Bertrand Gellie, Director Directorate General "Operations" European Patent Office Munich, Germany

"Experimental data - the standard to be met to support patentability of a potential biological pharmaceutical"Views of the European Patent Office(EPO) Bertrand Gellie, Director Directorate General "Operations" European Patent Office Munich, Germany Hyderabad, 14th October 2011

Roadmap Requirements for pharmacological data at the EPO with respect to: • sufficiency of disclosure • inventive step • industrial application • in the framework of patenting • Chemical products per se (with a pharmaceutical use, inter alia) • Processes for manufacturing them • First medical uses • Second or further medical uses (methods of treatment excluded)

Different types of pharmaceutical inventions • Chemical products per se • with a pharmaceutical use, inter alia • with a pharmaceutical use, only • Process for making pharmaceutical products • First medical use • Second or further medical use (methods of treatment excluded) • new use (key parameter: pharmacology) • known use but new administration form & posology (key parameter: galenics & pharmacokinetics) • known use but new dosage regime (key parameter: pharmacodynamics) • known use but new group of patients (key parameter: pharmacogenomics)

Foreword / Basic principles applied The EPO board of appeals in T 491/08 (October 2010) stated that • "there are intrinsic difficulties for a compound to be officially certified as a drug" • "many years of experimental tests and high developmental costs" and concluded that • "the patent system does not require absolute proof that the compound is approved as a drug before it may be claimed as such" however, • "the patent application must provide some information in the form of, for example, experimental tests, to the effect that the claimed compound, administered as stated in the claims, has a direct effect on a metabolic mechanism specifically involved in the disease" • "this mechanism must be either known from the prior art or demonstrated in the application per se" need of a directly or indirectly shown pharmacological activity and of a therapeutic indication

Foreword/ principles applied: When? T 491/08further teaches: • Once this evidence is available from the patent application, • then post-published evidence may be taken into account, • but only to back up the findings in the patent application in relation to the use of the ingredient as a pharmaceutical • not in itself to establish sufficiency of disclosure (referring to T 609/02) later submission of pharmaceutical data: YES ! but under conditions and only for I.S., not for sufficiency

Foreword/ principles applied: How? Presumption of sufficient disclosure T 491/08: " A presumption exists that, in general, a patent application relates to an invention which is disclosed in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art. The weight of arguments and evidence required to rebut this presumption depends on its strength. A strong presumption requires more substantial arguments and evidence than a weak one (following T 63/06). " burden of proof on the examiner

Chemical products per se (with pharmaceutical use) 1/10 • Claims pertaining to products per se are highly desirable since they confer absolute protection, independent of the alleged use of the products • Two situations: • the products have several uses among which a pharmaceutical use • the products have only a pharmaceutical use

Chemical products per se (with pharmaceutical use) 2/10 • If the products have only a pharmaceutical use or if the latter is preponderant in case of multiple uses: • the problem-solution approach used for assessing inventive step requires the alleged function to be "credible" i.e. to answer positively two questions (T 939/92 AgrEvo "Triazoles") • is the problem credibly solved by the invention? • is it solved for the whole ambit of the claim (which can cover thousands of compounds)? • whether the problem - the provision of a therapeutic effect - is solved, is a case by case matter • the necessary biological data depends on: • the breadth of the claims • the existence of common structural features between the different subgroups • the intrinsic strength of the molecular assembly constituting the core of the invention • the question of the support for & sufficiency of the biological data can then be other issues at the EPO • they are, however, to be considered separately

Chemical products per se (with pharmaceutical use) 3/10 • If the products have (an)other use(s) and the pharmaceutical use is NOT preponderant • inventive merit of the products may be recognised based on the inventive resolution of a non-pharmaceutical technical problem • then the question of the support for the biological data is in general not an issue at the EPO

Chemical products per se (with pharmaceutical use) 4/10 Case #1:new compounds belonging to a known class and exhibiting the same therapeutic effect as the rest of the class: • Is the problem solved? • This is mainly checked for the example compounds and the required level of evidence is the minimum necessary to be technically convincing • in that situation, the checking is a mere confirmation of general expectations • the "minimum" data mainly depends on technical considerations and may be possibly influenced by specific data to be found in the prior art • Is the problem solved by all compounds? • The probability that it is so, is high in this case • but still, it must be checked • Was the solution obvious? • the compounds are likely to experience serious difficulties with respect to obviousness as they behave exactly as the person skilled in the art would have expected them to • only if they exhibit a structural difference with the vicinal homologues, causing a slight but significant difference in their therapeutic profile, they might be presented as an alternative to existing solutions

