UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD. J KYLE BASS and ERICH SPANGENBERG. Petitioner

Transcription

1 UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD J KYLE BASS and ERICH SPANGENBERG Petitioner v. FRESENIUS KABI USA, LLC Patent Owner U.S. B2 Mailed: November 25, 2015 PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,476,010 AND MANDATORY NOTICES UNDER 37 C.F.R. 42.8

2 TABLE OF CONTENTS I. INTRODUCTION... 1 II. SUMMARY OF ARGUMENT... 1 III. MANDATORY NOTICES UNDER 37 C.F.R. 42.8(a)(1)... 2 A. Real Party-In-Interest Under 37 C.F.R. 42.8(b)(1)... 2 B. Related Matters Under 37 C.F.R. 42.8(b)(2)... 3 C. Lead And Back-Up Counsel Under 37 C.F.R. 42.8(b)(3)... 4 D. Service Information Under 37 C.F.R. 42.8(b)(4)... 4 IV. PAYMENT OF FEE UNDER 37 C.F.R V. REQUIREMENTS FOR INTER PARTES REVIEW UNDER 37 C.F.R A. Grounds For Standing Under 37 C.F.R (a)... 4 B. Identification of Challenge Under 37 C.F.R (b) And Statement of Precise Relief Requested... 5 VI. THRESHOLD REQUIRMENT FOR INTER PARTES REVIEW... 6 VII. THE LEVEL OF ORDINARIRY SKILL IN THE ART... 7 VIII. HOW THE CHALLENGED CLAIMS ARE TO BE CONSTRUED... 8 IX. STEMENT OF REASONS FOR RELIEF REQUESTED X. BACKGROUND AND STATE OF THE ART XI. SUMMARY OF 010 PATENT XII. GROUND 1: CLAIMS 1, 13-15,17, 18, 20, AND ARE OBVIOUS OVER THE PRIOR ART OF THE DIPRIVAN PDR, FARINOTTI, AND THE 864 PATENT i

3 XIII. GROUND 2: CLAIMS 1, 13-15,17, 18, 20, AND ARE OBVIOUS OVER THE PRIOR ART OF THE DIPRIVAN PDR, FARINOTTI, AND THE WO 043 PATENT XIV. SECONDARY CONSIDERATIONS, EVEN IF CONSIDERED, FAIL TO OVERCOME THE EVIDENCE OF OBVIOUSNESS XV. CONCLUSION ii

4 CASES CITED Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 (Fed. Cir. 2012), cert denied, 133 S. Ct (2013)...23, 26 Daiichi Sankyo Co. v. Apotex Inc., 501 F.3d 1254 (Fed. Cir. 2007)... 8 KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007)...22, 33 Leapfrog Enters. Inc. v. Fisher-Price Inc., 485 F.3d 1157 (Fed. Cir. 2007) Par Pharm. Inc. v. TWI Pharms., Inc., 773 F.3d 1186, No , 2014 U.S. App. LEXIS (Fed. Cir. Dec. 3, 2014) Richardson-Vicks, Inc. v. Upjohn Co., 122 F.3d 1476 (Fed. Cir. 1997) Zeneca, Inc. v. Shalala, 213 F.3d 161 (4th Cir. 2000) STATUTES, RULES & OTHER AUTHORITIES 35 U.S.C. 102(b)...passim 35 U.S.C. 103(a)...3, U.S.C. 314(a) C.F.R (b)...13 iii

5 EXHIBIT LIST Exhibit Reference # 1001 U.S Declaration of Thomas N. Feinberg, Ph.D 1003 Curriculum Vitae of Thomas N. Feinberg, Ph.D Smith et al., "Siliconization of Parenteral Drug Packaging 1004 Components," 1988, 42 J. of Parenteral Sci. and Tech. (1988 Supp.) 1005 Entry for Diprivan in the Physician's Desk Reference, 51st Edition, 1997, pp. 341, R. Farinotti, "Physio-chemical Interactions and Storage of Diprivan," Ann. Fr. Anesth. Reanim., 1994 (French 1007 Publication) Certified English-LanguageTranslation of Exhibit August 3, 2001 Web page for Diprivan FAQs Han et al., "Physical properties and stability of two emulsion 1009 formulations of propofol," Int'l J.of Pharmaceutics, 215 (2001) U.S. Patent No. 5,383, West Technical Support Bulletin 1999/013, "Evaluating B2- Coating as an Alternative to Silicone Oil," January 26, West Technical Report 2000/026, "B2-Coating Quantitative Particle Analysis," November 15, 2000 "Siliconization: As Applied to Containers and Closures," 1013 Bulletin of the Parenteral Drug Association, Vol. 22, No. 2 March/April U.S. Patent No. 5,714, Complaint from Civil Action No. 14-cv RGA (D. Del.), Dkt. 1 (filed February 6, 2014) 1016 Waiver of Service of Summons from Civil Action No. 14-cv RGA (D. Del.), Dkt. 5 (filed March 10, 2014) 1017 September 6, 2007 Response to Office Action, U.S. Serial No. 10/616, July 13, 2012 Office Action, U.S. Serial No. 10/616, December 16, 2010 Response to Office Action, U.S. Serial No. 10/616,709 iv

6 1020 February 4, 2013 Response to Office Action, U.S. Serial No. 10/616, May 15, 2013 Interview Summary, U.S. Serial No. 10/616, May 15, 2013 Notice of Allowability and Examiner's Amendment, 1023 U.S. Excerpts Serial from No. "Plaintiff 10/616,709 Fresenius Kabi USA, LLC's Opening Claim Construction Brief" in Civil Action No. 14-cv RGA 1024 (D. Webster's Del.) Third New International Dictionary (2002) selected page 1025 Colas, "Silicones in Pharmaceutical Applications," Dow Corning Healthcare Industries (2001) 1026 Hawley's Condensed Chemical Dictionary (13th ed. 1997) 1027 Dutch Diprivan Registration, 10 mg SmPC RVG Certified English-Language Translation of Exhibit Excerpts from file history of U.S. Patent No. 6,576,245 (Lundgren et al.) 1030 Declaration of Peggy Frandolig with attached Exhibits A and B (Exhs. 1011, 1012) Publication WO (Lundgren) 1032 In re Cuozzo Speed Techs., LLC, No , 2015 U.S. App LEXIS 1699, Slip. Op. at 16, 19 (Fed. Cir. Feb. 4, 2015) U.S. Patent No. 2,649, U.S. Patent No. 3,958, U.S. Patent No. 3,464, U.S. Patent No. 2,652,182 v

