Case: 1:16-cv-00651 Document #: 144 Filed: 08/07/18 Page 1 of 52 PageID #:5911
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE NORTHERN DISTRICT OF ILLINOIS
`EASTERN DIVISION
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`HOSPIRA, INC.,
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`FRESENIUS KABI USA, LLC,
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`Plaintiff,
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`Defendant.
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`Civil Action Nos. 1:16-cv-00651
` 1:17-cv-07903
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`Hon. Judge Rebecca R. Pallmeyer
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`v.
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`HOSPIRA’S RESPONSIVE POST-TRIAL BRIEF
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`Case: 1:16-cv-00651 Document #: 144 Filed: 08/07/18 Page 2 of 52 PageID #:5912
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`TABLE OF CONTENTS
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`I.
`II.
`
`II.
`
`INTRODUCTION ...............................................................................................................1
`SUMMARY OF THE TRIAL RECORD ............................................................................3
`A.
`The Patents ...............................................................................................................3
`B.
`The Farmos Phase I Clinical Studies .......................................................................4
`C.
`The 1994 License and Supply Agreement (“1994 Agreement”) .............................5
`D.
`The Precedex Concentrate New Drug Application (“NDA”) ..................................7
`E.
`The Spin-Off ............................................................................................................7
`F.
`The Precedex Premix Project ...................................................................................8
`G.
`FK’s Evidence of Inherency ..................................................................................10
`ARGUMENT .................................................................................................................................11
`I.
`THE 2% LIMITATION RENDERS THE CLAIMS NON-OBVIOUS ............................11
`A.
`FK failed to show the 2% limitation was inherently present in the prior art .........11
`1.
`FK was required to exclude the possibility that an embodiment of
`claim 6 would fail the 2% limitation..........................................................12
`Inherency cannot be shown by proving only that the inventor’s
`own work and the infringing product meet the limitation .........................12
`The 20 µg/mL samples from the IND disprove inherency ........................13
`3.
`FK’s new “reasonable expectation of success theory” is legally improper
`and unsupported by the record ...............................................................................14
`1.
`FK’s RES theory is contrary to the law .....................................................14
`2.
`FK failed to prove there was a reasonable expectation of success
`for the 2% limitation ..................................................................................17
`a.
`The evidence precludes a reasonable expectation of success
`that the 2% limitation would be met ..............................................18
`FK failed to prove a reasonable expectation of success for
`the 2% limitation ............................................................................20
`1)
`Dexmed is not “rock stable” ..............................................21
`2)
`Attorney argument is belied by the evidence .....................22
`THE CLAIMS ARE NOT OBVIOUS OVER THE IND ..................................................23
`A.
`The IND is not prior art under the on sale bar .......................................................24
`1.
`Neither Shafer nor the IND were on sale ...................................................24
`a.
`The IND is not an embodiment of Shafer ......................................24
`b.
`The 1994 Agreement did not trigger the on-sale bar .....................25
`
`2.
`
`B.
`
`b.
`
`i
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`B.
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`The IND is licensed ‘Know-How’ .....................................26
`1)
`The FDA letters cannot override the license ......................27
`2)
`The 2004 Hospira spinoff did not trigger the on-sale bar ..............28
`c.
`The IND was used for experimental purposes ...........................................30
`2.
`Shafer did not disclose an invention ready for patenting ...........................31
`3.
`The IND is not prior art under § 102(f) .................................................................33
`1.
`Shafer was not communicated to the inventors .........................................34
`2.
`Shafer was disclosed as part of a joint research effort ...............................35
`Shafer and Precedex Concentrate do not render the claims obvious .....................36
`C.
`THE CLAIMS OF THE ’106 PATENT ARE ENABLED ...............................................37
`A.
`The ’106 patent teaches a POSA how to make the claimed formulation ..............37
`B.
`The ’106 patent is not required to delineate every possible configuration
`that meets the 2% limitation ..................................................................................39
`CONCLUSION ..................................................................................................................41
`IV.
`PROPOSED FINDINGS OF FACT AND CONCLUSIONS OF LAW .......................................41
`I.
`FINDINGS OF FACT........................................................................................................41
`A.
`Obviousness ...........................................................................................................41
`B.
`Enablement of the ’106 patent ...............................................................................44
`CONCLUSIONS OF LAW ...............................................................................................44
`A.
