FEDERAL COURT OF AUSTRALIA

Idenix Pharmaceuticals LLC v Gilead Sciences Pty Ltd [2017] FCAFC 196

ORDERS

THE COURT ORDERS THAT:

1.    The appeal be dismissed.

2.    Within 14 days of the date hereof, the parties file and serve written submissions (limited to 3 pages) on the question of costs.

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

REASONS FOR JUDGMENT

THE COURT:

1    The appellants (Idenix) are the registered owners of patent no. 2003247084, titled “Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections” (the Idenix patent). The Idenix patent relates to compounds for the treatment of flaviviridae infections, including the hepatitis C virus (HCV) infection. 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 (the 350 application) or 14 May 2003 based on US patent application 60/470,949 (the 949 application).

2    The respondents (Gilead) are the registered owners of patent no. 2004253860 (the Clark patent). The Clark patent was filed on 21 April 2004 and published on 13 January 2005 but claims a priority date of 30 May 2003 based on the international patent application WO 2005/003147.

3    Gilead has sought to sell in Australia a pharmaceutical drug containing or comprising an effective amount of a compound called sofosbuvir to treat HCV. The disclosure of sofosbuvir was made in the Clark patent. Gilead commenced proceedings in this Court against Idenix seeking a declaration that claims 7 to 41 (inclusive) of the Idenix patent were invalid. It contended that the Idenix patent was invalid on the grounds that the patent did not disclose a manner of manufacture, lacked novelty, lacked fair basis, lacked utility, and lacked sufficiency. There was also an allegation of false suggestion.

4    In turn, Idenix brought a cross-claim alleging that Gilead threatened to infringe various claims of the Idenix patent through the supply of pharmaceutical compositions containing the compound sofosbuvir. Gilead conceded, subject to its invalidity assertions, that sofosbuvir infringed claims 7 and 8 as well as dependent claims 10 and 13 of the Idenix patent.

5    The primary judge found the Idenix patent to be invalid on the grounds of insufficiency in respect of claims 7 to 41 (Gilead Sciences Pty Ltd v Idenix Pharmaceuticals LLC (2016) 117 IPR 252; [2016] FCA 169). Her Honour also held claim 7 to be inutile. Otherwise, her Honour did not accept the balance of Gilead’s asserted grounds for invalidity. As a consequence of the primary judge’s conclusions, Idenix failed in its case of threatened infringement with the cross-claim being dismissed.

6    Idenix now appeals the primary judge’s decision on the basis that her Honour erred in her conclusions as to insufficiency, certain aspects of fair basis and inutility. Further and consequentially, Idenix contends that the primary judge erred in dismissing its cross-claim given that her Honour premised that dismissal on relevant claims of the Idenix patent being invalid.

7    Gilead has filed a notice of contention in which it challenges the primary judge’s conclusions that the Idenix patent was not invalid on the grounds of lack of novelty and other aspects of lack of fair basis.

8    For the following reasons, we would dismiss Idenix’s appeal. Moreover, if it is necessary to say so, we would also reject Gilead’s grounds of contention.

9    It is convenient to divide our discussion into the following sections:

(a)    Relevant background science – [10] to [81].

(b)    The patent specification – [82] to [101].

(c)    Earlier applications – [102] to [123].

(d)    The Clark patent – [124] to [131].

(e)    Grounds of appeal 1 to 8; lack of sufficiency – [132] to [238].

(f)    Novelty and lack of fair basis overview – [239] to [242].

(g)    Grounds of appeal 9 and 10; lack of fair basis – [243] to [254].

(h)    Grounds of appeal 11 and 12; lack of utility – [255] to [261].

(i)    Notice of contention ground 1; lack of novelty – [262] to [312].

(j)    Notice of contention ground 2; internal fair basis – [313] to [326].

(k)    Conclusion – [327].

RELEVANT BACKGROUND SCIENCE

10    Claim 7 of the Idenix patent claims:

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.

11    Claim 8 of the Idenix patent claims a compound of claim 7 wherein X is O and Y³ is H. Claim 9 claims a compound of claim 8 wherein R¹ and R² are H. It is not necessary to make reference to later dependent claims at this point.

12    In order to appreciate the nature of the composition(s) claimed including the potential synthesis thereof, and the parties’ submissions before us, it is necessary to set out the background science, a summary of which we have principally derived from the parties’ useful chemistry primers that were filed at first instance, the primary judge’s description and some additional matters drawn from the evidence before her Honour.

(a)    Organic chemistry

13    It is useful to begin with some common terminology used in organic chemistry relevant to the present issues.

14    First, “analogue” in the context of organic chemistry is a molecule or compound to which at least a single chemical change has been made relative to a natural compound. A “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. We will discuss nucleic acids and peptides later. An “enzyme” is a biological molecule that catalyses or accelerates a chemical reaction. A “reagent” is a compound usually used to help bring about chemical change in other compounds.

15    Second, a “functional group” is the term used in organic chemistry to describe structural elements that display particular chemical behaviours or properties. For example and relevant to the present case, one common functional group is a hydroxyl. A “hydroxyl” (also referred to as a hydroxy group) is commonly represented by the shorthand letters “OH”. It consists of an oxygen atom bonded to a hydrogen atom. In an organic compound, a hydroxyl attached to a carbon atom is referred to as an alcohol. Hydroxyls 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. Such a carbon atom is classified as a primary, secondary or tertiary carbon if it is bonded to one, two or three carbons, respectively. For example:

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

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

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

16    For completeness, a carbon is classified as a quaternary carbon when it is bonded to four other carbons. As such, a functional group such as a hydroxyl (which is not a carbon-containing group) cannot be attached to a quaternary carbon, given that a carbon atom only has four valence electrons and therefore can only form at most four covalent bonds. In other words, a quaternary carbon necessarily excludes the capacity to bond with a further functional group such as a hydroxyl.

17    Third, “heteroatom” is the term commonly used to describe any atom other than a carbon or hydrogen in an organic molecule. Further, a “ligand” is the name given to a molecule that binds specifically to a receptor site of another molecule. In other areas of chemistry ligands can be simple organic or inorganic molecules that coordinate (or bind) to metal atoms to form complexes.

18    Fourth, “polymorph” is a different crystalline form of the same compound. Polymorphs are not different compounds, just different solid states of a compound. The term “polymorphism” is the ability of a solid material to exist in more than one crystal structure. In pharmaceuticals, different polymorphs can have different pharmacokinetic profiles, often arising as a result of their different dissolution and absorption rates.

19    Fifth, 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. We will elaborate on some aspects of stereochemistry in a moment.

20    Finally, there is other terminology that we should also briefly mention at this point as we use it later in our reasons. The term “alkyl” refers to a saturated straight, branched or cyclic hydrocarbon, typically a chain of C₁ to C₁₀ including CH₃ (methyl) and so on. A halogen (halo) includes fluorine (F or Fluoro), chlorine (Cl or Chloro), bromine (Br or Bromo) or iodine (I or Iodo). A “substituent” is usually an element or group replacing a hydrogen on a part of a hydrocarbon chain. A “moiety” is best described as the characteristic part of a molecule. A “substrate” is a substance on which another substance acts and includes a substance affected by a catalyst or enzyme. The term “protected” refers to a process whereby a group is added to an oxygen, nitrogen or phosphorus atom to prevent further reaction. A “prodrug” is a chemical compound that on metabolism in the human body becomes active in a pharmaceutical sense. A Grignard reagent is an organometallic compound used in an organic synthesis. It usually takes the form RMgX, where X is a halogen atom, R is an organic radical and Mg is, of course, magnesium.

