IPR2018-00943
`Patent No. 7,919,499
`Petitioner’s Reply to Patent Owner’s Response
`Attorney Docket: AMNEAL 7.1R-005
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________
`
`AMNEAL PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`ALKERMES PHARMA IRELAND LIMITED,
`Patent Owner.
`
`____________________________
`
`Case IPR2018-00943
`Patent No. 7,919,499 B2
`____________________________
`
`
`
`
`PETITIONER’S REPLY TO
`PATENT OWNER’S RESPONSE
`
`
`
`5892704_1.docx
`
`

`

`TABLE OF CONTENTS
`
`TABLE OF AUTHORITIES ................................................................................... iii
`PETITIONER’S EXHIBIT LIST ............................................................................ iv
`I.
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`CLAIM CONSTRUCTION ............................................................................ 2
`
`A. “Single Injection” ..................................................................................... 2
`
`B. “The Serum AUC Of Naltrexone… Achieved By 50 mg/Day Oral
`Administration”......................................................................................... 3
`
`C. “Initial Oral Dose Of Naltrexone” ............................................................ 4
`
`III. THE CLAIMS ARE ANTICIPATED ............................................................. 4
`
`A. Grounds 1 And 2: Comer And Nuwayser ................................................ 4
`
`1. A POSA Can Calculate AUC ............................................................ 7
`
`2. Photoshop Is An Appropriate Technique ........................................... 7
`
`3. Time Zero (“Tzero”) ............................................................................. 8
`4. Sampling Frequency .......................................................................... 9
`
`5. Prior Dosing .....................................................................................10
`
`6. Starting With Cmax .........................................................................11
`
`7. Single Injection ................................................................................11
`
`8. The Claimed AUC Differential ........................................................12
`
`9. Comer Teaches “Treating” ..............................................................12
`
`B. Claims 10 And 11 Are Anticipated ........................................................14
`
`1. Alcohol Dependency ........................................................................14
`
`2. Administration Without An Initial Oral Dose .................................14
`
`i
`
`

`

`IV. THE CLAIMS ARE OBVIOUS....................................................................15
`
`A. Grounds 3 And 4: The Claims Are Obvious Over Comer, Nuwayser,
`Rubio, And Wright .................................................................................15
`
`1. The Combination Teaches A Method of Parenterally Administering
`Naltrexone Within The Claimed Dose Range .................................15
`
`2. Alkermes’ Criticisms .......................................................................17
`
`3. Claims 2, 6-9, And 11 Are Obvious ................................................17
`
`a.
`
`b.
`
`c.
`
`Claims 2 And 6 ......................................................................17
`
`Claims 7-9 ..............................................................................18
`
`Claims 2 And 11 ....................................................................18
`
`B. Ground 5: The Claims Are Obvious Over Nuwayser, Kranzler, Rubio,
`And Wright .............................................................................................19
`
`C. Ground 6: Alkermes’ 10-K And The Vivitrex™ Specimen Were Both
`Publicly Accessible and Render The Claims Obvious ...........................19
`
`V. ALKERMES’ SECONDARY CONSIDERATIONS FAIL .........................21
`
`A. Alkermes Fails To Prove Any Nexus .....................................................21
`
`B. Providing A 3x AUC Differential Does Not Satisfy A Long-Felt But
`Unresolved Need .....................................................................................23
`
`C. Vivitrol’s Praise Has Nothing To Do With An Increase In AUC ..........23
`
`VI. CONCLUSION ..............................................................................................24
`
`
`
`
`
`
`
`
`
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) .......................................................................... 16
`Baldwin Graphic Sys., Inc. v. Siebert, Inc.,
`512 F.3d 1338,1342 (Fed. Cir. 2008) ................................................................... 2
`Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) ............................................................................ 6
`Brown & Williamson Tobacco Corp. v. Phillip Morris Inc.,
`229 F.3d 1120 (Fed. Cir. 2000) .......................................................................... 21
`Custom Accessories, Inc. v. Jeffrey-Allan Indus.,
`807 F.2d 955 (Fed. Cir. 1986) ............................................................................ 20
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) ...................................................................... 6, 12
`Kimberly-Clark Corp. v. Johnson & Johnson,
`745 F.2d 1437 (Fed. Cir. 1984) .......................................................................... 20
`Meds. Co. v. Mylan Inc.,
`No. 11-cv-1285, 2014 U.S. Dist. LEXIS 38714
`(N.D. Ill. Mar. 25, 2014) ..................................................................................... 22
`Novartis AG v. Torrent Pharms., Ltd.,
`853 F.2d 1316 (Fed. Cir. 2017) .......................................................................... 22
`In re Omeprazole,
`483 F.3d 1364 (Fed. Cir. 2007) ............................................................................ 6
`Par Pharm., Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 16
`Santarus, Inc. v. Par Pharm, Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) .......................................................................... 17
`Therasense, Inc. v. Becton, Dickinson & Co.,
`593 F.3d 1289 (Fed. Cir. 2010), vacated on other grounds,
`374 F. App’x 35 (Fed. Cir. 2010) ....................................................................... 22
`
`
`
`
`iii
`
`

