WORKING SESSION
Recent case law on patenting biotechnological inventions
Richard ARNOLD - Judge of the Patents Court, London - Case law from the Court of Justice of the European Union
Case C-34/10 Brüstle v Greenpeace eV [2011] ECR I-0000
Oliver Brüstle was the proprietor of a German patent concerning isolated and purified neural precursor cells, processes for their production from embryonic stem cells and the use of such cells to treat neural defects (such as Parkinson's disease). There were ethical barriers to the use of cerebral tissue from human embryos, but the patent noted that embryonic stem cells are pluripotent and so can develop into all types of cells and tissues, thus offering a new way to produce cells for such transplantation. The patent aimed to enable the production of an almost unlimited number of the desired precursor cells, obtained from embryonic stem cells.
On application by Greenpeace, the Bundespatentgericht (German Federal Patent Court) declared the patent invalid in so far as it covered precursor cells obtained from human embryonic stem cells and processes for the production of those precursor cells. The BPatG held that the invention was unpatentable under the domestic provision which implemented Article 6 of European Parliament and Council Directive 98/44/EC of 6 July 1998 on the legal protection of biotechnological inventions ("the Biotech Directive"). Article 6 provides:
"1. Inventions shall be considered unpatentable where their commercial exploitation would be contrary to ordre public or morality; however, exploitation shall not be deemed to be so contrary merely because it is prohibited by law or regulation.
2. On the basis of paragraph 1, the following, in particular, shall be considered unpatentable:
…
(c) uses of human embryos for industrial or commercial purposes;
…"
On appeal, the Bundesgerichtshof (German Federal Court of Justice) referred three questions concerning the interpretation of Article 6(2)(c) to the Court of Justice of the European Union.
Question 1
"What is meant by the term 'human embryos' in Article 6(2)(c) of [the Directive]?
(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:
- unfertilised human ova into which a cell nucleus from a mature human cell has been transplanted;
- 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?"
The CJEU noted at [25]-[29] that the term "human embryo" is not defined in the Directive, and so must designate an autonomous concept of EU law which must be interpreted in a uniform manner throughout the EU. The Court then stated at [30] that:
"As regards the meaning to be given to the concept of 'human embryo' set out in Article 6(2)(c) of the Directive, it should be pointed out that, although the definition of human embryo is a very sensitive social issue in many Member States, marked by their multiple traditions and value systems, the Court is not called upon, by the present order for reference, to broach questions of a medical or ethical nature, but must restrict itself to a legal interpretation of the relevant provisions of the Directive …"
Having referred to recitals 16 and 38, the Court went on to hold:
"34. The context and aim of the Directive thus show that the European Union legislature intended to exclude any possibility of patentability where respect for human dignity could thereby be affected. It follows that the concept of 'human embryo' within the meaning of Article 6(2)(c) of the Directive must be understood in a wide sense.
35. Accordingly, any human ovum must, as soon as fertilised, be regarded as a 'human embryo' within the meaning and for the purposes of the application of Article 6(2)(c) of the Directive, since that fertilisation is such as to commence the process of development of a human being.
36. That classification must also apply to a non-fertilised human ovum into which the cell nucleus from a mature human cell has been transplanted and a non-fertilised human ovum whose division and further development have been stimulated by parthenogenesis. Although those organisms have not, strictly speaking, been the object of fertilisation, due to the effect of the technique used to obtain them they are, as is apparent from the written observations presented to the Court, capable of commencing the process of development of a human being just as an embryo created by fertilisation of an ovum can do so.
37. As regards stem cells obtained from a human embryo at the blastocyst stage, it is for the referring court to ascertain, in the light of scientific developments, whether they are capable of commencing the process of development of a human being and, therefore, are included within the concept of 'human embryo' within the meaning and for the purposes of the application of Article 6(2)(c) of the Directive."
Question 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?"
The CJEU first pointed out at [40] that:
"… the purpose of the Directive is not to regulate the use of human embryos in the context of scientific research. It is limited to the patentability of biotechnological inventions."
