Trials@uspto.gov
`571.272.7822
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`
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` Paper No. 47
`
` Entered: June 7, 2017
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`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 IPR2016-00254
`Patent 8,476,010 B2
`____________
`
`
`Before JACQUELINE WRIGHT BONILLA, Vice Chief Administrative
`Patent Judge, ZHENYU YANG, and TINA E. HULSE, Administrative
`Patent Judges.
`
`HULSE, Administrative Patent Judge.
`
`
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`
`
`
`571.272.7822
`
`
`
`
`
` Paper No. 47
`
` Entered: June 7, 2017
`
`
`
`
`
`
`
`
`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 IPR2016-00254
`Patent 8,476,010 B2
`____________
`
`
`Before JACQUELINE WRIGHT BONILLA, Vice Chief Administrative
`Patent Judge, ZHENYU YANG, and TINA E. HULSE, Administrative
`Patent Judges.
`
`HULSE, Administrative Patent Judge.
`
`
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`
`
`
`
`IPR2016-00254
`Patent 8,476,010 B2
`
`
`INTRODUCTION
`
`J Kyle Bass and Erich Spangenberg (collectively, “Petitioner”) filed a
`Petition requesting an inter partes review of claims 1, 13–15, 17, 18, 20, and
`24–28 of U.S. Patent No. 8,476,010 B2 (Ex. 1001, “the ’010 patent”).
`Paper 1 (“Pet.”). Fresenius Kabi USA, LLC (“Patent Owner”) filed a
`Preliminary Response to the Petition. Paper 6 (“Prelim. Resp.”).
`On June 8, 2016, we instituted an inter partes review of claims 1, 13–
`15, 17, 18, 20, and 24–28 of the ’010 patent on two grounds of obviousness.
`Paper 9 (“Dec. Inst.”), 19. Patent Owner filed a Response to the Petition.
`Paper 28 (“PO Resp.”). Petitioner filed a Reply to Patent Owner’s
`Response. Paper 31 (“Pet. Reply”).
`Patent Owner filed observations on the cross-examination of
`Petitioner’s declarant, Thomas N. Feinberg, Ph.D. Paper 36. Petitioner filed
`a response to Patent Owner’s observations. Paper 40.
`An oral hearing was held on March 13, 2016, a transcript of which has
`been entered in the record. Paper 46 (“Tr.”).
`We have jurisdiction under 35 U.S.C. § 6(b). This Final Written
`Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`For the reasons that follow, we determine that Petitioner has shown by
`a preponderance of the evidence that claims 1, 13–15, 17, 18, 20, and 24–28
`of the ’010 patent are unpatentable.
`Related Proceedings
`A.
`The parties identify several district court proceedings as relating to the
`’010 patent. Pet. 3; Paper 5, 1–2. None of the proceedings is currently
`pending, and Petitioner is not a party to any of the proceedings. Pet. 5.
`
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`Patent 8,476,010 B2
`Patent Owner also identifies Case No. IPR2015-00715, where a
`different Petitioner also challenged the ’010 patent. Paper 5, 2. That
`proceeding was terminated before institution. Dr. Reddy’s Labs., Inc. v.
`Fresenius Kabi USA, LLC, Case IPR2015-00715, Paper 12 (PTAB Apr. 2,
`2015).
`
`The ’010 Patent
`B.
`Propofol (2,6-diisopropylphenol) is a well-known intravenous
`anesthetic agent. Ex. 1001, 1:14–15. The ’010 patent relates to
`pharmaceutical formulations of propofol that are stored in containers having
`nonreactive, inert closures. Id. at 1:8–10. Propofol is a hydrophobic, water-
`insoluble oil that must be incorporated with solubilizing agents, surfactants,
`or an oil-in-water emulsion. Id. at 1:20–23.
`Propofol compositions have been the subject of several patents. Id. at
`1:26–27. The formulation described in U.S. Patent No. 5,714,520 is sold as
`Diprivan, which comprises “a sterile, pyrogen-free emulsion containing 1%
`(W/v) propofol in 10% (w/v) soybean oil.” Id. at 2:33–36. According to the
`Specification, the inventors recognized that the relatively high volume of
`soybean oil used in prior art formulations protects propofol from degradation
`in a container. Id. at 3:63–66. Thus, the Specification states that “at oil
`contents (and/or propofol solvent contents) lower than about 10% (w/v),
`degradation of propofol has been found to occur if the container closure is
`not inert or non-reactive to propofol.” Id. at 3:66–4:2. Preferred closures
`include those “coated or treated with inert materials such as siliconized
`polymer.” Id. at 9:43–45.