`

`1004
`
`1005
`1006
`
`1009
`1010
`
`1011
`
`1007
`1008
`
`PETITIONER’S EXHIBIT LIST
`Exhibit # Reference
`U.S. Patent No. 7,919,499 (“the ’499 Patent”)
`1001
`1002
`U.S. Serial Number 11/083,167, Office Action, May 5, 2009
`1003
`Serial No. 11/083,167, Declaration Under 37 C.F.R. § 1.132 of Elliot
`Ehrich (undated)
`U.S. Serial Number 11/083,167, Amendment and Response, Oct. 5,
`2009
`U.S. Serial Number 11/083,167, Office Action, Jan. 6, 2010
`U.S. Serial Number 11/083,167, Amendment and Response, Apr. 5,
`2010
`U.S. Serial Number 11/083,167, Final Rejection, July 20, 2010
`U.S. Serial Number 11/083,167, Amendment After Final, Oct. 20,
`2010
`U.S. Serial Number 11/083,167, Notice of Allowance, Dec. 1, 2010
`Sandra D. Comer et al., Depot naltrexone: long-lasting antagonism
`of the effects of heroin in humans, 159(4) Psychopharmacology
`(Feb. 2002), at 351-360
`Henry R. Kranzler et al., Sustained-Release Naltrexone for
`Alcoholism Treatment: A Preliminary Study, 22(5) Alcoholism:
`Clinical and Experimental Research (Aug. 1998), at 1074-79
`C.N. Chiang et al., Clinical Evaluation of A Naltrexone
`Sustained-Release Preparation, 16 Drug & Alcohol Dependence
`(1985), at 1-8
`T.N. Alim et al., Tolerability Study of A Depot Form of Naltrexone
`Substance Abusers, Problems of Drug Dependence,
`1994: Proceedings of the 56th Annual Scientific Meeting, The
`College on Problems of Drug Dependence, Inc., Vol. II: Abstracts,
`National Institute on Drug Abuse Research Monograph 153 (1995),
`at 253
`U.S. Patent No. 7,157,102 (“the ’102 Patent” or “Nuwayser”)
`U.S. Patent No. 6,306,425 (“Tice”)
`
`1012
`
`1013
`
`1014
`1015
`
`iv
`
`

`

`1017
`
`1018
`1019
`
`1020
`
`1021
`1022
`
`1023
`
`Exhibit # Reference
`U.S. Securities and Exchange Commission, FORM 10-K, Annual
`1016
`Report Pursuant to Section 13 or 15(d) of the Securities Exchange
`Act of 1934 for the fiscal year ended March 31, 2002. Alkermes, Inc.
`(July 2002)
`U.S. Trademark Application Serial Number 76/271,990, Allegation
`of Use of a Mark & specimen of the mark as used in commerce,
`Aug. 15, 2002 (“Vivitrex Specimen” or “Specimen”)
`U.S. Patent No. 6,264,987 (“the ’987 Patent” or “Wright”)
`S.J. Heishman et al., Safety And Pharmacokinetics of a New
`Formulation of Depot Naltrexone, Problems of Drug Dependence,
`1993: Proceedings of the 55th Annual Scientific Meeting, The
`College on Problems of Drug Dependence, Inc.,
`Volume II: Abstracts, National Institute on Drug Abuse Research
`Monograph 141 (1994)
`U.S. Patent and Trademark Office, 1265(2) Official Gazette of the
`United States Patent and Trademark Office, Trademarks, Dec. 10,
`2002
`Intentionally Left Blank
`Stewart B. Leavitt, PhD, ed., Evidence for the Efficacy of Naltrexone
`in the Treatment of Alcohol Dependence (Alcoholism), Addition
`Treatment Forum Naltrexone Clinical Update (2002 Clinco
`Communications, Inc.), at 1-8
`ReVia, Physicians’ Desk Reference 936-938 (53rd ed. 1999)
`(“PDR”)
`U.S. Patent No. 4,882,335 (“Sinclair”)
`Chiang et al., Kinetics of a naltrexone sustained-release preparation,
`36(5) Clin. Pharmacol. Ther. (Nov. 1984), at 704-08 “Kinetic of a
`naltrexone sustained-release preparation.”
`Reuning et al., Pharmacokinetic Quantitation of Naltrexone
`Release From Several Sustained-Release Delivery Systems,
`Naltrexone: Research Monograph 28 (R. E. Willette and G. Barnett,
`eds. National Institute on Drug Abuse 1980)
`Appeal Brief, Application No. 13/871,534, Oct. 19, 2015
`
`1024
`1025
`
`1026
`
`1027
`
`v
`
`

