ON APPEAL FROM HIGH COURT OF JUSTICE
CHANCERY DIVISION, PATENTS COURT
MR JUSTICE HENRY CARR
Strand, London, WC2A 2LL
B e f o r e :
LORD JUSTICE KITCHIN
LORD JUSTICE FLOYD
| REGENERON PHARMACEUTICALS, INC
||Appellant in Appeal No: A3/2016/1993
Respondent in Appeal No: A3/2016/1994
|- and -
|(1) KYMAB LIMITED
(2) NOVO NORDISK A/S
|Respondent in Appeal No: A3/2016/1993
Appellant in Appeal No: A3/2016/1994
Respondent in Appeal No: A3/2016/1993
Michael Tappin QC and James Whyte (instructed by Powell Gilbert LLP) for Kymab Limited
Hearing dates : 17- 20 October 2017
Crown Copyright ©
Lord Justice Kitchin:
The technical background in outline
Antibodies in therapy
Immunoglobulin locus size
The invention disclosed in the patents
"The technology used to establish these first-generation mice had several inherent limitations, including position effects due to the random integration of the transgene and upper limits on the length of the DNA that could be introduced into the mouse genome by means of zygote injection. As a result these mice had incomplete human antibody repertoires. In addition, these first-generation transgenes included both human variable and constant regions. Although these mice would be expected to produce fully human antibodies, there are sequence differences between human and mouse IgM constant regions and signaling proteins Iga and Igß. As a result, during the stage when an antibody functions as a B-cell receptor (BCR), the interaction between the human constant region and the mouse signaling proteins Iga and Igß may not be optimal, and reduced signaling could limit antibody class switching and affinity maturation, as well as B-cell differentiation into mature antibody-secreting plasma cells."
i) bacterial homologous recombination to engineer a desired genetic modification within a large cloned genomic fragment to create large targeting vectors ("LTVECs") for use in eukaryotic cells;
ii) introducing these LTVECs into eukaryotic cells to modify the endogenous chromosomal locus of interest; and
iii) using an assay for modification of allele ("MOA") of the parental allele that does not require sequence information outside of the targeting sequence, such as, for example, quantitative PCR to determine those eukaryotic cells in which the targeted locus has been modified as desired.
"In contrast to traditional methods, in which a difference in restriction fragment length spanning the entire homology arm or arms indicated the modification of one of two alleles, the quantitative TaqMan® method [an example of the MOA assay] will detect the modification of one allele by measuring the reduction in code number (by half) of the unmodified allele. Specifically the probe detects the unmodified allele and not the modified allele."
"1. A transgenic mouse that produces hybrid antibodies containing human variable regions and mouse constant regions, wherein said mouse comprises an in situ replacement of mouse VDJ regions with human VDJ regions at a murine chromosomal immunoglobulin heavy chain locus and an in situ replacement of mouse VJ regions with human VJ regions at a murine chromosomal immunoglobulin light chain locus."
"1. A method of modifying an endogenous immunoglobulin heavy chain variable region gene locus in an isolated mouse embryonic stem (ES) cell by an in situ replacement of V, D, and J gene segments of the endogenous locus with orthologous human V, D and J gene segments, to create a modified immunoglobulin locus that produces hybrid antibodies containing human variable regions and mouse constant regions, said method comprising:
a) obtaining a large cloned genomic fragment greater than 20kb containing orthologous human V, D, and J gene segments;
b) using bacterial homologous recombination to genetically modify the cloned genomic fragment of (a) to create a large targeting vector for use in a mouse ES cell (LTVEC);
c) introducing the LTVEC of (b) into a mouse ES cell to replace said V, D, and J segments in situ with the orthologous human V, D and J gene segments; and
d) using a quantitative assay to detect modification of allele (MOA) in the mouse ES cell of (c) to identify a mouse ES cell in which said V, D and J segments have been replaced in situ with the orthologous human V, D and J gene segments.
5. A genetically modified eukaryotic cell or a mouse comprising a genetically modified immunoglobulin heavy chain variable region locus obtainable by the method of any one of the preceding claims in situ in place of the endogenous
6. A mouse embryonic stem (ES) cell containing a genetically modified immunoglobulin heavy chain variable region gene locus obtainable by the method of any one of claims 1 to 4 in situ in place of the endogenous immunoglobulin heavy chain variable region gene locus."
"172. In my judgment, in situ replacement means replacing 'in the position of". The phrase is apt to describe a positional replacement and this is how it is used in context. The human sequences are to be inserted in the original position of the mouse segments juxtaposed with the mouse constant regions. The skilled person would appreciate that the patentee is using this language to distinguish targeted replacement from random insertion into the genome. This includes the case where the relevant murine sequence is deleted, and also the case where it is moved to a different location and inactivated.
