Skinny labels and 2nd medical use in Europe – update and overview
Dr. Niels Hölder, LL.M. Dr. Esther Pfaff, LL.M. Attorney at Law | Partner Counsel | Attorney at Law | WIPO Mediator Certified Specialist IP Lawyer
1 Skinny labels and 2nd medical use in Europe
Infringement of use claims: direct, indirect or both?
Ribavirin, Pregabalin & Co: European Case Law
Off label use: Who is responsible?
Rebate agreements: What can the generics do?
2 Introduction – Enforcement of 2nd Medical Use Patents
Art. 54: Novelty of known substance for new specific use in a therapeutic method
Art. 53: No patents for therapeutic methods practiced on the body
3 Life Science IP Seminar 2017 Introduction – Enforcement of 2nd Medical Use Patents
• BGH (Benzolsulfonylharnstoff): Use Claim – claim may cover non-patentable matter as long as it is not limited to it – Use claim (also) encompasses industrial activities (customization); – restrictions of doctors irrelevant – Use of compound X for treating disease Y
• EPO (G 1/83): Manufacturing Use Claim – claim must not cover therapeutic activity – Use claim must be limited to industrial activities – Not admissible anymore since G 2/08 – Old cases exist until 2035 (considering SPCs) – Use of compound X for making a medicament for the treatment of disease Y
• EPC 2000: Purpose Limited Compound Claim – Use need not be limited to industrial activity – Claim may restrict doctors – Substance X for use in the treatment of disease Y
4 Life Science IP Seminar 2017 Introduction – Enforcement of 2nd Medical Use Patents
Background Art. 52 (4) EPC (old version)
Methods for (…) therapy (…) practised on the (…) body shall not be regarded as inventions which are susceptible of industrial application (…)
Use of the subject matter of the invention
Enlarged Board of Appeal Federal Court of Justice Swiss-type Claim German use claim
industrial uses industrial uses
non-industrial uses non-industrial uses (in particular therapeutic method) (in particular therapeutic method)
Purpose-limited compound claim?
5 Life Science IP Seminar 2017 Introduction – Enforcement of 2nd Medical Use Patents
Enlarged Board of Appeal 19 February 2010 (G 2/08490 Official Journal EPO 10/2010):
“the EPC now allows use-related product claims directed to the substance itself whereas G 1/83 allowed claims to the use of a substance for the manufacture of the drug for a therapeutic indication ("Swiss-type claims"). It appears that the rights conferred on the patentee by the claim category under Article 54(5) EPC are likely broader, and could, in particular, lead to possible restrictions on the freedom of medical practitioners to prescribe or administer generics.”
6 Life Science IP Seminar 2017 Introduction – Enforcement of 2nd Medical Use Patents
The subject matter of a claim directed to the use of a substance for the treatment of a disease is the suitability of the substance for a specific medical purpose and, thus, ultimately an intrinsic characteristic of the substance (…). This corresponds in substance to a purpose-limited substance protection as provided for by (…) Art. 54 V EPC (…). This applies regardless of whether the patent claim is, according to its wording, directed to a purpose-limited compound substance protection, a use of the medicament or its customization for a specific medical purpose.” (BGH, GRUR 2016, 921, margin no. 83 – Pemetrexed)
7 Life Science IP Seminar 2017 Infringement Via Manifest Customization
In Principle: When is a Patent Infringed?
It is prohibited to (i) make, offer, put on the market, use, import or possess a patented product and to (ii) use a patented process (Sec. 9 GPA)
Realisation of all claim Preparatory Stage features
• No direct infringement • Actionable threat of infringement? Infringement • indirect infringemen?
8 Life Science IP Seminar 2017 Infringement Via Manifest Customization
Particularity applying only to Use Claims
Evidently preparing for protected use Realisation of all claim (formulation, packaging, etc.) features
Infringement Infringement
9 Life Science IP Seminar 2017 Manifest Customization - how?
Examples for „evident preparation“
Formulation Packaging/PIL
• Formulation of the medical • Information in Patient preparation according to Information Leaflet (PIL) or on requirements for a specific use the package, with explicit • E.g. formulation for a certain reference to dosage regime etc. – diseases/symptoms/dosag es – patient groups or other specific uses • Advertisements/Brochures not accompanying the product are irrelevant (HRC Düsseldorf, January 31, 2013, I-2 U 54/11 ”Cistus Incanus“)!
