Case: 1:16-cv-00651 Document #: 176 Filed: 12/17/18 Page 1 of 55 PageID #:6106
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`HOSPIRA, INC.,
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`Plaintiff,
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`FRESENIUS KABI USA, LLC,
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`Defendant.
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`THE UNITED STATES DISTRICT COURT
`FOR THE NORTHERN DISTRICT OF ILLINOIS
`EASTERN DIVISION
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`Nos. 16 C 651, 17 C 7903
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`Judge Rebecca R. Pallmeyer
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`MEMORANDUM OPINION AND ORDER
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`Plaintiff Hospira, Inc., a Delaware corporation with its primary place of business in Illinois,
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`manufactures pharmaceuticals and medical supplies. One of Hospira’s products is a chemical
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`compound known as dexmedetomidine, which Hospira sells to health care providers under the
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`brand name Precedex. Between 2012 and 2014, Hospira obtained four patents covering a new
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`product made from dexmedetomidine: U.S. Patent Nos. 8,242,158 (the “’158 Patent”), 8,338,470
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`(the “’470 Patent”), 8,455,527 (the “’527 Patent”), and 8,648,106 (the “’106 Patent”). (Complaint
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`in Case No. 16 C 651 [1] (“Pl.’s First Compl.”), 3.) The new product, known as Precedex Premix,
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`is a ready-to-use, diluted version of a Hospira product that has been on the market since 1999.
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`That product, known as Precedex Concentrate, is formulated at 100 micrograms per milliliter
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`(µg/mL) and must be diluted with saline to a concentration of 4 µg/mL before being administered
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`to patients. Precedex Premix has the same formulation and the same package configuration as
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`Precedex Concentrate but is pre-diluted with saline to a 4 µg/mL concentration.
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`Defendant Fresenius Kabi USA, LLC is an American subsidiary of a German
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`pharmaceutical manufacturer which is also registered in Delaware and headquartered in Illinois.
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`In December 2015, Fresenius Kabi notified Hospira that it had filed an abbreviated new drug
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`application (“ANDA”) with
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`the FDA, seeking approval
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`to market
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`its own proposed
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`dexmedetomidine products prior to the expiry of Hospira’s patents. (Answer to Complaint,
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`Affirmative Defenses, and Counterclaims in Case No. 16 C 651 [10] (“Def.’s First Ans.”), ¶ 16.)
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`Case: 1:16-cv-00651 Document #: 176 Filed: 12/17/18 Page 2 of 55 PageID #:6107
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`Hospira filed suit a month later, alleging patent infringement. (Pl.’s First Compl. 8-10.) In 2017,
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`Hospira obtained a fifth patent covering the same dexmedetomidine product—U.S. Patent No.
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`9,616,049 (the “’049 Patent”)—and filed a second complaint of patent infringement. (Complaint
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`in Case No. 17 C 7903 [1] (“Pl.’s Second Compl.”), 3, 5-6.)
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`Fresenius Kabi initially denied the allegations and counterclaimed for a declaration that
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`the patents are invalid, or, alternatively, that Fresenius Kabi’s actions will not infringe. (Def.’s First
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`Ans. 22; Answer to Complaint, Affirmative Defenses, and Counterclaims in Case No. 17 C 7903
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`[18] (“Def.’s Second Ans.”), 7, 14-15.)1 Following the court’s claim construction order in
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`November 2017, the parties jointly agreed to limit the number of patent claims asserted in both
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`actions. (Joint Stipulation in Case No. 16 C 651 [93] (“Joint Stipulation”), 2.) Since then, Hospira
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`has dropped all but claim 6 of the ’106 Patent and claim 8 of the ’049 Patent. Fresenius Kabi has
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`stipulated that its proposed product would infringe those claims, but maintains its challenges to
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`their validity. (Joint Stipulation 2-3.)
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`The court held a five-day bench trial on the issue of the validity of these claims on July 16,
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`2018 through July 20, 2018. Having reviewed the evidence presented at the trial and the parties’
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`briefs, the court concludes that Fresenius Kabi has established by clear and convincing evidence
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`that both claims are invalid as obvious.2
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`Dexmedetomidine
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`BACKGROUND
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`Dexmedetomidine is a chemical compound known as an alpha2-adrenoceptor agonist.
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`A.