173. The word "replacement" is used in the specification to describe both deletion and displacement/inactivation. The invention is concerned with the use of LTVECs and the MOA assay to enable the targeted insertion and detection of human variable V, D and J gene segments, in place of mouse variable V, D and J gene segments, whilst retaining the mouse constant segments. Given that inactivation was a well-known alternative to deletion at the priority date, I do not consider that it would make technical sense for the patentee to have excluded embodiments where the murine sequence had been moved to a different location and rendered inactive."
"Another embodiment of the invention is a method wherein the genetic modification to the endogenous gene or chromosomal locus comprises deletion of a coding sequence, gene segment, or regulatory element; insertion of a new coding sequence, gene segment, or regulatory element; creation of a conditional allele; or replacement of a coding sequence or gene segment from one species with an homologous or orthologous coding sequence from a different species." (emphasis added).
"The final steps in creating the human variable/mouse constant monoclonal antibody-producing mouse will be performing the equivalent variable region substitutions on the lambda and kappa light chain loci and breeding all three hybrid loci to homozygosity in the same mouse. The resultant transgenic mouse will have a genome comprising entirely human heavy and light chain variable gene loci operably linked to entirely endogenous mouse constant regions". (Emphasis added).
"The region to be modified and replaced using bacterial homologous recombination can range from zero nucleotides in length (creating an insertion into the original locus) to many tens of kilobases (creating a deletion and/or a replacement of the original locus)…"
"Since there will be only one, chimeric, heavy or light chain locus (as opposed to mutated immunoglobulin loci and with human transgenic loci integrated as distinct chromosomal locations for heavy and light chains in the currently available mice) there should be no trans-splicing or trans-rearrangements of the loci which could result in non-productive rearrangements or therapeutically irrelevant chimeric antibodies."
" 1. What is the correct construction of the term "in situ replacement" in claim 1 of the 287 patent and claim 1 of the 163 patent? In particular, does it mean:
(a) mouse V, D and J gene segments (or, as the case may be, mouse VDJ or VJ regions) have been deleted from the genome;
or does it also include cases in which:
(b) mouse V, D and J gene segments (or, as the case may be, mouse VDJ or VJ regions) have been
(i) displaced; or
(ii) displaced and inactivated?"
"…so the relevant murine variable segments must at least be moved (and inactivated) so that the human variable segments can be inserted in their position…"
"..questions of construction seldom arise in the abstract. That is why any sensible discussion of the meaning of language runs along the lines 'does it mean this, or that, or the other?', rather than the open-ended 'what does it mean?"
"… as I have pointed out before, even if you had only a few human Vs properly positioned relative to the mouse constant regions, you reap the full benefit of the invention. You would allow class switch recombination, somatic hypermutation all to benefit from the presence of these mouse constant regions."
The technical contribution of the patent
The examples of the patent
"Precise replacement of the mouse heavy chain locus variable region (VDJ) with its human counterpart is exemplified using a combination of homologous and site-specific recombination in the following example, which utilizes a two-step process. One skilled in the art will recognize that replacement of the mouse locus with the homologous or orthologous human locus may be accomplished in one or more steps. Accordingly, the invention contemplates replacement of the murine locus, in whole or in part, with each integration via homologous recombination."
"… the claim requires at least one endogenous V gene segment (as well as D and J gene segments), i.e. at least about 150 kb of mouse sequence, to be replaced with at least one orthologous V human gene segment (as well as D and J gene segments), i.e. at least about 75 kb of human genomic sequence. There is no doubt that at least about 75 kb of human genomic sequence is required to be inserted. Whether, in addition, at least about 150 kb of mouse sequence is required to be deleted depends upon the meaning of "in situ replacement" which I shall consider below. I will also consider whether claim 1 covers the case where the mouse sequence is deleted. "
i) The claim does not require the deletion of any sequence. It requires the replacement of at least one V, one D and one J mouse segment with the orthologous human V, D and J segments. But we accept the judge's finding that one V, and all the D and J segments of the mouse genome have a length of about 150 kb, including all the intergenic regions.
ii) We also have no doubt that the judge was entitled to find that a fragment containing one human V and all the human D and J segments will be about 75 kb in length, assuming it contains all the intergenic regions. There was an amply sufficient basis for this finding in the evidence of Professor Evans and Professor Howard. We return later in this judgment to the question of the length of the intergenic regions and whether they could be deleted.
iii) The specification describes at  (among other things) the replacement of 100 kb of mouse sequence with 200-300 kb of human sequence.
iv) The parties were agreed and the judge found that the claimed method imposes a practical limit on the size of the cloned fragment that can be introduced because an LTVEC produced by recombineering cannot be larger than about 300 kb in length.
v) It is a requirement of the claim that the cloned genomic fragment which is used to create the first LTVEC must be at least 20 kb in length and contain orthologous human V, D and J segments, and that is so whether or not the intergenic regions are deleted. However, that said, there is no limit to the number of steps that can be used to build up the rest of the reverse chimeric locus described in the specification.
