Exhibit No.
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY'S LABORATORIES, INC.
`Petitioner
`
`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. Unassigned
`
`EXHIBIT 1002- DECLARATION OF THOMAS N. FEINBERG, PH.D.
`
`Dr. Reddy's Laboratories
`v.
`Fresenius Kabi USA, LLC
`U.S. Patent No. 8,476,010
`Exhibit 1002
`
`Exh. 1002
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY'S LABORATORIES, INC.
`Petitioner
`
`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. Unassigned
`
`EXHIBIT 1002- DECLARATION OF THOMAS N. FEINBERG, PH.D.
`
`Dr. Reddy's Laboratories
`v.
`Fresenius Kabi USA, LLC
`U.S. Patent No. 8,476,010
`Exhibit 1002
`
`Exh. 1002
`
`
`
`I, THOMAS N. FEINBERG, PH.D., hereby declare and state as follows:
`
`1.
`
`I have been retained by the firm of Lerner, David, Littenberg,
`
`Krumholz & Mentlik, LLP ("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 not dependent or, or related to, the outcome of this matter. I have
`
`never before been retained by the firm in any capacity.
`
`2.
`
`I reside in Chapel Hill, North Carolina and am a citizen of the United
`
`States of America.
`
`3.
`
`I have a Ph.D. in Physical Chemistry from the University of North
`
`Carolina at Chapel Hill, which I received in 1991. Prior to that, I received an A.B.
`
`in Chemistry from Cornell University in 1985.
`
`4.
`
`I have 19 years of experience in the pbatmaceutical industry, with an
`
`emphasis on container/drug interactions, along with management of analytical
`
`R&D and quality control groups. I am presently the President of SCIO Analytical,
`
`LLC, which provides expert consulting services predominantly to pharmaceutical
`
`development organizations. Prior to founding SCIO Analytical, I was a Director of
`
`Development and Analytical Services for Catalent Pharma Solutions. All of my
`
`experience has been in contract analytical services, which has provided me with
`
`wide-ranging experience in product development issues and quality controL
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`5.
`
`I am, and have been, a member of several working groups and
`
`professional socjeties. A copy of my current curriculum vitae
`
`listing my
`
`professional and academic activities and my publications is attached hereto as
`
`Exhibit 1003.
`
`6.
`
`I have over 20 publications/presentations/posters and have run
`
`workshops to teach regulatory and scientific expectations for container/product
`
`interaction ( extractables & leachables) issues.
`
`7.
`
`I have reviewed U.S. Patent No. 8,476,010 ("the '010 Patent"). A
`
`copy of the '0 10 Patent is attached hereto as Exhibit 1001. I have also reviewed the
`
`references identified in this declaration, which are also attached as exhibits.
`
`8.
`
`I understand from counsel that patents are not written to be read by
`
`experts or by the general public. Instead they are written to be understandable to a
`
`person having ordinary skill in the appropriate art. I understand from counsel that
`
`factors relevant to the level of skill in the art include: the educational level of the
`
`inventor, the types of problems encountered in the art, prior art solutions to those
`
`proMems, the rapidity with which innovations are made, the sophistication of the
`
`technology, and the educational level of active workers in the field. From my
`
`experience, I believe a person of ordinary skill in this art prior to July 10, 2003,
`
`when the application for the '010 Patent was filed, would have been: someone with
`
`2
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`substantial research or industry expenence m pharmaceutical drug product
`
`development, including experience with sterile drugs and their packaging, and
`
`having a master's degree or doctorate in a related technical field, such as analytical,
`
`physical or organic chemistry, chemical engineering, pharmaceutics or related
`
`subje,ct matter. I consider myself to be a person of at least ordinary skill in this art,
`
`and would have been so in 2003.
`
`9.
`
`I have been advised by counsel that the claims at the end of a patent
`
`define the scope of the rights granted to the patentee. Claim 1 of the '0 10 is
`
`directed to a sterile container in which a sterile propofol formulation is packaged.
`
`The propofol is present in the formulation in an amount of from 0.5% to 10% by
`
`weight, along with a solvent, present in an amount of from about 0% to about 10%
`
`by weight. As the patent explains, "all references to weight percent are meant to be
`
`weight percent by volume of the composition." ('010 Patent, col. 5, lines 33-35.)
