Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 1 of 37 PageID #: 1427
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`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`
`Civil Action No. 15-697-RGA
`
`
`HOSPIRA, INC.,
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`
`
`AMNEAL PHARMACEUTICALS LLC,
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`
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`v.
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`
`
`
`
`
`
`Plaintiff,
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`Defendant.
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`
`
`
`AMNEAL’S OPENING POST-TRIAL BRIEF ON INVALIDITY
`
`
`Of Counsel:
`
`Steven A. Maddox
`Jeremy J. Edwards
`Matthew C. Ruedy
`Kaveh V. Saba
`Maddox Edwards PLLC
`1900 K Street N.W., Suite 725
`Washington, D.C. 20006
`(202) 830-0707
`smaddox@meiplaw.com
`jedwards@meiplaw.com
`mruedy@meiplaw.com
`ksaba@meiplaw.com
`
`
`
`
`
`
`Frederick L. Cottrell, III (#2555)
`Kelly E. Farnan (#4395)
`Christine D. Haynes (#4697)
`Richards, Layton & Finger, P.A.
`920 North King Street
`Wilmington, DE 19801
`(302) 651-7700
`cottrell@rlf.com
`farnan@rlf.com
`haynes@rlf.com
`
`Attorneys for Defendant-Counterclaim Plaintiff
`Amneal Pharmaceuticals LLC
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`
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`

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`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 2 of 37 PageID #: 1428
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`
`TABLE OF CONTENTS
`
`I. 
`
`II. 
`
`Introduction .......................................................................................................................................... 1 
`
`The Asserted Claims Were Obvious Based on the Prior Art Precedex Concentrate
`Product and Package Insert Alone, and in View of Other Literature on Parenteral
`Drug Products. ..................................................................................................................................... 2 
`
`A. 
`
`The Asserted Claims of the ’158, ’470, and ’527 Patents Are Obvious. ......................... 3 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`The Prior Art Precedex Concentrate Product and Package Insert
`Taught Practically Every Element of the Claimed Invention. ........................... 3 
`
`The Prior Art Precedx Concentrate Product and Package Insert
`Taught Practically Every Element of the Claimed Invention. ........................... 4 
`
`A Sealed Glass Container of 4 µg/mL Dex in Saline Was Obvious in
`Light of the Precedex Concentrate Product and Labeling and What
`Was Known in the Art. ............................................................................................ 5 
`
`Literature on Ready to Use Parenteral Products Provided Further
`Motivation to Achieve the Claimed Invention. .................................................... 7 
`
`Hospira Could Not Refute the Reasonable Expectation of Success in
`Storing the 4 µg/mL Dex Saline Formulation in Glass. ..................................... 8 
`
`B. 
`
`The ’106 Patent’s Additional Element of “No More Than About 2%
`Decrease” in Concentration at Five Months Is an Inherent Characteristic of
`the Obvious Composition in a Sealed Glass Container. ................................................... 9 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`Inherency in the Context of Obviousness Is a Question of Fact That
`Exists When a Limitation Is the Necessary or Natural Result of an
`Obvious Combination of Elements in the Prior Art. ........................................ 10 
`
`Hospira’s Interrogatory Admission and the ’106 Patent Provide Clear
`and Convincing Evidence of Inherency. ............................................................. 12 
`
`The Undisputed Experimental Evidence of Less than About 2%
`Concentration Decrease After Five Months in a Sealed Glass
`Container Also Proves Inherency. ........................................................................ 14 
`
`Hospira’s Arguments Against Inherency Are Not Rooted in
`Evidence and Are Legally Irrelevant. ................................................................... 16 
`
`C. 
`
`There Is No Commercial Success Indicative of Non-Obviousness. ............................ 19 
`
`III. 
`
`The ’106 Patent Is Indefinite Under Section 112. ......................................................................... 20 
`
`A. 
`
`Indefiniteness and the Interpretation of Intrinsic Evidence Is a Question of
`
`ii
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`