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`(’106 Patent, JTX 1, col. 1:34-36.) Among other things, dexmedetomidine is effective as a
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`sedative. (Id. at col. 1:36-37.) A Finnish corporation, Farmos Yhtyma Oy (“Farmos”), originally
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`1
`Fresenius Kabi also counterclaimed for a declaration that U.S. Patent No. 9,320,712 is
`invalid, or, alternatively, that Fresenius Kabi’s actions will not infringe. (Def.’s Second Ans. 15-
`17.)
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` 2
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`In light of this conclusion, the court does not reach Fresenius Kabi’s alternative argument
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`that claim 6 of the ’106 Patent is invalid for lack of enablement.
`2
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`isolated dexmedetomidine in the 1980s. (Hospira’s Post-Trial Responsive Brief [144] (“Hospira
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`Resp.”), 4.) In March 1990, Farmos obtained a patent that disclosed and claimed the compound:
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`U.S. Patent No. 4,910,214 (the “’214 Patent”), JTX 134.) The ’214 Patent also disclosed and
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`claimed the use of dexmedetomidine as a sedative. (Id. at cols. 3-4, col. 6:15-31.) The ’214
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`Patent expired in July 2013. (See Certificate Extending Patent Term Under 35 U.S.C. § 156, JTX
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`134 at 134.5.)
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`When the ’214 Patent issued, the FDA had not yet approved any dexmedetomidine
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`product. (Direct Examination of Dr. James Kipp at 254:7-10.)3 In 1989, Farmos applied to the
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`FDA
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`for an
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`investigational new drug application (“IND”)
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`to begin safety
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`testing
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`for
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`dexmedetomidine formulations in humans. (See IND Application, JTX 35.) Farmos proposed
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`and eventually conducted at least two safety studies of dexmedetomidine hydrochloride
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`(“dexmedetomidine HCl”) administered intravenously, meaning into a vein or veins. (IND
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`Application at JTX 35.63, 35.69; October 1990 IND Supplement, JTX 38 at 38.3, 38.10; Hospira
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`Resp. 4.) The concentration of dexmedetomidine in the formulation was 20 µg/mL. (IND
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`Application at JTX 35.69; October 1990 IND Supplement at JTX 38.10.) The formulation was
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`stored in flame-sealed glass tubes (“ampoules”) made from a kind of glass known in the
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`pharmaceutical industry as Type I glass. (IND Application at JTX 35.271, 273.) The parties agree
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`that the studies revealed adverse safety events and that Farmos abandoned efforts to study the
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`use of 20 µg/mL dexmedetomidine HCl in humans. (Hospira Resp. 5; Fresenius Kabi’s Opening
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`Post-Trial Brief [134] (“Fresenius Kabi Br.”), 32.)
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`B.
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`Precedex Concentrate
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`In 1994, Orion Corporation—which had by then acquired Farmos—licensed to Abbott
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`Laboratories (“Abbott”) the exclusive right to make, use, and sell dexmedetomidine for human use
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`in the United States and certain other territories. (1994 Dexmedetomidine License and Supply
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`3
`Citations to direct and cross examination of witnesses refer to the transcript of the July
`2018 bench trial.
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`3
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`Agreement, JTX 110 §§ 1.21, 1.27, 2.1.1; Hospira Resp. 5.) In 1999, Abbott obtained FDA
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`approval for a dexmedetomidine HCl drug formulated at a concentration of 100 µg/mL.
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`(Dexmedetomidine HCl Final Labeling (“Precedex Concentrate Label”), JTX 15 at 15.2.) Abbott
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`marketed the drug under the trade name Precedex, and it is now known as Precedex Concentrate.
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`(See Hospira Resp. 7.)
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`Dexmedetomidine HCl at a concentration of 100 µg/mL is too strong to administer directly
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`to patients. (See Precedex Concentrate Label at JTX 15.13; Hospira Resp. 7, 8.) Accordingly,
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`the Precedex Concentrate label directs hospital personnel to dilute the drug to a concentration of
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`4 µg/mL before intravenously infusing patients with the medication. (See Precedex Concentrate
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`Label at JTX 15.13.) The label provides instructions on how to perform the dilution. (See id.
