1. QMW lecture November 2015 - Biological Patents Lynn Kucernak GlaxoSmithKline Lynn.2.Kucernak@gsk.com

2. Agenda  Biotechnology inventions and products  Biotechnology patents - specific issues  Exclusions to patentability  Other criteria for patentability in relation to Biological inventions

3. Biotechnological products  Big business.  Vaccine market currently worth £5.2 billion per year (up 6% from 2003) –Wyeth’s Prevenar® vaccine makes >$1 billion per year.  Biopharmaceuticals market (including antibodies) currently over £10 billion per year – and increasing rapidly –Herceptin (mAb - breast cancer) ~$1.2bn in 2006  No real opposition to patents on such products –Possible “spill over” from issues raised in general to Biotech patents

4.  Biotechnological products per se –Recombinant proteins (erythropoietin) –Antibodies (Herceptin, Avastin) –Vaccines (Cervarix) Types of biotech inventions – part 1

5.  Claims based on genetic associations, eg. –Diagnostic claims  eg. testing for specific genes having an association with disease  Brca1 and breast cancer –Pharmacogenetics  selecting patients most likely to respond –Research Tools Types of biotech inventions - part 2

6. Research Tools  A biotech invention that aids research –transgenic animals or plants –gene and protein sequences (e.g. Gene promoter) –technologies that aid in screening for drugs –micro-organisms and cell lines –eg. Roche’s PCR technology platform

7. Biotechnology and patents Biological inventions are patentable in the same way as any other inventions [must be new, inventive and susceptible to industrial application] Long history of Biotech patents e.g. July 1873 Pasteur patented his improved method for making yeast at the FR patent office. However…..

8. Biotechnophobia!  Began in the US at the time of the Chakrabarty case (1980) –Bacterium capable of breaking down crude oil. Objected to by USPTO on basis that living things are not patentable –Court of Appeal overturned decision deciding that: Congress had intended patentable subject matter to "include anything under the sun that is made by man,"

9. Patenting Life!  Generally used as a rallying call regarding “ethical concerns” about the patenting of products derived from the human body –Although Art 53 EPC addresses these issues…  Errors at the EPO don’t help – EP0695351granted (the “Edinburgh patent”) and did not include the key words “non- human” in a claim which was then alleged (Greenpeace) to cover the cloning of humans. –EPO and proprietor unable to correct mistake - much embarrassment and negative publicity –14 opponents - EPO restricted the claim

10. Biopiracy and protection of Indigenous knowledge:  “Biopiracy” now defined in the OED as “bioprospecting, regarded as a form of exploitation of developing countries”. See also the Wikipedia definition and links.  Can be considered as the “appropriation and monopolisation of traditional populations knowledge and biological resources”.  There is an increasing concern regarding the “stealing” of indigenous knowledge from developing countries.  The Convention on Biodiversity (CBD) was signed at the Earth Summit in Rio in 1992 and came into force in Dec 1993.  Objectives include equitable sharing of benefits from use of genetic resources.  Has about 180 members, majority of countries, not the USA  Nagoya Protocol (part of the CBD) – into force 12 Oct 2014 – provides a legal framework for providers and users of genetic resources re benefit sharing

11. Biopiracy proposals:  Brazil, India, Pakistan, Peru, Thailand and Tanzania have proposed that the following be incorporated into TRIPS:  “where the subject matter of a patent application concerns, is derived from or developed with biological resources and/or associated traditional knowledge, Members shall requires applicants to disclose the country, from whom they were obtained, and as known after reasonable enquiry the country of origin. Members shall also require applicants to provide info for prior informed consent (PIC) and fair and equitable benefit sharing”  Increasingly countries are requiring patent applicants to disclose origin of biological materials and even PIC.

12. Problems re Disclosure of Origin reqts  Very significant burden on patentees, impractical, unclear.  How close to the original source does an invention need to be - where did HeLa cells or CHO cells come from?!  What about a vaccine based on work done in Belgium using a virus isolated from a bird in the UK which had flown there with flu from Vietnam? Do you need permission from Vietnam and a benefit sharing agreet before work begins ?  What should be the consequences of not meeting the requirements? Some countries state it should mean unenforceability of a patent.  What if the requirements are retroactive?  Many companies are already working with local peoples to harness knowledge and recompense appropriately.

