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
`Patent Owner
`
`U.S. Patent No. 8,476,010
`Issue Date: July 2, 2013
`
`Title: PROPOFOL FORMULATIONS WITH
`NON-REACTIVE CONTAINER CLOSURES
`
`
`
`
`
`
`
`
`
`
`
`
`Inter Partes Review No. IPR2016-00254
`
`__________________________________________________________________
`
`
`
`EXHIBIT 1044 – SUPPLEMENTAL DECLARATION OF THOMAS N.
`FEINBERG, PH.D.
`
`
`
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`J KYLE BASS and ERICH SPANGENBERG
`Petitioners
`
`v.
`
`FRESENIUS KABI USA, LLC
`Patent Owner
`
`U.S. Patent No. 8,476,010
`Issue Date: July 2, 2013
`
`Title: PROPOFOL FORMULATIONS WITH
`NON-REACTIVE CONTAINER CLOSURES
`
`
`
`
`
`
`
`
`
`
`
`
`Inter Partes Review No. IPR2016-00254
`
`__________________________________________________________________
`
`
`
`EXHIBIT 1044 – SUPPLEMENTAL DECLARATION OF THOMAS N.
`FEINBERG, PH.D.
`
`
`
`
`
`I, THOMAS N. FEINBERG, PH.D., hereby declare and state as follows:
`
`1.
`
`I have been retained by the Gonsalves Law Firm ("the firm") as an
`
`expert in connection with the above-captioned matter. I am being compensated for
`
`my time. My compensation in this matter is neither dependent nor related to the
`
`outcome of this matter. I have never before been retained by the firm in any capacity.
`
`I have been retained by counsel in connection with the above-captioned inter partes
`
`review (“IPR”) Petition. Specifically, I have been asked to prepare this
`
`Supplemental Declaration to address the Patent Owner’s Response as well as their
`
`exhibits including the expert declaration.
`
`2.
`
`I have reviewed the Patent Owner’s Response and its exhibits including
`
`the expert declaration.
`
`3.
`
`I have a substantial amount of experience and knowledge about the
`
`manufacturing and packaging of drug compositions like Diprivan®. I have over 20
`
`years of experience with the analytical requirements of drug packaging (Ex. 1002,
`
`Dr. Feinberg’s Declaration, ¶¶ 4-5; Ex. 1003, Dr. Feinberg’s Curriculum Vitae, pp.
`
`1-4).
`
`4.
`
`It is my opinion that a person of ordinary skill in the art (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 from the ‘864
`
`
`
`
`
`
`
`patent or the ‘043 patent, and reasonably expect success. No non-obvious
`
`differences exist between the combination and the claimed subject matter.
`
`5.
`
`I understand that the Patent Owner (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).
`
`6.
`
`It is my opinion that the PO’s argument is wrong. First, 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). 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 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.)
`
`2
`
`
`
`
`
`
`7.
`
`Another reference (Pharmaceutical Packaging Technology) 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 machines and
`
`insertion into the barrel or vial opening.
`
`(Ex. 1045, Pharmaceutical Packaging Technology, November 30, 2000 Chapter 12
`
`pg 361). As indicated by a study in another prior art reference (Sudo), the lubricated
`
`stopper was demonstrated to have the lowest sliding value of all tested examples
`
`(Ex. 2042, the Sudo ‘794 patent, col. 22, line 56).
`
`8.
`
`It is my opinion that the PO did not demonstrate that the prior art
`
`teaches away from the claimed invention.
`
`9.
`
`PO argued that “measurements of actual silicone oil contamination
`
`from siliconized stoppers exceed both pharmacopeial limits and the particle
`
`3
`
`
`
`
`
`
`distributions associated with Diprivan®” (Petition, p. 37). PO cites to several
`
`references (e.g., Smith, Vernon, 1968 Bulletin of the Parenteral Drug Association,
`
`the May 2003 edition of the Pharmaceutical & Medical Packaging publication, FDA
`
`correspondence, Sudo, the ‘504 patent, the ‘919 patent, and Mannermaa) in an
`
`attempt to support its argument (id. at pp. 37-43). Indeed, one of these prior art
`
`references, Sudo ‘794 patent, is another example of siliconization available to a
`
`POSA that would have been obvious to use to improve manufacturing ease.