`

`1029
`1030
`
`1034
`
`1035
`
`Exhibit # Reference
`G. Rubio et al., Naltrexone Versus Acamprosate: One Year
`1028
`Follow-Up of Alcohol Dependence Treatment, 36(5) Alcohol &
`Alcoholism (2001), at 419-425
`Intentionally Left Blank
`Declaration of Kinam Park Ph.D in Support of Inter Partes Review
`of U.S. Patent No. 7,919,499
`Curriculum Vita of Kinam Park
`1031
`U.S. Provisional Application No. 60/564,542
`1032
`1033 Manit Srisurapanont & Ngamwong Jarusuraisin, Naltrexone for the
`treatment of alcoholism: a meta-analysis of randomized controlled
`trials, 8 Int’l J. of Neuropsychopharmacology (2005), at 267-280
`Bouza Carmen et al., Efficacy and safety of naltrexone and
`acamprosate in the treatment of alcohol dependence: a systematic
`review, 99(7) Addiction (July 2004), at 811-828
`J.S. Hopkins et al., Naltrexone and Acamprosate Meta-Analysis of
`Two Medical Treatments for Alcoholism, 26(5) Alcoholism Clinical
`and Experimental Research, 2002 Scientific Meeting of the Research
`Society on Alcoholism and the 11th Congress of the Int’l Society for
`Biomedical Research on Alcoholism, June 28-July 3, 2002, San
`Francisco, California (Suppl. May 2002)
`Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations, Product Details for NDA 018932, REVIA
`(NALTREXONE HYDROCHLORIDE) 50MG
`Bioequivalence, Center for Drug Evaluation and Research,
`Application Number: 75-434, Naltrexone Hydrochloride Tablets,
`Eon Labs Manufacturing, Inc., at 1-8
`Synopsis, Naltrexone HCl, ALZA Corporation (Nov. 3, 2003)
`In-hwan Baek et al., Evaluation of the Bioequivalence of Two Brands
`of Naltrexone 50 mg Tablet in Healthy Volunteers, 16(1) Kor. J. Clin.
`Pharm. (2006), at 69-74
`TREXAN™, Physicians’ Desk Reference 936-938 (46 ed. 1992)
`(“PDR”), at 937-939
`Trademark Manual of Examining Procedure (TMEP) (3rd ed. Jan.
`2002), at 100-5 to 100-11
`
`1038
`1039
`
`1036
`
`1037
`
`1040
`
`1041
`
`vi
`
`

`

`1043
`1044
`
`1045
`
`1046
`
`1047
`
`Exhibit # Reference
`Orange Book: Approved Drug Products with Therapeutic
`1042
`Equivalence Evaluations, NALTREXONE (VIVITROL) FOR
`SUSPENSION, EXTENDED RELEASE 380MG/VIAL
`General Notices and Requirements, USP 32/NF 27 (2009) at 8
`Bertil Abrahamsson and Anna-Lena Ungell, Biopharmaceutical
`support in formulation development:A Practical Guide from
`Candidate Drug Selection to Commercial Dosage Form,
`Pharmaceutical Preformulation and Formulation (Mark Gibson ed.,
`Interpharm/CRC) (2004), 239-291, at 262
`Guidance for Industry. Bioavailability and Bioequivalence Studies
`for Orally Administered Products—General Considerations. FDA
`CDER (March 2003)
`Riddle et al., Anxiolytics, adrenergic agents, and naltrexone, 38(5) J.
`Am. Acad. Child. Adolesc. Psychiatry, 546-556 (May 1999)
`Food and Drug Administration, FDA PSYCHOPHARMACOLOGIC
`DRUGS ADVISORY COMMITTEE MEETING VIVITROL®
`(naltrexone for extended-release injectable suspension),
`NDA 21-897 (Sept. 16 2010)
`Intentionally Left Blank
`Rothenberg et al., Behavioral naltrexone therapy: an integrated
`treatment for opiate dependence, 23 J. of Substance Abuse
`Treatment (2002), at 351-360
`B.A. Johnson, Naltrexone long-acting formulation in the treatment of
`alcohol dependence, 3(5) Ther. Clin. Risk Manag., 741-749 (2007),
`at 742.
`Food and Drug Administration, Guidance for Industry,
`Exposure-response relationships – study design, data analysis, and
`regulatory applications, FDA CDER (April 2003)
`Food and Drug Administration, Guidance for Industry, Statistical
`approaches to establishing bioequivalence, FDA CDER (April 2003)
`Schenker et al., Antecedent liver disease and drug toxicity, 31 J. of
`Hepatology 1098-1105 (1999)
`Resume of Mike Ramstack, as obtained from LinkedIn
`Resume of Richard Reuning, as obtained from LinkedIn
`
`1048
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`1055
`
`vii
`
`