Drawing and naming organic molecules

21    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. For present purposes, we will only be referring to covalent bonds unless otherwise stated; hydrogen bonds and ionic bonds can be put to one side for the moment. A single line represents a single covalent bond (or a σ (sigma) bond). A double or triple line represents, simplistically speaking, double or triple covalent bonds (or π (pi) bonds) respectively. In a skeletal formula:

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

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

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

22    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; for example, the atoms are bonded to each other in a different order. Such 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. Stereochemistry is concerned with the two-dimensional and three-dimensional shape of molecules. Enantiomers and diastereoisomers are two types of stereoisomers.

23    Because stereochemistry is 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 using the following generally accepted drawing conventions:

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

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

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

(d)    a wavy (or wiggly) line indicates either: first, unknown or undefined stereochemistry; or second, a mixture of two stereoisomers but not necessarily a 50:50 mixture.

24    A “Haworth projection” is a common way of depicting a three-dimensional structure in two dimensions. 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 a 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:

25    It is the common convention to show organic molecules without illustrating all of the C and H atoms, as illustrated above. An organic chemist well appreciates that both the C and H atoms are present even though they are not explicitly labelled as such. A Haworth projection for glucose and an example nucleoside showing the C and H atoms and their numbering conventions is illustrated below:

26    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. The above diagram illustrates the different numbering systems used for carbohydrates (using glucose as an example) and nucleosides (using adenosine as an example).

27    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. Chemical elements may also be depicted 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. A Markush structure in a Haworth projection for a nucleoside is illustrated below:

Shapes of molecules

28    Where a carbon atom is bonded to four other atoms by single bonds, as illustrated below, the groups attached to the carbon atom are arranged in a tetrahedral arrangement that is 3-dimensional.

29    Where two carbon atoms are bonded to each other by a double bond, as illustrated below, the groups attached to the carbon atom are arranged in a planar arrangement that is 2-dimensional.

30    Where two carbon atoms are bonded to each other by a triple bond, as illustrated below, the groups attached to the carbon atom are arranged in a linear arrangement that is 1-dimensional.

Stereochemistry and chirality

31    The concept of chirality is important to organic chemistry and stereochemistry. The word “chiral” is a Greek term meaning “handed”. A chiral molecule is a molecule that has a non-superimposable mirror image, analogous to the left and right hands. 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.

32    Carbon is a good example of an atom that in a molecular form 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 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), as illustrated below. Although carbon is one of the most common types of chiral atoms, other atoms, such as sulphur or phosphorus, which can also form four bonds to four different groups, can be chiral.

33    In the illustration above, the structure on the left is an example of a chiral molecule having four different groups attached to the central chiral carbon atom, wherein the CH₃ group is projecting into the page, the OH group is projecting out of the page and the H atom and NH₂ group (amine group) are in the same plane as the page. The structure on the right is not chiral because it does not have four different groups attached to the central carbon atom.

34    Many naturally occurring organic molecules are chiral in the sense that they have at least one chiral carbon. For example, amino acids, sugars and nucleosides are usually chiral molecules. A nucleoside is made up of a sugar and a nucleobase. Because the nucleobase is typically a 2D structure, the chirality of nucleosides and nucleotides and their analogues tends to reside in the sugar. In the nucleoside example illustrated below, each of the circled carbons are chiral carbons:

35    It is convenient at this point to make the following observations for illustrative purposes concerning the above diagram:

(a)    First, the 1'-carbon is tetrahedral. It is also chiral because it is attached to four different groups: a nitrogen (N) within the nucleobase, an oxygen (O) (at the sugar ring oxygen position), a hydrogen (H) (at the 1' position in the “down” orientation which is not drawn) and a carbon (C) (at the 2' position).

(b)    Second, the 2'-carbon is tetrahedral. It is also chiral because it is attached to four different groups: a hydroxyl (OH), a hydrogen (H) (at the 2' position in the “up” orientation which is not drawn), and two different carbons (at the 1' position and 3' position). Despite the 1'- and 3'- attachments both being carbon, the 1'-carbon and 3'-carbon are considered to be different carbons due to the different groups that are in turn attached to those carbons.

(c)    Third, the 3'-carbon is tetrahedral. It is also chiral because it is attached to four different groups: a hydroxyl (OH), a hydrogen (H) (at the 3' position in the “up” orientation which is not drawn) and again two different carbons.

(d)    Fourth, the 4'-carbon is tetrahedral. It is also chiral because it is attached to four different groups: an oxygen (O) (at the sugar ring oxygen position), a hydrogen (H) (at the 4' position in the “down” orientation which is not drawn) and again, two different carbons.

(e)    Fifth, the 5'-carbon is tetrahedral but not chiral because it is not attached to four different groups. The 5'-carbon is attached to a carbon (C) (at the 4' position), a hydroxyl (OH), and two hydrogen atoms (H) (which are not drawn).

36    Two stereochemical configurations are possible for each chiral carbon atom. In most cases, the simple formula for calculating the total number of stereoisomers possible for any chiral molecule is 2^N, where “N” is the number of chiral carbons. Using the diagram just discussed, a nucleoside containing four chiral carbons has 2⁴ = 16 possible stereoisomers. A molecule such as a nucleoside having two or more chiral carbons can exist in a diastereoisomeric form (or as a diastereoisomer), being a particular type of one of these 16 possible stereoisomers.

37    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 (light filtered to select only a single plane) to the same degree but in opposite directions as illustrated below. This ability to rotate plane polarised light is referred to as optical activity.

38    If a solution of a molecule fails to rotate plane polarised light, this could be due to a number of reasons. For example, the solution could contain non-chiral molecules or it could contain a racemate. A racemic mixture is a mixture that contains two enantiomers in equal proportions.

39    The stereochemical configuration of a chiral atom can also be communicated by the way the compound is named. A commonly used convention for describing the stereochemical configuration of a chiral atom is by using the letters R and S. One 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.

40    The R and S configuration is then determined by orientating the molecule so that the group ranked fourth is pointing away from the observer. When orientated in this way, if the groups ranked 1, 2 and 3 travel in a clockwise direction the chiral centre is said to have an R configuration. If those groups travel in an anti-clockwise direction the chiral centre is said to have an S configuration.

41    The D and L terminology is another descriptor used in 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.

Organic chemical reactions

42    There are many types of organic reactions that organic chemists take advantage of in order to synthesise new molecules. These reactions can be categorised into various classes including substitution reactions, elimination reactions and addition reactions.

