COHAUSZ & FLORACK
`
`COHAUSZ B FLORACK • P.O. Box 10 18 30 D-40009 DOsseldorf
`BY ONLINE-FILING
`
`Europaisches Patentamt
`80298 Munchen
`
`Dusseldorf
`November 16, 2016
`
`Your reference
`
`Our reference
`160529EP-EING
`
`Direct dial
`0211 90490-0
`
`Patent Attorneys
`Dr. Arwed Burrichter
`Dr. Ralph Minderop
`Dr. Natalie Kirchhofer
`
`Opposition proceedings concerning European Patent 1 845 961 (06 706 291.9)
`
`Title of the Patent:
`Patent Proprietor:
`
`Treatment of thromboembolic disorders with rivaroxaban
`Bayer Intellectual Property GmbH / DE
`
`For and on behalf of the Patentee, Bayer Intellectual Property GmbH, we herewith submit
`
`PATENTEE'S RESPONSE TO THE NOTICES OF OPPOSITIONS
`
`filed by:
`
`Opponent 01:
`Opponent 02:
`Opponent 03:
`Opponent 04:
`Opponent 05:
`Opponent 06:
`Opponent 07:
`Opponent 08:
`Opponent 09:
`Opponent 010:
`Opponent 011:
`Opponent 012:
`Opponent 013:
`
`Breuer, Markus
`Actavis Group PTC ehf
`Zaklady Farmaceutyczne Polpharma S.A.
`Teva Pharmaceutical Industries Ltd.
`STADA Arzneimittel AG
`Generics [UK] Limited
`Abdi Ibrahim Ilac Sanayi ye Ticaret A.S.
`Wittkopp, Alexander
`Galenicum Health S.L.
`ABG Patentes, S.L.
`Stolmar, Matthias
`Hexal AG
`Kraus ft Weisert Patentanwilte PartGmbB.
`
`This submission is structured as follows:
`
`Patent- and Rechtsanwelte
`
`Partnerschaftsgesellschaft mbB • AG Essen PR 2301 • List of partners: www.cohausz-florack.de
`Bleichstralte 14 D-40211 Diisseldorf • Telephone +49 211 90490-0 • Facsimile +49 211 90490-49
`www.cohausz-florack.de • mail@cohausz-florack.de
`
`MYLAN - EXHIBIT 1015
`
`

`

`COHAUSZ & FLORACK
`
`TABLE OF CONTENTS
`
`A REQUESTS
`
`B DOCUMENTS
`
`C
`
`INTRODUCTORY COMMENTS
`
`6
`
`6
`
`12
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`C.1 Development of the claimed compound (rivaroxaban) and its once-daily dosage regimen were a milestone
` 12
`achievement in medicine
`
`C.2 Patentability of second medical use and dosage regimen claims as an important driver of innovation
`
`C.3 The Opposed Patent
`
`C.4 Claim construction
`
`D NO ADDED SUBJECT MATTER (ART. 100(c), 123(2) EPC)
`
`D.1 Summary of opponents' added matter arguments
`
`D.2 The feature "no more than once daily" in claim 1 complies with Art. 123(2) EPC
`
`D.2.1 Support for the feature "no more than once daily" in granted claim 1
`
`D.2.2
`
`"Once daily" and "no more than once daily" are used synonymously in the application as filed;
`no intermediate generalization present
`
`D.2.3
`
`The Examining Division's suggestion
`
` 15
`
` 17
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` 19
`
`21
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`21
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` 21
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` 22
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` 23
`
`24
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`D.3 Combination of features "half life of 10 hours" and "compound (I)" in cl. 1 complies with Art. 123(2) EPC 25
`
`E
`
`SUFFICIENCY OF DISCLOSURE AND ENABLEMENT (ART. 100(b), 83 EPC)
`
`El Summary of opponents' insufficiency arguments
`
`E.2 The Opposed Patent fulfills the requirements of Art. 100(b) and 83 EPC
`
`E.3 The opponents' insufficiency arguments lack merit
`
`The feature "Rapid-release tablet" is clear and enabled
`E.3.1
`E.3.1.1 Clarity objections under Art. 84 EPC form no ground of opposition
`The majority of opponents assert that "rapid-release tablet" is a term of art, which as such is
`E.3.1.2
`therefore clear and enabled
`E.3.1.3 Reference to the USP release method in para. [0030] of the Opposed Patent
`E.3.1.4 Reference to preparation method of D60 in para. [0030] of the Opposed Patent
`
`26
`
`26
`
`27
`
` 30
`
`30
` 31
`
`32
`33
`35
`
`E.3.2
`
`The feature "plasma concentration half life of 10 hours or less" is an intrinsic property of
`37
`rivaroxaban and therefore a redundant feature
`E.3.2.1 Plasma concentration half life of 10 hours or less does not define a patient group
`38
`E.3.2.2 Methods for monitoring blood plasma concentrations and determining half life were known 43
`01's, 08's, and 09's objections regarding "ranges of plasma concentration half lives" and the
`E.3.2.3
`necessity for "influencing or adjusting the half life" are nonsensical
` 44
`E.3.2.4 Conclusion on feature "Plasma concentration half life of 10 hours or less"
` 45
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`E.3.3
`
`The features "no more than once daily" and "once daily" are used synonymously in the Opposed
`Patent and exclude "less than once daily" dosaging
`
`45
`
`The patent's disclosure is enabled over the whole breadth of claim 1
`E.3.4