7 I. INTRODUCTION J Kyle Bass and Erich Spangenberg (collectively, "Petitioner") requests inter partes review of claims 1, 13-15, 17, 18, 20, and of U.S. Patent No. 8,476,010 ("the '010 Patent") (Exh. 1001). II. SUMMARY OF ARGUMENT Propofol, the subject pharmaceutical of the 010 Patent, is a well-known intravenous anesthetic agent that was first approved for marketing in the United States in 1989 and is sold under the proprietary name of Diprivan. Specifically, the '010 Patent is directed to a propofol formulation that is stored in containers having non-reactive, or inert closures (Exh col 1:8-10). Likewise, the nonreactive closures claimed by the 010 Patent as siliconized rubber stoppers, were also very well known at the time of the alleged invention. In addition to being inert toward the contents of pharmaceutical containers (see, e.g., U.S. 2,649,090 to Parsons, Ex. 1033) non-reactive closures, such as, specifically, siliconized butylrubber stoppers were known to have significant advantages over unsiliconized stoppers, exhibiting such desirable characteristics as such as lubricity (see, e.g., U.S. 3,958,572 to Lawhead, Exh. 1034), resistance to moisture transfer (see, e.g. U.S. 3,464,414 to Sponnoble, Exh. 1035) and ease of manufacture (see, e.g. U.S. 2,652,182 to Umbdenstock, Exh. 1036). These important advantages permitted siliconized stoppers, inter alia, to be used with a wide variety of pharmaceutical - 1 -

8 composition due to their inert characteristics, to be more easily inserted into and removed from containers, and to be manufactured more efficiently. Such design advantages provided ample motivation to modify prior art to replace unsilconized stoppers with siliconized stoppers. This minor and routine substitution would have been readily obvious to a person of ordinary skill in the art ("POSA") and not at all outside the realm of routine experimentation or design optimization. There would have been a reasonable expectation of being able to use such closures successfully in a propofol container system without extraordinary testing and research. III. MANDATORY NOTICES UNDER 37 C.F.R 42.8(a)(1) A. REAL-PARTY-IN-INTEREST UNDER 37 C.F.R 42.8(b)(1) Pursuant to 37 C.F.R. 42.8(b)(1), Petitioner certifies the following information: Other than J Kyle Bass and Erich Spangenberg, no other person (including any entity) has authority to direct or control (i) the timing of, filing of, content of, or any decisions or other activities relating to this Petition or (ii) any timing, future filings, content of, or any decisions or other activities relating to the future proceedings related to this Petition. All of the costs associated with this Petition are to be borne by J Kyle Bass and Erich Spangenberg. None of the RPI has any financial interest in any securities of Fresnius Kabi USA or its parent corporation, Fresnius SE & Co KGaA

9 B. RELATED MATTERS UNDER 37 C.F.R. 42.8(b)(2) Patent Owner has asserted the '010 Patent against Dr. Reddy's Laboratories, Ltd., in a litigation (dismissed) in the United States District Court for the District of Delaware. Fresenius Kabi USA, LLC v. Dr. Reddy's Labs., Ltd. et al., RGA (D. Del.) ("the Litigation"). The 010 Patent was also the subject of the below litigations: Fresenius Kabi USA, LLC v. Watson Laboratories, Inc. et al., DED-1-14-cv (Dismissed); Fresenius Kabi USA, LLC v. Emcure Pharmaceuticals USA, Inc. et al., DED cv (Dismissed); Fresenius Kabi USA, LLC v. Emcure Pharmaceuticals USA, Inc. et al., NJD-1-14-cv (Dismissed); Fresenius Kabi USA, LLC v. Agila Specialties Private Ltd. et al., DED-1-14-cv (Dismissed); Fresenius Kabi USA, LLC v. Mylan Laboratories Limited et al., WVND-1-14-cv (Dismissed); Fresenius Kabi USA, LLC v. Claris Lifesciences Ltd. et al., NJD-1-14-cv (Dismissed); Fresenius Kabi USA, LLC v. Claris Lifesciences Ltd. et al., DED-1-14-cv (Dismissed); Petition for Inter Partes Review by Dr. Reddy's Laboratories, Inc., PTAB-IPR (Terminated); Dr. Reddy's Laboratories, Inc. et al v. Fresenius Kabi USA, LLC., DED-1-15-cv (Terminated)

10 C. NOTICE OF LEAD AND BACKUP COUNSEL UNDER 37 C.F.R. 42.8(b)(3) Lead Counsel: Dr. Gregory J. Gonsalves Reg. No. 43, Beacon Lane Falls Church, VA (571) Backup Counsel: Christopher Casieri McNeely, Hare & War LLP 12 Roszel Road, Suite C104 Princeton, NJ Phone: D. NOTICE OF SERVICE INFORMATION UNDER 37 C.F.R. 42.8(b)(4) Please address all correspondence to the lead and backup counsel at the addresses shown above. Petitioner also consents to electronic service by e- mail at: IV. PAYMENT OF FEES UNDER 37 C.F.R The required fees are submitted herewith in accordance with 37 C.F.R (a) and 42.15(a). If any additional fees are due during this proceeding, the Office is authorized to charge such fees to Deposit Account No V. REQUIREMENTS FOR INTER PARTES REVIEW UNDER 37 C.F.R A. GROUNDS FOR STANDING UNDER 37 C.F.R (a) Petitioner certifies that the patent for which review is sought is available for inter partes review, and that Petitioner is not barred or estopped from requesting an inter partes review on the grounds identified in the petition - 4 -

