FEDERAL COURT OF AUSTRALIA

Gilead Sciences Pty Ltd v Idenix Pharmaceuticals LLC [2016] FCA 169

orders

THE COURT ORDERS THAT:

1.    The parties confer and file agreed or competing orders reflecting these reasons for judgment within 14 days.

Note:    Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.

REASONS FOR JUDGMENT

JAGOT J:

1.    THE DISPUTE

1.1    Introduction

1    Sofosbuvir is a new treatment for the Hepatitis C virus (HCV). The applicant (referred to below as Gilead) wishes to sell sofosbuvir in Australia.

2    Sofosbuvir is a compound having the following chemical structure:

3    This structure was disclosed in Gilead’s Australian patent no. 2004253860 filed on 21 April 2004 and published on 13 January 2005, but which claims a priority date of 30 May 2003 based on International Patent Application WO 2005/003147. Gilead’s patent is referred to as the Clark patent, being a reference to Jeremy Clark, one of the inventors.

4    The respondents (referred to collectively below as Idenix) contend that sofosbuvir infringes Idenix’s Australian patent no. 2003247084 (the Idenix patent). The Idenix patent was filed on 27 June 2003 and published on 19 January 2004, but claims earlier priority dates of 28 June 2002 based on US Patent Application 60/392,350 (referred to as the 350 application) or 14 May 2003 based on US Patent Application 60/470,949 (referred to as the 949 application).

5    Gilead concedes that sofosbuvir infringes claims 7 and 8 (as well as dependent claims 10 and 13) of the Idenix patent but contends that the Idenix patent is invalid on the grounds of lack of novelty, lack of internal fair basis, insufficiency, lack of utility, lack of manner of manufacture and false suggestion.

6    Claim 7 of the Idenix patent is as follows:

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; cholesterol; or a pharmaceutically acceptable leaving  group which when administered in vivo is capable of providing a compound  wherein R¹ and/or R² is independently H or phosphate;

X is O, S, SO₂, or 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.

7    Claim 8 also claims a compound of Formula (IX) but where X is O and Y³ is H.

8    Claim 10 claims 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 9 in a pharmaceutically acceptable carrier.

9    Claim 13 claims the composition of claim 10 wherein the Flaviviridae virus is HCV.

1.2    The allegations of invalidity – a brief overview

1.2.1    Lack of novelty

10    Gilead contends that the relevant claims of the Idenix patent are not fairly based on the priority documents on which Idenix relies, the 350 and 949 applications. As such, the Idenix patent is not entitled to the priority dates of 28 June 2002 or 14 May 2003, but is only entitled to the date on which the specification for the Idenix patent was filed, being 27 June 2003. If this is so, then assuming that the Clark patent is entitled to the priority date of 30 May 2003, the relevant claims of the Idenix patent would not be novel because the same invention is anticipated by the Clark patent.

1.2.2    Internal fair basis

11    Gilead contends that the relevant claims of the Idenix patent (claim 7 and all dependent claims) are not fairly based on the specification. In particular, Gilead contends that there is no real and reasonably clear disclosure in the specification of a compound which has an F (fluorine or fluoro) at the 2' down position together with methyl at the 2' up position, a nucleobase that includes natural bases, and a prodrug element only at the 5' position but such compounds are within claim 7 and dependent claims.

1.2.3    Insufficiency

12    Gilead contends that the Idenix patent does not sufficiently describe how to synthesise compounds falling within claim 7, in particular because it does not describe how to produce a compound that contains F at the 2' down position of the sugar ring of the compound and installing F at that position and a carbon containing group such as methyl (Me or CH₃) at the 2^' up position was not routine chemistry as at the claimed priority dates of the Idenix patent.

13    Gilead also contends that the Idenix patent does not identify which of the compounds within claim 7 are effective for the treatment of Flaviviridae infections or HCV and does not describe how to identify such compounds.

1.2.4    Lack of utility

14    Gilead contends that the Idenix patent claims that the compounds described are useful in the prevention and treatment of Flaviviridae infections including HCV but the relevant claims encompass compounds (or compositions or uses) that either cannot be made (those where Y³ is bromine (Br) or iodine (I)) or are inactive against Flaviviridae infections including HCV or are toxic or both.

1.2.5    Manner of manufacture

15    Gilead contends that the Idenix patent claims trillions of compounds which the patent asserts but does not demonstrate are useful in the prevention and treatment of Flaviviridae infections including HCV. As such, the Idenix patent contains an abstract idea but not a manner of manufacture.

1.2.6    False suggestion

16    Gilead contends that the Idenix patent makes representations about the making of compounds and their efficacy in the treatment of Flaviviridae infections including HCV which were false and material to the grant of the patent.

17    If any one or more of Gilead’s contentions is correct, the Idenix patent is (or relevant claims are) invalid.

2.    THE SCIENCE

2.1    Common general knowledge

18    There were a number of disputes between the parties about the knowledge that would be attributed to the skilled addressee of the Idenix patent. Despite this, the parties agreed that certain concepts would have been known to, accepted and assimilated by the bulk of persons skilled in the art with which the Idenix patent is concerned irrespective of the priority date of the patent. Accordingly, these may be accepted to form part of the common general knowledge (sometimes abbreviated to CGK in the submissions of the parties) by reference to which the Idenix patent is to be construed.

19    This common general knowledge concerns matters of organic, specifically nucleoside, chemistry and virology.

20    Apart from some basic information about nucleotides which I also consider to have been part of the common general knowledge of the skilled addressee of the Idenix patent, the following summary is based on the documents (a chemistry primer and virology primer) which were the subject of agreement between the parties. It should be noted that certain statements are not included in this summary, being matters I consider potentially inconsistent with specific submissions the parties made about the common general knowledge. If any inconsistency remains, this section is to be read subject to my specific findings about the common general knowledge, which appear below.

2.2    Organic and nucleoside chemistry

2.2.1    Chemical bonds

21    The sharing of electrons between two atoms can result in the creation of chemical bonds. Each single chemical bond contains two electrons.

22    Each C (carbon) atom has 4 electrons available to share with other atoms for bonding so that it can make four bonds with other atoms. Each H (hydrogen) atom has one electron available to share, meaning that hydrogen can form only one bond with another atom.

23    The bond created by the sharing of the electrons between C – H is covalent which means the bond is created by the sharing of electrons. The sharing of one pair of electrons is commonly referred to as a single bond. When two pairs of electrons are shared between the same two atoms, this is called a double bond. When three pairs of electrons are shared between the same two atoms, this is called a triple bond.

24    Covalent bonds are different to ionic bonds. Ionic bonds form due to an electrostatic attraction between two charged atoms or molecules. Charged atoms or molecules are known as ions. In an ionic bond, two or more ions of opposite charge are attracted to each other in an interaction that does not involve sharing electrons. Rather, an ionic interaction involves the pairing of opposite charges which are respectively positive and negative.

2.2.2    Organic chemistry terms

25    In the context of organic chemistry, an analogue is a molecule or compound to which at least a single chemical change has been made relative to a natural compound.

26    Conjugate is the name often given to a molecule where two or more classes of molecules are linked together. For example, a peptide that is attached to a nucleic acid is a conjugate.

27    An enzyme is a biological molecule that catalyses (or accelerates) a chemical reaction.

28    A functional group is the term organic chemists use to describe structural elements that exhibit particular chemical behaviours or properties. For example, one common functional group in organic chemistry is a hydroxyl.

29    A hydroxyl (also referred to as a hydroxy group) is commonly represented by the shorthand letters OH. A hydroxyl attached to a carbon atom is referred to as an alcohol. Hydroxyls (OH) are commonly referred to as primary, secondary or tertiary hydroxyls based on the classification of the carbon atom to which the OH substituent is bonded. A carbon is classified as a primary, secondary or tertiary carbon if it is bonded to one, two or three carbons, respectively. For example:

(1)    a primary hydroxyl (1° hydroxyl) is bonded to a carbon atom that has one further carbon atom attached;

(2)    a secondary hydroxyl (2° hydroxyl) is bonded to a carbon atom that has two further carbon atoms attached; and

(3)    a tertiary hydroxyl (3° hydroxyl) is bonded to a carbon atom that has three further carbon atoms attached.

30    The term heteroatom is the term commonly used to describe any atom other than a carbon or hydrogen in an organic molecule.

31    Ligand is the name given to a molecule that binds specifically to a receptor site of another molecule.

32    Polymorph is a different crystalline form of the same compound. Polymorphs are not different compounds, just different solid states of a compound.

33    Pharmacokinetics is the study of what happens to a drug once it is introduced into the body and in general terms involves the study of the absorption, distribution, metabolism and excretion of a drug.

34    Reagents are compounds usually used to help bring about chemical change in other compounds.

35    A molecule is considered a tautomer (or tautomeric) if it can exist in another form of itself, simply by an internal rearrangement of electrons and bonds. A tautomer can freely interconvert between its tautomeric forms. In general, one tautomeric form of a molecule will predominate over the others. For example, the nucleobases adenine, cytosine, guanine, thymine and uracil exist as tautomers.

36    Organic molecules can have the same molecular formula (i.e. have the same number of each type of atom) but may be different chemical substances. These molecules are called isomers. When two molecules have the same molecular formula but the atoms are connected differently, the molecules are known as structural isomers. Where two molecules have the same molecular formula and atoms are connected in the same way, but differ in their structural arrangement in space, the molecules are known as stereoisomers.

37    Stereochemistry is concerned with the two-dimensional (2D) and three-dimensional (3D) shape of molecules. Stereoisomers, as noted, are compounds which have the same chemical formula and the atoms bonded in the same order but the atoms are arranged differently in space. Enantiomers and diastereoisomers are two types of stereoisomers.

38    An aspect of organic chemistry and stereochemistry is the concept of chirality. The word chiral is a Greek term meaning “handed”. A chiral molecule is a type of molecule that has a non-superimposable mirror image, analogous to the left and right hands and these forms are typically referred to as enantiomers. The figure below illustrates the enantiomers of the amino acid alanine which has one chiral carbon. One structure is the enantiomer of the other. In nature, one enantiomeric form may be more prevalent than the other.

39    Carbon is a good example of an atom that can be chiral. A carbon atom can form four bonds. When a carbon atom has four groups attached to it through four single bonds, it is referred to as being in a tetrahedral arrangement. If each of the four groups attached to the carbon atom through four single bonds are different, then the carbon is a chiral carbon (also known as a stereocentre). Amino acids, sugars and nucleosides are usually chiral molecules.

40    Enantiomers have the same physical properties when analysed using non-chiral methods and can only be distinguished from each other in a chiral environment. The human body is an example of a chiral environment. Enantiomers rotate plane polarised light (which refers to light which has been filtered to select only light in a single plane) to the same degree but in opposite directions. This ability to rotate plane polarised light is referred to as optical activity. If a solution of a molecule fails to rotate plane polarised light, this could be due to a number of reasons including that the solution contains non-chiral molecules or it contains a racemate and is a racemic mixture, which is a mixture that contains two enantiomers in equal proportions.

2.2.3    Conventions for drawing and naming organic molecules

41    The simplest method for drawing an organic molecule uses a structural formula or skeletal formula. A structural formula shows how the atoms are bonded and each bond is represented by a single line. In a skeletal formula:

(1)    the hydrogen and carbon atoms are not illustrated, but the carbon atoms are represented by the intersection (or vertices and termini) of carbon chains;

(2)    the lines themselves represent the bond connecting the carbon atoms; and

(3)    any other non-hydrogen groups attached to the carbon atoms are illustrated.

42    Because stereochemistry is such an important concept in organic chemistry, a number of conventions have been devised in order to allow representation of 3D concepts on paper. The 3D stereochemistry of molecules can be illustrated on paper in 2D form by, for example, using the following generally accepted drawing conventions:

(1)    a solid wedge indicates that the bond or group is projecting out of the plane of the page towards the observer;

(2)    a broken hashed wedge indicates that the bond or group is pointing into the plane of the page away from the observer;

(3)    a straight line indicates that the bond or group is in the plane of the page; and

(4)    a wavy (or wiggly) line indicates either (1) unknown or undefined stereochemistry or (2) a mixture of two stereoisomers, but not necessarily a 50:50 mixture.

43    Haworth projections are used to depict rings of atoms and provide an illustration of the stereochemistry of the groups attached to the ring. By convention, the thickened line at the bottom of the sugar ring indicates atoms which are coming out of the page towards the observer. In a Haworth projection the substituents are drawn in the “up” and “down” orientation, which illustrates that these substituents are either above or below the plane of the sugar ring, respectively. An example of a Haworth projection for glucose is illustrated below:

44    It is common convention to show organic molecules without illustrating all of the C and H atoms, as illustrated above. However, an organic chemist understands that both the C and H atoms are present even though they are not explicitly labelled as “C” and “H”.

45    A Haworth projection for glucose and an example nucleoside showing the C and H atoms and their numbering conventions is illustrated below:

46    A Markush structure illustrates a group of compounds with common features, together with each of the variable groups which are typically labelled as R or other letters of the alphabet that do not depict chemical elements such as X, Y and Z. A Markush structure can also be expressed in a Haworth projection to illustrate the stereochemistry features of the compounds of the Markush structure. An example Markush structure in a Haworth projection for a nucleoside is illustrated below:

47    Carbon atoms on a sugar are numbered consecutively starting with number 1 which is assigned to the most highly oxidised carbon. In nucleoside chemistry the numbers of the carbons of the sugar are designated using the symbol (') termed “prime”, and the positions on the nucleobase are numbered using non-prime numbering. Prime numbering can be written in a number of accepted ways including 1', C1', 1'C and 1'-C. Figure 8 above illustrates the different numbering systems used for carbohydrates (using glucose as an example) and nucleosides (using adenosine as an example).

48    The stereochemical configuration of a chiral atom can be conveyed from the way the compound is named. A commonly used convention for defining the stereochemical configuration of a chiral atom is by using the letters R and S. An organic chemist can determine whether a chiral atom is of an R or S configuration by ranking the four different groups attached to the chiral atom. Each group is ranked by the atomic number of the atom closest to the chiral carbon atom. The group with the highest atomic number is ranked first, the group with the second highest atomic number is ranked second, the group with the third highest atomic number is ranked third, and the group with the smallest atomic number is ranked fourth.

49    The D and L terminology is another descriptor of stereochemistry as it relates to a sugar or an amino acid. Designation of a sugar as D or L is based on the orientation of a particular substituent. In the context of a nucleoside, it is the 4'-position which determines whether a nucleoside will be designated as D or L. If drawn as a Haworth projection and in the conventional orientation, when the substituent at the 4'-position is orientated above the plane of the ring it is a D nucleoside, and when below the plane of the ring, it is an L nucleoside.

2.2.4    Organic chemical reactions

50    In a typical substitution reaction (more correctly referred to as nucleophilic substitution and sometimes referred to as a displacement reaction) an atom or group of a molecule is replaced (substituted) with another atom or group. Nucleophilic substitution is generally taught in undergraduate organic chemistry and is one type of reaction between an electron donator (nucleophile, Nu-) and an electron acceptor (electrophile). Nucleophiles are electron-rich molecules and because of their excess of electrons, they tend to react with electron-poor molecules and are therefore classed “nucleus loving”. Electrophiles are electron-poor molecules and because of their lack of electrons, they tend to react with electron-rich molecules and are therefore classed “electron loving”.

51    In a typical elimination reaction, a hydrogen atom attached to one carbon atom is removed by a base and a group on an adjacent atom is removed (or eliminated). In elimination reactions, a new double bond is formed between the two participating carbon atoms.

52    A typical addition reaction is the opposite of an elimination reaction. A carbon to carbon double bond is converted to a carbon to carbon single bond and an additional atom or group is added to each of the participating carbon atoms.

2.2.5    Organic synthesis

53    Synthesis is the process of using a series of chemical reactions to break down, build up or reconstruct molecules. Often starting with simple, commercially available starting materials, a series of controlled organic reactions (or chemical transformations) is used to turn those materials into a compound of interest.

54    A reaction scheme is a standard tool used by organic chemists and represents a pictorial road map of the series of chemical reactions (i.e. a reaction sequence) which are performed in a particular order to form a compound of interest. Reaction schemes are also sometimes referred to as synthetic pathways or schemes.

55    Reagents used in reaction schemes can selectively react with a particular group out of a number of chemically similar groups (called a chemoselective reagent) or particular molecules having a particular stereochemistry or react to give a particular stereochemistry (called stereoselective reagents).

2.2.6    Amino acids, peptides and proteins

56    Amino acids are compounds that have a carboxyl group (-COOH, where C is carbon, O is oxygen and H is hydrogen) bound indirectly to an amino group (-NH₂ where N is nitrogen and H is hydrogen) and a side chain (commonly referred to as R).

57    Peptides, polypeptides and proteins are chains of amino acids joined together by peptide bonds.

58    The terms protein and polypeptide are frequently used interchangeably, with the term protein being more commonly used for a naturally occurring polypeptide. Proteins can be broken down or cleaved into fragments which may be termed peptides or polypeptides. Each of these fragments can be further broken down into their individual amino acids. Peptides, proteins and polypeptides can also be made by chemical synthesis or by recombinant methods.

2.2.7    Nucleosides and nucleotides

59    Nucleoside chemistry refers to the study, manipulation and use of a class of molecules known as nucleosides. The term nucleoside chemistry is also colloquially used to describe the study, manipulation and use of either nucleosides or nucleotides.

60    A nucleoside is a chemical compound which is made up of two parts:

(1)    a heterocyclic base (which is typically called a base or more precisely, a nucleobase however both terms can be used interchangeably); and

(2)    a sugar (for example, ribose in ribonucleic acid or RNA or a 2'-deoxyribose in deoxyribonucleic acid or DNA),

and the sugar and nucleobase are linked by a glycosidic bond.

61    The general structure of a nucleoside can be schematically represented as follows:

62    The structures of a naturally occurring ribonucleoside and deoxyribonucleoside (specifically a 2'-deoxyribonucleoside) are illustrated below:

63    A nucleotide comprises a nucleoside to which one or more phosphate groups has been covalently bonded. The process by which phosphate groups are added to the sugar group of a nucleoside is known as “phosphorylation”.

