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	England and Wales Court of Appeal (Civil Division) Decisions
You are here: BAILII >> Databases >> England and Wales Court of Appeal (Civil Division) Decisions >> Idenix Pharmaceuticals Inc v Gilead Sciences Inc & Ors [2016] EWCA Civ 1089 (08 November 2016) URL: http://www.bailii.org/ew/cases/EWCA/Civ/2016/1089.html Cite as: [2016] EWCA Civ 1089

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IN THE COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE
CHANCERY DIVISION (PATENTS COURT)
THE HON MR JUSTICE ARNOLD
[2014] EWHC 3916 (Pat)

		Royal Courts of Justice Strand, London, WC2A 2LL
		08/11/2016

Lord Justice Kitchin:

Introduction

1. Idenix Pharmaceuticals, Inc. ("Idenix" or "IPI") is the joint proprietor of European Patent (UK) No. 1 523 489 which describes and claims a family of nucleoside analogues for treating HCV and other Flaviviridae infections. These nucleoside analogues have 2'-methyl-up-2'-fluoro-down substituents on the sugar moiety. The application for the Patent, International Patent Application No. WO 2004/002999 ("the Application"), was filed on 27 June 2003. The Patent was granted on 12 March 2014.
2. In these proceedings, issued upon grant of the Patent, Idenix claimed that Gilead Sciences, Inc. and Gilead Sciences Ltd. (collectively "Gilead") had infringed the Patent by making and selling sofosbuvir, which they marketed under the brand name Sovaldi. Gilead denied infringement and counterclaimed for the revocation of the Patent on the grounds of lack of novelty over Gilead's own International Patent Application PCT/US2004/012472 ("the Pharmasset PCT"), lack of inventive step, insufficiency and added matter.
3. The allegation of lack of novelty raised an issue as to the entitlement to priority of the Pharmasset PCT. In short, Gilead could only rely upon the Pharmasset PCT to attack the novelty of the Patent if the Pharmasset PCT was entitled to claim priority from a US application, US 60/474,368 ("'368"), and Idenix asserted it was not, for reasons to which I shall come.
4. Gilead argued the Patent was invalid for lack of inventive step because it did not make a technical contribution. It was, it said, not plausible that substantially all of the compounds encompassed by the claims would be effective against Flaviviridae. Indeed, this proved to be, at least in part, common ground because Idenix's own expert on this issue, Dr Andrea Brancale, accepted in his first report that claim 1 covers classes of compounds which would not be thought likely to have antiviral activity. This led Idenix to make a conditional application to amend the Patent.
5. The allegation of insufficiency had three limbs. Gilead contended first, that the disclosure of the Patent did not make it plausible that substantially all of the claimed compounds would have activity against Flaviviridae. This allegation was clearly closely related to that of lack of inventive step. Secondly, the Patent did not enable the skilled person to synthesise without undue effort the 2'-methyl-up-2'-fluoro-down compounds falling within the claims. And thirdly, the Patent did not enable the skilled team to perform the invention across the breadth of claim 1 without undue effort.
6. Finally, I should say a word about the allegation of added matter. This had two limbs. The first was an attack on claim 1 as granted. Gilead contended that this claim, directed as it is to compounds of only one of the formulae disclosed in the Application, adds matter because it focuses attention on this formula whereas the skilled person reading the Application would never have thought it stood out. The second was an attack on claims 4 and 5 as granted. Here Gilead argued that the claims included limitations of which there was no adequate disclosure in the Application.
7. The action came on for trial before Arnold J in October 2014. It lasted for 11 days, in the course of which the judge heard evidence from four technical experts and four experts in US law. He also heard evidence from five witnesses of fact. In his judgment, given on 1 December 2014, he held that sofosbuvir fell within the scope of the claims of the Patent but that the Patent was invalid for lack of novelty, lack of inventive step and insufficiency. He rejected the allegation of added matter, save in relation to claim 4. He also refused to allow an amendment to claim 1 to delete those groups of compounds which Dr Brancale accepted that the skilled person would not expect to have activity. This amendment would, he held, result in the amended specification disclosing adding matter.
8. Upon this appeal Idenix contends the judge fell into error at almost every stage of his analysis. In summary, it contends that he:

i) wrongly held that the Pharmasset PCT was entitled to priority;

ii) fell into error in the way that he approached and assessed the common general knowledge, and that this fatally undermines his findings in relation to lack of inventive step and insufficiency;

iii) wrongly concluded the Patent lacked an inventive step; and that he ought to have found that it was plausible that the claimed molecules would have antiviral activity;

iv) fell into error in finding that the Patent was insufficient; in particular, he applied the wrong test of enablement and he erred in principle in the way he assessed the evidence, focusing unduly on the work of one individual and attaching inadequate weight to the expert evidence;

v) fell into error in addressing the issue of added matter both in relation to claim 4 of the Patent as granted and the proposed amended claim 1.

9. Gilead has filed a respondent's notice. It contends that the judge ought to have found that claim 1 of the Patent as granted was invalid for added matter.
10. It is convenient to deal with these issues in the following order: first, common general knowledge; secondly, inventive step; thirdly, insufficiency; fourthly, added matter and amendment; and finally, if and so far as necessary, novelty and the priority of the Pharmasset PCT. But before doing so, I must say a little about the technical background and the disclosure of the Application and the Patent.

Technical background

11. The judge set out the technical background in considerable detail from [38] to [177] of his judgment. For the purposes of this appeal, the following aspects of that technical background are of particular importance. They are drawn with gratitude from the judgment.

The building blocks

12. Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are large, complex, naturally-occurring organic molecules. They are polymers composed of monomers called nucleotides. Nucleotides consist of a five carbon (or "pentose") sugar, a heterocyclic aromatic base (or "nucleobase") and a phosphate moiety, as shown below:

13. A pentose bonded to a nucleobase without a phosphate moiety is referred to as a nucleoside. The bond formed between the sugar and nucleobase components of nucleosides is termed a glycosidic bond, and it is formed in a process known as glycosylation.
14. Pentoses are simple sugars. The pentoses found in RNA and DNA are D-ribose and D-2-deoxy-ribose respectively. They have a ring structure of one oxygen atom and four carbon atoms, as well as one carbon atom attached to the ring. Conventionally, the carbon atoms in the ring are numbered clockwise 1 to 4, while the carbon atom attached to the ring is numbered 5, as shown below:

15. Pentoses have multiple chiral centres. In this form of diagram, the sugar ring is represented as a planar structure. The bold wedged bonds indicate that the 2- and 3-carbon atoms of the sugar ring point towards the viewer whereas the oxygen atom points away from the viewer. The plain bonds pointing upwards and downwards from the sugar ring indicate that the attached substituents are respectively above and below the plane of the ring. These are commonly referred to as the "up" and "down" positions respectively.
16. Both DNA and RNA normally use combinations of four nucleobases each to perform their coding function. In RNA, these nucleobases are cytosine, uracil, adenine and guanine. In DNA, uracil is replaced by thymine. Adenine and guanine belong to the class of double-ringed nucleobases named purines, while cytosine, thymine and uracil are in the class of single-ringed nucleobases named pyrimidines.
17. When a sugar is bonded to a nucleobase and therefore forms part of a nucleoside, the carbon atoms in the sugar are numbered from 1' to 5', so that a distinction can be made between the positions in the sugar and in the nucleobase. When joined to the sugar via a glycosidic bond, the nucleobase adopts the up position in all naturally-occurring nucleosides.
18. A nucleotide comprises a nucleoside with one, two or three phosphate groups added to it. Where it is necessary to distinguish the number of phosphate groups attached, the compounds are generally termed nucleoside mono, di or triphosphates. Nucleotide triphosphates are key components in the synthesis of polynucleotides.
19. Copies of nucleic acids are made by the action of polymerase enzymes, which catalyse formation of bonds between individual nucleotides. The critical interaction in polymerase-catalyzed DNA or RNA synthesis involves the 3'-hydroxyl group of the nucleotide on the DNA or RNA of the so-called "primer" strand, which is complementary to the strand being copied. The 3'-hydroxyl of the growing primer strand attacks the first (or a) phosphate group of the incoming 5'-nucleotide triphosphate that forms a base pair with the template strand. This forms a 3',5'-phosphate diester linkage which builds up the backbone structure of the DNA or RNA. The other two phosphate groups form a diphosphate moiety which is cleaved off the nucleotide. This is a nucleophilic substitution reaction.

Flaviviridae

20. The Flaviviridae family is a large, diverse family of positive, single-stranded, enveloped RNA viruses, some of which cause a range of diseases in humans and animals. By June 2003 three genera in the Flaviviridae family had been recognised, namely flaviviruses, pestiviruses and hepaciviruses. The most important hepacivirus in terms of human disease is HCV. It was in 2003 and remains a serious global threat, and untreated infection is the leading cause of liver failure and liver cancer. The World Health Organisation has estimated that globally there are between 350,000 and 500,000 deaths from HCV each year.
21. Within the HCV species, there are a number of different genotypes; within genotypes, there are distinct subtypes; and there is also some degree of genetic variation in the virus population within an infected individual due to on-going mutations caused during the process of viral RNA replication. It is the ability of the virus to mutate that can give rise to the emergence of resistance to antiviral treatment. HCV genotypes differ in their geographical spread. At the time of trial, the predominant genotypes were GT1-6. In the UK, GT1 and GT3 genotypes were co-prevalent, each accounting for about 45% of infections.
22. The HCV genome consists of a single strand of positive-sense RNA. It is about 9,600 nucleotides in length and is initially translated as one long polyprotein of about 3,000 amino acids. This polyprotein is then cleaved to release three structural proteins and a number of non-structural proteins which are involved in protein processing and replication of the viral RNA. One of these non-structural proteins, NS5B, is essential for mediating replication of the viral genome and by 2013 it had been identified as a target for the development of antiviral therapies.

Structures of enzymes, including NS5B

23. Most metabolic reactions, including replication of nucleic acids, do not take place spontaneously and require enzymes to catalyse them. To do this, an enzyme must interact with its substrates. This interaction takes place in the enzyme's active site and depends upon the enzyme's complex three-dimensional structure and shape or conformation. Accordingly, an understanding of the crystal structures of enzymes and their substrates allows researchers to study how enzymes interact with their substrates, how they undergo changes in conformation and how they perform catalysis.
24. NS5B is an enzyme and it replicates viral RNA by accepting nucleoside triphosphates present in the host cell and incorporating them into the growing viral RNA chain. It does this by catalysing the formation of phosphodiester bonds between nucleotides. A certain amount was known about NS5B by June 2003. However, a crystal structure of the complete ternary structure, that is to say the structure of NS5B when complexed with its substrates, was not available and, in the absence of this information, it was not known how the amino acid residues in the active site of NS5B interact with the enzyme substrates to catalyse the formation of the phosphodiester bonds.

HCV treatment

25. The goal of treatment is to stop viral replication and so eliminate the virus from the infected individual. The standard therapy for HCV infection in June 2003 was a combination of pegylated interferon alpha ("IFN") and ribavirin ("RBV"), and it achieved one year cure rates of approximately 80% in GT2 and GT3 infections, but only 40-50% in GT1 infections.
26. IFN and RBV are both indirect inhibitors of viral replication. RBV is a broad-spectrum antiviral agent that greatly improves antiviral responses. IFN is a synthetic version of a naturally occurring protein made by cells of the immune system; it has multiple effects on the body, some of which are antiviral, and its mechanism of action is still not fully understood.
27. Combination therapy with IFN and RBV involves a complex treatment regime and causes severe adverse side effects in almost all patients. The treatment of last resort for patients with HCV is liver transplantation. But this too is far from satisfactory because the transplanted liver almost invariably becomes infected, and treating infection after liver transplantation is particularly complicated due to drug interactions between IFN and RBV and the immune suppressants administered to prevent transplant rejection.

Direct acting antivirals

28. By 2003 there was therefore a longstanding need for better treatments for HCV. In particular there was a need for more targeted drugs that would increase cure rates and decrease side effects. This led to research into drugs called direct acting antivirals ("DAAs"). Unlike IFN and RBV, DAAs are agents that interfere with specific steps in the viral replication cycle.
29. In developing DAAs for HCV, many research groups focused initially on protease inhibitors ("PIs") that target the protease responsible for mediating the cleavage of the non-structural HCV polyprotein and so prevent the cleavage of the polyprotein into its individual proteins. This in turn prevents those proteins from functioning and the virus from replicating. Although several potent PIs had been identified by 2003, it was not until 2011 that the first DAAs were approved for treatment of HCV.

Nucleoside analogues

30. A different strategy was to try to identify and make nucleoside analogues with beneficial activity. There is, as the judge explained, vast scope for designing such analogues but whether they can be made and whether they will work is a very different matter.
31. Cytotoxic nucleoside analogues have been used clinically for over 50 years in the treatment of many types of cancer and were known to cause cells to die in a variety of different ways. The harnessing of this technique for use in antiviral therapy requires the identification of rather different properties, however. Here cytotoxicity must be avoided and the aim is instead to kill the virus but not the cells which host it.
32. RBV is a nucleoside analogue and its antiviral properties were discovered in 1972. It is active against various unrelated RNA viruses from diverse families that share little genetic sequence homology, such as HCV and respiratory syncytial virus. How it works is still not fully understood but it does not interfere with a specific step in the viral replication cycle and so is not considered to be a DAA.
33. By June 2003 it was appreciated that therapeutic nucleoside analogues for the treatment of viral infection must have certain properties. The judge described those properties in these terms at [101]. They should:

i) enter the infected target cell;

ii) be phosphorylated within the host cell to the triphosphate form (or structural equivalent);

iii) bind to the viral polymerase, ideally at the active site, although there are other nucleoside binding sites on the viral polymerase which may be targeted;

iv) ideally not be recognized by host cell polymerases (or other cellular components), which could give rise to toxicity;

v) ideally be incorporated into the growing viral genome and then prevent its successful replication;

vi) if not incorporated, compete with natural nucleotides and so inhibit viral replication; and

vii) ideally, selectively prevent or inhibit viral replication without cytotoxicity.

34. The skilled person would also have known by 2003 of the antiviral activity and mechanism of action of a number of direct acting nucleoside analogues for use in the treatment of other diseases, such as zidovudine (AZT), lamivudine (3TC) and zalcitabine (ddC) for HIV; 3TC and tenofovir disoproxil fumarate (TDF) for HBV; acyclovir for herpes; and ganciclovir for cytomegalovirus.
35. A number of these DAAs have structures in which the 3'-hydroxyl group on the sugar moiety has been replaced with a non-natural substituent which means that, if incorporated into the growing nucleotide chain, they cannot mount a nucleophilic attack on an incoming nucleotide triphosphate, and in this way they prevent the chain from growing further. These are called "obligate chain terminators". Others have a structural equivalent of a 3'-hydroxyl group but nevertheless prevent the chain from growing further. They are called "non-obligate chain terminators".
36. The judge then made these findings about the skilled person's general knowledge concerning the specificity and selectivity of nucleoside analogues:

"107. … The skilled person in June 2003 would have known that, in general, activity of a nucleoside analogue against one virus species was not predictive of the nucleoside's activity against other virus species. Cross-reactivity of some direct acting nucleoside analogues between related viral species has been shown: for example, 3TC works against both HIV and HBV, and this has also been demonstrated for tenofovir. It is more common, however, for a nucleoside analogue that is effective therapeutically to be specific for a particular virus. For example, AZT works in HIV, but not in HBV. Furthermore, in general, if a compound is able to target structurally different viral polymerases, it may also target cellular polymerases and cause toxicities.

108. The nucleoside analogues that were active against HIV RT, which is a DNA polymerase, could not be predicted to be effective at preventing HCV replication. Deoxyribonucleosides, like the aforementioned HIV drugs, are structurally distinct from ribonucleosides that are the natural substrates for RNA polymerases."

37. As for the skilled person's state of knowledge of the potential use of nucleoside analogues for treating HCV, the judge continued:

"109. … By June 2003, the skilled person would have been aware that various research groups were interested in the potential of using nucleoside analogues for treating HCV by directly inhibiting NS5B activity. They would have been aware of the successful use of nucleoside analogues in the treatment of HIV, HBV, CMV and herpes virus infections. They would also have known that the efficacy of direct acting nucleoside analogues against Flaviviridae infections, and in particular HCV, had not been demonstrated in the clinic and that therefore no direct acting nucleoside analogues were on the market. It was not until sofosbuvir was approved that a direct acting nucleoside analogue was approved for use in the treatment of HCV."

38. That brought the judge to a consideration of the general strategy that the skilled person would adopt to the discovery of novel nucleoside analogues for the treatment of HCV. This would necessarily be a largely empirical task, the aim being to discover analogues which have activity but not toxicity, as he explained in these terms:

"110. In June 2003 (and still today) it was not possible to determine from a molecule's structure whether it would be effective in inhibiting HCV NS5B, and, in turn, in treating HCV. This is especially so because, as noted above, the ternary crystal structure of NS5B is not yet known and NS5B is a highly mobile molecule which undergoes conformational change as it catalyses the addition of ribonucleotides to the RNA chain. The development of nucleoside analogues to inhibit NS5B therefore was (and still is) largely empirical.

111. Generally, the approach to the discovery of novel nucleoside analogues for HCV infection involved the synthesis and testing of these compounds in order to discover which compounds had activity without toxicity. In theory, nucleoside analogues can be altered at most positions on the sugar ring and the base by the addition of a range of substituents. But to have antiviral activity, they still need to be recognised by cellular enzymes to phosphorylate the nucleoside analogue to the active triphosphate form and be recognised by the viral polymerase to catalyse its incorporation into the viral RNA chain. It was appreciated that even small changes in the nucleoside analogue can lead to significant changes in its activity. These changes can give rise to toxicity, inactivity or antiviral therapeutic potential. Once a promising candidate compound has been found, studies can be carried out to try to understand how its structure affects its mechanism of action. Typically, this involves making small changes to the structure and seeing how these affect its activity, enabling a picture to be built up of the structure-activity relationship."

39. The task was rendered harder still by a lack of suitable small animal models. The researcher would therefore have to use one or more of the following assays and techniques which were available in 2003. The first is the phosphorylation assay. This can be used to establish in vitro whether the candidate compound can be phosphorylated, an essential requirement if it is to be accepted by the active site of the polymerase. The second is the polymerase assay which can be used to assess whether a candidate compound inhibits polymerase activity. It is far from straightforward to carry it out, however. The third is to study the effect of the candidate compound upon a related virus, BVDV, as a surrogate for HCV. BVDV and HCV share a high degree of homology but, unlike HCV, BVDV could be cultured in cell lines in vitro, which permitted the testing of compounds to detect inhibition of viral replication. BVDV was, however, an imperfect model because, inter alia, there are important differences between the cell lines used to culture BVDV and human hepatocytes, the cells targeted by HCV in vivo. The fourth, known as the replicon assay, represented a major breakthrough and by 2003 it had become the gold standard for testing for anti-HCV activity. It involved the use of an engineered HCV genome or, at least initially, a portion of the HCV genome, which would replicate in human hepatocytes and in this way it provided a model in which the activity of the candidate compound could be tested.
40. The judge returned to the nature of the task facing a researcher seeking to identify new and efficacious molecules for the treatment of HCV in his judgment at [133] to [137]:

"133. … by 2003, nucleoside analogues had attracted a great deal of interest as potential candidates for the treatment of various diseases including cancer and viral infections. In general, these compounds contain chemical modifications in either the sugar or the nucleobase of the nucleoside or both. The aim of the modifications when developing antiviral compounds is to ensure that the biosynthesis of DNA and RNA of the target virus is affected, but this needs to be done without causing harm to healthy host cells (which produce their own DNA or RNA). The identification of such highly selective compounds was (and still is) a significant and challenging scientific task.

134. The skilled person approaching the synthesis of a nucleoside analogue in 2003 would have had a number of options for doing so, and the details of his approach would depend on the particular target nucleoside in question. In general, he would start by looking to see if the particular molecule was reported in the scientific literature and, if so, whether the details of its synthesis were given in any report. If there were no reports of the exact nucleoside analogue targeted, then the skilled person would examine whether related compounds had been reported, and determine whether reported syntheses of such compounds would provide guidance for a synthetic strategy. Key textbooks might also be consulted.

135. The skilled person might also carry out further, broader, literature searches relating to the structure of the desired compound. The skilled person would then use any helpful information in the key textbooks and the literature, as well as his common general knowledge, to consider how he might attempt a synthesis of the desired nucleoside analogue by carrying out a retrosynthetic analysis.

136. In very general terms, nucleoside analogue synthesis might be approached by modifying an existing nucleoside, that is, a sugar with the desired base already attached (often known as the "nucleoside route"), or by first preparing a sugar with the desired modifications before attaching the base by glycosylation (often known as the "sugar route"). The sugar route itself might involve either modifying a sugar which was already readily available, or starting with small molecules which could be used to build up the sugar with the desired modifications in place.

