Eli Lilly and Company Limited v Apotex Pty Ltd
[2013] FCA 214
FEDERAL COURT OF AUSTRALIA
Eli Lilly and Company Limited v Apotex Pty Ltd [2013] FCA 214
Citation: Eli Lilly and Company Limited v Apotex Pty Ltd [2013] FCA 214 Parties: ELI LILLY AND COMPANY LIMITED and ELI LILLY AUSTRALIA PTY LTD (ABN 39 000 233 992) v APOTEX PTY LTD (ABN 52 096 916 148) File number: VID 876 of 2009 Judge: MIDDLETON J Date of judgment: 15 March 2013 Catchwords: INTELLECTUAL PROPERTY – Patents – Construction of claims – Infringement of claims – Applicable principles – Skilled addressee – Revocation for invalidity – Novelty – Generic chemical disclosure – Prior art and common general knowledge – Selection patents – Inventive step – Secondary considerations – Commercial success – Sufficiency – Fair basis – Lack of clarity – Manner of new manufacture Legislation: Patents Act 1903-1950 (Cth)
Patents Act 1949 (UK)
Patents Act 1952 (Cth)Patents Act 1952-1955 (Cth)
Patents Act 1990 (Cth)Cases cited: Advanced Building Systems Pty Limited v Ramset Fasteners (Aust) Pty Limited (1998) 194 CLR 171
Aktiebolaget Hässle v Alphapharm Pty Limited (2002) 212 CLR 411
Aktiebolaget Hässle v Alphapharm Pty Ltd (1999) 44 IPR 593; [1999] FCA 628
Alphapharm Pty Ltd v H Lundbeck A/S (2008) 76 IPR 618; [2008] FCA 559
American Home Products Corporation [1994] APO 58 (28 September 1994)
Apotex Pty Ltd (formerly GenRx Pty Ltd) v Sanofi-Aventis (2008) 78 IPR 485; [2008] FCA 1194
Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162
Apotex Pty Ltd v Sanofi-Aventis (2009) 82 IPR 416; [2009] FCAFC 134
Apotex Pty Ltd v Sanofi-Aventis Australia Pty Ltd (No 2) (2012) 204 FCR 494
Australian Mud Company Pty Ltd v Coretell Pty Ltd (2011) 93 IPR 188; [2011] FCAFC 121
Beecham Group Ltd v Bristol Laboratories International SA (1978) RPC 521
Bristol-Myers Co v L’Oreal (1988) 12 IPR 275
Bristol-Myers Co v L’Oreal (1988) 12 IPR 275
Bristol-Myers Co v L’Oreal (1989) 16 IPR 652
Bristol-Myers Squibb Co v F H Faulding & Co Limited (2000) 97 FCR 524
Britax Childcare Pty Ltd v Infa-Secure Pty Ltd (2012) 290 ALR 47
British Acoustic Films Ltd v Nettlefold Productions (1936) 53 RPC 221
British Thomson-Houston Co Ltd v Corona Lamp Works Ltd (1922) 39 RPC 49
Ccom Pty Ltd v Jiejing Pty Ltd (1994) 51 FCR 260
Clay v ICI Australia Operations Pty Ltd (1984) 3 IPR 439
Commissioner of Patents v Ethyl Corporation (1969) 120 CLR 594
Commissioner of Patents v Microcell Limited (1959) 102 CLR 232
Commissioner of Patents v The Wellcome Foundation Limited (1983) 2 IPR 156
Commonwealth Industrial Gases Ltd v MWA Holdings Pty Ltd (1970) 180 CLR 160
Conor Medsystems Inc v Angiotech Pharmaceuticals Inc [2008] 4 All ER 621
Conor Medsystems Inc v University of British Columbia (2005) 223 ALR 74
Décor Corporation Pty Ltd v Dart Industries Inc (1988) 13 IPR 385
Dr Reddy’s Laboratories (UK) Ltd v Eli Lilly and Co Ltd [2010] RPC 9
Dura-Post (Aust) Pty Ltd v Delnorth Pty Ltd (2009) 177 FCR 239
EL Du Pont De Nemours & Co (Witsiepe’s) Application (1982) 1A IPR 297
Electric and Musical Industries Ltd v Lissen Ltd (1939) 56 RPC 23
Flexible Steel Lacing Company v Beltreco Ltd (2000) 49 IPR 331; [2000] FCA 890
Fresenius Medical Care Australia Pty Ltd v Gambro Pty Ltd (2005) 224 ALR 168; [2005] FCAFC 220
General Tire & Rubber Company v Firestone Tyre and Rubber Company Ltd (1971) 1A IPR 121
Grain Pool (WA) v Commonwealth of Australia (2002) 202 CLR 479
H Lundbeck A/S v Alphapharm Pty Ltd (2009) 177 FCR 151
Hoechst Aktiengesellschaft v Monsanto Company [1998] APO 13 (17 March 1998)
ICI Chemicals & Polymers Ltd v The Lubrizol Corporation Inc (2000) 106 FCR 214
ICI v Commissioner of Patents (2004) 213 ALR 399; [2004] FCA 1658
Imperial Chemical Industries Pty Ltd v Commissioner of Patents (2004) 213 ALR 399; [2004] FCA 1658
Innovative Agriculture Products Pty Ltd v Cranshaw (1996) 35 IPR 643
International Business Machines Corporation v Commissioner of Patents (1991) 33 FCR 218
Inverness Medical Switzerland GmbH v MDS Diagnostics Pty Ltd (2010) 85 IPR 525; [2010] FCA 108
ITW AFC Pty Ltd v Loi & Tran Pty Ltd (2008) 76 IPR 129; [2008] FCA 552
Jones v Dunkel (1959) 101 CLR 298
Kimberley-Clark Worldwide, Inc v Carter Holt Tissue Australia Pty Ltd [2002] APO 44 (19 November 2002)
Kimberly-Clark Australia Pty Limited v Arico Trading International Pty Limited (2001) 207 CLR 1
Kirin-Amgen Inc v Hoechst Marion Roussel Ltd (2004) 64 IPR 444
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (2004) 217 CLR 274
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (2005) 68 IPR 459; [2005] FCAFC 255
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) (2007) 235 CLR 173
Longbottom v Shaw (1891) 8 RPC 333Martin v Scribal Pty Ltd (1954) 92 CLR 17
Merck & Co Inc v Arrow Pharmaceuticals Ltd (2006) 154 FCR 31
Meyers Taylor Pty Limited v Vicarr IndustriesLimited (1977) 137 CLR 228
Minnesota Mining & Manufacturing Co v Tyco Electronics Pty Ltd (2002) 56 IPR 248; [2002] FCAFC 315
Minnesota Mining and Manufacturing Co & 3M Australia Pty Ltd v Beiersdorf (Aust) Ltd (1980) 144 CLR 253
National Research Development Corporation v Commissioner of Patents (1959) 102 CLR 252
Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513
NV Philips Gloeilampenfabrieken v Mirabella International Pty Limited (1993) 44 FCR 239
NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1995) 183 CLR 655
Olin Corporation v Super Cartridge Co Pty Ltd (1977) 180 CLR 236
Olin Mathieson Chemical Corporation v Biorex Laboratories Limited [1970] RPC 157
Pharmacia Aktiebolag v Ueno Fine Chemicals Industry Ltd (1995) 34 IPR 445
Pilja v Rapidjoint (2009) 80 IPR 648
Populin v HB Nominees Pty Ltd (1982) 41 ALR 471
PPG Industries Inc v Stauffer Chemical Company (1985) 5 IPR 496
Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC (No 2) (2006) 71 IPR 46
Re Application of Compagnies Reunies des Glaces et Verres Speciaux du Nord de la France (1930) 48 RPC 185
Re Beecham Group Ltd’s (Amoxycillin) Application [1980] RPC 261
Re IG Farbenindustrie (1930) 47 RPC 289
Rodi & Wienenberger AG v Henry Showell Ltd [1969] RPC 367
Sachtler GmbH & Company KG v RE Miller Pty Ltd (2005) 65 IPR 605; [2005] FCA 788
Sami S Svendsen Inc v Independent Products Canada Ltd (1968) 119 CLR 156
SNF (Australia) Pty Ltd v Ciba Specialty Chemicals Water Treatments Limited (2011) 92 IPR 46; [2011] FCA 452
SNF (Australia) Pty Ltd v Ciba Specialty Chemicals Water Treatments Ltd (2012) 204 FCR 325
Sumitomo Electric Industries Ltd v Metal Manufactures Ltd (1995) 32 IPR 185
Synthetic Turf Development Pty Ltd v Sports Technology International Pty Ltd (2005) 67 IPR 475
Technograph Printed Circuits Ltd v Mills & Rockley (Electronics) Ltd [1972] RPC 346
University of Georgia Research Foundation Inc v Biochem Pharma Inc (2000) 51 IPR 222
Wake Forest University Health Sciences v Smith & Nephew Pty Ltd (No 2) (2011) 92 IPR 496; [2011] FCA 1002
Welch Perrin and Company Pty Ltd v Worrel (1961) 106 CLR 588
Wellcome Foundation v VR Laboratories (1981) 148 CLR 262Date of hearing: 3, 4, 5, 6, 7, 10, 11, 12, 14, 17, 18, 19, 24, 25, 26, October 2011 & 9 November 2011 Place: Melbourne Division: GENERAL DIVISION Category: Catchwords Number of paragraphs: 764 Counsel for the Applicants: Mr B Caine SC with Ms K Howard SC Solicitor for the Applicants: Ashurst Australia Counsel for the Respondent: Mr DK Catterns QC with Mr AJ Maryniak Solicitor for the Respondent: DibbsBarker
IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
GENERAL DIVISION
VID 876 of 2009
BETWEEN: ELI LILLY AND COMPANY LIMITED
First ApplicantELI LILLY AUSTRALIA PTY LTD (ABN 39 000 233 992)
Second ApplicantAND: APOTEX PTY LTD (ABN 52 096 916 148)
Respondent
JUDGE:
MIDDLETON J
DATE OF ORDER:
15 March 2013
WHERE MADE:
MELBOURNE
THE COURT ORDERS THAT:
1.The parties confer and thereafter file and serve minutes of orders reflecting the reasons of the Court on or before 4:00pm on 29 March 2013.
Note:Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
GENERAL DIVISION
VID 876 of 2009
BETWEEN: ELI LILLY AND COMPANY LIMITED
First ApplicantELI LILLY AUSTRALIA PTY LTD (ABN 39 000 233 992)
Second ApplicantAND: APOTEX PTY LTD (ABN 52 096 916 148)
Respondent
JUDGE:
MIDDLETON J
DATE:
15 MARCH 2013
PLACE:
MELBOURNE
REASONS FOR JUDGMENT
INTRODUCTION
This proceeding concerns Australian Patent No. 643267 (the Patent). The invention described in the Patent comprises three main parts:
1.the compound olanzapine;
2.the processes for producing olanzapine; and
3.pharmaceutical compounds including olanzapine.
Olanzapine is a compound used in pharmaceutical products to treat schizophrenia, a debilitating psychiatric disease which affects approximately 1% of the population. Olanzapine has had considerable commercial and therapeutic success in the treatment of schizophrenia.