64    A nucleobase is a core component of a nucleoside and a nucleotide. Nucleobases naturally occurring in 2'-deoxyribonucleosides and 2'-deoxyribonucleotides are adenine (A), guanine (G), thymine (T) and cytosine (C). Nucleobases naturally occurring in ribonucleosides and ribonucleotides are adenine (A), guanine (G), cytosine (C) and uracil (U) (instead of thymine which is present in 2'-deoxyribonucleosides and 2'-deoxyribonucleotides only).

65    These nucleobases fall within two groups – purine and pyrimidine. A purine is a 5-membered ring fused to a 6-membered ring (each ring containing two nitrogen atoms). Guanine (G) and adenine (A) are members of a class collectively called purines. A pyrimidine is a single 6-membered ring (containing two nitrogen atoms). Thymine (T), cytosine (C) and uracil (U) are members of a class collectively called pyrimidines.

66    Positions on the nucleobase are distinguished from those on the sugar in a nucleoside by adopting non-prime numbering for the nucleobase.

67    Modifications can be made to the naturally occurring nucleobases to produce a nucleoside analogue or nucleotide analogue when the modified nucleobase is linked to the sugar (which may itself also be modified). Naturally occurring nucleosides and nucleotides can be altered at almost every position of the sugar ring or the nucleobase.

2.2.8    Sugars

68    The sugar component of a nucleoside or a nucleotide is a cyclic sugar. The sugar component of a natural ribonucleoside or ribonucleotide is ribose which is a five carbon sugar. The sugar component of a natural deoxyribonucleoside or deoxyribonucleotide is deoxyribose, specifically a 2'-deoxyribose which indicates that no hydroxyl (OH) is present at the 2'-position.

69    The ring of a ribose contains four carbon atoms and one oxygen atom. As noted earlier, the carbon atoms of the sugar in a nucleoside are identified using prime numbering and the 1'-carbon is known as the anomeric carbon. The remaining carbons on the sugar are then numbered consecutively in a clockwise manner.

70    The oxygen atom naturally present in a sugar ring and commonly drawn at the top of chemical structures for the sugar ring is referred to as the ring oxygen.

71    The sugar and nucleobase of a nucleoside are connected by a chemical linkage referred to as a glycosidic bond. In the laboratory, the process used to create a glycosidic bond and thereby attach the sugar to the nucleobase is known as glycosylation (glycosylation is a general term used to describe the attachment of a sugar to another molecule). Nucleosides and nucleotides (and analogues thereof) in which the nucleobase is attached by a nitrogen (N) atom to the anomeric carbon (1'-carbon position) of the sugar ring (a N - C linkage) are referred to as N-nucleosides.

72    When the nucleobase is a naturally occurring pyrimidine (cytosine, thymine or uracil) the 1'-carbon of the sugar attaches to the nitrogen at the 1-position on the nucleobase which is referred to as N1.

73    When the nucleobase is a naturally occurring purine (guanine or adenine) the 1'-carbon of the sugar attaches to the nitrogen at the 9-position on the nucleobase which is referred to as N9.

74    The nucleobase and sugar can also be connected via a carbon-carbon linkage. That is, the 1'-carbon of the sugar and a carbon in the nucleobase. These nucleosides are referred to as C-nucleosides.

75    While adenine, guanine, thymine, cytosine and uracil are naturally occurring nucleobases, the corresponding nucleosides containing adenine, guanine, thymine, cytosine and uracil nucleobases are referred to as adenosine, guanosine, thymidine, cytidine and uridine, respectively.

76    In general, the stereochemical configuration of nucleosides is described using D and L terminology (as described above) and alpha (α) and beta (β) terminology.

77    The α and β terminology refers to the orientation of the nucleobase at the 1'-position relative to the orientation of the substituent (or group) at the 4'-position. Where the nucleobase and substituent at the 4'-position are on the same side of the ring, a nucleoside is classified as a β-nucleoside and where the nucleobase and substituent at the 4'-position are on opposite sides of the ring, a nucleoside is classified as an α -nucleoside. The difference is shown below:

78    Although the α and β terminology is based on the orientation of the nucleobase relative to the substituent (group) on the 4'-position, the alpha and beta terminology is sometimes loosely used to describe whether substituents at any position on the sugar are on the α -face or β -face of the sugar ring.

79    The α and β terminology and the D and L terminology can be used together to describe the orientation and stereochemistry of nucleosides. For example, a nucleoside chemist understands that the name 2'-D or L-valine ester of β-D-2',6-dimethyl-cytidine indicates that:

(1)    the compound is derived from the nucleoside cytidine. The β -D indicates that the stereochemistry of the nucleoside is of a particular configuration: in this case it is in the configuration of the natural nucleoside;

(2)    there are two methyl groups in the nucleoside: one at the 2'-position on the sugar and one at the 6-position of the cytosine nucleobase; and

(3)    the OH group normally present at the 2'-position has been converted to a valine ester. The reference to 2'-D or L valine indicates that the stereochemistry of the valine ester is unspecified. That is, the valine may be in the D or L configuration.

80    One of the modifications that may be made to a natural nucleoside is the substitution of a carbon atom for the oxygen atom in the five-membered ring of the sugar of the nucleoside.

81    Carbohydrates that have a chemical structure that includes a five membered ring consisting of four carbon atoms and one oxygen atom are collectively identified by the term “furanose”. The ring structure of such carbohydrates is referred to as the “furanose ring”. The furanose ring in a nucleoside is shown in red below:

82    Nucleoside analogues in which a carbon atom has been substituted for the oxygen atom of the five-membered sugar are referred to as “carbocyclic nucleosides”. The ring structure of such compounds is referred to as a “carbocyclic ring”.

83    Prior to 2002, carbocyclic nucleosides had been reported as being more metabolically stable than natural nucleosides. This was reported as being due to the fact that they were not subject to the action of nucleoside phosphorylase and hydrolase enzymes that cleave the glycosidic linkage of natural nucleosides.

2.3    Nucleosides and nucleotides as antiviral drugs

84    HCV is a single-stranded RNA virus that infects liver cells in humans. HCV replicates using the intracellular machinery of its host cell. One of the key processes in the replication of HCV is the making of multiple copies of the HCV RNA. The enzyme responsible for this process is a viral RNA dependant- RNA-polymerase called NS5B.

85    One mechanism by which nucleoside analogues can act as antiviral drugs is by the inhibition of the viral polymerase. In order to do so, the nucleoside analogue must be recognised by the relevant enzymes involved in the processes of phosphorylation (to be converted into the active triphosphate form) and RNA synthesis (to be incorporated into the growing RNA chain) described above (i.e. be a suitable substrate for those enzymes). Once incorporated into the RNA chain, the nucleoside analogue disrupts growth of the chain, resulting in chain termination. In the case of HCV, the nucleoside analogue (in the triphosphate form) must be recognised by NS5B as a substrate to be incorporated into the growing RNA chain.

86    Where the nucleoside analogue does not possess a 3'-hydroxyl group, chain termination results because an incoming nucleotide cannot be attached to the RNA chain. Where the nucleoside analogue does possess a 3'-hydroxyl group, chain termination can still result where the modification(s) to the nucleoside analogue prevent the formation of a 3', 5'-phosphodiester bond with an incoming nucleoside. For example, the modification(s) may alter the conformation (shape) of the sugar ring so that the 3' -hydroxyl group is not correctly positioned for the formation of a 3', 5'-phosphodiester bond. Alternatively, the modification(s) may sterically hinder the formation of a 3',5'-phosphodiester bond.

87    An example of a prodrug modification at the 3'-position of a nucleoside is the addition of an acyl group. An acyl group is comprised of a carbonyl (C=O) attached to a carbon-containing group (R). When an acyl group is bonded to the oxygen atom of an hydroxyl group, the new group formed is called an ester.

88    The structure of a 2'-methyl-“up” nucleoside analogue with a 3'-acyl (or 3'-ester) prodrug modification is shown below. This is an example of a nucleoside prodrug. After metabolism in the body, the 2'-methyl-“up” nucleoside analogue is formed.

89    A specific example of an ester prodrug modification is the addition of valine. Valine is a naturally-occurring amino acid. Amino acids contain both an amino group (NH₂) and a carbocyclic acid group (COOH). The structures of valine and a nucleoside analogue with a 3'-valine prodrug modification are shown below.

90    An example of a prodrug modification at the 5'-position of a nucleoside is the addition of a phosphoramidate group. A phosphoramidate group is comprised of a phosphorus atom attached to:

(1)    an oxygen atom via a double bond;

(2)    two oxygen atoms via single bonds; and

(3)    a nitrogen atom via a single bond.

91    The structure of a 2'-methyl-“up” nucleoside with a 5'-phosphoramidate prodrug modification is shown below. This is an example of a nucleotide prodrug. After metabolism in the body, the 2'-methyl-“up” nucleoside monophosphate analogue is formed.

2.4    Virology

2.4.1    Viruses and virology

92    Virology is the study of viruses.

93    A virus is an infectious microorganism that replicates inside the cells of other organisms. A virus is composed of nucleic acid (either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA)) in a protein coat, which is able to deliver the nucleic acid to target (host) cells. This viral nucleic acid contains sufficient coding capacity to permit its replication to produce new virus. Viruses enter host cells via processes known as “adsorption” and “penetration”, and, once inside the host cell, the virus is uncoated, leaving the viral nucleic acid within the cytoplasm of the cell, from where it may or may not migrate to the nucleus. This means that it can be “translated” into proteins and “transcribed” into nucleic acid copies, enabling replication of the virus.

94    Pathogenesis is a general term meaning the study of the process of disease. In the context of viral infections, it refers to the study of the outcomes of viral infection, and the mechanisms of disease. Pathogenesis also involves investigation of the timing of the expression of certain host cellular proteins in response to viral infection, and the impact of viral proteins on cellular proteins, cell division or cell death.

2.4.2    The Flaviviridae family

95    The Flaviviridae are positive-sense, single-stranded RNA enveloped viruses. That is, the Flaviviridae genome:

(a)    consists of RNA (whereas some virus genomes consist of DNA);

(b)    consists of a single strand of RNA (whereas some RNA virus genomes are double-stranded); and

(c)    consists of “positive-sense” RNA (whereas some single-stranded RNA virus genomes consist of “negative-sense” RNA). The key difference between positive-sense and negative-sense RNA is that positive-sense RNA is similar to messenger RNA (mRNA) in that it can be used directly by host-cell machinery to produce new proteins, while negative-sense RNA must first be “transcribed” (see below) to produce positive-sense RNA before new proteins can be synthesised.

96    The Flaviviridae are “enveloped” viruses. This means the genome is encapsulated in a core (capsid) protein which is in turn enveloped by a lipid (i.e. fat or oil) envelope into which the envelope proteins are inserted. This is shown in the figure below, which is a diagram of HCV.

Figure 1 – ‘enveloped’ structure of HCV, a member of the Flaviviridae.

97    Within the Flaviviridae there are currently four genera, as shown in the table below. The fourth genus, pegivirus, was proposed in 2011 but the other three were recognised by 2002.

Table 1 Flaviviridae genera and example strains

98    Flaviviridae viruses were grouped together because they exhibited a certain sequence conservation as well as similarity in their genomic organisation and the general features of the lifecycle of the viruses, and they all replicate their genome via an RNA-dependent RNA polymerase. In addition, each virus shares similarities in virion morphology including the size and shape of the viral particle. However, each virus in the family was recognised as having a unique set of biological properties, such as, for example, host and cell type tropism and pathogenic properties, as well as different proteins and antigens.

99    Of the Flaviviridae, only HCV generally causes persistent (or chronic) infection in humans:

(a)    pestiviruses, GBV-A, GBV-B and GBV-D do not infect humans (GBV-A and GBV-B are monkey viruses, and GBV-D is a bat virus);

(b)    flaviviruses generally cause acute (i.e. self-limiting) infection in humans; and

(c)    GBV-C causes acute asymptomatic infection in humans.

100    “Viral replication” may refer to the entire process of producing new virus to be released from the host cell or the term “replication” may be used to describe the narrower step of copying the viral nucleic acid, or “viral genome” itself (which is one step in the broader replication of the virus, described below).

101    The diagram below sets out the general steps involved in replication of positive-sense RNA viruses (such as the Flaviviridae) from viral entry into the host cell through to the exit of new virus ready to infect new cells.

Figure 2 – General strategy for positive-sense virus replication.

102    Generally speaking, the process of viral replication for Flaviviridae is as follows:

(a)    The virus enters the cell and “uncoats” to release the viral RNA into the cytoplasm of the host cell.

(b)    The genetic information encoded in the viral RNA (i.e. genes) is utilised, in a process known as “translation”, to produce a “polyprotein” constituted by all the viral proteins in an immature state. Both during and after translation, the polyprotein is progressively cleaved (i.e. cut) by a combination of host-cell enzymes and enzymes within the polyprotein itself into the individual viral proteins. These viral proteins are necessary to produce new virus.

(c)    One of the proteins produced from the polyprotein, the RNA-dependent RNA polymerase (RdRP), then makes new copies of the viral RNA, in a process known as “transcription”. Transcription of positive-sense viral RNA produces a complementary, negative-sense strand. This results in the production of a double-stranded RNA molecule (i.e. incorporating both the original positive-sense RNA and the negative-sense RNA) that is then used as a template for the production of nascent (i.e. growing) positive-sense RNA. This positive-sense RNA is a copy of the original viral RNA. Although the above diagram shows only RdRP being involved in transcription, this is a simplified illustration. In fact, transcription uses a “replication complex” that contains a number of proteins necessary for the replication of the viral RNA. In most RNA viruses (including Flaviviridae), a number of host cell proteins contribute to viral RNA replication in the replication complex.

(d)    The positive-sense viral RNA that has been produced can then:

(i)    produce more viral proteins;

(ii)    produce more negative-sense RNA templates for synthesis of new positive-sense viral RNA; or

(iii)    be “encapsidated” by the capsid protein, which is then enveloped by the envelope proteins by budding into the lumen of the endoplasmic reticulum (a network of intracellular membranes) to produce new virus that is then secreted from the host cell (and can then infect new cells).

2.4.3    HCV classification

103    As noted above, HCV is a member of the Flaviviridae family, genus hepacivirus. HCV itself has recently (in 2014) been recognised as having seven genotypes (and 67 sub-types). Classification of viruses into genotypes and sub-types is based upon the similarity in their genome. HCV genotypes can vary by as much as 30% in gene sequence. Viruses within an HCV genotype typically contain more closely related sequences, and vary by approximately 20% in gene sequence, or 10% within sub-types.

2.4.4    HCV genome and proteins

104    HCV has a genome of approximately 9.6kb (i.e. the RNA strand consists of approximately 9,600 nucleotide bases).

105    Below is a diagram setting out the organisation of the HCV genome including, in particular, the genes coding for the viral proteins. The figure starts on the left-hand side with the 5' NTR, or 5' UTR, or 5' NCR (shorthand for “5 prime non-translated region”, “5 prime untranslated region” and “5' non coding region”, respectively), which is 341 nucleotides long and acts as an internal ribosome entry site (IRES). An IRES is a structure that allows the viral RNA to directly interact with a host cell’s protein-making machinery, called ribosomes, in order to translate new viral proteins. HCV is one of the few Flaviviridae with an IRES (GBV-B is another).

Figure 3 – Organisation of the HCV genome

106    The organisation of the HCV genome is also depicted below.

Figure 1: HCV genome (adapted from Dubuisson et al, "Interaction of hepatitis C virus proteins with host cell membranes and lipids" (2002) 12 Trends in Cell Biology 517 at 518).

107    As discussed above, during viral replication, the viral proteins are produced by translating the HCV genome to produce a polyprotein, which is co- and post-translationally (i.e. at the same time as, and after, translation) cleaved into the smaller mature proteins. The “structural” proteins (i.e. C, E1 and E2) are cleaved by host cell protease (an enzyme which breaks down the peptide bonds between amino acids), and the “non-structural” proteins are cleaved by viral enzymes. The “structural” proteins are so-called because they physically make up each virus particle (i.e. the capsid and protein coat described above). The “non-structural” proteins do not form part of the virus particle, but are produced as part of (and play a role in) the replication cycle inside a host cell.

108    The structural (C, E1 and E2) proteins are encoded by the core (C) and envelope (E1 and E2) genes respectively:

(a)    C protein: the main role of the HCV core protein is to form the capsid, which carries and protects the HCV genome. Once the capsid contains the HCV genome, the capsid and genome together are referred to as a nucleocapsid.

(b)    E1 and E2 proteins: the nucleocapsid is then enveloped in a lipid-based envelope in which the HCV envelope proteins are embedded.

109    The organisation of the HCV polyprotein is depicted below.

Figure 2: Structure of the HCV polyprotein (adapted from Knipe et al (eds.), Fields Virology (Lippincott Williams & Wilkins, 4th ed, 2001) 1129).

Note that one of the diamonds between the C and E1 proteins is not a cellular signal peptidase (as indicated in Figure 2) but a cellular signal peptide peptidase.

110    The remainder of the HCV genome encodes the non-structural, or NS, proteins:

(a)    p7 is thought to be an ion channel protein that is essential for efficient assembly and release of infectious virus particles. Although it is probably a non-structural protein it has sometimes been classified as a structural protein.

(b)    NS2 is thought to be required for viral morphogenesis (i.e. the process of assembling the structural proteins and viral genome into a complete virus particle). It self-cleaves from the polyprotein between NS2 and NS3.

(c)    NS3 is a multifunctional protein, with protease, helicase and ATPase activity. When acting as a protease, NS3 recognises and cleaves the HCV polyprotein into the individual, smaller, viral proteins. This protease activity is dependent on an interaction with NS2 and NS4A. Specifically, NS3 interacts with NS2 to cleave itself from NS2 and, thereafter, it requires NS4A as a cofactor to cleave the remaining non-structural proteins. When acting as a helicase, NS3 unwinds the viral RNA so that the RNA can be more efficiently copied by the viral replication complex. As an ATPase, it helps release the energy required to unwind the viral RNA, by releasing phosphate groups from ATP (adenosine triphosphate).