137. The skilled person would have known that the synthesis of nucleosides is often complicated, as a result of the number of chiral centers in the sugar ring and the number of reactive functional groups attached to the sugar (which might give rise to unwanted reactions and which would therefore need masking with suitable protecting groups, as to which see below). There would also be the need (in the case of the nucleoside route) to carry out the reaction on a molecule containing a sensitive functional group (the nucleobase) or the need (in the case of the sugar route) to carry out a glycosylation step to attach the nucleobase to the sugar and it was known in 2003 that in some circumstances this could be a difficult step."

41. The judge has here emphasised once again the challenging task facing a researcher seeking to identify new selective compounds in 2003. He has also identified two possible strategies for synthesising new nucleoside analogues: first, to modify an existing nucleoside, that is to say a sugar with the base already attached to it (the nucleoside route) or, alternatively, to prepare a sugar with the desired modification and then to attach the base to it by glycosylation (the sugar route). The skilled person would have known that any such synthesis is often complicated and may involve steps that are difficult to carry out.

The Application

42. Arnold J described the disclosure of the Application at length from [179] to [221]. It is not necessary for the purposes of this appeal to repeat that exercise. I need only refer to the following.
43. The Application is entitled "Modified 2' and 3'-Nucleoside Prodrugs for Treating Flaviviridae Infections". It then describes the field of the invention in these terms:

"The invention is in the area of pharmaceutical chemistry, and is in particular, a 2' and/or 3' prodrug of a 6-modified, 1', 2', 3', or 4'-branched pyrimidine nucleoside or 8-modified 1', 2', 3' or 4'-branched purine nucleoside for the treatment of a Flaviviridae infection, such as a hepatitis C virus infection."

44. There follows in the section entitled "Background of the Invention" a description of the relevant art including Flaviviridae viruses, HCV, and the treatment of HCV with interferon and a combination of interferon and ribavirin. Twelve different classes of additional methods of treatment of Flaviviridae infections are then described. Class (10) is of some importance for it discusses the use of branched nucleoside analogues to treat HCV. It reads (from page 9, line 29 to page 10, line 24):

"Idenix Pharmaceuticals discloses the use of branched nucleosides in the treatment of flaviviruses (including HCV) and pestiviruses in International Publication Nos. WO 01/90121 and WO 01/92282. Specifically, a method for the treatment of hepatitis C infection (and flaviviruses and pestiviruses) in humans and other host animals is disclosed in the Idenix publications that includes administering an effective amount of a biologically active, 1', 2', 3' or 4'-branched ß-D or ß-L nucleosides or a pharmaceutically acceptable salt or derivative thereof, administered either alone or in combination with another antiviral agent, optionally in a pharmaceutically acceptable carrier.

Other patent applications disclosing the use of certain nucleoside analogs to treat hepatitis C virus include: PCT/CA00/01316 (WO 01/32153; filed November 3, 2000) and PCT/CA01/00197 (WO 01/60315; filed February 19, 2001) filed by BioChem Pharma, Inc. (now Shire Biochem, Inc.); PCT/US02/01531 (WO 02/057425; filed January 18, 2002) and PCT/US02/03086 (WO 02/057287; filed January 18, 2002) filed by Merck & Co., Inc., PCT/EP01/09633 (WO 02/18404; published August 21, 2001) filed by Roche, and PCT Publications Nos. WO 01/79246 (filed April 13, 2001), WO 02/32920 (filed October 18, 2001) and WO 02/48165 by Pharmasset, Ltd.

PCT Publication No. WO 99/43691 to Emory University, entitled '2'-Fluoronucleosides' discloses the use of certain 2'-fluoronucleosides to treat HCV.

Eldrup et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16^th International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.)) described the structure activity relationship of 2'-modified nucleosides for inhibition of HCV.

Bhat et al. (Oral Session V, Hepatitis C Virus, Flaviviridae, 2003 (Oral Session V Hepatitis C Virus, Flaviviridae; 16^th International Conference on Antiviral Research (April 27, 2003, Savannah, GA.); p A75) describe the synthesis and pharmacokinetic properties of nucleoside analogues as possible inhibitors of HCV RNA replication. The authors report that 2'-modified nucleosides demonstrate potent inhibitory activity in cell-based replicon assays.

Olsen et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16^th International Conference on Antiviral Research (April 27, 2003, Savannah, GA.) p A76) also described the effects of the 2'-modified nucleosides on HCV RNA replication."

45. Idenix focus particularly on the presentations by Eldrup et al, Bhat et al and Olsen et al at the Savannah conference and I must return to these when addressing the common general knowledge.
46. The objects of the invention are set out at page 12, lines 1 to 10 and they include the provision of new compounds for the treatment of patients infected with HCV and, more generally, pestiviruses, flaviviruses or hepaciviruses.
47. The summary of the invention extends from page 12, line 11 to page 41, line 7. It is cast in terms of considerable breadth and includes a series of what are described as principal embodiments, one of which is Formula (IX) which I set out below. The Application says this about the activity of the compounds of the invention at page 38, lines 17 to 21:

"The ß-D and ß-L nucleosides of this invention may inhibit Flaviviridae polymerase activity. Nucleosides can be screened for their ability to inhibit Flaviviridae polymerase activity in vitro according to screening methods set forth more particularly herein. One can readily determine the spectrum of activity by evaluating the compound in the assays described herein or with another confirmatory assay."

48. The detailed description of the invention extends from page 41, line 20 to page 157, line 6. It includes a series of preferred embodiments and sub-embodiments, some of which are defined by reference to Formula (IX):

49. The substituents of this preferred embodiment and its sub-embodiments are these (page 100, lines 16 to 29):

"R¹, R², and R³ are independently H; phosphate; straight chained, branched or cyclic alkyl; acyl; CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; sulfonate ester; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; or a pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound where R¹, R², and/or R³ is independently H or phosphate;

X is O, S, SO₂ CH₂;

Base* is a purine or pyrimidine base;

R¹² is C(Y³)₃;

Y³ is independently H, F, Cl, Br, or I; and

R¹³ is fluoro.

50. In one sub-embodiment X is O, and Y³ is H. In another sub-embodiment, when X is O and Y³ is H, R¹, R² and R³ are also H.
51. I should add two points. First, the terms 'purine' and 'pyrimidine' are defined in very wide terms at page 104, lines 15 to 32. Secondly, the Application uses the term nucleoside to describe both nucleosides and nucleotides and, save where from the context otherwise appears, I shall do the same.
52. Methods of synthesis are described from page 119, line 30 to page 132, line 9. We are concerned only with the methods of synthesis of what are termed '2'-C-Branched Nucleosides'. The first involves glycosylation of a nucleobase with a modified sugar and is depicted in Scheme 3:

53. It is described in these terms from page 123, line 1 to page 124, line 3:

"The key starting material for this process is an appropriately substituted sugar with a 2'-OH and 2'-H, with the appropriate leaving group (LG), for example an acyl group or a halogen. The sugar can be purchased or can be prepared by any known means including standard epimerisation, substitution, oxidation and reduction techniques. The substituted sugar can then be oxidized with the appropriate oxidizing agent in a compatible solvent at a suitable temperature to yield the 2'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO₂, ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymer, CI₂-pyridine, H₂O₂-ammonium molybdate, NaBrO₂-CAN, NaOCI in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone) and N-bromosuccinimide.

Then coupling of an organometallic carbon nucleophile, such as a Grignard reagent, an organolithium, lithium dialkylcopper or R⁶ –SIMe₃ in TBAF with the ketone with the appropriate non-protic solvent at a suitable temperature, yields the 2'-alkylated sugar. The alkylated sugar can be optionally protected with a suitable protecting group, preferably with an acyl or silyl group, by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

The optionally protected sugar nucleoside can then be coupled to the BASE [sic] by methods well known to those skilled in the art, as taught by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be coupled to a silylated base with a Lewis acid, such as tin tetrachloride, titanium tetrachloride or a trimethylsilyltriflate in the appropriate solvent at a suitable temperature. Alternatively, a halo-sugar can be coupled to a silylated base with the presence of trimethylsilyltriflate.

Subsequently, the nucleoside can be deprotected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition 1991.

In a particular embodiment, the 2'-C-branched ribonucleoside is desired. The synthesis of a ribonucleoside is shown in Scheme 3. Alternatively, deoxyribo-nucleoside is desired. To obtain these nucleosides, the formed ribonnucleoside can optionally be protected by methods well known to those skilled in the art, as taught by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then the 2'-OH can be reduced with a suitable reducing agent. Optionally, the 2'-hydroxyl can be activated to facilitate reduction; i.e. via the Barton reduction."

54. The second is described as the modification of a pre-formed nucleoside and is depicted in Scheme 4:

55. This is described in similar terms save that the key starting material is an appropriately substituted nucleoside.
56. Various known assays to measure the activity of the disclosed compounds are set out from page 153, line 4 to page 156, line 17, but none measures anti-HCV activity. There is only one example (Example 26) which contains experimental data concerning anti-viral activity and toxicity, but the compound purportedly tested cannot be identified and, as the judge found, it cannot be concluded from the data whether the compound has any potentially useful therapeutic activity.
57. Finally, I should mention the claims. Claim 9 is directed to a compound of Formula (IX) as set out at [49] above. Claims 10 and 11 are directed to the sub-embodiments described at [50] above.

The Patent

58. The Patent describes the area in which the invention lies in these terms at [0001]:

"The invention is in the area of pharmaceutical chemistry, and is in particular, a 2'-branched pyrimidine nucleoside or 2'-branched purine nucleoside as defined in the claims. The invention is also a pharmaceutical composition comprising the nucleoside, and the nucleoside for use in a method for the treatment of a Flaviviridae infection, such as a hepatitis C virus infection."

59. There follows a description of the art in terms which are substantially the same as those appearing in the Application. Then there appears a summary of the invention:

"[0029] This invention relates to 2'-branched nucleosides, compositions thereof, and the nucleosides for use in methods as defined in the claims.

[0030] 3'-prodrugs of 2'-branched ß-D or ß-L nucleosides, or their pharmaceutically acceptable salts or pharmaceutically acceptable formulations containing these compounds are useful in the prevention and treatment of Flaviviridae infections and other related conditions such as anti- Flaviviridae antibody positive and Flaviviridae - positive conditions, chronic liver inflammation caused by HCV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-Flaviviridae antibody or Flaviviridae-antigen positive or who have been exposed to a Flaviviridae.

[0031] A method for the treatment of a Flaviviridae viral infection in a host, including a human, is also disclosed that includes administering an effective amount of a 3'- prodrug of a biologically active 2'-branched ß-D or ß-L nucleoside or a pharmaceutically acceptable salt thereof, administered either alone or in combination or alternation with another anti-Flaviviridae agent, optionally in a pharmaceutically acceptable carrier. The term 3'-prodrug, as used herein, refers to a 1', 2', 3' or 4'-branched ß-D or ß-L nucleoside that has a biologically cleavable moiety at the 3'-position, including, but not limited to acyl, and in one embodiment, a natural or synthetic D or L-amino acid, preferably an L-amino acid."

60. The specification proceeds to describe, inter alia, prodrugs, the principal and preferred embodiments of the invention and methods of synthesis in terms which are foreshadowed in the Application and which I have summarised, save that Example 26 is now identified as a reference example.
61. Turning now to the claims, claim 1 is a compound of Formula (IX):


or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² are independently H; phosphate; straight chained, branched or cyclic alkyl; acyl; CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; sulfonate ester; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; or a cholesterol;

X is O;

Base* is a purine or pyrimidine base;

R¹² is C(Y³)₃;

Y³ is H; and

R¹³ is fluoro.

62. Idenix also contended that the following further claims had independent validity:

2. The compound of claim 1, wherein R¹ and R² are H.

5. The compound of any one of claims 1-4, wherein Base* is cytosine, uracil, guanine, adenine, or thymine.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a host infected with a Flaviviridae, virus.

7. The compound for use of claim 6, wherein the virus is hepatitis C.

21. A pharmaceutical composition comprising an effective amount to treat a Flaviviridae infection of a compound, or a pharmaceutically acceptable salt thereof, of any of claims 1 to 5 in a pharmaceutically acceptable carrier.

24. The composition of claim 21, wherein the Flaviviridae virus is hepatitis C.

Amendment application

63. As I have mentioned, Idenix made a conditional application to amend claim 1 and delete from its scope those compounds which, on the evidence of its own expert, Dr Brancale, the skilled person would not expect to have activity, namely those compounds with any of the following substituents at R¹ and R²: "straight chained, branched or cyclic alkyl" and "benzyl, wherein the phenyl group is optionally substituted with one or more substituents".

The skilled team

64. There is no disagreement on this appeal about the skilled person to whom the Patent is addressed. It is a team comprising a medicinal chemist and a virologist, each with a PhD or equivalent research experience. The judge summarised the expertise of each member of the team in these terms:

"[245] The medicinal chemist would be experienced in the synthesis of organic compounds for medicinal applications. He would be likely to have some experience in the synthesis of nucleoside analogues.

246. The virologist would have expertise in the biology of the Flaviviridae virus family, and a particular interest in the antiviral activity of nucleoside analogues against Flaviviridae. He or she would be familiar with (and able to carry out) standard molecular- and cell-biological techniques, as well as activity assays."

65. Each side therefore called an expert virologist and an expert medicinal chemist. The virology experts were Professor Jeffrey Glenn for Idenix and Professor Matthias Götte for Gilead. The medicinal chemists were Dr Andrea Brancale for Idenix and Professor Geert-Jan Boons for Gilead.

The common general knowledge

66. That brings me to the common general knowledge of the skilled team. At the outset, Arnold J noted an unusual feature of this aspect of the case, namely that Idenix, the patentee, was asserting that more information formed part of the common general knowledge than Gilead. This, he thought, reflected the fact that Idenix was attempting to remedy the deficiencies in the Patent.
67. The judge also recorded that there was little dispute that all of the technical background (the relevant parts of which I have summarised earlier in this judgment) formed part of the common general knowledge and he then proceeded to address three issues about which the parties did not agree. The first was whether it was common general knowledge that 2'-methyl-up-2'-hydroxy-down nucleoside analogues had the potential to be efficacious in treating HCV. Idenix contended that it was but Gilead argued that it was not. The judge agreed with Gilead. His finding to that effect (at [297]) is challenged by Idenix on this appeal. Mr Andrew Waugh QC, who appears on its behalf, contends the judge fell into error in two ways, each of which amounts to an error of principle: first, he wrongly sought to determine whether it was known that 2'-methyl-up-2'-hydroxy-down nucleoside analogues were in fact active against HCV; and secondly, in considering whether this was part of the common general knowledge, he asked himself whether it was known by all those persons interested in this field. Mr Waugh contends that the judge set the bar too high in both respects and that he ought rather to have asked himself whether 2'-methyl-up-2'-hydroxy-down nucleoside analogues were generally regarded as a good basis for further action by the bulk of those engaged in the field. Furthermore, Mr Waugh continues, if the judge had approached the evidence and the issue before him correctly, he would have reached the conclusion that it was indeed common general knowledge that 2'-methyl-up-2'-hydroxy-down nucleoside analogues were a good basis for further action for it was known by the bulk of those engaged in the field that they were good candidates for the treatment of HCV. This is an issue of some importance for it forms an important part of Idenix's case that the invention which is described and claimed in the Patent is plausible.
68. The second issue concerned the effect of substituting a fluorine substituent for a hydroxyl one in a biologically active molecule. As to this, the judge found that such a change in a nucleoside would be expected seriously to affect the stereoelectronic properties of the molecule and could lead to a dramatic change in its biological properties. There is no challenge to this finding on this appeal.
69. The third issue concerned the extent to which the skilled team would have regarded the activity of a nucleoside analogue against one species of the Flaviviridae family as predictive of its activity against another species. Here the judge found that the skilled team could make an educated guess but would have to test to confirm the guess was correct. Again, this finding is not challenged on this appeal.
70. I return then to the challenge to the judge's finding that it was not part of the common general knowledge that 2'-methyl-up-2'-hydroxy-down nucleoside analogues had the potential to be efficacious in treating HCV. I must begin with some basic principles as to what does and what does not form part of the common general knowledge. These were explained by Aldous LJ in Beloit Technologies Inc v Valmet Paper Machinery Inc [1997] RPC 489 at pages 494 to 495:

"It has never been easy to differentiate between common general knowledge and that which is known by some. It has become particularly difficult with the modern ability to circulate and retrieve information. Employees of some companies, with the use of libraries and patent departments, will become aware of information soon after it is published in a whole variety of documents; whereas others, without such advantages, may never do so until that information is accepted generally and put into practice. The notional skilled addressee is the ordinary man who may not have the advantages that some employees of large companies may have. The information in a patent specification is addressed to such a man and must contain sufficient details for him to understand and apply the invention. It will only lack an inventive step if it is obvious to such a man.

It follows that evidence that a fact is known or even well-known to a witness does not establish that that fact forms part of the common general knowledge. Neither does it follow that it will form part of the common general knowledge if it is recorded in a document. As stated by the Court of Appeal in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd [1972] R.P.C. 457, at page 482, line 33:

'The two classes of documents which call for consideration in relation to common general knowledge in the instant case were individual patent specifications and "widely read publications".

As to the former, it is clear that individual patent specifications and their contents do not normally form part of the relevant common general knowledge, though there may be specifications which are so well known amongst those versed in the art that upon evidence of that state of affairs they form part of such knowledge, and also there may occasionally be particular industries (such as that of colour photography) in which the evidence may show that all specifications form part of the relevant knowledge.

As regards scientific papers generally, it was said by Luxmoore J. in British Acoustic Films (53 R.P.C. 221 at 250):

"In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art."

And a little later, distinguishing between what has been written and what has been used, he said:

"It is certainly difficult to appreciate how the use of something which has in fact never been used in a particular art can ever be held to be common general knowledge in the art."

Those passages have often been quoted, and there has not been cited to us any case in which they have been criticised. We accept them as correctly stating in general the law on this point, though reserving for further consideration whether the words "accepted without question" may not be putting the position rather high: for the purposes of this case we are disposed, without wishing to put forward any full definition, to substitute the words "generally regarded as a good basis for further action".'"

71. In Raychem Corporation's Patents [1998] RPC 31, Laddie J provided this important further guidance at page 40:

"The court is trying to determine in a common sense way how the average skilled but non-inventive technician would have reacted to the pleaded prior art if it had been put before him in his work place or laboratory. The common general knowledge is the technical background of the notional man in the art against which the prior art must be considered. This is not limited to material he has memorised and has at the front of his mind. It includes all that material in the field he is working in which he knows exists, which he would refer to as a matter of course if he cannot remember it and which he understands is generally regarded as sufficiently reliable to use as a foundation for further work or to help understand the pleaded prior art. This does not mean that everything on the shelf which is capable of being referred to without difficulty is common general knowledge nor does it mean that every word in a common text book is either. In the case of standard textbooks, it is likely that all or most of the main text will be common general knowledge. In many cases common general knowledge will include or be reflected in readily available trade literature which a man in the art would be expected to have at his elbow and regard as basic reliable information."

72. It follows that the common general knowledge is all that knowledge which is generally regarded as a good basis for further action by the bulk of those who are engaged in a particular field. It is that knowledge which those working in that field will bring to bear when they are reading or learn of a piece of prior art. It is not necessary that those persons have that knowledge in their minds, however. The common general knowledge includes material that they know exists and which they would refer to as a matter of course if they cannot remember it and which they understand is generally regarded as sufficiently reliable to use as a foundation for further work.
73. These principles are well known and are referred to by the judge in his own judgment in KCI Licensing v Smith & Nephew plc [2010] EWHC 1487, [2010] FSR 31 which he cited in his judgment the subject of this appeal at [250]. In these circumstances it may be thought unlikely that he lost sight of them in assessing the evidence before him. Nevertheless, I must now consider whether that is what he in fact did.
74. Idenix relied in support of its case upon a series of publications in 2002 and 2003 and upon certain presentations given at a conference in Savannah, Georgia in the spring of 2003, each of which is addressed in the judgment. I will deal with them in turn but before doing so must mention the evidence given by Dr Brancale in his three reports. Save for his evidence concerning the Savannah conference presentations, to which I will come, his evidence in his first report was contained in one paragraph in which he said no more than that "certain 2'-modified nucleoside analogues were known to have anti-HCV activities". The position was not much changed in his second and third reports. Again leaving aside his evidence as to the Savannah conference presentations and also his evidence as to the Carroll paper, to which I will also come, he did not suggest that any other publications had rendered it common general knowledge that 2'-methyl-up-2'-hydroxy-down nucleoside analogues had the potential to be efficacious in treating HCV. The fact that Dr Brancale did not himself mention a number of the publications upon which Professor Götte was cross-examined and upon which Idenix then relied was a matter to which the judge was plainly entitled to have regard, and I reject a submission made by Mr Waugh to the contrary.