13. EU Biotech Directive - History  Started in 1988  Failed in 1995  New mark II directive introduced shortly afterwards  Passed by EU parliament with large majority in May 1998 despite green opposition  EU member states required to implement the law within two years - i.e. July 2000 (but done v slowly!)  All new EU member states must implement the law before becoming members, also incorporated into the EPC

14. EU Biotech Directive - Has it worked?  Aim was to harmonise approaches to Biotechnology patent law across Europe.  Confirmed that (human) genes were patentable (but industrial application must be disclosed)  It has now FINALLY been implemented throughout Europe.  Implemented quite differently (and possibly unclearly) in different countries – has been described as “legislation for disharmony”.

15. Exclusions to Patentability in Europe: Art 53(b) EPC  Art 53 (b) European patents shall not be granted in respect of: plant or animal varieties or essentially biological processes for the production of plants or animals; this provision does not apply to microbiological processes or the products thereof.

16. Exclusions to Patentability: Art 53(b)  Does this mean that animals and plants can’t be patented? –Oncomouse –Plant Genetic Systems

17. OncoMouse: background  A laboratory mouse genetically modified to carry an activated oncogene  The activated oncogene increases susceptibility to cancer  OncoMouse is a good model for testing experimental anti-cancer drugs

18. OncoMouse: EPO history  European patent application 85304490.7 was filed in June 1985 by "The President and Fellows of Harvard College".  Application (EP 0 169 672) was refused by examining division, appeal filed, patent eventually issued in May 1992 and opposed by 17 opponents.  A decision upholding the patent in amended form was given in 2003, an appeal was filed, and decision eventually upheld in 2004.  Patent eventually revoked for failure to pay fees for grant and printing – deadline was after its expiry! –T 19/90 (appeal from Examining division OJEPO 12/1990, page 476 and OJEPO 10/1992, page 588) –T0315/03 (opp decision)

19. OncoMouse: is it an animal “variety” per Art 53(b)?  T19/90 Appeal from the Examining Division –Referred back to the Examining Division to decide:  whether the OncoMouse is an ‘animal variety’  Exam div wrong to exclude animals as such  Also discusses microbiological and biological processes for production – states patents are grantable for animals produced by a microbiological process

20. OncoMouse: Not an animal variety  OJEPO 10/1992, page 588 –Since mouse ‘mus’ is a genus, which is a taxonomic category higher than “species”, claims directed to transgenic mice were not considered to be excluded from Art53(b) –additionally held that no “essentially biological process” was involved (this would only apply to eg. natural breeding)

21. Plant varieties  Definitions of a “plant variety” exist –R26(4) EPC 2000 –‘UPOV’ International Convention for New Plant Varieties (1961; revised 1991) and the Community Regulation on Plant Variety Rights  UPOV set up to create a separate intellectual property right for plant breeders –administered in UK by the Plant Variety Rights Office (PVRO) –Variety must be distinct, uniform, stable and new –applicant has to provide a description and a quantity of seed/plant material

22. EPO Case law: plant varieties  T 356/93 Plant Cells/Plant Genetic Systems - technology  Claims covered, generically, genetically modified, herbicide resistant plants in which heterologous DNA had been inserted under the control of an appropriate promoter  The idea is that the DNA is expressed in the living plant to give a protein which neutralises glutamine synthetase inhibitors (used in herbicides) –Herbicide resistant plants

23. T 356/93 Plant cells/PLANT GENETIC SYSTEMS  Genetically engineered plants held to be unpatentable under the EPC!  Universally criticised as being a terrible decision: even by the President of the EPO  President thought that the reasoning of the Board - which seemed to say that generic claims embracing plant varieties were not patentable - was contrary to T 49/83* - and also OncoMouse; T 19/90  The point of law was referred to the Enlarged Board of Appeal by the President: G 3/95 – appeal found inadmissible! *Propagating material/CIBA-GEIGY, T 49/83, OJ. 3/1984, 112; claim for the treatment of a plant without creating a new species or variety approved

24. However...  To put this right a test case (T1054/96) was set up (“Novartis”)  This ultimately resulted in a referral to the Enlarged Board (G1/98), decided in December 1999  G1/98 held: A claim wherein specific plant varieties are not individually claimed is not excluded from patentability under Article 53(b) EPC even though it may embrace plant varieties.  This principle now set out in R27(b) EPC 2000

