Hospira, Inc. v. Fresenius Kabi USA, LLC (343 F. Supp. 3d 823, 2018)

United States District Court for the Eastern District of Illinois 2018-12-17

Patents

Citations

Full opinion text

REBECCA R. PALLMEYER, DISTRICT JUDGE

Plaintiff Hospira, Inc., a Delaware corporation with its primary place of business in Illinois, manufactures pharmaceuticals and medical supplies. One of Hospira's products is a chemical compound known as dexmedetomidine, which Hospira sells to health care providers under the brand name Precedex. Between 2012 and 2014, Hospira obtained four patents covering a new product made from dexmedetomidine: U.S. Patent Nos. 8,242,158 (the " '158 Patent"), 8,338,470 (the " '470 Patent"), 8,455,527 (the " '527 Patent"), and 8,648,106 (the " '106 Patent"). (Complaint in Case No. 16 C 651 [1] ("Pl.'s First Compl."), 3.) The new product, known as Precedex Premix, is a ready-to-use, diluted version of a Hospira product that has been on the market since 1999. That product, known as Precedex Concentrate, is formulated at 100 micrograms per milliliter (µg/mL) and must be diluted with saline to a concentration of 4 µg/mL before being administered to patients. Precedex Premix has the same formulation and the same package configuration as Precedex Concentrate but is pre-diluted with saline to a 4 µg/mL concentration.

Defendant Fresenius Kabi USA, LLC is an American subsidiary of a German pharmaceutical manufacturer which is also registered in Delaware and headquartered in Illinois. In December 2015, Fresenius Kabi notified Hospira that it had filed an abbreviated new drug application ("ANDA")

with the FDA, seeking approval to market its own proposed dexmedetomidine products prior to the expiry of Hospira's patents. (Answer to Complaint, Affirmative Defenses, and Counterclaims in Case No. 16 C 651 [10] ("Def.'s First Ans."), ¶ 16.) Hospira filed suit a month later, alleging patent infringement. (Pl.'s First Compl. 8-10.) In 2017, Hospira obtained a fifth patent covering the same dexmedetomidine product- U.S. Patent No. 9,616,049 (the " '049 Patent") -and filed a second complaint of patent infringement. (Complaint in Case No. 17 C 7903 [1] ("Pl.'s Second Compl."), 3, 5-6.)

Fresenius Kabi initially denied the allegations and counterclaimed for a declaration that the patents are invalid, or, alternatively, that Fresenius Kabi's actions will not infringe. (Def.'s First Ans. 22; Answer to Complaint, Affirmative Defenses, and Counterclaims in Case No. 17 C 7903 [18] ("Def.'s Second Ans."), 7, 14-15.) Following the court's claim construction order in November 2017, the parties jointly agreed to limit the number of patent claims asserted in both actions. (Joint Stipulation in Case No. 16 C 651 [93] ("Joint Stipulation"), 2.) Since then, Hospira has dropped all but claim 6 of the '106 Patent and claim 8 of the '049 Patent. Fresenius Kabi has stipulated that its proposed product would infringe those claims, but maintains its challenges to their validity. (Joint Stipulation 2-3.)

The court held a five-day bench trial on the issue of the validity of these claims on July 16, 2018 through July 20, 2018. Having reviewed the evidence presented at the trial and the parties' briefs, the court concludes that Fresenius Kabi has established by clear and convincing evidence that both claims are invalid as obvious.

BACKGROUND

A. Dexmedetomidine

Dexmedetomidine is a chemical compound known as an alpha2-adrenoceptor agonist. ( '106 Patent, JTX 1, col. 1:34-36.) Among other things, dexmedetomidine is effective as a sedative. (Id. at col. 1:36-37.) A Finnish corporation, Farmos Yhtyma Oy ("Farmos"), originally isolated dexmedetomidine in the 1980s. (Hospira's Post-Trial Responsive Brief [144] ("Hospira Resp."), 4.) In March 1990, Farmos obtained a patent that disclosed and claimed the compound: U.S. Patent No. 4,910,214 (the " '214 Patent"), JTX 134.) The '214 Patent also disclosed and claimed the use of dexmedetomidine as a sedative. (Id. at cols. 3-4, col. 6:15-31.) The '214 Patent expired in July 2013. (See Certificate Extending Patent Term Under 35 U.S.C. § 156, JTX 134 at 134.5.)

When the '214 Patent issued, the FDA had not yet approved any dexmedetomidine product. (Direct Examination of Dr. James Kipp at 254:7-10.) In 1989, Farmos applied to the FDA for an investigational new drug application ("IND") to begin safety testing for dexmedetomidine formulations in humans. (See IND Application, JTX 35.) Farmos proposed and eventually conducted at least two safety studies of dexmedetomidine hydrochloride ("dexmedetomidine HCl") administered intravenously, meaning into a vein or veins. (IND Application at JTX 35.63, 35.69; October 1990 IND Supplement, JTX 38 at 38.3, 38.10; Hospira Resp. 4.) The concentration of dexmedetomidine in the formulation was 20 µg/mL. (IND Application at JTX 35.69; October 1990 IND Supplement at JTX 38.10.) The formulation was stored in flame-sealed glass tubes ("ampoules") made from a kind of glass known in the pharmaceutical industry as Type I glass. (IND Application at JTX 35.271, 273.) The parties agree that the studies revealed adverse safety events and that Farmos abandoned efforts to study the use of 20 µg/mL dexmedetomidine HCl in humans. (Hospira Resp. 5; Fresenius Kabi's Opening Post-Trial Brief [134] ("Fresenius Kabi Br."), 32.)

B. Precedex Concentrate

In 1994, Orion Corporation-which had by then acquired Farmos-licensed to Abbott Laboratories ("Abbott") the exclusive right to make, use, and sell dexmedetomidine for human use in the United States and certain other territories. (1994 Dexmedetomidine License and Supply Agreement, JTX 110 §§ 1.21, 1.27, 2.1.1; Hospira Resp. 5.) In 1999, Abbott obtained FDA approval for a dexmedetomidine HCl drug formulated at a concentration of 100 µg/mL. (Dexmedetomidine HCl Final Labeling ("Precedex Concentrate Label"), JTX 15 at 15.2.) Abbott marketed the drug under the trade name Precedex, and it is now known as Precedex Concentrate. (See Hospira Resp. 7.)

