Regeneron Pharmaceuticals, Inc v Kymab Ltd & Anor

Here we must begin with the relevant findings of the judge, some (but by no means all) of which Regeneron seeks to challenge on this appeal.

The judge focused on claim 1 and Example 3 of the 287 patent. He reiterated his conclusion that:

The judge then held from [218]-[223] that, in light of the evidence of Professor Evans and Professor Stewart, neither replacement of 100 kb of mouse sequence by 200-300 kb of human sequence (termed “100 kb out, 200-300 kb in”), nor replacement of 150 kb of mouse sequence by 75 kb of human sequence (termed “150 kb out, 75 kb in”) would have been considered feasible at the priority date. In the judge’s mind, these combined unprecedented insertions with unprecedented deletions. He found that it was likely that neither would have worked.

Regeneron’s own work and attempts to put the invention into practice were considered by the judge from [224]-[228]. These confirmed his view that replacements on the scale of “100 kb out, 200-300 kb in” or “150 kb out, 75 kb in” would not have worked. He also found at [229] that the second approach of Example 3, that is to say using RMCE instead of homologous recombination, would not have worked either.

The judge considered next alternative approaches that the skilled team might apply using their common general knowledge. He directed his attention first to the work of Lynn Macdonald and others, including Dr Yancopoulos and Dr Murphy, published in

The second was an approach put to Professor Stewart in the course of his crossexamination by Mr Turner on behalf of Regeneron. This involved using a targeting vector to make a series of modest insertions (without deletion) by homologous recombination, starting at the proximal end of the locus and then proceeding towards the distal end, one insertion followed by another, each sufficiently small that it could be achieved, and in this way “shunting up” the native mouse sequence. The judge did not accept that this approach would have occurred to the unimaginative skilled team in light of the evidence of Professor Evans and Professor Stewart.

The third was to carry out a series of more modest insertions and deletions of perhaps 10 kb in length using LTVECs and the MOA assay and in this way achieve in the end the deletion of 150 kb of mouse sequence and the insertion of 75 kb of human sequence. The judge rejected the submission that this would allow the method of claim 1 of the 287 patent to be performed for the following reasons. To begin with, it would not carry out the method of the claim which required the replacement of at least one mouse V segment and the mouse D and J gene segments by at least one orthologous human V segment and the orthologous human D and J segments, that is to say about 75 kb of the human gene sequence. Further, the claim included within its scope single step replacements of “100 kb out, 200-300 kb in” and “150 kb out, 75 kb in”, and these could not be achieved. What was more and whilst it was true to say that the specification did refer to the repetition of steps (at [0036]-[0038]), this was a more generalised disclosure of the claimed method which involves a targeted replacement at the proximal end, followed by a targeted replacement at the distal end, followed by other steps in the middle. Finally, the specification did not contemplate this approach, neither of the experts had endorsed it and it ignored all the difficulties that the skilled team would have encountered in practice, as corroborated by the difficulties that Regeneron itself encountered.

The judge summarised his conclusions on enablement at [257]-[258] in these terms:

“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.”

The judge turned next to various additional insufficiency objections. He rejected those relating to the benefit of long homology arms, the use of MOA assay improvements and difficulties in identifying the 5’ end of the mouse locus. However, he accepted a submission by Kymab that a “16.6 kb out, 144 kb in” replacement achieved by Regeneron in the course of its development work was achieved using an improvement which was not disclosed in the patents and which would not have occurred to the skilled person, namely the use of a reduced amount of DNA. He thought this was an additional support for his conclusion that the claims were insufficient.

After the circulation of the draft judgment, Regeneron raised two further issues. It contended first, that following the teaching in the patents, the skilled person could insert human DNA comprising at least one V segment, and the D and J segments having a length of about 75 kb and invited the judge so to find.

The judge dealt with this issue from [278]-[281]. He concluded that this was another attempt by Regeneron to argue that that the claims were enabled across their breadth; that he had rejected all of the different ways that contention had been presented at trial; that this particular point had been before him; and that the evidence did not establish that the skilled team could have achieved an insertion of 75 kb and a deletion of 17 kb without undue effort. He held at [280]:

“[280] … Regeneron cites certain passages from the crossexamination 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 second issue concerned the possibility of additional insertions. Regeneron argued that the skilled person could perform additional insertion steps following the initial insertion of one V and the D and J segments of the human sequence and it invited the judge so to find. As an alternative, it asked the judge to confirm that he had not made a finding that the person skilled in the art, having inserted such a human sequence into the murine locus could not thereafter without undue effort insert further sequences. In the further alternative, it invited the judge to address its submission that it was not

The judge dealt with the second issue from [282]-[286]. He rejected all of Regeneron’s arguments. He held that this was a matter he had already addressed in finding that the reverse chimeric locus could not be built up in a series of steps and so shunting up the mouse sequence; that Kymab’s case had been adequately pleaded; and that the reason the issue had not been addressed by the experts in their reports was that it had only emerged during the cross-examination of Professor Stewart.

Upon this appeal, Regeneron does not challenge all of the judge’s findings. In particular, it does not question his finding that, at the priority date of the 287 patent, the skilled team could not have deleted 100 kb of mouse sequence and inserted 200300 kb of human sequence in a single step. Nor does it challenge his finding that it was not possible to delete 150 kb of mouse sequence and insert 75 kb of human sequence in a single step.

It contends instead that the judge has focused unduly on the details of Example 3 and failed properly to consider whether the skilled team could have made mice falling within claim 1 of the 163 patent and cells and mice within claims 5 and 6 of the 287 patent by gene targeting and, in particular, by inserting a minigene construct containing a subset of the V, D and J segments at the proximal end of the mouse immunoglobulin variable region using traditional techniques of homologous recombination. It says there was no dispute that such a construct of up to 20 kb in length could have been made and inserted successfully.

Further, it continues, the judge ought to have found that the skilled team could have implemented the reverse chimeric locus without undue effort by using the LTVEC and MOA technology the patent describes and making simple and obvious adjustments to Example 3.

The first of these adjustments would have been to reduce the size of the inserts in the LTVECs by cutting down the number of V, D and J regions they contain and then to carry out the deletion of the mouse sequence in a separate step. In particular, it continues, the skilled team could have implemented the teaching with an insert in LTVEC 1 of about 50-75 kb in length. Further, the team could have shortened the insert further still by cutting out the intergenic regions to make a minigene.

Then, as taught in the specification at [0126], the skilled team could have inserted an additional variable region sequence of 50-75 kb in length at the distal end of the mouse locus, using a similarly modified LTVEC 2.

Finally, having performed an insertion at the proximal and distal ends of the mouse gene locus, the skilled team could have deleted the intervening mouse sequence without difficulty using SSR, as Professor Stuart accepted in his second report at [104]. The team could also have added more human V segments having a length of up to about 10 kb between the LTVEC 1 and LTVEC 2 insertions.

For these reasons, continues Regeneron, the specification of each of the patents did enable the skilled team to implement the invention and make products and perform the method described in the claims in issue and the judge ought so to have found.