The first applicant, Eli Lilly and Company Ltd, is the registered proprietor of the Patent. The second applicant, Eli Lilly Australia Pty Ltd, is the exclusive licensee of the Patent in Australia. It supplies and markets pharmaceutical goods containing olanzapine under the product names Zyprexa, Zyprexa Zydis Wafer, Zyprexa Relprevv and Zyprexa IntraMuscular. It is convenient to refer to the applicants collectively as ‘Eli Lilly’.
The respondent, Apotex Pty Ltd (Apotex), manufactures and supplies ‘generic’ brands of pharmaceutical products. On 26 November 2009, Apotex received approval from the Therapeutic Goods Administration (TGA) to market generic olanzapine pharmaceutical products in Australia. Apotex obtained registration on the Australian Register of Therapeutic Goods as the sponsor of 50 olanzapine products. Until the determination of this proceeding, Apotex has been restrained from acting upon such approval or registration.
THE ISSUES
Eli Lilly contended that Apotex, by obtaining registration as the sponsor of olanzapine products, threatened to infringe claims 1, 2, 3 and 4 of the Patent by proposing to exploit olanzapine during the term of the Patent: s 13 Patents Act 1990 (Cth) (the 1990 Act).
Apotex, by way of cross-claim, sought revocation of the Patent. Apotex argued that the Patent should be revoked under the Patents Act 1952 (Cth) (the 1952 Act) on the following grounds:
(a)the invention was not novel (s 100(1)(g));
(b)the invention was obvious and did not involve an inventive step (s 100(1)(e));
(c)the complete specification of the Patent did not comply with the requirements of s 40 of the 1952 Act, namely:
(i)if the invention was found to be a “selection patent”, then the invention claimed was not fully (or “sufficiently”) described under s 40(1)(a);
(ii)the specification did not end with a claim or claims defining the invention (s 40(1)(b));
(iii)the claims of the Patent were not clear (s 40(2)); and
(iv)the claims were not fairly based on the matter described in the specification (s 40(2)); and
(d)the invention, so far as claimed in any claim of the complete specification, was not an invention within the meaning of the 1952 Act, or further or alternatively, was not a manner of manufacture (s 6 of the Statute of Monopolies and s 100(1)(d) of the 1952 Act).
RELEVANT LEGISLATIVE PROVISIONS
Before turning to address these issues in detail, there is a preliminary issue that needs to be mentioned. Eli Lilly and Apotex agreed that both the 1990 Act and the 1952 Act apply to this proceeding. The 1952 Act applied to the grounds of invalidity upon which Apotex sought to rely. The 1990 Act applied to the issue of infringement.
This is due to the date on which the Patent was filed and granted, and the date of commencement of this proceeding. The Patent was filed on 22 April 1991, and granted on 25 February 1994. The priority date of the Patent is 25 April 1990 (the date on which United Kingdom Patent Application No. 9009229 was filed, from which the Patent in suit essentially derives). The 1990 Act commenced on 30 April 1991. Section 230 of the 1990 Act repealed the 1952 Act.
Section 228(7) of the 1990 Act, read together with s 228(2)(za) of the 1990 Act, allows the Governor-General to make such transitional and savings provisions as are necessary or convenient as a result of the repeal of the 1952 Act and the enactment of the 1990 Act.
Specifically, s 228(7) provides that:
Despite the repeal of the 1952 Act by this Act, regulations made under paragraph (2)(za) may provide for the continued operation of specified provisions of the 1952 Act in relation to prescribed persons or matters, or in prescribed circumstances.
Chapter 23 of the 1990 Act and the regulations made under that Act contain certain transitional and savings provisions that relate to patent applications lodged under the 1952 Act and patents granted on such applications.
The relevant transitional provisions of the 1990 Act provide:
233 Patents granted under 1952 Act
(1)Subject to this Chapter and the regulations, this Act applies in relation to a standard patent or a petty patent granted under the 1952 Act as if the patent had been granted under this Act.
…
(4)Objection cannot be taken to a patent mentioned in subsection (1), and such a patent is not invalid, so far as the invention is claimed in any claim, on any ground that would not have been available against the patent under the 1952 Act.
234 Applications under 1952 Act
…
(2) Where, before the commencing day:
(a)a patent application had been lodged under the 1952 Act; and
(b)a complete specification, or a petty patent specification, had been lodged under that Act in respect of the application; and
(c)the application had not been withdrawn or finally dealt with;
then, subject to this Chapter and the regulations, this Act applies on and after that day:
(d)in relation to the application as if it were a complete application made under this Act; and
(e)in relation to the petty patent specification as if it were a complete specification filed under this Act in respect of the application.
…
(5) Objection cannot be taken to:
(a)an application mentioned in subsection (2); or
(b)a patent granted on such an application;
and such a patent is not invalid, so far as the invention is claimed in any claim, on any ground that would not have been available against the application or patent, as the case may be, under the 1952 Act.
Schedule 1—Dictionary
In this Act, unless the contrary intention appears:
application, in Chapter 15, means a patent application, and includes a relevant international application.
The relevant provisions of the Patents Regulations 1991 (Cth) provide:
23.26 Certain actions and proceedings
(1)The 1952 Act applies to an action or proceeding made or started under that Act and not finally dealt with or determined before the commencing day:
(a)in which the validity of a patent is disputed; or
(b)concerning infringement of a patent.
(2)The 1952 Act applies to an action or proceeding in which the validity of a patent granted under the Patents Act 1990 on an application made under the 1952 Act is disputed.
The commencing day referred to in reg 23.26(1) is 30 April 1991.
The 1990 Act applies to patents granted under the 1952 Act, “as if the patent had been granted under [that] Act” (s 233(1)). The 1990 Act also applies to applications made, but not finally dealt with, under the 1952 Act (s 234(2)). If the patent was applied for or granted under the 1952 Act, then the patent (or application) cannot be invalid on any ground that would not have been available under the 1952 Act (ss 233(4) and 234(5)).
However, the 1990 Act does not stipulate which Act applies to determine the validity of a patent that was applied for under the 1952 Act, but ultimately granted under the 1990 Act. Regulation 23.26(2) provides for this event. The 1952 Act applies to determine the validity of patents granted under the 1990 Act but applied for under the 1952 Act. It should be noted that this reg 23.26(2) applies to issues of validity, not infringement. This is apparent from the preceding reg 23.26(1), which provides that the 1952 Act applies to the determination of both validity as well as infringement where a patent was granted under the 1952 Act and the proceeding was commenced before 30 April 1991. By contrast, reg 23.26(2) is silent as to infringement.
From s 234(5) of the 1990 Act it is clear that Apotex cannot succeed in impugning the validity of any claim of the Patent unless it is shown that the invention claimed could have been revoked under the 1952 Act.
As Lockhart J said in NV Philips Gloeilampenfabrieken v Mirabella International Pty Limited (1993) 44 FCR 239 at 253-254 in relation to s 233(4) of the 1990 Act (which is in language to the same effect as s 234(5) of the Act):
In my opinion the evident intent of s 233(4) is to ensure that the grounds of revocation under the 1990 Act (which, though in some cases are expressed in different terms, are essentially the same as the grounds previously available under s 100 of the 1952 Act) apply as the grounds for revocation of a 1952 Act patent; but with this important qualification, namely, that the elements of each ground of revocation under the 1990 Act apply only to the extent that they replicate in substance the elements that previously constituted a ground of revocation under the 1952 Act. Hence, if a ground of revocation under the 1990 Act omits an element which was a necessary part of a ground under the 1952 Act, the patentee has the benefit of it. On the other hand, if a ground under the 1990 Act contains an element not previously present under the 1952 Act, it cannot apply in aid of revocation of the 1952 Act patent. In short, a 1952 Act patentee is not to be worse off than he would have been if the 1952 Act had continued to operate, but he may be better off if the 1990 Act treats a former element of a ground of revocation as being no longer necessary.
BACKGROUND
Australian Patent No. 643267 and Related Patents
On 26 November 1974, Lilly Industries Ltd filed GB provisional application number 51240.
This provisional application led to a family of patents, including AU 506340 (the 340 Patent) and GB 1 533 235 (the 235 Patent). Both the 340 Patent and the 235 Patent (the genus patents) claimed a class of compounds that included olanzapine, although it is not mentioned specifically. The genus patents are effectively identical.
The complete specifications for the 340 Patent and the 235 Patent were filed on 21 November 1975 and 24 November 1975 respectively. By s 22 of the Patents Act 1949 (UK) and s 68 of the 1952 Act, the term of each of the genus patents was 16 years from the date of filing.
The genus patents claim a vast number of compounds. The named inventors of the Patent and the genus patents included Dr Jiban Kumar Chakrabarti and Dr David Edward Tupper. During the 1980s, Dr Chakrabarti, Dr Tupper and others published a series of papers relating to their work on antipsychotic compounds, including compounds covered by the genus patents. Eli Lilly conducted clinical trials from 1986 onwards. Eli Lilly made its product commitment in 1990.
The application for the Patent was filed on 22 April 1991. The genus patents were published in 1977 (AU) and 1978 (UK). The Patent was published on 7 November 1991. The term of the Patent was extended to 5 March 2012. It seems that the patentee has effectively had continuing patent protection for olanzapine from 1977 until the expiry of the Patent. There was some suggestion made by counsel for Apotex of Eli Lilly “evergreening”, namely, being able to in effect re-monopolise olanzapine in the 1990s via the Patent, having initially obtained patent protection in the 1970s with the grant of the 235 Patent. Of course, this observation cannot impact upon the principles to be applied in this proceeding. The outcome must be the same as if the 235 Patent was claimed and owned by a third party unconnected to Eli Lilly.
Returning to the matters in issue in this proceeding, it is important to note that the genus patents are an important basis for some of the grounds of invalidity pleaded by Apotex.
In answer to the significant attack upon the validity of the Patent, Eli Lilly contended that the provisional application and the genus patents do not clearly disclose olanzapine, being only one among the trillions of compounds they mathematically encompass.
I make this preliminary observation. Many of the compounds relevant to this proceeding are closely related, as the general structure of each indicates. This is not unusual. Apparent similarities in the chemical structures may exist, but very different pharmaceutical effects may still occur. As will be seen, flumezapine and ethyl flumezapine have similar structures, but produce very different side effects when used as drugs. Therefore, one must be careful not to assume that just because the compounds may be similar, arriving at a suitable compound is necessarily easily achieved or readily predictable with any confidence. In this proceeding, I became satisfied on the evidence before me of the immense research and intellectual endeavour undertaken to reach the compound the subject of the Patent. Importantly, with the search for a drug to treat schizophrenia, progress was impeded by the ignorance of the real causes and pathogenesis of schizophrenia.
Agreed Chemistry Primer
It is necessary to have some background knowledge of the principles of chemistry relevant to this proceeding. Accordingly, before setting out the key aspects of the Patent, it is appropriate to set out some principles contained in the chemistry primer agreed upon by the parties and presented to the Court.
Chemistry
Chemistry is that part of science which deals with the composition, structure, properties and reactions of matter.
The building blocks of matter are atoms, which are made up of protons, neutrons and electrons.
An atom can be visualised as a small, exceptionally dense nucleus comprised of protons and neutrons, surrounded by a relatively large volume of electrons. Protons are positively charged, neutrons are not charged and electrons are negatively charged. In a neutral atom, the number of electrons is the same as the number of protons.
The chemistry of an atom is largely determined by the behaviour of its electrons. As a result, chemists typically employ a simple model of the nucleus, and focus more attention on the properties of the electrons. At its simplest, the nucleus provides the positive charge to bind the negatively charged electrons in atoms.