`

`1061
`
`Exhibit # Reference
`Resume of Steve Wright, as obtained from LinkedIn
`1056
`1057
`U.S. Patent No. 3,332,950
`1058
`Filing Details for Alkermes Inc. 10-K dated July 1, 2002 from the
`Security and Exchange Commission’s EDGAR Online Filing System
`1059 WayBack Machine capture of Security and Exchange Commission’s
`Information Page regarding the Electronic Data Gathering, Analysis,
`and Retrieval System (EDGAR), June 6, 2002
`1060 WayBack Machine capture of Security and Exchange Commission’s
`Regulatory Overview of the Electronic Data Gathering, Analysis, and
`Retrieval System (EDGAR), June 6, 2002
`Supplemental Declaration of Kinam Park Ph.D in Support of
`Petitioner’s Reply to Patent Owner’s Response
`Declaration of Sara K. Quinney, Pharm.D., Ph.D in Support of
`Petitioner’s Reply to Patent Owner’s Response
`Curriculum Vita of Sara Kay Quinney
`1063
`1064 Marco Bertoletti et al., Effect of liver cirrhosis on the systemic
`availability of naltrexone in humans, 27 J. of Hepatology 505-511
`(1997)
`Physician’s Desk Reference, 2663, 3052-3053 (55th ed. 2001)
`1065
`1066 Michael R. Franklin, PhD, Drug Absorption, Distribution,
`Metabolism, and Excretion, Ch.54 The Science and Practice of
`Pharmacy 1107-1111 (22nd ed. 2013)
`Steven B. Johnson, PharmD, Bioavailability and Bioequivalence
`Testing, Ch.18 Remington 349-359 (22nd ed. 2013)
`Barbara J. Mason, Ph.D. et al., A Pharmacokinetic and
`Pharmacodynamic Drug Interaction Study of Acamprosate and
`Naltrexone, 27:4 Neuropsychopharmacology 596-606 (2002)
`Bioavailability and Bioequivalence Studies for Orally Administered
`Drug Products ____ General Considerations, Guidance for Industry,
`U.S. Department of Health and Human Services Food and Drug
`Administration Center for Drug Evaluation and Research (CDER)
`(July 2002)
`Raymond E. Galinsky et al., Probenecid Enhances Central Nervous
`System Uptake Of 2’,3’ – Dideoxyinosine by Inhibiting
`
`1062
`
`1067
`
`1068
`
`1069
`
`1070
`
`viii
`
`