Dexmedetomidine HCl at a concentration of 100 µg/mL is too strong to administer directly to patients. (SeePrecedex Concentrate Label at JTX 15.13; Hospira Resp. 7, 8.) Accordingly, the Precedex Concentrate label directs hospital personnel to dilute the drug to a concentration of 4 µg/mL before intravenously infusing patients with the medication. (SeePrecedex Concentrate Label at JTX 15.13.) The label provides instructions on how to perform the dilution. (See id. (directing hospital personnel to add 2 mL of Precedex Concentrate to 48 mL of 0.9 percent sodium chloride solution, which produces a total volume of 50 mL).) The label also provides other important information about the drug, including its contents: 118 µg/mL of dexmedetomidine HCl (equivalent to 100 µg/mL of dexmedetomidine base) and 9 milligrams (mg) of sodium chloride in water. (Id. at JTX 15.2; see also id. (stating that Precedex Concentrate is "preservative-free," "contains no additives or chemical stabilizers," and has a pH of 4.5 to 7.0).) In addition, the label states that the "partition coefficient" of Precedex Concentrate "in octanol: water at pH 7.4 is 2.89." (Id. ) Dr. James Kipp, Fresenius Kabi's expert on formulation chemistry, explained that the higher a molecule's partition coefficient, the more lipophilic-meaning likely to interact with plastic-it is. (Direct Examination of Dr. Kipp at 290:22-292:3.) A partition coefficient of 2.89 is high, according to Dr. Kipp. (Id. at 292:4-8.) Finally, the Precedex Concentrate label discloses that it is supplied only in 2 mL clear glass vials and 2 mL clear glass ampoules. (Precedex Concentrate Label at JTX 15.14.) It is undisputed that the vials and ampoules are made from Type IA sulfur-treated glass, and that the vials are sealed with coated rubber stoppers. (See, e.g. , Fresenius Kabi Br. 1; Direct Examination of Dr. Priyanka Roychowdhury at 153:6-9, 154:14-19; Direct Examination of Dr. Kipp at 310:6-9 (testifying that Precedex Concentrate "includes a sealed glass container as its final packaging configuration, with a Teflon-coated stopper").)

Abbott transferred its rights in dexmedetomidine to Hospira in 2004 when it spun Hospira off as an independent business.

(See, e.g. , 2004 Separation and Distribution Agreement, JTX 109 at 109.16-17, 25, 82.)

C. The Patented Invention

1. Development Process

i. Ready-to-Use Product

In 2006, Hospira decided to develop a ready-to-use dexmedetomidine drug-that is, a formulation pre-diluted to the 4 µg/mL concentration used in humans. (Hospira Resp. 8; September 2006 Hospira Precedex Line Extension Proposal ("2006 Premix Proposal"), JTX 72.) The drug, now known as Precedex Premix, is the subject of the patents-in-suit.

In a September 2006 internal document, Hospira observed that hospitals incur "added cost and inconvenience" when their pharmacy departments need to "take the 2 mL vial and convert it to patient ready." (2006 Premix Proposal at JTX 72.2.) Hospira also noted that a ready-to-use product would "have high value to the customer from both a convenience and cost standpoint." (Id. )

Dr. Priyanka Roychowdhury, who has a Ph.D. in pharmaceutics, and Dr. Robert Cedergen, who has a Ph.D. in biochemistry, worked on the development of Precedex Premix while they were employed at Hospira. (Direct Examination of Dr. Roychowdhury at 130:18-131:16; Direct Examination of Dr. Cedergen at 197:18-21, 199:1-20.) They are the named co-inventors of the patents-in-suit. (See '106 Patent, JTX 1; '049 Patent, JTX 2.) Dr. Roychowdhury testified at trial that from the perspective of a pharmaceutical formulator, a ready-to-use product has obvious advantages; any formulator would be motivated to make a ready-to-use product if there is a patient need for it; and a patient need for it existed before 2012. (Direct Examination of Dr. Roychowdhury at 141:12-15; 143:1-6; 148:23-25.) Drs. Roychowdhury and Cedergen also acknowledged that they did not come up with the idea for Precedex Premix; rather, someone at Hospira instructed them to make it. (Id. at 140:23-141:2; Direct Examination of Dr. Cedergen at 201:13-19.)

According to Drs. Roychowdhury and Cedergen, the Precedex Concentrate label informed their understanding that their goal was to make a 4 µg/mL formulation. (See Direct Examination of Dr. Cedergen at 202:2-20; Direct Examination of Dr. Roychowdhury at 134:12-18.) The label, Dr. Roychowdhury testified, also disclosed the appropriate formulation for Precedex Premix. (Direct Examination of Dr. Roychowdhury at 134:19-135:2.) In other words, she agreed, there is "no difference between the formulation of the further diluted Precedex [C]oncentrate versus the Precedex [P]remix product[.]" (Id. at 137:20-138:10.) Hospira's corporate representative, Dr. Rao Tata-Venkata, who has a Ph.D. in organic chemistry, likewise testified that when "the concentrated product ... [is] diluted in the intended diluent, it gives rise to the solution that would ultimately be identical to the already made solution of the premix." (Deposition Designation for Dr. Rao Tata-Venkata ("Tata-Venkata Dep.") at 10:7, 172:17-21.)

ii. Storage Container

Dr. Roychowdhury testified that while she was developing Precedex Premix, she knew that Precedex Concentrate was stored in glass. (Direct Examination of Dr. Roychowdury at 135:18-20.) She also testified that she knew from her experience as a formulator that glass is unlikely to have issues with adsorption (the adhesion of molecules to a surface) or absorption (the entrance of molecules into a material)-both of which affect drug potency. (Id. at 150:12-151:8; see also Tata-Venkata Dep. at 82:15-83:10 (similar).) Dr. Cedergen similarly agreed that absent evidence to the contrary, glass is assumed to be nonreactive. (Direct Examination of Dr. Cedergen at 205:14-18.) And a Hospira document from 2006 confirms that the company foresaw "[n]o major issues" with storing Precedex Premix in glass. (2006 Premix Proposal at JTX 72.5; see also May 2007 Precedex Line Extension Meeting Minutes, DTX 413 (stating that Hospira had conducted tests which showed that "the product appears to be stable in the glass vial").)

