Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
`
`
`Filed on behalf of J Kyle Bass and Erich Spangenberg
`By: Dr. Gregory Gonsalves
`Reg. No. 43,639
`2216 Beacon Lane
`Falls Church, Virginia 22043
`(571) 419-7252
`gonsalves@gonsalveslawfirm.com
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`J. KYLE BASS and ERICH SPANGENBERG
`Petitioners
`
`v.
`
`FRESENIUS KABI USA, LLC
`
`
`IPR Trial No. IPR2016-00254
`
`Petitioner’s Reply for Inter Partes Review of U.S. Patent No. 8,476,010
`
`
`
`
`
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
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`
`
`
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`

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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`THE CHALLENGED CLAIMS ARE OBVIOUS OVER THE
`DIPRIVAN PDR, FARINOTTI, AND THE ‘864 PATENT OR THE
`WO ‘043 PATENT. ......................................................................................... 4
`
`A. A POSA Would Have Been Motivated To Combine The
`Teachings Of Propofol From The Diprivan PDR and Farinotti
`With The Teachings Of A Siliconized Bromobutyl Stopper
`From The ‘864 Patent Or The WO’043 Patent. .................................... 5
`
`1.
`
`2.
`
`Contrary To PO’s Position, The Motivation To Combine
`Teachings Of The Prior Art Need Not Come From The
`Prior Art Itself And Need Not Have The Same Rationale
`As The ‘010 patent ...................................................................... 5
`
`The Manufacturing Advantages Of A Siliconized
`Bromobutyl Stopper Would Have Motivated A POSA To
`Use That Stopper In A Container Of A Propofol
`Composition ................................................................................ 7
`
`B.
`
`The Prior Art Does Not Teach Away From Using A Siliconized
`Bromobutyl Stopper In A Container Of A Propofol
`Composition, As Claimed By The ‘010 Patent. ..................................11
`
`1.
`
`2.
`
`PO’s Argument That The Risk Of Silicone Particle
`Contamination Discussed In Certain References Would
`Have Taught Away From Using A Siliconized Stopper
`With Diprivan® Is Not Supported By The Evidence And
`Is Not Commensurate With The Scope Of The Claims ...........13
`
`PO’s Argument That Diprivan® Was Particularly
`Subject To Silicone Particle Contamination Is Not
`Commensurate With The Scope Of The Claims ......................21
`
`C.
`
`It Would Have Been Obvious To Try The Claimed Siliconized
`Bromobutyl Stopper With A Container Of A Propofol
`Composition. .......................................................................................24
`
`III. CONCLUSION. .............................................................................................27
`
`
`
`ii
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`EXHIBIT LIST PURSUANT TO 37 C.F.R. § 42.63(e)
`
`
`
`1004
`
`Exhibit # Reference
`1001
`U.S. Patent No. 8,476,010
`1002
`Declaration of Thomas N. Feinberg, Ph.D
`Curriculum Vitae of Thomas N. Feinberg, Ph.D
`1003
`Smith et al., "Siliconization of Parenteral Drug Packaging
`Components," 1988, 42 J. of Parenteral Sci. and Tech. (1988
`Supp.)