In its written submissions Regeneron has taken a further point. It contends that the judge fell into error in accepting Kymab’s submission that its success in inserting 144 kb of human sequence and deleting 16.6 kb of mouse sequence in one step was attributable to an improvement which was not disclosed in the patents and would not have occurred to the skilled person, namely the use of a reduced amount of DNA. It says that this was a contrived point with which Regeneron was ambushed at trial and upon which the judge should have placed no reliance at all.

Kymab responds that on the judge’s findings of fact and his analysis of the scope of the claims, his conclusion that each of the claims in issue was invalid for insufficiency was inevitable. It says that Regeneron deployed a number of ways the skilled team could perform the claimed inventions, and that the judge addressed and rejected each of them. It necessarily follows that the claims are insufficient, and that remains the case despite all the points now advanced by Regeneron on this appeal.

Kymab also argues that the reason the judge did not address the contentions now advanced by Regeneron on this appeal is that he was never asked to, and that it is far too late for Regeneron to raise them now. The factual aspects of those contentions should have been raised in evidence and put to Kymab’s experts; and then the contentions should have been developed before the judge in submissions. If and in so far as the judge failed to deal with them, they should have been raised with him after he provided his judgment to the parties in draft and before he handed it down, but they did not do so.

What is more, Kymab continues, the arguments now developed by Regeneron are unsound in fact and in law and do not in any way undermine the overall conclusions to which the judge came.

These rival submissions therefore give rise to a number of issues: first, whether it is open to Regeneron to rely upon its arguments before this court or whether it is foreclosed from doing so by the position it took before the judge; secondly and on the assumption it is open to Regeneron to rely upon these arguments, whether they have any factual foundation; and thirdly, whether these arguments and any findings we consider it appropriate to make provide a basis for reversing the judge’s findings of insufficiency. These issues inevitably overlap but in the interests of clarity we will consider them separately. We address the first and second in this section of our judgment. We shall deal with the third later in our judgment after considering the law.

We must start, however, by explaining the concept of the minigene. This was addressed by Professor Howard in his first report when addressing the common general knowledge. There he described a minigene as a genetically engineered construct which includes the rearrangeable V, D and J segments, whilst non-essential DNA sequences (such as introns) have been removed. Professor Stewart provided much the same explanation of the term minigene in the annex to his first report which contained a glossary of terms and definitions which were common general knowledge at the priority date.

Professor Howard also described from [94]-[100] how minigenes had been used in the approach first proposed in the 1980s for the generation of mouse strains transgenic for human immunoglobulin genes which involved transferring human immunoglobulin genes to mice using plasmids, yeast artificial chromosomes or phage vectors. These vectors were constructed to carry either a transgene reflecting the native sequence of human immunoglobulin loci, or alternatively a minigene.

Professor Stewart gave a similar account in his first report at [67]. There he said that it was common general knowledge during the 1990s that a number of transgenic mice were generated which carried human immunoglobulin genes in germ-line configurations on minigene constructs.

Our consideration of this issue must start with Kymab’s pleaded case of invalidity. Kymab attacked each of the patents on various grounds. For the purposes of this appeal, we can focus on the following. It alleged first, that the patents lacked novelty in light of PCT/US91/00245 published as WO 91/10741 on 25 July 1991

Secondly, the patents were obvious in the light of three publications: Kucherlapati; a US Patent 5,770,429 (“Lonberg”); and a publication entitled “The Preparation of Human Antibodies from Mice Harbouring Immunoglobulin Loci” published in 1997 in the textbook “Transgenic animals; generation and use” (“Brüggemann”).

Thirdly, the patents were insufficient. This allegation had many different limbs, some of which fell away. Others were resolved by the judge in favour of Regeneron. So, for the purposes of this appeal, we can focus on the following. Kymab contended first, that claim 1 of the 287 patent encompassed but did not enable the in situ replacement of an entire endogenous murine immunoglobulin heavy chain variable region gene locus with an entire orthologous human gene locus carried in a single vector.

Kymab also contended that claim 1 of the 287 patent was not enabled because (among other things) the skilled team could not without undue effort:

Similar allegations were made in relation to the product claims of the 287 patent and claim 1 of the 163 patent.

It is to be noted that Kymab did not assert that it was not possible to insert 75 kb (or less) of human sequence using the LTVECs of the specification. Nor did it assert that it was not possible to make smaller insertions by conventional techniques of homologous recombination. Indeed, as we will see in a moment, it was part of Kymab’s case that such smaller insertions could be made and that it was obvious to make cells and mice falling within the product claims of both patents in light of the cited prior art.

Coming now to the reports of the experts, Professor Evans expressed the opinion that the person skilled in the art could have made a mouse with a reverse chimeric immunoglobulin heavy or light chain locus comprising human orthologous variable V, D and J gene segments using the techniques described in the 287 patent and the common general knowledge. He acknowledged, however, that the skilled team would have been unlikely to attempt to conduct the in situ replacement of the entire mouse locus in a single step using homologous recombination. He thought that the skilled team would instead modify the mouse locus in a series of steps as described in the specification at [0128] and [0129].

Professor Evans also addressed the particular allegations made by Kymab and which we have set out at [158] above. As part of his evidence, he expressed the view that it would not have been any problem for the skilled person to insert at least 75 kb of an orthologous human sequence by a single site SSR step.

Professor Stewart focused a good deal of his attention on the teaching of the patents when considering what they enabled. He provided a commentary on the various methods that are taught and, in coming to Example 3, identified the various difficulties the skilled team would have had in trying to implement what it teaches.

Professor Howard and Professor Stewart also addressed the prior art that Kymab had cited and, in particular, Kucherlapati and Lonberg. In this connection and as we elaborate below, Professor Howard explained that it would have been obvious to the skilled team to include as many human variable segments as possible and to replace the mouse variable region, and that this might be achieved using a minigene construct engineered to include the re-arrangeable human V, D and J segments. Professor Stewart thought it would have been feasible to replace part of the mouse immunoglobulin variable locus with the corresponding part of the human immunoglobulin variable locus using a minigene construct up to about 20 kb in length containing a subset of the human variable region gene segments to replace the mouse J gene segments.

It was against this background that the action came on for trial. The parties had to address a large number of issues, many of considerable complexity. In these circumstances we do not find it surprising that each was not able to anticipate precisely how the other would develop its case. However, we have been taken to aspects of Regeneron’s written and oral submissions from which we are satisfied that in opening it did make it clear that it was part of its case not only that the claims in issue do not require in situ replacement of all or even a substantial part of the endogenous locus in a single step, but also that it was not necessary to insert the entire human locus or to delete the entire mouse locus to obtain the benefits of the invention. It also contended that the teaching of the patents could be implemented by inserting shorter sequences than those described, carried on a BAC and engineered to contain the V, D and J segments without the intergenic regions, that is to say using a minigene approach.

At the trial the experts were cross-examined and, as we shall see, Mr Turner explored with Professor Stewart the ability of the skilled team to implement the teaching of Example 3, and to make and use not only the constructs which are disclosed there but also shorter constructs of, say, 75 or 50 kb in length, with and without the intergenic regions. There was no challenge to the evidence of Professor Stewart and Professor Howard about the ability of the skilled team to make a minigene construct.