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`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 3 of 37 PageID #: 1429
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`
`B. 
`
`C. 
`
`D. 
`
`Law for the Court, Applying General Principles of Claim Construction. .................... 20 
`
`The Intrinsic Evidence and Undisputed Facts Render Claim 6 of the ’106
`Patent Indefinite as a Matter of Law. ................................................................................ 23 
`
`Dr. Linhardt’s Opinion Is Irrelevant as a Matter of Law. .............................................. 25 
`
`Even If Not Legally Irrelevant, Dr. Linhardt’s Opinion Is Irrelevant as a
`Matter of Fact. ....................................................................................................................... 27 
`
`IV. 
`
`The Proper Construction of “Sealed Glass Container” and “Ready to Use” ........................... 28 
`
`A. 
`
`B. 
`
`“Sealed Glass Container” Should Be Given Its Plain and Ordinary Meaning
`from the Intrinsic Evidence. ............................................................................................... 28 
`
`“Ready to Use” Should Be Given Its Straight-Forward Definition in the
`Patent. ..................................................................................................................................... 29 
`
`The Claims Are Anticipated or Obvious Based on Trissel. ......................................................... 30 
`
`Conclusion ........................................................................................................................................... 30 
`
`
`
`V. 
`
`VI. 
`
`
`
`
`
`iii
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`

`

`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 4 of 37 PageID #: 1430
`
`
`Federal Cases
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`3form, Inc. v. Lumicor, Inc.,
`678 F. App’x 1002 (Fed. Cir. 2017) ................................................................................................... 11, 16
`
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) ........................................................................................................... 11, 13
`
`Asyst Techs., Inc. v. Emtrak, Inc.,
`544 F.3d 1310 (Fed. Cir. 2008) .................................................................................................................. 19
`
`Atlas Powder Co. v. Ireco Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) .................................................................................................................. 18
`
`Bell Atl. Network Servs. v. Covad Commc'ns Grp.,
`262 F.3d 1258 (Fed. Cir. 2001) .................................................................................................................. 26
`
`Biosig Instruments, Inc. v. Nautilus, Inc.,
`783 F.3d 1374 (Fed. Cir. 2015) .................................................................................................................. 26
`
`Brown v. 3M,
`265 F.3d 1349 (Fed. Cir. 2001) .................................................................................................................. 18
`
`Butamax Advanced Biofuels v. Gevo, Inc.,
`117 F. Supp. 3d 632 (D.Del. 2015) .................................................................................................... 23, 26
`
`Dow Chem. Co. v. Nova Chem. Corp.,
`803 F.3d 620 (Fed. Cir. 2015) ................................................................................................ 21, 22, 23, 27
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .................................................................................................................... 19
`
`General Elec. Co. v. Joiner,
`522 U.S. 136 (1997) ................................................................................................................................ 9, 26
`
`Glaxo Inc. v. Novopharm Ltd.,
`52 F.3d 1043 (Fed. Cir. 1995) .................................................................................................................... 16
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .................................................................................................................. 11
`
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) ................................................................................................... 2, 9, 11, 13
`
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988) ................................................................................................................. 2, 9
`
`iv
`
`

`

`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 5 of 37 PageID #: 1431
`
`
`J.T. Eaton & Co. v. Atl. Paste & Glue Co.,
`106 F.3d 1563 (Fed. Cir. 1997) .................................................................................................................. 20
`
`King Pharm., Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) .................................................................................................................. 14
`
`Knauf Insulation, Inc. v. Rockwool Int’l A/S,
`680 F. App’x 956 (Fed. Cir. 2017) ..................................................................................................... 16, 17
`
`Lighting Ballast Control LLC v. Philips Elecs. N. Am. Corp.,
`790 F.3d 1329 (Fed. Cir. 2015) .................................................................................................................. 26
`
`Martek Biosciences Corp. v. Nutrinova, Inc.,
`579 F.3d 1363 (Fed. Cir. 2009) .................................................................................................................. 29
`
`Merck & Co. v. Teva, Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005). ................................................................................................................. 19
`
`Merck Sharp & Dohme Corp. v. Hospira Inc.,
`221 F. Supp. 3d 497 (D. Del. 2016) (Andrews, J.) .................................................................................. 19
`
`Nautilus, Inc. v. Biosig Instruments, Inc.,
`134 S. Ct. 2120 (2014) .......................................................................................................................... 20, 21
`
`Omeprazole Patent Litig.,
`483 F.3d 1364 (Fed. Cir. 2007) .................................................................................................................. 13
`
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`120 F. Supp. 3d 468 (D. Md. 2015), aff’d, 624 F. App’x 756 (Fed. Cir. 2015) ....................... 11, 16, 18
`
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .................................................................................................................. 10
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................................................................... 2
`
`Phillips v. AWH Corp.,
`415 F.3d 1303, 1318 (Fed. Cir. 2005) (en banc) ............................................................................... 26, 30
`
`Profectus Tech. LLC v. Huawei Tech. Co., Ltd.,
`823 F.3d 1375 (Fed. Cir. 2016) .................................................................................................................. 26
`
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) .................................................................................................................. 19
`
`Teva Pharm. USA, Inc. v. Sandoz, Inc.,
`789 F.3d 1335 (Fed. Cir. 2015) .............................................................................................. 21, 22, 23, 25
`
`v
`
`

