“I think one can draw from this case that the Court, in considering the skills of the notional ‘person skilled in the art’ for the purposes of obviousness will have regard to the reality of the position at the time. What the combined skills (and mindsets) of real research teams in the art is what matters when one is constructing the notional research team to whom the invention must be obvious if the Patent is to be found invalid on this ground.”
“This case law was confirmed in T 500/91 – ‘BIOGEN II’. The board ruled that the average skilled person - who might also be a team of specialists in the relevant field - operated at a practical level, and the technical development which might normally be expected of him did not include solving technical problems through scientific research. From the notional skilled person nothing more can be expected than the carrying out of experimental work by routine means within the framework of the normal practice of filling gaps in knowledge by the application of existing knowledge (T 886/91, T 223/92, T 530/95, T 791/96).”
“Experts—overriding duty to the court 35.3(1) It is the duty of experts to help the court on matters within their expertise. (2) This duty overrides any obligation to the person from whom experts have received instructions or by whom they are paid. … Contents of report 35.10(1) An expert’s report must comply with the requirements set out inPractice Direction 35 . (2) At the end of an expert’s report there must be a statement that the expert understands and has complied with their duty to the court. (3) The expert’s report must state the substance of all material instructions, whether written or oral, on the basis of which the report was written. …”
“2.1 Expert evidence should be the independent product of the expert uninfluenced by the pressures of litigation. 2.2 Experts should assist the court by providing objective, unbiased opinions on matters within their expertise, and should not assume the role of an advocate. 2.3 Experts should consider all material facts, including those which might detract from their opinions.”
“3.1 An expert’s report should be addressed to the court and not to the party from whom the expert has received instructions. 3.2 An expert’s report must: (1) give details of the expert’s qualifications; (2) give details of any literature or other material which has been relied on in making the report; (3) contain a statement setting out the substance of all facts and instructions which are material to the opinions expressed in the report or upon which those opinions are based; (4) make clear which of the facts stated in the report are within the expert’s own knowledge; (5) say who carried out any examination, measurement, test or experiment which the expert has used for the report, give the qualifications of that person, and say whether or not the test or experiment has been carried out under the expert’s supervision; (6) where there is a range of opinion on the matters dealt with in the report – (a) summarise the range of opinions; and (b) give reasons for the expert’s own opinion; (7) contain a summary of the conclusions reached; (8) if the expert is not able to give an opinion without qualification, state the qualification; and (9) contain a statement that the expert – (a) understands their duty to the court, and has complied with that duty; and (b) is aware of the requirements of Part 35, this practice direction and the Protocol for Instruction of Experts to give Evidence in Civil Claims. 3.3 An expert’s report must be verified by a statement of truth in the following form – ‘I confirm that I have made clear which facts and matters referred to in this report are within my own knowledge and which are not. Those that are within my own knowledge I confirm to be true. The opinions I have expressed represent my true and complete professional opinions on the matters to which they refer.’” 3.2 An expert’s report must: (1) give details of the expert’s qualifications; (2) give details of any literature or other material which has been relied on in making the report; (3) contain a statement setting out the substance of all facts and instructions which are material to the opinions expressed in the report or upon which those opinions are based; (4) make clear which of the facts stated in the report are within the expert’s own knowledge; (5) say who carried out any examination, measurement, test or experiment which the expert has used for the report, give the qualifications of that person, and say whether or not the test or experiment has been carried out under the expert’s supervision; (6) where there is a range of opinion on the matters dealt with in the report – (a) summarise the range of opinions; and (b) give reasons for the expert’s own opinion; (7) contain a summary of the conclusions reached; (8) if the expert is not able to give an opinion without qualification, state the qualification; and (9) contain a statement that the expert – (a) understands their duty to the court, and has complied with that duty; and (b) is aware of the requirements of Part 35, this practice direction and the Protocol for Instruction of Experts to give Evidence in Civil Claims. ‘I confirm that I have made clear which facts and matters referred to in this report are within my own knowledge and which are not. Those that are within my own knowledge I confirm to be true. The opinions I have expressed represent my true and complete professional opinions on the matters to which they refer.’”
“1. Introduction Expert witnesses perform a vital role in civil litigation. It is essential that both those who instruct experts and experts themselves are given clear guidance as to what they are expected to do in civil proceedings. The purpose of this Protocol is to provide such guidance…. 2. Aims of Protocol 2.1 This Protocol offers guidance to experts and to those instructing them in the interpretation of and compliance with Part 35 of the Civil Procedure Rules (CPR 35 ) and its associated Practice Direction (PD 35 ) and to further the objectives of the Civil Procedure Rules in general. It is intended to assist in the interpretation of those provisions in the interests of good practice but it does not replace them. It sets out standards for the use of experts and the conduct of experts and those who instruct them. The existence of this Protocol does not remove the need for experts and those who instruct them to be familiar with CPR35 andPD35 . … 3. Application … 3.3 Experts, and those instructing them, should be aware that some cases may be ‘specialist proceedings’ (CPR 49 ) where there are modifications to the Civil Procedure Rules. Proceedings may also be governed by other Protocols. Further, some courts have published their own Guides which supplement the Civil Procedure Rules for proceedings in those courts. They contain provisions affecting expert evidence. Expert witnesses and those instructing them should be familiar with them when they are relevant. … 4. Duties of experts 4.1 Experts always owe a duty to exercise reasonable skill and care to those instructing them, and to comply with any relevant professional code of ethics. However when they are instructed to give or prepare evidence for the purpose of civil proceedings in England and Wales they have an overriding duty to help the court on matters within their expertise (CPR 35.3 ). This duty overrides any obligation to the person instructing or paying them. Experts must not serve the exclusive interest of those who retain them. … 4.3 Experts should provide opinions which are independent, regardless of the pressures of litigation. In this context, a useful test of ‘independence’ is that the expert would express the same opinion if given the same instructions by an opposing party. Experts should not take it upon themselves to promote the point of view of the party instructing them or engage in the role of advocates. … 8. Instructions 8.1 Those instructing experts should ensure that they give clear instructions, including the following: … (c) the purpose of requesting the advice or report, a description of the matter(s) to be investigated, the principal known issues and the identity of all parties; …”
“While some degree of consultation between experts and legal advisers is entirely proper, it [is] necessary that expert evidence presented to the court should be, and should be seen to be, the independent product of the expert, uninfluenced as to form or content by the exigencies of litigation.”
“I meant, my Lord, in the sense that I have never been an antibody engineer or a molecular immunologist. My role would be as part of a team, if you like, [a] hypothetical role, in working with the team to help them achieve the end of expressing and producing an antibody. As a molecular biologist who has no experience of doing just that with antibodies, though I have done it with other proteins, and who has no deep knowledge or real interest in antibody structure per se, then I can only look in from outside. I am not an expert in antibody structure, antibody function or antibody engineering. So I do not sit here as an expert in those topics. In that sense I am looking in from outside.”
“A composition of matter comprising a plurality of cells containing diverse combinations of first and second DNA sequences encoding first and second polypeptides which form heteromeric receptors, one or both of said polypeptides being expressed as fusion proteins on the surface of a cell.”
“A cloning system for the coexpression of two or more DNA sequences encoding polypeptides which form a heteromeric receptor, comprising a set of first vectors having a diverse population of first DNA sequences and a set of second vectors having a diverse population [of] second DNA sequences, said first and second vectors having two pairs of restriction sites symmetrically oriented about a cloning site for containing said first and second populations of DNA sequences so as to allow only the operational combination of vector sequences containing said first and second DNA sequences.”
“The size of the mammalian antibody repertoire is difficult to judge, but a figure of the order of 10 6 to l0 8 different antigen specificities is often quoted. With some of the reservations discussed below, a phage library of this size or larger can readily be constructed by a modification of the method described. Once an initial combinatorial library has been constructed, heavy and light chains can be shuffled to obtain libraries of exceptionally large numbers.” 165. In relation to diversity, the authors say: “In principle, the diversity, characteristics of the naive (unimmunized) in vivo repertoire and corresponding phage library are expected to be similar in that both involve a random combination of heavy and light chains. However, different factors act to restrict the diversity expressed by an in vivo repertoire and phage library.”
“In practical terms the phage library is much easier to access. The screening methods used have allowed one to survey the gene products of at least 50,000 clones per plate so that 10 6 to 10 7 antibodies can be readily examined in a day.”
“Foreign DNA fragments can be inserted into filamentous phage gene III to create a fusion protein with the foreign sequence in the middle. The fusion protein is incorporated into the virion, which retains infectivity and displays the foreign amino acids in immunologically accessible form. These ‘fusion phage’ can be enriched more than 1000-fold over ordinary phage by affinity for antibody directed against the foreign sequence. Fusion phage may provide a simple way of cloning a gene when an antibody against the product of that gene is available.”
“Foreign DNA fragments can be inserted into a minor coat protein gene of filamentous phage, creating a fusion protein that is incorporated into the virion; we call these particles ‘fusion phage’. The foreign amino acids are displayed on the surface, allowing fusion phage bearing antigenic determinants from a target gene to be purified in infectious form by affinity to antibody directed against the gene product. Here we introduce fusion-phage vectors that accept foreign DNA inserts with little effect on phage function; and describe affinity purification of virions bearing a target determinant from a 10 8 fold excess of phage not bearing the determinant, using minute amounts of antibody. These ‘antibody-selectable’ vectors are a promising alternative to conventional expression systems for using antibodies to clone genes, though the ability to isolate rare clones from actual libraries remains to be demonstrated.”
“Tens of millions of short peptides can be easily surveyed for tight binding to an antibody, receptor or other binding protein using an ‘epitope library.’ The library is a vast mixture of filamentous phage clones, each displaying one peptide sequence on the virion surface. The survey is accomplished by using the binding protein to affinity purify phage that display tight-binding peptides and propagating the purified phage in Escherichia coli. The amino acid sequences of the peptides displayed on the phage are then determined by sequencing the corresponding coding region in the viral DNA’s. Potential applications of the epitope library include investigation of the specificity of antibodies and discovery of mimetic drug candidates.”
“The present invention relates to binding substances. The present invention also relates to methods for the production of binding substances eg binding molecules and to the biological binding molecules produced by these methods. The present invention also relates to: a) the production of antibodies, receptor molecules and fragments and derivatives of these antibodies and receptor molecules; b) viruses encoding the above identified molecules which viruses have the ability to present said molecules at their surfaces; c) packages comprising a virus and an above identified molecule presented at the viral surface; and d) screening techniques utilising the unique properties of these packages.”