According to Dr. Roychowdhury, her team had the capability in 2007 to begin manufacturing Precedex Premix in glass vials. (Direct Examination of Dr. Roychowdhury at 151:18-152:8.) Hospira, however, instructed her to experiment with plastic containers instead. (Id. at 152:9-11.) Dr. Roychowdhury discovered right away that dexmedetomidine interacts with a common plastic called PVC and should not be stored in it. (Id. at 149:1-22.) She therefore reverted to glass and tested only one kind: Type IA sulfur-treated glass. (Id. at 152:20-153:9.) Dr. Roychowdhury did not know at the time that Precedex Concentrate was stored in that kind of glass; rather, she identified it as the best option based on her "knowledge and experience." (Id. at 153:4-9.)

Dr. Roychowdhury and her team also determined that Precedex Premix vials, like Precedex Concentrate vials, should be sealed with coated rubber stoppers. (Id. at 154:14-19.) Dr. Roychowdhury testified that she reached this conclusion "[a]fter a series of evaluations" that lasted two to three months. (Id. at 154:16; Cross Examination of Dr. Roychowdhury at 181:7-11.) But she also testified that at the time, she knew Precedex Concentrate used coated rubber stoppers "to avoid interaction with the drug." (Direct Examination of Dr. Roychowdhury at 135:21-136:1.) A development report she prepared confirms that "it was planned to implement coated stoppers in order to mimic the current product[.]" (Unsigned Hospira Development Report, JTX 62 at 62.12; Direct Examination of Dr. Roychowdhury at 166:15-19.)

iii. Stability Testing

Dr. Cedergen testified that the low concentration of Precedex Premix (4 µg/mL) was the main challenge he and Dr. Roychowdhury faced in developing the product. (Cross Examination of Dr. Cedergen at 233:2-5; see also id. at 233:6-9 (stating that at "such a low concentration, any loss in drug would result in a high relative percentage drop in potency"); Cross Examination of Dr. Roychowdhury at 177:22-23, 178:12-13 (testifying that 4 µg/mL is the least concentrated product she has ever worked on and that at 4 µg/mL "the issues of stability are magnified").) In addition, Dr. Tata-Venkata testified that he was not aware of any studies regarding dexmedetomidine at a concentration of less than 100 µg/mL and stored in a glass container before Hospira began its work on dexmedetomidine. (Tata-Venkata Dep. at 273:4-13.) Notably, however, Fresenius Kabi's formulation chemistry expert Dr. Kipp testified that any concentration in the microgram level is considered low, and Dr. Roychowdhury agreed that a concentration of 100 µg/mL is considered low. (Direct Examination of Dr. Kipp at 286:10-12; Direct Examination of Dr. Roychowdhury at 135:14-17.)

Dr. Roychowdhury and her team studied the stability of 4 µg/mL dexmedetomidine HCl for five months under normal long-term storage conditions and accelerated storage conditions. (Direct Examination of Dr. Roychowdhury at 159:20-24 (discussing Hospira April 2010 Development Report ("April 2010 Dev. Report"), JTX 51 at 51.33).) "Normal long-term storage conditions" refers to storage at room temperature (twenty-five degrees Celsius) and sixty percent relative humidity. (See April 2010 Dev. Report at JTX 51.33; Direct Examination of Dr. Kipp at 324:7-9 (stating that "normal storage conditions" refers to storage at room temperature).) "Accelerated storage conditions" here refers to storage at forty degrees Celsius and seventy-five percent relative humidity with inverted vials. (See April 2010 Dev. Report at JTX 51.33.) When vials are inverted, the stopper is "in constant contact with the fluid inside the bottle," which is considered a worst-case scenario for maintaining stability. (See, e.g. , Cross Examination of Dr. Kipp at 441:18-22.)

Dr. Roychowdhury and her team measured the initial concentration of the formulation and then took only five measurements: one for each month. (April 2010 Dev. Report at JTX 51.33.) Dr. Roychowdhury testified that she observed a loss in concentration of about four percent in the sample stored under accelerated conditions. (Direct Examination of Dr. Roychowdhury at 170:14-25.) In the sample stored under normal conditions, however, the observed drop in concentration was just 2.3 percent. (Id. at 159:20-160:14.) Dr. Roychowdhury and her team also conducted stress testing for 4 µg/mL dexmedetomidine HCl. (Id. at 163:11-14.) Dr. Roychowdhury agreed that the formulation did not degrade when it was exposed to "extreme acidic and alkaline conditions." (Id. at 163:25-164:6.) Only when the team added oxidative reagents such as hydrogen peroxide to the drug, placed it in an oven heated to fifty degrees Celsius, and left it there for twenty-four hours did they observe "[s]ome minor degradation." (Id. at 164:10-24; April 2010 Dev. Report at JTX 51.60.) Interpreting these test results, the team's development report states, "It can be concluded that the degradation of dexmedetomidine HCl is very small even under extreme oxidative conditions." (April 2010 Dev. Report at JTX 51.60.)

Hospira received FDA approval to market Precedex Premix in 2013. (Direct Examination of Fresenius Kabi's Transactions Expert Peter Lankau at 57:4-6.) It sells the product in 20 mL, 50 mL, and 100 mL Type I glass vials sealed with coated rubber stoppers. (Tata-Venkata Dep. at 152:24-153:6; Direct Examination of Dr. Roychowdhury at 153:6-9, 154:14-19.)

2. Patents-in-Suit

Between 2012 and 2017, Hospira obtained five patents covering Precedex Premix, including those asserted in this action: the '106 Patent, which issued on February 11, 2014, and the '049 Patent, which issued on April 11, 2017. ( '106 Patent, JTX 1; '049 Patent, JTX 2.) The priority date for both patents is January 4, 2012. ( '106 Patent, JTX 1; '049 Patent, JTX 2; Hospira Resp. 4.) Hospira asserts only claim 6 of the '106 Patent and claim 8 of the '049 Patent.

In the '106 and '049 Patents, Hospira summarizes its invention as "premixed pharmaceutical compositions of dexmedetomidine, or a pharmaceutically acceptable salt thereof, that are formulated for administration to a patient, without the need to reconstitute or dilute the composition prior to administration." ( '106 Patent, JTX 1, col. 2:7-11; '049 Patent, JTX 2, col. 2:9-13.) The '106 and '049 Patents cover the same basic subject matter-the medication itself-and share a title: "Dexmedetomidine Premix Formulation." ( '106 Patent, JTX 1; '049 Patent, JTX 2.) The patents also share a common specification.