`
`10. But none of the references cited by Petitioner would have taught away
`
`from the claimed invention of using a siliconized bromobutyl stopper in a container
`
`of a propofol composition for many reasons. First, many of the references cited by
`
`Petitioner do not mention that the particulate contamination exceeds either the
`
`pharmacopeial limits or levels in Diprivan®. For example, Smith does not disclose
`
`that any particulates from siliconized stoppers would exceed pharmacopeial limits
`
`or the levels associated with Diprivan® (see e.g., Exhibit 2035, Smith, col. 58).
`
`Rather, Smith indicates only that testing would need to be performed to determine
`
`whether any contamination would be meaningful as I have previously stated in my
`
`deposition transcript:
`
`speaking from the expertise that I have in extractibles [sic] and
`
`leachables, is that there are lots of measurable differences, and you will
`
`always find leachables. Whether that's meaningful, it really depends
`
`4
`
`
`
`
`
`
`upon the formulation, the use of the formulation, a lot of other
`
`parameters. So it's leachables and the silicone oil that could potentially
`
`be there is just one dimension of what you have to consider if this were
`
`a choice
`
`(id. at 58:10). Likewise, the PO’s use of Vernon, the 1968 Bulletin of the Parenteral
`
`Drug Association, the May 2003 edition of the Pharmaceutical & Medical Packaging
`
`publication, and the FDA correspondences as examples of prior art to teach away
`
`from the use of siliconized stoppers, does not disclose that any particulates from
`
`siliconized stoppers would exceed pharmacopeial limits or the levels associated with
`
`Diprivan® (see e.g., Ex. 2043, Vernon, ¶ [0005]; Ex. 1013; Ex. 2055, p. 4; and Ex.
`
`2049). That is, these four references teach merely that drug compositions must be
`
`tested for contaminates. This teaching is unremarkable because tests established by
`
`the pharmacopeia in the United States, Europe, and Japan to measure particulate
`
`contamination were routinely performed on drug compositions at the time of the
`
`invention of the ‘010 patent (Ex. 1043, Davis Tr. p. 67, ll. 10-25). A mere indication
`
`that there is some particulate contamination and that the amount of contamination
`
`must be tested would not have been nearly enough to teach away from the claimed
`
`invention of using a siliconized bromobutyl stopper in a container of a propofol
`
`composition.
`
`5
`
`
`
`
`
`
`11.
`
` I also note that the publication dates of Vernon and the FDA
`
`correspondence are August 7, 2003 and January 20, 2006 respectively, after the
`
`priority date of the ‘010 patent of July 10, 2003. I understand that 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. 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.
`
`12.
`
`In addition, it is my opinion that PO’s argument lacks any meaningful
`
`or credible expert support. Dr. Davis’s analysis of the particulate data resulting from
`
`the immersion of 10 stoppers into a container of water (Ex. 2036, Davis Decl., 41)
`
`is wrong because it does not account for the fact that the number of particulates shed
`
`from 10 stoppers would have been 10 times the number of particulates shed from the
`
`single stopper in a container of a propofol composition, that is claimed by the ‘010
`
`patent.
`
`13. 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 only about half of the surface area of an inserted stopper is exposed to the
`
`6
`
`
`
`
`
`
`solution in the container (Ex. 2036, Davis Decl., 41). Thus, Dr. Davis’s particulate
`
`analysis — as he admitted under cross-examination at his deposition — is too high
`
`by a factor of over 20 (Ex. 1043, Davis Tr., p. 78, ll. 5-16; p. 79, l. 18 – p. 80, l. 4).
`
`14. Dr. Davis also erred in stating that Sudo reports finding 680 particles
`
`of 10µm per milliliter of water for the silicone oil treated stopper because Sudo did
`
`not report any such finding. Sudo instead reported finding a total of 680 particles of
`
`10 µm in 300 milliliters of water (Ex. 2042, the Sudo ‘794 patent, cols. 21-22, Table
`
`1 defining the Peeling Quantity Number as “Quantity of fine particles, number of
`
`particles of 10µm in diameter [± 3 particles]). Accordingly, Dr. Davis’s particulate
`
`calculation is off by an additional factor of 300.
