biotech santé | biomarqueurs et cellules souches : que peut-on vraiment protéger par brevet ? par...

Les points sur les i

Koen VANHALST, Mandataire agréé - Office Européen des Brevets, Cabinet De Clercq & Partners

Biomarqueurs et cellules souches : que peut-on vraiment protéger par brevet ?

Avec le soutien de :

© 2011 DCP

Patenting in Life Sciences: Stem cells & Biomarkers

Koen Vanhalst

European Patent Attorney December 15, 2011

Liege Creative

[email protected]

De Clercq & Partners E. Gevaertdreef 10a B-9830 Sint-Martens-Latem

+32(0)9 280 23 40 +32(0)9 280 23 45 www.dcp-ip.com [email protected]

© 2011 DCP

Patenting in Life Sciences:

q Excluded subject-matter

q Criteria of patentability

q Experimental support needed?

q Claiming Biomarker(s)

q Stem cell specific issues

© 2011 DCP

q Moral or ethical reasons

•  Methods of treatment or diagnosis performed on the human or animal body (Art. 53(a) EPC)

•  Cloning of human beings, commercial use of human embryo’s (Art. 53(a) / Rule 28 EPC / EU Directive 98/44/EC)

•  Other immoral issues (letter bombs, anti-personnel mines,…) (Art. 53(a) EPC)

Patenting in Life Sciences: Excluded subject-matter

© 2011 DCP

Patenting in Life Sciences: Excluded subject-matter

q Legal reasons

•  Plant or animal varieties and non-microbiological « essentially biological » processess (crossing and selection of plants) > UPOV agreement on breeders rights (Art. 53(b) EPC)

•  Mathematical methods, mental acts, business methods, … > no « invention », use copyright (Art. 52(2) EPC)

•  Software, aesthetic creations > no « invention », use copyright (Art. 52(2) EPC)

© 2011 DCP

Patenting in Life Sciences: Criteria of patentability

q  Novelty (Art. 54 EPC) Any prior disclosure or use of the claimed subject-matter, in writing or orally takes away novelty of the invention: not patentable

q  Inventive step (Art. 56 EPC) If it would be obvious for a « person skilled in the art » to make the modifications to the prior art leading to the invention, it is obvious and hence: not patentable

q  Industrial Applicability (Art. 57 EPC) Low threshold, but in principle, if something does not have an industrial applicability: not patentable

© 2011 DCP

Patenting in Life Sciences: Criteria of patentability

q  Sufficiency of diclosure (Art. 83 EPC)  The invention claimed should be « workable » over the

whole of the claimed scope

q  Clarity of the claims (Art. 84 EPC)

It should be clear for a skilled person what the claim protects, i.e. when a third party would infringe the patent or not and whether prior art is covered or not

q  Unity of invention (Art. 82 EPC) The EPO does not want to search and examine more than one invention for the price of one

© 2011 DCP

Patenting in Life Sciences: Experimental support needed?

q  The less experimental evidence included, the more difficult to obtain a patent: « quid pro quo »

q  Some inventions require more evidence than others •  Medical therapeutic methods •  Selection inventions of known generic concept •  Inventions that lie close to the prior art: obvious? •  New use of a known compound: proof of the new effect •  …

q  Convince the examiner that your invention indeed has the effect it purports

to have. If not: no inventive step! « plausibility test »

q  Examples: positive: T_1450/07 T_1540/07 T_1834/09 … negative: T_1329/04 T_1306/04 T_1452/06 …

© 2011 DCP

Biomarkers: What?

q  Genetic biomarkers •  New gene (e.g. Neutrokine-α: Eli Lilly v. HGS) •  Mutations (e.g. BRCA1: Myriad) •  Gene profiling

q  Protein biomarkers •  e.g. NT-pro-BNP in blood, antibody microarrays, antigen microarrays

q  mRNA’s, microRNA’s, TUCrs… •  Differential expression

q  Pharmacogenomics •  Influence of genetic variation (e.g. gene expression or SNP

polymorphisms) on drug response

q  Epigenetics •  Differential methylation

q  Analytes •  Metabolites (lactate)

q  …

From: http://www.sciencemag.org/cgi/content/full/291/5507/1221/F1

© 2011 DCP

Biomarkers: Why?

q Diagnosis (marker for present or future disease state, marker for responsiveness to drug treatment)

q Personalized medicine

q Drug discovery/therapy q New targets q Clinical trial enrolment

q …

© 2011 DCP

Patenting in Life Sciences: Claiming biomarkers

q  Clarity issues •  Sequences needed?