De Francesco and Rice (2003)

75. The first of the publications relied upon by Idenix was an article by Raffaele De Francesco and Charles Rice entitled "New therapies on the horizon for hepatitis C: are we close?", Clin. Liver Dis., 7, 211-243 (2003). This is a review of the progress made in the search for new and more specific anti-HCV therapies, and it was referred to by Professor Götte in his report as representative of the sort of information which was common general knowledge in June 2003.
76. In a section of the article entitled "HCV-encoded enzymes and their inhibitors" and under the sub-heading "NS5B RNA-dependent polymerase", the article explains that NS5B is required for the RNA synthesis steps necessary for viral replication and that it is possible that specific inhibitors of this enzyme could be found that block HCV replication with negligible associated activity.
77. Set in this text is figure 6(B) entitled "Chemical structures of selected inhibitors of the NS5B RNA-dependent RNA polymerase activity":

IMAGE 7

78. Compound 13 is beta-D-2'-methyl-ribofuranosyl-guanosine, a nucleoside analogue with 2'-methyl-up-2'-hydroxy-down substituents and is mentioned in this passage which appears under the sub-heading "Nucleoside analogues" on page 228 :

"Novel series of nucleosides that are candidates for the treatment of HCV are being developed, and some have been described in the recent patent literature [131-133]. In particular the discovery of oral, once-daily nucleosides potentially useful for the treatment of all HCV genotypes was recently reported [134]. Among these, beta-D-2'-methyl-ribofuranosyl-guanosine (Fig 6, compound 13) was found to be phosphorylated in cultured cells and orally bioavailable in primates [133]."

Interestingly, the only nucleoside analogue that thus far was shown to be therapeutically useful against HCV infection is the broad-spectrum antiviral agent D-ribavirin …"

79. This is followed (at page 229) by a section entitled "Non-nucleoside inhibitors" and here compounds 14 to 21 in figure 6B are identified as inhibitors of NS5B.
80. The article concludes with the following assessment of "Prospects for new HCV therapies" (at page 233):

"A myriad of new therapies for treating HCV are in various stages of preclinical and clinical development. As reviewed here, these include nucleic acid-based approaches (antisense and ribozymes), small molecule inhibitors of essential HCV-encoded enzymes (protease, helicase, and polymerase), immune modulation, and immunotherapy. As more details of the HCV life cycle are elucidated, new targets and approaches will be discovered. Drug development is difficult, expensive, and always agonizingly slow for patients in need and their physicians. Nonetheless, a broad effort has been mounted for HCV, and substantial progress has been achieved. The prospects for new HCV treatments are bright. The next few years will be very exciting as the first candidates move through clinical trials and, hopefully, into widespread clinical use."

81. The judge summarised his view as to the effect of this article in two paragraphs. At [264] he said this:

"Idenix particularly rely on the passage which mentions compound 13, which is a 2'-methyl-up-2'-hydroxy-down nucleoside analogue. All this passage says about compound 13, however, is that it was "found to be phosphorylated in cultured cells and orally bioavailable in primates". This does not demonstrate anti-HCV activity…"

82. Then, after referring to the various references mentioned in this passage, none of which reported anti-HCV activity for nucleoside analogues with methyl-hydroxy substituents at the 2' position, he continued:

"265. It follows that, even if the skilled team took a particular interest in compound 13 in the De Francesco and Rice article and chased down the references, they would not know whether compound 13 had any anti-HCV activity. As Dr Brancale accepted, the skilled team would know that, in order to identify whether a nucleoside analogue such as compound 13 was active against HCV, it was necessary to test its activity using at least one of the in vitro assays that were available. I would add that WO 01/90121 is the only one of the references which was mentioned by Dr Brancale in the passage from his first report quoted above, and as previously noted, he did not suggest that the content of that application was common general knowledge. "

83. Mr Waugh vigorously attacks these conclusions. He submits the judge was wrong to dismiss the teaching of the paper in this way because it expressly describes compound 13 as being one of a group of nucleosides which are potentially useful for the treatment of HCV and furthermore, he continues, this teaching is capable of forming part of the common general knowledge.
84. I of course accept that compound 13, beta-D-2'-methyl-ribofuranosyl-guanosine, is one of those compounds identified in the article as being potentially useful for the treatment of HCV but the judge cannot be criticised for considering the basis for that observation. In that regard it seems to me that he has summarised the teaching of the article in terms which are entirely fair. The article says that compound 13, a nucleoside analogue, is one of a number of compounds which have been shown to inhibit NS5B. It also says that compound 13 is phosphorylated in cultured cells and orally bioavailable in primates. But it does not suggest that compound 13 has been tested for anti-HCV activity in one or more of the in vitro assays or has been shown to possess anti-HCV activity in any other way. Nor does it suggest that any activity can be attributed to the 2'-methyl-up-2'-hydroxy-down substituents. Moreover, the skilled person would not learn anything more about the anti-viral properties of the compound from the documents referenced in the passage from the article set out at [78] above. These are all matters which the judge was entitled to take into account in considering whether Idenix had made good its case. I am satisfied that the judge was entitled to find that the paper did not make it common general knowledge that 2'-methyl-up-2'-hydroxy-down nucleoside analogues had the potential to be efficacious in treating HCV.

De Francesco et al (2003)

85. The second is another review article by Dr De Francesco and four other authors entitled "Approaching a new era for hepatitis C virus therapy: inhibitors of the NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase", Antiviral Research, 58, 1-16 (2003). This article was produced by Gilead and put to Dr Brancale in cross-examination. As the judge noted, its teaching about beta-D-2'-methyl-ribofuranosyl-guanosine (now identified as compound 11) is very much the same as that in the De Francesco and Rice article. The judge considered that it took Idenix no further forward and I agree with him.

Walker and Hong (2002)

86. The third is a review article by Michelle Walker and Zhi Hong, "HCV RNA-dependent RNA polymerase as a target for antiviral development", Current Opinion in Pharmacology, 2, 1-9 (2002). This article was produced by Idenix and put to Professor Götte in cross-examination. Both of the authors were leaders in the field, as Professor Götte accepted, but there was no evidence that this publication was routinely read by medicinal chemists or virologists interested in developing anti-HCV therapies.
87. The article says that the need for a cure for HCV infection has led many pharmaceutical companies to search for compounds with superior efficacy and nominal toxicity. It continues that several compounds have been identified which have the potential to inhibit various targets encoded by HCV and that a primary focus has been on finding inhibitors for the NS5B polymerase. A table of such polymerase inhibitors is provided on page 5 of the review, and one of the three illustrated examples is beta-D-2'-methyl-ribofuranosyl-guanosine, here identified as compound (c). However, the text explains that detailed biological information is not yet available, making it difficult to evaluate the mechanisms of action of this nucleoside. Again, therefore, this article does little to assist Idenix in making good its case on common general knowledge.

Walker, Hong et al (2003)

88. The fourth is another review article by Walker, Hong and three other authors, "Hepatitis C virus therapies: current treatments, targets and future perspectives", Antiviral Chemistry & Therapy, 14, 1-21 (2003).
89. This article was produced by Idenix and put to Professor Götte in cross-examination. Once again, he accepted that the authors were leading scientists in the field. However, just as in the case of Current Opinion in Pharmacology, the journal in which the earlier article by Walker and Hong appeared, there was no evidence that this journal was one which medicinal chemists or virologists interested in developing anti-HCV therapies would routinely read.
90. The article refers to various nucleoside analogues, four of which are depicted in figure 6. One of these is beta-D-2'-methyl-ribofuranosyl-guanosine and another is a very similar compound which has adenine as the nucleobase rather guanine. I also accept that there is a note of optimism in this article and that it describes the state of the work on HCV as having yielded the identification of new classes of compounds with great potential to serve as potent anti-HCV therapies. However, Professor Götte considered that the message of optimism was not referable specifically to 2'-methyl-up-2'-hydroxy-down nucleoside analogues.
91. Drawing the threads together thus far, the judge concluded that it had not been established that it was common general knowledge that 2'-methyl-up-2'-hydroxy-down nucleoside analogues had the potential to be efficacious in treating HCV. For the reasons I have summarised, this finding is unassailable. It therefore remains to consider the Carroll paper and the Savannah conference presentations.

Carroll et al (2003)

92. The fifth is a paper by Steven Carroll and 17 other authors entitled "Inhibition of Hepatatis C Virus RNA Replication by 2'-Modified Nucleoside Analogues", J. Biol. Chem., 278, 11979-11984. It was published online on 27 January 2003 and in print on 4 April 2003. It was not referred to by Dr Brancale in his first report but in his second report he said it was widely read and known.
93. The paper describes various 2' nucleoside analogues including beta-D-2'-methyl-ribofuranosyl-guanosine. The abstract refers to activity in the replicon assay and concludes:

"Thus, the 2'-modifications of natural substrate nucleosides transform these molecules into potent inhibitors of HCV replication."

94. The judge was not persuaded the contents of this article formed part of the common general knowledge at the priority date and the heart of his reasoning is contained in these two paragraphs of his judgment:

282. The Carroll paper was not referred to by Dr Brancale in his first report. (By contrast Prof Götte did refer to it in, and exhibit it to, his first report.) In his second report, Dr Brancale said (at paragraph 47) that the Carroll paper was "very widely read and known, not least because it was a peer reviewed article in a highly regarded scientific journal". In context, Dr Brancale was clearly suggesting that the Carroll paper had become common general knowledge by 27 June 2003, but his reasons for saying this are unconvincing, and even more so given that he did not mention it in his first report.

283. Furthermore, although Prof Götte agreed that the Journal of Biological Chemistry was one of the leading journals in the field and agreed that a biochemist with an interest in nucleoside research like himself would read it, there is no evidence that it was routinely read by all medicinal chemists with an interest in anti-HCV nucleoside research. Prof Götte accepted that the Carroll paper had subsequently come to be regarded as an important paper, but he did not agree that it was regarded as important at the time. He himself had read the Carroll paper at the time, but that was because it related to his research interests."

95. Mr Waugh submits the judge fell into error here in two respects: first, he wrongly took into account that the paper was not mentioned in the first round of Idenix's expert evidence; secondly, he applied too high a standard in holding that there was no evidence that the publication in which it appeared was routinely read by all medicinal chemists with an interest in anti-HCV research.
96. I do not find either of these criticisms persuasive. The judge was entitled to have regard to the fact that Dr Brancale did not mention this paper in his first report. Indeed, as we have seen, he said no more than that certain modified 2' nucleoside analogues were known to have anti-HCV activities. Furthermore, this was a paper which was published online only five months before the priority date and in print only three months before that date and there was no evidence that it was picked up and reported upon or was the subject of comment by others in either of those periods. It is true that Professor Götte agreed that the Journal of Biological Chemistry was a leading journal, but he also said that this was a paper that would have been of interest at that time to those workers who, like him, were working with and had focused their research upon nucleosides and nucleotides and their interactions with enzymes, and that the importance of the paper came to be appreciated over the years (and so, by implication, some time later) as more became known about these types of compounds. Against this background, it seems to me that the heart of the judge's reasoning is clear and accords with the evidence. He rejected Idenix's case based upon this paper because there was no evidence that, by the priority date, its contents had become generally known by the bulk of the wider community of medicinal chemists with an interest in anti-HCV research. This finding cannot be criticised.

The presentations at the Savannah conference

97. The 16th International Conference on Antiviral Research was held at Savannah, Georgia, USA between 27 April and 1 May 2003. It was a major conference attended by some 400 persons from academia and the pharmaceutical industry. However, as Dr Brancale accepted (and the judge recorded at [287]) it would not have been attended by all medicinal chemists with an interest in anti-HCV analogues. Indeed, although Dr Brancale attended it, Professor Götte did not.
98. Idenix rely upon the first three presentations on the third day of the conference. They were given by teams of authors from Merck and two other organisations:

i) Eldrup et al, "Structure Activity Relationship of 2' Modified Nucleosides for Inhibition of Hepatatis C Virus";

ii) Bhat et al, "Synthesis and Pharmacokinetic Properties of Nucleoside Analogues as Possible Inhibitors of HCV RNA Replication";

iii) Olsen et al, "2' Modified Nucleoside Analogs as Inhibitors of Hepatatis C RNA Replication".

99. Abstracts of these presentations were published at the conference and elsewhere at the end of April and they disclosed that a number of 2'-modified nucleosides had been identified as potent inhibitors of HCV, but they gave no indication of the nature of those 2'-modifications. For this reason Idenix focused on the disclosures made during the course of the presentations themselves. Dr Brancale was sufficiently interested in what he had heard to ask for copies of the authors' slides and he annexed them to his first report. Among them are slides showing that the authors presented data from a replicon assay demonstrating that 2'-C-Me-Adenosine and 2'-C-Me-Guanosine were potent inhibitors of HCV.
100. The judge observed that, although Dr Brancale was interested in these presentations, there was no evidence they attracted particular attention. He then expressed his conclusion in these terms:

"292. Dr Brancale's evidence was that, although the precise data presented in these presentations would not have been common general knowledge, he thought that the general message conveyed by them, namely that 2'-methyl-up-2'-hydroxy-down nucleoside analogues were showing very promising anti-HCV activity, would have been. Prof Götte disagreed. In my judgment the evidence falls a long way short of showing that even the general message conveyed by these presentations was common general knowledge by 27 June 2003. "

101. Mr Waugh submits that here the judge again fell into error because he had earlier focused upon the acceptance by Dr Brancale that the conference had not been attended by all medicinal chemists with an interest in anti-HCV nucleoside anologues. Moreover, continues Mr Waugh, this error permeated the judge's whole approach to the evidence, and is demonstrated by the questions he himself asked Dr Brancale. So, for example, he asked Dr Brancale whether all academics interested in HCV would have attended the conference.
102. I reject these criticisms. The Savannah conference took place only shortly before the priority date and lasted for four days. The presentations upon which Idenix relied took place early on its third day and were not identified as a highlight of the conference in the July 2003 edition of ISAR News, the newsletter of the International Society for Antiviral Research. Nor was there any evidence they were picked up in any other publication before the priority date. In these circumstances it was plainly relevant to consider what proportion of those medicinal chemists with an interest in anti-HCV nucleoside analogues attended the conference and the judge cannot be criticised for exploring this issue. Moreover, I can detect no error of approach in the way the judge arrived at his conclusion. At the end of the day he preferred the evidence of Professor Götte and I have no doubt he was entitled to hold that the general message conveyed by these presentations was not common general knowledge by the priority date.

Conclusion on common general knowledge

103. I would therefore reject this ground of appeal. I am satisfied the judge was entitled to hold that Idenix had not established that it was part of the skilled team's common general knowledge as at 27 June 2003 that 2'-methyl-up-2'-hydroxy-down nucleoside analogues had the potential to be efficacious in treating HCV.

Obviousness

104. Gilead contended that the claims in issue were invalid for obviousness because they made no technical contribution to the art. It was, it continued, simply not plausible that substantially all of the compounds falling within the scope of these claims would be effective against Flaviviridae.
105. The principles underpinning an objection of this kind were recently considered by the Court of Appeal in Generics (UK) Limited trading as Mylan v Yeda Research and Development Co. Limited [2013] EWCA Civ 925, [2014] RPC 121. The need for a technical contribution is inherent in the problem and solution approach adopted by the EPO, as Floyd LJ explained:

"37. Neither the European Patent Convention ("EPC") nor the Patents Act 1977 includes amongst the available grounds of invalidity of a granted patent an objection that the patent does not make a technical contribution to the art. However the "problem and solution" approach adopted by the EPO under the EPC to the ground of lack of inventive step necessarily involves isolating from the patent (in comparison with the prior art) some technical contribution or effect. The EPO adopt this approach in order to formulate a technical problem which is solved by the patent – achieving that technical effect – as a precursor to asking whether the patent solves that problem in an obvious or non-obvious way."

106. Floyd LJ then turned to the important decisions of the Boards of Appeal of the EPO in T 939/92 AgrEvo/Triazoles [1996] EPOR 171 and T 1329/04 Johns Hopkins University School of Medicine/ Growth Differentiation Factor [2006] EPOR 8 from which he derived these principles:

"39. As with any consideration of obviousness, the technical results or effects must be shared by everything falling within the claim under attack. This follows from the fundamental principle of patent law, which underpins many of the grounds of objection to validity, that the extent of the monopoly conferred by a patent must be justified by the technical contribution to the art. If some of the products covered by a claim demonstrate a particular property, but others do not, then the technical problem cannot be formulated by reference to that property. Either the products which do not exhibit the property must be excised from the claim by amendment, or the problem must be formulated by reference to some other, perhaps more mundane, technical contribution common to the whole claim."

107. It follows that the scope of the monopoly claimed must correspond to and be justified by the technical contribution or, put another way, everything falling in the scope of the claim must be inventive. In the case of a claim to a new class of chemical compounds, the selection of those compounds must not be arbitrary but justified by a technical effect which distinguishes the claimed compounds from many other compounds. Moreover, this technical effect must be shared by substantially all of the claimed compounds.
108. Importantly for present purposes, the decision of the Board in Johns Hopkins also addressed the question of the extent to which the technical effect needs to be supported by the evidence disclosed in the specification or can be established by later evidence. In that regard the Board said this at [12]:

"12. The appellant filed post-published evidence … establishing that GDF-9 was indeed a growth differentiation factor. This cannot be regarded as supportive of an evidence which would have been given in the application as filed since there was not any. The said post-published documents are indeed the first disclosures going beyond speculation. For this reason, the post-published evidence may not be considered at all. Indeed, to do otherwise would imply that the recognition of a claimed subject-matter as a solution to a particular problem could vary as time went by. Here, for example, had the issue been examined before the publication date of the earliest relevant post-published document, GDF-9 would not have been seen as a plausible solution to the problem of finding a new member of the TGF-Beta superfamily and inventive step would have had to be denied whereas, when examined thereafter, GDF-9 would have to be acknowledged as one such member. This approach would be in contradiction with the principle that inventive step, as all other criteria for patentability, must be ascertained as from the effective date of the patent. The definition of an invention as being a contribution to the art, i.e. as solving a technical problem and not merely putting forward one, requires that it is at least made plausible by the disclosure in the application that its teaching solves indeed the problem it purports to solve. Therefore, even if supplementary post-published evidence may in the proper circumstances also be taken into consideration, it may not serve as the sole basis to establish that the application solves indeed the problem it purports to solve."

109. The claimed technical effect must therefore be plausible in light of the teaching of the specification and the common general knowledge. The claimed technical effect cannot be established solely by post-published evidence.
110. Reverting to Mylan v Yeda, Floyd LJ then proceeded to consider the decision of the House of Lords in Conor Medsystems Ltd v Angiotech Pharmaceuticals Inc [2008] UKHL 49, [2008] RPC 28 and the decision of the Court of Appeal in Dr Reddy's Laboratories (UK) Ltd v Eli Lilly and Co Ltd [2009] EWCA Civ 1362, [2010] RPC 9 before summarising the position in these terms at [49]:

"49. I would summarise the position thus far in the following way:

(i) Article 56 of the EPC is in part based on the underlying principle that the scope of the patent monopoly must be justified by the patentee's contribution to the art;

(ii) If the alleged contribution is a technical effect which is not common to substantially everything covered by a claim, it cannot be used to formulate the question for the purposes of judging obviousness;

(iii) In such circumstances the claim must either be restricted to the subject matter which makes good the technical contribution, or a different technical solution common to the whole claim must be found;

(iv) A selection from the prior art which is purely arbitrary and cannot be justified by some useful technical property is likely to be held to be obvious because it does not make a real technical advance;

(v) A technical effect which is not rendered plausible by the patent specification may not be taken into account in assessing inventive step;

(vi) Later evidence may be adduced to support a technical effect made plausible by the specification;

(vii) Provided the technical effect is made plausible, no further proof of the existence of the effect is to be demanded of the specification before judging obviousness by reference to the technical effect propounded."

111. What then is meant by plausible in this context? I believe that helpful guidance was given by the Supreme Court in Human Genome Sciences, Inc v Eli Lilly & Co [2011] UKSC 51, [2012] RPC 6 in explaining the way in which the requirement of industrial applicability in Articles 52 and 57 of the EPC extends to a patent for biological material. Lord Neuberger, with whom the other members of the court agreed, summarised (at [107]) the principles to be derived from the decisions of the Boards of Appeal of the EPO and which should, he held, be taken as the law. As he there explained, the patent must disclose a practical application for the claimed product and that a plausible or reasonably credible claimed use or even an educated guess as to such a use could be sufficient for that purpose. On the other hand, a merely speculative use does not suffice.
112. Lord Hope, with whom Lord Walker, Lord Hope and Lord Clarke agreed, provided this further guidance at [149]:

"149 In paras.6–8 of its judgment in ZymoGenetics [T 0898/05] the TBA contrasted a product whose structure was given but whose function was undetermined or obscure or only vaguely indicated with one which was "definitely described and plausibly shown to be usable". In the former case, the granting of a patent might give the patentee unjustified control over others who were actively investigating in that area and who might eventually find ways to exploit it. In the latter, because it was plausibly shown to be "usable", it might be considered to display concrete benefits. As these benefits are assumed not yet to have been confirmed by research, the exercise that these passages indicate is necessarily one of prediction. That is why the Board used the word "plausibly". I would not quarrel with Jacob L.J.'s comment, after consulting the Shorter Oxford English Dictionary, that the sense that word conveys is that there must be some real reason for supposing that the statement is true: para.111. The important point, however, is that the standard is not any higher than that. Further experiments are not needed if sufficient information is provided in the description, when common general knowledge is taken into account, to show that a positive answer can be given to the question whether a profitable use can readily be identified: ZymoGenetics, para.20."