i) As with claim 1, they include products in which 100 kb of endogenous sequence has been deleted and 200-300 kb of orthologous sequence has been inserted and products in which 150 kb of endogenous sequence has been deleted and 75 kb of orthologous sequence has been inserted.
ii) Unlike claim 1, they contain no limitation as to the use of LTVECs or the MOA assay. Provided that the product in issue has the characteristics of a product made by the process of the claim, it does not matter how it is in fact produced.
iii) They contain no limit as to the amount of endogenous sequence which must be deleted and so include products in which the entire endogenous heavy chain sequence has been deleted.
iv) They contain no limit as to the amount of orthologous sequence which has been inserted and so include products in which the entire orthologous heavy chain sequence has been inserted.
i) The claim is not confined to a single product. It includes mice in which different amounts of mouse V, D and J regions (of the heavy chain) and mouse V and J regions (of the light chain) have been replaced by human V, D and J regions and V and J regions, respectively. So it includes, for example, a mouse in which one V, one D, and one J region (of the heavy chain) and one V and one J region (of the light chain) have been replaced, and mice in which several such regions have been replaced.
ii) As with claim 1 of the 287 patent, it includes products in which 100 kb of endogenous sequence have been deleted and 200-300 kb of orthologous sequence have been inserted; and products in which 150 kb of endogenous sequence have been deleted and 75 kb of orthologous sequence have been inserted.
iii) Unlike claim 1 of the 287 patent, this claim contains no requirement that LTVECs or the MOA assay must be used.
iv) The expressions "VDJ regions" and "VJ regions" as used in this claim are broad and encompass the whole mouse and human variable gene loci. Accordingly the claim extends to a mouse in which the entire murine variable gene locus has been replaced with the entire human variable gene locus.
What the skilled team could do
The findings of the judge
i) the minimum replacement by LTVEC1 as described in  is a deletion of 100 kb of mouse sequence and an insertion of 200-300 kb of human sequence;
ii) the minimum replacement required by claim 1 involves a larger deletion (of 150 kb) but a smaller insertion (of 75 kb);
iii) the claim also includes the case where the relevant mouse sequence has been displaced and deactivated, and the case where the relevant mouse sequence has been deleted.
"257. For these reasons, I have concluded that the whole subject matter defined in the claim 1 of the 287 Patent was not capable of being performed at the priority date without undue burden and without invention. The difficulty does not relate to some hypothetical puzzle at the edge of the claim, but rather to the central disclosure of the specification, and the amounts of genetic sequence of which it contemplates the deletion and insertion. None of the methods of the 287 Patent for achieving this, as disclosed in Example 3 would have worked. The task contemplated was unprecedented and could not have been achieved, if at all, without a great deal of creative thinking at the priority date. I do not accept that all embodiments within the claim are unified by a single principle of a reverse chimeric locus. This is not a principle that enables the method to be performed, rather it is the result of successfully carrying out the method. Accordingly, the insufficiency objection succeeds in respect of claim 1 of the 287 Patent.
258. It follows that claims 5 and 6 of the 287 Patent and claim 1 of the 163 Patent are also invalid for insufficiency. I have concluded that they are of considerably wider scope than claim 1 of the 287 Patent. Even if I had concluded that claim 1 of the 287 Patent was not of excessive breadth, I would still have concluded, for the reasons set out above, that these wider claims were insufficient."
" … Regeneron cites certain passages from the cross-examination of Prof. Stewart. I have already considered Prof. Stewart's evidence on this issue, and the parties' submissions in their written and oral closings. In my judgment, this evidence did not establish that a '17 Kb out, 75 Kb in' replacement could have been achieved by the skilled person in 2001 using the methods disclosed in the patent or other standard techniques. I have reached the opposite conclusion, for the reasons set out in detail in this judgment."
The arguments on appeal – an outline
Is Regeneron too late?
i) use an LTVEC to delete at least 100 kb of an endogenous murine variable region gene locus in a single homologous recombination step;
ii) insert 200-300 kb of an orthologous human gene locus carried on the same LTVEC and as part of the same homologous recombination step as (i); or
iii) use a modified human BAC to insert a fragment of at least 75 kb of an orthologous human variable region gene locus, or to replace at least 100 kb of an endogenous murine gene locus with at least 75 kb of an orthologous human variable region gene locus in a single RMCE step.
"In a complex case, it might well be prudent, and certainly not out of place, for the judge, having handed down or delivered judgment, to ask the advocates whether there are any matters which he has not covered. Even if he does not do this, an advocate ought immediately, as a matter of courtesy at least, to draw the judge's attention to any material omission of which he is then aware or then believes exists. It is well-established that it is open to a judge to amend his judgment, if he thinks fit, at any time up to the drawing of the order. In many cases, the advocate ought to raise the matter with the judge in pursuance of his duty to assist the court to achieve the overriding objective (CPR 1.3, which does not as such apply to these proceedings); and in some cases, it may follow from the advocate's duty not to mislead the court that he should raise the matter rather than allow the order to be drawn. It would be unsatisfactory to use an omission by a judge to deal with a point in a judgment as grounds for an application for appeal if the matter has not been brought to the judge's attention when there was a ready opportunity so to do. Unnecessary costs and delay may result. I should make it clear that there are general observations for assistance in future cases, and that I make no criticisms of Counsel in this case."