`Entry for Diprivan® in the Physician's Desk Reference, 51st
`Edition, 1997, pp. 341, 2939-2945
`R. Farinotti, "Physio-chemical Interactions and Storage of
`Diprivan®," Ann. Fr. Anesth. Reanim., 1994 (French Publication)
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`
`
`Certified English-Language Translation of Exhibit 1006
`
`®
`FAQs
`August 3, 2001 Web page for Diprivan
`Han et al., "Physical properties and stability of two emulsion
`formulations of propofol," Int'l J.of Pharmaceutics, 215 (2001)
`207-220
`U.S. Patent No. 5,383,864
`West Technical Support Bulletin 1999/013, "Evaluating B2-
`Coating as an Alternative to Silicone Oil," January 26, 1999
`West Technical Report 2000/026, "B2-Coating Quantitative
`Particle Analysis," November 15, 2000
`"Siliconization: As Applied to Containers and Closures," Bulletin
`of the Parenteral Drug Association, Vol. 22, No. 2 March/April
`1968
`U.S. Patent No. 5,714,520
`Complaint from Civil Action No. 14-cv-00160-RGA (D. Del.),
`Dkt. 1 (filed February 6, 2014)
`Waiver of Service of Summons from Civil Action No. 14-cv-
`00160-RGA (D. Del.), Dkt. 5 (filed March 10, 2014)
`September 6, 2007 Response to Office Action, U.S. Serial
`No. 10/616,709
`July 13, 2012 Office Action, U.S. Serial No. 10/616,709
`
`iii
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`1019
`
`1020
`
`December 16, 2010 Response to Office Action, U.S. Serial
`No. 10/616,709
`February 4, 2013 Response to Office Action, U.S. Serial
`No. 10/616,709
`
`1021
`
`May 15, 2013 Interview Summary, U.S. Serial No. 10/616,709
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`May 15, 2013 Notice of Allowability and Examiner's Amendment,
`U.S. Serial No. 10/616,709
`Excerpts from "Plaintiff Fresenius Kabi USA, LLC's Opening
`Claim Construction Brief" in Civil Action No. 14-cv-00160-RGA (D.
`Del.)
`Webster's Third New International Dictionary (2002) selected page
`
`Colas, "Silicones in Pharmaceutical Applications," Dow Corning
`Healthcare Industries (2001)
`Hawley's Condensed Chemical Dictionary (13th ed. 1997)
`
`Dutch Diprivan® Registration, 10 mg SmPC RVG 25809
`
`Certified English-Language Translation of Exhibit 1027
`
`Excerpts from file history of U.S. Patent No. 6,576,245
`(Lundgren et al.)
`Declaration of Peggy Frandolig with attached Exhibits A and B
`(Exhs. 1011, 1012).
`Publication WO 20000012043 (Lundgren)
`In re Cuozzo Speed Techs., LLC, No. 2014-1301, 2015 U.S. App.
`LEXIS 1699, Slip. Op. at 16, 19 (Fed. Cir. Feb. 4, 2015)
`
`1033
`
`U.S. Patent No. 2,649,090
`
`1034
`
`U.S. Patent No. 3,958,572
`
`1035
`
`U.S. Patent No. 3,464,414
`
`1036
`
`U.S. Patent No. 2,652,182
`
`1037
`
`Declaration of Dr. Gregory J. Gonsalves (served but not filed)
`
`1038
`
`Entry for Diprivan® in the Physician's Desk Reference, 51st
`Edition, 1997, pp. 341, 2939-2945. (served but not filed)
`
`
`
`iv
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`1039
`
`1040
`
`1041
`
`R. Farinotti, "Physio-chemical Interactions and Storage of
`Diprivan®," Ann. Fr. Anesth. Reanim., 1994. (served but not filed)
`
`Webster's Third New International Dictionary (2002) selected page
`(served but not filed)
`Hawley's Condensed Chemical Dictionary (13th ed. 1997). (served
`but not filed)
`
`1042
`
`Notarized Affidavit of Mr. Christopher Butler (served but not filed)
`
`1043
`
`Transcript of deposition of Dr. Stanley Davis
`
`1044
`
`Supplemental Declaration of Thomas N. Feinberg, Ph.D.
`
`1045
`
`Pharmaceutical Packaging Technology, November 30, 2000 Chapter
`12
`
`
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`v
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`I.
