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FJ Fernandez Brañas

Latest case law of the EPO in Biotechnology: Interpretation and Application of the European Patent Convention to the Recent Technological Developments. FJ Fernandez Brañas. 17-12-2010. Overview. Cell Therapy and human Embryonic stem cells (G2/06) Pharmaceutical uses and Personalized Therapy

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FJ Fernandez Brañas

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  1. Latest case law of the EPO in Biotechnology: Interpretation and Application of the European Patent Convention to the Recent Technological Developments FJ Fernandez Brañas 17-12-2010

  2. Overview • Cell Therapy and human Embryonic stem cells (G2/06) • Pharmaceutical uses and Personalized Therapy • Computer Prediction of Function of Genes and Proteins • Sequencing errors and Priority • Inventive step, Reproducibility and post-published evidence • Latest G-Decisions G1/07 and G1/08

  3. Limitation or revocation proceedings Appeal proceedings Opposition proceedings Overview: Case Law Development by the BoA "T" Decisions (Technical Board) "G" Decisions (Enlarged Board) Refusal of application Applicant Substantive examination Grant of European patent EPO CASE LAW Opposition by third parties possible Public domain

  4. Legal provisions European Patent Convention 1973, 2000

  5. Patentability of cells and hESC • Concept of microorganism understood broadly by BoA (G1/98, T356/93): pro- and eukaryotic cells, bacteria, virus...etc are included • As microbiological processes and the products thereof are patentable inventions according to the EPC (Art 53b EPC), patents have been granted concerning • human adult cells • human adult stem cells • human foetal cells • plant cells • bacterial cells • virus • all non-human animal cells

  6. Patentability of cells • However, no patents have been granted relating to • Human Embryonic Stem Cells (Rule 28(c) EPC) • Human Germ cells (Recital 16, EU directive 98/44)

  7. Article 53 (a) EPCRule 28 EPC (Article 6.2(c) of Directive 98/44/EC, july-1998) Under Article 53(a) EPC, European patents shall not be granted in respect of biotechnological inventions which, in particular, concern the following: • (a) processes for cloning human beings; • (b) processes for modifying the germ line genetic identity of human beings; • (c) uses of human embryos for industrial or commercial purposes; • (d) processes for modifying the genetic identity of animals which are likely to cause them suffering without any substantial medical benefit to man or animal, and also animals resulting from such processes.

  8. Human Embryonic stem cells 06.11.1998

  9. Application refused by ED. Appealed under T1374/04 Referral G2/06 Application withdrawn after the ruling of G2/06

  10. Claim 1 of the WARF patent • A cell culture comprising primate embryonic stem cells which (i) are capable of proliferation in vitro 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.

  11. Decision G2/06 of 25.11.2008 • Human stem cell cultures which can only be obtained by destroying human embryos are not patentable. • This decision is not concerned with the general question of patentability of inventions relating to human stem cells or stem cell cultures. • WARF's request for a preliminary ruling on the issue by the European Court of Justice was rejected for lack of an institutional link between the EPO appeal boards and the EU.

  12. Human Embryonic Stem Cells, What Next? • Case (a) : Cells obtained exclusively from human embryos • T0522/04 • Case (b) : Cells obtained from established publicly available cell lines • Case (c) : Reference to human embryos and established cell lines • Case (d): No reference to the origin of the hES cells used • In cases (b), (c) and (d) the subject-matter is in principle patentable, provided that, at the relevant filing date, the invention could be reproduced by a method which does not result in use or destruction - of human embryos. • Examples (c)(d): • EP05740642, EP07719932, all granted by the ED • T128/92, T815/90

  13. Cell Therapy Provenge: Autologous APC stimulated with PAP-GM-CSF and re-infused into the patient Patent Granted 11.01.2007

  14. Medical Uses Methods for the treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body Article 53(c) EPC

  15. Medical uses Product:"Substance X" novel over 1st medical use: "Substance X for use in medicine" novel over 2nd medical use: "Substance X for use in treating Parkinson's novel over Further medical use: "Substance X for use in treating MS" Absolute Protection Use limited protection

  16. Medical Uses: The treatment process Disease Compound Drug Formulation Route of Administration Patient group Dosage Regime

  17. Route of Administration T51/93 Use of HCG for the manufacture of a medicament for treating male infertility "by subcutaneous administration" Prior art: same by intramuscular administration  subcutaneous novel and inventive over intramuscular administration; Conclusion: • difference in mode of administration basis for a new therapeutic use, • analogous approach in T138/95; T233/96. • Technical effect essential to acknowledge Inventive step