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`(directing hospital personnel to add 2 mL of Precedex Concentrate to 48 mL of 0.9 percent sodium
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`chloride solution, which produces a total volume of 50 mL).) The label also provides other
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`important information about the drug, including its contents: 118 µg/mL of dexmedetomidine HCl
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`(equivalent to 100 µg/mL of dexmedetomidine base) and 9 milligrams (mg) of sodium chloride in
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`water. (Id. at JTX 15.2; see also id. (stating that Precedex Concentrate is “preservative-free,”
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`“contains no additives or chemical stabilizers,” and has a pH of 4.5 to 7.0).) In addition, the label
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`states that the “partition coefficient” of Precedex Concentrate “in octanol:water at pH 7.4 is 2.89.”
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`(Id.) Dr. James Kipp, Fresenius Kabi’s expert on formulation chemistry, explained that the higher
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`a molecule’s partition coefficient, the more lipophilic—meaning likely to interact with plastic—it is.
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`(Direct Examination of Dr. Kipp at 290:22-292:3.) A partition coefficient of 2.89 is high, according
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`to Dr. Kipp. (Id. at 292:4-8.) Finally, the Precedex Concentrate label discloses that it is supplied
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`only in 2 mL clear glass vials and 2 mL clear glass ampoules. (Precedex Concentrate Label at
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`JTX 15.14.) It is undisputed that the vials and ampoules are made from Type IA sulfur-treated
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`glass, and that the vials are sealed with coated rubber stoppers. (See, e.g., Fresenius Kabi Br.
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`1; Direct Examination of Dr. Priyanka Roychowdhury at 153:6-9, 154:14-19; Direct Examination
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`of Dr. Kipp at 310:6-9 (testifying that Precedex Concentrate “includes a sealed glass container as
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`4
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`its final packaging configuration, with a Teflon-coated stopper”).)
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`Abbott transferred its rights in dexmedetomidine to Hospira in 2004 when it spun Hospira
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`off as an independent business. (See, e.g., 2004 Separation and Distribution Agreement, JTX
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`109 at 109.16-17, 25, 82.)
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`C.
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`The Patented Invention
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`1.
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`Development Process
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`i.
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`Ready-to-Use Product
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`In 2006, Hospira decided to develop a ready-to-use dexmedetomidine drug—that is, a
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`formulation pre-diluted to the 4 µg/mL concentration used in humans. (Hospira Resp. 8;
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`September 2006 Hospira Precedex Line Extension Proposal (“2006 Premix Proposal”), JTX 72.)
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`The drug, now known as Precedex Premix, is the subject of the patents-in-suit.
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`In a September 2006 internal document, Hospira observed that hospitals incur “added
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`cost and inconvenience” when their pharmacy departments need to “take the 2 mL vial and
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`convert it to patient ready.” (2006 Premix Proposal at JTX 72.2.) Hospira also noted that a ready-
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`to-use product would “have high value to the customer from both a convenience and cost
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`standpoint.” (Id.)
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`Dr. Priyanka Roychowdhury, who has a Ph.D. in pharmaceutics, and Dr. Robert
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`Cedergen, who has a Ph.D. in biochemistry, worked on the development of Precedex Premix
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`while they were employed at Hospira. (Direct Examination of Dr. Roychowdhury at 130:18-
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`131:16; Direct Examination of Dr. Cedergen at 197:18-21, 199:1-20.) They are the named co-
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`inventors of the patents-in-suit. (See ’106 Patent, JTX 1; ’049 Patent, JTX 2.) Dr. Roychowdhury
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`testified at trial that from the perspective of a pharmaceutical formulator, a ready-to-use product
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`has obvious advantages; any formulator would be motivated to make a ready-to-use product if
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`there is a patient need for it; and a patient need for it existed before 2012. (Direct Examination of
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`Dr. Roychowdhury at 141:12-15; 143:1-6; 148:23-25.) Drs. Roychowdhury and Cedergen also
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`acknowledged that they did not come up with the idea for Precedex Premix; rather, someone at
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`5
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`Hospira instructed them to make it. (Id. at 140:23-141:2; Direct Examination of Dr. Cedergen at
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`201:13-19.)
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`According to Drs. Roychowdhury and Cedergen, the Precedex Concentrate label informed
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`their understanding that their goal was to make a 4 µg/mL formulation. (See Direct Examination
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`of Dr. Cedergen at 202:2-20; Direct Examination of Dr. Roychowdhury at 134:12-18.) The label,
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`Dr. Roychowdhury testified, also disclosed the appropriate formulation for Precedex Premix.