`Claim Construction ................................................................................................44
`B.
`Obviousness ...........................................................................................................44
`C.
`Enablement of the ’106 patent ...............................................................................45
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`
`III.
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`II.
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`ii
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`Case: 1:16-cv-00651 Document #: 144 Filed: 08/07/18 Page 4 of 52 PageID #:5914
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`
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`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Adaptix, Inc. v. Alcatel-Lucent, Inc.,
`2015 WL 12712287 (E.D. Tex. June 26, 2015) .......................................................................35
`
`Advanced Fiber Techs. (AFT) Trust v. J&L Fiber Servs., Inc.,
`2015 WL 1472015 (N.D.N.Y. Mar. 31, 2015) ........................................................................41
`
`Allergan, Inc. v. Sandoz Inc.,
`726 F.3d 1286 (Fed. Cir. 2013)................................................................................................16
`
`Allergan Sales, LLC v. Sandoz, Inc.,
`717 F. App’x 991 (Fed. 2017) .................................................................................................16
`
`Alloc, Inc. v. Pergo, Inc.,
`2008 WL 1968301 (E.D. Wis. May 1, 2008)...........................................................................35
`
`Amneal Pharm. LLC, v. Hospira Inc.,
`No. IPR2016-0580, Paper 11 (P.T.A.B. February 3, 2017) .......................................................4
`
`August Tech. Corp. v. Camtek, Ltd.,
`655 F.3d 1278 (Fed. Cir. 2011)................................................................................................15
`
`Cumberland Pharm. Inc. v. Mylan Institutional LLC,
`846 F.3d 1213 (Fed. Cir. 2017)................................................................................................34
`
`Diodem, LLC v. Lumenis Inc.,
`2005 WL 6225364 (C.D. Cal. Sept. 15, 2005) ........................................................................29
`
`Eli Lilly & Co. v. Zenith Goldline Pharm., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006)................................................................................................30
`
`Endo Pharm. Inc. v. Teva Pharm. USA, Inc.,
`--- F. App’x ---, 2018 WL 2230923 (Fed. Cir. 2018), vacated in unrelated part
`on other grounds, 729 F. App’x 936 (Fed. Cir. 2018) .......................................................16, 40
`
`Endo Pharm. Sols., Inc. v. Custopharm Inc.,
`894 F.3d 1374 (Fed. Cir. 2018)......................................................................................2, 11, 12
`
`Gambro Lundia AB v. Baxter Healthcare Corp.,
`110 F.3d 1573 (Fed. Cir. 1997)................................................................................................34
`
`iii
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`

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`Helsinn Healthcare S.A. v. Teva Pharm. USA, Inc.,
`855 F.3d 1356 (Fed. Cir. 2017)....................................................................................24, 32, 33
`
`Honeywell Int’l, Inc. v. United States,
`609 F.3d 1292 (Fed. Cir. 2010)................................................................................................15
`
`Hospira, Inc. v. Amneal Pharm., LLC,
`285 F. Supp. 3d 776, 799-800 (D. Del. 2018) .....................................................................4, 13
`
`In re Hamilton,
`882 F.2d 1576 (Fed. Cir. 1989)................................................................................................31
`
`In re Kollar,
`286 F.3d 1326 (Fed. Cir. 2002)................................................................................................25
`
`In re Oelrich,
`666 F.2d 578 (C.C.P.A. 1981) .................................................................................................11
`
`In re Omeprazole Patent Litig.,
`536 F.3d 1361 (Fed. Cir. 2008)................................................................................................33
`
`Intelligent Bio-Sys. Inc., v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016)..........................................................................................14, 15
`
`Invitrogen Corp. v. Clontech Labs., Inc.,
`429 F.3d 1052 (Fed. Cir. 2005)..........................................................................................37, 39
`
`Mas-Hamilton Grp. v. LaGard, Inc.,
`156 F.3d 1206 (Fed. Cir. 1998)................................................................................................25
`
`Medicines Co. v. Hospira, Inc.,
`827 F.3d 1363 (Fed. Cir. 2016)..........................................................................................24, 25
`
`Micro-Magnetic Indus., Inc. v. Advance Automatic Sales Co.,
`488 F.2d 771 (9th Cir. 1973) ...................................................................................................29
`
`Millennium Pharm., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017)......................................................................................2, 11, 12
`
`Milwaukee Elec. Tool Corp. v. Snap-On Inc.,
`271 F. Supp. 3d 990, 1016 (E.D. Wis. 2017) ...........................................................................34
`
`Moleculon Research Corp. v. CBS, Inc.,
`793 F.2d 1261 (Fed. Cir. 1986)................................................................................................25
`
`New England Braiding Co. v. A.W. Chesterton Co.,