10 Life Science IP Seminar 2017 Infringement Via Manifest Customization Use Claim VS. Label Claim: The Ribavirin Decision (RC Düsseldorf, February 24, 2004, 4a O 12/03)
EP 903 148, Claim 1
1. Use of Ribavirin 2. for making a pharmaceutical composition 3. for treating a chronic Hepatitis-C 4. wherein patient did not respond to interferone-α 5. patient has a viral load of greater than 2 million copies/ml
RC Düsseldorf, GRUR-RR 2004, 193 - Ribavirin
11 Life Science IP Seminar 2017 Infringement Via Manifest Customization
Defendant's package leaflet
For the treatment of patients with chronic Hepatitis C who have not responded to treatments with alpha-interferon on account of contra-interception or intolerance.
12 Life Science IP Seminar 2017 Infringement Via Manifest Customization
Scope of Protection: Realisation of purpose-related features
Ribavirin for treating:
Non- responders Non- + responders Viral load
Use Label Claim
No Infringement!
13 Life Science IP Seminar 2017 Infringement Via Manifest Customization
An example for an infringing case would be:
Non- Non- responders responders with viral load Use Label Claim
14 Life Science IP Seminar 2017 Infringement Via Manifest Customization
Ribavirin Main Findings
• Treatment of "non-responders" known in the art • specific use (patient population) distinguishing claimed use from prior art not be found in the package leaflet. • The size of the patient population falling under the feature (more than 50 %) does not matter– otherwise protection would not be purpose-limited anymore • No direct infringement • No indirect infringement (doubtful) • No remedies (such as warning notice)
15 Life Science IP Seminar 2017 Introduction – Enforcement of 2nd Medical Use Patents
The problem of “Skinny Labelling“ (Art. 11 EC/2004/27)
• European Medicines legislation allows generic applicants to carve out indications/dosage forms from the PIL which are protected by a patent.
• No visible manifest customization for the protected use
• The situation is further exacerbated by: • Prescriptions not referring to a specific indication • Governments encourage prescriptions to be written by INN and not by brand • Pharmacists often have to dispense the cheapest possible medicine (in Germany e.g. § 129 SGB V)
16 Life Science IP Seminar 2017 Off-label use: Direct or Indirect Infringement
Manufacturing Formulation/PIL Prescription Pharmacy Sale Intake
Direct or Indirect Infringement by the manufacturer?
• Rationale of indirect infringement – Protection against acts leading to infringements – Protection of combination products involving, e.g. spare parts
• Requirements for indirect infringements: Offer or delivery in Germany of means relating to an essential element of the invention if supplier knows or if it is obvious that his customer intends to use the means for using the invention in Germany without authorization.
17 Life Science IP Seminar 2017 Off-Label Use – the „Doctor Problem“
Offlabel Prescription: Does the doctor directly infringe?
Manufacturing Formulation/PIL Prescription Pharmacy Sale Intake
• Swiss-type Use Claim: Use of compound X for the manufacture of a medicament for use in the treatment of disease Y Arguably not – doctor does not manufacture a medicament.
• German-type Use Claim: Use of substance X for treating disease Y Arguably so – doctor uses the compound for treating the disase.
• Purpose limited compound claim: X for use in the treatment of Y Arguably so – doctor uses the claimed substance for the claimed purpose – use of a patented product is a prohibited activity.
18 Life Science IP Seminar 2017 Off-Label Use : Gap of Protection
Gap of Protection
Protection limited to products that are
(i) directly and (ii) specifically customized / adapted for the invetive use
No protection against off-label use and skinny labelling?
19 Life Science IP Seminar 2017 Direct Infringement Via Manifest Customization
Manufacturing Formulation/PIL Prescription Pharmacy Sale Intake
Previous legal advice :
• To avoid an infringement lawsuit for direct infringement, all information accompanying the product should be checked very carefully
• If a recommendation for the „specific use“ as defined by the patent can be derived from this information, the patent will be infringed
• With these guidelines, it seemed difficult to bring a case for off- label use
20 Life Science IP Seminar 2017
Direct Infringement Via Manifest Customization
Manufacturing Formulation/PIL Prescription Pharmacy Sale Intake
It was all peaceful and quiet in the world of 2nd medical use patent enforcement.