`
`3
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`Patent 8,476,010 B2
`
`Illustrative Claim
`C.
`Petitioner challenges claims 1, 13–15, 17, 18, 20, and 24–28 of
`the ’010 patent, of which claim 1 is the only independent claim.
`Claim 1 is illustrative and is reproduced below:
`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.
`
`4
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`IPR2016-00254
`Patent 8,476,010 B2
`D. Grounds of Unpatentability Instituted for Trial
`We instituted trial on the following grounds:
`
`Reference
`Diprivan PDR1 in view of
`Farinotti2 and van den Heuvel3
`Diprivan PDR in view of
`Farinotti and Lundgren4
`
`Basis
`§ 103
`
`§ 103
`
`Claims challenged
`1, 13–15, 17, 18, 20, and
`24–28
`1, 13–15, 17, 18, 20, and
`24–28
`
`ANALYSIS
`
`The Level of Ordinary Skill in the Art
`A.
`Petitioner asserts that a person of ordinary skill in the art would have
`been someone with substantial research or industry experience in
`pharmaceutical drug product development, including experience with sterile
`drugs and their packaging, and having at least a master’s degree or doctorate
`in a related technical field, such as analytical, physical or organic chemistry,
`chemical engineering, pharmaceutics or related subject matter or having
`equivalent experience in such fields. Pet. 8. In its Preliminary Response,
`Patent Owner largely agreed with Petitioner’s definition, with the exception
`that Patent Owner’s definition requires experience with propofol and drug
`product emulsions, emulsion systems and their packaging. Prelim. Resp. 19.
`In our Decision to Institute, we adopted Patent Owner’s definition,
`given the claims recite compositions of propofol in a container. Dec. Inst. 5.
`
`
`1 Physicians’ Desk Reference, Product Identification Guide and Product
`Information for Diprivan, 341, 2939–45 (1997) (“Diprivan PDR,” Ex. 1005).
`2 R. Farinotti, Interactions physicochimiques et mode de conservation du
`Diprivan ® [Physio-Chemical Interactions and Storage of Diprivan®], 13
`Ann. Fr. Anesth. Reanim. 453–56 (1994) (Ex. 1006). Citations to Farinotti
`in this Decision are to the certified translation provided as Ex. 1007.
`3 J.G. van den Heuvel, US 5,383,864, issued Jan. 24, 1995 (Ex. 1010).
`4 Lundren et al., WO 00/12043, published Mar. 9, 2000 (Ex. 1031).
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`Patent 8,476,010 B2
`Patent Owner notes that Petitioner’s declarant, Dr. Feinberg, agreed that this
`addition to the definition was appropriate. PO Resp. 5 (citing Ex. 2035,
`203:11–15). Based on the complete trial record, we see no reason to deviate
`from our prior definition of a person of ordinary skill in the art. That is, we
`adopt the level of ordinary skill set forth by Patent Owner. Moreover, we
`note that the prior art itself further demonstrates the level of skill in the art at
`the time of the invention. Cf. Okajima v. Bourdeau, 261 F.3d 1350, 1355
`(Fed. Cir. 2001) (explaining that specific findings regarding ordinary skill
`level are not required “where the prior art itself reflects an appropriate level
`and a need for testimony is not shown”) (quoting Litton Indus. Prods., Inc. v.
`Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir. 1985)).
`Patent Owner challenges the expertise of Petitioner’s declarant, Dr.
`Feinberg. PO Resp. 6–7. In particular, Patent Owner asserts that because
`Dr. Feinberg lacks expertise in emulsion formulations, manufacturing, and
`propofol, his opinions should be given limited weight. Id. Petitioner, on the
`other hand, challenges the credibility of Dr. Davis, asserting that Dr. Davis
`has no experience in filling and packaging pharmaceutical products. Pet.
`Reply 1 (citing Ex. 1043, 38:9–12).
`The record shows Dr. Feinberg has some experience with emulsion
`drug products (Ex. 2035, 16:15–21), with the use of siliconization to
`improve manufacturing efficiency with drug products (id. at 26:6–27:20),
`and possibly with propofol, although Dr. Feinberg could not recall (id. at
`23:8–24:23). Dr. Davis admits he does not have experience in filling and
`packaging of pharmaceutical products, but testifies that a person of ordinary
`skill in the art, as necessary, would consult someone with such experience.