25. Furthermore...  Genetically modified plants/varieties are not necessarily to be treated as products of microbiological processes (otherwise all genetically modified plant varieties would be patentable without further argument)  Confirmed by Rule 27(c) which confirms that plant or animal varieties are not patentable even if they are the result of a microbiological process

26. The rationale being...  Inventions ineligible for protection under the plant breeders’ rights system were intended to be patentable under the EPC –But also exclude from patentability matter which is eligible for protection under the plant breeders’ rights system

27. Broccoli and Tomatoes… G2/07 – Broccoli (1) case and G1/08 Tomato (1) case  Re “essentially biological processes” –protests in July 2010 outside the EPO during 2 day prelim hearing by farmers and greenpeace activists arguing that patents covering vegetables should never have been granted and must be stopped.  EBA in Dec 2010 held that selection and breeding methods involving merely sexually crossing whole genomes – not patentable

28. Broccoli and Tomatoes…part 2  Further questions of law referred to the Enlarged B of Appeal (2 cases G2/12 and G2/13)  These were to clarify whether plants or plant parts obtained from non-patentable breeding methods (e.g. Biolog processes) are patentable – decided that they are patentable

29. Enough of Art 53(b) - how about the Article 53(a) - morality - exclusion?  European patents shall not be granted in respect of: (a) inventions the publication or exploitation of which would be contrary to “ordre public” or morality, provided that the exploitation shall not be deemed to be so contrary merely because it is prohibited by law or regulation in some or all of the Contracting States. –This provision has been a weapon for many oppositions against biotech patents by political groups

30. Rule 28 EPC 2000 – exceptions to patentability (Art 53a)  R28 gives examples of inventions that fall foul of A53(a): (a) Processes for cloning human beings (b) processes for modifying the germ line genetic identify of human beings (c) use 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 animals made by such processes

31. Article 53(a) – Case law This has come up, inter alia, in:  Harvard oncomouse (T19/90)  Plant Genetic Systems (T 356/93)  Relaxin (OJEPO 6/1995, 388)  Edinburgh Patent: EP 0695351

32. EPO position on Article 53(a) - Oncomouse  Oncomouse - need to perform balancing test to see whether invention is contrary to morality –Need to weigh up the suffering of the animal and possible risks to the environment, against the benefit to mankind of the invention

33. EPO position on Article 53(a) – PGS (see T356/93)  PGS: Morality and ordre public treated separately  Morality: Not wrong as such in the light of conventionally accepted standards of European culture  Ordre public i.e. security (also incl protection of the environment): ‘It would be unjustified to deny a patent under Article 53(a) EPC on the basis of possible, not yet conclusively documented hazards.’

34. EPO position on Art 53(a) – Relaxin (T0272/95) “…the allegation that human life is being patented is unfounded. It is worth pointing out that DNA is not “life” but a chemical substance which carries genetic information and can be used as an intermediate in the production of proteins which may be medically useful. The patenting of a single human gene has nothing to do with the patenting of human life. Even if every gene in the genome were cloned (and possibly patented), it would be impossible to reconstitute a human being from the sum of its genes” Also burden of proof on opponents to show an invention falls foul of A 53a EPO Opposition Division in the RELAXIN case OJEPO 6/1995, 388

35. Patentability of embryonic stem cells  EPO - OD in T1079/03 (“Edinburgh” patent) held Rule 28(c) EPC exclusion to include human stem cells obtained by previous destruction of embryos –Patent maintained in amended form - modified human and animal stem cells other than embryonic stem cells

36. Patentability of embryonic stem cells  On basis of Edinburgh decision, Wisconsin Alumni Research Foundation (WARF) case refused at ED level. Claims did not relate to human embryos, but to immortalised cell lines obtained from human embryos. –Applicant appealed against refusal by the Examining Division– In T1374/04 (November 2005) the Technical Board decided to refer questions of law to the Enlarged Board of Appeal:

37. WARF questions referred to the EBA – G2/06. 1. Does Rule 23d(c) (R28 EPC 2000) EPC apply to an application filed before its entry into force? 2. If yes, does Rule 23d(c) EPC forbid the patenting of claims directed to products (here: human embryonic stem cell cultures) 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, if the said method is not part of the claims? 3.If the answer to question 1 and 2 is no, does Article 53(a) EPC forbid patenting such claims? 4. Is it of relevance that after the filing date the same products could be obtained without having to recur to a method necessarily involving the destruction of human embryos (here: eg derivation from available human embryonic cell lines)

