Gilead Sciences Pty Ltd v Idenix Pharmaceuticals LLC
[2016] FCA 169
•2 March 2016
FEDERAL COURT OF AUSTRALIA
Gilead Sciences Pty Ltd v Idenix Pharmaceuticals LLC [2016] FCA 169
File number: NSD 48 of 2013 Judge: JAGOT J Date of judgment: 2 March 2016 Catchwords: PATENTS – novelty – whether claims of respondents’ patent fairly based on matter disclosed in priority documents – real and reasonably clear disclosure of the claims in the priority documents established – respondents’ patent entitled to priority date of priority document – respondents’ patent not invalid for lack of novelty
PATENTS – internal fair basis – whether claims of respondents’ patent fairly based on matter described in specification – real and reasonably clear disclosure of the claims in the specification established – respondents’ patent not invalid for lack of internal fair basis
PATENTS – sufficiency – whether respondents’ patent describes the invention fully – whether patent enables the skilled addressee to produce something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty – insufficiency established
PATENTS – utility – whether claims of the respondents’ patent useful – certain claims of respondents’ patent invalid for inutility
PATENTS – manner of manufacture – respondents’ patent not invalid on basis of a lack of a manner of manufacture
PATENTS – false suggestion – respondents’ patent not invalid on basis of false suggestion
Legislation: Evidence Act 1995 (Cth) s 140
Patents Act 1990 (Cth) ss 18, 40, 43, 138
Federal Court Rules 2011 (Cth) r 34.50
Patents Regulations 1991 (Cth) reg 3.12
Cases cited: Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59; (2002) 212 CLR 411
Alphapharm Pty Ltd v H Lundbeck A/S [2008] FCA 559; (2008) 76 IPR 618
American Home Products Corp v Novartis Pharmaceuticals UK Limited [2000] RPC 547
AMP Inc v Utilux Pty Ltd (1971) 45 ALJR 123
Apotex Pty Ltd v Sanofi-Aventis [2008] FCA 1194; (2008) 78 IPR 485
AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99; (2014) 226 FCR 324
AstraZeneca AB v Apotex Pty Ltd; AstraZeneca AB v Watson Pharma Pty Ltd; AstraZeneca AB v Ascent Pharma Pty Ltd [2015] HCA 30
Atlantis Corporation Pty Ltd v Schindler (1997) 39 IPR 29
Austal Ships Pty Ltd v Stena Rederi Aktiebolag [2005] FCA 805; (2005) 66 IPR 420
Bickford v Skewes (1835) 1 QB 938
Biogen Inc v Medeva PLC [1997] RPC 1
British Thomson-Houston Co Ltd v Corona Lamp Works Ltd (1922) 39 RPC 49
Burroughs Corp (Perkins’) Application [1974] RPC 147
CCOM Pty Ltd v Jiejing Pty Ltd (1994) 51 FCR 260
Chiron Corporation v Murex Diagnostics Ltd [1996] RPC 535
Coopers Animal Health Australia Ltd v Western Stock Distributors Pty Ltd (1987) 15 FCR 382
D’Arcy v Myriad Genetics Inc [2015] HCA 35; (2015) 325 ALR 100
Decor Corporation Pty Ltd v Dart Industries Inc (1988) 13 IPR 385
Edison and Swan Electric Light Co v Holland (1889) 6 RPC 243
Eli Lilly and Co v Pfizer Overseas Pharmaceuticals [2005] FCA 67; (2005) 218 ALR 408
Expo-Net Danmark A/S v Buono-Net Australia Pty Ltd (No 2) [2011] FCA 710
F Hoffman-La Roche & Co AG v Commissioner of Patents (1971) 123 CLR 529
Fallshaw Holdings Pty Ltd v Flexello Castors & Wheels Plc (1993) 26 IPR 565
Genentech Inc v The Wellcome Foundation Ltd (1988) 15 IPR 423
Grant v Commissioner of Patents [2006] FCAFC 120; (2006) 69 IPR 221
H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70; (2009) 177 FCR 151
Henriksen v Tallon Ltd (No 2) [1965] RPC 434
ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc [1999] FCA 345; (1999) 45 IPR 577
Idenix Pharmaceuticals Inc v Gilead Sciences Inc [2014] EWHC 3916
In the matter of an application for a patent by I.G. Farbenindustrie Aktiengesellschaft (1939) 56 RPC 249
Inverness Medical Switzerland GmbH v MDS Diagnostics Pty Ltd [2010] FCA 108; (2010) 85 IPR 525
Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8; (2001) 207 CLR 1
Kinabalu Investments Pty Ltd v Barron & Rawson Pty Ltd [2008] FCA 314; (2008) 75 IPR 370
Leonardis v Sartas No 1 Pty Ltd (1996) 67 FCR 126
Leonhardt v Kalle (1895) 12 RPC 103
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21; (2007) 235 CLR 173
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58; (2004) 217 CLR 274
