an
`inter partes review “unless . . . there is a reasonable likelihood that the
`petitioner would prevail with respect to at least 1 of the claims challenged in
`the petition.” 35 U.S.C. § 314(a). Applying that standard, and upon
`consideration of the information presented in the Petition and the
`Preliminary Response, we deny the Petition and do not institute an inter
`partes review.
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`II.
`
`BACKGROUND
`
` Related Matters
`The parties identify two district court litigations involving the ’260
`patent: Abraxis Bioscience, LLC v. Actavis LLC, 2:16-cv-01925-JMV-MF
`(D.N.J. April 6, 2016) and Abraxis Bioscience, LLC v. Cipla Ltd.,,
`2:16-cv-09074-JMV-MF (D.N.J. Dec. 7, 2016). See Pet. 4; Paper 4, 1–2.
`Petitioner identifies three additional petitions for inter partes review
`challenging other patents owned by Abraxis: U.S. Patent No. 7,820,788 B2
`in IPR2017-01101; U.S. Patent No. 7,923,536 B2 in IPR2017-01103; and
`U.S. Patent No. 8,138,229 B2 in IPR2017-01104. Pet. 4.
`
` The ’260 Patent (Ex. 1001)
`The ’260 patent, titled “Formulations of Pharmacological Agents,
`Methods for the Preparation thereof and Methods for the Use Thereof”
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`IPR2017-01100
`Patent 8,853,260 B2
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`issued on October 7, 2014. Ex. 1001, [45], [54]. The ’260 patent relates to
`“compositions and methods useful for the in vivo delivery of substantially
`water insoluble pharmacologically active agents (such as the anticancer drug
`paclitaxel) in which the pharmacologically active agent is delivered in the
`form of suspended particles coated with protein (which acts as a stabilizing
`agent).” Id. at Abst. Such compositions are suitable for parenteral
`administration in aqueous suspension, thereby obviating the need for use of
`an emulsion containing a polyethoxylated castor oil, such as cremaphor, that
`may produce an allergic reaction in a patient. Id. at 9:44–56, 3:3–22 (using
`cremaphor to solubilize Taxol linked to severe hypersensitivity reactions in
`humans requiring premedication with corticosteroids and antihistamines and
`large dilution resulting in large volumes for infusion and long infusion
`times). The ’260 patent further describes a method for reproducibly forming
`unusually small nanoparticles (less than 200 nm diameter), which can be
`sterile-filtered to avoid heat coagulation of the protein (e.g. human serum
`albumin) from autoclaving. Id. at 10:3–14, 26–32.
`The ’260 patent further describes such compositions for in vivo
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`delivery of a substantially water insoluble pharmacologically active agent
`such as paclitaxel as follows.
`Invention compositions comprise substantially water insoluble
`pharmacologically active agents (as a solid or liquid) contained
`within a polymeric shell. The polymeric shell is a crosslinked
`biocompatible polymer. The polymeric shell, containing
`substantially water insoluble pharmacologically active agents
`therein, can then be suspended in a biocompatible aqueous liquid
`for administration.
`Id. at 10:15–25.
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`IPR2017-01100
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`Human serum albumin is used in the polymeric shell to take
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`advantage of its capability to bind Taxol to enhance Taxol’s absorption on
`the surface of the particles. Id. at 10:52–55. The ’260 patent states that
`“[s]ince albumin is present on the colloidal drug particles (formed upon
`removal of the organic solvent), formation of a colloidal dispersion which is
`stable for prolonged periods is facilitated, due to a combination of electrical
`repulsion and steric stabilization.” Id. at 10:55–59.
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`One variation of the formulations is described in the ’260 patent as
`a polymeric shell containing a solid core of biologic produced by
`initially dissolving the biologic in a volatile organic solvent (e.g.
`benzene), forming the polymeric shell and evaporating the
`volatile solvent under vacuum, e.g., in an evaporator, spray drier
`or freeze-drying the entire suspension. This results in a structure
`having a solid core of biologic surrounded by a polymer coat.
`This latter method is particularly advantageous for delivering
`high doses of biologic in a relatively small volume.
`Id. at 25:57–66.
