Bioinformatics and Gene Discovery

Center for Biological Sequence Analysis, DTU, June 12, 2007

Jens Viktor Nørgaard, Symphogen A/S

Agenda

• • • • • • • • • Commercials What is a patent Patentability basics • Novelty, inventive step & other criteria Claims Inventors Timelines Patents as information source Searching for patent information Ethics and patent law

Who am I

• • • • • • MSc in Forestry, PhD in Genetics & Biochemistry (Royal Agricultural University, now University of Copenhagen) 10 years of academic research, University of Copenhagen Patent consultant since 1998 European Patent Attorney 2003 Director of IPR, Symphogen AS Previously: NsGene (Biotech), Hoiberg (Patent Attorneys)

What is a patent attorney?

• • • • Represents clients/employer before patent authorities No authorisation requirements in Denmark Authorisation required in a number of countries: United Kingdom, Germany, France, United States, Japan, EPO (European Patent Office) Qualifications (European patent attorney): • Scientific degree; MSc, PhD or equivalent • • • Linguistic skills, writing & speaking Business attitude Patent training > 3 years • Pass a qualifying exam

What does a patent attorney do

• • • • • • • • • Writing patent applications Preparing legal documents Monitoring dead-lines Searching for and analysing technical information Providing legal opinions on patent issues Preparing and filing responses to patent authorities Training of scientists/clients/students/trainees Strategic advice/planning to Universities and Corporations License negotiations and agreements

Links

• Training of Danish patent attorneys (Certified Danish Patent Attorney): http://www.difi.dk/ • How to become a European Patent Attorney: http://www.european-patent office.org/epo/pubs/pat_attorney/pdf/patbro_ e.pdf

Patents?

What is a patent?????

What is a Patent?

• Which rights arise from a granted patent?

Patents I

• • • A patent application - ”paid-for publication”, source of information A granted patent – a legal document defining an injunction right & a right to claim damages A patent does not give the owner any right to exploit the invention • Determined by other’s patents and by legislation

Patents II

• • • Agreement between inventor and society • • Inventor gets a time-limited monopoly Society gets a description of the invention Patenting forces publication • • Stimulates exchange of information Stimulates research and development Alternative to patents • Secrecy

Patentability Requirements

Patentability Requirements

• • • • • • • • • Novelty Inventive step Clarity Conciseness Enablement Sufficiency of disclosure Utility Industrial applicability Exceptions to patentability

Novelty

Novelty

• • • • Novelty = not available to the public on the date of filing Available = made available to the public without any confidentiality barriers A compound (including proteins and genes) is not known merely because it is found in nature (e.g. an mRNA in a cell, a protein in a plant) Compounds can be made available by • decribing the structure of the compound (structural formula or sequence) • • describing a method of producing/synthesising describing a method of isolating/purifying the compound

State of the Art (known) 1.

a cup 2.

a cup 3.

a cup 4.

a cup 5.

a cup

The Concept of Novelty

Patent Application 1.

a cup with a handle (novel) 2.

a 15 cm tall cup (novel) 3.

a cup adapted to hold coffee (non-novel) 4.

a red cup (novel) 5.

a container for liquid (not novel)

The Concept of Novelty

State of the art 1.

cells secrete a protein with activity X 2.

the protein with acivity X can be purified from organism Y using method Z 3.

protein with sequence ...

Patent application 1.

an isolated protein with sequence ... having activity X 2.

an isolated protein with sequence ... having activity X 4.

5.

peptide with sequence: ypskpdnpgedapaedmaryysalr hyinlitrqry (NPY) conservative substitutions can be made in NPY 3.

4.

5.

glycosylated protein with sequence ...

peptide with sequence: ypskpdnpgeeapaedmaryysalr hyinlitrqry peptide with sequence: ypskpdnpgeeapaedmaryysalr hyinlitrqry

The Concept of Novelty

State of the art 1.

gene X was cloned using primers A and B 2.

3.

genes 1 to N can be used for treating diseases 1 to N gene x promotes cell division Patent application 1.

gene X having sequence ...........

2.

