Case 1:15-cv-00697-RGA Document 45-4 Filed 04/28/16 Page 1 of 72 PageID #: 767
`
`Causes of low mixed venous 0 2 content
`(Smv02) include anemia, pulmonary disease,
`carboxyhemoglobin, low cardiac output, and
`increased tissue metabolic needs. The ratio of
`Sa02 to (Sa02 - SmvOy determines the ad(cid:173)
`equacy of 0~ delivery. 1he ideal ratio is 4:1,
`whereas 2: Its the minimwn acceptable ratio
`to maintain aerobic metabolic needs.
`cardiac output: Cardiac output (CO) is
`melll!ured by intermittent bolus injection of
`ice water or, in neW catheters, continuoos warm
`thermodilution. The cardiac index divides the
`CO by body surface ru'el\ to correct for patient
`size (see Table 222-3).
`Other variables can be calculated from CO.
`They include systemic and pulmonaty vascu(cid:173)
`lar resistance and tight venuicul ar stroke
`work (RVSW) and left ventricular stroke
`work (L VSW).
`CompUcations and precautions: PACs may
`be difficult to insert. Cardiac mhythmias are
`the most comri:ion comptication. Pulmonary
`infarct1on secondary to overinflated or per(cid:173)
`manenlly wedged balloons, pulmonary artery
`perforation, intracardiac petforation, valvular
`injury, and endocarditis may occur. Rarely,
`the catheter may curl into a knot within the
`right venuicle (especially in patients with
`
`Table 222-3. NORMAL VALUES FOR
`CARDIAC INDEX AND
`RELATED MEASUREMENTS
`
`MEASUREMENT
`
`0 2 uptake
`Arteriovenous 0 2
`difference
`Cardiac index
`Stroke index
`Total systemic
`resislance
`Total pulmonary
`resistance
`Pulmonary arteri(cid:173)
`olar resistance
`
`UNITS ± SO
`143 ± 14.3 mUmin/m2
`4.1 ±0.6dL
`
`3.5 ± 0.7 Uminim2
`46 ± 8.1 mUbeatim2
`ll30 ± ~~g dynes-
`sec-em
`205 ± 51 dynes-se<:-cm·5
`
`67 ± 23 dynes-sec-cm·5
`
`SD = standard deviation.
`Adapted from Ban·au-Boyes BG, Wood EH:
`Cardiac output and related measUl~menLs and
`pressure values in the tight heart and associated
`vessels, together with an analysis of the hemo(cid:173)
`dynamic response to the inhalation of high
`oxygen mixtures in healthy subjects. )Oimlal of
`Lalxnvtmy and ClinicalMedic:iue 51:72- 90, 1958. ·
`
`CHAPTER 222
`
`Ill Patient
`
`2247
`
`VASCULAR ACCESS
`A number of procedures are used to gain
`vascular access.
`
`(1
`
`capnometry uses a similar cor(cid:173)
`:en elevated sublingual Pco2
`~id systemiC hypoperfusion to monitor shock
`noninvasive sensor placed under
`1is device is easier to use tl1an gas(cid:173)
`cine tonometry and responds quickly to perfu~
`th resuscitation.
`r.~copy
`
`Peripheral Vein Catheterization
`Most patients' needs fm· !V fluid and drugs
`can be mel with a percutaneous peripheral
`venous catheter. Venous cutdown can be
`used when percutaneous catheter insertion is
`not feasible. Typical cutdown sites are the
`cephalic vein in the ann and the saphenous
`vein at the ankle.
`Common complications (eg,local infection,
`venous thrombosis, thrombophlebitis. inter(cid:173)
`stitial fluid extravasation) can be reduced by
`using a meticulous sterile technique during
`insertion and by replacing or removing the
`catheters within 72 h.
`
`Central Venous Catheterization .
`Patients needing secure or long-term vas(cid:173)
`cular access (eg. to receive antibiotics, che(cid:173)
`motherapy, or TPN) are best u·eated with a
`central venous catheter (CVC). CVCs allow
`infusion of solutions that are too concentrated
`or iiTitating for peripheral veins and allow
`monitoring of central venous pressure (CVP(cid:173)
`see p. 2299).
`Procedure: CVCs arc inserted using sterile
`technique and a local anesthetic (eg, I%
`lidocaine). The superior vena cava is entered
`via percmaneous puncture of the subclavian
`or the internal or external jugular vein or by
`venous cutdown on the basilic vein. The in(cid:173)
`ferior vena cava may be entered through the
`common femoral vein percutaneously or by
`cutdown on the saphenous vein. The choice
`of site depends on operator preference and
`patient habitus and ambulatory status. How(cid:173)
`ever, femoral venous catheters have a slightly
`higher rate of complications than those above
`the waist. Also, during cardiac arrest, fluid
`and drugs given through a femoral or saphe(cid:173)
`nous vein eve often fail to circulate above
`the diaphragm because of the increased in(cid:173)
`tmthoracic pressure generated by CPR. In
`this case, a subclavian o1· internal jugulru· ap(cid:173)
`proach may be preferred.
`If possible, the patient's coagulation status
`and platelet count should be nonnalized be(cid:173)
`fore CVC insertion. Percutaneous femoral
`lines mtist be inserted below the inguinallig(cid:173)
`amem. Otherwise, laceration of the external
`iliac vein or artery above the inguinal ligament
`may result in retroperitoneal hemorrhage; ex(cid:173)
`ternal compression of these vessels is nearly
`impossible. The subclavian vein also is not
`
`CC-JA160
`
`