•  Well defined markers?

•  Synonyms?

•  Splice variants?

q  Results shown for all biomarkers?

•  Are all claimed markers performing the function you entail them to?

•  Is it merely a research program to identify the best biomarker?

© 2011 DCP


q Lack of unity •  Choose the right one(s)…

•  Structural feature unifying different ones

•  Functional feature unifying different ones?

q Novelty issues •  Prior art discloses a list of (overlapping) markers

•  Selection inventions

•  Not new but very inventive?

•  2nd medical use type claims (swiss type or EPC2000 format)

© 2011 DCP


q What about freedom to operate? •  Numerous patents around claiming (lists of) biomarker(s)

•  Are your commerical methods/products falling within the scope of existing or future patents/applications?

q What about enforcement? •  Is your patent strong enough?

o  Panel of markers claimed: circumventing?

o  Minimal group claimed

o  Still specific/sensitive

q Patent eligible subject-matter? •  Is there a real technical contribution?

•  Is it merely a discovery?

© 2011 DCP

Patenting in Life Sciences: Claiming biomarkers:

DNA claims and diagnostic claims

q  Bilski case in the US: machine-transformation test

q  Myriad cases (US and AU): BRCA1 mutations for screeningfor breast cancer risk:is isolated DNA patentable?

q  Prometheus v. Mayo (US) Checking analytes in blood for fine-tuning therapy

© 2011 DCP

Patenting in Life Sciences: Claiming biomarkers: Neutrokine-α case UK v. EPO

HGS patent EP 0 939 804:

Discloses full length nucleotide and polypeptide sequence of a novel protein, Neutrokine-α. q  Identified by HGS from proprietary databases using bioinformatics (in

silico cloning)

q Characterised as a new member of TNF ligand superfamily on the basis of distinct, conserved domains, sequence homology and structural features

q Tissue expression data included in the application q Specification lists a number of possible applications for the protein,

and antibodies raised against it, based on membership of the TNF ligand superfamily and known activities of other TNF ligands‒ i.e. involvement in immune and inflammatory disorders

© 2011 DCP


HGS patent EP 0 939 804:

Claims (as amended) include inter alia: q Full length sequence and EC-domain of Neutrokine-α

q Antibodies that bind to Neutrokine-α q Pharmaceutical and diagnostic compositions comprising the gene,

polypeptide, or antibodies to Neutrokine-α

q No medical use claims

© 2011 DCP


HGS patent EP 0 939 804: the stakes

q  HGS (with GSK) developed BENLYSTA® a MAb to Neutrokine-α, obtained MAs in both the US and EU in 2011 for treating Lupus (autoimmune disease). Ongoing Phase II trials for RA and other immune related diseases / immune-related cancers

q  Eli Lilly also has a MAb in clinical trial for treating Lupus, RA and for other immune-related diseases and immune-related cancers

q  Eli Lilly attempted to revoke the patent in the UK on the basis of •  lack of industrial application; •  insufficiency; and •  obviousness.

q  Eli Lilly also opposed the patent before the EPO

© 2011 DCP


UK HGS vs. Eli Lilly court cases:

q  UK Patents Court (J Kitchin) •  No industrial applicability •  Pharmaceutical composition claims are obvious: no technical contribution to

the art

q  UK Court of Appeal (LJ Jacob) •  The UK Court of Appeal urged the TBA of the EPO to speed up the appeal

procedure in order to incorporate the reasoning in their decision •  TBA upheld the patent •  Yet CoA decided that there was no IA

q  UK Supreme Court: •  UK Court of Appeal was wrong in denying IA! •  Referred the case back to the CoA to decide on the other issues •  The saga did not yet come to an end…