Martin Engineering Co v Trison Holdings Pty Ltd (1989) 14 IPR 330
May & Baker Ltd v Boots Pure Drug Co Ltd (1950) 67 RPC 23
Minnesota Mining and Manufacturing Co v Beiersdorf (Aust) Ltd (1980) 144 CLR 253
Morgan v Seaward (1836) 1 Webs R 170
National Research Development Corporation v Commissioner of Patents (1959) 102 CLR 252
Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513
Nichia Corporation v Arrow Electronics Australia Pty Ltd [2015] FCA 699
No-Fume Ltd v Frank Pitchford & Co Ltd (1935) 52 RPC 231
Novartis AG v Hospira Pty Ltd [2012] FCA 1055; (2012) 98 IPR 185
NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1993) 44 FCR 239
Pfizer Inc v Commissioner of Patents [2005] FCA 137; (2005) 141 FCR 413
Photocure ASA v Queen's University At Kingston [2005] FCA 344; (2005) 216 ALR 41
Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC [2008] FCAFC 82; (2008) 77 IPR 449
Ranbaxy Laboratories Ltd v AstraZeneca AB [2013] FCA 368; (2013) 101 IPR 11
Rescare Ltd v Anaesthetic Supplies Pty Ltd (1992) 111 ALR 205
Seafood Innovations Pty Ltd v Richard Bass Pty Ltd [2011] FCAFC 83; (2011) 92 IPR 1
Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth [2011] FCAFC 132
Synthetic Turf Development Pty Ltd v Sports Technology International Pty Ltd [2004] FCA 1179
The Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262
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
WM Wrigley Jr Co v Cadbury Schweppes Pty Ltd [2005] FCA 1035; (2005) 66 IPR 298
Yamazaki Mazak Corporation v Interact Machine Tools (NSW) Pty Ltd (1991) 22 IPR 79
Zipher Ltd v Markem Systems Ltd [2009] FSR 1
Date of hearing: 14 – 18, 21 – 24, 28 – 30 September 2015, 1, 6 – 9 October 2015 Date of last submissions: 24 November 2015 Registry: New South Wales Division: General Division National Practice Area: Intellectual Property Sub-area: Patents and Associated Statutes Category: Catchwords Number of paragraphs: 689 Counsel for the Applicant: Mr DK Catterns QC, Mr C Dimitriadis SC and Mr NR Murray Solicitor for the Applicant: Herbert Smith Freehills Counsel for the Respondents: Mr AJL Bannon SC and Mr PW Flynn Solicitor for the Respondents: Jones Day ORDERS
NSD 48 of 2013
BETWEEN: GILEAD SCIENCES PTY LTD (ACN 072 611 708)
Applicant
AND: IDENIX PHARMACEUTICALS LLC
First Respondent
UNIVERSITA DEGLI STUDI DI CAGLIARI
Second Respondent
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
Third Respondent
UNIVERSITE DE MONTPELLIER
Fourth Respondent
AND BETWEEN: IDENIX (CAYMAN) LIMITED (and others named in the Schedule)
First Cross-Claimant
AND: GILEAD SCIENCES PTY LTD (ACN 072 611 708) (and another named in the Schedule)
First Cross-Respondent
JUDGE:
JAGOT J
DATE OF ORDER:
2 march 2016
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.
1 THE DISPUTE
[1]
1.1 Introduction
[1]
1.2 The allegations of invalidity – a brief overview
[10]
1.2.1 Lack of novelty
[10]
1.2.2 Internal fair basis
[11]
1.2.3 Insufficiency
[12]
1.2.4 Lack of utility
[14]
1.2.5 Manner of manufacture
[15]
1.2.6 False suggestion
[16]
2 THE SCIENCE
[18]
2.1 Common general knowledge
[18]
2.2 Organic and nucleoside chemistry
[21]
2.2.1 Chemical bonds
[21]
2.2.2 Organic chemistry terms
[25]
2.2.3 Conventions for drawing and naming organic molecules
[41]
2.2.4 Organic chemical reactions
[50]
2.2.5 Organic synthesis
[53]
2.2.6 Amino acids, peptides and proteins
[56]
2.2.7 Nucleosides and nucleotides
[59]
2.2.8 Sugars
[68]
2.3 Nucleosides and nucleotides as antiviral drugs
[84]
2.4 Virology
[92]
2.4.1 Viruses and virology
[92]
2.4.2 The Flaviviridae family
[95]
2.4.3 HCV classification
[103]
2.4.4 HCV genome and proteins
[104]
2.4.5 Development of HCV anti-virals
[113]
2.4.6 Surrogate models
[114]
2.4.7 HCV protease and polymerase assays
[117]
2.4.8 HCV replicons
[118]
2.4.9 Modifications to the HCV Replicon system
[133]
2.4.10 The drug discovery process
[138]
3 THE EXPERTS – A BRIEF OVERVIEW
[146]
3.1 The affidavit evidence
[146]
3.2 Professor Furneaux
[149]
3.3 Dr Lambert
[153]
3.4 Professor Gowans
[157]
3.5 Dr Tucker
[160]
3.6 Dr Cox
[163]
3.7 Dr Clemens
[166]
3.8 Professor Meier
[172]
3.9 Dr Borthwick
[177]
3.10 Professor Barrett
[186]
3.11 Professor Patterson
[192]
4 THE SKILLED ADDRESSEE
[196]
4.1 The issues
[196]