`
` Illustrative Claim
`Of the challenged claims, claim 1 is independent. Claim 1 is
`illustrative of the claimed subject matter and recites:
`A pharmaceutical formulation comprising:
`1.
`paclitaxel at a concentration between 5 mg/ml and 15 mg/ml,
`wherein the pharmaceutical formulation is an aqueous
`suspension that is stable for at least 3 days under at least
`one of room temperature or refrigerated conditions,
`wherein the pharmaceutical formulation comprises
`nanoparticles comprising a solid core of paclitaxel and an
`albumin coating,
`and wherein the size of the nanoparticles in the formulation is
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`less than 400 nm.
`Ex. 1001, 67:32–42.
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` The Asserted Ground of Unpatentability
`Petitioner asserts that claims 1–27 of the ’260 patent are unpatentable
`as obvious over the combination of Desai,1 Shively,2 Liversidge,3 and
`Remington’s Pharmaceutical Sciences.4 Pet. 6. Petitioner supports its
`assertions with the testimony of Cory J. Berkland, Ph.D. (Ex. 1002) and
`Edmund J. Elder, Jr., Ph.D., R.Ph. (Ex. 1034).
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`III. ANALYSIS
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`A. Claim Construction
`The Board interprets claims in an unexpired patent using the “broadest
`reasonable construction in light of the specification of the patent.” 37 C.F.R.
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46
`(2016). Under that standard, claim terms are given their ordinary and
`customary meaning in view of the specification, as would be understood by
`one of ordinary skill in the art at the time of the invention. In re Translogic
`Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special definitions
`for claim terms must be set forth with reasonable clarity, deliberateness, and
`precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`
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`1 Neil P. Desai et al., U.S. Patent No. 5,439,686, issued August 8, 1995.
`(Exhibit 1003, “Desai”).
`2 Merrick L. Shively, U.S. Patent No. 5,407,683, issued April 18, 1995.
`(Exhibit 1004, “Shively”).
`3 Gary G. Liversidge et al., U.S. Patent No. 5,399,363, issued March 21,
`1995. (Exhibit 1005, “Liversidge”).
`4 George Zografi, Ph.D. et al., Chapter 19: Disperse Systems in
`REMINGTON’S PHARMACEUTICAL SCIENCES, 257–309 (18th ed. 1990); G.
`Briggs Phillips, Ph.D. et al., Chapter 78: Sterilization in REMINGTON’S
`PHARMACEUTICAL SCIENCES, 1470–1480 (18th ed. 1990) (collectively,
`Exhibit 1006, “Remington’s Pharmaceutical Sciences”).
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`Petitioner proposes that we construe the following four claim phrases:
`“wherein the pharmaceutical formulation is . . . stable for at least 3 days
`under at least one of room temperature or refrigerated conditions;” “wherein
`the solid core is substantially free of polymeric material;” “wherein a portion
`of the paclitaxel is contained within the albumin coating and a portion of the
`paclitaxel is associated with the free albumin;” and “wherein the average
`diameter of the nanoparticles is no greater than about 200 nm.” Pet. 21–25.
`Except for determining whether the first claim phrase relating to the stability
`of the claimed formulation—“wherein the pharmaceutical formulation is . . .
`stable for at least 3 days under at least one of room temperature or
`refrigerated conditions”— is limiting, an issue we will address in the context
`of the analysis of the challenge to the claims, we determine that no claim
`term requires construction for purposes of this decision. See Vivid Techs.,
`Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (“[O]nly
`those terms need be construed that are in controversy, and only to the extent
`necessary to resolve the controversy.”); see Prelim. Resp. 3 (generally
`accepting for purposes of Decision on Institution Petitioner’s proposed claim
`constructions).
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` Principles of Law
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`differences between the claimed subject matter and the prior art are such that
`the subject matter, as a whole, would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations including: (1) the scope and content of the prior art;
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`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of ordinary skill in the art; and, when presented, (4) objective
`evidence of nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18
`(1966). We are also mindful that the prior art itself can reflect the
`appropriate level of ordinary skill in art. See Okajima v. Bourdeau, 261 F.3d
`1350, 1355 (Fed. Cir. 2001).5
`We analyze the asserted grounds of unpatentability in accordance with
`the above-stated principles.