11 because: (1) Petitioner is not the patent owner; (2) Petitioner has not filed a civil action challenging the validity of a claim in the patent; (3) Petitioner has not been served with a complaint alleging infringement of the patent; (4) the estoppel provisions of 35 U.S.C. 315(e)(1) do not prohibit this IPR; and (5) the patent is not described in 3(n)(1) of the Leahy-Smith America Invents Act and so is available for IPR pursuant to 37 C.F.R (a)(2). B. IDENTIFICATION OF CHALLENGE UNDER 37 C.F.R (a) AND STATEMENT OF PRECISE RELIEF REQUESTED Petitioner requests that claims 1, 13-15, 17, 18, 20, and of the '010 Patent be held unpatentable based on the following. IPR of the 010 Patent is requested in view of the following prior art: (1) the 1997 Physician s Desk Reference entry for Diprivan ( Diprivan PDR ) (Exh. 1005); (2) the article entitled "Physio-chemical Interactions and Storage of Diprivan," by Farinotti, Ann. Fr. Anesth. Reanim., 1994, 13: ("Farinotti") (Exh. 1006) 1 ; (3) U.S. Patent No. 5,383,864 to van den Heuvel issued January 24, 1995 ("the 864 Patent") (Exh. 1010); and (4) WO 2000/ to Lundgren et al. issued March 9, 2000 ( the WO 043 Patent ) (Exh. 1031). Each of the publications listed above is available as prior art against the 010 Patent under 1 A certified English-language translation of this French publication is included as Exhibit

12 pre-aia 35 U.S.C. 102(b) because each was published more than one year before July 10, 2003, which is the filing date of the earliest application to which the 010 Patent claims priority. The following combinations of the above-listed publications renders claims 1, 13-15, 17, 18, 20, and of the 010 Patent obvious under pre-aia 35 U.S.C. 103(a): Ground 1. Claims 1, 13-15, 17, 18, 20, and are obvious over the Diprivan PDR, in view Farinotti, and the 864 Patent. Ground 2. Claims 1, 13-15, 17, 18, 20, and are obvious over the Diprivan PDR, in view of Farinotti and the WO 043 Patent. Copies of the documents cited above are all filed herewith. The above grounds for unpatenability are supported by the Declaration of Dr. Thomas N. Feinberg ( the Feinberg Declaration ) (Exh. 1002) also filed herewith. VI. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter - 6 -

13 pertains. 35 U.S.C. 103(a). Underlying factual determinations in an obviousness analysis include (1) the scope and content of the prior art, (2) the level of ordinary skill in the art, (3) the differences between the claimed invention and the prior art, and (4) objective indicia of nonobviousness. See Merck & Co. v. Teva Pharms. USA, Inc., 395 F.3d 1364, 1369 (Fed. Cir. 2005) (citing Graham v. John Deere Co., 383 U.S. 1, (1966)). The scope and content of the prior art, the level of ordinary skill in the art, and the differences between the claimed invention and the art relevant to this Petition are addressed for each statutory ground of rejection upon which this Petition is based. In this regard, Inter Partes Review of the claims identified below is requested on the grounds that these claims are unpatentable for failing to meet the requirements of 35 U.S.C. 103(a). All of the limitations of claims 1, 13-15, 17, 18, 20, and of the '010 Patent are taught or suggested in the prior art and one of ordinary skill in the art would have been motivated to combine the teachings of the cited references with a reasonable expectation of success, as explained in detail below. Copies of the references rendering these claims unpatentable are filed herewith. 37 C.F.R. 42.6(c). VII. THE LEVEL OF ORDINARY SKILL IN THE ART Factors relevant to determining the level of skill in the art include: the educational level of the inventors, the types of problems encountered in the art, - 7 -

14 prior art solutions to those problems, the rapidity with which innovations are made, the sophistication of the technology, and the educational level of active workers in the field. Daiichi Sankyo Co. v. Apotex Inc., 501 F.3d 1254, 1256 (Fed. Cir. 2007). In the field of the alleged invention, a person of ordinary skill in the art at the time of the invention would have been someone with substantial research or industry experience in pharmaceutical drug product development, including experience with sterile drugs and their packaging, and having at least a master's degree or doctorate in a related technical field, such as analytical, physical or organic chemistry, chemical engineering, pharmaceutics or related subject matter or having equivalent experience in such fields. (Exh. 1002, Feinberg Decl. 8.) VIII. HOW THE CHALLENGED CLAIMS ARE TO BE CONSTRUED In inter partes review, a claim term is to be given its "broadest reasonable construction in light of the specification as understood by one of ordinary skill in the art. See 37 C.F.R (b) Claim 1 of the 010 reads as follows: 1. A sterile pharmaceutical composition of propofol in a container, comprising: -a container which includes a closure and a composition in the container, and - 8 -

15 -the composition in the container comprising from 0.5% to 10% by weight propofol and from about 0 to about 10% by weight solvent for propofol, -where when the composition in the container sealed with the closure is agitated at a frequency of cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 93% of the starting concentration (w/v) of the propofol; -where the closure is selected from the group consisting of siliconized bromobutyl rubber, metal, and siliconized chlorobutyl rubber. A. "From About Zero To About 10%" Claim 1 requires that the propofol composition have "from about 0 to about 10% by weight solvent for propofol." The patent owner recently construed this phrase in the Litigation to mean approximately 0 to approximately 10% solvent by weight, including compositions with 10% soybean oil. (See Exh. 1023, at 5 (citing Merck & Co. v. Teva Pharms. USA, Inc., 395 F.3d 1364, (Fed. Cir. 2005)) for the proposition that "about" means "approximately"; id. at 5-6 (asserting that "there is no support in the intrinsic record" for a construction that excludes exactly 10% by weight solvent). To support this construction, the patent owner cited certain intrinsic evidence, including a passage from the specification that states that "the water - 9 -