(d)    NS4B anchors the virus replication complex to a structure within the host cell called the endoplasmic reticulum. For positive-sense RNA viruses like HCV, viral replication is more efficient when it is anchored to a cellular structure.

(e)    The function of NS5A is not known but it is thought to play a role in morphogenesis and the maturation of the virus particle. Despite the fact that its role is not well understood, compounds that inhibit NS5A have been developed as anti-viral therapies.

(f)    NS5B is the HCV RNA-dependent RNA polymerase. This polymerase is responsible for making new copies of viral RNA.

111    The NS5B RNA-dependent RNA polymerase is responsible for generating a negative or antisense copy of the viral genome and subsequently using the negative copy as a template for generating positive-strand RNA that could be translated, further transcribed, or packaged into new viruses. The building blocks of RNA are nucleotides. The nucleotide species utilised by the polymerase as the RNA building block is the nucleoside 5' triphosphate. Modified versions of nucleotides or their precursor nucleosides (nucleotide or nucleoside analogues) can be used to prevent replication of HCV RNA.

112    There are a number of steps in the HCV life cycle. Briefly, those steps are as follows:

(a)    The first step is attachment of the virus to the hepatocyte. This occurs via binding of the virus to receptors found on the cell surface.

(b)    Following binding to the receptor, the virus is internalised in the cell via a process called endocytosis.

(c)    Once inside the cell, the viral particle disassembles and releases the viral RNA genome in the cytoplasm.

(d)    In the next step, the RNA genome is recognised by the cellular protein synthesis machinery (ribosome) and it is translated into a polyprotein.

(e)    Then the polyprotein is subsequently cleaved by the concerted action of cellular and viral proteases into at least 10 individual proteins, including structural and non-structural proteins.

(f)    The non-structural proteins NS3 to NS5B form a so-called RNA replication complex, the function of which is to make new copies of the viral RNA.

(g)    Newly-synthesised viral RNA genomes can be translated as in step (d) above, further transcribed or interact with the structural proteins to produce new viral particles.

(h)    The newly-formed viral particles will exit from the cell and infect surrounding hepatocytes. The HCV life cycle is depicted below.

Figure 3: The HCV life cycle (extracted from Shi and Lai, "Hepatitis C viral RNA: challenges and promises" (2001) 58 Cellular and Molecular Life Sciences 1276 at 1285).

2.4.5    Development of HCV anti-virals

113    Although HCV was identified in 1989, by June 2002 HCV researchers still could not grow HCV in cell culture. It was not until 2005 that a strain of HCV was reported that could be grown in the lab (this strain is known as JFH-1).

2.4.6    Surrogate models

114    Due to the limitations associated with in vivo animal models and the inability to culture HCV in vitro prior to 2005, early studies of HCV often relied on “surrogate” models. HCV surrogate models sought to mimic the human and HCV biological and viral systems and usually comprised a non-HCV virus (such as BVDV) together with a non-human biological system.

115    Surrogates were ways to study general replication strategies of these viruses, on the assumption that they would be similar between all Flaviviridae family members (including HCV).

116    From around 1994-1995, BVDV was used as a surrogate model for HCV. BVDV is a pestivirus in the Flaviviridae family and, unlike HCV, is able to replicate in cell culture.

2.4.7    HCV protease and polymerase assays

117    The direct screening of potential HCV inhibitors may be done with in vitro polymerase and protease/helicase enzyme assays.

2.4.8    HCV replicons

118    A replicon is a nucleic acid molecule that contains all the sequences necessary for its own replication. In the case of the HCV Replicon, the nucleic acid molecule contains all of the RNA sequence required for replication of the HCV RNA genome.

119    Replicons are self-replicating RNA molecules that are generated by genetic engineering and allow researchers to study aspects of viral replication. Replicons can also be used as a screening assay for anti-viral compounds. The first replicon was developed in the mid-1990s using Kunjin, an Australian isolate of WNV (which is a flavivirus). HCV replicons were developed in 1999. As discussed below, reports of the first HCV replicons in 1999 revolutionised HCV research and drug development.

120    The diagram below compares the organisation of the HCV genome (a) with a typical HCV replicon genome (b).

Figure 4 – Organisation of the HCV genome (a) and a typical HCV replicon genome (b).

121    Structurally, classical HCV replicons encode the non-structural proteins of a virus together with a “Neo-selection” system in place of the structural protein genes, and with viral 5' and 3' UTRs. The Neo-selection system consists of:

(a)    a neomycin resistance gene, or Neo. Neo expression in a cell confers resistance on that cell to being killed by the addition of neomycin (an antibiotic). If a cell contains a replicon, then replication of that replicon results in the Neo gene also being expressed. Accordingly, only cells successfully transfected with replicons and expressing proteins will be able to grow in cell culture containing neomycin; and

(b)    an IRES from encephalomyocarditis virus, or EMCV. As discussed above, an IRES is used to initiate the translation of viral proteins. Because the Neo gene is inserted into the replicon genome, a second IRES is also introduced (one to drive the translation of Neo and one to drive the translation of the HCV non-structural proteins). The EMCV IRES is commonly used to drive translation of proteins in engineered RNA sequences.

122    As the Neo-selection system replaces the HCV structural genes, these replicons cannot produce new virus particles which can be secreted from the cell.

123    As discussed above, the first replicon was developed in the mid-1990s using Kunjin. However, although Kunjin is a flavivirus, the differences between the proteins of Kunjin and HCV meant that the Kunjin replicon could be used to study WNV but could not be used to study HCV or screen for anti-virals with anti-HCV activity. It was not until 1999 that HCV replicons were first developed, independently, in two laboratories: Lohmann and Bartenschlager in Heidelberg, Germany, and Professor Rice’s laboratory in the United States.

124    The development of the first HCV replicons in 1999 provided a much more authentic assay in terms of screening compounds for anti-HCV activity. The replication complex is similar to that in a genuinely HCV infected cell, so the complex interactions between virus-virus proteins and virus-host cell proteins will take place in replicon-transfected cells that will not take place in isolated polymerase or protease assays. Testing is relatively straightforward: compounds of interest are added to a cell culture system in which replicons are successfully replicating, and one observes whether the replication is subsequently inhibited. Originally, this could be done either by leaving the neomycin selection on (such that cells in which replicons ceased replicating would die), or by quantifying the level of replication using a technique such as quantitative RT-PCR. HCV replicons have since been specifically adapted to drug screening with the inclusion of a reporter gene, such as luciferase (which confers bioluminescence), enabling a visual output of the level of replicon activity within cells: if the candidate compound inhibited the virus, the expression of the reporter gene would also be inhibited which results in a measurable decrease in bioluminescence.

125    The design of the HCV Replicon was inspired by the notion that structural proteins are not required for genome replication of several positive-strand RNA viruses, including flaviviruses and pestiviruses, and by the successful design of self-replicating replicons for other Flaviviridae, such as the Kunjin virus and BVDV reported in 1997 and 1998, respectively.

126    The HCV Replicon was derived from the genome of the viral strain Con-1, which was isolated and cloned from the liver of an HCV-infected patient. The Con-1 genome used by Professor Bartenschlager and his team contained the sequences encoding for both the structural and non-structural HCV proteins referred to, respectively, above.

127    Professor Bartenschlager’s group modified the Con-1 genome by deleting the region encoding for the HCV structural proteins and replacing it with the neomycin phosphotransferase (neo) gene. The neo gene codes for the expression of neomycin phosphotransferase, which confers resistance to the antibiotic action of neomycin or its analogue G418. Thus, in a heterogeneous cell population, only those cells that express the neo gene survive treatment with neomycin or G418, while other cells will die. The inclusion of the neo gene therefore permitted the selection of cells supporting efficient replication of the HCV Replicon.

128    The HCV Replicon contained the following elements:

(a)    the HCV 5'-UTR and the first portion of the capsid protein fused to the neo selectable marker;

(b)    an IRES from the encephalomyocarditis virus (EMCV), which is important to direct the translation of the downstream HCV proteins;

(c)    the HCV non-structural proteins NS3 to NS5B; and

(d)    the HCV 3'-UTR.

The elements of the HCV Replicon are depicted below.

Figure 4: Structure of the HCV Replicon (adapted from Lohmann et al, "Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line" (1999) 285 Science 110 at 111).

129    Professor Bartenschlager’s group also reported that HCV Replicons could be maintained in a human hepatoma (liver cancer) cell line (Huh-7) (HCV Replicon system). That is, the HCV Replicon could be taken up by Huh-7 cells and undergo replicon replication.

130    Briefly, the work of Professor Bartenschlager’s group involved the following: a DNA plasmid containing the HCV Replicon sequence was transcribed in vitro to generate HCV Replicon RNA. Transfection of Huh-7 cells with HCV Replicon RNA followed by selection with G418 resulted in a low number of surviving cell colonies. These cells replicated HCV Replicon RNA to high levels (1000 to 5000 copies of positive-strand RNA per cell). The cell colonies were then isolated from the plate and expanded to establish a cell line that carried stably-replicating HCV Replicons. These steps are depicted below.

Figure 5: Establishment of cell clones that carry self-replicating HCV replicons (extracted from Bartenschlager et al, "Hepatitis C Virus Replicons: Potential Role for Drug Development" (2002) 1 Nature Reviews Drug Discovery 911 at 913).

131    The HCV Replicon system was the first cell-based system which made it possible to measure HCV RNA replication. This permitted the evaluation of candidate compounds for their ability to inhibit HCV replication in Huh-7 cells. The HCV Replicon system thus provided a way to measure anti-HCV activity of a candidate compound in a cell-based system.

132    In order to screen candidate compounds for anti-HCV activity, using the HCV Replicon system, the following steps are involved:

(a)    expose the HCV Replicon cell line to the candidate compound at a particular (fixed) concentration for a period of time that typically ranges from between two to four days; and

(b)    measure the extent of inhibition by the candidate compound by measuring viral RNA or viral protein levels. To do this, the cells are lysed and viral RNA levels are measured using quantitative PCR methodology and/or viral protein levels are measured using ELISA methodology, both of which were, well prior to June 2002, standard laboratory techniques.

The HCV Replicon assay thus enables the calculation of the percentage reduction in viral RNA or viral protein with respect to a control (that is, without the candidate compound). This is taken as a measure of the extent of inhibition of viral replication.

2.4.9    Modifications to the HCV Replicon system

133    The HCV Replicon could be established only in a very small fraction of cells (in the order of a few cells out of hundreds of thousands of transfected cells).

134    On 8 December 2000, a paper by Blight et al, “Efficient initiation of HCV RNA replication in cell culture” (2000) 290 Science 1972, reported versions of the HCV Replicon that carried adaptive mutations which favoured replication in cultured cells, yielding systems of increased replication efficiency (the Blight-modified HCV Replicon).

135    These adaptive mutations were identified following sequence analyses of HCV Replicon RNAs replicating in cell colonies after G418 selection. Most highly adaptive mutations lie within the NS48, NS5A and NSSB coding regions, although adaptive mutations can be found in NS3 or NS4A as well.

136    The impact of these mutations on the efficiency of HCV replication and G418-resistant cell­ colony formation was tested by generating HCV replicons containing one or more of these mutations and determining the number of cell colonies after transfection of these replicons and G418 selection. Depending on the particular mutation, an increase in the efficiency of colony formation could be as high as 10,000-fold compared to the wild type HCV Replicon. It was also found that the combination of more than one mutation, for example, one in NS5A with one in NS3, could confer superior efficiency compared to single adaptive mutations.

137    Prior to June 2002, it would have been possible to test NS5B polymerase inhibition of a candidate compound against any HCV genotype using a polymerase assay with the purified NS5B polymerase from each genotype.

2.4.10    The drug discovery process

138    Given the nature of the screening process, it is expected that the assay will result in both false positives and false negatives. In light of this, the next step in this phase is to “cherry-pick” individual compounds that scored as actives in the initial assay and undertake a “Confirmatory Assay”. This involves repeating the inhibition assay as replicates, that is, running multiple parallel assays on the compound. This is expected to eliminate any false positives.

139    Having eliminated false positives in the Confirmatory Assay, the next step in this phase is to evaluate the inhibitory “potency” of individual compounds over a range of concentrations. The potency is measured as IC₅₀ or EC₅₀ in biochemical assays or cell-based assays, respectively.

140    In order to obtain an IC₅₀ value, serial dilutions of the test compound are evaluated in a biochemical assay, and the percentage inhibition corresponding to each concentration is measured. These results are usually displayed graphically by plotting percentage inhibition as a function of the compound concentration. Typically, this data is fitted to a theoretical IC₅₀ curve by a computer program which generates a value representing the concentration of the test compound (inhibitor) at which 50% inhibition of the target biological activity is observed or predicted from the plot. This value is referred to as the IC₅₀ (inhibitory concentration) value.

141    In a cell-based antiviral assay, EC₅₀ (effective concentration) is the concentration of the test compound (inhibitor) at which 50% inhibition of viral replication in the cell is observed. The EC₅₀ value is calculated using the methodology discussed above, on data obtained from a cell-based assay. However, cell-based assays may have a degree of non-specificity. Cell-based assays are not measuring the direct effect of the antiviral on the virus. Rather, they are measuring the effect of the antiviral on the virus-infected cell.

142    When a cell-based assay is used, it is important to determine whether the observed inhibitory activity is due to the test compound inhibiting the target biological activity or interfering with cell functions not related to the target biological activity leading to cell death. This is done by way of a cytotoxicity assay run in the same cell line used for the primary biological assay typically in the absence of the virus.

143    Prior to June 2002, there were a number of cytotoxicity assays available. The MTT assay is a calorimetric assay in which MTT is converted to a blue-violet colour by activity of mitochondrial enzymes. As mitochondria function only in live cells, the assay gives a measure of cell viability. Analysis of the data obtained from this assay is carried out in the same manner as discussed above to yield a CC₅₀ (cytotoxicity concentration) value, that is, the concentration of the test compound at which a reduction of cell viability of 50% is observed.

144    The CC₅₀ value is then compared to the EC₅₀ value. When the CC₅₀ value is significantly higher than the EC₅₀ value, this is an indication that the biological target of interest is inhibited without significantly affecting cell viability.

145    When there is little or no difference between the EC₅₀ and CC₅₀ values, it is not possible to assess the extent to which the test compound has inhibited the biological target. This is because such a result can be interpreted in a number of ways: the test compound is inhibiting the biological target but is also inhibiting a function that is important for viability of the cells used in the assay. For example, an inhibitor of a viral polymerase could be cytotoxic because it is also an inhibitor of a cellular polymerase or because it inhibits a totally unrelated but important cell function. Alternatively, the compound may not be inhibiting the target biological activity but it nevertheless inhibits an important cell function leading to lack of cell viability.

3.    THE EXPERTS – A BRIEF OVERVIEW

3.1    The affidavit evidence

146    Many of the experts gave extensive evidence in affidavits about their interpretation of the Idenix patent and the 350 application. While parts of that evidence involved opinions not necessarily based on the specialised knowledge and experience of the expert it was not possible to exclude that material as inadmissible lay opinion for three reasons. First, given the complexity of the subject being considered, it was not always possible to identify when expert opinion stopped and lay opinion started. Second, the strands of evidence were intertwined so that excision of inadmissible lay opinion may have undermined the meaning of the remaining evidence. Third, some of the affidavits were very long documents, making it undesirable to use the hearing time available for the purpose of a detailed examination of admissibility of evidence for possibly little meaningful outcome.

147    That said, it would have been more helpful if the affidavits had consistently set out the background material which the expert considered to be the basic knowledge in their field of expertise in a section separate from the application of the expert’s own particular knowledge to the terms of the patent. It also would have been more helpful if the experts had been instructed to give their opinions assuming that certain terms in patent specifications may take alternative meanings where those terms did not involve the application of any expertise. In the present case, the two examples that spring to mind are the meaning of the words “and/or” and “Base is as defined herein” which, as will become apparent, appear in the 350 application and the Idenix patent, and which the experts purported to construe. I can see no risk to the integrity of expert evidence from an expert being instructed to assume that certain ordinary English words may take more than one meaning and for the expert to be asked to give an opinion about matters within their expertise on each assumed alternative basis. If this is seen to be inappropriate in any case then, at the least, the expert should be saved the potential embarrassment of cross-examination on the expert’s reading of ordinary English words (particularly where they are known or likely to be the subject of dispute as in the present case) by being instructed to assume that those words have a particular meaning.

148    In the brief overview of the evidence below I have focused on the expert’s principal opinions, leaving aside much of their evidence consisting of interpretation of documents which is better dealt with in the context of resolving the issues in dispute. In particular, I do not consider in this brief overview the experts’ conclusions (where given) about whether the 350 application and Idenix patent disclose a prodrug at the 5' position alone when an “and/or” formula is used to describe prodrugs at the 2', 3' and/or 5' positions because these conclusions (in contrast to some of the material informing these conclusions with which the conclusions were intertwined) are not a matter for expert opinion at all.

3.2    Professor Furneaux

149    Richard Furneaux is a chemist with over 40 years’ experience in organic and carbohydrate chemistry. He is the Director (with the title Professor) of the Ferrier Research Institute at the Victoria University of Wellington, New Zealand. The Ferrier Research Institute is a group of 27 scientists specialising in strategic carbohydrate chemistry research for application in the pharmaceutical, industrial chemical and functional food sectors.

150    Professor Furneaux’s principal opinions in respect of the Idenix patent as set out in his affidavits were that:

(1)    Fluorination reactions at primary and secondary hydroxy groups can be unpredictable and no reaction or a number of competing reactions can occur (displacement without inversion, displacement with inversion, elimination, or rearrangement).