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` Asserted Obviousness over Desai, Shively, Liversidge, and
`Remington’s Pharmaceutical Sciences
`Petitioner asserts that claims 1–27 of the ’260 patent are unpatentable
`under 35 U.S.C. § 103 because the subject matter of those claims would
`have been obvious over the combination of Desai, Shively, Liversidge, and
`Remington’s Pharmaceutical Sciences. Pet. 6, 25–63. Patent Owner
`disputes Petitioner’s assertion. See generally Prelim. Resp. On this record,
`we determine that Petitioner has not established a reasonable likelihood that
`it would prevail in showing the challenged claims are obvious over the
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`5 Petitioner asserts that a person of ordinary skill in the art would have “an
`advanced degree in chemistry, chemical engineering, pharmaceutics,
`pharmacy, or a related discipline, and/or having experience formulating
`compounds for use in pharmaceutical compositions, including nanoparticle
`suspensions, for several years.” Pet. 6 (citing Ex. 1002 ¶ 19; Ex. 1034 ¶ 22).
`For purposes of the decision on institution, Patent Owner does not challenge
`Petitioner’s stated level of ordinary skill in the art. Prelim. Resp. 3. For
`purposes of this Decision on Institution, we apply Petitioner’s asserted level
`of ordinary skill as it is commensurate with the sophistication of the
`technology and the educational level of those active in the field. See In re
`GPAC, 57 F.3d 1573, 1579 (Fed. Cir. 1995).
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`combination of Desai, Shively, Liversidge, and Remington’s Pharmaceutical
`Sciences.
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`1. Desai
`Desai describes encasing a water insoluble pharmacologically active
`agent such as taxol in a polymeric shell formulated from a biocompatible
`polymer such as albumin. Ex. 1003, 1:12–15; 6:36–37. Desai further
`describes how to make such a formulation as follows:
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`In accordance with the present invention, the polymer (e.g., a
`protein) is selectively chemically crosslinked through the
`formation of disulfide bonds through, for example, the amino
`acid cysteine that occurs in the natural structure of a number of
`proteins. A sonication process is used to disperse a dispersing
`agent containing dissolved or suspended pharmacologically
`active agent into an aqueous solution of a biocompatible
`polymer bearing sulfhydryl or disulfide groups (e.g., albumin)
`whereby a shell of crosslinked polymer is formed around fine
`droplets of non-aqueous medium.
`Id. at 4:52–63.
`The polymeric shell more preferably has a cross-sectional diameter of
`less than 5 microns, and most preferably a cross-sectional diameter of less
`than 1 micron for an intravenous route of administration. Id. at 5:36–40.
`Desai’s Example 9 describes preparing crosslinked, protein-walled
`polymeric shells of albumin containing a solid core of pharmaceutically
`active agent. Id. at 15:48–16:22.
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`2. Shively
`Shively describes taxol-in-oil solutions used to prepare oil-in-water
`emulsions for pharmaceutical use in anti-tumor therapy. Ex. 1004, Abst.
`Using this method, up to about 10 mg/ml concentration of taxol-in-oil is
`achievable allowing delivery of a pharmaceutically relevant dose of taxol in
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`IPR2017-01100
`Patent 8,853,260 B2
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`a significantly lower amount of the pharmaceutical preparation. Id. at 4:55–
`59. Shively states that the “final emulsions of this invention carry from 0.5-
`5 mg/ml of taxol, thus allowing delivery of the drug in up to one one-
`hundredth or less of the volume now used without toxic cosolvents or
`cremophores.” Id. at 4:60–63.
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`3. Liversidge
`Liversidge describes dispersible particles of “a crystalline anticancer
`agent having a surface modifier adsorbed on the surface thereof in an
`amount sufficient to maintain an effective average particle size of less than
`about 1000 nm.” Ex. 1005, Abst. Liversidge further states that in
`particularly preferred embodiments, “the effective average particle size is
`less than about 400 nm,” and in some embodiments, it is less than about
`300 nm. Id. at 5:1–5.