`

`Case 1:15-cv-00697-RGA Document 45-4 Filed 04/28/16 Page 2 of 72 PageID #: 768
`
`3577
`~--- ----
`
`of1587
`1747,1750,1750,1753
`of 1587
`496, 174~ 1754-1755
`of1589
`infection of .1420
`(747, 1750, 1753-1754
`ofl587
`1747, 1755-1756
`injury to 2770
`of 1587, 1589
`
`Index
`------------------------ -----
`ve protein (continued)
`Crohn's disease (continued)
`hepatic innammation in 249
`osteomyelitis and 371
`protein-energy undernutrition and 16
`primary sclerosing cholangitis and 278
`1eference vnlues for 3493
`treatment of 167-169, 171-172
`in rheLimatic fever 2863
`ulcerative colitis vs 166
`ne 3426, 3500
`uveitis and 609
`as dietary supplement 3426
`Cromoglycate 2529
`urinary reference values for 3500
`Cromolyn 1116, 1116
`·
`kinase 301, 3494
`in asthma 1879
`in mastocytosis !125
`as cardiac enzyme 2104
`Cronkhite-Canada syndrome 132
`as skeletal muscle enzyme 30 I
`reference values for 3494
`CROS hearing aid 437
`Cross-dressing 1571
`Crowlidae polyvalent immune Fab
`antivenom 3318
`Crutamiton 712
`Croup 1410, 1844,2732,2879-2881
`epiglottitis vs 476
`pseudomembranous 2878
`spasmodic 2880
`Crow-Fukase syndrome 807
`Cruciate ligaments 3217
`injury to 3217
`Crutches 3457,3459,3460
`Crying 2735-2737,2736--2737
`paroxysmal (see Colic)
`in stranger anxiety 27 50
`Cryoglobulinemia 982, 2399
`hepatitis C and 249, 256
`Cryoprecipitate I 039
`Cryopyrinopathies 3028
`Cryotherapy
`in actinic keratoses 674
`in prostate crmeer 2472
`in warts 717
`Cryptococcosis 1329-J 330
`HIV infection and 1446
`India ink stain for 1166
`Cryptogenic organizing pneumonia 1946,
`1948, 1950 1951,1953
`Cryptorchidism 2476, 2892, 2894, 2987-2988
`Cryptosporidiosis 148, 150, 1338, 1339,
`1341, 1369-1370
`Crystalloid solutions 2298
`Crystals
`calcium oxalate 352, 355
`calcium phosphate 352, 355
`calcium pyrophosphate dihydrate 351,
`.352, 354--355
`Charcot-Leyden 987
`monosodium urate 349-·354, 352, 2441
`synovial fluid examination for 287,349
`urinary 2309,2309,2310, 2703
`
`reflex 1593, 1617
`poisoning 3364
`285
`ICresce.nti'c glomerulonephritis 2393-2396,
`2394
`I poisoning 3364
`syndrome 310-311
`•r .... : .. :.-·- endemic 2888
`Jcreut.c.'""' t-Jakob disease 1729-1730
`
`plate, fracture of 3233
`cartilage, pressure on 2275
`aryngeal incoordination 122
`yrotomy 2277, 2278
`syndrome 3002
`ajjar syndrome 218
`hemorrhagic fever 1400,
`
`1431
`
`extraintestinalmanifestations of 167
`gingiva in 518
`
`CC-JA161
`
`