`

`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 6 of 37 PageID #: 1432
`
`
`Therasense, Inc. v. Becton, Dickinson & Co.,
`593 F.3d 1289 (Fed. Cir. 2010),reh’g en banc granted, opinion vacated on other grounds, 374 F. App’x 35
`(Fed. Cir. 2010),and opinion reinstated in part, 649 F.3d 1276 (Fed. Cir. 2011) ..................................... 19
`
`Toro Co. v. Deere & Co.
`355 F.3d 1313 (Fed. Cir. 2004) .................................................................................................................. 11
`
`Transcend Med., Inc. v. Glaukos Corp.,
`No. 13-830, 2015 WL 5546988 (D. Del. Sept. 18, 2015) .................................................. 22, 23, 25, 26
`
`vi
`
`

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`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 7 of 37 PageID #: 1433
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`
`I.
`
`Introduction
`
`Hospira’s claims to the same sealed glass container and formulation of dexmedetomidine
`
`(“dex”) taught by its own prior art product and labeling are obvious. Further, its claim to “no more
`
`than about 2% decrease in [] concentration” at five months likewise is obvious. This is because such
`
`stability is an inherent property of the obvious sealed glass container and dex formulation. Prior to
`
`trial, Hospira correctly asserted that this inherency is taught in the patent. At trial, Hospira insisted
`
`that all the data presented for such dex in sealed glass containers met the 2% limitation, as construed
`
`by Hospira to mean the long-term measure of stability.
`
`Hospira’s prior art 100 µg/mL saline solution of dex in a sealed glass container, combined
`
`with instructions to dilute to 50 mL of 4 µg/mL solution, provided all the elements of the claimed
`
`invention. The choice of glass also was obvious in light of what was known in the profession and
`
`literature. And, there is overwhelming evidence in the literature and marketplace of motivation to
`
`have pursued such a pre-diluted product.
`
`Hospira presented essentially two arguments in response, but failed to offer any properly
`
`supported expert proof. First, Hospira asserted that a person of ordinary skill could not have had a
`
`“reasonable expectation of success” because 4 µg/mL was a lower concentration than 100 µg/mL.
`
`Like most of Hospira’s case, however, its evidence was the mere ipse dixit of Dr. Robert Linhardt, a
`
`carbohydrate chemist with little or no experience in parenteral packaging and formulation. Dr.
`
`Linhardt’s opinion was not supported by any literature, contemporaneous documents, testimony,
`
`testing, or verifiable examples of any problems with glass at 4 µg/mL. Indeed, Hospira’s own
`
`inventor admitted that from the outset of undertaking the pre-mix project, the inventors in fact
`
`expected to find a workable formulation and package. Throughout their work, they used sealed
`
`glass as a control, and fallback solution.
`
`1
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`

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`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 8 of 37 PageID #: 1434
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`Second, Hospira offered Dr. Linhardt’s conclusory opinion that “no more than about 2%”
`
`of dex at five months is not an inherent property of the claimed formulation in sealed glass. In so
`
`doing, Dr. Linhardt contradicted the teaching of the patent, Hospira’s own interrogatory answer,
`
`and all the empirical data presented by the experts in this case. Again, however, Dr. Linhardt failed
`
`to present any supporting literature, documents, or testing to show that the claimed sealed glass
`
`container of 4 µg/mL actually failed to exhibit that claimed property. Instead, he merely recited a list
`
`of things which he said theoretically might cause such a failure, down to and including the plumbing in
`
`the plant. This kind of speculation is insufficient to overcome evidence of inherency, as a matter of
`
`law.
`
`In any event, the claimed 2% limitation is indefinite as a matter of law, in light of the
`
`indisputable intrinsic evidence and the undisputed facts. Interpretation of the intrinsic evidence is a
`
`question of law for the Court. Accepting an expert’s opinion about that evidence over the plain text
`
`of the documents is reversible error. And Dr. Linhardt’s interpretation of the extrinsic evidence
`
`opinions likewise must be dismissed because it contradicts the intrinsic evidence, and lacks any
`
`supporting objective evidence of meaning.
`
`II.
`
`The Asserted Claims Were Obvious Based on the Prior Art Precedex Concentrate
`Product and Package Insert Alone, and in View of Other Literature on Parenteral
`Drug Products.
`
`A patent claim is invalid as obvious where it is shown “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 in doing so.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1361 (Fed. Cir. 2007).
`
`“Obviousness does not require absolute predictability of success . . . all that is required is a
`
`reasonable expectation of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (quoting In re
`
`O’Farrell, 853 F.2d 894, 903–04 (Fed. Cir. 1988)).
`
`2
`
`