`
`15. A POSA would have properly understood Sudo to disclose particulate
`
`contamination of 34 particles per stopper, well below the pharmacopeial limit of
`
`3000 particles for a container of less than 100 milliliters, published in British
`
`Pharmacopeia XIII (Ex. 2047, A257-258). A POSA would know to divide the
`
`provided numbers by a factor of 10 to arrive at the “peeling quantity” per stopper.
`
`Additionally, the test is of the entire stopper which means that both tops and sides in
`
`addition to the sealing surfaces were tested. All surfaces may shed particles. A POSA
`
`would know that all surfaces shed particles and, wanting to know how many particles
`
`theoretically would be shed by only the sealing surface, would divide the “peeling
`
`quantity” found per stopper (factor of 10) by an additional factor of at least 2.
`
`7
`
`
`
`
`
`
`Therefore, Sudo would teach that the number of particles for a stopper with
`
`lubrication would not be 680, but 680 divided by 20 which equals 34. A POSA would
`
`have a reasonable opinion that the number of particles per stopper, regardless of the
`
`volume, would be 34 well below the BP limit of 3,000 particles for a container
`
`containing less than 100 milliliters.
`
`16.
`
`I also note that Dr. Davis made the same mistakes in his analysis of the
`
`data from Mannermaa that he did with the data from Sudo. Like the test in Sudo,
`
`the Mannermaa test measured the number of particulates shed from 10 stoppers
`
`immersed in 200 milliliters of a solution (Ex. 2041, Mannermaa, p. 73). Thus, Dr.
`
`Davis should have divided the measured number of particulates by 20 to account for
`
`the facts that ten stoppers would shed about ten times as many particulates as one
`
`stopper and that a stopper immersed in a solution would shed less than half of the
`
`particulates as a stopper installed in a container. But Dr. Davis again failed to divide
`
`the measured number of particulates by twenty (Ex. 2036, Davis Decl, ¶¶ 47-48).
`
`17.
`
`In addition, PO’s arguments with respect to both Mannermaa and the
`
`‘919 patent are not commensurate with the scope of the claims because the test
`
`results in both documents were obtained after autoclave, a sterilization procedure
`
`that would have significantly increased the number of particulates shed from the
`
`tested stoppers.
`
`18. Also, a POSA would have viewed the results from the references cited
`
`8
`
`
`
`
`
`
`by PO with skepticism because a POSA would have understood that particulate
`
`testing is a very exacting procedure that is prone to error. Indeed, the BP 2002
`
`Appendix XIII cautioned that interference must not be present while making
`
`particulate measurements (Ex. 2048, BP 2002 Appendix XIII, p. A258). For
`
`example, a POSA would have been particularly skeptical of the results disclosed in
`
`the ‘504 patent because the patent does not provide any details about how its testing
`
`was performed and does not reference any of the standard tests (see e.g., Ex. 2040,
`
`‘504 patent, cols. 8-9).
`
`19. Moreover, a POSA would have been further skeptical of the results in
`
`the ‘504 patent because they differ significantly from the results of particulate
`
`measurements that are disclosed in other references. As discussed by the PO, “the
`
`‘504 patent disclosed the stoppers ‘treated with silicone had in excess of 10,000 [5
`
`μM] particles per stopper’ while untreated stoppers (as well as stoppers with the
`
`polyparaxylylene coating claimed by the ’504 Patent) had fewer than 300 5 μM
`
`particles per stopper. .. The ’504 Patent disclosure of 10,000 5μM particles per
`
`stopper vastly exceeds the Han, Davis and Washington report that Diprivan® has
`
`only 120-200 5μM particles per container.” These values do not agree with those
`
`disclosed by Sudo (the ‘794 patent) above, namely 34 particles per stopper for
`
`siliconized stoppers. The values in the ‘504 patent clearly do not agree with those in
`
`the ‘794 patent. Therefore, a POSA would think that the ‘504 patent had significant
`
`9
`
`
`
`
`
`
`interference.
`
`20.