Independent claim 1 and dependent claim 6 of the '106 Patent read as follows:

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.

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.

( '106 Patent, JTX 1, col. 26:18-24, 41-43.)

Independent claim 1 and dependent claim 8 of the '049 Patent read as follows:

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.

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.

( '049 Patent, JTX 2, col. 26:12-18, 42-45.)

After a claim construction hearing in December 2016, this court construed the disputed term "ready to use" to mean "formulated to be suitable for administration to a patient without dilution or reconstitution," and determined that no construction was required for the disputed term "sealed glass container." Hospira, Inc. v. Fresenius Kabi USA, LLC , Case No. 16 C 651, 2017 WL 5891058, at *9 (N.D. Ill. Nov. 27, 2017).

D. Prior Art

The parties agree that the prior art includes the '214 Patent, Precedex Concentrate, and the following references. (See, e.g. , Fresenius Kabi Br. 40-41; Hospira Resp. 44.)

1. Dexdomitor

Dexdomitor is a ready-to-use, 500 µg/mL dexmedetomidine HCl formulation indicated for commercial veterinary use. (Dexdomitor Label, DTX 288 at 288_0001; Direct Examination of Dr. Kipp at 284:15-286:9.) The European Medicines Evaluation Agency authorized use of the product 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)[.]" (James G. Cain, Dexmedetomidine and Hextend: Their Role in Trauma Care , INT'L TRAUMA CARE , 2007 ("Cain"), JTX 16 at 16.2).)

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 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.

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 Application at JTX 35.277.) It used an assay measurement technique called High Performance Liquid Chromatography (HPLC), for which the relative standard deviation is not more than three percent. (Id. at JTX 35.273, 275; Direct Examination of Dr. Kipp at 331:10; Fresenius Kabi Br. 15.) Farmos measured assay percentages between ninety-seven and 100, and two measurements showed percentage increases. (IND Application at JTX 35.277.) Farmos concluded from the data that the formulations "ha[d] not significantly changed during the storage." (Id. at JTX 35.276.)

Dr. Kipp explained that the measured fluctuations in assay percentage reflect what he called "noise," or weighing and measurement errors. (Direct Examination of Dr. Kipp at 330:21-331:2.) So although it is true that an assay percentage cannot actually increase, he opined, "a POSA would look at the data and say that th[e] variability is certainly within 3 percent of the expected noise[.]" (Id. at 331:11-20.) Dr. Kipp also opined that the language in the '106 Patent supports this interpretation. Namely, the word "about" modifies the "about 2%" limitation, and the patent specification defines the word "about" as being "within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on ... limitations of the measurement system." (Id. at 332:13-20, 333:2-3 (quoting '106 Patent, JTX 1, col. 5:31-35).)

To account for the assay variability and reach a conclusion regarding the stability of IND Batch NI 027 L1, Dr. Kipp plotted the measured concentration versus time and conducted a simple linear regression. (Id. at 334:3-6.) Dr. Kipp testified that the resulting regression line is "completely flat ... and any deviations from that line would be due to statistical error." (Id. at 334:20-25.) He concluded, therefore, that the regression line for IND Batch NI 027 L1 does not show anything close to more than two percent loss at five months. (Id. at 335:1-5.) In fact, according to Dr. Kipp, there was "no decrease in drug concentration throughout the whole study." (Id. at 336:10-11.)

iii. Whether Concentration Affects Stability

Dr. Kipp also analyzed whether the concentration of dexmedetomidine affects its stability. (Id. at 341:11-12.) In his expert report, Dr. Kipp noted that he "compared the mean rates of change in drug concentration for 200, 100, 20, and 4 mcg/mL dexmedetomidine formulation data[.]" (Expert Report of Dr. Kipp ("Kipp Report"), DTX 457, ¶¶ 362-63.) A comparison of this nature, Dr. Kipp explained in his expert report, "allow[s] a POSA to determine the slopes of the lines in order to determine when these concentrations ... would decrease by 2%." (Id. ¶ 363.) At trial, Dr. Kipp did not describe these calculations in detail. But as the court understands his report, Dr. Kipp applied the mean rate of change for each concentration to stability data from actual batches at that concentration and, using linear regression, "determine[d] how many months would be necessary to show 2% loss of concentration." (Id. ) For the 4 µg/mL and 20 µg/mL formulations, Dr. Kipp used the same Precedex Premix and Farmos IND data discussed above. (See id. ) For the 100 µg/mL

and 200 µg/mL formulations, Dr. Kipp used data from the Precedex Concentrate NDA. (See id. )

Dr. Kipp conducted two analyses for the data: one applying the assumption that dexmedetomidine follows a zero-order loss model and one applying the assumption that it follows a first-order loss model. (Id. ¶ 363 & n.2; Redirect Examination of Dr. Kipp at 466:24-467:1.) Under zero-order kinetics, "the rate of reaction is not proportional to the concentration of drug in a solution," so that "at lower concentrations, the percentage of drug loss is greater than it is at higher concentrations." (Cross Examination of Dr. Kipp at 404:4-8; Colloquy Between the Court and Dr. Kipp at 468:12-14.) Under first-order kinetics, "the rate of a reaction is proportional to the concentration of a drug in solution," so that the percentage loss of a drug is the same at high concentrations as at low concentrations. (Cross Examination of Dr. Kipp at 405:5-8; Colloquy Between the Court and Dr. Kipp at 468:17-19.)