`

`Case 1:15-cv-00697-RGA Document 45-4 Filed 04/28/16 Page 3 of 72 PageID #: 769
`
`3640
`
`Index
`
`Infliximab 169, 172, 1087
`in rheumatoid arthritis 339, 339
`Influenza 1396, 1405-1408, 1925
`a vi an (bird fJ u) 1408·-1409
`COPD and 1897
`drugs for 1407
`swine 1409-1410
`vaccine against 1171, l/74-ll75,
`1176-1177,1408,1929,2718,2720,
`2722,3109
`in Kawasaki disease 2937
`in pediatric HIV infection 2859
`Informed consent ::1469
`Infrapatellar tendinitis 2913
`Infrared heat therapy 3459, 3461
`Ingestion 76
`Ingrown toenail 736
`lnhalational fever 1976
`Inhalation challenge test 1980
`Inheritance (see Chrornosome[sJ; Genes)
`Inherited disorders (see Genetic disorders)
`Inherited disorders of metabolism ::1009--3026
`Inhibin B 2339
`Injury (see also Fracture; Trauma)
`birth 2769-2774
`head 3218-3227,3219,3221,3222,3225
`overuse 3296
`spinal cord 3227-3231, 3228, 3230
`spleen 986
`1nocybe poisoning 1614, 3337
`INR (international normalized ratio) 227. 971,
`3496
`Insect
`in ear canal 456
`stings by 3308· -3309 (see also Bites And
`stings)
`Insecticides 64 7
`poisoning with 3340-3341, 3363
`Insemination, intrauterine 2594
`Insomnia 1703-1715,1705, 1707
`dmgs and 1705, 1711
`in elderly 3103
`futal 1731
`physical disorders and 1487
`psychophysiologic 1711
`SSRls and 1547
`Inspiratory flow rate 2283
`Insufficient sleep syndrome 17!1
`Insula 1t'i37
`Insulin (see also Diabetes mellitus)
`allergic reaction to 875
`blood levels of 2, 3496
`in calcium channel blocker poisoning 3327
`
`--------~
`
`Insulin (cominued)
`in chronic pancreatitis 146
`dawn phenomenon with 875
`in diabetes mellitus 873. 874. 882
`in diabetic ketoacidosis 885
`growth factor effects on 759
`infection-related production of 1152
`in neonatal hyperglycemia 2796
`in nonketotic hyperosmolar syndrome 886
`in pheochromocytoma 802
`potassium levels and 831
`in pregnancy 2639, 2640
`preoperative 3447
`preparations of 873, 874
`regimens for type l diabetes mellitus 875
`regimens for type 2 diabetes mellitus 876
`resistance to 868, 87 !, 875, 1110, 2082
`antiretrovirals and 1453
`pregnancy and 2625
`in septic shock 2302
`Somogyi phenomenon with 875
`for surgical procedures 882
`surreptitious administration of !99
`for total parenteral nutrition 24
`Insulinase 2625
`Insulin-like growth factor I (lGF-1) 759
`measurement of 760, 765, 769
`in children 767
`Insulin-like growth factor binding protein
`type 3 (IGFBP-3) 767
`lnsulinoma 198-200, 199
`hypoglycemia and 888
`in MEN syndromes 910, 910
`Insttlin resistance syndrome 64--65, 65
`Insulin tolerance test 765, 767
`Insurance, medical 3157, 34 73-3480
`Medicaid 3l6 .1-31 t'i2
`Medicare 3155-3161
`private 3163, 3475
`!NT ACS (intracorneal rii1g segments) 574
`Integrase inhibitors 1450, 1451
`in children 2857
`Intellectual disability (mental retardation)
`3044-3048,3045,3047
`chromosomal abnormalities and 3045
`diagnosis of 3046, 3047
`in Down syndrome 3000
`in fetal alcohol syndrome 2799
`in fragile X syndrome 2998
`prevention of 3048
`Intelligence quotient (IQ) 3044
`Intensive care (see Critically ill patient)
`Intention tremor !774, 1775
`
`Intercostal retractions 1826
`Intercourse, sexual (see Sexual activity)
`Interdisciplinary team 3115-3116
`lnterferon(s)
`in cancer 1060, 1067, 1072
`in chronic hepatitis 257, 258
`in hepatitis C 258
`in viral infection 1395
`Interferon-a 1067
`in essential thrombocythemia 998
`in genital warts 14 7 I
`hyperthyroidism and 781
`immune function of I 084
`therapeutic use of 1088, 1090
`tremors ancll775
`in warts 718
`Tnterfcron-a2b
`in mastocytosis 1125
`in polycythemia vera 1003
`Interferon-~
`immune function of !OR4
`in multiple sclerosis 1782
`therapeutic use of 1088, 1090
`lnte!feron-y
`in atopic dermatitis 665
`in chro11ic granulomatous disease 110
`fever and 1152
`immune function of 1080, 1081, 1084
`receptor defects of I 093
`therapeutic use of /088, 1090
`lntcrleukin(s)
`in cancer 1058, 1072
`immune function of 1084
`lnterlcukin-1
`fever and 1152
`immune function of 1080
`Interleukin-2 1088
`receptor for, protein-energy
`undernutrition and 16
`Tnterleukin-6 1152
`Interleukin-11 1088
`lnterleukin- 12
`deficiency of 1093
`t·eceptor ~I defect of !093
`Intermittent pneumatic compression
`(see Pneumatic compression)
`International normalized ratio (JNR) 22~
`971,3496
`International prognostic index (!PI) 102:
`Internuclear ophthalmoplegia 1750, 175
`1781
`Interphalangeal joints
`deformities of 386
`
`CC-JA162
`
`