© 2011 DCP


The case before the EPO:

Plausibility test v. in silico cloning: T_18/09

Three interrelated issues important for the EPO:

•  Enablement,

•  Industrial applicability and

•  Inventive step

© 2011 DCP




Enablement:

•  TBA saw no problem with enablement, since all aspects of the claimed invention could be easily reproduced without undue burden

o  Polypeptide and nucleic acid sequence o  Antibodies directed to said Polypeptide sequence o  Pharmaceutical and diagnostic compositions comprising said polypeptides or antibodies

© 2011 DCP


The case before the EPO: Plausibility test v. in silico cloning: T_18/09

Industrial Applicability:

•  TBA acknowleged Industrial Applicability: o  Structural plausibility o  The skilled person expected neutrokine-α to have the same effect as other TNF-ligands

o  The tissue distribution itself already provides basis for industrial aplicability

o  The opponent (Lilly) could not substantiate any alleged technical difficulties to test the proposed effects of Neutrokine-α : same standard as for enablement: verifiable facts needed

© 2011 DCP




Inventive Step:

•  TBA acknowleged Inventive Step:

o  Closest prior art document put forward by Lilly was a clone from the IMAGE library

o  Not accepted by the Board o  Lilly tried with the argument of « automated pipeline screening » o  Also not accepted by the Board o  Closest prior art according to the Board was a document disclosing nine

family members and the problem to be solved was the provision of a further family member.

o  Inventive, since apparently when using conserved regions amongst these nine family members would not result in the discovery of Neutrokine-α …

© 2011 DCP


Conclusions

•  In silico cloning is not per se unpatentable

•  The type of claims will however likely be limited to what you actually « made » or contributed to the art

•  Therapeutic, diagnostic or other use claims will be very difficult to obtain based on e.g. a mere tissue distribution experiment

•  Again: quid pro quo is the EPO motto

© 2011 DCP

Stem Cells: What?

From: Wikipedia

© 2011 DCP

Stem Cells: Why?

q Tissue regeneration •  Bone or cartilage reconstruction

•  Cardiovascular cells for treating heart failure

•  Neural cells to treat brain damage

•  insulin producing beta cells to treat diabetes

q Basic research q Screening methods for identifying new biomarkers

q Toxicity tests q …

© 2011 DCP

Patenting in Life Sciences: Stem cell specific issues

q Clarity issues for differentiated or isolated subpopulations of cells •  Result to be achieved •  Functional definitions •  No clear phenotype or expression pattern (grey in stead of black and

white)

q  Novelty issues •  The method of e.g. differentiating a stem cell into a spcific cell type

may be very inventive, but •  The differentiated cells obtained thereby for e.g. tissue engineering

need to resemble the naturally occurring diferentiated and functional cell : new?

q Moral issues •  Commercial use of human embryo’s is not allowed •  Are stem cells human embryo’s?

© 2011 DCP

Patenting in Life Sciences: Stem cells: moral issues

The WARF case: G2/06: the claims

"1. A cell culture comprising primate embryonic stem cells which (i) are capable of proliferation in vitro [sic] culture for over one year, (ii) maintain a karyotype in which all chromosomes normally characteristic of the primate species are present and are not noticeably altered through culture for over one year, (iii) maintain the potential to differentiate to derivatives of endoderm, mesoderm, and ectoderm tissues throughout the culture, and (iv) are prevented from differentiating when cultured on a fibroblast feeder layer."

© 2011 DCP

Patenting in Life Sciences: Stem cell moral issues

The WARF case: G2/06: the issues:

•  The Examining Division refused the application under Article 97(1) EPC 1973 for the reason that claims 1 to 7, 9 and 10 did not comply with the requirements of Article 53(a) EPC 1973 in conjunction with Rule 23d(c) [now 28(c)] EPC, because, as regards the generation of human embryonic stem cell cultures, the use of human embryos as starting material was described in the application as originally filed as being indispensable.

