`
`
`
`
`Paper No. __
`Filed: December 22, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`
`PETITIONER
`
`V.
`
`FOREST LABORATORIES HOLDINGS LIMITED
`
`PATENT OWNER
`
`___________________
`
`CASE NO.: IPR2016-00379
`PATENT NO. 6,545,040
`FILED: JANUARY 24, 1992
`ISSUED: 4/8/2003
`INVENTORS: XHONNEUX AND VAN LOMMEN
`TITLE: METHOD OF LOWERING THE BLOOD PRESSURE
`___________________
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 6,545,040
`
`

`

`
`
`
`
`Patent No. 6,545,040
`
`TABLE OF CONTENTS
`
`TABLE OF AUTHORITIES .................................................................................... iv 
`
`PETITIONER’S EXHIBIT LIST ............................................................................. vi 
`
`I. 
`
`Introduction ...................................................................................................... 1 
`
`A. 
`
`B. 
`
`C. 
`
`Summary of the IPR Challenge ............................................................. 1 
`
`Summary of Prior Art and Grounds Presented ..................................... 4 
`
`Petitioner’s Experts ............................................................................... 6 
`
`II. 
`
`Background Science ........................................................................................ 7 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`Stereochemistry and Terminology ........................................................ 8 
`
`Stereochemisty in Biology and New Drug Research .......................... 11 
`
`β-blocking Drugs ................................................................................. 12 
`
`Chromatography and Stereochemical Separations.............................. 14 
`
`III.  The ’040 Patent .............................................................................................. 16 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`E. 
`
`Claims of the ’040 Patent .................................................................... 16 
`
`Prior Art Background—the ’362 Patent (Van Lommen) .................... 19 
`
`The ’040 Patent Specification ............................................................. 23 
`
`’040 Patent Prosecution History .......................................................... 24 
`
`Foreign Counterparts to the ’040 Patent Invalidated .......................... 25 
`
`IV.  The Person of Ordinary Skill in the Art (POSITA) ....................................... 25 
`
`V. 
`
`Claim Construction ........................................................................................ 28 
`
`A. 
`
`Ordinary and Customary Meaning ...................................................... 28 
`
`
`
`ii
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`

`

`
`
`B. 
`
`
`
`Patent No. 6,545,040
`
`Claim 1: “a composition consisting of . . .” and Claim 2: “a
`pharmaceutical composition consisting of . . . .” ................................ 28 
`
`VI.  Detailed Explanation of the Asserted Grounds of Unpatentability ............... 30 
`
`A. 
`
`Legal Standards ................................................................................... 30 
`
`B.  Motivation to Combine the References Generally .............................. 32 
`
`C. 
`
`Ground 1: Claims 2, 3, 4, 5 and 6 are rendered obvious by the
`’362 Patent in combination with the Handbook of
`Chromatography. ................................................................................. 37 
`
`D.  Ground 2: Claim 1 is rendered obvious by the ’362 Patent in
`combination with the Handbook of Chromatography, in further
`view of Okamoto. ................................................................................ 44 
`
`E. 
`
`F. 
`
`G. 
`
`Ground 3: Claim 1 is rendered obvious by the ’362 Patent in
`combination with the Handbook of Chromatography, in further
`view of Armstrong............................................................................... 50 
`
`The alleged “unexpected results” do not overcome the prima facie
`case of obviousness. ............................................................................ 54 
`
`The Grounds presented in this petition are not redundant of issues
`considered during prosecution of the ’040 Patent. .............................. 56 
`
`VII.  Mandatory Notices and Certifications ........................................................... 57 
`
`A. 
`
`B. 
`
`Grounds for Standing (37 C.F.R. § 42.104) ........................................ 57 
`
`Payment of Fees (37 C.F.R. § 42.15(a) and § 42.103(a)) ................... 57 
`
`C.  Mandatory Notices (37 C.F.R. § 42.8(b)) ........................................... 57 
`
`1. 
`
`2. 
`
`3. 
`
`Real Parties-In-Interest (37 C.F.R. § 42.8(b)(1)) ...................... 57 
`
`Related Judicial Matters (37 C.F.R. § 42.8(b)(2)) .................... 58 
`
`Lead and Back-up Counsel (37 C.F.R. § 42.8(b)(3) and
`Service Information (37 C.F.R. § 42.8(b)(4)). .......................... 59 
`
`
`
`iii
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`