`

`Case 1:15-cv-00697-RGA Document 45-4 Filed 04/28/16 Page 4 of 72 PageID #: 770
`Case 1:15-cv-OO697-RGA Document 45-4 Filed 04/28/16 Page 4 of 72 PagelD #: 770
`
`EXHIBIT 6
`
`EXHIBIT 6
`FILED UNDER SEAL
`
`FILED UNDER SEAL
`
`

`

`Case 1:15-cv-00697-RGA Document 45-4 Filed 04/28/16 Page 5 of 72 PageID #: 771
`Case 1:15-cv-OO697-RGA Document 45-4 Filed 04/28/16 Page 5 of 72 PagelD #: 771
`
`EXHIBIT 7
`EXHIBIT 7
`
`CC—JA173
`
`CC-JA173
`
`

`

`Case 1:15-cv-00697-RGA Document 45-4 Filed 04/28/16 Page 6 of 72 PageID #: 772
`Case 1:14-cv-00487-GMS Document 59 Filed 08/21/15 Page 1 of 17 PageiD #: 531
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`HOSPIRA, INC. and ORION
`CORPORATION,
`
`Plaintiffs,
`
`v.
`
`EUROHEAL TH INTERNATIONAL SARL and
`WEST-WARD PHARMACEUTICAL CORP.,
`
`Defendants.
`
`HOSPIRA, INC. and ORION
`CORPORATION,
`
`Plaintiffs,
`
`v.
`
`EUROHEAL TH INTERNATIONAL SARL and
`WEST-WARD PHARMACEUTICAL CORP.,
`
`Defendants.
`
`)
`)
`)
`)
`)
`) C.A. No. 14-487 GMS
`)
`)
`)
`)
`)
`)
`
`)
`)
`)
`)
`)
`) C.A. No. 14-1008 GMS
`)
`)
`)
`)
`)
`
`PLAINTIFFS' OPENING CLAIM CONSTRUCTION BRIEF
`
`OF COUNSEL:
`
`Thomas J. Mel oro
`Heather M. Schneider
`Dan Constantinescu
`WILLKIE F ARR & GALLAGHER LLP
`787 Seventh A venue
`New York, NY 10019
`Telephone: (212) 728-8000
`tmeloro@willkie.com
`hschneider@willkie.com
`dconstantinescu@willkie.com
`
`Richard K. Herrmann (I.D. #405)
`Mary B. Matterer (I.D. #2696)
`MORRIS JAMES LLP
`500 Delaware Avenue, Suite 1500
`Wilmington, DE 19801
`(302) 888 6800
`rherrmann@morrisjames.com
`mmatterer@morrisjames.com
`
`Attorneys for Plaintiffs
`Hospira, Inc. and Orion Corporation
`
`CC-JA174
`
`

