Trials@uspto.gov
`Tel: 571-272-7822
`
`Paper 7
`Entered: October 10, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`
`
`
`
`ACTAVIS LLC,
`Petitioner,
`
`v.
`ABRAXIS BIOSCIENCE LLC,
`Patent Owner.
`
`Case IPR2017-01101
`Patent 7,820,788 B2
`
`
`Before JEFFREY N. FREDMAN, RAMA G. ELLURU, and
`SUSAN L. C. MITCHELL, Administrative Patent Judges.
`
`MITCHELL, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`

`

`IPR2017-01101
`Patent 7,820,788 B2
`
`
`I. INTRODUCTION
`
`A. Background
`Petitioner Actavis LLC (“Petitioner”) filed a Petition (Paper 2, “Pet.”)
`requesting an inter partes review of claims 1–12 (the “challenged claims”)
`of U.S. Patent No. 7,820,788 B2 (Ex. 1001, “the ’788 patent”). Patent
`Owner Abraxis Bioscience, Inc. (“Patent Owner”) filed a Preliminary
`Response. Paper 6 (“Prelim. Resp.”).
`We have authority to determine whether to institute an inter partes
`
`review under 35 U.S.C. § 314 and 37 C.F.R. § 42.4(a). To institute an inter
`partes review, we must determine that the information presented in the
`Petition shows “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). For the reasons set forth below, we conclude that Petitioner has
`established a reasonable likelihood that it would prevail in showing the
`unpatentability of at least one of the challenged claims of the ’788 patent.
`Therefore, we institute an inter partes review for claims 1–12 of the ’788
`patent.
`
`B. Related Proceedings
`Petitioner indicates that the ’788 patent was asserted in Abraxis
`BioScience, LLC v. Actavis LLC, 2:16-cv-09074-JMV-MF (D.N.J. April 6,
`2016), and in Abraxis BioScience, LLC v. Cipla Ltd., 2:16-cv-09074-JMV-
`MF (D.N.J. Dec. 7, 2016). Pet. 4–5; Paper 4, 2. Petitioner has also filed
`three additional requests for inter partes review of other patents owned by
`Abraxis, two of which are related to the ’788 patent: IPR2017-01100
`(involving U.S. Patent No. 8,853,260 B2); IPR2017-01103 (involving U.S.
`
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`IPR2017-01101
`Patent 7,820,788 B2
`
`Patent No. 7,923,536 B2); and IPR2017-01104 (involving U.S. Patent No.
`8,138,229 B2). Pet. 5.
`
`C. The ’788 Patent (Ex. 1001)
`The ’788 patent involves methods of formulating pharmaceuticals
`with carriers to “reduce one or more side effects.” Ex. 1001, 3:55–62. Such
`methods specifically involve formulating taxol (paclitaxel), an agent active
`against carcinomas, (id. at 4:31–33), with albumin, a protein found in human
`plasma (id. at 5:7–18).
`The ’788 patent specifically prefers that the composition “have a
`particle or droplet size less than about 200 nanometers” (id. at 9:52). The
`’788 patent states that:
`While the ratio of protein to pharmaceutical agent will have to
`be optimized for different protein and pharmaceutical agent
`combinations, generally the ratio of protein, e.g., albumin, to
`pharmaceutical agent is about 18:1 or less (e.g., about 15:1,
`about 10:1, about 5:1, or about 3:1). More preferably, the ratio
`is about 0.2:1 to about 12:1. Most preferably, the ratio is about
`1:1 to about 9:1.
`Id. at 11:60–67. The ’788 patent also prefers a formulation “essentially free
`of cremophor” because “cremophor typically is used as a solvent for
`paclitaxel, and is associated with side effects that can be severe” (id. at 12:1–
`6).
`
`D. Illustrative Claims
`Of the challenged claims, claim 1 is the sole independent claim of the
`’788 patent. The remaining challenged claims 2–12 depend directly or
`indirectly from claim 1. Claim 1 is illustrative of the challenged claims and
`recites:
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`IPR2017-01101
`Patent 7,820,788 B2
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`
`1. 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 particles, wherein the
`particles 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.