`

`1072
`
`1074
`
`1075
`
`1076
`
`1077
`
`1071
`
`Exhibit # Reference
`Cerebrospinal Fluid Efflux, 257:3 J. of Pharmacology and
`Experimental Therapeutics pages 972-978 (1991)
`Susan N. Hunt, Pharm.D. et al., Effect of smoking on theophylline
`disposition, 19:5-1) Clinical Pharmacology and
`Therapeutics 546-551 (1976)
`K.C. Yeh & K.C. Kwan, A Comparison of Numerical Integrating
`Algorithms by Trapezoidal, Lagrange, and Spline Approximation, 6:1
`J. of Pharmacokinetics and Biopharmaceutics 79-98 (1978)
`1073 M.J. Gardner et al., EFFECTS OF TOBACCO SMOKING AND
`ORAL CONTRACEPTIVE USE ON THEOPHYLLINE
`DISPOSITION, 16 Br. J. Clin. Pharmac. 271-280 (1983)
`John G. Wagner & James W. Ayres, Bioavailability assessment:
`methods to estimate total area (AUC 0-∞) and total amount excreted
`∞) and importance of blood and urine sampling scheme with
`(Ae
`application to digoxin, 5:5 J. of Pharmacokinetics and
`Biopharmaceutics 533-557 (1977)
`Zhiling Yu & Francis L. S., An Evaluation of Numerical Integration
`Algorithms for the Estimation of The AUC in Pharmacokinetics
`Studies, 16 Biopharmaceutics and Drug Disposition 37-58 (1995)
`C. Ediss & Y.K. Tam, An Interactive Computer Program for
`Determining Areas Bounded by Drug Concentration Curves Using
`Lagrange Interpolation, 34:3 J. of Pharmacological and
`Toxicological Methods 165-168 (Nov. 1995)
`Rajesh Krishna et al., Increased Intracellular Drug Accumulation
`and Complete Chemosensitization Achieved in Multidrug-Resistant
`Solid Tumors by Co-Administering Valspodar (PSC 833) With
`Sterically Stabilized Liposomal Doxorubicin, 85 Int. J. Cancer
`131-141 (2000)
`Sara Rae Hamilton et al., Pharmacokinetics and Pharmacodynamics
`of Hyaluronan Infused into Healthy Human Volunteers, 3 The Open
`Drug Metabolism J. 43-55 (2009)
`Nikolaj Kunøe et al., Injectable and Implantable sustained release
`naltrexone in the treatment of opioid addiction, 77:2 British J. of
`Clinical Pharmacology 264-271 (2012)
`Joi L. Dunbar et al., Single- and Multiple-Dose Pharmacokinetics of
`
`1078
`
`1079
`
`1080
`
`ix
`
`

`

`1085
`
`1086
`
`1087
`
`1081
`
`Exhibit # Reference
`Long-acting Injectable Naltrexone, 30:3 Alcoholism: Clinical and
`Experimental Research 480-490 (Mar. 2006)
`Nowsheen Goonoo et al., Naltrexone: A review of existing sustained
`drug delivery systems and emerging nano-based systems, 183 J. of
`Controlled Release 154-166 (2014)
`1082 Malcom Rowland & Thomas N. Tozer, Clinical Pharmacokinetics
`Concepts and Applications (3rd ed. 1995)
`1083 Milo Gibaldi & Donald Perrier, Pharmacokinetics, 1 Drugs and
`Pharmaceutical Sciences (2d ed. rev. expanded 2007)
`1084 M.J. Kogan et al., Estimation of the Systemic Availability and Other
`Pharmacokinetic Parameters of Naltrexone in Man After Acute and
`Chronic Oral Administration, 18:1 Research Communications in
`Chemical Pathology and Pharmacology 29-34 (Sept. 1977)
`Phoenix WinNonlin® User Guide, Phoenix WinNonlin 8.1, Certara
`(2018)
`K. Fotherby et al., Pharmacokinetic Study of Different Doses of
`Depo Provera, 22:5 Contraception 527-536 (Oct. 1980)
`K. Fotherby et al., A Preliminary Pharmacological Trial of the
`Monthly Injectable Contraceptive Cycloprovera, 25:3 Contraception
`261-271 (Feb. 1982)
`Kah Hay Yuen et al., Comparative Bioavailability Study of a Generic
`Naltrexone Tablet Preparation, 25:3 Drug Development and
`Industrial Pharmacy 353-356 (1999)
`1089 Malcolm Rowland & Thomas N. Tozer, Clinical Pharmacokinetics
`and Pharmacodynamics Concepts and Applications (4th ed.2011)
`
`1088
`
`x
`
`

`

`I.
`
`INTRODUCTION
`Parenterally administering a long-acting dose of 310-480 mg of naltrexone
`
`to substance abusers was known. Tice taught administering up to 350 mg using a
`
`biocompatible polymer. (Ex. 1015, 4:35-38.) Comer and Nuwayser, separate
`
`accounts of the same clinical study, did so also using 384 mg of naltrexone in
`
`PLGA, the claimed polymer.
`
`Yet Alkermes argues that this art does not disclose a pharmacokinetic
`
`parameter—Area Under the Curve or “AUC”— resulting from administering
`
`Comer or Nuwayser or its relationship to the AUC of daily oral naltrexone. But
`
`neither these AUCs values, nor their relationship to one another, can make an
`
`otherwise known method patentable.
`
`Alkermes also argues that the art is somehow so deficient that a POSA could
`
`not even determine the AUC or make the needed comparison. But since the
`
`method is known, or at least obvious, the relationship between AUCs must also
`
`exist, whether explicitly disclosed or not. And Alkermes’ criticisms are
`
`disingenuous, as both the ’499 Patent itself and the Ehrich Declaration (which was
`
`the basis for its allowance) suffer these very same alleged deficiencies. As for
`
`Dr. Berkland’s and Alkermes’ criticism of Dr. Park’s use of Photoshop as unusual,
`
`they do so only because they are unable to say it is inaccurate or incorrect.
`
`(Ex. 1062 ¶ 49.)
`
`
`
`

