Case 1:15-cv-00697-RGA Document 119 Filed 01/22/18 Page 1 of 55 PageID #: 2852
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`HOSPIRA, INC.,
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`Plaintiff;
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`v.
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`AMNEAL PHARMACEUTICALS, LLC,
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`Defendant.
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`Civil Action No. l 5-cv-697-RGA
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`MEMORANDUM OPINION
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`Arthur G. Connolly, III and Ryan P. Newell, CONNOLLY GALLAGHER LLP, Wilmington, DE;
`Bradford P. Lyerla, Sara T. Horton, and YusufEsat, JENNER & BLOCK LLP, Chicago, IL.
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`Attorneys for Plaintiffs
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`Frederick L. Cottrell, III, Kelly E. Farnan, and Christine D. Haynes, RICHARDS, LAYTON &
`FINGER, P.A., Wilmington, DE; Steven A. Maddox, Jeremy J. Edwards, Matthew C. Ruedy, and
`Kaveh V. Saba, MADDOX EDWARDS PLLC, Washington, D.C.
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`Attorneys for Defendant.
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`January J:/b 2018
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`Case 1:15-cv-00697-RGA Document 119 Filed 01/22/18 Page 2 of 55 PageID #: 2853
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`Plaintiff brought this patent infringement action against Amneal Pharmaceuticals, LLC in
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`2015.
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`(D.1. 1). At issue in this case are ready-to-use formulations of the compound
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`dexmedetomidine. Dexmedetomidine itself is claimed in U.S. Patent No. 4,910,214 ("the '214
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`patent"), which is not at issue in this case. The '214 patent issued on March 20, 1990 and expired
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`on July 15, 2013. (Trial Transcript ("Tr.") 1081:9-12, 1082:10-15; '214 patent; D.I. 96-1at37). 1
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`Dexmedetomidine, which is the d-enantiomer of racemic 4-[1-(2,3-dimethylphenyl)ethyl]-lH-
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`imidazole, is a sedative and is the active ingredient in Hospira's Precedex products. ('106 patent
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`at 1 :26-28, 1 :34-37; Tr. 5:6-9). Amneal filed Abbreviated New Drug Application ("ANDA")
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`No. 207551, seeking to engage in the commercial manufacture, use, and sale of generic versions
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`ofHospira's 4µg/mL dexmedetomidine products ("Precedex premix") in 50 mL and 100 mL glass
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`vials. (D.I. 96-1 at 3-4; PTX-63 at p. 6).
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`Since its FDA approval in 1999, Hospira's original Precedex product (100 µg/mL
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`dexmedetomidine hydrochloride), also known as Precedex concentrate, has been sold in a 2 mL
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`glass vial. (Tr. 6:11-15; D.I. 96-1at2). Before Precedex concentrate is administered to a patient,
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`it must be diluted to an appropriate concentration per the instructions on the Precedex concentrate
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`label. (Tr. 6:17-20). The delay in drug administration to patients and increased risks of dosing
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`error and contamination associated with this dilution step led Hospira to develop ready-to-use
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`formulations ofPrecedex. (Id at 7:7-10). In 2013, Hospira received FDA approval for 50 mL and
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`100 mL glass bottles containing a ready-to-use 4 µg/mL formulation of dexmedetomidine
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`hydrochloride. (D.I. 96-1 at 2). FDA approval of the same formulation in a 20 mL glass vial
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`followed in 2014. (Id at 3).
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`1 The trial transcript is available on the docket at D.I. 114-117. It is consecutively paginated.
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`Case 1:15-cv-00697-RGA Document 119 Filed 01/22/18 Page 3 of 55 PageID #: 2854
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`The Court held a bench trial from August 21-24, 2017. Plaintiff asserts that Defendant's
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`ANDA submission constitutes infringement of claims 3 and 4 of U.S. Patent No. 8,242,158 ("the
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`'158 patent"), claim 4 of U.S. Patent No. 8,338,470 ("the'470 patent"), claim 5 of U.S. Patent
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`No. 8,455,527 ("the'527 patent"), and claim 6 of U.S. Patent No. 8,648,106 ("the '106 patent").