In its written closing submissions, Regeneron maintained its position that the skilled team could perform the method of claim 1 of the 287 patent by inserting into the mouse immunoglobulin locus at least one human V segment and the human D and J segments upstream of the mouse constant regions, either with or without the deletion of mouse D and J segments, and that this would involve the insertion of about 75 kb of the orthologous human sequence. Mr Turner elaborated these points in his oral closing submissions and in doing so again made the point that if the team had any difficulty inserting a construct of 75 kb in length, it could be shortened by deleting the intergenic regions and making a minigene.

As we have explained, the judge did not address the issue of minigenes in the draft of the judgment he supplied to the parties. Upon receipt of that draft, Regeneron then drew to the judge’s attention two matters which it believed to be material and with which, so it said, the judge had failed to deal: first, that following the teaching in the patents the skilled team could insert a human sequence of about 75 kb in length and comprising at least one V segment and D and J segments; and secondly, that after inserting such a sequence the skilled team could perform additional insertions. It did not invite the judge to address minigenes, however.

Having covered the ground, we can now return to the issue before us and whether it is open to Regeneron to rely upon the use of minigenes in support of this appeal. We consider the following points to be particularly material.

First, Kymab’s pleaded allegations of insufficiency were carefully framed. We find it striking that, in giving details of what the skilled team could not achieve without undue effort, it did not assert that the specification did not enable the insertion of a fragment of an orthologous human variable gene locus up to 75 kb in length using the first approach of Example 3, that is to say homologous recombination using BACs with long homology arms and the MOA assay. A fragment of this size has particular significance because, as Mr Tappin emphasises, it can encompass one human V segment and the human D and J segments.

Secondly, we consider it was in these circumstances reasonable for Regeneron’s experts to focus their attention in their reports on the allegations of insufficiency which Kymab had made, of which there were many.

Thirdly, Kymab was itself asserting that it was obvious at the priority date in the light of the cited prior art to make cells and mice falling within the product claims by using homologous recombination and a minigene construct of up to 20 kb in length engineered to include human orthologous variable V, D and J segments. Regeneron took issue with the suggestion that the cited art rendered it obvious to make a reverse chimeric locus but it has never disputed that, given that idea, the skilled team could carry out the necessary insertion without undue effort using a minigene. In our judgment Mr Turner’s submission that this much appeared to be common ground has considerable force.

Fourthly, we are satisfied that, at trial, Mr Turner made clear in his opening submissions that Regeneron relied upon the use of minigenes as a way of implementing the teaching of the patents. This gave Mr Tappin, on behalf of Kymab, an opportunity to question Regeneron’s experts if he wished to do so. Mr Turner then explored the issue with Professor Stewart in the course of his cross-examination. Finally, Mr Turner reiterated Regeneron’s reliance upon the use of minigenes in his closing submissions in the manner we have described.

In our view these matters point in favour of allowing Regeneron to rely upon the evidence concerning the use of minigenes in support of its appeal. The one matter that has caused us considerable concern is that Regeneron did not raise the issue with the judge when it received the draft judgment. It is axiomatic that if an advocate believes that a judge has not dealt with a material issue then it should be drawn to the judge’s attention pursuant to that advocate’s duty to assist the court and to further the overriding objective. In Re T (Contact: Alienation: Permission to Appeal) [2002] EWCA Civ 1736; [2003] 1 FLR 531, Arden LJ said at [50]:

“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.”

We think it highly unsatisfactory that this course was not followed by Regeneron in this case. Quite apart from the consequences to which Arden LJ referred, it means that, if we allow Regeneron to develop its arguments before this court, we must either make an assessment of the evidence without the benefit of a reasoned decision of the trial judge, or remit it to him for his assessment with all the costs and delay that would entail.

In the end, however, we have come to the conclusion that the failure by Regeneron to raise the issue with the judge after receiving the draft judgment should not preclude it from relying upon it upon this appeal. As we shall explain, the relevant evidence is not extensive and was given primarily by Kymab’s experts. Further, it is evidence

For all of these reasons, we decide the first issue in favour of Regeneron. It is not precluded from developing before this court its contention that the judge fell into error in failing to find that the skilled team could have implemented the teaching of the patents by using their common general knowledge and adopting simple and obvious adjustments to Example 3, including the use of minigenes.

We begin with the question whether it was possible to make a reverse chimeric locus and so also products falling within each of the product claims in issue by using techniques which were part of the common general knowledge at the priority date. For this we must go to the evidence of Professor Stewart and Professor Howard and two of the publications to which they referred.

Professor Stewart pointed in his first report to Kucherlapati and explained at [193] that this application disclosed the creation of mouse ES cells in which the immunoglobulin heavy chain variable region had been replaced in whole or in part by the equivalent portion of the human immunoglobulin heavy chain variable region using homologous recombination. Professor Stewart continued at [194] that the skilled team would have appreciated at the priority date that the largest replacement that could be made by homologous recombination would be less than 20 kb. Therefore, the replacement of the mouse immunoglobulin heavy chain region with the human heavy chain region would require more than 100 rounds of homologous recombination. In Professor Stewart’s view, this would have represented a massive project at the priority date which would have taken many years to complete. Regeneron accepts for the purposes of this appeal that this could not have been achieved at the priority date without undue effort.

However, Professor Stewart then introduced at [195] of his first report the possibility of using minigenes:

“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.”

Professor Stewart returned to this issue in his second report at [102]–[105]. Here he reiterated that a minigene construct of up to 20 kb in length could contain a subset of the human immunoglobulin variable region gene segments (V, D and J gene segments in the case of the heavy chain, and V and J gene segments in the case of the light chain). He understood from Professor Howard that the skilled immunologist would have wanted to replace the mouse J region with the 20 kb gene construct in such a way that the mouse J gene segments would be deleted and so prevent the formation of fully mouse antibodies. He continued at [103]:

“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, …”

Professor Stewart illustrated this approach in this figure in which the mouse sequence is shown in blue, and the human in red:

Much the same point was made by Professor Howard in his first report in the context of Kucherlapati. He said at [128]-[129] that the skilled immunologist would have understood that a useful antibody repertoire could be achieved from a subset of variable region gene segments, and that the minimum size of a cloned genomic construct containing one human V, one D and one J segment (i.e. spanning from the beginning of the most proximal V segment to the end of the most distal J segment in the human heavy chain locus) would be approximately 75 kb in length. But, as an alternative, the skilled team could have used smaller minigene constructs (engineered to include rearranged V, D and J segments).

The use of minigenes was picked up by Professor Stewart again in considering Lonberg. This publication is referred to in Example 3 of the 287 patent at [0114] and, in discussing it in his first report, Professor Stewart asked himself what steps the skilled team would have taken at the priority date if tasked with making a transgenic mouse that expressed chimeric antibodies of the kind it describes. After considering and rejecting random transgenesis as an option, Professor Stewart addressed the possibility of using gene targeting. In that connection, he said this at [204]:

“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.”

In the end the judge rejected the attack based upon Kucherlapati, not because he rejected the evidence of the experts concerning the use of minigenes but because aspects of its teaching were not clear and, more fundamentally, it did not disclose the reverse chimeric locus or, so far as claim 1 of the 287 patent was concerned, the use of LTVECs or the MOA assay. The attack based upon Lonberg was abandoned by Kymab during the course of Mr Tappin’s closing speech on its behalf.