`

`II. CLAIM CONSTRUCTION
`“Single Injection”
`A.
`It is now Alkermes’ position that the broadest reasonable interpretation of
`
`parenterally administering a long acting formulation is “a single injection of a long
`
`acting formulation”―meaning a single shot. (Resp. 5-7.) This “single injection”
`
`language appears nowhere in the claims or specification, and nothing supports so
`
`limiting the claims. (Ex. 1061 ¶¶ 15-23.)
`
`Alkermes points to the use of “the step” and “a long acting formulation” in
`
`the claims as meaning “singular.” But the opposite is true; indeed, the opposite is
`
`the rule. See Baldwin Graphic Sys., Inc. v. Siebert, Inc., 512 F.3d 1338,1342 (Fed.
`
`Cir. 2008) (“[t]his court has repeatedly emphasized that an indefinite article ‘a’ or
`
`‘an’ in patent parlance carries the meaning of ‘one or more’…. The subsequent use
`
`of definite articles ‘the’ or ‘said’ in a claim to refer back to the same claim term
`
`does not change the general plural rule.”). That the working examples illustrate
`
`using a single shot does not mean that only one shot was claimed. (Ex. 1061 ¶ 17.)
`
`This is just Alkermes’ attempt to read limitations into the claims.
`
`Indeed, the ’499 Patent focuses on the difference between an injectable
`
`formulation given once every 28 days and once-a-day oral dosing for 28 days. In
`
`this context, clearly the ’499 Patent is claiming the number of doses used during
`
`the claimed period rather than how many shots, or how many pills, were needed to
`
`administer the claimed dose. A doctor prescribing a 400 mg dose of ibuprofen is
`
`2
`
`

`

`indifferent to giving it as one 400 mg tablet or two 200 mg tablets. (Ex. 1061
`
`¶¶ 19-20.)
`
`Finally, given that the claimed method uses a long acting formulation
`
`designed to release naltrexone over four weeks, are we really to believe that giving
`
`two 190 mg shots moments apart makes any patentable difference? And if so,
`
`wouldn’t there have been some discussion of this in the specification or file
`
`history?
`
`B.
`
`“The Serum AUC Of Naltrexone…
`Achieved By 50 mg/Day Oral Administration”
`Nowhere does the ’499 Patent provide the serum AUC of oral naltrexone.
`
`That either renders the claims indefinite or should at least permit a POSA to use
`
`any published oral data. (Pet. 17-19; Exs. 1030 ¶ 43; 1061 ¶¶ 9-11.) The Board
`
`concluded, however, that the Ehrich Declaration suggests specific values for the
`
`AUC of once daily oral naltrexone. (ID 11-12.) While accepting the Board’s
`
`position, Petitioner maintains its concern that the declaration is not part of the
`
`specification and should not be used to provide critical information completely
`
`absent from the specification.
`
`In its Response, Alkermes states that to the extent the term needs to be
`
`defined, that definition is “about 30 µg h/L” or about 1.25 ng·day/mL. (Resp. 8.)
`
`At least in that, it appears that all of the experts, and the Board, are in agreement.
`
`(Exs. 2055 ¶ 34, 1061 ¶¶ 12-14, 31.) This corresponds with the AUC reported in
`
`3
`
`