`
`INTRODUCTION
`
`Patent Owner’s (PO’s) arguments must fail because they (i) are not
`
`commensurate with the scope of any of the challenged claims, (ii) are based on an
`
`incorrect understanding of the law of obviousness, (iii) are based on references such
`
`as Vernon (Ex. 2043) and the FDA correspondence (Ex. 2049) that were published
`
`after the date of invention of the ‘010 patent, and (iv) are based on sloppy work by
`
`its expert, Dr. Davis, who admitted under oath that he does not have any experience
`
`in the filling or packaging of drugs like propofol, which is recited in the claims of
`
`the ’010 patent (Ex. 1043, Davis Tr., p. 38, ll. 9-12).
`
`For example, PO’s argument that the risk of silicon particle contamination
`
`would have taught away from a siliconized stopper is not commensurate with the
`
`scope of the claims of the ‘010 patent because it is based on data derived from one
`
`particular method of sterilization necessitating autoclaving, which is not required by
`
`the claims. When using an autoclave for sterilization, a container of propofol is
`
`subjected to high-pressure (100 kPa (15 psi)) steam (121 °C (250 °F)) for at least 15
`
`minutes after the insertion of the stopper into the container, thereby increasing the
`
`shedding of particulates from the stopper into the contents of the container. The
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`claims, however, are not limited to any particular sterilization method, including
`
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`1
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`autoclaving1. Indeed, the Specification of the ‘010 patent states that many different
`
`methods of sterilization can be used such as aseptic manufacturing and filter
`
`sterilization, thereby significantly reducing any shedding of particulates from the
`
`stopper.
`
`PO’s teaching away argument is also based on a faulty analysis by its expert,
`
`Dr. Davis, who relied upon particulate data resulting from the immersion of 10
`
`stoppers into a container of water (Ex. 2036, Davis Decl. ¶ 50). Dr. Davis’s analysis
`
`did not account for the fact that the number of particulates shed from 10 stoppers
`
`would have been about 10 times the number of particulates shed from a single
`
`stopper, which would have been used in a container of a propofol composition (id.).
`
`Dr. Davis’s analysis also did not account for the fact that the number of particulates
`
`shed from a stopper that is immersed in a solution would have been more than 2
`
`times the number of particulates shed from a stopper inserted into a container
`
`because less than half of the surface area of the stopper would be exposed to the
`
`solution in the container (id.) as compared to one completely immersed in a liquid.
`
`
`1 The only mention of any analysis related to potential propofol degradation in
`
`claim 1 is based on a simple shake test at 300-400 cycles/minute for 16 hours at
`
`room temperature. There is no mention whatsoever of a particular sterilization
`
`protocol related to particulate contamination.
`
`
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`2
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`Thus, Dr. Davis’s particulate analysis — as he admitted under cross-examination at
`
`his deposition — is too high by a factor of at least 20 (Ex. 1043, p. 78, ll. 4-16 and
`
`p. 79, ll. 13 – p. 80, l. 4).
`
`PO’s teaching away argument improperly relies on references such as Vernon
`
`(Ex. 2043) and the FDA correspondence (Ex. 2049) that were published after July
`
`10, 2003 which is the date of the earliest application to which the ‘010 Patent claims
`
`priority. An obviousness determination requires a comparison of the claimed subject
`
`matter and the prior art, to determine whether or not the claimed subject matter of
`
`the patent as a whole would have been obvious, at the time of the invention, to a
`
`person of ordinary skill in the art. 35 U.S.C. § 103. References published after the
`
`date of invention of the ‘010 patent like Vernon and the FDA correspondence clearly
`
`could not have taught away from the claimed invention of the ‘010 patent at the time
`
`of the invention.
`
`PO’s argument that use of a siliconized rubber stopper would have adversely
`
`affected the stability of Diprivan is also not commensurate with the scope of the
`
`claims because the claims encompass a 10% soybean oil solvent and a POSA would
`
`have known at the time of the invention of the ‘010 patent that the loss of propofol
`
`within a 10% soybean oil solvent would not nearly have reached unacceptable levels
`
`with a siliconized bromobutyl stopper (Ex. 1001, ‘010 patent, col. 25, ll. 26-39 (“the
`
`data shows that the oil in the formulation protected propofol from degradation”)).