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`(Direct Examination of Dr. Roychowdhury at 134:19-135:2.) In other words, she agreed, there is
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`“no difference between the formulation of the further diluted Precedex [C]oncentrate versus the
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`Precedex [P]remix product[.]” (Id. at 137:20-138:10.) Hospira’s corporate representative, Dr. Rao
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`Tata-Venkata, who has a Ph.D. in organic chemistry, likewise testified that when “the
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`concentrated product . . . [is] diluted in the intended diluent, it gives rise to the solution that would
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`ultimately be identical to the already made solution of the premix.” (Deposition Designation for
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`Dr. Rao Tata-Venkata (“Tata-Venkata Dep.”) at 10:7, 172:17-21.)
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`ii.
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`Storage Container
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`Dr. Roychowdhury testified that while she was developing Precedex Premix, she knew
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`that Precedex Concentrate was stored in glass. (Direct Examination of Dr. Roychowdury at
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`135:18-20.) She also testified that she knew from her experience as a formulator that glass is
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`unlikely to have issues with adsorption (the adhesion of molecules to a surface) or absorption (the
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`entrance of molecules into a material)—both of which affect drug potency. (Id. at 150:12-151:8;
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`see also Tata-Venkata Dep. at 82:15-83:10 (similar).) Dr. Cedergen similarly agreed that absent
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`evidence to the contrary, glass is assumed to be nonreactive. (Direct Examination of Dr.
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`Cedergen at 205:14-18.) And a Hospira document from 2006 confirms that the company foresaw
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`“[n]o major issues” with storing Precedex Premix in glass. (2006 Premix Proposal at JTX 72.5;
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`see also May 2007 Precedex Line Extension Meeting Minutes, DTX 413 (stating that Hospira had
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`conducted tests which showed that “the product appears to be stable in the glass vial”).)
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`According to Dr. Roychowdhury, her team had the capability in 2007 to begin
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`6
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`manufacturing Precedex Premix in glass vials. (Direct Examination of Dr. Roychowdhury at
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`151:18-152:8.) Hospira, however, instructed her to experiment with plastic containers instead.
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`(Id. at 152:9-11.) Dr. Roychowdhury discovered right away that dexmedetomidine interacts with
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`a common plastic called PVC and should not be stored in it. (Id. at 149:1-22.) She therefore
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`reverted to glass and tested only one kind: Type IA sulfur-treated glass. (Id. at 152:20-153:9.)
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`Dr. Roychowdhury did not know at the time that Precedex Concentrate was stored in that kind of
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`glass; rather, she identified it as the best option based on her “knowledge and experience.” (Id.
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`at 153:4-9.)
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`Dr. Roychowdhury and her team also determined that Precedex Premix vials, like
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`Precedex Concentrate vials, should be sealed with coated rubber stoppers. (Id. at 154:14-19.)
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`Dr. Roychowdhury testified that she reached this conclusion “[a]fter a series of evaluations” that
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`lasted two to three months. (Id. at 154:16; Cross Examination of Dr. Roychowdhury at 181:7-11.)
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`But she also testified that at the time, she knew Precedex Concentrate used coated rubber
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`stoppers “to avoid interaction with the drug.” (Direct Examination of Dr. Roychowdhury at 135:21-
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`136:1.) A development report she prepared confirms that “it was planned to implement coated
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`stoppers in order to mimic the current product[.]” (Unsigned Hospira Development Report, JTX
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`62 at 62.12; Direct Examination of Dr. Roychowdhury at 166:15-19.)
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`iii.
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`Stability Testing
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`Dr. Cedergen testified that the low concentration of Precedex Premix (4 µg/mL) was the
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`main challenge he and Dr. Roychowdhury faced in developing the product. (Cross Examination
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`of Dr. Cedergen at 233:2-5; see also id. at 233:6-9 (stating that at “such a low concentration, any
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`loss in drug would result in a high relative percentage drop in potency”); Cross Examination of Dr.
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`Roychowdhury at 177:22-23, 178:12-13 (testifying that 4 µg/mL is the least concentrated product
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`she has ever worked on and that at 4 µg/mL “the issues of stability are magnified”).) In addition,
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`Dr. Tata-Venkata testified that he was not aware of any studies regarding dexmedetomidine at a
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`concentration of less than 100 µg/mL and stored in a glass container before Hospira began its
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`7
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`work on dexmedetomidine. (Tata-Venkata Dep. at 273:4-13.) Notably, however, Fresenius
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`Kabi’s formulation chemistry expert Dr. Kipp testified that any concentration in the microgram level
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`is considered low, and Dr. Roychowdhury agreed that a concentration of 100 µg/mL is considered
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`low. (Direct Examination of Dr. Kipp at 286:10-12; Direct Examination of Dr. Roychowdhury at
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`135:14-17.)