43    In a typical substitution reaction, usually 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. For example, one chemical atom or group attached to a tetrahedral carbon is replaced or substituted by another group. An example of a substitution reaction is the following:

44    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. An example of an elimination reaction is the following:

45    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 with an additional atom or group added to each of the participating carbon atoms. An example of an addition reaction is the following:

46    Nucleophilic substitution is a type of reaction between an electron donator (nucleophile) and an electron acceptor (electrophile). Nucleophiles can be described as electron-rich molecules. Because of their excess of electrons, they tend to react with electron-poor molecules and are therefore described as “nucleus loving”. Electrophiles are electron-poor molecules. Because of their lack of electrons, they tend to react with electron-rich molecules and are therefore described as “electron loving”.

Organic synthesis

47    Generally speaking, 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 materials, a series of controlled organic reactions or chemical transformations are used to turn those materials into a compound of interest. 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. reaction sequence) that are performed in a particular order to form a compound of interest. Reaction schemes are sometimes referred to as synthetic pathways or simply, schemes. In the laboratory, after each step in a reaction scheme it may be necessary to purify the intermediate product (that is, remove the product of interest from the surrounding reagents, solvents and other molecules which were used to perform the reaction step or were a by-product of it) before subjecting the product of interest to the next reaction step (purification) and also to use analytical chemistry techniques to characterise the intermediate and end product to confirm that the reaction step sought to occur did actually occur (characterisation). While in some cases, two or more synthetic steps may be carried out before purification and characterisation, this is less common.

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

49    Analytical chemistry consists of qualitative and quantitative analysis. Qualitative analysis relates to the identification of a compound or substance in a given sample. Quantitative analysis relates to determining the relative amount or purity of a given sample. Some techniques used in analytical chemistry include spectroscopy and chromatography. Atoms and molecules absorb and emit different types of radiation in ways that are characteristic of their composition and structure. Spectroscopy is the science of using the absorption and emission of radiation by atoms and molecules to determine the structure of molecules or elements present. Chromatography describes a class of techniques used to separate different components of a mixture generally using a solid matrix and a fluid (or mobile) system. For the moment it is not necessary to delve into the detail of liquid or gas chromatography

(b)    Amino acids, peptides and proteins

50    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). Amino groups and carboxyl groups are examples of functional groups. The basic structure of a so-called α-amino acid can be represented pictorially as follows:

51    The amino acid shown above contains a central carbon (known as an alphacarbon) to which is bonded a hydrogen atom (H), an -NH₂ group (amino group) and a -COOH group (carboxyl group). The remainder of the molecule is a variable group represented by the letter R. In this case R refers to a side chain group of the amino acid. It is important to note that each amino acid has a different side chain.

52    There are 20 different amino acids. Four nucleotides encode for these acids. DNA is read in blocks of three sequential nucleotides known as codons. Each codon codes for a particular amino acid, but most amino acids can be encoded by more than one codon. Each amino acid can be referred to by a single letter abbreviation or a three letter abbreviation of its name. Amino acids are the building blocks of peptides and proteins in nature. Peptides, polypeptides and proteins are chains of amino acids joined together by peptide bonds. Generally speaking, the order in which amino acids are connected to each other in a chain determines the function of that protein. A peptide bond is formed by the carboxyl group of one amino acid bonding to the amino group of a second amino acid. Accordingly, in a chain of amino acids, one of the terminal (or end) amino acids will have a “free” (unbound) amino group, with the amino acid at the other end of the chain having a “free” carboxyl group. The amino-group end of a protein, peptide or polypeptide is called the N-terminus and the carboxyl-group end of the protein, peptide or polypeptide is called the C-terminus. For illustrative purposes, a peptide bond formed between the amino acids, serine and glutamic acid is shown below:

53    The terms protein and polypeptide are frequently used interchangeably, with the term protein 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, polypeptides and proteins can also be made by chemical synthesis or by recombinant methods.

(c)    Nucleosides and nucleotides

54    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.

55    A nucleoside is a chemical compound which is made up of two parts: (a) a heterocyclic base, which is typically called a base or more precisely, a nucleobase (both terms can be used interchangeably); and (b) a sugar, for example, ribose in ribonucleic acid (RNA) or a 2'-deoxyribose in deoxyribonucleic acid (DNA). The nucleobase and the sugar are linked by a glycosidic bond. A nucleotide is a chemical compound made up of three parts: (a) two parts consist of the nucleoside; and (b) the third part consists of a phosphate group replacing the hydrogen on the oxygen atom attached to the 5' carbon. For present purposes, we will in the main refer to nucleosides.

56    The structures of a naturally occurring ribonucleoside and deoxyribonucleoside (specifically a 2'-deoxyribonucleoside where there is no hydroxyl group on the 2' carbon on the sugar ring) are illustrated below:

57    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).

58    Positions on the nucleobase are distinguished from those on the sugar ring in a nucleoside by adopting non-prime numbering for the nucleobase and are defined according to agreed conventions. The nucleobases just mentioned fall into two groups: purine and pyrimidine.

59    By definition, a purine is a 5-membered ring fused to a 6-membered ring, with each ring containing 2 nitrogen atoms, wherein the nitrogen and carbon atoms are arranged such that:

(a)    in the 6-membered ring the two nitrogen atoms are at the 1 and 3 position;

(b)    in the 5-membered ring the two nitrogen atoms are at the 7 and 9 positions; and

(c)    the carbon atoms are at the 2, 4, 5, 6 and 8 positions, as illustrated below:

60    Guanine (G) and adenine (A) are purines. The structure of guanine and adenine nucleobases are illustrated below:

61    By definition, a pyrimidine is a single 6-membered ring, which contains 2 nitrogen atoms wherein the nitrogen atoms are at the 1 and 3 position in a so-called 1, 3-relationship, and the carbon atoms are at the 2, 4, 5 and 6 position, as illustrated below:

62    Thymine, cytosine and uracil are pyrimidines. The structure of cytosine (C), thymine (T) (present in DNA only) and uracil (U) (present in RNA only) nucleobases are illustrated below:

63    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 itself may also be modified.

64    The sugar component of a nucleoside or nucleotide is a cyclic sugar. The sugar component of a natural ribonucleoside or ribonucleotide is ribose which is a 5 carbon sugar. The sugar component of a natural deoxyribonucleoside or deoxyribonucleotide is deoxyribose, specifically a 2'-deoxyribose which indicates (as we have already said) that no hydroxyl is present at the 2' position.

65    The ring of a ribose contains 4 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 according to the well-defined numbering conventions used by organic chemists, and as shown below for the nucleoside adenosine.

66    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.

67    As illustrated below, 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 their analogues, 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.

68    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, as illustrated below for cytidine:

69    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, as illustrated below for adenosine:

70    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. It is not necessary to illustrate such an arrangement.

71    Modifications can be made to the naturally occurring sugar to produce a nucleoside or nucleotide analogue. As discussed, 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.

72    Generally speaking, the stereochemical configuration of nucleosides is described using D and L terminology and alpha (α) and beta (β) terminology. The categorisation of a nucleoside as D or L is determined by reference to the substituent (or group) at the 4' position. 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. As illustrated below, where the nucleobase and substituent at the 4' position (which is CH₂OH in the example above) are on the same side of the ring, a nucleoside is classified as a β-nucleoside. If they appear on opposite sides of the ring, a nucleoside is classified as an α-nucleoside.