Dr. Kipp testified that his calculations for each assumption yielded "very similar" results, including that none of the calculations for any concentration predicted a loss in concentration at five months even close to approaching two percent. (Cross Examination of Dr. Kipp at 411:7-8; Redirect Examination of Dr. Kipp at 450:1-4.) He acknowledged that his calculations showed some variability, and that some calculations appeared to predict increases in concentration. (Redirect Examination of Dr. Kipp at 450:5-12, 451:12-13.) According to Dr. Kipp, because "you obviously can't generate drug from nothing," the calculations showing increases in concentration reflect "that there is no change whatsoever." (Id. at 450:13-15.) Overall, he testified, the variability in the data is attributable to "noise." (Cross Examination of Dr. Kipp at 410:8-9.) Dr. Kipp concluded his calculations showed that "in fact," dexmedetomidine is "a very stable drug." (Id. )

In cross examining Dr. Kipp, Hospira's counsel asked a series of questions about the first two calculations Dr. Kipp conducted assuming a zero-order loss model. (Cross Examination of Dr. Kipp at 408:15-409:8.) Those calculations were based on actual samples containing 200 µg/mL and 100 µg/mL dexmedetomidine HCl and predicted that the drug would reach two percent loss at 60.1 and 23.2 months, respectively. (See id. ) Hospira pointed out that if one were to use 4 µg/mL instead of 200 µg/mL or 100 µg/mL as the concentration (Co) in the following equation-which describes zero-order kinetics-the time to reach two percent loss would be 1.2 months and .93 months, respectively. (See id. at 413:4-16, 414:6-11.)

(See id. at 413:4-9, 414:6-11.) In response, Dr. Kipp explained why he believes Hospira's calculation is an improper extrapolation. (Id. at 464:21-22.) According to Dr. Kipp, where the actual data shows no change in concentration, as he argues the data shows here, one cannot determine whether the drug follows a zero- or first-order loss model. (See, e.g. , id. at 465:4-6;

Colloquy Between the Court and Dr. Kipp at 468:22-25.) So although one can always fit a regression line to actual data using a zero-order or first-order loss model, one cannot fit the line to other concentrations because "the parameter may change as well." (Cross Examination of Dr. Kipp at 464:19-465:1.) Dr. Kipp testified that "if you look at the data itself and you do the math, you are still seeing ... no loss at 4 [µg/mL]." (Colloquy Between the Court and Dr. Kipp at 468:2-6.) Although the trial testimony is not entirely clear, the court understands Dr. Kipp to be saying that (1) the rate constant in the equation pictured above is derived from other calculations, which themselves are based on actual data from 100 µg/mL or 200 µg/mL concentrations, or (2) he used a different sequence of concentration-specific calculations, perhaps including the equation pictured above, to predict the time it would take actual samples to reach two percent loss. Either way, Hospira's proposed calculation improperly combines a Co value of 4 µg/mL with other variables derived from data at other concentrations. This reading is supported by the fact that Dr. Kipp did calculate predictions for 4 µg/mL batches, and those calculations predicted that every batch would take far longer than .93 or 1.2 months to reach two percent loss. (See id. )

2. Fresenius Kabi's Witness Shweta Mowli

Ms. Shweta Mowli, who has a bachelor's degree in chemistry and biology and a master's degree in analytical chemistry, works as a project manager for Fresenius Kabi's dexmedetomidine ready-to-use project. (Direct Examination of Ms. Mowli at 717:21-718:3, 719:7-16.) Previously, she worked for eight years as a scientist in Fresenius Kabi's formulation group, including on at least five liquid pharmaceutical drugs. (Id. at 719:7-25.) Ms. Mowli testified that Fresenius Kabi measured the stability of its ready-to-use product for the ANDA it submitted to the FDA. (Cross Examination of Ms. Mowli at 735:22-24.) According to Ms. Mowli, the studies show that Fresenius Kabi's ready-to-use product lost less than two percent of its initial concentration after six, twelve, and eighteen months of storage at room temperature. (Id. at 735:22-736:7.)

3. Hospira's Statistics Expert Dr. Stephan Ogenstad

Dr. Stephan Ogenstad earned a bachelor's degree in mathematics, statistics, and computer science and a Ph.D. in statistics. (Direct Examination of Dr. Ogenstad at 743:1-2.) He testified at trial as an expert in statistics, biostatistics, and statistical analysis of pharmaceutical data. (Id. at 749:2-8.) Dr. Ogenstad analyzed stability data for Precedex Premix (4 µg/mL) and Fresenius Kabi's ready-to-use product (4 µg/mL). He also analyzed data from IND Batch NI 027 L1 (20 µg/mL), as well as another set of data from the Farmos IND that Dr. Kipp did not review: IND Batch OK 29 (20 µg/mL). Finally, he analyzed data for 100 µg/mL and 200 µg/mL formulations of Precedex Concentrate.

i. Precedex Premix and Fresenius Kabi's Ready-to-Use Product (4 µg/mL)

Dr. Ogenstad measured stability data for Precedex Premix and Fresenius Kabi's ready-to-use product packaged in 20 mL, 50 mL, and 100 mL vials. (Direct Examination of Dr. Ogenstad at 775:6-10; see also Ogenstad Regression Graphs, PTX 66 at 66.21-27.) Dr. Ogenstad acknowledged that the data for Precedex Premix shows no more than two percent loss at five months, but pointed out that the stability varies among the volumes tested: the data shows "almost no loss at all" for the 100 mL product, about one percent loss at five months for the 50 mL product, and close to two percent loss at five months for the 20 mL product. (Direct Examination of Dr. Ogenstad at 751:11-12, 777:9-14; see also Cross Examination of Dr. Ogenstad at 779:2-10.) Dr. Ogenstad also agreed that the data for the Fresenius Kabi batches shows no more than two percent loss at five months. (See Cross Examination of Dr. Ogenstad at 779:2-10.)

ii. IND Batch NI 027 L1 (20 µg/mL)

According to Dr. Ogenstad, Dr. Kipp's conclusion regarding the stability of IND Batch NI 027 L1 is unreliable because it is based on only five data points (six including time zero). (Id. at 749:23-750:6, 753:21-25.) Furthermore, according to Dr. Ogenstad, the measurements reflect "quite a lot of variability." (Id. at 750:6-8.) Dr. Ogenstad testified that under these circumstances, the data "would be very different" if the measurements were taken again. (Id. at 753:25-754:5.) He added that because the regression line through the data is positive-which signifies an impossible increase in concentration-a statistician would not conclude that the data shows no loss in concentration, but instead that the data is incomplete or incorrect. (See id. at 755:16-25.)