•  The use of a human embryo as starting material for the generation of a product of industrial application (i.e. the claimed embryonic stem cell cultures) meant a use thereof for industrial purposes within the meaning of Rule 23d(c) [now 28(c)] EPC and was thus prohibited under the said provision in conjunction with Article 53(a) EPC 1973.

© 2011 DCP


The WARF case: G2/06: reasoning:

•  “35. In view of the questions referred, this decision is not concerned with the patentability in general of inventions relating to human stem cells or human stem cell cultures. It holds unpatentable inventions concerning products (here: human stem cell cultures) which can only be obtained by the use involving their destruction of human embryos.”

© 2011 DCP


The WARF case: G2/06: The answers of the EBA

•  Question 1: Rule 28(c) EPC (formerly Rule 23d(c) EPC) applies to all pending applications, including those filed before the entry into force of the rule.

•  Question 2: Rule 28(c) EPC (formerly Rule 23d(c) EPC) forbids the patenting of claims directed to products which – as described in the application – at the filing date could be prepared exclusively by a method which necessarily involved the destruction of the human embryos from which the said products are derived, even if the said method is not part of the claims.

© 2011 DCP


The EPO’s practice after G2/06 was:

•  Refuse applications, if having regard to the entire teaching of the application, the human embryonic stem cells (hESC) could at the filing date of the application only be obtained by isolation from human embryos necessarily involving their destruction: •  Excluded from patentability are claims to process of deriving hESC, hESC as

product, method applied to such hESC and any product by applying such a method to these hESCs

•  Allowable applications, if the application disclosed a way to carry out the invention whereby the hESC are not exclusively derived by destroying human embryos (or if such a way must be considered to be part of the standard general knowledge of a person skilled in the art). Methods and products relating to these hESC would be patentable if they comply with all other EPC requirements

•  Patentable are also: “non-human” ESC and adult stem cells

© 2011 DCP


The Brüstle case: CJ-EU C-34/10

•  Prof. Brüstle holds a European patent on neuronal precursor cells, derived from human embryonic stem cells, for treating patients with neurological disorders such as Parkinson's disease

•  Greenpeace started invalidation proceedings before the German Federal Patent Court (Bundespatentsgericht) to have the patent revoked on the grounds that the use of human embryos for industrial or commercial purposes is excluded from patentability under Article 2 of German Patent Law, implementing the Biotechnology Directive.

•  The German Federal Patent Court partially followed the demand of Greenpeace and partially revoked the patent, after which Professor Brüstle filed an appeal against the decision with the German Federal Court (Bundesgerichtshof). The German Federal Court referred some clarifying questions to the CJ-EU before making its final decision.

© 2011 DCP

Patenting in Life Sciences: The Brüstle case: CJ-EU C-34/10

The questions:

1. What is meant by the term 'human embryos' in Article 6(2)(c) of Directive 98/44/EC?

(a) Does it include all stages of the development of human life, beginning with the fertilisation of the ovum, or must further requirements, such as the attainment of a certain stage of development, be satisfied? (b) Are the following organisms also included:

1. unfertilised human ova into which a cell nucleus from a mature human cell has been transplanted;

2. unfertilised human ova whose division and further development have been stimulated by parthenogenesis?

(c) Are stem cells obtained from human embryos at the blastocyst stage also included?

© 2011 DCP


The questions:

2. What is meant by the expression 'uses of human embryos for industrial or commercial purposes'? Does it include any commercial exploitation within the meaning of Article 6(1) of the Directive, especially use for the purposes of scientific research?

3. Is technical teaching to be considered unpatentable pursuant to Article 6(2)(c) of the Directive even if the use of human embryos does not form part of the technical teaching claimed with the patent, but is a necessary precondition for the application of that teaching,

(a) because the patent concerns a product whose production necessitates the prior destruction of human embryos,

(b) or because the patent concerns a process for which such a product is needed as base material?