“Whilst monoclonal antibodies, their fragments and derivatives have been enormously advantageous, there are nevertheless a number of limitations associated with them.”
“Secondly, a key aspect in the isolation of monoclonal antibodies is how many different antibody producing cells with different specificities, can be sampled compared to how many need to be sampled in order to isolate a cell producing antibody with the desired specificity characteristics (Milstein, C., Royal Soc. Croonian Lecture, Proc. R. Soc. London B. 239; 1-16, (1990)). For example, the number of different specificities expressed at anyone time by lymphocytes of the murine immune system is thought to be approximately 10 7 and this is only a small proportion of the potential repertoire of specificities. However, during the isolation of a typical antibody producing cell with a desired specificity, the investigator is only able to sample 10 3 to 10 4 individual specificities. The problem is worse in the human, where one has approximately 10 12 lymphocyte specificities, with the limitation on sampling of 10 3 or 10 4 remaining.”
“Conversely, some of these techniques can exacerbate the screening problems. For example, large separate heavy and light chain libraries have been produced from immunized mice and combined together in a random combinatorial manner prior to screening (Huse, W.D. et al., 1989, Science 246, 1275- 1281). Crucially however, the information held within each cell, namely the specific combination of one light chain with one heavy chain, is lost. This loses most, if not all, of the advantage gained by using immunization protocols in the animal. Currently, only libraries derived from single heavy chain variable domains (dAbs; Ward, E.S., et a1., 1989, supra.) do not suffer this drawback, but because not all antibody heavy chain variable regions are capable of binding antigen, more have to be screened. In addition, the problem of directly screening many different specificities in prokaryotes remains to be solved.”
“The ideal system would allow the sampling of very large numbers of specificities (eg of the order of 10 6 and higher) rapid sorting at each cloning round, and rapid transfer of genetic material coding for the binding molecule from one stage of the production process, to the next stage.”
“It has already been shown that antibody fragments can be secreted through bacterial membranes with the appropriate signal peptide (Skerra, A., and Pluckthun, A., 1988, Science 240, 1038-1040; Better, M. et al., 1988, Science 240, 10411043). However, it has not been shown how an antibody or antibody fragment can be held on the bacterial cell surface in a configuration which allows efficient sampling of its antigen binding properties.”
“The problem of how to use bacteriophages is in fact a difficult one. The antibody molecule must be inserted into the phage in such a way that the integrity of the phage coat is not undermined, and the antibody itself should be biologically active. Thus the antibody should fold efficiently and correctly and be presented for antigen binding. However, solving the problem for antibody molecules and fragments would also provide a general method for the screening of many receptor molecules.”
“Surprisingly, the applicants have been able to construct a bacteriophage that expresses and presents on its surface large binding molecules (eg large biologically functional antibody molecules) and which remains intact and infectious. The applicants have called the structure which comprises a virus particle and a binding molecule presented at the viral surface a ‘package’. Where the binding molecule is an antibody (or a fragment or derivative of an antibody), the applicants call the package a phage antibody. However, except where the context demands otherwise, where the term phage antibody is used generally it should also be interpreted as referring to any package comprising a virus particle and a binding molecule presented at the viral surface.”
“For example, V-gene repertoires could be made in vitro by combining unrearranged V genes, with D and J segments. Libraries of pAbs could then be selected by binding to antigen, hypermutated in the antigen-binding loops in vitro and subjected to further rounds of selection and mutagenesis.”
“The present invention provides a method for producing a package which method comprises the steps of: a) inserting a nucleotide sequence encoding the binding molecule within a viral genome; b) culturing the virus containing said nucleotide sequence, so that said binding molecule is expressed by the virus presented at its surface. The present invention also provides a method for producing a binding molecule specific for a particular epitope which comprises producing a package as described above and the additional step of screening for said binding molecule by binding of said molecule to said epitope. The method may comprise one or more of the additional steps of: i) separating the package from the epitope; ii) recovering said package; and iii) using the inserted nucleotide sequence in a recombinant system to produce the binding molecule separate from the virus. The screening step may isolate the nucleotide sequence encoding the binding molecule of desired specificity, by virtue of said binding molecule being expressed in association with the surface of the virus. In the above methods, the binding molecule may be an antibody, or a fragment or derivative of an antibody. Alternatively, the binding molecule may be an enzyme or receptor and fragments/ derivatives of any such enzymes or receptors. In the above methods, the virus may be a filamentous Fspecific bacteriophage. The filamentous F-specific bacteriophage may be fd. In particular, it may be a tetracycline resistant version of fd known as fd tet. The nucleotide sequence may be inserted within the gene III region of fd. The sequence may be inserted after the signal sequence of gene III, preferably after amino acid+1 of the mature protein. The site for insertion may be flanked by short sequences corresponding to sequences which occur at each end of the DNA to be inserted. … … In the above methods the nucleotide sequences inserted within the viral genome may be derived from eg mammalian spleen cells or peripheral blood lymphocytes. The mammal may be immunised or non-immunised. Alternatively, the nucleotide sequence may be derived by the in vitro mutagenesis of an existing antibody coding sequence. The phage particle presenting said binding molecule may remain intact and infectious.”
“As previously mentioned, the present invention also provides novel screening systems and assay formats. In these systems and formats the gene sequence encoding the binding molecule (eg the antibody) of desired specificity is separated from the general population having a range of specificities by the fact of its binding to a specific target (eg the antigen or epitope). Thus, the present invention provides a method of screening a population of phage antibodies (where the binding molecule is an antibody) for a phage antibody with a desired specificity, which comprises contacting said population of phage antibodies with a desired epitope and separating phage antibody which binds to said epitope, from said epitope. The means for separating any binding phage antibodies may be varied in order to obtain binding phage antibodies with different binding affinities for said epitope.”
“Although these phages do not kill their host during normal replication, disruption of some of their genes can lead to cell death (Kornberg, A., 1980 supra.) This places some restraint on their use. The applicants have recognized that gene III of phage fd is an attractive possibility for the insertion of biologically active foreign sequences. The protein itself is only a minor component of the phage coat and disruption of the gene does not lead to cell death (Smith, G. 1988, Virology 167: 156-165). Furthermore, it is possible to insert some foreign sequences (with no biological function) into various positions within this gene (Smith, G., 1985 Science 228: 1315-1317., Parmley, S.F. and Smith, G.P Gene: 73 (1988) p. 305-318., and de la Cruz, V.F., et al., 1988, J. Biol. Chem., 263: 4318-4322). In these cases, although the infectivity of the virion was disrupted, the inserted sequences could be detected on the phage surface.”
“The insertion is large, 100-200 amino acids; the antibody derived domain must fold efficiently and correctly to retain antigen-binding; and most of the functions of gene III must be retained.”
“Surprisingly, by manipulating gene III of bacteriophage fd, the present applicants have been able to construct a bacteriophage that expresses on its surface large biologically functional antibody molecules and which remains intact and infectious. Furthermore, the phages bearing antibodies of the correct specificity, can be selected from a background where the majority of phages do no [sic] show this specificity.”
“The efficiency of this screening procedure for phage antibodies and the ability to create very large libraries means that the immunisation techniques developed to increase the proportion of screened cells producing antibodies of interest will not be an absolute requirement. The technique allows the rapid isolation of antigen-binding specificities, including those that would be difficult or even unobtainable by conventional techniques, for example, catalytic or anti-idiotypic antibodies. Removal of the animal altogether is now possible once a complete library of the immune repertoire has been constructed.” constructed.”
“The applicants have also devised a series of novel screening techniques that are practicable only because of the unique properties of phage antibodies. The general outline of some screening procedures is illustrated in figure 2. The population/library of phage antibodies to be screened could be generated from immunised or other animals; or be created in vitro by mutagenising pre-existing phage antibodies… This population can be screened in one or more of the formats described below with reference to figure 2, to derive those individual phage antibodies whose antigen binding properties are different from sample c.”
“Clearly, alternative constructions will be apparent to those skilled in the art. For example, M13 and/or its host bacteria could be modified such that its gene III could be disrupted without the onset of excessive cell death; the modified fd gene III, or other modified protein, could be incorporated into a plasmid containing a single stranded phage replication origin, such as pUC119, superinfection with modified phage such as K07 would then result in the encapsulation of the phage antibody genome in a coat partially derived from the helper phage and partly from the phage antibody gene III construct.”
“The results … show that the antibody bearing-phage had the same pattern of reactivity as the original D1.3 antibody … , and bound to hen egg-white lysozyme, but not to turkey egg-white lysozyme, human lysozyme or bovine serum albumin. The specificity of the phage is particularly illustrated by the lack of binding to the turkey egg-white lysozyme that differs from hen egg-white lysozyme by only 7 amino acids.”
“It is possible to express the light chain from within the pAb genome by, for example, cloning an expression cassette into a suitable place in the phage genome. Such a suitable place would be the intergenic region which houses the multicloning sites engineered into derivative [sic] of the related phage M13 (see, for example, Yanisch-Perron, C. et al., Gene 33, p103119, (1985)).”
“The results (Figure 11) showed that when the heavy and light chain Fab derivatives from the original antibody D1.3 were present, the pAb bound to lysozyme. pAb expressing the fd VHCH1 fragment did not bind to lysozyme unless grown in cells also expressing the light chain. This shows that a functional Fab fragment was produced by an association of the free light chain with the VHCHl fragment fused to gene III and expressed on the surface of the pAb.”
“Bass et al., in December 1990 (after the earliest priority date for the 5 present application) describe deleting part of gene III of the filamentous bacteriophage M13 and inserting the coding sequence for human growth hormone (hGH) into the Nterminal site of the gene. The growth hormone displayed by M13 was shown to be functional. (Bass, S., et al. Proteins, Structure, Function and Genetics (1990) 8: 309-314). A functional copy of gene III was always present in addition, when this fusion was expressed. A Protein Engineering Corporation patent application W090/02809 proposes the insertion of the coding sequence for bovine pancreatic trypsin inhibitor (BPTI) into gene VIII of M13. However, the proposal was not shown to be operative. For example, there is no demonstration of the expression of BPTI sequences as fusions with protein VIII and display on the surface of M13. Furthermore this document teaches that when a fusion is made with gene Ill, it is necessary to use a second synthetic copy of gene Ill, so that some unaltered gene III protein will be present. The embodiments of the present application do not do this. In embodiments where phagemid is rescued with M13K07 gene III deletion phage, there is no unaltered gene III present.”