`Ex. 1043, 37:15–38:12.
`
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`Patent 8,476,010 B2
`We find a person of ordinary skill in the art would have had
`experience with propofol and drug product emulsions, emulsion systems,
`and their packaging. Dr. Feinberg has less experience than Dr. Davis with
`propofol and emulsions, whereas Dr. Davis has less experience than Dr.
`Feinberg with pharmaceutical packaging. Given their relative experiences,
`we decline to discount the opinion of either declarant based solely on their
`differing areas of expertise.
`Claim Construction
`B.
`In an inter partes review, the Board interprets claim terms in an
`unexpired patent according to the broadest reasonable construction in light
`of the specification of the patent in which they appear. 37 C.F.R. § 100(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016). Under
`that standard, and absent any special definitions, we give claim terms their
`ordinary and customary meaning, 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. See
`In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`The parties do not contest the constructions of the following terms:
`
`Term
`“from about 0 to about 10% by
`weight solvent for propofol”
`
`“siliconized”
`
`“inert to propofol”
`
`Proposed Construction
`“from approximately zero to
`approximately 10% solvent by
`weight, a range that includes 10%”
`“surface-treated, coated, or
`manufactured with silicone or one
`or more siloxane polymers”
`“having no significant reactivity to
`propofol”
`
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`IPR2016-00254
`Patent 8,476,010 B2
`Pet. 8–12; PO Resp. 5. Based on the record before us, we construe these
`terms as noted above.
`Moreover, having considered the complete trial record, we determine
`that it is unnecessary to expressly construe any additional claim terms for
`purposes of this Decision. See 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)).
`Principles of Law
`C.
`To prevail in this inter partes review of the challenged claims,
`Petitioner must prove unpatentability by a preponderance of the evidence.
`35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d).
`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 the
`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 skill in the art; and (4) objective evidence of nonobviousness.
`Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`“[A] patent composed of several elements is not proved obvious
`merely by demonstrating that each of its elements was, independently,
`known in the prior art.” KSR, 550 U.S. at 418. “[I]t can be important to
`identify a reason that would have prompted a person of ordinary skill in the
`relevant field to combine elements in the way the claimed new invention
`
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`IPR2016-00254
`Patent 8,476,010 B2
`does.” Id. Moreover, a person of ordinary skill in the art must have had a
`reasonable expectation of success of doing so. PAR Pharm., Inc. v. TWi
`Pharms., Inc., 773 F.3d 1186, 1193 (Fed. Cir. 2014).
`“A reference may be said to teach away when a person of ordinary
`skill, upon reading the reference, would be discouraged from following the
`path set out in the reference, or would be led in a direction divergent from
`the path that was taken by the applicant.” In re Gurley, 27 F.3d 551, 553
`(Fed. Cir. 1994). A “reference will teach away if it suggests that the line of
`development flowing from the reference's disclosure is unlikely to be
`productive of the result sought by the applicant.” Id.
`We analyze the instituted grounds of unpatentability in accordance
`with the above-stated principles.
`D. Obviousness over Diprivan PDR, Farinotti, and van den Heuvel
`Petitioner asserts that claims 1, 13–15, 17, 18, 20, and 24–28 are
`unpatentable as obvious over Diprivan PDR, Farinotti, and van den Heuvel.
`Pet. 22–34. Patent Owner opposes Petitioner’s assertion. PO Resp. 23–51.
`Based on the full trial record, we determine that Petitioner has established by
`a preponderance of the evidence that claims 1, 13–15, 17, 18, 20, and 24–28
`are unpatentable over the cited art.
`Diprivan PDR (Ex. 1005)
`1.
`Diprivan PDR provides product information regarding Diprivan.
`Diprivan PDR states propofol is very slightly soluble in water and is
`formulated in a white, oil-in-water emulsion. Ex. 1005, 2939. Diprivan
`contains 10 mg/ml of propofol and 100 mg/ml of soybean oil (id.) in either a
`50 or 100 mL infusion vial with a rubber stopper (id. at 2945).
`
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`Patent 8,476,010 B2
`
`Farinotti (Ex. 1007)
`2.
`Farinotti describes the physiochemical interactions and stability of
`Diprivan. Farinotti explains that propofol is a phenol, which may oxidize in
`the presence of oxygen into two degradation products. Ex. 1007, 453.