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`(Tr. 3:15-20; D.I. 101 at 3). The asserted patents are part of the same patent family and share a
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`common specification. (D.I. 96 at 4).
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`Independent claim 1 and dependent claims 2-4 of the '158 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 4 µg/mL disposed within a sealed
`glass container.
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`2. The ready to use liquid pharmaceutical composition of claim 1, further
`comprising sodium chloride at a concentration of between about 0.01 and about 2.0
`weight percent.
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`3. The ready to use liquid pharmaceutical composition of claim 2, wherein
`the sodium chloride is present at a concentration of about 0.9 weight percent.
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`4. The ready to use liquid pharmaceutical composition of claim 1, wherein
`the composition is formulated as a total volume selected from the group consisting
`of 20 mL, 50 mL and 100 mL.
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`(' 15 8 patent at claims 1-4).
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`Independent claim 1 and dependent claim 4 of the '470 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.
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`4. The ready to use liquid pharmaceutical composition of claim 1, wherein
`the dexmedetomidine or pharmaceutically acceptable salt thereof is at a
`concentration of about 1 to about 7 µg/mL.
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`('470 patent at claims 1, 4).
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`Independent claim 1 and dependent claim 5 of the '527 patent read as follows:
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`1. A method of providing sedation to a patient in need thereof, the method
`comprising administering to the patient an effective amount of a composition,
`wherein the composition comprises dexmedetomidine or a pharmaceutically
`acceptable salt thereof at a concentration of about 0 .005 to about 50 µg/mL, wherein
`the composition is a ready to use liquid pharmaceutical composition for parenteral
`administration to the patient disposed within a sealed glass container.
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`5. The method of claim 1, wherein
`the dexmedetomidine or
`pharmaceutically acceptable salt thereof is at a concentration of about 4 µg/mL.
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`('527 patent at claims 1, 5).
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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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`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 at claims 1, 6).
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`I. LEGAL ST AND ARDS
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`A. Claim Construction
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`"It is a bedrock principle of patent law that the claims of a patent define the invention to
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`which the patentee is entitled the right to exclude." Phillips v. AWH Corp., 415 F.3d 1303, 1312
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`(Fed. Cir. 2005) (en bane). "'[T]here is no magic formula or catechism for conducting claim
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`construction.' Instead, the court is free to attach the appropriate weight to appropriate sources 'in
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`light of the statutes and policies that inform patent law."' Soft View LLC v. Apple Inc., 2013 WL
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`4758195, at *1 (D. Del. Sept. 4, 2013) (quoting Phillips, 415 F.3d at 1324) (alteration in original).
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`When construing patent claims, a court considers the literal language of the claim, the patent
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`specification, and the prosecution history. Markman v. Westview Instruments, Inc., 52 F.3d 967,
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`979-80 (Fed. Cir. 1995) (en bane), aff'd, 517 U.S. 370 (1996). Of these sources, "the specification
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`is always highly relevant to the claim construction analysis. Usually, it is dispositive; it is the
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`single best guide to the meaning of a disputed term." Phillips, 415 F .3d at 1315.
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`"[T]he words of a claim are generally given their ordinary and customary meaning ....
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`[This is] the meaning that the term would have to a person of ordinary skill in the art in question
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`at the time of the invention, i.e., as of the effective filing date of the patent application." Id. at
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`1312-13. "In some cases, the ordinary meaning of claim language as understood by a person of
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`skill in the art may be readily apparent even to lay judges, and claim construction in such cases
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`involves little more than the application of the widely accepted meaning of commonly understood
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`words." Id. at 1314.
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`When a court relies solely upon the intrinsic evidence-the patent claims, the specification,
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`and the prosecution history-the court's construction is a determination oflaw. See Teva Pharms.