Implementation of the teaching
"The only way it would have been feasible to create a transgenic mouse in which part of the immunoglobulin variable region was replaced by part of the human immunoglobulin variable region at the priority date would be to use a small minigene construct up to approximately 20 kb in length containing a subset of the human immunoglobulin variable region gene segments."
"103. This would involve the replacement of less than 5 kb of mouse sequence (spanning the J gene segments) with the 20 kb minigene construct. As I explained at paragraph 37 of my First Report, replacements of this size were technically feasible at the Priority Date. Furthermore, I believe that the targeting construct that would have been used by the Skilled Genetic Engineer would have contained homology arms of the length commonly used at the Priority Date (i.e. 1-5 kb), designed such that the human minigene construct would replace the J region of the mouse immunoglobulin variable region, …"
"204. As I explained above in relation to Kucherlapati, although it would have been desirable to create a transgenic mouse containing the entire human immunoglobulin variable region, for the reasons already described, this would not have been technically feasible at the Priority Date. The Skilled Genetic Engineer would therefore have used a minigene construct containing a subset of the V, D and J segments, which would be inserted at the proximal end of the mouse immunoglobulin variable region in place of the J segments. Such minigene constructs are described in Lonberg in column 15, lines 37 to 63."
"Q. But if we can just take it in stages. My question to you is, if the skilled person was concerned that an insert, and I think you are alluding to an insert of 200 kb, was too big, an obvious option for the skilled person would be to say, I will put in a 75 kb insert. That would be an obvious ----
MR. JUSTICE HENRY CARR: He has already said yes, I think.
THE WITNESS: Yes.
MR. TURNER: I do apologise, my Lord, if I missed that. I am sorry, professor. Let us then have a look at X12. Keep the patent out. Let us have a look at X12. This is the human locus and I am looking at the bottom strand. One can see there are -- I do not know if one calls them strictly intergenic regions or introns, but I am talking about the gaps between the D and the first V and the gap between the first V and the second V. Do you call them introns or intergenic regions in the context of this locus?
A. This is not a normal gene. I do not know what immunologists would call these ----
Q. Let us call them gaps. You could certainly take out sequence from those gaps, could you not? You could do that by recombineering? That would be one way of ----
A. Reduce the distance between the two Vs?
Q. For example, yes. If you wanted to put two Vs in, you could just say do some recombineering, delete out 30 ----
A. Yes, absolutely. In fact, I said that one way of doing this would be to make a minigene, and that is in my report.
Q. Yes, that is ----
A. The minigene would involve indeed reducing the distance between the coding regions, the V and the D and the J coding regions.
"Q. If you could indulge me and let us just ignore what Regeneron did for a moment. Let us perhaps, first of all, look at the strategy that is suggested in this patent. Let us go back to page 40, figure 4B. The suggestion is to then put a second LTVEC in at the 5 prime region. Again, as a strategy, there is nothing wrong with that, is there?
A. You are talking about LTVEC2?
A. LTVEC2 suffers from the same improbabilities as LTVEC1.
A. Again, the skilled genetic engineer and his team or her team would, you know, flounder around trying to do the described exercise and then come to the conclusion that it needed to be redesigned.
Q. Let us assume you are putting in your second insert at the 5 prime end and you decide to go with, let us say, 50 kb this time. You put in two or three Vs and a loxP site at the 5 prime end. There is nothing wrong with that, is there?
A. I believe you would be able to do something like that, yes. Make it a more realistic exercise and target the 5 prime end, yes."
"Q. Now, yesterday we discussed the making of LTVEC and as I have said, I do not want to go over that again. I want you to assume you have now made an LTVEC which contains, let us say, between 75 and 150, if we can take the range, human insert, which is going to go in at that locus we have been talking about and you have decided to make a small deletion of Js and maybe a D, so let us say 17 kb. So you are putting in 75 or a little more and you are taking out 17 kb. That is your intended experiment. The person skilled in the art in doing this has reduced the techniques to practise, has got them working well, has done his workup experiments or her workup experiments and is using of course long homology arms and the MOA assay. Provided that manipulation is performed diligently at a reasonable trial and error, that will work, will it not?
A. What, sorry?
Q. What you are trying to do is you are trying to put in 75 or perhaps a little more of Vs, Ds and Js.
Q. We are back into the ES cell now.
Q. And you are trying to make a deletion of about 17 kb. I am asking you to assume that. You have your LTVEC. Everything is working well. The ES cells are working well. The techniques are working well.