`
`Ex. 1001, 38:17–24.
`
`E. The Asserted Grounds of Unpatentability
`Petitioner contends that the challenged claims are unpatentable based
`on the following grounds and asserted references. Pet. 1–4, 6.
`References
`Basis
`Claims Challenged
`§ 102(b)
`1–9, 11–12
`§ 103(a)
`1–12
`§ 103(a)
`1–12
`
`Desai1
`Desai
`Desai, Kadima,2 and
`Liversidge3
`
`Petitioner relies also on the Declaration of Cory Berkland, Ph.D. Pet.
`1–60; see Ex. 1002.
`
`II. ANALYSIS
`A. Claim Interpretation
`In an inter partes review, claim terms in an unexpired patent are given
`their broadest reasonable construction in light of the specification of the
`patent in which they appear. 37 C.F.R. § 42.100(b); Cuozzo Speed Techs.,
`LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016). Under the broadest
`
`
`1 WO 99/00113 A1, published Jan. 7, 1999 (Ex. 1006, “Desai”).
`2 WO 00/06152 A1, published Feb. 10, 2000 (Ex. 1004, “Kadima”).
`3 US 5,399,363, issued Mar. 21, 1995 (Ex. 1005, “Liversidge”).
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`reasonable interpretation approach, claim terms are given their ordinary and
`customary meaning as would be understood by one of ordinary skill in the
`art in the context of the entire disclosure. In re Translogic Tech., Inc., 504
`F.3d 1249, 1257 (Fed. Cir. 2007). We determine that the following claim
`language needs to be discussed.
`
`1. “the weight ratio of albumin to paclitaxel in the composition”
`Petitioner offers an interpretation of the claim phrase “the weight ratio
`of albumin to paclitaxel in the composition” and “the ratio (w/w) of albumin
`to the paclitaxel in the pharmaceutical composition” as “at least the albumin-
`paclitaxel ratio in the starting ingredients used to make the composition.”
`Pet. 18, 20 (citing Ex. 1002 ¶ 53). Petitioner states a “skilled artisan reading
`[the ’788 patent’s] examples would understand that the ‘ratio of albumin to
`paclitaxel’ was based on the amounts used to make the composition.” Pet.
`19 (citing Ex. 1002 ¶ 36).
`Patent Owner disagrees, and offers an interpretation that the “claimed
`ratio term should be construed to mean the weight ratio of albumin-to-
`paclitaxel in the finished pharmaceutical composition for injection.” Prelim.
`Resp. 10 (emphasis added). Patent Owner states
`the claim requires that the ratio be of the albumin to paclitaxel
`“in the composition,” and that “composition” is plainly the
`“pharmaceutical composition for injection”—i.e., the finished
`pharmaceutical product. (Id., claim 1.). . . . Thus, based on the
`plain claim language, the ratio refers to the claimed finished
`pharmaceutical product, not the albumin and paclitaxel starting
`materials prior to the formation of the nanoparticles.
`
`Prelim. Resp. 11. Patent Owner notes “the prosecution history confirms this
`construction. . . . The Examiner . . . understood that the 9:1 ratio was
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`referring to the finished nanoparticle pharmaceutical composition.” Prelim.
`Resp. 12–13.
`
`We agree with Patent Owner’s proposed construction at this stage of
`the proceeding on the record before us. The ’788 patent claims use the
`definite article “the” to signal that there is antecedent basis for
`“the composition” in the claim phrase “the weight ratio of albumin to
`paclitaxel in the composition.” See ’788 patent, claim 1. The article “the”
`refers to “a pharmaceutical composition for injection” in the preceding
`language of claim 1. See ’788 patent, 38:17–24. Therefore, the reasonable
`interpretation from the intrinsic evidence requires “the composition” to be
`the “pharmaceutical composition for injection.” See Warner–Lambert Co. v.