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`USA, Inc. v. Sandoz, Inc., 135 S. Ct. 831, 841 (2015). The court may also make factual findings
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`based upon consideration of extrinsic evidence, which "consists of all evidence external to the
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`patent and prosecution history, including expert and inventor testimony, dictionaries, and learned
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`treatises." Phillips, 415 F.3d at 1317-19. Extrinsic evidence may assist the court in understanding
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`the underlying technology, the meaning of terms to one skilled in the art, and how the invention
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`works. Id. Extrinsic evidence, however, is less reliable and less useful in claim construction than
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`the patent and its prosecution history. Id.
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`B. Obviousness
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`A patent claim is invalid as obvious under 35 U.S.C. § 103 "if the differences between the
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`subject matter sought to be patented and the prior art are such that the subject matter as a whole
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`would have been obvious at the time the invention was made to a person having ordinary skill in
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`the art to which said subject matter pertains." 35 U.S.C. § 103; see also KSR Int'/ Co. v. Teleflex
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`Inc., 550 U.S. 398, 406-07 (2007). The determination of obviousness is a question oflaw with
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`underlying factual findings. See Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342,
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`1360 (Fed. Cir. 2012). "The underlying factual inquiries include (1) the scope and content of the
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`prior art; (2) the differences between the prior art and the claims at issue; (3) the level of ordinary
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`skill in the art; and (4) any relevant secondary considerations .... " Western Union Co. v.
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`MoneyGram Payment Sys., Inc., 626 F.3d 1361, 1369 (Fed. Cir. 2010) (citing Graham v. John
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`Deere Co., 383 U.S. 1, 17-18 (1966)).
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`A court is required to consider secondary considerations, or objective indicia of
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`nonobviousness, before reaching an obviousness determination, as a "check against hindsight
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`bias." See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d
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`1063, 1078-79 (Fed. Cir. 2012). Relevant secondary considerations include commercial success,
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`long felt but unsolved needs, failure of others, praise, unexpected results, and copying, among
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`others. Graham, 383 U.S. at 17-18; Ruiz v. A.B. Chance Co., 234 F.3d 654, 662-63 (Fed. Cir.
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`2000); Tex. Instruments Inc. v. U.S. Int'/ Trade Comm 'n, 988 F.2d 1165, 1178 (Fed. Cir. 1993).
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`Secondary considerations of nonobviousness are important because they "serve as insurance
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`against the insidious attraction of the siren hindsight .... " WL. Gore & Assocs., Inc. v. Garlock,
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`Inc., 721 F.2d 1540, 1553 (Fed. Cir. 1983).
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`A patentee is not required to present evidence of secondary considerations. See Prometheus
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`Labs., Inc. v. Roxane Labs., Inc., 805 F.3d 1092, 1101-02 (Fed. Cir. 2015). There must be enough
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`evidence, however, for a finding that a given secondary consideration exists by a preponderance
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`of the evidence. See Apple, Inc. v. Samsung Elec. Co., Ltd., 839 F.3d 1034, 1053 (Fed. Cir. 2016)
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`(en bane). If there is, then the probative value of each secondary consideration will be considered
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`in light of the evidence produced. That does not mean, though, that the burden of persuasion on
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`the ultimate question of obviousness transfers to the proponent of the secondary consideration.
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`Pfizer, Inc. v. Aptoex, Inc., 480 F.3d 1348, 1359 (Fed. Cir. 2007). That burden stays always with
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`the patent challenger. Id. at 1359-60.
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`A party asserting that a patent is invalid as obvious must "show by clear and convincing
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`evidence that a skilled artisan would have been motivated to combine the teachings of the prior art
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`references to achieve the claimed invention, and that the skilled artisan would have had a
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`reasonable expectation of success in doing so." Id. at 1361. That "expectation of success need
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`only be reasonable, not absolute." Id. at 1364. "Whether an ordinarily skilled artisan would have
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`reasonably expected success ... is measured as of the date of the invention[] .... " Amgen Inc. v.