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`Patent No. 6,545,040
`
`VIII.  Conclusion ..................................................................................................... 59 
`
`
`
`TABLE OF AUTHORITIES
`
`Cases 
`
`Aventis Pharma Deutschland GMBH v. Lupin, Ltd.,
`499 F.3d 1293 (Fed. Cir. 2007) ................................................... passim
`
`Conoco, Inc. v. Energy & Environmental International, L.C.,
`460 F.3d 1349 (Fed. Cir. 2006) .......................................................... 29
`
`Gnosis S.p.A., v. Merck & CIE,
`Case IPR2013-00117, Paper No. 71, (PTAB 2014) ........................... 56
`
`Graham v. John Deer Co. of Kan. City,
`383 U.S. 1 (1966) .......................................................................... 30, 31
`
`In re GPAC,
`57 F.3d 1573 (Fed. Cir. 1986) ............................................................ 26
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................... 56
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007).......................................................... 31, 43, 49, 54
`
`Merck & CIE v. Gnosis S.P.A.,
`2015 U.S. App. LEXIS 21927, __ F.3d __
`(Fed. Cir. Dec. 17, 2015) .................................................................... 56
`
`Otsuka Pharmaceuticals. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) .......................................................... 31
`
`Spectrum Pharmacueticals, Inc. v. Sandoz, Inc.,
`802 F.3d 1326 (Fed. Cir. 2015) .......................................................... 31
`
`35 U.S.C. § 103 ............................................................................................. 30
`
`Statutes 
`
`
`
`iv
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`

`

`
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`Patent No. 6,545,040
`
`Other Authorities 
`
`Manual of Patent Examining Procedures § 2111.03
`(9th ed. 2015) ....................................................................................... 29
`
`Manual of Patent Examining Procedures § 2141.03,
`(9th ed. 2015) ...................................................................................... 26
`
`Regulations 
`
`37 C.F.R. § 42.100(b) ................................................................................... 28
`
`37 C.F.R. § 42.103(a) .................................................................................... 57
`
`37 C.F.R. § 42.104(a) .................................................................................... 57
`
`37 C.F.R. § 42.15(a) ...................................................................................... 57
`
`37 C.F.R. § 42.8(b)(1) ................................................................................... 57
`
`37 C.F.R. § 42.8(b)(2) ................................................................................... 58
`
`
`
`
`
`v
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`

`

`
`
`
`
`Patent No. 6,545,040
`
`Exhibit #
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`PETITIONER’S EXHIBIT LIST
`
`Description
`
`U.S. Patent No. 6,545,040 B1 to Xhonneux, et al. (“the
`’040 Patent”), Apr. 8, 2003.
`
`Excerpts of Prosecution History for the ‘040 Patent
`(application No. 07/825,488).
`
`Excerpts of Ex Parte Reexamination Prosecution History
`for the ’040 Patent (Reexamination Request 90/008,356).
`
`U.S. Patent No. 4,654,362 to Van Lommen et al. (“the
`’362 Patent”), Mar. 31, 1987.
`
`HANDBOOK OF CHROMATOGRAPHY, Vol. II, at 1-101
`(Zweig and Sherma, ed.) (1972).
`
`Yoshio Okamoto, et al., Optical Resolution of β-Blockers
`by HPLC on Cellulose Triphenylcarbamate Derivatives,
`15 Chemistry Letters at 1237-1240 (1986).
`
`Daniel W. Armstrong, et al., Separation of Drug
`Stereoisomers by the Formation of β-Cyclodextrin
`Inclusion Complexes, 232 SCIENCE at 1132-1135 (1986).
`
`Daniel W. Armstrong, Chiral Stationary Phases for High
`Performance Liquid Chromatographic Separation of
`Enantiomers: A Mini-Review, 7(S-2) Journal of Liquid
`Chromatography at 353-376 (1984).
`
`Daniel W. Armstrong, et al., Enantiomeric Separations in
`Chromatography, 19 CRC Critical Reviews in Analytical
`Chemistry at 175-190 (1988).
`
`
`
`vi
`
`