Until…
21 Life Science IP Seminar 2017 Off-Label Use – Overview on European case law
Pregabalin et al. – a litigation wave hits the European courts
22 Life Science IP Seminar 2017 Off-Label Use – Update on European case law
Pregabalin et al. – a litigation wave hits the European courts:
• Warner-Lambert v. various generics (Pregabalin)
• Novartis v. Sun (Zoledronic acid) • MSD/Teva (Ribavirin)
• Warner-Lambert v. Generics (Pregabalin), Court of Appeal PI proceedings
• Warner-Lambert v. Hexal et al. (Pregabalin)
23 Life Science IP Seminar 2017 Off-Label Use – UK Case Law
Warner-Lambert vs. Actavis (High Court of Justice, January 21, 2015, HC-2014-001795)
• Warner-Lambert („WL“; Pfizer group) markets pregabalin (Lyrica®) for epilepsy, generalised anxiety disorder and neuropathic pain • WL’s patent claims „pregabalin … for the preparation of a pharmaceutical composition for treating pain (claim 1), in particular neuropathic pain (claim 3)“ • 50% of sales related to neuropathic pain • Generics applied for “skinny label“ for pregabalin for the indications of epilepsy and generalised anxiety disorder • WL requested provisional and permanent injunction specifying various measures to be taken by the generics
24 Life Science IP Seminar 2017 Off-Label Use – UK Case Law
High Court (Justice Arnold): • Injunction refused • Decisive criteria : Subjective intention to infringe • Relevant state of mind: doctor, pharmacist, and patient • Doctor knows the condition, but not the specific product (original/generic) • Pharmacist knows the product, but not the condition • Patient’s intention limited to doing what the doctor says • Foreseeability of protected us not sufficient • No pharmaceutical composition is „prepared“ by wholesaler or pharmacist • No indirect infringement by prescription • Indirect infringment requires possible direct infringement further down the supply chain • Arnold „proposal“: Prescriptions should be made under brand name to permit enforcement of 2nd medical use patents; legislator should change regulatory requirements – not very helpful
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Off-Label Use – UK Case Law
Arnold overruled by CoA on May 28, 2015/13 October 2016 • Relevant claims found invalid; nonetheless comments on infringement (obiter) • „issue (…) is, and remains, one of great difficulty” • “attempt to strike the right balance”; considering • German "only packaging will do” approach - practical, but inadequate • Spanish “encouragement” approach (e.g. MA) – wider, but still narrow • French “has the generic done enough to prevent infringing use” approach - • Danish “labelling” approach technical - too technical • Dutch “act of manufacture” approach – open • EPO TBA “limited to product of process” approach – similar to German approach • Secretary of State of Health: policy – not permeating patent law • “spectrum of different approaches” • Packaging only? Process step or mental element? • Aiming/Targeting? • Encouragement? • Discouragement required?
26 Life Science IP Seminar 2017 Off-Label Use – UK Case Law
Arnoled overruled by CoA on May 28, 2015/13 October 2016 • The term „for“ in the claim relates to the ultimate intentional use rather than to a process step; • „making pregabalin for patients to whom it will be intentionally administered for treating pain” • Link between manufacture and ultimate intentional use • Forseeability? • Intention? • Manufacturer knowing of such use uses the invention like a manufacturer actively desiring it • Intentional use does not require that individual persons (doctor/pharmacist/patient) know about such use in specific cases • Direct infringement if manufacturer • can reasonably foresee ultimate use for the patented indication • Does not take all reasonable measures to prevent such use
27 Life Science IP Seminar 2017 Off-Label Use – UK Case Law
Which counter-measures are then required by generics?