In our judgment it is clear from this evidence that, notwithstanding the judge’s conclusion about the teaching of Kucherlapati, the concept of the minigene was common general knowledge at the priority date and we have no doubt that the skilled team seeking to implement the teaching of the patents would have appreciated that it was possible to create a transgenic mouse in which part of the mouse immunoglobulin variable region had been replaced by part of the human immunoglobulin variable region by using a small minigene construct of up to 20 kb in length containing a subset of the human V, D and J segments (in the case of the heavy chain) and a subset of the V and J segments (in the case of the light chain), and that this could have been achieved by homologous recombination and without undue effort.

That brings us to the alternative way of implementing the various aspects of the teaching, namely by the use of the techniques described in Example 3 (that is to say, LTVECs and the MOA assay) with obvious adjustments. Here, for the reasons we have given, we must consider the expert evidence given in cross-examination at the trial in rather more detail than is usually the case on an appeal.

Professor Stewart maintained in his oral evidence that Example 3, as described, would have presented a real challenge and would not have worked. He was then asked about possible modifications to the experimental protocols it contains. He explained that, faced with the failure of Example 3 and other deficiencies in the description, the skilled team might have become alarmed and uncertain as to what the patent was teaching, but that an obvious way forward would have been to make the strategy more realistic and reduce the size of the inserts to, say, 75 kb in length (see day 6, p.910, line 12 - p.912, line 2).

In this connection Professor Stewart also accepted that the skilled team would have known that another way of reducing the length of the inserts would have been to remove the intergenic regions by making a minigene. Here he was asked questions by reference to a diagram of the human immunoglobulin variable gene locus produced by Regeneron for the trial and identified as X12:

The following interchange then took place with Professor Stewart on day 6, p.911, line 20 – p.912, line 25):

“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.

This minigene could then have been inserted at the 3’ or proximal end of the mouse genome in LTVEC 1.

Mr Turner explored with Professor Stewart the position at the 5’ or distal end and LTVEC 2 on day 6, p.913, line 22 – p.914, line 18:

“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?

Q. Yes.

A. LTVEC2 suffers from the same improbabilities as LTVEC1.

Q. Right.

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.”

Mr Turner returned to the same question a little later on the same day and, in another important passage of the evidence, explored with Professor Stewart whether an insertion into the mouse genome of a segment of human sequence of about 75 kb in length and a deletion from the mouse genome of a segment of about 17 kb in length could have been achieved (day 6, p.924, line 17 – p.926, line 2):

“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. A. Yes.

Q. We are back into the ES cell now.

A. Yes.

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. A. Good.

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?

A.

Yes.”

Basing himself on this evidence, Mr Turner submits that it would have been obvious to the skilled team seeking to implement the method of claim 1 of the 287 patent:

Further, submits Mr Turner, this protocol would have worked and could have been implemented without undue effort, and the judge should have so held.

Mr Tappin counters that the skilled team could not have implemented Example 3 as described without undue effort and that, in these circumstances, the burden of proving that the claimed inventions could be implemented in some other way lay on Regeneron and it was a burden that it could not and did not discharge. The judge dealt with the suggestions for implementation put forward on behalf of Regeneron both at trial and after the judgment had been provided to the parties in draft, and he rejected each and every one of them.

Mr Tappin also submits that Professor Evans set out in his reports the various steps that he thought the skilled team would take to try and make Example 3 work. However, he did not at any point suggest the use of minigenes and so it was never properly explored in evidence. To the contrary, Mr Tappin continues, it was common ground that the minimum length of fragment required to implement the method of claim 1 of the 287 patent was 75 kb and the judge has made an express finding that the skilled team could not have inserted such a fragment into the mouse genome without undue effort. Here and elsewhere, says Mr Tappin, we are being asked to interfere with findings of fact made by the trial judge and that is something which we should not do.

We have carefully evaluated these submissions and the evidence to which we have referred and our conclusions are these.

First and by way of recap, we are satisfied, for the reasons we have given, that the use of minigenes was part of the common general knowledge. Further, it was Professor Stewart’s evidence and we accept that it was technically feasible at the priority date to replace 5 kb of mouse sequence (spanning the J segments) with a 20 kb minigene construct containing a subset of the human immunoglobulin variable region segments (V, D and J gene segments in the case of the heavy chain, and V and J segments in the case of the light chain). In our judgment and given the idea of the reverse chimeric locus, it would have been obvious to the skilled team and technically feasible to produce a transgenic mouse that would produce hybrid antibodies containing human variable regions and mouse constant regions, and in which mouse V, D and J segments had been replaced with human V, D and J segments in the mouse immunoglobulin heavy chain gene locus, and mouse V and J segments had been replaced with human V and J segments in the immunoglobulin light chain gene locus.

Secondly, we have no doubt that it would also have been obvious to the skilled team, faced with what the judge described as the unprecedented insertions and deletions described in the Example 3, to make the insertions shorter. It would also have been perfectly apparent to the skilled team that any necessary deletions could be carried out in a separate step and that there were well known and effective ways of achieving this, including SSR.

Thirdly and as the judge found, a cloned genomic fragment of the human immunoglobulin heavy chain variable gene locus that contains one V segment and all of the D and J gene segments will be about 75 kb in length, including the intergenic regions. But of course, deletion of some of the intergenic regions would make it considerably shorter. In that regard, we have already seen that it was common ground that a 20 kb fragment of the human immunoglobulin variable locus could contain V, D and J segments. But the point is also made good by the locus map identified at trial as X12 which was explored with Professor Stewart in cross-examination in the passage of his evidence we have cited above and is given further support by figure 31 of the Lonberg citation relied upon by Kymab to which we were taken by Mr Turner during the course of the hearing.

Fourthly, we have given anxious consideration to Mr Turner’s submission that we should reverse the judge’s finding concerning the feasibility of using LTVECs and the MOA assay to effect and detect the targeted insertion into the mouse endogenous immunoglobulin heavy (or light) chain locus of a cloned human gene fragment of 75kb and the deletion of 17 kb from that locus. We recognise the force of Mr Turner’s submission in light of the evidence of Professor Stewart that we have cited at [191] and [193]-[194] above. The opinion that Professor Stewart expressed there was not, to our minds, dependent on any work that Regeneron had carried out after the priority date; nor was it dependent upon the use by Regeneron of a particular improvement called the 3hVH vector, as Kymab appears to have suggested. Nevertheless, as Lewison LJ explained in Fage UK Ltd v Chobani UK Ltd [2014] EWCA Civ 5, [2014] FSR 29 at [114], appellate courts have been repeatedly warned by decisions at the highest level not to interfere with findings of fact by trial judges unless compelled to do so and, in the circumstances of this case, where the judge has had the benefit of hearing the expert witnesses give their evidence, that warning is particularly apposite. We therefore reject Mr Turner’s submission.

For like reasons we also decline to interfere with the judge’s finding that the use by Regeneron of a reduced amount of DNA in the course of its development work would not have occurred to the skilled person seeking to implement the teaching of the specification.

Fifthly, that does not mean to say that the skilled team could not perform the method of claim 1 of the 287 patent, however, for that team would also have appreciated the possibility of using minigenes in that method, just as they would have appreciated the possibility of using minigenes to achieve targeted insertions of sequences of up to 20 kb in length using homologous recombination. Here we are not asked to reverse a finding of fact for the judge made no finding that this was not feasible and we have seen no effective answer to the submission by Mr Turner that Professor Stewart accepted that this was a viable approach in the course of his cross-examination on day 6 in the passages we have recited at [191] and [193]-[194] above, and that in this way a sequence of at least 50 kb could be inserted in one step using the LTVEC technology and detected using the MOA assay.