113. This question was also examined in the recent decision of the Court of Appeal in Warner-Lambert Company LLC v Generics (UK ) Ltd (trading as Mylan) and ors [2016] EWCA Civ 1006 in the context of an appeal against a finding that Swiss claims (claims to the use of a product to make a medicine for a particular therapeutic purpose) were insufficient. Floyd LJ referred to the decisions of the Boards of Appeal of the EPO in T 0609/02 Salk Institute for Biological Studies, Johns Hopkins and AgrEvo/Triazoles, the decision of the House of Lords in Conor and the decision of the Supreme Court in Human Genome Sciences before summarising the position in this way at [46] to [47]:

"46. The EPO and domestic cases do, however, indicate that the requirement of plausibility is a low, threshold test. It is designed to prohibit speculative claiming, which would otherwise allow the armchair inventor a monopoly over a field of endeavour to which he has made no contribution. It is not designed to prohibit patents for good faith predictions which have some, albeit manifestly incomplete, basis. Such claims may turn out to be insufficient nonetheless if the prediction turns out to be untrue. A patent which accurately predicts that an invention will work is, however, not lightly to be revoked on the ground that the prediction was based on the slimmest of evidence. Thus, the claims will easily be seen not to be speculative where the inventor provides a reasonably credible theory as to why the invention will or might work. The same is true where the data in the specification is such that the reader is encouraged to try the invention.

47. We heard argument as to whether the invention is only to be treated as plausible if the reader of the specification would be encouraged to try the invention with a reasonable prospect of success, thereby bringing the test for plausibility into line with that sometimes used in the context of obviousness. I do not accept that there is any reason to align the tests in this way. A test designed to prevent speculative claiming need go no further than requiring the patentee to show that the claim is not speculative: the specification does not need to provide the reader with any greater degree of confidence in the patentee's prediction than that."

114. In my judgment the same approach should be adopted in considering obviousness and whether a technical effect is plausible in the light of the teaching in the specification and the common general knowledge. There must be a real reason for supposing that the claimed invention will indeed have the promised technical effect.
115. Arnold J began his assessment with three preliminary points. The first was that the claims of the Application were, as he put it, stupendously broad. He continued:

"444. …They could well have covered as many as a trillion compounds. Furthermore, it was common ground between Prof Götte and Dr Brancale that it was not plausible that all the compounds claimed would be effective against Flaviviridae. Counsel for Gilead characterised the Application as a "land grab", and in my view that is a fair description. It does not necessarily follow that the Patent is invalid, however."

116. Secondly and importantly, it was common ground that, so far as the compound claims were concerned, inventive step should be assessed not on the basis that they were just claims to compounds, but rather on the basis that they were claims to compounds with anti-Flaviviridae activity. As Arnold J observed, were it otherwise they would lack an inventive step on the basis that the only technical problem they solved was the provision of additional nucleoside analogues.
117. Thirdly, it was Idenix's case that the compounds of claim 1 could be made by the skilled team without undue difficulty and using conventional techniques. Arnold J assumed for the purpose of assessing inventive step that Idenix was correct on this issue.
118. Arnold J then turned to the claims and began with claim 1 of the Patent as granted. He held that, considered as at the priority date, it was not plausible that substantially all of the compounds covered by the claim had anti-Flaviviridae activity. It followed that the claim covered compounds which made no technical contribution to the art.
119. In my opinion this finding was inevitable in light of the evidence of Dr Brancale which the judge summarised in these terms at [447]:

"447. … Claim 1 of the Patent is much narrower in scope than the claims in the Application. Nevertheless, it still covers a very large number of compounds, on a conservative estimate at least 50 billion compounds. Gilead contend that, considered as at 27 June 2003, it was not plausible that substantially all the compounds covered by claim 1 would be effective against Flaviviridae. I can deal with this contention quite shortly, because it is Idenix's own evidence that claim 1 covers classes of compounds which it was not plausible would be effective. Dr Brancale expressed the opinion in paragraphs 201-202 of his first report that compounds of Formula (IX) would not have been thought likely to have antiviral activity where R¹ and R² were either "straight chained, branched or cyclic alkyl" or "benzyl, wherein the phenyl group is optionally substituted with one or more substituents". It was for this reason that Idenix made their conditional application to amend."

120. That brought the judge to claim 1 as proposed to be amended. He held once again that the skilled team would not have considered it plausible that substantially all of the compounds covered by this claim would have anti-Flaviviridae activity. His eleven reasons for reaching that conclusion merit recitation in full:

"451. First, the Patent contains no experimental data to suggest that any of the claimed compounds may be effective. The only experimental data is in Example 26, but that example (i) is expressly acknowledged to relate to a compound which falls outside the claim, (ii) relates to an unidentifiable compound which does not appear to contain fluorine and (iii) does not establish that the compound has any potentially therapeutically useful activity.

452. Secondly, the Patent contains no rationale for the assertion that the claimed compounds may be effective. On the face of the Patent, the assertion appears to be nothing more than speculation.

453. Thirdly, the specification adds nothing to the common general knowledge of the skilled team as to what nucleoside analogues might exhibit Flaviviridae, and in particular anti-HCV, activity. It was known in June 2003 that certain nucleoside analogues could inhibit replication in certain viruses, since such analogues had been used successfully in HIV and HBV therapy. It was also known that NS5B was a potential target for direct acting nucleoside analogues and this was an area of active research. Accordingly, as a matter of common general knowledge, it was plausible that as yet untested nucleoside analogues might exhibit anti-HCV activity through their effect on NS5B. The Patent contains nothing which makes this more plausible. Still less does it contain anything to make it more plausible that the compounds claimed in claim 1 – as opposed to, for example, other compounds claimed in the Application – might exhibit such activity. In particular, the passage at [0022(10)] (corresponding to page 9 line 29 – page 10 line 24 of the Application, quoted in paragraph 181 above) which is relied on by Idenix does not do so. As I have said, it is simply part of the recitation of prior art and it does not identify the 2'-modified nuclesides [sic] which were the subject of the Eldrup, Bhat and Olsen presentations at the Savannah conference.

454. Fourthly, Idenix's attempt to fill the gaps in the specification by raising the level of the skilled team's common general knowledge was unsuccessful. Idenix's case on plausibility as presented in counsel for Idenix's closing submissions started from the premise that it was common general knowledge that the 2'-methyl-up-2'-hyxroxy-down nucleoside analogues being investigated by Merck which were the subject of the Carroll paper and the presentations at the Savannah conference had activity in the HCV replicon and acted as chain terminators of the HCV RNA-dependent RNA polymerase. I have found that this was not the case.

455. Fifthly, even if Idenix's attempt to fill the gaps in the specification by raising the level of the skilled team's common general knowledge had succeeded, it would have been self-defeating. Even if it was correct that, for example, the Carroll paper was common general knowledge, and therefore the skilled team would bring that knowledge to their reading of the Patent, it would remain the case that the Patent added nothing to their knowledge. If it was plausible in the light of the information in the Carroll paper that the claimed compounds would be effective, that would not demonstrate that the Patent had made any technical contribution to the art.

456. Sixthly, counsel for Idenix relied on the fact that Prof Götte had accepted that the compounds claimed in claims 9-11 of the Application were highly structurally related to the Merck 2'-methyl-up-2'-hydroxy-down compounds. This does not assist Idenix, however. Prof Götte was clear that this did not make it plausible that the claimed compounds would be effective against HCV, rather this had to be tested. Furthermore, it was part of the skilled team's common general knowledge that small structural changes could have a substantial effect on activity and/or toxicity. Still further, as I have explained, Idenix failed to establish that the skilled team would have regarded fluorine as an isostere for a hydroxyl group. On the contrary, the skilled team would have appreciated that substituting fluorine for hydroxyl could seriously affect the properties of the molecule, and in particular its biological activity.

457. Seventhly, counsel for Gilead pointed out that counsel for Idenix had approached his cross-examination of Professor Götte by asking whether compounds with the structure of claim 10 of the Application "would at least be plausible in the sense of worth testing". He submitted this could not be the right question and that an affirmative answer could not provide a basis for patentability. As Prof Götte explained, because the art in 2003 was largely empirical, almost any nucleoside analogue was worth testing. Thus the question was merely restating the common general knowledge. I agree with this.

458. Eighthly, when the specification tells the skilled team at [0042] (corresponding to page 38 lines 17-21 of the Application, quoted in paragraph 188 above) that the nucleosides of the invention "may inhibit Flaviviridae polymerase activity" and "can be screened" for such activity using known assays, the specification is simply inviting the skilled team to carry out a screening programme to find out for themselves whether the nucleosides have activity or not. If they do that and find something that works, Idenix claim it.

459. Ninthly, Dr Brancale conceded in paragraph 196 of his first report that the effectiveness of the 2'-methyl-up-2'-fluorine-down substitution which is the key feature of the claimed compounds could not have been predicted in June 2003 on the basis of what was known. Furthermore, he accepted in cross-examination that his opinion that it was plausible that compounds with that substitution would be effective anti-HCV agents was not based on anything in the Patent, but upon what other people had published. Still further, as explained above, Dr Brancale's evidence on this topic has to be approached with caution given his belief that claims could be supported by data which the patentee had kept hidden.

460. Tenthly, there is evidence that, if the skilled team did make and test the claimed compounds, they would not necessarily get a positive result if they then tested such compounds using the BVDV-based assays described in the Patent. The Clark Paper records in Table 2 that 2'-deoxy-2'-fluoro-2'-C-methylcytidine is inactive in the BVDV assay.

461. Lastly, even if a compound tested positive against BVDV in such an assay, the skilled team would know that this was not predictive of activity against other Flaviviridae, and in particular HCV. Thus the Clark Paper records that 2'-deoxy-2'-fluoro-2'-C-methylcytidine was active against HCV in the replicon assay."

121. Mr Waugh has vigorously attacked this reasoning. He contends that Arnold J erred in principle in a number of different ways, the first being that he failed properly to consider whether the skilled team would have had reason to believe that the compounds covered by the claim would have anti-Flaviviridae activity and instead set the bar too high. In particular, continues Mr Waugh, the judge wrongly approached the issue on the basis that experimental data were required and that the absence of any such data was fatal to validity.
122. I am quite unable to accept these submissions. Arnold J directed himself by reference to the authorities and then sought to determine whether the skilled team would have considered it plausible that substantially all of the compounds covered by the claims would have anti-Flaviviridae activity. There is nothing in his reasoning to suggest that in so doing he failed properly to understand the meaning of the word 'plausible' in this context. Indeed he cited the critical part of paragraph [149] of the judgment of Lord Hope in Human Genome Sciences, Inc v Eli Lilly & Co. Moreover, he was plainly entitled to take into account the fact that the Patent contains no experimental data to suggest that any of the claimed compounds might be effective. This was relevant to but not determinative of the issue before him and was just one of the matters which led him to his ultimate conclusion.
123. Mr Waugh contends, secondly, that Arnold J fell into error in that he failed to appreciate that the technical contribution of the Patent is the identification of a class of nucleoside analogues, characterised by 2'-methyl-up-2'-fluoro-down substituents on the sugar moiety, which are promising candidates for the treatment of HCV or other Flaviviridae infections. Moreover, Mr Waugh continues, the 2'-methyl-up-2'-fluoro-down motif constitutes the pharmacophore or critical structural feature which confers upon the claimed molecules their activity, and that this feature in and of itself amounts to a technical contribution which renders these molecules non-obvious and merits patent protection. Furthermore, says Mr Waugh, it was entirely plausible that this motif would confer activity upon the claimed molecules in light of the contents of the specification and the common general knowledge that 2'-methyl-up-2'-hydroxy-down nucleoside analogues were known to be promising candidates for use in anti-HCV therapy and had potent activity. In further support of this submission, Mr Waugh referred us to various passages in the evidence, including parts of the cross-examination of Professor Götte in which he accepted first, that the 2'-methyl-up-2'-hydroxy-down analogues described in the Carroll paper and discussed at the Savannah conference were structurally highly related to the analogues claimed in the Patent; and secondly, that, in light of the Carroll paper and the work presented at the Savannah conference, 2'- modifications would be one place to start to look for active analogues and that the Carroll paper would provide a rationale for doing so.
124. In my judgment these submissions founder for a number of reasons. At the outset it is, I think, important to have in mind the critical question in relation to the compound claims, namely whether it was plausible that substantially all of the compounds covered by those claims would have anti-Flaviviridae activity. It was common ground that the issue of inventive step should be assessed on this basis.
125. Secondly, I accept that all of the claimed compounds have 2'-methyl-up-2'-fluorine-down substituents but, as the judge explained, there is nothing in the specification by way of experimental data to suggest that substantially all of these compounds are effective against Flaviviridae. The only example which contains any experimental data is Example 26 but this is outside the scope of the claims and is, in any event, uninformative for the reasons the judge gave. Moreover, there is nothing in the specification by way of a theory or rationale as to why the claimed compounds may be effective. Indeed, the limited nature of the prediction the patentees were themselves prepared to make is apparent from the statements in the specification that "the nucleosides of the invention may inhibit Flaviviridae polymerase activity" and that these nucleosides "can be screened for their ability to inhibit Flaviviridae polymerase activity in vitro according to screening methods set forth more particularly herein". In short, as the judge put it, on the face of the Patent, the assertion that the claimed compounds may be effective appears to be no more than speculation.
126. Thirdly, the common general knowledge provides Idenix with only limited assistance. In June 2003 it was known that certain nucleoside analogues could be used to treat HIV, HBV, herpes and cytomegalovirus. It was also known that the non-structural protein NS5B was essential for mediating the replication of the HCV viral genome, that NS5B had been identified as a target for the development of anti-viral therapies and that the inhibition of NS5B was an area of active research. On the other hand, it was also a matter of common general knowledge that so little was known of the ternary structure of NS5B and its substrates that it was not possible to predict from the structure of a nucleoside analogue whether it would be effective. In the result, the development of analogues to inhibit NS5B was known to be largely empirical.
127. Fourthly, the attempt by Idenix to establish that the contents of the Carroll paper and the presentations made at the Savannah conference were matters of common general knowledge failed. The judge held, and for the reasons I have given was entitled to hold, that it was not a matter of common general knowledge that 2'-methyl-up-2'-hydroxy-down nucleoside analogues had the potential to be efficacious in treating HCV. Nor would this have been apparent to the reader of that part of the Application and the Patent recited at [44] above. There is nothing here which would identify for the reader the 2' nucleoside analogues the subject of the Eldrup, Bhat and Olsen presentations.
128. Fifthly, it is true that Professor Götte accepted that the 2'-methyl-up-2'-hydroxy-down analogues described in the Carroll paper and discussed at the Savannah conference were structurally highly related to the analogues claimed in the Patent, but he also made it quite clear that any such analogues would have to be tested and that there was no way to predict anti-viral activity in advance of such testing. Indeed, he continued, absent testing, any such prediction would be a matter of speculation. These important qualifications are also apposite to the evidence Professor Götte gave to the effect that, in light of the Carroll paper and the work presented at the Savannah conference, 2'- modifications would be one place to start to look for active analogues and that the Carroll paper would provide a rationale for doing so. This is far from an acceptance that it was plausible that the claimed analogues would have activity. Moreover, I am satisfied that the judge's finding that the skilled team would have appreciated that substituting fluorine for hydroxyl in the 2'- position could seriously affect the properties of the analogue, including its biological properties, was properly founded in the evidence.
129. In my judgment Idenix has not identified any error of principle in the way the judge addressed the issue of obviousness and I have no doubt that he was entitled to reach the conclusion he did on the evidence before him. No basis has been shown upon which this court can interfere with his finding that it was not plausible that substantially all of the compounds covered by claim 1 as proposed to be amended would have anti-Flaviviridae activity.
130. Mr Waugh has not advanced any argument which would support the independent validity of any of the subsidiary claims relied upon if claim 1, as proposed to be amended, is invalid. Accordingly, I would dismiss the appeal against the finding that the Patent is invalid for obviousness.

Insufficiency

131. There were three insufficiency attacks upon the Patent, each of which succeeded: first, the disclosure of the Patent, read in light of the common general knowledge, did not make it plausible that the invention would work across the scope of the claims, whether as granted or as proposed to be amended; secondly, the Patent did not enable the skilled team to perform the invention without undue burden because it did not enable them to make any of the 2'-methyl-up-2'-fluoro-down analogues claimed without undue effort; and thirdly, the invention could not be performed across the breadth of the claims without undue burden because making and testing the analogues to find those which were active would amount to a research project.
132. I will explain the reasons for the judge's findings in relation to each of these attacks and address the various criticisms made of those reasons by Idenix but first I must set out the relevant legal principles.

The legal principles

133. I summarised the general principles of the law of insufficiency in Eli Lilly v Human Genome Sciences [2008] EWHC 1903 (Pat), [2008] RPC 29 at [239]:

"239. The specification must disclose the invention clearly and completely enough for it to be performed by a person skilled in the art. The key elements of this requirement which bear on the present case are these:

(i) the first step is to identify the invention and that is to be done by reading and construing the claims;

(ii) in the case of a product claim that means making or otherwise obtaining the product;

(iii) in the case of a process claim, it means working the process;

(iv) sufficiency of the disclosure must be assessed on the basis of the specification as a whole including the description and the claims;

(v) the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification;

(vi) the specification must be sufficient to allow the invention to be performed over the whole scope of the claim;

(vii) the specification must be sufficient to allow the invention to be so performed without undue burden."

134. I elaborated upon those principles in Regeneron Pharmaceuticals Inc and Bayer Pharma AG v Genentech Inc [2013] EWCA Civ 93, [2013] RPC 28 at [95] to [103]. The following points are material to this appeal.
135. The extent of the disclosure necessary to make the patent sufficient depends upon the nature of the invention, the scope of the claims and the art in which the invention is made, as I explained in Regeneron at [97]:

"97. … the question whether the specification adequately discloses the invention is one of degree. I put it this way in Novartis AG v Johnson & Johnson Medical Ltd [2009] EWHC 1671 in a passage cited by the judge in this case:

"236. Whether the specification discloses an invention clearly and completely enough for it to be performed by a person skilled in the art involves a question of degree. It is impossible to lay down any precise rule because the degree of clarity and completeness required will vary depending on the nature of the invention and of the art in which it is made. On the one hand, the specification need not set out every detail necessary for performance. The skilled person must be prepared to display a reasonable degree of skill and use the common general knowledge of the art in making routine trials and to correct obvious errors in the specification, if a means of correcting them can readily be found. Further, he may need to carry out 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. On the other hand, he should not be required to carry out any prolonged research, enquiry or experiment: Mentor Corporation v Hollister Inc. [1993] R.P.C. 7.""

136. The sensitivity of the requirement of enablement to the nature of the invention and the claim in issue is well illustrated by the case of a claim to the use of a product to make a medicine for a particular therapeutic purpose. I said this in Regeneron at [103]:

"103. … the Boards of Appeal of the EPO have recognised that in the case of a claim to the use of a product to make a medicine for a particular therapeutic purpose it would impose too great a burden on the patentee to require him to provide absolute proof that the compound has approval as a medicine. Further, it is not always necessary to report the results of clinical trials or even animal testing. Nevertheless, he must show, for example by appropriate experiments, that the product has an effect on a disease process so as to make the claimed therapeutic effect plausible. It was put this way in T609/02 Salk at [9]:

"…It is a well-known fact that proving the suitability of a given compound as an active ingredient in a pharmaceutical composition might require years and very high developmental costs which will only be borne by the industry if it has some form of protective rights. Nonetheless, variously formulated claims to pharmaceutical products have been granted under the EPC, all through the years. The patent system takes account of the intrinsic difficulties for a compound to be officially certified as a drug by not requiring an absolute proof that the compound is approved as a drug before it may be claimed as such. The boards of appeal have accepted that for a sufficient disclosure of a therapeutic application, it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported. Yet, this does not mean that a simple verbal statement in a patent specification that compound X may be used to treat disease Y is enough to ensure sufficiency of disclosure in relation to a claim to a pharmaceutical. It is required that the patent provides some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se. Showing a pharmaceutical effect in vitro may be sufficient if for the skilled person this observed effect directly and unambiguously reflects such a therapeutic application (T 241/95, OJ EPO 2001, 103, point 4.1.2 of the reasons, see also T 158/96 of 28 October 1998, point 3.5.2 of the reasons) or, as decision T 158/96 also put it, if there is a "clear and accepted established relationship" between the shown physiological activities and the disease (loc. cit.). Once this evidence is available from the patent application, then post-published (so-called) expert evidence (if any) may be taken into account, but only to back-up the findings in the patent application in relation to the use of the ingredient as a pharmaceutical, and not to establish sufficiency of disclosure on their own.""