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`F. Hoffman-La Roche Ltd, 580 F.3d 1340, 1362 (Fed. Cir. 2009).
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`C. Anticipation
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`"To show that a patent claim is invalid as anticipated, the accused infringer must show by
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`clear and convincing evidence that a single prior art reference discloses each and every element of
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`a claimed invention." Silicon Graphics, Inc. v. ATI Techs., Inc., 607 F.3d 784, 796 (Fed. Cir. 2010).
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`"[E]very element of the claimed invention [must be] described, either expressly or inherently, such
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`that a person of ordinary skill in the art could practice the invention without undue
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`experimentation." Callaway Golf Co. v. Acushnet Co., 576 F.3d 1331, 1346 (Fed. Cir. 2009). As
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`with infringement, the court construes the claims and compares them against the prior art. See
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`Enzo Biochem, Inc. v. Applera Corp., 599 F.3d 1325, 1337 (Fed. Cir. 2010).
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`D. Indefmiteness
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`A patent must "inform those skilled in the art about the scope of the invention with
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`reasonable certainty." Nautilus, Inc. v. Biosig Instruments, Inc., 134 S. Ct. 2120, 2129 (2014). To
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`determine indefiniteness, courts examine "the patent record-the claims, specification, and
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`prosecution history-to ascertain if they convey to one of skill in the art with reasonable certainty
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`the scope of the invention claimed." Teva Pharms. USA, Inc. v. Sandoz, Inc., 789 F.3d 1335, 1341
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`(Fed. Cir. 2015). "[I]f necessary, a court may consult extrinsic evidence to understand the meaning
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`of a term in the relevant art." Transcend Med., Inc. v. Glaukos Corp., 2015 WL 5546988 at *5 (D.
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`Del. Sept. 18, 2015) (citation omitted).
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`E. Infringement
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`A patent is infringed when a person "without authority makes, uses, offers to sell, or sells
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`any patented invention, within the United States ... during the term of the patent .... " 35 U.S.C.
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`§ 271(a). A two-step analysis is employed in making an infringement determination. See
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`Markman, 52 F.3d at 976. First, the court must construe the asserted claims to ascertain their
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`meaning and scope. See id. The trier of fact must then compare the properly construed claims
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`with the accused infringing product. See id. This second step is a question of fact. Bai v. L & L
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`Wings, Inc., 160 F.3d 1350, 1353 (Fed. Cir. 1998). "Literal infringement of a claim exists when
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`every limitation recited in the claim is found in the accused device." Kahn v. Gen. Motors Corp.,
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`135 F.3d 1472, 1477 (Fed. Cir. 1998). "If any claim limitation is absent from the accused device,
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`there is no literal infringement as a matter oflaw." Bayer AG v. Elan Pharm. Research Corp., 212
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`F.3d 1241, 1247 (Fed. Cir. 2000). The patent owner has the burden of proving infringement by a
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`preponderance of the evidence. See SmithKline Diagnostics, Inc. v. Helena Labs. Corp., 859 F.2d
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`878, 889 (Fed. Cir. 1988).
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`For jurisdictional purposes, 35 U.S.C. § 271(e)(2)(A) defines filing an ANDA application
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`for a drug covered by a patent as an act ofinfringement. 35 U.S.C. § 27l(e)(2)(A); see also Glaxo,
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`Inc. v. Novopharm, Ltd., 110 F.3d 1562, 1569 (Fed. Cir. 1997) ("[Section] 271(e)(2) provided
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`patentees with a defined act of infringement sufficient to create case or controversy jurisdiction to
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`enable a court to promptly resolve any dispute concerning infringement and validity."). "Because
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`drug manufacturers are bound by strict statutory provisions to sell only those products that comport
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`with the AND A's description of the drug, an ANDA specification defining a proposed generic drug
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`in a manner that directly addresses the issue of infringement will control the infringement inquiry."