`

`Case 1:15-cv-00697-RGA Document 45-4 Filed 04/28/16 Page 7 of 72 PageID #: 773
`Case 1:14-cv-00487-GMS Document 59 Filed 08/21/15 Page 2 of 17 PageiD #: 532
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ................................................................................................................. i
`
`TABLE OF AUTHORITIES .......................................................................................................... ii
`
`I. BACKGROUND ON PRECEDEX AND THE '867 PATENT .......................................... !
`
`II. LEGAL STANDARDS FOR CLAIM CONSTRUCTION ................................................. 3
`
`III. HOSPIRA'S PROPOSED CONSTRUCTIONS ARE SUPPORTED BY THE
`INTRINSIC EVIDENCE AND UNDERSTANDING OF SKILLED ARTISANS ........... .4
`
`A.
`
`"Dexmedetomidine" ................ : ........................................................................... 4
`
`B.
`
`"Intensive Care Unit" ........................................................................................... 6
`
`C.
`
`"Sedating a Patient in an Intensive Care Unit" .................................................... 8
`
`D.
`
`"Arousable and Orientated" ............................................................................... 11
`
`E.
`
`"Loading Dose" and "Maintenance Dose" ........................................................ 12
`
`IV. CONCLUSION .................................................................................................................. l4
`
`CC-JA175
`
`

`

`Case 1:15-cv-00697-RGA Document 45-4 Filed 04/28/16 Page 8 of 72 PageID #: 774
`Case 1:14-cv-00487-GMS Document 59 Filed 08/21/15 Page 3 of 17 PageiD #: 533
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Edwards Lifesciences LLC v. Cook Inc.,
`582 F.3d 1322 (Fed. Cir. 2009) ............................................................................................ 5
`
`Hoescht Celanese Corp. v. BP Chems. Ltd.,
`78 F .3d 1575 (Fed. Cir. 1996) ......................................................................................... · ..... 5
`
`Markman v. Westview Instruments, Inc.,
`517 u.s. 370 (1996) ............................... : ............................................................................. 3
`
`Phillips v. AWH Corp.,
`415 F .3d 1303 (Fed. Cir. 2005) ................................................................................... .3, 4, 5
`
`Teva Pharms. USA, Inc. v. Sandoz, Inc.,
`135 S. Ct. 831 (2015) ....................................................................................................... 3, 4
`
`Vitronics Corp. v. Conceptronic, Inc.,
`90 F .3d 1576 (Fed. Cir. 1996) .................................. ,. ........................................................... 3
`
`ii
`
`CC-JA176
`
`

`

`Case 1:15-cv-00697-RGA Document 45-4 Filed 04/28/16 Page 9 of 72 PageID #: 775
`Case 1:14-cv-00487-GMS Document 59 Filed 08/21/15 Page 4 of 17 PageiD #: 534
`
`Plaintiffs Hospira, Inc. and Orion Corporation (collectively, "Hospira") respectfully
`
`submit this Opening Claim Construction Brief in support of Hospira' s proposed constructions of
`
`claim terms from U.S. Patent No. 6,716,867 (the '"867 patent," JNT-PRECEDEX 00388264-74).
`
`There are six terms at issue for construction: (I) "dexmedetomidine"; (2) "intensive care
`
`unit"; (3) "sedating a patient in an intensive care unit"; ( 4) "arousable and orientated";
`
`(5) "loading dose"; and (6) "maintenance dose." The last two terms are used in conjunction
`
`throughout the patent and thus are addressed together. For the reasons discussed below,
`
`Hospira's proposed constructions are fully supported by the intrinsic evidence, are consistent
`
`with the understanding of a person of ordinary skill in the art, and should be adopted by the
`
`Court.
`
`I.
`
`BACKGROUND ON PRECEDEX AND THE '867 PATENT
`
`This is a patent infringement action arising under the Hatch-Waxman Act concerning an
`
`attempt by Eurohealth International SARL and West-Ward Pharmaceutical Corp. (collectively,
`
`"Eurohealth") to sell generic copies of a unique sedative called Precedex, whose active
`
`ingredient is dexmedetomidine.
`
`The '867 patent covers the use of Precedex in a method of sedating a patient in an
`
`intensive care unit ("ICU") wherein the patient remains arousable and orientated. This method
`
`of sedation allows critically ill patients to remain sedated, yet communicate with caregivers and
`
`family. Precedex has changed the landscape of sedation for ICU patients and has garnered over
`
`$1 billion in sales and recommendations from leading practitioners.
`
`Precedex is approved for two indications: (1) "sedation of initially intubated and
`
`mechanically ventilated patients during treatment in an intensive care setting"; and (2) "sedation
`
`of non-intubated patients prior to and/or during surgical and other procedures." (Ex. A, Precedex
`
`CC-JA177
`
`