`970 F.2d 878 (Fed. Cir. 1992)..................................................................................................34
`
`iv
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`

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`Otsuka Pharm. Co., Ltd. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012)................................................................................................12
`
`PAR Pharm. Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014)..........................................................................................11, 15
`
`Pfaff v. Wells Elecs., Inc.,
`525 U.S. 55 (1998) ...................................................................................................................24
`
`Polara Eng’g Inc v. Campbell Co.,
`894 F.3d 1339 (Fed. Cir. 2018)................................................................................................30
`
`Rivera v. Int’l Trade Comm’n,
`857 F.3d 1315 (Fed. Cir. 2017)................................................................................................33
`
`Robert Bosch, LLC v. Pylon Mfg. Corp.,
`700 F. Supp. 2d 625 (D. Del. 2010) .........................................................................................34
`
`Star Sci., Inc. v. R.J. Reynolds Tobacco Co.,
`655 F.3d 1364 (Fed. Cir. 2011)................................................................................................15
`
`Vizio, Inc. v. ITC,
`605 F.3d 1330 (Fed. Cir. 2010)................................................................................................15
`
`STATUTES
`
`35 U.S.C. § 102 (2012) ......................................................................................................... passim
`
`35 U.S.C. § 103 (2011) .................................................................................................................35
`
`35 U.S.C. § 112 (2011) .................................................................................................................13
`
`Uniform Commercial Code Article 2 ..................................................................................6, 25, 28
`
`
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`v
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`I.
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`INTRODUCTION
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`Before Drs. Priyanka Roychowdhury and Robert Cedergren did it, no one had
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`demonstrated that a ready-to-use 4 µg/mL formulation of dexmedetomidine (“dexmed”) could be
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`disposed in a sealed glass container such that it would lose “not more than about 2%” of its
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`potency in a five month period. That contribution to the art by the named inventors was novel.
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`The trial record before the court establishes that beyond argument. Moreover, before Hospira
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`did it, no one offered for sale or sold a ready-to-use dexmed formulation at a concentration of 4
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`µg/mL disposed in a sealed glass container.
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`Because the named inventors and Hospira were first, and obtained patents for their
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`invention, Fresenius Kabi (“FK”) failed at trial to prove either its on-sale theory or its
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`inventorship theory, to the extent those theories are based on anticipation. FK adduced no
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`evidence that claim 6 of U.S. Patent No. 8,648,106 (“the ’106 patent”) or claim 8 of U.S. Patent
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`No. 9,616,049 (“the ’049 patent”) was anticipated.1 Perhaps it never intended to do so.
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`Instead, at trial and in its opening brief, FK focused on its theory that the inventions of
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`the claims-in-suit are obvious in view of any one of three separate combinations:
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`• Concentrate Label plus POSA
`• Concentrate Label plus Dexdomitor
`• Concentrate Label plus Investigational New Drug Application No. 32,934 (“IND”)
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`But the problem that proved to be insurmountable for FK with all three of these
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`combinations is that none renders claim 6 of the ’106 patent obvious unless FK also proves that
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`the “not more than about 2%” limitation (“the 2% limitation”) is an inherent property of the
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`claim. This FK has failed to do and that failure is fatal to its obviousness theories.2
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`1 Anticipation means that someone else did the identical thing before the named inventors.
`2 FK’s reasonable expectation of success theory does not excuse it from the requirement to prove
`inherency, as discussed in Argument Section I.B.1, infra.
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`FK’s expert, Dr. James Kipp, analyzed eighteen examples (sets of stability data) that FK
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`argues show the 2% limitation is inherent. But that argument flaunts, and FK does not cite, two
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`of the most recent—and controlling—cases from the Federal Circuit. In Endo Pharm. Sols., Inc.