© 2011 DCP


q  In March 2011, the Advocate General of the CJ- EU issued his opinion on the case

q  18 October 2011, the CJ-EU published its ruling…

© 2011 DCP


The answers of the CJ-EU

“Article 6(2)(c) of Directive 98/44/EC of the European Parliament and the Council of July 1998 on the legal protection of biotechnological inventions must be interpreted as meaning that:

- any human ovum after fertilization, any non-fertilised human ovum into which the cell nucleus from a mature human cell has been transplanted and any non-fertilised human ovum whose division and further development have been stimulated by parthenogenesis constitute a ‘human embryo’ within the meaning of Article 6(2)(c) of the Directive. - it is for the referring court to ascertain, in the light of scientific developments, whether a stem cell obtained from a human embryo at the blastocyst stage constitutes a ‘human embryo’ within the meaning of Article 6(2)(c) of the Directive”

© 2011 DCP



“The exclusion from patentability concerning the use of human

embryos for industrial or commercial purposes in Article 6(2)(c) of the Directive also covers use for purposes of scientific research, only use for therapeutic or diagnostic purposes which are applied to the human embryo and are useful to it being patentable”

© 2011 DCP



“The answer to the third question is therefore that Article 6(2)(c) of the Directive excludes an invention from patentability where a technical teaching which is the subject-matter of the patent application requires the prior destruction of human embryos or their use as base material, whatever the stage at which that takes place and even if the description of the technical teaching claimed does not refer to the use of human embryos.”

© 2011 DCP


The reasoning of the CJ-EU

The Court of Justice states in its reasoning that: “The fact that destruction (of the human embryo) may occur at a

stage long before the implementation of the invention, as in the case of the production of embryonic stem cells from a lineage of stem cells the mere production of which implied the destruction of human embryos is, in this regard, irrelevant.”

© 2011 DCP

The reasoning of the CJ-EU

The Court of Justice states in its reasoning that: “Not to include in the scope of the exclusion from patentability set out in Article 6(2)(c) of the Directive technical teaching claimed, on the ground that it does not refer to the use, implying their prior destruction, of human embryos would make the provision redundant by allowing a patent applicant to avoid its application by skilful drafting of the claim.”

Patenting in Life Sciences:The Brüstle case: CJ-EU C-34/10

© 2011 DCP


q  The Court of Justice further states that their decision is in line with Enlarged Board decision G2/06 of the European Patent Office q  Remarkably though, the EPO itself does not interpret G2/06 as excluding

the use of human embryonic stem cells from patentability, if these could have been obtained from a cell line or other source without destruction of a human embryo at the time of filing the patent application (i.e. from May 2003 onwards)

q  What will the EPO do? q  According to President Benoît Battistelli, the EPO is going to implement the

Ruling of the CJ-EU – EPO is working out further guidelines at this moment

q  EU member states will also be bound by the CJ-EU decision on patentability of stem cells

q  Conversion to national patent application in non-EU member states not bound by CJ-EU decision might be possible

© 2011 DCP


To conclude:

•  hES cells = embryo’s: for the national courts to decide, but…

•  Using hES cells for which an embryo was destroyed 8 years ago in order to establish a cell-line = immoral and hence not patentable

•  What about progenitors or differentiated cells derived from such stem cells?

•  Just how far do you have to go back to be moral or immoral?

© 2011 DCP

Patenting in Life Sciences: differentiated stem cells

•  Differentiated cells from iPS and Mesenchymal stem cells are patentable but…

•  Make sure they are distinguishable from naturally occurring or previously obtained cells

•  Characterise them as good as possible!

© 2011 DCP

What happened to the goal of the Biotech Directive?

1.  Whereas biotechnology and genetic engineering are playing an increasingly important role in a broad range of industries and the protection of biotechnological inventions will certainly be of fundamental importance for the Community’s industrial development;

2.  Whereas, in particular in the field of genetic engineering, research and development require a considerable amount of high-risk investment and therefore only adequate legal protection can make them profitable;

biotech santé | biomarqueurs et cellules souches : que peut-on vraiment protéger par brevet ? par...

Health & Medicine