`

`Case 1:15-cv-00697-RGA Document 45-4 Filed 04/28/16 Page 10 of 72 PageID #: 776
`Case 1:14-cv-00487-GMS Document 59 Filed 08/21115 Page 5 of 17 PageiD #: 535
`
`Prescribing Information at JNT-PRECEDEX 00388275.)1 Both ofthese indications overlap with
`
`the '867 patent because both methods of sedation can be performed by medical personnel in an
`
`ICU setting on an ICU patient. The patent claims are not restricted to intubated patients.
`
`Sedation of ICU patients is needed for many reasons. As the patent explains, patients
`
`recovering from critical illness have reported unpleasant memories of anxiety, pain, fatigue,
`
`weakness, and thirst, as well as the presence of catheters and procedures such as physiotherapy.
`
`('867 patent col. 1 :32-38.) Sedation ofiCU patients ensures that they are comfortable and
`
`relaxed and can tolerate unpleasant procedures. (' 867 patent col. 1 :38-41.)
`
`As the inventors explained in the '867 patent, the preferred level of sedation for critically
`
`ill patients is for them to be arousable, but the available sedatives when the patent was filed did
`
`not allow for that level of sedation. Conventional sedatives, when used in the amount needed to
`
`provide adequate sedation, did not maintain arousability and orientation. (May 2, 2003
`
`Amendment and Request for Continued Examination at JNT-PRECEDEX00371801.) For
`
`example, propofol and midazolam resulted in prolonged sedation, oversedation, prolonged
`
`weaning, respiratory depression, and lack of orientation and cooperation. ('867 patent col. 1:5 8-
`
`2:3.) The only other a 2-agonist that had been evaluated for ICU sedation at that time was
`
`clonidine, but it had only been used with other active agents and it could not be used to sedate
`
`critically ill patients because of its unpredictable hemodynamic effects. ('867 patent col. 2:40-
`
`56.)
`
`In contrast to the state of the art at the time of the invention, the quality ofiCU sedation
`
`achieved with Precedex is unique. Patients are arousable and orientated, and can respond to
`
`questions. This method of sedation was so unprecedented that ICU nurses had to be warned that
`
`Citations to "Ex.
`" refer to Exhibits to the Declaration of Heather M. Schneider in
`Support of Plaintiffs' Opening Claim Construction Brief filed concurrently herewith.
`
`2
`
`CC-JA178
`
`