`E.3.4.1 Specifying a dose in claim 1 is not necessary for an enabling disclosure (09, 010 and 012)
`It is credible that clinical efficacy is achieved for therapy and prophylaxis of "thromboembolic
`E.3.4.2
` 51
`disorders" in general
`55
`It is credible that the therapeutic effect can be achieved over all patient groups
`
` 48
`48
`
`E.3.4.3
`
`E.3.5 Rebuttal of specific objections to Example 1 of the Opposed Patent
`
`E.4 Conclusion on Sufficiency of Disclosure
`
`F NOVELTY (ART. 100(a), 54 EPC)
`
`F.1 Summary of opponents' novelty arguments
`
`F.2 General considerations regarding novelty of medical use claims
`
`F.3 Novelty over D1
`
`F.4 Novelty over D2 and D11
`
`F.4.1 D2/D11 does not disclose the use of a tablet
`
`57
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` 60
`
`61
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`61
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` 61
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`62
`
`65
`
` 65
`
`67
`F.4.2 D2/D11 does not disclose dosage regimens for the treatment of thromboembolic disorders
`71
`The claims of the Opposed Patent do not include administration to healthy people
`F.4.2.1
` 74
`Case Law on clinical trial disclosures and novelty of second medical use claims
`F.4.2.2
`The pharmacodynamic assay results reported in D2 are not predictive of the clinical efficacy of
`F.4.2.3
`75
`the claimed dosage regimen
`
`F.5 D29 is no prior art under Art. 54(2) EPC
`
`G
`
`INVENTIVE STEP (ART. 100(a), 56 EPC)
`
`G.1 Summary of opponents' inventive step arguments
`
`G.2 The claimed invention
`
`G.3 The closest prior art
`
`G.4 The distinguishing features vis-à-vis the claimed invention
`
`G.5 The objective technical problem
`
`G.6 The invention solves the objective technical problem
`
`G.6.1 Data contained in the Opposed Patent
`
`76
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`79
`
`79
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` 81
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`82
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` 82
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`83
`
`83
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`83
`
`85
`G.6.2 Post-published data
`G.6.2.1 EMA 2008 CHMP AR: prevention of venous thromboembolism (RECORD 1-3 phase III trials) 87
`G.6.2.2 ROCKET AF phase III trial: Prevention of Stroke and Systemic Embolism in patients with AF 88
` 90
`G.6.2.3 Treatment of VTE (EINSTEIN DVT and EINSTEIN PE phase III trials)
`G.6.2.4 Difference between od vs. bid dosaging of rivaroxaban (ODIXa HIP2 and ODIXa-OD-HIP)
` 91
`
`G.6.3 The invention credibly solves the problem across the whole claim scope
`
`94
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`G.7 Non-obviousness of the claimed once-daily dosage regimen
`
`G.7.1 Claimed invention is contrary to conventional wisdom; no reasonable expectation of success
`G.7.1.1 The ximelagatran example taught towards a bid administration of rivaroxaban
`
`G.7.2 With once-daily dosaging, skilled person would have feared too high fluctuations in drug
`concentration given the short half life of rivaroxaban
`
`95
`
`96
`98
`
`99
`
`G.7.3 Skilled person would have refrained from od dosaging due to fear of Cmax-associated bleeding 105
`
`G.7.3.1 Bleeding complications in clinical trials of anticoagulants developed in parallel (razaxaban,
`idraparinux) were a warning to the skilled person
`
`108
`
`G.7.4 The therapeutic window for rivaroxaban was neither known nor expected to be large enough for
`110
`once-daily dosaging
`G.7A.1 Meaning of the terms "therapeutic index", "therapeutic range", and "therapeutic window"
`110
`G.7.4.2 The boundaries of the therapeutic window cannot be inferred from phase I PD data
`112
`G.7.4.3 The prior art only referred to a "relatively" large therapeutic window for factor Xa inhibitors;
`114
`in general, anticoagulants were considered narrow therapeutic window drugs
`G.7.4.4 The therapeutic window of anticoagulants was known to be small in comparison to other, non-
`117
`toxic drugs
`118
`G.7.4.5 D14 supports non-obviousness of the claimed dosage regimen
`
`G.7.5 Desired increase in patient compliance does not provide reasonable expectation of success
`
`G.7.6 Non-compliance and the "missed dose argument" speak against once-daily dosaging
`
`G.7.7
`
`In the field of drug development, skilled person adopts no "try and see" attitude
`
`G.8 Non-obviousness of the combination of once-daily dosaging and rapid-release tablet
`
`G.9 Starting from D2/D11, the claimed solution was not obvious in light of D3/D12 or D15/D17
`
`G.9.1 D2/D11 does not suggest the claimed solution
`