`

`
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`
`
`Patent No. 6,545,040
`
`Veronika R. Meyer, PRACTICAL HIGH-PERFORMANCE
`LIQUID CHROMATOGRAPHY, (Valerie Cottrell translation),
`Ch. 22 at 246-253 (1988).
`
`Veronika R. Meyer, PRACTICAL HIGH-PERFORMANCE
`LIQUID CHROMATOGRAPHY, (Valerie Cottrell translation),
`Ch. 25 at 269-301 (1988).
`
`Stig G. Allenmark, CHROMATOGRAPHIC
`ENANTIOSEPARATION – METHODS AND APPLICATIONS,
`Ch. 4 at 42-63 (1988).
`
`Stig G. Allenmark, CHROMATOGRAPHIC
`ENANTIOSEPARATION – METHODS AND APPLICATIONS,
`Ch. 5 at 64-74 (1988).
`
`Stig G. Allenmark, CHROMATOGRAPHIC
`ENANTIOSEPARATION – METHODS AND APPLICATIONS,
`Ch. 7 at 90-145 (1988).
`
`Stig G. Allenmark, CHROMATOGRAPHIC
`ENANTIOSEPARATION – METHODS AND APPLICATIONS,
`Ch. 8.3 at 158-177 (1988).
`
`Chiral Phase HPLC Columns, Bakerbond™, J.T. Baker
`Research Products (1983).
`
`G. Gŭbitz and S. Mihellyes, Optical Resolution of β-
`blocking Agents by Thin-layer Chromatography and
`High-Performance Liquid Chromatography as
`Diastereomic R-(--)-1-(1-naphthyl)ethylureas, 314
`Journal of Chromatography at 462-466 (1984).
`
`W. Lindner, et al., Liquid Chromatographic Separation of
`Enantiomeric Alkanolamines via Diastereomeric Tartaric
`Acid Monoesters, 316 Journal of Chromatography at 605-
`616 (1984).
`
`
`
`vii
`
`

`

`
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`
`
`Patent No. 6,545,040
`
`Jorgen Hermansson, Resolution of Racemic
`Aminoalcohols β-Blockers), Amines and Acids as
`Enantiomeric Derivatives Using a Chiral α1-Acid
`Glycoprotein Column, 325 Journal of Chromatography at
`379-384 (1985).
`
`Gȍran Schill, et al., Chiral Separations of Cationic and
`Anionic Drugs on an α1-Acid Glycoprotein-Bonded
`Stationary Phase (Enantiopac®), II. Influence of Mobile
`Phase Additives and pH on Chiral Resolution and
`Retention, 365 Journal of Chromatography at 73-88
`(1986).
`
`CYCLOBOND HANDBOOK, Advanced Separation
`Technologies Inc. (1987).
`
`M. Krstulovic, et al., Direct Enantiomeric Separation of
`Betaxolol with Applications to Analysis of Bulk Drug and
`Biological Samples, 452 Journal of Chromatography, at
`477-483 (1988).
`
`CHIRAL SEPARATIONS, (D. Stevenson and I. D. Wilson,
`eds., 1988) (excerpts).
`
`H. Y. Aboul-Enein and I. Ali, HPLC enantiomeric
`resolution of nebivolol on normal and reversed amylose
`based chiral phases, 56 Pharmazie, at 214-216 (2001).
`
`Imran Ali and Hassa Y. Aboul-Enein, Enantioseparation
`of some clinically used drugs by HPLC using cellulose
`Tris (3,5-dichlorophenylcarbamate) chiral stationary
`phase, 17 Biomed. Chromatogr. at 113-117 (2003).
`
`L. A. Fingerhut, et. al., Health and Disease in the United
`States, 1 Ann. Rev. Public Health at 1-36 (1980).
`
`David S. Goldstein, Plasma Catecholamines and
`Essential Hypertension – an Analytical Review, 5
`HYPERTENSION at 86-99 (1983).
`
`
`
`viii
`
`

`

`
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`
`
`Patent No. 6,545,040
`
`Edward Freis, M.D., Validity of Therapy For Mild
`Hypertension, 30 Ann. Rev. Med. at 81-89 (1979).
`
`L.H. Opie, Hypertension in General Practice, Part I.
`Examination and Investigation of a Patient with
`Hypertension, SA MEDICAL JOURNAL at 955-960 (1980).
`
`William B. Stason, Opportunities for Improving the Cost-
`Effectiveness of Antihypertensive Treatment, 81 The
`American Journal of Medicine at 45-49 (1986).
`
`Van de Water, et al. Cardiovascular effects of dl-
`nebivolol and its enantiomers – a comparison with those
`of atenolol, 156 European Journal of Pharmacology at 95-
`103 (1988).
`
`David B. Bylund, Adrenergic Receptors: Historical
`Perspectives From the 20th Century, The Adrenergic
`Receptors in the 21st Century, Chapter 1 (Dianne M.
`Perez, ed., 2006).
`
`Noboru Toda, et al., Selectivity and Steric Effects of
`Metoprolol Isomers on Isolated Rabbit Atria, Arteries
`and Tracheal Muscles, 207 The Journal of Pharmacology
`and Experimental Therapeutics at 311-19 (1978).
`
`Keitaro Hashimoto, The Relation Between the Current
`Underlying Pacemaker Activity and Beta-Adrenoceptors
`in Cardiac Purkinje Fibres: A Study Using Adrenaline,
`Procaine, Atenolol and Penbutolol, 307 Naunyn-
`Schmiedeberg’s Arch. Pharmacol. at 9-19 (1979).
`
`J. Kaumann and J. R. Blinks, Stimulant and Depressant
`Effects of β-Adrenoceptor Blocking Agents on Isolated
`Heart Muscle, 311 Naunyn-Schmiedeberg’s Arch.
`Pharmacol. at 205-218 (1980).
`
`
`
`ix
`
`