`
`The container includes a closure which can be made of siliconized bromobutyl
`
`rubber, metal or siliconized chlorobutyl rubber. Finally, the packaged formulation
`
`must retain at least 93% of the initial propofol concentration (specified previously
`
`as 0.5% to 10% weight by volume) under a specified accelerated stability test. The
`
`accelerated stability test directs the sealed container to be agitated at a frequency of
`
`300-400 cycles per minute for 16 hours at room temperature.
`
`3
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`10. The term "siliconized" is used in claim 1 but it is not defined in the
`
`patent. A person of ordinary skill as of the date listed above would have
`
`understood this to mean "surface-treated with an organic silicone." "Silicone" is
`
`not defined in the patent either, but a person of ordinary skill would have
`
`understood it to mean "a general tenn describing a solid or liquid polymer made up
`
`of silicon-oxygen-silicon bonds in which hydrocarbon groups are bonded directly
`
`to all or a portion of the silicon atoms." This is a Glossary entry from Smith et al.,
`
`"Siliconization of Parenteral Drug Packaging Components," 1998 Journal of
`
`Parenteral Science and Technology, Technical Report No. 12, at S12.
`
`("Smith
`
`el a!.") (Exhibit 1004). In summary, "siliconized" would mean a closure that is
`
`surface-treated with one or more siloxane polymers.
`
`11. Typically siliconization will either be accomplished by surface
`
`coating a closure with silicone oil (such as polydimethylsiloxane) or bonding
`
`(and/or bridging) a closure with functionalized siloxane polymers designed to
`
`surface react with the closure under certain conditions.
`
`12. Claim 17 which is dependent on claim 1 states "[t]he sterile
`
`pharmaceutical composition in a container according to claim 1, wherein the
`
`closure is coated with a material inert to propofol." Claim 18 is also dependent on
`
`claim 1 and states "[t]he sterile pharmaceutical composition in a container
`
`4
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`according to claim 1, wherein the closure consists essentially of a material that is
`
`itself inert to propofol." The term "inert" has been defined earlier in the patent
`
`(col. 4, lines 47-51 and col. 8, lines 39-43) to mean that the closure itself is non(cid:173)
`
`reactive to propofol such that it does "not cause significant degradation or loss in
`
`potency of the propofol formulation." As recognized by the patentee, in the
`
`presence of 10% soybean oH all closures were non-reactive with propofol, hence
`
`inert. (See col. 27, lines 4-7). At lower levels of soybean oil, siliconized, Teflon
`
`and metal closures are inert. (See col. 9, lines 43-46 and col. 10, Jines 4-5.)
`
`13. The 1997 PDR entry for Diprivan 1% Injectable Emulsion, attached
`
`hereto as Exhibit 1005, teaches that Diprivan is a sterile pharmaceutical
`
`composition of propofol. The propofol concentration is 10 milligrams per
`
`milliliter (equivalent to 1% weight by volume, within the claimed range of 0.5% to
`
`10%), and the lipid component (solvent) is soybean oil at a concentration of 100
`
`milligrams per milliliter (1 0% weight by volume, within the claimed range from
`
`about 0 to about 10%). The formulation also contains other excipients with
`
`specified concentrations. This sterile formulation is isotonic and has a pH of 7-8.5.
`
`This formulation is packaged in ampules (glass), infusion vials (also glass, 2 sizes)
`
`and pre-filled syringes. Although there are no descriptions of the pre-filled syringe
`
`5
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`packaging materials, the infusion vials (containers) are supplied with a rubber
`
`stopper (closure).
`
`14. While the PDR entry does not describe the use of a bromobutyl rubber
`
`stopper for propofol sterile injectable emulsion, other prior art references clearly
`
`show that Diptivan used such a closure. A journal article from 1994, R. Fatinotti,
`
`"Physio-chemical Interactions and Storage ofDiprivan," Ann. Fr. Anesth. Reanim.,
`
`1994, at p. 454, teaches that the rubber stopper used on Diprivan is specifically a
`
`bromobutyl rubber.
`
`("Farinotti") (Exhibit 1 006). A cettified English-language
`
`translation of Farinotti is attached as Exhibit 1007. Additional references from a
`
`manufacturer of Diprivan confirm this information. A manufacturer acknowledged
`
`in 1996 that "the bung of the vials is an elastomeric formulation of 100%
`
`bromobutyl rubber .... " (Internet web page for Diprivan® discussing Diprivan®
`
`"Common Clinical Questions", item 2, "Does DIPRIV AN contain Latex?")
`
`(Exhibit 1008.)
`
`15.