`G.9.2 Neither D3/D12 nor D15/D17 suggest the claimed solution
`
`120
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`121
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`123
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`124
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`126
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`128
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`130
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`135
`135
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`G.9.3 Phase I study results (D2/D11, D3/D12, D15/D17) did not suggest that a once-daily dosage regimen
`131
`would be effective
`G.9.3.1 D2/D11 and D15/D17 provide no evidence for a sustained therapeutic effect of rivaroxaban 131
`G.9.3.2 Clinical efficacy and the boundaries of the therapeutic window are only determined in
`phase II and III studies
`G.9.3.3 Phase I pharmacodynamic surrogate parameters are not predictive of clinical endpoints
`In vitro clotting or thrombin generation assays do not predict clinical efficacy of a dosage
`G.9.3.4
`regimen
`G.9.3.5 Dose-response relationships determined with in vitro assays in healthy subjects rarely
`correlate with the dose-clinical efficacy relationship observed in patients
`
`137
`
`140
`
`G.9.4
`
`Inventive step in light of the known dosage regimen of LMWHs such as enoxaparin (D13, D41) or
`141
`nadroparin (D34)
`
`G.9.5
`
`Inventive step in light of the sustained inhibition reported for TAP (D6)
`
`G.9.6 Rivaroxaban's mechanism of action did not suggest a sustained effect (012)
`
`G.9.7 D2/D11 in combination with D16 or D27 (09)
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`G.10 Other problem-and-solution approaches exercised by the opponents
`
`G.10.1 D1 as closest prior art (01, 04, and 05)
`G.10.1.1 Non-obviousness based on D1 alone
`G.10.1.2 Non-obviousness based on D1 in combination with the other art cited
`
`G.10.2 D3/D12 or D15/D17 as closest prior art (04, 08, 09, and 012)
`
`G.10.3 D16 or D27 as closest prior art (09)
`
`H AUXILIARY REQUESTS
`
`H.1 Auxiliary Request 1 (AR1)
`
`H.2 Auxiliary Request 2 (AR2)
`
`H.3 Auxiliary Request 3 (AR3)
`
`H.4 Auxiliary Request 4 (AR4)
`
`H.5 Auxiliary Request 5 (AR5)
`
`H.6 Auxiliary Request 6 (AR6)
`
`H.7 Auxiliary Request 7 (AR7)
`
`H.8 Auxiliary Request 8 (AR8)
`
`H.9 Auxiliary Request 9 (AR9)
`
`H.10 Auxiliary Requests 10 to15 (AR10-AR15)
`
`H.11 Auxiliary Requests 16 to 21 (AR16-AR21)
`
`H.12 Auxiliary Requests 22 to 27 (AR22-AR27)
`
`I
`
`CONCLUDING REMARKS
`
`151
`
`151
`152
`155
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`155
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`156
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`158
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`158
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`158
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`159
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`159
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`160
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`161
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`COHAUSZ 4FLORACK
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`A REQUESTS
`
`(1)
`
`It is requested as Main Request to reject the oppositions and maintain the patent as granted.
`
`(2)
`
`As an auxiliary measure, it is requested to maintain the patent in amended form on the basis
`
`of one of Auxiliary Requests 1 to 27 enclosed herein (see section H below).
`
`(3)
`
`Should the Opposition Division not be minded to grant the Main Request, Oral Proceedings
`
`are requested.
`
`B DOCUMENTS
`
`(4)
`
`A consolidated list of documents submitted by the opponents with a cross-reference table to
`
`opponents' numbering is attached as Annex A.
`
`(5)
`
`Patentee submits documents D1a, D9a-D9e, D25a, and D46 to D87.
`
`A complete list of the documents D1 to D87 on file is attached as Annex B and given in the
`following:
`
`Reference
`
`D1
`
`US 2003/153610 Al
`
`D1a WO 2001/47919 Al
`
`D2
`
`D3
`
`D4
`
`D5
`
`D6
`
`D7
`
`D8
`
`D9
`
`Kubitza, D et al., "Multiple dose escalation study investigating the pharmacodynamics,
`safety, and pharmacokinetics of BAY 59-7939 an oral, direct factor Xa inhibitor in healthy
`male subjects." Blood, vol. 102, no. 11, 2003, Part 1, Abstract no. 3004.
`
`Kubitza, D et al., "Single dose escalation study investigating the pharmacodynamics,
`safety, and pharmacokinetics of BAY 59-7939 an oral, direct factor Xa inhibitor in healthy
`male subjects." Blood, vol. 102, no. 11, 2003, Part 1, Abstract no. 3010.
`
`Aulton, ME. Pharmaceutics: The science of dosage form design. 2nd ed., Churchill
`Livingstone, 2002.