`

`
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`
`
`
`
`Patent No. 6,545,040
`
`James E. Clifton, et al., Arylethanolamines Derived from
`Salicylamide with α- and β-Adrenoceptor Blocking
`Activities. Preparation of Labetalol, Its Enantiomers,
`and Related Salicylamides, 25 Journal of Medicinal
`Chemistry at 670-679 (1982).
`
`David E. McClure, et al., Antihypertensive β-Adrenergic
`Blocking Agents: N-Aralkyl Analogues of 2-[3](tert-
`Butylamino)-2-Hydroxypropoxy]-3-cyanopyridine, 26
`Journal of Medicinal Chemistry at 649-657 (1983).
`
`A.B. Jeppsson, et al.,Steric Aspects of Agonism and
`Antagonism at β-adrenoceptors; Experiments with the
`Enantiomers of Terbutaline and Pindolol, 54 Acta
`Pharmacol. et Toxicol. at 285-291 (1984).
`
`Arthur A. Hancock, Analysis of the Hypotensive Effects
`of Medroxalol and Its Enantioners, Clin. and Exper.
`Hyper.-Theory and Practice, A6(3), at 659-684 (1984).
`
`Kazuo Honda, et al., Adrenoceptor Blocking and
`Cardiovasucular Effects of the Optical Isomers of
`Amosulalol (YM-09538), a Combined α- and β-
`Adrenoceptor Blocking Agent, and the Corresponding
`Desoxy Derivative (YM-11133) in Rats, 41 Japan. J.
`Pharmacol. at 459-466 (1986).
`
`Petrus J. Pauwels, et al., The Receptor Binding Profile of
`the New Antihypertensive Agent Nebivolol and Its
`Stereoisomers Compared With Various β-Adrenergic
`Blockers, 34 Molecular Pharmacology at 843-861 (1988).
`
`Van de Water, et al., Pharmacological and Hemodynamic
`Profile of Nebivolol,* a Chemically Novel, Potent, and
`Selective β1-Adrenergic Antagonist, 11 Journal of
`Cardiovascular Pharmacology at 552-563 (1988).
`
`Raymond Xhonneux, et al., The l-enantiomer of nebivolol
`potentiates the blood pressure lowering effect of the d-
`enantiomer, 181 European Journal of Pharmacology at
`261-265 (1990).
`
`x
`
`

`

`
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`
`
`
`Patent No. 6,545,040
`
`G. Van Lomen, et al., Synthesis and Pharmacological
`Properties of Nebivolol, a new antihypertensive
`compound, 45 Journal de pharmacie de Belgique at 355-
`360 (1990).
`
`M. Midol-Monet, Cardiovascular Effects of
`intracerebroventricular Injections of (+)-Nebivolol and
`its Enantiomers—a Comparison with those of Metoprolol
`in the Rat, 43 J. Pharm. Pharmacol. at 504-509 (1991).
`
`Van Peer, et al., Clinical Pharmacokinetics of Nebivolol
`A Review, 3 Drug Investigation at 25-30 (1991).
`
`Carsten D. Siebert, et al., Stereochemical Comparison of
`Nebivolol with other β-Blockers, 20 Chirality at 103-109
`(2008).
`
`Irving W. Wainer and Thomas D. Doyle, Stereisomeric
`Separations, 2 LC Magazine (1984).
`
`Actavis UK Limited and Janssen Pharmaceutica N.V.,
`Case No: HC0700 572 (2008),In the High Court of
`Justice, Chancery Division, Patent Court (UK), 2008
`EWHC 1422 (Pat).
`
`Declaration under 37 CFR § 42.53(a) by Dr. Daniel W.
`Armstrong (Dec. 10, 2015).
`
`Daniel W. Armstrong Curriculum Vitae (2015).
`
`Declaration under 37 CFR § 42.53(a) by Ronald W.
`Millard, Ph.D. (Dec. 11, 2015).
`
`Ronald Wesley Millard Curriculum Vitae (Dec. 2015).
`
`
`
`xi
`
`