4.2 Who is the skilled addressee?
[198]
4.3 What common general knowledge should be attributed to the skilled addressee?
[210]
5 LACK OF NOVELTY?
[252]
5.1 The issue
[252]
5.2 The legislation
[253]
5.3 The principles
[256]
5.4 The 350 application - overview
[280]
5.5 The 350 application - consideration
[301]
5.5.1 The competing cases
[301]
5.5.2 Conclusion
[308]
5.5.3 Response to competing cases
[309]
5.5.4 Basic facts
[316]
5.5.5 F at the 2' down position
[324]
5.5.6 Modified or natural bases?
[330]
5.5.7 Prodrugs at the 5' position only
[346]
5.5.8 The expert evidence
[386]
5.6 The 949 application – overview
[392]
5.7 The 949 application – consideration
[400]
5.8 Conclusions
[415]
6 INTERNAL FAIR BASIS?
[418]
6.1 The issue
[418]
6.2 The specification of the Idenix patent – an overview
[421]
6.3 Consideration
[422]
6.4 Conclusions
[432]
7 SUFFICIENCY?
[433]
7.1 The issues
[433]
7.2 The legislation
[434]
7.3 The principles
[435]
7.4 The competing cases – the synthesis issue
[442]
7.5 The Idenix documents – the synthesis issue
[447]
7.5.1 Initial observations
[447]
7.5.2 The content of the Idenix documents
[459]
7.5.3 Further observations
[504]
7.6 Other evidence – the synthesis issue
[527]
7.6.1 Introduction
[527]
7.6.2 Schemes 3, 4 and 9
[537]
7.6.3 Professor Meier
[545]
7.6.4 Dr Borthwick
[552]
7.6.5 Professor Furneaux
[562]
7.6.6 Professor Patterson
[583]
7.6.7 The Clark patent
[592]
7.6.8 Other articles
[597]
7.7 The AMRI experiments
[600]
7.8 Further observations
[604]
7.9 The treatment issue
[616]
8 UTILITY?
[626]
8.1 The issues
[626]
8.2 The principles
[628]
8.3 Discussion
[633]
9 MANNER OF MANUFACTURE?
[655]
9.1 The issue
[655]
9.2 Gilead’s case
[657]
9.3 Discussion
[658]
10 FALSE SUGGESTION?
[661]
10.1 The issues
[661]
10.2 Discussion
[668]
10.3 Conclusions
[687]
11 CONCLUSIONS
[688]
REASONS FOR JUDGMENT
JAGOT J:
1. THE DISPUTE
1.1 Introduction
Sofosbuvir is a new treatment for the Hepatitis C virus (HCV). The applicant (referred to below as Gilead) wishes to sell sofosbuvir in Australia.
Sofosbuvir is a compound having the following chemical structure:
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.
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).
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.
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.
Claim 8 also claims a compound of Formula (IX) but where X is O and Y3 is H.
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.
Claim 13 claims the composition of claim 10 wherein the Flaviviridae virus is HCV.
1.2 The allegations of invalidity – a brief overview
1.2.1Lack of novelty
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.
1.2.2Internal fair basis
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.
1.2.3Insufficiency
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.
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.
1.2.4Lack of utility
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.
1.2.5Manner of manufacture
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.
1.2.6False suggestion
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.
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
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.
This common general knowledge concerns matters of organic, specifically nucleoside, chemistry and virology.
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
2.2.1Chemical bonds
The sharing of electrons between two atoms can result in the creation of chemical bonds. Each single chemical bond contains two electrons.
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.
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.
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.
2.2.2Organic chemistry terms
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.
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.
An enzyme is a biological molecule that catalyses (or accelerates) a chemical reaction.
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.
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.
The term heteroatom is the term commonly used to describe any atom other than a carbon or hydrogen in an organic molecule.
Ligand is the name given to a molecule that binds specifically to a receptor site of another molecule.
Polymorph is a different crystalline form of the same compound. Polymorphs are not different compounds, just different solid states of a compound.
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.
Reagents are compounds usually used to help bring about chemical change in other compounds.
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.
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.
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.
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.
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.
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.
2.2.3Conventions for drawing and naming organic molecules
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.
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.
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:
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”.
A Haworth projection for glucose and an example nucleoside showing the C and H atoms and their numbering conventions is illustrated below:
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:
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).
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.
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.
2.2.4Organic chemical reactions
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”.
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.
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.
2.2.5Organic synthesis
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.
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.
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).
2.2.6Amino acids, peptides and proteins
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).
Peptides, polypeptides and proteins are chains of amino acids joined together by peptide bonds.
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.
2.2.7Nucleosides and nucleotides
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.
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.