`
`Lieberman, HA, Lachman, L, and Schwartz, JB. PHARMACEUTICAL DOSAGE FORMS
`Tablets Volumes. 2nd ed., Marcel Dekker, Inc., 1989.
`
`Leadley Jr, RJ. "Coagulation factor Xa inhibition: biological background and rationale."
`Current Topics in Medicinal Chemistry, vol. 1, no. 2, 2001, pp. 151-159.
`
`Foster, RW. Basic Pharmacology. 2nd ed., Butterworths, University of Manchester, 1986,
`p. 255.
`
`"Xarelto® Dosing and transition management." Janssen Pharmaceuticals, Inc., April 2015.
`
`Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS. 10th
`ed., The McGraw-Hill Companies, Inc., 2001, Chapter 1, pp. 1-29.
`
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`COHAUSZ & FLORACK
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`Reference
`
`D9a Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS. 7th ed.,
`Macmillan Publishing Company, 1985, Chapter 1, pp. 3-34.
`
`D9b Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS. 10th
`ed., The McGraw-Hill Companies, Inc., 2001, Appendix II, pp. 1917-1924.
`
`D9c Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS. 10th
`ed., The McGraw-Hill Companies, Inc., 2001, 10th ed. 2001, Chapter 55, pp. 1519-1531.
`
`D9d Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS. 10th
`ed., The McGraw-Hill Companies, Inc., 2001, Chapter 3, pp. 48-56.
`
`D9e Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS. 7th ed.,
`Macmillan Publishing Company, 1985, Chapter 58, pp. 1338-1352
`
`D10
`
`D11
`
`D12
`
`"Rote Lister' 2004", Editio Cantor Verlag fur Medizin und Naturwissenschaften GmbH,
`Aufendorf, 2004, entries #20 001 and #20 002.
`
`Kubitza, D et al. "Multiple dose escalation study investigating BAY 59-7939 - an oral, direct
`factor Xa inhibitor - in healthy male subjects." Pathophysiol Haemost Thromb, vol. 33
`(Suppl. 2), 2003, p. 98, Abstract no. P0080
`
`Kubitza, D et al., "Single dose escalation study of BAY 59-7939 - an oral, direct factor Xa
`inhibitor - in healthy male subjects." Pathophysiol Haemost Thromb, vol. 33 (suppl. 2),
`2003, p. 98, Abstract no. P0081
`
`D13
`
`Fareed, J et al. "Pharmacodynamic and pharmacokinetic properties of enoxaparin." Clin
`Pharmacokinet, vol. 42, no.12, 2003, pp. 1043-1057.
`
`D14 Rowland, M and Tozer, TN. Clinical Pharmacokinetics: concepts and applications.
`Williams and Wilkins, 2005, pp. 83-105.
`
`D15 Harder, S et al, "Effects of BAY 59-7939, an innovative, oral, direct actor Xa inhibitor, on
`thrombin generation in healthy volunteers." Pathophysiol Haemost Thromb, vol. 33 (suppl.
`2), 2003, p. 97, Abstract P0078
`
`D16
`
`Perzborn, E et al. "In vitro and in vivo studies of the novel antithrombotic agent BAY 59-
`7939-an oral, direct Factor Xa inhibitor." Journal of Thrombosis and Haemostasis, vol. 3,
`2005, pp. 514-521.
`
`D16a Confirmation of online publication date of D16
`
`D17 Harder, S et al. "Effects of BAY 59-7939, an oral, direct factor Xa inhibitor, on thrombin
`generation in healthy volunteers." Blood, vol. 102, no. 11, 2003, Abstract no. 3003.
`
`D18 Ritschel, WA and Bauer-Brandl, A. Die Tablette: Handbuch der Entwicklung, Herstellung
`und Qualitatssicherung 2nd ed., Editio Canto Verlag Aulendorf, 2002, p. 1.
`
`D19
`
`Kearon, C. "Duration of venous thromboembolism prophylaxis after surgery." CHEST, vol.
`124, no. 6 (Supplement), 2003, pp. 386S-392S.
`
`D20 Derendorf, H, Granmatte, T, and Schafer, HG. "Pharmakokinetik: Einfuhrung in die
`Theorie und Relevanz fur die Arzneimitteltherapie". 2nd ed., Wissenschaftliche
`Verlagsgesellschaft mbH Stuttgart, 2002.
`
`D21 Weinz, C et al. "Metabolism and distribution of [74C]BAY 59-7939 - an oral, direct factor Xa
`inhibitor - in rat, dog and human." Drug Metabolism Reviews, vol. 36 (Suppl), 2004,
`Abstract no. 196.
`
`D22
`
`Vrijens, B and Heidbuchel, H. "Non-vitamin K antagonist oral anticoagulants:
`considerations on once-vs. twice-daily regimens and their potential impact on medication
`adherence." Europace, vol. 17, no. 4, 2015, pp. 514-523.