3.

gene 5 for treatment of obesity......

use of gene x as a growth factor

Inventive Step Non-obviousness

Inventive Step/Non-obviousness

• Inventive step/”non-obviousness” • Difference between prior art and invention must be of a certain ”size” • • • • No patents for trivial inventions Patents promote technical progress, not stand-still Non-obvious for the person skilled in the art Person skilled in the art • • • •

Fictitious person Not a Nobel prize winner Average skills Knows everything (all languages) but is conservative, does not go against established prejudice, does not try to enter unpredictable areaas nor take uncalculable risks

Inventive Step/Non-obviousness

• • • • Complex arguments Room for creativeness Large differences between major patent autorities: EP, JP, US: New sequence (new compound, new structure) • US – any new stucture is non-obvious • JP – a significant and unexpected effect must be associated with the new structure, or undue difficulty in obtaining new sequence • EP – was the sequence difficult to make? any unexpected technical effects associated with the new sequence? was it obvious to try and see?

The Concept of Inventive Step

State of the art (known) 1.

a cup 2.

a cup 3.

a cup 4.

a cup 5.

a cup Patent application 1.

a cup with a handle (inventive?) 2.

a 15 cm tall cup (inventive?) 3.

a cup adapted to hold coffee (non-novel) 4.

a red cup (inventive?) 5.

a container for liquid (not novel)

The Concept of Inventive Step

State of the art 1.

cells secrete a protein with activity X 2.

the protein with acivity X can be purified from organism Y using method Z 3.

protein with sequence ...

Patent application 1.

an isolated protein with sequence ... having activity X 2.

an isolated protein with sequence ... having activity X 4.

5.

peptide with sequence: ypskpdnpgedapaedmaryysalr hyinlitrqry (NPY) conservative substitutions can be made in NPY 3.

4.

5.

glycosylated protein with sequence ...

peptide with sequence: ypskpdnpgeeapaedmaryysalr hyinlitrqry peptide with sequence: ypskpdnpgeeapaedmaryysalr hyinlitrqry

The Concept of Inventive Step

State of the art 1.

gene X was cloned using primers A and B 2.

genes 1 to N can be used for treating diseases 1 to N 3.

4.

gene x promotes cell division an EST annotated as having homology to an enzyme with activity Y Patent application 1.

gene X having sequence ...........

2.

gene 5 for treatment of obesity......

3.

4.

use of gene x as a growth factor isolated and purified protein having sequence X and enzyme activity Y

Clarity, Sufficiency, Enablement, Utility

Clarity, Sufficiency, Enablement

• ”Quality requirements” • • • No short cuts by trying to keep part of the invention secret No short cuts by filing too early – before invention is complete Legal certainty (possible for 3rd party to determine scope of claims)

Clarity, Conciseness

• • The claims must be clear and concise Results in many definitions: • Sequence homology • Binding specificity • • • • • Competition for antigen/epitope Binding affinities Alignment Hybridisation High stringency

Sufficiency, Written Description

• • • • Description must be sufficient Sufficiency – when the skilled person can carry out the invention – don’t try to leave anything out Also a question of credibility Written description – you must show that you were in possession of the invention upon filing – do not file before you completed the invention

Utility

• Industrial applicability/”utility” • • USA – credible, substantial and specific utility (a use for the invention) – high hurdle, used by the Patent Office to refuse trivial or premature applications EPO – the industrial applicability of a sequence must be given in the application (Biotekdirektivet) – low hurdle

Patent Claims

Patent Claims

• • • The claim defines the invention The claim must satisfy the patentability requirements The description may only be used to interpret the features of the claims

Rights arising from Patent I

• Productpatent – forbid others to: • make, use, offer for sale, sell, import • Claims • • • 1. An isolated polypeptide comprising the amino acid sequence of SEQ ID No. 2, or a biologically active sequence variant having at least 70% sequence identity to SEQ ID No. 2.

2. A pharmaceutical composition comprising protein X.

3. An expression vector comprising a sequence coding for protein X.

Rights arising from Patent II

• • Method patent – forbid others to • Use the method • Method of manufacture also protects the products Claims: 1. Use of protein X for the preparation of a pharmaceutical composition.

2. Use of protein X for the preparation of a medicament for the treatment of disease Y.

3. A method for identifying a compound with activity X, comprising testing the compound in screening assay Y. 4. A method of producing protein X, comprising culturing a host cell transfected with vector Y and recovering protein X from the culture medium.