73    Although the α and β terminology is based on the orientation of the nucleobase relative to the substituent on the 4' position, the α and β 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.

74    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 in the illustration below, a nucleoside chemist understands that the name 2'-D or L-valine ester of β-D-2', 6-dimethyl-cytidine indicates the following:

(a)    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.

(b)    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.

(c)    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.

(d)    The use of nucleosides and nucleotides as antiviral drugs

75    In order to appreciate the invention claimed in the Idenix patent, it is convenient to now make brief mention of the use of nucleosides and nucleotides as antiviral drugs. We have conveniently drawn from the primary judge’s helpful description at [84] to [91] of her reasons.

76    HCV is a single-stranded RNA virus that infects human liver cells. 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 dependent- RNA-polymerase called NS5B.

77    Nucleoside analogues can act as antiviral drugs. They can do so by the inhibition of the relevant 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 a growing RNA chain) so as to be a suitable substrate for those enzymes. The nucleoside analogue, once incorporated into the RNA chain, disrupts the growth of the chain. This results 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.

78    If the nucleoside analogue does not possess a 3'-hydroxyl group, chain termination results because an “incoming” nucleotide cannot be attached to the RNA chain. But if the nucleoside analogue does possess a 3'-hydroxyl group, chain termination can still occur if the modification(s) to the nucleoside analogue prevents 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.

79    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. 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 human body, the 2'-methyl-“up” nucleoside analogue is formed.

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

81    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 an oxygen atom via a double bond, two oxygen atoms via single bonds and a nitrogen atom via a single bond. 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.

THE PATENT SPECIFICATION

82    The specification begins by describing and incorporating by reference three earlier US provisional applications, two of which are the 350 application and the 949 application. We will elaborate on these two applications and their significance later in our reasons. The specification at page 1, line 9 to page 2, line 16 then describes the field of the invention and its background in the following terms:

83    In relation to the hepatitis C virus, the following description was given at page 3, line 22 to page 4, line 24:

84    In relation to some methods of treatment, page 7, lines 6 to 19 stated the following:

85    It was also said at page 9, line 27 to page 10, line 12:

86    The specification at page 12, lines 11 to 32 set out a summary of the invention in the following terms:

87    A more detailed description was given commencing at page 41, lines 20 to 30, the opening paragraph of which stated:

88    Various embodiments including preferred embodiments were then set out, including the following at page 91, line 19 to page 92, line 33:

89    We would note at this point that pages 91 and 92 of the 350 application include similar passages.

90    The specification at page 100, lines 6 to 29 also stated the following:

91    As we have said earlier, page 91 of the 350 application also described the compound of Formula (IX).

92    On pages 103 to 107 of the specification there are various definitions given for functional groups and other terminology. One that we would note at this point (page 104, line 14) is stipulated in the following terms: “The term ‘halo’, as used herein, includes chloro, bromo, iodo and fluoro”. It is also to be noted that there is no definition at this point for “base” (there are definitions elsewhere that define it to mean “purine or pyrimidine base”) or “nucleoside base” or reference to the adjective “natural” in combination therewith, although there is a discussion (page 104) of “purine” and “pyrimidine” bases.

93    At page 119, line 30 to page 120, line 7 of the specification, a section describing processes for preparation commenced with the following:

94    More relevant to the issues that concern us (as will become apparent later) is the synthesis of 2'-C-branched nucleosides with two general methods being discussed. Reference was made at page 122, line 21 to page 123, line 14 to the following:

95    This section continued at page 123, line 31 to page 124, line 5 in the following terms:

96    Thus far we have referred to what the specification described as glycosylation of the nucleobase with an appropriately modified sugar. The specification then goes on to talk about (page 124) the modification of a pre-formed nucleoside (still in the context of the discussion beginning on page 122 as to the general synthesis of 2'-C-branched nucleosides). In relation to that part of the specification dealing with the modification of a pre-formed nucleoside, the following was said at page 125, lines 7 to 20:

97    The specification at page 131, line 15 to page 132, line 9 also discussed the general synthesis of certain prodrugs in the following terms:

98    The specification describes 26 examples beginning with the discussion of Example 1 on page 132. What should be said at the outset by us is that 24 of the 26 examples purportedly set out examples for the preparation of relevant compounds and in that sense can be taken to describe methods for the synthesis of particular compounds. But what is noteworthy at this point is what is not said. There is no express disclosure of the 8 steps reaction scheme pathway to produce a compound within claim 7 (with the 2' position methyl “up” and the 2' position fluorine “down”) as propounded by Idenix both before the primary judge and before us, let alone the precursor identified by counsel for Idenix. At trial, emphasis seems to have been placed before her Honour on Example 2. Example 2 at page 135 is described as follows (in part):

99    It should readily be apparent that this is not a synthesis to produce a fluorinated 2' carbon with the required stereochemistry as stipulated for a compound falling within claim 7. Indeed it is a ribo-nucleoside rather than a de-oxyribo-nucleoside. Moreover, Scheme 9 (as is described) has the nucleobase added as step (d). Idenix’s 8 steps synthesis propounded to her Honour and us starts with step 1 as beginning from a “natural nucleobase”, whether purchased or synthesised.

100    The specification at page 157, lines 11 to 16 concludes (before the claims) with the following general statement:

101    The claims are set out commencing from page 158. It is only necessary to set out claims 7 to 13 at pages 189 to 190 which are in the following terms:

Earlier applications

102    As we have already identified, the Idenix patent claims (page 1) the benefit of priority from:

(a)    US provisional application No. 60/392,350 (the 350 application) – priority date 28 June 2002; and

(b)    US provisional application No. 60/470,949 (the 949 application) – priority date 14 May 2003.

103    Indeed the Idenix patent states (page 1, line 8) that “the disclosures of each … are incorporated herein by reference”. However, apart from this introductory statement in the specification, nothing further is said. It is necessary to elaborate further at this point on both the 350 application and the 949 application as they are relevant to later arguments that we will discuss concerning the issues of, inter-alia, external fair basis and internal fair basis.

(a)    The 350 application

104    The primary judge discussed the 350 application at [280] to [391] of her reasons. We would incorporate by reference her Honour’s description as to what that application consists of and discloses, without the need to set it out.

105    Idenix’s contention before her Honour was that the invention claimed in claim 7 and dependent claims of the Idenix patent was in fact disclosed in Formula (IX) of the 350 application (see pages 91 and 92).

106    There is little difference between the description concerning Formula (IX) on pages 91 and 92 of the 350 application and the description at page 91 of the Idenix patent save in minor respects. For example, in the Idenix patent, the words before the three formulae are expressed differently with reference to “a pharmaceutically acceptable salt or prodrug”, although these words are after the formulae in each case in any event. But in the Idenix patent, reference is also made to stereoisomeric, tautomeric or polymorphic forms above and below the formulae. Further, there are references immediately after the formulae in the Idenix patent to “R⁴, R⁵, Y³ …and X* … as defined above”. But none of these differences are material for present purposes.