The general structure of a nucleoside can be schematically represented as follows:
The structures of a naturally occurring ribonucleoside and deoxyribonucleoside (specifically a 2'-deoxyribonucleoside) are illustrated below:
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”.
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).
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.
Positions on the nucleobase are distinguished from those on the sugar in a nucleoside by adopting non-prime numbering for the nucleobase.
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.
2.2.8Sugars
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.
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.
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.
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.
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.
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.
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.
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.
In general, the stereochemical configuration of nucleosides is described using D and L terminology (as described above) and alpha (α) and beta (β) terminology.
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:
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.
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.
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.
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:
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”.
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
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.
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.
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.
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 body, the 2'-methyl-“up” nucleoside analogue is formed.
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.
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.
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
2.4.1Viruses and virology
Virology is the study of viruses.
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.
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.
2.4.2The Flaviviridae family
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.
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.
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.
Family Genus Example strains (viruses) Flaviviridae flavivirus yellow fever virus (YFV), dengue virus (DENV), West Nile virus (WNV) pestivirus bovine viral diarrhoea virus (BVDV) hepacivirus HCV, GB virus B (GBV-B) pegivirus GB virus A (GBV-A) (or simian pegivirus, SPgV), GB virus C (GBV-C) (or human pegivirus, HPgV), GB virus D (GBV-D) (or bat pegivirus, BPgV) Table 1 Flaviviridae genera and example strains
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.
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.
“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).
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.
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).
2.4.3HCV classification
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.
2.4.4HCV genome and proteins
HCV has a genome of approximately 9.6kb (i.e. the RNA strand consists of approximately 9,600 nucleotide bases).
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
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).
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.
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.
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.
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.
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.
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).
2.4.5Development of HCV anti-virals
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).
2.4.6Surrogate models
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.
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).
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.
2.4.7HCV protease and polymerase assays
The direct screening of potential HCV inhibitors may be done with in vitro polymerase and protease/helicase enzyme assays.
2.4.8HCV replicons
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.
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.
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).
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.
As the Neo-selection system replaces the HCV structural genes, these replicons cannot produce new virus particles which can be secreted from the cell.
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.
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.
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.
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.
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.
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).
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.
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).
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.
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.
2.4.9Modifications to the HCV Replicon system
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).
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).
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.
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.
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.
2.4.10The drug discovery process
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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
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.
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.
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.
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
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.
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…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.
Given the matters referred to above, including the way in which the skilled addressee would construe the Idenix patent, I accept this submission. Assessed in this way none of the evidence proves lack of utility in this regard.
Insofar as the articles are concerned, because I prefer Idenix’s approach to the “promise” of the invention (which undermines the usefulness of the articles because their content is not capable of negativing that “promise”), it is not necessary to say much about their admissibility.
In the present case the problem for Gilead is that Dr Lambert’s evidence added nothing to the articles. For the articles to be admissible, they would have to be admissible on their own terms and not because they provided the foundation for any evidence from Dr Lambert. This is because Dr Lambert did not use his expertise to locate the articles and in his evidence did no more than construe the articles in circumstances where there is no suggestion that in so doing Dr Lambert brought to bear his own expertise. The circumstances are thus different from those considered by Lindgren J in Alphapharm v Lundbeck at [711]-[783] in which his Honour rejected a hearsay objection. In the particular circumstances in which Gilead seeks to make use of the articles the subject of Dr Lambert’s evidence, I consider the hearsay objection should be upheld. I do not agree with Idenix, however, that the articles are an experimental proof within the meaning of r 34.50 of the Federal Court Rules 2011 (Cth).
Dealing with the substance of the articles, Gilead did not answer Idenix’s submission that, as a compound within claim 7 is not a 2' prodrug, Gilead had to prove that a 3' prodrug of the invention within claim 7 was not useful in treating Flaviviridae infections but the articles on which it relied do not involve 3' prodrugs at all. In common with the nature of the “promise” of the invention, this point also appears to put paid to Gilead’s case of lack of utility based on compounds within claim 7 being ineffective to treat HCV and/or toxic.
For these reasons I consider it unnecessary to consider Idenix’s submissions about each article other than to say that they exposed many limitations on the use that could be made of this part of Dr Lambert’s evidence of the kind that discloses why evidence of a hearsay character intended to be used for hearsay purposes, if admitted, tends to lack reliability and cogency when tested.
For these reasons Gilead’s case of lack of utility based on the claims of the invention in claim 7 being ineffective against HCV or toxic should not be accepted.
9. MANNER OF MANUFACTURE?
9.1 The issue
By s 18(1)(a) of the Act “an invention is a patentable invention for the purposes of a standard patent if the invention, so far as claimed in any claim is a manner of manufacture within the meaning of section 6 of the Statute of Monopolies”. Failure to fulfil this requirement is a ground on which a patent may be revoked under s 138(3)(b) of the Act.