“[0038] Phagemids have been mentioned above. The applicants have realised and demonstrated that in many cases phagemids will be preferred to phage for cloning antibodies because it is easier to use them to generate more comprehensive libraries of the immune repertoire. This is because the phagemid DNA is approximately 100 times more efficient than bacteriophage DNA in transforming bacteria (see example 15). Also, the use of phagemids gives the ability to vary the number of gene III binding molecule fusion proteins displayed on the surface of the bacteriophage (see example 13). For example, in a system comprising a bacterial cell containing a phagemid encoding a gene III fusion protein and infected with a helper phage, induction of expression of the gene III fusion protein to different extents, will determine the number of gene III fusion proteins present in the space defined between the inner and outer bacterial membranes following superinfection. This will determine the ratio of gene III fusion protein to native gene III protein displayed by the assembled phage. [0039] Expressing a single fusion protein per virion may aid selection of antibody specificities on the basis of affinity by avoiding the ‘avidity’ effect where a phage expressing two copies of a low affinity antibody would have the same apparent affinity as a phage expressing one copy of a higher affinity antibody. In some cases however, it will be important to display all the gene III molecules derived by superinfection of cells containing phagemids to have fusions (e.g. for selecting low affinity binding molecules or improving sensitivity on ELlSA). One way to do this is to superinfect with a bacteriophage which contains a defective gene Ill. The applicants have therefore developed and used a phage which is deleted in gene Ill. This is completely novel.”
“Specific Binding Pair [0052] This describes a pair of molecules (each being a member of a specific binding pair) which are naturally derived or synthetically produced, One of the pair of molecules, has an area on its surface, or a cavity which specifically binds to, and is therefore defined as complementary with a particular spatial and polar organisation of the other molecule, so that the pair have the property of binding specifically to each other. Examples of types of specific binding pairs are antigenantibody, biotin-avidin, hormone-hormone receptor, receptorligand, enzyme-substrate, IgG-protein A. … Library [0078] A collection of nucleotide eg DNA, sequences within clones. … Derivative [0083] This is a substance which derived from a polypeptide which is encoded by the DNA within a selected bacteriophage particle. The derivative polypeptide may differ from the encoded polypeptide by the addition, deletion, substitution or insertion of amino acids, or by the linkage of other molecules to the encoded polypeptide. These changes may be made at the nucleotide or protein level. For example the encoded polypeptide may be a Fab fragment which is then linked to an Fc tail from another source. Alternatively markers such as enzymes, flouresceins [sic] etc may be linked to eg Fab, scFv fragments.” [0052] This describes a pair of molecules (each being a member of a specific binding pair) which are naturally derived or synthetically produced, One of the pair of molecules, has an area on its surface, or a cavity which specifically binds to, and is therefore defined as complementary with a particular spatial and polar organisation of the other molecule, so that the pair have the property of binding specifically to each other. Examples of types of specific binding pairs are antigenantibody, biotin-avidin, hormone-hormone receptor, receptorligand, enzyme-substrate, IgG-protein A. Library [0083] This is a substance which derived from a polypeptide which is encoded by the DNA within a selected bacteriophage particle. The derivative polypeptide may differ from the encoded polypeptide by the addition, deletion, substitution or insertion of amino acids, or by the linkage of other molecules to the encoded polypeptide. These changes may be made at the nucleotide or protein level. For example the encoded polypeptide may be a Fab fragment which is then linked to an Fc tail from another source. Alternatively markers such as enzymes, flouresceins [sic] etc may be linked to eg Fab, scFv fragments.”
“Smith et al described the display of peptides on the outer surface of phage but they did not describe the display of protein domains. Peptides can adopt a range of structures which can be different when in free solution, than when bound to, for example, an antibody, or when forming part of a protein (Stanfield, R.1. et al., (1990) Science 248, p712-719). Proteins in general have a well defined tertiary structure and perform their biological function only when adopting this structure. For example, the structure of the antibody D1.3 has been solved in the free form and when bound to antigen (Bhat, T.N. et al., (1990) Nature 347, p483-485). The gross structure of the protein is identical in each instance with only minor variations around the binding site for the antigen. Other proteins have more substantial conformation changes on binding of ligand, for instance the enzymes hexokinase and pyruvate dehydrogenase during their catalytic cycle, but they still retain their overall pattern of folding. This structural integrity is not confined to whole proteins, but is exhibited by protein domains. This leads to the concept of a folded unit which is part of a protein, often a domain, which has a well defined primary, secondary and tertiary structure and which retains the same overall folding pattern whether binding to a binding partner or not. The only gene sequence that Smith et al., described that was of sufficient size to encode a domain a minimum of perhaps 50 amino acids) was a 335bp fragment of a βgalactosidase corresponding to nucleotides 861-1195 in the βgalactosidase gene sequence (Parmley, S. Smith, G.P. 1988 supra. This would encode 112 amino acids of a much larger 380 amino acid domain. Therefore, prior to the present application, no substantially complete domain or folded unit had been displayed on phage.”
“In all embodiments of the invention filamentous bacteriophage particles containing a phagemid genome are employed. Display at the surface of particles containing a phage genome is not part of the invention and mention of this in this document, including the experimental examples, is for the purpose of illustration.”
“[0323] It is considered a truism of bacterial genetics that when mutant and wild-type proteins are co-expressed in the same cell, the wild-type protein is used preferentially. This is analogous to the above situation wherein mutant (i. e. antibody fusion) and wild-type gene III proteins (from M13K07) are competing for assembly as part of the pUC119 phagemid particle. It is therefore envisaged that the majority of the resulting pUC 119 phage particles will have fewer gene III-antibody fusion molecules on their surface than is the case for purely phage system described for instance in example 2. Such phagemid antibodies are therefore likely to bind antigen with a lower avidity than fd phage antibodies with three or more copies of the antibody fusion on their surfaces (there is no wild-type gene III, in the system described, for instance, in example 2), and provide a route to production of phage particles with different numbers of the same binding molecule (and hence different acidities [sic] for the ligand/antigen) or multiple different binding specificities on their surface, by using helper phage such as M13K07 to rescue cells expressing two or more gene III-antibody fusions. [0324] It is also possible to derive helper phage that do not encode a functional gene III in their genomes (by for example deleting the gene III sequence or a portion of it or by incorporating an amber mutation within the gene). These defective phages will only grow on appropriate cells (for example that provide functional gene III in trans, or contain an amber supressor [sic] gene), but when used to rescue phage antibodies, will only incorporate the gene III antibody fusion encoded by the phagemid into the released phage particle.”
“This improvement in transformation efficiency is practically useful in the generation of phage antibodies libraries that have large repertoires of different binding specificities.”
“To demonstrate the utility of phage for the selection of antibodies from repertoires, the first requirement is to be able to prepare a diverse, representative library of the antibody repertoire of an animal and display this repertoire on the surface of bacteriophage fd.”
“Thus the ability to select antibody provided by the use of phage antibodies (as in example 17) is essential to readily isolate antibodies with antigen binding activity from randomly combined VH and VL domains. Very extensive screening would be required to isolate antigen binding fragments if the random combinatorial approach of Huse et al. 1989 (supra) were used.”
“The library prepared in example 16 was used to demonstrate that ability of the phage system to select antibodies on the basis of their antibody specificity.”
“Therefore phage antibodies can be selected on the basis of the antigen affinity displayed.”
“[0386] To fully realise the potential of the phagemid cloning system, a helper phage lacking gene III is desirable. Rescue of gene III fusions with such a helper phage would result in all the progeny phagemids having a gene III fusion on their capsid, since there would be no competition with the wild type molecule. [0387] Control over the number of fusion molecules contained on each phage will provide particularly useful. For example, a gene III deficient helper phage can be used to rescue low affinity antibodies from a naive repertoire, in which high avidity will be necessary to isolate those phage bearing the correct antibody specificity. The unmutated helper phage can then be used when higher affinity versions are constructed, thereby reducing the avidity component, and permitting selection purely on the basis of affinity. This will prove a surprisingly successful strategy for isolation and affinity maturation of antibodies from naive libraries.”
“For isolation of an antibody with a desired high affinity, it is necessary to be able to select an antibody with only a few fold higher affinity than the remainder of the population. This will be particularly important when an antibody with insufficient affinity has been isolated, for example, from a repertoire derived from an immunised animal, and random mutagenesis is used to prepare derivatives with potentially increased affinity. In this example, mixtures of phage expressing antibodies of different affinities directed against hen egg lysozyme were subjected to a panning procedure. It is demonstrated that phage antibodies give the ability to select for an antibody with a Kd of 2nM against one with a Kd of 13nM.”
“It will sometimes be desirable to increase the diversity of a pool of genes cloned in phage, for example a pool of antibody genes, or to produce a large number of variants of a single cloned gene. There are many suitable in vitro mutagenesis methods. However, an attractive method, particularly for making a more diverse population of a library of antibody gene, is to use mutator strains. This has the advantage of generating very large numbers of mutants, essentially limited only be the number of phage that can be handled. The phage display system allows full advantage to be takeoff this number to isolate improved or altered clones.”
“Hence, the use of mutator strains generates a diverse range of mutants in phage antibodies when they are used as hosts for clones for gene III fusions. In this case some of the clones exhibit higher ELISA signals probably due to increased stability to proteolytic attack. The mutator strains can therefore be used to introduce into a clone or population of clones. This diversity should generate clones with desirable characteristics such as higher affinity or specificity. Such clones may then be selected following display of the proteins on phage.”
“[1] A method for producing a molecule with binding specificity for a particular target, which method comprises: [2] producing a population of filamentous bacteriophage particles displaying at their surface a population of binding molecules having a range of binding properties, [3] wherein the binding molecules comprise antibody antigen binding domains for complementary specific binding pair members, [4] wherein the binding molecules are displayed at the surface of the filamentous bacteriophage particles by fusion with a gene III protein of the filamentous bacteriophage particles, [5] and wherein each filamentous bacteriophage particle contains nucleic acid encoding the binding molecule expressed from the nucleic acid and displayed by the particle at its surface; [6] selecting for a filamentous bacteriophage particle displaying a binding molecule with a desired binding property by contacting the population of filamentous bacteriophage particles with a particular target [7] so that individual binding molecules displayed on filamentous bacteriophage particles with the desired binding property bind to said target; [8] separating bound filamentous bacteriophage particles from the target; [9] recovering separated filamentous bacteriophage particles displaying a binding molecule with the desired binding property; [10] isolating nucleic acid encoding the binding molecule from separated filamentous bacteriophage particles; [11] inserting nucleic acid encoding the binding molecule, or a fragment or derivative thereof with binding specificity for the target, in a recombinant system; and [12] producing in the recombinant system separate from filamentous bacteriophage particles a molecule with binding specificity for the target, [13] wherein the molecule is said binding molecule or a fragment or derivative thereof with binding specificity for the target.”