107    Now there is little doubt (and Gilead so conceded before her Honour) that the structural formula of Formula (IX) in the 350 application covers a compound within claim 7 of the Idenix patent. But the question for her Honour was whether there was a real and reasonably clear disclosure in the 350 application of a compound (fitting within claim 7 of the Idenix patent) where:

(a)    The substituent at the 2' down position was fluorine;

(b)    The base may be a natural base; and

(c)    The compound was a 5'-only prodrug.

108    Her Honour held (at [329]) that there was a real and reasonably clear disclosure in the 350 application of a compound with fluorine in the 2' down position.

109    But her Honour held (at [345]) that there was no real and reasonably clear disclosure in the 350 application of a relevant compound with a natural base (as compared with a modified base).

110    Further, her Honour held (at [385]) that there was no real and reasonably clear disclosure in the 350 application of a relevant compound with a prodrug at the 5' position only.

111    We will leave for the moment passages from the 350 application dealing with the “base” question. As for the 5'-only prodrug question, we would note the following.

112    First, in the opening section (page 1) there is, in relation to the invention, a description of a “2' and/or 3' prodrug”.

113    Second, on pages 8-13 (before the first principal embodiment is discussed) there is reference to the following:

    “2' and 3'-prodrugs”;

    “2' or 3'-prodrug”;

    “2'-prodrug [which] includes biologically cleavable moieties at the 2' and/or 5' positions”; so the option appears to be either a 2'-prodrug or a 2' and 5'- prodrug when read in context;

    a “3'-prodrug [which] includes biologically cleavable moieties at the 3' and/or 5' positions”; so the option appears to be either a 3'-prodrug or a 3' and 5'-prodrug when read in context; and

    other types being 2', 3' and 5' prodrugs.

114    We say in context, for although one grammatical reading of “and/or” where it appears might suggest a 5'-only prodrug, when you read the multitude of examples it is well apparent to us that there is no real and reasonably clear disclosure of a 5'-only prodrug. So much is apparent from the other passages in the 350 application. Indeed, parts of the 350 application point away from a 5'-only prodrug. So, for example at page 39, lines 15 to 28 the following is said:

The invention as disclosed herein is a compound, a method and composition for the treatment of a Flaviviridae infection in human and other host animals. The method includes the administration of an effective anti-Flaviviridae treatment amount of a 2' and/or 3'-prodrug of a 1', 2', 3' or 4'-branched β-D or β-L nucleoside as described herein or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. The compound of this invention either possesses antiviral (i.e., anti-HCV) activity, or is metabolized to a compound that exhibits such activity.

The 2' and/or 3'-prodrugs of a 1', 2', 3' or 4'-branched β-D or β-L nucleoside are acyl derivates of a secondary or tertiary alcohol alpha to a secondary or tertiary carbon. Due to the steric hindrance of these prodrugs over the 5'-prodrugs, an acyl derivative of a primary alcohol, these prodrugs differentially modulate the biological properties of the molecule in vivo. It has been discovered that the 2' and/or 3'-prodrugs of a 1', 2', 3' or 4'-branched β-D or β-L nucleoside can provide a drug with increased half-life and improved pharmacokinetic profile.

115    Further, if one considers the summary of the invention (pages 41 to 43), there is in our view no disclosure of a 5'-only prodrug. The summary is replete with references to a “2' and/or 3'-prodrug”. Further, it may be noted that there was a Table in evidence before her Honour (annexure RHF-12 to one of the affidavits of Professor Furneaux) well demonstrating that when one analysed all of the Examples 1 to 24, there was no 5'-only prodrug exemplified, whether alone or in combination.

116    Finally, we would make the point that various passages of the application are dealing with modified bases. For example, see page 7, lines 19 to 26, the bases described from page 48, reference to phraseology such as “Base is as defined herein” (page 57, line 21 and page 91, line 8) and Figure 1 (after page 5297 – that page reference indicating the sheer length of the application and the many permutations of the compounds claimed).

(b)    The 949 application

117    The 949 application claimed as an invention methods and compositions for the treatment of infections caused by a coronavirus, togavirus or picornavirus including administering an effective amount of nucleosides of the disclosed formula. It relevantly discloses for present purposes a composition of Formula (AA). We note that claim 1 of the 949 application is a method claim which comprises administering a nucleoside analogue that has the structure of Formula (AA) or a pharmaceutically acceptable salt or prodrug thereof.

118    It is appropriate to set out Formula (AA) as described at pages 17-19 as follows:

119    It is also appropriate to set out Formula (II):

120    We would also note in relation to Formula (II) that the expression “R³ [is] defined as above” refers back to page 20 which provides a very substantial list of potential substituents including “halo”, which can be taken to include “fluoro” or a fluorine atom.

121    Her Honour discussed the 949 application at [392] to [417] of her reasons.

122    It is well apparent that a compound meeting the description of claim 7 of the Idenix patent is within Formula (AA) and Formula (II) of the 949 application.

123    Gilead contended before her Honour that there was no real and reasonably clear disclosure in the 949 application of a compound of claim 7 or the use of such a compound to treat a flaviviridae infection as claimed in claim 10. Her Honour rejected such arguments. Gilead’s notice of contention that we will discuss later addresses them.

Clark patent

124    Various issues concerning the question of sufficiency, which we will come to in a moment, require discussion of the Clark patent.

125    Application AU2004253860 was filed on 21 April 2004 as a PCT International Patent application in the name of Pharmasset Ltd, with the inventor being Jeremy Clark. It has a priority date of 30 May 2003.

126    Under the “Summary of the Invention” on pages 15 and 16, the following is said:

127    Claim 1 is in the following form:

128    But methods of synthesis are also claimed. For example, claim 13 comprises a method of synthesising a nucleoside of claim 1 comprising glycosylating a relevant pyrimidine. Claim 14 refers to a method of such synthesis comprising selective deprotection. Claim 20 refers to a method of synthesis with reference to the Examples.

129    Section VIII of the Clark patent sets out (as it is headed) a detailed Synthetic Protocol (pages 70 to 87). The Section opens with the following statement:

130    Pages 72 to 76 are in the following form:

131    Then there are detailed worked examples. Example 1 describes in detail the synthesis to get the target compound starting with a carbohydrate. Example 2 details a synthesis to get the target compound starting with cytidine. Example 3 starts with chloropurine riboside. Example 4 starts with chloro-2'-deoxy-2'-fluoro-2'-C-methylpurine.

grounds of appeal 1 to 8; lack of sufficiency

(a)    Preliminary matters

132    Section 40(2)(a) of the Act at the relevant time provided:

Specifications

…

(2)    A complete specification must:

(a)    describe the invention fully, including the best method known to the applicant of performing the invention …

133    Gilead contended before the primary judge that the Idenix patent did not sufficiently describe how to synthesise compounds falling within claim 7. It was said that claim 7 did not describe how to produce a compound (sometimes referred to in these reasons as the target compound) that contained fluorine at the 2' down position of the sugar ring of the compound and a carbon-containing group, such as a methyl group, at the 2' up position on that ring. It was said that this was not routine chemistry as at the priority date(s) claimed for the Idenix patent. It was said that both the starting point and the method of synthesis to produce the target compound were not sufficiently described in the specification.

