UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`J KYLE BASS and ERICH SPANGENBERG,
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`Petitioner
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`v.
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`FRESENIUS KABI USA, LLC,
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`Patent Owner
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`Case IPR2016-00254
`U.S. Pat. No. 8,476,010 B2
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`PATENT OWNER’S OBSERVATIONS ON CROSS-EXAMINATION OF
`PETITIONERS’ REPLY WITNESS
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`J KYLE BASS and ERICH SPANGENBERG,
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`Petitioner
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`v.
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`FRESENIUS KABI USA, LLC,
`
`Patent Owner
`
`Case IPR2016-00254
`U.S. Pat. No. 8,476,010 B2
`
`PATENT OWNER’S OBSERVATIONS ON CROSS-EXAMINATION OF
`PETITIONERS’ REPLY WITNESS
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`1.
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`In Ex. 2064 (316:23-317:25), Dr. Feinberg admitted that that as of 2003 (or
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`the time of the ’010 invention), “it was a well-accepted principle that sterile drugs
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`should be manufactured using aseptic processing only when terminal sterilization
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`is not feasible.” Dr. Feinberg further admitted that U.S. regulatory guidance (Ex.
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`2060) also states that it was “a well-accepted principle that sterile drugs should be
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`manufactured using aseptic processing only when terminal sterilization is not
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`feasible.” Dr. Feinberg also admitted that “it’s feasible to use autoclave with the
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`invention of the ’010 patent” and that “you don’t have to use a different
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`sterilization process.” (Ex. 2064 at 286:3-15.) Dr. Feinberg further admitted that
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`Diprivan is “actually manufactured with heat sterilization” and that he “is not
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`aware of any other manufacturer that does propofol manufacturing that uses other
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`sterilization processes.” (Ex. 2064 at 285:6-20.) This testimony is relevant
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`because it shows that terminal sterilization is the only appropriate method of
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`sterilizing the claimed formulations, contradicting Petitioners’ argument that a
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`POSA could use aseptic manufacture or sterile filtration with silicone oil-treated
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`stoppers as an alternative to terminal sterilization by autoclave in the
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`manufacturing process for formulations claimed in the ’010 patent (see Petitioners’
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`Reply at 21-23). This testimony also contradicts Dr. Feinberg’s opinion that
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`although references such as “Mannermaa, the ’919 patent and Lehr would have
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`discouraged a POSA from using autoclave, they would not have discouraged a
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`3
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`POSA from the claimed invention using other sterilization techniques.” (Ex. 1044
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`at ¶ 24.)
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`2.
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`In Ex. 2064 (344:8-15), Dr. Feinberg admitted that “filter sterilization is
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`not suitable for Diprivan,” as taught in prior art Ex. 2052. This testimony is
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`relevant because it contradicts Petitioners’ argument that a POSA would consider
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`sterile filtration as an alternative to terminal sterilization by autoclave (see
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`Petitioners’ Reply at 21-23).
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`3.
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`In Ex. 2064 (307:22-308:9), Dr. Feinberg admitted that “European
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`regulatory guidance [(Ex. 2061)] says that packaging material that is incompatible
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`with heat sterilization cannot itself be the sole reason for adopting aseptic
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`processing,” and that “European regulatory guidance directs the manufacturers to
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`choose the best sterilization method for the formulation and select the packaging
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`accordingly.” This testimony is relevant because it shows that the prior art taught
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`that incompatibility between the patented propofol formulations and an autoclaved
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`silicone oil treated rubber stopper is not a sufficient reason to adopt aseptic
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`processing, contradicting Petitioners’ argument that a POSA would have been
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`motivated to use aseptic manufacture or sterile filtration instead of terminal
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`sterilization by autoclave in the manufacturing process for the claimed
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`formulations. This testimony also contradicts Dr. Feinberg’s testimony that
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`although references such as “Mannermaa, the ’919 patent and Lehr would have
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`4
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`discouraged a POSA from using autoclave, they would not have discouraged a
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`POSA from the claimed invention using other sterilization techniques.” (Ex. 1044
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`at ¶ 24.)
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`4.
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`In Ex. 2064 (288:22-289:2; 290:10-16), Dr. Feinberg admitted that “the
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`European Pharmacopoeia [(Ex. 2059)] recommends selecting a container to allow
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`the optimum sterilization method” and that “the European Pharmacopoeia
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`recommends terminal sterilization whenever possible.” This testimony is relevant
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`because it shows that the prior art taught that drug product containers should be
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`selected to allow terminal sterilization since it is the preferred sterilization method,
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`contradicting Petitioners’ argument that a POSA would consider using aseptic
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`manufacture or sterile filtration with the claimed invention after concluding that a
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`silicone oil treated closure is incompatible with terminal sterilization.
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`5.