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`Dr. Roychowdhury and her team studied the stability of 4 µg/mL dexmedetomidine HCl for
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`five months under normal long-term storage conditions and accelerated storage conditions.
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`(Direct Examination of Dr. Roychowdhury at 159:20-24 (discussing Hospira April 2010
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`Development Report (“April 2010 Dev. Report”), JTX 51 at 51.33).) “Normal long-term storage
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`conditions” refers to storage at room temperature (twenty-five degrees Celsius) and sixty percent
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`relative humidity. (See April 2010 Dev. Report at JTX 51.33; Direct Examination of Dr. Kipp at
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`324:7-9 (stating that “normal storage conditions” refers to storage at room temperature).)
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`“Accelerated storage conditions” here refers to storage at forty degrees Celsius and seventy-five
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`percent relative humidity with inverted vials. (See April 2010 Dev. Report at JTX 51.33.) When
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`vials are inverted, the stopper is “in constant contact with the fluid inside the bottle,” which is
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`considered a worst-case scenario for maintaining stability. (See, e.g., Cross Examination of Dr.
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`Kipp at 441:18-22.)
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`Dr. Roychowdhury and her team measured the initial concentration of the formulation and
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`then took only five measurements: one for each month. (April 2010 Dev. Report at JTX 51.33.)
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`Dr. Roychowdhury testified that she observed a loss in concentration of about four percent in the
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`sample stored under accelerated conditions. (Direct Examination of Dr. Roychowdhury at 170:14-
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`25.) In the sample stored under normal conditions, however, the observed drop in concentration
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`was just 2.3 percent. (Id. at 159:20-160:14.) Dr. Roychowdhury and her team also conducted
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`stress testing for 4 µg/mL dexmedetomidine HCl. (Id. at 163:11-14.) Dr. Roychowdhury agreed
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`that the formulation did not degrade when it was exposed to “extreme acidic and alkaline
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`conditions.” (Id. at 163:25-164:6.) Only when the team added oxidative reagents such as
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`8
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`

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`hydrogen peroxide to the drug, placed it in an oven heated to fifty degrees Celsius, and left it there
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`for twenty-four hours did they observe “[s]ome minor degradation.” (Id. at 164:10-24; April 2010
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`Dev. Report at JTX 51.60.) Interpreting these test results, the team’s development report states,
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`“It can be concluded that the degradation of dexmedetomidine HCl is very small even under
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`extreme oxidative conditions.” (April 2010 Dev. Report at JTX 51.60.)
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`
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`Hospira received FDA approval to market Precedex Premix in 2013. (Direct Examination
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`of Fresenius Kabi’s Transactions Expert Peter Lankau at 57:4-6.) It sells the product in 20 mL,
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`50 mL, and 100 mL Type I glass vials sealed with coated rubber stoppers. (Tata-Venkata Dep.
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`at 152:24-153:6; Direct Examination of Dr. Roychowdhury at 153:6-9, 154:14-19.)
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`2.
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`Patents-in-Suit
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`Between 2012 and 2017, Hospira obtained five patents covering Precedex Premix,
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`including those asserted in this action: the ’106 Patent, which issued on February 11, 2014, and
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`the ’049 Patent, which issued on April 11, 2017. (’106 Patent, JTX 1; ’049 Patent, JTX 2.) The
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`priority date for both patents is January 4, 2012. (’106 Patent, JTX 1; ’049 Patent, JTX 2; Hospira
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`Resp. 4.) Hospira asserts only claim 6 of the ’106 Patent and claim 8 of the ’049 Patent.
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`In the ’106 and ’049 Patents, Hospira summarizes its invention as “premixed
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`pharmaceutical compositions of dexmedetomidine, or a pharmaceutically acceptable salt thereof,
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`that are formulated for administration to a patient, without the need to reconstitute or dilute the
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`composition prior to administration.” (’106 Patent, JTX 1, col. 2:7-11; ’049 Patent, JTX 2, col. 2:9-
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`13.) The ’106 and ’049 Patents cover the same basic subject matter—the medication itself—and
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`share a title: “Dexmedetomidine Premix Formulation.” (’106 Patent, JTX 1; ’049 Patent, JTX 2.)