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`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 9 of 37 PageID #: 1435
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`The asserted claims are claims 3 and 4 of U.S. Patent No. 8,242,158 (“the ’158 patent”),
`
`claim 4 of U.S. Patent No. 8,338,470 (“the ’470 patent”), claim 5 of U.S. Patent No. 8,455,527 (“’527
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`patent”), and claim 6 of U.S. Patent No. 8,468,106 (“the ’106 patent”).
`
`While the precise language of each asserted claim varies, the claimed compositions in total
`
`contain the following components: (1) “a ready to use liquid pharmaceutical composition for
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`parenteral administration”; (2) comprising dex or a salt of dex “at a concentration of about 4
`
`µg/mL”; (3) with “sodium chloride . . . at a concentration of about 0.9 weight percent”; (2)
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`“disposed within a sealed glass container”; and (3) with a “total volume selected from the group
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`consisting of 20 mL, 50 mL and 100 mL.” (JTX-1 at 26:4–8, 26:12–18; JTX-2 at 26:22–26, 26:35–
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`38; JTX-3 at 25:25–32, 26:9–11; JTX-4 at 26:17–24, 26:41–43; Tr. 508:11–509:10.)
`
`Claim 6 of the ’106 patent additionally requires that the composition “exhibits no more than
`
`about 2% decrease in the concentration” of dex “for at least five months.” (JTX-4 at 26:17–24.)
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`Although the asserted claim of the ’106 patent is invalid as indefinite as a matter of law (see Section
`
`III below), it also is inherently obvious if the Court accepted Dr. Linhardt’s ipse dixit that the term
`
`refers to the long-term measurement of stability.1
`
`A.
`
`The Asserted Claims of the ’158, ’470, and ’527 Patents Are Obvious.
`
`1.
`
`The Prior Art Precedex Concentrate Product and Package Insert
`Taught Practically Every Element of the Claimed Invention.
`
`The asserted claims of the ’158, ’470, and ’527 patents are obvious in light of the prior art
`
`Precedex product in a sealed glass vial and what was known to the person of ordinary skill.2
`
`
`1 Claim 5 of the ’527 patent is a method of sedation by administering the same composition. It was
`undisputed that this method of administering the composition is not new—it is the same
`administration used with the prior art Precedex product. (Tr. 1140:21–1141:3.)
`2 Amneal’s expert, Dr. Alpaslan Yaman, and Hospira’s expert, Dr. Linhardt, provided similar
`definitions of the person of ordinary skill in the art (“POSA”). (Tr. 268:4–20, 506:23–507:17.) Dr.
`Yaman testified that adopting Dr. Linhardt’s definition would not change his conclusions. (Tr.
`507:18–508:10.)
`
`3
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`