• The court found sufficient that Actavis notified the superintendent pharmacists that its product should not be used for the patented indication
• The court found unnecessary: • Notifying every Clinical Commission Group, Health Board and Social Care Trust, ensuring that the guidance was consistent all over the UK • Briefing ist sales team and telemarketing team accordingly • Emphasising in a number of trade publications that its product should not be used for the patented indication
28 Life Science IP Seminar 2017 Off-Label Use – UK Case Law
UK counsels currently recommend:
• Delete information on the patented indication as far as possible
• Notify pharmacists
• Notify procurement bodies
• Ensure that a bid in a tender for supply of the drug clearly excludes the patented indication
• Notify sales team to ensure compliance
29 Life Science IP Seminar 2017 Off-Label Use – NL Case Law
Novartis vs. Sun
• Novartis‘ patent claimed the use of zoledronic acidin the preparation of a medicament for the treatment of osteoporosis in a specific dosage range, form and regime • Sun marketed its generic under skinny label – only indication for Paget‘s disease in PIL • Rare Condition, in 97% of cases medicine will be actually used to treat Osteoporosis • Sun won a tender not distinguishing between Paget’s disease or osteoporosis • The Hague District Court refused PI – no manufacture of the product
30 Life Science IP Seminar 2017 Off-Label Use – NL Case Law
Decision of Court of Appeal (PI proceedings)
• Generic manufacturer should have been aware of infringing use and should have done more to prevent it
• Should have known: Amount of sales not attributable to Paget‘s disease Health insurer made Sun its preferred supplier for all indications • Should have done more: Should not have registered for tender with health insurer, not absolved because conditional tendering is legally impossible! Notifications to wholesalers, pharmacists, etc. were not sufficient
• Conclusion as well: Call for the legislator to harmonize drug and patent law
31 Life Science IP Seminar 2017 Off-Label Use – NL Case Law
PI Proceedings: Indirect infringement confirmed • Patent claims purpose-limited process rather than purpose limited product • Interim decision: indirect infringement of a Swiss Type claim not legally possible • Referral to the Supreme Court, judgment handed down on April 14, 2017 • Supreme Court confirmed Court of Appeal: • Indirect infringement legally possible – no need to align with District Court • Carve out itself not sufficient to avoid liability • It is up to the party to show what it has done to prevent infringement • Measures by a generic do not have to prevent infringement entirely but should make use more difficult
32 Life Science IP Seminar 2017 Off-Label Use – NL Case Law
• Main Proceedings: Direct infringement confirmed • Hague District Court, Judgment of April 5, 2017 • Sun knew/could foresee that its product will be used in the Netherlands for the treatment of osteoporosis. • MA had been obtained for both the patented and the non- patented indication • Medicinal products are prescribed without mentioning the indication • No carve-out in the online versions of the SmPC • Sun has unconditionally (without limitation to off-patent indications) participated in the tender • Sun should have reduced the volume of its sales • Sun had not made sufficient effort to prevent infringing use What is „sufficient effort“?
33 Life Science IP Seminar 2017 Off-Label Use – ES Case Law
Decision of Court of Appeal Barcelona, July 5, 2016
• Warner-Lambert filed for a provisional injunction against generic companies; their only counter-measure against infringement had been a „skinny-label“ • On first instance the provisional measure was rejected, the skinny-label was considered a sufficient safeguard
• On appeal, the court ordered the defendants
„to inform the persons and bodies to whom they have offered their generic medicinal products and in particular to those acquiring the said medicinal products, that, while the patent is in force, such medicinal products must not be prescribed or dispensed for, and to refrain from supplying the aforementioned medicinal products if there is reasonable evidence that their product will be used for [protected indication]“
34 Life Science IP Seminar 2017 Off-Label Use – DK Case Law
Maritime and Commercial High Court, Judgment dated June 25, 2015
• Warner-Lambert v Krka and (lots of) others
• WL requested Pis against Krka and each of the 220 individually named pharmacies in Denmark. • Pharmacists are required to label the product with the condition for which the medicine was to be taken • Pharmacists were found to directly infringe and were injuncted • In contrast, the request to order Krka to ensure that the pharmaceutical be neither distributed or dispensed for pain treatment was rejected for not being sufficiently clear to be enforced
35 Life Science IP Seminar 2017 Off-Label Use – European Case Law
Summary
• More scope for originators to take action where it is foreseeable that a generic will be used for a patented indication
• Skinny label is not enough effort to avoid patent infringement
• Cases related only to Swiss type claims, remains to be seen how courts will handle EPC 2000 second medical use claims
• Call for the legislator to align pharmaceutical law to support the enforcement of 2nd Medical Use patents
36 Life Science IP Seminar 2017 Off-Label Use – German Case Law
Germany - Parallel PI proceedings Warner-Lambert vs. Hexal et al. (RC Hamburg, Decision of April 2, 2015, 327 O 67/15)
• Same drug, same patent, different defendants
• Warner-Lambert filed for a PI against conclusion of discount agreements by defendants with insurance companies without any restriction to the patented indication
• Injunctive relief requested only when offer by health insurance is unconditional and generic did not notify insurer that it would not supply for use for the patented indication etc.
37 Life Science IP Seminar 2017 Off-Label Use – German Case Law
Decision of the RC Hamburg
• PI was granted, no main action has been filed
• unconditional supply agreements with an insurance company indirect infringement
• No manifest customization via PIL needed
• The manufacture as such for use for the protected indication shall be a manifest customization (express deviation from “Ribavirin“)
• Pharmaceutical law such as provision on “skinny labelling“ and legal constraints to the pharmacist to sell the cheapest drug etc. shall not be ranked higher than patent law
Criticism
Manufacture as such cannot be „manifest customization“ because at the time of manufacture, actual use of individual unit is not foreeable
If manufacture was customization, patent would be directly infringed rather than indirectly.