`
`In Example 34 of the '010 patent, Diprivan was tested by the
`
`applicants' shaker test with the result that the concentration relative to the control
`
`(HPLC value prior to shaking) was 99.3%. This is the same test described in claim
`
`1 and commercial Diprivan meets the 93% acceptance criterion stipulated in the
`
`claim. In Example 37 of the '010 patent, a formulation identical to Diprivan (10%
`
`6
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`soybean oil and 1.2% lecithin, with a bromobutyl rubber stopper) was exposed to
`
`accelerated stability conditions (40 oc and 75% relative humidity for 2 months).
`
`The recovery of propofol for this formulation was also good, 96.8%. This shows
`
`that in the presence of 10% soybean oil, the bromo butyl rubber stopper is non(cid:173)
`
`reactive to propofol.
`
`Indeed, the patentee explains in the '010 Patent "at the
`
`relatively high volume of soybean oil used in prior art formulations, the soybean
`
`oil apparently protects propofol from degradation" (see col. 3, lines 63-66) and that
`
`prior art formulations containing 10% soybean oil prevent "propofol degradation in
`
`the absence of non-reactive or inert closures .... " (See col. 27, lines 4-7). Thus,
`
`the patentee explains that regardless of the closure selected, all choices will be
`
`non-reactive to propofol at 10% soybean oil.
`
`16. The shaker test used by the applicant as a measure of formulation
`
`stability was well-known in the literature. This test, like others, is used in the
`
`industry during development, and is intended to be a predictor for actual long-term
`
`stability testing to be submitted to the FDA. Han specifically used this test (300
`
`cycles per minute for 16 hours at room temperature) to investigate propofol
`
`formulations including Diprivan.
`
`Jihong Han et a!. , Physical properties and
`
`stability of two emulsion formulations of propofol, 215 Nos. 1-2, International J. of
`
`7
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`Pharmaceutics 207-20 (Mar. 14, 2001) ("Han") (Exhibit 1009). Under the
`
`conditions specified in Han, Diprivan retained emulsion stability.
`
`17. Consistent with the examples presented by the patentee on Diprivan,
`
`Farinotti (page 454) shows that Diprivan, as an approved pharmaceutical product,
`
`has good stability: "[t]he storage in diverse conditions (ampoules, vials) at an
`
`ambient temperature (25 °C) for three years did not show any changes in the
`
`characteristics of the drug." Additionally, Farinotti confirms that Diprivan is
`
`packaged with a bromobutyl stopper: "we note good stability of Diprivan and a
`
`lack of adsorption of propofol on bromobutyl stopper. There is no interaction
`
`between the stopper and the lipid emulsion."
`
`18. US patent 5,114,794 to Sudo et al. ("Sudo"), attached hereto as
`
`Exhibit 1010, teaches the preparation of rubber stoppers, including bromobuty 1
`
`(designated as "BIIR") (coL 8, lines 17-1 8), with modified surface treatments
`
`including polysiloxane (i.e., siliconized rubber). (Col. 2, lines 24-31; col. 6, lines
`
`3-18; col. 6, lines 36-42; see, e.g. , Example 8, shown in Table 1, made using
`
`modified polysiloxanes B-3 and C-4, respectively; col. 17, lines 16-40; col. 18, line
`
`55 - col. 19, line 10.) These coatings provide "excellent heat resistance as well as
`
`lubricity that it can readily be fitted to instruments or machines," (col. 2, lines 18-
`
`20). "The coated rubber article of the present invention can be used as a medical
`
`8
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`rubber stopper for a powdered preparation, freeze-dried medicament or liquid
`
`injection medicament," (col. 9, lines 49-53). Diprivan ts a liquid injection
`
`medicament.
`
`19. Knowing the prior art and wanting to make a propofol formulation to
`
`be packaged in a vial, a person of ordinary skill would start by examining the
`
`properties of the existing products, including Diprivan. The prior art clearly
`
`teaches acceptable formulation components (propofol, soybean oil, glycerol,
`
`EDTA, egg lecithin) and packaging components (Type 1 glass and bromobutyl
`
`stopper).
`
`20. As also noted in the '0 10 patent, there were (as of the filing date)
`
`certain bromobutyl rubber stoppers available. The four available options were
`
`uncoated bromobutyl stoppers, silicone oil treat~ed, bonded coating with silicone, or
`
`fluorinated polymer such as Teflon. Uncoated stoppers, neither silicone oil treated
`
`nor bonded coating, while having good properti~es including low propofol reactivity
`
`with 10% soybean oil formulations and low cost, had known issues with regard to
`
`machinability. On automated filling lines, uncoated stoppers would stick to each
`
`other and to the filling line (hopper) assemblies. This would necessitate either
`
`frequent line maintenance (possibly stopping) and/or low line speed. Neither of
`
`these options would be optimal from an operations perspective.