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`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 10 of 37 PageID #: 1436
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`2.
`
`The Prior Art Precedx Concentrate Product and Package Insert
`Taught Practically Every Element of the Claimed Invention.
`
`The most significant prior art and the first place a POSA would look to prior to 2012 is the
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`Precedex Concentrate product and its associated 2010 package insert (also known as the labeling).
`
`(Tr. 509:16–510:18.) This prior art product was approved in 1999 and sold as a 100 µg/mL dex
`
`concentration stored in a glass vial. (Tr. 510:19–511:2.) The 2010 labeling discloses that the
`
`formulation was for intravenous infusion following dilution and indicated for sedation of patients.
`
`(Tr. 511:13–512:9; DTX-23 at 5014.) This was an explicit disclosure of the claimed method of
`
`sedation and parenteral administration elements. (Id.)
`
`Likewise, the 2010 labeling explicitly disclosed the exact 4 µg/mL concentration required for
`
`administration and claimed by the patents-in-suit. (Tr. 512:10–513:3; DTX-23 at 5014, 5026–27.) It
`
`also explicitly disclosed the claimed 0.9 percent sodium chloride—as the only ingredient other than
`
`dex in both the concentrate and diluted formulation. (Tr. 513:4–514:16.) Notably, the 2010 labeling
`
`teaches that the product is preservative-free and contains no additives or chemicals stabilizers,
`
`indicating that the drug is stable and not oxygen sensitive. (Tr. 660:22–662:8, 697:24–698:6.)
`
`Moreover, the labeling explicitly taught the claimed 50 mL total volume of the dilute formulation,
`
`which was known to be a standard volume in the art. (Tr. 513:23–514:21, 837:15–838:3.)
`
`The 2010 labeling also taught the exact type of packaging claimed in these patents—a sealed
`
`glass container—specifically in the form of a glass vial. (Tr. 515:3–516:2; DTX-23 at 5014, 5032.) It
`
`is undisputed that a POSA would have understood this disclosure to refer to USP Type I glass,
`
`sealed with a rubber stopper, since that is the only kind of glass vial used in the parenteral industry.
`
`(Tr. 515:8–21.) Further, the labeling instructed a POSA not to use natural rubber, though POSAs
`
`had long used solely synthetic rubber stoppers anyway. (Tr. 516:3–19; DTX-23 at 5017.) Finally, a
`
`POSA would have also examined the physical prior art product and readily confirmed it to use
`
`Type I glass and a coated synthetic stopper. (Tr. 516:20–518:7; DTX-534.)
`
`4
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`

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`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 11 of 37 PageID #: 1437
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`None of the above disclosures was disputed. That is, the prior art product and labeling
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`explicitly taught every element of the allegedly inventive composition, except for storing the known
`
`ready to use 4 µg/mL formulation in the known sealed glass container. (Tr. 518:8–520:5.)
`
`3.
`
`A Sealed Glass Container of 4 µg/mL Dex in Saline Was Obvious in
`Light of the Precedex Concentrate Product and Labeling and What
`Was Known in the Art.
`
`The prior art Precedex sealed glass product, labeling, and instructions to make the claimed
`
`50 ml of 4 µg/ml formulation of dex in saline, rendered obvious the claimed sealed glass container
`
`of 50 ml of 4 µg/ml formulation of dex in saline, as in the asserted claims of the ’158, ’470, and ’527
`
`patents. Indeed, POSAs knew that the most obvious thing to do in a line extension like this was to
`
`use what has already been developed and proven—in this case a Type I glass vial and coated
`
`stopper. (Tr. 533:12–534:17; DTX-202 at 147052 (“Existing products or products of a similar class
`
`or type many times mimic the packaging used on the first marketed product . . . .”).)
`
`In this case, Hospira’s contemporaneous documents confirm this kind of reliance on the
`
`prior product. For instance, a Hospira internal report concluded: “Hence for Precedex Injection, it
`
`was planned to implement coated stopper in order to mimic the current product and prevent any
`
`drug adsorption.” (DTX-206 at 858011 (emphasis added); Tr. 570:10–21.) Likewise, Hospira stated
`
`that the absence of technical issues with glass for the new product “is consistent with the
`
`currently marketed Precedex concentrated solution that is packaged in a glass vial.” (DTX-203
`
`at 545119 (emphasis added), Tr. 568:23–570:9.)
`
`Beyond the obviousness of the sealed glass container from the prior product and labeling, it
`
`was well-known prior to 2012 that glass was the gold standard for injectables. (Tr. 525:5–526:24.)
`
`Glass was used successfully for decades because it was known to be inert, was not expected to
`
`present potency problems, and thus was expected to work. (Id.; Tr. 156:13–157:10, 182:13–183:9.)
`
`This understanding was reflected throughout the authoritative pharmaceutical literature. (Tr.
`
`5
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`