38. G2/06 – the answers (Nov 2008)  The provision relates to “inventions” not merely the wording of the claims. It is the teaching of the application as a whole that matters.  WARF invention was immoral (to the extent it related to human embryonic stem cells).  It was irrelevant that, subsequent to the filing date the invention could be performed in an “innocuous manner”.  Board clearly emphasised that this ruling was not relevant to the patentability in general of inventions relating to human stem cells, but only to those which can only be obtained by destroying human embryos.

39. Stem cells cont...  UK IPO revised practice in Feb 2009 in light of G2/06 (and Brustle) and again in 2012 in view of CJEU decision on patentability of human embryos  Will not now grant patents on processes for obtaining stem cells from human embryos or for stem cells that can only be obtained via the destruction of human embryos  CJEU Decision Oct 2011 (in Brustle v Greenpeace): Effectively prohibits patenting of inventions derived from human embryos (if it requires their destruction).

40. Stem cells and human embryos...  CJEU Brustle decision (C-34/10) in Oct 2011 – defined scope of term “human embryo” fairly broadly as ”any organism that is capable of commencing the process of development of a human being”  Ruled that exclusion from patentability applies to any invention which requires the destruction of human embryos (even if the claims of the patent do not refer to embryos)

41. Stem cells and human embryos contd  Another ref made in July 2013 by UK high CT to CJEU  case is International Stem Cell Corporation ("ISCC") v Comptroller General of Patents. The question referred concerns whether stem cells obtained from parthenogenetically stimulated human ova are excluded from patentability as "human embryos".  ISCC argues that the CJEU ruling on Brüstle's technology does include parthenogenetically-activated ova. On the contrary, ISCC argued that parthenogenetically activated stem cells were not excluded from patentability.

42. Stem cells and human embryos contd  CJEU decided that parthenotes did not fall within the intended scope of “human embryo”  CT also clarified definition of term human embryo – it includes a non-fertilised ovum that has the capacity of developing into a human but not a non-fertilised ovum that lacks this ability  Will see how the EPO and nat patent offices interpret the ISCC decision as the CJEU left it up to nat offices to determine on a case by case basis if an unfertilised human ovum can develop to a human

43. EPC: Other criteria for patentability  A52(2)(a): “Discoveries” not to be regarded as inventions –Are natural products, proteins and genes “discovery” or invention?  Rules 26, 27, 28 and 29 EPC 2000 –Rule 26 EPC 2000: Definitions –Rule 27 EPC 2000: Patentable biotechnological inventions –Rule 28 EPC 2000: Exceptions to patentability –Rule 29 EPC 2000: The human body and its elements

44. Rule 27 EPC 2000: Patentable biotechnological inventions – “Isolated elements” Biotechnological inventions shall also be patentable if they concern: (a) biological material which is isolated from its natural environment or produced by means of a technical process even if it previously occurred in Nature.

45. Rule 29(1) EPC 2000 - The human body and its elements  The human body, at the various stages of its formation and development, and the simple discovery of one of its elements including the sequence or partial sequence of a gene, cannot constitute patentable inventions –Based on article 5.1 of the Biotech Directive

46. Rule 29(2) EPC 2000 - The human body and its elements  Rule 29(2) EPC 2000 an element isolated from the human body or otherwise produced by means of a technical process, including the sequence or partial sequence of a gene, may constitute a patentable invention, even if the structure of that element is identical to that of a natural element. –Based on article 5.2 of the Biotech Directive –Contrast With Myriad decision in USA June 2013

47. Rule 29(3) EPC 2000 - The human body and its elements  Rule 29(3) EPC 2000 The industrial application of a sequence or partial sequence of a gene must be disclosed in the patent application

48. Other requirements for patentability Article 54 EPC - Novelty  A natural product is novel if it is claimed in a form in which it does not occur in nature, and thus is patentable if all other criteria for patentability are satisfied. –That is, a claim which covers a gene sequence in-situ is not novel. –an isolated gene sequence is novel