`Farinotti states that “[s]torage in diverse conditions (ampoules, vials) at an
`ambient temperature (25ºC) for three years did not show any changes in the
`characteristics of the drug.” Id. at 454. Farinotti further states that in glass
`vial packaging, Diprivan has good stability and “a lack of adsorption of
`propofol on the bromobutyl stopper.” Id.
`van den Heuvel (Ex. 1010)
`3.
`van den Heuvel relates to a pre-filled injection device with a liquid
`diazepam formulation. Ex. 1010, 1:8–11. van den Heuvel states that it is an
`object of the invention to provide a device where the diazepam formulation
`“can be stored in prolonged contact with at least one rubber sealing member
`without unacceptable deterioration in quality of said formulation taking
`place.” Id. at 2:40–46. van den Heuvel further states that bromobutyl
`rubber, in contrast with chlorobutyl rubber, does not cause unacceptable
`deterioration in quality after prolonged contact with the diazepam
`formulation. Id. at 2:62–66. van den Heuvel discloses the results of storage
`stability testing of liquid diazepam formulations using different rubber
`stoppers. Id. at 4:53–5:39. The rubber stoppers and glass barrels are pre-
`treated “in the conventional manner by washing, siliconising and sterilising.”
`Id. at 4:61–64. The barrels are stored at a given temperature for a given
`period of time and then the diazepam concentration is determined by high
`performance liquid chromatography (“HPLC”). Id. at 5:1–4.
`
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`Patent 8,476,010 B2
`
`Analysis
`4.
`Regarding claim 1, Petitioner asserts that Diprivan PDR in view of
`Farinotti teaches each limitation of claim 1 except the use of a “siliconized”
`bromobutyl rubber stopper. Pet. 23–25. Having reviewed the arguments
`and evidence, we agree with Petitioner and note that Patent Owner does not
`dispute Petitioner’s argument. For example, Diprivan PDR discloses a
`composition in a vial with a rubber stopper with 1% propofol by
`weight/volume, which is within the 0.5% to 10% range claimed. Ex. 1005,
`2939, 2945; Ex. 1002 ¶ 13. Although Diprivan PDR does not specify the
`type of rubber used for the closure, Farinotti teaches that the closures used in
`Diprivan were bromobutyl rubber stoppers. Ex. 1007, 454. Diprivan PDR
`also states that Diprivan contains 10% soybean oil, which is within the
`claimed range of “from about 0% to about 10%” for the solvent. Ex. 1005,
`2939; Ex. 1002 ¶ 13.
`Regarding the “stability limitation,”5 we agree with Petitioner that this
`limitation is an inherent property of Diprivan that the patentee of the ’010
`patent has observed and confirmed through testing. Pet. 23–24; Ex. 1002
`¶¶ 15–16. For instance, Example 34 of the ’010 patent discloses the testing
`of various propofol compositions with rubber closures, including Diprivan,
`for propofol degradation or potency. Ex. 1001, 25:10–45; see also id. at
`23:21–23. The testing method involves agitating vials of propofol at a
`
`
`5 For ease of reference, we refer to the limitation “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” as
`“the stability limitation.”
`
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`Patent 8,476,010 B2
`frequency of 300–400 cycles/minute at room temperature for 16 hours and
`comparing HPLC assay results of the samples before and after testing to
`determine if there is a loss in potency or concentration of propofol in the
`formulations, as required by claim 1. Id. at 23:29–34. Example 34 discloses
`that 99.3% of the propofol in Diprivan remained after the stability testing.
`Id. at 25:31. That result is consistent with the Specification’s statement that
`prior art formulations containing 10% soybean oil, like Diprivan, are
`protected from propofol degradation. See id. at 27:4–7, 3:63–66; Ex. 1002
`¶ 15.