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`Abbott Labs. v. TorPharm, Inc., 300 F.3d 1367, 1373 (Fed. Cir. 2002). Therefore, "when a drug
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`manufacturer seeks FDA approval to market a generic compound within the scope of a valid patent,
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`it is an infringement as a matter oflaw." Sunovion Pharms., Inc. v. Teva Pharms. USA, Inc., 731
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`F.3d 1271, 1280 (Fed. Cir. 2013). When an ANDA is silent with respect to at least one claim
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`limitation of the patents at issue, however, Sunovion does not apply, and "the relevant inquiry is
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`whether the patentee has proven by a preponderance of the evidence that the alleged infringer will
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`likely market an infringing product." Ferring B. V. v. Watson Labs., Inc.-Fla., 764 F.3d 1382, 1388
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`(Fed. Cir. 2014) (citation omitted).
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`II. DISPUTED CLAIM CONSTRUCTIONS
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`The parties dispute the constructions for "ready to use" and "sealed glass container," each
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`of which appear in all of the asserted claims. Although the parties stipulated that Defendant's
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`proposed ANDA products meet the "ready to use" limitation for purposes of infringement, they
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`dispute the plain meaning of the term for purposes of assessing invalidity. (Tr. 4:10-15). There
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`was no stipulation with respect to the "sealed glass container" limitation for purposes of assessing
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`infringement. (Id. at 3 :22-4:8).
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`At trial, Plaintiff argued for a construction defining the plain meaning of "ready to use" as
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`"formulated to be suitable for administration to a patient upon manufacture without dilution or
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`reconstitution." (Id. at 262:9-263:1). Defendant asserts that the plain meaning of "ready to use"
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`is "requiring no further dilution or reconstitution before administration to a patient." (Id. at 581: 12-
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`19). The common specification of the asserted patents reveals that the patentees acted as their own
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`lexicographers with respect to this term. In a section titled "Definitions," the specification states
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`that "ready to use" formulations "refer to premixed compositions that are suitable for
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`administration to a patient without dilution." (See, e.g., '106 patent at 3:66-4:2). Therefore, I
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`conclude that the construction of "ready to use" is "suitable for administration to a patient without
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`dilution."
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`During trial, I proposed several constructions for "sealed glass container." (Tr. 1176:2-
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`21 ). Among those constructions was "a container that is closed tightly to maintain sterility."
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`(Tr.1176:12-20). The parties appear to have agreed to this construction.
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`(D.I. 100 at 34-35
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`("Amneal submits that either of the Court's two proposed definitions of 'sealed' would be proper,
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`so long as a further tamper-[ evident limitation] is not added."); D.I. 101 at 5 n.3 ("So long as this
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`construction includes the limitation of 'glass,' Hospira agrees that this proposed meaning is
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`supported by the record because a sealed container in this context maintains sterility."); see also
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`'106 patent at 9:9-15 (disclosing a sealed glass container packaging embodiment that "can
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`maintain the sterility of, or prevent the contamination of, a premixed dexmedetomidine
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`composition")). Accordingly, I will construe "sealed glass container" as "a glass container that is
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`closed tightly to maintain sterility."
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`III. VALIDITY OF THE '158, '470, '527, AND '106 PATENTS
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`The' 158, '470, and' 106 patents each describe ready-to-use pharmaceutical compositions
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`of dexmedetomidine or a pharmaceutically acceptable salt thereof for parenteral administration,
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`disposed within a sealed glass container. The asserted claims of these patents claim or encompass
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`dexmedetomidine concentrations of 4 µg/mL. Certain asserted claims contain additional
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`limitations, such as the presence of sodium chloride at a concentration of about 0 .9 weight percent
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`in the dexmedetomidine formulation (' 158 patent at claim 3), certain volumes of the
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`dexmedetomidine formulation (id. at claim 4), and formulations losing no more than about 2%
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`dexmedetomidine concentration at 5months('106 patent at claim 6). Asserted claim 5 of the '527
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`patent claims a method of providing sedation to a patient via parenteral administration using a
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`4 µg/mL dexmedetomidine formulation disposed within a sealed glass container. ('527 patent at
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`claim 5).