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`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 12 of 37 PageID #: 1438
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`532:20–533:11; DTX-202 at 147055 (“Glass has always been the traditional gold standard for
`
`pharmaceutical packaging.”) Tr. 527:4–528:16; DTX-219 at 147601 (“The most common packaging
`
`for liquid and freeze-dried injectables is the glass vial (Figure 2).”), 147606 (“Glass is employed as
`
`the container material of choice for most small volume injectables.”).)
`
`A POSA also would have known that Type I glass is the only kind of glass vial used in the
`
`parenteral industry. (Tr. 515:8–515:14.) As described in the textbook of Sterile Drug Products,
`
`“Type I glass will be suitable for all products . . . .” (DTX-200 at 146620; Tr. 528:17–531:10.) This
`
`is due to its “excellent barrier properties and inertness.” (DTX-210 at 147518; Tr. 531:20–532:19.)
`
`Indeed, in the very sedative class of drugs most relevant to dex, there were numerous drugs (e.g.,
`
`propofol, diazepam, midazolam, fentanyl citrate) that were already commercially available in glass, in
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`ready to use concentrations, as reflected in the Handbook on Injectable Drugs (2011). (Tr. 534:18–
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`535:23; DTX-535 at 476, 669, 1075, 1335.)
`
`Even the sole treatise (Remington’s) that Dr. Linhardt pointed to at his deposition taught in
`
`2006 that “[g]lass is employed as the container material of choice for most SVIs [small volume
`
`injectables],” which refers to volumes up to 100 mL. (DTX-553 at 809; Tr. 987:10–989:7, 991:5–13,
`
`992:3–11, 528:1–9.) Dr. Linhardt did not claim that Remington’s would have somehow modified
`
`this by 2012. (Tr. 990:22–24.) Instead, he tried to disavow Remington’s—first just the parts he
`
`disagreed with, then all of it as out of date, and then only after 2003—and at one point seemed to
`
`disavow printed treatises entirely. (Tr. 990:5–21, 995:14–996:4.) This testimony was inconsistent
`
`with his deposition and not credible. (Tr. 996:17–998:14.)
`
`At bottom, a POSA would have tried glass, even if alongside with plastic. Indeed, that is
`
`exactly what the POSAs at Hospira did, when it tested plastic but used glass as the control standard,
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`and as the safe choice if needed (which it was). (Tr. 156:13–157:10.) After all, it was well-known in
`
`the art that “[n]o plastic material can match type I glass for impermeability and chemical inertness.”
`
`6
`
`