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`v. Custopharm Inc., the Court held that inherency cannot be proven by examples alone. 894 F.3d
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`1374, 1381-82 (Fed. Cir. 2018). And in Millennium Pharm., Inc. v. Sandoz Inc., the court held
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`that the inventors’ own work may not be cited to show inherency. 862 F.3d 1356, 1367 (Fed.
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`Cir. 2017). Yet, that is precisely what FK attempted at trial. All eighteen of Dr. Kipp’s
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`examples are directly from the inventors. In its post-trial brief, FK now includes data for its own
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`generic product. But those examples are also dependent on the inventors’ work. FK stipulated
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`to infringement, and FK’s scientists relied on the inventors’ patent to create FK’s infringing
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`product.
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`Even apart from FK’s failure to prove inherency, the combinations it argues do not
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`establish obviousness. The first combination, the concentrate label, plus the knowledge of a
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`POSA, was considered by the Patent Office. (JTX 7.81, JTX 7.100-101.) The second
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`combination, the concentrate label plus Dexdomitor, makes no sense. Dexdomitor is formulated
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`at 500 µg/mL, and does not teach a POSA that dexmed can be stable when formulated at 4
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`µg/mL. Dexdomitor is 125 times more concentrated than the claims. Stability of such a high
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`concentration has no relevance to predicting stability at a formulation of 4 µg/mL.
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`Finally, FK’s third obviousness combination, the concentrate label plus the IND, fails
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`because the IND is not prior art. FK devoted much of its time at trial attempting to convert the
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`IND into prior art. It pursues two theories to attempt to achieve this. First, it argues that the
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`IND was on sale, though its theory really relies on the alleged sale of the Shafer clinical protocol
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`2
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`study.3 Second, it argues that the IND investigators invented a ready-to-use formulation and
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`provided the formulation to Hospira. FK reasons that if it can show that Shafer was on sale, or
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`was available to Hospira, then the IND is prior art. This is why the parties spent many hours
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`during trial arguing about whether the IND/Shafer was on sale.
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`Unfortunately for FK, its theories here are contrary to the law. If it wants to treat Shafer
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`as prior art, then it must show that an embodiment of the study protocol was on-sale and the
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`protocol was ready for patenting. Alternatively, it must show that Shafer was communicated to
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`the named inventors before they conceived of the claimed invention. FK has not proved either.
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`Finally, FK failed to prove its non-enablement defense by clear and convincing evidence.
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`To successfully make out that defense, FK must prove that a POSA would have to conduct
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`undue experimentation before the POSA could practice the invention of claim 6 of the ’106
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`patent. Dr. Kipp could identify only an implausible glass-cork combination that would
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`supposedly require undue experimentation to achieve the 2% limitation. He conceded, however,
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`that any needed experimentation would be routine to a POSA. Thus, FK failed to meet its
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`burden of proof on non-enablement as well.
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`FK failed to prove any of its invalidity defenses by clear and convincing evidence. As
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`FK has stipulated that it infringes the claims in suit, the court should enter judgment for Hospira.
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`II.
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`SUMMARY OF THE TRIAL RECORD
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`A.
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`The Patents
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`The ’106 patent issued on February 11, 2014 to named inventors Priyanka
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`Roychowdhury and Robert Cedergren. (JTX 1.) It was assigned to Hospira. The ’049 patent
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`3 The Shafer study was a Phase I Clinical Study described in the 1989 version of the IND. FK
`refers to the Shafer study as “the Farmos invention.” (D.I. 134, Fresenius Kabi Op. Br. (“Br.”)
`2.) That is misleading. It is referred to as “Shafer” herein.
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`3
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`issued on April 11, 2017 to the same named inventors and was also assigned to Hospira. (JTX
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`2.) The ’106 and ’049 patents have the same priority date of January 4, 2012. (JTX 1; JTX 2.)
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`The ’106 patent has been the subject of prior litigation. On January 22, 2018, Judge
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`Richard G. Andrews of the U.S. District Court for the District of Delaware held that claim 6 of
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`the ’106 patent is valid, rejecting (among other defenses) the argument that claim 6 was obvious
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`in that the “not more than about 2%” limitation is inherent. Hospira, Inc. v. Amneal Pharm.,
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`LLC, 285 F. Supp. 3d 776, 799-800 (D. Del. 2018). The ’106 patent was also the subject of a
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`Petition to Institute Inter Partes Review (a request that the Patent Office again consider the
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`patentability of the claim). In February 2017, the Patent Trial and Appeal Board declined to
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`institute an IPR, finding no substantial question of patentability.4 Amneal Pharm. LLC, v.