38 Life Science IP Seminar 2017 Off-label use: German Case Law Higher Regional Court Düsseldorf (HRC)
Manufacturing Formulation/PIL Prescription Pharmacy Sale Intake
HRC Düsseldorf extends possible scenarios for direct infringement (decision of 5 May 2017 – I-2 W 5/17)
• According to FCJ case law, the subject matter of a German-type use claim is the suitability of the compound for the claimed use, i.e. an intrinsic characteristic of the substance (FCJ, Arzneimittelgebrauchs- muster) • Use claim has the same scope of protection like a purpose limited compound claim • Purpose-limited compound claims protect i.a. against manufacturing, offering and marketing for the claimed use • Customization not required if purpose otherwise facilitated • The same applies to Swiss-type claims
39 Life Science IP Seminar 2017
Off-label use: German Case Law Higher Regional Court Düsseldorf (HRC)
“Due to the purpose-limited compound protection a direct use of the purpose-limited compound patent requires that the required therapeutic purpose, to which the protection is limited, is an innate characteristic of the marketed product.
This can be achieved by manifest customization of the medicinal composition for its sale (…) such that its use for the protected therapeutic use is foreseeable (…).
As according to the FCJ the protection of a Swiss-type claim is the objective suitability of the medicament for the use according to the patent, the supplier’s liability is also possible without manifest customization (….), namely provided that (…) firstly, that the product is suitable for the claimed use and secondly, that the supplier makes use of circumstances which ensure similar to a manifest customization that the product will be used according to the patent.”
Decision of the Higher Regional Court Düsseldorf, I -2 W 5/17 of 5 May 2017
40 Life Science IP Seminar 2017 Off-label use: German Case Law
Manufacturing Formulation/PIL Prescription Pharmacy Sale Intake
2 Ways of Direct Infringement
1. Manifestly customized drug
2. Non-customized drug sold for the protected indication
• It is sufficient if the product is suitable by design AND • If the manufacturer takes advantage of circumstances which facilitate the protected use in the same way as a manifest customization
41 Life Science IP Seminar 2017 Off-label use: German Case Law
Criticism
• Only because the suitability of a product for a purpose is the subject matter of a use claim regardless of its wording (German/Swiss/purpose limited), the scope of protection need not necessarily be the same • Swiss-type claims were intended to have a scope of protection which is narrower as compared to a purpose- limited compound claim in order to exclude certain activities which the purpose-limited compound claim does not/need not exclude • FCJ did not intend to rule on the scope of protection in its Pemetrexed decision • HRC Düsseldorf does not clarify whether and how the generics can ensure that their products are used for non- patent uses only
42 Life Science IP Seminar 2017 Off-label use: German Case Law
Manufacturing Formulation/PIL Prescription Pharmacy Sale Intake
Current legal advice with regard to direct infringement: • It is difficult for a generic company marketing a product with a protected 2nd indication to entirely exclude the risk of infringement
• Tenders by health insurances for rebate schemes can only be entered into with safeguards towards the protected indication
• However: It is not clear whether such safeguards can really avoid an infringement. The product is suitable for the protected indication and the manufacturer may well know of its use from sales figures!
• Düsseldorf assumes direct infringement where the supplier takes advantage of circumstances leading to infringing use.
Warning letters/warning notices or comparable measures may be considered by the courts to exclude taking advantage
43 Life Science IP Seminar 2017
Battlefield shifts to the regulation of tender proceedings of health insurances!
44 Life Science IP Seminar 2017 Battlefield shifts to the regulation of tender proceedings of health insurances
• European administrative courts/board/Procurement chambers equally face a litigation wave at the moment
• Innovative drug manufacturers try e.g. to block „open house tenders“ including a protected indication by sueing health insurance companies (generic companies are not a party to these proceedings)
• Health insurance companies currently test out various alternatives to draft their tenders
• A regulatory strategy vis-à-vis procurement is a vital part of every generic defense strategy!
45 Life Science IP Seminar 2017 Thank you for your attention!
Dr. Esther Pfaff [email protected] Counsel | Attorney at Law | WIPO Mediator
46 Life Science IP Seminar 2017