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`Defendant argues that all the asserted claims are invalid as obvious, and further asserts that
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`claim 3 of the '158 patent, claim 4 of the '470 patent, and claim 5 of the '527 patent are invalid as
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`anticipated. (D.I. 100 at 8, 36). Additionally, Defendant contends that claim 6 of the '106 patent
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`is indefinite under 35 U.S.C. § 112. (Id. at 26).
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`A. Findings of Fact
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`1. For the product claims, the person of ordinary skill in the art ("POSA") holds an advanced
`degree, such as a Ph.D., M.D., or Pharm.D., in chemistry, pharmacology, or pharmaceutical
`development.
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`2. For the method of treatment claim, the POSA would have some formal education in
`science, chemistry, pharmacology or pharmaceutical development, and would have several
`years of experience administering pharmaceuticals to patients,
`including clinical
`experience in anesthesia or sedation and familiarity with parenteral injections. The
`POSA's practical experience may vary depending on the POSA's level of formal
`education.
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`3. The priority date for the asserted patents is January 4, 2012. (D.I. 96-1 at 5).
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`4. Each of the asserted patents is assigned to Hospira. (D.I. 96-1 at 2).
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`5. The Precedex Concentrate product, the 2010 Precedex concentrate label, Cain, and Trissel
`are prior art to the asserted patents. (D.I. 96-1 at 5-8).
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`6. Evidence supporting commercial success of Plaintiffs Precedex Premix product is weak
`due to the '214 blocking patent covering the dexmedetomidine compound and due to
`Plaintiffs business practices in marketing its Precedex Premix product.
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`7. Each of claims 3 and 4 of the '158 patent, claim 4 of the '470 patent, and claim 5 of the
`'527 patent is obvious over the 2010 Precedex concentrate label and the Precedex
`concentrate product, in view of the pharmaceutical packaging knowledge in the art.
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`8. Claim 6 of the '106 patent is not obvious over the 2010 Precedex concentrate label and the
`Precedex concentrate product, in view of the pharmaceutical packaging knowledge in the
`art.
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`9. Trissel does not anticipate any of the asserted claims.
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`10. Trissel does not render any of the asserted claims obvious in view of the pharmaceutical
`packaging knowledge in the art.
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`B. Conclusions of Law
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`1. Obviousness of the '158, '470, and '527 Patents
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`Defendant argues that in view of pharmaceutical packaging knowledge in the art, the
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`asserted claims are obvious over the prior art Precedex concentrate product in combination with
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`the 2010 label accompanying it, or obvious over Trissel. (D.I. 100 at 3, 36). Plaintiff responds
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`that the asserted claims are not obvious because the prior art did not disclose a ready-to-use
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`4 µg/mL dexmedetomidine solution or suggest development of such a solution, the USPTO issued
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`the patents-in-suit over the Precedex concentrate product and the accompanying label, and
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`commercial success of the Precedex premix product supports nonobviousness. (D.I. 106 at 7, 9,
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`10, 16).
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`a. Scope and Content of the Prior Art
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`L
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`Background
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`The prior art recognized that it was not unusual for new products "of a similar class or type
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`[to] mimic the packaging used on the first marketed product, even if newer materials and
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`alternative material fabrication, [or] manufacturing ... offer significant advantages." (DTX-202
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`at p. 189). As of the priority date, glass had a long history as a successful pharmaceutical
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`packaging material, and was considered "the traditional gold standard for pharmaceutical
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`packaging." (Id. at p. 192; Tr. 525:5-526:4). A 2010 literature review recognized glass as "the
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`container material of choice for most small volume injectables." (DTX-219 at p. 12; see also id.