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`The patents also share a common specification.
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`Independent claim 1 and dependent claim 6 of the ’106 Patent read as follows:
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`1. A ready to use liquid pharmaceutical composition for parenteral administration
`to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt
`thereof disposed within a sealed glass container, wherein the liquid pharmaceutical
`composition when stored in the glass container for at least five months exhibits no
`more than about 2% decrease in the concentration of dexmedetomidine.
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`9
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`6. The ready to use liquid pharmaceutical composition of claim 1, wherein the
`dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration
`of about 4 µg/mL.
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`(’106 Patent, JTX 1, col. 26:18-24, 41-43.)
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`
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`Independent claim 1 and dependent claim 8 of the ’049 Patent read as follows:
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`1. A ready to use liquid pharmaceutical composition for parenteral administration
`to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt
`thereof at a concentration of about 0.005 to about 50 µg/mL disposed within a
`sealed glass container, wherein the liquid pharmaceutical composition has a pH of
`about 2 to about 10.
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`8. The ready to use liquid pharmaceutical composition of claim 1, wherein the
`dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration
`of about 4 µg/mL.
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`(’049 Patent, JTX 2, col. 26:12-18, 42-45.)
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`
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`After a claim construction hearing in December 2016, this court construed the disputed
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`term “ready to use” to mean “formulated to be suitable for administration to a patient without
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`dilution or reconstitution,” and determined that no construction was required for the disputed term
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`“sealed glass container.” Hospira, Inc. v. Fresenius Kabi USA, LLC, Case No. 16 C 651, 2017
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`WL 5891058, at *9 (N.D. Ill. Nov. 27, 2017).4
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`D.
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`Prior Art
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`The parties agree that the prior art includes the ’214 Patent, Precedex Concentrate, and
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`the following references.5 (See, e.g., Fresenius Kabi Br. 40-41; Hospira Resp. 44.)
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`1.
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`Dexdomitor
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`Dexdomitor is a ready-to-use, 500 µg/mL dexmedetomidine HCl formulation indicated for
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`commercial veterinary use. (Dexdomitor Label, DTX 288 at 288_0001; Direct Examination of Dr.
`
`
`4
`This court also construed the disputed term “intensive care unit,” which is unique to the
`’527 Patent and irrelevant for present purposes. See id. at *8.
`
`Fresenius Kabi argues, and Hospira disputes, that the Farmos IND is prior art. As the
`
`court will discuss, it has determined that Fresenius Kabi has proven the asserted claims are invalid
`as obvious irrespective of whether the Farmos IND is prior art. The court, therefore, offers no
`conclusions on this issue.
`
` 5
`
`
`
`10
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`Case: 1:16-cv-00651 Document #: 176 Filed: 12/17/18 Page 11 of 55 PageID #:6116
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`Kipp at 284:15-286:9.) The European Medicines Evaluation Agency authorized use of the product
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`throughout the European Union in 2002. (Dexdomitor Label at DTX 288_0001; see also
`
`EUROPEAN MED. AGENCY, EPAR SUMMARY FOR THE PUBLIC, DEXDOMITOR, 3 (2012),
`
`https://www.ema.europa.eu/documents/overview/dexdomitor-epar-summary-public_en.pdf.)
`
`The Dexdomitor label states that the product is stored in a 10 mL glass vial sealed with a coated
`
`rubber stopper. (Id. at DTX 288_0002.) It also states that the product has a two-year shelf-life.
`
`(Id. at DTX 288_0001.) Finally, it states that in stability tests, “[a]ll parameters remained
`
`essentially unchanged at all storage conditions and no difference between inverted and upright
`
`containers could be noted.” (Id. at DTX 288_0005.)
`
`
`
`
`
`2.
`
`References Relating to Ready-to-Use Drug Formulations
`
`A November 2011 article by John Fanikos states, among other things, that ready-to-use
`
`drug formulations “can reduce the probability of errors related to” drug preparation “while providing
`
`timely treatment.” (John Fanikos, Premixed Products Improve Safe Medication Practices: Recent
`
`Innovations of Amiodarone IV, PHARMACY PRAC. NEWS, Nov. 2011 (“Fanikos”), JTX 19 at 19.2.)