Sixthly, the judge rejected Regeneron’s contentions (so far as they were made) that the skilled team could have implemented the teaching of Example 3 at the priority date using the techniques described in the Macdonald paper; by making repeated insertions using homologous recombination and so ‘shunting up’ the native mouse sequence; or by building up the desired sequence in the mouse immunoglobulin variable region gene locus by repeated BAC insertions. As we have explained, he also rejected Regeneron’s submissions after circulation of the draft judgment as to the feasibility of making a targeted insertion of about 75 kb of the human sequence or performing repeated small sequential insertions. But the judge did not reject as unworkable the teaching in Example 3 that there should be a targeted insertion at the proximal end of the mouse immunoglobulin variable region gene locus (using LTVEC 1), followed by a targeted insertion at the distal end of the locus (using LTVEC 2), followed by further steps in the middle to delete any unwanted mouse sequences (using SSR) and to insert a further human sequence of up to about 10 kb in length (using RMCE). In our judgment the evidence establishes that all of these steps would have been obvious and feasible and could have been performed without undue effort in light of the teaching of Example 3 and the common general knowledge.

In our judgment it follows that it would have been apparent to the skilled team in light of the teaching of the patents and the common general knowledge how to modify the endogenous immunoglobulin heavy chain variable region gene locus of an isolated mouse ES cell by an in situ replacement of V, D and J gene segments of the endogenous gene locus with orthologous human V, D and J segments to create a modified locus that produced hybrid antibodies containing human variable regions and mouse constant regions. It would also have been apparent to the skilled team that one way of achieving this would have been to use a cloned genomic fragment greater than 20 kb containing orthologous human V, D and J gene segments; to use bacterial homologous recombination to modify this cloned genomic fragment to create an LTVEC for use in a mouse ES cell; to introduce the LTVEC into a mouse ES cell to replace the V, D and J segments in situ with the orthologous human V, D and J segments; and to use the MOA assay to detect the mouse ES cells in which this replacement had occurred. In this way the skilled team could have made a reverse chimeric locus containing several V segments without undue effort.

This appeal raises once again the issue of the permissible scope of a patent claim having regard to the ground for revocation in s.72(1)(c) of the Patents Act 1977 that the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art. This provision corresponds to the ground of opposition in Article 100(b) of the European Patent Convention (the “EPC”) and reflects the requirements of Article 83 EPC. We should also mention Article 84 EPC which provides that the claims must be clear and concise and supported by the description. This gives effect to the same legal principle that the patent monopoly should be justified by the technical contribution to the art that the disclosure of the invention has made.

Certain general principles of relevance to this appeal were not in dispute:

It is now well established that the skilled team must be able to perform the invention without undue effort. The approach of the Boards of Appeal of the EPO was explained in T 226/85 Stable bleaches/UNILEVER:

“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 law has developed in this jurisdiction in the same way. In Mentor Corp. v Hollister Inc. [1991] FSR 557 Aldous J said this:

“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.”

On appeal, Lloyd LJ (with whom Stuart-Smith and Scott LJJ agreed) approved that summary of the law: [1993] RPC 7 at 14. Lloyd LJ added this further guidance at 1213:

“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 [1973] 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.”

Finally, we would emphasise that the sufficiency of the description is a matter which must be assessed having regard to the nature of the invention, the character of the technical field in which the invention is made, and the abilities of the skilled team: see, for example, Halliburton v Smith International Inc [2006] EWCA Civ 1715 at [13], [18]-[21].

That brings us to the legal issue at the heart of this appeal, namely the extent to which and the manner in which an invention must be enabled across the whole scope of the claim. The answer to this question has been explored in a number of decisions of the Technical Boards of Appeal of the EPO to which we were taken in the course of the appeal hearing (and which, as is now well established, are of great persuasive authority in construing a provision such as s.72(1) of the 1977 Act which is so framed as to have, as nearly as practicable, the same effects in the United Kingdom as the corresponding provision of the EPC: see, for example, Merrell Dow Pharmaceuticals Inc v H. N. Norton & Co Ltd [1996] RPC 76 at 82). It is not necessary in this judgment to address each of those decisions, however, and we shall focus on those which illustrate the principles which are relevant to this appeal and upon which the parties particularly relied. It is convenient to take them in chronological order.

The first is T 0292/85 Polypeptide expression/GENENTECH I. Here the application disclosed a new method of transforming bacteria using plasmids which contained a homologous regulon in conjunction with a heterologous DNA insert encoding a

The Board of Appeal disagreed. It observed that, in appropriate cases, it is only possible to define the invention in a way which gives fair protection having regard to the nature of the invention described, by using functional terminology:

“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.”

Then the Board explained that the objection against the use of broad functional terminology such as “plasmid” and “bacteria” was, in the circumstances of this case, untenable, and, importantly, that the need for fair protection governed considerations of the scope of claims and the requirements for sufficient disclosure:

“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.”

The Board turned next to the possibility that it might not be possible to put the invention into effect with some components and held that this was immaterial provided that some suitable variants were known to the skilled person. Further, in considering the legitimate scope of the claims it emphasised the need to have regard to the character of the invention:

“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.”

The Board therefore rejected the argument that the claims were insufficient. It held that disclosure was adequate and sufficient in the circumstances and there was enough information to apply the subject matter of the invention for the stated purpose.

The next decision of the Board of Appeal is T 0409/91 Fuel Oils/EXXON. Here the claimed invention lay in the field of fuel oils and the need to ensure that the wax crystals which form at low temperatures are as small as possible. Claim 1 of the main request was directed to fuel oils in which those crystals had a particle size of less than 4000 nm. The Opposition Division rejected the main request for two reasons: first, there was no teaching how to obtain a fuel oil in which the wax crystal size would be less than 1000 nm; and secondly, the need to have the crystals as small as possible was already known in the art and any patentable invention could only lie in the choice of the superior additive which would produce the crystals of the desired size, but no such additive was specified in the claim.

On appeal, the Board had no difficulty rejecting the main request, for the claims related to fuel oils containing wax crystals smaller than 1000 nm but no way of obtaining such fuel oils was disclosed or could be found in the common general knowledge. In the words of the Board:

“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.”

An auxiliary request which differed from claim 1 of the main request by introducing a lower limit of the particle size of 1000 nm was also rejected under both Articles 83 and 84 EPC. In addressing Article 84, the Board said this:

“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 subjectmatter which, after reading the description, would still not be at the disposal of the person skilled in the art.”

Then, in addressing Article 83, The Board continued:

“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.”

The insuperable problem facing the applicant, however, was that the claims extended to the use of any additives but no information was given which would enable the skilled person to perform the invention with additives other that those described in the specification. Accordingly, the claimed monopoly was not justified by the applicant’s contribution to the art. It did not allow the skilled person to perform the invention over the whole range of the claim, and having regard to the technical contribution, this deficiency was fatal to the validity of the claim.