`

`
`
`
`
`Patent No. 6,545,040
`
`I.
`
`Introduction
`
`Petitioner, Lower Drug Prices for Consumers, LLC, (“Petitioner”) hereby
`
`requests an Inter Partes Review (“IPR”) of Claims 1-6 of U.S. Patent No.
`
`6,545,040 C1 (herein “the ’040 Patent”) (Ex. 1001) pursuant to 35 U.S.C. §§ 311-
`
`319 and 37 C.F.R. § 42.100 et seq.
`
`A.
`
`Summary of the IPR Challenge
`
`The ’040 Patent relates to the pharmaceutical compound known today as
`
`nebivolol hydrochloride (or simply “nebivolol”), which is sold in the United States
`
`by Forest Laboratories under the brand name BYSTOLIC in tablet form for the
`
`treatment of hypertension. (Ex. 1002 at 253-257; Ex. 1052 at ¶¶72-73.)
`
`Nebivolol is within the class of hypertension drugs known as β-blockers,
`
`i.e., drugs that reduce a patient’s blood pressure by blocking β-adrenergic receptors
`
`in the body. (See, e.g., Ex. 1041.) As sold commercially in the United States,
`
`nebivolol is a racemic mixture of two mirror-image stereoisomers (i.e.,
`
`enantiomers) —the RSSS enantiomer and the SRRR enantiomer. (Ex. 1002 at 256-
`
`257.) Nebivolol (BYSTOLIC) as sold by Forest Labs is identical to what is
`
`described in Claim 2 of the ’040 Patent. (Id.) Claim 1 of the ’040 Patent separately
`
`claims the single RSSS enantiomer alone. (Ex. 1001, ’040 Patent at Claim 1; Ex.
`
`1052 at ¶73.)
`
`
`
`1
`
`

`

`
`
`
`
`Patent No. 6,545,040
`
`As recognized by the Board of Patent Appeals and Interferences during
`
`prosecution of the ’040 Patent, these exact same enantiomers were previously
`
`disclosed in the prior art, U.S. Patent No. 4,654,362 (Ex. 1004)—albeit as an
`
`unresolved mixture of four stereoisomers, in the compound labeled “Compound
`
`84” of the ’362 Patent. (Ex. 1050 at ¶¶59-61, 63-64; Ex. 1002 at 140-42 and 198-
`
`99.) Thus, this IPR petition presents the issue: are the claimed enantiomers of the
`
`’040 Patent patentable in light of the disclosed Compound 84 of the prior art ’362
`
`Patent. (Ex. 1050 at ¶¶64-65.)
`
`The legal issues presented herein are essentially identical to the issues
`
`decided in Aventis Pharma Deutschland GMBH v. Lupin, Ltd., 499 F.3d 1293
`
`(Fed. Cir. 2007). In Aventis, the Federal Circuit held that a patent claiming a
`
`compound of purified stereoisomers was obvious where those same stereoisomers
`
`had been disclosed in the prior art as an unresolved mixture with other
`
`stereoisomers of the same molecule. See id. at 1300-03. As the Aventis case makes
`
`clear, single enantiomers of chiral compounds are not patentable over their
`
`unresolved mixtures where a POSITA (1) would have been motivated to create the
`
`purified stereoisomeric forms of the unresolved mixture, and (2) would have been
`
`able to carry out the required stereochemical separation without undue
`
`experimentation. See id.
`
`
`
`2
`
`