`
`
`
`Guidelines from the Canadian Society of Hospital Pharmacists, published in March 2008,
`
`instruct that “to help reduce the potential for error and the nursing time involved in handling and
`
`administering medications[,]” pharmacies should “provide medications in identified dosage units
`
`ready for administration, wherever possible and practical[.]” (CANADIAN SOC. OF HOSP.
`
`PHARMACISTS, GUIDELINES FOR DRUG-USE CONTROL (2008) (“CSHP Guidelines”), DTX 301 at
`
`301_0001, 0015.)
`
`
`
`An article by James G. Cain published in 2007 states that in or around 2007, the pharmacy
`
`at Cain’s hospital was using “premixed syringes of dexmedetomidine (10 mL with 4 mcg/mL)[.]”6
`
`(James G. Cain, Dexmedetomidine and Hextend: Their Role in Trauma Care, INT’L TRAUMA CARE,
`
`2007 (“Cain”), JTX 16 at 16.2).)
`
`
`6
`Mcg is another abbreviation for microgram (µg). (See Direct Examination of Dr. Kipp at
`284:3-10 (discussing Cain).)
`
`
`
`11
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`Case: 1:16-cv-00651 Document #: 176 Filed: 12/17/18 Page 12 of 55 PageID #:6117
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`
`
`
`
`3.
`
`References Relating to Glass Storage Containers
`
`An article by Gregory A. Sacha published in 2010 states that “[f]or decades, glass sealed
`
`ampoules were the most popular primary packaging system for small volume injectable products.”
`
`(Gregory A. Sacha, et. al., Practical Fundamentals of Glass, Rubber, and Plastic Sterile
`
`Packaging Systems, PHARMACEUTICAL DEV. & TECH., 2010 (“Sacha”), JTX 24 at 24.3.) According
`
`to Sacha, this was because a drug packaged in a glass ampoule has the potential to interact with
`
`only one, as opposed to multiple, packaging materials. (See id.) Sacha further states that “glass
`
`vial[s]” are now the “most common packaging for liquid and freeze-dried pharmaceuticals.” (Id.)
`
`
`
`A treatise commonly used in the pharmaceutical industry states that “[t]raditionally, glass
`
`has been the most widely used container for pharmaceutical products[.]” (REMINGTON: THE
`
`SCIENCE OF PRACTICE AND PHARMACY (21st ed. 2006) (“Remington”), JTX 20 at 20.13.) Glass is
`
`widely used, Remington explains, “to ensure inertness, visibility, strength, rigidity, moisture
`
`protection, ease of re-closure, and economy of packaging.” (Id.)
`
`E.
`
`
`
`The “About 2%” Limitation of the ’106 Patent
`
` Hospira does not appear to dispute that if one practices the ’106 Patent, a 4 µg/mL
`
`dexmedetomidine HCl formulation is stable for FDA purposes (though neither party explicitly
`
`defined FDA stability parameters). (See, e.g., Direct Examination of Dr. Roychowdhury at 139:24-
`
`140:2 (testifying that “premix is now a pharmaceutical product” and “has been proven to be stable
`
`throughout manufacturing, throughout storage, up to the expired date at its long-term storage
`
`condition”).) Hospira’s counsel himself acknowledged during his closing argument that “from the
`
`standpoint of the FDA, we know what we need to know to be confident that it’s stable.” (Closing
`
`Argument of Mr. Bradford Lyerla at 858:14-16.) A major point of contention between Fresenius
`
`Kabi and Hospira, however, is whether 4 µg/mL dexmedetomidine HCl—when stored at room
`
`temperature in a Type I glass vial, sealed with a coated rubber stopper—will always “exhibit[] no
`
`more than about 2% decrease in the concentration of dexmedetomidine” at five months. (’106
`
`Patent, JTX 1, col. 26:21-24 (the “about 2%” limitation).) Hospira’s case for non-obviousness
`
`
`
`12
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`Case: 1:16-cv-00651 Document #: 176 Filed: 12/17/18 Page 13 of 55 PageID #:6118
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`depends largely on the argument that a 4 µg/mL formulation stored under these conditions will
`
`not always meet that limitation. (See Hospira Resp. 1, 11-23.)