16 miscible solvent or the water-immiscible solvent is present in an amount that is preferably from 0 to 10% by weight of the composition" (Exh. 1001, at 5:36-38) (Exh. 1023, at 6.) The patent owner also cited portions of the prosecution history in which the examiner amended the term "less than 10% by weight solvent for propofol" (see Exh. 1019, at 2) to "from about 0 to about 10% by weight solvent for propofol" (Exh. 1022, at 2). (Exh. 1023, at 7.) Petitioner accepts the patent owner's position as the broadest reasonable interpretation of the phrase in inter partes review. Accordingly, Petitioner accepts as the broadest reasonable construction for purposes of this proceeding the patent owner's construction of "from about zero to about 10% by weight solvent for propofol" to mean from approximately zero to approximately 10% solvent by weight, a range that includes 10%. The reference to "about 10% by weight solvent," in accordance with the explanation in the patent, is "meant to be weight percent by volume of the composition." (Exh. 1001, 5:33-35.) B. "Siliconized" Although "siliconized" is not defined in the specification or prosecution history of the '010 Patent, its definition is well known, and it means surface-treated or coated with a silicone. (Exh. 1002, Declaration of Thomas Feinberg ("Feinberg Decl.") 10; Webster s Third New Int l Dictionary 2118 (2002) (Exh. 1024, at 2118), defining "siliconize" as "to treat or coat (as with a lens) with a silicone";

17 Colas, "Silicones in Pharmaceutical Applications," Dow Corning Corporation (2001) (Exh. 1025), at 19 ("Siliconisation encompasses the surface treatment of many parenteral packaging components with silicones."); Smith et al., Siliconization of Parenteral Drug Packaging Components, 1988, 42 J. of Parenteral Sci. and Tech. (1988 Supp.) ("Smith et al.") (Exh. 1004), at S4, S8-S9, describing "siliconization" of parenteral drug packaging components by applying silicones.) "Silicone," in turn, refers to polymer substances including siloxanes, and thus having silicon-oxygen-silicon bonds. (Exh. 1002, Feinberg Decl. 10; Exh. 1004, at S12, defining "silicone" as "a general term 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"; Hawley's Condensed Chemical Dictionary 997 (13th ed. 1997) (Exh. 1026), defining "silicone" as "any of a large group of siloxane polymers based on a structure consisting of alternate silicon and oxygen atoms with various organic radicals attached to the silicon."). Accordingly "siliconized," in the context of the challenged claims and the applicable claim construction standard, refers to a closure that is surface-treated, coated, or manufactured with silicone or one or more siloxane polymers. (Exh. 1002, Feinberg Decl. 10.) C. "Inert To Propofol" The phrase "inert to propofol" in challenged claims 17 and 18 means having

18 no significant reactivity to propofol. This interpretation is consistent with how a POSA would have understood this phrase in light of the specification, which uses the terms "inert" and "non-reactive" interchangeably. (Exh. 1002, Feinberg Decl. 12; Exh. 1001, at 1:8-10 ("the invention pertains to propofol formulations that are stored in containers having non-reactive, or inert closures"); see also id. 3:63-4:2, 4:47-48, 8:41-42.) As the specification further explains, an "inert" closure does not cause "significant" degradation of the propofol formulation. (Id. at 4:46-50.) Thus, in the context of the '010 Patent, "inert" means having no significant reactivity to propofol. (Exh. 1002, Feinberg Decl. 12.) IX. STATEMENT OF REASONS FOR RELIEF REQUESTED In the specification of the '010 Patent and during patent prosecution, the patentee focused on the putative instability of propofol formulations containing less than 10% of a soybean oil solvent when exposed to some uncoated rubber stoppers. But because the challenged claims include solvent concentrations of 10%, the instability problem identified by the patentee is not pertinent to the challenged claims. As the '010 Patent admits, at 10% w/v of soybean oil, propofol formulations, including commercial Diprivan, are completely stable with different types of stoppers. Thus, there is no stability "problem" to be solved. Given that a POSA would have had ample motivation to replace the Diprivan unsilconized stopper with a siliconized version for reasons separate and apart from stability (e.g

19 ease of insertion, ease of manufacture, etc.), the use of a different stopper was readily obvious and an unpatentable modification. Furthermore, given the relatively small number of available closure options, it would have been obvious to try any one of them and it would have been reasonable to expect that siliconized rubber stoppers would prove successful. X. Background and State of the Art The '010 Patent confirms that commercial Diprivan was previously well known and exhibited several features claimed in the 010 Patent at the time of filing (Exh. 1001, 2:33-39). A Diprivan formulation was described in prior art U.S. Patent No. 5,714,520 ("the '520 Patent") (Exh. 1014) as a sterile propofol emulsion containing 1% propofol w/v and 10% soybean oil w/v, along with other excipients. (Exh. 1001, 2:33-39; Exh. 1014, 7:5-15; Exh. 1002, Feinberg Decl. 24.) The '520 Patent also discloses other claimed elements of the 010 Patent, including that the composition is sterile (Exh. 1014, 4:38-39) and that it may be packaged in 50 ml or 100 ml vials (id., 7:65-67). The 010 Patent also claims a requirement for propofol stability based on an accelerated stability test. Diprivan had already met that test at the time of filing. (Exh. 1002, Feinberg Decl. 15; Exh. 1001, 25:15-32.) As reported in example 34 of the '010 Patent, the patentee tested "[c]ommercially available Diprivan," containing 10% soybean oil, 1.2% lecithin, 1% propofol and a "Rubber 1" stopper,