Having held at [41] that "the grant of a patent implies, in principle, its industrial or commercial application", the Court went on to hold:
"43. Although the aim of scientific research must be distinguished from industrial or commercial purposes, the use of human embryos for the purposes of research which constitutes the subject-matter of a patent application cannot be separated from the patent itself and the rights attaching to it.
44. The clarification in recital 42 in the preamble to the Directive, that the exclusion from patentability set out in Article 6(2)(c) of the Directive 'does not affect inventions for therapeutic or diagnostic purposes which are applied to the human embryo and are useful to it' also confirms that the use of human embryos for purposes of scientific research which is the subject-matter of a patent application cannot be distinguished from industrial and commercial use and, thus, avoid exclusion from patentability."
As the Court noted, this interpretation is the same as that adopted by the Enlarged Board of Appeal of the EPO in relation to Rule 28(c) of the Implementing Regulations to the EPC in G 2/06 Use of embryos/WARF, OJ EPO 2009, 306.
Question 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:
- because the patent concerns a product whose production necessitates the prior destruction of human embryos,
- or because the patent concerns a process for which such a product is needed as base material?"
In considering this question, the CJEU noted at [48] that "the removal of a stem cell from a human embryo at the blastocyst stage entails the destruction of that embryo". It went on to hold:
"49. Accordingly, on the same grounds as those set out in paragraphs 32 to 35 above, an invention must be regarded as unpatentable, even if the claims of the patent do not concern the use of human embryos, where the implementation of the invention requires the destruction of human embryos. In that case too, the view must be taken that there is use of human embryos within the meaning of Article 6(2)(c) of the Directive. The fact that destruction 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 that regard, irrelevant.
50. 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 concerned redundant by allowing a patent applicant to avoid its application by skilful drafting of the claim."
Again, the Court noted that this interpretation was the same as that adopted by the Enlarged Board in G 2/06.
Case law from England and Wales
Human Genome Sciences Inc v Eli Lilly and Co [2011] UKSC 51, [2012] RPC 6
The patent in suit disclosed and claimed the nucleotide and amino acid sequence of a novel member of the TNF ligand superfamily of proteins called Neutrokine-α. Both Kitchin J (as he then was) ([2008] EWHC 1903 (Pat), [2008] RPC 29) and the Court of Appeal ([2010] EWCA Civ 33, [2010] RPC 14) held that the patent was invalid on the ground that the claimed inventions did not satisfy the requirement of industrial applicability under sections 1(1)(c) and 4 of the Patents Act 1977 corresponding to Articles 52(1) and 57 EPC.
The reasoning of Kitchin J was in essence that the patentee had done no more than find Neutrokine-α and identify it as member of the TNF ligand superfamily and that the indications of industrial application in the patent were no more than speculation. Thus the specification contained an astonishing range of diseases and conditions which Neutrokine-α and antibodies to Neutrokine-α might be used to diagnose and treat but there was no data of any kind to support the claims made. The skilled person would consider it totally far-fetched that Neutrokine-α could be used in relation to them all and would be driven to the conclusion that the authors had no clear idea what the activities of the protein were and so included every possibility. The fact that, in the light of the skilled person's common general knowledge, Neutrokine-α might be expected to play a role in regulating the activities of B cells and T cells and play an unspecified role in regulating the immune and inflammatory response did not reveal how it could be used to solve any particular problem. Neither the patent nor the common general knowledge identified any disease or condition which Neutrokine-α could be used to diagnose or treat. Its functions were, at best, a matter of expectation and then at far too high a level of generality to constitute a sound or concrete basis for anything except a research project.
The Court of Appeal agreed with this conclusion. It noted that in T 18/09 the EPO Technical Board of Appeal had reached a different conclusion, but also noted that the evidence before the English courts was different to that before the EPO.
The Supreme Court allowed the patentee's appeal. The leading judgment was given by Lord Neuberger and Lord Hope delivered a concurring judgment.