`Liversidge describes making a formulation of nanoparticulate taxol in
`Examples 11 through 16. Id. at 12:19–13:8. Liversidge also describes using
`Tween or PVA in these formulations of nanoparticulate taxol achieving a
`final particle size of 327 nm and 365 nm, respectively. Id. at 12:20–33.
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`4. Remington’s Pharmaceutical Sciences
`Remington Pharmaceutical Sciences is a textbook describing disperse
`systems, including colloidal dispersions, and sterilization technology, in
`general. See generally Ex. 1006.
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`5. Analysis
`Petitioner asserts that Desai discloses a formulation of nanoparticles
`having a solid core of paclitaxel and an albumin coating in Example 9.
`Pet. 26 (citing Ex. 1002 ¶ 91). Petitioner also asserts that it would have been
`obvious to prepare Desai’s albumin-paclitaxel nanoparticles with a size less
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`IPR2017-01100
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`than 400 nm, as required by claim 1, in light of the following teachings:
`(1) Desai’s teaching that “preferred particle radii fall in the range of about
`0.1 up [about 200 nm] to about 5 micron [about 10,000 nm]” (Ex. 1003,
`9:15–16); (2) Remington’s teaching that sterile filtration is the method of
`choice for heat-labile parenteral products requiring a filter pore size of 220
`nm (Ex. 1006, 62); and (3) Liversidge’s teaching of less than 400 nm
`effective average particle size (Ex. 1005:1–5). Pet. 27–30.
`Petitioner further relies on Shively’s teachings to establish that it
`would have been obvious to suspend Desai’s nanoparticles at a 5 mg/ml
`concentration of paclitaxel. Pet. 31–33. For instance, Petitioner states that
`Desai indicates that it is desirable to have relatively high concentrations of
`taxol to minimize patient discomfort and length of hospital stays. Id. at 31
`(citing Ex. 1003, 10:19–21, 5:25–27). Petitioner points out that Shively
`expressly teaches raising the concentration to 5 mg/ml of taxol. Id. at 31
`(citing Ex. 1004, 4:59–62). Petitioner asserts that although Shively’s
`formulations are emulsions versus Desai’s colloids, both address the
`concentration of paclitaxel and “a skilled artisan would have been motivated
`to combine Shively’s 5 mg/ml paclitaxel concentration with Desai’s
`albumin-coated nanoparticles.” Pet. 32 (citing Ex. 1002 ¶ 106).
`Finally, Petitioner asserts that the requirement of claim 1 that the
`claimed formulation “is stable for at least 3 days under at least one of room
`temperature or refrigerated conditions,” hereinafter, the “stability
`limitation,” is an inherent property of the formulation requiring no additional
`showing to establish that the challenged claims would have been obvious.
`Pet. 33–36. Petitioner points to statement in the Specification of the ’260
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`patent itself and statements by the inventor and the Examiner of the ’260
`patent. Id. at 34–35.
`Patent Owner disagrees that Desai teaches the size limitation or
`inherently or otherwise satisfies the stability limitation for the claimed
`formulations. Prelim. Resp. 14–40. Patent Owner also asserts that one of
`ordinary skill in the art would not have any reason to combine the teachings
`of Desai, Shively, Liversidge, and Remington’s Pharmaceutical Sciences, or
`have any reasonable expectation of success in doing so. Id. at 42–56.
`We agree with Patent Owner that Petitioner at least has failed to
`establish that the stability limitation of the challenged claims is taught by the
`combination of references.
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`a. Alleged Inherent Stability of the Claimed Pharmaceutical
`Formulation
`Petitioner has failed to show that the stability limitation of the claims
`is an inherent property of the claimed formulation. Petitioner points to two
`references in the Specification of the ’260 Patent that refer to a particular
`commercial embodiment of the formulation, CapxolTM. Ex.1001 14:23–25
`(stating that the problem of precipitation is alleviated because of “inherent
`stability” of CapxolTM), 66:15–17 (same), cited in Pet. 34.
`Although rooted in an anticipation context, inherency does apply in an
`obviousness context in a more circumscribed way. Par Pharmaceutical, Inc.