Gilead contends that claim 7 and dependent claims represent either an arbitrary selection of different components from the broad range of possibilities comprehended by the formulas of the claims or an attempt to define a multitude of theoretical compounds, or compositions or uses of such compounds, irrespective of whether or not those compounds could have been made by the person skilled in the art as at the priority date of the claims or would have been understood by the person skilled in the relevant art to be useful as at the priority date of the claims, and thus are not a manner of manufacture as required.
9.2 Gilead’s case
Gilead’s case on this issue traversed many of the other grounds. Insofar as its submissions can be confined to the present ground it appears that Gilead’s contentions involve the following propositions:
(1)The Idenix patent “covers a large number of compounds that are said to be useful in treating Flaviviridae and in particular HCV, but it presents no evidence that any of the compounds in fact have that activity (or, for that matter, have even been made), nor which, if any, of the compounds described have activity against particular Flaviviridae”. This, I note, is factually correct.
(2)It “is not a manner of manufacture merely to postulate a range of compounds and a possible utility that can only be ascertained by making and testing each compound” (citing, in support, May & Baker Ltd v Boots Pure Drug Co Ltd (1950) 67 RPC 23 (May & Baker) and National Research Development Corporation v Commissioner of Patents (1959) 102 CLR 252 (NRDC)) which is what the Idenix patent involves. Putting it another way, “a claim to a vast genus of compounds cannot be a manner of manufacture … unless a sufficient number have been made and tested to support a generalising rationale” (citing, in support, Biogen Inc v Medeva PLC [1997] RPC 1 at 23 and 49 and American Home Products Corp v Novartis Pharmaceuticals UK Limited [2000] RPC 547 at [53]).
(3)“Merely to list trillions of possible compounds does not satisfy the NRDC “test” of an “artificial effect of economic utility”; and merely to draw a Markush structure encompassing such possible compounds is not an invention” (Chiron Corporation v Murex Diagnostics Ltd [1996] RPC 535).
(4)“…the specification merely claims an abstract idea or a “principle”” (NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1993) 44 FCR 239) and amounts to no more than a “mere idea or mere desideratum” (Burroughs Corp (Perkins’) Application [1974] RPC 147 at 160, cited in Grant v Commissioner of Patents [2006] FCAFC 120; (2006) 69 IPR 221 at [18]).
(5)The Idenix patent provides no consideration for the statutory monopoly as there is nothing of economic utility provided on the face of the specification (D’Arcy v Myriad Genetics Inc [2015] HCA 35; (2015) 325 ALR 100 (D’Arcy) at [28]).
(6)The test is not answered by the mere fact that a compound is claimed. In D’Arcy, submissions that the claim in suit was to a compound and therefore a manner of manufacture were rejected at [6], [85], [88], [94].
9.3 Discussion
It may be accepted that the categories of case in which a claimed invention does not represent a manner of manufacture are not closed and that the issue is to be determined on a case-by-case basis (D’Arcy at [4]-[5], [18], [23]). Other than this I do not see the circumstances in D’Arcy are analogous to the present case. D’Arcy involved “a new class of claim [that] involves a significant new application or extension of the concept of “manner of manufacture”” (at [28]) and, as such, called for consideration of a wide range of factors which would not unfairly be described as extending to questions of policy. I do not see the present case as enlivening the same considerations. Claims 7 to 9 are to chemical compounds, and the principal dependent claims (claims 10 to 26) are to pharmaceutical compositions. The circumstances which led the High Court in D’Arcy not to accept the characterisation of the isolated nucleic acid coding for the mutations or polymorphisms on the BRCA1 gene as a claim to a chemical compound are not involved in the present case.
Apart from this I accept Idenix’s submission that Gilead’s case on this issue is difficult, if not impossible, to separate from its contentions of lack of sufficiency and utility. I accept also the relevance of Idenix’s submission that “sofosbuvir, which Gilead admits infringes claim 7, is said by Gilead to be a highly efficacious compound i.e. a compound within claim 7 which has been made and which is efficacious”. The relevance of this is that it indicates that Gilead’s case, however it is put, is founded on the insufficiency and inutility of the Idenix patent rather than the claimed compounds not being a manner of manufacture. It does not matter that Gilead made sofosbuvir after the date of the Idenix patent. What matters is that this compound, if the Idenix patent is valid, infringes claim 7.
Further, the various cases on which Gilead relied each depended on the particular specification and claims involved and, in the UK cases, were subject to a different statutory regime. It is not possible to discern from them any unifying principle that suggests a lack of a manner of manufacture merely by reason of the large number of compounds claimed or the fact that the inventor has not in fact made any of the compounds. Given that, as Idenix said, “a valid patent may be obtained for something stumbled upon by accident, remembered from a dream … if it otherwise satisfies the requirements of the legislation” (The Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262 at 286), the case which Gilead makes, in my view, does not involve any matter which goes to the lack of a manner of manufacture as opposed to insufficiency and inutility.
10. FALSE SUGGESTION?
10.1 The issues
By s 138(3)(d) of the Act a patent may be revoked on the ground “that the patent was obtained by fraud, false suggestion or misrepresentation”.