`Regarding the “siliconized” bromobutyl rubber stopper limitation, van
`den Heuvel discloses the use of siliconized bromobutyl rubber stoppers with
`a liquid diazepam formulation. Ex. 1010, 4:56–5:1, 5:8–32 (Table A and
`Table B). Petitioner asserts that a person of ordinary skill in the art would
`have had a reason to substitute a siliconized bromobutyl rubber stopper of
`van den Heuvel for the bromobutyl rubber stopper of Diprivan because van
`den Heuvel states a desire to develop a pharmaceutical composition that can
`be stored in prolonged contact with at least one rubber sealing member
`“without unacceptable deterioration in quality.” Pet. 26 (citing Ex. 1010,
`2:43–46). Dr. Feinberg explains that the siliconized bromobutyl rubber
`closures fulfilled that desire by providing an inert sealing member that did
`not react with the pharmaceutical composition. Ex. 1002 ¶ 18. Petitioner
`further asserts that the known advantages of using siliconized rubber
`closures, such as improved machinability, processing efficiencies, and ease
`of insertion or lubricity, would have further motivated an ordinary artisan to
`use a siliconized bromobutyl rubber stopper with a reasonable expectation of
`success. Pet. 26–27 (citing Ex. 1002 ¶¶ 20, 21, 23; Ex. 1004, S4).
`
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`
`Reason to Combine
`a.
`After reviewing the arguments and evidence, we are persuaded that a
`person of ordinary skill in the art would have had a reason to use a
`siliconized bromobutyl rubber stopper with the claimed propofol
`formulation. Consistent with our Institution Decision, we remain
`unpersuaded by Petitioner’s argument that an ordinary artisan reading van
`den Heuvel would have concluded that it was the siliconization of the
`bromobutyl rubber stoppers that imparts a stable solution of diazepam. See
`Pet. 26 (citing Ex. 1010, col. 5, Table A and Table B). Indeed, Petitioner’s
`declarant, Dr. Feinberg, testified that he agrees with our determination. Ex.
`2035, 208:24–209:4. van den Heuvel concludes that “chlorobutyl stoppers
`cause a considerably larger decrease of the diazepam content than the
`stoppers manufactured from . . . bromobutyl rubber.” Ex. 1010, 5:34–37.
`But because both the chlorobutyl stoppers and the bromobutyl stoppers were
`siliconized, and van den Heuvel does not compare the use of siliconized
`stoppers to unsiliconized stoppers, the results of Tables A and B suggest
`nothing about the effect of siliconizing stoppers on the stability of the
`formulation. See Ex. 2036 ¶ 84.
`Nevertheless, having considered the full trial record, we are persuaded
`that a person of ordinary skill in the art would have recognized the
`advantages of siliconizing rubber closures, such as ease or efficiency during
`manufacture, and would have had a reason to siliconize the bromobutyl
`rubber closure of Diprivan with a reasonable expectation of success. See Ex.
`1002 ¶¶ 20–24; Ex. 1004, S4. Dr. Feinberg testifies in his declaration that
`“[u]ncoated stoppers . . . while having good properties including low
`propofol reactivity with 10% soybean oil formulations and low cost, had
`known issues with regard to machinability.” Ex. 1002 ¶ 20. The “known
`
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`issues” include sticking to each other and to the filling line assemblies that
`would necessitate frequent line maintenance or low line speed. Id.; Ex. 1044
`¶¶ 6–7 (citing Ex. 1004, S4; Ex. 1045, 361).
`Patent Owner argues that any purported manufacturing benefits of
`siliconization would not have motivated a person of ordinary skill in the art
`to replace the commercially successful Diprivan rubber stoppers because
`Petitioner does not offer any evidence that Diprivan stoppers experienced
`any sticking problems or other manufacturing issues. PO Resp. 28–29.
`Patent Owner notes that Petitioner’s declarant, Dr. Feinberg admitted that he
`was not aware of any reports of sticking issues with Diprivan stoppers or of
`any prior art suggesting siliconizing Diprivan stoppers would improve
`manufacturing efficiency. Id. at 29–30 (citing Ex. 2035, 73:6–17, 157:20–
`25).
`
`We are not persuaded by Patent Owner’s argument. It is well settled
`that “[a] suggestion, teaching, or motivation to combine the relevant prior art
`teachings does not have to be found explicitly in the prior art, as the
`teaching, motivation, or suggestion may be implicit from the prior art as a
`whole, rather than expressly stated in the references.” In re Kahn, 441 F.3d
`977, 987 (Fed. Cir. 2006) (emphasis added). That the prior art does not
`include explicit reports of manufacturing issues with Diprivan rubber
`stoppers in particular is not fatal to Petitioner’s argument. We are persuaded
`by the weight of the evidence that it was understood by a person of ordinary
`skill in the art that rubber stoppers generally have issues with friction during
`manufacturing, which is commonly cured by adding silicone oil to the
`stoppers. See, e.g., Ex. 1004, S4 (“Machinability is greatly improved
`through the use of lubricated packaging components. Siliconization of
`rubber products reduces the friction present between the rubber closure and
`
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`the metallic machinery.”); Ex. 1045, 361 (“Most closures are lightly coated
`with silicone oil, [which] reduces considerably the inherent tackiness in
`many rubber formulations. The main advantage of a silicone oil coat is that
`it facilitates the stoppering operation by lubricating the passage of the
`closures through assembly machines and insertion into the barrel or vial
`opening.”); Ex. 1002 ¶¶ 20–22.