`v. TWI Pharmaceuticals, Inc., 773 F.3d 1186, 1195 (Fed. Cir. 2014). For
`instance, “mere recitation of a newly discovered function or property,
`inherently possessed by things in the prior art, does not distinguish a claim
`drawn to those things from the prior art.” Id. (quoting In re Oelrich, 666
`F.2d 578, 582 (CCPA 1981)). To find the functional stability limitation of
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`the challenged claims inherent in the claimed formulation, however, the
`stability property must necessarily be present in the claimed formulation,
`i.e., the functional stability limitation is the “natural result” of the claimed
`formulation. Id. The fact that the claimed stability probably may result
`from the claimed formulation is insufficient to establish that it is inherent.
`We determine that Petitioner has not shown adequately on this record
`that the stability limitation of the challenged claims is inherent. Petitioner’s
`reliance on two references in the Specification of the ’260 patent to allegedly
`show the “inherent” stability of CapxolTM, an alleged claimed formulation, is
`not sufficient to persuade us that all formulations meeting the limitations of
`the challenged claims necessarily have stability of the aqueous suspension of
`the pharmaceutical formulation “for at least 3 days under at least one of
`room temperature or refrigerated conditions.” See Pet. 34; Ex. 1001, 67:35–
`37. For instance, Petitioner points us to the following disclosure from the
`’260 Specification that describes an “inherent stability” of the specific
`“new” formulation, CapxolTM:
`A recognized problem with TAXOL formulation is the
`precipitation of paclitaxel in indwelling catheters. This results in
`erratic and poorly controlled dosing. Due to the inherent stability
`of the colloidal solution of the new formulation, CapxolTM, the
`problem of precipitation is alleviated.
`Ex. 1001, 14:20–25, 66:13–17 (similar language). This disclosure is limited
`to the “inherent” stability of CapxolTM. Without any further qualification,
`however, this disclosure does not teach that the CapxolTM formulation is
`coextensive with all claimed formulations such that stability is inherent for
`all formulations prepared according to the requirements of the challenged
`claims. Also, neither of these references in the Specification of the ’260
`patent discusses the length of time or under what temperature conditions that
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`CapxolTM is stable, both specific requirements of the stability of the claimed
`formulations.
`Similarly, equally unavailing is Petitioner’s reference to the ’260
`patent’s description of how using human serum albumin facilitates stability
`of a colloidal dispersion of colloidal drug particles with Taxol because of “a
`combination of electrical repulsion and steric stabilization.” Pet. 34 (quoting
`Ex. 1001, 10:55–59); see also Pet. 35 (providing inventor’s statement to
`FDA that steric stabilization from albumin “keeps these nanoparticles
`stable” and Examiner’s assessment of declaratory evidence concerning
`“stable high drug loading” in the composition). The specific language to
`which Petitioner refers states:
`In addition, advantage is taken of the capability of human
`serum albumin to bind Taxol, as well as other drugs, which
`enhances the capability of Taxol to absorb on the surface of the
`particles. Since albumin is present on the colloidal drug particles
`(formed upon removal of the organic solvent), formation of a
`colloidal dispersion which is stable for prolonged periods is
`facilitated, due to a combination of electrical repulsion and steric
`stabilization.
`Ex. 1001, 10:52–59. These statements concerning albumin’s “facilitation”
`of the stability of a colloidal dispersion of albumin and taxol does not
`persuade us that the claimed formulations necessarily are stable “for at least
`3 days under at least one of room temperature or refrigerated conditions” as
`required by the claims. See Prelim. Resp. 26–27.
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`b. Desai’s Alleged Disclosure of Stability of the Claimed
`Pharmaceutical Formulation
`Petitioners also assert that even if the stability limitation is not an
`inherent property of the claimed formulation, “a skilled artisan would have
`reasonably expected that Desai’s albumin-paclitaxel nanoparticles,
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`formulated to be smaller than 400 nm and suspended at a concentration of
`5 mg/ml, would remain stable for at least three days. Such stability was a
`key consideration that was routinely optimized by skilled formulators as of
`June 1997.” Pet. 36 (citing Ex. 1002 ¶ 109; Ex. 1034 ¶ 43). Petitioner relies
`on data provided for Examples 4 and 5 of Desai to show that Desai discloses
`favorable stability for its compositions that allegedly include the formulation
`of claim 1 of the ’260 patent. Id. at 36–37.