Lord Neuberger held at [91] that, given "the importance of UK patent law aligning itself, so far as possible, with the jurisprudence of the EPO", the right approach was to "take the law as being that laid down in the Board's jurisprudence", but that that did not necessarily mandate the same outcome as the Board had arrived at in T 18/09. Accordingly, the question for the Supreme Court to consider was whether or not the courts below had followed the EPO's jurisprudence. He held that they had not.
Lord Neuberger summarised the Board's jurisprudence on the requirements of Article 57 in relation to biological material as follows at [107]:
"The general principles are:
(i) The patent must disclose 'a practical application' and 'some profitable use' for the claimed substance, so that the ensuing monopoly 'can be expected [to lead to] some … commercial benefit' (T 870/04, para.4; T 898/05, paras.2 and 4);
(ii) A 'concrete benefit', namely the invention's 'use … in industrial practice' must be 'derivable directly from the description', coupled with common general knowledge (T 898/05, para.6; T 604/04, para.15);
(iii) A merely 'speculative' use will not suffice, so 'a vague and speculative indication of possible objectives that might or might not be achievable' will not do (T 870/04, para.21; T 898/05, paras.6 and 21);
(iv) The patent and common general knowledge must enable the skilled person 'to reproduce' or 'exploit' the claimed invention without 'undue burden', or having to carry out 'a research programme' (T 604/04, para.22; T 898/05, para.6);
Where a patent discloses a new protein and its encoding gene:
(v) The patent, when taken with common general knowledge, must demonstrate 'a real as opposed to a purely theoretical possibility of exploitation' (T 604/04, para.15; T 898/05, paras.6, 22 and 31);
(vi) Merely identifying the structure of a protein, without attributing to it a 'clear role', or 'suggest[ing]' any 'practical use' for it, or suggesting 'a vague and speculative indication of possible objectives that might be achieved', is not enough (T 870/04, paras.6–7, 11 and 21; T 898/05, paras.7, 10 and 31);
(vii) The absence of any experimental or wet lab evidence of activity of the claimed protein is not fatal (T 898/05, paras.21 and 31; T 1452/06, para.5);
(viii) A 'plausible' or 'reasonably credible' claimed use, or an 'educated guess', can suffice (T 1329/04, paras.6 and 11; T 640/04, para.6; T 898/05, paras.8, 21, 27 and 31; T 1452/06, para.6; T 1165/06 para.25);
(ix) Such plausibility can be assisted by being confirmed by 'later evidence', although later evidence on its own will not do (T 1329/04, para.12; T 898/05, para.24; T 1452/06, para.6; T 1165/06, para.25);
(x) The requirements of a plausible and specific possibility of exploitation can be at the biochemical, the cellular or the biological level (T 898/05, paras.29–30);
Where the protein is said to be a family or superfamily member:
(xi) If all known members have a 'role in the proliferation, differentiation and/or activation of immune cells' or 'function in controlling physiology, development and differentiation of mammalian cells', assigning a similar role to the protein may suffice (T 1329/04, para.13; T 898/85, para.21; T 1165/06, paras.14 and 16; T 870/04, para.12);
(xii) So 'the problem to be solved' in such a case can be 'isolating a further member of the [family]' (T 1329/04, para.4; T 604/04, para.22; T 1165/06, paras.14 and 16);
(xiii) If the disclosure is 'important to the pharmaceutical industry', the disclosure of the sequences of the protein and its gene may suffice, even though its role has not 'been clearly defined' (T 604/04, para.18);
(xiv) The position may be different if there is evidence, either in the patent or elsewhere, which calls the claimed role or membership of the family into question (T 898/05 para.24; T 1452/06, para.5);
(xv) The position may also be different if the known members have different activities, although they need not always be 'precisely interchangeable in terms of their biological action', and it may be acceptable if 'most' of them have a common role (T 870/04, para.12; T 604/04, para.16; T 898/05, para.27)."