`

`Case 1:15-cv-00697-RGA Document 45-4 Filed 04/28/16 Page 11 of 72 PageID #: 777
`Case 1:14-cv-00487-GMS Document 59 Filed 08/21/15 Page 6 of 17 PageiD #: 536
`
`a patient's attempt to communicate while sedated with Precedex did not mean that the patient
`
`was undersedated. (May 2, 2003 Amendment and Request for Continued Examination at JNT(cid:173)
`
`PRECEDEX00371803.) In addition, Precedex does not cause respiratory depression and can be
`
`used on intubated or non-intubated patients and during ventilator weaning. ('867 patent col.
`
`4:62-66; 13:45-52.)
`
`II.
`
`LEGAL STANDARDS FOR CLAIM CONSTRUCTION
`
`Claim construction is a question of law for the Court. Markman v. Westview Instruments,
`
`Inc., 517 U.S. 370,372 (1996). However, claim construction also has "evidentiary
`
`underpinnings" and may involve the resolution of subsidiary factual disputes. Teva Pharms.
`
`USA, Inc. v. Sandoz, Inc., 135 S. Ct. 831,841 (2015).
`
`First, the Court examines "the words of the claims themselves" to define the scope of the
`
`patented invention." Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996).
`
`The Court generally must give claim terms their "ordinary and customary meaning," which is
`
`"the meaning that the term would have to a person of ordinary skill in the art in question at the
`
`time of the invention, i.e., as of the effective filing date of the patent application." Phillips v.
`
`AWHCorp., 415 F.3d 1303, 1312-13 (Fed. Cir. 2005) (en bane).
`
`Second, the Court should review "the specification to determine whether the inventor has
`
`used any terms in a manner inconsistent with their ordinary meaning." Vitronics, 90 F.3d at
`
`1582. The specification "is always highly relevant to the claim construction analysis. Usually, it
`
`is dispositive; it is the single best guide to the meaning of a disputed term." !d.
`
`Third, the Court should consider the patent's prosecution history if it is in evidence. This
`
`may demonstrate "how the inventor understood the invention and whether the inventor limited
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`the invention in the course of prosecution, making the claim scope narrower than it would
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`otherwise be." Phillips, 415 F.3d at 1317.
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`3
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`Finally, the Court may use extrinsic evidence, "including expert and inventor testimony,
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`dictionaries, and learned treatises." !d. at 1317. In some cases the Court "will need to look
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`beyond the patent's intrinsic evidence and to consult extrinsic evidence in order to understand,
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`for example, the background science or the meaning of a term in the relevant art during the
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`relevant time period." Teva, 135 S. Ct. at 841.
`
`III. HOSPIRA'S PROPOSED CONSTRUCTIONS ARE SUPPORTED BY THE
`INTRINSIC EVIDENCE AND UNDERSTANDING OF SKILLED ARTISANS
`
`A.
`
`"Dexmedetomidine"
`
`Dexmedetomidine is the active ingredient in Precedex, which contains the hydrochloride
`
`salt form of the drug. (See Ex. A, Precedex Prescribing Information at JNT-PRECEDEX
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`00388289.) The claim construction dispute between the parties is whether the word
`
`"dexmedetomidine" in the patent claims is limited to the free base form or can include the salt
`
`form as well. Based on the specification and prosecution history, the proper construction of this
`
`term is "substantially pure, optically active dextrorotary stereoisomer of medetomidine, as
`
`the free base or pharmaceutically acceptable salt." Eurohealth's proposed construction is
`
`nearly identical but omits "or pharmaceutically acceptable salt," thus limiting the claim to the
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`free base form ofthe drug. Eurohealth's proposal is inconsistent with the intrinsic evidence and
`
`should not be adopted by the Court.
`
`Dexmedetomidine is an a2-agonist that is the d-enantiomer ofmedetomidine. ('867
`
`patent col. 2:66-3 :8; 3: 19-20.) The specification and prosecution history clearly state that the
`
`term "dexmedetomidine" includes both the free base and pharmaceutically acceptable salt forms.
`
`The specification explains that "[t]he chemical form for [dexmedetomidine] can be the free base
`
`or an acid addition salt" and lists numerous acid addition salts that may be used. ('867 patent
`
`4
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`col. 5:31-40). In addition, the form ofdexmedetomidine used in the examples ofthe '867 patent
`
`is the hydrochloride (HCl) salt. ('867 patent col. 5:53-55; 7:4-6, 7:62-64.)
`
`Further, during prosecution the applicants specified on two occasions that
`
`'dexmedetomidine' includes pharmaceutically acceptable salt forms as well as the free base.
`
`(August 9, 2002 Amendment at JNT-PRECEDEX 00371768 ("When applicants refer to
`
`"dexmedetomidine" as used in the invention, that term includes pharmaceutically acceptable
`
`salts of that compound as well."); May 2, 2003 Amendment and Request for Continued
`
`Examination at JNT-PRECEDEX 00371797 ("Moreover, when applicants refer in this
`
`Amendment to 'dexmedetomidine' as used in the invention, that term is meant to include
`
`pharmaceutically acceptable salts ofthe compound as well.") (emphases added)).
`
`The intrinsic evidence unambiguously demonstrates that "dexmedetomidine" includes
`
`pharmaceutically acceptable salt forms. See Phillips, 415 F.3d at 1317; see also Hoescht
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`Celanese Corp. v. BP Chems. Ltd., 78 F.3d 1575, 1578 (Fed. Cir. 1996) (explaining that a
`
`patentee may ascribe meanings other than the ordinary meaning if the special definition of the
`
`term is clearly stated in the specification or prosecution history). While Eurohealth may argue
`
`that the recital of"dexmedetomidine or a pharmaceutically acceptable salt thereof' in claims 1 to