Chemical products per se (with pharmaceutical use) 5/10 Case#2: new compounds close to structural homologues but exhibiting a different therapeutic profile: • Is the problem solved? • the behaviour of the new compounds being unexpected, it is then essential to check carefully the presence of this unexpected character for each example • the required level of biological evidence for this is not different from the previous situation, only the extent of the check is broader • no easy generalisation is possible • still, certain indications such as therapeutic window or toxicological data are NOT required • Is the problem solved for all compounds? • the EPO examiners are - in such a case of alleged exception - more demanding as to the evidence that all or most of the claimed compounds exhibit the new therapeutic use • this demand focuses, however, more on the generalisation of the phenomenon than on an accumulation of redundant evidence for a limited amount of compounds only • Was the solution obvious? • the comparison must be made with other compounds solving the same therapeutic problem hence in general NOT with the closest structural homologues in this case • the distance they exhibit with respect to their homologues exhibiting another effect is therefore not very relevant although it speaks in favour of an unexpected effect • the fact that the compounds solve the problem for the whole ambit of the claim is, this time, not detrimental to their obviousness credibility of generalisation distribution of examples

Chemical products per se (with pharmaceutical use) 6/10 Case #3: new compounds structurally different from their closest homologues, exhibiting a therapeutic effect for some relevant parameter equal to or higher than with existing drugs • Is the problem solved? • the behaviour of the new compounds being unexpected, it is then again essential to check carefully the reality of this for each example • required level of experimental evidence same as in the previous situation • all example products must credibly solve the problem, independent of the fact that the prior art - in terms of structure or activity - is remote • Is the problem solved for all compounds? • the EPO examiners are - in such a case of alleged exception - demanding as to the evidence that all or most of the claimed compounds exhibit the new therapeutic use • this demand is, however, more on the credibility of generalisation than on an accumulation of redundant experimental evidence • the prior art being remote, accepting a generalisation commensurate to the scientific input made is logical • Was the solution obvious? • In general NOT obvious since the skilled person would not have expected these compounds to behave as evidenced and, possibly, to a such a high degree intellectual demonstration possible objective quality of innovation counts

Chemical products per se (with pharmaceutical use) 7/10 Time for submitting (biological) evidence relevant to inventive step • The most efficient evidence is that filed with the originally filed patent application • A mere statement without ANYproper experimental data that the products exhibit the therapeutic activity which is at stake does not suffice • this deficiency cannot be cured by later filed evidence • In case of a redefinition of the problem rendered necessary by the pressure exerted by the prior art resulting in a less ambitious problem to be solved, a supplementary therapeutic effect can be put forward and demonstrated in a later submission • however, it must be unambiguouslymentioned in the description as originally filed or be directly and unambiguously deducible from it, in connection with the main broader therapeutic problem which could not be maintained as the problem to be solved • T 1329/04 is even more strict (requiring "plausible" instead of "credible") but still an isolated decision (speculative biotech invention; contra T 433/05, T1396/06 ...)

Chemical products per se (with pharmaceutical use) 8/10 Sufficiency of disclosure & industrial application • The invention must be reproducible by the skilled person, without undue burden for him/her • In the case of new chemical products, the requirement of sufficiency must be met essentially with respect to the synthesis of the product • the requirement is applied strictly in the case of products exhibiting a particular new structure • particular attention is given to polymorphs (but most of them fail already because of inventive step) • analogous syntheses are, however, submitted to less strictness • but indications which have their place solely in an application of marketing authorization such as the therapeutic window or toxicological data are NOT required experimental parametric identification

Chemical products per se (with pharmaceutical use) 9/10 Sufficiency of disclosure & industrial application • The core of the invention being the compounds per se and not their use, sufficiency of disclosure with respect to experimental data is not a crucial issue • The breadth of claims for new chemical products is not regulated at the EPO under "sufficiency of disclosure", neither is it under "clarity" ("AgrEvo", T939/92) • Insufficiency can nevertheless become an issue for products per se ifthere are serious doubts about their real structure or the possibility of obtaining or separating them • As reminded by decision T 1437/07 the requirements of sufficiency of disclosure are identical for a prior art document and a patent. • Chemical products can be made by industry: industrial application is therefore not an issue • since EPC 2000, methods of therapy are no longer regarded as lacking industrial application but are excluded by mere convention (Art. 53(c)) and this has an effect on pharmaceutical products and pharmaceutical uses claims