Although all atoms are comprised of the same components (protons, neutrons and electrons), different atoms have different chemical properties. The chemical properties of an atom are determined by the number and arrangement of electrons. As noted above, in a neutral atom, the number of electrons is the same as the number of protons. Atoms can become negatively charged by gaining electrons, or positively charged by losing electrons, but the number of electrons on a neutral atom is always the same, and is equal to the number of protons. Accordingly, chemists define different atoms, or elements, by reference to the number of protons. This is known as the atomic number of the element. For example, an atom that has six protons is an atom of the element carbon; an atom that has eight protons is an atom of the element oxygen.
Each element is allocated a symbol. A symbol for an element consists of up to three letters, where the first letter is uppercase, and the remainder lowercase. By way of example, the chemical symbols for some relevant elements are provided below.
Element
Symbol
Hydrogen
H
Carbon
C
Nitrogen
N
Oxygen
O
Sulfur
S
Fluorine
F
Chlorine
Cl
Atoms have the ability to combine with atoms of the same or other elements to form compounds. The forces that hold the atoms together in a compound are called chemical bonds. Electrons can form chemical bonds in different ways. The manner in which the electrons form a chemical bond within a compound may affect the manner in which that compound interacts with other compounds. For example, the manner in which the electrons form chemical bonds within a drug molecule may affect the way that the drug molecule interacts with other molecules, such as biological receptors.
There are broadly two types of chemical bonds, distinguished by the behaviour of the electrons of the bonded atoms.
In one type of chemical bond, one atom transfers one or more electrons to the other atom. The atom that loses the electron(s) becomes positively charged (as the number of electrons is now less than the number of protons) and the atom that gains the electron(s) becomes negatively charged (as the number of electrons now exceeds the number of protons). The charged atoms are called ions, and this type of chemical bonding is called ionic bonding.
The other way that atoms can form chemical bonds to other atoms is by sharing electrons. These bonds are called covalent bonds, and the resulting collection of atoms is called a molecule. A simple way of thinking about a molecule is that the shared electrons are located between the atoms, providing a region of negative charge to which the positively charged nuclei (made up of positively charged protons and neutral neutrons) of the atoms are attracted. This is known as the localised electron model.
If the two bonded atoms are identical, then the electrons are shared equally between them. This is called pure covalent bonding. If the atoms are different, the electrons are not shared equally between them. This is called polar covalent bonding. Polar covalent bonding, and the effect of polar covalent bonds within a molecule on the interaction of that molecule with other molecules are discussed in more detail below.
Molecules can be represented in different ways. The simplest method is the molecular formula, in which the symbols of the elements comprising the compound are listed, together with numerical subscripts indicating the number of atoms of each element. For example, the molecular formula for water is H2O, indicating that a molecule of water contains two hydrogen atoms and one oxygen atom. More information about a molecule is provided by the structural formula (or simply structure), in which the individual bonds between atoms are shown by lines. Structural formulae indicate connectivity of atoms and may or may not indicate the shape of the molecule. For example, water may be represented in either of the ways set out in Figure 1 below, with the structural formula on the right indicating the shape of the molecule.
Figure 1
Not all of the electrons of an atom have the potential to be involved in interactions with the electrons of other atoms. The electrons of an atom have different discrete energies. These discrete energies are described as orbitals. Each orbital can only accommodate a certain number of electrons; the first orbital can contain up to two electrons and the second, up to eight. Once each orbital is full, any further electrons added to the atom are forced to occupy a higher energy orbital. It is only the electrons of highest energy (valence electrons) that interact with the electrons of other atoms. An atom that has a full highest energy orbital is stable. Most of the chemical properties of an atom are determined by the number of valence electrons and the propensity of the atom to share valence electrons with other atoms (in the case of covalent bonds), or donate or receive valence electrons to or from other atoms (in the case of ionic bonds), to achieve a full highest energy orbital. In most cases, a full highest energy orbital consists of eight electrons. Hydrogen is a relevant exception, requiring only two electrons to complete its highest energy orbital.
Neutral atoms of different elements will have different numbers of total electrons, but may have the same number of valence electrons, and thus exhibit similar chemical behaviour. The periodic table of the elements arranges elements in vertical columns or groups based on the number of valence electrons in a neutral atom of each element.
Discussed below, by way of example, are the groups of elements in the periodic table known as the halogens (Group VII) and the noble gases (Group VIII).
The halogens include the elements fluorine (symbol F) and chlorine (symbol Cl). Although neutral atoms of the halogens will have different numbers of total electrons, (corresponding to the number of protons in the nucleus), the number of valence electrons of each halogen is seven.
Atoms of the noble gas elements contain a full highest energy orbital (eight electrons), and do not therefore need to interact with other atoms to achieve stability. This manifests itself in their chemical behaviour – they do not tend to readily react with other elements.
Electronegativity and Intermolecular Forces
When electrons are shared in a covalent chemical bond between atoms of different elements, the electrons are not shared equally. That is, the covalent bond is a polar covalent bond, as opposed to a pure covalent bond. The different affinities of atoms of different elements for the electrons in a bond are described by a property called electronegativity: the ability of an atom in a molecule to attract electrons to itself.
The electronegativity of an atom of a particular element is a function of two effects. First, elements with a larger number of protons have a more positively charged nucleus, which is generally more attractive to the negatively charged valence electrons of the atom, and the valence electrons of the other atom to which it is chemically bonded. Second, complete orbitals of electrons between the nucleus and the valence electrons insulate the positive nucleus both from the valence electrons of the atom and from the other atom to which it is chemically bonded. The first effect means that electronegativity increases from left to right across the periodic table. The second effect means that electronegativity decreases from the top to the bottom of the periodic table (the noble gases are excluded from this analysis as they do not tend to form chemical bonds at all). Accordingly, the most electronegative element is fluorine (symbol F).
Electrons carry a negative charge, so the uneven distribution of electrons within a chemical bond means an uneven distribution of charge across the bond: the atom of the more electronegative element will acquire a small negative charge, and the atom of the less electronegative atom a small positive charge. These small charges are conventionally represented by the Greek letter delta (δ). They are different to the full positive and negative charges created by the transfer of electrons in ionic bonding. The separation of charges across the chemical bond in this manner is called a dipole.
Using a molecule of hydrogen fluoride as an example, the fluorine atom is considerably more electronegative than the hydrogen atom. As a result, the shared electrons that comprise the chemical bond spend more of their time in the vicinity of the fluorine atom than the hydrogen atom, resulting in the fluorine end of the molecule acquiring a small negative charge, and the hydrogen end of the molecule, now deficient in electrons, acquiring a small positive charge. This is illustrated in Figure 2 below:
Figure 2
The distribution of electrons within a molecule has a significant effect on the way in which the molecule interacts with other molecules, whether the other molecules are molecules of the same compound, or molecules of a different compound (eg the interaction between a drug molecule and a biological receptor).
Again using hydrogen fluoride as an example, groups of hydrogen fluoride molecules tend to orient themselves in the pattern shown in Figure 3 below. This is because the small negative charges at the fluorine ends of the molecules tend to be attracted to the small positive charges at the hydrogen ends of other molecules.
Figure 3
The forces between molecules are known as intermolecular forces, as opposed to the chemical bonds within molecules. Intermolecular forces vary in strength, but are not as strong as the chemical bonds within a molecule. The strongest intermolecular forces are created where there is the most uneven distribution of electrons within the molecules, as this results in the greatest charge separation.
Organic Chemistry
Organic chemistry is the study of the chemistry of carbon-based compounds, also commonly known as organic compounds. Most drugs are organic compounds. Carbon has four valence electrons in its highest energy orbital, and demonstrates a propensity to share an additional four electrons to complete that orbital and achieve stability. Carbon demonstrates a considerable degree of flexibility in the manner in which it achieves this, enabling an extraordinary number of carbon-based compounds with a wide variety of properties.
For example, carbon has the capacity to form bonds that involve more than one pair of shared electrons. Bonds involving two pairs of electrons are known as double bonds. Bonds involving three pairs of electrons are known as triple bonds. Collectively, they are described as multiple bonds. These are illustrated in Figure 4 below using the structural formulae of the gases ethane, ethene (ethylene) and ethyne (acetylene). Each carbon has four valence electrons to contribute to bonding, and each hydrogen has one.
Figure 4
In ethane, each carbon has four valence electrons and gains a share of an electron in each of three bonds to hydrogen, and a share in an electron in the bond to the other carbon, making a complete highest energy orbital of eight. In ethene, each carbon gains a share of an electron from each of two bonds to hydrogen, but gains a share of two electrons in the double bond to the other carbon for a total of eight. In ethyne, each carbon has a share in an electron from the bond to hydrogen, and a share in three electrons from the triple bond to the other carbon.
The structures of ethane, ethene and ethyne also serve to illustrate the concept of saturation. A carbon atom that is attached to the maximum number of other atoms allowed by the four valence electrons in its highest energy orbital (ie 4) is described as saturated. The two carbon atoms of ethane are saturated. A carbon atom that has the capacity to attach to another atom, such as those in ethene and ethyne, are described as unsaturated carbon atoms.
The ability of carbon to engage in multiple bonds exposes a limitation of the localised electron model discussed above. A component of many organic compounds is a ring of six carbon atoms, with each carbon atom having a single hydrogen atom attached. This is commonly known as a benzene ring. The structural formula (or, simply, the structure) of benzene can be drawn two ways, each depicting alternating single and double bonds (see Figure 5 below).
Figure 5
In reality, the distribution of electrons within the ring of carbon atoms is a hybridisation of both structural formulae. That is, instead of alternating double and single bonds, the properties of benzene are more consistent with six identical bonds of a character intermediate between double and single bonds. In other words, instead of being localised in the three double bonds, six electrons are evenly spread – delocalised – around the ring. For this reason, the structural formula of benzene is often depicted as set out in Figure 6 below.
Figure 6
The fact that the delocalisation of electrons in a benzene ring must be depicted in this way is sometimes referred to as ‘resonance’ or ‘mesomerism’ (about which more will be said later). The delocalisation of electrons around a ring in the manner characteristic of benzene can result in particularly stable molecules and is a property known as aromaticity. Benzene may be described as an aromatic ring. Aromatic rings have specific chemical properties as a result of this particular stability, and of the concentration of delocalised electrons at the centre of the molecule.
The structural formula of benzene can be used to illustrate two conventions that are widely used when representing the structural formulae of organic compounds. First, where hydrogen atoms are attached to carbon atoms, the symbols for hydrogen atoms and the bonds to the hydrogen atoms are omitted from the structural formulae. We know carbon must be involved in bonds which result in it sharing eight electrons, so the existence of the correct number of hydrogen atoms attached to the carbon atom is implied. Secondly, carbon atoms may simply be omitted from the structure. Applying these two conventions, the structure of benzene is more commonly represented as depicted in Figure 7 below.
Figure 7
These two conventions greatly simplify the representations of the structural formulae of organic compounds.
Electron Withdrawing Groups
In organic chemistry, atoms or groups of atoms within a molecule may be characterised as electron withdrawing groups or electron donating groups. This characterisation is made relative to hydrogen. For example, a fluorine atom will draw electrons to itself more than a hydrogen atom would if it occupied the same position in a molecule. Electron withdrawing groups contain one or more highly electronegative atoms. Fluorine is the second strongest electron withdrawing group, with the other halogens following immediately thereafter in order of decreasing electronegativity. The electron withdrawing effects of the halogen atoms were known prior to 1990.