`
`
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`3
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`PO’s argument that the ‘864 patent and the WO’043 patent do not provide a
`
`motivation to combine is based on an improper understanding of the law on
`
`obviousness because the law does not require record evidence of an explicit teaching
`
`of a motivation to combine in the prior art. Ball Aerosol v. Ltd. Brands, 555 F.3d
`
`984, 89 USPQ2d 1870 (Fed. Cir. 2009). Rather, common sense and ordinary
`
`creativity can be used to provide motivation to combine references. KSR
`
`International Co. v. Teleflex Inc, 550 U.S. 398, 420 (2007). And as explained by the
`
`Petitioner’s expert, manufacturing benefits would have motivated a POSA to
`
`combine the teachings of propofol in the Diprivan PDR with the teachings of a
`
`siliconized bromobutyl stopper in either the ‘864 patent or the WO’043 patent (Ex.
`
`1002, Dr. Feinberg Decl., ¶¶ 20-25).
`
`For these reasons as explained more fully below, PO’s arguments with respect
`
`to each of the instituted obviousness grounds are not commensurate with the scope
`
`of the claims and are not supported by proper expert testimony. Accordingly, the
`
`challenged claims are obvious and should be canceled.
`
`
`
`II. THE CHALLENGED CLAIMS ARE OBVIOUS OVER THE
`DIPRIVAN PDR, FARINOTTI, AND THE ‘864 PATENT OR THE WO
`‘043 PATENT.
`
`A POSA would have been motivated to combine the teachings of propofol from
`
`the Diprivan PDR and Farinotti with the teachings of a silonized bromobutyl stopper
`
`
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`4
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`from the ‘864 patent or the ‘043 patent, with a reasonable expectation of success. No
`
`non-obvious differences exist between the combinations and the claimed subject
`
`matter.
`
`A. A POSA Would Have Been Motivated To Combine The Teachings
`Of Propofol From The Diprivan PDR and Farinotti With The
`Teachings Of A Siliconized Bromobutyl Stopper From The ‘864
`Patent Or The WO’043 Patent.
`
`1.
`
`Contrary To PO’s Position, The Motivation To Combine
`Teachings Of The Prior Art Need Not Come From The Prior
`Art Itself And Need Not Have The Same Rationale As The
`‘010 patent
`
`PO argued that “the ‘864 and WO ‘043 patent themselves provide no
`
`motivation to combine the silicone oil treated closures disclosed in those patents
`
`with Diprivan® as disclosed by the PDR and Farinotti” (PO Response, p. 23). PO
`
`also argued that a “POSA would not have expected that a siliconized bromobutyl
`
`rubber stopper would improve the stability of Diprivan or otherwise solve the
`
`problem faced by the inventors of the ‘010 patent” (id. at p. 22).
`
`But the PO’s arguments are based on an improper understanding of the law of
`
`obviousness. First, the law does not require record evidence of an explicit teaching
`
`of a motivation to combine in the prior art:
`
`[T]he analysis that "should be made explicit" refers not to the teachings
`
`in the prior art of a motivation to combine, but to the court’s analysis. .
`
`. . Under the flexible inquiry set forth by the Supreme Court, the district
`
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`court therefore erred by failing to take account of 'the inferences and
`
`creative steps,' or even routine steps, that an inventor would employ and
`
`by failing to find a motivation to combine related pieces from the prior
`
`art.
`
`Ball Aerosol v. Ltd. Brands, 555 F.3d 984, 993, 89 USPQ2d 1870, 1877 (Fed. Cir.
`
`2009).
`
`Second, the law does not require that the prior art suggest the combination to
`
`achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn,
`
`441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question
`
`arises in the context of the general problem confronting the inventor rather than the
`
`specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic
`
`Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005)
`
`(“One of ordinary skill in the art need not see the identical problem addressed in a
`
`prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d
`
`1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688,
`
`16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed
`
`below).