(2)    As he put it:

I was not aware of chemistry as at June 2002 that would enable me to introduce a fluorine into a tertiary carbon on a sugar or nucleoside. Given my experience with fluorination, and my understanding of the nature of fluorine, together with the reported unpredictability of the reaction pathways and stereochemical outcomes of fluorination reactions, I would not have considered fluorination of a tertiary hydroxy group to be routine chemistry. To the contrary, it would have required significant research and experimentation.

151    Professor Furneaux also observed that the Idenix patent contains 23 different formulas which encompass an extraordinarily large number of compounds, estimated to be in the many trillions. Claim 7 of the Idenix patent, he said, covers between 129,000 and in excess of 25 trillion compounds.

152    Professor Furneaux also gave extensive oral evidence which will be considered below in the context of the issues to be resolved.

3.3    Dr Lambert

153    John Lambert is an organic chemist of over 26 years’ experience in the application of organic chemistry to drug discovery and development. He was the Vice President, Drug Development at Biota Pharmaceuticals Inc, which is a biopharmaceutical company that focuses on the discovery and development of new anti-infective medicines, particularly antiviral compounds.

154    Dr Lambert explained that:

at June 2002 and June 2003 my knowledge and expertise primarily related to organic chemistry generally and more specifically nucleoside chemistry and antivirals. In January 2004, when I commenced work at Biota Inc, I undertook a review of the commercial status of drug development in relation to hepatitis C virus (HCV). I refer to this review … as my HCV Review and it was through my HCV Review that I acquired an up to date understanding of HCV research and HCV drug development.

…

My understanding and knowledge of viruses, including HCV, is as a result of my 14

years’ work with organic compounds intended for use as antivirals, 3 years of which (from approximately 2004 to 2007) specifically related to HCV antivirals…

155    Dr Lambert’s principal opinions in respect of the Idenix patent as set out in his affidavits were that:

(1)    There is an indefinite number of permutations and combinations that are possible for each of the formulas in the patent. As he put it:

While I am unable to calculate the precise number of compounds covered by the Patent Specification, I estimate that it encompasses millions, if not billions, of compounds… I am confident that the Patent Specification encompasses more nucleoside analogues than have ever been synthesised or reported in the literature…

The breadth of compounds covered by the Patent Specification is primarily a result of the high degree of structural variation within each Formula described in the Patent Specification.

(2)    In order to synthesise a compound within claim 7 of the patent he would need to undertake further research, including review of primary literature, perform retrosynthetic analysis to design the synthesis and conduct experimentation, processes which would not be straightforward or predictable.

(3)    To determine the biological activity of any compound of claim 7, he would need to design an appropriate reaction scheme using retrosynthetic analysis and synthesise the compound and, if the synthesis was successful, test the compound in an appropriate biological assay to determine if it was effective against Flaviviridae, including HCV.

156    Dr Lambert also gave oral evidence which will be considered below in the context of the issues to be resolved.

3.4    Professor Gowans

157    Eric Gowans is a virologist of over 30 years’ experience, with specialist expertise in HCV and other viruses within the Flaviviridae family. He is an Honorary Professor in Molecular Biosciences, University of Adelaide and was the Executive Director and Head of the Virus Research Laboratory at the Women’s and Children’s Health Research Institute. He has also done some work in anti-viral drug discovery and development and is reasonably familiar with the process of drug discovery and development.

158    Professor Gowans’ principal opinions in respect of the Idenix patent as set out in his affidavits were that:

(1)    The patent provides no evidence that the compounds are in fact effective treatments for Flaviviridae infections.

(2)    It is very unlikely that the large number of compounds encompassed by the patent would have anti-Flaviviridae or anti-HCV activity and it is unlikely that such a large number of compounds could be tested to determine whether they had such activity using the methods described in the patent.

159    Professor Gowans also gave oral evidence which will be considered below in the context of the issues to be resolved.

3.5    Dr Tucker

160    Simon Tucker is a virologist with experience in the development of nucleoside analogues for treating, amongst other diseases, HCV. He was the Vice President of Research at Biota Scientific Management Pty Ltd and was responsible for the management of Biota’s entire research portfolio (other than clinical research), including virologists and chemists. He was involved in Biota’s HCV project in which Biota synthesised and screened novel nucleoside analogues to determine whether they were active against HCV.

161    Dr Tucker’s principal evidence as set out in his affidavit was that:

(1)    Due to the difficulties in culturing HCV, another option that has been used to screen potential anti-HCV compounds is surrogate assays. These assays were primarily used before replicon systems became available (in the late 1990s for HCV), but were also used after that time as well.

(2)    By June 2002 the primary screening systems that were generally used to test for anti-HCV activity were assays using a replicon system or biochemical assays, such as RNA polymerase assays or protease assays. Biota’s HCV project utilised both replicon assays and polymerase assays.

(3)    The purpose of biochemical assays, as with replicon assays, is to determine whether a compound inhibits some part of the replication process of the virus. However, a polymerase assay specifically determines whether a compound inhibits one particular viral enzyme (i.e. the polymerase), whereas a compound can be effective in a replicon assay if it inhibits any of a number of steps in the viral replication cycle.

(4)    Before a nucleoside analogue can be tested in a polymerase assay, it must first be converted to its triphosphate form, as polymerase will only recognise and act on nucleoside triphosphates.

(5)    It is necessary to determine the EC₅₀ (or Effective Concentration 50%) for any compound being tested, which is the concentration of the compound that inhibits replicon replication by 50%. It is also necessary to determine the compound’s CC₅₀ (or Cytotoxic Concentration 50%), being the concentration of the compound that kills half of the cells. Once the EC₅₀ and CC₅₀ are determined, compounds are ranked by comparing their ratio of CC₅₀ to EC₅₀ (which is referred to as the cytotherapeutic index) and their relative EC₅₀. Ideally, the cytotherapeutic index should be as large as possible.

(6)    When screening a number of compounds for anti-viral activity, it is possible to automate at least some steps of both polymerase assays and replicon assays in order to increase the number of compounds that can be screened in a given period of time. There is a variety of levels of high-throughput screening, from millions of compounds down to thousands of compounds. Polymerase assays, in particular, are amenable to high throughput screening if a large number of compounds are being screened.

(7)    In the case of nucleoside analogues, large scale screens (e.g. including hundreds of thousands of compounds) are not common. This is because nucleoside analogue libraries tend to be much smaller than libraries of other types of small molecule organic compounds. As at June 2002, he was not aware of any companies or groups that had libraries containing more than 10,000 nucleoside analogues (even those companies with historical experience in the field).

(8)    In Biota’s HCV project the project teams screened in the order of hundreds, and possibly single-digit thousands (i.e. less than 10,000), of nucleoside analogues, many of which were evaluated in several different assays.

(9)    It would not be possible to screen 20 billion, or 25 trillion, nucleoside analogue compounds for anti-HCV (or anti Flaviviridae) activity as at June 2002, June 2003 or May 2010 because he has not heard of a compound library containing that number of nucleoside analogues (or indeed a compound library containing that many organic compounds of any description) and screening this number of compounds would not be feasible. He has been involved in screens ranging from tens of thousands of compounds to between 500,000 and 1,000,000 compounds. Screens of 500,000 to 1,000,000 compounds generally took between approximately 6 months and one year to complete and analyse the results of, depending on the complexity of the assay and the resources available. To increase the number of compounds into the billions or trillions – i.e. a thousand to million-fold increase – is not feasible. For example, assuming that a million compounds could be screened within 6 months, it would take 10,000 years to screen 20 billion compounds. The number of hits generated from a screen of that size would also be too large to be practically analysed.

162    Dr Tucker also gave oral evidence which will be considered below in the context of the issues to be resolved.

3.6    Dr Cox

163    Susan Cox is a virologist. At both June 2002 and June 2003 she was Director of Virology Research at Australian Medical Research and Development (Amrad), from which Avexa Limited (Avexa) was later founded. As Director of Virology Research at Amrad, she had, and continues to have, oversight of all virology work being conducted at Amrad. Between 2002 and 2010, Amrad had a number of anti-viral screening projects, which focused mainly on HIV, HBV and HCV. Amrad’s HCV project continued for approximately 8 years from around 2002 to around 2009, and involved screening libraries of compounds, including some nucleoside analogues, for anti-HCV activity.

164    Dr Cox’s principal evidence as set out in her affidavit was that:

(1)    At June 2002 Amrad had a compound library containing approximately 15,000 compounds, which grew to around 100,000 compounds by 2010. Of these there were included a small number of nucleoside analogues (i.e. in the 100s).

(2)    In 2002 and 2003, Amrad’s HCV project involved using a BVDV assay to screen compounds and HCV polymerase assay which was used to screen particular compounds that had been selected based on their structure or on their activity in the BVDV assay. This process was used because Amrad, which had limited resources and other projects with higher priority, did not have available to it a replicon system in 2002 and 2003, although such systems were available at that time. Amrad gained access to a replicon system in 2006.

(3)    For the same reasons, Amrad also did not have access to robotic screening techniques as at June 2002 and 2003. Such systems, however, were available at that time.

(4)    Over the eight year period of its HCV project Amrad screened an estimated 50,000 compounds.

165    Dr Cox also gave oral evidence which will be considered below in the context of the issues to be resolved.

3.7    Dr Clemens

166    Alexander Clemens is a chemist specialising in synthetic organic chemistry. He is employed by Albany Molecular Research, Inc. (AMRI), which provides contract research and manufacturing services to the pharmaceutical and biotechnology industries.

167    During the period 25 to 30 August 2014, he conducted a synthesis that is depicted in the following scheme (the Deoxo-Fluor Scheme):

168    In the same period he also carried out analytical work to characterise the products of that synthesis.

169    Dr Clemens explained that:

The Deoxo-Fluor Scheme comprises two reactions. The first, indicated on the left-hand side of Figure 1, involves the reaction of a protected 2' -methyl nucleoside (the compound labelled as compound 1 in Figure 1) with Deoxo-Fluor and anhydrous pyridine in anhydrous dichloromethane (the Fluorination Reaction). The desired product of the Fluorination Reaction is the protected 2'-fluoro nucleoside (the compound labelled as compound 2 in Figure 1). The second reaction in the Deoxo-Fluor Scheme, indicated on the right-hand side of Figure 1 involves the reaction of the protected 2'-fluoro nucleoside with ammonium fluoride in methanol to produce the 2'-fluoro nucleoside, labelled in Figure 1 as compound 3 (the Deprotection Reaction).

170    Based on his analysis Dr Clemens was satisfied that the product he isolated from the sequence of Fluorination and Deprotection Reactions was compound 3.

171    Dr Clemens also gave oral evidence which will be considered below in the context of the issues to be resolved.

3.8    Professor Meier

172    Chris Meier is an organic chemist with specialist expertise in the synthesis of nucleosides and nucleotides for medicinal purposes. He is a Professor of Organic Chemistry at the University of Hamburg.

173    Professor Meier’s evidence as set out in his affidavits included the following (the opinions he expressed relating to the position as at 2002 and 2003):

(1)    Nucleoside and nucleotide analogues have been studied (and used) in the treatment of viral infection in humans, including HCV infection, for many years.

(2)    HCV viral RNA replication involves a viral RNA-dependent-RNA polymerase called NS5B, an enzyme which synthesises new RNA strands using 5'-ribonucleoside triphosphates from the host liver cell as its substrate. Thus, the NS5B-catalysed synthesis is an ideal target for intervention. However, because of dephosphorylation in the bloodstream by enzymes called phosphatases and inability to penetrate the liver cell membrane scientists have developed and were continuing to develop nucleotide prodrugs (pro-nucleotides), which are compounds in which the 5'-monophosphate, 5'-diphosphate or 5'-triphosphate group of a nucleotide or a nucleotide analogue is masked (or “protected”) through chemical modification. By 2002, there were a number of approaches adopted in designing pro-nucleotides, the aim being to mask (or protect) the 5'-phosphate group(s) of the nucleotide analogue to prevent dephosphorylation (loss of phosphate groups) in the bloodstream and to neutralise the negative charges of the 5'-phosphate group(s) resulting in the formation of a neutral (uncharged) compound which is capable of crossing the cellular membrane. Accordingly, the ideal nucleotide analogue for intracellular delivery was the 5'-triphosphate form. The 5'-diphosphate form may also be a suitable candidate for intracellular delivery since this would require only one further phosphorylation for conversion into the 5'-triphosphate form. In summary:

Although the detailed mechanism of the inhibition of HCV polymerase was not understood at that time [2002 and 2003], scientists had established that conversion of the nucleoside analogue into the 5'-triphosphorylated form is a prerequisite for the nucleoside analogue to bind to the RNA-dependent RNA polymerase in order to inhibit its function.

174    Professor Meier said that if he had been provided with the 350 application and was seeking to identify the most promising candidate compounds to evaluate in the context of an anti-HCV drug discovery project he would approach the task taking into account the intended biological target of the compounds (as an anti-HCV drug) as well as their proposed mechanism of action (inhibition of polymerase). For numerous reasons set out in his affidavits, Professor Meier concluded that, if given this task, he would have undertaken a synthesis resulting in a nucleoside analogue with modifications at the 2' position of methyl-“up” and fluoro-“down” and a lipophilic phosphate pro-drug moiety at the 5' position attached to a natural base (uracil) (which, it should be noted, is the structure of sofosbuvir). A summary of this proposed synthesis, prepared by Gilead, is as set out below:

175    In respect of the Idenix patent, key modifications that Professor Meier would have identified in June 2002 if he had sought to identify candidate compounds from the patent to evaluate in the context of an anti-HCV drug discovery project were the branch modification of the methyl group in the 2'-“up” position together with the fluoro in the 2'-“down” position and the use of a 5'-nucleotide analogue pro-drug by the addition of a stabilized phosphate to the 5' position. For the purpose of the required synthesis, he was aware in 2002 of the organometallic reagents such as the Grignard reagents (for example, methylmagnesium bromide), methyllithium, and trimethylaluminium that could be used to introduce a methyl group in the 2' position. He was also aware and had used the reagent diethylaminosulfur trifluoride (DAST) to introduce fluoro in the 2'-“up” position of a nucleoside analogue. In his words:

Prior to June 2002 I had used DAST to introduce a fluoro atom at the 2' position of a nucleoside analogue and was aware that a DAST fluorination reaction typically proceeded with inversion of stereochemistry.

I was aware that to introduce a fluoro atom at the 2' position of a nucleoside I would require a hydroxy group as the functional group at the 2' position. Therefore I was aware that it was necessary to introduce the methyl modification to the 5-membered ring of the nucleoside first, leaving the functional OH group to enable the fluoro substitution. I was also aware, that DAST fluorination reaction typically proceeds with inversion of stereochemistry. Therefore I was aware that the required starting material for a DAST reaction would have had a methyl group in the “down” position and a hydroxy group in the “up” position.

176    Professor Meier also gave extensive oral evidence which will be considered below in the context of the issues to be resolved.

3.9    Dr Borthwick

177    Alan Borthwick is a drug design and medicinal chemistry consultant employed since 2006 at DrugMoIDesign, London, an independent consultancy which provides support and expertise in drug design to academia and the pharmaceutical industry. He was awarded a PhD in organic chemistry in 1972. He was employed by the Glaxo group between 1971 and 2006.

178    While employed by Glaxo Dr Borthwick was involved in numerous drug design projects including, in the period between 1985 and 1994, a project involving the design and synthesis of carbocyclic nucleosides known as the Herpes and Retrovirus Project (or HSV project). As he described it:

This project involved the development of a number of compounds that progressed to exploratory development candidates. These included the chiral nucleosides carbocyclic (+)-(E)-5-(2-bromovinyl)-2'-deoxyuridine (against varicella zoster virus), carbocyclic 2'-ara-fluoroguanosine (against herpes simplex virus 1 and herpes simplex virus 2), carbocyclic 2'-deoxy-4'-hydroxyguanosine and carbocyclic 8-aza-2'-ara-fluoroguanosine.

179    As part of the HSV project Dr Borthwick led a team of four to five organic chemists who worked under his supervision. Two of these scientists had PhD qualifications and the others had graduate degrees in organic chemistry. The HSV project proceeded over a number of years and involved numerous steps which Dr Borthwick described. As Dr Borthwick put it, having regard to his knowledge and experience:

…the first step in the project was to conduct a literature search to seek to identify any nucleoside derivatives that were known to have activity against human herpes viruses. I recall that the search involved a review of papers of which I was aware at the time and the references cited therein. I recall that the search revealed a number of nucleoside analogues, namely IDU, FMAU and FIAU, that had been reported in the literature as having activity against HSV-1 and HSV-2.

…

The next search involved interrogating the literature for reports of the synthesis of carbocyclic nucleosides with a purine or pyrimidine nucleobase coupled to a carbocyclic ring with hydroxyl groups at the 2-, 3- and 5-positions of the carbocyclic ring.

180    Another step involved a literature search of the use of DAST in the conversion of alcohols to alkyl fluorides (the DAST Search). As a result of this search Dr Borthwick became aware of a number of papers dealing with fluorination by DAST. He considered that these literature reports demonstrated that DAST reacts with secondary and tertiary hydroxyl groups to deliver fluorine in a single step with inversion of configuration. As such, for the HSV project, and as one of many steps, he decided to use DAST to introduce a fluorine at the 2-“up” position of the carbocyclic aminotriol ring system by replacement with inversion of the 2-“down” hydroxyl group. The first attempt did not result in fluorination. Analysis of the results disclosed that participation of a neighbouring group amino trityl group had occurred which prevented the nucleophilic substitution of the fluorine at the 2-position. Dr Borthwick thus decided to protect the amino group with a dinitrophenyl (DNP) protecting group so it was less likely to participate in the DAST reaction. The second attempt at fluorination, where the 3- and 5-hydroxyl groups were also protected with TIPS (tetraisopropyldisiloxanyl protecting group, also referred to as TIPDS), resulted in the replacement of the hydroxyl group by fluorine with inversion of configuration (the desired product). The reaction also gave the protected fluorohydrin as a by-product. The mixture was separated and purified into the individual compounds by chromatography on silica. As the HSV project proceeded, Dr Borthwick carried out fluorination steps involving DAST and other fluorinating reagents with various results being obtained as he described.