Gilead contends that the Idenix patent was obtained by false suggestion or misrepresentation insofar as the patent made the so-called “Compound Representations” and “Treatment Representations”.
As Gilead put it in written submissions (albeit in a summary format) the Compound Representations are to the effect that the applicants for the Idenix patent had made the compounds (the First Compound Representation) in formula IX or had made and tested a sufficient range of those compounds to enable a sound prediction to be made (the Second Compound Representation) or that there are otherwise “reasonable grounds…to believe” that the compounds could be made (the Third Compound Representation).
The Fourth Compound Representation relied upon by Gilead is that:
…one or more of the processes for the preparation of compounds described at p119 line 30 – p152 line 17 (CB1:1-0121-0154) can be used to synthesise every compound within the class of compounds of Formula (IX) without new inventions or additions or prolonged study of matters presenting initial difficulty.
Gilead also contends that the Idenix patent represents that the applicants for the patent had in fact demonstrated (the First Treatment Representation) or had tested a sufficient range of compounds to enable a sound prediction to be made (the Second Treatment Representation) or had reasonable grounds to believe (the Third Treatment Representation) that the compounds were effective against HCV.
Gilead’s case is that all of these representations are false because:
Not only had the compounds not been made but even if they had, it is simply not feasible to test the inordinate number of compounds covered by claim 7, and it was common ground that, in the context of nucleoside analogues, even small changes in the structure can have a dramatic impact on function and activity.
In respect of Example 26 (referred to above in the context of internal fair basis), Gilead contends that the Idenix patent represents that the data presented in Example 26 demonstrates that the compounds of the invention, including those claimed in claim 7 are, or are likely to be, effective for the treatment of Flaviviridae infections, including HCV (the Example 26 Representation). This representation, it is said, is false because the activity of compounds falling within the claims, including claim 7, cannot be determined or inferred from the data presented in Example 26.
10.2 Discussion
It is clear from the evidence that, if the Idenix patent made any of the representations (except, perhaps, the Third and Fourth Compound Representations and the Third Treatment Representation), those representations would be false. This is because the evidence of all experts who dealt with these issues was to the effect that:
(1)The applicants for the Idenix patent had not made all of the compounds in formula IX of the Idenix patent and, indeed, may be inferred not to have made any such compounds.
(2)As such, the applicants could not have tested a sufficient range of those compounds to enable a sound prediction to be made that these compounds could be made or had anti-viral activity in respect of Flaviviridae infections, including HCV.
Whether the Third Compound Representation was false depends on the scope of the representation (which was somewhat unclear). If the representation is said to be that the applicants for the patent had reasonable grounds to believe that all of the compounds in the Idenix patent could be made then, on the evidence, the representation would be false. This is because the evidence leads to the inference that it is not possible to make a compound with Br or I at the 2' up position (R12) in the formula in claim 7 (an issue discussed above in the context of utility). The applicants for the Idenix patent, I infer from this evidence, could not have had reasonable grounds to believe that a compound within claim 7 could be made with Br or I at the 2' up position (R12). If, however, the representation is said to be that the applicants for the patent had reasonable grounds to believe that some or even one of the compounds could be made then, on the evidence, the position may well be different. As explained below, it is unnecessary to resolve this issue.
Whether the Fourth Compound Representation is false depends on the outcome of the sufficiency argument. As discussed above, I have resolved the issue of sufficiency in Gilead’s favour. It follows that, if made, the Fourth Compound Representation is false. Again, however, I consider it unnecessary to resolve this issue.
Whether the Third Treatment Representation is false depends on the scope of the representation (which was also somewhat unclear). If the representation is said to be that the applicants for the patent had reasonable grounds to believe that all of the compounds in the Idenix patent were effective against HCV, on the evidence, the representation would be false. This is because all of the experts agreed that it was impossible to know or predict this, as biological assays would be required. If the representation is said to be that the applicants for the patent had reasonable grounds to believe that some or even one of the compounds in the Idenix patent were effective against HCV then, on the evidence, the position may well be different. It is also unnecessary to resolve this issue.
If the representation in respect of Example 26 was made then, on the evidence, it was false. This is because all of the experts agreed that the activity of compounds falling within the claims, including claim 7, cannot be determined or inferred from the data presented in Example 26.
The difficulty for Gilead relates to the question whether any of the representations were made. Gilead’s case depended solely on the face of the Idenix patent. It did not suggest that there were any collateral dealings between the Commissioner and the applicants for the Idenix patent which were relevant. Insofar as the face of the Idenix patent is concerned none of the experts considered that any of the representations were made. Each of the experts who read the Idenix patent knew that it could not be the case that all of the compounds had been made or that all would be effective against Flaviviridae infections, including HCV. They knew that it was impossible to predict whether any compound would be effective against Flaviviridae infections, including HCV without undertaking biological assays. They inferred that the applicants for the Idenix patent had not made any compounds of the invention or tested any such compounds for effectiveness against Flaviviridae infections, including HCV because they expected that, if any such work had been done, it would have been presented in the Idenix patent and it was not. They also knew that Example 26 had nothing to do with the compounds of the invention.