`Apotex Corp., 316 F.3d 1348, 1356 (Fed. Cir. 2003) (quoting Am. Bus Ass’n
`v. Slater, 231 F.3d 1, 4–5 (D.C. Cir. 2000) (“[I]t is a rule of law well
`established that the definite article ‘the’ particularizes the subject which it
`precedes. It is a word of limitation as opposed to the indefinite or
`generalizing force of ‘a’ or ‘an.’”).
`
`Consequently, the broadest reasonable interpretation of the
`“pharmaceutical composition” is that it refers to the final product because it
`is injected into the patient. Thus, we agree with Patent Owner on this record
`that the 9:1 ratio of “the composition” in claim 1 of the ’788 patent must be
`the ratio of albumin to paclitaxel in the final product for injection into the
`patient. We also agree with the Patent Owner that the Specification of the
`’788 patent and the prosecution history also tend to support this
`interpretation, but we need not rely on such evidence here to construe the
`claim term at this stage of the proceeding as the plain language of the claim
`supports our interpretation. See Prelim. Resp. 11–13.
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`
`2. “a particle size of less than about 200 nm”
`Petitioner offers an interpretation of the claim term “a particle size of
`less than about 200 nm” to include “particle sizes of 220 nm or less,
`measured as the Z-average diameter using a Malvern Zetasizer.” Pet. 21
`(citing Ex. 1002 ¶ 54). Petitioner points out that “every example in the ʼ788
`patent that mentions particle size refers to ‘the typical average diameter’ of
`the particles and discloses a particle size range of ‘50–220 nm (Z-average,
`Malvern Zetasizer).’” Pet. 21 (citing Ex. 1002 ¶ 39; Ex. 1001, Examples 1,
`2, 4–14, 47–49).
`
`Patent Owner states that except for the claim term discussed above,
`“[a]ny other terms do not need construction as they are not determinative of
`any dispute presented by the Petition.” Prelim. Resp. 16–17.
`Because the parties do not disagree about whether the art teaches the
`claimed particle sizes, see Pet. 21, 23–24; Prelim. Resp. 16–17, and our
`decision does not require an express construction to resolve any dispute at
`this point in the proceeding, we do not need to interpret expressly the claim
`term “a particle size of less than about 200 nm.” See, e.g., Wellman, Inc. v.
`Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011) (“[C]laim terms
`need only be construed ‘to the extent necessary to resolve the
`controversy.’”) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`200 F.3d 795, 803 (Fed. Cir. 1999)).
`
`B. Section 325(d) – Discretion to Decline to Institute
`Patent Owner urges us to decline to institute the asserted grounds
`under 35 U.S.C. § 325(d) because the ground “Petitioner’s asserted art was
`already before the Office, and Petitioner’s arguments based on that art are
`the same or substantially the same as what the Office considered (i.e., that
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`the skilled person would have optimized the ratio of albumin to paclitaxel in
`the composition).” Prelim. Resp. 17 (citing Pet. 14). Patent Owner
`concludes that “[b]ecause Desai provides no relevant disclosures beyond that
`which the Office considered regarding [another reference], Petitioner’s use
`of Desai adds nothing new . . . . Without any new evidence or other reason
`to revisit the Examiner’s determinations, the Petition merely seeks to have
`the Board second-guess the Examiner.” Id. at 18–19.
`Under § 325(d), we have discretion to “reject the petition or request
`because[] the same or substantially the same prior art or arguments
`previously were presented to the Office.” 35 U.S.C. § 325(d). Considering
`all of the relevant facts and circumstances, Patent Owner’s argument is
`insufficient to persuade us to exercise our discretion to deny the Petition.