Q. And now you are going to do this manipulation. It is going to work, is it not?
A. If you had asked me that question in 2001, I would have said I have no idea. This is very ambitious. I have no idea if this is going to work. I hope it does, really, you know, I would like to see experiments like that work, but in 2001 I could not have given you an answer. In 2015 we know the answer.
Q. And the answer is?
i) to use an LTVEC 1 containing human V, D and J segments of 50 to 75 kb in length;
ii) to use an LTVEC 2 containing human V segments of 50 to 75 kb in length;
iii) to delete the mouse V segments in the middle with SSR; and
iv) to insert by SSR in the place of the deleted mouse V segments around 10 kb of human V segment sequence.
i) the sufficiency of the disclosure is to be assessed having regard to the specification as a whole, including the description and the claims;
ii) the disclosure is to be considered through the eyes of the skilled person or, as here, the skilled team to whom the patent is addressed; and
iii) the skilled person may use his or her common general knowledge to supplement the information contained in the specification.
The degree of enablement
"8. Even though a reasonable amount of trial and error is permissible when it comes to the sufficiency of disclosure in an unexplored field or, – as in this case -, where there are many technical difficulties, there must then be available adequate instructions in the specification or on the basis of common general knowledge which would lead the skilled person necessarily and directly towards success through the evaluation of initial failures or through an acceptable statistical expectation rate in the case of random experiments."
"The section requires the skilled man to be able to perform the invention, but does not lay down the limits as to the time and energy that the skilled man must spend seeking to perform the invention before it is insufficient. Clearly there must be a limit. The sub-section, by using the words, clearly enough and completely enough, contemplates that patent specifications need not set out every detail necessary for performance, but can leave the skilled man to use his skill to perform the invention. In so doing he must seek success. He should not be required to carry out any prolonged research, enquiry or experiment. He may need to carry out the ordinary methods of trial and error, which involve no inventive step and generally are necessary in applying the particular discovery to produce a practical result. In each case, it is a question of fact, depending on the nature of the invention, as to whether the steps needed to perform the invention are ordinary steps of trial and error which a skilled man would realise would be necessary and normal to produce a practical result."
"In each case sufficiency will thus be a question of fact and degree, depending on the nature of the invention and the other circumstances of the case.
But if a working definition is required then one cannot do better than that proposed by Buckley L.J. in giving the judgment of the Court of Appeal in Valensi v British Radio Corporation  R.P.C. 337. After referring to a number of earlier authorities, including Edison & Swan v Holland, he said:
'We think that the effect of these cases as a whole is to show that the hypothetical addressee is not a person of exceptional skill and knowledge, that he is not to be expected to exercise any invention nor any prolonged research, inquiry or experiment. He must, however, be prepared to display a reasonable degree of skill and common knowledge of the art in making trials and to correct obvious errors in the specification if a means of correcting them can readily be found.'
Then a little later:
'Further, we are of the opinion that it is not only inventive steps that cannot be required of the addressee. While the addressee must be taken as a person with a will to make the instructions work, he is not to be called upon to make a prolonged study of matters which present some initial difficulty: and, in particular, if there are actual errors in the specification—if the apparatus really will not work without departing from what is described—then, unless both the existence of the error and the way to correct it can quickly be discovered by an addressee of the degree of skill and knowledge which we envisage, the description is insufficient.'
In that case there was a mistake in the specification. But Buckley L.J.'s language is equally apt to cover an omission. Aldous J said that the Valensi test is as apposite under the 1977 Act as it was under the 1949 Act. I agree."
Enablement across the scope of the claim
"3.1. Components of the future
3.1.1 Recombinant plasmids embrace, as components, various regulons which have not yet been provided and may, one day, represent inventions on the basis of some merit of their own. The same applies to the basic plasmid, which has been modified to possess the characteristics of the claim. The original plasmid might have complex structures to be developed in the future. Bacteria transformed with the claimed plasmids embrace mutant or modified forms not yet known. According to the Examining Division this situation contradicts the suggested requirement that all embodiments within the claims should be reproducible at will by the skilled person without having to make an invention.
3.1.2 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. … 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.
3.1.3 What is also important in the present case is the irrelevancy of the particular choice of a variant within the functional terms "bacteria", "regulon" or "plasmid". It is not just that some result within the range of polypeptides is obtained in each case but it is the same polypeptide which is expressed, independent of the choice of these means. A term of this kind must, of course, be clear and enable the skilled person to find suitable specimens without undue difficulty. In the present application enough choice is available, although some vehicles and hosts are preferred for practical reasons."
"3.1.5 The above examples show that the need for a fair protection governs both the considerations of the scope of claims and of the requirements for sufficient disclosure. Unless variants of components are also embraced in the claims, which are, now or later on, equally suitable to achieve the same effect in a manner which could not have been envisaged without the invention, the protection provided by the patent would be ineffectual. Thus it is the view of the Board that an invention is sufficiently disclosed if at least one way is clearly indicated enabling the skilled person to carry out the invention. Consequently, any non-availability of some particular variants of a functionally defined component feature of the invention is immaterial to sufficiency as long as there are suitable variants known to the skilled person through the disclosure or common general knowledge, which provide the same effect for the invention. The disclosure need not include specific instructions as to how all possible component variants within the functional definition should be obtained.