181    Dr Borthwick was provided with a chemical structure (referred to in his evidence as figure 69) as follows and was told the base was a natural nucleobase, namely uracil, cytosine, thymine, adenine or guanine:

182    Dr Borthwick said figure 69 represents a number of compounds, each of which is a nucleoside analogue having 3'- and 5'-hydroxyl (OH) groups, a natural nucleobase (“base”) at the 1'-“up” position and a 2'-methyl (CH₃)-“up” and 2'-fluoro-“down” configuration. He was instructed to treat figure 69 as his Target Compounds. Dr Borthwick was asked to review section VII of the Idenix patent and provide his opinion whether that section discloses information regarding the synthesis of a Target Compound.

183    According to Dr Borthwick:

(1)    The Idenix patent describes the synthesis of a compound which has the configuration of the Target Compounds at the 2'-position, specifically a methyl group in the 2'-“up” position and a functional group in the 2'-“down” position (in this case a tertiary hydroxyl group). The illustration of this configuration is of particular significance for the synthesis of a 2'-methyl-“up”-2'-fluoro-“down” modified nucleoside because Scheme 9 in the patent shows that such a compound has been synthesised. Also, a fluoro group was known to be a bioisostere of a hydroxyl group; that is, the fluoro group (F) and hydroxyl group (OH) share physical and chemical characteristics, including that they are both small electron withdrawing groups and are able to form hydrogen bonds with other functionalities, meaning that they would be expected to behave similarly in a biological environment.

(2)    He therefore would have expected that the Target Compounds, which have a 2'-methyl-“up”-2'-fluoro-“down” configuration, could be synthesised.

(3)    In devising a synthesis for the Target Compounds, he identified, as the immediate precursor (to react with DAST), a compound which, at the 2'-position, had the inverse stereochemistry to the compounds of interest, that is, a 2'-methyl-“down”-2'-hydroxyl-“up” nucleoside analogue. Thereafter, based on a detailed process of reasoning set out in his affidavit, Dr Borthwick said that he would have:

…devised a synthesis in which Matsuda compound 12a (the Matsuda Precursor) was made, according to the instructions provided in the Matsuda Paper, and then treated the compound with DAST, expecting the reaction to give the 2'-methyl-“up”-2'-fluoro-“down” nucleoside analogue which is TIPDS-protected at the 3'- and 5'-hydroxyl groups, and protected at the 4-position of the nucleobase with an ethoxy group; that is, a protected Target Compound…

[and then:]

…would have reacted the compound in Figure 87 with TBAF to remove the TIPDS group followed by either sodium hydroxide to give the Target Compound with a uracil nucleobase or ammonia in methanol to give the Target Compound with cytosine nucleobase.

(4)    Dr Borthwick described this as Target Synthesis 1. The Matsuda Precursor is identified in a paper by Akira Matsuda et al, “Alkyl Addition Reaction of Pyrimidine 2'-Ketonucleosides: Synthesis of 2'-Branched-Chain Sugar Pyrimidine Nucleosides” (1988) 36(3) Chemical and Pharmaceutical Bulletin 945 (the Matsuda Paper).

(5)    Another approach that Dr Borthwick would have considered in synthesising the Target Compounds is to take the Matsuda Precursor and replace the TIPDS protecting group at the 3'- and 5'-positions with benzoate protecting groups before undertaking the DAST reaction, which he described as Target Synthesis 2.

(6)    Dr Borthwick also would choose a uracil nucleobase in the first instance as it is structurally simpler than the purine nucleobases (adenine and guanine) and is versatile in that it can be converted into the cytosine nucleobase, meaning that two nucleosides with different nucleobases can be prepared using the one reaction scheme.

184    In summary Dr Borthwick considered that:

…[t]he Matsuda Paper gives a complete synthesis for the Matsuda Precursor [and] the DAST reaction with this precursor was well precedented in the literature prior to June 2002 and therefore its use to treat the Matsuda Precursor would not involve “trial and error experimentation”.

185    Dr Borthwick also gave extensive oral evidence which will be considered below in the context of the issues to be resolved.

3.10    Professor Barrett

186    Anthony Barrett is the Glaxo Professor of Organic Chemistry and the Director of the Wolfson Centre for Organic Chemistry in Medical Science in the Department of Chemistry at Imperial College of Science, Technology and Medicine in London and the Sir Derek Barton Professor of Synthetic Chemistry and Head of the Synthesis Section in the Department of Chemistry at Imperial College.

187    Professor Barrett explained the analytical techniques that in his experience were used routinely in the field of organic chemistry prior to June 2002 to separate and characterise the products of a synthetic reaction. He said in his affidavit that:

(1)    Separation of the products of a chemical reaction is frequently required because, typically, syntheses will result in the formation of a mixture of products.

(2)    Separation of the products of a reaction can be performed in many ways including by distillation, liquid extractions and recrystallisations but, most commonly, scientists use chromatography to separate and purify reaction products, particularly when the reactions are first carried out on a small scale.

(3)    There are many different types of chromatography but each is based on similar principles, namely that two or more compounds partition differently between a mobile phase, usually a solvent or mixture of solvents, and a stationary phase, usually an inorganic solid such as silica or alumina. Chromatography is usually carried out by allowing a solution containing the mixture of products to flow through the stationary phase. Due to the differences in partition, the products of the mixture progress (elute) at different rates through the stationary phase and are collected separately and evaporated. Components that interact more strongly with the stationary phase will be eluted more slowly and thereby collected later.

(4)    The three most commonly used types of chromatography are TLC (thin layer chromatography), column chromatography, and HPLC (high-performance liquid chromatography). HPLC is a more sophisticated chromatographic technique in which the solution mobile phase is pumped under significant pressure through a very finely divided stationary phase and the eluted solution monitored for composition change by a detector, often an ultraviolet spectrometer detector. HPLC has the advantage that it can be carried out in tandem with mass spectrometry in an LC-MS (Liquid Chromatography - Mass Spectrometry) instrument. LC-MS refers to the separation and identification technique of liquid chromatography (HPLC) coupled directly with mass spectrometry so as to measure the molecular weights of the compound or compounds present in each eluted fraction.

(5)    NMR (nuclear magnetic resonance) spectroscopy is the most important spectroscopic technique that is used for the structural characterisation of compounds. It allows a chemist to determine either completely or partially, depending on molecular complexity, the structure of a compound by giving information on the types of groups of atoms present and their relative connectivities.

(6)    When a synthetic chemist is seeking to synthesise an unknown compound for the first time, he or she will typically monitor the course of the reaction using TLC and/or with another technique such as analytical HPLC or LC-MS.

188    Professor Barrett was provided with extracts from the laboratory notebook of Dr Griffon (referred to as the Griffon Notebook) and a document titled “Jean-François GRIFFON - Audrey CHAPPE, PROGRESS REPORT No 26*: February 1^st - February 28, 2003 period” (referred to as the Griffon Progress Report). Professor Barrett explained the synthesis described in these documents. He also said:

I have…been asked to express an opinion as to whether the Deoxo-Fluor® reactions and deprotections recorded in the Griffon Notebook resulted in the formation of the “desired product” namely, the uridine derivative with the 2'-CH₃ (methyl) “up” and the 2'-F (fluoro) substituent “down” (compound 6a). As I have discussed above, the Griffon Notebook includes information of only one of the reaction products from each of the syntheses being isolated, purified and characterised, and does not include a record of further examination of any the other products that were clearly formed. On this basis, it is not possible for me to provide my view, based on the Griffon Notebook and Griffon Progress Report, as to whether such a compound was indeed formed from the Griffon syntheses.

However, I do note that the reaction described gave rise to a number of products about which there is no information to indicate that they were isolated, purified and characterised.

189    Professor Barrett was also provided with extracts relating to the experiments carried out by Dr Clemens (referred to as the AMRI experiments). He concluded that the product isolated in the AMRI Experiments contained a compound having the same structure as Clark compound 9, although the AMRI product was not completely pure. Clark compound 9 is 2'-deoxy-2'-fluoro-2'-C-methyluridine as reported in the Clark 2005 paper (Jeremy Clark et al, “Design, Synthesis, and Antiviral Activity of 2'-Deoxy-2'-fluoro-2'-C-methylcytidine, a Potent Inhibitor of Heptatis C Virus Replication” (2005) 48 Journal of Medicinal Chemistry 5504).

190    Professor Barrett was asked to compare the experiments carried out by Dr Griffon with those carried out by Dr Clemens. He concluded that the experiments “used the same quantities of reactant, reagents and solvents and reaction conditions for both the fluorination and deprotection steps”. Professor Barrett said:

Given the close similarities between the experimental procedure recorded in the Griffon Notebook in respect of the Griffon Fluorination and deprotection and that recorded in the AMRI Notebook, it is my opinion that the Griffon Fluorination would most likely also have resulted in the formation of the nucleoside, compound 6a.

191    Professor Barrett was not required to give oral evidence.

3.11    Professor Patterson

192    Steven Patterson is an organic chemist and is a Professor in the Center for Drug Design at the University of Minnesota. He was employed as a discovery chemist by Pharmasset between 2000 and 2004.

193    Professor Patterson was asked to recall the synthesis by Pharmasset of the compound which came to be designated as PSI-6130. PSI-6130 has the structure set out below:

194    The synthesis of this compound was carried out by Jeremy Clark, one of the Pharmasset chemists who reported to Dr Pankiewicz. Amongst other things Professor Patterson records that:

…I recall that Dr Pankiewicz said to Mr Clark that he should prepare the compound from the nucleoside cytidine. Dr Pankiewicz told Mr Clark that by protecting the 3' and 5' positions, oxidising the 2'-OH to the ketone and treating the ketone with methyl lithium or methyl magnesium bromide, he could obtain the tertiary alcohol at the 2' position of the nucleoside. Dr Pankiewicz further suggested to Mr Clark during this discussion that the tertiary alcohol could be treated with DAST as the fluorinating reagent.

…

During the conversation in which Dr Pankiewicz suggested to Mr Clark that he use DAST as a fluorinating reagent, Dr Pankiewicz said that he thought the application of DAST to a tertiary alcohol would be novel chemistry. I understood Dr Pankiewicz to be referring to the fact that the conversion of the 2'-OH “up”, 2'-Me “down” nucleoside to make a 2'-Me “up”, 2'-F “down” nucleoside analogue involved a tertiary alcohol at the 2' position, that is, an OH attached to three carbon atoms. I told Dr Pankiewicz my view that there was a host of literature support for a successful DAST fluorination of a tertiary alcohol as would be required for Mr Clark to fluorinate the nucleoside.

195    Professor Patterson was not required to give oral evidence.

4.    THE SKILLED ADDRESSEE

4.1    The issues

196    It is common ground between the parties that the Idenix patent and the priority documents (the 350 and 949 applications) are to be read through the eyes of the skilled addressee and in light of the common general knowledge.

197    There was disagreement between the parties about the identity of the skilled addressee and the common general knowledge that would be attributed to that person.

4.2    Who is the skilled addressee?

198    In Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8; (2001) 207 CLR 1 (Kimberly-Clark ) the High Court said at [24]:

It is well settled that the complete specification is not to be read in the abstract; here it is to be construed in the light of the common general knowledge and the art before 2 July 1984, the priority date; the court is to place itself “in the position of some person acquainted with the surrounding circumstances as to the state of [the] art and manufacture at the time”.

199    That person is the skilled addressee of the patent (or priority document).

200    Idenix contended that:

The skilled addressee of the ‘350 Application is a medicinal chemist with expertise in the use and synthesis of nucleoside and nucleotide analogues and prodrugs of such compounds as anti-Flaviviridae (including anti-HCV) agents. Only Professor Meier has such experience.

201    According to Idenix Professor Furneaux is not representative of the skilled addressee because:

Professor Furneaux is not a medicinal chemist. He is not a nucleoside chemist. He is a carbohydrate chemist whose only experience in the synthesis and use of nucleoside analogues at the priority date was the Schramm Collaboration, which involved the construction of a sugar analogue (with a nitrogen atom in place of the ring oxygen atom) followed by construction of a particular nucleobase “from scratch”.

202    Idenix also contended that Dr Lambert was not the skilled addressee because “he had no experience in introducing fluorine into a nucleoside as at June 2002/June 2003 or even today” and said that he would have handed the task of preparing any nucleoside to his “nucleoside synthetic team”.

203    In support of its case that Professor Meier represents the skilled addressee Idenix submitted that:

…although the relevant skilled addressee is a team comprising a nucleoside chemist and a medicinal chemist (as well as a virologist), this does not mean that all such chemists are relevantly the skilled addressee. The particular discipline under consideration here is the development of nucleoside analogues for use as antiviral drugs in the field of Flaviviridae, including HCV. The relevant skill is that of a nucleoside chemist working in conjunction with a medicinal chemist (i.e. with a particular focus of creating nucleoside analogues for use as anti-Flaviviridae drugs).

204    Idenix also said:

…the question of whether particular knowledge has formed part of the common general knowledge is not determined, as Gilead would suggest, by identifying whether particular articles or literature references were known by the majority of the four experts (Dr Borthwick, Professor Meier, Professor Furneaux and Dr Lambert) as at June 2002/June 2003. Evidence of at least one expert plus supporting publication material can suffice, all the more so where it is accepted that the skilled addressee is a team.

205    Gilead responded as follows:

To characterise Professor Meier as a “medicinal chemist” rather than a “nucleoside chemist” (or more generally, an “organic chemist”) is to draw an irrelevant distinction in this case. There is no dispute that Dr Borthwick and Professor Furneaux meet the latter description. So does Professor Meier, plainly. In addition, both Dr Borthwick and Professor Furneaux fairly meet the former description, as their work has been on the development and chemical synthesis of compounds that are intended for evaluation for therapeutic use. There is no relevant distinction between the three of them for this purpose. Indeed, Dr Borthwick described himself in his affidavit as a “drug design and medicinal chemistry consultant” and he confirmed this view in his oral evidence.

Accordingly, information that was known to Professor Meier but not to Dr Borthwick and Professor Furneaux is not common general knowledge in this case.

206    I consider that the approach for which Idenix advocates is liable to result in error. If the skilled addressee “is not an avatar for expert witnesses whose testimony is accepted by the court” but a tool for analysis (AstraZeneca AB v Apotex Pty Ltd; AstraZeneca AB v Watson Pharma Pty Ltd; AstraZeneca AB v Ascent Pharma Pty Ltd [2015] HCA 30 at [23]) then it cannot be correct to focus on whether one or other expert witness can be taken to represent the skilled addressee. The relevant issue is the common general knowledge that should be attributed to the skilled addressee given the area of discourse to which the relevant documents relate.

207    Idenix contended that the relevant area of discourse may be characterised as the development of nucleoside analogues for use as antiviral drugs for Flaviviridae infections, including HCV. Gilead said this characterisation is so specific that it “is almost to require a person to have worked on the development of the invention in suit”. Given the terms of the Idenix patent I do not consider Idenix’s characterisation unreasonable. This does not mean, however, that every expert must have expertise across the entire spectrum of the area of discourse in order to give evidence relevant to the common general knowledge. Nor does it mean that, insofar as the chemistry is concerned, the skilled addressee is a person with specialist, even unique (as in the case of Dr Borthwick), experience in the fluorination of a tertiary hydroxyl. As Idenix no doubt intended, to adopt this approach would pitch the debate at a level of specificity ensuring Professor Meier and Dr Borthwick alone could be representative of the skilled addressee. I do not accept this and I also do not accept that the evidence given by Professor Furneaux and Dr Lambert is immaterial to the common general knowledge of the skilled addressee.

208    Professor Furneaux is an organic chemist of over 40 years’ experience including, as it happens, in fluorination. His work in respect of nucleoside analogues is not mere “dabbling” as Idenix would have it. Dr Lambert’s experience in synthesising nucleoside analogues started in the early 1990s and continued thereafter. He described himself as an organic chemist with over 26 years’ experience in organic chemistry and the application of organic chemistry to drug discovery and drug development. His knowledge includes matters relating to virology and HCV, as well as nucleoside chemistry. The fact that he had not attempted to introduce fluorine into a nucleoside and would hand over the actual synthesis tasks to another expert does not mean that his expertise is unrepresentative of the skilled addressee. The skilled addressee is not a nucleoside or medicinal chemist with specialist expertise in introducing fluorine into nucleosides. Professor Furneaux is representative of the kind of chemist who would be part of the team comprising the notional skilled addressee of the Idenix patent. Dr Lambert is also the kind of expert to whom the relevant documents were addressed. The fact that he was towards the beginning of his career in 2002 does not undermine this conclusion. Professor Furneaux’s and Dr Lambert’s evidence about what each treated as background knowledge for those involved in the field, accordingly, is relevant to the drawing of inferences about the common general knowledge.

209    As will be apparent, there was no debate that the common general knowledge that ought to be attributed to the skilled addressee involved more than one field of expertise – in particular nucleoside chemistry and virology. Whether the label “medicinal chemist” or “nucleoside chemist” should be placed on the notional skilled addressee is immaterial. The issue is the knowledge which the skilled addressee is taken to have, which is the common general knowledge of the skilled addressee of documents dealing with the development of nucleoside analogues for use as antiviral drugs for Flaviviridae infections, including HCV. As Gilead submitted, the need for inferences about the common general knowledge to be based on the evidence:

… cannot be avoided by artificially constructing a skilled team to include a person … with highly specific and unusual knowledge gained through literature searches or idiosyncratic experience not shared by others in the field. Nor can it be avoided by artificially excluding others who happen not to possess that knowledge. The common general knowledge is a general body of knowledge known and used by all those in the field.

4.3    What common general knowledge should be attributed to the skilled addressee?

210    To resolve the disagreement between the parties it is necessary to have regard to the applicable principles.

211    In Minnesota Mining and Manufacturing Co v Beiersdorf (Aust) Ltd (1980) 144 CLR 253 (Minnesota Mining), Aickin J (with whom the other members of the Court agreed) said at 292:

The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge.