Claim Types, Product

• • • • • • • • • Nucleic acid Polypeptide Antibody Expression vector Screening assay (kit) Array Pharmaceutical composition Cells Data carrier

Claim Types, Methods

• • • • • • • Method of treatment (of disorder) Medical use (any therapeutic use) Second medical use (disease specific therapeutic use) Diagnostic use Method of preparing compound/protein Method of identifying modulator of activity Method of isolating compound/protein/gene

Inventors

Why??

• • European Patent Convention (Art 60) • The right to a European Patent belongs to the inventor or his successor in title.

US-statute • • Applications are filed in the name of the inventors Inventorship is required to be accurate

Who is an inventor

• Not an award for good work!

• No justice at all!

• Inventorship is conception

Conception

• • • • • ”the formation in the mind of the inventor of a definite and permanent idea of the complete and operative invention” Conception is more than a goal Must include how to make and use without undue experimentation Reduction to practise (=testing an invention conceived by another) does not make you an inventor Is the mental part of the invention, not the constructive part

Joint inventions

• • • • Joint conceivers are joint inventors Do not need to work together Do not need to make the same type or amount of work Do not need to contribute to every claim

Timelines

The Typical Life of an International Application

PCT Patent Application Process

0 12 16 18 28 30 MONTHS

Patenting Process

• • • First filing– timing Early filing – •

Easier to get novelty

•

Enablement, sufficiency, utility?

Later filing – •

More time to prove function (of a gene or protein)

•

Longer patent term (evergreening of Pharmaceutical products)

Patenting Process

0 12 16 18 28 30 • • • • Filing of updated PCT-application Filed within 12 months of the first filing Claims priority from the earlier filing => prior art is anything published before the priority date One single application in one language can give patents in 130+ countries (1 May, 2007, 137 countries)

Patenting Process

0 12 16 18 28 30 • • • Novelty search (database search) Identification and classification of publications (patent applications and scientific papers) Possibility to evaluate the fate of the patent application

Patenting Process

0 12 16 18 28 30 • Publication of the application 18 months from first filing

Patenting Process

0 12 16 18 28 30 • • Preliminary examination – • A possibility to evaluate the patentability • Dialog with examiner at EPO or PRV (Swedish PTO); written procedure, but possibilty for interview International preliminary report on patentability • Report on the patentability • Preliminary, so not binding on national authorities

Patenting Process

0 12 16 18 28 30 • Entry into national phase (US, JP, CA, AU, IN, CN, etc) or regional phase (Europe, Eurasia, Africa).

• Selection of countries • • • Geographic strategy Language - translations Costs

Patenting Process

0 12 16 18 28 30 • • • • The application is adjusted to national law Patent grant/refusal Possibility for opposition from third parties Can be maintained up to 20 years from PCT filing date

Patents and Applications as Information Source

How to Read a Patent Application

Patent Applications Layout I

• • • • • Frontpage • Bibliographic information Background of the invention • Corresponds to introduction Summary of the invention • Copy of the indpendent claims, perhaps arguments Brief description of the drawings • Figure legends Detailed description • Definitions, description of alternatives, variations, uses • Supports sub-claims, fall-back positions, enablement, how to make and use the invention

Layout II

• • • • Examples • Materials & methods, results, rarely any discussion Claims • Main claims and independent claims Drawings (not Figures!) • Always at the end of the application Sequence listing • Amino acid and nucleotide sequences • Made according to special formal requirements

International (PCT) Applications

• • • •

APPLICATIONS!! NOT PATENTS

Filed locally (e.g. Denmark) Treated and published centrally (WIPO, EPO, USPTO, PRV, JPO).

Potentially covers 137 countries (holes in South America and the Arab world)

PCT Countries

PCT-applications

• • • Filed, searched, published, examined Timeline: priority year, published after 18 months, PCT phase ends after 2½ years Example: WO 2006/007853 (Symphogen)

PCT application

US-applications/Patents

• • US-applications published at 18 months • Long numbers, US2007020279 A1 (Johnson et al) US-patents, published at issue • • Granted patents Short numbers, fx US 5,824,307 (Johnson et al)

US-patent

US-application

EP-patents

• • • Applications published at 18 months Most are published as PCT applications (WO number) Published as B1 publication at grant

Granted European patent

Finding Patent Information for Free

Finding Patent Information – for Free

• • espacenet • Link: http://ep.espacenet.com

• Simple search functions • • • Publication as pdf-file – full document/page by page USPTO • Abstract from the application OCR text available for English, French and German language applications Link: http://www.uspto.gov/patft/index.html