The effect of an electron withdrawing group is not limited to the carbon atom to which it is attached. For example, a strongly electron withdrawing group such as fluorine attached to a benzene ring will exert an effect on the distribution of electrons over the whole ring.
Olanzapine
Olanzapine is an organic compound. The chemical formula for olanzapine is C17H20N4S. This indicates that in each molecule of olanzapine, there are 17 carbon atoms, 20 hydrogen atoms, 4 nitrogen atoms and one sulfur atom. The chemical formula for olanzapine is not capable of unambiguously describing olanzapine – there are a number of different compounds that share this chemical formula.
The structure of olanzapine is shown in Figure 8 below:
Figure 8
Using the two conventions illustrated for benzene above, the structural formula of olanzapine can be more simply represented as Figure 9 below:
Figure 9
This is the manner in which the structure of olanzapine is represented in the Merck Index, which is an encyclopaedia of chemicals, drugs and biologicals produced periodically and on a not-for-profit basis by the New Jersey-based pharmaceutical company, Merck & Co Inc. Chemically, this structure is identical to the structure in Figure 8 above.
The representation of the structural formula of olanzapine which appears on p 3 of the Patent is set out in Figure 10 below. This structural formula is slightly different to that set out in the Merck Index, but is an equally clear representation of the identical chemical compound.
Figure 10
The difference lies in the manner in which the six-membered ring containing two nitrogen atoms (a piperazine ring), which is located at the top right of the structural formula, is depicted. The only difference is that the representation in the Patent attempts to depict the planar arrangement of the atoms of the piperazine ring (ie that they are in a different plane to the rest of the structure), whereas the Merck Index does not.
The structural formulae represented in Figures 8 to 10 above are two-dimensional representations of molecules that exist in three dimensions. Once the connectivity of the atoms (the structural formula) is known, the molecule can be oriented in different ways but still represent the same compound. That is, if the structure is turned upside down, or rotated, the two-dimensional representation can appear quite different, while still representing the same molecule. Using the core tricyclic structure of olanzapine as an example, all of the four structural formulae shown in Figure 11 below represent the same core tricyclic structure.
Figure 11
Frequently, a two-dimensional structural formula of a molecule gives little indication of the three-dimensional shape of the molecule. The three-dimensional shape of the molecule is relevant to the interaction of the molecule with its biological receptor. The spatial arrangement of bonds around a particular atom is relatively inflexible, with departures from the optimum arrangement leading to unstable or strained molecules. For example, a saturated carbon atom (ie a carbon atom bonded to four other atoms) adopts a tetrahedral arrangement of those bonds, as the electrons in each bond repel the electrons in the other bonds such that they are evenly distributed in three-dimensional space.
A way of representing a molecule that allows for these spatial constraints, and so provides an indication of the three-dimensional shape of the molecule, is the ball and stick model. “Annexure A” to these reasons is a copy of a ball and stick model for olanzapine generated using ChemBioDraw Ultra, version 12, published by CambridgeSoft (which, for convenience, will simply be referred to as “ChemDraw” hereafter).
The ball and stick model in Annexure A is oriented in the same way as the structural formulae illustrated in Figure 10 above. The benzene ring is shown on the left of the molecule, the piperazine ring is shown at the top of the molecule and the thiophene ring is shown on the right of the molecule. Carbon atoms are represented in grey, hydrogen in white, nitrogen in blue and sulfur in yellow. The relative sizes of the atoms are represented in a ball and stick model (for example, the sulfur atoms are obviously larger than the carbon atoms, which are, in turn, larger than the hydrogen atoms), but the atoms are deliberately reduced in size so as to highlight the framework of covalent bonds that hold the atoms together. From the ball and stick model, it is apparent that the core tricyclic ring system of olanzapine is not planar as it is represented by the structural formulae in the Merck Index. “Annexure B” to these reasons contains the same ball and stick model that appears in Annexure A, in which the structural features of olanzapine are indicated.
A closer approximation of the actual three-dimensional appearance of the olanzapine molecule is the space-filling model, in which the atoms are represented by spheres, the size of which is proportional to the size of the atoms. Space-filling models are useful for visualising the shape of the molecule, which is important in considering how the molecule will interact with a biological receptor. “Annexure C” to these reasons is a copy of the space-filling model generated for olanzapine using ChemDraw. The space-filling model in Annexure C is oriented in the same way as the structural formulae shown on p 3 of the Patent and the Merck Index, and the ball and stick models of Annexures A and B. “Annexure D” to these reasons is a copy of the space-filling model that appears in Annexure C, in which the structural features of olanzapine are indicated.
Drug Molecule–Receptor Interactions
Most drugs exert their effects on a patient by interacting with a biological molecule such as a receptor. Receptors are proteins. The receptor protein is often located partly inside the cell, partly within the cell wall and partly outside the cell. They function to recognise and bind a particular chemical substance, and thereby activate a specific biological process within the cell.
Proteins are made up of basic structural units known as amino acids, which form polypeptide chains. Proteins consist of one or more polypeptide chains. Polypeptide chains are formed by amino acids bonded together by peptide bonds between the carboxyl groups and amino groups of adjacent amino acid residues, as illustrated in Figure 12 below.
Figure 12
There are twenty standard amino acids from which polypeptides, and thereby proteins, are formed. All of the amino acids have part of their structure in common – the differences lie in a part of the molecule called the side chain (represented by ‘R’ in Figure 12 above). The twenty side chains differ in size, shape, charge, the type and strength of the intermolecular forces they can form with other molecules (including drug molecules) and their chemical reactivity.
Despite the fact that amino acids are connected linearly in polypeptide chains, proteins are not linear. Proteins have well-defined three-dimensional structures. A stretched-out or randomly arranged polypeptide chain will not have biological activity. The biological activity of a protein arises from its conformation, being its three-dimensional shape. The types of amino acids in the protein will specify the conformation of the protein.
The interaction between a receptor and a drug molecule is often described by reference to the interaction of a lock (the receptor) with a key (the drug molecule). However, this is a considerable oversimplification. The interaction between a drug molecule and a receptor is also governed by the intermolecular forces between the two. So, as well as the three-dimensional physical shapes of the drug molecule and the part of the protein with which it interacts, the distribution of charge (electrons) affects the interaction. For example, if the portion of the drug molecule that aligns with an electron deficient (and therefore relatively positively charged) amino acid residue is also positively charged, then it will be repelled, at least reducing, if not preventing, interaction of the two molecules.
As of 25 April 1990, little was known at a molecular level about drug-receptor interactions. Usually, but not always, a drug will interact with a receptor in a non-covalent binding manner and several types of interactions may contribute to the non-covalent binding. For example, hydrophobic interactions will often provide the major driving force, however, hydrogen and ionic binding may also be important, especially for the specificity of the binding of the drug molecule to the receptor. For example, the location of a charged group on a drug molecule in proximity to a hydrophobic portion of the receptor may serve to weaken the binding interaction. The structural features of a drug molecule which determine its affinity for the receptor are often distinct from those which determine its activity at the receptor, that is, the ability to stimulate a biological response. The affinity of a drug molecule for the receptor will be the net result of the various interactions which occur between complementary portions of the drug and its receptor. Activity is generally related to other structural features of the drug molecule that tend to promote conformational changes in the receptor molecule that then initiate a series of interactions, which ultimately result in a biological response.
Acids, Bases and Pharmaceutically Acceptable Salts
Acids are compounds that produce hydrogen ions (being a hydrogen atom from which the electron is removed, generating a positive charge, namely, H+) when dissolved in water. The more acidic the compound, the more hydrogen ions it produces. Bases are compounds that can accept a hydrogen ion when dissolved in water. Bases do this by donating a pair of electrons to the electron deficient hydrogen ion. This basic concept was refined in 1923 by J.N. Bronsted who proposed a simple definition for acids and bases:
(a)An acid is a species having a tendency to lose a hydrogen ion.
(b)A base is a species having a tendency to accept a hydrogen ion.
Every acid has a corresponding (conjugate) base. For example, in water, hydrochloric acid donates a hydrogen ion to a water molecule to give a hydronium ion and a chloride ion, both of which are highly solvated by water.
In this reaction, water is acting as a base by accepting a hydrogen ion from HCl, which in turn is acting as an acid by donating a hydrogen ion. For any acid and for any base:
In this case, AH is an acid and A- is its conjugate base, and B is a base and BH+ is its conjugate acid. Every acid has its conjugate base associated with it, and every base has its conjugate acid associated with it.
The product of the reaction between an acid and a base is called a salt. For example, the product of the reaction of hydrochloric acid and the base sodium hydroxide is the salt sodium chloride (table salt).
Drug molecules may be acids or bases. For some drug molecules, it is useful to make salts. Making a drug in the form of a salt may render it more soluble in water, more readily made into tablets, etc. For other drugs, the base (sometimes called the free base) or acid (sometimes called the free acid) is the more useful form. Salts made by adding acids to drug molecules that are bases may be called acid addition salts. When a salt of a drug molecule is ingested, it dissolves in the aqueous environment of the stomach and/or gastrointestinal tract. It is only when the drug is dissolved that it can be absorbed through the stomach or intestine and it can dissociate into the free acid or base from which it was formed. The extent of dissociation depends on a number of factors including the acidity or basicity (alkalinity) of the solution in which the drug molecule is absorbed. Making a drug in the form of a salt does not change the mechanism by which the drug molecule interacts with the relevant biological receptor or receptors.
Olanzapine is a base, which may be reacted with an acid to form a salt.
THE PATENT
With this background in mind, I now turn to the Patent.
The title of the Patent is “2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-(2,3-b)(1,5)-benzodiazepine and the process for making the same”. The inventors named in the Patent are Jiban Kumar Chakrabarti, Terrence Michael Hotten and David Edward Tupper.
The Invention Described
The Patent opens by stating that “[t]his invention relates to novel organic compounds and the use thereof as pharmaceuticals.”
The Patent then outlines the context in which the compound in question was developed (at p 1a):
Currently there are many drugs available for the treatment of disorders of the central nervous system. Amongst these drugs is a category known as antipsychotics for treating serious mental conditions such as schizophrenia and schizo-phreniform illnesses. The drugs available for such conditions are often associated with undesirable side effects, and there is a need for better products that control or eliminate the symptoms in a safer and more effective way. Furthermore, many patients do not respond or only partially respond to present drug treatment, and estimates of such partial- or non-responders vary between 40% and 80% of those treated.
Ever since antipsychotics were introduced it has been observed that patients are liable to suffer from drug-induced extra pyramidal symptoms which include drug-induced Parkinsonism, actute dystonic reactions, akathisia, tardive dyskinesia and tardive dystonia… The great majority of drugs available for treatment of schizoprenia are prone to produce these extra pyramidal side effects when used at dosages that yield a beneficial effect on the symptoms of the disease. The severity of adverse events and/or lack of efficacy in a considerable number of patients frequently results in poor compliance or termination of treatment.
Other side effects of antipsychotics listed in the Patent include the potential for a sedative effect and depression. Long-term use could lead to irreversible conditions such as tardive dyskinesia and tardive dystonia (at p 2).