“One might have thought there was nothing more to say on this topic after Kirin-Amgen Inc v Hoechst Marion Roussel Ltd[2005] RPC 9 . The judge accurately set out the position, save that he used the old language of Art.69 EPC rather than that of the EPC 2000, a Convention now in force. The new language omits ‘the terms of’ from Art.69. No one suggested the amendment changes the meaning. We set out what the judge said, but using the language of the EPC 2000: [182] The task for the court is to determine what the person skilled in the art would have understood the patentee to have been using the language of the claim to mean. The principles were summarised by Jacob LJ in Mayne Pharma Pty Ltd v Pharmacia Italia SpA[2005] EWCA Civ 137 and refined by Pumfrey J in Halliburton Energy Services Inc v Smith International (North Sea) Ltd[2005] EWHC 1623 (Pat) following their general approval by the House of Lords in Kirin-Amgen Inc v Hoechst Marion Roussel Ltd[2005] RPC 9 . An abbreviated version of them is as follows: (i) The first overarching principle is that contained in Article 69 of the European Patent Convention. (ii) Article 69 says that the extent of protection is determined by the claims. It goes on to say that the description and drawings shall be used to interpret the claims. In short the claims are to be construed in context. (iii) It follows that the claims are to be construed purposively - the inventor's purpose being ascertained from the description and drawings. (iv) It further follows that the claims must not be construed as if they stood alone - the drawings and description only being used to resolve any ambiguity. Purpose is vital to the construction of claims. (v) When ascertaining the inventor's purpose, it must be remembered that he may have several purposes depending on the level of generality of his invention. Typically, for instance, an inventor may have one, generally more than one, specific embodiment as well as a generalised concept. But there is no presumption that the patentee necessarily intended the widest possible meaning consistent with his purpose be given to the words that he used: purpose and meaning are different. (vi) Thus purpose is not the be-all and end-all. One is still at the end of the day concerned with the meaning of the language used. Hence the other extreme of the Protocol - a mere guideline - is also ruled out by Article 69 itself. It is the terms of the claims which delineate the patentee's territory. (vii) It follows that if the patentee has included what is obviously a deliberate limitation in his claims, it must have a meaning. One cannot disregard obviously intentional elements. (viii) It also follows that where a patentee has used a word or phrase which, acontextually, might have a particular meaning (narrow or wide) it does not necessarily have that meaning in context. (ix) It further follows that there is no general ‘doctrine of equivalents.’ (x) On the other hand purposive construction can lead to the conclusion that a technically trivial or minor difference between an element of a claim and the corresponding element of the alleged infringement nonetheless falls within the meaning of the element when read purposively. This is not because there is a doctrine of equivalents: it is because that is the fair way to read the claim in context. (xi) Finally purposive construction leads one to eschew the kind of meticulous verbal analysis which lawyers are too often tempted by their training to indulge.” [182] The task for the court is to determine what the person skilled in the art would have understood the patentee to have been using the language of the claim to mean. The principles were summarised by Jacob LJ in Mayne Pharma Pty Ltd v Pharmacia Italia SpA[2005] EWCA Civ 137 and refined by Pumfrey J in Halliburton Energy Services Inc v Smith International (North Sea) Ltd[2005] EWHC 1623 (Pat) following their general approval by the House of Lords in Kirin-Amgen Inc v Hoechst Marion Roussel Ltd[2005] RPC 9 . An abbreviated version of them is as follows: (i) The first overarching principle is that contained in Article 69 of the European Patent Convention. (ii) Article 69 says that the extent of protection is determined by the claims. It goes on to say that the description and drawings shall be used to interpret the claims. In short the claims are to be construed in context. (iii) It follows that the claims are to be construed purposively - the inventor's purpose being ascertained from the description and drawings. (iv) It further follows that the claims must not be construed as if they stood alone - the drawings and description only being used to resolve any ambiguity. Purpose is vital to the construction of claims. (v) When ascertaining the inventor's purpose, it must be remembered that he may have several purposes depending on the level of generality of his invention. Typically, for instance, an inventor may have one, generally more than one, specific embodiment as well as a generalised concept. But there is no presumption that the patentee necessarily intended the widest possible meaning consistent with his purpose be given to the words that he used: purpose and meaning are different. (vi) Thus purpose is not the be-all and end-all. One is still at the end of the day concerned with the meaning of the language used. Hence the other extreme of the Protocol - a mere guideline - is also ruled out by Article 69 itself. It is the terms of the claims which delineate the patentee's territory. (vii) It follows that if the patentee has included what is obviously a deliberate limitation in his claims, it must have a meaning. One cannot disregard obviously intentional elements. (viii) It also follows that where a patentee has used a word or phrase which, acontextually, might have a particular meaning (narrow or wide) it does not necessarily have that meaning in context. (ix) It further follows that there is no general ‘doctrine of equivalents.’ (x) On the other hand purposive construction can lead to the conclusion that a technically trivial or minor difference between an element of a claim and the corresponding element of the alleged infringement nonetheless falls within the meaning of the element when read purposively. This is not because there is a doctrine of equivalents: it is because that is the fair way to read the claim in context. (xi) Finally purposive construction leads one to eschew the kind of meticulous verbal analysis which lawyers are too often tempted by their training to indulge.”
“The 10 14 combinations are then subjected to selection (see later for selection formats) as disclosed by the present invention. This selection will then produce a population of phages displaying a particular combination of H and L chains having the desired specificity.”
“We submit that ‘specificity’ in a general sense means the binding or lack of binding (determined at a cut-off affinity chosen by the skilled addressee) to one or more antigens/epitopes in the universe of antigens/epitopes. The ‘desired specificity’ is the specificity towards the antigen of interest. A population has a range of binding specificities where there is any difference in specificity among members of the population.”
“The embodiments of the present application do not do this. In embodiments where phagemid is rescued with M13K07 gene III deletion phage, there is no unaltered gene III present.”
“The applicants have therefore developed and used a phage which is deleted in gene III. This is completely novel.”
“180. In order for a claimed invention to be entitled to priority from an earlier application, it must, in the words of section 5(2)(a) of the 1977 Act, be ‘supported by matter disclosed’ in that earlier application. Article 87(1) of the European Patent Convention expresses the requirement as being that priority can only be accorded in respect of ‘the same invention’ as one in the earlier application. Section 5 is one of the sections which is declared to be intended to have the same effect as the corresponding provision of the EPC: see section 130(7). 181. In case G2/98 [2001] OJEPO 413, [2002] EPOR 167 the Enlarged Board of Appeal of the European Patent Office equated ‘the same invention’ in Article 87(1) with ‘the same subject-matter’ in Article 87(4). It expressed the requirement for claiming priority as follows: ‘The requirement for claiming priority of “the same invention”, referred to in Article 87(1) EPC, means that priority of a previous application in respect of a claim in a European patent application in accordance with Article 88 EPC is to be acknowledged only if the skilled person can derive the subject-matter of the claim directly and unambiguously, using common general knowledge, from the previous application as a whole.’ 182. The Court of Appeal explained this requirement in Unilin Beheer NV v Berry Floor NV[2004] EWCA Civ 1021 ,[2005] FSR 6 at [48] as follows: ‘The approach is not formulaic: priority is a question about technical disclosure, explicit or implicit. Is there enough in the priority document to give the skilled man essentially the same information as forms the subject-matter of the claim and enables him to work the invention in accordance with that claim?’ 183. As Kitchin J observed in Abbott Laboratories Ltd v Evysio Medical Devices plc[2008] EWHC 800 (Pat) ,[2008] RPC 23 at [228], after citing G2/98 and Unilin v Berry: ‘So the important thing is not the consistory clause or the claims of the priority document but whether the disclosure as a whole is enabling and effectively gives the skilled person what is in the claim whose priority is in question. I would add that it must ‘give’ it directly and unambiguously. It is not sufficient that it may be an obvious development of what is disclosed.’” ‘The requirement for claiming priority of “the same invention”, referred to in Article 87(1) EPC, means that priority of a previous application in respect of a claim in a European patent application in accordance with Article 88 EPC is to be acknowledged only if the skilled person can derive the subject-matter of the claim directly and unambiguously, using common general knowledge, from the previous application as a whole.’ ‘The approach is not formulaic: priority is a question about technical disclosure, explicit or implicit. Is there enough in the priority document to give the skilled man essentially the same information as forms the subject-matter of the claim and enables him to work the invention in accordance with that claim?’ ‘So the important thing is not the consistory clause or the claims of the priority document but whether the disclosure as a whole is enabling and effectively gives the skilled person what is in the claim whose priority is in question. I would add that it must ‘give’ it directly and unambiguously. It is not sufficient that it may be an obvious development of what is disclosed.’”
“The aim of this example was to demonstrate that the scFv format used in example 2 was only one way of display antibody fragments in the pAb system.”
“It is entirely possible that the reduced infectivity of fUSE1Lac335 virions is largely due to this breakdown. Despite its reduced infectivity, fUSE1-Lac335 can be effectively affinity purified as will be demonstrated in the next section.”
“(a) fUSE vectors display foreign antigenic determinants with little loss of phage function The new fusion phage vectors, fUSE1 and fUSE2, accept inserts in gene III with little or no loss of phage function; inserts are stable. The foreign [amino acids] encoded in the inserts are expressed on the surface of the phage; two clones carrying fragments of a target gene were shown to express determinants recognized by antibody to the gene product. These results demonstrate the ability of fUSE vectors to accept inserts up to 335 bp (perhaps more) and express the foreign [amino acids] encoded in the inserts on the surface of the virion. Some inserts by their very nature will affect pIII function. Inserts that contain anchor domains or other hydrophobic segments may stop transfer of pH1 into the host membrane (Davis and Model, 1995) and presumably would not be tolerated. Inserts that exceed 335 bp may lead to excessive breakdown of the fusion protein or otherwise impair pIII function, so for the time being we recommended [sic] using fragments of 100-300 bp.”