`
`9
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`21. The known solution to these issues, as of the filing date, included
`
`either use of silicone oil which would be sprayed onto the stoppers prior to
`
`charging a line (Smith et al., page S8), or use of a stopper with inherent low
`
`surface friction (such as one with a bonded siliconized or fluorinated polymer (e.g.,
`
`Teflon) coating). 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.).
`
`22. As also noted in the '0 10 patent, the two types of coated or treated
`
`stoppers included "siliconized polymer or Teflon/fluoropolymer coated/treated
`
`closures" (col. 9, lines 45-46). Sudo clearly shows that siliconized (bridged and
`
`bonded) stoppers have low surface friction properties, as measured by differences
`
`in "Sliding Value (kg)," shown in Table 6. Non-treated synthetic rubber (from col.
`
`10
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`23, lines 30-39) showed as much as 80-fold higher surface friction compared to
`
`siliconized synthetic rubber (from col. 25, line 53 through col. 26, line 2). Silicone
`
`coatings were an acceptable and available option for bromobutyl stoppers, as
`
`evidenced by Sudo. Additional coatings included the B2 coating, described in a
`
`West Technical Support Bulletin 1999/013~
`
`11Evaluating B2-Coating as an
`
`Alternative to Silicone Oil11 (26 Jan 1999) (Exhibit 1011). The B2-Coating is
`
`described in this West Technical Support Bulletin as a 11polymerized silicone
`
`coating11
`
`; it is also described as a 11Cross-linkable polydimethylsiloxane coating
`
`applied to the surface of rubber closures II in West Technical Report 2000/026 "B2-
`
`Coating Quantitative Particle Analysis" (11/ 15/00) (Exhibit 1012). This B2
`
`product was made under license from Daikyo (id. ), the assignee of the Sudo patent,
`
`and appears to be a commercial embodiment of the Sudo patent.
`
`23. Given the known formulation stability of Diprivan as evidenced by
`
`the patentee and Farinotti, along with the teachings of Sudo and its commercial
`
`embodiment (including West technical bulletins and reports), a substitution of a
`
`siliconized stopper for an uncoated rubber stopper on a glass vial containing a
`
`propofol formulation containing 10% soybean oil would have been a reasonable
`
`course of action. A person of ordinary skill would have had an expectation of
`
`success with this substitution. Success, in this context, would include fewer
`
`11
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`manufacturing problems compared to uncoated stoppers. It also would have been
`
`expected that this substitution would not have resulted in less stability for the
`
`emulsion nor in increased propofol degradation.
`
`Indeed, the patentee refers to
`
`"siliconized polymers" of the prior art as "inert materials," coL 9, lines 43-46. This
`
`observation reflects the well-known property of silicones, as described in the 1968
`
`Bulletin of the Parenteral Drug Association Vol. 22 (2) page 66: "their chemical
`
`and biological inertness." (See Exhibit 1013.) Also, as noted above, as the patentee
`
`recognized, in the presence of 10% soybean oil~ the stopper should be non-reactive
`
`to propofol.
`
`24. All components will have finite tolerances during the manufacturing
`
`process. U.S patent 5,714,520, attached hereto as Exhibit 1014, which the '010
`
`Patent cites for its characterization of Diprivan, lists the standard amount for
`
`soybean oil in a 1% Diprivan formulation as 1 0.0%. (Exh. 1014, col. 8, lines 43-
`
`52.) During manufacturing and any subsequent analysis, this means that the
`
`soybean oil content must round to that number (including the stated decimal point).
`
`Amounts as low as 9.95% and as high as 10.04% will round to 10.0%. Acceptance
`
`of such variability would be particularly appropriate because an excipient (rather
`
`than an active ingredient) is at issue here. It is possible that wider manufacturing
`
`specifications were accepted by the regulatory agency, but I have seen no evidence
`
`12
`
`Declaration ofThomas Fcinberg.DOCX
`
`Exh. 1002
`
`
`
`of this and would assume this conservative estimate. Given this tolerance, soybean
`
`oil content of 9.95% (less than 10%), would result in no discernible change in
`
`stability of propofol in 1% propofol formulations.
`
`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).
`
`Thomas N. Feinbe g
`
`13
`
`Decl:mnion of fh(>mas Feinl>crg.D( }( ·x
`
`Exh. 1002
`
`
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