137. It is permissible for a claim to describe an invention in general terms provided it is plausible in light of the disclosure and the common general knowledge that the invention will work with anything falling within the scope of those terms. I put it this way in Regeneron at [98] to [101]:

"98. … it is permissible to define an invention using general terms provided the patent discloses a principle of general application in the sense that it can reasonably be expected the invention will work with anything falling within the scope of these terms. As Lord Hoffmann said in Biogen Inc. v Medeva plc [1977] R.P.C. 1 at pp.48–49:

"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 patent 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."

99 . In Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2004] UKHL 46, [2005] RPC 9 Lord Hoffmann further explained the concept of a principle of general application in this way:

"112. In my opinion there is nothing difficult or mysterious about [a principle of general application]. 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."

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."

138. The meaning of the term plausible in this context was explained by Floyd LJ in the passages from the decision in Warner-Lambert v Generics which I have cited at [113] above.
139. Finally, it is in particular circumstances permissible to limit a claim by adding a functional requirement but it must still be possible to perform the invention across the scope of the claim without undue effort. I dealt with this is Regeneron at [102]:

"102. … patentees not infrequently seek to avoid the possibility that a claim covers products or methods which do not work by inserting a functional limitation. Such a claim may be allowed by the EPO if the invention can only be defined in such terms or cannot otherwise be defined more precisely without unduly restricting its scope. But, it must still be possible to perform the invention across the scope of the claim without undue effort. As I said in Novartis v Johnson & Johnson at [244]:

"…In the case of a claim limited by function, it must still be possible to perform the invention across the scope of the scope of the claim without undue effort. That will involve a question of degree and depend upon all the circumstances including the nature of the invention and the art in which it is made. Such circumstances may include a consideration of whether the claims embrace products other than those specifically described for achieving the claimed purpose and, if they do, what those other products may be and how easily they may be found or made; whether it is possible to make a reasonable prediction as to whether any particular product satisfies the requirements of the claims; and the nature and extent of any testing which must be carried out to confirm any such prediction.""

Plausibility

140. The judge addressed this in one paragraph. He held that, for the reasons he had given in relation to obviousness, the disclosure of the Patent, read with the benefit of the common general knowledge, did not make it plausible that the invention would work across the scope of the claims. Accordingly, all of the claims were invalid for insufficiency. In my judgment this finding was inevitable and correct.

Undue burden to perform the invention

141. As the judge explained at [470], Gilead alleged that the Patent did not adequately enable the skilled team to perform the invention of claim 1 because it did not enable them to synthesise the 2'-methyl-up-2'-fluoro-down compounds claimed without undue burden. The allegation was focused upon the 2'-methyl-up-2'-fluoro-down substituents on the ribose ring; Gilead did not contend that the skilled team would have any difficulty making a molecule with the other substituents covered by the Markush formula in claim 1.
142. The judge addressed this allegation in a lengthy section of his judgment extending from [470] to [594]. He gave careful consideration to the teaching of the Patent, the expert evidence of Professor Boons and Dr Brancale, the evidence of numerous attempts by scientists at Idenix to synthesise 2'-methyl-up-2'-fluoro-down nucleoside analogues, the evidence of the work of Mr Clark and other chemists at a company within the Pharmasset group of companies (collectively "Pharmasset"), and to certain experiments carried out by Idenix for the proceedings and upon which the experts expressed their opinions. It is convenient to give an outline of the judge's findings, reasoning and conclusions before addressing the arguments and contentions advanced by Idenix upon this aspect of the appeal.

The Patent

143. I begin with the Patent. It was common ground that the Patent does not contain any instructions for synthesising any of the 2'-methyl-up-2'-fluoro-down compounds claimed. However, Idenix argued that schemes 3 and 4 (see [52] to [55] above) do give the skilled team some assistance because they disclose synthetic pathways to 2'-methyl-up-2'-hydroxy-down compounds. Idenix also relied upon the fact that the specification identifies organolithium as one of the possible reagents for making such compounds from precursors with a ketone at the 2' position.
144. The judge was not impressed, for the reasons he gave at [571] to [573]:

"571. In my judgment, however, the specification gives the skilled person little assistance. First, as Prof Boons pointed out, if the skilled person studied the text accompanying Schemes 3 and 4 (at [0117]-[0121] corresponding to page 123 line 1 – page 124 line 3 of the Application, quoted in paragraph 206 above, and [0122]-[0125]), he would wonder if it was written by someone who knew what they were talking about. The specification describes the production of the ketone by an oxidation step. Among the possible oxidising agents listed in the specification for this reaction, however, are Jones' reagent, an aggressive mixture of chromic acid and sulphuric acid which one would not use on a nucleoside, Collins' reagent and Corey's reagent, which again are aggressive reagents, and Raney nickel, which is a reducing agent, not an oxidising agent. I should say that counsel for Idenix objected in his closing submissions that this evidence was given in response to a question which I asked Prof Boons. I do not accept that objection, since my question arose out of counsel's cross-examination and Prof Boons' evidence. More importantly, counsel submitted that Gilead had not taken any point about the oxidation reaction. That is true, but Gilead do contend that the specification does not assist the skilled person to synthesise the claimed compounds.

572. Secondly, organolithium is just one of a list of possible reagents. Furthermore, no specific mention is made of methyl lithium, still less are appropriate reaction conditions given, nor is any reference given to Matsuda II.

573. Thirdly, even if the skilled person proceeds down this path, he is still faced with the problem of how to achieve stereospecific fluorination of the tertiary carbon. The specification gives the skilled person no assistance with this whatsoever. On their face, where R⁶ is methyl, Scheme 3 and Scheme 4 produce a 2'-methyl-up-2'-hydroxy-down compound. Fluorinating that compound would require retention of the stereochemistry, which would rule out an S_N2 reaction. In fact, however, organolithium reagents are generally not stereoselective, and so the product of the methylation reaction would be expected to be a mixture of isomers. It should then be possible to separate out the 2'-methyl-down-2'-hydroxy-up compound, which in principle it should be possible to fluorinate with inversion of the stereochemistry by an S_N2 reaction. But the specification says nothing about this, and the skilled person is left to work it out for himself. The skilled person is also left to find a fluorinating agent and reaction conditions which will achieve stereospecific fluorination of the tertiary carbon, rather than one of the competing reactions such as elimination."

145. He therefore concluded that the Patent did not give any real assistance to the skilled team seeking to make the claimed 2'-methyl-up-2'-fluoro-down nucleoside analogues.

The experts

146. The experts were agreed that, before starting the synthesis of a new compound, the medicinal chemist would first work out the possible reaction routes leading to it, usually using a retrosynthetic analysis, that is to say, approaching the synthesis back to front. That said, there was a marked difference between them as to how easily that could be done.
147. Dr Brancale expressed the view that it could be done in a few months. The skilled chemist would consider the two routes generally shown in figures 3 and 4 of the Patent and described in the accompanying text. One would be to start from the simple D-ribose derivative and subsequently introduce the necessary modifications at the 2' position and the desired nucleobase, and the other would be to start from the D-nucleoside and subsequently carry out the necessary modifications at the 2' position of the sugar moiety. Following the sugar route, the first step would be to oxidise 2'-carbon to produce a ketone; then the methyl group at the 2' position would be introduced using a methylation agent such as methyl lithium; the two resulting isomers would then be separated by standard methods; and finally, as the third reaction step, a fluorination agent, such as DAST, as described in the well-known text book by March, Advanced Organic Chemistry: Reactions, Mechanisms (5^th ed, 2001), or Deoxo-Fluor, would be used to provide the nucleophilic fluorine. Following the nucleoside route, the skilled medicinal chemist would follow the method of Matsuda et al, "Radical Deoxygenation of Tert-Alcohols in 2'-Branched-Chain Sugar Pyrimidine Nucleosides: Synthesis and Antileukemic Acitivity of 2'-Deoxy-2' (S)-Methylcytidine", Chem. Pharm. Bull., 35, 3967-3970 (1987) - referred to by the judge as "Matsuda I" - again followed by nucleophilic fluorination using DAST or Deoxo-Fluor.
148. The judge did not find Dr Brancale's evidence persuasive and that was so for the reasons he set out from [577] to [584]. Those reasons were, in outline, these. First, the evidence was inevitably tainted by hindsight because Dr Brancale had read an important paper by Mr Clark, to which I refer at [160] below, before conducting his retrosynthetic analysis. Secondly, he had mentioned nothing in his report about the particular challenges of fluorinating a tertiary carbon atom (that is to say a carbon atom attached to three other carbon atoms) such as that at the 2' position. Thirdly, although he gave evidence that the first thing the skilled person would do would be to undertake a literature search, he gave no evidence as to what the result of that search would be. Fourthly, it was far from clear that any relevant Matsuda paper would have been found on a literature search. Fifthly, although DAST was indeed described in March as being an important reagent which converts primary, secondary and tertiary alcohols to fluorides in high yields under mild conditions, March also said, and Dr Brancale accepted, that tertiary substrates seldom undergo nucleophilic substitution at all and that elimination is always a possible side reaction, and with tertiary substrates usually predominates. Indeed, it continued, with a few exceptions, nucleophilic substitutions at a tertiary carbon have little or no preparative value.
149. As for Professor Boons, he was of the view that the task of making any of the claimed compounds would have been a research project which represented a significant challenge and would have had an uncertain outcome. The judge accepted his evidence, which he summarised in these terms at [585]:

"585. Prof Boons' opinion in summary was that making any of the claimed compounds was a research project which represented a significant synthetic challenge and which was of uncertain outcome. He had conducted a literature search on the synthesis of 2'-methyl-2-fluoro nucleosides, and had found that no such synthesis of such a compound, regardless of stereochemistry, had been reported by June 2003. There was literature relating to 2'-methyl sugars/nucleosides and, separately, to 2'-fluoro nucleosides, but it would not have been thought possible to combine these teachings. A major difference between what had been reported and what needed to be accomplished was the nature of the fluorine at the 2' position: synthesis of a secondary fluorine at the 2' position had been reported, but not the synthesis of a tertiary fluorine at the 2' position. The tertiary fluorine would fundamentally alter the reaction pathways compared to a nucleoside with a secondary fluorine at the 2' position. The skilled person undertaking a retrosynthetic analysis would have been confronted with a number of possible routes, all of which would have had potential difficulties associated with them, and the skilled person would not have known in advance which, if any, might have led successfully to the product. Nucleophilic substitution of a tertiary alcohol was just one possible step on one of these routes, but it was known to be difficult with competing reactions, including elimination and migration reactions. In addition to nucleophilic substitution, it was also known that fluorination could be attempted using electrophilic addition, but again this would be difficult to control. Accordingly, if asked to carry out this project, Prof Boons would have asked for a year's funding for a post-doctoral worker, would not have considered that success could be predicted and would have considered a successful synthesis worthy of publication in a peer-reviewed journal. Prof Boons formed this view before he knew about the numerous failed attempts by Dr Griffon. He subsequently reviewed various documents relating to these attempts, and concluded that they reflected a project of significant complexity with numerous failures, very much along the lines he had anticipated."

Dr Griffon

150. Dr Griffon, a Research Scientist in the Idenix nucleoside analogues group, was assigned the task of making a 2'-methyl-up-2'-fluoro-down nucleoside analogue at an Idenix chemistry team meeting in the University of Montpellier (where Idenix had a laboratory) on 28 March 2002. This meeting was attended by, among others, Dr Dick Storer (his supervisor and Senior Vice-President of Chemistry at Idenix) and Dr Gosselin (Dr Griffon's former PhD supervisor and the Director of Research at Idenix's Montpellier laboratory). Dr Storer and Dr Gosselin were, the judge held, highly experienced research chemists.
151. Over the course of the next two years, Dr Griffon tried eleven different strategies for making a 2'-methyl-up-2'-fluoro-down nucleoside analogue. By December 2002, Dr Griffon had tried three strategies, each of which had failed. On 2 December, a meeting took place between Dr Griffon, Dr Storer, Dr Adel Mousa (also of Idenix) and Professor Fleet of Oxford University. At this meeting the efforts made by Dr Griffon were discussed and suggestions were made as to how to take the project forward.
152. Further suggestions were made by Professor Fleet in January 2003. In that same month, Dr Storer wrote to Dr Paul Coe, an organofluorine expert at the University of Birmingham, asking for his assistance in relation to work on targets which involved fluorine. There followed work by Dr Griffon both with a modification of the third strategy and with a fourth and fifth strategy, all of which failed.
153. In February 2003, Dr Griffon began to follow a new strategy, his sixth, which was explained by the judge at [488]:

"Having tried and failed with his first five strategies, Dr Griffon commenced a new approach in February 2003, which involved making a 3'-5'-protected 2'-hydroxy-up-2'-methyl-down nucleoside and then fluorinating it using Deoxo-Fluor ("Strategy 6"), as shown below.

[Diagram or picture not reproduced in HTML version - see original .rtf file to view diagram or picture] Strategy 6"
154. He made various attempts to carry out the fluorination step, the first of which was described by the judge in these terms:

"492. Dr Griffon first attempted the fluorination step on 13 February 2003. He proceeded to deprotect the hydroxyl groups before attempting to separate and analyse the reaction products. He completed his analysis of the reaction products on 17 February 2003. He monitored the reaction using TLC, first viewing the plate under UV light and then staining it with 10% sulphuric acid in methanol and heating it. He pasted into his laboratory notebook the stained TLC plates for the crude reaction mixture (i) after 5½ hours, (ii) after leaving the reaction overnight and (iii) after deprotection. The last of these three appears to show four main spots which charred with the staining and two very small spots which had been visible under UV, and had been circled in pencil by Dr Griffon, but which did not char. Dr Griffon then analysed the mixture by analytical HPLC. He then separated the crude reaction mixture using silica gel chromatography into three components. The first component he presumed to be the uracil base. The second component, which appeared to be the major product, he analysed by MS, ¹H and ¹⁹F NMR. This turned out to be the 2' ethenyl derivative i.e. the elimination product. The third component he presumed to be the deprotected starting material. He recorded his work, including the analytical data, on pages 12 and 14 of his laboratory notebook for that period."

155. Dr Griffon repeated the reaction using slightly different conditions and in due course reported that one new compound had been formed, the 2'-ethenyl derivative referred to by the judge in the passage of his judgment cited immediately above, and concluded the strategy had failed. Nevertheless, Idenix contended at trial that the products of the reaction (described on page 12 of Dr Griffon's notebook) did in fact include the desired 2'-methyl-up-2'-fluoro-down nucleoside analogue and it was to this that its litigation experiments were directed, as I shall explain. There is one other matter I must mention. Dr Griffon did not use DAST for the fluorination step because he did not think it would work.
156. In April 2003 Dr Griffon and another colleague attended a course called "Making and Using Fluoroorganic Molecules" given by two academics from the University of Leicester. A number of different fluorination reagents were discussed, including DAST. In that same month, Dr Coe responded to the letter sent to him by Dr Storer in February. He suggested four schemes for the synthesis of 2'-methyl-up-2'-fluoro-down nucleoside analogues, none of which involved nucleophilic fluorination of a tertiary alcohol on a sugar with DAST.
157. Over the course of the next few months, Dr Griffon tried two of the schemes suggested by Dr Coe. These, his seventh and eighth strategies, also failed. In November 2003 the project was temporarily abandoned. In February 2004 the project was revived. In March 2004 and with the benefit of input from other Montpellier team PhD chemists, Dr Griffon pursued three further strategies, his ninth, tenth and eleventh, but again, each of them failed. He finally stopped work on the project in the summer of 2004, asking in his final report: "Question: Due to the synthetic difficulties encountered, is it worthwhile to continue to consider this series as future targets?"

Dr Stewart and Ms Wang

158. The project was then handed over to two other scientists at Idenix, Dr Stewart and Ms Wang. They were given Dr Griffon's final report and Dr Stewart was in contact with Dr Griffon by email and received his assistance. Further, Dr Stewart did a comprehensive literature search which occupied his time for two hours each day for six months. He also had regular meetings with Professor Fleet.
159. As the judge put it, the route upon which Dr Stewart ultimately alighted was suggested by Professor Fleet. It involved the displacement of a triflate leaving group on a five or six membered lactone using TBAF or TSAF as a fluorinating agent. It was only at this point that Dr Stewart attempted a DAST reaction. This was on a 2'-methyl-up-2'-hydroxy-down lactone and produced a 2'-methyl-down-2'-fluoro-up configuration (that is to say, the wrong way round). It was nevertheless described by Dr Stewart as a breakthrough. Further attempts to produce a molecule with the correct configuration failed until after Idenix had received some information from a Pharmasset employee who was being interviewed for a role at Idenix and it was conveyed to Dr Stewart that Pharmasset had made the compound from a nucleoside. Shortly afterwards, Dr Stewart made some changes to his reaction scheme, which included lowering the temperature at which DAST was used, and not long thereafter Ms Wang made a compound with the correct configuration.

Mr Clark

160. Mr Clark did not give evidence but his notebooks were disclosed by Gilead. He was at the relevant time a junior and inexperienced chemist at Pharmasset. However, he worked with other scientists including Dr Schinazi, a leader in the field. The work of Dr Clark and his colleagues was in due course published in two papers, "Design, Synthesis and Antiviral Activity of 2'-Deoxy-2'-fluoro-2'-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication", J. Med. Chem., 48, 5504-5508 (2005) (referred by the judge as "the Clark Paper"), and "Synthesis of 2-Deoxy-2-fluro-2-C-Methyl-Ribofuranoses", J. Carbohydr. Chem., 25, 461-470 (2006) (referred to by the judge as "Clark II"). They describe the synthesis of 2'-methyl-up-2'-fluoro-down nucleoside analogues by both sugar and nucleoside routes.
161. The judge summarised his conclusions about the work of Mr Clark in these two paragraphs:

"568. Counsel for Idenix informed me, without contradiction by counsel for Gilead, that Mr Clark was a relatively junior and inexperienced chemist who did not have a PhD. On the other hand, he did not work alone, as can be seen from the fact that the Clark Paper had 14 authors, including Dr Schinazi, who counsel for Idenix not merely accepted, but asserted, was a leader in the field at that time, while Clark II had five authors, including Dr Schinazi.

569. The conclusion that I draw from Mr Clark's work is that he and his colleagues did succeed in synthesising a 2'-methyl-up-2'-fluoro-down compound much more quickly than the Idenix team. The question is why. In my view, the explanation lies in a combination of skill and luck. When Mr Clark and his colleagues carried out their retrosynthetic analysis, it evidently occurred to them at a reasonably early stage that, if they took the sugar route, there were two key reactions to be achieved: conversion of the ketone to the 2'-hydroxy-up-2'-methyl down compound followed by S_N2 fluorination of the tertiary alcohol in that compound with inversion of the stereochemistry to give the 2'-methyl-up-2'-fluoro down compound. When planning the first reaction, it would appear that their literature searches turned up Matsuda II. As for the second reaction, it would appear from their comments in the Clark Paper and Clark II that they appreciated that stereospecific fluorination of the tertiary alcohol was likely to be challenging, but their searches turned up Singh and Shreeve, Wachmeister and Yang. Encouraged by the first two papers, they followed Wachtmeister's method, but using DAST rather than Deoxo-Fluor and omitting the pyridine. It is unclear why they used DAST and not Deoxo-Fluor. It is also unclear why they omitted the pyridine, whether this would have been expected to make any difference and whether this in fact did make any real difference. Whatever the answers to these questions, it is clear from the Clark Paper and Clark II that the success of the fluorination reaction was considered worthy of specific comment in publications in two high profile journals."

The experiments

162. As I have mentioned, Idenix relied upon certain experiments carried out for the purpose of this litigation to establish that, in pursuing his sixth strategy in February 2003, Dr Griffon had in fact made a 2'-methyl-up-2'-fluoro-down nucleoside analogue. Specifically it sought to establish, inter alia, that, when the experiment referred to on page 12 of Dr Griffon's notebook from February 2003 is repeated, 2'-fluoro-2'-methyl uridine is obtained as a reaction product at an approximate yield of 15.7%.
163. Arnold J addressed this issue from [532] to [549]. He explained that Idenix originally served a Notice of Experiments seeking to establish various facts, including the fact set out immediately above; Gilead declined to admit those facts and requested an opportunity to witness a repeat of the experiments; and that the repetition was duly carried out by a scientist, Dr Alex Clemens, in a contract laboratory and witnessed by representatives of both Idenix and Gilead. Dr Clemens did not give evidence, however.
164. Gilead did not contest at trial that, in light of the repeat, following the protocol set out in the Notice, 2'-fluoro-2'-methyl uridine was produced as a minor product. However, it did contend that the experiments had no probative value. For that purpose it relied upon the evidence of Professor Boons that there were significant differences between the protocol followed by Dr Clemens and the procedure followed by Dr Griffon and further, that neither the approach of Dr Griffon's nor that of Dr Clemens represented what the average skilled person would have done in June 2003.
165. The judge accepted Gilead's submissions but not all of the detailed points upon which it relied. He found first, that no explanation had been given as to why the Idenix protocol differed from that used by Dr Griffon and, in the absence of such an explanation, the natural inference was that the differences must have been thought likely to improve Idenix's prospects of getting the desired result; and secondly, two of the differences may have affected the result and did not accord with the approach that the skilled person would have adopted in June 2003. Further, he was not persuaded that Dr Griffon's approach to the reaction was one that would have been followed by the skilled person in any event.