`

`the Ehrich Declaration for Alkermes’ oral dosing of 50 mg naltrexone daily;
`
`30.5 µg h/L. (Ex. 1003, at 4 of 6 (Cohort A).)
`
` “Initial Oral Dose Of Naltrexone”
`C.
`Alkermes equates “initial” with “first” in claim 11—meaning a patient
`
`cannot have received any oral dose ever prior to the parental administration.
`
`(Resp. 10-11.) Alkermes’ interpretation is not reasonable. It excludes patients who
`
`tried oral naltrexone, but failed for compliance reasons—the very patients that the
`
`’499 Patent allegedly addresses. (Exs. 1001, 1:25 (“Patient compliance is a serious
`
`problem.”); 1061 ¶¶ 24-25, 28.)
`
`Instead, the art makes clear that there is a difference between “treatment”
`
`and prior treatment, detoxification, tolerance, and the like. (Exs. 1010, at 353;
`
`1015, 5:65-6:11; 1030 ¶ 49; 1061 ¶¶ 26-27) Petitioner’s is the far more reasonable
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`broadest reasonable interpretation.
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`III. THE CLAIMS ARE ANTICIPATED
`A. Grounds 1 And 2: Comer And Nuwayser
`Comer and Nuwayser explicitly disclose parenterally administering to opioid
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`addicts a long acting 380 mg formulation of naltrexone and PLGA. (Exs. 1030
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`¶¶ 66-77, 89, 96, 103, 106-107; 1061 ¶¶ 66-73.) Both disclose achieving blood
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`levels the art recognized as therapeutic. (Exs. 1061 ¶¶ 79-81; 1062 ¶ 36.) And both
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`provide superimposable pharmacokinetic plots (blood concentration versus time),
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`which, as Petitioner’s pharmacology and pharmacokinetics expert Dr. Sara
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`4
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`Quinney, PharmD, Ph.D. (Ex. 1062 ¶¶ 1-15) explains, given the small patient
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`sample size, tells a POSA that Comer and Nuwayser are separate accounts of the
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`identical study (Exs. 1062 ¶¶ 90-93; 1030 ¶¶ 76-77; 1061 ¶ 69). Nothing else is
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`needed to anticipate these method claims.
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`Comer’s method administers a 384 mg dose that falls within the claimed
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`range. (Pet. 22-24; Ex. 1030 ¶¶ 70, 76, 87.) Comer does not recite the specifics of
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`its formulation but identifies the formulation as “Depotrex,” which a POSA knows
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`from Nuwayser is a specific PLGA depot formulation. (Pet. 22-24, 26-27;
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`Ex. 1061 ¶ 68.) Comer anticipates.
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`Nuwayser discloses the method and the formulation but not the dose
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`expressly. (Pet. 26-27; Ex. 1030 ¶¶ 75-77, 96.) But for a given formulation, the
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`pharmacokinetics are inevitable, something confirmed by Dr. Quinney. (Exs. 1062
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`¶¶ 38, 40, 91-93; 1061 ¶ 68.) Nuwayser provides an express disclosure of the
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`formulation and provides its pharmacokinetic plot in Fig. 7. That plot can result
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`from only one dose—a dose within the range claimed. (Exs. 1061 ¶ 69; 1062
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`¶¶ 92-93.) Nuwayser anticipates as well.
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`Indeed, as Dr. Quinney notes, given the relatively small patient sample size
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`used in both Comer and Nuwayser, the fact that their pharmacokinetic plots are
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`superimposable, the common author/inventor and the like, a POSA would know
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`5
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`

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`that they are both reports of the same study and would therefore know that the dose
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`used in Nuwayser was that used in Comer―384 mg. (Ex. 1062 ¶¶ 90-93.)
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`Alkermes argues that Comer and Nuwayser are deficient as they do not
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`report on AUC or make a comparison to the AUC of daily oral dosing. But the
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`AUC and differential are nothing more than consequences of performing the
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`claimed steps—steps that were known—and cannot confer patentability. See
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`In re Kao, 639 F.3d 1057, 1070 (Fed. Cir. 2011) (pharmacokinetic property “adds
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`nothing of patentable consequence” when claimed as a limitation); see also
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`Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1380 (Fed. Cir.
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`2001)
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`(cannot obtain patent on known use of known process); and
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`In re Omeprazole, 483 F.3d 1364, 1373 (Fed. Cir. 2007) (citing inter alia,
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`Verdegaal Bros., Inc. v. Union Oil & Co., 814 F.2d 628, 633 (Fed. Cir. 1987) (the
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`recognition of a new aspect of a known process in not patentable invention of a
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`novel process)).
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`Most of Alkermes’ remaining arguments against Grounds 1 and 2 (as well as
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`the corresponding obviousness Grounds) are based on unwarranted attacks on the
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`credibility of Dr. Park and allegations that a POSA could not determine AUC from
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`the references as he did. In view of Alkermes’ criticism, Dr. Park offers further
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`explanations of his prior opinions in his Supplemental Declaration filed herewith.
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`(Ex. 1061 ¶¶ 1-6, 29.) And Dr. Quinney reviewed the record and agrees with
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`6
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`