`For example, Petitioner relies on a declaration from Dr. Berkland, which
`Patent Owner does not allege is duplicative of evidence previously presented
`to the Office. See Tandus Flooring, Inc. v. Interface, Inc., Case IPR2013-
`00333, 2013 WL 8595289, at *2 (PTAB Dec. 9, 2013) (Paper 16) (declining
`to deny petition under § 325(d) where petitioner presented new declaration
`evidence); Chimei Innolux Corp. v. Semiconductor Energy Lab. Co., Case
`IPR2013-00066, 2013 WL 8595548, at *5 (PTAB Apr. 24, 2013) (Paper 10)
`(same). Also, the Examiner relied upon testimonial evidence that was not
`subject to cross-examination in determining patentability of the claims that
`are contested in this proceeding, and Desai was not prior art upon which the
`Examiner relied for any rejection. See Ex. 1023. We, therefore, determine
`that Petitioner’s petition does not present the same or substantially the same
`prior art or arguments previously presented to the Office.
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`
`C. Principles of Law
`A claim is unpatentable under 35 U.S.C. § 102 if a single prior art
`reference expressly or inherently describes each and every limitation as set
`forth in the claim. See Perricone v. Medicis Pharm. Corp., 432 F.3d 1368,
`1375 (Fed. Cir. 2005); Verdegaal Bros., Inc. v. Union Oil Co., 814 F.2d 628,
`631 (Fed. Cir. 1987). “A single prior art reference may anticipate without
`disclosing a feature of the claimed invention if such feature is necessarily
`present, or inherent, in that reference.” Allergan, Inc. v. Apotex Inc., 754
`F.3d 952, 958 (Fed. Cir. 2014) (citing Schering Corp. v. Geneva Pharm.,
`339 F.3d 1373, 1377 (Fed. Cir. 2003)).
`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;
`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of ordinary skill in the art; and (4) objective evidence of
`nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`In that regard, an obviousness analysis “need not seek out precise
`teachings directed to the specific subject matter of the challenged claim, for
`a court can take account of the inferences and creative steps that a person of
`ordinary skill in the art would employ.” KSR, 550 U.S. at 418. In KSR, the
`Supreme Court also stated that an invention may be found obvious if trying a
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`course of conduct would have been obvious to a person having ordinary
`skill:
`
`When there is a design need or market pressure to solve a
`problem and there are a finite number of identified, predictable
`solutions, a person of ordinary skill has good reason to pursue
`the known options within his or her technical grasp. If this leads
`to the anticipated success, it is likely the product not of
`innovation but of ordinary skill and common sense. In that
`instance the fact that a combination was obvious to try might
`show that it was obvious under § 103.
`KSR, 550 U.S. at 421. “KSR affirmed the logical inverse of this statement
`by stating that § 103 bars patentability unless ‘the improvement is more than
`the predictable use of prior art elements according to their established
`functions.’” In re Kubin, 561 F.3d 1351, 1359−60 (Fed. Cir. 2009) (citing
`KSR, 550 U.S. at 417).
`We are mindful that the level of ordinary skill in the art also is
`reflected by the prior art of record.4 See Okajima v. Bourdeau, 261 F.3d
`1350, 1355 (Fed. Cir. 2001); In re GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir.
`1995); In re Oelrich, 579 F.2d 86, 91 (CCPA 1978).
`We analyze the asserted grounds of unpatentability in accordance with
`the above-stated principles.
`
`
`4 Petitioner states that the level of skill in the art at the time of the invention
`is a person who has a “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. 7 (citing Ex. 1002 ¶ 19).
`Patent Owner “adopts Petitioner’s definition of a POSA” at this stage of the
`proceeding. See Prelim. Resp. 9. We, therefore, apply Petitioner’s stated
`level of ordinary skill in the art, which is supported by Dr. Berkland,
`because of the sophistication of the technology and the educational level of
`those who work in this area. See In re GPAC, 57 F.3d at 1579.
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`
`D. Anticipation by Desai
`
`Petitioner contends that claims 1–9 and 11–12 are unpatentable under
`35 U.S.C. § 102(b) as anticipated by Desai. Pet. 6, 22. Petitioner asserts
`that “Desai as a whole is directed to ‘particulate vehicles for the intravenous
`administration of pharmacologically active agents,’ and describes albumin as
`a ‘carrier protein’ and ‘the natural carrier of the drug in the blood stream.’”