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`Reference
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`D23 Oberpichler-Schwenk, H. "Rivaroxaban - der erste orale Faktor-Xa-Hemmer."
`Medizinische Monatsschrift fur Pharmazeuten, vol. 31, no. 11, 2008, pp. 412-416.
`
`D24
`
`D25
`
`European Pharmacopeia. 5th ed., published 15 June 2004, Section 2.9.3 Dissolution Test
`for Solid Dosage Forms, pp. 228-230.
`
`Birkett, DJ. "Pharmacokinetics made easy", Chapter 11 "Designing dose regimens." Aust
`Prescr, vol. 19, no. 3, 1996.
`
`D25a Birkett, DJ. Pharmacokinetics Made Easy. The McGraw-Hill Companies, Inc., 2002, pp.
`20-23.
`
`D26 US 2007/0026065 Al
`
`D27 Roehrig, S et al. "Discovery of the novel antithrombotic agent BAY 59-7939, an orally
`active, direct Factor Xa inhibitor." Alfred Burger Award Symposium - Recent Advances
`towards Novel Cardiovascular Therapies, 228th ACS Meeting, 22-26 August 2004, 2004,
`Abstract No. 156.
`
`D28 UK High Court Judgment in Hospira UK Limited v. Genentech Inc., [2014] EWHC 1094
`(Pat), April 10, 2014.
`
`D29
`
`Internet printout from www.clinicaltrialsregister.eu, EudraCT Number 2004-002171-16
`dated December 29, 2015
`
`D30 Rowland, M and Tozer, TN. Clinical Pharmacokinetics: concepts and applications. 3rd ed.,
`1995, Chapter 1, pp. 1-7.
`
`031 Patrono, C et al. "Platelet-active drugs: the relationships among dose, effectiveness, and
`side effects." CHEST, vol. 119, no. 1 (suppl), 2001, pp. 39S-63S.
`
`D32 Mueck, W et al. "Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban."
`Clin Pharmacokinet, vol. 53, no. 1, 2014, pp. 1-16.
`
`D33
`
`D34
`
`D35
`
`D36
`
`Internet printout from https://clinicaltrials.gov, "Dose-ranging study of once-daily regimen of
`BAY 59- 7939 in the prevention of VTE in patients undergoing elective total hip
`replacement (ODIXaHIP-OD) dated January 11, 2016
`
`Abstract of article by Charbonnier, BA et al. "Comparison of a once daily with a twice daily
`subcutaneous low molecular weight heparin regimen in the treatment of deep vein
`thrombosis." Thromb and Haemost, vol. 79, no. 5, 1998, pp. 897-901.
`
`Turpie, AGG et al. "BAY 59-7939: an oral, direct Factor Xa inhibitor for the prevention of
`venous thromboembolism in patients after total knee replacement. A phase II dose-ranging
`study." Journal of Thrombosis and Haemostasis, vol. 3, no. 11, 2005, pp. 2479-2486.
`
`Kubitza, D et al. "Safety, pharmacodynamics, and pharmacokinetics of single doses of
`BAY 59-7939, an oral, direct factor Xa inhibitor." Clinical Pharmacology & Therapeutics,
`vol. 78, no. 4, 2005, pp. 412-421.
`
`D37 Griffin JP and O'Grady J. The Textbook of Pharmaceutical Medicine. 4th ed., BMJ Books,
`2002, pp. 225-226 & 238-239.
`
`D38 US Pharmacopeia (USP29), Chapter 1088: "In vitro and in vivo evaluation of dosage
`forms"
`
`D39 Harron, D et al. "Bopindolol: A review of its pharmacodynamic and pharmacokinetic
`properties and therapeutic efficacy." Drugs, vol. 41, no. 1, 1991, pp. 130-149.
`
`D40 Center for Drug Evaluation and Research, "Clinical Pharmacology and Biopharmaceutics
`Review(s).", Application No. 0224060rig1s000, Addenum to April 6, 2009 Review, NDA 22-
`406, Submission Date December 30, 2010.
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`Reference
`
`D41
`
`D42
`
`D43
`
`Internet printout from www.clevelandclinicmeded.com dated November 27, 2015,
`Pharmacotherapy Update, vol. VI, no. 1, January/February 2003, "Enoxaparin Clinical
`Pearl."
`
`Fareed, J et al. "Studies on the mechanism of action of BAY 59-7939 — an oral, direct
`Factor Xa inhibitor." Pathophysiol Haemost Thromb, vol. 33 (suppl2), 2003, P0077.
`
`Lieberman, HA and Lachman, L. Pharmaceutical dosage forms. Volume 1-Tablets, Marcel
`Dekker Inc., 1980, pp. 172-181.
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`D44 Mattsson, S. "Pharmaceutical binders and their function in directly compressed tablets:
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`Faculty of Pharmacy 238, Acta Universitatis Upsaliensis, Uppsala, 2000.
`
`D45 Rasenack, N and Muller, BW. "Crystal habit and tableting behavior." International Journal
`of Pharmaceutics, vol. 244, no. 1, 2002, pp. 45-57.