The third decision of the Board of Appeal is T 0435/91 Detergents/UNILEVER, another case in which the claim in issue extended to products, here additives defined by function, but where the specification failed to disclose a concept fit for generalisation which would enable the skilled person to find other additives across its the scope. The Board explained:

“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.”

The fourth decision of the Board of Appeal is T 0694/92 Modifying plant cells/MYCOGEN which once again emphasised the need to be sensitive to the nature of the invention and the contribution it has made to the art in assessing the sufficiency of the disclosure. Here the claims were directed to a general way of genetically modifying a plant cell by inserting a plant gene comprising a plant promoter and a plant structural gene into T-DNA in a particular configuration and then transferring that combination into a plant cell so that the cell would express the protein encoded for by the gene. The question for the Board was how to find the appropriate balance between, on the one hand, the technical contribution to the art made by the disclosure of the invention and, on the other hand, the wording of the claims so that the scope of protection was fair and adequate. It reasoned as follows:

“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).

The Board answered this question later in the decision. It held that the actual contribution to the state of the art by the disclosure of the patent lay in providing experimental support for the transfer into and expression in plant cells of a DNA encoding a particular protein, phaseolin, under the control of its own promoter. It was in effect the successful completion of an experiment anticipated by an oral disclosure made before the priority date, and the disclosure of the patent did not enable the skilled person to achieve the expression of other genes under the control of their own promoters in different plant cells. The claims were therefore insufficient.

The decision of the Board of Appeal in T 0636/97 Erythropoetin II/KIRIN AMGEN is also of some interest. This decision concerned the patent the subject of the Board’s own earlier decision T 412/93 and the decision of the House of Lords in Kirin-Amgen Inc v Hoechst Marion Roussel [2004] UKHL 46, [2005] RPC 9, to which we will come. For present purposes, we need refer only to the discussion by the Board of the balance to be drawn between the need for fair protection and the requirement imposed by Article 83 EPC that the disclosure must be sufficient to enable the claimed invention to be performed across its scope:

“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.”

The final decision of the Board of Appeal to which we must refer is T 1743/06 Amorphous silica/INEOS. Here the claim was directed to amorphous silica characterised by a series of parameters. The term amorphous silica comprised a host of chemical compounds which might or might not satisfy the requirements in the claims. The Board held the relevant claims were not sufficient because the lack of guidance as to how to find amorphous silicas which satisfied the parameter requirements of the claims across their scope meant the skilled person would be faced with a research program:

“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.”

The decisions of the Boards of Appeal in Detergents/UNILEVER, Modifying plant cells/MYCOGEN and Amorphous silica/INEOS were considered by the Court of Appeal in Novartis AG and anor v Johnson & Johnson Medical Ltd and ors [2010] EWCA Civ 1039. Jacob LJ (with whom Patten and Ward LJJ agreed) explained that the heart of the test is: “Can the skilled person readily perform the invention over the whole area claimed without undue burden and without needing inventive skill”. That is of course true. But in our judgment it is apparent from these decisions and the decisions of the Boards of Appeal in Polypeptide expression/GENENTECH I, Fuel oils/EXXON and Erythropoetin II/KIRIN AMGEN that, in assessing whether the skilled person can adequately perform the invention across the scope of the claim, the following points are also important.

First, it is not the law that a specification must necessarily enable the skilled person to make or perform all of the embodiments of a claimed invention. Were it otherwise, claims would be insufficient if they covered inventive improvements. But, as the decision in Polypeptide expression/Genentech I makes clear, in appropriate cases, a claim may embrace variants which may be provided or invented in the future and which achieve the same effect in a manner which could not have been envisaged without the invention.

Secondly, the assessment of insufficiency must be sensitive to the nature of the invention and the facts of the particular case. If the character of the invention is one of general methodology or is such that the invention is of general application then it may be permissible to claim it in general terms, even though the specification does not enable every way of arriving at its subject matter. Otherwise, as the Board explained in Modifying plant cells/MYCOGEN, no dominant patent could ever 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.

Thirdly, it is a general principle that the protection afforded by the claims must correspond to the technical contribution to the art made by the disclosure of the invention. The patentee is entitled to fair protection having regard to the nature and character of the invention he has described.

That brings us to the leading authorities in this jurisdiction. Here we must start with the decision of the House of Lords in Biogen v Medeva [1997] RPC 1. It is helpful to have the relevant facts in mind. It was known at the priority date that the only available source of DNA for the hepatitis B virus (HBV) was the infective particle, the Dane particle. Professor Murray, the inventor, purified some DNA from Dane particles and cut it into fragments which were as large as possible. He then made a particular form of recombinant plasmid which he used to transform E. coli. He found that the bacteria expressed polypeptides with HBV antigen specificity. The inventive concept (for what he had done was indeed inventive) was the notion that the creation of large genomic fragments of eukaryotic DNA inserted into a particular plasmid and introduced into E. coli would work or, put another way, he had the idea of trying to express unsequenced eukaryotic DNA in a prokaryotic host. However, the claimed monopoly extended rather wider. It was, in effect, a product-by-process claim and encompassed any recombinant DNA molecule which expressed the genes of any HBV antigen in any host cell, and any way of making a DNA molecule which would achieve the necessary expression. This was significant because, once the DNA sequence of the Dane particle became known, no one would choose to proceed in the way Professor Murray did. A person skilled in the art would instead choose enzymes to digest the sites closest to the gene which expressed an antigenic fragment of the polypeptide; and, once they became available, that person would also use vectors for mammalian cells.

Against this background, Lord Hoffmann came to consider the concept of an enabling disclosure. He said this at 47-49:

“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) [1989] 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. [1992] 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. [1994] 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) [1994] 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.””

A little later, in considering whether the disclosure of the priority document contained an enabling disclosure which supported the claims, Lord Hoffmann held that the trial judge’s findings that Professor’s Murray’s invention worked was one that was open to him and should be respected. But that was not the end of the matter because the question here was not whether the claimed invention could deliver the goods, but whether the claim covered other ways in which they might be delivered which owed nothing to the teaching of the patent or any principle it disclosed. In that connection, he explained at 50-51:

“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.”

This was such a case for Professor Murray’s contribution consisted in showing that, despite the uncertainties which then existed over the DNA of the Dane particle, known recombinant techniques could be used to make the antigens in a prokaryotic host cell. But this contribution did not justify a claim to a monopoly of any recombinant method of making the antigens. It was too broad, not because of an inability to achieve all the promised results, but because the same results could be produced by different means.

We draw the following points from this decision:

Lord Hoffmann provided further guidance in Kirin-Amgen Inc v Hoechst Marion Roussel [2004] UKHL 46, [2005] RPC 9. A team from Amgen was the first to clone and sequence the gene for erythropoetin (“EPO”). Once that sequence had been discovered it was possible to make the polypeptide by conventional methods of recombinant DNA technology. Amgen was in due course granted a patent with claims to a DNA sequence for use in securing expression in a prokaryotic or eukaryotic host cell of EPO, and to the recombinant polypeptide itself. The question arose as to whether these claims were sufficiently broad to encompass EPO made by any form of recombinant technology, so including a process used by Transkaryotic Therapies Inc (“TKT”) which made EPO by introducing exogenous DNA into a cell and in that way activating the endogenous EPO gene, and if they were, whether they were insufficient.