`Pet. 22–23. Also, Petitioner asserts that “Example 1 of Desai discloses a
`method of producing albumin-paclitaxel nanoparticles with a typical average
`diameter of 160–220 nm,” and “Desai expressly ‘enables the reproducible
`production of unusually small nanoparticles of less than 200 nm in
`diameter.” Pet. 22–24.
`Petitioner asserts with regard to the albumin-paclitaxel ratio that:
`Example 1 of Desai discloses an albumin-paclitaxel ratio of
`about 9:1 by providing that “30 mg paclitaxel is dissolved in 3.0
`ml methylene chloride,” which “was added to 27.0 ml of human
`serum albumin solution (1% w/v).” EX1006, 62.5 A skilled
`artisan would have known that 27 ml of 1% (w/v) albumin
`contains 270 mg of albumin, which, when combined with 30 mg
`of paclitaxel, necessarily results in a composition with an
`albumin-paclitaxel weight ratio of 270:30—i.e., a ratio of exactly
`9:1. EX1002 ¶100. That is an express disclosure of the claimed
`9:1 ratio. Even if Patent Owner were to argue that it is not
`expressly disclosed because the language “9:1” does not appear,
`the listing of the ingredients and their amounts in the example is
`still an inherent disclosure of the claimed ratio.
`(Pet. 24–25).
`
`
`5 We will follow Petitioner’s convention in referring to Petitioner’s assigned
`page numbers for Exhibit 1006 rather than the original page numbers.
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`
`Patent Owner asserts that this ground fails, among other reasons,
`because “Petitioner relies on its incorrect construction of the ratio term as
`referring to the amounts of the starting ingredients as opposed to the finished
`nanoparticle composition,” and the measurements in Example 1 of Desai
`upon which Petitioner relies to show the claimed ratio “concern the starting
`amounts of the albumin and paclitaxel ingredients—before the many steps
`are conducted that are required to form a composition.” Prelim. Resp. 21.
`Patent Owner asserts
`as explained by Patent Owner’s declarant and nanoparticle
`formulation expert, Dr. Nicholas A. Peppas (EX2001), a POSA
`would understand that the process described in Example 1 would
`lead to substantial loss of paclitaxel, and thus the finished
`pharmaceutical product would have a higher ratio of albumin to
`paclitaxel than the 9:1 starting ratio.
`
`Prelim. Resp. 25 (citing Ex. 2001 ¶¶ 28–36). Patent Owner asserts this loss
`of paclitaxel is based on evidence showing “paclitaxel rapidly and
`nonspecifically adsorbs (sticks and accumulates) to most surfaces, including
`plastic, glass, and metal.” Prelim. Resp. 26.
`
`1. Desai (Ex. 1006)
`Desai teaches using “anti-cancer drugs, e.g., Taxol, in the form of
`nanoparticles.” Ex. 1006, 26:12–13.
`
`Capxol™ is a novel, cremophor-free formulation of the
`anticancer drug paclitaxel . . . . Capxol™ is a lyophilized powder
`for reconstitution and intravenous administration.
` When
`reconstituted with a suitable aqueous medium such as 0.9%
`sodium chloride injection or 5% dextrose injection, Capxol™
`forms a stable colloidal solution of paclitaxel. The size of the
`colloidal suspension may range from 20nm to 8 microns with a
`preferred range of about 20-400 nm. The two major components
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`
`of Capxol™ are unmodified paclitaxel and human serum
`albumin (HSA).
`Ex. 1006, 27:29–28:13. Desai teaches “Capxol™ is merely a shorthand
`means of reference to protein-coated paclitaxel nanoparticles produced by
`the method of Example 1” and that “[e]ach vial of Capxol™ contains 30 mg
`of paclitaxel and approximately 400 mg of human serum albumin.”