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`In Ex. 2064 (299:19-300: 21), Dr. Feinberg admitted that that European
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`regulatory guidance (Ex. 2060) states that “the use of alternate packaging materials
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`should be thoroughly investigated before any decision to use non-terminal
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`sterilization process is made” and that “terminal sterilization of the final container
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`should be used whenever possible.” This testimony is relevant because it shows
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`that the prior art taught that drug product containers should be selected to allow
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`terminal sterilization since it is the preferred sterilization method, contradicting
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`Petitioners’ argument that a POSA would consider using aseptic manufacture or
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`5
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`sterile filtration after concluding that a silicone oil treated closure is incompatible
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`with terminal sterilization.
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`6.
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`In Ex. 2064 (278:22-279:15), Dr. Feinberg admitted that Ex. 1047
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`discloses that “a closure for an injectable product has to fulfill the following the
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`requirements” including that “it must be capable of sterilization at least once or
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`twice by autoclaving.” This testimony is relevant because it demonstrates that the
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`prior art taught that compatibility with terminal sterilization is considered a
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`requirement for a closure for an injectable product, contradicting Petitioners’
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`argument that a POSA would consider using a closure that would require aseptic
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`manufacture or sterile filtration with the claimed formulations.
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`7.
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`In Ex. 2064 (233:4-8), Dr. Feinberg admitted that “the advantages of
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`manufacturing efficiency are essentially economic as distinct from, for example,
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`the efficacy of the drug and medical use.” This testimony is relevant because it
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`indicates that commercial efficiency is the principal motivation for Petitioners’
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`proposed combinations of prior art.
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`8.
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`In Ex. 2064 (308:10-24), Dr. Feinberg admitted that European regulatory
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`guidance (Ex. 2061) “is saying commercial reasons like manufacturing efficiency
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`[] should not be used as justification for using a sterilization method other than
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`terminal sterilization.” This testimony is relevant because it indicates that the prior
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`art taught that commercial efficiency is not a sufficient basis to change the
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`6
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`sterilization method from terminal sterilization, contradicting Petitioners’ argument
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`that a POSA would consider using aseptic manufacture or sterile filtration with the
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`claimed formulations.
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`9.
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`In Ex. 2064 (309:10-310:6), Dr. Feinberg admitted he did not have an
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`opinion regarding whether a POSA following European regulatory guidelines
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`would “adopt aseptic manufacturing techniques, including filtration sterilization,
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`so that they could use a siliconized rubber stopper instead of an unsiliconized
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`rubber stopper that was compatible with autoclaving.” This testimony is relevant
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`because it contradicts Petitioners’ argument that a POSA would consider using
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`aseptic manufacture or sterile filtration with the claimed formulations.
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`10. In Ex. 2064 (347:23-348:7), Dr. Feinberg admitted that “assuming that a
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`manufacturer has access to both terminal sterilization and aseptic manufacturing
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`facilities,” he did not “have any reason to dispute that it would be less expensive to
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`manufacture Diprivan with terminal sterilization.” Dr. Feinberg also admitted that
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`“generally speaking, it’s less expensive to manufacture drugs using terminal
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`sterilization than aseptic manufacturing techniques.” (Ex. 2064 at 344:20-345:3.)
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`This testimony is relevant because it contradicts Petitioners’ argument that
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`economic considerations would motivate a POSA to use the proposed combination
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`with the more expensive sterilization methods suggested by Petitioners.
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`7
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`11. In Ex. 2064 (348:8-15), Dr. Feinberg admitted that he “didn’t consider
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`whether aseptic manufacturing would be more or less expensive than terminal
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`sterilization” as part of his opinions in this proceeding. This testimony is relevant
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`because it indicates that Petitioners failed to compare the purported economic
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`benefits associated with silicone oil treated stoppers to the economic costs
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`associated with the sterilization methods proposed by Petitioners.
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`12. In Ex. 2064 (281:6-19), Dr. Feinberg admitted that “with a terminally
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`sterilized product, it can be non-aseptic [during manufacture] and then you sterilize
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`it at the very end” but that “with aseptic manufacture, you have to sterilize each
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`part separately, and then, once each piece is sterilized, you have to keep the whole
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`process in an aseptic environment until it is sealed and ready to go.” (Id. at 281:6-
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`19.) This testimony is relevant because it illustrates the significant additional
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`expenses associated with aseptic manufacturing.
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`13. In Ex. 2064 (334:6-335:11), Dr. Feinberg testified that a manufacturer
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`seeking to use aseptic manufacturing must validate a sterilization procedure as
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`generally described in Ex. 2063. More specifically, “if a manufacturer wants to
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`use aseptic manufacturing, including with drug filtration, they need to have a
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`designated area large enough to manufacture the drug in which the air quality is
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`highly monitored, the surfaces are highly monitored, and the air pressure is highly
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`monitored to assure that no microbes -- or attempt to minimize the possibility of
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`8
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`contamination.” (Id. at 335:12-24.) This testimony is relevant because it
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`illustrates the significant additional expenses associated with aseptic
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`manufacturing.