`
`I understand that Mannermaa disclosed that siliconized rubber stoppers
`
`produced particulates exceeding the limits “after being subjected to autoclave heat
`
`sterilization” (PO’s Response, p. 47). The same data set includes (stopper number
`
`4, pp. 74 and note on page 76, “[s]topper 4 had no surface siliconization…”
`
`According to Mannermaa’s own data set, stopper 4 had almost 500 particles per
`
`milliliter greater than 5 µm after heat sterilization. This is not in agreement with
`
`what was known about Diprivan® from Han, Davis and Washington 2001 (Exh.
`
`1009, Table 1 pg. 208) of between 120 and 200 particles per milliliter greater then
`
`5µm. It should also be noted that the lower number disclosed by Han, Davis and
`
`Washington (120) for the number of particles in a 50 milliliter container of Diprivan®
`
`would be 6,000. This number exceeds the pharmacopeial limit of 3000. This
`
`highlights to a POSA the difficulty in this type of measurement to remain skeptical
`
`of any prior art with respect to particulates.
`
`21. PO similarly argued that “the ‘919 Patent likewise demonstrates
`
`unacceptable contamination levels after autoclaving” (id.). An additional reference
`
`relied upon by PO, Lehr (Exhibit 2043, Lehr, p. 519), completes the PO’s argument
`
`teaching away from stoppers that shed particulates due to “particle contamination
`
`may not pose a major threat in intact tissue, [it] may severely compromise tissue
`
`perfusion in patients with prior microvascular compromise of vital organs (i.e. after
`
`10
`
`
`
`
`
`
`trauma, major surgery, or sepsis).” The inclusion of this reference would not teach
`
`away from a POSA from the combination of a siliconized bromobutyl stopper,
`
`Farinotti and the Diprivan® PDR. The Lehr reference is redundant to the requirement
`
`of normal pharmaceutical development to limit the number of particulates as
`
`required by normal pharmacopeial testing.
`
`22. But PO’s arguments using Mannermaa, the ‘919 patent in combination
`
`with Lehr are not commensurate with the scope of the claims because the particulate
`
`data in Mannermaa and the ‘919 patent were obtained from autoclaving and the
`
`claims are not limited to autoclaving (Ex. 1001, ‘010 patent, col. 27, l. 55 – col. 33,
`
`l. 14). Indeed, not a single one of the claims of the ‘010 patent recites autoclaving
`
`(id.). Moreover, the Specification of the ‘010 patent indicates that the invention is
`
`not limited to autoclaving and instead, encompasses other sterilization techniques
`
`such as aseptic manufacture and sterile filtration: “[t]he present invention's
`
`composition is a sterile aqueous formulation and is prepared by standard
`
`manufacturing techniques using, for example, aseptic manufacture, sterile filtration
`
`or terminal sterilization by autoclaving” (id. at col. 7, ll. 31-34).
`
`23. Also, a POSA at the time of the invention of the ‘010 patent would have
`
`understood that the number of particulates shed from a stopper after autoclaving
`
`would have been significantly higher than the number of particulates shed from the
`
`stopper after other sterilization techniques like aseptic manufacture and sterile
`
`11
`
`
`
`
`
`
`filtration. That is, the siliconized bromobutyl stopper with a different sterilization
`
`technique would have shed significantly fewer particulates than those reported in
`
`Mannermma, the ‘919 patent and Lehr for the autoclave sterilization technique.
`
`24. Thus, although Mannermma, the ‘919 patent and Lehr may have
`
`discouraged a POSA from using autoclave, they would not have discouraged a
`
`POSA from the claimed invention using other sterilization techniques because none
`
`of the claims require autoclave and because significantly fewer particles would be
`
`shed with other sterilization techniques than those reported for autoclave.
`
`25.
`
`I noticed that PO also argued that “Lomax et al. reported that ‘propofol
`
`strips the silicone lubricant from the inside barrel of plastic syringes’” (PO’s
`
`Response, p. 13). PO made the same argument with respect to Capes (id.).
`
`26. But PO’s arguments with respect to Lomax and Capes are also not
`
`related to the claims because both references relate to the stripping of silicone oil
`
`from the barrel of a plastic syringe and the claims of the ’010 patent do not recite a
`
`plastic syringe coated with silicone oil (Ex. 1001, ‘010 patent, col. 27, l. 55 – col.
`
`33, l. 14). Indeed, I noticed that the Board has already recognized that “the
`
`references [Lomax and Capes] cited [by PO] refer to silicone-lubricated syringes,
`
`and not to siliconized rubber stoppers” (Paper No. 9, Institution Decision, June 8,
`
`2016, p. 11).