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`Hospira Inc., No. IPR2016-0580, Paper 11 (P.T.A.B. February 3, 2017).
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`B.
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`The Farmos Phase I Clinical Studies
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`In the 1980s, Farmos Yhtymay Oy (“Farmos”), a company in Finland, developed a new
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`molecule called dexmedetomidine. Farmos obtained a composition of matter patent on the
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`dexmed molecule, U.S. Patent No. 4,910,214 (the “’214 patent”). (JTX 134.) The ’214 patent
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`issued in 1990. (Id.) Dexmed appeared to have potential for use as a sedative in humans. In
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`1989, Farmos applied to the U.S. Food & Drug Administration (“FDA”) for an IND to begin
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`testing dexmed formulations in humans. (JTX 35.)
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`Farmos conducted at least two Phase I clinical studies of dexmed at a 20 µg/mL
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`concentration. (JTX 35.63; JTX 38.) These studies were experimental and, as is true of all
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`Phase I studies, they were designed first and foremost to test for safety in humans and not for
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`4 These prior litigations are matters of public record. Counsel for FK referred to and
`characterized the prosecution history of the patents in suit during the trial (Tr. 837:7-19), but
`omitted that the Patent Office declined to institute an IPR on the ’106 patent in 2017.
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`4
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`frequency, concentration, stability or other characteristics that would be tested later before a New
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`Drug Application could be submitted to the FDA for approval. (Tr. 590:1-591:7 (Seaton).)
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`FK calls one of these Phase I clinical studies, conducted by Dr. Steven Shafer, the
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`“Farmos invention.” (Br. 2, 24; JTX 38; see supra n.3.) But this study was a failure. (JTX
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`34.45; DTX 334.0005.) There were too many “adverse events.” (JTX 34.45.) It made people
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`sick. 20 µg/mL was a high dose and too potent to be safe for humans. (Tr. 524:12-21, 526:23-
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`527:1.) As Hospira’s expert anesthesiologist Dr. Michael Ramsay explained, Dr. Shafer’s
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`experiment demonstrated that the 20 µg/mL concentration was not ready-to-use. (Tr. 684:24-
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`685:16.) It would have to be diluted before it could be safely injected into the human blood
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`stream. (Tr. 684:24-685:16.) Farmos thereafter abandoned further experiments at 20 µg/mL and
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`began experimenting with lower doses that would be safe for humans. (Tr. 526:23-527:11;
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`536:12-537:7.) FK adduced no evidence concerning Farmos’ experiments following the failed
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`Phase One clinical trials at 20 µg/mL. There was no evidence at trial that these experiments
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`involved ready-to-use, stable formulations that would work for their intended purpose.
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`C.
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`The 1994 License and Supply Agreement (“1994 Agreement”)
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`By 1994, Farmos, then known as Orion Corporation (“Orion”), offered to sell ampoules
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`of dexmed to Abbott Laboratories (“Abbott”) formulated at 200 µg/mL. (JTX 110.60, 110.114.)
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`These high concentration ampoules were described as “finished product.” (JTX 110.114.)
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`This offer was part of the 1994 License and Supply Agreement between Orion and
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`Abbott. (JTX 110.) The 1994 Agreement had two parts. First, Orion licensed the ’214 patent
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`and Orion’s dexmed “know-how” to Abbott. (JTX 110.15 at § 2.1.1.) Second, Orion made the
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`described offer to supply dexmed to Abbott in either of two embodiments: in powdered bulk
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`form or in 2 mL ampoules formulated in a concentration of 200 µg/mL. (JTX 110.60, 110.114.)
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`Before trial, FK filed a motion for partial summary judgment arguing, in part, that Orion’s offer
`
`5
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`

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`to sell ampoules was an offer to sell the inventions claimed in the patents-in-suit. (D.I. 104.)
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`Such an offer would be subject to Article 2 of the Uniform Commercial Code (“UCC”). FK
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`abandoned this theory at trial.