The Patent identifies three antipsychotic drugs which were widely used prior to, and up to the time of, the priority date of the Patent. These are: haloperidol, clozapine and chlorpromazine. According to the Patent, haloperidol “has been reported as causing a high incidence of extra pyramidal symptoms and may also cause tardive dyskinesia”. Clozapine, it is noted, was “introduced with the claim that it is free from extra pyramidal effects”. However, in some patients it caused agranulocytosis, a condition which lowers white blood cell count and which can be life threatening. As such, clozapine can only be used under “strict medical observation and supervision” (at p 2). Chlorpromazine, the Patent states, “has long been in use but [its] safety has been called into question”. It also exhibits an undesirable tendency to raise liver enzyme levels (at p 3).
The Patent also refers to a class of antipsychotic compounds – thienobenzodiazepines – which were the subject of the 235 Patent. Page 2 of the Patent depicts the structural nucleus of a subset of thienobenzodiazepines referred to in the 235 Patent. This depiction is reproduced here:
The Patent states that the “lead compound” from this group was flumezapine (7-fluoro-2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]-benzodiazepine). Flumezapine was the subject of a clinical trial. According to the Patent, 17 patients were treated with flumezapine before the trial was terminated due to an “unacceptably high incidence of raised enzyme levels in the treated patients… indicating the possibility of toxicity”. Blood samples taken from patients showed them to be in “substantial excess of normal values” of the enzyme creatinine phosphokinase (CPK), and liver enzymes serum glutamate oxalacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT). The Patent reports that extrapyramidal side effects (EPS) emerged in two patients in the trial (p 3). The extrapyramidal system is a neural network involved in motor activities such as movement and coordination.
Eli Lilly contended that the reference to the “lead compound from this group” is an important part of the description of flumezapine. Eli Lilly submitted that synthesis of a new drug typically involves synthesis of a very large number of compounds before a compound is identified that is sufficiently active, has the right pharmacokinetic profile, is not toxic, and is able to be chemically synthesised on a large scale. The words “lead compound from this group”, ascribed to flumezapine, indicate that Eli Lilly had selected it from the group of thienobenzodiazepines in the 235 Patent because years of discovery and preclinical research led to the conclusion that it was the best compound in the class. Apotex did not agree with this assertion. The significance of flumezapine will become apparent in due course. However, it is important to keep in mind that the Patent, as I am about to recite, indicates the discovery of the compound that was said to be superior not only to flumezapine but also to other related compounds.
Olanzapine, the Compound of the Invention
The Patent then goes on to tell the reader about olanzapine, and states at pp 3 to 4 of the Patent:
We have now discovered a compound which possesses surprising and unexpected properties by comparison with flumezapine and other related compounds.
The compound of the invention is of the formula [“formula (I)”]
or an acid addition salt thereof. The free base of formula (I) is 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine.
The parties agreed that the structural depiction of formula (I) on p 3 of the Patent specification unambiguously depicts a single compound, now known as olanzapine.
Eli Lilly submitted that the structural formula of olanzapine (formula (I)) and the chemical name quoted immediately after it are used consistently in the specification to describe the compound of the invention. Apotex submitted this chemical name – as repeated in the claims of the Patent – is not the name for olanzapine. I will return to this point in detail later.
The Patent then continues:
The compound of the invention has given surprising and excellent results, described in greater detail below, in experimental screens for testing activity on the central nervous system and in clinical trials, which results indicate its usefulness for the relatively safe and effective treatment of a wide range of disorders of the central nervous system.
The Benefits of Using Olanzapine Observed From Pre-Clinical and Clinical Studies
The Patent then describes the benefits of olanzapine observed from the studies conducted, which include that olanzapine (at pp 4-6):
(a)is useful in treating a wide range of central nervous system (CNS) disorders, including psychotic conditions such as schizophrenia, schizophreniform diseases, acute mania, and – in lower doses – mild anxiety states;
(b)exhibits high activity at “surprisingly low dosage levels” in humans, specifically at lower dosage levels than were expected after initial animal testing;
(c)produces a low incidence of only mild and transient elevation of liver enzymes in patients treated with therapeutic doses;
(d)produces lower plasma levels of CPK than flumezapine, “indicating a lower adverse effect on muscular tissue”;
(e)causes lower elevation of prolactin levels than other “currently used neuroleptic drugs”;
(f)caused no observed alteration of white blood cell count in clinical studies; and
(g)did not show any rise in cholesterol levels in a dog study comparing olanzapine with the ethyl analogue at 8mg/kg, whereas the ethyl analogue showed a significant rise.
The Patent then concludes on olanzapine’s clinical performance (at p 6):
Overall, therefore, in clinical situations, the compound of the invention shows marked superiority, and a better side effects profile than prior known antipsychotic agents, and has a highly advantageous activity level.
The Patent then states that the compound of the invention “can be used both in its free base and acid addition salt forms”. It lists the preferable pharmaceutically acceptable acid addition salts and other acid addition salts (at p 6).
I observe that the information provided by the Patent is obviously based on experimental work and chemical tests, and is relatively fulsome for a pharmaceutical compound said to be new.
Processes For Producing Olanzapine
Two processes for producing the compound of formula (I) (olanzapine) are described in the Patent. They are (pp 6-7):
(a) reacting N-methylpiperazine with a compound of the formula
in which Q is a radical capable of being split off, or
(b) ring-closing a compound of the formula
The Patent indicates that appropriate reaction conditions and suitable values of Q can readily be chosen for these processes.
Animal Models and In Vitro Data
The Patent presents results based on two animal behavioural models using well-established procedures, showing that olanzapine has useful CNS activity. In particular, the results from the animal models show that olanzapine (at p 13):
(a)antagonised apomorphine-induced climbing behaviour and hypothermia in mice, indicating that the compound might have efficacy as an antipsychotic in humans; and
(b)inhibited a conditioned avoidance response in rats, but induced catalepsy only at much higher doses, indicating that olanzapine is less likely to induce EPS in the clinic.
The Patent then states that olanzapine (at p 13):
… has been found to have a favourable profile of activity in a number of in vitro binding assays, designed to measure the degree of binding to neural receptors.
In particular, olanzapine is active at both the dopamine D1 and D2 receptors, the muscarinic and cholinergic receptors, and at the 5-HT-2 and 5-HT-IC receptors (at pp 13-14).
From these data, the Patent concludes at p 14:
This profile of activity in in vitro receptor binding assays, like that observed in the behavioural tests, would indicate that the compound is effective in the treatment of psychotic conditions but is less likely to induce extra pyramidal side-effects.
Dosage and Administration
The Patent teaches the dosage range that is effective to treat different conditions, including mild anxiety and psychotic disorders in adult humans. The Patent also discusses methods of administration of pharmaceutical compositions containing olanzapine, including suitable carriers for olanzapine and formulations thereof (at pp 14-16).
Examples
The invention is then illustrated by examples. Pages 17 to 23 of the Patent give details of seven examples. The first two examples describe two different ways to synthesise olanzapine. The remaining five examples relate to pharmaceutical formulations containing olanzapine.
The Invention Claimed
The specification ends in seven claims.
(a)Claim 1 is directed to a single compound (namely, 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b][1,5]benzodiazepine) or its acid addition salts.
(b)Claim 2 is limited to the single compound (2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b][1,5]benzodiazepine) which is the subject of claim 1.
(c)Claims 3 and 4 are directed to pharmaceutical compositions which include the compound of claim 1 or its acid addition salts with a diluent or carrier.
(d)Claim 5 is directed to a process for producing the compound of claim 1.
(e)Claim 6 is directed to an intermediate compound associated with the production of the compound of claim 1.
(f)Claim 7 is an “omnibus” claim.
I note that only claims 1 to 4 and 7 are in issue in this proceeding.
WITNESSES
Eli Lilly relied on the following witnesses:
(a)Dr Alan Duncan Robertson, who swore affidavits dated 16 December 2010, 24 June and 12 September 2011. Dr Robertson was cross-examined. Dr Robertson holds a Bachelor of Science (Hons) Degree (1978) and a PhD in synthetic organic chemistry (1981) from the University of Glasgow. Dr Robertson completed a post-doctoral fellowship with the Science and Engineering Research Council at the University of Sussex between 1981 and 1984. He then worked for Wellcome Foundation Ltd where, as a Senior Research Scientist, he worked on a migraine drug marketed as Zomig. In 1992 Dr Robertson migrated to Australia to work for FH Faulding and Company Limited where he managed the development of generic injectable drugs. This role involved reading patents and working the inventions described.
(b)Professor David Earl Nichols, who swore affidavits dated 17 December 2010 and 24 June 2011. Professor Nichols was cross-examined. Professor Nichols received a Bachelor’s Degree in Chemistry in 1969 from the University of Cincinnati, and a PhD in Medicinal Chemistry from the University of Iowa in 1973. He completed two years of post-doctoral work there and then moved to Purdue University, where he is currently the Robert C and Charlotte P Anderson Distinguished Chair in Pharmacology. At the priority date, Professor Nichols was a Professor of Pharmacology and Medicinal Chemistry at Purdue University. He has conducted research into drugs that modify consciousness and dopamine receptors, and has particular expertise in the study of small molecules affecting the CNS.
(c)Dr Benventuto Capuano, who affirmed an affidavit dated 1 July 2011. Dr Capuano was cross-examined. At the time of swearing his affidavit, Dr Capuano was a Senior Lecturer at the Faculty of Pharmacy & Pharmaceutical Sciences, Monash University. He completed a Bachelor of Applied Science (Applied Chemistry) Degree in 1987, followed by a Master of Pharmacy (1991) and a PhD with the Department of Medicinal Chemistry at Monash University (2001). At the priority date, Dr Capuano was a Masters student and Assistant Lecturer at the Victorian College of Pharmacy. Dr Capuano’s PhD was entitled “The Design, Synthesis and Pharmacological Evaluation of Clozapine Analogues for the Treatment of Schizophrenia”. This examined the differences between “typical” and “atypical” antipsychotic drugs, the available antipsychotic drugs before the priority date and their structural features. Dr Capuano’s PhD included a discussion on key textbooks in the area.
(d)Dr Ian Alexander Pullar, who affirmed an affidavit dated 28 July 2011, which largely related to a witness statement that he gave in proceedings regarding the United Kingdom equivalent of the Patent. Dr Pullar was cross-examined. Dr Pullar, a neuropsychopharmacologist, received a Bachelor of Science Degree in 1966 and completed a PhD in Neuroscience in 1971. He was an employee of Eli Lilly from June 1975 until his retirement on 31 January 2005. From 1975 to 1987, Dr Pullar was Head of the CNS Pharmacology group at an Eli Lilly research facility, Erl Wood, in Surrey, United Kingdom. After 1987, he continued as a Senior Research Scientist within Eli Lilly’s Global CNS Pharmacology group. The Pharmacology group was responsible for the research of drugs for the treatment of schizophrenia and depression.
(e)Professor Gordon Frederick Stuart Johnson, who swore an affidavit dated 17 May 2011. Professor Johnson was cross-examined. At the time of swearing his affidavit, Professor Johnson was an Emeritus Professor of Psychological Medicine at the University of Sydney. Professor Johnson completed a Bachelor of Medicine Degree and Bachelor of Surgery Degree in 1959. From 1963 to 1964, Professor Johnson trained in psychological medicine in Sussex, UK, and received a Diploma of Psychological Medicine from the Royal College of Physicians & Surgeons UK. Between 1969 and 1970, Professor Johnson was a co-investigator in clinical trials relating to drugs used to treat schizophrenia and bipolar disorder. From 1970 to 1971, he was actively involved in clinical research with new potential psychotropic compounds (drugs for treating mental illnesses) at Schering and Ciba Pharmaceuticals. Professor Johnson has published over 100 articles, reviews, and chapters in books.