Chemical products per se (with pharmaceutical use)10/10 Conclusions in the case of chemical products per se claims • At the EPO, the standard to be met by experimental data to support inventive step of a biological pharmaceutical which is a NEW chemical product per se is • dictated by the problem-solution approach • rarely dependent on the closest prior art used for assessing inventive step • the minimum necessary for technically demonstrating the existence of the relevant therapeutic effect corresponding to the technical problem to be solved and for allowing a proper comparison to be made with the closest prior art • In addition, more than the abundance of the submitted experimental data, the relevance of it for the assessment of the inventive step is ofimportance • The EPO does not systematically require from applicants a defined standard "package" for supporting experimental data • The European Patent convention (EPC) does not have any specific provision in this respect • the examination is made "case by case" • The EPO leaves the amount and nature of experimental data in the applicants' hands • Applicants bear all the consequences in case of insufficiency of their supporting experimental data • for non essential & secondary aspects (however, connected to the main core of the invention), this data can be filed later, during examining proceedings • Sufficiency of disclosure & industrial application are in general not an issue in that case

Processes for making chemical products per se (with pharmaceutical use) • Experimental data as a support for patentability of processes for the manufacture of a biological pharmaceutical can be an issue at the EPO • It happens rather seldom and mainly when the technical steps of the process influence the therapeutic properties of the final products such as bioavailability • the necessary data highly depends on the case • no systematic full evidence is required at filing date • submission after the filing is admissible as long as it merely consists of an "expansion" of originally filed data • In case of a process for producing amorphous form or polymorphs of known (or unknown) pharmaceutical products or new co-crystals thereof, the criterion of sufficiency of disclosure is often a critical issue • No general rule as to how to meet the latter • It is essentially case dependent • Industrial application absolutely not an issue

First medical use • Claims to a first medical use can impart a parallel life, sometimes even a new life, to a chemical product known per se, having so far only a non-therapeutic use • However, they are frequently filed nowadays at the same time as product per se claims • At the EPO, first medical use claims are an exception to the general rule of not granting protection to "products bound to a use" • These claims, however, intend to protect a USE and not a product, even if their format could give the impression that they are product claims • The use protects any industrial involvement of a molecule for providing a drug for a pharmaceutical use, in particular for the manufacture of a medicament in all its aspects • The use in any case DOES NOT cover a method of therapeutic treatment

First medical use • The core of the invention is no longer the product(s) but the functional relationship between the product(s) and a therapeutic use • Accordingly, the patentability revolves more around the reality of the use than around the extent of the class of products concerned • The EPO examiners are demanding with respect to the pharmacological data for such inventions • BUT according to established case law of the Boards of Appeal (e.g. decision T 1001/01 of 11 October 2007) the Applicants are NOT required to provide clinical data obtained in humans at the filing date of the application • Data must be sufficient to make credible the therapeutic activity • T 809/07: no guarantee an invention can be carried out if the patent affords the skilled person no clue as to how he can achieve this aim not only for the examples but also outside for the claimed subject-matter without an undue burden of research • Data must be sufficient to demonstrate the inventive step • In T 1329/04 the Board also stated that as to the quality of the evidence, "absolute proof" of the achievement of an effect is NOT required for the effect to be "credible" or "plausible" • The EPO examiners are less demanding as to the generalisation of the invention to the whole class of products involved, since the invention is in the use • Experimental data only necessary to make the function credible

First medical use • The molecule being proposed for the first time for use in the pharmaceutical field, the claim covering this use can be either broad or specific • If it is broad it covers any form of involvement in the manufacture of a medicament in general • Justification of this broad coverage: the opening of a series of therapeutic uses and new domains for future further innovations by the innovatormust be rewarded according to European patent philosophy • Sufficiency of disclosure is already met if one therapeutic indication is convincingly shown • If it is limited, it covers any form of involvement in the manufacture of a medicament for treating a specific disease or group of diseases • Such a claim is seemingly more limited but may be interpreted as also covering any other pharmaceutical use in certain European countries • Sufficiency of disclosure must be shown on that very therapeutic application

First medical use In the case of a broad first medical use in the form: • "Product X for use as a medicament" • "Product X for a pharmaceutical use" • the support for the claim must be that at least one therapeutic use is disclosed and supported in the patent application as originally filed • this supposes: • the indication of at least one pharmacological effect togetherwith • at least one indication of a therapeutic indication deriving from the former is enough

First medical use In the case of a broad first medical use in the form: • "Product X for use as a medicament" • "Product X for a pharmaceutical use" • the pharmacological effect must be supported by convincing experimental data carried out either • on cell cultures or immobilized biological markers/receptors carried out in vitro or in silico which are regarded by the skilled person in the field as reliable evidence tools for illustrating said effect in vivo • or on animal models regarded as appropriate for reasonably inferring the possibility of a treatment of human beings • the mere demonstration of the ability of a product to bind with a biological receptor is not enough if the skilled person can not identify the corresponding pharmacological effect