“In fUSE vectors, in contrast, the amino acids encoded by the foreign inserts are displayed on the virion itself. This allows recombinant phage to be purified in infectious form by affinity to antibody; thus antibody is used directly to select for the desired clones.”
“Screening a λgt11 library of 10 5-10 6 clones is an arduous undertaking requiring relatively large amounts of antibody. Biopanning, on the other hand, has the potential of isolating rare fusion phage clones from libraries with as many as 10 9 productive clones with only two biopannings and an intermediate amplification. It also requires minute amounts of antibody… ”
“(e) Prospects for an ‘epitope library’ An ‘epitope library’ would contain, say, 10 8 clones expressing a short, synthetic random coding sequence. Such a library might be expected to contain clones reactive with almost any anti-protein antibody, since protein epitopes are typically about 6 [amino acids] long and virtually all 64 million 6 [amino acid] epitopes would be represented multiple times in different contexts. Biopanning the epitope library with an antibody of interest and sequencing the inserts in a number of positive clones might provide information about the epitope(s) recognized by the antibody, information that could be used, for example, to design vaccines, identify genes, or map epitopes without the need to clone the relevant natural gene fragments.”
“Recently the separate groups of Winter and Lerner have cloned and expressed the antibody repertoire in E. coli using plasmid or lambda phage technology (Sastry et al. Proc. Natl. Acad. Sci. USA 1989; Ward et al Nature 1989; Orlandi et al Natl. Acad. Sci. 1989; Huse et al, In Press, Science). Extensions of their results open the possibility of circumventing the hybridoma methodology to prepare antibodies and ultimately may lead to a generic antibody library which would obviate the need to immunize animals. As one begins to approach these goals, questions concerning the size and screening of the antibody repertoire emerge. This meeting will address these issues and hopefully speed up progress toward creating antibodies in vitro.”
“Of course, the primary idea was that it is really worth pursuing antibodies displayed on filamentous phage, which we now call phage antibodies, as a new way of expanding cloning the immune response, as Greg Winter’s group put it, because it would allow for selection of very rare antibodies for antigenbinding out of huge libraries. So that idea of phage antibody libraries was very vigorously put forth and I was trying to promote this idea as being something to try.”
“Q. And did you to your recollection express those concerns to the people at Banbury? A. I do not think I used complicated language that is like the language that you are using. You have to realise that I was trying to sell this as an idea to try. That was my goal in this talk. I was hoping to try it myself, but I also was interested in recruiting other people to try it. So I do not think I was parsing out in any sort of detail the exact nature of the hurdles that had to be crossed. I mentioned them would be more like it. I think it is fair to say that I was trying to be upbeat about the possibility of this technology. Q. And no doubt your audience realised that? A. I think at lot of them did realise that, yes. … Q. Very well, professor. In any case, you recognised it was a challenge. A. Certainly. Q. And you conveyed to the audience that it was a challenge. A. Yes. … MR. JUSTICE ARNOLD: … Can you go back to what you were asked about the Banbury Conference. Mr. Meade was asking you some questions about the extent to which you had articulated to the participants in the conference your concerns about what you were proposing. In answering those questions, you said that this was an idea that you were interested in doing yourself, but you were also trying to recruit others. I am not sure I have got your language exactly accurate, but that is roughly what you said. Could you just explain to me a little more what you mean by that. A. I thought that if people who worked in the area of expressing the cloned antibodies, who get interested in using phage display for creating phage antibody libraries, that would be a really big advance in the field and it would also be a big advance for a phage display. Although I was very interested in doing the experiments myself, in fact I would have been very glad to have published the first experiment on phage antibodies, I was also really interested in getting other people to work on it as well. Q. So you were encouraging ---- A. That was why I was not disappointed really when I saw the McCafferty et al paper. Q. So do I understand from that that you were encouraging the participants to try it themselves as well? A. Yes. I am not sure I would say that in so many words I said, ‘Hey, come on, why don’t you guys do this?’ but since I was giving out the idea freely, I think the implication was that I was interested in getting people to try this themselves.”
“(1)(a) Identify the notional ‘person skilled in the art’; (b) Identify the relevant common general knowledge of that person; (2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it; (3) Identify what, if any, differences exist between the matter cited as forming part of the ‘state of the art’ and the inventive concept of the claim or the claim as construed; (4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?”
“The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.”
“In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation’s Patent[1967] RPC 479 , by saying that the notion of something being obvious to try was useful only in a case where there was a fair expectation of success. How much of an expectation would be needed depended on the particular facts of the case.”
“... The fact that other persons (or teams) were also working on the same project might suggest that is was ‘obvious to try’ or that it was ‘an interesting area to explore’, but it does not necessarily imply that there was ‘a reasonable expectation of success’. ‘A reasonable expectation of success’, which should not be confused with the understandable ‘hope to succeed’, implies the ability of the skilled person to reasonably predict, on the basis of the existing knowledge before the starting of a research project, a successful conclusion to the said project within acceptable time limits. The more unexplored a technical field of research is, the more difficult is the making of predictions about its successful conclusion and, consequently, the lower the expectation of success.”
“MR. THORLEY: …. Is there anything in this paper which you believe is necessary to achieve success which would not be something carried out by the skilled person implementing Parmley and Smith? Is there some magic trick in McCafferty to making it work or does it just work? A. I know of no magic trick and ---- MR. JUSTICE ARNOLD: Well, let us get away from the expression ‘magic trick’. Is there anything described in McCafferty that strikes you as clever above and beyond implementing Parmley and Smith? A. No, my Lord, except the sense that they have gone against the advice of Parmley and Smith and decided to do it anyway and made it work. Q. I appreciate your point about going against the advice. Concentrating on the ‘and they made it work’, there is no technical procedure that they adopted to make it work that was out of the ordinary at that time. Is that correct? A. Yes, I think that is a correct statement.”
“Inserts that exceed 335 bp may lead to excessive breakdown of the fusion protein or otherwise impair pIII function, so for the time being we recommended using fragments of 100-300 bp.”
“There are, however, several important limitations in using such fusion phage to identity altered peptides or proteins with new or enhanced binding properties. First, it has been shown [citing Parmley & Smith] that fusion phage are useful only for displaying proteins of less than 100 and preferably less than 50 resides, because large inserts presumably disrupt the function of gene III and therefore phage assembly infectivity….”
“However, fusion phage have been shown to be mainly useful for displaying small inserts, probably, because the large inserts have an adverse effect on the infectivity of pIII (Parmlee [sic] and Smith…”
“The description in [Parmley & Smith] of the applicability of bacteriophage expression for the display of short epitope sequences provides no motivation to use a bacteriophage system for the expression of a first and second polypeptide that form heteromeric receptors.”
“Q. But in terms of the factors that are identified here, proteolytic systems, folding, background and pulling out the specific antibody from the library, and what he called the overwhelming background of non-specific binding, those would all be reasonable anxieties that the ordinary skilled person considering antibody phage display in 1990, listening to Professor Smith at Banbury, would have, are they not? A. Anxieties as to the extent that it would work. Q. Yes. You agree? A. Right. It is certainly going to work over some extent; and the bigger the extent, the better. Q. The question is, ‘Can you actually pull the clone out?’ At the end of the day, that is the question, is it not? A. The question is, ‘What percentage of clones are you going to be able to pull out? How often is it going to be successful?’ These are the factors that you are going to optimise to make it more generally successful rather than less generally successful.”
“MR. JUSTICE ARNOLD: … On the one hand, Professor Smith says he was, to use his expression, ‘very vigorously putting forth this idea and trying to promote this as being something to try’ and, on the other hand, he is recognising what Mr. Meade has described as anxieties. Your response to that is, ‘That is all about the limits of the technology.’ Trying to put yourself into the shoes of the ordinary skilled person, hearing what Professor Smith had said at the Banbury Conference, in your opinion, would they be sufficiently encouraged by the overall message to go away and try it or not? A. Yes. Q. Can you just briefly explain why? A. Because any new technology has limitations about the range over which it is going to work. I think Professor Smith is giving us here the idea that there is going to be some range it is going to work, but you have got to be cautious about assuming exactly how big that range is.”
“Q. When you came back on the hypothesis that you were at Banbury and you came back and read Parmley and Smith, would you not say to yourself that the mere fact that Professor Smith was intending to go ahead with -- I think he was scFv’s, was he not -- must indicate that he has some confidence that he can go beyond 300 base pairs? A. Yes. I would put it slightly differently, but you will not be unhappy with what I say. Q. How very civil of you. A. He would be confident that it is worth trying. I would never get the impression that he was confident that it would work, but he was confident enough to say, ‘I am going to try it, it is worth doing, but I am aware of the possible reasons for failure and I will try to deal with them’.”
“… If you got the clone, someone sent you that, and you knew its sequence, then to just put it into a phage vector or a phagemid vector and try the experiment and see what happened we are talking of months, a few months, six months maybe. It depends on the skills and how well things go, but that order of magnitude. Once you have got the clone, it is not a long period to where you are first testing whether it has worked or not.”
“Q. …. The person listening at the Banbury Conference, I would suggest to you, if they knew about Parmley and Smith or saw the reservation in Parmley and Smith about the size of the insert would have said to themselves, whatever Dr. Smith has done in the past 18 months, something must have encouraged him to think that it was worthwhile to try an antibody fragment of 750 base pairs. A. Yes, indeed, it is likely so. It is why I said it was surprising to me that he did not make any experiment in this interval of time about antibodies. …”
“Q. Let me suggest this. The first thing you would want to try would be to see whether you could successfully insert either a VH or an scFv fragment. A. You mean in terms of molecular DNA, yes. To insert, I mean, to insert into the sequence of the phage, also phagemid. Q. Exactly, in the way that Parmley and Smith did, except now you are inserting an antibody fragment rather than an epitope. A. Yes. Q. How much work is involved in doing that? A. It is a cloning. Once you know the site, you have to think about the cloning site. I guess it is not a lot of work to do that.”
“I also hope to construct a library of fusion phage displaying cloned antibodies with a vast array of different antigen-binding specificities, so that clones encoding antibodies of defined specificity can be affinity-purified with antigen. This way of obtaining monoclonal antibodies would be much easier than present methods …”
“Finally, let me plea for 5 years in return for a much curtailed budget. It’s obvious that I’ll need that long, especially considering that my laboratory will have been unfunded for over a year and that I’ll have to train a new technician. Perhaps the project seems ‘speculative,’ but what can I reasonably be expected to be able to report that will make it decisively less so after 2 years’ funding (when I’ll be forced to renew if I get only 3 years) - even granted that my vision is thoroughly sound in all essentials and that I undertake the task with commendable competence and energy, as indeed I will?”