(f)Professor Guy Manning Goodwin, who swore affidavits dated 4 July 2011 and 18 October 2011. Professor Goodwin was not cross-examined. At the time of swearing his first affidavit, Professor Goodwin was the Head of the Department of Psychiatry and WA Handley Professor of Psychiatry at Merton College, University of Oxford. He was, and has been since 1980, a practising psychiatrist. Professor Goodwin has authored or co-authored over 300 scientific papers, review articles and technical publications in the areas of neuroscience, psychiatry and disorders and function of the CNS. Of these, 35 were co-authored with Australian colleagues.
(g)Dr Jeffery Allen Engelhardt, who swore an affidavit dated 24 June 2011. Dr Engelhardt was cross-examined. At the time of swearing his affidavit, Dr Engelhardt was a President and Senior Pathologist of Experimental Pathology Laboratories Incorporated. Dr Engelhardt was employed by Eli Lilly and Company Ltd from 1988 to February 2004 as a veterinary pathologist. His affidavit largely concerned his involvement in animal toxicity studies, conducted in relation to the development of olanzapine, in particular, the dog study D07290 (Lilly Dog Study) conducted by Eli Lilly.
(h)Professor John Emery Bauer, who affirmed an affidavit dated 29 June 2011. Professor Bauer was not cross-examined. His affidavit largely concerned the Lilly Dog Study and comparative dog toxicology studies. Professor Bauer was not involved in the Lilly Dog Study. Professor Bauer was, at the time of affirming his affidavit, a Professor at Texas A&M University and a Director of the Comparative Nutrition Research Laboratory at the College of Veterinary Medicine at the same institution. Professor Bauer conducted research on animal nutrition and metabolism, particularly focusing on cholesterol, lipoprotein and serum lipid metabolism in companion animals such as dogs.
(i)Professor Ronald Thisted, who swore an affidavit dated 28 June 2011. Professor Thisted was not cross-examined. Professor Thisted was, at the time of swearing his affidavit, the Chairman of the Department of Health Studies at the University of Chicago, as well as a Professor of the Departments of Statistics, Health Studies, Anesthesia and Critical Care and the Undergraduate College at the University of Chicago. He was also a Professor of the Committee on Clinical Pharmacology and Pharmacogenomics. Professor Thisted obtained a PhD in statistics from Stanford University in 1977, and has published a book on statistical computation and over 100 original articles in peer-reviewed journals (including medical journals). He has also published peer-reviewed articles in statistics journals. Professor Thisted’s evidence largely concerned the interpretation and analysis of the Lilly Dog Study and comparative dog toxicology studies.
(j)Dr Karl Arthur Traul, who affirmed an affidavit dated 24 June 2011. Dr Traul was not cross-examined. At the time of affirming his affidavit, Dr Traul was the President of K A Traul Pharmaceutical Consulting. Dr Traul obtained a Bachelor’s Degree in Biology in 1963 from the University of Akron, Ohio, a Master of Science in 1965 and later a PhD from Ohio State University in 1969. Between 1969 and 1980 he worked in cancer research and drug safety for Pfizer Pharmaceuticals, ultimately as Laboratory Head and Project Leader. Dr Traul then worked in the area of toxicology for various companies, including Exxon Corporation and American Cyanamid. From 1995 he has worked as a consultant in toxicology and regulatory affairs. Dr Traul largely gave evidence on the Lilly Dog Study and comparative dog toxicology studies.
(k)Mr Steven Michael Harrill, who affirmed an affidavit dated 19 August 2011. Dr Harrill was cross-examined. Dr Harrill was, at the time of affirming his affidavit, the Global Brand Director – Neuroscience, of Eli Lilly and Company (US). Mr Harrill has a Bachelor’s Degree in Chemistry and Masters of Business Administration. Mr Harrill has worked for Eli Lilly and Company (US) since July 1985 in various positions. Mr Harrill largely gave evidence on the marketing and sales of various Eli Lilly products.
(l)Ms Shihui Yuan, who affirmed an affidavit dated 3 August 2011. Ms Yuan was not cross-examined. Ms Yuan is the Marketing Director of the Bio-medicines business unit of the second applicant, Eli Lilly Australia, and has been so since May 2011. Ms Yuan has an American Language and Literature Degree. After graduating, Ms Yuan worked for Shanghai Loudon Far East, which was a market research firm specialising in the pharmaceutical industry. Since 2001 Ms Yuan has held various marketing roles at Eli Lilly. In her various roles, she has had considerable responsibility for the marketing of Zyprexa products, which contain olanzapine as their active ingredients. Ms Yuan largely gave evidence on the sales of Zyprexa products, and the market share enjoyed by Eli Lilly for these products.
(m)Dr Andreas von Falck, who swore an affidavit dated 1 August 2011. Dr von Falck was not cross-examined. Dr von Falck is a partner at the law firm Hogan Lovells International LLP, in the Düsseldorf office. Dr von Falck holds a PhD in International Civil Procedural Law from Freiburg University. Since the European Autumn of 2006, Dr von Falck has represented Eli Lilly in the German proceedings relating to European Patent EP 0454436, the corresponding patent to the Australian Patent in suit. Dr von Falck gave evidence as to steps he undertook to locate a Professor Mager. Professor Mager was co-author of an article known as the “Schauzu Article” (or simply “Schauzu”) in this proceeding.
(n)Ms Miriam Gundt, who affirmed an affidavit dated 1 August 2011. Ms Gundt was not cross-examined. Ms Gundt was a colleague (Senior Associate) of Dr von Falck at Hogan Lovells International LLP. Ms Gundt gave similar evidence to that of Dr von Falck.
Apotex relied on the following witnesses:
(a)Professor David St Clair Black, who swore affidavits dated 23 December 2010 and 15 September 2011. Dr Black was cross-examined. At the time of swearing his first affidavit, Dr Black was the Professor of Organic Chemistry at The University of New South Wales. He was also the Secretary-General of the International Union of Pure and Applied Chemistry (IUPAC). Dr Black has a Bachelor of Science Degree with First Class Honours in Organic Chemistry (1959) and a Master of Science (1960). He received a PhD from Cambridge University in 1963, which related to the basic chemistry of 1-pyrroline 1-oxides and the application of these nitrones to the synthesis of the corrin ring system of vitamin B12. After working at Monash University, Dr Black took up his current position in 1983. Since this time, his research has been in relation to heterocyclic chemistry of indoles, nitrones and oxaziridines; heterocyclic and coordination chemistry applied to the synthesis of new heterocalixarenes; and new generic hetereocyclic systems.
(b)Dr Keith Geoffrey Watson, who swore affidavits dated 23 December 2010, 14 June and 23 September 2011. Dr Watson was cross-examined. At the time of swearing his affidavits, Dr Watson was a Special Fellow and Head of Laboratory at the Walter and Eliza Hall Institute of Medical Research, and an Honorary Professorial Fellow within the Faculty of Medicine, Dentistry and Health Sciences at The University of Melbourne. Dr Watson obtained a Bachelor of Science Degree from Monash University in 1969. In 1973, he was awarded a PhD in chemistry by the same institution. From 1977, he worked as a synthetic organic chemist on biologically-oriented projects, each requiring the optimisation of drug-like molecules with biological activity. Between 1987 and 1991, Dr Watson was made a Senior Principal Research Scientist at ICI Australia Central Research Laboratories in Victoria, and his work focused on designing novel inhibitors of acetolactate synthase. Between 1991 and 1994, Dr Watson took a position as Principal, and later Senior Principal Research Scientist, at CSIRO (Division of Chemicals and Polymers). During this period, he undertook research on the synthesis of novel acetylcholinesterase inhibitors as potential drugs for the treatment of Alzheimer’s disease.
(c)Ms Melissa Anne McGrath, who swore affidavits dated 23 December 2010 and 17 February 2011. Ms McGrath was not cross-examined. Ms McGrath was, at the time of swearing her first affidavit, a Senior Associate at DibbsBarker, being the solicitor for Apotex. Exhibited to Ms McGrath’s affidavits were various documents upon which Apotex sought to rely in the proceeding, including correspondence with Eli Lilly’s solicitors and information relating to the dates upon which certain patent specifications were open for public inspection.
(d)Ms Gaye Michelle Gericke, who affirmed an affidavit dated 17 February 2011. Ms Gericke was not cross-examined. At the time of affirming her affidavit, Ms Gericke was the Acting Manager of the Document Supply Service at the National Library of Australia. Ms Gericke gave evidence in relation to an article Apotex tendered from the publication Die Pharmazie – in particular, that the article had been received by the Library and made available to the Australian public in both German and English prior to 24 April 1990.
I make these comments about the witnesses and their evidence.
The parties agreed that, putting aside evidence that either party did not press or they agreed was objectionable, all the evidence was to be admitted subject to final submissions addressing weight or relevance. In this proceeding, that was an appropriate course to adopt, and I have so proceeded.
No issue of credit arose in this proceeding, in the sense of a witness being said to be deliberately not telling the truth, or not attempting to assist the Court. Within the level of skill of each expert witness, each one answered directly and according to his own particular view of the relevant science. The competence of each witness was not in contention. Some comments were directed to the extensive earlier involvement of Professor Nichols in litigation involving similar issues to those in this proceeding. However, I do not consider this has in any way impacted upon the giving of his evidence.
These general comments apply to all witnesses, including Professor Black. However, in the case of Professor Black, particular care must be taken in relying on his evidence. On important matters, I have discounted it when assessed against the evidence of the other experts. I am mindful of the observations made by the Full Court of this Court in Fresenius Medical Care Australia Pty Ltd v Gambro Pty Ltd (2005) 224 ALR 168; [2005] FCAFC 220 at 194 [175], where a witness, in giving evidence relating to inventive step, already knows the answer. There is no one determinative matter in assessing the evidence of such a witness, and his or her evidence is not necessarily to be disregarded entirely. Nevertheless, “the insidious effects” or “misuse” of hindsight are particularly acute in the case of the evidence in chief of Professor Black. Accordingly, and for the reasons outlined below, I have not found his evidence helpful other than where he supported the evidence given by other experts (which usually occurred in the course of his cross-examination).
First, Professor Black did not provide useful expert evidence on the question of inventive step. As I have indicated, Professor Black’s evidence in chief was essentially a hindsight reconstruction. At the outset of preparing his evidence, he was given the structure of olanzapine. He was then given a series of questions taking him through the information relied upon by Apotex and leading him – step by step – to the structure of olanzapine, which he agreed he kept in his mind. This deprived his evidence of any real value in assessing inventive step when considered in the context of other evidence before the Court.
Further, Professor Black approached the task of developing a new compound based on the 235 Patent solely from the perspective of ease of synthesis, without considering the biological activity of the compounds or their potential side effects. This was because of Professor Black’s view that the biological effects of the compounds were unknown until they had been made and tested. Professor Black had no expectation that his variation of the substituents of the compounds would produce a better drug than flumezapine or a body useful for any other purpose.