`
`D46 Bayer Annual Report 2015, 2015, p. 70 and p. 156.
`
`D47
`
`"Fast Facts — About XARELTO° (rivaroxaban)." Janssen Pharmaceuticals, Inc., November
`2011.
`
`D48a Summary of Product Characteristics for "Xarelto 10 mg film-coated tablets." European
`Medicines Agency, last updated July 1, 2015.
`
`D48b Summary of Product Characteristics for "Xarelto 20 mg film-coated tablets." European
`Medicines Agency, last updated May 20, 2016.
`
`D49
`
`D50
`
`D51
`
`D52
`
`D53
`
`"Highlights of Prescribing Information" and "Full Prescribing Information" for XARELTO°
`(rivaroxaban)." Janssen Pharmaceuticals, Inc., revised May 2016.
`
`Krauspe, R. "Der erste orale Faktor-Xa-lnhibitor Rivaroxaban (Xarelto®) zur
`Thromboseprophylaxe - eine neue Dimension." PZ Innovationspreis 2009, September 26,
`2009, Dusseldorf, Germany.
`
`"Thrombosen verhindern - eine Tablette kann Leben retten: Kurzbeschreibung der Institute
`und Unternehmen zu ihren nominierten Projekten Nominierte 2009." Deutscher
`Zukunftspreis, 2009.
`
`"Xarelte: Eine neue Dimension der Thromboseprophylaxe." version DE/2, Bayer Schering
`Pharma AG, May 2009.
`
`"Bayer's Xarelto® Recognised with 2010 International Prix Galien Award.", Bayer, October
`7, 2010.
`
`D54 Bayer Annual Report 2009, 2009, p. 38.
`
`D55
`
`"Deutscher Zukunftspreis 2009 fur Frank Misselwitz, Dagmar Kubitza und Elisabeth
`Perzborn." Pressemitteilung des Bundesprasidialamtes, December 2, 2009.
`
`D56
`
`European Patent Office. "Communication pursuant to Article 94(3) EPC." July 26, 2010.
`
`D57 Overview Table showing Opponents statements re half life being inherent property.
`
`D58 Overview Table showing Opponents statements re rapid-release tablet is common and
`therefore well-defined.
`
`D59
`
`"CHMP Assessment Report for Xarelto." European Medicines Ageny, Evaluation of
`Medicines for Human Use, Doc. Ref.: EMEA/543519/2008, 2008.
`
`D60 WO 2005/060940 A2
`
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`

`COHAUSZ & FLORACK
`
`Reference
`
`D61
`
`D62
`
`D63
`
`Search Results from Thomson Innovation regarding PCT-application recited in para [0031]
`of Opposed Patent
`
`Fulgraff, G and Palm D. Pharmakotherapie: Klinische Pharmakologie. 11th ed., Urban &
`Fischer Verlag Munchen, 2001, pp. 114-123.
`
`Schmutzler, R and Novotny, U. Antikoagulation in Klinik und Praxis. ComMed Basel,
`Verlagsagentur, 1999, Chapter 4, pp. 76-93.
`
`D64 Dugina, TN et al. "Receptors of the PAR family as a link between blood coagulation and
`inflammation." Biochemistry, vol. 67, no. 1, 2002, pp. 65-74.
`
`D65
`
`D66
`
`D67
`
`D68
`
`D69
`
`"Points to consider on clinical investigation of medicinal products for prophylaxis of intra-
`and post-operative venous thromboembolic risk." The European Agency for the Evaluation
`of Medicinal Products, Committee For Proprietary Medicinal Products,
`CPMP/EWP/707/98, London, June 29, 2000.
`
`European Patent Office. "Annex to Communication under Rule 71(3) EPC." November 13,
`2014.
`
`Jaehde et al. Lehrbuch der Klinischen Pharmazie. 2nd ed., Wissenschaftliche
`Verlagsgesellschaft mbH Stuttgart, 2003, Chapter 9, pp. 129-139.
`
`Pschyrembel Klinisches WOrterbuch. 258th ed., Walter de Grunyter & Co., 1997, p. 714.
`
`"Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001
`on the Community code relating to medicinal products for human use (OJ L 311,
`28.11.2001, p. 67)." November 28, 2012.
`
`D70
`
`"EU Clinical Trials Register goes live." European Medicines Agency - Science, medicines,
`health, March 22, 2011.
`
`D71 Raffaella, C and Novak, A. "Publication of Study 'EurdraCT Number 2004-002171-
`16/Sweden'." European Medicines Agency Service Desk.
`
`D72
`
`Patel, MR et al. "Rivaroxaban versus warfarin in nonvalvular atrial fibrillation." N Engl J
`Med, vol. 365, no. 10, 2011, pp. 883-891.
`
`D73 Bayer Annual Report 2011, 2011, pp. 110-111.