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`14. In Ex. 2064 (335:25-336:12), Dr. Feinberg admitted that a manufacturer
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`would “need to classify the level of air quality in each section depending upon
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`where it is in the process because you'll have a robing room that's separate from the
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`floor where the people are supposed to be from the actual manufacturing area, and
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`each of the barriers in each of the entrances and exits between those different
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`sections all need to be specified and monitored to some degree.” This testimony is
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`relevant because it illustrates the significant additional expenses associated with
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`aseptic manufacturing.
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`15. In Ex. 2064 (336:13-21), Dr. Feinberg admitted that “the materials that are
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`actually used in the manufacturing process need [] to go in, be sterilized, and then
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`move from step to step to step in the manufacturing process from when they're
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`created to when they're combined, to when it's filled into the container, to when the
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`container is sealed, to when it gets out.” And he also admitted that “each of those
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`movements of material from one part of the sterile environment to another all
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`needs to be monitored to make sure that none of these mechanical processes
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`introduce contamination” and that “there's extra monitoring at the beginning when
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`things go into the environment and maybe somewhat less but also significantly
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`9
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`when they come out to make sure that going in and out of the clean environment
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`doesn't introduce contamination.” (Id. at 336:22-337:13.) This testimony is
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`relevant because it illustrates the significant additional expenses associated with
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`aseptic manufacturing.
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`16. In Ex. 2064 (337:14-338:3), Dr. Feinberg admitted that manufacturers
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`must perform testing with media fills, “a process of putting media where bacteria
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`could grow, moving it through the manufacturing process, and then testing it
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`afterwards to see if bacteria actually contaminated it.” This testimony is relevant
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`because it illustrates the significant additional expenses associated with aseptic
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`manufacturing.
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`17. In Ex. 2064 (256:6-19), Dr. Feinberg admitted that “for the unsiliconized
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`stoppers after heat sterilization [Mannermaa (Ex. 2041)] reports 5,000 particles per
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`stopper of 5 microns or greater.” “And for the siliconized stoppers after heat
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`sterilization Mannermaa reports 12,000 to 45,000 particles between 5 and 32
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`microns per stopper.” This testimony is relevant because it contradicts Dr.
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`Feinberg’s testimony that Dr. Davis overstated the number of particles reported by
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`Mannermaa by not dividing the measured number of particulates by 20. (Ex. 1044
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`at ¶ 16.)
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`18. In Ex. 2064 (258:11-259:10), Dr. Feinberg admitted that the ’504 patent’s
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`(Ex. 2040) disclosure that stoppers that “were treated with silicone had in excess of
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`10
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`10,000 particles per stopper” is consistent with “Mannermaa’s report that its
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`analysis of silicone-treated stoppers produced 12,000 to 45,000 particles of 5
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`microns or larger.” This testimony is relevant because it contradicts Dr. Feinberg’s
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`testimony that a “POSA would have been skeptical of the results in the ’504 patent
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`because they differ significantly from the results of particulate measurements that
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`are disclosed in other references.” (Ex. 1044 at ¶ 19.)
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`19. In Ex. 2064 (255:12-17), Dr. Feinberg admitted that “if you’re measuring
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`particles per milliliter per stopper and you want to find out the number of particles
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`per stopper, you have to multiply by the number of milliliters.” This testimony is
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`relevant because it contradicts Dr. Feinberg’s testimony that a POSA would have
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`understood Sudo to disclose only 34 particles per stopper, below the
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`pharmacopeial limit of 3000 particles. (Ex. 1044 at ¶ 15.)
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`20. In Ex. 2064 (271:18-23), Dr. Feinberg admitted that Petitioners’ Ex. 1045
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`states that “the problems with interaction of a parenteral product and the rubber
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`closure are well documented in the literature.” In Ex. 2064 (318:6-9), Dr. Feinberg
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`also admitted that U.S. regulatory guidance (Ex. 2062) states that “a potential
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`source of contamination is the siliconization of rubber stoppers.” This testimony is
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`relevant because it supports Prof. Davis’s opinion that problems associated with
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`siliconization of container closures were well known and documented before the
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`invention of the ’010 patent.
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`11
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`21. In Ex. 2064 (259:17-263:4), Dr. Feinberg admitted that although a rough
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`surface will have a larger surface area than a smooth surface (259:17-260:8), he
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`did not “discuss roughness” in his original or supplemental declaration (261:3-9)
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`and does not have an opinion regarding whether “the inside of a syringe barrel [is]
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`smoother, rougher or [has] the same roughness as the exposed face of a rubber
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`stopper” (262:16-23). This testimony is relevant because it undermines the
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`reliability of Dr. Feinberg’s opinion that the surface area of the syringe barrels of
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`Lomax and Capes is much greater than the surface area of one end of the stopper
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`claimed in the ’010 patent. (Ex. 1044 at ¶ 27.)