3.1.6 The Examining Division's tentative suggestion that such terms should be restricted to those available in the art has no basis in existing law. Unless broad, yet proper terminology is allowable, subsequent investigations by third parties might be encouraged to concentrate on finding alternatives outside the claims instead of trying to pursue progress through dependent inventions. The lack of recognition of the full significance and the interdependency of technical contributions could adversely affect progress in the area of microbiology and biochemistry.
3.1.7 In view of the above, it is also irrelevant that some of the variants of bacterial strains or regulons might only exist in private collections or can only be found in locations or derived from sources which are inaccessible or were only transiently available to the public. As long as there are means available for performing the invention, such exceptional circumstances cannot counteract the possibility that the invention can be carried out."
"3.3.2 … The present application is, however, not concerned with the problem of obtaining a finite set of particular products, as in the cited decision. The character of the invention this time is one of general methodology which is fully applicable with any starting material, and is, as it was already stated, also independent from, the known, trivial, or inventive character of the end-products. The transformed bacteria, as well as the claimed plasmids are agents and genetic precursors in a process of transformation, expression and recovery leading to the programmed products, and as long as the system works reliably at every stage there is no obligation to exclude future starting materials."
"2 ….in order to fulfil the requirement of Article 83 EPC, the application as filed must contain sufficient information to allow a person skilled in the art, using his common general knowledge, to carry out the invention within the whole area that is claimed."
"3.3 … 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 (see T 133/85, OJ EPO 1988, 441). This means that the definitions in the claims should essentially correspond to the scope of the invention as disclosed in the description. In other words, as was stated in Decision T 26/81 (OJ EPO 1982, 211, point 4 of the reasons), the claims should not extend to subject-matter which, after reading the description, would still not be at the disposal of the person skilled in the art."
"3.5 …. In the Board's judgment, the disclosure of one way of performing the invention is only sufficient within the meaning of Art. 83 EPC if it allows the person skilled in the art to perform the invention in the whole range that is claimed, as was already stated in point 2 above."
"2.2.1. … In the Board's judgment the criteria for determining the sufficiency of the disclosure are the same for all inventions, irrespective of the way in which they are defined, be it by way of structural terms of their technical features or by their function. In both cases the requirement of sufficient disclosure can only mean that the whole subject-matter that is defined in the claims, and not only a part of it, must be capable of being carried out by the skilled person without the burden of an undue amount of experimentation or the application of inventive ingenuity.
The peculiarity of the "functional" definition of a component of a composition of matter resides in the fact that this component is not characterised in structural terms, but by means of its effect. Thus this mode of definition does not relate to a tangible component or group of components, but comprises an indefinite and abstract host of possible alternatives, which may have quite different chemical compositions, as long as they achieve the desired result. Consequently, they must all be available to the skilled person if the definition, and the claim of which it forms a part, is to meet the requirements of Article 83 or 100(b) EPC. This approach is based on the general legal principle that the protection covered by a patent should correspond to the technical contribution to the art made by the disclosure of the invention described therein, which excludes that the patent monopoly be extended to subject-matter which, after reading the patent specification, would still not be at the disposal of the skilled person …
There cannot, of course, be a clear-cut answer to the question of how many details in a specification are required in order to allow its reduction to practice within the comprehensive whole ambit of the claim, since this question can only be decided on the basis of the facts of each individual case. Nevertheless, it is clear that the available information must enable the skilled person to achieve the envisaged result within the whole ambit of the claim containing the respective "functional" definition without undue difficulty, and that therefore the description with or without the relevant common general knowledge must provide a fully self-sufficient technical concept as to how this result is to be achieved."
"5 … In certain cases a description of one way of performing the claimed invention may be sufficient to support broad claims with functionally defined features, for example where the disclosure of a new technique constitutes the essence of the invention and the description of one way of carrying it out enables the skilled person to obtain without undue burden the same effect of the invention in a broad area by use of suitable variants of the component features … . In other cases, more technical details and more than one example may be necessary in order to support claims of a broad scope, for example where the achievement of a given technical effect by known techniques in different areas of application constitutes the essence of the invention and serious doubts exist as to whether the said effect can readily be obtained for the whole range of applications claimed …. However, in all these cases, the guiding principle is always that the skilled person should, after reading of the description, be able to readily perform the invention over the whole area claimed without undue burden and without needing inventive skill …. On the other hand, the objection of lack of sufficient disclosure presupposes that there are serious doubts, substantiated by verifiable facts …." (Citations omitted).