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`Dr. Park that not only is Photoshop an appropriate tool that can be used to
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`determine area in this circumstance, but that a POSA could indeed determine AUC
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`from Comer and Nuwayser. (Ex. 1062 ¶¶ 16-18, 94-95.) And even Alkermes
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`admits that if Dr. Park’s AUC calculation is correct—and it most certainly is as
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`demonstrated herein—then the art teaches the claimed AUC differential.
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`(Resp. 10.)
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`A POSA Can Calculate AUC
`1.
`To a POSA, both Comer and Nuwayser include a pharmacokinetic profile
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`from which an AUC can necessarily be calculated using any number of known
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`methods. (Exs. 1061 ¶ 30; 1062 ¶¶ 19-26, 38-44.) As for Alkermes’ allegations
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`that a POSA would not and could not determine that AUC, it is wrong and
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`disingenuous—if not outright hypocritical as its own procedures raise similar
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`questions.
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`Photoshop Is An Appropriate Technique
`2.
`AUC results from plotting blood concentration of a drug versus time and
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`then calculating the area under that curve using modern computers or “old school”
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`manual techniques. Just as a mile can be measured by laying 5280 rulers end to
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`end or by using GPS, Photoshop can be used instead of either special purpose
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`computer programs or hand drawing trapezoids. Dr. Park merely used Photoshop
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`as a tool to convert the relevant area into “pixels” of uniform size that could be
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`accurately summed. Dr. Park did not “invent” this method. (Exs. 1061 ¶¶ 60-65;
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`7
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`1062 ¶ 45; 1078, at 47.) Dr. Quinney reviewed the Photoshop method and found
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`that a POSA would consider it suitable. (Ex. 1062 ¶¶ 46-49.) Indeed, the AUC
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`resulting from both Photoshop and a manual calculation are the same. (Exs. 1062
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`¶ 50; 1061 ¶¶ 36, 64-65; 1030 ¶ 69.) Dr. Berkland and Alkermes have criticized
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`Dr. Park’s use of Photoshop as unusual only because they are unable to criticize it
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`as inaccurate or incorrect. (Ex. 1062 ¶ 49.) So contrary to Alkermes’ allegations
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`(Resp. 33-34), what Dr. Park did is neither new nor “flawed.”
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`Whether one uses computer integration of a fitted curve, draws trapezoids
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`between data points, counts squares on a graph, or divides the area into pixels and
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`counts them, all provide an acceptable answer. (Ex. 1062 ¶¶ 41-44.) And
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`techniques for determining AUC were known in 2004. (Exs. 1025, at 706; 1030
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`¶¶ 56, 67; 1061 ¶¶ 60, 63.) It is the AUC—not the interchangeable method used to
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`determine it—that is important here. (Exs. 1061 ¶ 64; 1062 ¶¶ 40-42, 45, 94.) Yet
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`it is the method Alkermes disputes, not the result.
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`Time Zero (“Tzero”)
`3.
`Alkermes complains that neither reference recites taking a blood sample at
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`Tzero thereby preventing an AUC calculation. Before addressing that concern, it’s
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`worth remembering that a POSA already knew much about naltrexone and its
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`pharmacokinetics. In fact, by 2004, naltrexone and its use to treat addiction via
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`daily tablets and long term injections were all well known. (Ex. 1062 ¶ 29.) With
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`8
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`that in mind, a POSA would not consider a Tzero reading to be necessary in this
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`instance. Unlike IV administration where a drug immediately enters the
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`bloodstream, the claimed depot method involves the gradual release over 28 days
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`or more. At Tzero, there would be no reasonable expectation of any release or any
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`impact on AUC. Indeed, in the context of a formulation designed to release drug
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`over 28 days, a POSA would expect two hours to be a perfectly reasonable starting
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`point given that it represents only about 3/1000ths of the total release period.
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`(Exs. 1061 ¶¶ 32-38; 1062 ¶¶ 52-59.)
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`Finally, nothing in the ’499 Patent or Ehrich Declaration suggest that a Tzero
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`reading was, or must be, taken. (Ex. 1062 ¶ 60.) Nor did Alkermes criticize Tice
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`for not reporting a Tzero. Thus a lack of Tzero would not prevent a POSA from
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`calculating AUC from either Comer or Nuwayser. (Id. ¶ 57.)
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`Sampling Frequency
`4.
`Alkermes complains of insufficient sampling. (Resp. 17-18.) But it fails to
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`explain how often one must sample blood over the course of a month. What is
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`being tested is whether drug is present in the bloodstream above the therapeutic
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`threshold. This is certainly accomplished by the sampling reported in the
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`references. And it’s the same sampling frequency used in the clinical trial reported
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`in the Ehrich Declaration. (Compare Ex. 2007, at 16 and Ex. 1010 Fig. 1.) If
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`enough data was collected for Ehrich to calculate th