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`at p. 7 (recognizing glass as "the most common packaging for liquid and freeze-dried injectables");
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`DTX-200 at pp. 79-80 (noting in discussion of glass interactions with drug products that "Type I
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`glass will be suitable for all products ... "and noting the use of treated glass to resolve any product
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`incompatibilities with glass); DTX-553 at p. 809 ("Glass is employed as the container material of
`
`choice for most [small-volume injectables]")). A small-volume injectable, or "small volume
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`parenteral, is anything less than a hundred mLs as opposed to [a large-volume parenteral], which
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`is above a hundred mLs." (Tr. 528:1-9).
`
`Glass has several properties that make it desirable for pharmaceutical packaging. Among
`
`these are its impermeability and its largely inert chemical nature. (DTX-202 at p. 192). Although
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`glass is not completely inert, its long history and known chemistry allow packaging engineers to
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`alleviate any problems that arise with using glass as a pharmaceutical packaging material for a
`
`particular product. (Id. at p. 192; DTX-553 at p. 809 (noting that disadvantages of glass "can be
`
`minimized by the proper selection of the glass composition")). For example, treated glass may be
`
`used to address problems such as adsorption of the active ingredient to the surface of the glass
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`Case 1:15-cv-00697-RGA Document 119 Filed 01/22/18 Page 14 of 55 PageID #: 2865
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`packaging. (DTX-200 at p. 80).
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`Glass pharmaceutical packaging does, however, have some chemical and physical
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`drawbacks. (DTX-202 at p. 199). If the glass container is comprised of migratory oxides, such
`
`oxides may leach from the glass container into the solution inside it, leading to an increase in the
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`pH of the solution or other unintended chemical reactions. (DTX-553 at p. 809). Some glass
`
`compounds are vulnerable to attack by solutions with certain characteristics, and glass flakes may
`
`be dislodged into the solution inside the glass container if such an attack occurs. (Id.). Glass may
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`shatter if mishandled during shipping or during use in the clinical setting. (Tr. 940:20-941 :6).
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`Additionally, glass packaging is more expensive to manufacture and transport than plastic
`
`packaging. (DTX-202 at p. 199). The prior art recognized, however, that the use of treated glass
`
`could address many of the chemical drawbacks to glass pharmaceutical packaging. (DTX-553 at
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`p. 81 O; DTX-200 at p. 80).
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`As of the priority date, clinicians also demonstrated a general preference for ready-to-use
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`pharmaceuticals. (DTX-43 at p. 5 ("At a 2008 national consensus conference on the safety of
`
`intravenous drug delivery systems, there was a clear preference for manufacturer-prepared
`
`completely ready-to-use IV medication in all settings .... ")). Ready-to-use pharmaceuticals
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`demonstrated the potential to improve patient safety through eliminating errors associated with
`
`dilution from a concentrate form, such as errors in dosing, preparation technique, drug, or base
`
`solution. (Tr. 522:15-523:15; DTX-44 at p. 56 ("Premixed formulations may obviate a variety of
`
`admixture-related problems, including admixture preparation errors, delays in administration, and
`
`interruptions in pharmacy workflow."); DTX-46 at p. 177 (concluding, in neonatal unit university
`
`hospital study of relative safety gains for specific tools, that "the involvement of a clinical
`
`pharmacist and the introduction of ready-to-use syringes for selected drugs have been shown to be
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`Case 1:15-cv-00697-RGA Document 119 Filed 01/22/18 Page 15 of 55 PageID #: 2866
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`the most cost-effective tool.")). Additional benefits of ready-to-use formulations include reduced
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`delays in administering medication to patients and minimizing waste and costs. (DTX-44 at p. 56
`
`("The use of premixed solutions obviates the need for admixture or other manipulations prior to
`
`clinical use, thereby ... improving efficiency and patient safety, facilitating adherence to policies
`
`and procedures, and minimizing waste and costs.")).