The House of Lords held the relevant claims were not infringed so it was not necessary to determine this allegation of insufficiency. In the circumstances, Lord Hoffmann did not express a concluded view but nevertheless considered whether the sequence information that Amgen had disclosed in the patent and which TKT needed to perform its process constituted a principle of general application, as the trial judge had held. Having earlier reiterated the principle that the disclosure of a specification must enable the invention to be performed to the full extent of the monopoly claimed, and that whether a specification is sufficient or not is highly sensitive to the nature of the invention, Lord Hoffmann elucidated what was meant by the phrase “a principle of general application”:

“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) [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.”

Lord Hoffmann was of the view that the facts of the case did not support the application of this principle because the specification did not disclose a way of making EPO in sufficiently general terms to include the TKT process. It disclosed only how to make EPO by introducing exogenous DNA coding for EPO into a host cell. The TKT method was not a version of Amgen’s method which could reasonably be expected to work just as well. It was different. Further, an invention was not enabled by the disclosure in the specification simply because it could not be worked without that disclosure. The disclosure must not only be necessary, it must be sufficient.

Lord Hoffmann then addressed a point made by the Court of Appeal, namely that the law contemplates that patents will not lack sufficiency, even though the claims cover inventive improvements, and said that:

“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.”

H Lundbeck A/S v Generics (UK) Ltd [2008] EWCA Civ 311, [2008] RPC 19 concerned a claim to the (+) enantiomer of a well-known racemate called citalopram. The patentee, Lundbeck, found a way to separate the enantiomers and found that the

A further appeal to the House of Lords was dismissed: [2009] UKHL 12, [2009] RPC 13. The House agreed with the Court of Appeal. Lord Neuberger explained that, in the context of a simple product claim such as that in issue, the technical contribution, at least in the absence of special factors, was the product itself.

We believe the following further points of relevance to this appeal can be taken from the decision of the House of Lords in Kirin-Amgen and the decisions of the Court of Appeal and the House of Lords in Lundbeck:

Finally we should mention the decision of the Court of Appeal in Regeneron Pharmaceuticals Inc v Genentech Inc [2013] EWCA Civ 93, [2013] RPC 28, to which the judge referred. This appeal concerned a patent claim directed to the use of a human vascular endothelial growth factor (“hVEGF”) antagonist, such as an isolated hVEGF receptor, in the preparation of a medicament for the treatment of a noncancerous disease characterised by excessive blood vessel growth. Genentech, the owner of the patent, claimed it was infringed by the use of a product developed by Regeneron called VEGF-Trap, a chimeric molecule containing two monomers linked together. Regeneron denied its molecule fell within the scope of the claims and argued that the patent was insufficient because the monopoly claimed was far too broad and encompassed the use of a vast number of antagonists which it did not enable. It contended, among other things, that it was not possible at the filing date to make a reasonable prediction based upon the teaching in the patent and the general knowledge that hVEGF antagonists would be useful in the treatment of all diseases of the kinds contemplated and that it would involve undue effort to find which antagonists were effective against which diseases. It also argued that if the claims were broad enough to cover VEGF-Trap, they covered products they did not enable.

In discussing the general legal principles applicable to the insufficiency attack, Kitchin LJ (with whom Longmore and Moses LJJ agreed) said this at [100]-[101]:

“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.”

Applying these principles, the court found no reason to interfere with the judge’s findings rejecting the broad insufficiency attacks. The court then turned to the infringement - insufficiency squeeze, upheld the judge’s finding that VEGF-Trap fell

This exposition is, we believe, entirely consistent with the principles we have identified. A claim is not insufficient simply because it encompasses inventive improvements provided they embody the technical contribution the disclosure of the invention has made to the art.

We summarised the arguments developed by Mr Turner on behalf of Regeneron earlier in this judgment. They have at their heart the contention that the judge failed properly to appreciate the nature and extent of the contribution to the art that the disclosure of the invention has made; fell into error in deciding what the disclosure of the patent in fact enabled; and ought to have found that, having regard to the principles we have explained, the specification of each of the patents did disclose the claimed invention clearly enough and completely enough for it to be performed by a person skilled in the art.

Mr Tappin, for Kymab, argues that each of Regeneron’s submissions is flawed. He submits that the claims are to classes of products (claim 1 of the 163 patent and claims 5 and 6 of the 287 patent) or classes of processes (claim 1 of the 287 patent). As for the claims to classes of products, they include genetically modified cells and mice in which the entire mouse immunoglobulin variable region loci have been replaced with the orthologous human loci. Such cells and mice were specifically envisaged by the patents, and the patents assert that the skilled person could make them by using their teaching. However, on the judge’s findings of fact, the patents do not enable such cells or mice or many other types of genetically modified products falling within the scope of the claims. As for claim 1 of the 287 patent, this encompasses the replacement, by homologous recombination, of at least the mouse D and J gene segments at the proximal end of the locus with several orthologous human V segments and the human D and J gene segments which involves the replacement of at least about 100 kb of mouse sequence with about 200 to 300 kb of human sequence. But again, the specification does not enable such replacement. Indeed, says Mr Tappin, vast swathes of the claims are not enabled. The law requires these claims to be enabled across their breadth, and they are not.

Mr Tappin also submits that the patents do not disclose any principle of general application and certainly not any principle which enables the skilled person to make products or carry out methods across the scope of the claims. Achievement of the replacement of the entire murine loci with the orthologous human loci cannot be regarded as an improvement invention; and the deficiencies in the specification cannot be excused on the basis that it might be possible to make something falling within a small corner of the claims. The judge directed himself properly as to the law and arrived at an overall conclusion which was, on the basis of his findings of fact, inevitable.

The judge considered that all of the product claims were of broader scope than claim 1 of the 287 patent and so, in considering the parties’ submissions, we shall start with claim 1 of the 163 patent. The following points are, we think, particularly material in light of the findings we have made and the principles we have sought to explain. We can at this stage express them quite shortly.

As we have seen, this claim is drawn in general language and is of broad scope. But each of the mice it encompasses has the reverse chimeric locus, that is to say, it is a mouse which produces hybrid antibodies containing human variable regions and mouse constant regions, and in which mouse V, D and J segments have been replaced with human V, D and J segments at a chromosomal immunoglobulin heavy chain locus, and mouse V and J segments have been replaced with human V and J segments at a chromosomal immunoglobulin light chain locus.

The disclosure of the reverse chimeric locus was, as we have described, a major contribution to the art for it provided the answer to a significant problem which those working in the field had faced, namely that transgenic mice produced by conventional methods were immunologically sick. Transgenic mice with the reverse chimeric locus do not suffer from this deficiency.

The character of this invention is therefore such that any transgenic mouse which falls within the scope of the claim and so produces hybrid antibodies containing the human variable regions and mouse constant regions will benefit from the technical contribution the disclosure of the 163 patent has made to the art, and will do so irrespective of the antigen which is used to challenge the mouse. In our judgment it is properly described as a principle of general application.

As for the ability of the skilled team seeking to implement the teaching of the 163 patent at the priority date, we are satisfied for the reasons that we have given that the skilled team, equipped with the common general knowledge, could have produced without undue effort a transgenic mouse falling within the scope of the claim by making a minigene construct of up to 20 kb in length containing a subset of the human V, D and J segments (in the case of the heavy chain) and a subset of the V and J segments (in the case of the light chain), and that this could have been achieved by conventional techniques of homologous recombination.