The parties accepted that this evidence of the experts reflected how the skilled addressee, on the basis of the common general knowledge in the field, would construe the Idenix patent. In other words, while some of the experts, from their evidence as a whole, may be inferred to have found the Idenix patent a perplexing and somewhat confusing document, none of them read it as making any of the representations on which Gilead relies.
This, no doubt, is the reason for Gilead’s concession that the only way in which it could succeed in respect of its false suggestion case is if, for this purpose, the Idenix patent is not to be construed as the skilled addressee would construe it but, rather, as the Commissioner should be inferred to have construed it. As the argument was put for Gilead in oral submissions:
We all accept that the commissioner is an expert person. The court gives deference to her delegate’s decision in appeals from their decisions…and she is also presumed to have, and in fact does have, she and her examiners and other delegates, scientific background, but that’s not the same as the level of team that our friends are going to be asserting is capable, like Professor Borthwick, of fluorinating a compound, etcetera, or of the level of Professor Gowans. So…we submit that, just stepping back as a matter of reality, the commissioner is going to give these statements full faith and credit.
…
The examiner who is sitting there has got a scientific background, but not the expertise of the skilled addressee of a team in a case such as this.
Gilead relied on Ranbaxy at [134] to support its proposition that the Commissioner ought not to be taken to read the Idenix patent as the skilled addressee would have read it. Rather, the Commissioner would have read the Idenix patent “with the will to believe what [s]he finds set down in it” (May & Baker at 36). In Ranbaxy at [134] it was said:
[134] It may also be that his Honour was of the view that the statements, objectively considered, were such as were intended to induce a favourable decision concerning the grant of the Enantiomer Patent. However, such a proposition may not be self-evident. Having regard to the evidence as to how CSI measurements would be understood by the relevant expert addressee of the Enantiomer Specification, namely, as indicating a ranking and not an absolute score, it is possible that that is how the CSI Table was understood by the Commissioner or the Commissioner’s delegate. Accordingly, it does not necessarily follow that the contents of the CSI Table materially contributed to the Commissioner’s decision.
In Ranbaxy the statements in issue were made in a specification of a patent and in a letter from a patent attorney to the Commissioner. In respect of the patent specification the Full Court said this:
[96] It is for the Court to construe a specification, although the Court will do so in the light of evidence as to usage of language by the relevant skilled addressee of the specification, to the extent that language is used in a manner that is different from ordinary English usage. In order to do so, the Court must place itself in the position of a person skilled in the art as at the priority date. Thus, the Court would have regard to evidence of what a person skilled in the art would understand from the language, information or data in a specification or what such language, information or data would disclose to the relevant skilled addressee. Ultimately, of course, the question of what representations are made in a specification is a matter for the Court to determine.
…
[98] However, there is no express statement in the Enantiomer Specification that the measure of the increase in activity is ten-fold. There is no representation that the CSI Table reflects all of the CSI data available to Warner-Lambert. In addition, there was evidence that the relevantly skilled addressee would understand the table as giving no more than a ranking of the respective activity found in relation to each of the compounds listed. And, the skilled addressee would understand that there may be results that, for various reasons, would be rejected.
When dealing with the question whether the specification was misleading the Full Court at [140] said:
It was common general knowledge that, on resolution or synthesis to obtain the enantiomers, one of them would most likely have an activity of twice that of the racemate. In the ordinary course, that would make a patent claiming the enantiomer not novel or obvious. The Enantiomer Specification asserts a surprising result. It asserts, by statement and by supporting data, that the enantiomer has an unexpected and surprising level of activity of more than twice that of the racemate. That was a false representation. When the examiner questioned the patentability of a claim to an enantiomer where the racemate had been prior published, the representation was repeated and affirmed. The statements in the patent attorneys’ letter were made in response to the examiner’s objection, which if not overcome, would have led to rejection of the patent application. The statements sought to overcome the objection. Warner-Lambert succeeded in overcoming the objection based on want of novelty and the Enantiomer Patent was granted. The inference is clearly open, and should be drawn, that the grant of the Enantiomer Patent was made because the examiner accepted the truth of the representation.
Given these statements I do not consider that [134] of the Full Court’s reasons can be understood as suggesting that the issue of false suggestion arising from the face of a patent is to be determined on the basis of some construction of the patent different from that which would be reached by the skilled addressee. To the contrary the Full Court resolved the issue on the basis of the understanding the skilled addressee (with the benefit of the common general knowledge) would have of the specification.
The fact that the Commissioner is taken to be willing to believe the statements in a specification does not advance Gilead’s case. The concept of the skilled addressee does not involve the reading of a patent with a view to disbelieving it.
Gilead did not identify any authority to support its submission that, for the purposes of false suggestion, a patent may be construed other than as the skilled addressee would construe it. Nor did it identify a principled basis for such an approach. The argument appears to be that the field of discourse of the Idenix patent is so specialised that it would be unrealistic to attribute to the Commissioner the common general knowledge of the skilled addressee. Without that knowledge, it is said, the Commissioner would read the Idenix patent as making the representations.