`

`
`
`
`
`Patent No. 6,545,040
`
`The evidence presented by Petitioner with this IPR petition makes clear that
`
`the claims of the ’040 Patent are obvious under the legal standards set forth in
`
`Aventis. A POSITA at the critical date of the ’040 Patent in March 1988, would
`
`have been highly motivated to select Compound 84 of the ’362 Patent as a base
`
`compound for further new drug research as a potential cardioselective β-blocker
`
`drug. (Ex. 1052 at ¶¶76-77, 83-84.) The standard new drug investigation protocols
`
`at the time for β-blockers required obtaining stereochemically purified forms of the
`
`compound if possible—both the racemate combination of enantiomers, and also
`
`purified single enantiomers. (Id. at ¶¶63-70, 85-87.)
`
`Moreover, the chromatography techniques for performing the required
`
`stereochemical separation of Compound 84 had been perfected well before the
`
`’040 Patent’s priority date. (Ex. 1050 at ¶¶40-47, 52-56.) A POSITA at the time
`
`would have expected that Compound 84 could be successfully separated into
`
`purified stereochemical forms without undue experimentation. (Id. at ¶¶55-56.)
`
`During the early 1980s, rapid advances in high-performance liquid
`
`chromatography (“HPLC”) using chiral stationary phase columns had essentially
`
`perfected techniques for chiral separation of enantiomers. (Ex. 1050 at ¶42-447.)
`
`Prior to the ’040 Patent, every known β-blocker drug had been successfully
`
`separated using HPLC. (Id. at ¶46; Exs. 1006, 1007, 1017, 1018, 1019, 1020.)
`
`
`
`3
`
`

`

`
`
`
`
`Patent No. 6,545,040
`
`Taken together, this evidence shows that the claims of the ’040 Patent are
`
`not patentable. A POSITA at the time of the invention would have been highly
`
`motivated to stereochemically resolve Compound 84 of the ’362 Patent to create
`
`purified stereochemical forms of the compound, and would have been able to do so
`
`without undue experimentation using well known chromatography techniques.
`
`Under Aventis, Claims 1 and 2 of the ’040 Patent are obvious over the prior art
`
`presented herein. Claims 3-6 of the ’040 Patent add nothing more than trivial
`
`limitations which do not sustain patentability, as discussed below.
`
`B.
`
`Summary of Prior Art and Grounds Presented
`
`The Grounds of Invalidity presented in this IPR petition are based upon the
`
`following four prior art references:
`
` Exhibit 1004: U.S. Patent No. 4,654,362—filed October 12, 1984 as a
`
`continuation-in-part of an application filed on December 5, 1983.
`
`This reference is referred to herein as the “’362 Patent” or “Van
`
`Lommen.” It is cited and discussed extensively in the specification of
`
`the ’040 Patent. See, e.g., Ex. 1001 at Col. 1:13-67.
`
` Exhibit 1005: Handbook of Chromatography, Volume II, Zweig &
`
`Sherma (editors), CRC Press (1972). This reference is referred to
`
`herein as “Handbook of Chromatography.” It is a handbook that
`
`describes well known, conventional chromatography techniques that
`
`
`
`4
`
`