Rather than fit a simple regression line to the data, therefore, Dr. Ogenstad testified that a statistician would interpret the data by producing measures of uncertainty. (Id. at 754:8-9.) Dr. Ogenstad explained that he did so by, among other things, generating thirty-six data points to illustrate what the data might show if the stability experiment were repeated. (Id. at 756:5-8, 760:6-7.) Dr. Ogenstad generated this simulated data using an algorithm that accounted for the "not more than three percent" standard deviation used for HPLC measurements. (Id. at 757:9-759:8; 761:2-5.) In this sense, he testified, the simulated data "follows the actual observations" disclosed in the Farmos IND. (See id. at 760:20-22.) Dr. Ogenstad opined that his algorithm generated "an enormous scatter of data points." (Id. at 760:6-10.) He analyzed the data using confidence bands, a measure of uncertainty that predicts with ninety-five percent confidence where the true regression line falls within certain boundaries. (Id. at 763:7-21.) According to Dr. Ogenstad, the "confidence bands show very clearly that this regression line, instead of being positive, could be extremely negative." (Cross Examination of Dr. Ogenstadat 786:2-4.) Overall, Dr. Ogenstad testified, "It's possibly more than 2 percent degradation." (Direct Examination of Dr. Ogenstad at 750:23-751:1.) On cross examination, however, he acknowledged that the regression line he actually presented to the court shows that there was less than two percent loss in concentration at five months. (Cross Examination of Dr. Ogenstad at 786:6-23.)

iii. IND Batch OK 029 (20 µg/mL)

Dr. Ogenstad applied the same methodology to analyze the data from IND Batch OK 029, another stability study of 20 µg/mL dexmedetomidine HCl stored at room temperature for up to twenty-five months. (Id. at 769:14-770:4; IND Batch OK 029 Stability Study, JTX 39 at 39.1.) In Dr. Ogenstad's view, the data showed "a very large amount of variability" and reflected "likely more than 2 percent degradation." (Direct Examination of Dr. Ogenstad at 751:3-5, 771:8-25.) He acknowledged on cross-examination, however, that the authors of the stability study for IND Batch OK 29 had concluded that "[t]he content of the active ingredient has remained unchanged during three months' storage at stress conditions and 25 months at room temperature." (Cross Examination of Dr. Ogenstad at 790:4-10; see also IND Batch OK 029 Stability Study at JTX 39.4.) Although Dr. Kipp did not consider IND Batch OK 029 for his expert report, he testified that he reviewed Dr. Ogenstad's analysis and determined that the regression line for the data "does not show ... any appreciable change in drug concentration versus time over five months." (Direct Examination of Dr. Kipp at 343:8-18.)

iv. Precedex Concentrate (100 µg/mL and 200 µg/mL)

Dr. Ogenstad testified that the stability data he analyzed for Precedex Concentrate (100 µg/mL and 200 µg/mL formulations) shows that the drug experienced no more than two percent loss at five months. (Direct Examination of Dr. Ogenstad at 767:20-768:7; Ogenstad Regression Graphs at PTX 66.18-19; Redirect Examination of Dr. Ogenstad at 792:23-793:25.)

F. Chemical Structure of Dexmedetomidine

Fresenius Kabi and Hospira also offered expert testimony regarding the chemical structure of dexmedetomidine. The court summarizes that testimony below.

1. Fresenius Kabi's Expert Dr. Kipp

Dr. Kipp characterized dexmedetomidine as a "very small", "inherently very stable" molecule. (Direct Examination of Dr. Kipp at 320:5-6.) The following diagram depicts a dexmedetomidine molecule:

(Fresenius Kabi Br. 5.) The line segments in the diagram represent chemical bonds. (Direct Examination of Dr. Kipp at 320:9-10.) The lines on the outside of the hexagonal ring represent carbon-carbon chemical bonds arranged in what is called an "aromatic ring structure." (Id. at 320:11-24.) An aromatic ring structure has "special stability" because it contains six pi electrons. (Id. at 320:14-321:1.) Dr. Kipp explained that six pi electrons is a "magic number when it comes to the stabilization of this type of ring, and it's very hard to make modifications to that structure." (Id. at 321:2-4.) The structure, therefore, is "chemically fairly inert, and especially under normal storage conditions, you would not expect a lot of chemical change to occur." (Id. at 321:4-6.) He further testified that the pentagonal ring containing N and NH "shows aromatic stabilization for much the same reason." (Id. at 322:3-20.)

Dr. Kipp also explained that dexmedetomidine contains no hydrolyzable groups, meaning "organic chemical groups ... that react more readily with water." (Id. at 322:21-323:15.) Due to the molecule's aromatic ring structure, he stated, hydrolysis will not affect it under room-temperature storage conditions. (Id. at 343:6-11.) He pointed out that Precedex Concentrate and Dextomidor are formulated with water; if the dexmedetomidine compound had a hydrolyzable group, one would have seen it in the formulations for those products; yet the products had no "reported issues with hydrolysis." (Id. at 323:16-24.)

In addition, Dr. Kipp testified about the potential for dexmedetomidine to experience degradation through oxidation, meaning "the removal of electrons by oxygen or another oxidizing species from an organic molecule." (Id. at 324:4-5.) The molecule itself does not contain oxidizable groups like catechol or phenol, he noted, and due to the aromatic ring structure, oxidation will not affect the molecule under room-temperature storage conditions. (Id. at 324:6-19.) Discussing the carbon-hydrogen bond in the middle of the diagram, Dr. Kipp recognized that hydrogen abstraction might occur, but said this would happen only "oxidatively under ... very stringent conditions." (Id. at 325:2-21.) Similarly, he testified that the CH3 (methyl) components "might be potential sites of oxidation, but in order to get any type of oxidation to occur, you have to really hit on it with a strong oxidizing agent[.]" (Id. at 325:25-326:7.)

The '106 Patent shows that oxidation can occur with dexmedetomidine when one adds hydrogen peroxide, which is a strong oxidizing agent, and then places the formulation in an oven at sixty degrees Celsius for eight hours. (Id. at 326:18-20, 327:1-6 (discussing '106 Patent, JTX 1, tbl. 4).) Even under these conditions, which Dr. Kipp characterized as "very extremely harsh" and having no connection to real-life conditions, the patent discloses a loss in concentration of only about twelve percent. (Id. at 326:18-20, 327:7-11.) Again, Dr. Kipp pointed out, if oxidation were a problem with dexmedetomidine, one would have seen oxidation issues reported for Precedex Concentrate and Dexdomitor. (Id. at 327:12-17.) But in fact, no such issues were reported. (Id. at 327:18-20.)