134    Gilead also contended before the primary judge that the Idenix patent did not identify which of the compounds within claim 7 were effective for the treatment of flaviviridae infections or HCV and did not describe how to identify such compounds.

135    It was common ground before her Honour that a compound that is within claim 7 is the 2'-methyl-“up”-2'-fluoro-“down” nucleoside with the structure set out in the projection on the right below labelled “target compound”. It was also common ground that the immediate precursor for a fluorination reaction to produce the target compound is the 2'-hydroxy-“up”-2'-methyl-“down” nucleoside of the structure set out in the projection on the left below labelled “precursor compound”:

136    The hydroxyl group (OH) in the precursor compound is attached to a carbon further attached to three carbons and accordingly is a tertiary OH. By a chemical reaction with a fluorinating reagent, the hydroxyl group can be displaced by fluorine and the relative position on the 2' carbon inverted as appears in the target compound, such that the methyl group on the 2' carbon is “up” (previously “down”) and the fluorine is “down” (the hydroxyl group displaced by fluorine being previously “up”).

137    It was accepted before the primary judge that the precursor compound in the projection above was a potential precursor for a fluorination reaction to produce the target compound. But it was disputed before her Honour whether the skilled person would choose such an approach or start with or obtain the relevant precursor compound (as contended by Idenix) to then attempt the fluorination reaction to obtain the target compound.

138    It appears to have been accepted by the parties before her Honour and before us that the Idenix patent does not expressly describe any synthesis of a claim 7 compound. All that it appears to relevantly state is that “[t]he nucleosides of the present invention can be synthesized by any means known in the art” (page 119 lines 31-32, set out at [93] of these reasons above) (at [527] of her Honour’s reasons). Accordingly, the skilled addressee was not given any express method for producing the target compound (as we have described), but rather was left to construe the Idenix patent in light of the common general knowledge to develop such a method, including the starting point, steps in the synthesis and necessary precursor compounds.

139    The principal issue before the primary judge on this aspect was whether at the priority date (putting to one side for the moment the dispute between the parties as to the precise date), a person skilled in the art who was armed with the Idenix patent and relying only upon common general knowledge could have synthesised a compound of claim 7 (relevantly, for present purposes, the target compound that we have described) without new invention or addition or a prolonged study of matters presenting initial difficulty.

140    Now it was accepted in the evidence before the primary judge that by reacting the precursor compound with the reagent diethylaminosulfur trifluoride (DAST) (where fluorination would proceed with displacement and inversion) or Deoxo-Fluor (a DAST analogue with a similar function), and subsequent de-protection, one could obtain the target compound. For simplicity, we will describe this as the DAST route or DAST for short-hand. But DAST is not referred to in the Idenix patent, whether in the part relating to synthesis or otherwise. Idenix contended before her Honour that regardless of this absence of reference in the Idenix patent, DAST was within the common general knowledge of the skilled addressee at the priority date. Moreover, Idenix contended that the absence of specific reference to DAST as a method of synthesis did not justify a finding that claims 7 to 41 of the Idenix patent were invalid for insufficiency. Contrastingly, Gilead contended that DAST was not within the common general knowledge, let alone for the synthesis necessary or desirable to produce the target compound. Accordingly, it contended that the relevant claims of the Idenix patent were invalid for insufficiency.

141    The primary judge found that claims 7 to 41 of the Idenix patent did not comply with s 40(2)(a) of the Act and were therefore invalid for insufficiency on the basis that the specification did not enable the skilled addressee to make a compound within claim 7 at the priority date without new invention, addition or a prolonged study of matters presenting initial difficulty. Idenix has challenged that finding generally (ground 1) and specifically (grounds 2 to 8) in, if we may say so, an overly elaborate way and with a view, it would seem, to having us conduct a re-trial of the complex factual questions litigated before her Honour who had the benefit of, inter-alia, considering and reflecting upon the complex expert testimony adduced before her.

142    Idenix has contended before us that the primary judge’s findings on the insufficiency question were incorrect for the following reasons:

(a)    First, it says that the primary judge erred in failing to find that the Clark patent admitted and demonstrated that applying the DAST route was within the common general knowledge of the skilled addressee (ground 2 with 8 sub-paragraphs of particulars).

(b)    Second, it says that the primary judge erred (grounds 3 & 4) in the following respects (detailed particulars omitted):

3.    The primary judge erred in finding that each of the synthetic routes recorded in the Idenix Documents (both tried and contemplated) (with the exception of the February 2003 Deoxo-Fluor Route (the Deoxo-Fluor Route)):

(a)    involved an exercise of the common general knowledge at the priority date; and

(b)    were relevant to, and indeed provided “a very strong basis” and "powerful evidence" of, the insufficiency of the Idenix Patent,

including by failing to consider, on a route by route basis, whether any evidence specific to that route supported a finding that the particular route was part of the common general knowledge: Reasons at [448]-[458], [506]-[509], [512] and related findings at [535] and [605].

4.    The primary judge erred in making findings based on inferences drawn from the Idenix Documents as to, and in relation to, the content of common general knowledge to be attributed to the skilled addressee of the Idenix Patent and the work recorded in the Idenix Documents.

(c)    Third, it says that the primary judge erred in her treatment of the expert evidence in determining the content of the common general knowledge of the skilled addressee of the Idenix patent and relevant priority documents (ground 5 with 9 sub-paragraphs of particulars). In essence, Idenix would have us engage in the task that on one view requires Idenix to demonstrate that her Honour’s evidentiary findings were “glaringly improbable”, “contrary to compelling inferences” or shown to be wrong by “incontrovertible facts or uncontested testimony”: Robinson Helicopter Company Inc v McDermott (2016) 331 ALR 550; [2016] HCA 22 at [43]. If that is the standard, we would say now that Idenix in its submissions before us has not come anywhere near to satisfying or meeting such a threshold. Indeed, the preponderance of evidence before her Honour well justified her factual findings. But as we will discuss in a moment, a more nuanced position dealing with the appropriate standard for appellate review is to be applied concerning evaluative questions the subject of expert evidence involving matters of degree and judgment.

(d)    Fourth, Idenix says that the primary judge erred (ground 6) in the following respect:

6.    The primary judge erred in finding that the following facts or matters were not part of the common general knowledge of the skilled addressee of the Idenix Patent and the priority documents as at the relevant priority date and in making the findings underpinning those conclusions:

(a)    the facts and matters referred to in the Reasons at [221]-[249] and [552];

(b)    the publications and review articles listed in sub-paragraphs (a) to (d) and (f) to (o) of paragraph 138 of Professor Meier’s second affidavit: Reasons at [218], [389];

(c)    the Barros Paper and the Yang Paper: Reasons at [598]; and

(d)    the Hudlicky Paper: Reasons at [599].

(e)    Fifth, it says that the primary judge erred in finding that the skilled addressee could not make a compound within claim 7 without new invention or prolonged study of matters on the basis of the instruction in the Idenix patent using only the common general knowledge (ground 8 with 23 sub-paragraphs of particulars).