212    In Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59; (2002) 212 CLR 411, Gleeson CJ, Gaudron, Gummow and Hayne JJ said:

[31] The primary judge rejected Alphapharm’s submission that the common general knowledge of the skilled formulator in Australia included material which the formulator might find by conducting computer searches and the like, being means available to and used by formulators. His Honour correctly did so because the corollary of the submission was that information should be treated as part of the common general knowledge in Australia, even in the absence of evidence of its general acceptance and assimilation by what he called “the formulating community”. This was a proposition which Lehane J recognised was foreclosed by the authority of this Court, in particular by Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd.

…

[57]…There was no finding that what was disclosed by those documents had entered the common general knowledge of those in Australia experienced in the practical work of formulating drugs for therapeutic use. Rather, reliance was placed upon the notion, illegitimate after Minnesota Mining, of a “routine literature search”.

213    Justice Middleton summarised the law as follows in Ranbaxy Laboratories Ltd v AstraZeneca AB [2013] FCA 368; (2013) 101 IPR 11:

[215] Common general knowledge is knowledge actually known or used by skilled addressees generally, or accepted by “the bulk of those who are engaged in the particular art”: see British Acoustic Films Ltd v Nettlefold Productions (1936) 53 RPC 221 at 250 (British Acoustic Films). As the High Court emphasised in Aktiebolaget Hässle [v Alphapharm Pty Ltd (2002) 212 CLR 411; 194 ALR 485; 56 IPR 129; [2002] HCA 59] at [31], information cannot be treated as part of the common general knowledge unless there is “evidence of its general acceptance and assimilation” by persons skilled in the art.

…

[217] As I noted in Eli Lilly [and Company Ltd v Apotex Pty Ltd (2013) 100 IPR 451; [2013] FCA 214], information does not constitute common general knowledge merely because it might be found, for example, in a journal, even if widely read by persons in the art: see Wake Forest University Health Sciences v Smith & Nephew Pty Ltd (No 2) (2011) 92 IPR 496; [2011] FCA 1002 at [96], citing British Acoustic Films at 250 (which was also affirmed in General Tire at IPR 135; RPC 480–1). Reference in this regard is made to the words of Luxmoore J in British Acoustic Films (1936) 53 RPC 221 at 250, cited by Lehane J in Aktiebolaget Hässle v Alphapharm Pty Ltd (1999) 44 IPR 593; [1999] FCA 628 at [39]:

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.

[218] In Alphapharm [Pty Ltd v H Lundbeck A/S (2008) 76 IPR 618; [2008] FCA 559], Lindgren J observed that (at [221]):

[221] … [I]t was held in Astra [Aktiebolaget Hassle v Alphapharm Pty Ltd (2002) 212 CLR 411] that information recorded in a document, even a document widely circulated within the art, is not part of general common knowledge merely because the skilled addressee could be expected to locate it. The question is whether it is “generally accepted without question” or “generally regarded as a good basis for further action” by the bulk of those in the art.

214    In ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc [1999] FCA 345; (1999) 45 IPR 577 (ICI Chemicals) at [112] Emmett J said:

The common general knowledge is the technical background to the hypothetical skilled worker in the relevant art. It is not limited to material which might be memorised and retained at the front of the skilled workers mind but also includes material in the field in which he is working which he knows exists and to which he would refer as a matter of course. It might, for example, include:

•    standard texts and handbooks;

•    standard English dictionaries;

•    technical dictionaries relevant to the field;

•    magazines and other publications specific to the field.

215    The competing submissions of the parties are to be assessed consistently with these principles. It follows that I do not necessarily accept Idenix’s submissions as follows:

Thirdly, even though a particular journal article may not be able to be instantly recalled by an expert, this does not mean that the article and its teaching have not been assimilated into the common general knowledge. This is particularly the case in the field under consideration where the evidence establishes that those working in the field follow the literature as and when it is published even though they may later have to conduct literature searches to remind themselves of the specific details of its contents.

Fourthly, the evidence establishes that, in this field, one of the primary methods by which knowledge is disseminated is by publications. While a particular researcher’s work may not of itself indicate whether the methodology employed by the researcher is common general knowledge, the fact is that by publication and re-publication of that researcher’s work, the information becomes part of the common general knowledge of researchers in that field. That conclusion can be reached where there is evidence from a relevant expert with that knowledge supported by publication evidence.

216    I do not necessarily accept these submissions because they are expressed at a level of principle rather than proof in the particular case. Justice Emmett’s observations in ICI Chemicals are consistent with the authorities. Justice Emmett is not suggesting anything more than that the common general knowledge might include information in articles (etc) if the skilled addressee knows the article (etc) exists and would refer to it as a matter of course. In other words, what his Honour is allowing for is that the skilled addressee does not have to have instant recall of every matter for it to be common general knowledge. If the skilled addressee knows that certain information exists in an article (etc) and would refer to that document as a matter of course to refresh his or her memory about the details of that which the skilled addressee already knows in broad outline then those details might themselves form part of the common general knowledge. Justice Emmett is not suggesting that merely because the skilled addressee could locate a document and, having located it, could read and assimilate its contents, the document and its contents would form part of the common general knowledge. This would be inconsistent with Minnesota Mining, in particular, that the common general knowledge is the background knowledge and experience which is available to all in the trade. For the possibility which Emmett J recognised in ICI Chemicals to arise there would have to be evidence that the particular document was known and would be referred to as a matter of course by those in the field.

217    Idenix’s submissions, accordingly, go too far. It may be accepted that instant recall of an article is not required. This does not mean, however, that documents found by searching for a subject-matter, rather than by some form of recall or reminder of what is already known to exist, are common general knowledge. This is so irrespective of the fact that experts in the field read widely. Further, it is not the case that mere publication and republication proves that a document and its contents have entered the common general knowledge. Nor is it the fact that a document and its contents necessarily form part of the common general knowledge merely because one expert knows or has managed to locate it and assimilate its contents. Such a document may or may not form part of the common general knowledge. The relevant inferences are to be drawn on the basis of the whole of the evidence.

218    In particular, much of Idenix’s case about the common general knowledge appeared to be premised on the assumption that everything Professor Meier knew was necessarily part of the common general knowledge because Professor Meier is a medicinal chemist and the team representing the skilled addressee would include a medicinal chemist. I do not find that chain of reasoning persuasive. While I accept that the relevant area involves a high level of skill, Professor Meier struck me as a leader in his field with knowledge extending far beyond that which might properly be attributed to the skilled addressee having only the common general knowledge known to, assimilated by and generally accepted by all or the bulk of those working in the field. Before 2002 he had read and knew of papers of which none of the other experts were aware. In his second affidavit at para 138 he said that he had “read and was familiar with the following publications and review articles describing different methods and reagents for introducing fluorine atoms at different positions of a nucleoside with appropriate stereochemistry” after which he listed a series of articles in sub paras (a) to (o) including his own article Chris Meier et al, “CycloSal Pronucleotides of 2'-Fluoro-ara-and 2'-Fluoro-ribo- 2',3'-dideoxyadenosine as a Strategy to Bypass a Metabolic Blockade” (1999) 42 J Med Chem 1615-1624. These articles which Professor Meier had assimilated and absorbed by 2002 were not demonstrated to be part of the common general knowledge of nucleoside or medicinal chemists apart from Professor Meier. Further, the fact that Professor Meier approached the 350 application and the Idenix patent with more than the common general knowledge is confirmed by his evidence that:

For example, when we worked on this fluorinated nucleoside analogues in ’99 and before, of course we run literature surveys on – on fluorinated nucleosides. And, of course, we found papers – a lot of papers describing fluorination reactions.

219    In other words it is apparent from his evidence that Professor Meier had a particular expertise in the fluorination of nucleoside analogues by reason of work he had done in 1999 as part of which he had read and assimilated lots of papers about fluorination reactions. While some familiarity with fluorination reactions might be imputed to the skilled addressee of the 350 application and the Idenix patent it would be wrong to conceive of the skilled addressee as having specialist experience and expertise in that regard by reason of personal involvement in the fluorination of nucleosides (or, in the case of Dr Borthwick, carbocyclic nucleosides). Neither the 350 application nor the Idenix patent is directed towards such a narrow topic as the fluorination of nucleosides. I do not accept that the skilled addressee can be treated as having available as part of the common general knowledge all of the expertise and experience in the fluorination of nucleosides that Professor Meier and Dr Borthwick had by reason only of their involvement in particular projects for that purpose.

220    Given the specificity of some of the issues which Idenix said – and which Gilead denied – formed part of the common general knowledge of the skilled addressee, it is necessary to deal with the disputes on an issue-by-issue basis. In the following paragraphs I identify the fact or matter said to form part of the common general knowledge of the skilled addressee in italics before setting out my conclusions about whether or not that fact or matter forms part of the common general knowledge.

221    Dr Borthwick’s work in relation to the fluorination of a tertiary hydroxyl group at the 4'-position of a carbocyclic nucleoside using DAST with inversion published in the Journal of the Chemical Society, Chemical Communications in 1990 and a second synthesis by Dr Borthwick published in Bioorganic & Medicinal Chemistry Letters in 1993 (Annexures AB-42 and AB-44): Idenix contended that this formed part of the common general knowledge noting that Professor Furneaux and Dr Lambert both said that they routinely read this journal prior to June 2002.

222    I do not accept that this work or the articles recording this work formed part of the common general knowledge in 2002 or 2003 (or subsequently). The mere fact that the work was published in a respected journal that was routinely read by organic chemists does not mean that the work entered the common general knowledge. If that were so, every article in that journal would be taken to form part of the common general knowledge of an organic chemist. There is a difference between experts routinely reading certain journals and the existence of those articles, let alone the information within those articles, being part of the common stock of knowledge relating to the art, known to and generally accepted by the bulk of those who work in the relevant field. Further, the fact that Dr Borthwick’s articles were cited in footnotes to another paper (referred to as the Wachtmeister Paper) does not transform the articles or the Wachtmeister Paper (which neither Dr Borthwick nor Professor Furneaux knew about) into common general knowledge.

223    As Gilead put it:

(a)    The only witness who gave any evidence of having been aware of that [Dr Borthwick’s] work was Dr Borthwick. This is hardly surprising, since he conducted it.

(b)    Given his position, Dr Borthwick’s evidence as to his awareness of the work cannot inform the question whether the work was generally known to skilled persons in the field at the relevant date.

(c)    Dr Borthwick did not purport to give any evidence that the work was generally known to skilled persons in the field at the relevant date.

(d)    It is clear from Professor Furneaux’s evidence that he was not aware of Dr Borthwick’s work at the relevant date.

(e)    Dr Meier did not suggest he was aware of Dr Borthwick’s work at the relevant date, amongst the many publications he did list in his affidavit.

(f)    There is no evidence that Dr Lambert was aware of Dr Borthwick’s work at the relevant date. This was not put to him in cross-examination.

(g)    Idenix’s own documents show that Dr Borthwick’s work was not referred to by Idenix’s team of scientists and external consultants – an actual team of skilled persons in the field who were working on the task at hand.

(h)    Dr Borthwick himself conducted literature searches by reference to keywords including “tertiary fluoride and nucleoside”, “tertiary fluoronucleoside” and “tertiary fluoro nucleoside”, being searches he said he would have conducted in addressing the task at hand – and these did not turn up Annexures AB-42 or AB-44 [Dr Borthwick’s publications] or indeed any of his other publications.

224    I am persuaded that Gilead is also right when it says:

This last point is significant, because it suggests that, far from having been part of the common general knowledge, Dr Borthwick’s work in Annexures AB-42 and AB-44 was not even ascertainable by a “routine literature search” of the kind the High Court held in Aktiebolaget Hässle was not sufficient to meet the relevant standard for information to be part of the common general knowledge.

225    I also agree with Gilead that:

… the fact that Professor Furneaux routinely read the journal in question but was not aware of Dr Borthwick’s publications provides a good illustration of the distinction between published information and common general knowledge that was emphasised in Aktiebolaget Hässle.

226    The Middleton Paper: Gilead agreed that the Middleton Paper, and its contents, had entered the common general knowledge before 2002. This is consistent with the evidence including that of Professor Furneaux that the Middleton Paper is a seminal publication concerning the fluorination of hydroxyl groups. As Gilead submitted, however, the Middleton Paper is not an example that assists Idenix to bring other, more obscure, less well known publications within the common general knowledge.

227    The McAtee Paper: Idenix contended that this formed part of the common general knowledge at 2002 but there was no evidence of the requisite kind supporting this inference. As Gilead said:

No witness gave evidence that he or she was aware of it at the relevant date. Dr Lambert gave evidence that he was not.

228    I do not accept that the McAtee Paper or its contents had entered the common general knowledge by 2002 or subsequently.

229    The use of DAST to fluorinate a tertiary hydroxyl group with inversion: Idenix did not identify any basis for this use forming part of the common general knowledge other than the work of Dr Borthwick. Given that Dr Borthwick’s work was not part of the common general knowledge I do not accept that the use of DAST to fluorinate a tertiary hydroxyl group with inversion was part of the common general knowledge by 2002 or subsequently. As discussed below, I am satisfied that this use was far indeed from common general knowledge at the relevant times.

230    The use of DAST to fluorinate a secondary hydroxyl group on a nucleoside with inversion: Gilead accepted that by 2002 the use of DAST to fluorinate a secondary hydroxyl group on a nucleoside had been conducted and reported but said some care was required in identifying the knowledge that was common general knowledge. I agree. The evidence disclosed that it was common general knowledge that DAST could be used to fluorinate a secondary hydroxyl group on a nucleoside but, as explained in more detail in the context of the sufficiency issue, it was also common general knowledge that these reactions could be unpredictable and could result in a number of competing reactions, including fluorination with inversion, fluorination without inversion, or result in an elimination or rearrangement product with no fluorination at all. The skilled addressee also knew as part of the common general knowledge that there are differences between a secondary hydroxyl group and a tertiary hydroxyl group including for the purpose of any fluorination reaction.

231    The first, and only, common general knowledge method that would come to mind for the introduction of a tertiary fluoro group at the 2'-“down” position of a nucleoside analogue would be fluorination of a tertiary 2'-hydroxyl “up” nucleoside with DAST (or DAST equivalents) with inversion: As explained in the context of sufficiency below I do not accept that the evidence supports this proposition.

232    A proposed mechanism of action of the compounds as anti-Flaviviridae drugs was the inhibition of Flaviviridae polymerase activity: Gilead accepted that this was part of the common general knowledge of the skilled addressee as at 2002. I agree.

233    Conversion to the 5'-triphosphorylated form of a nucleoside analogue in an HCV infected liver cell was a prerequisite for inhibiting the HCV polymerase (i.e. the 5'- triphosphorylated form was the “active species”): Gilead accepted that it was common general knowledge that the 5'-triphosphorylated form of a nucleoside analogue was the “active species” but not that conversion to the 5'-triphosphorylated form of a nucleoside analogue in an HCV infected liver cell was a prerequisite for inhibiting the HCV polymerase. I agree with Gilead that the evidence does not support the inference that the common general knowledge extends as far as Idenix would have it merely by reason of Professor Meier’s evidence.

234    The 5'-nucleoside analogue triphosphate will only be recognised by the polymerase (and hence result in inhibition) if it is able to mimic the natural nucleoside: I do not accept that this formed part of the common general knowledge. Dr Lambert, who is representative of the skilled addressee insofar as nucleoside chemistry is concerned, said:

I agree that a nucleoside analogue or nucleotide analogue must be recognised and phosphorylated by cellular enzymes in order to be incorporated into a growing RNA chain and thereby act as an antiviral. However, in my opinion this does not mean that nucleoside analogues and nucleotide analogues must always closely resemble the structure of natural nucleosides. For example, I set out at paragraph 81 of my First Affidavit the chemical structures of nucleoside and nucleotide analogues that I was aware were in use globally as antivirals for a number of different viruses in around the time I performed my HCV Review. Of these chemical structures I note that acyclovir (for the treatment of HSV), adefovir dipivoxil (for the treatment of HBV) and tenofovir disoproxil (for the treatment of HIV) all significantly depart from the structure of the natural nucleoside.

235    Given this evidence I do not see how it can be said that it was widely known and accepted in the art that the 5'-nucleoside analogue triphosphate will only be recognised by the polymerase (and hence result in inhibition) if it is able to mimic the natural nucleoside.

236    Two different prodrug strategies could be used – a nucleoside prodrug strategy and nucleotide prodrug strategy: Gilead accepted that this was part of the common general knowledge by 2002. I agree.

237    The nucleoside prodrug strategy focuses on prodrug moieties at the 2'- and 3'- positions to improve the uptake of the nucleoside analogue into the cell, and after entry to the cell the prodrug moiety is cleaved, leaving the nucleoside analogue to be phosphorylated to the 5'-mono-, 5'-di-, and 5'-triphosphate forms by the metabolism in the cell: As Gilead said, while it was common general knowledge that it was desirable for a nucleoside analogue to be phosphorylated by metabolism in cells, and that prodrug strategies were, in general, utilised to overcome limitations of a parent compound including cellular uptake, the evidence does not support an inference that it was common general knowledge that prodrug moieties are at the 2' and 3' positions or that the only reason for them is improved uptake. In common with Gilead’s other qualifications below it is apparent that Idenix’s characterisation of the common general knowledge is founded on Professor Meier’s evidence. As discussed, however, I am not satisfied that the skilled addressee armed with the common general knowledge in 2002 or 2003 knew everything that Professor Meier knew (even on the basis that the skilled addressee is a team including a nucleoside chemist, or medicinal chemist as Idenix would have it, and a virologist). Dr Lambert and Professor Furneaux did not share this knowledge and their state of knowledge is not able to be dismissed as immaterial to this issue as Idenix would have it.