"4.5. For the board it is a fundamental principle of patent law that a claim can validly cover broad subject matter, even though the description of the relevant patent does not enable every method of arriving at that subject matter to be carried out. Otherwise no dominant patent could exist, and each developer of a new method of arriving at that subject matter would be free of earlier patents. In many cases in the field of biotechnology, patent protection would then become illusory. This is not to say that some claims might not be too broad in scope and not be enabled over their whole scope for the purpose of Article 83 EPC (see for example decisions T 409/91-3.3.1 (OJ EPO 1994, 653), but this was not considered to be the case in respect of Claim 1 by this board in T 412/93 on the evidence before the board and this is res judicata. The boards have considered this question of allowability of a broad claim versus the requirements of Article 83 EPC, strictly on a case by case basis, influenced by the extent to which the information in the patent could be used to develop further embodiments without a major conceptual leap."
"1.9 The skilled person is thus confronted with the uncontested fact that he has a lot of process variables affecting the claimed parameters, but once he has encountered failure in one parameter value, there is no clear guidance enabling him to adjust the multitude of process steps in order to arrive with certitude at silicas meeting the parameter requirements defined in claim 1 of both requests at issue.
Even though a reasonable amount of trial and error is permissible when it comes to assessing sufficiency of disclosure, there must still be adequate instructions in the specification, or on the basis of common general knowledge, leading the skilled person necessarily and directly towards success, through evaluation of initial failures. This is not the case here, since the preparation of the amorphous silicas claimed is made dependent on the adjustment of different process parameters for which no guidance is given in the patent in suit, so that the broad definition of an amorphous silica as presently claimed is no more than an invitation to perform a research program in order to find a suitable way of preparing the amorphous silicas over the whole area claimed."
"What has been less clear is what the concept of an enabling disclosure means. Part of the difficulty has been caused by a misinterpretation of what the Technical Board of Appeal of the E.P.O. said in Genentech I/Polypeptide expression (T 292/85)  O.J. E.P.O. 275. This was a patent for a plasmid suitable for transforming a bacterial host which included an expression control sequence or "regulon" which could enable the expression of foreign DNA as a recoverable polypeptide. The Examining Division was willing to grant a patent only in respect of the plasmids, bacteria and polypeptides known at the date of application. The Technical Board of Appeal allowed the appeal, saying that the Examining Division had taken too narrow a view of the requirement of enabling disclosure:
"What is also important in the present case is the irrelevancy of the particular choice of a variant within the functional terms `bacteria', `regulon' or `plasmid'. It is not just that some result within the range of polypeptides is obtained in each case but it is the same polypeptide which is expressed, independent of the choice of these means.… Unless variants of components are also embraced in the claims, which are, now or later on, equally suitable to achieve the same effect in a manner which could not have been envisaged without the invention, the protection provided by the patent would be ineffectual … The character of the invention this time is one of general methodology which is fully applicable with any starting material, and is, as it was already stated, also independent from the known, trivial, or inventive character of the end-products." [references omitted]
In other words, the applicants had invented a general principle for enabling plasmids to control the expression of polypeptides in bacteria and there was no reason to believe that it would not work equally well with any plasmid, bacterium or polypeptide. The patent was therefore granted in general terms.
In Mölnlycke AB v. Procter & Gamble Ltd.  F.S.R. 549, however, Morritt J. interpreted this decision to mean that it was a general rule of European patent law that an invention was sufficiently disclosed if the skilled man could make a single embodiment. This interpretation was followed by Aldous J. in Chiron Corporation v. Organon Teknika Ltd.  F.S.R. 202, although I think I detect in his judgment some surprise that the E.P.O. should have adopted such a mechanistic and impoverished approach to the concept of enabling disclosure. As we shall see, he applied the same rule in the present case.
In fact the Board in Genentech I/Polypeptide expression was doing no more than apply a principle of patent law which has long been established in the United Kingdom, namely, that the specification must enable the invention to be performed to the full extent of the monopoly claimed. If the invention discloses a principle capable of general application, the claims may be in correspondingly general terms. The patentee need not show that he has proved its application in every individual instance. On the other hand, if the claims include a number of discrete methods or products, the patentee must enable the invention to be performed in respect of each of them.
Thus if the patentee has hit upon a new product which has a beneficial effect but cannot demonstrate that there is a common principle by which that effect will be shared by other products of the same class, he will be entitled to a patent for that product but not for the class, even though some may subsequently turn out to have the same beneficial effect: see May & Baker Ltd. v. Boots Pure Drug Co. Ltd. (1950) 67 R.P.C. 23, 50. On the other hand, if he has disclosed a beneficial property which is common to the class, he will be entitled to a patent for all products of that class (assuming them to be new) even though he has not himself made more than one or two of them.
Since Genentech I/Polypeptide expression the E.P.O. has several times reasserted the well established principles for what amounts to sufficiency of disclosure. In particular, in Exxon/Fuel Oils (T 409/91)  O.J. E.P.O. 653, paragraph 3.3 , the Technical Board of Appeal said of the provision in the European Patent Convention equivalent to section 14(5)(c) of the Act:
"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.""