“I was satisfied that antibody phage display … was being pursued by the CAT group and by others, including the group at Scripps. I also did not regard myself as having any claim to scientific priority in the field of phage antibodies, because I considered phage display of antibodies to be a fairly obvious extension of the newly-invented single-chain antibodies and our published work on phage display in general (especially … Parmley and Smith …) to the ongoing work by Greg Winter’s group, Lerner’s group at Scripps, and others, whose efforts to ‘clone the immune response’ were very prominent in the community of molecular biologists by the end of 1988. I have been asked whether I would have continued work on phage display of antibodies were it not for the fact that CAT and Scripps were also working on it. I am sure that I would have done so, as I believed that the strategy was sound and the approach had enormous potential.”
“The conformational constraint posed upon an SCA [i.e. scFv] not in solution but on the surface of a filamentous phage, the expected instability of an insert of the length of a SCA and observed degradation of the products of such inserts, as well as the possibility of periplasmic degradation, rendered the success to express a functional SCA on the surface of a filamentous phage quite unpredictable at the time of filing. No reasonable expectation of success was available from my work on antigen fusions in ‘Smith and ‘Parmley & Smith’.”
“In 1989, Frank Breitling and I decided that phage display might be a good method for screening large libraries of antibody genes for a particular specificity. After George Smith's work displaying epitopes on phage for screening of epitope libraries with specific antibodies, the idea that antibodies, instead of epitopes, could be screened in this way seemed to us to be a straight-forward step to take at the time. All the essential elements of the techniques we proposed to use had already been published. For example, Plückthun and Skerra had already shown expression of soluble antibody fragments in E.coli (assembly of Fv fragments in the periplasm, and later, Fab assembly in the periplasm).”
“We felt that this was not correct and perhaps a little unfair, since our paper reported use of a phagemid vector instead of a phage vector which we considered important for library screening since the presentation of the antibody fragment was regulated independently from phage production, and we expected this to be an advantage in regard of library propagation. In our view the use of phagemid techniques made library creation more efficient and easier, and was a different implementation of the phage display technology which had not been published for antibodies before.”
“Q. Do you see any inconsistency between saying you thought the idea was obvious and now being an inventor on a patent to antibody phage display which indeed has been licensed out? A. Yes, but we know there are at least three other groups working on the same thing and also other patents were on the same thing made at the same time. You can see from that that the idea obviously was around and we were not the only ones to work on that. Actually we were very late with our patent as far as I remember from what I know about the other patents. I do not see the connection between the patent, because the patent is a kind of commercial protection law and it not necessarily has to do with the academic process of getting the idea, the proof of principle.”
‘Furthermore, Article 84 EPC also requires that the claims must be supported by the description, in other words, it is the definition of the invention in the claims that needs support. In the Board's judgment, this requirement reflects the general legal principle that the extent of the patent monopoly, as defined by the claims, should correspond to the technical contribution to the art in order for it to be supported, or justified.’” 467. The second passage is at page 50 line 36 – page 51 line 8: 471. “But the fact that the skilled man following the teaching of Biogen 1 would have been able to make HBcAg and HBsAg in bacterial cells, or indeed in any cells, does not conclude the matter. I think that in concentrating upon the question of whether Professor Murray's invention could, so to speak, deliver the goods across the full width of the patent or priority document, the courts and the E.P.O. allowed their attention to be diverted from what seems to me in this particular case the critical issue. It is not whether the claimed invention could deliver the goods, but whether the claims cover other ways in which they might be delivered: ways which owe nothing to the teaching of the patent or any principle which it disclosed. 472. It will be remembered that in Genentech I/Polypeptide expression the Technical Board spoke of the need for the patent to give protection against other ways of achieving the same effect ‘in a manner which could not have been envisaged without the invention’
“I return therefore to consider the technical contribution to the art which Professor Murray made in 1978 and disclosed in Biogen 1. As it seems to me, it consisted in showing that despite the uncertainties which then existed over the DNA of the Dane particle - in particular, whether it included the antigen genes and whether it had introns - known recombinant techniques could nevertheless be used to make the antigens in a prokaryotic host cell. As I have said, I accept the judge's findings that the method was shown to be capable of making both antigens and I am willing to accept that it would work in any otherwise suitable host cell. Does this contribution justify a claim to a monopoly of any recombinant method of making the antigens? In my view it does not. The claimed invention is too broad. Its excessive breadth is due, not to the inability of the teaching to produce all the promised results, but to the fact that the same results could be produced by different means. Professor Murray had won a brilliant Napoleonic victory in cutting through the uncertainties which existed in his day to achieve the desired result. But his success did not in my view establish any new principle which his successors had to follow if they were to achieve the same results. The inventive step, as I have said, was the idea of trying to express unsequenced eukaryotic DNA in a prokaryotic host. Biogen 1 discloses that the way to do it is to choose the restriction enzymes likely to cleave the Dane particle DNA into the largest fragments. This, if anything, was the original element in what Professor Murray did. But once the DNA had been sequenced, no one would choose restriction enzymes on this basis. They would choose those which digested the sites closest to the relevant gene or the part of the gene which expressed an antigenic fragment of the polypeptide. The metaphor used by one of the witnesses was that before the genome had been sequenced everyone was working in the dark. Professor Murray invented a way of working with the genome in the dark. But he did not switch on the light and once the light was on his method was no longer needed. Nor, once they could use vectors for mammalian cells, would they be concerned with the same problem of introns which had so exercised those skilled in the art in 1978. Of course there might be other problems, but Biogen 1 did not teach how to solve them. The respondents Medeva, who use restriction enzymes based on knowledge of the HBV genome and mammalian host cells, owe nothing to Professor Murray's invention.”
“A recombinant polypeptide having part or all of the primary structural conformation of human or monkey erythropoietin as set forth in Table VI or Table V or any allelic variant or derivative thereof … characterised by being the product of eucaryotic expression of an exogenous DNA sequence and which has higher molecular weight by SDS-PAGE from erythropoietin isolated from urinary sources.” erythropoietin isolated from urinary sources.”
“112. [The passage in Lord Hoffmann’s speech in Biogen v Medeva referring to a ‘principle of general application’] gave rise to a good deal of argument about what amounted to a ‘principle of general application’. In my opinion there is nothing difficult or mysterious about it. It simply means an element of the claim which is stated in general terms. Such a claim is sufficiently enabled if one can reasonably expect the invention to work with anything which falls within the general term. For example, in Genentech I/Polypeptide expression (T 292/85) [1989] O.J. EPO 275, the patentee claimed in general terms a plasmid suitable for transforming a bacterial host which included an expression control sequence to enable the expression of exogenous DNA as a recoverable polypeptide. The patentee had obviously not tried the invention on every plasmid, every bacterial host or every sequence of exogenous DNA. But the Technical Board of Appeal found that the invention was fully enabled because it could reasonably be expected to work with any of them. 113. This is an example of an invention of striking breadth and originality. But the notion of a ‘principle of general application’ applies to any element of the claim, however humble, which is stated in general terms. A reference to a requirement of ‘connecting means’ is enabled if the invention can reasonably be expected to work with any means of connection. The patentee does not have to have experimented with all of them. 114. In my opinion the facts did not support the application of this principle. Assuming the claims can be read, as the judge thought, to include any way of making EPO by recombinant DNA technology, the specification does not disclose a way of making it in sufficiently general terms to include the TKT process. It discloses only how to make EPO by introducing exogenous DNA coding for EPO into a host cell. The TKT method is not a version of this process which, although untried, could reasonably be expected to work just as well. It is different.”
“There is, however, in the opinion of the Board, no such requirement in the European Patent Convention, nor is such principle established in normal patent practice within the Contracting States. The suggested features in the claims are essentially functional terms in this particular context, in spite of structural connotations, and may cover an unlimited number of possibilities. It follows that the features may generically embrace the use of unknown or not yet envisaged possibilities, including specific variants which might be provided or invented in the future. This Board concurs with the decision of another Board (T 68/85 - 3.3.1., Synergistic herbicides, OJ EPO 1987, 228) in which the possibility of using functional terminology in claims was approved if ‘such features cannot otherwise be defined more precisely without restricting the scope of the invention’ and their reduction to practice was not an undue burden. The Board sees no valid reason why this should not be equally true for the field of biotechnology as in other fields of technology. In appropriate cases, such as the present, it is only possible to define the invention (the matter for which protection is sought - Article 84 EPC) in a way which gives a fair protection having regard to the nature of the invention which has been described, by using functional terminology in the claims.”
“This definition shows that the subject matter of claim 2 relates to a vast catalogue of derivatives of human t-PA of unspecified structure having any unspecified function of human t-PA. There is no dispute that the present description provides a disclosure of the production of human t-PA in a recombinant system. However, in the Board’s judgement, the examples and the information given are not sufficient to allow a person skilled in the art, using common general knowledge, to perform the invention without undue burden in the whole area claimed, especially in consideration of the broad functional meaning attributed to the quoted parameter. Claim 2 leaves the skilled addressee guessing as to whether any derivative of human t-PA which fulfils only one of the functions typical of this molecule is a derivative meant by the claim. In this respect, the Board, in line with the quoted case law, considers the patent in suit to be insufficient and thus to contravene the requirements of Article 83 EPC. Furthermore, the area covered by the claim is not clearly defined, which is contrary to the provisions of Article 84 EPC.”
“43. The Appellants object that the disclosure of the present invention is not sufficiently clear and complete for it to be carried out by the skilled person. In particular, they submit that: … (v) Not a single example of a functional derivative is provided in the description of the patent in suit. Though, a wealth of possible derivatives are claimed. This is nothing more than an invitation to carry out a research programme in order to find suitable derivatives of human t-PA (cf. decision T 435/91 supra). … (v) Not a single example of a functional derivative is provided in the description of the patent in suit. Though, a wealth of possible derivatives are claimed. This is nothing more than an invitation to carry out a research programme in order to find suitable derivatives of human t-PA (cf. decision T 435/91 supra). 44. In respect of the above objections, the Board's view is as follows: ... (v) When given a basic molecular structure (here: the nucleotide sequence and deduced amino acid sequence of human t-PA) and an activity to be tested (here: capability of catalyzing the conversion of plasminogen to plasmin, binding to fibrin, and tPA’s immunological properties), the average skilled person can be expected to be able to prepare without application of inventive skill or undue experimentation generic functional derivatives of the molecule by way of amino acid deletion, substitution, insertion, addition or replacement within the framework of routine trials. 45. In summary, in the Board's judgement, none of the objections put forward by the Appellants can lead to the conclusion that the disclosure of the claimed subject-matter is not sufficiently clear and complete for it to be carried out by a person skilled in the art. Consequently, the requirements of Article 83 EPC are met by the patent in suit.”