`

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`
`
`Patent No. 6,545,040
`
`substantially pre-date the ’040 Patent. This publication was not
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`considered during examination of the ’040 Patent.
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` Exhibit 1006: Yoshi Okamoto, et al., Optical Resolution of β-
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`Blockers by HPLC on Cellulose Triphenylcarbamate Derivatives, 15
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`Chemistry Letters at 1237-1240 (1986). This reference is referred to
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`herein as “Okamoto.” It demonstrates the successful stereochemical
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`separation of five known β-blocker drugs using HPLC
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`chromatography. This publication was not considered during
`
`examination of the ’040 Patent.
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` Exhibit 1007: Armstrong, et al., Separation of Drug Stereoisomers by
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`the Formation of β-Cyclodextrin Inclusion Complexes, 232 Science at
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`1132-1135 (1986). This reference is referred to herein as
`
`“Armstrong.” It demonstrates the successful stereochemical
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`separation of two known β-blocker drugs using β-cyclodextrin based
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`chiral stationary phase columns for HPLC. This publication was not
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`considered during examination of the ’040 Patent.
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`The following table summarizes the grounds of unpatentability presented in
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`this petition:
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`5
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`
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`Patent No. 6,545,040
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`Ground No. Claims
`1.
`2,3,4,5,6
`
`2.
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`1
`
`3.
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`1
`
`Basis for Challenge
`Obviousness under
`35 U.S.C. §103
`
`Obviousness under
`35 U.S.C. §103
`
`Obviousness under
`35 U.S.C. §103
`
`Prior Art References
`Exhibit 1004 (’362
`Patent)
`
`in view of
`
`Exhibit 1005 (Handbook
`of Chromatography)
`Exhibit 1004 (’362
`Patent)
`
`and
`
`Exhibit 1005 (Handbook
`of Chromatography)
`
`in further view of
`
`Exhibit 1006 (Okamoto)
`Exhibit 1004 (’362
`Patent)
`
`and
`
`Exhibit 1005 (Handbook
`of Chromatography)
`
`in further view of
`
`Exhibit 1007
`(Armstrong)
`
`
`C.
`
`Petitioner’s Experts
`
`In support of this IPR petition, Petitioner submits declarations from two
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`experts, each of whom hold impeccable qualifications in their respective fields of
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`expertise, and each of whom were personally involved in relevant research and
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`6
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`Patent No. 6,545,040
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`academic activities in and prior to March, 1988 (the alleged priority date of the
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`’040 Patent).
`
`Exhibit 1050 is the declaration of Dr. Daniel W. Armstrong (University of
`
`Texas at Arlington), a pioneer in the development of chiral separation using HPLC
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`chromatography. (Ex. 1050 at ¶9-13.) In the early-and mid-1980s, Dr. Armstrong
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`personally oversaw the development of the first β-cyclodextrin HPLC columns and
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`co-founded Advanced Separation Technologies, the company that first
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`commercialized these chiral columns. (Id. at ¶98.) He is the co-author of one of the
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`prior art references submitted for purposes of Ground 3 in this IPR petition,
`
`Exhibit 1007 (“Armstrong”).
`
` Exhibit 1052 is the declaration of Dr. Ronald W. Millard (University of
`
`Cincinnati). Among many other qualifications, in March 1988 Dr. Millard was
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`personally involved in overseeing cardiovascular new drug research (including β-
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`blocker drugs), and also publishing, editing, collecting and disseminating peer-
`
`reviewed cardiovascular research literature. (Ex. 1052 at ¶¶7-15.)
`
`II. Background Science
`
`The background science discussed in this section is based upon scientific
`
`knowledge and principles that were well known to a POSITA as of the priority
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`
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`7
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`Patent No. 6,545,040
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`date of the ’040 Patent,1 unless otherwise specifically noted. (Ex. 1050 at ¶27; Ex.
`
`1052 at ¶30.)
`
`A.
`
`Stereochemistry and Terminology
`
`The basic principles of stereochemistry discussed in the Federal Circuit’s
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`Aventis opinion are equally applicable to this petition. See Aventis, 499 F.3d at
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`1295-96. The terminology used herein is further explained in basic undergraduate
`
`
`
`1 Petitioner will assume herein that the priority date of the ’040 Patent is March 23,
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`1988 based on the ’040 Patent’s relationship to application no. 07/172,747 filed
`
`on that date. The ’040 Patent, however, claims this priority date through its
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`relationship to an intervening continuation-in-part application filed on March 16,
`
`1989 (application no. 07/325,181). The continuation-in-part application added
`
`substantial new subject matter to the specification. It is not clear that the ’747
`
`application, standing alone, is sufficient to support the claims of the issued ’040
`
`Patent; and the burden of proof is on the patent owner to establish its entitlement
`
`to the earlier priority date. Nonetheless, because the art relied upon in this
`
`petition substantially pre-dates the alleged March 23, 1988 priority date,
`
`Petitioner will assume (without admitting) that this is the valid priority date for
`
`purposes of this Petition.
`
`
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`8
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`Patent No. 6,545,040
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`organic chemistry textbooks that would have been well known to a POSITA at the
`
`time of the ’040 Patent. (Ex. 1050 at ¶36.)
`
`Chiral molecules are stereogenic molecules that can exist in various three-
`
`dimensional configurations. Stereochemistry is a branch of chemistry that studies
`
`the three-dimensional aspects of molecules. Stereoisomers are isomers that share
`
`an identical chemical formula and the same atom connectivity (i.e., all atoms
`
`bonded in the same order or sequence), but have different three-dimensional
`
`arrangements of the atoms or chemical groups. (Ex. 1050 at ¶29.) Chiral molecules
`
`are possible because of the presence of an asymmetric atom (typically carbon) that
`
`serves as the “chiral center” for the molecule. The asymmetric chiral center allows
`
`for multiple three-dimensional configurations of the same chemical elements, with
`
`each configuration referred to as a separate stereoisomer. (Id. at ¶30.)
`
`In stereochemistry, various stereoisomers of a chiral molecule are typically
`
`labelled according to the orientation of each chiral center, with one orientation
`
`designated as “(R)-” (for Rectus or right) and “(S)-” (for Sinister or left). For a
`
`molecule with one chiral center (and therefore two possible stereoisomers), one of
`
`the stereoisomers is the R-isomer and the other is the S-isomer. For a molecule
`
`with two chiral centers, there would be four possible stereoisomers, which would
`
`be labelled: (RR), (RS), (SR) and (SS). A molecule with three chiral centers would
`
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`9
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`Patent No. 6,545,040
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`have eight possible stereoisomers: (RRR), (RRS), (RSR), (SRR), (SSR), (SRS),
`
`(RSS), and (SSS), etc. (Id. at ¶32.)
`
`Two stereoisomers are either “enantiomers” or “diastereomers” in relation to
`
`each other. Two stereoisomers are said to be enantiomers if they are non-
`
`superimposable mirror images of each other (often compared to the left and right
`
`hand of a human). Enantiomers are three-dimensionally incapable of being
`
`superimposed on one another. Therefore, they are different molecular species. If
`
`two stereoisomers are enantiomers, and they exist in equal amounts in a mixture
`
`(i.e., 1:1 or 50/50 mixtures) they are referred to as “racemates.” For a molecule
`
`with three chiral centers, for example, the following stereoisomers would be
`
`racemates: (RRR and SSS), (RRS and SSR), (RSR and SRS), and (SRR and RSS).
`
`(Id. at ¶33.) Diastereomers, on the other hand, are stereoisomers which are neither
`
`mirror images nor superimposable. (Id. at ¶34.)
`
`While enantiomers have the same physical and chemical properties,
`
`diastereomers do not. For example, while enantiomers have the same solubility in
`
`an organic solvent and will elute on an achiral chromatography column at the same
`
`time, diastereomers have different solubilities and different elution times. Thus,
`
`diastereomers may be separated from one another by using a variety of ordinary
`
`techniques, e.g., selective crystallization, conventional chromatography, distillation
`
`
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`10
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`