20 made of bromobutyl rubber. (Id at 23:51, 25:27-37.) Diprivan exhibited 99.3% retention of propofol following shaking in its container at a frequency of cycles/minute for 16 hours -- the same accelerated stability test recited in the claims (Id., 23:21-34, 25:10-31). Further, this test methodology was known in the prior art. (Han et al., "Physical properties and stability of two emulsion formulations of propofol," Int'l Journal of Pharmaceutics, 215 (2001) , at 217 (Exh. 1009); Exh. 1002, Feinberg Decl. 16.) A registration document for a 1% Diprivan product in the Netherlands similarly stated that the product had at least three years of shelf stability. (Exh. 1028, at 13 and at 12, Section ) Because Diprivan, in the real world, was stable for several years, the patentee's reliance on an arbitrary test that merely simulates actual stability (Exh. 1001, 4:51-58, 27:45-52) cannot make the composition any more stable for physician or patient use, or confer patentability. 2 Exh is a certified English-language translation of Exh. 1027, a Dutch registration document for Diprivan, stating that the product registration in the Netherlands was issued on December 5, (Exh. 1028, at 13.) This document was obtained from the drug information database of the Dutch Medicines Authority, publicly available at which is updated on a weekly basis with new registrations

21 Regarding the supposed invention of the use of a siliconized rubber stopper, as far back as 1950, U.S. Patent No. 2,649,090 recognized the utility of siliconizing rubber stoppers in order to provide a surface sealing substance on the rubber stoppers to render the rubber more inert towards the contents of vials useful in pharmaceutical work (Exh col 1:18-21 and col 3:47). Other advantages delineated in the art included ease of manufacture, better sealing of closed containers, reduce moisture permeability, greater lubricity, and the ability of the stoppers to be sterilized (Exh col 1: 9-27, col 2:46-49). U.S. 2,652,182 (Exh. 1036) issued in 1953 taught siliconized rubber stoppers having improved properties which [are] adapted for use in machines for automatically and mechanically stoppering vials or bottles. In particular, to rubber stoppers having improved properties and which are adapted for use in packaging certain drugs and therapeutic materials in bottles or vials under sterile conditions (Exh col 1:4-9) The improvement was accomplished by a lubricating coating of a polymeric silicone on the surface of the rubber (Exh col 2:3-11 and col 3:40-45) The siliconized rubber stoppers exhibited ease of manufacture (i.e. they did not stick together during production runs) and were easier to assemble into the final pharmaceutical bottle or vial. (Exh ). In 1968, the art recognized that "rubber closures may also be siliconized to provide 'machinability' in order to maintain economical rates of production." (Exh

22 1013, at 69, Abstract.) Similarly, Smith taught in 1988 that "[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." (Exh. 1004, at S4; Exh. 1002, Feinberg Decl. 21.) A Dow Corning article published in 2001 likewise taught the siliconization of parenteral packaging components, such as stoppers, "to ease machinability." (Exh. 1025, at 19, 22.) The West publications noted the "benefits" of "lubricity and processability" conferred by siliconized closures such as the B2. (Exh ) Thus, the art recognized that siliconization was known to provide improved economical rates of production, reduced clumping and a reduction in other costly line disruptions that might occur with unsiliconized stoppers. (Exh. 1002, Feinberg Decl ) Smith confirms an additional advantage of siliconization, noting that it "lowers the friction between the vial and the closure. This decrease in friction reduces the force necessary to insert vial stoppers properly." (Exh. 1004, at S4; Exh. 1002, Feinberg Decl. 21.) Smith also notes that sealability -- the integrity of the closure seal -- "is improved by siliconization of the closure." (Exh. 1004, at S4; Exh. 1002, Feinberg Decl. 21.) In 1969 U.S. Patent 3,464,414 indicated that butyl rubber stoppers, specifically, were amenable to siliconization in order to prevent[] moisture

23 transmission to a pharmaceutical composition as well as to increase lubricity by exhibiting easy displacement of the butyl plug that was siliconized (Exh Abstract and col 1:14-17). Further as to the bromobutyl rubber stopper, a manufacturer of commercial Diprivan acknowledged that "the bung of the vials is an elastomeric formulation of 100% bromobutyl rubber..." (Exh. 1008, Internet web page for Diprivan discussing Diprivan "Common Clinical Questions", item 2, "Does DIPRIVAN contain Latex?") 3 (Exh. 1002, Feinberg Decl. 14.) The well-known property of silicones, were described in the 1968 Bulletin of the Parenteral Drug Association Vol. 22 (2), page 66: "their chemical and biological inertness." (Exh. 1013, at 66; see also, Exh. 1025, at 8 (noting "low chemical reactivity displayed by silicones").) The patentee's testing showed that, inherently, the 10% soybean oil in prior art formulations prevents propofol degradation, supporting a reasonable expectation that known, inert, siliconized 3 Exh was an Internet web page publicly available prior to The Web archive shows that it was available at least by August 3, (Exh ) Furthermore, during prosecution of U.S. Patent No. 6,576,245 (effective filing August 24, 1999), Astra Zeneca, a marketer of Diprivan, submitted Exh as prior art, and the examiner initialed the reference as available in (Exh )

24 stoppers used with such a formulation would provide acceptable stability or more succinctly, not interfere with known stability profiles. (Id., 27:4-7; see also id., 3:63-66; Exh. 1002, Feinberg Decl. 15, 23.) All of the information described above would have been known or readily accessible by a person of ordinary skill in the art at the time of the invention. (Exh. 1002, 10-24). XI. SUMMARY OF THE '010 PATENT A. The Prosecution History Of The '010 Patent The '010 Patent underwent ten years of prosecution, during which the patentee repeatedly argued that the inert closure of its alleged invention distinguished the claims over the prior art. (See, e.g., September 6, 2007 Response (Exh. 1017), at ) For nearly a decade, the examiner rejected those contentions. (See, e.g., July 13, 2012 Office Action (Exh. 1018), at 5.) In the interim, the patentee amended the solvent limitation of application claim 1 (which became claim 1 of the '010 Patent), by modifying the original phrase "less than about 10% by weight solvent for propofol" to recite "less than 10% by weight solvent for propofol." (Dec. 16, 2010 Amendment (Exh. 1019), at 2.) This amendment, however, also did not result in allowance of the claims. On February 4, 2013, the patentee amended application claim 1 to require