Despite Professor Black’s original approach, cross-examination demonstrated that the path he would have chosen (based on his starting point of the 235 Patent) would not have led to olanzapine. In particular, it showed that he would have been directly led as a matter of course to make one of the compounds described in the examples in the 235 Patent.
Further, as I will address later in the context of determining the identity of the skilled addressee in this matter, Professor Black is a synthetic organic chemist. The invention of the Patent concerns the development of a safe and effective drug, namely, the compound olanzapine, which is useful in the treatment of schizophrenia. Professor Black has had no relevant experience in medicinal chemistry. He has not worked on any compound that has become a commercial drug, nor with antipsychotic drugs.
In fact, before 1990, Professor Black had not done any work at all on the development of a drug. As he stated during cross-examination:
the chemistry I did was not directed specifically at making a drug; that’s not the way you go about doing academic research… the aim was not necessarily to make a drug but to invent new chemistry.
Whilst since 1990 Professor Black has been involved in a collaborative project to develop some anti-cancer agents, his role has been limited to making compounds.
Neither the 235 Patent, nor thienobenzodiazepines themselves, were common general knowledge before 1990. Professor Black did not read the 235 Patent before 1990. He only read it for the purposes of this proceeding. Professor Black only learned about thienobenzodiazepines for the purposes of this proceeding. Professor Black had not heard of flumezapine before giving evidence in this proceeding. His evidence was primarily based upon information contained in the 235 Patent.
It may also be useful to repeat the comments made by the Full Court of this Court in Merck & Co Inc v Arrow Pharmaceuticals Ltd (2006) 154 FCR 31, although that case was not decided under the 1952 Act. The Full Court said:
63. Microcell, NRDC and Philips establish the following propositions:
1.The opening words of s18(1) (“a patentable invention is an invention that “) impose a threshold requirement that the “patentable invention” be an “invention”, that is to say an “alleged” “manner of new manufacture” within s6 of the Statute of Monopolies (Philips at 663).
2.That requirement will not be met if, on the face of the specification, the subject matter:
(a)lacks the necessary quality of inventiveness under the Statute of Monopolies (Philips at 664);
(b)is not new (NRDC at 262, Philips at 664).
3.A new use of an old substance is not an invention if its known properties make it suitable for that use – in such a case the new purpose is “no more than analogous to the purposes for which the utility of the substance is already known” (NRDC at 262).
4.But there will be an invention if the new use consists in taking advantage of a hitherto unknown or unsuspected property of the substance (NRDC at 262).
64.Clearly, it is not sufficient that a claimant simply asserts “newness”. It is necessary that the specification be “construed and understood”. Technical terms may need explanation, but that is by no means uncommon in cases of this kind. We acknowledge the need to avoid incursion into areas correctly addressed under other sections of the Act. See Bristol-Myers.
This passage indicates the significance of only looking at the terms of the specification in this context. In other words, the inquiry in the context of the 1990 Act is on what is disclosed on the face of the specification. Returning then to Ramset (1998) 194 CLR 171, being the authority I will follow, it would appear that the reasoning of the majority in that case would leave no room for any consideration of inventiveness, other than by consideration of s 100(1)(e) of the 1952 Act. Even information apparent from the face of the specification could not (as a matter of logic based on the reasoning of the majority) be considered in the context of the statutory definition of invention at the revocation stage.
The High Court’s explanation of s 100(1)(d) in Ramset (1998) 194 CLR 171 may well be justified when understood in the context of the historical development of patent law. The first enactment that protected monopolies for inventions was the Statute of Monopolies 1623. It did not set out the grounds upon which a patent could be challenged. Under the rubric of “manner of new manufacture”, the courts elaborated various grounds on which revocation could be sought (Ramset (1998) 194 CLR 171 at 184). The word “new” in “manner of new manufacture” is an historical artefact. Under the 1952 Act, the obviousness and novelty grounds of revocation are dealt with specifically and exhaustively under ss 100(1)(e) and (g). Accordingly, the word “new” in the definition of “invention” has no work to do under s 100(1)(d). This is what the majority held in Ramset (1998) 194 CLR 171.
Of course, in applying the 1952 Act and s 100(1)(e), it may be more difficult to show lack of inventiveness, than just relying on the face of the specification if no inventive step is so disclosed. This is because of the requirement, referred to earlier in these reasons, for there to be reliance in the application of s 100(1)(e) of the 1952 Act on common general knowledge, which must be proved.
I point out that the position in relation to these considerations will be quite different in applying the 1990 Act: see eg Bristol-Myers Squibb Co v F H Faulding & Co Limited (2000) 97 FCR 524.
However, I do not need to go any further into this area of uncertainty, because at the very least, for Apotex to progress its argument in respect of manner of manufacture, it must be shown that the alleged invention was not, on the face of the specification, a manner of new manufacture. In my view, this has not shown by Apotex in this proceeding.
The specification reveals the new qualities of the compound of the invention and positively asserts that there is an invention. On the basis of the specification itself, olanzapine is disclosed as a new compound with advantages over earlier compounds, as discussed in these reasons. On this aspect of the attack, the Court may not “go behind” these statements, ie rely on extrinsic evidence: see Apotex v Sanofi-Aventis (2009) 82 IPR 416 at 449 to 451 (per Bennett and Middleton JJ); Pilja v Rapidjoint (2009) 80 IPR 648 at 655 [41]; Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC (No 2) (2006) 71 IPR 46 at 103 [206]. This is sufficient for there to be no so-called ‘threshold’ problem in the Patent, as alleged by Apotex.
Conclusion – Manner of Manufacture
Even if the ground of “manner of new manufacture” was available as sought to be relied upon by Apotex, I am satisfied that the Patent on its face describes and claims a “manner of new manufacture”.
SECTION 40 REQUIREMENTS
I turn now to sufficiency of description.
Sufficiency
Apotex alleges that the complete specification of the Patent lacks sufficiency of full description, on the basis that it does not adequately describe the advantages of olanzapine over all other compounds within the genus of compounds described in the 340 Patent.
Apotex alleges that the complete specification does not describe the invention fully, in that “being a selection from the genus of compounds”, the specification “does not disclose, explain or demonstrate the advantages claimed for the compound named in claims 1 to 4 and 7 over all other compounds within that genus”.
I do not consider that special principles of sufficiency apply to a patent which is determined to satisfy the principles of selection for the purposes of novelty.
In relation to the issue of novelty, a patent either satisfies the criteria for assessing novelty, or it does not. As indicated by the High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (2004) 217 CLR 274 (Lockwood No 1) at 290, 291 [43], [46] and 301 [70], the requirement of sufficiency is a separate inquiry which must not be conflated with other grounds of invalidity.
By s 138(3)(f) of the 1990 Act, and by s 100(1)(c) of the 1952 Act, a patent may be revoked on the ground that it does not comply with the requirements of s 40. Section 40(2)(a) of the 1990 Act and s 40(1)(a) of the 1952 Act provide that a complete specification must describe the invention “fully”.
The applicable principles are stated in Blanco White QC, Patents for Inventions, 5th ed (1983) at [4-502] as follows (citations omitted):
To be proper and sufficient, the complete specification as a whole (that is, read together with the claims, and in the light of the drawings, if any) must in the first place contain such instructions as will enable all those to whom the specification is addressed to produce something within each claim “by following the directions of the specification, without any new inventions or additions of their own” and without “prolonged study of matters which present some initial difficulty.”
In Kimberly-Clark (2001) 207 CLR 1, the High Court rejected an argument based on Sami S Svendsen Inc v Independent Products Canada Ltd (1968) 119 CLR 156 (Sami Svendsen) that a reader ought to be able to discern the invention from the specification. Instead, the High Court adopted the principles set out in Blanco White QC’s text, and upheld the following test of sufficiency of full description at 17 [25]:
The question is, will the disclosure enable the addressee of the specification to produce something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty?
In Lockwood No 1 (2004) 217 CLR 274, the High Court reiterated its approval for this approach, confirming at 297 [60] (citations omitted):
For the purposes of s 40(2)(a), it is not necessary for the inventor to disclose all the alternative means; it is enough that there is disclosure in the sense of enabling the addressee of the specification to produce something within each claim without new inventions or additions or prolonged study of matters presenting additional difficulty.
The High Court also noted at 311 to 312 [103]:
One source of these unfairnesses was said to be the fact that s 40(2)(a), on the construction given by this Court in Kimberly-Clark, is complied with if the complete specification enables the addressee to produce something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty: but Doric, whilst willing to attempt to sap life from Kimberly-Clark, prudently eschewed any attack upon that binding authority.
In Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (2005) 68 IPR 459; [2005] FCAFC 255, the Full Federal Court (when determining certain issues remitted by the High Court following its decision in Lockwood No 1 (2004) 217 CLR 274) convincingly rejected the principles in Sami Svendsen (1968) 119 CLR 156 at 499 to 502 [182]-[198]. In particular, the Full Federal Court noted at 500 to 501 [190]-[195]:
It was put by Doric that the consistory clause “misleads the reader as to the particular improvement”. This, it was said, was not the lock release means because the addition of such means were already present in a number of other locks produced in evidence… But this is to mix up the test for sufficiency with other grounds of invalidity such as want of novelty…
More fundamentally however, we think that the element of Sami Svendsen relied on is not good law…
Courts of high authority have consistently held that an applicant for a grant is not, pursuant to the statutory requirements to describe the invention, under an obligation to identify the inventive step involved.
It is also useful to keep in mind some further observations, usefully collated by Kenny J in SNF (Australia) (2011) 92 IPR 46; [2011] FCA 452 at 98 [234] (which were accepted on appeal):
234 A specification is not insufficient merely because some experiment of a routine character (as distinct from prolonged study of matters presenting initial difficulty) is necessary in the particular case: see Blanco White at 131 [4-504]; Kimberly-Clark ([24]-[25]); and No-Fume Ld v Frank Pitchford & Co Ld (1935) 52 RPC 231 (No-Fume) at 238, 243-5. Nor is a specification insufficient because it fails to give detailed instructions as to matters which a “practical person … would naturally settle, and expect to have to settle … himself,” provided he “would find no difficulty in so doing”: British Ore Concentration Syndicate Ld v Minerals Separation Ld (1909) 26 RPC 124 at 139. Further, Blanco White states at 131 [4-505]:
[A]lthough the specification must disclose the method of carrying out the invention, and not merely the result to be obtained [Vidal Dyes v Levinstein (1912) 29 RPC 245 at 266] any general description is enough if in fact the desired result can be obtained with certainty [Vidal Dyes at 279-280] and without invention [No-Fume v Pitchford (1935) 52 RPC 231 at 238]. Thus a general instruction to use “any suitable material” [Bickford v Skewes (1835) 1 WPC 214 at 218-219] or “known methods” [I G Farbenindustrie (1939) 56 RPC 249] or to use chemical reagents of a general class (leaving it to the addressee to determine which members of the class will operate satisfactorily) [Leonhardt v Kalle (1895) 12 RPC 103 at 116], will be sufficient if it enables the addressee to put the invention into practice. … Nor will vagueness or obscurity of instructions render the specification insufficient if an addressee would have no serious difficulty in understanding what he had to do [cf Whatmough v Morris (1940) 57 RPC 177 at 199].