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`22. In Ex. 2064 (235:8-241:16), Dr. Feinberg admitted that the Smith reference
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`(Ex. 1004) describes “alternate ways of lubricating rubber stoppers to gain
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`manufacturing advantages that are not based on silicone oil,” including “the
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`internal addition of paraffin wax” (236:12-16), “the internal addition of
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`polyethylene” (236:17-20), “the internal application of other compounds” (236:21-
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`237:3), “surface chlorination” (237:16-19) for which “there are multiple techniques
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`for applying” (238:8-11), “the addition of an olefinic film or coating” (238:12-18),
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`“with a fluorocarbon polymer” (238:19-22) or “through chemical modification”
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`(240:6-10). Dr. Feinberg further admitted that the ’504 patent (Ex. 2040) disclosed
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`using “polyparaxylylene as a method of lubricating rubber stoppers.” (Ex. 2064 at
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`241:13-16.) This testimony is relevant because it contradicts Dr. Feinberg’s
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`12
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`testimony and Petitioners’ argument that there were only a small, finite, number of
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`solutions to the purported machinability problems.
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`23. In Ex. 2064 (244:15-245:22), Dr. Feinberg admitted that a POSA could
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`also use “metal closures” (244:15-18), “a polyethylene closure” (244:19-22), “a
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`polypropylene closure” (244:23-245:2), or “a nylon, polyurethane,
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`polyvinylchloride, poly acrylate, polycarbonate, or the like as alternatives to rubber
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`stoppers” (245:3-7) as described in the specification of the ’010 patent (Ex. 1001 at
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`cols. 10-11). This testimony is relevant because it contradicts Dr. Feinberg’s
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`testimony and Petitioners’ argument that there were only a small, finite, number of
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`solutions to the purported machinability problems.
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`24. In Ex. 2064 (263:20-264:15), Dr. Feinberg admitted that the 10/167,122
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`patent application associated with the ’030 publication (Ex. 2043) was filed prior
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`to 2003 with a provisional application filed Jun. 20, 2001. This testimony is
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`relevant because it contradicts Petitioners’ argument that Patent Owner improperly
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`relied on Ex. 2043.
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`25. In Ex. 2064 (270:22-271:4), Dr. Feinberg admitted that “Ex. 2049 shows
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`that Wyeth, as an example of industry, eliminated silicone oil lubricant to prevent
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`silicone particle contamination in the same time frame prior to the ’010 invention.”
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`This testimony is relevant because it supports Patent Owner’s argument that Wyeth
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`was an example of industry movement away from siliconization (see Patent
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`13
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`Owner’s Response at 39) and contradicts Petitioners’ argument that Patent Owner
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`improperly relied on Ex. 2049.
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`26. In Ex. 2064 (268:4-13), Dr. Feinberg admitted that “clinical evidence prior
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`to 2003 indicates that intravenous treatments with lower level of particulate
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`contamination are associated with the reduction of the incidence of adverse events”
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`as described in Ex. 2049 at 2 (citing Mannermaa, Ex. 2041 and Lehr, Ex. 2053).
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`This testimony is relevant because it supports Patent Owner’s contention that
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`particulate contamination was known to be associated with adverse events prior to
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`the patented invention and contradicts Petitioners’ argument that Patent Owner
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`improperly relied on Ex. 2049.
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`Date: January 11, 2017
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`Respectfully submitted,
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`/Eleanor M. Yost/
`Eleanor M. Yost
`Registration No. 58,013
`Goodwin Procter LLP
`901 New York Avenue NW
`Washington, DC 20001
`P: 202.346.4000
`F: 202.346.4444
`eyost@goodwinlaw.com
`Attorneys For Patent Owner
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`14
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`CERTIFICATE OF SERVICE
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`The undersigned hereby certifies that a copy of the foregoing PATENT
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`OWNER’S OBSERVATIONS ON CROSS-EXAMINATION OF
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`PETITIONERS’ REPLY WITNESS was served electronically via e-mail on
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`
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`
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`/Eleanor M. Yost/
`Eleanor M. Yost
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`January 11, 2017 on the following:
`
`Dr. Gregory Gonsalves
`2216 Beacon Lane
`Falls Church, Virginia 22043
`(571) 419-7252
`gonsalves@gonsalveslawfirm.com
`
`Christopher Casieri
`McNeely, Hare & War LLP
`chris@miplaw.com
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`Counsel for Petitioners J Kyle Bass
`and Erich Spangenberg
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`
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`Dated:
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`January 11, 2017
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`2
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