  18. Patient group T19/86 (BoA 3.3.1) Claim: Use of live attenuated Aujeszky-virus for the manufacture of a vaccine for intranasally protecting maternally immune pigs against Aujeszky's disease." Prior art: vaccination of sero-negative piglets with live attenuated virus. Effect: achievement of a solid immunity in neonatal piglets Conclusion: treatment of Aujeszky's disease in neonatal, sero-positive pigs novel and inventive over same treatment in sero-negative pigs. Same approach in T893/90 (control bleeding in non-hemophilic vs. hemophilic mammals), T885/91 (patients with lever disease), T1399/04 (patients with HCV genotype 1 and a specific viral load in blood ...etc)

  19. Patient group, Personalized Therapy? • No BoA Decision yet taken where the issue at stake is the definition of the patient population by a genetic background. Some patents have however been granted by ED. • Essential in all cases: • to show data which evidences the relationship between the selected population and the pharmacological effect (no arbitrary selection). • to have a very well defined and clear patient population either by physiological or pathological status (T19/86, TT893/90, T1399/04) or by genetic background.

  20. Dosage Regime • EP94306847: • ....Nicotinic acid for use in the treatment, by oral administration, once per day prior to sleep, of hyperlipidaemia........ • Refused by ED: difference with prior art (once per day prior to sleep) is a medical activity excluded from patentability and cannot render the claim new • Appeal case: T1319/04 • Referral to EBoA

  21. Dosage Regime G2/08 If a medicament is known to treat an illness, Article 54(5) EPC does not exclude patenting of this medicament for use in a different treatment of the same illness. Such patenting is also not excluded where a dosage regime is the only claimed feature not comprised in the state of the art. Where the subject-matter of a claim is rendered novel only by a new therapeutic use of a medicament, such claim may no longer be in the "Swiss-type claim" format. (time limit 3 months after publication in OJ)

  22. However.....Unexpected results are needed! • T1409/06: • Claim: ...Granisetron...for treatment of post-operative nausea and vomiting, wherein Granisetron is administered in a 1 mg to 3 mg unit dose. • Patent shows that best effect is obtained by adm. of 1 to 3 mg • BoA: finding the optimum dosage is a matter of routine experimentation. No evidence of any unexpected effect attributed to the unit dose of 1 to 3 mg. • Revoked for lack of inventive step

  23. Genes and Proteins: Industrial Applicability (Art 57) and computer assignment of function EP97930715: BDP1 (tyrosine phosphatase). Application refused. BoA decision (T870/04) confirms that when the function of a substance is not known or is complex and not completely understood and no practical, profitable application (e.g. pharmaceutical, diagnostic tool) can be envisaged, no industrial applicability can be acknowledged). Same conclusion in T0641/05 (putative GPCR), (T1452/06, Serin Protease) . The purpose of granting a patent is not to reserve an unexplored field of research for an applicant. I.A. accepted: T0604/04 (Chemokine receptor), T0898/05 (probative value of computer assigned function accepted), T 0018/09 (Neutrokine-alpha), T1165/06 (IL-17 related protein),

  24. T0018/09 (Neutrokine alpha) • Industrial applicability accepted by the BoA: • belongs to the TNF ligand superfamily (by computer assignment) • is expressed in activated T cells, however without experimental evidence (like other TNF ligand members) • stimulates proliferation of leukocytes (no experimental evidence) • according to the BoA, no doubts substantiated by evidence against said facts • practical exploitation of the invention is therefore disclosed • Several prior art documents disclosed the screening of libraries with the conserved C-terminal or D-domain of TNF -ligand members. However no further member was found.

  25. T0018/09 (Neutrokine alpha)....National proceedings • Patent was found invalid by a Court in GB (England and Wales) • High Court of Justice Court of Appeal (case A3/2008/2673) in GB found the patent invalid after the appeal of the patent proprietor Human Genome Sciences Inc (with E Lilly as Claimant) • The Court found that the patent application did not meet the requirement of Industrial applicability

  26. Priority Right (Art.87-89 EPC) and sequencing errors T351/01 (TFP factor, 5 bases difference in non coding regions), T70/05 (9 aa difference, apoptosis receptors), T30/02 (xylanase, two additional guanine residues at 3' end): Loss of priority. • T1213/05 (BRCA1 gene, Myriad-I) "17q-Linked breast and ovarian cancer susceptibility gene” 15 nucleotide difference with priority document, 6 silent and 9 resulting in aa change (99,84 % identity with prio document): Loss of priority The argument, that a claim which explicitly refers to a DNA sequence comprising a coding sequence for a specific polypeptide should be entitled to claim priority from an earlier application disclosing a DNA sequence deviating from the claimed one within the margin of error of the used sequencing method, is not compatible with the EBA’s conclusion in Opinion G 2/98 that the requirement for claiming priority of “the same invention”, referred to in Article 87(1) EPC........