“… In selecting chemical compounds possessing the necessary capability, all [the skilled person] has to rely on is the information provided in the application in suit. In the absence of any selection rule in the application in suit, not even in the form of a structure-activity relationship on the basis of which he could identity from the outset suitable compound classes, the skilled person must resort to trial-and-error experimentation on arbitrarily selected compounds using the screening method cited in the application in suit to identify within the host of possible alternative compounds those which stimulate the soluble guanylate cyclase independently of the heme group in the enzyme. Nor does he have any information at his disposal in the application in suit leading necessarily and directly towards success through the evaluation of initial failures. Nor would the simple structural identification of one suitable compound class of general formula (I) in the application in suit be of any help to the skilled person. To find all the suitable alternatives, he would therefore have to test every conceivable chemical compound for the claimed capability; this represents for the skilled person an invitation to perform a research programme and thus an undue burden …”
“Moreover, the fact that claim 1 is formulated as a ‘reachthrough claim’ [defined earlier by the Board as ‘a claim to future inventions based on the one now being disclosed’] would cast doubt on the sufficiency of the invention’s disclosure throughout the entire area claimed, since this openended formulation as stated above in point 2 is also directed at future inventions based on the present one, i.e. inventions not yet made by the priority date of the application in suit.”
“A process for the synthesis of citalopram, in which a process for the synthesis of [5-cbx] according to claim 1 is contained.”
“The decision as to whether there was an extension of disclosure must be made on a comparison of the two documents read through the eyes of a skilled addressee. The task of the Court is threefold: (1) To ascertain through the eyes of the skilled addressee what is disclosed, both explicitly and implicitly in the application. (2) To do the same in respect of the patent [as proposed to be amended]. (3) To compare the two disclosures and decide whether any subject matter relevant to the invention has been added whether by deletion or addition. The comparison is strict in the sense that subject matter will be added unless such matter is clearly and unambiguously disclosed in the application either explicitly or implicitly.”
“4. In Richardson-Vicks' Patent[1995] RPC 568 at 576 I summarised the rule in a single sentence: ‘I think the test of added matter is whether a skilled man would, upon looking at the amended specification, learn anything about the invention which he could not learn from the unamended specification.’ I went on to quote Aldous J in Bonzel. His formulation is helpful and has stood the test of time. 5. The reason for the rule was explained by the Enlarged Board of Appeal of the EPO in G1/93 ADVANCED SEMICONDUCTOR ‘I think the test of added matter is whether a skilled man would, upon looking at the amended specification, learn anything about the invention which he could not learn from the unamended specification.’ I went on to quote Aldous J in Bonzel. His formulation is helpful and has stood the test of time. PRODUCTS/Limiting feature [1995] EPOR 97 at [Reasons 9]: 500. ‘With regard to Article 123(2) EPC, the underlying idea is clearly that an applicant shall not be allowed to improve his position by adding subject-matter not disclosed in the application as filed, which would give him an unwarranted advantage and could be damaging to the legal security of third parties relying upon the content of the original application.’ 6. Mr Richard Arnold QC provided a clear articulation as to how the legal security of third parties would be affected if this were not the rule: ‘The applicant or patentee could gain an unwarranted advantage in two ways if subject-matter could be added: first, he could circumvent the "first-to-file" rule, namely that the first person to apply to patent an invention is entitled to the resulting patent; and secondly, he could gain a different monopoly to that which the originally filed subject-matter justified.’ 7. Kitchin J has recently helpfully elaborated upon the Bonzel formulation in European Central Bank v Document Security Systems[2007] EWHC 600 (Pat) ,26th March 2007 : ‘[97] A number of points emerge from this formulation which have a particular bearing on the present case and merit a little elaboration. First, it requires the court to construe both the original application and specification to determine what they disclose. For this purpose the claims form part of the disclosure (s.130(3) of the Act), though clearly not everything which falls within the scope of the claims is necessarily disclosed. [98] Second, it is the court which must carry out the exercise and it must do so through the eyes of the skilled addressee. Such a person will approach the documents with the benefit of the common general knowledge. [99] Third, the two disclosures must be compared to see whether any subject matter relevant to the invention has been added. This comparison is a strict one. Subject matter will be added unless it is clearly and unambiguously disclosed in the application as filed. [100] Fourth, it is appropriate to consider what has been disclosed both expressly and implicitly. Thus the addition of a reference to that which the skilled person would take for granted does not matter: DSM NV's Patent[2001] RPC 25 at [195]-[202]. On the other hand, it is to be emphasised that this is not an obviousness test. A patentee is not permitted to add matter by amendment which would have been obvious to the skilled person from the application. [101] Fifth, the issue is whether subject matter relevant to the invention has been added. In case G1/93, Advanced Semiconductor Products, the Enlarged Board of Appeal of the EPO stated (at paragraph [9] of its reasons) that the idea underlying Art. 123(2) is that that an applicant should not be allowed to improve his position by adding subject matter not disclosed in the application as filed, which would give him an unwarranted advantage and could be damaging to the legal security of third parties relying on the content of the original application. At paragraph [16] it explained that whether an added feature which limits the scope of protection is contrary to Art. 123(2) must be determined from all the circumstances. If it provides a technical contribution to the subject matter of the claimed invention then it would give an unwarranted advantage to the patentee. If, on the other hand, the feature merely excludes protection for part of the subject matter of the claimed invention as covered by the application as filed, the adding of such a feature cannot reasonably be considered to give any unwarranted advantage to the applicant. Nor does it adversely affect the interests of third parties. [102] Sixth, it is important to avoid hindsight. Care must be taken to consider the disclosure of the application through the eyes of a skilled person who has not seen the amended specification and consequently does not know what he is looking for. This is particularly important where the subject matter is said to be implicitly disclosed in the original specification.’ 8. When amendment of a granted patent is being considered, the comparison to be made is between the application for the patent, as opposed to the granted patent, and the proposed amendment (see the definition of ‘additional matter’ in s.76(1)(b)). It follows that by and large the form of the granted patent itself does not come into the comparison. This case was to some extent overcomplicated by looking at the granted patent, particularly the granted claim 1. 9. A particular, and sometimes subtle, form of extended subject matter (what our Act calls ‘additional matter’) is what goes by the jargon term ‘intermediate generalisation’. Pumfrey J described this in Palmaz's European Patents[1999] RPC 47 , 71 as follows: ‘If the specification discloses distinct sub-classes of the overall inventive concept, then it should be possible to amend down to one or other of those sub-classes, whether or not they are presented as inventively distinct in the specification before amendment. The difficulty comes when it is sought to take features which are only disclosed in a particular context and which are not disclosed as having any inventive significance and introduce them into the claim deprived of that context. This is a process sometimes called “intermediate generalisation”.’”
“A method according to any one of claims 26 to 30, wherein nucleic acid derived from a selected or screened rgdp is used to express said sbp member or a fragment or derivative thereof in a recombinant host organism.”
“A method according to anyone of the preceding claims wherein the rgdps formed by said expression are selected or screened to provide an individual sbp member or a mixed population of said sbp members associated in their respective rgdps with nucleic acid encoding said sbp member or a polypeptide chain thereof.”
“A method of producing a multimeric member of a specific binding pair (sbp), which method comprises: expressing in a recombinant host organism a first polypeptide chain of said sbp member or a genetically diverse population of that type of sbp member fused to a component of a secreted replicable genetic display package (rgdp) which thereby displays said polypeptide at the surface of the package, and expressing in a recombinant host organism a second polypeptide chain of said multimer and causing or, allowing the polypeptide chains to come together to form said multimer as part of said rgdp, at least one of said polypeptide chains being expressed from nucleic acid that is capable of being packaged using said component therefor, whereby the genetic material of each said rgdp encodes a said polypeptide chain.”
“The present invention also provides rgdps as defined above and members of specific binding pairs e.g. binding molecules such as antibodies, enzymes, receptors, fragments and derivatives thereof, obtainable by use of any of the above defined methods. The derivatives may comprise members of the specific binding pairs fused to another molecule such as an enzyme of a Fc tail”
“Q. And is it possible to tell for any particular mutant whether it just lost specificity or whether it was specific for something else? A. I think you have to test it. You can speculate, but I think basically you have to test it.”
“If one makes 30,000 variants of that, something that is really well adjusted to where it binds to, the chance of getting another binder to something else is very slim. Having said that, and I think that is what I mean and probably most people would say to you, if you search the universe of possible antigens, including everything that is on the moon, we would probably find another specificity. That is all we are saying.”
“Subject to the provisions of this section, a person infringes a patent for an invention if, but only if, while the patent is in force, he does any of the following things in the United Kingdom in relation to the invention without the consent of the proprietor of the patent, that is to say— … (c) where the invention is a process, he disposes of, offers to dispose of, uses or imports any product obtained directly by means of that process or keeps any such product whether for disposal or otherwise.”
“If the subject-matter of the European patent is a process, the protection conferred by the patent shall extend to the products obtained directly by such process.”
“A Community patent shall confer on its proprietor the right to prevent all third parties not having his consent: … (c) from offering, putting on the market, using or importing or stocking for these purposes the product obtained directly by a process which is the subject-matter of the patent.”
“A patent shall confer on its owner the following exclusive rights: … (b) where the subject-matter of the patent is a process, to prevent third parties not having the owner’s consent from the act of using the process, and from the acts of: using, offering for sale, selling or importing for these purposes at least the product obtained directly by that process.”