Finally, Dr. Kipp opined that a POSA would have had a very good understanding of organic chemistry; recognized the chemical properties just discussed by looking at the molecule; and concluded that dexmedetomidine would be "rock stable" over "any long period of time." (See id. at 319:2-6, 321:16-23, 322:21-323:15, 324:20-325:1.)

2. Hospira's Pharmaceutical Chemistry and Drug Formulation Expert Dr. Robert Linhardt

Dr. Robert Linhardt has a bachelor's degree in chemistry, a master's degree in organic chemistry, and a Ph.D. in organic chemistry. (Direct Examination of Dr. Linhardt at 801:10-12.) He has decades of experience working on stability-related issues in pharmaceutical products, including low-molecular-weight compounds. (Id. at 801:25-802:4, 804:11-21.) Dr. Linhardt testified at trial as an expert in pharmaceutical chemistry and drug formulation. (Id. at 807:10-14.)

Dr. Linhardt agrees with Dr. Kipp that the aromaticity of the two rings imparts special stability on the molecule. (Id. at 818:10-819:15, 824:22-24.) He nevertheless testified that the molecule has "elements of instability in the methyl groups" and in the NH group of the pentagonal ring. (Id. at 819:20-820:4, 824:24-825:1.) The methyl and NH groups, Dr. Linhardt testified, are vulnerable to oxidation. (Id. at 820:3-4, 823:1-824:18.) Dr. Linhardt stated that although Dr. Kipp acknowledged the possibility of oxidation in the methyl groups under extreme conditions, he failed to discuss the possibility of oxidation in the NH group-where, according to Dr. Linhardt, oxidation is more likely to occur. (Id. at 821:4-9.) Dr. Linhardt asserts that instability is "a property of the molecule itself," regardless of concentration, and that the "about 2%" limitation is not inherent to dexmedetomidine. (Id. at 813:10-12, 825:14-18; Colloquy Between the Court and Dr. Linhardt at 825:2-6.)

When asked on cross examination whether he could "identify the conditions or time frame in which any oxidation ... would occur" by looking at the compound, Dr. Linhardt testified only that "it's likely that that oxidation will occur in the presence of an oxidant, like oxygen, or a proxy oxidant, like hydrogen peroxide[.]" (Cross Examination of Dr. Linhardt at 830:21-831:2.) And although he opined that a POSA would "look at [the] compound and predict that oxidation could occur," he acknowledged that "a POSA would likely test that prediction." (Id. at 827:25-828:5.)

LEGAL STANDARDS

Fresenius Kabi argues that claim 6 of the '106 Patent and claim 8 of the '049 Patent are invalid as obvious under 35 U.S.C. § 103(a). (Fresenius Kabi Br. 39.) A patent claim is invalid as obvious under 35 U.S.C. § 103(a)"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 pertains." 35 U.S.C. § 103(a) (2006) ; see also KSR Int'l Co. v. Teleflex Inc. , 550 U.S. 398, 406, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007). The determination of obviousness is a question of law that turns on underlying factual findings. See, e.g. , ZUP, LLC v. Nash Mfg., Inc. , 896 F.3d 1365, 1371 (Fed. Cir. 2018). "The underlying factual inquiries include (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 art; and (4) any relevant secondary considerations, such as commercial success, long felt but unsolved needs, and the failure of others." Western Union Co. v. MoneyGram Payment Sys., Inc. , 626 F.3d 1361, 1369 (Fed. Cir. 2010) (citing Graham v. John Deere Co. , 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966) ); see also, e.g. , ZUP, LLC , 896 F.3d at 1371.

As the party contending that the asserted claims are invalid as obvious, Fresenius Kabi "must demonstrate 'by clear and convincing evidence that a skilled artisan would have been motivated to combine the teachings of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success from doing so.' " Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc. , 752 F.3d 967, 973 (Fed. Cir. 2014) (quoting Procter & Gamble Co. v. Teva Pharm. USA, Inc. , 566 F.3d 989, 994 (Fed. Cir. 2009) ); see also Microsoft Corp. v. i4i Ltd. P'Ship , 564 U.S. 91, 95, 131 S.Ct. 2238, 180 L.Ed.2d 131 (2011) (holding that an invalidity defense must be proved by clear and convincing evidence).

FINDINGS OF FACT

1. A person of ordinary skill in the art ("POSA") is someone who possesses either (1) a Ph.D. in a pharmaceutically related science and two to three years of experience in pharmaceutical formulation, or (2) a master's degree in a pharmaceutically related science and three to four years of experience in pharmaceutical formulation.

A POSA would collaborate with other individuals as needed.

2. Drs. Kipp, Linhardt, Roychowdhury, and Cedergen are POSAs, as is Ms. Mowli.

3. The priority date for the '106 and '049 Patents is January 4, 2012.

4. Prior art includes the '214 Patent, Precedex Concentrate, Dexdomitor, Fanikos, the CSHP Guidelines, Cain, Remington, and Sacha because these references were published or otherwise available before January 4, 2012.

5. Precedex Concentrate combined with the knowledge of a POSA, including knowledge that would be informed by Fanikos, the CSHP Guidelines, Cain, Remington, and Sacha, taught a ready-to-use, sealed glass container with 4 µg/mL dexmedetomidine HCl.

6. A POSA would have been motivated to combine the disclosures in Precedex Concentrate, Fanikos, the CSHP Guidelines, Cain, Remington, and Sacha to create a ready-to-use 4 µg/mL dexmedetomidine HCl formulation, stored in a Type I glass vial, sealed with a coated rubber stopper.

7. Precedex Concentrate combined with Dexdomitor expressly disclosed a ready-to-use, sealed glass container with 4 µg/mL dexmedetomidine HCl.

8. A POSA would have been motivated to combine the disclosures in Precedex Concentrate and Dexdomitor to create a ready-to-use 4 µg/mL dexmedetomidine HCl formulation, stored in a Type I glass vial, sealed with a coated rubber stopper.

9. All stability data in the record for 4 µg/mL dexmedetomidine HCl formulations stored in Type I glass vials, sealed with coated rubber stoppers, and stored at room temperature shows that there was "no more than about 2%" loss in concentration at five months.

10. The "about 2%" limitation of the '106 Patent is inherent in a 4 µg/mL dexmedetomidine HCl formulation, stored in a Type I glass vial sealed with a coated rubber stopper, and stored at room temperature for five months.