The judge's overall conclusion

166. The judge then expressed his final conclusion on this insufficiency attack:

"594. Drawing these threads together, the conclusion I have reached is that the Patent does not enable the skilled person to make the claimed compounds without undue burden. The specification gives the skilled person no meaningful assistance, and so the skilled person has to rely upon his common general knowledge. The skilled person would undertake a retrosynthetic analysis, and would be immediately confronted with the problem that his target compound contained a tertiary fluorine with a particular stereochemistry. He would appreciate that making such a compound would be difficult and challenging, and there would a large number of potential routes to consider. The skilled person's prospects of success would depend on both skill and luck. If he was skilled and lucky, he could hit upon a successful synthesis fairly quickly, as Mr Clark and his colleagues did. If he was skilled but unlucky, he could spend many months on the problem without success, as Dr Griffon did. "

The appeal

167. Mr Waugh has challenged the judge's approach to this issue in a number of ways. I shall deal with them in turn. But first it is worth restating that a finding of insufficiency, like a finding of obviousness, involves an assessment and the weighing of a number of factors. In these circumstances and absent an error of principle, an appellate court will be very cautious in differing from the judge's evaluation: see SmithKline Beecham's Patent [2006] RPC 323 at [38] per Lord Hoffmann; Halliburton Energy Services Inc v Smith International (North Sea) Ltd and anor [2006] EWCA Civ 1715 at [24] to [25] per Jacob LJ.
168. Mr Waugh contends that the judge erred as a matter of principle in assessing the issue of enablement by reference to too high a standard. In particular, he continues, the judge sought to ascertain whether the skilled person could have made the 2'-methyl-up-2'-fluoro-down nucleoside analogues by a "routine" method and that he ought rather to have considered whether arriving at a method whereby such analogues could be made would have required "undue effort". What is more, says Mr Waugh, this error is reflected in the way the judge approached the possibility of the skilled person having to conduct a literature search regarding DAST. The judge dealt with that issue at [591] to [592]:

"591. In addition, counsel for Idenix cross-examined Prof Boons at some length on the scientific literature regarding DAST. The purpose of the cross-examination was to try to establish that the statement in March was supported by the literature. But counsel did not put to Prof Boons the primary reference given by March for his statement, reference 1158, which is W.J. Middleton, "New Fluorinating Reagents. Dialylaminosulfur Fluorides". J. Org. Chem., 40, 574-578 (1975), even though that paper was included in the bundle produced by Idenix for Prof Boons' cross-examination. Instead, he put the following:

i) Reference 1157, M. Hudlicky, "Fluorination with Diethylaminosulfer Trifluoride and Related Aminofluorosulfuranes", Org. Reactions, 35, 513-647 (1988) ("Hudlicky").

ii) United States Patent No. 3,914,265 to Middleton, which is reference 9 in Hudlicky.

iii) W. Dmowski, "Replacement of Oxygen by Fluorine" in Hudlicky and A.E. Pavlath (eds), Chemistry of Organic Fluorine Compounds II: A Critical Review (Americal Chemical Society, 1995) at 199-262.

iv) A paper co-authored by Prof Boons, D. Noort et al, "Synthesis of a Potential Inhibitor of UDP-Glucuronosyltransferase", Bioorg. & Med. Chem. Letters, 2, 583-588 (1992).

v) A.D. Borthwick et al, "Chiral Carbocyclis Nucleosides: The Synthesis and Antiviral Activity of 4'-Hydroxy and 4'-Fluorocarbocyclic-2'-Deoxyguanosines", Bioorg. & Med. Chem. Letters, 3, 2577-2580 (1993).

vi) Wachtmeister.

592. Leaving aside the fact that none of these papers apart from Borthwick et al had been cited by Dr Brancale, it was not established a skilled person carrying out a retrosynthetic analysis in June 2003 would have conducted a literature search which would have turned up these references. Furthermore, if the skilled person had to conduct such a literature search, rather than simply relying on March, that in itself would suggest that the synthesis was far from routine."

169. Focusing on [592] immediately above, Mr Waugh submits that the judge's refusal to allow the skilled person to read the relevant literature is an illustration of his erroneous approach for such reading is part of the everyday work of the average medicinal chemist.
170. I cannot accept these submissions. At the outset the judge directed himself by reference to the relevant legal principles and he then identified the allegation with which he was dealing in clear and entirely unobjectionable terms at [470]:

"Gilead allege that the Patent does not enable the skilled team to perform the invention in claim 1 without undue burden because it does not enable them to synthesise the 2'-methyl-up-2'-fluoro down compounds claimed. The allegation is focused upon the 2'-methyl-up-2'-fluro-down substitutions on the ribose ring; Gilead do not contend that the skilled team would have any difficulty with regard to the other substitutions covered by Markush formula in claim 1 … " (emphasis added)

171. There followed a detailed assessment by the judge of all of the material and evidence before him, beginning with the factual evidence and the experiments and then the more general evidence, including that of the experts. The judge expressed his final conclusion on this issue at [594] (cited above at [166]). Here again the judge plainly had in mind the correct test, namely whether the disclosure of the Patent enabled the skilled person to make the claimed compounds without undue burden. Now it is true that, in the course of his analysis, the judge considered whether the taking of a particular step would have been a routine matter. But this was entirely appropriate. A patentee need not describe the ordinary steps which the skilled person would expect to have to take to implement the invention, and it is perfectly apt to describe these steps as "routine". If, on the other hand, the skilled person is required to carry out work which is far from routine then this may be a matter which suggests the disclosure is insufficient. All will depend upon the nature of the art in which the invention is made and the attributes of the skilled person.
172. I turn then to the particular matter to which the judge was directing his attention, namely the literature to which he referred at [591] to [592], and whether, as Mr Waugh submits, he ought to have held that finding and reading such literature was part of the everyday work which the average medicinal chemist would expect to have to carry out.
173. I have no doubt that in some circumstances the skilled person may reasonably be expected to carry out a literature search in order to implement aspects of the teaching of a specification. Whether that is so or whether the fact that such a search is necessary suggests that the teaching of the specification is insufficient will depend upon all the circumstances including the nature and purpose of the search that is required.
174. In this case, the judge had earlier found that, although March was a standard text which the skilled person would routinely consult, it was a very long book which was "packed with detail". Further, had the skilled person started by reminding himself of the general principles regarding aliphatic nucleophilic substitution reactions, he would have found the statement in March that tertiary substrates seldom undergo nucleophilic substitution at all and that, with a few exceptions, nucleophilic substitutions at a tertiary carbon have little or no preparative value. What is more, only one of the publications put to Professor Boons had been referred to by Dr Brancale and the selection did not include the primary reference cited by March in support of the aspect of its teaching upon which Idenix relied. In all these circumstances it seems to me the judge cannot be criticised for considering as he did that the need for a search which would have revealed them all suggested that the synthesis was far from routine. Moreover, this was, in any event, a secondary point for, as the judge said at [592], it was never established that a skilled person carrying out a retrosynthetic analysis in June 2003 would have conducted a literature search which would have turned up these references. What is more, the judge did not find the cross-examination of Professor Boons persuasive for the reasons he went on to explain.
175. Mr Waugh submits next that the judge fell into error by focusing predominantly and unduly upon the efforts of Dr Griffon to make a 2'-methyl-up-2'-fluoro-down analogue and that he ought rather to have assessed the problem facing the skilled person objectively and in light of the teaching of the Patent and the common general knowledge. Further, continues Mr Waugh, the judge failed properly to recognise that Dr Griffon's approach was idiosyncratic and did not reflect that of the ordinary skilled medicinal chemist for two reasons: first, he was seeking to devise a high yield process; and secondly, he only analysed what he believed to be the major products of his reactions. Moreover, the litigation experiments carried out by Idenix showed that Dr Griffon had in fact made a 2'-methyl-up-2'-fluoro-down analogue and that had he followed the approach of the ordinary skilled chemist and analysed each of his reaction products, he would have recognised it.
176. Once again, I have not found these submissions persuasive. First, I do not accept that the judge focused unduly upon the work of Dr Griffon. It is true that the judge dealt with this work first and at some length, but that is because he chose to deal with the factual evidence before addressing the evidence of the experts, and because the work of Dr Griffon was carried out over a considerable period of time and involved a large number of different strategies. After addressing all of the evidence of fact, the judge then went on to address the teaching of the Patent, the experiments and the expert evidence. He cannot be criticised for taking this course.
177. Secondly, I recognise that, in assessing whether a patent such as that in issue in this case is insufficient, the work of one individual chemist may not be representative of that of the ordinary skilled person for one or more of a wide range of reasons. For example, the patent specification may contain important and useful information of which the chemist was not aware; or the chemist may have missed the obvious; or the chemist may have adopted an eccentric approach. On the other hand, the work of such a chemist may be representative of that of the ordinary skilled person and, if the judge is properly satisfied that is so, it seems to me that it is entirely appropriate to take it into account.
178. These were all matters of which the judge was fully conscious. He considered with great care the suggestion that Dr Griffon's thinking was driven by a desire to make relatively large amounts of the target compound and he rejected it at [517]:

"517. The picture which emerged in cross-examination was somewhat different. Although Dr Griffon repeatedly said that he was seeking yields of 20-30%, or even 30-50%, it is clear from his laboratory notebooks that he sometimes isolated and characterised products at lower yield, including ones at 15% and 16%. Furthermore, Dr Griffon started multiple experiments with amounts of starting material in the region of 50-100 mg, where getting 100-200 mg of product would simply have been impossible. Still further, Dr Griffon's Progress Reports make no mention of him only seeking high yields and do not use language which suggests that only major reaction products were considered. Yet further, Dr Griffon accepted that he had pursued his research with great persistence: his attitude to his experiments had been "never give up"."

179. The judge then addressed the submission that Dr Griffon was idiosyncratic in his failure to analyse the minor reaction products in the next two paragraphs of his judgment:

"518. Above all, it is clear that Dr Griffon was not so poor a synthetic chemist that he did not ask himself what the minor products of reactions were. This is demonstrated in particular by the very evidence that Idenix rely upon and which formed the basis for their Experiments. As discussed above, Dr Griffon's TLC analysis of the crude deprotected reaction mixture revealed the presence of a number of products. Dr Griffon separated three of these. It is true that he only characterised one of them, which he hoped might be the fluorinated compound, but turned out not to be; but he still thought about what the other two were. Because he believed he knew what they were, he did not characterise them. (I should make it clear that Idenix do not suggest that Dr Griffon was mistaken in his belief as to the identity of the other two products.) I do not believe that, having got as close to his goal as he had by then, if Dr Griffon had thought that one of the other minor products of the reaction was 2'-fluoro-2'-methyl uridine, he would not have attempted to separate and analyse it.

519. Furthermore, there is another, and in my view more plausible, reason, why at the time he did not think that the small spot which he ultimately suggested was 2'-fluoro-2'-methyl uridine was the target compound. As Prof Boons explained, that spot did not char when stained with the sulphuric acid, indicating that it did not contain a carbohydrate moiety."

180. We have been taken in the course of this appeal to a good deal of the evidence and I am satisfied the judge was entitled to make these findings. The judge expressed his conclusion on this point at [521]. He found that there was nothing idiosyncratic about Dr Griffon's work and that, on the contrary, it represented a sustained effort by a chemist who was representative of the skilled person to synthesise 2'-fluoro-2'-methyl uridine, and that at the time he reasonably believed he had been unsuccessful. In my judgment this was a conclusion for which the judge had a proper basis in the evidence.
181. It must also be remembered that Dr Griffon was assisted not only by Dr Storer and Dr Gosselin but also by Professor Fleet and Dr Coe. Mr Waugh says the judge erred in speculating what they may have suggested to Dr Griffon. I cannot accept this criticism. The judge dealt with this suggestion in an entirely appropriate way at [522]:

"522. Furthermore, Dr Griffon was not working on his own, but received extensive advice from relevant experts. Counsel for Idenix sought to downplay the assistance Dr Griffon had received from others by arguing that there was no evidence that they were aware of his idiosyncratic approach. I do not accept this argument for two reasons. First, I do not accept that Dr Griffon's approach was idiosyncratic. Secondly, the evidence indicates that Dr Griffon explained to experts such as Prof Fleet and Dr Coe what approaches he had tried and what the results had been. If they had thought that he ought to have succeeded with a reaction that had apparently failed, I am sure they would have suggested that he try it again."

182. Mr Waugh has also taken us to the other factual evidence. He submits the judge ought to have attached more weight to the fact that there were four people working on the synthesis at the relevant time, Dr Stewart, Ms Wang, Dr Griffon and Mr Clark. Of these, continues Mr Waugh, only one, Dr Griffon, had difficulty in identifying the successfully synthesised 2'-fluoro-2'-methyl analogue. Dr Stewart and Ms Wang used DAST as their first fluorinating agent and were successful straight away. Similarly, Mr Clark, a junior employee at Pharmasset with no doctoral research experience, was able to synthesise a 2'-fluoro-2'-methyl analogue very easily.
183. In my judgment the picture painted by Mr Waugh is far from complete. As the judge explained, Dr Stewart and Ms Wang took over the project from Dr Griffon. They were armed with his report summarising the work he had done and Dr Stewart was in contact with him by email. Dr Stewart also had the benefit of assistance from Professor Fleet and carried out a comprehensive literature search which took, on average, two hours a day for six months. Even then his first attempts to use DAST to produce a fluoro-methyl analogue with the correct stereochemistry failed and it was not until after Idenix received some information from the Pharmasset employee that either Dr Stewart or Ms Wang were successful. As for Mr Clark, neither side called him to give evidence for perfectly understandable reasons. Nevertheless, the judge considered the work recorded in his notebooks with great attention and I am wholly unpersuaded it is appropriate for this court to revisit the conclusions to which he came at [569] (cited above at [161]).
184. Turning next to the Patent, Mr Waugh submits that the points taken by the judge are of a hair-splitting kind, rely upon evidence which was elicited by the judge in the course of his own questioning of Professor Boons, would not affect the ability of the skilled person to implement its teaching and should not have formed any part of the judge's analysis. Indeed, says Mr Waugh, they illustrate the lack of an objective approach which the judge should have brought to bear to the evidence.
185. These are serious charges but in my judgment they have not been made out. The judge dealt with the teaching of the Patent in the manner I have summarised at [143] to [145] above. Idenix accepts, as it must, that the Patent does not contain any instruction on how to make a 2'-methyl-up-2'-fluoro-down analogue falling within the claims. Critically, the Patent does not explain how to fluorinate a tertiary carbon in the 2' position of the sugar moiety of a molecule with the other characteristics necessary to produce a 2'-fluoro-2'-methyl analogue with the correct stereochemistry. What is more, the judge was entitled to explore the extent of the Patent's disclosure with Professor Boons and I reject any suggestion that he overstepped the mark in such a way as to call into question his objectivity. No doubt it was at least in part a result of the paucity of the Patent's teaching that the experts were agreed that the skilled person seeking to make the claimed analogues would conduct a retrosynthetic analysis.
186. That brings me to the expert evidence. Mr Waugh submits there was, at the end of the day, little effective challenge to the evidence of Dr Brancale. By way of contrast, he continues, Dr Boons accepted that, on a literature search, the Matsuda work would be turned up "in a heartbeat" and that this demonstrates that use of a standard organometallic agent will bring about the necessary methylation with the desired stereochemistry. Mr Waugh continues that the final step, fluorination, can be achieved by DAST which Professor Boons accepted is the most commonly applied reagent for that purpose and is, in any event, described in March. Further, says Mr Waugh, the Patent itself discloses the use of organometallic reagents for methylation and that either scheme 3 or scheme 4, followed by fluorination with DAST, will result in the claimed 2'-methyl-2'-fluoro-analogues.
187. Attractively though these submissions have been presented, I do not accept them and they seem to me to amount in large part to an attempt to re-argue the case which the judge rejected. The key points with which Mr Waugh has not adequately grappled are those which are addressed by the judge from [576] to [593] of his judgment. Both experts took the view that the skilled person would carry out a retrosynthetic analysis but they differed as to what that would involve. I have summarised Dr Brancale's evidence earlier in this judgment but I reject the suggestion that there was little challenge to it. It emerged that he had read the Clark Paper before he considered the issue of a retrosynthetic analysis and so his view was tainted by hindsight; he accepted that fluorinating a tertiary carbon was difficult and challenging; and he failed properly to consider what the outcome of a literature search by the skilled person would have been and instead assumed that it would have turned up the key references upon which he relied, including Matsuda I or a related paper paper by Matsuda and others entitled A. Matsuda et al., "Alkyl addition reaction of pyrimidine 2'-ketonucleosides: Synthesis of 2'-branched-chain sugar pyrimidine nucleosides. (Nucleosides and nucleotides LXXXI.)", Chem. Pharm. Bull., 36, 945-953 (1988). As for fluorination, Dr Brancale did not explain how the skilled person would have used March, including those aspects of it to which I have referred.
188. Turning to Professor Boons, he considered that making any of the claimed compounds would be a research project which represented a significant synthetic challenge with an uncertain outcome. The judge rejected the suggestion that he had raised a series of theoretical problems which would not have troubled the skilled person and the contention that he had overstated the complexities of the retrosynthetic analysis. As for the methylation step, Professor Boons did agree that a skilled person who was trying to make a 2'-hydroxy-up-2'-methyl-down compound and carried out a literature search would find the work of Matsuda "in a heartbeat" but, as the judge explained at [588]:

"… His point was a different one, namely that the 2'-hydroxy-up-2'-methyl-down compound is only one possible precursor and that one only arrives at that precursor working backwards in the retrosynthetic analysis if and when one has solved the problem of fluorinating the tertiary alcohol. Unless the skilled person perceives a solution to that problem, his retrosynthetic analysis will be likely to work back by other routes."

Finally and as to the fluorination step, Professor Boons was clear and the judge accepted that the fluorination of a tertiary carbon was difficult and challenging.

189. In my judgment Mr Waugh has not established any ground upon which we can interfere with the judge's findings and I believe the position was well summed up by the judge in these terms at [593]:

"593. … The question is whether the skilled person carrying out a retrosynthetic analysis would have (i) planned to follow a route in which the final step (i.e. the first step in the retrosynthetic analysis) involved nucleophilic fluorination of a tertiary alcohol, (ii) thought of using DAST to carry out that step and (iii) had a reasonable expectation that the reaction to work. Prof Boons' evidence was clear that he did not think it likely that the skilled person would plan such a route, or that the skilled person would have been likely to use DAST (he said that he himself would not have used it), or that the skilled person would have had a reasonable expectation of success. As I have indicated, I consider that Prof Boons' evidence is supported by Dr Griffon's work. But it is also supported by the fact that Prof Fleet did not suggest the use of DAST to Dr Griffon (he proposed electrophilic substitutions) and by the fact that Dr Coe's comments on the use of DAST made it clear that he expected it to lead to elimination and migration reactions. "

190. It only remains to deal with the experiment. Mr Waugh contends that the judge erred in principle because he approached it as if Idenix bore the burden of proof both in relation to the fact sought to be proved and the allegation of insufficiency. He says that once Gilead having accepted that, following the protocol set out in the Notice of Experiments, 2'-fluoro-2'-methyl uridine was produced, Idenix had discharged any burden of proof that lay upon it. Further, if Gilead wanted to argue that, notwithstanding this result, the differences between the protocol set out in the Notice and that followed by Dr Griffon meant that the skilled person would not have identified the product then the burden lay upon it to prove this by reply experiments, and that it did not do.
191. In my judgment, there is nothing in this point. First, I detect nothing in the judgment to suggest that the judge at any stage thought that the burden of proving that the Patent was sufficient lay upon Idenix. It plainly did not. It was for Gilead to establish that the Patent was insufficient. Turning to the experiments, Idenix sought by its Notice an admission of the fact that, when the experiment referred to on the relevant page of Dr Griffon's notebook was repeated, 2'-fluoro-2'-methyl uridine was obtained as a minor reaction product in a particular yield. Gilead did not make the admission and so the burden of proving that fact lay upon Idenix. The judge was entitled to hold that it had failed to discharge that burden because, notwithstanding the production in the experiment of 2'-fluoro-2'-methyl uridine, the protocol in the Notice differed from that used by Dr Griffon in two respects for which no explanation was given and which might have affected the result. Further, the protocol in the Notice did not in any event accord with the approach that the average skilled person would have adopted in June 2003. In all of these circumstances the judge's conclusion that the experiment did not materially assist Idenix in defending itself against the allegation of insufficiency necessarily followed.