`
`D74
`
`D75
`
`D76
`
`The EINSTEIN Investigators. "Oral rivaroxaban for symptomatic venous
`thromboembolism." N Engl J Med, vol. 363, no. 26, 2010, pp. 2499-510.
`
`The EINSTEIN-PE Investigators. "Oral rivaroxaban for the treatment of symptomatic
`pulmonary embolism." N Engl J Med, vol. 366, no. 14, 2012, pp. 1287-1297.
`
`Prins, MH et al. "Oral rivaroxaban versus standard therapy for the treatment of
`symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE
`randomized studies." Thromb J, vol. 11, 2013, pp. 1-10.
`
`D77
`
`Linkins, LA and Weitz JI. "New Anticoagulant Therapy." Annu Rev Med, vol. 56, 2005, pp.
`63-77.
`
`D78a Aktories et al. Ailgemeine und spezielle Pharmakologie und Toxikologie. 9th ed., Elsevier
`GmbH, Munchen, 2005, pp. 72-74.
`
`D78b Aktories et al. Allgemeine und spezielle Pharmakologie und Toxikologie. 9th ed., Elsevier
`GmbH, Munchen, 2005, pp. 82-84.
`
`D79 Hauptmann, J and Sturzebecher J. "State of the art article: Synthetic inhibitors of thrombin
`and factor Xa: From Bench to bedside." Thrombosis Research, vol. 93, 1999, pp. 203-241.
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`D80a Mutschler, E et al. Mutschler Arzneimittelwirkungen. 8th ed., Wissenschaftliche
`Verlagsgesellschaft mbH Stuttgart, 2001, pp. 48-51.
`
`D8Ob Mutschler, E et al. Mutschler Arzneimittelwirkungen. 8th ed., Wissenschaftliche
`Verlagsgesellschaft mbH Stuttgart, 2001, p. 497.
`
`D81
`
`D82
`
`D83
`
`Schwarz, JA. Leitfaden Klinische Priffungen von Arzneimitteln und Medizinprodukten. 3rd
`ed., Editio Cantor Verlag fur Medizin und Naturwissenschaften GmbH, Aulendorf, 2005,
`pp. 63-65.
`
`Page, C et al. Integrated pharmacology. 2nd ed., Mosby International Ltd, 2002, pp. 210-
`211
`
`Summary of Product Characteristics for "Eliquis 2.5 mg film-coated tablets." European
`Medicines Agency, last updated January 22, 2016.
`
`D84 Meier, J et al. Biopharmazie: Theorie und Praxis der Pharmakokinetik. Georg Thieme
`Verlag Stuttgart, 1981, Chapter 11.2.2, pp. 322-325.
`
`D85
`
`D86
`
`Stapff, M. Arzneimittelstudien. 2nd ed., W. Zuckschwerdt Verlag GmbH, 2001, Chapter C5,
`pp. 48-49.
`
`Bisio, A et al. "Structural features of low-molecular-weight heparins affecting their affinity to
`antithrombin." Thromb Haemost, vol. 102, 2009, pp. 865-873.
`
`D87 Harenberg, J et al. "Update of the recommendations on biosimilar low-molecular-weight
`heparins from the Scientific Subcommittee on Control of Anticoagulation of the
`International Society on Thrombosis and Haemostasis." Journal of Thrombosis and
`Haemostasis, vol. 11, no. 7, 2013, pp. 1421-1425.
`
`Annex A
`
`Annex B
`
`Cross-reference table with list of opponents' documents D1-D45
`
`Complete list of documents D1-D87 on file
`
`Annex C
`
`Feature Analysis of granted claims
`
`(6)
`
`Of the documents cited by the opponents, documents D1, D2, and D3 were considered during
`
`examination. D1 (as Dia), D2, D9 (as 1985 edition, see D9a), D14, D16, D25 (as 2000 edition)
`
`and D27 are cited in the Opposed Patent.
`
`(7)
`
`Documents D2 and D11, D3 and D12, as well as D15 and D17 contain almost identical
`
`disclosures in their respective pairs and will be discussed hereinafter together as "D2/D11",
`
`"D3/D12" and "D15/D17".
`
`(8)
`
`Documents D8, D22, D23, 026, D28, D29, D32, D35, D36, and D40 cited by the opponents
`
`were published after the priority date of the patent and do not form prior art under Art. 54(2)
`
`or (3) EPC.
`
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`

`COHAUSZ & FLORACK
`
`C
`
`INTRODUCTORY COMMENTS
`
`(9)
`
`As set out in detail herein below, the subject matter of EP 1 845 961 B1 (hereinafter: "the
`
`Opposed Patent") fulfills the requirements of the European Patent Convention. The
`
`opponents' allegations to the contrary are not founded, properly substantiated, or in line with
`
`the case law of the Technical Boards of Appeal of the European Patent Office (EPO).
`
`Consequently, the oppositions should be rejected.