`
`"Motivation to combine may be found in many different places and forms."
`
`Par Pharm. Inc. v. TWI Pharms., Inc., 773 F.3d 1186, No. 2014-1391, 2014 U.S.
`
`App. LEXIS 22737, at *24 (Fed. Cir. Dec. 3, 2014) (citations omitted). Thus, for
`
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`example, a challenger is not limited to the same motivation that the patentee had. Id.
`
`(citing Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012),
`
`cert denied, 133 S. Ct. 1736 (2013)). In contrast and contrary to PO’s position,
`
`common sense and ordinary creativity can be used to provide motivation to combine
`
`references. KSR International Co. v. Teleflex Inc, 550 U.S. 398, 420 (2007).
`
`Thus, PO’s position on the motivation to combine is based on an incorrect
`
`understanding of the law of obviousness and for this reason alone, has no merit.
`
`
`
`2.
`
`The Manufacturing Advantages Of A Siliconized
`Bromobutyl Stopper Would Have Motivated A POSA To Use
`That Stopper In A Container Of A Propofol Composition
`
`PO argued that the purported manufacturing benefit of siliconization would
`
`not have “motivate[d] a POSA to replace the commercially successful stoppers used
`
`with Diprivan® with the closures disclosed in the ‘864 and WO ‘043 patents”
`
`(Petition, p. 28). PO’s argument has no merit for three separate and independent
`
`reasons.
`
`First, this argument — like so many of PO’s arguments — is not
`
`commensurate with the scope of the claims. The claims do not require the
`
`replacement by a manufacturer of commercially successful stoppers in its
`
`Diprivan® commercial product;
`
`the claims
`
`instead
`
`require “[a] sterile
`
`pharmaceutical composition of propofol in a container, comprising … the closure is
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`selected from the group consisting of siliconized bromobutyl rubber” (Ex. 1001, col.
`
`27, l. 25 – col. 28, l. 2). In other words, the issue as to whether the claims of the ‘010
`
`patent are obvious is not resolved by performing a business analysis as to whether a
`
`Diprivan® manufacturer would change stoppers in its commercial product; it is
`
`instead resolved by determining whether a POSA would have been motivated to use
`
`a siliconized bromobutyl rubber stopper in a container of a propofol composition
`
`and reasonably expected success from the teachings of propofol from the Diprivan
`
`PDR and Farinotti combined with the teachings of a siliconized bromobutyl stopper
`
`from the ‘864 patent or the ‘043 patent. KSR International Co. v. Teleflex Inc, 550
`
`U.S. 398, 420 (2007).
`
`Second and contrary to PO’s unsupported allegation, there is substantial
`
`evidence that a POSA would have been motivated to use a siliconized bromobutyl
`
`rubber stopper in a container of a propofol composition to address machinability
`
`problems with rubber stoppers (e.g., friction between the rubber closure and metallic
`
`machinery, clumping of parts, excessively high required insertion force). As
`
`explained by Petitioner’s expert, Dr. Feinberg, “Smith et al. discusses the advantages
`
`(page S4) of siliconization: ‘[m]achinability is greatly improved through the use of
`
`lubricated packaging components. Siliconization of rubber products reduces the
`
`friction present between the rubber closure and the metallic machinery. Lubrication
`
`helps eliminate clumping of parts as they are smoothly fed from hoppers to machine
`
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`paths. These lubricated components then easily transverse down machine guides,
`
`reducing any possible problems, which are ultimately very costly in terms of lost
`
`production time.’ Smith also outlines two other important characteristics of
`
`siliconized rubbers — reduction of insertion force (page S4, Section III. B.) and
`
`sealability (Section III. C.)” (Exhibit 1010, Dr. Feinberg Declaration, p. 10
`
`(emphasis added)). Dr. Feinberg similarly stated at his deposition that “[a]
`
`packaging choice in my experience is generally pushed for economic and operational
`
`purposes generally more than anything else” (Exh. 2035, col. 80, ll. 5-7).