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`FK also presented a theory that Orion sold the IND to Abbott and that triggered the on-
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`sale bar, making Shafer prior art to the asserted claims, even though Shafer was never available
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`to a POSA. (Br. 26-29.) Neither the facts nor the law support this theory. The IND was not the
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`subject of a sale. The 1994 Agreement is unambiguous. Orion’s know-how was licensed to
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`Abbott, not sold. (JTX 110.15.) Both Peter Lankau, FK’s expert, and Christopher Seaton,
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`Hospira’s expert, agree that the IND is “know-how” as defined in the 1994 Agreement. (Tr.
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`102:15-103:15, 108:5-7 (Lankau); 605:3-606:5; 643:4-10 (Seaton).) Abbott agreed to pay
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`royalties to Orion for the licensed know-how. (JTX 110.23.) If the Agreement was terminated,
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`then the license to the know-how would end and the IND would be returned to Orion. (JTX
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`110.80-81.)
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`FK attempted at trial to rewrite Orion’s license to Abbott by offering evidence of
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`correspondence with the FDA where Orion or Abbott referred to the IND as having been
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`transferred from Orion to Abbott. (See e.g., DTX 350; DTX 353.) But this does not transform a
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`license into a sale. As Mr. Seaton explained, the FDA does not know or care who owns the IND.
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`(Tr. 617:1-620:20.) When sponsorship of an IND is transferred, the FDA cares only that the
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`transferee has rights to the know-how that comprises the IND. (Id.) As Mr. Seaton further
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`explained, those rights can be acquired equally by sale or by license. (Id.) To ascertain which is
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`true in a particular case, one has to look at the agreement between the parties, not their separate
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`correspondence with the FDA. (See Tr. 596:7-601:19 (Seaton).) The 1994 Agreement here
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`establishes that the IND was not sold. It was licensed.
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`6
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`

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`Although FK disputes the effect of the license on its on-sale theory, there is no dispute
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`that Orion never offered to sell or sold an embodiment of claim 6 of the ’106 patent to Abbott.
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`That is, Orion never offered to sell to Abbott a formulation of dexmed at 4 µg/mL disposed
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`within a sealed glass container. That did not exist in 1994. Nor is there any evidence that Orion
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`offered to sell an embodiment of the Shafer study. That is, Orion never offered to sell Abbott a
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`formulation of dexmed at 20 µg/mL disposed within a sealed glass container, a formulation that
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`in any event did not work for its intended purpose. (JTX 110.61, supra p. 5.)
`
`D.
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`The Precedex Concentrate New Drug Application (“NDA”)
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`In 1999, Abbott submitted an NDA for dexmed to the FDA. The NDA was approved in
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`December 1999 and the new product was branded as Precedex Concentrate. (JTX 15.2.)
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`Precedex Concentrate is formulated at 100 µg/mL. (JTX 15.14.) It must be diluted at the
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`hospital to 4 µg/mL to be safe to inject into a human’s blood stream. (JTX 15.13.)
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`E.
`
`The Spin-Off
`
`In 2004, Abbott spun off its Hospital Supply Division as a stand-alone company. That
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`company became Hospira. (Tr. 626:8-628:5.) The Separation and Distribution Agreement
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`(“2004 Agreement,” JTX 109) between Abbott and Hospira is not a sales agreement. (Tr. 629:1-
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`6.) Mr. Lankau agrees that “the actual transaction itself would not have been considered a sale.”
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`(Tr. 117:1-21.) He further concurs that the recitals in the 2004 Agreement do not use the word
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`“sale” at all. (Id.) Nor does the 2004 Agreement mention the IND. (Tr. 118:5-16.)
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`Notwithstanding, FK argues that Abbott “sold” the IND to Hospira in the transaction. (Br. 29-
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`30.) FK points to the fact that Hospira assumed a debt obligation that formerly was Abbott’s as
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`part of the transaction and that Hospira’s first annual report states that Hospira owns Precedex
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`(among many other assets) as a result of the separation transaction. (Id.) Neither of these facts is
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`evidence that Abbott “sold” the IND to Hospira. Though sponsorship of the IND was transferred
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`7
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`Case: 1:16-cv-00651 Document #: 144 Filed: 08/07/18 Page 14 of 52 PageID #:5924
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`to Hospira as part of the separation transaction, that is not a “sale” under the UCC or in any other
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`sense that is relevant to the on-sale bar. In any event, it is undisputed that Abbott never offered
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`to sell or sold to Hospira a dexmed formulation at 4 µg/mL (or at 20 µg/mL) disposed within a
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`sealed glass container. (Tr. 118:17-119:8 (Lankau).)