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`Patent No. 6,545,040
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`(if volatile), extraction techniques and so forth. Conversely, enantiomers can only
`
`be separated by specific stereoselective techniques. (Id. at ¶34.)
`
`B.
`
`Stereochemisty in Biology and New Drug Research
`
`Stereochemistry is important in the field of new drug research, and those
`
`who engage in such research are familiar with its principles. Many
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`pharmacologically active compounds are “chiral drugs” with one or more chiral
`
`centers. It is well known in medicine and pharmacokinetics that the human body is
`
`highly selective to the stereochemical properties of many chiral compounds, such
`
`that different isomers of the same compound can have different physiological
`
`effects. Indeed, the human body is essentially a chiral structure incorporating many
`
`chiral drug targets, such as enzymes, receptors and ion channels. It is not
`
`uncommon for the pharmacological properties of a compound to reside principally
`
`or even exclusively in a single stereoisomeric form. (Ex. 1052 at ¶¶57-59.)
`
`Well before the priority date of the ’040 Patent, it was well-understood in
`
`the field of drug discovery that stereoselectivity was an important focus of research
`
`and development, and that advances in chromatographic separation of
`
`stereoisomers and enantiomers would allow for more targeted investigation of
`
`purified stereochemical forms of compounds of interest. (Ex. 1052 at ¶¶60; see
`
`also, e.g., Ex. 1048; Ex. 1007 at 002.) Laboratory and clinical new drug research
`
`
`
`11
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`

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`Patent No. 6,545,040
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`would routinely test both racemic mixtures of enantiomers and also purified single
`
`enantiomers to understand their stereoselective effects. (Ex. 1052 at ¶61.)
`
`C.
`
`β-blocking Drugs
`
`β-blocker drugs are a class of drugs used to treat hypertension. They lower
`
`blood pressure by serving as a β1-adrenergic receptor antagonist. (Ex. 1052 at ¶¶46,
`
`52-55.) The first commercially available β-blocker was propranolol, which was
`
`discovered in 1964 and approved by the FDA in 1967. Propranolol has been hailed
`
`as one of the greatest medical achievements of the 20th Century, and Sir James
`
`Black was awarded a Nobel Prize in 1988 for his work in discovering and
`
`developing the drug. (Id. at ¶54.) Propranolol is a non-selective β-blocker, i.e., it
`
`serves as an antagonist to both β1- and β2-adrenergic receptors. It has long been
`
`known, however, that there are advantages to “cardioselective” drugs that are
`
`antagonists to β1-receptors only. (Id. at ¶¶53, 56.)
`
`β-blocking drugs are a prominent example of the body’s stereoselectivity to
`
`pharmacologically active compounds, and in fact are among the earliest drugs so-
`
`studied. Pharmacological studies testing the effect of individual stereoisomers for
`
`β-blockers on cardiovascular variables in tissues from warm-blo