`
`Another reference (Pharmaceutical Packaging Technology Ex. 1045)
`
`similarly indicates that a POSA would have been motivated to use a siliconized
`
`bromobutyl rubber stopper in a container of a propofol composition to address
`
`machinability problems with rubber stoppers (e.g., friction between the rubber
`
`closure and metallic machinery, clumping of parts, excessively high required
`
`insertion force):
`
`Most closures are lightly coated with silicone oil, such as a
`
`polydimethyl siloxane, as a means of reducing particulate formation
`
`as it acts as a lubricant between closures. It also 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
`
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`machines and insertion into the barrel or vial opening.
`
`(Ex. 1045, Pharmaceutical Packaging Technology, November 30, 2000 Chapter 12
`
`pg. 361 (emphasis added)). “As indicated by a study in another prior art reference
`
`(Sudo Ex. 2042), the lubricated stopper was demonstrated to have the lowest sliding
`
`value of all tested examples” (Ex. 1044, Dr. Feinberg’s Supplemental Decl., ¶ 7; Ex.
`
`2042, the Sudo ‘794 patent, col. 22, line 56).
`
`Third, Petitioner’s expert Dr. Feinberg has substantially more experience and
`
`knowledge about the manufacturing and packaging of drug compositions like
`
`Diprivan® than PO’s expert Dr. Davis. Indeed, Dr. Davis admitted under oath at his
`
`deposition that he does not have any experience in the filling and packaging of drug
`
`compositions:
`
`Q. Doctor Davis, do you, yourself, have experience in filling and
`
`packaging of pharmaceutical products?
`
`A. No
`
`(Ex. 1043, Davis Tr. p. 38, ll. 9-12). That is, PO’s allegation that a POSA would not
`
`have been motivated by the manufacturing benefits of siliconization is unsupported
`
`by testimony from an expert with experience in pharmaceutical packaging and thus,
`
`amounts to mere attorney argument that should not be given any weight. In re
`
`Huang, 100 F.3d 135, 139-40 (Fed. Cir. 1996) (Arguments of counsel and
`
`discussions of caselaw, standing alone, cannot take the place of factually supported
`
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`10
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`objective evidence.); In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (Attorney
`
`argument is not evidence.); In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997)
`
`(Lawyer’s arguments and conclusory statements, which are unsupported by factual
`
`evidence, are entitled to little probative value.).
`
`In sharp contrast, Petitioner’s expert, Dr. Feinberg, is an expert in
`
`manufacturing and packaging of drug compositions having over 20 years of
`
`experience with the physical and commercial requirements of drug packaging (Ex.
`
`1002, Dr. Feinberg’s Declaration, ¶¶ 4-5; Ex. 1003, Dr. Feinberg’s Curriculum
`
`Vitae, pp. 1-4).
`
`For these three groups of reasons, the manufacturing advantages of a
`
`siliconized bromobutyl stopper would have motivated a POSA to use that stopper
`
`with a propofol composition, as recited in the claims of the ‘010 patent.
`
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`B.
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`The Prior Art Does Not Teach Away From Using A Siliconized
`Bromobutyl Stopper In A Container Of A Propofol Composition,
`As Claimed By The ‘010 Patent.
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`To teach away, the prior art must disparage or otherwise discourage the
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`approach followed by the inventor. See In re Peterson, 315 F.3d 1325, 1332 (Fed.
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`Cir. 2003). “The prior art’s mere disclosure of more than one alternative does not
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`constitute a teaching away from any of these alternatives because such disclosure
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`does not criticize, discredit, or otherwise discourage the solution claimed….” In re
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004); see also In
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`re Berg, 320 F.3d 13 10, 13 16 (Fed. Cir. 2003) (The disclosure of alternative means
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`for accomplishing an invention’s objective does not teach away from the invention.).