• • • • • Simple and advanced search tools Patent number search Free text search OCR text available Publication available in Tiff format, page by page

Finding Patent Information – for Free

• Patentscope (WIPO) • Link: http://www.wipo.int/pctdb/en/ • • Advanced, simple, or structured search functions Abstract from the application • • • OCR text available for English, French and German language applications Publication as pdf-file Other documents (priority documents etc) as pdf file

Downloading Patent Documents for Free

• • • pdf’s of European patents and applications (since 2004): https://publications.european-patent office.org/PublicationServer/search.jsp

pdf’s of PCT applications from Patentscope (WIPO): http://www.wipo.int/pctdb/en/ pdf’s of PCT applications file inspection at EPO: http://www.epoline.org/portal/public/!ut/p/kcxml/04_ Sj9SPykssy0xPLMnMz0vM0Y_QjzKLN4i3dAHJgFjGpvq RqCKOcAFvfV P_NxU_QD9gtzQiHJHRUUA43OWZA!!/delta/base64xm l/L3dJdyEvUUd3QndNQSEvNElVRS82XzBfOUc!

Finding Patent Information

• • • Blast searches in patent database at NCBI: http://www.ncbi.nlm.nih.gov/BLAST/ Example: Find US patents covering persephin: http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val =2935710 • Copy sequence • • Paste into NCBI Blast (pat) http://www.ncbi.nlm.nih.gov/BLAST/ Searching.....

• • • • Copy patent number Go to http://www.uspto.gov/patft/index.html

Go to Patent Number Search Paste number - search

Limitations of NCBI Blast

• • • Accession policy appears inconsistent / random Only a small fraction of patented sequences are found at NCBI Alternatives: • • Search for gene names Commercial sequence databases (Chemical Abstracts Registry, PCT-gen (WIPO), DGene (Derwent))

Ethics and Patent Law

Ethics and Patent Law

• • Why ethics?

Controversial issues: • Patents on life (Dolly the Sheep, Harvard Onco-mouse) • • • • • • Plant patents Human genes Stem cells Human embryos (cryopreserved embryos) Breast cancer diagnostics (brca genes) Computer programs

Ethics and patent law

• ”Non-controversial” issues: • Patents on weapons • Patents on nuclear power plants/weapons • • Patents on chain-saws Industrial fishing equipment

Greenpeace

• • • • Greenpeace believes the EPO is abusing patent law for the benefit of the few multinational giants that control the genetic engineering industry.

Over 150 patents on human and animal genes and over 50 patents on seeds have been granted by the EPO since it started applying the EU Patents Directive in 1999.

Greenpeace opposes the wording of the EU Patents Directive and calls for a re-negotiation of the Directive at the EU level.

Greenpeace opposes patents on life. The sell-out of biological diversity and intellectual property rights that restrict access to plant genetic resources must stop. (source: Greenpeace Web-site)

Greenpeace reports

• • http://www.greenpeace.org/raw/content/inter national/press/reports/greenpeace-patents on-life-in.pdf

http://www.greenpeace.org/international/pres s/reports/the-true-cost-of-gene-patents

For & Against Patents on Genes

• • • • • Not novel – but novel in isolated (=available) form Not invented by the inventor – but isolated by the

inventor

Isolation is no invention – but the isolated gene can

solve a technical problem and has utility

Immoral to patent life – why? – living creatures

(animals, plants, microorganisms) have been regarded as goods for centuries

Patenting genes is contrary to development – mere

allegation, do not confuse patent applications with valid patents

Ethics

• • • Allegation: gene claims are way too broad • • • Cover all uses (product claims) Gene claims should be restricted to use (Biotechnology directive as implented in France and Germany) Stops research My answer: gene claims should have same scope as all other claims • • • Traditional compound claims cover all uses Why should gene patent stop development and research while patents in other fields enhance research?

Again: do not confuse patent applications with valid granted claims Part of the problem: • • • • Backlog of human gene patent applications results in uncertainty Sequence non-obviousness in the US USPTO grants invalid patents Very limited research exemption in the US

Human Gene Patent Applications

• • • • • • • The result of high-througput sequencing Genes predicted with software No biological data Limited expression data (rarely quantitative) Long list of genes (several 1000) Laundry list of possible functions Laundry list of possible uses • Diagnostics • • Therapeutics Screening

Good Hunting!