238    The nucleotide prodrug strategy focuses on delivering a nucleotide analogue into the cell by using a prodrug moiety at the 5' position, which is cleaved after entry to the cell. The aim of nucleotide prodrug strategy is to mask or protect the 5'-phosphate group(s) of the nucleotide analogue to prevent dephosphorylation in the bloodstream and to reduce the negative charges of the 5' phosphate group(s) so as to make it able to cross the cell membrane more easily. The delivery of a 5'-nucleoside analogue mono-, di- or triphosphate to the cell avoids any limitation in the conversion of a nucleoside analogue to the 5'-mono-, 5'- di- or 5'-triphosphate form: Gilead made this submission:

Gilead accepts that it was CGK that, to the extent that it was practicable to deliver a 5'-nucleoside analogue mono-, di- or triphosphate to the cell, this could avoid any limitation in the conversion of a nucleoside analogue to the 5'-mono-, 5'-di- or 5'-triphosphate form.

However, Gilead does not accept that this item was otherwise CGK. In particular, it was not CGK that the prodrug moiety at the 5' position is “cleaved after entry to the cell”; to the contrary, at least a phosphorous containing group was intended to remain in place as a substrate for subsequent phosphorylation.

239    I agree with Gilead that Idenix’s identification of the common general knowledge goes too far for the same reasons as set out above.

240    Stable modifications at the 2'- and/or 3'-positions were known and AZT in HIV treatment was such an example: Gilead made this submission, which I accept:

Gilead accepts that, at a general level, it was CGK that nucleoside analogues could be modified at the 2'- and/or 3'-positions, amongst other positions, and that such modifications at those or other positions could potentially be stable. Gilead also accepts that the existence of the compound AZT and its use in HIV treatment were CGK.

However, Gilead does not accept that this item was otherwise CGK. In particular, Gilead does not accept that it was CGK that modifications at the 2'- and/or 3'-positions of nucleoside analogues would be stable such that modifications at those positions would be preferred or tried first.

Nor does Gilead accept that the detail beyond the general structure of AZT was CGK. In addition, it should also be noted that AZT was for use in HIV treatment, not HCV treatment as asserted for the invention.

241    The majority of antiviral compounds available in June 2002 had stable modifications at either the 2'- or 3'-positions: Dr Lambert’s evidence is inconsistent with this forming part of the common general knowledge. Dr Lambert identified a number of antivirals known as at 2002 which did not involve modifications at these positions. I thus do not accept that this proposition is necessarily accurate, and still less that it formed part of the common general knowledge at the relevant times.

242    Stable modifications at the 2'- and/or 3'-down positions would mimic the natural nucleosides: Given the discussion above about the lack of a need to mimic the natural nucleosides this could not have been part of the common general knowledge at 2002.

243    Compounds which had one or more stable modifications at the 2'-position were known: Gilead accepted that this fact was part of the common general knowledge.

244    A stable double modification at the 2'-position was known for Gemcitabine: Again, based on Dr Lambert’s evidence, I consider Idenix’s proposition goes too far. I accept that the existence of the compound Gemcitabine was part of the common general knowledge at 2002. I do not accept that it was common general knowledge of the skilled addressee that Gemcitabine had a stable double modification at the 2'-position. Nor do I accept that it was part of the common general knowledge at 2002 or subsequently that the skilled person working on an anti-HCV or anti-Flaviviridae treatment would necessarily look to the anti-tumour field for guidance.

245    Certain nucleoside analogues that had a methyl modification of the sugar ring had been shown to have antiviral or anti-tumour activity: While this is knowledge Dr Lambert had, this alone does not prove that this was part of common general knowledge at 2002 or subsequently. I am not satisfied on the evidence that it should be inferred that this was part of the common general knowledge of the skilled addressee at the relevant times.

246    Fluorine was known to medicinal chemists as the “magic atom” because introducing it into a compound often causes interesting changes in bioactivity: This was evidence of Professor Meier. The difficulty is that while the other relevant experts knew that fluorine was a potential candidate substituent, they did not treat fluorine as a “magic atom” in the sense Professor Meier did. They considered that fluorine was one of a number of known potential substituents the biological effect of which was not predicable. Unlike Professor Meier, Dr Lambert did not know in 2002 that fluorine’s ability to mimic a hydroxyl group made it uniquely suited to nucleoside analogues as a replacement of OH in the sugar portion of a nucleoside. The reason for this, I infer, is that as Professor Furneaux acknowledged this was something he would expect “somebody who was interested in having a fluorine in a carbohydrate” of his skill to know but he could not say more than that many chemists would have considered the value of introducing fluorine into an organic molecule.

247    Accordingly, I consider that it was part of the common general knowledge that fluorine was a known potential candidate substituent with the potential for biological activity which could not necessarily be predicted and no more.

248    The introduction of a fluoro atom in the 2'-down position of a nucleoside was shown to provide higher chemical stability, and some fluorinated nucleosides were shown to provide high inhibitory activity against viral replication, for example HIV: This was Professor Meier’s evidence but, beyond this, there is no basis for inferring that this was part of the common general knowledge at the relevant times.

249    Natural bases were readily obtainable and they most closely resembled (or mimicked) the natural nucleoside: Gilead accepted this was part of the common general knowledge at the relevant times. I agree.

250    It is also appropriate here to note that to the extent Idenix might have submitted that everything in the Red Books (the Journal of Carbohydrate Chemistry) about the fluorination of secondary and tertiary hydroxyls were part of the common general knowledge, I disagree. None of the experts suggested that they had absorbed and assimilated all of that information as part of the generally accepted knowledge in their field of endeavour.

251    Insofar as other matters were asserted by one or the other parties to constitute part of the common general knowledge at the relevant dates, I deal with the assertions in the context of the issue of sufficiency below.

5.    LACK OF NOVELTY?

5.1    The issue

252    The principal issue is whether claim 7 of the Idenix patent is fairly based on matter disclosed in either the 350 application or the 949 application. Idenix concedes that if claim 7 is not fairly based on matter disclosed in either the 350 application or the 949 application then claim 7, and all claims dependent on claim 7 (claims 8 to 41), are invalid for lack of novelty by reason of the Clark patent.

5.2    The legislation

253    The relevant legislation is the Patents Act 1990 (Cth) (the Act) and Patents Regulations 1991 (Cth) (the regulations) as in force at the competing priority dates.

254    Each claim of a patent has a priority date (s 43(1)). The priority date of a claim is the date of filing of the specification or, where the regulations provide for the determination of a different date as the priority date, the date determined under the regulations (s 43(2)). Regulation 3.12(1)(b) provides that if a claim is fairly based on matter disclosed in one or more priority documents, the priority date of the claim is the date of filing of the priority document.

255    The 350 and 949 applications are priority documents. Accordingly, if claim 7 of the Idenix patent is fairly based on matter disclosed in either the 350 or 949 applications, the priority date will be the date of the filing of the 350 or 949 applications (as applicable) and not the date of the filing of the Idenix patent specification. In either event the priority date of claim 7 will be before the priority date of the Clark patent and, as a result, the Clark patent will not destroy the novelty of claim 7 (and dependent claims). If claim 7 is not fairly based then Idenix concedes that the invention claimed in claim 7 (and dependent claims) was not novel as required by s 18(1)(b)(i) of the Act and, accordingly, was not patentable.

5.3    The principles

256    The content of the relevant principles was agreed but their application to the present case was not.

257    In Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58; (2004) 217 CLR 274 (Lockwood) the High Court said:

[46] … a lack of fair basing is a distinct ground for revocation. Hence the “inventiveness” or “meritoriousness” of, or the technical contribution made by, the specification are issues to be examined if there is an objection under s 18(1)(b) of the Act for want of novelty or absence of an inventive step (ie obviousness). There is no reason to introduce them into the fair basing question.

…

[68] Erroneous principles. The comparison which s 40(3) calls for is not analogous to that between a claim and an alleged anticipation or infringement. It is wrong to employ “an over meticulous verbal analysis”. It is wrong to seek to isolate in the body of the specification “essential integers” or “essential features” of an alleged invention and to ask whether they correspond with the essential integers of the claim in question.

[69] “Real and reasonably clear disclosure”. Section 40(3) requires, in Fullagar J’s words, “a real and reasonably clear disclosure.” But those words, when used in connection with s 40(3), do not limit disclosures to preferred embodiments.

The circumstance that something is a requirement for the best method of performing an invention does not make it necessarily a requirement for all claims; likewise, the circumstance that material is part of the description of the invention does not mean that it must be included as an integer of each claim. Rather, the question is whether there is a real and reasonably clear disclosure in the body of the specification of what is then claimed, so that the alleged invention as claimed is broadly, that is to say in a general sense, described in the body of the specification.

Fullagar J’s phrase serves the function of compelling attention to the construction of the specification as a whole, putting aside particular parts which, although in isolation they might appear to point against the “real” disclosure, are in truth only loose or stray remarks.

…

[71] … The correct way of answering the question is to examine the body of the specification in order to see what it describes as the invention.

…

[87] Finally, it is necessary to consider the trial judge’s citation of Atlantis Corporation Pty Ltd v Schindler [(1997) 39 IPR 29] for the proposition that to couch a claim “in the same terms as the description of the invention in the specification” did not of itself, by that mere “coincidence of language”, establish fair basing. That proposition is correct, but it is not fatal to the Patentee’s position in this case. A “coincidence of language” between a claim and part of the body of a specification does not establish fair basing if that part of the language of the specification does not reflect the description of the invention in the light of the specification as a whole… In short, the case is distinguishable. Here, the Patentee does not rely on mere “coincidence of language”: it contends that the language used, unlike that employed in the Atlantis Case, does describe the invention.

258    In Inverness Medical Switzerland GmbH v MDS Diagnostics Pty Ltd [2010] FCA 108; (2010) 85 IPR 525, Bennett J noted at [142] that the principles from Lockwood relevant to internal fair basis also applied in an external fair basis context:

In Lockwood Security Products v Doric Products Pty Ltd (2004) 217 CLR 274; 212 ALR 1; 62 IPR 461; [2004] HCA 58 (Lockwood), the High Court stated at [69] that the fair basing requirement in s 40(3) of the 1990 Act requires a “real and reasonably clear disclosure” of what is then claimed. The High Court said that it is wrong to apply an “over meticulous verbal analysis” and the comparison is not analogous to that between a claim and an alleged anticipation or infringement: at [68]. The correct analysis is whether “the invention is broadly, that is to say in a general sense, described in the body of the specification” or whether it “travel[s] beyond the matter disclosed”: Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR 79 at 95; 11 IPR 289 at 301 per Gummow J, quoted with approval in Lockwood at [69]; Synthetic Turf Development Pty Ltd v Sports Technology International Pty Ltd (2005) 67 IPR 475; (2006) AIPC 92-166; [2005] FCAFC 270 at [26] (Synthetic Turf); Lockwood at [57]. Disclosure is not limited to preferred embodiments set out in the specifications: Lockwood at [69]. These principles are equally applicable to determining whether the claims in a divisional patent are fairly based on matter disclosed in a parent patent or a priority document.

259    In CCOM Pty Ltd v Jiejing Pty Ltd (1994) 51 FCR 260 at 280 the Full Court said:

…it is well established that a claim may be fairly based on matter in the specification which is not verbal description but accompanying drawings; these of course, are to be read by the skilled addressee: Societe des Usines Chimiques Rhone-Poulenc v Commissioner of Patents (1958) 100 CLR 5 at 11, per Fullagar J; Halsbury's Laws of England, (4th ed, 1981), Vol 35, pp 301, 303.

260    Other cases dealing with internal fair basis are also relevant. Given that internal fair basis is also in issue in this case, it is convenient to deal with those cases immediately.

261    In Seafood Innovations Pty Ltd v Richard Bass Pty Ltd [2011] FCAFC 83; (2011) 92 IPR 1 Bennett J said:

[35] Claim 1 is, of course, no broader than the broadest consistory clause but that is not in itself sufficient for fair basis. The first question is whether the claim is fairly based on the description of the invention or, as put by Bass, whether claim 1 “travels beyond” the invention as described. The parties accept that the principles to be applied are found in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 1) (2004) 217 CLR 274; 212 ALR 1; 62 IPR 461; [2004] HCA 58 (Lockwood (No 1)), in which the High Court set out the approach to be taken in assessing compliance with the fair basis requirement in s 40(3) of the Act. Their Honours made it clear that s 40(3) does not raise questions that properly arise under s 18 of the Act. That is, a consideration of s 40(3) does not import a consideration of novelty or innovative step. The key to an understanding of the application of s 40(3) is an understanding of the invention described in the specification. It is necessary to examine the body of the specification in order to see what it describes as the invention. In doing so, it is wrong to employ an “over meticulous verbal analysis” or to seek to isolate in the body of the specification “essential integers” or “essential features” of an alleged invention and to ask whether they correspond with the essential integers of the claim in question. The requirement for a real and reasonable clear disclosure does not limit those disclosures to a preferred embodiment.

[36] It is therefore necessary to ascertain how the invention is described in the common specification of the innovation patents…

…

[39] …Bass’ analysis seeks to isolate essential integers from the body of the specification in understanding the described invention. This is contrary to the approach identified by the High Court in Lockwood (No 1). As is apparent from Lockwood (No 1), a narrow embodiment of a broad claim does not render the claim invalid for lack of fair basis. A claimed invention within the scope of the broadest description of the invention in the specification is fairly based.

262    In Photocure ASA v Queen's University At Kingston [2005] FCA 344; (2005) 216 ALR 41 Merkel J at [134] said:

…When s 40(3) requires that a patent’s claims must be fairly based on “the matter described in the specification”, it refers back to the description of the invention required by s 40(2): see Lockwood at [53]. That is not limited to the examples. Rather, the specification must be read as a whole in order to ascertain what it discloses as the invention.

263    In Pfizer Inc v Commissioner of Patents [2005] FCA 137; (2005) 141 FCR 413 (Pfizer v Commissioner of Patents) Bennett J said:

[69] In Imperial Chemical Industries Pty Ltd v Commissioner of Patents (2004) 213 ALR 399 [[2004] FCA 1658], Crennan J considered at [64]-[68] whether an alleged anticipatory document containing a broad chemical claim encompassing many, even thousands of compounds discloses, sub silentio, a particular compound from the broad class referred to. Her Honour referred to University of Georgia at 233 and 237 and the distinction there made between “paper disclosure” and “enabling disclosure” as “sound”. Her Honour was also of the view that it was in the context of novelty that the latter had relevance.

[70] Implicit in the reasoning of Crennan J in Imperial Chemical Industries, is that disclosure of the broad class does disclose the members of that class. It may not be an enabling disclosure but still be a “real and reasonably clear disclosure”.

…

[72] In TA Blanco White, Patents for Inventions (4th ed, Stevens & Sons, London, 1974) the author states at 4–109, footnote 62:

Prima facie, a general disclosure of a class is a disclosure of all members of the class, however obscure and whatever the consequences.

[73] Roche [F Hoffman-La Roche & Co AG v Commissioner of Patents (1971) 123 CLR 529] is authority for the proposition that where a large class of compounds is disclosed, claims to individual compounds forming part of that class are fairly based on the disclosure. Gibbs J held that the fact that the first basic application disclosed a class of chemical compounds, including those in the proposed claims was sufficient to provide fair basis (at 541). He rejected the submission that the compound per se should have been disclosed.

[74] Further, absence of exemplification does not mean absence of fair basis (Roche at 541–542; Doric at 60). There is no requirement that each single compound be specifically claimed (Roche at 539, applying Societe Des Usines Chimiques Rhone-Poulenc v Commissioner of Patents (1958) 100 CLR 5). That is, there is a “real and reasonably clear disclosure” of that single compound by reason of its inclusion in the class.

264    It should also be noted that in F Hoffman-La Roche & Co AG v Commissioner of Patents (1971) 123 CLR 529 (Roche) at 542-543 Gibbs J observed as follows:

If a basic application disclosed a large class of compounds, all of which were claimed to be of pharmaceutical utility, and it were found that the claim was false, in that only some of the compounds were useful, or it appeared that some of the compounds had a particular and peculiar value, there would be much to be said for the view that a claim limited to those compounds selected for their utility or special value would not be fairly based on matter disclosed in the basic application, at least if the basic application did not itself provide a guide to that selection…

265    In Decor Corporation Pty Ltd v Dart Industries Inc (1988) 13 IPR 385 Sheppard J stated as follows at 412 to 413:

A reading of the specification as a whole leaves one with the impression that very great advantage was seen by the draftsman, and thus the inventor, in using a surface which was corrugated or fluted. Indeed, as one reads the specification, one is so impressed with this feature of the description, repeated as it is on numerous occasions, sometimes with the addition of the word “plaited”, that it comes as quite a surprise to find the words missing from the claims. It is then that one must remember the rules of construction which are to be applied and take care to give effect to them. One must also give weight to the paragraph (relied upon by the learned primary judge), which leads from the description of the preferred embodiment to the claims, in which it is said that the invention may be embodied in other specific forms without departing from the spirit of the essential characteristics thereof and that the present embodiments are to be considered in all respects as illustrative and not restrictive.

Having given the matter the anxious consideration which I have indicated, I have reached the conclusion that the word “biased” in the claims is not to be restricted in its meaning so as to apply only to corrugated, fluted or similar surfaces which are biased in the sense that they have a predisposition to move in a particular way.

266    In Coopers Animal Health Australia Ltd v Western Stock Distributors Pty Ltd (1987) 15 FCR 382 at 389 Fox J said:

The fact that there may be a further working out of details before the complete specification is lodged does not mean that the provisional specification can always be used as giving a priority date to something which is worked out and contained in the specification. In particular, the selection of one compound with special qualities from a class of compounds disclosed in the provisional is not permissible for that purpose: Hoffman-La Roche (supra) at 542 [F Hoffman-La Roche & Co AG v Commissioner of Patents (1970) 123 CLR 529]; Re British Drug Houses Ltd's Application [1964] RPC 237 at 244.