(f)    Sixth, it says that the primary judge erred in failing to accept that based on the results of the AMRI experiments, it could be inferred that the target compound was made using the Deoxo-Fluor route (ground 7 with 4 sub-paragraphs of particulars). It says that the techniques adopted in the AMRI experiments were techniques used in the field of organic chemistry prior to June 2002.

143    In terms of the principal themes of Idenix’s criticisms, Idenix says that the primary judge erred in her conclusion that the DAST route was not within the common general knowledge for the following reasons. First, it says that the primary judge wrongly assumed that sufficiency could not be satisfied by mere disclosure of the invention itself plus common general knowledge. Second, it says that the primary judge wrongly construed the Idenix patent as teaching the skilled addressee nothing about making a claim 7 compound (at [537]) and as teaching “away” from such a compound (at [538] to [541]). Third, it says that the primary judge wrongly treated as relevant and “determinative” the evidence of Idenix’s internal failures to synthesise the target compound, without evidence that those failed methods were common general knowledge methods available to the skilled addressee. Fourth, it says that the primary judge wrongly treated Professor Furneaux as personifying or embodying the relevant skilled addressee and paid insufficient regard to French CJ’s description in AstraZeneca AB v Apotex Pty Ltd (2015) 257 CLR 356 at [23]; we would say now that there is no substance in that criticism.

144    In our view, the primary judge’s reasons involved no error. As her Honour correctly concluded at [615], the disclosure of the Idenix patent, when considered with the common general knowledge, did not meet the requirement of s 40(2)(a) applying the relevant test for sufficiency as expounded in Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (2001) 207 CLR 1. The relevant test as framed by the High Court in Kimberly-Clark is (see at [25]): “… will the disclosure enable the addressee of the specification to produce something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty?” But this is precisely the question that was posed and applied by her Honour.

145    The principal question raised by s 40(2)(a) is whether the disclosure of the Idenix patent enabled the skilled addressee to make a compound within claim 7 “without new inventions or additions or prolonged study of matters presenting initial difficulty”. In our view there was clear and compelling evidence before the primary judge justifying her finding that the requirement was not met. Indeed, part of the evidence before her Honour was material demonstrating that Idenix was unable to obtain a claim 7 compound despite having a team of skilled scientists and external expert consultants engaged in a prolonged attempt to do so for a period of nearly three years. Idenix was apparently unable to produce any embodiment of the invention that it had claimed without new inventions or additions or prolonged study of matters presenting initial difficulty, even after having (on its own argument) supposedly a sufficient description of that invention in hand. Moreover, in terms of relative timing, it would seem that Idenix only succeeded in making the target compound after it obtained the Clark patent, which described and thus enabled such a synthesis. Now of course none of these matters are determinative of the question that her Honour had to address, but they are hardly helpful to Idenix’s position. The primary judge was correct to give some weight to this evidence and to find that in conjunction with the other evidence, proof of insufficiency was established.

146    We would make another general observation at this point. The primary judge was engaged in an evaluative exercise involving matters of degree and judgment that, in the context of the manner in which the case was conducted, has an affinity with the test for inventive step, notoriously a “jury question”. It involved the court placing itself in the position of the hypothetical skilled person as at the priority date in 2002 or 2003 in order to determine whether or not something within each claim could be made without new inventions or additions or prolonged study of matters presenting initial difficulty. In that task she had to consider and weigh the expert evidence before her. Generally speaking, an appellate court should not interfere with findings made in such a setting unless they are erroneous in principle or plainly and obviously wrong (Metricon Homes Pty Ltd v Barrett Property Group Pty Ltd (2008) 248 ALR 364; [2008] FCAFC 46 at [20]) or where there is a sufficiently clear difference of opinion (Branir Pty Ltd v Owston Nominees (No 2) Pty Ltd (2001) 117 FCR 424 at [29] per Allsop J (as he then was, Drummond and Mansfield JJ agreeing)). Perhaps the latter may be considered a lower threshold, although in that respect we are inclined to adopt the observations in Optical 88 Ltd v Optical 88 Pty Ltd (2011) 197 FCR 67 (Cowdroy, Middleton and Jagot JJ) at [25] to [34]. But on any view, and accepting that we must come to our own conclusion, after giving due respect and weight to her Honour’s findings we do not have any or any sufficiently clear difference of opinion on the evaluative questions that her Honour considered and determined. It may not unfairly be said that Idenix has used the opportunity on appeal before us simply to “put the dice into the box for another throw” (Optical 88 Ltd at [29] and the cases there cited).

147    Before proceeding further, there is one matter that it is convenient to dispose of now. Gilead has submitted that it is notable that similar findings to those made by the primary judge have been made in other jurisdictions where Idenix’s related patents were said to have been challenged on equivalent grounds. These jurisdictions apparently included the United Kingdom, Germany, Norway, Canada and the European Patent Office. Reference was made, for example, to Idenix Pharmaceuticals, Inc v Gilead Sciences, Inc [2014] EWHC 3916 (Pat) at [470] to [594] per Arnold J and on appeal [2016] EWCA Civ 1089 at [141] to [192] per Kitchin LJ; our attention was also drawn to his Lordship’s observations at [209] but on a separate issue that we are not presently discussing. It is also said that consistent factual findings have been made in Gilead’s favour in proceedings in the United States. Whilst we note such submissions, we have put such jury points to one side; they are not probative of the issue that her Honour had to resolve on the evidence before her and that we need to consider.

148    It is convenient at this point to now deal with the specific attacks made by Idenix concerning her Honour’s findings by reference to the specific grounds of appeal (grounds 2 to 8). It is convenient to re-order these grounds as we have done in the following discussion.

(b)    Teaching of the specification and common general knowledge (ground 8)

149    The primary judge found that to obtain the target compound, the skilled addressee would undertake a “retrosynthetic analysis” (at [612]). Such analysis identifies the reaction route to the target compound, including the precursor in the penultimate step. Idenix says that DAST and Deoxo-Fluor were the most commonly known means for displacing with inversion a secondary hydroxyl group to introduce fluorine in a nucleoside. We have emphasised secondary at this point to contrast with what we have in the present context being the need to displace a tertiary hydroxyl group. It is said that the primary judge’s finding that it was not known to use DAST or Deoxo-Fluor on a tertiary hydroxyl group at the priority date involved error (at [229] and [605]); we note that her Honour in fact said that it was not a commonly known method to fluorinate and invert a tertiary hydroxyl. In any event, Idenix contends that regardless of that finding, any perceived uncertainty as to the likelihood of success of using DAST or Deoxo-Fluor to introduce fluorine in place of a tertiary hydroxyl group was not evidence that the skilled addressee was unable to produce the target compound employing common general knowledge. It is said that such a method was used by Dr Borthwick and Mr Clark on a tertiary hydroxyl group and it was asserted that this was the method that occurred to Professor Furneaux if he could not use knowledge obtained from non-common general knowledge research. Idenix contends, with respect rather superficially in our view, that the suitability and application of the DAST method was the same (in terms of common general knowledge) whether it was a secondary or tertiary hydroxyl group.