`Ex. 1006, 38:17–29. Example 1 of Desai teaches
`
`30 mg paclitaxel is dissolved in 3.0 ml methylene chloride. The
`solution was added to 27.0 ml of human serum a[l]bumin
`solution (1% w/v). The mixture was homogenized for 5 minutes
`at low RPM (Vitris homogenizer, model: Tempest I.Q.) in order
`to form a crude emulsion, and then transferred into a 30 high
`pressure homogenizer (Avestin). The emulsification was
`performed at 9000-40,000 psi while recycling the emulsion for
`at least 5 cycles. The resulting system was transferred into a
`Rotary evaporator, and methylene chloride was rapidly removed
`at 40°C, at reduced pressure (30 mm Hg), for 20-30 minutes. The
`resulting dispersion was translucent, and the typical diameter of
`the resulting paclitaxel particles was 160-220 (Z-average,
`Malvern Zetasizer).
`Ex. 1006, 62:25 to 63:6.
`In Example 4, Desai teaches the “dispersion is filtered through a 0.22
`micron filter (Millipore), without any significant change in turbidity, or
`particle size. HPLC analysis of the Taxol content revealed that more than
`97% of the Taxol was recovered after filtration.” Ex. 1006, 65:24–27.
`Example 16 of Desai summarizes a preferred manufacturing process with 1
`gram of paclitaxel and 431 ml of a 3% albumin solution that is filtered
`during the manufacturing process. Ex. 1006, 75:17–77:24.
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`
`Analysis
`2.
`Petitioner asserts “the fact that Example 1 of Desai discloses
`quantities of paclitaxel and albumin in a 9:1 ratio is sufficient to establish a
`reasonable likelihood of anticipation.” Pet. 29. Petitioner asserts “there is
`no evidence that Example 1 results in any loss of paclitaxel during
`manufacturing that would affect the composition’s albumin-paclitaxel ratio.
`There is no mention in Desai of any paclitaxel loss, and no reason why any
`of Example 1’s steps would result in such loss.” Pet. 30 (citing Ex. 1002
`¶ 113). Petitioner supports this assertion by noting
`a skilled artisan would have understood that Example 16 is
`consistent with Example 1 but more specifically describes the
`production of Capxol™. Ex. 1006, 75 (Example 16, the
`“Presently Preferred Manufacturing Process.”) . . . Example 16
`uses 1 g (i.e., 1,000 mg) of paclitaxel, which results initially in
`an albumin-paclitaxel ratio of 12.93:1. Id.; EX1002 ¶¶ 68–70,
`118. The resulting suspension is sterile filtered using a 200 nm
`filter before being filled into vials containing 30 mg of paclitaxel,
`and then lyophilized. EX1006, 76–66.
`That filtration step in Example 16 results in a ratio of
`13.3:1. Ex. 1002 ¶ 70. . . . Thus, a skilled artisan would have
`understood that the precise method of obtaining Capxol™’s
`13.3:1 ratio was disclosed in Example 16—not Example 1—
`which instead results in a 9:1 ratio. Id. ¶ 118.
`Pet. 32.
`In addition, Petitioner’s Declarant, Dr. Berkland, states regarding
`Example 49 of the ’536 patent that: “In other words, 135 mg of paclitaxel
`was combined with 1,350 mg of albumin (27 ml of 5% w/v solution),
`corresponding to a 10:1 ratio.” Ex. 1002 ¶ 37. Dr. Berkland concludes
`“therefore, the albumin-paclitaxel ratio of Example 49 was either
`‘calculated’ based on the starting materials, or measured after the process
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`steps were completed, at which point the ratio remained the same as the ratio
`of starting materials.” Id. Dr. Berkland also points out that: “There is no
`suggestion in the ʼ788 patent that the ratio of albumin to paclitaxel
`materially changes during the manufacturing process. Nor is there any
`disclosed assay or discussion of how to measure or predict the ratio of
`albumin to paclitaxel in the final pharmaceutical composition.” Id. ¶ 38.