11. A POSA would have a considerable understanding of organic chemistry. Based on his or her understanding of the chemical properties of dexmedetomidine, a POSA would have expected it to be stable in room-temperature storage conditions for at least five months.

12. Precedex Concentrate disclosed that the formulation had a pH range of 4.5 to 7.0, which is within the range of two to ten claimed in claim 8 of the '049 Patent.

13. A POSA would have been motivated to ensure that the pH range of a ready-to-use dexmedetomidine product fell within two and ten.

13. Evidence supporting secondary considerations is weak because the '214 Patent restricted production of any dexmedetomidine drug between March 1990 and July 2013.

DISCUSSION

A. Obviousness of the '106 Patent

Fresenius Kabi argues that claim 6 of the '106 Patent is invalid as obvious. According to Fresenius Kabi, the prior art expressly disclosed the following claim limitations: a ready-to-use, sealed glass container with 4 µg/mL dexmedetomidine HCl. (Fresenius Kabi Br. 9.) In its post-trial brief, Hospira does not specifically rebut this contention, but as the court will discuss below, makes several arguments that suggest it has not conceded the point. More central to the parties' dispute is the "about 2%" limitation of the '106 Patent. Fresenius Kabi acknowledges that the prior art did not expressly disclose this limitation. (See, e.g. , Cross Examination of Dr. Kipp at 391:9-13 (testifying that "there's nothing that discloses, outside of the patents-in-suit, the ... 2 percent limitation").) Fresenius Kabi, however, relies on the doctrine of inherency to supply it. (Fresenius Kabi Br. 16-18; see PAR Pharm., Inc. v. TWI Pharm., Inc. , 773 F.3d 1186, 1194-95 (Fed. Cir. 2014) (stating that in some circumstances, "inherency may supply a missing claim limitation in an obviousness analysis").) Hospira's key arguments for non-obviousness are that Fresenius Kabi has failed to prove by clear and convincing evidence (1) the inherency of the "about 2%" limitation and (2) that a POSA would have been motivated to combine the prior art teachings with a reasonable expectation of success. (Hospira Resp. 11-23.) The court addresses the parties' arguments in turn.

1. Ready-to-Use, Sealed Glass Container with 4 µg/mL Dexmedetomidine HCl

Fresenius Kabi contends that a ready-to-use, sealed glass container with 4 µg/mL dexmedetomidine HCl was disclosed in the following combinations of references: (1) Precedex Concentrate and the knowledge of a POSA, and (2) Precedex Concentrate and Dexdomitor. (Fresenius Kabi Br. 9-10.) Fresenius Kabi also argues that a POSA would have been motivated to combine the disclosed limitations to create a ready-to-use 4 µg/mL dexmedetomidine HCl formulation, stored in a Type I glass vial, sealed with a coated rubber stopper. (Id. at 9-14.) For the following reasons, the court agrees.

i. Precedex Concentrate and the Knowledge of a POSA

Precedex Concentrate has been on the market since 1999. Its label discloses the exact contents of its formulation, including that it contains no preservatives, additives, or chemical stabilizers. (SeePrecedex Concentrate Label at JTX 15.2.) A named co-inventor of the '106 Patent, Dr. Roychowdhury, admitted that the label taught her the formulation and that there is "no difference between the formulation of the further diluted Precedex [C]oncentrate versus the Precedex [P]remix product[.]" (Direct Examination of Dr. Roychowdhury at 134:19-135:2, 137:20-138:10.) Hospira's corporate representative, Dr. Tata-Venkata, gave similar testimony. (Tata-Venkata Dep. at 172:17-21.) The Precedex Concentrate label also discloses that the formulation must be diluted to 4 µg/mL before being administered to humans and sets forth the steps to perform the dilution. (SeePrecedex Concentrate Label at JTX 15.13.) Drs. Roychowdhury and Cedergen testified they knew from the label that their goal was to make a 4 µg/mL formulation. (Direct Examination of Dr. Roychowdhury at 134:12-18; Direct Examination of Dr. Cedergen at 202:2-20.) For these reasons, the court concludes that the Precedex Concentrate label disclosed how to make the 4 µg/mL formulation.

The court also concludes that Precedex Concentrate disclosed a glass container as a storage material for dexmedetomidine HCl. The label, for example, expressly states that the product is packaged in glass vials (Precedex Concentrate Label at JTX 15.14), and Dr. Roychowdhury testified that while she was developing Precedex Premix, she knew this was the case. (Direct Examination of Dr. Roychowdhury at 135:18-20.) The evidence also shows that a POSA would have known from his or her experience in the pharmaceutical industry that glass, and specifically Type I glass, was a suitable storage material for the drug. Indeed, Drs. Roychowdhury and Tata-Venkata testified they knew that glass was unlikely to have issues with adsorption or absorption (id. at 150:12-151:8; Tata-Venkata Dep. at 82:15-83:10); Dr. Cedergen testified that he assumes glass is non-reactive absent evidence to the contrary (Direct Examination of Dr. Cedergen at 205:14-18); and Dr. Roychowdhury testified that she chose Type I glass as the storage material for Precedex Premix because she knew from experience that it was the best type of glass for the product. (Direct Examination of Dr. Roychowdury at 153:4-9.) The court further finds that in addition to Precedex Concentrate, Remington and Sacha disclosed glass as the most widely used storage material for liquid pharmaceuticals. (Remington at JTX 20.13; Sacha at JTX 24.3.) These references, read with the Precedex Concentrate label, would have taught a POSA that glass was an appropriate storage material for dexmedetomidine HCl.

In addition, the court concludes that Precedex Concentrate disclosed the use of a coated rubber stopper to seal the Type I glass vial. Dr. Roychowdhury, for example, testified that while she was developing Precedex Premix, she knew that Precedex Concentrate used coated rubber stoppers "to avoid interaction with the drug." (Direct Examination of Dr. Roychowdhury at 135:21-136:1.) In fact, a development report she authored states that Hospira "planned to implement coated stoppers in order to mimic the current product[.]" (Unsigned Hospira Development Report at JTX 62.12.) Dr. Kipp, for his part, testified that Precedex Concentrate "include[d] a sealed glass container as its final packaging configuration, with a Teflon-coated stopper." (Direct Examination of Dr. Kipp at 310:6-9.)

The court also has little difficulty in concluding that a POSA would have known from his or he