`
`
`
`The ’106 Patent itself discloses only one set of five-month stability data for 4 µg/mL
`
`dexmedetomidine HCl. (JTX 1, Example 6.) This is the data that Dr. Roychowdhury and her
`
`team collected during the stability testing, described above. (See April 2010 Dev. Report at JTX
`
`51.33; Direct Examination of Dr. Roychowdhury at 170:25-171:6; Redirect Examination of Dr.
`
`Roychowdury at 192:7-22.) The data shows a loss in concentration of about 2.3 percent at five
`
`months when the formulation was stored at room temperature in an upright Type I glass vial
`
`sealed with a coated rubber stopper. (April 2010 Dev. Report at JTX 51.33.) Dr. Roychowdhury
`
`testified that she considers 2.3 percent to be within two percent. (Direct Examination of Dr.
`
`Roychowdhury at 162:6-10.) The ’106 Patent also discloses the results of an additional stress
`
`test conducted for 4 µg/mL dexmedetomidine HCl. (JTX 1, Example 4& tbl. 4.) Among other
`
`things, the test shows that the formulation experienced degradation of 12.7 percent after it was
`
`mixed with hydrogen peroxide and baked in an oven at sixty degrees Celsius for eight hours. (Id.;
`
`see also id. at col. 17:25-27.)
`
`
`
`At trial, Fresenius Kabi and Hospira offered testimony from expert and fact witnesses
`
`regarding the “about 2%” limitation. The court summarizes that testimony below.
`
`
`
`
`
`1.
`
`Fresenius Kabi’s Formulation Chemistry Expert Dr. James Kipp
`
`Dr. Kipp earned bachelor’s and master’s degrees in chemistry, and a Ph.D. in organic
`
`chemistry. (Direct Examination of Dr. Kipp at 244:18-23.) He has thirty-five years of experience
`
`in the formulation of pharmaceutical products and testified at trial as an expert on formulation
`
`chemistry. (Id. at 243:22-244:6.) For purposes of the “about 2%” limitation, Dr. Kipp analyzed
`
`several sets of stability data. According to Dr. Kipp, the data shows that none of the tested
`
`samples lost more than two percent of their concentration at five months in storage at room
`
`temperature.
`
`
`
`
`
`
`
`13
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`Case: 1:16-cv-00651 Document #: 176 Filed: 12/17/18 Page 14 of 55 PageID #:6119
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`
`
`
`
`
`
`i.
`
`Stability Data for Precedex Premix (4 µg/mL)
`
`Dr. Kipp analyzed stability data for Precedex Premix in 20 mL, 50 mL, and 100 mL glass
`
`vials. (Direct Examination of Dr. Kipp at 339:8-340:13.) He did not test samples himself, but
`
`rather used the data Hospira submitted in its supplemental New Drug Application (“NDA”) for
`
`Precedex Premix. (Id. at 337:17-24.) Dr. Kipp analyzed three batches of data for each vial size,
`
`including upright and inverted vials for each batch. (Id. at 340:22-24.) In total, therefore, he
`
`analyzed eighteen batch configurations. (Id.) Dr. Kipp conducted a simple linear regression of
`
`the data for each configuration. (Id. at 338:4-6, 339:2-4.) According to Dr. Kipp, a simple linear
`
`regression provides “the best approximation for what the actual values are at each point” and is
`
`what a person of ordinary skill in the art (“POSA”) “would normally do.” (Id. at 334:3-11.) The
`
`regression lines, he testified, showed nothing approaching a loss as great as two percent at five
`
`months. (Id. at 340:19-341:2.)
`
`
`
`
`
`
`
`ii.
`
`Stability Data for IND Batch 027 L1 (20 µg/mL)
`
`Dr. Kipp also analyzed stability data that Farmos included in its original IND submission
`
`for 20 µg/mL dexmedetomidine HCl (“IND Batch 027 L1”). (Id. at 329:13-20; IND Application at
`
`JTX 35.272.) Farmos stored IND Batch 027 L1 in a clear glass ampoule at twenty-five degrees
`
`Celsius for twelve months. (IND Application at JTX 35.273.) Farmos reported the original assay
`
`percentage, or the percentage of the drug relative to the labeled amount, as ninety-eight. (Id. at
`
`JTX 35.277; Direct Examination of Dr. Kipp at 330:11-20.) Farmos then took one stability
`
`measurement at each of five time-points: two, three, six, nine, and twelve months. (IND
`