`
`IL
`
`Precedex Concentrate Product and Package Insert
`
`The pnor art Precedex concentrate product
`
`is a 100 µg/mL
`
`formulation of
`
`dexmedetomidine in 0.9% sodium chloride disposed within a 2 mL glass vial. (Tr. 510:20-511 :2).
`
`The Package Insert is the label that accompanies the Precedex concentrate product. (DTX-23 at
`
`p. 5014). It displays a revision date of September 2010, and indicates that Precedex concentrate
`
`is approved for intensive care sedation and procedural sedation. (Id.). The 2010 label includes
`
`instructions to dilute the Precedex concentrate product with 0.9% sodium chloride to achieve
`
`50 mL of a 4 µg/mL dexmedetomidine formulation, to be administered intravenously.
`
`(Id. at
`
`pp. 5014, 5016). Strict aseptic technique is required during dilution, and the label counsels against
`
`the use of natural rubber with the product, instead recommending the use of administration
`
`components made of synthetic or coated rubber. (Id. at pp. 5016-17). No additives or chemical
`
`stabilizers are present in Precedex concentrate. (Id. at p. 5027). According to the label, each 2 mL
`
`glass vial is intended for a single use only, and vials of Precedex concentrate are to be stored at
`
`room temperature, "with excursions allowed from 15 to 30°C." (Id. at p. 5032).
`
`m.
`
`Trissel
`
`Trissel is a study published in 2002 that sought to determine the "physical compatibility of
`
`Precedex with 95 selected other drugs." (DTX-120 at Abstract). Since Precedex is commonly
`
`used in intensive care settings, patients receiving Precedex are likely receiving other drugs
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`I I
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`Case 1:15-cv-00697-RGA Document 119 Filed 01/22/18 Page 16 of 55 PageID #: 2867
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`simultaneously. (Id. at p. 230). To test compatibility, the Trissel authors used a 15 mL borosilicate
`
`glass screw-cap culture tube to mix 5 mL of a 4 µg/mL formulation of Precedex (to mimic the
`
`Precedex concentration administered to patients) with 5 mL of each of the drugs tested. (Id.). To
`
`achieve the 4 µg/mL Precedex formulation, the authors diluted the Precedex concentrate product
`
`with 0.9% sodium chloride injection to a concentration of 4 µg/mL per the instructions on the label
`
`accompanying the Precedex concentrate product. (Id.). The authors tested for compatibility at 15
`
`minutes, 1 hour, and 4 hours after sample preparation. (Id.). One of the control samples consisted
`
`of 4µg/mL Precedex, diluted from the Precedex concentrate product with 0.9% sodium chloride
`
`injection. (Id.). The Trissel authors concluded that, "Precedex is physically compatible for4 hours
`
`at room temperature with 93 drugs evaluated in this study during simulated Y-site administration."
`
`(Id. at p. 233).
`
`b. Comparing Prior Art and Claimed Subject Matter
`
`As an initial matter, Plaintiff urges that the asserted claims are nonobvious over the
`
`Precedex concentrate product and the 2010 label in part because the patent examiner considered
`
`these references during prosecution, and ultimately issued the asserted claims over the references.
`
`(D.I. 106 at 7-8). According to Plaintiff, "the examiner explicitly considered and rejected
`
`Amneal's arguments that the 2010 package insert disclosed a 'known' ready-to-use solution in a
`
`'known' sealed glass container." (Id. at 8). The examiner's findings, however, are not entitled to
`
`deference here. Novo Nordisk AIS v. Caraco Pharm. Labs., Ltd., 719 F.3d 1346, 1357 (Fed. Cir.
`
`2013) ("The present case is a district court challenge to an issued patent brought under the Hatch-
`
`Waxman Act, not a challenge to a PTO rejection ... [so t]he initial determinations by the PTO in
`
`determining to grant the application are entitled to no deference .... "). Nor does the clear and
`
`convincing evidence standard to prove invalidity change based on what the examiner considered.
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`Case 1:1