See also D Falconer, W Aldous and D Young, Terrell on the Law of Patents (London, 12th ed, 1971) pp 82-3 [219]; D Young, A Watson, S Thorley and R Miller, Terrell on the Law of Patents (London, 14th ed, 1994) pp 100-101 [5.09-5.10], R Miller, G Burkill, C Birss and D Campbell, Terrell on the Law of Patents (London, 17th ed, 2011) pp 421 [13-27], all editions citing Plimpton v Malcolmson (1876) 3 Ch D 531 at 576 and Edison and Swan Electric Light Co v Holland (1889) 6 RPC 243 at 277-278.
Conclusion – Sufficiency
It is clear from these authorities that if the specification provides enough information to enable the skilled addressee to perform a single embodiment that falls within the scope of each claim (without new inventions or additions or prolonged study of matters presenting initial difficulty), the invention has been fully described. There is no further obligation to adequately disclose the advantages of a “selection” invention.
In any event, as referred to earlier in these reasons, the Patent does describe the advantages of olanzapine.
Fair Basis
I now turn to the fair basis ground.
Introduction
At paragraphs 3(a) and (b) of Apotex’s Consolidated Particulars of Invalidity, Apotex alleges that claims 1 to 4 are not fairly based for the same reasons that Apotex relies on to deny infringement, that is, the compound claimed is not the compound represented on p 3 of the Patent. This argument fails for the reasons set out relating to construction and infringement.
Legal Principles
The principles of law governing fair basis are well-established.
Section 40(3) of the 1990 Act and s 40(2) of the 1952 Act both provide that the claim or claims must be fairly based on the matter described in the specification.
In Lockwood No 1 (2004) 217 CLR 274, the High Court explained that s 40(3) of the 1990 Act requires that the claims are directed to the same invention as identified in the specification, when read as a whole.
In Lockwood (2004) 217 CLR 274 at 294 [54], the High Court held that s 40(3) requires a comparison to be made between the claims and what is described in the specification. The Court added (at 300 [68]):
It is wrong to employ “an over meticulous verbal analysis”. It is wrong to seek to isolate in the body of the specification “essential integers” or “essential features” of an alleged invention and to ask whether they correspond with the essential integers of the claim in question.
(Citations omitted)
The Court in Lockwood No 1 went on to say (at 300 [69]):
Section 40(3) requires, in Fullagar J’s words, “a real and reasonably clear disclosure”. But those words, when used in connection with s 40(3), do not limit disclosures to preferred embodiments.
The circumstance that something is a requirement for the best method of performing an invention does not make it necessarily a requirement for all claims; likewise, the circumstance that material is part of the description of the invention does not mean that it must be included as an integer of each claim. Rather, the question is whether there is a real and reasonably clear disclosure in the body of the specification of what is then claimed, so that the alleged invention as claimed is broadly, that is to say in a general sense described in the body of the specification.
Fullagar J’s phrase serves the function of compelling attention to the construction of the specification as a whole, putting aside particular parts which, although in isolation they might appear to point against the “real” disclosure, are in truth only loose or stray remarks.
(Citations omitted)
For an application of Lockwood No 1 (2004) 217 CLR 274, see Synthetic Turf Development Pty Ltd v Sports Technology International Pty Ltd (2005) 67 IPR 475 at 479 [26], in which the Full Federal Court affirmed that:
Fair basing for the purposes of s 40(3) of the Act requires a comparison between the matter described in the specification and the claim which defines the scope of the monopoly; the claim to a product must not travel beyond the matter disclosed in the specification. … Fair basis requires a real and reasonably clear disclosure of what is then claimed … . The question is what the body of the specification read as a whole discloses as the invention …
Apotex contended that the chemical name “2-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b][1,5] benzodiazepine”, used in claims 1 and 2, is not the same as the compound identified by the chemical structure on p 3, lines 20 to 26, which is stated to be the compound of the invention. Apotex contended that, consequently, claims 1 to 4 and claim 7 are not fairly based.
As I have found, on a proper construction “2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno(2,3-b)(1,5)-benzodiazapene”, as used in claims 1 and 2, is to be construed by the relevant skilled addressee to equate to the following structure:
On p 3 of the Patent specification, it is stated:
We have now discovered a compound which possesses surprising and unexpected properties by comparison with flumezapine and other related compounds.
The compound of the invention is of the formula
or an acid addition salt thereof. The free base of formula (I) is 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno(2,3-b)(1,5)-benzodiazapene.
The language of the specification reflects the description of the invention in the light of the specification as a whole.
Conclusion – Fair Basis
Accordingly, I find that claims 1 to 4 are fairly based on the specification because there has been a real and reasonably clear disclosure of “2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno(2,3-b)(1,5)-benzodiazapene” in the specification according to the principles in Lockwood No 1 (2004) 217 CLR 274.
Lack of Clarity and Lack of Definition of Invention
I now turn to the grounds of lack of clarity and lack of definition of invention. These two grounds can be conveniently dealt with together.
Apotex pleaded that claims 1 to 4 and 7 of the Patent should be revoked on the ground that they are not clear as required by s 40(2) of the 1952 Act, ie they claim the compound with the chemical name, “2-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-(2,3-b)(1,5) benzodiazepine”, not olanzapine. Apotex also relied upon s 40(1)(b) of the 1952 Act which required that the specification define the invention.
Legal Principles
Apotex put forward its construction of the Patent as considered at length at the commencement of these reasons for judgment. Apotex also submitted in the alternative that the use of the chemical name in claims 1 and 2 renders it unclear.
These grounds can only be successful if there is an irresolvable ambiguity or uncertainty. The issue only arises if an ambiguity remains after the claim has been properly construed.
The consideration is whether, on a reasonable view, the claim has meaning. In its Outline of Closing Submissions, Apotex cited the following passage from Blanco White QC’s text, Patents for Inventions (5th ed) (at 4-701):
…a claim is bad if no reasonably certain construction can be given to it, or it is fairly and equally open to diverse meanings. But the rule goes further than this. A court is not bound to find a meaning for a claim, nor to approach a claim with the "conviction that its language is capable of a reasonable construction when carefully examined" that is the due of an Act of Parliament. Thus a claim may be bad for uncertainty although the court could find its true meaning (and would do so if the words concerned appeared in a commercial contract) if it is so obscure that "its proper construction must always remain a matter of doubt". …
See also Wake Forest No 2 (2011) 92 IPR 496; [2011] FCA 1002 at 624 to 625 [819].
Justice Hely in Flexible Steel Lacing (2000) 49 IPR 331; [2000] FCA 890 (which concerned pulley lagging used in conveyor systems) found both method and product claims invalid for lack of clarity, saying:
·at 355 [107]: “the equivocations in the drawings… do not resolve the puzzle created by the uncertainties and inconsistencies in the text. The method claim is fairly open to more than one meaning not because of grammatical problems but because, even to a skilled reader, it would not be clear which of two methods [it] describes. That problem cannot be overcome by the expectation on the part of a skilled worker, to which I earlier referred”.
·at 359 to 360 [131]: “the product claim is obscure; it is fairly and equally open to diverse meanings… Another possibility is that the claim embraces both. Sometimes, ambiguity or insufficiency in description can be resolved by a skilled addressee through the application of commonsense and common knowledge: cf Innovative Agriculture Products Pty Ltd v Cranshaw (1996) 35 IPR 643 at 666. I do not think that this is such a case”.
In Martin v Scribal Pty Ltd (1954) 92 CLR 17 at 59, Dixon CJ, when considering a claim alleged to be invalid for ambiguity, stated the duty of the Court and the test of ambiguity in relation to a claim in the following terms:
If we were concerned only with a written instrument operating inter partes and not generally these difficulties would easily be overcome by construction. But the principles governing the definition of a monopoly operating over the public at large require a description which is not reasonably capable of misunderstanding. If an ambiguity is purposely introduced in order to produce a vagueness in the boundaries of a monopoly this purposeful introduction of an ambiguity destroys the patent, whether the ambiguity be great or small. Here, there is no reason to suppose that there was any such design. The following passage, however, in the judgment of Lord Parker (Natural Color Kinematograph Co Ltd (In liquidation) v Bioschemes Ltd (1951) 32 PRC 256 at 269) describes what is the duty of the court and provides the test of ambiguity: “Further, though it may be true that in construing an instrument inter partes the Court is bound to make up its mind as to the true meaning, this is far from being the case with a Specification. It is open to the Court to conclude that the terms of a Specification are so ambiguous that its proper construction must always remain a matter of doubt, and in such a case, even if the Specification had been prepared in perfect good faith, the duty of the Court would be to declare the Patent void.
(Emphasis added)
If more than one meaning could be attributed to a claim and a skilled reader would be unable to resolve the ambiguity, then uncertainty, obscurity and lack of cogent meaning would render that claim unclear.
However, in this proceeding, it has been possible to ascertain what the invention is from a fair reading of the specification as a whole. I adopt here my conclusions on the question of construction, which apply equally to Apotex’s allegations of lack of clarity and failing to define the invention. I have not reached the position where I have concluded that the construction of the claims is, and will always remain, a matter of doubt. The relevant skilled team will be able to ascertain the precise extent of the monopoly claimed. Any ambiguity, if there was such, is resolved by reading the Patent as a whole. The claims are thus not invalid for lack of clarity or for failure to define the invention on the basis of the above principles.
I should also indicate, although it is not the situation confronting me, that the mere existence of some imprecision in the challenged claims does not necessarily render them unclear. All expressions used must be read and understood in a practical, commonsense manner.
I conclude that the claims are clear and do not lack clarity under s 40(2) nor do they fail to define the invention as required by s 40(1)(b).
CONCLUSION
Eli Lilly has been successful in its application, and the grounds of revocation relied upon by Apotex have been rejected.
To give the parties the opportunity to consider any issues relating to the formulation of orders (including costs), I will direct that the parties confer and thereafter file and serve minutes of orders reflecting the reasons of the Court on or before 4:00pm on 29 March 2013.
I certify that the preceding seven hundred and sixty-four (764) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Middleton. Associate:
Dated: 15 March 2013
ANNEXURE ‘A’
Ball and Stick model of olanzapine created by ChemBioDraw Ultra, version 12, published by CambridgeSoft
·Atom coloured yellow is Sulfur
·Atom coloured blue is Nitrogen
·Atom coloured grey is Carbon
·Atom coloured white is Hydrogen
·Pink represents lone pair of electrons
Model oriented as in Australian Patent No. 643267 and as below:
ANNEXURE ‘B’
Ball and Stick model of olanzapine created by ChemBioDraw Ultra, version 12, published by CambridgeSoft
·Atom coloured yellow is Sulfur
·Atom coloured blue is Nitrogen
·Atom coloured grey is Carbon
·Atom coloured white is Hydrogen
·Pink represents lone pair of electrons
Molecule oriented as in Australian Patent No. 643267 and as below:
ANNEXURE ‘C’
Space-filling model of olanzapine created by ChemBioDraw Ultra, version 12, published by CambridgeSoft
·Atom coloured yellow is Sulfur
·Atom coloured blue is Nitrogen
·Atom coloured grey is Carbon
·Atom coloured white is Hydrogen
Model oriented as in Australian Patent No. 643267 and as below:
ANNEXURE ‘D’
Space-filling model of olanzapine created by ChemBioDraw Ultra, version 12, published by CambridgeSoft
·Atom coloured yellow is Sulfur
·Atom coloured blue is Nitrogen
·Atom coloured grey is Carbon
·Atom coloured white is Hydrogen
Model oriented as in Australian Patent No. 643267 and as below:
178
18
0