49. Other requirements for patentability Article 57 EPC - Industrial Application  Generally a very easy requirement to meet, but...  R29(3) EPC 2000 - the industrial application of a sequence or a partial sequence of a gene must be disclosed in the patent application  To the EPO this means that you must show that at the time of filing you were aware of a credible use of the DNA (e.g. as a DNA vaccine or in gene therapy) or the encoded protein as therapeutic or screening target –cannot be fixed during prosecution

50. HGS V Lilly – UK High CT (July 2008)  Mr. Justice Kitchin considered EP, UK and US case law on industrial applicability, plus the Biotech Directive and identified some key principles.  Key amongst these is that it there must be evident to the skilled person a practical way of exploiting the invention.  In return for a monopoly, the patentee must make a full disclosure of his invention, including a practical use to which it can be put. A patent is not a hunting license to find such a use.

51. HGS V Lilly – UK High CT  July 2008 judgement: patent held invalid for lack of industrial application in 1996 as it was only subsequent research which had shown that the proteins and abs in the patent had a therapeutic use – asserts the patent did little more than speculate as to how Neutrokine alpha may be useful  Also held invalid on basis of lack of inventive step

52. HGS V Lilly – Ct of Appeal (Feb 2010)  Upheld the decision of Kitchin J that the EP (UK) patent was invalid on the grounds of lack of industrial applicability  LJ Jacob: “In reality one was faced with a research program to see which, if any, of the possible uses of the Neutrokine alpha or its antagonists was real”  None of the post-published evidence put forward by HGS was considered

53. HGS V Lilly – UK Supreme CT….  Supreme CT granted HGS permission to appeal the decision of CT of Appeal, 3 day hearing in July 2011  Supreme CT Decision issued 2 Nov 2011  Decision reversed that of lower courts – evidence of clinical tests not needed in a patent application to show industrial application  Supreme Ct decision pointed to policy aims that Biotech investment should be encouraged, cited EPO case law to support a lower threshold for industrial applicability, UK should align their interpretation of the EPC with that of other states

54. HGS case at the EPO  At first instance (OD), the case was refused for similar reasons to that in the UK high court (Dec 2008).  The Technical Board of Appeal upheld the patent (2010) (see T0018/09).  Industrial applicability, sufficiency and inventive step were heard together.  The Board held that the patent plausibly provided a new member of the TNF family, and that it had an immediate and concrete technical benefit.  The patent showed homology to other TNF family members, and also showed that the gene had all the TNF domains and a tissue distribution consistent with the TNF family.  The patent predicted that the protein would be implicated in diseases of the immune system.

55. Infringement/Enforceability of gene patents – v complex area:  Monsanto v Cefetra (ECJ DECISION 2010)  Monsanto holds an EP patent that covers modified soybean DNA sequences conferring herbicide resistance (“Roundup Ready”)  Cefetra makes soy meal in Argentina originating from the herbicide resistant plants (no Monsanto patent in Arg) and exports it to EP.  The soymeal (containing dead versions of the DNA seq covered by Monsantos EP patent) was seized by Dutch customs and Monsanto sued Cefetra on the grounds they were importing a patented product (the DNA seq) into the Netherlands  Cefetra contended that Dutch law was overridden by the EU Biotech directive

56. Monsanto v Cefetra  The Biotechnology Directive requires that member states grant patents on “biotechnological inventions” (Article 1), but then provides more specifically in Article 9 that:  The protection conferred by a patent on a product containing or consisting of genetic information shall extend to all material... in which the product is incorporated and in which the genetic information is contained and performs its function.  Referred by the Dutch Courts to the ECJ.  ECJ (July 2010) found Dutch law did violate A 9 of the Biotech directive.  ECJ also held that a gene must be performing its function at the time of the infringing act to be protected.  Because the DNA seq in the imported material were “dead material” and so not performing their function, no longer any protection

57. Some things to think about?  Moral issues are always subjective - who should decide?  Should patent offices really be the determiners of public policy?  Remember that a patent is a negative right, and does not necessarily give you the right to carry out your invention - a key misunderstanding by the media and the public.  Can we really have European wide standards?

58. And finally….  Patenting in biotechnology is a tricky area – v complex and evolving  But it’s where the action is! - in terms of case law - in terms of politics (e.g. EU Biotech Directive and its implementation, Myriad in the US) - In terms of broader ethical questions - In terms of importance to the Industry - And continues to be a subject of heated debate!