25 that the closure be "selected from the group consisting of siliconized bromobutyl rubber, a non-rubber selected from the group consisting of metal, plastics, and mixtures thereof, and siliconized chlorobutyl rubber." (February 4, 2013 Response (Exh. 1020), at 2.) During an April 30, 2013 interview, the examiner stated that if this proposed claim eliminated "plastic" closures, it would be allowable. (May 15, 2013 Interview Summary (Exh. 1021), at 6.) According to the examiner, although one of the cited references disclosed inert Fluorotec coatings, it did not disclose other inert materials for the closure that the claims recited, such as siliconized rubber. (Id.) The examiner issued a Notice of Allowability on May 15, 2013, allowing all pending claims based on an Examiner's Amendment in which the term "plastic" was removed from the closure limitation of claim 1. (May 15, 2013 Examiner's Amendment (Exh. 1022), at 2.) The amendment also changed the phrase "less than 10% by weight solvent for propofol" to "from about 0 to about 10% by weight solvent for propofol." (Id.) The applicants did not object to these amendments, and in fact approved them. (Id.) The patent issued on July 2, It is clear from this prosecution history that the claim amendments requiring siliconized rubber or metal stoppers were what resulted in allowance of the claims. B. The Specification of The '010 Patent The '010 Patent is directed to a propofol formulation in a container (a vial or

26 syringe) having a closure. As the specification explains, because propofol is waterinsoluble, prior art propofol compositions, including commercial Diprivan, commonly used 10% soybean oil as a solvent for the propofol. (Exh. 1001, 1:20, 2:33-36, 25:10-46.) According to the patentee, however, it was known that using 10% soybean oil created a risk of hyperlipidemia in some patients undergoing long-term sedation. (Id., 2:5-19.) This created a motivation in the prior art to try reduced levels of oil. Neither this problem, nor the idea of reducing the amount of soybean oil, was discovered by the inventors of the 010 patent. (Id., 1:66-2:4.) The patentee reportedly learned that propofol compositions with low soybean oil content (from 0-5% soybean oil) degraded to varying degrees when stored in containers having certain bromobutyl rubber stoppers. (Id. at 3:45-4:2, 25:27-37.) The patentee's proposed solution was simply to try a different known stopper. (Id. at 3:59-4:2, 4:47-58.) Existing stoppers included those coated or treated with inert materials such as silicone polymer or Teflon/fluoropolymer. (Id. At 9:43-46.) Among siliconized stoppers, siliconized bromobutyl rubber and siliconized chlorobutyl rubber stoppers were noted as suitable and claimed. (Id. At 9:46-52.) The patentee also claimed nonreactive metal stoppers. (Id. at 10:4-10.) In a series of experiments memorialized in Examples 31-34, the patentee tested propofol formulations free of soybean oil and reported that they exhibited instability when stored in vials with halogenated, uncoated rubber stoppers. (Id. At

27 23:16-25:45.) These tests used an accelerated stability technique involving shaking of the container at a rate of cycles/minute for 16 hours to test for propofol degradation. (Id. at 23:21-34, 25:20-24.) Improvements in stability (i.e., less propofol degradation) were observed when propofol formulations containing 3% soybean oil were used. (Id., Example 33, 24:37-61.) Indeed, for some propofol formulations, acceptable stability was achieved even with low levels of oil despite the use of conventional, uncoated bromobutyl rubber stoppers. (Id. (93% or better stability for "Rubber 2" and "Rubber 3" bromobutyl stoppers).) Only one particular bromobutyl rubber stopper, identified as "Rubber 1," had unacceptable stability. In Example 34, the patentee compared the stability of commercially available Diprivan having 10% soybean oil with other formulations having 5% soybean oil or less, when exposed to the Rubber 1 bromobutyl rubber stopper. A formulation with no soybean oil (0%) was reported to have 77% propofol degradation. At 3% soybean oil, the patentee reported 47% degradation, and at 5% soybean oil, it reported 17% degradation. (Id. at 25:27-37.) At 10% soybean oil, i.e., for commercially available Diprivan, there was virtually no Degradation -- more than 99% of propofol was retained. (Id., 25:32, 25:37.) No tests were conducted for any formulation containing soybean oil at levels between 5 and 10%. These examples confirm that Diprivan, having 10% soybean oil, was stable regardless of the type of stopper that was used. (Id., 25:38-39 "The data shows that

28 the oil in the formulation protected propofol from degradation.") Some halogenated rubber stoppers, on the other hand, were found to destabilize propofol formulations containing 5% soybean oil or less. If and when this occurred, however, the patent taught that it could be addressed by merely using a different closure, such as a different bromobutyl rubber stopper or one that had been coated with, for example, silicone or Teflon. (Id., 9:43-46, 24:10-61, Exhs. 32, 33.) XII. Ground 1: Claims 1, 13-15, 17, 18, 20, and are Obvious over the prior art of the Diprivan PDR, Farinotti, and the 864 Patent. The obviousness inquiry is a question of law based on four factual predicates: (1) "the scope and content of the prior art," (2) the "differences between the prior art and the claims at issue," (3) "the level of ordinary skill in the pertinent art," and (4) "secondary considerations" such as "commercial success, long felt but unsolved needs, failure of others, etc." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, (2007) (citing Graham v. John Deere Co., 383 U.S. 1, (1966)); (a). KSR reaffirmed that "[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." KSR, 550 U.S. at 416. "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 U.S. App. LEXIS 22737, at *24 (Fed. Cir. Dec. 3, 2014) (citations omitted). Thus, for