`Specifically, Petitioner states that:
`Example 4 teaches that “protein-walled polymeric shells”
`containing paclitaxel were obtained in “a stable white milky
`suspension.”
` Ex. 1003, 12:62–64.
` Example 5 further
`characterizes the stability of Example 4, and demonstrates the
`stability of albumin shells suspended in saline “at three different
`temperatures (i.e., 4°C., 25°C., and 38°C.).” Id. at 13:10–18.
`“Stability was measured by the change in particle counts over
`time.” Id. at 13:12–14.
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`Id. at 13:20–30. “As demonstrated by the above data, the
`concentration of counted particles (i.e., polymeric shells)
`remains fairly constant over the duration of the experiment . . .
`indicating good polymeric shell stability under a variety of
`temperature conditions over almost four weeks.” Id. at 13:33–
`39.
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`Pet. 36–37.
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`Based on these teachings of Desai from Example 4, which is directed
`to the preparation of an albumin protein shell containing soybean oil, and
`Example 5, which is directed to the stability of polymeric shells, Petitioner
`concludes that a skilled artisan would have reasonably expected that the
`pharmaceutical formulation would have been stable for three days under
`either refrigerated or room temperature conditions. Pet. 37. Petitioner
`reasons that because based on the “fairly constant” concentration of counted
`particles as shown in Example 5, “the composition would exhibit
`(i) substantially no precipitation and (ii) substantially no increase in particle
`size,” showing the stability of the formulation. Id.
`Petitioner further asserts the following in support of its reasoning.
`From the “fairly constant” concentration of counted particles as shown in
`Table 1 above for Example 5, Petitioner asserts that one of skill in the art
`would have understood that these formulations exhibited no substantial
`precipitation or creaming. Pet. 37 (citing Ex. 1002 ¶ 112). Petitioner states
`further that:
`If the particles had either precipitated (fallen) or creamed (risen)
`out of suspension, the number of particles in suspension would
`have decreased. Given that Desai’s particles remained in
`suspension for nearly four weeks, a skilled artisan would have
`reasonably expected that the particles of claim 1 would remain
`in suspension for at least three days.
`Pet. 37–38 (citing Ex. 1002 ¶ 113).
`Dr. Berkland testifies that:
`Although the particles used in Example 5 contained
`soybean oil rather than paclitaxel, which is denser and thus less
`buoyant than oil, a skilled artisan in June 1997 would have
`understood that the purpose of Example 5 was to demonstrate the
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`stability of albumin-coated paclitaxel particles. Indeed, Desai as
`a whole is directed to the “delivery of substantially water
`insoluble pharmacologically active agents (such as the anticancer
`drug taxol)”—not soybean oil. To a skilled artisan reading
`Example 5 in context, the fact that Desai’s albumin shells
`stabilized an aqueous suspension of soybean oil (which, like
`paclitaxel, does not dissolve in water) would have been a
`significant accomplishment with broad applicability to other
`insoluble products, including paclitaxel.
`Ex. 1002 ¶ 114 (citations omitted); Pet. 38–39. Petitioner also asserts that
`Desai’s statement that the concentration of counted particles remaining
`“fairly constant” also shows that Desai’s particles did not change size,
`supports Petitioner’s position that Desai shows stable particles as required
`by the challenged claims. Pet. 41 (citing Ex. 1002 ¶ 128). Petitioner relies
`on Liversidge to confirm a reasonable expectation of such stability. Pet. 42–
`43.
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`To further support this conclusion that Desai teaches the claimed
`stability, Petitioner offers a comparison between the density of soybean oil
`and albumin-paclitaxel nanoparticles in relation to the diameter of each
`particle, about 1,350 nm for the soybean oil particles versus 200 nm for the
`albumin-paclitaxel nanoparticles, to show that “a skilled artisan would have
`understood that even if the difference in density could affect stability, the
`equally significant difference in size would have minimized that effect.”