Lord Neuberger considered that the decision in T 18/09 was consistent with the Board's jurisprudence, whereas the decisions of the courts below were not for the following reasons:
"108. … Kitchin J. concluded that (a) the Patent discloses Neutrokine-α as a new member of the TNF ligand superfamily; (b) all known members of the superfamily had pleiotropic effects, (c) there were some features which all those known members shared, such as expression by T-cells and a role in the regulation of T-cell proliferation and T-cell mediated responses; (d) however, there were other features which some family members had, but others did not; (e) it would be anticipated that the activities of Neutrokine-α 'might relate to T-cells and, in particular, be expressed on T-cells and be a co-stimulant of B-cell production; that it might play a role in the immune response and in the control of tumours and malignant disease; that it might have an effect on B-cell proliferation'; (f) subsequent research has confirmed that was indeed the case; (g) there was a search for new members of the family as they were of interest to the pharmaceutical industry.
109. In those circumstances, it seems to me that … the disclosure of the existence and structure of Neutrokine-α and its gene sequence, and its membership of the TNF ligand superfamily should have been sufficient, taking into account the common general knowledge, to satisfy the requirements of Article 57, in the light of the principles which I have attempted to summarise in para.107 above. Points (viii), (ix) and (x) appear to apply so far as the plausibility of at least some of the claims are concerned, and points (xi), (xii) and (xiii) all appear to be satisfied, given the evidence in relation to the TNF ligand superfamily (and point (xiv) cannot be invoked by Eli Lilly).
110. … I derive considerable assistance from the approach set out at T 18/09, para.22, which appears to me to be entirely consistent with the Board's earlier jurisprudence (as summarised in para.107 above), and the application in the ensuing four paragraphs, of that approach to the Board's view of what constituted the centrally relevant facts, which (subject to the arguments considered in the next section of this judgment) do not appear to me to be inconsistent with the findings made by Kitchin J.
111. … the Board's conclusion was effectively this, that the disclosure of what was accepted to be a new member of the TNF ligand superfamily (coupled with details of its tissue distribution) satisfied Article 57, because all known members were expressed on T-cells and were able to co-stimulate T-cell proliferation, and therefore Neutrokine-α would be expected to have a similar function. This conclusion was supported, or reinforced, by the statement that Neutrokine-α was expressed in B-cell and T-cell lymphomas (referred to in T 18/09, para.30), and indeed by the interest and effort in the pharmaceutical industry in finding a new member of the superfamily (as explained by Kitchin J. at [2008] R.P.C. 29, paras.72–74)."
MedImmune Ltd v Novartis Pharmaceuticals UK Ltd [2011] EWHC 1669 (Pat)
MedImmune was the joint owner and exclusive licensee of two patents for an antibody screening technique known as "antibody phage display". MedImmune claimed that Novartis had infringed the patents by selling a product called ranibizumab (trade mark Lucentis), a treatment for wet age-related macular degeneration in eyes which had been developed by Genentech. Novartis counterclaimed for revocation of the patents, attacking on the grounds of (1) lack of priority leading to invalidity over intervening prior art, (2) obviousness over a talk given by the scientist who developed the related technique of antigen phase display, (3) insufficiency and (4) added matter. The patents were held to be invalid for lack of priority and obviousness, but not insufficiency or added matter. It was also held that, if they had been valid, they would not have been infringed on the correct construction of the claims. On the other hand, it was held that, if ranibizumab was produced by a process falling within the claims, then it was a product obtained by means of that process. For the present purposes, the most interesting aspects of the decision are those concerning insufficiency and the issue of whether the product was obtained directly by means of the process.
Insufficiency
The court reviewed the law in light of three decisions of the House of Lords (namely Biogen v Medeva plc [1997] RPC 49, Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2004] UKHL 46, [2005] RPC 9 and Generics (UK) Ltd v H. Lundbeck A/S [2009] UKHL 12, [2009] RPC 13) and three decisions of EPO Technical Boards of Appeal (namely T 292/85 Genentech 1/Polypeptide expression OJ EPO 1989, 275, T 923/92 Genentech/Human t-PA OJ EPO 1996, 564 and T 1063/06 Bayer Schering Pharma AG /Reach-through claim OJ EPO 2009, 516).