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`F.
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`The Precedex Premix Project
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`In 2006, Hospira decided to attempt to formulate a ready-to-use (or “premix”) version of
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`Precedex, a version that would not have to be diluted at the hospital. (JTX 72.2.) The project
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`was assigned to Drs. Roychowdhury and Cedergren. (Tr. 131:17-132:6, 232:7-22.) A premix
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`version would have to be formulated at 4 µg/mL. (E.g., Tr. 134:15-18.) That concentration was
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`known to be effective and safe for injection into a human and was required by the label of
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`Precedex Concentrate for dilution before administration. (E.g., Tr. 134:3-11.)
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`Drs. Roychowdhury and Cedergren testified that the principal challenge for them to
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`successfully formulate a premix version of Precedex was to achieve adequate stability at such a
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`low concentration. (Tr. 180:4-15, 233:2-9.) 4 µg/mL is extraordinarily low for a pharmaceutical
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`drug. None of the formulators who testified at trial had ever worked before with such a low
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`concentration in a drug formulation. (Tr. 178:7-13 (Roychowdhury), 361:13-21 (Kipp), 723:23-
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`724:3 (Mowli).) Even a slight loss of potency in such a low concentration can cause the
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`formulation to “fall out of spec.” (Tr. 146:2-20, 726:5-18.) Dr. Kipp employed a formula in his
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`analysis that illustrates the hyper-sensitive relationship between concentration and instability.
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`(407:24-408:2, 413:4-10.) Dr. Kipp’s equation5 shows that as concentration is lowered, the
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`stability of a drug plummets. (Tr. 411:5-20, 412:22-415:4, 465:12-21.)
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`5 This equation applies for a zero-order model of loss, which Dr. Kipp assumed for Dexmed
`because he did not determine the order of loss. (Tr. 403:1-23, 405:17-24.) Dr. Kipp’s failure to
`determine the model of loss belies FK’s claim that it proved that the 2% limitation is inherent.
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`8
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`Case: 1:16-cv-00651 Document #: 144 Filed: 08/07/18 Page 15 of 52 PageID #:5925
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`The inventors’ job was even more difficult because they had no reason to expect success
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`when they began work. Virtually nothing was known to a POSA about the stability of dexmed at
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`that time. (Tr. 139:8-13, 382:4-8, 391:9-14, Venkata Dep. 219:22-220:5, 272:22-273:13.)
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`At trial, Dr. Kipp called the dexmed molecule “rock stable.” (See e.g., Tr. 324:22-325:1;
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`339:22-25; 341:25-342:9.) But Dr. Kipp’s analysis was incomplete. Hospira’s expert Dr. Robert
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`Linhardt demonstrated that Dr. Kipp was opining on only a part of the dexmed molecule, and
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`that there are other parts of the molecule that are susceptible to degradation. (See e.g., Tr.
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`819:20-824:18.) In particular, Dr. Linhardt explained that dexmed is susceptible to oxidation, a
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`phenomenon that the inventors documented as part of their work and reported in the patent. (Tr.
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`820:5-14, 823:1-824:18, 830:16-831:2; JTX 51.51; JTX 1.11, 17:25-28.)
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`Drs. Roychowdhury and Cedergren had no knowledge of the IND. (Tr. 132:11-12,
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`233:20-22.) But even if they had, it would not have given them any sort of head start. The
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`evidence shows that Farmos never attempted to formulate at 4 µg/mL. To the extent Farmos ran
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`two Phase I experiments at 20 µg/mL, one required dilution (Tr. 496:18-22), and the other was
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`unsuccessful. Both were abandoned after the earliest stage of experimentation. (Tr. 521:2-7,
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`531:2-6 (Maile).)
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`Further, Dr. Stephen Ogenstad, the only bio-statistician to testify, explained that the
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`stability data in the IND did not provide reliable evidence as to the stability of dexmed even at
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`the concentration of 20 µg/mL, which is five times higher than the claimed concentration. (Tr.
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`749:15-750:8.) Dr. Ogenstad opined that this data was too varia