`Pet. 40 (citing Ex. 1002 ¶ 117); see Pet. 40–41, IX, App. Of Calculations
`(calculating the expected stability of the claimed nanoparticle formulation by
`comparing its expected mean displacement due to Brownian motion (“x”) to
`its expected rate of sedimentation under Stokes’ law (“h”)).
`We agree with Patent Owner that the disparities between the teachings
`of Desai’s examples and the claimed formulations, discussed below, are too
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`great to support a reasonable likelihood that Petitioner would prevail in
`showing any challenged claim would have been obvious in light of the
`claimed combination of references. See KSR, 550 U.S. at 421 (stating “[a]
`factfinder should be aware, of course, of the distortion caused by hindsight
`bias and must be cautious of arguments reliant upon ex post reasoning”).
`Petitioner’s ex post reasoning to show otherwise is unpersuasive.
`As Patent Owner points out, the polymeric shells of Example 5 of
`Desai, which were made according to Example 2, not Example 4, contain
`soybean oil, not paclitaxel, and the particles are much larger, 1.35+0.73
`microns, than the claimed pharmaceutical formulation. See Prelim. Resp.
`29–30; Ex. 1003, 13:10–19; 11:63–67. Even assuming, as Petitioner asserts,
`that Example 5 describes the stability of the polymeric shells of Example 4,
`Example 4 has polymeric shells containing taxol dissolved in soybean oil,
`not the claimed solid core of paclitaxel. See Prelim. Resp. 30 (citing Ex.
`1003, 12:49–64). We agree with Patent Owner that “Petitioner provides no
`evidence that Example 5’s stability data regarding soybean-oil particles is
`predictive of, or even relevant to, the stability of the solid-core particles
`claimed in the ’260 patent.” Prelim. Resp. 30.
`We also agree with Patent Owner that Petitioner’s comparison
`between the density of soybean oil and albumin-paclitaxel nanoparticles in
`relation to the diameter of each particle, about 1,350 nm for the soybean oil
`particles versus 200 nm for the albumin-paclitaxel nanoparticles, does not
`bridge the gap to provide evidentiary supports for Petitioner’s conclusion
`that Desai teaches the claimed stability. See Prelim. Resp. 29–30. As Patent
`Owner notes, there are flaws, as discussed below, in Petitioner’s
`assumptions made for, and the calculations of, the expected stability of the
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`claimed nanoparticle formulations by comparing expected mean
`displacement due to Brownian motion to expected rate of sedimentation
`under Stokes’ law. See Prelim. Resp. 32–37. For example, Dr. Berkland
`uses comparative particle density alone without any support or reference to
`any evidence to establish that Desai’s Example 5 provided a skilled artisan
`with a reasonable basis to expect that albumin shells containing solid
`paclitaxel would similarly remain stable against sedimentation. Ex. 1002
`¶ 116; see Prelim. Resp. 31 (stating “[s]cientifically, Petitioner fails to cite to
`any art where the stability of nanoparticles was predicted based solely on
`particle density, or otherwise establish the validity of its single-factor
`analysis.”). Also, Petitioner uses the density of soybean oil, not albumin-
`soybean-oil particles, when comparing to the density of albumin-paclitaxel
`nanoparticles. See Ex. 1002 ¶ 116; Prelim. Resp. 31–32.
`There also are flaws in Petitioner’s Stokes’ law analysis because
`Petitioner uses the viscosity of water and not the viscosity of the claimed
`suspension of 5–15 mg/ml paclitaxel and albumin. We agree with Patent
`Owner that as both paclitaxel and albumin would affect the viscosity of the
`suspension, Petitioner should have taken such viscosities into account in its
`calculations. See Prelim. Resp. 35.
`Accordingly, for at least these reasons, we are not persuaded the
`record before us establishes a reasonable likelihood that Petitioner will
`prevail in showing that the subject matter of claims 1–27 would have been
`obvious over the combination of Desai, Shively, Liversidge, and
`Remington’s Pharmaceutical Sciences.
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`IV. CONCLUSION
`Taking account of the information presented in the Petition and the
`Preliminary Response, and the evidence of record, we determine that
`Petitioner fails t