`
`5 of the '867 patent is redundant ifthe term "dexmedetomidine" already includes
`
`pharmaceutically acceptable salts, redundancy is irrelevant if the specification supports the
`
`proposed construction. See, e.g., Edwards Lifesciences LLC v. Cook Inc., 582 F.3d 1322, 1330
`
`(Fed. Cir. 2009) (ignoring any redundancy created by the claim construction in favor of a
`
`construction "demanded by the specification"). Hospira's construction should be adopted.
`
`5
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`B.
`
`"Intensive Care Unit"
`
`Hospira proposes that this term be construed as "any setting that provides care to
`
`critically ill patients, typically characterized by high nurse-to-patient ratios, continuous
`
`medical supervision, and intensive monitoring." Hospira's construction is consistent with the
`
`intrinsic evidence and the understanding of a person of skill in the art. Eurohealth's proposed
`
`construction is superficially similar ("any setting that provides intensive care, characterized by
`
`continuous medical supervision and intensive monitoring") but does not provide any assistance
`
`for the Court because it defines "intensive care unit" using the term "intensive care." This
`
`circular definition leaves out the most important element of an ICU-that it provides care to
`
`critically ill patients. In fact, it is the critically ill nature ofthe patients that drives the other
`
`features of"intensive care," which are the high-nurse-to-patient ratio, the continuous medical
`
`supervision, and the intensive monitoring.
`
`Hospira's construction starts with the '867 patent specification, which states that "the
`
`word intensive care unit includes any setting that provides intensive care." ('867 patent col.
`
`1:18-2019, 3:49-51; 4:44-45.) Intensive care has a well understood plain and ordinary meaning
`
`to persons of skill in the art, which is care provided to critically ill patients, typically
`
`characterized by high nursing-to-patient ratios, continuous medical supervision, and intensive
`
`monitoring. For example, this is demonstrated by medical dictionary definitions:
`
`[A] hospital facility for provision of intensive nursing and medical
`care of critically ill patients, characterized by high quality and
`quantity of continuous nursing and medical supervision and by use
`of sophisticated monitoring and resuscitative equipment; may be
`organized for the care of specific patient groups, e.g., neonatal or
`newborn ICU, neurological ICU, pulmonary ICU.
`
`(Ex. B, Stedman's Concise Medical Dictionary (4th ed. 2001) at JNT-PRECEDEX 00388300.)
`
`A separate area in the hospital where extremely sick patients are
`cared for. The ICUs are manned 24 hours a day by physicians and
`
`6
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`specially trained nurses. They are also equipped with life-support
`apparatus.
`
`(Ex. C, The New American Medical Dictionary and Health Manual ( 7th ed.1999) at JNT-
`
`PRECEDEX 00388303). As the Merck Manual explains, "ICUs have a high nurse:patient ratio
`
`to provide the necessary high intensity of service, including treatment and monitoring of
`
`physiologic parameters." (Ex. D, The Merck Manual of Diagnosis and Treatment (19th ed.
`
`2011) at JNT-PRECEDEX 00388306-307.)
`
`Hospira's construction is fully supported by and demonstrated throughout the intrinsic
`
`evidence. The '867 patent states at least eight times that ICU patients are critically ill:
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`"Patients recovering from an episode of critical illness have reported factors they
`found most distressing during their ICU stay .... " ('867 patent col. 1 :31-33);
`
`"At the moment, there is no universally accepted sedative regimen for critically
`ill patients." ('867 patent col. 1 :42-43);
`
`"The preferred level of sedation for critically ill patients has changed
`considerably in recent years." ('867 patent col. 2:15-16);
`
`"According to Tryba et al., clonidine has its limitations in sedating critically ill
`patients mainly because of its unpredictable hemodynamic effects, i.e.,
`bradycardia and hypotension, so that it must be titrated for each individual
`patient." ('867 patent col. 2:40-45);
`
`"Long term treatment of critically ill patients with clonidine has been reported to
`be associated with such rebound effects as tachycardia and hypertension ('867
`patent col. 2:45-47);
`
`"An ideal sedative agent for a critically ill patient should provide sedation at
`easily determined doses with ready arousability together with hemodynamic
`stabilizing effects." ('867 patent col. 2:57-59);
`
`"Lack of respiratory depression should allow dexmedetomidine to be used also
`for non-ventilated, critically ill patients who require sedation, anxiolysis,
`analgesia, and hemodynamic stability yet must remain oriented and easily
`aroused." ('867 patent col. 4:62-66); and
`
`•
`
`"The cases described above illustrate the benefits of dexmedetomidine sedation in
`critically ill patients." ('867 patent col. 13:41-42).
`
`7
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`CC-JA183
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`(emphases added.) Moreover, the case studies in Example 3 describe the critically ill state ofthe
`
`patients in the Precedex clinical trials. (See generally '867 patent col. 8:53-13 :41.)
`
`Hospira's construction is also supported by the prosecution history. Eurohealth
`
`apparently tries to ignore the critically ill condition of the patient because of an amendment in
`
`which the applicants changed the claim from a patient "in need a/intensive care" to a patient "in
`
`an intensive care unit." (See, e.g., Joint Claim Construction Statement, No. 14-487, D.I. 53 at 3.)
`
`But that amendment did not change the applicant's consistent explanation that the ICU is a place
`
`in which care is provided to critically ill patients. Even after making that amendment, applicants
`
`clearly explained this to the examiner: "ICU patients are critically ill, recovering from surgical
`
`intervention, trauma, cardiorespiratory disease, severe infection or other ser