`
`C.1 Development of the claimed compound (rivaroxaban) and its once-daily dosage regimen were
`a milestone achievement in medicine
`
`(10)
`
`The opponents have cited a very large number of documents and put forth a variety of
`
`arguments and assertions, but the fact remains that the claimed dosage regimen for treating
`
`thromboembolic disorders is nowhere disclosed in or suggested by any piece of prior art.
`
`(11)
`
`The INN for 5-Chloro-N-({(5S)-2-oxo-3-14-(3-oxo-4-morpholinyl)pheny11-1,3-oxazolidin-5-yll-
`
`methyl)-2-thiophenecarboxamide, the compound recited in claim 1 of the Opposed Patent, is
`
`rivaroxaban (also referred to as BAY 59-7939 in the prior art). Rivaroxaban was first
`
`synthesized and identified by Bayer, and was subsequently jointly developed with Janssen
`
`Research & Development, LLC. It is marketed under the brand name Xarelto® by Bayer and in
`
`the US by Janssen Pharmaceuticals, Inc. (see D46, Bayer Annual Report 2015, p. 70, 2' and
`
`5th para.).
`
`(12)
`
`The dosage regimen recited in claim 1 of the Opposed Patent is characterized by the once-
`
`daily administration of rivaroxaban in the form of a rapid-release tablet for at least five
`
`consecutive days. To date, Xarelto® has been approved in the claimed dosage regimen in
`
`more than 130 countries worldwide and has been successfully launched in more than 80
`
`countries, including Australia, Canada, China, Japan, the US, and within the European Union
`
`(see D46, p. 70, 2" and 3rd para. and D47, "Fast Facts — About XARELTO®", p. 1, left col.,
`penultimate bullet point). Rivaroxaban has been approved for more indications in the area of
`
`venous and arterial thromboembolism than any of the other non-vitamin-K-dependent oral
`
`anticoagulants (see D46, p. 70, 2"d para.).
`
`(13)
`
`The European Medicines Agency (EMA) has authorized rivaroxaban as an antithrombotic
`
`agent given once daily as a rapid-release tablet for the following indications (see the SmPCs
`
`for rivaroxaban 10 mg and 20 mg, attached as D48a and D48b, respectively):
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`COHAUSZ & FLORACK
`
`1. Prevention of venous thromboembolism (VIE) in adult patients undergoing elective hip or
`knee replacement surgery (D48a, section 4.1).
`
`2. Prevention of stroke and systemic embolism in adult patients with non-valvular atrial
`fibrillation (SPAF) with one or more risk factors, such as congestive heart failure,
`hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischemic attack
`
`(D48b, section 4.1, 151 para.).
`
`3. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention
`of recurrent DVT and PE in adults (D48b, section 4.1, 2' para.).
`
`(14)
`
`Similarly, the US FDA has authorized rivaroxaban 10 mg, 15 mg, and 20 mg for the following
`indications in the claimed once-daily dosage regimen (see D49, the FDA's "Highlights of
`Prescribing Information" for Xarelto®, p. 1, sections "INDICATIONS AND USAGE" and
`
`"DOSAGE AND ADMINISTRATION"):
`
`1. To reduce the risk of stroke and systemic embolism in patients with non-valvular atrial
`
`fibrillation.
`
`2. For the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the
`
`reduction in the risk of recurrence of DVT and of PE.
`
`3. For the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip
`
`replacement surgery.
`
`(15)
`
`In addition to the currently approved indications, the use of rivaroxaban in the claimed dosage
`regimen is also being investigated in a broad range of other thromboembolic disorders. The
`extensive program of clinical trials evaluating rivaroxaban in the authorized indications as well
`as other potential indications makes it the most studied and published oral factor Xa inhibitor
`in the world (D47, p. 1, left col., 2' diamond-shaped bullet point).
`
`(16) More than 20 million Xarelto -prescriptions have been written in the US alone to treat or help
`reduce the risk of DVT and PE blood clots and strokes. In fact, Xarelto® is now the most
`prescribed blood thinner in its class in the US (https://www.xarelto-us.com). With worldwide
`annual sales of 2.252 billion EUR in 2015, Xarelto® has blockbuster status (see D46, p. 156,
`
`Table 3.13.3).
`
`(17)
`
`Thromboembolic disorders are the most frequent cause of morbidity and mortality in most
`industrialized countries (Opposed Patent, para. [0004]). In Europe, more people die of venous
`thromboembolism than of breast cancer, prostate cancer, AIDS, and car accidents together.
`Without thrombosis prophylaxis, up to 60% of patients having undergone hip- or knee
`
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`

`COHAUSZ & FLORACK
`
`replacement surgery develop a thrombosis (see D50, Statement of Prof. Dr. med. Krause, p. 2,
`
`1" para. and Opposed Patent, table in para. [0018]). Left untreated, blood clots can detach
`
`from existing thrombi and travel via the circulation to the lung causing pulmonary embolism.
`
`Here, blood clots in the lung block oxygen supply, which can cause acute right heart failure
`
`and death, or chronically lead to right heart failure and chronic thromboembolic pulmonary
`
`hypertension