`Moreover, several references offered by Patent Owner teach this same
`understanding. See, e.g., Ex. 2024, 2:26–37 (“By their nature, elastomeric
`objects have a relatively high coefficient of friction . . . . This hampers their
`ability to be transported in filling equipment and similar machinery . . . . In
`order to overcome this problem, the elastomeric seals in many cases are
`coated with some lubricant, for instance silicone oil.”); Ex. 2040, 1:56–2:6
`(“In the prior art, the high coefficient of friction of rubber stoppers and other
`rubber materials which are being fed to closure devices and other
`pharmaceutical devices has been the limiting factor in the speed of the
`machine. . . . One solution which has been proposed to improve the general
`processibility of rubber closures . . . is the use of silicone oil as a coating on
`the outside of the stoppers.”).
`Patent Owner asserts that there can be no motivation to combine prior
`art references to solve a problem that nobody knows exists. PO Resp. 30–31
`(citing Novartis Pharm. Corp. v. Par Pharm., Inc., 48 F. Supp. 3d 733, 758
`(D. Del. 2014); Leo Pharms. Prods., Ltd. v. Rea, 726 F.3d 1346, 1355 (Fed.
`Cir. 2013)). But Petitioner did not need to show that there was a known
`machinability problem with the Diprivan rubber stoppers to establish a
`reason to combine. See Unwired Planet, LLC v. Google Inc., 841 F.3d 995,
`1003 (Fed. Cir. 2016) (agreeing with Petitioner that it “does not need to
`show that there was a known problem with the prior art system in order to
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`Patent 8,476,010 B2
`articulate the required rational underpinning for the proposed combination”).
`Nevertheless, unlike the cited cases where the art did not appreciate or
`suggest the existence of the problem, it is clear from the evidence of record
`that it was known in the art that rubber stoppers generally have
`manufacturing issues related to their high coefficient of friction, and that
`those issues are commonly addressed by siliconizing the rubber stoppers.
`Accordingly, we find the weight of the evidence sufficient to support
`Petitioner’s argument that a person of ordinary skill in the art would have
`had a reason to use siliconized rubber stoppers with Diprivan to improve the
`machinability of those stoppers. See KSR, 550 U.S. at 420 (“Under the
`correct analysis, any need or problem known in the field of endeavor at the
`time of invention and addressed by the patent can provide a reason for
`combining the elements in the manner claimed.”) (emphasis added).
`b.
`Teaching Away
`Patent Owner makes a number of arguments as to why a person of
`ordinary skill in the art would have been discouraged to siliconize the
`Diprivan rubber stopper. PO Resp. 31–49. We address each argument in
`turn.
`
`First, Patent Owner asserts that even if a person of ordinary skill in the
`art would have thought to replace the stopper in Diprivan, “the practical and
`regulatory burdens in doing so would discourage this type of change.” Id. at
`31–32. In particular, Patent Owner argues that any changes to the approved
`packaging and manufacturing lines risks significant additional regulatory
`review. We are not persuaded. “Motivation to combine may be found in
`many different places and forms; it cannot be limited to those reasons the
`FDA sees fit to consider in approving drug applications.” Allergan, Inc. v.
`Sandoz Inc., 726 F.3d 1286, 1291–92 (Fed. Cir. 2013)). We are not
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`Patent 8,476,010 B2
`convinced that “risks” of “burdens,” or possible application of a
`“conservative” approach to stopper changes, as they pertain to regulatory
`review, rise to the level of teaching away. PO Resp. 31–32.