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`“A known or obvious composition does not become patentable simply because it has
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`been described as somewhat inferior to some other product for the same use.” In re
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`Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994).
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`PO did not demonstrate that the prior art teaches away from the claimed
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`invention for several separate and independent reasons.
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`First, PO’s argument that the risk of silicone particle contamination would
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`have taught away from a siliconized stopper is not commensurate with the scope of
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`the claims of the ‘010 patent because it is based on data derived from one particular
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`method of sterilization utilizing an autoclave that substantially increases the
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`potential of silicon particle contamination, which is not required by the claims.
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`Second, PO’s argument is based on a faulty analysis by its expert, Dr. Davis,
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`who relied upon particulate data resulting from the immersion of 10 stoppers into a
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`container of water (Ex. 2036, Davis Decl., ¶¶ 50 and 73). Dr. Davis’s calculations
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`are wrong because he did not consider that one stopper would shed only about one
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`tenth as many particulates as ten stoppers and that a stopper installed in a container
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`would shed less than half the particulates as one that was immersed in water (id.)
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`since significantly less surface area of the stopper was in physical contact with the
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`composition inside the container. Thus, PO’s teaching away argument is not based
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`on any credible, expert testimony.
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`Third, some of the references relied upon by the PO were published several
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`years after the date of invention of the ‘010 patent and therefore, could not have
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`possibly taught away from the claimed invention at the time of the invention.
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`1.
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`PO’s Argument That The Risk Of Silicone Particle
`Contamination Discussed In Certain References Would
`Have Taught Away From Using A Siliconized Stopper With
`Diprivan® Is Not Supported By The Evidence And Is Not
`Commensurate With The Scope Of The Claims
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`PO argued that “measurements of actual silicone oil contamination from
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`siliconized stoppers exceed both pharmacopeia limits and the particle distributions
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`associated with Diprivan®” (Petition, p. 37). PO cites to several references (e.g.,
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`Smith, Vernon, 1968 Bulletin of the Parenteral Drug Association, the May 2003
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`edition of
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`the Pharmaceutical & Medical Packaging publication, FDA
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`correspondence, Sudo, the ‘504 patent, the ‘919 patent, and Mannermaa) in an
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`attempt to support its argument (id. at pp. 37-43).
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`But none of the references cited by Petitioner would have taught away from
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`the claimed invention of using a siliconized bromobutyl stopper in a container of a
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`propofol composition for four separate and independent reasons.
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`First, as explained by Dr. Feinberg, “many of the references cited by Petitioner
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`do not mention that the particulate contamination exceeds either the pharmacopeia
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`limits or levels in Diprivan®. For example, Smith does not disclose that any
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`particulates from siliconized stoppers would exceed pharmacopeia limits or the
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`levels associated with Diprivan® (see e.g., Exhibit 2035, Smith, col. 58)” (Ex. 1044,
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`Dr. Feinberg’s Supplemental Decl., ¶ 10). Rather, Smith indicates only that testing
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`would need to be performed to determine whether any contamination would be
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`meaningful as explained by Dr. Feinberg at his deposition:
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`speaking from the expertise that I have in extractibles [sic] and
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`leachables, is that there are lots of measurable differences, and you will
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`always find leachables. Whether that's meaningful, it really depends
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`upon the formulation, the use of the formulation, a lot of other
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`parameters. So it's leachables and the silicone oil that could potentially
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`be there is just one dimension of what you have to consider if this were
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`a choice
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`(Exh. 2035, 58:10). Likewise, Vernon, the 1968 Bulletin of the Parenteral Drug
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`Association, the May 2003 edition of the Pharmaceutical & Medical Packaging
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`publication, and the FDA correspondence do not disclose that any particulates from
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`siliconized stoppers would exceed pharmacopeia limits or the levels associated with
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`Diprivan® (see e.g., Ex. 2043, Vernon, ¶ [0005]; Ex. 1013; Ex. 2055, p. 4; and Ex.