  27. T0666/05 (BRCA1 gene, Myriad-III) still same invention Claim 1: A method for diagnosing a predisposition for breast and ovarian cancer in a human subject which comprises determining whether there is germline alteration 185delAG -> ter39 in the BRCA1 gene in a tissue sample of said subject, said alteration indicating a predisposition to said cancer. T80/05 (Myriad-II): Claim directed to detection of frameshift mutations in BRCA1. 15 nucleotide difference with priority document, 6 silent and 9 resulting in aa change. Priority OK, deviations in sequences would not affect amplification and identification of frameshift mutations. Priority validly claimed. T0250/06: differences with priority document (seven bases), still same invention: Claim 1: recombinant nucleic acid molecule comprising nucleotide sequence...... which hybridizes under conditions of low stringency to a probe of figure 5 Priority Right (Art.87-89 EPC)

  28. Post-published evidence Filing date Publication application Grant Post-published evidence: comparative examples, unexpected advantage, proof of reproducibility

  29. Article 56 EPC - Inventive step - plausibility/post-published evidence T 1329/04 (GDF-9, Johns Hopkins unv.) • Closest prior art discloses members of the TGF-β family, and shows that members have seven cysteine residues with characteristic spacing and high degree of homology (70%). • Problem to be solved by present application: isolating a further member of the TGF-β superfamily • Solution: polynucleotide of SEQ ID NO:3 encoding the polypeptide of SEQ ID NO:4, denoted GDF-9 ...

  30. Article 56 EPC - Inventive step - plausibility/post-published evidence T 1329/04 • is it plausible that GDF-9 constitutes a further member of the TGF-β superfamily? • GDF-9 lacks the 'seven cysteine residue pattern' characteristic for TGF-β superfamily members. • GDF-9 has low homology (30%) to other TGF-β members. • the application only discloses that expression of GDF-9 is localised in ovarian tissues, but no function of the molecule => there is not enough evidence in the application to make at least plausible that a solution was found to the problem which was purportedly solved ...

  31. Article 56 EPC - Inventive step - plausibility/post-published evidence T 1329/04 (GDF-9, • post-published evidence: • establishing that GDF-9 was indeed a growth differentiation factor not accepted by the BoA  The said post-published documents are indeed the first disclosures going beyond speculation. For this reason, the post-published evidence may not be considered at all. Indeed, to do otherwise would imply that the recognition of a claimed subject-matter as a solution to a particular problem could vary as time went by.

  32. Following T 1329/04... • T 1306/04: confirms T 1329/04 (human PD-1 cDNA, post-published evidence regarding diagnosis of SLE, only vague reference to diagnosis of diseases in general in the application as filed: late evidence not accepted, solution of technical problem not plausible/credible) • T 1336/04: In spite of the lack of experiments in the application as filed, structure of the enzyme and prior art evidence that the application provides a bona-fide plausible solution to the problem of providing alternative endoglucanases. • T 0433/05 (Art. 56 EPC), T 1262/04, T0157/03 (Art. 83 EPC) late evidence also accepted.

  33. Article 83 (reproducibility) and post-published evidence • T0699/06: morphogens for stimulating non-skeletal tissue regeneration. Only evidence for r-human OP1. Late evidence not accepted (Art 83). • T609/02: if the application discloses only a vague indication of a medical use of a compound, later more detailed evidence cannot remedy the fundamental insufficiency. • Clinical trials not needed • verbal statements not sufficient • In vitro tests may be sufficient, as long as they evidence the effect of the compound on the metabolic mechanism involved in the disease... • post-published evidence only to back up the findings of the patent application.

  34. G1/07 - Surgical methods (Article 53(c)) • Exclusion of methods of surgery applied to all physical interventions in the human or animal body which require profession al medical skills to be carried out and which involve substantial health risks. • Methods involving invasive surgical techniques, which are generally carried out in a safe non-medical, commercial environment (e.g. a cosmetic salon) and on non-critical parts of the body, such as tattooing, piercing, hair removal by laser radiation, and micro-abrasion of skin are acceptable. • Analogous arguments apply to methods relating to routine interventions in the medical field which make use of in principle safe routine techniques, even when of invasive nature (reasons, point 3.4.2.2).

  35. G1/08, essentially biological processes (Article 53(b) • processes for producing plants containing (!) or consisting of crossing and selection are not patentable; • - the approach of T 320/87 (essence of the invention and the impact of human intervention as criteria for judging patentability) is also invalid; • - adding processing steps up-or downstream do not render the claims patentable; • - technical means, such as markers, used in such processes are patentable per se; • - a process involving inserting a gene or trait into a plant by genetic engineering does not rely on recombination of whole genomes and the natural mixing of plant genes, and is hence patentable. However, the claim may not contain crossing or selecting steps.

  36. Thank you for your attention

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