Conclusion

192. It follows that that the judge was right to hold that the Patent was insufficient because it did not enable the medicinal chemist to synthesise the 2'-methyl-up-2'-fluoro down compounds claimed without undue burden.

Undue burden across the breadth of the claim

193. The judge approached this issue on the assumptions that, contrary to his earlier findings, the Patent when read with the common general knowledge (i) makes it plausible that the claimed compounds have anti-Flaviviridae activity and (ii) enables the medicinal chemist to synthesise substantially all of the claimed compounds without undue burden.
194. The judge summarised the parties' rival contentions at [596] and [597]:

"596. … Gilead contend that the Patent does not enable the skilled team to perform the invention across the breadth of claim 1 without undue burden. The basis for this contention is simple: even once the medicinal chemist has made one of the compounds, the virologist has to test it for antiviral activity. There is no dispute that testing a compound for anti-Flaviviridae activity would be routine work which in itself would not be unduly burdensome. But the claim covers billions of compounds and the Patent gives the skilled team no clue as to where to start. Dr Brancale accepted that it would take 3-6 days to synthesise a straightforward nucleoside analogue and that a more complicated case might take 2-3 months. As discussed above, the Patent suggests using BVDV assays to identify active compounds, but 2'-deoxy-2'-fluoro-2'-C-methylcytidine is inactive in the BVDV assay. Admittedly, the virologist would know from his common general knowledge that the gold standard assay was the replicon assay, and 2'-deoxy-2'-fluoro-2'-C-methylcytidine turns out to be active in the replicon assay. But what this emphasises is that the Patent is setting the skilled team a substantial research project to select, synthesise and test the claimed compounds relying upon their own common general knowledge and claiming the results if they are successful.

597. Idenix's answer to this contention is that Gilead have not established that any of the claimed compounds do not work. Accordingly, Idenix say that the invention can be performed across the breadth of the claims without undue burden, because the medicinal chemist can make the compounds without undue burden and the virologist can test them without undue burden."

195. He then expressed his conclusion in concise terms at [598]:

"598. The Patent does not suggest that all of the claimed compounds have an anti-Flaviviridae activity, however. On the contrary, all it says is that they can be screened for such activity. Even if it is plausible that the claimed compounds do have such activity, it is clear from the evidence that they may turn not to do so [sic] when tested. Accordingly, I agree with Gilead that the Patent does not enable the skilled team to perform the invention across the breadth of the claim without undue burden because it sets the skilled team a research project and claims the results."

196. Mr Waugh submits that the judge fell into error for there is no requirement that a claimed invention must be shown to work for every member of the claimed class of compounds and that, on the basis of the assumptions the judge made, he ought to have found that the Patent does disclose the invention in manner sufficiently clear for it to be performed by a person skilled in the art.
197. I have some concern about addressing an issue of this kind on the basis of assumptions which are cast in such general terms. Moreover, a claim is not insufficient just because it covers a very large number of molecules. I also detect a tension between, on the one hand, an assumption that it is possible to make a reasonable prediction that all of the claimed molecules will have activity and, on the other hand, the teaching of the Patent and the expert evidence that they will not. Having said that, I recognise that a patent which presents to the skilled team a research project before they can work the claimed invention in a reasonable way will be insufficient. In all these circumstances I incline to the view that the judge was entitled to come to the conclusion he did; however, since it is not necessary to express a final conclusion on this issue, I shall not do so. It seems to me that issues of this kind are better addressed in the light of the particular facts of the cases in which they arise.

Overall conclusion on insufficiency

198. For the reasons I have given, I would dismiss the appeal against the judge's finding that claim 1 of the Patent as granted and as proposed to be amended is invalid for insufficiency. Idenix did not advance at trial any argument in support of independent validity of any of the subsidiary claims if claim 1 as proposed to be amended was invalid and that remains the position on this appeal.

Added matter

199. There were three issues before the court:

i) whether claim 1 as granted adds matter; the judge held that it does not and Gilead appeals against this finding;

ii) whether claims 4 and 5 as granted add matter; the judge held that claim 4 does add matter and Idenix appeals against this finding; he also held that claim 5 does not and there is no appeal by Gilead against this finding;

iii) whether the claims as proposed to be amended add matter; the judge held that they do and Idenix again appeals against this finding.

200. The principles are not in dispute and were explained by the Court of Appeal in Vector Corpn v Glatt Air Techniques Ltd [2007] EWCA Civ 805, [2008] RPC 10 at [4] to [9] and reiterated with further elaboration by the Court of Appeal in Nokia Corporation v IPCom GmbH & Co KG [2012] EWCA Civ 567, [2013], RPC 5 at [46] to [60].

Claim 1 as granted

201. Gilead alleged at trial that claim 1 of the Patent as granted adds matter because it focuses the attention of the skilled team on the sub-class of compounds of Formula (IX) to the exclusion of the compounds of the 22 other formulae disclosed in the Application. Further, searching for compounds worth taking forward amongst all of those described in the Application was like looking for a needle in a haystack whereas the disclosure of the Patent substantially altered the area to be searched and so changed the teaching.
202. The judge dealt with this allegation in concise terms at [605]:

"605. I do not accept this argument. Although I agree that the Application is of stupendous breadth, one of many of the classes of compounds which it specifically identifies as a preferred embodiment of the invention is the subclass identified on page 100. Furthermore, the message that that subclass is one of the classes of particular interest is reinforced by claims 9-11. I do not consider that the skilled team would learn anything new about that embodiment of the invention as a result of claim 1 as granted being restricted to that subclass and claims to the other classes of compounds being abandoned. Accordingly, I reject the allegation of added matter in relation to claim 1."

203. I believe the judge was right on this issue and at the end of the day I did not understand Dr Justin Turner QC, who has appeared for Gilead, seriously to contend to the contrary. The compounds of Formula (IX) were identified and described as a distinct class in the Application and claimed in claims 9 to 11. No subject matter relevant to the invention has been added in claim 1 of the Patent. The compounds of Formula (IX) are clearly and unambiguously disclosed in the Application.

Claim 4 as granted

204. The point here is a short one. The judge held that this adds matter for the following reason. In the Application the term Base* in the compound of Formula (IX) is defined as "a purine or pyrimidine base", and this expression is in turn defined at page 104 by way of a non-exhaustive list encompassing a very large number of bases. By contrast, the term Base* in claim 4 of the Patent is limited to eight bases, namely cytosine, uracil, guanine, adenine, thymine, hypoxanthine, 5-fluorouracil and 5-fluorocytosine.
205. Although Idenix has challenged this finding upon this appeal, I do not believe that Mr Waugh has developed any effective submission as to why the judge was wrong. He submits simply that limiting the scope of this particular term does not teach the addressee anything new. I disagree. There is no disclosure in the Application of this particular set of bases. Accordingly, the judge was right to find that claim 4 adds matter.

The claims as proposed to be amended

206. Idenix sought to amend the claims because, as I have explained, Dr Brancale accepted in his evidence that it was not plausible that the compounds of Formula (IX) as defined in claim 1 of the Patent would be effective against Flaviviridae where R¹ and/or R² were "straight chained, branched or cyclic alkyl" or "benzyl, wherein the phenyl group is optionally substituted with one or more substituents". It therefore sought to add a limitation so as to exclude these from the list of possible R¹ and R² substituents.
207. The judge held this would add matter for the reasons advanced by Gilead, which he summarised at [610]:

"610. … Counsel for Gilead submitted that, by deleting certain substituents from the list of substituents for R¹ and the list of substituents for R², Idenix was creating a narrower sub-class of compounds which was neither disclosed in the Application nor clearly and unambiguously derivable from it. Furthermore, to make matters worse, Idenix's own evidence was that it was plausible that this new sub-class was effective against Flaviviridae, whereas this was not the case for the broader class. Accordingly, the skilled team would learn something new about the invention from the amended claim …"

208. Mr Waugh submits that the judge was wrong to accept these submissions. He says that the judge failed to consider the added matter attack though the eyes of the skilled person who is equipped with the common general knowledge. This addressee would know, just as Dr Brancale knew, that the compounds sought to be deleted would not work. Accordingly, the proposed amended claims would not teach the skilled person anything new.
209. I reject these submissions. First, it is clear that there is no express disclosure in the Application of the sub-class of compounds the subject of proposed amended claim 1. Secondly, the judge has not found that the skilled person would draw the distinction between the compounds falling within the scope of the claim as granted and those falling within the claim as proposed to be amended upon which Mr Waugh relies. It is true that Dr Brancale said that such a distinction could be drawn but the judge did not accept his evidence. Thirdly, it follows from the foregoing that the Patent as proposed to be amended would add matter. It would disclose a new and narrower class of compounds which is not disclosed in the Application or clearly and unambiguously derivable from it. The judge was right to hold that the amendment was not allowable.

Can the granted claims be allowed to stand if they are partially invalid?

210. Mr Waugh has argued that the court has a discretion to allow a patentee to retain, without amendment, partially valid claims and that the judge ought to have exercised that discretion in favour of Idenix in this case. For the purposes of this appeal I am prepared to accept without deciding that the court does indeed have such a discretion. Nevertheless, I have no doubt that the judge was right not to exercise that discretion in favour of Idenix. This is not a case in which the skilled person would recognise that there is a small subset of compounds which do not have the required activity. The claims are systemically deficient. It would not be in the public interest to allow claim 1 to stand as it is and the judge was right so to hold.

Novelty

Introduction

211. It is not therefore necessary to address the question of novelty. Nevertheless, it is appropriate to explain the issues to which this question gives rise and give an indication of my views in relation to them, albeit as briefly as possible.
212. As I explained at the outset, Gilead alleged that the Patent was anticipated by the Pharmasset PCT - PCT/US 2004/012472. Although the Pharmasset PCT was published after the filing date of the Application, it claims priority from '368 - US application US 60/474,368 - which was filed on 30 May 2003, that is to say before the filing date of the Application. It was accepted that if the Pharmasset PCT is entitled to priority then it anticipates all of the claims of the Patent save for claims 20 and 37.
213. Any invention disclosed in '368 was made by Mr Clark in the course of his employment by Pharmasset Inc., a company incorporated under the laws of the State of Georgia, USA ("Pharmasset Georgia"). However, the applicant for the Pharmasset PCT was Pharmasset Limited, a company incorporated under the laws of Barbados ("Pharmasset Barbados"). The critical question is whether, on 21 April 2004, the date of filing of the Pharmasset PCT, Pharmasset Barbados was Mr Clark's successor in title.
214. Gilead contended that Pharmasset Barbados was Mr Clark's successor in title by one of three routes:

i) Mr Clark's rights to the invention vested in Pharmasset Georgia under the terms of his contract of employment ("the Clark Agreement"). All such rights were assigned to Pharmasset Barbados by an agreement between Pharmasset Barbados and Pharmasset Georgia ("the R&D Agreement") which was itself governed by the law of Georgia ("Route 1").

ii) If the R&D Agreement was not effective to transfer legal title to the invention, it was nevertheless effective to transfer the entire beneficial interest in the invention to Pharmasset Barbados ("Route 2"), and that is sufficient for priority purposes.

iii) All of Mr Clark's rights in the invention were assigned directly to Pharmasset Barbados as Pharmasset Georgia's designee under clause 6.2 of the Clark Agreement ("Route 3").

The background facts

215. Clause 6.2 of the Clark Agreement provided in material part that:

"Employee hereby assigns and agrees to assign to [Pharmasset Georgia], its successors, assigns or designees, all of Employees rights to inventions, … patents, …relating to the development … of antiviral and anticancer agents which, during the term of Employee's employment by [Pharmasset Georgia], Employee makes, develops of conceives … in the course of such employment …"

Idenix accepts that this clause effected a transfer of any rights in '368 from Mr Clark to Pharmasset Georgia.

216. Pharmasset Georgia was a wholly owned subsidiary of Pharmasset Barbados. The companies were incorporated on the advice of PricewaterhouseCoopers ("PWC"). PWC proposed that (what would become) Pharmasset Barbados would purchase technology and engage (what would become) Pharmasset Georgia to undertake research and development in the USA. The costs of the work would be paid for by Pharmasset Barbados, together with an adminsitration fee. Pharmasset Barbados would own any intellectual property that was developed by Pharmasset Georgia. This intellectual property was to be owned by Pharmasset Barbados for tax reasons. Pharmasset Barbados would be able to license this intellectual property and would have the right to receive any royalties or other revenues. This income would be received in Barbados where the tax rate was lower than in the USA.
217. These arrangement were formalised in the R&D Agreement which had been assented to by both Pharmasset Georgia and Pharmasset Barbados by the spring of 2000. There is no dispute that at all relevant times there was a binding contract between the two companies on the terms of that agreement. Pharmasset Barbados duly paid the research and development costs and the administrative fees in accordance with its terms. Further, Mr Roberts, an attorney originally employed by Pharmasset Georgia, arranged for confirmatory assignments to be executed by Pharmasset Georgia's employee inventors in favour of Pharmasset Barbados, and patent applications, such as the Pharmasset PCT, were filed in the name of Pharmasset Barbados.
218. In June 2004 Pharmasset Barbados was "redomesticated" and became Pharmasset, Inc, a company incorporated under the law of the State of Delaware ("Pharmasset Delaware"). In July 2004 Pharmasset Georgia merged into Pharmasset Delaware and in January 2012 Pharmasset Delaware was acquired by Gilead.

The issues

219. The three routes to which I have referred gave rise to a series of issues.

Route 1

220. Issue 1: Gilead contended and the judge accepted that, applying Georgia law, the R&D Agreement amounted to an assignment of (or at least an agreement to assign) Pharmasset Georgia's rights to the invention to Pharmasset Barbados. Idenix contends he erred in so doing. It argues that the R&D Agreement conferred on Pharmasset Barbados no more than an exclusive licence.
221. Issue 2: Gilead also argued and the judge held that the wording of the R&D Agreement amounted to an immediate assignment of those rights in accordance with Federal patent law. Idenix contends (on the assumption it has lost on Issue 1) that he ought to have held that it amounts to no more than an agreement to assign them.
222. Issue 3: Gilead contended and the judge accepted that the R&D Agreement was signed. If so, and assuming the judge was also right on issues 1 and 2, then, under Federal law, legal title to the invention was transferred to Pharmasset Barbados. However, Idenix argues that his finding was based upon fallacious reasoning, was contrary to the evidence and was not open to the judge.
223. Issue 4: Would the absence of a signature have mattered? Idenix contended that it would indeed have mattered and that section 261 of Title 35 of the United States Code ("35 USC §261") requires an instrument conveying legal title to a patent application or any interest in it to be signed by the assignor. The judge did not decide this point both in light of his finding that the R&D Agreement had been signed and in light of his further finding on issue 5 below. Idenix argues that this point should now be decided in its favour.

Route 2

224. This route is relevant if (i) the R&D Agreement is, on its proper interpretation, merely an agreement to assign rather than an immediate assignment or (ii) the R&D Agreement was not signed and this matters. It gives rise to issue 5.
225. Issue 5: The judge held that if, contrary to his earlier findings, Pharmasset Barbados was the beneficial owner of the invention then this was sufficient to make it the successor in title for the purpose of claiming priority. Idenix contends that he erred in so doing.

Route 3

226. Issue 6: The judge held that if the R&D Agreement amounted to at least an agreement to assign but that neither Route 1 nor Route 2 worked for one reason or another then the Pharmasset PCT was entitled to priority by Route 3 and the "designee" language in clause 6.2 of the Clark Agreement. Idenix contends that here too the judge fell into error.

The appeal

Issue 1

227. This is a straightforward issue of construction. It was the subject of fully developed submissions at the hearing of the appeal and is important because, if the R&D Agreement amounts only to an exclusive licence, the claim to priority cannot succeed.
228. There was no dispute as to the relevant principles of Georgia law. They are (numbered according to the parties' agreed statement):

(12) The construction of a contract involves three steps. First, the trial court must decide whether the contract language is clear and unambiguous. If it is, the trial court simply enforces the contract according to its clear terms which are given their usual and common meaning; the contract alone is looked to for meaning. Next, if the contract is ambiguous in some respect, the court must apply the rules of contract construction to resolve the ambiguity. Finally, if the ambiguity remains after applying the rules of contract construction, the issue of what the ambiguous language means and what the parties intended must be resolved by the fact finder.

(13) … A contract is to be construed by ascertaining the intention of the parties at the time they entered into the agreement.

(14) A contract that may originally have been vague, indefinite and/or uncertain may later acquire more precision and become enforceable because of the subsequent words or actions of the parties. Whether or not this is possible depends on the facts and how vague, indefinite and/or uncertain the Court considers the contract to be.

(16) A Court should avoid an interpretation of a contract which renders any of its terms meaningless or mere surplusage. The construction which will uphold a contract in whole and in every part is to be preferred and the whole contract should be looked to in arriving at the construction of any part.

229. The R&D Agreement provides in material part:

"WHEREAS, [Pharmasset Barbados] is the owner of all right, title, and interest in certain intangible property in Exhibit A to this Agreement and Know-How relating to the Products (the 'Intellectual Property')

…

ARTICLE I

DEFINITIONS

…

1.7 Improvements. "Improvements" shall mean any findings, discoveries, inventions, additions, modifications, formulations, or changes made by either [Pharmasset Barbados] or [Pharmasset Georgia] during the term of this Agreement that relate to Intellectual Property or the Project.

…

1.11 Project or Projects. 'Project' or 'Projects' shall mean research project listed in Exhibit D to this Agreement.

…

ARTICLE III

GRANT OF RIGHT TO USE INTANGIBLE PROPERTY

3.1 Grant by [Pharmasset Barbados] [Pharmasset Barbados] grants to [Pharmasset Georgia] the nonexclusive right to use, develop, and enjoy the Intellectual Property for the purpose of completing the Project, subject to the terms and conditions of this Agreement.

…

3.3 Grant by [Pharmasset Georgia] [Pharmasset Georgia] grants to [Pharmasset Barbados] an exclusive, irrevocable, royalty-free right to use, develop, and enjoy any Improvements.

…

ARTICLE V

OWNERSHIP

5.1 Intellectual Property Ownership. [Pharmasset Georgia] acknowledges [Pharmasset Barbados]'s exclusive right, title, and interest in and to the Intellectual Property. [Pharmasset Georgia] shall not at any time do or cause to be done, or fail to do or cause to be done, any act or thing, directly or indirectly, contesting or in any way impairing [Pharmasset Barbados]'s right, title or interest in the Intellectual Property. Every use of any Intellectual Property by [Pharmasset Georgia] shall inure to the benefit of [Pharmasset Barbados].

5.2 Ownership of Rights. [Pharmasset Barbados] shall at all times, during or after the term of this Agreement, be the sole owner of all rights relating to or emanating from Intellectual Property, Know How, Improvements, or other matters developed in, or related to, a Project.

….

ARTICLE VI

TERM AND TERMINATION

…

6.3 Rights and Duties on Termination. On termination of this Agreement [Pharmasset Georgia] shall return all Intellectual Property, Know-How, Improvements, and any and all confidential information disclosed to it by [Pharmasset Barbados] in its possession to [Pharmasset Barbados], and all such aforementioned items shall be the exclusive property of [Pharmasset Barbados].

…

ARTICLE VIII

MISCELLANEOUS PROVISIONS

…

8.6 Further Assurances. Each party hereby covenants that it shall execute and deliver such deeds and other documents as may be required to implement any of the provisions of this Agreement.

...

8.9 Captions. Titles or captions of articles and paragraphs contaned in this Agreement are inserted only as a matter of convenience and for reference, and in no way define, limit, extend, or describe the scope of this Agreement or the intent of any provision hereof.