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`2049). As explained by Dr. Feinberg, “these five references teach merely that drug
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`compositions must be tested for contaminates” (Ex. 1044, Dr. Feinberg’s
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`Supplemental Decl., ¶ 10). This teaching is unremarkable because as agreed by both
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`of the experts in this IPR proceeding, tests established by the pharmacopeia in the
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`United States, Europe, and Japan to measure particulate contamination were
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`routinely performed on drug compositions at the time of the invention of the ‘010
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`patent and are well within the skill set of a POSA (Ex. 1043, Davis Tr. p. 67, ll. 10-
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`25; Ex. 1044, Dr. Feinberg’s Supplemental Decl, ¶ 10). As further explained by Dr.
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`Feinberg, “[a] mere indication that there is some particulate contamination and that
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`the amount of contamination must be tested would not have been nearly enough to
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`teach away from the claimed invention of using a siliconized bromobutyl stopper in
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`a container of a propofol composition” (Ex. 1044, Dr. Feinberg’s Supplemental
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`Decl, ¶ 10).
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`Second, PO’s argument is improper because it relies upon references that were
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`published after the date of invention of the ‘010 patent. The publication dates of at
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`least Vernon and the FDA correspondence are August 7, 2003 and January 20, 2006
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`respectively, after the priority date of the ‘010 patent of July 10, 2003. An
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`obviousness determination requires a comparison of the claimed subject matter and
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`the prior art, to determine whether or not the claimed subject matter of the patent as
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`a whole would have been obvious, at the time of the invention, to a person of
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`ordinary skill in the art. 35 U.S.C. § 103. “References published after the date of
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`invention of the ‘010 patent like Vernon and the FDA correspondence clearly could
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`not have taught away from the claimed invention of the ‘010 patent at the time of
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`the invention” (Ex. 1044, Dr. Feinberg’s Supplemental Decl, ¶ 11 (emphasis
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`added)).
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`Third, PO’s argument lacks any meaningful or credible expert support. As
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`explained by Dr. Feinberg, “Dr. Davis’s analysis of the particulate data resulting
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`from the immersion of 10 stoppers into a container of water (Ex. 2036, Davis Decl.,
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`¶¶ 50, 73) is wrong because it does not account for the fact that the number of
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`particulates shed from 10 stoppers would have been about 10 times the number of
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`particulates shed from the single stopper in a container of a propofol composition,
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`that is claimed by the ‘010 patent” (Ex. 1044, Dr. Feinberg Decl., ¶ 12). “Dr. Davis’s
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`analysis also did not account for the fact that the number of particulates shed from a
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`stopper that is immersed in a solution would have been more than 2 times the number
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`of particulates shed from a stopper inserted into a container because only about half
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`of the surface area of an inserted stopper is exposed to the solution in the container
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`(Ex. 2036, Davis Decl., ¶¶ 50, 73)” (Ex. 1044, Dr. Feinberg’s Supplemental Decl, ¶
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`12). Thus, Dr. Davis’s particulate analysis is too high by a factor of over 20, as he
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`admitted under cross-examination at his deposition (Ex. 1044, Dr. Feinberg’s
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`Supplemental Decl, ¶ 13; Ex. 1043, Davis Tr., p. 78, ll. 5-16; p. 79, l. 18 – p. 80, l.
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`4). Clearly, Dr. Davis retreated from his declaration testimony at his deposition (id.).
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`His declaration testimony did not hold up to cross-examination (id.).
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`Reply To Patent Owner’s Response for Inter Partes Review of USPN 8,476,010
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`Dr. Davis also erred in stating that Sudo reports finding 680 particles of 10
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`micrometers2 per milliliter of water for the