267    Justice Fox concluded that the claim was not fairly based on the provisional specification in that case because (at 390-391):

The patent claim concerning DGBE is not simply a more specific application of what is claimed in the provisional specification. It is the result of further experimentation and can properly be regarded as involving an inventive step. Indeed, the whole product is different from any which could be regarded as part of an invention disclosed in the provisional specification. It is true that the same chemical names are to be found at one point or another in the provisional specification, but what has since been arrived at, although in a sense derived from various ingredients mentioned in the provisional specification, is itself a special product. A reading, or a study, of the provisional specification would not lead readily, or by a process of selection, to what is set forth in the patent claim.

268    Justice Beaumont at 399 noted that while DGBE was mentioned in the provisional specification this was insufficient:

It is true that DGBE is mentioned in the provisional on a number of occasions and is specifically picked up in two of the examples. But its mention is not, of course, enough. It must form a basis for the later claim.

269    In Justice Beaumont’s view there was “an attempt to place a very different complexion upon the character of the invention” which resulted in lack of fair basis (at 400).

270    In AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99; (2014) 226 FCR 324 at [244], albeit in a different context but nevertheless concerning the concept of disclosure, Besanko, Foster, Nicholas and Yates JJ said:

A very general description of an invention in a specification before amendment might not contain a real and reasonably clear disclosure of more specific embodiments of the invention subsequently disclosed and claimed after amendment. Similarly, in the case of a claim to a pharmaceutical formulation, the description of the invention in the specification before amendment might allow for the use of particular classes of chemicals with which to make the formulation, while the amended claim might positively exclude their use for that purpose.

271    Later, Besanko, Foster, Nicholas and Yates JJ said this:

[285] It may be accepted that the present case is not one where the prior disclosure is simply in relation to a large class of compounds of which the subject matter of the invention in suit is but one of such compounds. Dealing with disclosures of that nature, Jacob LJ in Dr Reddy’s Laboratories (UK) Ltd v Eli Lilly and Co Ltd [2010] RPC 9 at [26] said:

... An old question and answer runs as a follows: “Where does a wise man hide a leaf? In a forest.” It is, at least faintly, ridiculous to say that a particular leaf has been made available to you by telling you that it is in Sherwood Forest. Once identified, you can of course see it. But if not identified you know only the generality: that Sherwood Forest has millions of leaves.

[286] Later at [28], his Lordship said:

I would add that I would regard the listing out of a great number of compounds as opposed to the use of a Markush formula in the same way. To say a particular book is identified by saying “the books in the Bodleian” is no different from saying it is identified by providing access to the catalogue of the Bodleian.

272    Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth [2011] FCAFC 132 (Sigma v Wyeth) also contains relevant statements, specifically in respect of external fair basis. Justice Bennett said:

[78] There is no dispute that regard must be had to the whole of the Priority Document, including the claims. This involves an assessment of statements in the Priority Document in context. There is no dispute that the comparison must be conducted as a matter of substance. However, Wyeth submits that, by analogy with the fair basing of a complete patent specification on a provisional specification, ‘a development along the same line of thought which constitutes or underlies the invention described in the earlier document’ may be regarded as fairly based on matter disclosed in the earlier document (Delnorth Pty Ltd v Dura-Post (Aust) Pty Ltd (2008) 78 IPR 463 at [20] per Gyles J, citing Stauffer Chemical Co’s Application [1977] RPC 33 at 54). Those observations cannot, however, derogate from the requirement that the earlier document must in substance disclose the claimed invention. Even if that invention were further developed in the later document, it must be the same invention. Additionally, a disclaimer of the scope of the invention described in the earlier document cannot be disregarded in assessing the external fair basis of the subsequent claim on that earlier document.

[79] The necessity of putting stray phrases, parts of sentences or parts of paragraphs into the context of the whole of the Priority Document answers many of Wyeth’s submissions on external fair basis. It is correct that, as Wyeth submits, there is a reference in the specification of the Priority Document to the provision of an ER encapsulated formulation containing venlafaxine hydrochloride, unlimited by reference in that sentence to the particular spheroid formulation the subject of the later examples. However, the beginning of that sentence is ‘in accordance with this invention’ an ER formulation is provided. The next sentence commences with ‘through administration of the venlafaxine formulation of this invention, there is provided a method’. The Priority Document does not assert that it provides a method unrestricted to the formulation described. To the contrary, it asserts that some formulations, such as a hydrogel formulation, have not worked.

273    Justice Bennett continued as follows in Sigma v Wyeth:

[90] That is, it is not simply a matter of matching a consistory clause or other stray phrases with a claim. It is a question of comparing the invention claimed with the invention disclosed. Frequently, indeed most often, there is no real difference; sometimes there is.

[91] Fair basis requires a “real and reasonably clear disclosure” in the body of the specification of what is claimed (Lockwood (No 1) at [69]). If the consistory clause is not consistent with the description of the invention in the body of the specification considered as a whole, or is wider than that invention, the mere insertion of a statement mirroring the claim does not, of itself, provide fair basis for the claim. If the consistory clause must be understood in a particular way to be consistent with the rest of the specification, and if so understood it does not describe the invention claimed, there is no fair basis (Lockwood (No 1) at [99]).

274    Similarly, in Sigma v Wyeth Yates J at [243] concluded that “the consistory clauses do not reflect the description of the invention in the light of the specification as a whole: Lockwood at [87]; Atlantis Corporation Pty Ltd v Schindler (1997) 39 IPR 29 at 50”. Justice Nicholas at [170] also considered that “the consistory clauses do not do so [provide a fair basis] because they do not reflect the description of the invention contained in the specification when read as a whole”.

275    As explained in the cases below, these statements must be understood against the fact that a priority document may disclose more than one invention, the consequence being that part or parts of a priority document might be relied upon to satisfy the requirement of fair basis under reg 3.12.

276    In Leonardis v Sartas No 1 Pty Ltd (1996) 67 FCR 126 (Leonardis v Sartas) at 139, Burchett, Hill and Tamberlin JJ contrasted the language used in s 40(3) (internal fair basis) with that in regs 3.12(1)(b) and (c), pointing out that s 40(3) refers to the “the matter described”, while reg 3.12 refers to the claim being fairly based “on matter disclosed”:

… Whatever the precise effect of the definite article in s 40(3), in the regulation, its absence plainly suggests that the fair basis in question need not relate to all the matters disclosed in the respective documents referred to in pars (b) and (c). Paragraph (b), as is made clear by subreg (2)(a), relates to s 38 of the Act, subs (1) of which provides:

“If an applicant makes a provisional application, the applicant may make one or more complete applications associated with the provisional application at any time within the prescribed period.”

This indicates that the provisional application may provide fair basis for several complete applications, and the absence of a definite article which might require one claim to be fairly based on all the matter disclosed in a provisional application seems deliberate and appropriate. That the draftsman’s choice of words was deliberate is also suggested by the final words of reg 3.12(1)(b), in which the expression “the matter” is used to refer to the particular matter that provides the fair basis. Just as the nature of a provisional application, having regard to s 38, may explain the reference to “matter” in par (b), so the nature of a divisional application may explain the use of the same word, again without any article, in par (c).

277    At 143-144 in Leonardis v Sartas their Honours said:

In Societe des Usines Chimiques Rhone-Poulenc v Commissioner of Patents [(1958)

100 CLR 5] at 28-29, Fullagar J said that “a particular specification may quite reasonably be regarded either as disclosing one invention only or as disclosing two or more inventions”. It is plain that Fullagar J thought a claim might be “fairly based on matter disclosed” in a provisional specification within the meaning of s 45(5) of the Patents Act 1952 (Cth), although other inventions were also disclosed in the same provisional specification. Beaumont J, in Coopers Animal Health Australia Ltd v Western Stock Distributors Pty Ltd [(1987) 15 FCR 382] at 400, made the same point when he said:

“[I]t is open to a party to describe more than one invention in a provisional. Further, the respective functions of the provisional and the complete must be kept steadily in mind: for the purposes of the provisional, it is sufficient to ‘describe’ the invention; by contrast, the complete shall ‘fully describe’ the invention, including its best method of performance and shall end with a single claim ‘defining’ the invention.”

He rejected the fair basing of the ingredient DGBE involved in that case, not on the ground that it could not be separately claimed in the complete specification, but on the ground that in the provisional specification its role was “so subsidiary and so incidental to the main thrust and orientation of that specification that one would hesitate to describe it as forming a basis for the later claim”, and, at any rate, one could not regard that claim as “fairly” so based.

278    In Vehicle Monitoring Systems Pty Ltd v Sarb Management Group Pty Ltd (trading as Database Consultants Australia) (No 2) [2013] FCA 395; (2013) 101 IPR 496 Yates J said:

[120] Regulations 3.12(1)(b) and (c) each require, relevantly, that the claim be “fairly based on matter disclosed” in the specification from which priority is claimed.

[121] The parties accepted that the expression “fairly based” has the same meaning in this context as it has in s 40(3) of the Act dealing with internal fair basing, namely that there be “a real and reasonably clear disclosure” in the compared specification of that which is claimed: Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (2004) 217 CLR 274; 212 ALR 1; 62 IPR 461; [2004] HCA 58 at [69] (Lockwood). However, the test of fair basis for determining the priority date of a claim is not the same as the test under s 40(3). Under s 40(3), the invention as claimed must be “fairly based on the matter described in the specification”. This comparison alludes to the coordinate requirement of s 40(2)(a) that the complete specification – of which the claims form part – must describe the invention fully. There is no corresponding requirement in relation to a priority document.

…

[126] …some part or parts of the overall disclosure made in the prior specification can provide “matter” on which a claim can be fairly based for the purpose of assigning a priority date to that claim….

…

[143] …The specification makes plain that the invention it describes is not one limited to embodiments involving a portable or mobile data collection apparatus. It also makes plain that the invention it describes includes embodiments that employ a persistent wide area network. The recognition in the specification that some embodiments of the invention have advantages that others do not – because, advantageously a portable or mobile data collection device can be used – does not mean that the other described embodiments cannot be claimed validly.

279    To the same effect in Nichia Corporation v Arrow Electronics Australia Pty Ltd [2015] FCA 699 Yates J said:

[56] In Vehicle Monitoring Systems Pty Ltd v Sarb Management Group Pty Ltd (t/as Database Consultants Australia) (No 2) (2013) 101 IPR 496 at [122], I pointed out that the test of fair basis for determining the priority date of a claim is not the same as the test for fair basis under s 40(3) of the Act, which concerns claim width and is directed, in a general sense, to ensuring internal consistency between that which is described as the invention, and that which is claimed as the invention. This difference is reflected in the language of s 40(3), which requires that a claim be fairly based on “the matter described in the specification”. In reg 3.12(1)(b), the inquiry is whether the claim is fairly based on “matter disclosed”. The significance of the omission of the definite article “the” in relation to “matter” in the test applied under reg 3.12(1)(b) was specifically referred to and discussed in Leonardis v Sartas No 1 Pty Ltd (1996) 67 FCR 126 at 139, where the Full Court made clear that some part or parts of the overall disclosure made in the relevant priority document can provide “matter” on which a claim can be fairly based for the purpose of assigning a priority date to the claim.

[57] Regard should also be had to the use of the word “disclosed” in reg 3.12(1)(b), contrasted with the word “described” in s 40(3). The word “described” as used in s 40(3) focuses attention on the invention that is required to be fully described in the specification: see s 40(2). However, in its particular context, the word “disclosed” in reg 3.12(1)(b) is a more general expression which, in conjunction with the word “matter”, reinforces that priority can be claimed by reference to some part or parts of the priority document.

5.4    The 350 application - overview

280    The 350 application consists of 5301 pages about 5000 of which comprise tables identifying different substituents for certain chemical formulas. It is a complex document. It cannot be said that clarity is its hallmark. It is difficult to understand (even for the experts) and rife with ambiguity. Given this, the fact that it was the focus of so much attention during the hearing in respect of the claimed lack of external fair basis when the 949 application is also available for this purpose is difficult to understand. Ultimately, I have resolved the ambiguities in the 350 application against Idenix in respect of external fair basis, but I accept that the issue is by no means free from doubt (rather like the 350 application itself). Given the extensive submissions put, this part of the reasons is itself more detailed than might be thought necessary given I have reached the view that the 949 application does provide a fair basis for the Idenix patent.

281    The title of the application is modified 2' and 3'-nucleoside prodrugs for treating Flaviviridae.

282    The Field of the Invention section states:

This invention is in the area of pharmaceutical chemistry, and is in particular, a 2' and/or 3' prodrug of 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, and in particular, hepatitis C virus.

283    The Background includes the following:

The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide…HCV causes a slow growing viral infection and is the major cause of cirrhosis and hepatocellular carcinoma…

…

HCV is an enveloped virus containing a positive-sense single-stranded RNA genome of approximately 9.4kb. The viral genome consists of a 5' untranslated region (UTR), a long open reading frame encoding a polyprotein precursor of approximately 3011 amino acids, and a short 3' UTR. The 5' UTR is the most highly conserved part of the HCV genome and is important for the initiation and control of polyprotein translation. Translation of the HCV genome is initiated by a cap-independent mechanism known as internal ribosome entry. This mechanism involves the binding of ribosomes to an RNA sequence known as the internal ribosome entry site (IRES).

284    This section also describes the need for new treatments for HCV given the limitations of the existing treatments which include Ribavirin and Interferon and a combination of the two.

285    In a sub-section of the Background a heading “Additional Reference Disclosing Methods to Treat HCV Infections” appears. That sub-section states that Idenix was the first to disclose branched nucleosides, and their use in the treatment of HCV and flaviviruses and pestiviruses in International Publication Nos. WO 01/90121 (referred to as the 121 patent) and WO 01/92282.

286    The Background concludes that:

In light of the fact that the hepatitis C virus, and flaviviruses and pestiviruses has reached epidemic levels worldwide, and has tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat hepatitis C that has low toxicity to the host.

Therefore, it is an object of the present invention to provide a compound, method and composition for the treatment of a host infected with hepatitis C virus.

It is another object of the invention to provide a compound, method and composition for the treatment of a Flaviviridae infection, preferably an HCV infection, with increased half-life.

It is yet another object of the invention to provide a compound for the treatment of a Flaviviridae infection, preferably an HCV infection, with improved pharmacokinetics.

It is yet another object of the invention to provide a compound for the treatment of a Flaviviridae infection, preferably an HCV infection, to modulate the biological properties of the parent compound.

287    A lengthy section follows headed “Summary of the Invention”. It states:

2' and 3' -Prodrugs of 1', 2', 3' or 4' -branched β-D or β-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.

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 2' or 3'- prodrug of a biologically active 1', 2', 3' or 4' -branched β -D or β -L nucleosides 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 1', 2', 3' or 4' -branched, as used in this specification, refers to a nucleoside that has an additional non-natural substituent in the 1', 2', 3' or 4'-position as well as an additional non-natural substituent in the 8-position in the purine base or 6-position in the pyrimidine base. The term 2' -prodrug, as used herein, refers to a 1', 2', 3' or 4'-branched β -D or β -L nucleoside that has a biologically cleavable moiety at the 2' 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. The term 3' -prodrug, as used herein, refers to a 1', 2', 3' or 4'-branched β -D or β -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.

288    Numerous embodiments, examples of embodiments and sub-embodiments then appear. The text which describes these embodiments (etc) uses the words:

    2' and/or 5'

    3' and/or 5'

    2', 3' and/or 5'

    2',3'

    2',5'

    3',5'

    2', 3', 5'.

289    Twenty three principal embodiments follow each of which involves a chemical structure. Formulas I to XII involve methods of treatment comprising administering an effective treatment amount of a compound of each formula or a pharmaceutically acceptable salt or prodrug thereof. Formulas XIII to XXIII involve a compound of the formula or a pharmaceutically acceptable salt or prodrug thereof.

290    Formula IX appears as follows:

In a fifth principal embodiment, a method for the treatment of a host infected with a Flaviviridae is provided, comprising administering an effective treatment amount of a compound of Formula (VIII), (IX) or (X):

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R¹, R², R³ and X are as defined above;

Base* is a purine or pyrimidine base as defined herein

each R¹² is independently a substituted alkyl…[9 lines of text follow]…

each R¹³ is independently substituted alkyl…[17 lines of text follow]…

…or fluoro…

291    This summary section concludes in these terms:

In particular, the present invention provides the following:

(a)    a compound of Formula (XIII) -(XXIII), or its pharmaceutically acceptable salt or prodrug thereof;

(b)    pharmaceutical compositions comprising a compound of Formula (XIII) -(XXIII), or its pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or dileuent;

(c)    pharmaceutical compositions comprising a compound of Formula (XIII) -(XXIII), or its pharmaceutically acceptable salt or prodrug thereof, with one or more other effective antiviral agent, optionally with a pharmaceutically acceptable carrier or dileuent;

(d)    pharmaceutical compositions for the treatment of a Flaviviridae infection in a host comprising a compound of Formula (I) -(XXIII), or its pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or dileuent;

(e)    pharmaceutical compositions for the treatment of a Flaviviridae infection in a host comprising a compound of Formula (I) -(XXIII), or its pharmaceutically acceptable salt or prodrug thereof, with one or more other effective antiviral agent, optionally with a pharmaceutically acceptable carrier or dileuent;

(f)    methods for the treatment of a Flaviviridae infection in a host comprising a compound of Formula (I) -(XXIII), or its pharmaceutically acceptable salt or prodrug thereof, optionally with a pharmaceutically acceptable carrier or dileuent;

(g)    methods for the treatment of a Flaviviridae infection in a host comprising a compound of Formula (I) -(XXIII), or its pharmaceutically acceptable salt or prodrug thereof, with one or more other effective antiviral agent, optionally with a pharmaceutically acceptable carrier or dileuent;

(h)    uses for a compound of Formula (I) -(XXIII), or its pharmaceutically acceptable salt or prodrug thereof, optionally with a pharmaceutically acceptable carrier or dileuent, for the treatment of a Flaviviridae infection in a host;

(i)    uses for a compound of Formula (I) -(XXIII), or its pharmaceutically acceptable salt or prodrug thereof, with one or more other effective antiviral agent, optionally with a pharmaceutically acceptable carrier or dileuent, for the treatment of a Flaviviridae infection in a host;