…"

230. It was agreed that any invention described and claimed in '368 was conceived as part of a project listed in Exhibit D and therefore amounts to an "Improvement" within the meaning of the R&D Agreement.
231. Mr Piers Acland QC, who has argued this part of the appeal on behalf of Idenix, submits that the opening recital to the agreement establishes what is meant by the term "owner", for Exhibit A includes details of six exclusive licences granted by third parties to Pharmasset Barbados. Hence "owner", when used in relation to Pharmasset Barbados' interests in the Intellectual Property, is used to mean "having the exclusive rights to", whether as exclusive licensee or as proprietor.
232. Turning next to article 3, Mr Acland argues that the language is clear and unambiguous. By clause 3.1, Pharmasset Georgia is granted the nonexclusive right to use the Intellectual Property for the purposes of the Project. On the other hand, by clause 3.3, any Improvements made by Pharmasset Georgia in the exercise of that right are the subject of an exclusive licence in favour of Pharmasset Barbados. So, submits Mr Acland, title to the Improvements must remain vested in Pharmasset Georgia.
233. As for clause 5, Mr Acland submits that the words "owner" and "ownership" are used here and in the first recital in the same way, and that they mean "having the exclusive rights to", including as exclusive licensee. It is therefore appropriate to describe Pharmasset Barbados as the owner of the rights in the Improvements because, by clause 3.3, it is the exclusive licensee of those rights. Furthermore, this is the only way in which clauses 3 and 5 can be read together.
234. Accordingly, continues Mr Acland, consideration of the R&D Agreement as a whole drives the conclusion that Pharmasset Barbados acquired only an exclusive licence to use, develop and enjoy any Improvements. Indeed, the interpretation contended for by Gilead would render clause 3.3 redundant.
235. Mr Acland has presented these submissions attractively but I do not accept them. My reasons are these. First, article 5 deals with the ownership of rights as between Pharmasset Georgia and Pharmasset Barbados and is clear in its terms. Clause 5.1 addresses Intellectual Property and provides that the title to this property is and shall remain in Pharmasset Barbados. Clause 5.2 deals with Improvements, among other matters, and says that at all times, both during and after the agreement, Pharmasset Barbados is to be the sole owner of all rights relating to such Improvements. On the face of this article, the parties agreed that rights of ownership of the Intellectual Property and the Improvements should, so far as they were available, vest in Pharmasset Barbados.
236. Secondly, this interpretation of article 5 is consistent with the first recital. This says that, as between the parties, Pharmasset Barbados is the owner of all rights in the Intellectual Property. It is also consistent with clause 6.3. On termination, all Intellectual Property and Improvements are to be returned to Pharmasset Barbados.
237. Thirdly, I recognise that Pharmasset Barbados may be an exclusive licensee rather than owner of some Intellectual Property. I acknowledge too that the terms "owner" and "ownership" are therefore broad enough to encompass the rights to exclusive licences granted to Pharmasset Barbados by third parties. But this does not affect the position that Pharmasset Barbados and Pharmasset Georgia agreed that, as between themselves, all rights of ownership of the Intellectual Property and Improvements should vest in Pharmasset Barbados.
238. Fourthly, article 3 is dealing with the right to use, not ownership. It provides, by clause 3.1, that Pharmasset Georgia has a right to use the Intellectual Property for the purpose of completing the Project, subject to the terms of the agreement. It also provides, by clause 3.3, that Pharmasset Georgia grants to Pharmasset Barbados an exclusive and irrevocable licence to use any Improvements. This does not purport to address the issue of ownership of the Improvements, however. It simply provides, in all likelihood out of an abundance of caution, that Pharmasset Georgia can at no time assert any right to restrict Pharmasset Barbados from using the Improvements.
239. Fifthly, I recognise that the court should avoid an interpretation of an agreement which makes any term mere surplusage and that the whole contract should be looked to in arriving at the construction of any part of it. But so too, the object of interpretation is to ascertain the intention of the parties at the time they entered into the agreement. In my judgment, the intention of the parties emerges clearly from the R&D Agreement when considered as a whole and it is that the title to the Intellectual Property and the Improvements should vest in Pharmasset Barbados.
240. Sixthly, I agree with the judge that the surrounding circumstances also make it clear that it was the intention of the parties that Pharmasset Barbados should own the Improvements for tax reasons. I believe the judge summarised the position fairly and accurately at [404]:

"404. …. it is clear from the surrounding circumstances that it was the parties' intention that Pharmasset Barbados should own the Improvements, for tax reasons. It is also clear that the parties acted upon the understanding that this was the effect of the R&D Agreement. Thus it was Pharmasset Barbados which obtained confirmatory assignments from inventors like Mr Clark, Pharmasset Barbados which filed patent applications such as the Pharmasset PCT and Pharmasset Barbados which granted licences. Accordingly, to the extent that the R&D Agreement is ambiguous or uncertain, it should be interpreted to give effect to that intention and understanding in accordance with agreed principles (12), (13) and (14)."

241. I am therefore satisfied that the judge came to the right conclusion on issue 1. In my judgment the R&D Agreement amounted to an assignment of (or at least an agreement to assign) Pharmasset Georgia's rights to any invention in '368 to Pharmasset Barbados.

Issue 2

242. If, as I believe to be the case, the R&D Agreement did not operate as an exclusive licence then Idenix contends that it amounts to an agreement to assign future patent rights rather than an immediate assignment of those rights.
243. This issue is governed by Federal law. There is no dispute as to the relevant principles. They are (numbered according to the parties' agreed statement):

(19) To assign legal title in a patent application, patents, or any interest therein, the assignment must comply with 35 USC §261 which reads:

"Applications for patent, patents, or any interest therein, shall be assignable in law by an instrument in writing".

(20) In certain circumstances, legal title to a patent may be transferred by operation of law.

(21) Although no particular form of words is required to effect an immediate or automatic assignment of legal title to present or future patent rights, the instrument of transfer must be unambiguous and show a clear and unmistakable intent to part with such rights in the patent.

(22) Under Federal law, when considering whether there has been a valid transfer of patent rights (including the right to apply for future patents) under a given agreement, there is a distinction between wording which creates an immediate or automatic assignment (where the transfer of legal title occurs by operation of law and no further action by the holder of such rights is needed) and wording which creates an obligation to assign rights at a later date, requiring some future act by the holder of rights to transfer legal title.

(27) Where there is a valid and enforceable immediate and automatic assignment of all the rights in an invention, patent application, or patent that does not yet exist, the assignee holds equitable title in the invention, patent application or patent. Upon the invention being made, the patent application being filed, or the patent being issued, the transfer of legal title occurs by operation of law without any further act being required.

(28) Where there is a valid and enforceable promise to assign in the future all the rights in an invention, patent application or patent that does not yet exist, the promisee holds equitable title in the invention, patent application or patent. Upon the invention being made, the patent application being filed, or the patent being issued, the promisee is entitled to demand the transfer of the legal title and to compel the same by way of civil proceedings. Subject to principle (20) above, for a promisee holding such an equitable interest to gain legal title to an invention, patent application, or patent, the promisor must transfer legal title by a written assignment from the promisor-assignor, after the invention is made, the patent application is filed, or the patent is issued.

244. I believe the judge was right to hold that clause 5.2 of the R&D Agreement amounts to an immediate assignment of future rights, not an agreement to assign those rights. It says that Pharmasset Barbados shall at all times, during or after the term of this Agreement, be the sole owner of all rights relating to or emanating from Intellectual Property, … Improvements, or other matters developed in, or relating to, a Project (emphasis added). This is the language of an immediate assignment, not an agreement to assign in the future. It shows an unambiguous, clear and unmistakable intent to assign with immediate effect all rights in Improvements to Pharmasset Barbados.
245. The judge was of the view that clause 8.6 did not detract from this conclusion. I agree with him. Such clauses are often used to ensure that any necessary legal formalities are complied with.
246. Accordingly, subject to issues 3 and 4, upon the invention in '368 being made, the transfer of legal title occurred by operation of law. In any event (and assuming it has lost on Issue 1) Idenix accepts that clause 5.2 was sufficient to confer beneficial title on Pharmasset Barbados.

Issue 3

247. Was the R&D Agreement signed? The judge held that it was. Mr Acland submits he was plainly wrong to have done so. He also submits that there are errors in the judge's reasoning and that he relied upon matters upon which no weight could properly be placed. I have found this a troubling issue for reasons I will explain.
248. The background facts are set out by the judge from [335] to [342] and may be summarised as follows. A draft of the R&D Agreement was approved at a meeting of the board of directors of Pharmasset Barbados in Hawaii on 11 December 1999. That meeting was also attended by representatives of Pharmasset Georgia, including Dr Schinazi (who was a director of both companies), Mr Kuhl, Mr Roemer and Dr Otto. No meeting of the board of directors of Pharmasset Georgia was convened, however. It was probably thought to be unnecessary because all important decisions concerning the Pharmasset business were taken at the level of the Pharmasset Barbados board and the representatives of Pharmasset Georgia who were present agreed with the key terms of the R&D Agreement. Further, the two companies had always operated according to its terms.
249. It was the practice of Pharmasset Barbados that important agreements, such as the R&D Agreement, should, for tax purposes, be signed by a director located in Barbados, at that time Mr Pritchard. But in May 2000, following a request from PWC for documents needed for an audit, it emerged that the R&D Agreement had not been signed. Neither Mr Kuhl (who was at that time employed by Pharmasset Georgia as Chief Financial Officer of Pharmasset) nor Mr Roberts (both of whom gave evidence) had a specific recollection of what happened next. However, the available documents show that on 5 May 2000 Mr Kuhl sent to Mr Roberts and Ms Metzger (Pharmasset's senior in-house lawyer at the time) an email, which was copied to Dr Schinazi, saying:

"1. Let's have the PSL/PSI agreement signed and dated (December xx, 1999 – the date the B of D authorized it at the HI meeting). I suggest that it be signed for LTD in Barbados, the next time we have them sign documents. Kathleen [Metzger] or Alan [Roemer] could sign it.

…

Let's get all of this together early next week to be sent to PWC Barbados. We do not have to send a signed agreement to PWC, the fact that Board approved it is good enough."

250. A few days later Mr Roberts made an electronic copy of a file which contained the draft R&D Agreement, removed the "Draft dated DATE " header from the text and printed it out. The five exhibits to the agreement were located in a file bearing a post-it note in Mr Roberts' handwriting reading "Originals of final draft of Exhibits".
251. No signed copy of the R&D Agreement has been found, however. The only evidence to support Gilead's case was, in the words of the judge at [342]:

"342. … Mr Roberts' recollection of having seen a signed copy bearing the signatures of Mr Pritchard and Dr Schinazi on behalf of Pharmasset Barbados together with two other signatures on behalf of Pharmasset Georgia made by persons whose names Mr Roberts could not recall. Mr Roberts could not recall when this happened, save that it was some time during his tenure at Pharmasset Georgia. Neither signature was particularly distinctive, nor were Mr Pritchard and Dr Schinazi identified by name in the document which Mr Roberts recalls that he saw. Mr Roberts' evidence was that the reason why this stuck in his mind was that it was the only time he could recall seeing an agreement signed on behalf of Pharmasset Georgia as well as Pharmasset Barbados. Every other document he could recall had only been signed on behalf of Pharmasset Barbados."

252. As I have said, Idenix accepted that the terms of the R&D Agreement had been assented to by both parties by May 2000, if not before, but contended that six factors, taken together, compelled the conclusion that the R&D Agreement had never been signed. Those six factors were, in summary, these. First, no less than 12 versions of the R&D Agreement had been retained, some in electronic form and some as hard copies. If the R&D Agreement had been signed, an executed copy would exist alongside the numerous drafts. Secondly, the R&D Agreement was an important document. Had it been signed, a copy would have been retained. Thirdly, no plausible reason had been given for the signed R&D Agreement having been lost. Fourthly, it was Pharmasset's standard practice to have two copies of every agreement signed, one for each party. Fifthly, Mr Roberts accepted that, if the R&D Agreement had been signed, he would have made one or two copies and would have distributed them to whoever might be interested. Sixthly, Gilead did not lead evidence from anyone who might have signed the R&D Agreement. Mr Roberts and Mr Kuhl gave evidence to the effect that, if the R&D Agreement was to be signed and Dr Schinazi was involved, then it would have been signed. However, no reason was given for Dr Schinazi's failure to give evidence. Further, as the judge observed, the same was true of Mr Pritchard, Mr Roemer, Ms Metzger and Mr Brown. As I shall explain, each of these persons was in a position to give relevant evidence.
253. The judge recognised that these were powerful submissions but considered that there were three factors which supported the conclusion that the R&D Agreement had been signed. First, there was documentary evidence that the R&D Agreement was prepared for signature in May 2000. Secondly, he had found the evidence of Mr Roberts that he had seen a signed version of the R&D Agreement credible and persuasive. And thirdly, the inherent probabilities. As the judge put it at [350]:

"… how likely is it that a document which was important for tax purposes and which had been specifically requested by PWC for the purposes of an audit was not signed? Furthermore, how likely is it that lightning struck twice i.e. that, having failed to get the R&D Agreement executed following the board meeting on 11 December 1999, Pharmasset again failed to do so following the request from PWC? Finally, how likely is it that, having gone to the trouble of preparing the exhibits to the R&D Agreement so that it could be executed, Pharmasset nevertheless did not get it signed?"

254. The judge acknowledged that he was troubled by the absence of evidence from Dr Schinazi, Mr Pritchard, Mr Roemer, Ms Metzger or Mr Brown. Nevertheless, he did not regard this as determinative:

"351. …. Let it be assumed that none of them has any recollection of either signing the R&D Agreement or seeing a signed version. I am still left with the documentary evidence, Mr Roberts' evidence and the inherent probabilities."

255. He then reasoned:

"352. The most troubling point is the absence of any original or copy of the signed agreement. I agree with counsel for Idenix that, for the various reasons he gave, this is very hard to explain if the R&D Agreement was indeed signed. Nevertheless, it is not impossible. For example, it is possible, if unlikely, that there was only one original, that no copies were made of it and that the original was lost during the archiving project.

353. I am left to weigh the documentary evidence, Mr Roberts' evidence and the inherent probabilities which favour execution against the improbability of no copy of a signed agreement surviving if it was signed. On the balance of probabilities, I conclude that the R&D Agreement was signed."

256. Mr Acland has vigorously attacked the judge's reasoning and conclusions. He points first of all to the three factors relied upon by the judge as supporting the contention that the R&D Agreement had been signed. He recognises the strength of the second factor but submits, in my view correctly, that the first and third are not founded upon an evaluation of all the relevant evidence. In particular, the judge appears to have taken no account of the fact that Mr Kuhl's email of 5 May 2000 made clear that the priority was to get the R&D Agreement to PWC and that this copy did not need to be signed. Moreover, the likelihood is that the copy documents were prepared by Mr Roberts to address that priority and there was no evidence that any step was taken by him or anyone else to get them signed. What is more, there was no evidence that any steps were taken to get the R&D Agreement signed after the board meeting in December 1999, and so there was no basis for the judge's observation about the improbability of lightning having struck twice.
257. I am also concerned that the judge failed properly to appreciate the significance of the absence of any evidence from the other potentially important witnesses. Dr Schinazi and Mr Pritchard were said by Mr Roberts to have signed the R&D Agreement, and Dr Schinazi was involved in day-to-day operations and was copied in on the email of 5 May 2000. Moreover, Mr Roemer and Ms Metzger were the two individuals who were authorised to sign the R&D Agreement on behalf of Pharmasset Georgia. Furthermore, Dr Schinazi, Mr Roemer, Ms Metzger and Mr Brown all kept corporate documents in their possession. There was no suggestion that these individuals were not available to give evidence; indeed Dr Schinazi had made a declaration for the purposes of proceedings before the EPO.
258. The judge dealt with this absence of evidence at [351] by assuming that none of these potential witnesses had any recollection of either signing the R&D Agreement or seeing a signed version of it. For my part, I do not believe that was an assumption that the judge was entitled to make. It may be that one or more of them could have given evidence which would have been directly supportive of Idenix's case. Mr Acland also submits and I accept that if it were indeed the case that none of these individuals had any recollection of having signed the R&D Agreement or seeing a signed copy then, far from being a neutral matter, this might well have undermined the evidence of Mr Roberts.
259. Mr Andrew Lykiardopoulos, who has argued this part of the appeal on behalf of Gilead, submits as follows. The judge approached the issue correctly, had the benefit of hearing Mr Roberts give his evidence and carefully considered the documents. He then evaluated the evidence and arrived at a finding on the balance of probabilities. In doing so he made no error of principle and his finding is carefully reasoned and properly founded in the evidence.
260. I acknowledge that the judge was clearly impressed by the evidence of Mr Roberts and found him a reliable witness. Nevertheless, I think there is considerable force in the points made by Mr Acland and which I have summarised. I incline to the view that if the judge had approached the matter correctly he would or ought to have found that Gilead had failed to make out its case. I am, however, concerned that we may not have been taken to all of the relevant transcript and documentary evidence and since it is not necessary to arrive at a final conclusion on this issue, I prefer not to do so.

Issue 4

261. This issue arises in the event that the R&D Agreement constituted an immediate assignment of the invention described in '368 to Pharmasset Barbados but was not signed. It raises a point of US law, namely whether it was necessary for Pharmasset Georgia to sign the agreement in order to transfer legal title to the invention. The judge did not address it and Mr Acland submits that, should it be necessary to decide it, we should refer it back to the judge. For the reasons I have explained, it is not necessary to do so.

Issue 5

262. This issue arises in two scenarios, both of which assume that the R&D Agreement was not an exclusive licence: first, if the R&D Agreement constituted an agreement to assign any invention described in '368 to Pharmasset Barbados rather than an assignment; and secondly, if the R&D Agreement constituted an assignment but it was not signed and US law required the signature of Pharmasset Georgia in order to transfer legal title. The question then is whether the possession by Pharmasset Barbados of equitable title to the invention was sufficient to make it a "successor in title" within the meaning of Article 4(A) of the Paris Convention.
263. The judge held that equitable title was sufficient. He referred to two decisions to that effect: first, his own decision in KCI Licensing Inc v Smith & Nephew plc [2010] EWHC 1487 (Pat), [2010] FSR 31 (at [50] to [54] and [69] to [71]) and secondly, to the decision of Birss J in HTC Corporation v Gemalto SA and Gemalto NV [2013] EWHC 1876 (Pat), [2014] RPC 9 at [134]. He then stated (at [419]) that he was not persuaded that his own decision in KCI was wrong.
264. The critical part of Arnold J's reasoning in KCI is set out in the judgment at [70]. There, after considering the decision of the Legal Board of Appeal of the EPO in J19/87 Burr-Brown/Assignment [1988] EPOR 350, he said this:

"… Article 4(A) of the Paris Convention and Article 87(1) of the EPC are provisions in international treaties whose operation cannot depend upon the distinction drawn by English law, but not most other laws, between legal and equitable title. When determining whether a person is a 'successor in title' for the purposes of the provisions, it must be the substantive rights of that person and not his compliance with the legal formalities that matter."

265. Mr Acland submits as follows. The judge's analysis starts correctly but jumps to the wrong conclusion. The signatories to the Paris Convention have a diversity of legal traditions and it is only the common law that distinguishes between equitable and legal ownership. Accordingly, the treatment of equitable interests in English law cannot have any bearing on what the signatories to the Paris Convention meant by the expression 'successor in title' in Article 4(A). Instead, one must search for and identify a notion of ownership and transfer of ownership that is common to all of those signatories.
266. It is my provisional view that the decisions on this issue in KCI and HTC are correct, that the Paris Convention does not purport to identify the requirements for the effective transfer of title to an invention and that these matters are left to the relevant national law. Indeed this appears to be the approach of the Boards of Appeal of the EPO: see, for example, T 0205/14 of 18 June 2015. In these circumstances the notion that it is the transfer of the substantive right and title to the invention which is important makes eminently good sense. Nevertheless, it emerged during argument that there may be other materials and decisions which bear on this issue and to which our attention has not been drawn. Accordingly and having regard also to the fact that it is not necessary in this appeal to express a final view on this issue, it seems to me that it is better left to be decided in another case.

Issue 6

267. This concerns Route 3 and depends upon the "designee" language of clause 6.2 of the Clark Agreement. This reads, so far as relevant:

"Employee hereby assigns and agrees to assign to [Pharmasset Georgia], its successors, assigns, or designees, all of Employee's rights to inventions …"

268. It was Gilead's contention that, if Routes 1 and 2 fail, Pharmasset Barbados was Pharmasset Georgia's designee. Its primary case here was that the R&D Agreement designated Pharmasset Barbados as the owner of the invention. In the alternative, it contended that Pharmassset Barbados had been designated by the parties' conduct, such as by the execution by Mr Clark of a confirmatory assignment in favour of Pharmasset Barbados on 16 October 2003 and the filing of the PCT by Pharmasset Barbados, both of which were done with Pharmasset Georgia's consent.
269. The judge accepted Gilead's primary case for the reasons he set out at [424]:

"… clause 5.2 of the R&D Agreement does not use the language of assignment, it uses the language of ownership. I see no reason why this aspect of the agreement cannot take effect through the mechanism of designation rather than the mechanism of assignment. Accordingly, I would if necessary hold that the Pharmasset PCT was entitled to priority through Route 3. It is not necessary to consider Gilead's alternative case."

270. Mr Acland submits that the judge has here fallen in to error. He argues that Route 3 is not only wholly inconsistent with Gilead's case on Routes 1 and 2 but is also contrary to the understanding of Pharmasset Georgia and Pharmasset Barbados at the time. It is, he says, no more than a lawyer's construct. As for the alternative case, raised upon this appeal by Gilead by respondent's notice, Mr Acland contends that this ignores and is contrary to 35 USC §261. These points were not elaborated in oral submissions, however, and I will say no more about them.

Overall conclusion

271. For the reasons I have given, I would dismiss this appeal.

Lord Justice Floyd:

272. I agree.

Lord Justice Patten:

273. I also agree.