`
`27. A POSA at the time of the invention of the ‘010 patent would have
`
`12
`
`
`
`
`
`
`understood that the number of particulates shed from the barrel of a plastic syringe
`
`would have been significantly higher than the number of particulates shed from one
`
`of the ends of a stopper. In particular, the particulate amounts shed from an object
`
`to a propofol composition increases with the surface area of the object that is exposed
`
`to the composition. The surface area of the syringe barrels of Lomax and Capes is
`
`much greater than the surface area of one end of the stopper claimed in the ‘010
`
`patent (id.). I noticed that Dr. Davis admitted that he “wouldn’t be surprised if there
`
`was a relationship [of the number of shed particulates] with the surface area” (Ex.
`
`1043, p. 92, ll. 14-15). In other words, the siliconized bromobutyl stopper would
`
`have shed significantly fewer particulates than those reported in Lomax and Capes
`
`for the barrel of the syringe (id.). Thus, although Lomax and Capes may have
`
`discouraged a POSA from using a silicone oil coating in the barrel of a syringe, they
`
`would not have discouraged a POSA from using a siliconized bromobutyl stopper in
`
`a container of a propofol composition because significantly fewer particles would be
`
`shed from the end of a stopper than from those reported in Capes and Lomax for a
`
`syringe.
`
`28. At the time of the invention of the ‘010 patent, there was a need to solve
`
`machinability problem with rubber stoppers including friction between the rubber
`
`closure and metallic machinery, clumping of parts, excessively high required
`
`insertion force. And there were only a small, finite, number of rubber stoppers as
`
`13
`
`
`
`
`
`
`solutions to the machinability problems.
`
`29.
`
`I noticed that Dr. Davis testified at his deposition that all the stoppers
`
`that would have been feasible to use with a container of a propofol composition are
`
`listed in only one small portion of the ‘010 patent (Ex. 1043, Davis Tr. p. 44, l. 9 –
`
`p. 45, l. 3). As I noted in my initial declaration, only a small percentage of the
`
`stoppers listed in the ’010 patent were coated with a lubricant to address the
`
`machinability problems of friction between the stopper, and both the machinery and
`
`the container (Ex 1002, Dr. Feinberg Decl., ¶ 20). In other words, there were only a
`
`few stopper solutions to the known machinability problems at the time of the
`
`invention of the ‘010 patent.
`
`30.
`
`It is my opinion that it would have been obvious to a POSA to try the
`
`siliconized bromobutyl stopper from this short list of solutions because siliconized
`
`stoppers were known to reduce friction between the stopper and both the machinery
`
`and the container. Also, a POSA would not have been dissuaded from using a
`
`siliconized bromobutyl stopper because the conflicting and inconsistent data in the
`
`references does not nearly establish that any particulates shed from the stopper
`
`would have exceeded the limits set by phamacopeial standards. Rather, the data
`
`would have merely encouraged a POSA to conduct the standard, well-known,
`
`particulate tests. In addition, there is no data in any of the references indicating that
`
`the loss of propofol in a 10% soybean oil solution as claimed in the ‘010 patent
`
`14
`
`
`
`
`
`
`would have exceeded the claimed limits.
`
`31. For these reasons, it is my opinion that it would have been obvious to a
`
`POSA at the time of the invention of the ‘010 patent to try a siliconized bromobutyl
`
`stopper with a container of propofol in a 10% soybean oil solution from the finite
`
`list of about 10 feasible solutions and to reasonably expect success in light of the
`
`knowledge that the use of siliconized stoppers would have reduced friction and
`
`would not have led to particulate and loss problems that exceeded the limits.
`
`I hereby declare under penalty of perjury under the laws of the United States
`
`of America that the foregoing is true and correct, and that all statements made of my
`
`own knowledge are true and that all statements made on information and belief are
`
`believed to be true. I understand that willful false statements and the like are
`
`punishable by fine or imprisonment, or both (18 U.S.C. § 1001).
`
`
`
`Executed on:
`
`
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`
`
`
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`
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`
`
`
`
`Thomas N. Feinberg
`
`
`
`
`
`
`
`15
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