"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". This shows that there is more than one way in which the breadth of a claim may exceed the technical contribution to the art embodied in the invention. The patent may claim results which it does not enable, such as making a wide class of products when it enables only one of those products and discloses no principle which would enable others to be made. Or it may claim every way of achieving a result when it enables only one way and it is possible to envisage other ways of achieving that result which make no use of the invention."
i) The extent of the patent monopoly, as defined by the claims, must correspond to the technical contribution to the art its disclosure has made in order for it to be justified.
ii) The specification must enable the invention to be performed to the full extent of the monopoly claimed. But if the invention discloses a principle capable of general application, the claims may be in correspondingly general terms.
iii) If the patentee has found a new product which has a beneficial effect but cannot demonstrate there is a common principle by which that effect will be shared by other products of the same class, he will be entitled to a patent for that product but not for the class. But if he has disclosed a beneficial property which is common to the class, he will be entitled to a patent for all the products of that class even though he has not himself made more than one or two of them.
iv) There is more than one way in which the breadth of the claim may exceed the technical contribution to the art embodied in the invention. The patent may claim results which it does not enable, such as making a wide class of products when it enables only one of those products and discloses no principle which would enable others to be made. Or it may claim every way of achieving a result when it enables only one way and it is possible to envisage other ways of achieving that result which make no use of the invention.
"112 This 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)  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."
"117 … it is of course correct so far as it goes. The choice of a particular form of an integer falling within the terms of the claim may improve the way the invention works and be in itself an inventive step. The specification is not insufficient merely because it does not enable the person skilled in the art to make such an invention. The use of the improvement is still a way of working the original invention. But TKT does not rely upon the fact that the use by TKT of an endogenous EPO gene was inventive. Their objection is that it is not a way of making EPO which is disclosed, even in the most general terms, by the specification. As the point does not arise, I do not propose to express a concluded view. But, unlike the Court of Appeal, I think that the breadth of claim objection may well have been a good one."
"34 Thus, as a matter of construction, the House of Lords interpreted the claim as being to a class of products which satisfied the specified conditions, one of which was that the molecule had been made by recombinant technology. That expression obviously includes a wide variety of possible processes. But the law of sufficiency, both in the United Kingdom and in the EPO, is that a class of products is enabled only if the skilled man can work the invention in respect of all members of the class. The specification might show that this has been empirically demonstrated or it might disclose a principle which can reasonably be expected to apply across the class: see T 292/85 Polypeptide expression/GENENTECH  O.J. E.P.O. 275; T409/91 Fuel Oils/EXXON  O.J. E.P.O. 653; Kirin-Amgen Inc v Hoechst Marion Roussel Ltd  RPC 9, . But the specification in Biogen described only one method of making the molecule by recombinant technology and disclosed no general principle. It was easy to contemplate other methods about which the specification said nothing and which would owe nothing to the matter disclosed."
i) a principle of general application is simply an element of a claim which is stated in general terms;
ii) a claim containing such an element is sufficiently enabled if the skilled person can reasonably expect the invention to work with anything which falls within the general term; and
iii) a particular form of an element of a claim may improve the way the invention works and be inventive. However, the patent is not insufficient simply because the specification does not enable that improvement. It is still a way (albeit an improved way) of working the original invention.
"100 It must therefore be possible to make a reasonable prediction the invention will work with substantially everything falling within the scope of the claim or, put another way, the assertion that the invention will work across the scope of the claim must be plausible or credible. The products and methods within the claim are then tied together by a unifying characteristic or a common principle. If it is possible to make such a prediction then it cannot be said the claim is insufficient simply because the patentee has not demonstrated the invention works in every case.
101 On the other hand, if it is not possible to make such a prediction or if it is shown the prediction is wrong and the invention does not work with substantially all the products or methods falling within the scope of the claim then the scope of the monopoly will exceed the technical contribution the patentee has made to the art and the claim will be insufficient. It may also be invalid for obviousness, there being no invention in simply providing a class of products or methods which have no technically useful properties or purpose."
"173 This does not, however, mean the patent is insufficient. A claim for an invention of broad application may properly encompass embodiments which may be provided or invented in the future and which have particularly advantageous properties, provided such embodiments embody the technical contribution made by the invention. VEGF-Trap does indeed embody the technical contribution made by the patent; it has a therapeutic effect in patients suffering from ARMD by treating the angiogenesis associated with that condition, and it does so by binding to VEGF and inhibiting its biological activity. VEGF-Trap is therefore one of those improvements which Lord Hoffmann had in mind in Kirin-Amgen  UKHL 46,  RPC 9 at ."
The application of the law
Conclusion on insufficiency
i) Kymab's appeal is dismissed.
ii) Regeneron's appeal is allowed.