150    In our opinion, Idenix’s assertion that DAST and Deoxo-Fluor were the most commonly known means for displacing with inversion a secondary hydroxyl to introduce fluorine in a nucleoside did not accurately reflect the primary judge’s finding that the process was unpredictable with complicating and competing reactions (at [230]) and that “there was no commonly known method of introducing fluorine into a nucleoside at the 2'-position at all” (at [605]). Generally, Idenix’s submissions failed to take proper account of a range of relevant considerations including whether the proposed fluorination was of a secondary or tertiary hydroxyl group, whether the compound in question was a natural nucleoside or carbocyclic nucleoside (where a carbon atom has been substituted for the oxygen atom of the five-membered otherwise sugar ring), and also the position on the ring to be fluorinated. Just for completeness, we would note at this point that there was evidence before her Honour suggesting that a carbocyclic nucleoside was more stable as it was not subject to the action of nucleoside phosphorylase and hydrolase enzymes, which cleave the glycosidic linkage of natural nucleosides.

151    Idenix takes issue with what it says to be the primary judge’s reasoning that the skilled addressee would undertake a research project before attempting to synthesise the target compound and that such a research project necessarily involved non-common general knowledge material. Idenix says that the primary judge failed to address the question of whether the skilled addressee could make the target compound if confined to the common general knowledge. Idenix says that if the person skilled in the art was confined to common general knowledge, they could have employed known means, namely DAST or Deoxo-Fluor, to the precursor compound with a tertiary hydroxyl, regardless of any doubts. Idenix contends that, in essence, the gravamen of the primary judge’s reasoning was that it was “inventive” to try using DAST or Deoxo-Fluor on a tertiary hydroxyl (at [612]), which it says is a conclusion that was not supported on the evidence.

152    Idenix contends that the primary judge’s finding that the precursor could not be made by the skilled addressee using common general knowledge (at [612]) involved error and could not stand with evidence to the contrary. It is said that this finding was also inconsistent with her Honour’s findings that by inference, all of the internal Idenix work involved the use of common general knowledge, which work included the successful making of the precursor. It is also said that it was inconsistent of the primary judge to use Professor Furneaux’s evidence that the Idenix work was a “typical research project” as evidence of work using common general knowledge (at [453]) but using his evidence that he would undertake “research” to make the target compound as indicating his need to use non-common general knowledge (at [576(1)]).

153    Idenix says that contrary to the primary judge’s reasons, the Idenix patent is sufficient as the skilled addressee could make a compound within claim 7 simply by looking at the terms of the claim and armed only with the common general knowledge and without invention or prolonged study of matters presenting initial difficulty. The Idenix patent states that “[t]he nucleosides of the present invention can be synthesized by any means known in the art”. Idenix says that there is no statement in the Idenix patent that making the nucleosides of claim 7 would present any difficulty or that the skilled addressee would have to employ anything other than a known method to make a compound within claim 7. Accordingly, it is said that contrary to the primary judge’s reasons, the Idenix patent directs the skilled addressee to known processes, rather than to processes which require non-common general knowledge research. Further, it is said that it was common ground at trial and among the experts that none of the Schemes described in the examples set out in the Idenix patent were expressed to be directed specifically to making a claim 7 compound. Thus Idenix contends that no skilled addressee could have been misled onto an incorrect path by precisely following a scheme which they knew was directed to a different product.

154    But in our view the primary judge correctly recognised that the claims formed part of the description in the Idenix patent (Kimberly-Clark at [14]), and accepted Idenix’s identification of the target compound as a compound within claim 7 that the addressee would seek to make. The point made by her Honour was that Idenix’s formulation of the sufficiency test omitted the requirement that it is the disclosure in the complete specification that must enable the addressee to produce something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty (at [436], [578] and [612]).

155    Further, in our opinion the statement in the specification “nucleosides of the present invention can be synthesized by any means known in the art” does not assist Idenix. First, “known” is not necessarily co-extensive with common general knowledge. Second, Idenix’s submission that such a stipulation directed the skilled addressee away from non-common general knowledge research is contradicted by the evidence. As Gilead correctly submitted, both Dr Borthwick and Professor Meier relied on sources outside common general knowledge, including but not limited to the Matsuda paper, in developing their target syntheses. Moreover, Professor Furneaux considered the synthesis to be complicated and would have had to have conducted significant research and experimentation. Moreover, Idenix’s team of skilled scientists and consultants carried out such research and experimentation over a lengthy period but without success. Generally, the evidence before her Honour well demonstrated that a route of synthesis of a claim 7 compound was not common general knowledge as at the priority date.

156    Idenix asserts that the primary judge erred in finding that Schemes 3, 4 and 9 of the Idenix patent teach nothing relevant to making a compound within claim 7. It says that such a finding was based on a flawed unstated premise, namely, that schemes directed to other end products could not contain any relevant information (at [537] to [539] and [543]); we would note at this point that Idenix’s description of her Honour’s reasons is, like some other characterisations of her Honour’s reasons by Idenix, not accurate. Idenix submits that the Idenix patent describes the synthesis of 2'-branched nucleosides at pages 122 to 125. Starting from either a sugar (the sugar route) or a nucleoside (the nucleoside route), it says that the Idenix patent discloses that these compounds can be synthesised by: (i) oxidising the 2'-OH group to yield the 2'-keto compound; (ii) reacting the 2'-keto compound with an organometallic reagent (for example, a Grignard reagent or an organolithium) to yield the 2'-alkylated compound (for example, the 2'-methyl-“down”-2'-hydroxyl-“up” nucleoside); and (iii) in the case of the sugar route, coupling the alkylated sugar to a nucleobase to yield the 2'-alkylated nucleoside. Idenix says that for such reaction steps, the Idenix patent teaches that the sugar or nucleoside can be “optionally protected with a suitable protecting group, preferably with an acyl or silyl group, by methods well known to those skilled in the art, as taught by Greene et al” (pages 123 to 124). It says that the Idenix patent then states that in particular embodiments the 2'-C-branched ribonucleoside is desired, that is, a 2'-branched methyl-“up”-2'-hydroxyl-“down” nucleoside. But it is said that those words do not limit the preceding text.

157    Idenix also contends that contrary to the primary judge’s finding at [612], the synthesis of the precursor was also a matter of routine. It says that the skilled addressee when reading the text and schemes as a whole would be able to arrive at the precursor. Specifically, it says that the skilled addressee could oxidise the 2'-OH group of a nucleoside to give the 2'-keto nucleoside, which would then be reacted with an organometallic reagent (such as a Grignard reagent) to give the precursor. It says that the skilled addressee would have expected the application of a Grignard reagent to the 2'-keto nucleoside in Scheme 4 (being an asymmetric cyclic ketone) to result in a mixture of both isomers, being the depicted 2'-methyl-“up”-2'-hydroxyl-“down” nucleoside as well as the un-depicted 2'-methyl-“down”-2'-hydroxyl-“up” nucleoside (precursor). It then says that the separation of individual isomers from the mixture was routine chemistry. Idenix submits that, contrary to the primary judge’s finding, the skilled addressee could have relied on Scheme 4, together with common general knowledge, to obtain the precursor.