`Patent Owner counters that
`Example 1’s method is used to produce Capxol™, and “[e]ach
`vial of Capxol™ contains 30 mg of paclitaxel and approximately
`400 mg of human serum albumin,” i.e., a 13.3:1 albumin-to-
`paclitaxel ratio for the finished product. (EX1006, 36:16–19,
`28–29.) Thus, the ratio of albumin to paclitaxel does not remain
`9:1 for the finished product. Rather, the ratio increases almost
`50%.
`
`Prelim. Resp. 22. Patent Owner further asserts “Petitioner attempts to run
`away from this confirmation by incorrectly arguing that a POSA would
`understand that Capxol™ was produced not by Desai’s Example 1, but
`rather by its Example 16.” Prelim. Resp. 22–23. Patent Owner asserts
`“Petitioner’s assertion is directly contradicted by the explicit teachings of
`Desai, which clearly states that ‘Capxol™ . . . is produced by the method of
`Example 1.’” Prelim. Resp. 23.
`
`Patent Owner also asserts that
`as explained by Patent Owner’s declarant and nanoparticle
`formulation expert, Dr. Nicholas A. Peppas (EX2001), a POSA
`would understand that the process described in Example 1 would
`lead to substantial loss of paclitaxel, and thus the finished
`pharmaceutical product would have a higher ratio of albumin to
`paclitaxel than the 9:1 starting ratio.
`
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`Prelim. Resp. 25 (citing Ex. 2001 ¶¶ 28–36). Patent Owner states that:
`“Due to its notoriously high hydrophobicity and other properties, paclitaxel
`rapidly and nonspecifically adsorbs (sticks and accumulates) to most
`surfaces, including plastic, glass, and metal.” Prelim. Resp. 26 (citing
`Ex. 2001 ¶ 25; 2031–2036 (pinpoint citations omitted)).
`We are not persuaded on this record that Desai’s Example 1 is
`necessarily used to produce Capxol™. Rather, we agree with Petitioner’s
`interpretation of Desai’s statement that Capxol™ is “produced by the
`method of Example 1” as exemplary, rather than limiting. Because
`Example 1 of Desai only combines 30 mg of paclitaxel with 270 mg
`albumin, Petitioner’s interpretation is consistent with Desai’s further
`statement, in the same paragraph, that: “Each vial of Capxol™ contains 30
`mg of paclitaxel and approximately 400 mg of human serum albumin.”
`Ex. 1006, 36:17–29. If Example 1 were the process used to produce
`Capxol™, the amounts of albumin should be identical, not different.
`We further agree that the current evidence of record, as supported by
`Dr. Berkland, better supports the position that Example 16 represents the
`process used to produce Capxol™ itself. Specifically, Example 16 is titled
`“[p]resently [p]referred [m]anufacturing [p]rocess” and exemplifies filling
`vials with 30 mg of paclitaxel. Ex. 1006, 73:16–17, 74:23–24; Ex. 1002 ¶¶
`68–69.
`Furthermore, Example 4 of Desai could be reasonably understood as
`teaching a specific working example demonstrating an actual experiment
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`where 97% of the starting amount of Taxol is recovered after filtration.
`Ex. 1006, 63:9–28.6
`Thus, as Petitioner points out, the manufacturing process of Example
`16 results in a 12.93:1 ratio, and based on Example 4, “one would expect to
`recover approximately 97% of the paclitaxel after sterile filtration, thereby
`raising the 12.93:1 ratio of albumin to paclitaxel in the starting materials of
`Example 16 to 13.3:1, i.e., the ratio of Capxol as disclosed in Desai.”
`Ex. 1002 ¶ 70; Pet. 32.
`Example 1 is therefore reasonably read as one of several alternative
`embodiments shown by Desai that was not the final process used to produce
`Capxol™, while Example 16 is a process that matches the ratios used to
`produce Capxol™. See Ex. 1002 ¶¶ 65–66.
`Therefore, on this record, the combination of teachings in Example 1
`of Desai of a 9:1 starting ratio of albumin to paclitaxel combined with the
`teaching in Example 4 that 97% of the Taxol was recovered after filtration,
`reasonably supports Petitioner’s position that Desai teaches a cancer
`treatment using a final pharmaceutical composition with a ratio of albumin
`to paclitaxel that is “about 9:1” as required by claim 1 of the ’788 patent.