Novartis argued that the breadth of the claims asserted by MedImmune exceeded the technical contribution to the art made by the invention. Novartis characterised the claims as "reach-through claims by stealth", on the basis that they claim the results of research by others extending well beyond the teaching of the specification. Thus in the present case, ranibizumab was alleged to infringe these claims even though (a) the specification did not mention antibodies for the treatment of age-related macular degeneration, (b) the specification did not identify the monoclonal antibody with which Genentech started, (c) the specification did not teach the skilled person how to humanise such a murine antibody, (d) the specification did not teach the team what changes were required to improve the affinity of the humanised antibody and (e) the specification teaches the skilled team nothing about other techniques which Genentech had employed.
On the assumption that the claims were to be construed as MedImmune contended, the claims extended to post-phage display mutation of (i) identifying a target, (ii) making an antibody library, (iii) screening that library by phage display, (iv) mutating the antibody fragment that was identified by phage display to improve its binding properties and (v) making that mutant in a recombinant system. Novartis argued that the technical contribution of the patents lay solely in step (iii), and that the patents taught the skilled team nothing about steps (i), (ii), (iv) or (v). Furthermore, Novartis said that, even so far as step (iii) was concerned, the technical contribution made by the patents was merely that screening by phage display is faster and easier than screening by the prior art technique called "plaque lift". According to Novartis, there was no evidence to show that the patented method is superior to prior art methods such as plaque lift in terms of finding binding molecules, although MedImmune disputed this.
Arnold J rejected this argument at [491] for the following reasons:
"In my judgment MedImmune is correct to characterise the invention disclosed in the Patents as a principle of general application. At its core, it is a technique for selecting a binding molecule of interest from amongst a potentially large population of other binding molecules. The technique does not depend on the precise identity of the binding molecule. On the contrary, part of the usefulness of the technique is that it can be applied to a diverse range of binding molecules, fragments and derivatives. Nor does the technique depend on the precise application which the user has in mind. Nor does implementation of the technique for the purpose of a new application involve undue burden on the part of the skilled team. …"
Product obtained directly by means of a process
MedImmune alleged infringement under section 60(1)(c) of the Patents Act 1977 corresponding to Article 64(2) EPC and Article 25(c) CPC. The leading English case on this provision is the decision of the Court of Appeal in Pioneer Electronics Capital Inc v Warner Music Manufacturing Europe GmbH [1997] RPC 757, in which Nourse LJ reviewed a number of German decisions and concluded at 771:
"This review of the relevant German authorities between 1897 and 1977 demonstrates their interconnection with a consistent thread: the product obtained directly by means of a patented process is the product with which the process ends; it does not cease to be the product so obtained if it is subjected to further processing which does not cause it to lose its identity, there being no such loss where it retains its essential characteristics."
Novartis accepted that, if the loss of identity test adopted in Pioneer v Warner was applied in the present case, then ranibizumab was a product obtained directly by the processes of the claim asserted by MedImmune. Novartis argued, however, that it could not be right to apply the loss of identity test without qualification in a case such as the present one. Instead, the test which should be applied was to focus upon the inventive claim, or inventive part of the claim, and ask whether the allegedly infringing product is obtained directly from that process. In support of this, Novartis pointed out that the claim of one of the patents which was alleged to be infringed (a) was narrower than claims were which were not alleged to be infringed and (b) differed from the claim which was relied on as being inventive only in the addition of conventional manufacturing steps.
Arnold J rejected this argument at [546]-[548] for three reasons. First, Pioneer v Warner was binding upon the Patents Court and the loss of identity test adopted by the Court of Appeal in that case was a general test stated without qualifications. Secondly, the Court of Appeal in that case had treated Dr Bruchhausen's analysis as authoritative. He was of the opinion that the issue depended on the manner in which the claims were drafted and that it was legitimate for the patentee to obtain protection going beyond an inventive intermediate by framing claims to the whole process. Thirdly, the argument was fundamentally one about territoriality. Novartis did not dispute that, if MedImmune was right on construction, then the claimed inventions were used by Genentech to produce ranibizumab. What Novartis was really saying was that MedImmune should have to sue Genentech for patent infringement in the USA, rather than Novartis in England. While the patent system is territorial, it is not rigidly so.