`Patent Owner next argues that a person of ordinary skill in the art
`would have been discouraged from using a siliconized stopper because of
`safety concerns with silicone oil contamination. Id. at 32–49. According to
`Patent Owner, the dangers of particulate contamination were well known in
`the art. Id. at 34–36. Because of those dangers, the United States and
`British Pharmacopeias set standards establishing strict limits on particulate
`contamination in parenteral drug products. Id. at 36–37. For emulsions
`having reduced clarity (like propofol) and that are supplied in containers less
`than 100 ml, the 2002 British Pharmacopoeia states: “The preparation
`complies with the test if the average number of particles in the units tested
`does not exceed 3000 per container equal to or greater than 10 μm and does
`not exceed 300 per container equal to or greater than 25 μm.” Ex. 2047,
`A257–A258. For emulsions in containers greater than 100 ml, the 2002
`British Pharmacopoeia states: “The preparation complies with the test if the
`average number of particles present in the units tested does not exceed 12
`per milliliter equal to or greater than 10 μm and does not exceed 2 per
`milliliter equal to or greater than 25 μm.” Id. at A257. The U.S.
`Pharmacopoeia’s standard is consistent with the British standard. See Ex.
`2048, 2729 (Table 2).
`Having set forth the standard for acceptable particle contamination,
`Patent Owner then asserts that several references suggest that siliconized
`rubber stoppers exceed the limits of contamination, thereby teaching away
`from the claimed invention. We are not persuaded that the references are as
`clear as Patent Owner contends. For example, Patent Owner asserts that
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`Sudo6 “reports finding 680 particles of 10 μM [sic, μm] per milliliter for the
`silicone oil treated stopper compared to only 60 such particles for untreated
`silicone.” PO Resp. 41 (citing Ex. 2042). Patent Owner continues, stating
`“[t]his level of contamination is equivalent to 34,000 particles of 10 μM [sic,
`μm] in a 50 mL container of Diprivan®, vastly in excess of the [British
`Pharmacopeia] limit of 3,000 particles of that size.” Id. (citing Ex. 2036
`¶¶ 72–74).
`We disagree with Patent Owner’s interpretation of Sudo’s data. Sudo
`teaches that 10 rubber stoppers were added to a bottle containing 300 ml of
`fine particle-free water. Ex. 2042, 21:59–61. The bottle was then shaken for
`60 seconds and allowed to stand for 60 minutes. Id. at 21:61–63. The liquid
`was then flowed through a particle counter to measure the “peeling
`quantity,” which is defined as the “quantity of fine particles, number of
`particles of 10 μm in diameter (± 3 particles).” Id. at 21:63–68, Table 1 n.1.
`Table 1 indicates that the “Peeling Quantity (Number)” for the siliconized
`stopper (Comparative Example 2) is 680. Id., Table 1. We, therefore, credit
`the testimony of Petitioner’s declarant, Dr. Feinberg, who testifies that Sudo
`discloses a total of 680 particles of 10 μm in diameter in 300 ml of water.
`Ex. 1044 ¶ 14; Ex. 2042, Table 1. Thus, 680 particles of 10 μm diameter in
`300 ml of water (i.e., 2.3 particles/ml) does not exceed the pharmacopoeia
`standard of less than 12 particles/ml. See Ex. 2047, A257. We, therefore,
`find that Sudo does not teach away from the use of siliconized rubber
`stoppers.
`
`
`6 Sudo et al., US 5,114,794, issued May 19, 1992 (Ex. 2042).
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`Patent Owner also argues that Romberg7 (“the ’504 patent”), Thijs8
`(“the ’919 patent”), and Mannermaa9 each teaches away because of their
`data regarding particle contamination for siliconized rubber stoppers. PO
`Resp. 42–44. Romberg discloses that the siliconized stoppers placed in 150
`ml of filtered deionized water had more than 10,000 particles of 5 μm or
`more. Ex. 2040, 8:62–9:2. Thijs discloses that the siliconized rubber
`stoppers, after being in contact with 2 ml of particle free water under steam
`sterilization conditions, had 50,000 particles of 2 μm or more per ml of fluid.
`Ex. 2024, Table. And, according to Patent Owner, Mannermaa discloses
`that siliconized stoppers produced between 1200 and 4500 particles of 5 μm
`or larger per ml. Ex. 2041, Figure 3.
`Having considered the evidence and arguments, we are unable to
`discern whether the particle contamination results of Romberg, Thijs, and
`Mannermaa exceed the acceptable amount of particle contamination. The
`pharmacopoeia standards set forth the acceptable number of particles that
`are 10 μm in diameter or larger. Ex. 2047, A257–A258; Ex. 2048, 2729
`(Table 2). Here, th
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