We are also satisfied that the skilled team seeking to implement the teaching of the 163 patent and equipped with the common general knowledge could have produced without undue effort a transgenic mouse falling within the scope of the claim by using LTVECs and the MOA assay in the manner we have described.

It is true to say that the transgenic mice produced by either of the methods described in the immediately foregoing paragraphs would have had only a subset of the human V gene segments. We also recognise that there was a perception at the priority date that the greater the number of human V gene segments that had been inserted into the transloci, the more varied the human antibody expression was likely to be. Nevertheless, as we have also seen, a transgenic mouse of this kind with only a few human V gene segments would have had an immunological response which was close to that of wild type mice.

These points, taken together, strongly suggest to us that the 163 patent does disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art. The character of the invention is one of general application. It applies to any mouse challenged with any antigen and the benefit it confers will be shared by every mouse falling within the scope of the claim. The skilled team would reasonably expect the invention to work across the scope of the claim and that expectation would be correct. What is more, there is nothing in the claim which could have been envisaged without the invention and, were protection to be limited to only those embodiments which could have been made at the priority date without undue effort, the protection provided by the patent would have rapidly become ineffectual.

Is the patent nevertheless insufficient because it was not possible at the priority date to perform Example 3 as described, or because it was not possible to delete 100 kb of mouse sequence and insert 200-300 kb of human sequence as illustrated in Figure 4 in a single step, or because it was not possible to delete 150 kb of mouse sequence and insert 75 kb of human sequence in one step? We do not believe it is. The following further matters are particularly relevant in this regard.

First and as we have shown, it is well-established that the skilled person is not bound to carry out the invention precisely as described and can use the common general knowledge to perform the invention and make any obvious changes that may be necessary, provided of course that any work involved is not undue.

Secondly, the evidence established that the skilled team would have regarded the implementation of Example 3 as extremely challenging and in these circumstances the obvious thing to have done would have been to shorten the inserts. The team would also have understood that there was no need to carry out deletions in the same step as insertions, and that any necessary deletions could be effected without undue difficulty in a later and separate step.

Thirdly and for the reasons we have given, we are satisfied that the skilled team could have produced transgenic mice within the scope of the claim without undue effort at the priority date and that such mice would have had a near wild type response.

Fourthly, the law does not require a patentee to enable each and every embodiment of a claimed invention. As the authorities recognise, a claim may encompass inventive improvements of what is described and a specification is not insufficient merely because it does not enable the person skilled in the art to make every such invention. It is important, however, that any such improvement is still a way of working the original invention. In this case we have no doubt that this is the case: there is no mouse falling within the scope of claim 1 of the 163 patent which does not embody the reverse chimeric locus and enjoy the benefits it brings.

Fifthly, if the claim of a patent is adequately enabled across its breadth and its scope is commensurate with the technical contribution the disclosure of the invention has made to the art, the patent does not cease to be sufficient simply because the specification promises too much. As we have explained, the skilled team would have recognised that Example 3, as described, presented a real challenge, and that the example would not have worked. But they would also have appreciated that an obvious way forward was to reduce the size of the inserts, and by proceeding in this way and in the manner we have described could have implemented the claimed invention without undue effort.

For all of these reasons, we have come to the conclusion that claim 1 of the 163 patent does not exceed the contribution to the art which the disclosure of its specification has made. We are satisfied that the extent of the patent monopoly, as defined by claim 1, does correspond to that technical contribution to the art and that it is adequately enabled across its scope.

We come next to claim 1 of the 287 patent and in our judgment very similar considerations apply. It is a claim to a method which is drawn in broad terms but each of the individual methods which it encompasses is a method of making a reverse chimeric locus in an isolated mouse ES cell by the replacement of V, D and J gene segments of the endogenous immunoglobulin heavy chain variable gene locus with orthologous human V, D and J segments. Further, each of the methods uses LTVECs to bring about the necessary modification of the endogenous chromosomal locus of interest and the MOA assay to detect those ES cells which have been modified successfully. It is, in short, a claim to a particular way of producing the reverse chimeric locus.

The methods of claim 1 therefore incorporate both aspects of the invention that we have described. They are all methods of producing within ES cells a reverse chimeric locus in the heavy chain variable region such that the cells will produce hybrid antibodies containing human variable regions and mouse constant regions. But they are also methods which involve the use of the MOA assay which was itself a significant technical contribution to the art for, in the words of the patent, it empowered the use of LTVECs as targeting vectors and reduced the time for identifying correctly modified eukaryotic cells from several days to a few hours.

In our judgment the character of the invention of claim 1 is such that any person carrying out a method falling within the scope of the claim will benefit from the technical contribution the disclosure of the specification has made to the art in both respects. The product of the method is an ES cell containing the reverse chimeric locus of the invention, and the method itself allows the skilled person to use LTVECs to carry out the modification, with all the benefits that attend the use of these large targeting vectors.

That said, the other points that we have made in connection with the enablement of claim 1 of the 163 patent are equally apposite here. We accept that the skilled person could not have carried out the large deletions and insertions described in Example 3 without inventive improvements but the skilled team would have appreciated that the obvious thing to do was to shorten the inserts and to carry out any necessary deletions in a separate step, and the result would have been the production of ES cells that had a near wild type response.

More fundamentally, the invention is not a way of achieving insertions and deletions of any particular length but rather a methodology of making the reverse chimeric locus in which successful integrations using LTVECs are detected by using the MOA assay. The character of the invention is one of general application. The method is applicable to any ES cell and the MOA assay will detect those cells in which the successful recombination event has occurred, whatever the length of the insert.

Just as in the case of claim 1 of the 163 patent, we have come to the conclusion that claim 1 of the 287 patent is adequately enabled across its breadth. There is nothing in the claim which could have been envisaged without the disclosure of the invention, and, having regard to the nature and extent of the contribution the disclosure of the invention has made to the art, the scope of the claim is no more than necessary to confer fair protection on Regeneron.

Claims 5 and 6 of the 287 patent raise no separate issues. It necessarily follows from our findings in relation to claim 1 that they too are adequately enabled across their scope.

We are conscious that in so deciding we are arriving at a conclusion which is different from that of an experienced patent judge. However, we have had the benefit of hearing fully developed argument upon aspects of the evidence which did not receive the same degree of attention at trial; we have come to the conclusion that the judge erred in his approach to the interpretation of claim 1 of the 287 patent; and we are satisfied that, in assessing the sufficiency of the disclosure of the patents, he did not attach sufficient weight to the character of the invention as claimed in each of the claims in issue, the contribution that its disclosure has made to the art and the need to confer a fair degree of protection on the patentee.

For all of these reasons we are satisfied that the specifications of the patents do disclose the claimed inventions clearly enough and completely enough for them to be performed by a person skilled in the art. We note the Board of Appeal reached the same conclusion in the case of the 287 patent (T 2220/14 of 9 November 2015). We have recently been notified that on 7 February 2018 the Opposition Division upheld the validity of the 163 patent on the basis of the claims as granted. The written decision is not yet available.

For the reasons we have given: