“It will be appreciated from what has been said above that researchers often want to screen large libraries of antibodies or antigens for an antibody or antigen of interest. In 1990 an established technique for doing this was a method called “replica plate-lift”
“(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 aa [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 aa 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 pIII 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.”
“(e) Prospects for an ‘epitope library’ An ‘epitope library’ would contain, say, 10 8 clones expressing a short, synthetic random codingsequence. Such a library might be expected to contain clones reactive with almost any anti-protein antibody, since protein epitopes are typically about 6 aa long and virtually all 64 million 6 aa 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.”
“366. At this point Professor Smith raised the question “Will it fold right?”, recognising the possibility that in such an environment the conformation of the SCA might be compromised. He explained that some of the pIII protein was embedded in the inner membrane, with the bulk in the periplasm, which was then transferred into the growing virion. He went on, however, to say that, if folding were a concern, use could be made of a known approach for producing recombinant proteins in bacterial cells, where a process of denaturation using 6M urea at pH 2.2 and renaturation is employed in order to achieve the required folding. Such an approach was potentially feasible in the context of fusion phage because phage could survive the conditions involved. 367. Professor Smith then said that, although degradation might be an impediment to the successful display of large peptides, as had been suggested in Parmley & Smith, the contrary view was that it might be of benefit. The “lon” and “deg” systems of bacteria exist to remove malfolded proteins. He therefore suggested that such degradation might result in the removal of malfolded SCAs, which might work in the experimenter’s favour and make the detection of correctly-folded SCAs (if they were not degraded) cleaner. 368. Professor Smith also suggested that, if the SCA on the surface of the fusion phage interfered with the phage’s ability subsequently to infect bacteria, it could simply be removed with trypsin.”
“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.”
“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 etc may be linked to eg Fab, scFv fragments.”
“[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 domainsfor 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.”
“(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 patentee is entitled to have the question of obviousness determined by reference to the claim and not to some vague paraphrase based upon the extent of his disclosure in the description.”
“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 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.”
“Each case depends upon the invention and the surrounding facts. No formula can be substituted for the words of the statute. In every case the Court has to weigh up the evidence and decide whether the invention was obvious. This is the statutory task.”
“The question of whether an invention was obvious had been called “a kind of jury question” (see Jenkins L.J. in Allmanna Svenska Elektriska A/B v. The Burntisland Shipbuilding Co. Ltd. (1952) 69 R.P.C. 63, 70) and should be treated with appropriate respect by an appellate court. It is true that in Benmax v. Austin Motor Co. Ltd. [1955] A.C. 370 this House decided that, while the judge's findings of primary fact, particularly if founded upon an assessment of the credibility of witnesses, were virtually unassailable, an appellate court would be more ready to differ from the judge's evaluation of those facts by reference to some legal standard such as negligence or obviousness. In drawing this distinction, however, Viscount Simonds went on to observe, at page 374, that it was “subject only to the weight which should, as a matter of course, be given to the opinion of the learned judge”
“400. What is decisive in the present case is the evidence concerning the questions of size, infectivity, breakdown and folding identified above. Dr Huse, Professor Brammar and Dr Teillaud were all agreed that size per se was not an issue. So far as infectivity is concerned, as Dr Huse pointed out, Parmley & Smith expressly states that the lac335 fusion phage could be effectively affinity-purified despite its reduced infectivity. Nevertheless, I think it is clear that the skilled team would be concerned at the reduced infectivity, and the suggestion that it was due to breakdown. Thus the main points are breakdown and folding. Dr Huse’s evidence was the skilled team would have a reasonable expectation of success despite what was said about the former and the absence of any discussion of the latter, whereas Professor Brammar and Dr Teillaud disagreed. 401. Both Professor Brammar and Dr Teillaud highlighted the statement in Parmley & Smith that: “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.”
“… I consider that there can be no serious dispute that Professor Smith’s talk made it obvious to try phage display of antibodies provided that there was a sufficient expectation of success having regard to the other factors considered above. The only question is whether it would have given the skilled team a reasonable expectation of success within a reasonable time.”
“ Subject to consideration of the secondary evidence relied on by each side, the conclusion which I draw from the evidence is that Professor Smith’s talk at the Banbury Conference would have given the skilled team a reasonable expectation of success within a reasonable time. Not merely did he explicitly propose antibody phage display, but in addition he said that he was going to do the experiment. Furthermore, he addressed the concerns which arose out of Parmley & Smith and gave reasons as to why he nevertheless considered the experiment worth carrying out, as well as explaining potential solutions if problems were encountered. Finally, his tone was one of encouragement.”
“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?”
“Although Professor Smith accepted in cross-examination that the project described in the application was speculative, at least so far as the antibody phage display was concerned, it appears from the document that it was the reviewers who had described his epitope library proposal as speculative, and that at the time Professor Smith did not agree with this. Finally, the time scale envisaged is clearly driven both by Professor Smith’s need for funding, particularly given the consequences of the refusal of the previous application, such as the need to train a new technician, and by the “much curtailed budget”, which only allowed for one research assistant. It also reflects the fact that he intended first to work on the epitope library, as indeed he did, and that at the end of the five years he hoped to be screening large libraries with multiple antigens.”
“With regard to folding, he said during the interview that this “loomed large in his thinking”
“In some ways this is the best piece of evidence in MedImmune’s favour, but again it must be taken in context. I understood Professor Smith to mean that he would want to assign a project to a PhD student which was more clearly certain of success. (It appears that he did not have a post-doctoral student available to do the work at the time.) Professor Smith accepted that he could not confidently say in advance, “Oh yes, that is going to work”; but equally he was clear that he thought that there was reasonable likelihood of success.”
“In saying this, I am not overlooking the fact that Professor Smith’s experiment did not quite arrive at implementing the core inventive concept, since it does not appear to have involved selection by binding from a population with a range of specificities (or at least it is not clear that it did). It nevertheless demonstrated the principle of antibody phage display.”
“Taking all of the different factors and evidence discussed above into account, my conclusion is that the claimed inventions were obvious in the light of Professor Smith’s talk at the Banbury Conference. Professor Smith explicitly proposed antibody phage display, and the skilled team would have had a reasonable expectation that this would succeed in a reasonable period of time.”
“Patentability is justified because the prior idea which was thought not to work must, as a piece of prior art, be taken as it would be understood by the person skilled in the art. He will read it with the prejudice of such a person. So that which forms part of the state of the art really consists of two things in combination, the idea and the prejudice that it would not work or be impractical. A patentee who contributes something new by showing that, contrary to the mistaken prejudice, the idea will work or is practical has shown something new. He has shown that an apparent “lion in the path” is merely a paper tiger. Then his contribution is novel and non-obvious and he deserves his patent.”
“MR JUSTICE ARNOLD: …. 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.” …. Trying to put yourself into the shoes of the ordinary Banbury Conference, in your opinion, would they be sufficiently encouraged by the overall message to go away and try it or not? 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.”
“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’.” 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’.”
“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. …” surprising to me that he did not make any experiment in this interval of time about antibodies. …”
“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?”
"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."
“228. 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 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) packaging comprising a virus and an above identified molecule presented at the viral surface; and d) screening techniques utilising the unique properties of these packages. ”
“It has been shown that the function of binding antigens can be performed by fragments of a whole antibody. Binding fragments are the FV fragment which comprises the VL and VH of a single arm of the antibody, and the dAb fragment (Ward, E.S. et al., Nature 341, 544-546 (1989); which consists of a single heavy chain variable domain (VH). Although the FV fragment is coded for by separate genes, it has proved possible to construct a linker that enables them to be made as a single protein chain (known as single chain FV (scFv); Bird, R.E. et al., Science 423, 423-426 (1988) Huston, J.S. et al., Proc. Natl. Acad. Sci., USA 85, 5879-5883)) by recombinant methods. Whilst monoclonal antibodies, their fragments and derivatives have been enormously advantageous, there are nevertheless a number of limitations associated with them.”
“The use of pAbs may also allow the construction of entirely synthetic antibodies. 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 applicant has also shown that enzymes can be expressed on the phage surface. Useful applications of this invention include the cloning of enzyme coding genes, or the design and selection of mutant enzymes with enhanced properties on particular substrates. For example, conditions can be used whereby the enzyme (or modified enzyme) binds a particular substrate., product or intermediate (or analogues of them) to identify from a library containing a desired activity or by subjecting phage already expressing the enzyme, to in vitro mutagenesis, followed by selection of those variants with a desired level of binding and/or catalysts.”
“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 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 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.”
“The disclosure made by the present applicants is important and provides a significant breakthrough in the technology relating to the production of biological binding molecules, their fragments and derivatives by the use of recombinant methods.”
“Art 52 Patentable Inventions (1) European patents shall be granted for any inventions which are susceptible of industrial application, which are new and which involve an inventive step. Art 56 Inventive Step An invention shall be considered as involving an inventive step if, having regard to the state of the art, it is not obvious to a person skilled in the art.”
“So at bottom the question is simply whether the invention is obvious. Any paraphrase or other test is only an aid to answering the statutory question.”
“I have endeavoured to refrain from coining a definition of “obviousness” which counsel may be tempted to cite in subsequent cases relating to different types of claims. Patent law can too easily be bedevilled by linguistics and the citation of a plethora of cases about other inventions of different kinds. The correctness of a decision upon an issue of obviousness does not depend upon whether or not the decider has paraphrased the words of the Act in some particular verbal formula. I doubt whether there is any verbal formula which is appropriate to all classes of claims.”
“I would, however, desire to associate myself particularly with what Diplock, LJ said as to the undesirability of coining phrases for the purpose of paraphrasing the words of the Act.”
“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.”
“Whenever anything inventive is done for the first time it is the result of the addition of a new idea to the existing stock of knowledge. Sometimes, it is the idea of using established techniques to do something which no one had previously thought of doing. In that case, the inventive idea will be doing the new thing. Sometimes, it is finding a way of doing something which people had wanted to do but could not think how. The inventive idea would be the way of achieving the goal. In yet other cases, many people may have a general idea of how they might achieve a goal but not know how to solve a particular problem which stands in their way. If someone devises a way of solving the problem, his inventive step will be that solution, but not the goal itself or the general method of achieving it.”
“… obviousness connotes something which would at once occur to a person skilled in the art who was desirous of accomplishing the end.” (Emphasis added)
“27 Patentability is justified because the prior idea which was thought not to work must, as a piece of prior art, be taken as it would be understood by the person skilled in the art. He will read it with the prejudice of such a person. So that which forms part of the state of the art really consists of two things in combination, the idea and the prejudice that it would not work or be impractical. A patentee who contributes something new by showing that, contrary to the mistaken prejudice, the idea will work or is practical has shown something new. He has shown that an apparent “lion in the path” is merely a paper tiger. Then his contribution is novel and non-obvious and he deserves his patent. 28 Where, however, the patentee merely patents an old idea thought not to work or to be practical and does not explain how or why, contrary to the prejudice, that it does work or is practical, things are different. Then his patent contributes nothing to human knowledge. The lion remains at least apparent (it may even be real) and the patent cannot be justified.” (Emphasis in original)
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