`

`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 13 of 37 PageID #: 1439
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`(DTX-202 at 147094; Tr. 536:24–537:1, 538:5–18.) And plastic was known to present multiple
`
`technical problems that may be difficult to resolve, unlike glass—even according to both of
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`Hospira’s own inventors. (Tr. 156:13–21, 537:3–538:4, 1011:7–1012:12, 538:19-22; DTX-553 at
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`812; DTX-63 at 4916 (racemate of dex “known to interact with PVC and polystyrene”).) Again, this
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`is corroborated by the POSAs at Hospira, who noted the potential problems with plastics, and the
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`absence of expected issues with glass, at the outset of the premix project. (Tr. 566:16–567:16, JTX-
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`26.5.)
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`4.
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`Literature on Ready to Use Parenteral Products Provided Further
`Motivation to Achieve the Claimed Invention.
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`The motivation to make a ready to use liquid dex product at the administered concentration
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`of 4 µg/mL in normal saline was pervasive in the literature. In fact, Amneal’s expert Dr. James Cain
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`and his hospital were so motivated by a lack of a manufacturer-prepared ready to use 4 µg/mL
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`product that they institutionalized premix syringe preparation, reflected in Dr. Cain’s 2007
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`publication. (DTX-3 at 63184; Tr. 740:15–745:12; 748:3–749:8.) Dr. Yaman explained that in
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`addition to the motivation from the 2010 labeling itself, a POSA in industry would be highly
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`motivated by this “voice of the customer,” as he called it. (Tr. 520:13–521:16.)
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`More generally, the prior art reflects a strong motivation to develop manufacturer prepared
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`ready to use injectable medications, particularly in the hospital setting. (Tr. 524:24–525:4, 563:8–14,
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`564:8–17, 759:11–19; DTX-43 (“At a 2008 national consensus conference on the safety of
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`intravenous drug delivery systems, there was a clear preference for manufacturer-prepared
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`completely ready-to-use IV medications in all settings . . . .”); Tr. 751:1–754:21; DTX-44 at 56
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`(“Avenues to improve the safety associated with the use of IV medications include the development
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`of manufacturer-derived premixed solutions.”); Tr. 522:12–523:20; 757:23–758:23; DTX-111; Tr.
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`523:21-524:23; DTX-46; Tr. 756:18–757:22.)
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`7
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`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 14 of 37 PageID #: 1440
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`5.
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`Hospira Could Not Refute the Reasonable Expectation of Success in
`Storing the 4 µg/mL Dex Saline Formulation in Glass.
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`Hospira’s primary argument was that there could be no reasonable expectation of success in
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`glass because the 4 µg/mL concentration is a lower than the prior art 100 µg/mL. Yet, Hospira’s
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`Dr. Robert Cedergren testified that at the outset of the project, “there was an expectation as of
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`December 2006 that [he was] going to find a successful acceptable formulation” for the premix
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`4 µg/ml “by September 2007.” (Tr. 839:19–24.) That is because 100 µg/mL was already a low
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`concentration at the microgram level that had long been proven to work, and there was nothing in
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`the prior art, or even internally at Hospira, expressing that the lower concentration was in fact a real
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`concern in glass. (Tr. 552:1–10, 558:10–559:5, 708:8–22.) Even Hospira’s Dr. Priyanka
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`Roychowdhury admitted that 100 µg/mL was regarded as a low concentration formulation. (Tr.
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`140:6–12.) Thus, the prior art demonstrated that the drug could be successfully formulated at a very
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`low concentration in glass.
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`It is not surprising, therefore, that Hospira failed to offer any evidence of “no reasonable
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`expectation of success,” other than Dr. Linhardt’s ipse dixit—not a single contemporaneous
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`document relating to dex, or even a single prior art document of failure in formulating a 4 µg/mL
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`formulation of any drug (much less one which already had a 100 µg/mL formulation in glass on the
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`market). Rather, like the POSA, Hospira employees had a reasonable expectation that a formulation
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`in sealed glass would work at the desired concentration. Their challenge, however, had been to see
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`if they could make one in plastic, which was known to have issues to diminish potency. Hospira
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`used glass a control in its evaluation of plastics, because glass was expected to work—as it had
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`worked with 100 µg/mL. (Tr. 142:1–20, 156:13–157:10.)
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`Hospira relied on Dr. Linhardt’s conclusory assertion that “sometimes it’s impossible to
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`formulate a drug as a ready to-use because the concentration of the excipients won’t protect a
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`reasonable shelf life because it’s not very stable at ready to use conditions.” (Tr. 923:4–10 (emphasis
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`8
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`Case 1:15-cv-00697-RGA Document 100 Filed 09/18/17 Page 15 of 37 PageID #: 1441
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`added).) Dr. Linhardt’s equally improvisatory opinion as to what would be required for a reasonable
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`expectation of success amounts to a mere recitation of all development work done by Hospira—
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`assays to define routes of degradation, evaluation of packaging material, evaluation of different
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`excipients, evaluation of different pH’s, and more unspecified work. And even then, he still would
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`not agree that one would have a reasonable expectation of success. (Tr. 1008:8–1009:14.)
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`This was plainly inconsistent with the legal standard of a mere “reasonable expectation”
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`required by the case law. In re Kubin, 561 F.3d at 1360; In re O’Farrell, 853 F.2d at 903–04. It was
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`also the type of conclusory expert testimony that courts need not even admit, much less credit.
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`General Elec. Co. v. Joiner, 522 U.S. 136, 146 (1997).
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`B.
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`The ’106 Patent’s Additional Element of “No More Than About 2% Decrease”
`in Concentration at Five Months Is an Inherent Characteristic of the Obvious
`Composition in a Sealed Glass Container.
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`Amneal presented two kinds of clear and convincing evidence that the “no more than about
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`2% decrease” limitation is simply an inherent characteristic of the obvious 4 µg/mL dex formulation
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`disposed in a sealed glass container. Each kind results in the obviousness of the claims of the ’106
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`patent, just like the other three asserted patents to which it is terminally disclaimed.
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`First, Hospira itself stated that according to the patents, 4 µg/mL dex and normal saline in a
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`sealed glass container in the absence of degradative compounds would exhibit the claimed stability.
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`This came in response to Amneal’s interrogatory asking for any evidence that this limitation is not
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`inherent. As confirmation of this i