I consider the submission confronts a number of difficulties. Without evidence, it is not possible to know if the Commissioner subjectively understood the Idenix patent as making the representations. Nor is it possible to identify any particular standard by reference to which that question can be answered. If the patent is not to be construed as the skilled addressee would construe it for this purpose, then the approach to construction might change on a patent-by-patent basis depending upon the skills of the Commissioner and delegates and the field of discourse of the patent. It is one thing for the Commissioner to assert that she was in fact misled (which is not the present case). It is another to infer, without any evidence of the skills available to the Commissioner, that because a patent involves a highly specialised art she understood it to make representations that the skilled addressee would not have understood to be made.
Gilead’s submissions would also create difficulty in respect of the issue of the materiality of the representations. As Idenix submitted, it is clear that the question is whether it can be inferred that the Commissioner was actually misled by the representations and not whether the representations were merely likely to mislead or deceive the Commissioner. Further, the fact that the Commissioner has not chosen to give evidence is relevant to whether the inference should be drawn or not. Without evidence from the Commissioner the materiality issue is to be resolved by asking whether the representations (if made) were objectively likely to contribute to the grant of the Idenix patent (Ranbaxy at [83] citing Synthetic Turf Development Pty Ltd v Sports Technology International Pty Ltd [2004] FCA 1179 at [2], and WM Wrigley Jr Co v Cadbury Schweppes Pty Ltd [2005] FCA 1035; (2005) 66 IPR 298 at [123] – [130]). The test of objective likelihood makes sense if the patent is to be construed as the skilled addressee would construe it. It makes less sense if, without any evidence from the Commissioner, the patent is to be construed on some other basis. Indeed, it is impossible to formulate what that other basis might be. The Commissioner is accepted not to be a layperson so a test based on that standard would be inappropriate. In some fields of discourse the Commissioner might possess all of the common general knowledge of the person skilled in the art. In others, the Commissioner might possess some but not all of that knowledge.
For these reasons, I do not consider the approach which Gilead advocates in the present case is tenable. Absent evidence from the Commissioner that she was in fact misled, I cannot see any basis upon which it should be inferred that the Commissioner construed the Idenix patent other than as the skilled addressee would construe it. If construed as the skilled addressee would construe it, Gilead concedes that none of the alleged misrepresentations are made by the Idenix patent.
There are other reasons for rejecting Gilead’s false suggestion case. Leaving aside the content of the common general knowledge which led all of the experts not to read the Idenix patent as Gilead contends, there is no statement in the Idenix patent that the applicants themselves synthesised any compound. On that basis, it is unclear how the First and Second Compound Representations and First and Second Treatment Representations could have been made. There is no statement of belief about the capacity to make any compound “without new inventions or additions or prolonged study of matters presenting initial difficulty”. This is a legal construct relating to the law of sufficiency. Indeed, there is no statement in the Idenix patent about any beliefs or states of mind. As such, it is unclear how the Third and Fourth Compound Representations or Third Treatment Representation could have been made.
Example 26 is different. There is some evidence that a person without the common general knowledge of chemistry that the skilled addressee is taken to have might wrongly believe that Example 26 is a compound encompassed by the Idenix patent. Professor Gowans, a virologist, assumed this to be the case, acknowledging that he is not a chemist and thus did not understand the structure of the compound the subject of Example 26 (Compound F). I am not prepared to infer that the Commissioner wrongly made the same assumption. There is no evidence she did. It would be no more than speculation to infer that the Commissioner understood Example 26 to be a compound encompassed by the Idenix patent given that the skilled addressee would immediately recognise that to be impossible. Nor is there evidence from which it would be inferred that the Example 26 Representation was material to the Commissioner’s decision to grant the Idenix patent.
10.3 Conclusions
I do not accept Gilead’s case that the Idenix patent was obtained by false suggestion or misrepresentation.
11. CONCLUSIONS
For the reasons set out above I am satisfied that Gilead’s challenges to the validity of the Idenix patent should be accepted in respect of the grounds of insufficiency and inutility to the extent that claim 7 includes compounds which cannot be made. I do not accept the balance of Gilead’s contentions.
The parties should confer and submit agreed or competing orders reflecting these reasons for judgment within 14 days.
I certify that the preceding six hundred and eighty-nine (689) numbered paragraph is a true copy of the Reasons for Judgment herein of the Honourable Justice Jagot. Associate:
Dated: 29 February 2016
SCHEDULE OF PARTIES
NSD 48 of 2013 Cross- Claimants
Second Cross-Claimant
UNIVERSITA DEGLI STUDI DI CAGLIARI
Third Cross-Claimant
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
Fourth Cross-Claimant
UNIVERSITE DE MONTPELLIER
Fifth Cross-Claimant
Idenix Pharmaceuticals LLC
Cross- Respondents
Second Cross-Respondent
GILEAD SCIENCES INC
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