`This conclusion of a 9:1 ratio in Desai is also supported because the
`identical processes are performed in Examples 1 and 4 of Desai and
`Example 49 of the ’788 patent. Example 49 of the ’536 patent teaches
`
`
`6 We note that Petitioner (or Patent Owner) may still avail themselves of
`37 C.F.R. § 42.65(b) and experimentally reproduce the process of Example 1
`of Desai to unequivocally demonstrate whether a starting ratio of 9:1
`albumin-paclitaxel does or does not result in a final ratio that is “about 9:1”
`as required by claim 1 of the ’536 patent.
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`135 mg of paclitaxel was dissolved in 3.0 ml methylene chloride.
`The solution was added to 27 ml of human serum albumin
`solution (5% w/v). Deferoxamine was added as necessary. The
`mixture was homogenized for 5 minutes at low RPM (Vitris
`homogenizer, model Tempest I.Q.) in order to form a crude
`emulsion, and then transferred into a high pressure homogenizer
`(Avestin). The emulsification was performed at 9000-40,000 psi
`while recycling the emulsion for at least 5 cycles. The resulting
`system was transferred into a rotary evaporator, and methylene
`chloride was rapidly removed at 40° C., at reduced pressure (30
`mm Hg) for 20-30 minutes. The resulting dispersion was
`translucent, and the typical average diameter of the resulting
`paclitaxel particles was in the range 50-220 nm (Z-average,
`Malvern Zetasizer). . . . The calculated ratio (w/w) of albumin
`to paclitaxel in this invention composition is approximately 10.
`Ex. 1001, 35:59–36:11.
`Therefore, Example 49 of the ’788 patent used a starting ratio of 10:1
`albumin to paclitaxel (Ex. 1002 ¶ 37) and stated, after the process was
`complete, that the “calculated ratio (w/w) of albumin to paclitaxel in this
`invention composition is approximately 10.” Ex. 1001, 36:10–11. Given
`the similarities in the processes between Example 49 of the ’788 patent and
`Examples 1 and 4 of Desai, we determine that Desai’s examples would
`likewise yield amounts of ingredients in Capxol™ that was not significantly
`different than the starting ratios of materials.
`
`We recognize Patent Owner’s assertion that paclitaxel would be lost
`during Desai’s processing as supported by Dr. Peppas.7 Prelim. Resp. 26–27
`(citing Ex. 2001 ¶¶ 27–34). Patent Owner and Dr. Peppas, however, do not
`cite specific evidence regarding quantitative amounts of paclitaxel that
`
`
`7 We note that Patent Owner may wish to provide evidence from actual
`Capxol™ or Abraxane® production that demonstrates significant loss of
`paclitaxel during commercial synthesis of the nanoparticles.
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`would have been lost during the processing performed in the Examples of
`Desai, but rather provide general citations regarding the solubility or
`adsorption of paclitaxel in other solvent systems (see, e.g., Ex. 2034–2041).
`Even Fukazawa (Ex. 2036), the closest quantitative comparison to Desai,
`though not in the same microparticle context as Desai, does not necessarily
`support Patent Owner’s position. In Fukazawa, while paclitaxel was shown
`to be heavily adsorbed to regular polystyrene microplates, low adsorption
`microplates showed much lower adsorption levels of paclitaxel, as little as
`10% (see Ex. 2036, Fig. 6). A 10% change in the 9:1 ratio of Example 1 of
`Desai could reasonably be interpreted to remain “about 9:1” as required by
`claim 1 of the ’788 patent.
`
`Accordingly, we find that Petitioner has successfully shown that it has
`a reasonable likelihood that it would prevail on one of claims 1–9 and 11–12
`as anticipated by Desai.
`
`E. Obviousness over Desai alone or in combination with Kadima and
`Liversidge
`Petitioner contends that claims 1–12 are unpa