Novartis also argued that the patents were within the scope of Article 8(2) of the Biotech Directive, and that the effect of Article 8(2) was to circumscribe the protection conferred by the patents, with the result that (even if they would otherwise infringe by virtue of section 60(1) of the 1977), Novartis' acts in relation to ranibizumab did not infringe. Article 8(2) provides:
"The protection conferred by a patent on a process that enables a biological material to be produced possessing specific characteristics as a result of the invention shall extend to biological material directly obtained through that process and to any other biological material derived from the directly obtained biological material through the propagation or multiplication in an identical or divergent form and possessing those same characteristics."
Arnold J rejected this argument at [572]-[576] for the following reasons. First, he considered that the correct approach was to consider the protection conferred by the relevant claim. The claims asserted by MedImmune were claims to processes for the production of binding molecules. The binding molecules were not biological materials as defined in Article 2(1)(a) of the Directive. It was immaterial that the processes involved biological materials. Secondly, if Article 8(2) did apply to claims such as these, it would have surprising consequences. In particular, it would be difficult, if not impossible, to obtain patent protection for recombinant methods of producing proteins, since proteins are not "biological materials" within the definition in Article 2(1)(a), yet recombinant methods of producing them involve the production of biological materials. Thirdly, it appeared from Advocate General Jacobs' analysis in Case C-377/98 Kingdom of the Netherlands v European Parliament and Council of the European Union [2001] ECR I-7079 that the purpose of Article 8(2) was not to limit the protection conferred by process claims in patents for biotechnological inventions, but, if anything, to extend it.
Regeneron Pharmaceuticals Inc v Genentech Inc [2012] EWHC 657 (Pat)
Genentech was the proprietor of a patent for the use of a human VEGF (vascular endothelial growth factor) antagonist in the preparation of a medicament for the treatment of a non-neoplastic (i.e. non-cancerous) disease. Genentech claimed that Regeneron and Bayer would infringe the patent by marketing VEGF Trap Eye for the treatment of age-related macular degeneration. Regeneron and Bayer alleged that the patent was invalid on the grounds of lack of novelty, lack of inventive step and insufficiency. Floyd J held that the patent was valid and infringed.
Regeneron and Bayer alleged that the patent was insufficient on a number of grounds, only the first of which will be considered here. They argued that it was not possible to make a reasonable prediction from the data in the patent that anti-VEGF therapy would be effective in all non-neoplastic diseases as claimed. Accordingly, they said that the patent was insufficient for undue breadth of claim. Floyd J rejected this argument for the following reasons:
"189. I consider that the patent discloses a principle of general application within the meaning of the authorities insofar as it claims anti-VEGF antagonism as a treatment for all non-neoplastic diseases. The tumour data in the patent establish that VEGF blockade is likely to be a successful strategy for treatment in cancer. The skilled reader would appreciate that the reason it is likely to be successful is because blocking VEGF is a sufficient intervention to prevent angiogenesis, at least in models of cancer. It is common ground that it is possible to extrapolate that reasoning to at least some non-neoplastic diseases. …"
"191. It would of course not be possible to make a fair prediction if the evidence showed that angiogenesis was significantly different in character from disease to disease, so that entirely different molecules might be the target for VEGF antagonism in different diseases. In my judgment the evidence did not show this at all. ... Once the inventors had shown that blockade of VEGF was sufficient to prevent pathological angiogenesis in tumours, it was reasonable to predict that it would be sufficient in other diseases. Of course the patent had not proved that this was the case – but it does not have to. If the patent is to be held insufficient, therefore, it cannot be simply on the basis that it claims a therapeutic effect in all non-neoplastic diseases."