“The Dusseldorf Higher Regional Court [in a decision in 1977] and also Hahn and Flesche allow themselves to be guided by the desire to provide the proprietors of process patents with effective protection against the possibility that, after the patented teaching was made use of in a patent-free foreign country to make intermediates, the imported end products obtained abroad from the intermediates are put into circulation in the territory of the patent. This desire to ensure that the patent proprietor gets his due reward for the disclosure of his invention when his invention is taken advantage of in the territory of his patent through the sale of the end products is perfectly legitimate and commendable. However, if the inventor fails to ensure adequate protection for his invention through an appropriate form of words in his patent, an interpretation which has his interests at heart must not lead to a broad interpretation of the concept of ‘direct products of a process’ which is no longer covered by the wording and legislative intentions. The West German Supreme Court has left it to the inventor, whether in the case of an invention which concerns the manufacture of a new substance from which new substances with surprising useful properties can be manufactured, he will be satisfied with the protection for the production process up to stage of the intermediate or whether he wants to extend his protection to the overall process, including the making of the end product, which latter option may be disadvantageous for him if the further processing of the intermediate to the endproduct take place in the patent-free foreign country or in the non-industrial sector, since in those cases he will not have a weapon against the use of the process (B.G.H.Z. 51, 378, 387 - Disiloxan). In addition the inventor in the case of such inventions has the option of achieving, through an appropriate wording of the claims, that not only the process up to and including the manufacture of the intermediate but also the overall process via the manufacture of the intermediate and up to and including further processing to the end product is put under protection.”
“Therefore the issue ultimately is whether the product made by the invention is altered by further processing in essential properties … The question as to which properties are essential in the sense mentioned must consequently be asked again from patent-legal aspects and having regard to the concrete invention. Since it is crucial for the indispensable evaluative judgment to what extent the inventive step is embodied in, and marks, the end-product at issue, it is especially important to what extent further changes affect specifically those properties of the product of the patent which are essential from the aspect of the concrete inventive concept and were the reason for the patent being granted in the first place … … the sole criterion is to what extent the changes affect the essence of the product. Even the subsequent change to the chemical structure therefore does not necessarily lead to the loss of ‘directness’; on the contrary, the question to be examined is which significance any change to the chemical structure has from the aspect of the concrete inventive concept.”
“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. That was the test applied by the Düsseldorf Oberlandesgericht in 1977 no less than by the Reichsgericht in 1909 (the Ossal case) and 1916 (binding agents for pigment dyes). Indeed the essence of Dr. Bruchhausen’s criticisms of the Düsseldorf decision, as I understand them, was not so much that an incorrect test had been adopted as that it had been incorrectly applied to the facts of the case.”
“Since the authorities in the Netherlands, Switzerland, Denmark and Austria disclose no difference of approach from that adopted in Germany, the loss of identity test may be taken to represent the test adopted by European law. The question whether the product with which the patented process ends retains its essential characteristics or not being one of fact and degree, there will often be difficulty in applying the test to the facts of particular cases. In the present case … there is no such difficulty. In my judgment the actions are bound to fail and Aldous J. was right to strike them out.”
“93. … Smith do not design or manufacture bits within the jurisdiction, so infringement of claim 3 is alleged by virtue of subs.60(1)(c) of the Patents Act 1977 . The invention is a process, and so the product sold in the United Kingdom must be obtained directly by means of the claimed process. ‘Obtained directly’ has been considered in two cases cited to me, particularly Pioneer Electronics Capital Inc v Warner Music Manufacturing Europe GmbH [1997] R.P.C. 757 , and a decision Halbleiter-bauelemente in the Landgericht Düsseldorf May 6, 1997. The Court of Appeal have held that ‘obtained directly’ means ‘without intermediary’ or immediately. This seems to exclude the possibility of further processing: but the Halbleiterbauelemente case suggests that further use or processing may take place provided that its effect is not to obscure the qualities of the product directly obtained. 94. The result of the performance of the claimed method is, if I am right on the question of construction, a CAD file containing a design of bit balanced under design conditions. The CAD file is input to a numerically controlled milling machine to produce (separately) the cones, either milled in one piece with the teeth or with recesses to receive the inserts, which are themselves milled to the design recorded in the CAD file. The cones are then assembled with the associated bearings, seals and other ironmongery into a bit body. Is the result ‘directly obtained’ by means of the process? 95. Smith’s approach to this question is understandably to point to the design as the endpoint of the claimed process, and to decompose the subsequent manufacturing process into as many steps as reasonably possible. Whatever is using the CAD files resulting from a session with the simulation software is not obtained directly by use of the process but (I paraphrase) by employing the design in further manufacture. They identify the following [six] steps as producing ‘an independent article which is not the thing that came out of the claimed process’: … 96. I do not think that it is sensible to view manufacture and design as in some way resulting in separate products. Design is no doubt interesting in the abstract, but when it is used it cannot be divorced from the article made to it.The Registered Designs Act 1949 and its predecessors encouraged lawyers to consider a design as something complete in itself and distinct from any article, but from the point of view of a bit designer the design exists only as a depiction of a bit that is to be made and used. There is no doubt that the criterion with which the claimed method is concerned depend upon the bit shape as a whole (I shall discuss this further when I consider insufficiency) and it follows, it seems to me, that there is no intermediate between this method and the resulting bit, which is as much the direct product of the design process as it is the product of the manufacturing process of which the design is part.”
“31. Mr. Watson [counsel for Cargill], as I understand it, says that the starting point is the product and then an objective assessment is to be taken of whether the process results in a loss of the essential characteristics of that product. In the present case the product is the original plant created by the process but even if one ignores the fact that the soymeal is not produced from that product but from its progeny and assumes that it is the original plant which has produced the soymeal, the process of producing meal from plant is such, it is argued for Cargill, as inevitably to destroy the essential characteristics of the plant. 32. Mr. Tappin [counsel for Monsanto] says that this is the wrong approach and that one can only assess the essential characteristics of the product by reference to the inventive concept which has led to the patent in the first place. It is therefore arguable that the central characteristics of the plant have, on his submissions, indeed been retained in the meal but this is an issue of fact and degree which can only be judged after receipt of evidence with which it is not appropriate or proportionate to deal on a summary application. 33. Mr. Watson says, correctly, that I am bound by the Court of Appeal which lays down the test which I have set out and submits that no reference is made in that test to any inventive concept. However Nourse LJ in adopting that test specifically referred to it as the test applied by the Düsseldorf Oberlandesgericht in 1977 and in its decision that court certainly did refer to inventive concept in the context of the legal patent aspects. It is at least strongly arguable, and if it were necessary for me to decide I would do so in that sense, that Nourse LJ was indicating his acceptance of the test and approach adopted by that court, including its reference to the patent legal aspects and having regard to the concrete invention or inventive concept. Certainly, in deciding whether or not to grant summary judgment I consider that Mr. Tappin’s approach is probably right and that Mr. Watson’s approach is probably wrong. I do not need to make a final determination on that issue, it will be a matter for the judge at trial or at a full hearing of the summary judgment application.”
“Any provision of, or made under, this Act is to have effect in relation to patent or an application for a patent which concerns a biotechnology invention, subject to the provisions of Schedule A2.”
“(8) Whereas legal protection of biotechnological inventions does not necessitate the creation of a separate body of law in place of the rules of national patent law; whereas the rules of national patent law remain the essential basis for the legal protection of biotechnological inventions given that they must be adapted or added to in certain specific respects in order to take adequate account of technological developments involving biological material which also fulfil the requirements for patentability; … (13) Whereas the Community’s legal framework for the protection of biotechnological inventions can be limited to laying down certain principles as they apply to the patentability of biological material as such, such principles being intended in particular to determine the difference between inventions and discoveries with regard to the patentability of certain elements of human origin, to the scope of protection conferred by a patent on a biotechnological invention, to the right to use a deposit mechanism in addition to written descriptions and lastly to the option of obtaining non-exclusive compulsory licences in respect of interdependence between plant varieties and inventions, and conversely; … (46) Whereas, in view of the fact that the function of a patent is to reward the inventor for his creative efforts by granting an exclusive but time-bound right, and thereby encourage inventive activities, the holder of the patent should be entitled to prohibit the use of patented self-reproducing material in situations analogous to those where it would be permitted to prohibit the use of patented, non-self-reproducing products, that is to say the production of the patented product itself; …”
“For the purposes of this Directive, inventions which are new, which involve an inventive step and which are susceptible of industrial application shall be patentable even if they concern a product consisting of or containing biological material or a process by means of which biological material is produced, processed or used.”
“1. The protection conferred by a patent on a biological material possessing specific characteristics as a result of the invention shall extend to any biological material derived from that biological material through propagation or multiplication in an identical or divergent form and possessing those same characteristics. 2. 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.”
“The protection conferred by a patent on a product containing or consisting of genetic information shall extend to all material, save as provided in Article 5(1), in which the product is incorporated and in which the genetic information is contained and performs its function.”
“121. A patent for a product normally gives the holder the exclusive right to manufacture that product (subject to compliance with applicable laws and regulations). In the case of patented material which is capable of reproducing itself, the value of the patent would clearly be eroded if it did not extend to future generations of such material. For example, if the purchaser of patented seeds were able to use the seeds produced by the crop grown from the purchased seeds, the value of that patent would be much reduced. Article 8(1) accordingly states that in such cases the protection conferred by the original patent extends to future generations of biological material derived through propagation or multiplication. Recital 46 expresses that principle in terms of the patent-holder’s entitlement ‘to prohibit the use of patented self-reproducing material in situations analogous to those where it would be permitted to prohibit the use of patented, non-self-reproducing products, that is to say the production of the patented product itself’. (With regard to seeds, as discussed above Article 11(1) derogates from that protection in prescribed circumstances and for a fee.) 122. Article 8(2) similarly adapts a well-known principle of traditional patent law to the exigencies of biotechnological inventions. Where the subject-matter of a patent is a process, the protection conferred by the patent extends to the products directly obtained by such a process. That principle has been incorporated in international patent legislation since at least 1958, when Article 5 quater was inserted into the Paris Convention. It finds expression in Article 64(2) of the European Patent Convention, which provides: ‘If the subject-matter of a European patent is a process, the protection conferred by the patent shall extend to products directly obtained by such process.’ 123. If the products so obtained are themselves capable of replication, the problem discussed in paragraph 121 will arise. For example, a patented process may result in the production of a micro-organism which can be cloned. If such material could be freely propagated by a purchaser, the value of the process patent would be nullified. Article 8(2) accordingly makes it clear that the protection conferred on biological material directly obtained by a patented process extends to future generations of that material.”
‘If the subject-matter of a European patent is a process, the protection conferred by the patent shall extend to products directly obtained by such process.’
“Accordingly, the answer to the first question is that Article 9 of the Directive must be interpreted as not conferring patent right protection in circumstances such as those of the case in the main proceedings, in which the patented product is contained in the soy meal, where it does not perform the function for which it was patented, but did perform that function previously in the soy plant, of which the meal is a processed product, or would possibly again be able to perform that function after it had been extracted from the soy meal and inserted into the cell of a living organism.”