First medical use In the case of a broad first medical use in the form: • "Product X for use as a medicament" • "Product X for a pharmaceutical use" • the therapeutic use can be either merely mentioned if it is obvious from the pharmacological effect(s) or it can be illustrated by data • the mere indication of pharmacological data does not suffice if the skilled person is unable to make the link with a disease which can be treated, hence with the therapeutic use • T 241/95 (OJ 2001, 103) "selective occupation of a hormone receptor not to be considered as a therapeutic application; discovery that a substance selectively binds a (serotonin) receptor, even if representing an important piece of scientific knowledge, still needs to find a practical application as a defined, real treatment of any pathological condition" • a few examples of treated patients is desirable, but not indispensable • results of advanced clinical studies are, as a general rule, not necessary • a higher level of technico-medical details might be required when a piece of prior art disclosed data which lead to different (negative) conclusions than the alleged invention • e.g. clinical phase I data to counter pre-clinical data on animals • again: a patent application is NOT a request for a marketing authorisation This approach has the advantage of favouring full and early protection of innovative research

Second and further medical use • Progress in pharmaceutical sciences goes in many different directions • Finding new active entities is no longer the sole, main axis of industrial development • Innovation shifts to a certain extent from new entities towards improvements based on in depth exploration of biological phenomena & adaptation to individual patient: • new use of already known drugs (implying savings on certain development costs) • new ways of using known drugs for treating the same disease (with genuine therapeutic advances) such as • new administration routes & new dosage forms • new dosage regimes • new patient group targets (pharmacogenomics) • In general, the molecules concerned by the claim are relatively limited and (very) well known: • consequently, the room for uncertainty as to therapeutic effect is more limited as well • a particular case is that of "reach through" claims involving potentially already known drugs

Second and further medical use • The core of the invention is no longer in the product(s), it resides in the finding of a new medical use or in an improvement to a known one, one or more medical uses being known for the product(s) • The EPO examiners pay generally even more attention to pharmacological data since the core of the invention is more focused on purely therapeutic aspects • Their amount is in general just as high as for first medical use when the new use is very different from the previous (first) one • Their amount must be in general higher when the new use is close to the previous (first one) for proving inventive step • of course, the prior art to be considered is still to be chosen among products exhibiting the same use as claimed • The level of required data is maximum, if the use is the same, the invention only residing in an improvement of the therapeutic effect due to administration route, dosage,dosage form or dosage regime

Second and further medical use • With respect to sufficiency of disclosure, the level of the requirement is the same as for a first medical use • Case Law: • In T 609/02, the Board of Appeal stated that • "attaining the claimed therapeutic effect is a functional technical feature of the claim" (referring to G 2/88 and G 6/88, OJ EPO 1990, 93 and 114) and • "unless this is already known to the skilled person at the priority date, the application must disclose the suitability of the product to be manufactured for the claimed therapeutic application" (see also T 491/08)

Thank you for your kind attention The opinions expressed in this document are those of the author and may not necessarily represent the official opinions of the European Patent Office

Patent Application filed by requester under competitive pressure first to file principle comes first in time in a drug's life creates an exclusive right (right to forbid) must fulfil legal requirements of general application mainly defined by Civil Law and (to a certain extent only) by Case Law can difficultly be made stricter appeal & external intervention (third parties observations & opposition) largely possible often covers products which will not come on the market Marketing Authorisation filed by requester under financial& commercial pressure first to get principle comes second in time in a drug's life creates a personal commercial & administrative right (right to do) to a certain extent only an exclusive right as well(data exclusivity) must fulfil legal requirements defined by Administrative Law by Health Authorities can be easily be made stricter no or little possibility of appeal relates to products very likely to come on the market Differences between patent application & application for marketing authorisation for a drug (1/2)

Patent Application content practically immobilized after filing no technical tests carried out by Office the requirements for public health connected inventions are same as for other inventions from less sensitive areas level historically adapted for promoting innovation international harmonisation of requirements fairly advanced (PCT, regional patent offices) requirements difficultly influenced by state policy some exceptions: patentability of genes in general not connectable with marketing authorisation exception: content of public part of OTHER marketing authorisation files usable as anticipation at a later stage - when a patent - SPCs duration conditioned by marketing authorisation Patent Offices & Health Authorities often cooperate together in certain Countries but only for the exertion of right (Doha agreement implementation) Marketing Authorisation content can be supplemented during procedure analytical expertises carried out by Office public health being at stake, level of requirements is very high and can vary quickly international harmonisation diversely advanced few regional agreements can be largely influenced by state policy influence of FDA possible connection with patents (but not with patent applications) active: US Orange Book, Canadian NOC ... passive: SPCs duration calculation Differences between patent application & application for marketing authorisation for a drug (2/2)

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Bertrand Gellie, Director Directorate General "Operations" European Patent Office Munich, Germany