29 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 (2013)). A. The Prior Art of the Diprivan PDR and Farinotti The differences between claim 1 and the prior art are minor. Virtually all elements of claim 1 were present in prior art describing a commercially available Diprivan product. The Diprivan PDR (Exh. 1005), was not of record during prosecution of the 010 Patent application. It describes Diprivan as a sterile pharmaceutical composition of propofol, in either 50 or 100 ml vials that have rubber stoppers (Exh. 1005, at 2939, 2945) thus meeting the requirement of a sterile pharmaceutical composition of propofol in a container that includes a closure. (Exh. 1002, Feinberg Decl. 13.) The composition described contains 10 mg/ml of propofol (i.e., 1% propofol by weight/volume), which is within the 0.5% to 10% range claimed. (Exh. 1005, at 2939; Exh. 1002, Feinberg Decl. 13.) Further, the propofol in Diprivan is carried in 100 mg/ml of soybean oil, i.e., 10% solvent w/v, which is within the claimed range of "from about 0% to about 10%" for the solvent (id., at 2939). (Exh. 1002, Feinberg Decl. 13.) The stability of Diprivan, as shown by the claimed shaker test or otherwise, is an inherent property of the prior art that the patentee observed and confirmed through testing. Nevertheless, the shaker test as described was well known to

30 POSA at the time of the invention as described above (Exh. 1002, 15-16). Accordingly, it does not distinguish the claims from Diprivan PDR nor confer patentability. Par Pharm., 2014 U.S. App. LEXIS 22737, at *18, (claim limitation may be established by inherency in obviousness analysis where "the patent itself defined the limitation at issue as a 'property that is necessarily present'" or the feature is the "natural result" of the combination of prior art elements) (citations omitted). The patentee's observations were also consistent with the prior art. Farinotti taught that Diprivan, as an approved pharmaceutical product, had excellent shelf stability and, in fact "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." (Exh. 1007, at 454; Exh. 1002, Feinberg Decl. 17.) Furthermore, based on its testing of the prior art, the patentee explained that prior art formulations containing 10% soybean oil inherently prevent "propofol degradation" even "in the absence of non-reactive or inert closures..." (id., 27:4-7; see also id., 3:63-66). Thus, the formulations remain stable and non-reactive regardless of the closure selected. (Exh. 1002, Feinberg Decl. 15.) This is further confirmation that commercial Diprivan, with 10% soybean oil, inherently met the accelerated stability requirement as indicated above. While the Diprivan PDR does not identify the particular type of rubber used

31 for the closure, Farinotti recognized that the closures used with commercially available Diprivan were bromobutyl rubber stoppers. (Exh 1007, at 454; Exh. 1002, Feinberg Decl. 14.) Farinotti, therefore, teaches a brombutyl rubber stopper for use in as a closure in a container of a pharmaceutical composition of propofol. B. The Prior Art 864 Patent Thus, the only difference between claim 1 and commercial Diprivan, as reflected in the Diprivan PDR entry in view of Farinotti, is the type of rubber stopper used. While commercial Diprivan used a bromobutyl rubber stopper according to Farinotti, the claims require the use of a siliconized bromobutyl rubber stopper. The substitution of one known rubber stopper for another, however, was entirely obvious. The 864 Patent, which was not of record during prosecution teaches a pharmaceutical composition in a container with a closure as a pre-filled injection device comprising a pharmaceutical formulation stored in prolonged contact with at least one rubber sealing member (Exh col 2:40-46). The 864 Patent further taught the closure is siliconized bromobutyl rubber: Rubber stoppers are pretreated in the conventional manner by washing, siliconizing and sterilizing. The barrel is then dispensed with the above diazepam formulation and sealed at each end by means of the rubber stoppers. For the experiments three types of rubber are

32 compared with each other, namely chlorobutyl rubber (Cl-bu), and two qualities of bromobutyl rubber: Br-bu 1 and Br-bu 2. (Exh. 1010, col 4:61-5:1). The 864 Patent further taught the siliconized bromobutyl rubbers impart a stable solution over time. (Exh. 1010, col 5. Table A and Table B for Br-bu 1 and Br-bu 2 ). C. There Was Ample Motivation To Substitute A Siliconized Bromobutyl Rubber Stopper For The Bromobutyl Rubber Stopper Of Commercial Diprivan The 864 Patent specifically explained that the art desired to develop a liquid pharmaceutical composition wherein the formulation can be stored in prolonged contact with at least one rubber sealing member without unacceptable deterioration in quality of the said formulation taking place. (Exh col 2:43-46) As the 864 Patent taught, and as explained by Dr. Feinberg, its siliconized bromobutyl rubber closures fulfilled this desire by providing an inert sealing member that did not react with the pharmaceutical contained therein. (Exh. 1002, 18) In addition, the art discussed above as state of the art repeatedly explains the advantages of siliconized products, advantages relevant to anyone manufacturing a sterile packaged propofol formulation. These known advantages (e.g. improved machinability, processing efficiencies, and ease of insertion or lubricity) would have provided a POSA ample motive, albeit possibly a different motive than the patentee, to modify the commercial Diprivan packaging by substituting siliconized bromobutyl stoppers. Alcon, 687 F.3d at 1369 ("the

33 motivation to modify a prior art reference to arrive at the claimed invention need not be the same motivation that the patentee had"). These other known design incentives would have likewise motivated persons of skill in the art to use siliconized bromobutyl rubber closures for commercial Diprivan as discussed above. Thus, there were long recognized advantages to the use of siliconized rubber stoppers that would have motivated a POSA to replace non-siliconized versions with siliconized bromobutyl rubber stoppers. D. A Person of Ordinary Skill In The Art Would Have Had A Reasonable Expectation Of Success The above discussion establishes that siliconized rubber stoppers, including siliconized bromobutyl rubber stoppers, were known. There were also very good reasons to use them in propofol packaging instead of unsiliconized bromobutyl rubber stoppers. And assuredly, a POSA would have had a reasonable expectation that in substituting siliconized bromobutyl rubber stoppers for their unsiliconized counterparts, one would achieve the improved machinability, processing efficiencies, and ease of insertion for which they were specifically designed. (Exh. 1004, at S4; Exh. 1002, Feinberg Decl , 23.) Nor would siliconizing the stopper be expected to negatively impact any of the other features of Diprivan. Diprivan was inherently more than 99% stable. The use of a siliconized bromobutyl stopper would have been expected to provide at

34 least equivalent stability, because silicone was known to be a non-reactive material and would not increase propofol degradation. (Exh. 1002, Feinberg Decl. 23; Exh. 1013, at 66, 69; Exh. 1001, 9:43-46.) Indeed, as the patentee recognized, "siliconized polymers" of the prior art were "inert materials." (Exh. 1001, 9:43-46.) Accordingly, such a modified system would be expected to meet the stability limitation of claim 1, just as the prior art Diprivan system did. (Exh. 1002, Feinberg Decl. 23.) A chart summarizing the foregoing analysis appears below: The 010 Patent Diprivan PDR, Farinotti, and the 864 Patent 1. A sterile pharmaceutical The Diprivan PDR entry (Exh. 1005) composition of propofol in a taught a sterile pharmaceutical container, comprising: composition of propofol in a vial (50 or 100 ml) having a rubber stopper. (Exh. 1005, at 2939, 2945; Exh. 1002, Feinberg Decl. 13.) a container which includes a closure and a composition in the container, and the composition in the container comprising from 0.5% to 10% by weight propofol and from about 0 to about 10% by weight solvent for propofol, The Diprivan PDR entry taught Diprivan as being a propofol composition available in either a 50 or 100 ml vial (container) having a rubber stopper (closure). (Exh. 1005, at 2939, 2945; Exh. 1002, Feinberg Decl. 13.) The Diprivan PDR entry taught Diprivan as having 10 mg/ml of propofol (i.e., 1% propofol by weight/volume). (Exh. 1005, at 2939; Exh. 1002, Feinberg Decl. 13.) The propofol is carried in 100 mg/ml of soybean oil,

35 (The '010 Patent explains that "all references to weight percent are meant to be weight percent by volume of the composition." ('010 Patent, 5:33-35).) i.e., 10% solvent w/v. (Exh. 1005, at 2939; Exh. 1002, Feinberg Decl. 13.) where when the composition in the container sealed with the closure is agitated at a frequency of cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 93% of the starting concentration (w/v) of the propofol; The composition of the Diprivan PDR entry maintained 99.3% of its original propofol concentration following shaking in its sealed container at a frequency of cycles/minute for 16 hours at room temperature. (Exh. 1001, 23:21-32, 25:15-31 (noting that "[c]ommercially available Diprivan" was tested according to the method "described above," i.e., the method of Example 31); see also id., 3:63-66, 27:4-7; Exh. 1002, Feinberg Decl. 15.) Farinotti also taught that Diprivan, an approved pharmaceutical product, was stable for three years when stored in vials at room temperature and "did not show any changes in the characteristics of the drug." (Exh. 1007, at 454; Exh. 1002, Feinberg Decl. 17.) Farinotti taught commercial Diprivan uses a bromobutyl rubber stopper. (Exh 1007, at 454.) where the closure is selected from the group consisting of siliconized bromobutyl rubber, metal, and siliconized chlorobutyl rubber. The 864 Patent taught a pharmaceutical composition in a container with a closure as a pre-filled injection device comprising a barrel, wherein a liquid diazepam formulation can be stored in

36 prolonged contact with at least one rubber sealing member (Exh. 1010, col 2:40-46). The 864 Patent further taught the closure is siliconized bromobutyl rubber. Rubber stoppers are pretreated in the conventional manner by washing, siliconizing and sterilizing. The barrel is then dispensed with the above diazepam formulation and sealed at each end by means of the rubber stoppers. For the experiments three types of rubber are compared with each other, namely chlorobutyl rubber (Cl-bu), and two qualities of bromobutyl rubber: Br-bu 1 and Br-bu 2. (Exh. 1010, col 4:61-5:1) The 864 Patent further taught the siliconized bromobutyl rubbers impart a stable solution over time. (Exh. 1010, col 5. Table A and Table B for Br-bu 1 and Br-bu 2 ) E. Dependent Claims 13-15, 17, 18, 20, and Claim 13 is dependent on independent claim 1 and requires the solvent to be a water-immiscible solvent while claims 14 and 15 further limits the waterimmiscible solvent to soybean oil. The Diprivan PDR teaches soybean oil as a solvent, which is a water-immiscible solvent. (E.g., Exh. 1005, at 2939; Exh. 1002, Feinberg Decl., 13; Exh cl.15 ("the water-immiscible solvent is soybean oil").) Claim 17 is dependent on independent claim 1 and requires that the closure

37 be coated with a material inert to propofol. The 864 Patent teaches the closure coated with a material inert to propofol since the siliconized coating of the bromobutyl rubber stoppers disclosed by the 864 Patent are inert to propofol. (Exh. 1002, Feinberg Decl. 18, 22-23; Exh. 1013, at 66; Exh. 1001, 9:43-46.) Silicone was known to be a non-reactive material and would not increase propofol degradation. (Exh. 1002, Feinberg Decl. 23; Exh. 1013, at 66; Exh. 1001, 9:43-46; Exh. 1025, at 8.) In addition, at the 10% level of soybean oil in prior art Diprivan, the coated stopper would be inert regardless of the closure selected. (Exh. 1001, 27:4-7; see also id., 3:63-66; Exh. 1002, Feinberg Decl. 15.) The modified packaging system for Diprivan discussed above (i.e., with a siliconized bromobutyl rubber stopper) would, therefore, have a stopper coated with a material inert to propofol. Claim 18 is dependent on claim 1 and includes the requirement that the closure consist essentially of a material that is itself inert to propofol. A bromobutyl rubber stopper coated with the siliconized coating of the 864 Patent would consist of a material -- siliconized bromobutyl rubber -- that is inert to propofol, as explained in the above analysis of claim 17. Claim 20 is dependent on independent claim 1 and requires that the closure comprise siliconized bromobutyl rubber. The 864 Patent taught the closure is siliconized bromobutyl rubber. Rubber stoppers are pretreated in the